Organic Synthesis Strategy and Control

Organic Synthesis

Organic Synthesis:
Strategy and Control
Paul Wyatt
Senior Lecturer and Director of Undergraduate Studies, School of Chemistry,
University of Bristol, UK
and
Stuart Warren
Reader in Organic Chemistry, Department of Chemistry,
University of Cambridge, UK

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Library of Congress Cataloging-in-Publication Data
Wyatt, Paul.
Organic synthesis: strategy and control / Paul Wyatt and Stuart Warren.
p. cm.
Includes bibliographical references.
ISBN: 978-0-470-48940-5
ISBN: 978-0-471-92963-5
1. Organic compounds – Synthesis. 2. Stereochemistry. I. Warren, Stuart
G. II. Title.
QD262.W89 2007
547´.2–dc22 2006034932
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
ISBN: 978-0-471-48940-5 (HB)
ISBN: 978-0-471-92963-5 (PB)
Typeset in 10/12pt Times by Thomson Digital
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Contents
Preface vii
A: Introduction: Selectivity
1. Planning Organic Syntheses: Tactics, Strategy and Control 3
2. Chemoselectivity 9
3. Regioselectivity: Controlled Aldol Reactions 27
4. Stereoselectivity: Stereoselective Aldol Reactions 43
5. Alternative Strategies for Enone Synthesis 55
6. Choosing a Strategy: The Synthesis of Cyclopentenones 71
B: Making Carbon–Carbon Bonds
7. The Ortho Strategy for Aromatic Compounds 91
8. σ-Complexes of Metals 113
9. Controlling the Michael Reaction 127
10. Specifi c Enol Equivalents 139
11. Extended Enolates 155
12. Allyl Anions 173
13. Homoenolates 189
14. Acyl Anion Equivalents 203
C: Carbon–Carbon Double Bonds
15. Synthesis of Double Bonds of Defi ned Stereochemistry 223
16. Stereo-Controlled Vinyl Anion Equivalents 255
17. Electrophilic Attack on Alkenes 277
18. Vinyl Cations: Palladium-Catalysed C–C Coupling 307
19. Allyl Alcohols: Allyl Cation Equivalents (and More) 339
D: Stereochemistry
20.
21.
22.
23.
24.
25.
26.
27.
Control of Stereochemistry – Introduction 371
Controlling Relative Stereochemistry 399
Resolution 435
The Chiral Pool — Asymmetric Synthesis with Natural Products as
Starting Materials — 465
Asymmetric Induction I Reagent-Based Strategy 505
Asymmetric Induction II Asymmetric Catalysis: Formation of C–O
and C–N Bonds 527
Asymmetric Induction III Asymmetric Catalysis: Formation of C–H
and C–C Bonds 567
Asymmetric Induction IV Substrate-Based Strategy 599

vi Contents
28. Kinetic Resolution 627
29. Enzymes: Biological Methods in Asymmetric Synthesis
30. New Chiral Centres from Old — Enantiomerically Pure
651
Compounds & Sophisticated Syntheses — 681
31. Strategy of Asymmetric Synthesis 717
E: Functional Group Strategy
32. Functionalisation of Pyridine 749
33. Oxidation of Aromatic Compounds, Enols and Enolates
34. Functionality and Pericyclic Reactions: Nitrogen Heterocycles by
777
Cycloadditions and Sigmatropic Rearrangements
35. Synthesis and Chemistry of Azoles and other Heterocycles with Two
809
or more Heteroatoms 835
36. Tandem Organic Reactions 863
General References 893
Index 895

Preface
We would like to thank those who have had the greatest infl uence on this book, namely the undergraduates
at the Universities of Bristol and Cambridge. But, particularly we would like to thank
the organic chemists at Organon (Oss), AstraZeneca (Alderley Park, Avlon Works, Mölndal and
Macclesfi eld), Lilly (Windlesham), Solvay (Weesp) and Novartis (Basel) who contributed to the
way the book was written more than they might realise. These chemists will recognise material
from our courses on The Disconnection Approach, Advanced Heterocyclic Chemistry, New Synthetic
Methods and Asymmetric Synthesis. Additionally we would like to thank the participants
at the SCI courses organised by the Young Chemists Panel. All these industrial chemists participated
in our courses and allowed us to fi nd the best way to explain concepts that are diffi cult to
grasp. This book has changed greatly over the ten years it was being written as we became more
informed over what was really needed. The book is intended for that very audience – fi nal year
undergraduates, graduate students and professional chemists in industry.
PJW
SGW
July 2006

Section A:
Introduction: Selectivity
1. Planning Organic Syntheses: Tactics, Strategy and Control ............................................. 3
2. Chemoselectivity ..................................................................................................................... 9
3. Regioselectivity: Controlled Aldol Reactions ..................................................................... 27
4. Stereoselectivity: Stereoselective Aldol Reactions ............................................................. 43
5. Alternative Strategies for Enone Synthesis ........................................................................ 55
6. Choosing a Strategy: The Synthesis of Cyclopentenones .................................................. 71

1
Planning Organic Syntheses:
Tactics, Strategy and Control
The roll of honour inscribed with successful modern organic syntheses is remarkable for the
number, size, and complexity of the molecules made in the last few decades. Woodward and
Eschenmoser’s vitamin B 12 synthesis, 1 completed in the 1970s, is rightly regarded as a pinnacle of
achievement, but since then Kishi 2 has completed the even more complex palytoxin. The smaller
erythromycin and its precursors the erythronolides 3 1, and the remarkably economical syntheses of
the possible stereoisomers of the cockroach pheromones 2 by Still 4 deal with a greater concentration
of problems.
1
erythronolide A
HO
O
O
O
OH
OH
OH
OH
Less applauded, but equally signifi cant, is the general advance in synthetic methods and their
industrial applications. AstraZeneca confess that it took them nearly a century to bring Victor
Grignard’s methods into use, but are proud that Corey’s sulfur ylid chemistry made it in a decade.
Both are used in the manufacture of the fungicide fl utriafol 5 3.
F
F
O
F
F
Me
Me S CH2
RCO3H
Br2
H 2O
F
X
OH
F
Optically active and biodegradable deltamethrin 6 4 has taken a large share of the insecticide
market, and asymmetric hydrogenation is used in the commercial synthesis of DOPA 5 used to
treat Parkinson’s disease. 7 These achievements depend both on the development of new methods
and on strategic planning: 8 the twin themes of this book.
F
F O N
F
O
N
N
O
+
O
MgI
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd
base
Cl
O
F
OH
N
N
N
F
Cl
2
periplanone-B
F
3
Flutriazole
fungicide
AlCl3
COCl
F

4 1 Planning Organic Syntheses: Tactics, Strategy and Control
Br
Br
R R
O
O
H
S
CN
O
HO
HO
NH2 CO2H 4
5
deltamethrin
(S)-L-(–)-DOPA
To make any progress in this advanced area, we have to assume that you have mastered the
basics of planning organic synthesis by the disconnection approach, roughly the material covered
in our previous books. 9 There, inspecting the target molecule, identifying the functional groups,
and counting up the relationships between them usually gave reliable guidelines for a logical
synthesis. All enones were tackled by some version of the aldol reaction; thus 6 would require the
attack of enolate 7 on acetone. We hope you already have the critical judgement to recognise that
this would need chemoselectivity in enolising 7 rather than acetone or 6, and regioselectivity in
enolising 7 on the correct side.
O
6
aldol
O
+
O O
In this book we shall explore two new approaches to such a problem. We shall see how to make
specifi c enol equivalents for just about any enolate you might need, and we shall see that alternative
disconnections such as 6a, the acylation of a vinyl anion 8, can be put into practice. Another
way to express the twin themes of this book is strategy and control: we solve problems either
by fi nding an alternative strategy or by controlling any given strategy to make it work. This will
require the introduction of many new methods - a whole chapter will be devoted to reagents for
vinyl anions such as 8, and this will mean exploring modern organometallic chemistry.
O O
+
X
6a
8 9
We shall also extend the scope of established reactions. We hope you would recognise the aldol
disconnection in TM 10, but the necessary stereochemical control might defeat you. An early
section of this book describes how to control every aspect of the aldol reaction: how to select
which partner, i.e. 11 or 12, becomes an enolate (chemoselectivity), how to control which enolate
of the ketone 12 is formed (regioselectivity), and how to control the stereochemistry of the product
10 (stereoselectivity). As we develop strategy, we shall repeatedly examine these three aspects of
control.
R 1
OH
10
O
R 2
aldol
?
R1 R2 O O
O
H
+
?
11 12
The target molecules we shall tackle in this book are undoubtedly more diffi cult in several ways
than this simple example 10. They are more complex quantitatively in that they combine functional
7
R 2

groups, rings, double bonds, and chiral centres in the same target, and qualitatively in that they
may have features like large rings, double bonds of fi xed confi guration, or relationships between
functional groups or chiral centres which no standard chemistry seems to produce. Molecules 1 to
5 are examples: a quite different one is fl exibilene 13, a compound from Indonesian soft coral. It
has a fi fteen-membered ring, one di- and three tri-substituted double bonds, all E but none
conjugated, and a quaternary centre. Mercifully there are no functional groups or chiral centres.
How on earth would you tackle its synthesis? One published synthesis is by McMurry. 10
H
2.
O
14
MeO
OMe
OHC
1 Planning Organic Syntheses: Tactics, Strategy and Control 5
17
1. 2 x BuLi
ZrCp 2Cl
OMe
HO
1. PCC
2. H ,
MeO
15; 78% yield
CH(OMe) 3
16; 83% yield
Pd(OCOCF 3) 2
19; 76% yield from 16 + 18
This short synthesis uses seven metals (Li, Cr, Zr, Pd, Ti, Zn, and Cu), only one protecting
group, achieves total control over double bond geometry, remarkable regioselectivity in the Zr-Pd
coupling reaction, and a very satisfactory large ring synthesis. The yield in the fi nal step (52%)
may not look very good, but this is a price worth paying for such a short synthesis. Only the fi rst
two steps use chemistry from the previous books: all the other methods were unknown only ten
years before this synthesis was carried out but we shall meet them all in this book.
An important reason for studying alternative strategies (other than just making the compound!)
is the need to fi nd short cheap large scale routes in the development of research lab methods into
production. All possible routes must be explored, at least on paper, to fi nd the best production
method and for patent coverage. Many molecules suffer this exhaustive process each year, and
some sophisticated molecules, such as Merck’s HIV protease inhibitor 20, a vital drug in the fi ght
against AIDS, are in current production on a large scale because a good synthesis was found by
this process. 11
N
N
t-BuNH
N
O
You might think that, say organometallic chemistry using Zr or Pd would never be used in
manufacture. This is far from true as many of these methods are catalytic and the development
of polymer-supported reagents for fl ow systems means that organo-metallic reagents or enzymes
may be better than conventional organic reagents in solution with all the problems of by-product
disposal and solvent recovery. We shall explore the chemistry of B, Si, P, S, and Se, and of metals
18
OH
20; Crixivan
O
Ph
O
H
N
O
TiCl 3
Zn/Cu
Cp2ZrHCl
17
13; flexibilene, 52% yield
OH

6 1 Planning Organic Syntheses: Tactics, Strategy and Control
such as Fe, Co, Ni, Pd, Cu, Ti, Sn, Ru and Zr because of the unique contribution each makes to
synthetic methods.
In the twenty years since McMurry’s fl exibilene synthesis major developments have changed
the face of organic synthesis. Chiral drugs must now be used as optically pure compounds and
catalytic asymmetric reactions (chapters 25 and 26) have come to dominate this area, an achievement
crowned by the award of the 2001 Nobel prize for Chemistry to Sharpless, Noyori and
Knowles. Olefi n metathesis (chapter 15) is superseding the Wittig reaction. Palladium-catalysed
coupling of aromatic rings to other aromatic rings, to alkenes, and to heteroatoms (chapter 18)
makes previously impossible disconnections highly favourable. These and many more important
new methods make a profound impact on the strategic planning of a modern synthesis and fi nd
their place in this book.
A Modern Synthesis: Fostriecin (CI-920)
The anti-cancer compound Fostriecin 21 was discovered in 1983 and its stereochemistry elucidated
in 1997. Not until 2001 was it synthesised and then by two separate groups. 12 Fostriecin is
very different from fl exibilene. It still has alkene geometry but it has the more challenging threedimensional
chirality as well. It has plenty of functionality including a delicate monophosphate
salt. A successful synthesis must get the structure right, the geometry of the alkenes right, the
relative stereochemistry right, and it must be made as a single enantiomer.
O
O
HO
O O
P
O
OH
21; Fostriecin (CI-920)
The brief report of Jacobsen’s total synthesis starts with a detailed retrosynthetic analysis.
The compound was broken into four pieces 21a after removal of the phosphate. The unsaturated
lactone 24 (M is a metal) could be made by an asymmetric oxo-Diels-Alder reaction from diene 22
and ynal 23. The epoxide 25 provides a second source of asymmetry. One cis alkene comes from
an alkyne 26 and the rest from a dienyl tin derivative 27.
RO
O
21a
Disconnection of
Fostriecin (CI-920)
Diels-
Alder
O
O
O
O M
The synthesis is a catalogue of modern asymmetric catalytic methods. The epoxide 25 was
resolved by a hydrolytic kinetic resolution (chapter 28) using a synthetic asymmetric cobalt complex.
The asymmetric Diels-Alder reaction (chapter 26) was catalysed by a synthetic chromium
Na
OH
O O
HO
P
O
S
H
S
OH
SnBu 3
SiMe3
O
SiMe3 22 23 24 25 26 27
OH
O
Na
OH
OH
OR

complex. The vinyl metal derivative 24 was made by hydrozirconation of an alkyne (this at least
is similar to the fl exibilene synthesis) and the secondary alcohol chiral centre was derived from
the dithian 26 by hydrolysis to a ketone and asymmetric reduction with a synthetic ruthenium
complex (chapter 24). The dienyl tin unit 27 was coupled to the rest of the molecule using catalytic
palladium chemistry (chapter 18). Almost none of these catalytic methods was available in 1983
when fl exibilene was made and such methods are a prominent feature of this book. Organic synthesis
nowadays can tackle almost any problem. 13
Please do not imagine that we are abandoning the systematic approach or the simpler reagents
of the previous books. They are more essential than ever as new strategy can be seen for what
it is only in the context of what it replaces. Anyway, no-one in his or her right mind would use
an expensive, toxic, or unstable reagent unless a friendlier one fails. Who would use pyrophoric
tertiary butyl-lithium in strictly dry conditions when aqueous sodium hydroxide works just as
well? In most cases we shall consider the simple strategy fi rst to see how it must be modifi ed. The
McMurry fl exibilene synthesis is unusual in deploying exotic reagents in almost every step. A
more common situation is a synthesis with one exotic reagent and six familiar ones. The logic of
the previous books is always our point of departure.
The organisation of the book
The book has fi ve sections:
A: Introduction, selectivity, and strategy
B: Making Carbon-Carbon bonds
C: Carbon-Carbon double bonds
D: Stereochemistry
E: Functional Group Strategy
The introductory section uses aldol chemistry to present the main themes in more detail and
gives an account of the three types of selectivity: chemo-, regio-, and stereo-selectivity. We shall
explore alternative strategies using enones as our targets, and discuss how to choose a good route
using cyclopentenones as a special case among enones. Each chapter develops strategy, new
reagents, and control side-by-side. To keep the book as short as possible (like a good synthesis),
each chapter in the book has a corresponding chapter in the workbook with further examples,
problems, and answers. You may fi nd that you learn more effi ciently if you solve some problems
as you go along.
References
1 References 7
General references are given on page 893
1. R. B. Woodward, Pure Appl. Chem., 1973, 33, 145; A. Eschenmoser and C. E. Wintner, Science, 1977,
196, 1410; A. Eschenmoser, Angew. Chem., Int. Ed. Engl., 1988, 27, 5.
2. Y. Kishi, Tetrahedron, 2002, 58, 6239.
3. E. J. Corey, K. C. Nicolaou, and L. S. Melvin, J. Am. Chem. Soc., 1975, 97, 654; G. Stork and S. D.
Rychnovsky, J. Am. Chem. Soc., 1987, 109, 1565; Pure Appl. Chem., 1987, 59, 345; A. F. Sviridov, M. S.
Ermolenko, D. V. Yashunsky, V. S. Borodkin and N. K. Kochetkov, Tetrahedron Lett., 1987, 28, 3835,
and references therein.
4. W. C. Still, J. Am. Chem. Soc., 1979, 101, 2493. See also S. L. Schreiber and C. Santini, J. Am. Chem.
Soc., 1984, 106, 4038; T. Takahashi, Y. Kanda, H. Nemoto, K. Kitamura, J. Tsuji and Y. Fukazawa,
J. Org. Chem., 1984, 51, 3393; H. Hauptmann, G. Mühlbauer and N. P. C. Walker, Tetrahedron Lett.,
1986, 27, 1315; T. Kitahara, M. Mori and K. Mori, Tetrahedron, 1987, 43, 2689.

8 1 Planning Organic Syntheses: Tactics, Strategy and Control
5. P. A. Worthington, ACS Symposium 355, Synthesis and Chemistry of Agrochemicals, eds D. R. Baker,
J. G. Fenyes, W. K. Moberg, and B. Cross, ACS, Washington, 1987, p 302.
6. M. Elliott, A. W. Farnham, N. F. Janes, P. H. Needham, and D. A. Pullman, Nature, 1974, 248, 710;
M. Elliott, Pestic. Sci., 1980, 11, 119.
7. J. Halpern, H. B. Kagan, and K. E. Koenig, Morrison, vol 5, pp 1–101.
8. Corey, Logic; Nicolaou and Sorensen.
9. Designing Syntheses, Disconnection Textbook, and Disconnection Workbook.
10. J. McMurry, Acc. Chem. Res., 1983, 16, 405.
11. D. Askin, K. K. Eng, K. Rossen, R. M. Purick, K. M. Wells, R. P. Volante and P. J. Reider, Tetrahedron
Lett., 1994, 35, 673; B. D. Dorsey, R. B. Levin, S. L. McDaniel, J. P. Vacca, J. P. Guare, P. L. Darke,
J. A. Zugay, E. A. Emini, W. A. Schleif, J. C. Quintero, J. H. Lin, I.-W. Chen, M. K. Holloway, P. M. D.
Fitzgerald, M. G. Axel, D. Ostovic, P. S. Anderson and J. R. Huff, J. Med. Chem., 1994, 37, 3443.
12. D. L. Boger, S. Ichikawa and W. Zhong, J. Am. Chem. Soc., 2001, 123, 4161; D. E. Chavez and E. N.
Jacobsen, Angew. Chem., Int. Ed., 2001, 40, 3667.
13. D. Seebach, Angew. Chem. Int. Ed., 1990, 29, 1320; K. C. Nicolaou, E. J. Sorensen and N. Winssinger,
J. Chem. Ed., 1998, 75, 1225.

2
Chemoselectivity
Defi nitions
Introduction: three types of control
Chemoselectivity: simple examples and rules
Chemoselectivity by Reactivity and Protection: An anti-Malaria Drug
Protection to allow a less reactive group to react
When Protection is not Needed
Dianions: wasting reagent to achieve selectivity
Chemoselectivity by Reagent: The Pinacol Rearrangement
Selectivity between secondary and tertiary alcohols by reagent
Corey’s longifolene synthesis
Chemoselectivity in Enol and Enolate Formation
General discussion of enols and enolates
Formation of specifi c enol equivalents
Lithium enolates, enamines and silyl enol ethers
Enamines
Silyl enol ethers
Synthesis of the ant alarm pheromone mannicone
Examples of Chemoselectivity in Synthesis
Synthesis of lipstatin, rubrynolide and hirsutene
Defi nitions
Introduction: three types of control
Behind all grand strategic designs in organic synthesis must lie the confi dence that molecules can
be compelled to combine in the ways that we require. We shall call this control and divide it into three
sections by mechanistic arguments. These sections are so important that we shall devote the next three
chapters to the more detailed explanation of just what the divisions mean. If you can recognise what
might go wrong you are in a better position to anticipate the problem and perhaps avoid it altogether.
Our three types of control are over chemoselectivity (selectivity between different functional groups),
regioselectivity (control between different aspects of the same functional group), and stereoselectivity
(control over stereochemistry). Examples of selectivity of all three kinds are given in The Disconnection
Approach: Chemoselectivity in chapter 5, Regioselectivity in chapter 14, and Stereoselectivity in
chapters 12 and 38. These aspects will not be addressed again in the present book.
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

10 2 Chemoselectivity
Chemoselectivity: simple examples and rules
Chemoselectivity is the most straightforward of the three types and might seem too elementary
to appear in an advanced textbook. Counting the number of protecting groups in the average
synthesis reveals this as a naive view. Selectivity between functional groups might involve:
(a) Selective reaction of one among several functional groups of different reactivity, as in the
reduction of the keto-acid 2 to give either product 1 or 3 at will.
O
OH
?
CO2H
(b) Selective reaction of one of several identical functional groups, as in the conversion of the
symmetrical diacid 5 to the half ester, half acid chloride 4, or the lactone 6 in which one of the two
acids has been reduced. There is a more subtle example of this at the end of the chapter.
MeO2C
(c) Selective reaction of a functional group to give a product which could itself react with the
same reagent, as in the classical problem of making a ketone 8 from an acid derivative 7 without
getting the alcohol 9 instead.
Organic chemists are developing ever more specifi c reagents to do these jobs. These reagents
must carry out the reaction they are designed for and must not:
(i) react with themselves.
(ii) react with functional groups other than the one they are aimed at.
(iii) react with the product.
O
1 2
3
4
O
COCl
R 1 OEt
?
substitution
HO2C
CO 2H
CO 2H
Proviso (ii) is obvious, but (i) and (iii) perhaps need some explanation. It seems hardly worth
stating that a reagent should not react with itself, but it is only too easy to suggest using a reagent
such as 11 without realising that the organo-metallic reagent will act as a base for its own hydroxyl
group 12 and destroy itself. The traditional solution to this problem is protection of the OH group
in 10 but ideally we should like to avoid protection altogether though this is not yet possible.
HO
7
R 2 –Metal
?
O
5
R 1 R 2
and not
?
?
reduction
OH
OH
R1 R2 R2 8 9
Br
Mg
HO
MgBr
HO
10 11
n-butanol
O H MgBr
H , H2O
O CH3work-up OH CH3 12 13 n-butanol
O
6
O

Proviso (iii) is more obvious and yet perhaps more often catches people out. It is not always clear
in exactly what form the product is produced in the reaction mixture, though a good mechanistic
understanding and careful thought should reveal this. The reaction between the simple aldehyde
14 and chloral (Cl 3C.CHO) looks like a straightforward route to the aldol 17, and might reasonably
be carried out via the enamine 16.
CHO HN N
+
O
However, mixtures of 16 and chloral, in any proportion, give only the 2:1 adduct 20 which can
be isolated in 83% yield. 1 Obviously the immediate product 19 reacts with chloral at least as fast
as does 16. Fortunately the synthesis can be rescued by acid-catalysed cleavage of 20 with HCl
which gives a good yield of the target 17.
Cl 3C
O
14 15
16
N
O
O
CCl3
N
Enamines are excellent at Michael additions and another plausible synthesis which “goes
wrong” is the addition of acrolein to cyclohexanone mediated by the enamine 21 formed this time
with pyrollidine.
If the product is isolated by distillation, a good yield (75%) of the bicyclic ketone 23 is obtained. 2
A more detailed investigation disclosed that 24 is the immediate product, that 23 is formed from
it on distillation, and that the expected Michael adduct 22 can be isolated in good yield simply
by the hydrolysis of 24. In other words, don’t distil! If things “go wrong” in a synthesis, this may
be a blessing, as here. There are lots of ways to control Michael additions, but few ways to make
bicyclic ketones like 23, and this is now a standard method. 3 The moral is to make sure you know
what is happening, and to be prepared to welcome the useful and unexpected result.
O
O
Cl 3C.CHO
?
Cl 3C
Cl 3C.CHO O
OH
17
CCl 3
CHO
Cl3C O N
18 19 20
O
+
HN
O
2 Defi nitions 11
N
N
?
CHO
21 22
23 24
N
O
N
O
CHO
O

12 2 Chemoselectivity
Chemoselectivity by Reactivity and Protection: An anti-Malaria Drug
We need to see some of these principles in action and a proper synthesis is overdue. The anti-malarial
drug amopyroquine 25 might have been derived from quinine as it has a quinoline nucleus. It also has
fi ve functional groups – three amines (all different - one aromatic, one tertiary, and one secondary), a
phenol and an aryl chloride. There are four rings, three aromatic and one saturated heterocyclic.
There are many possible disconnections, but we should prefer to start in the middle of the molecule
to achieve the greatest simplifi cation. Disconnection 25a would require a nucleophilic displacement
(X a leaving group) on an unactivated benzene ring 27 and looks unpromising. Disconnection 25b
requires nucleophilic displacement at position 4 in a pyridine ring, an acceptable reaction because of
the electron-withdrawing effect of the nitrogen atom in the ring, so this is the better route, though we
may be apprehensive about controlling the chemoselectivity as there are three potential nucleophiles
in 26 and two potential electrophiles in 28.
X
OH
b
a
NH2 OH
Cl N
+
H2N N
25
Cl
N
+
X
N
28
26 29
27
Further disconnections of 26 by the Mannich reaction 4 and of 28 by standard heterocyclic
methods give simple starting materials. 5
Cl
H 2N
28
HN
Cl N
Cl
N
25
Amopyroquine
26a
X
N
OH
FGI
Protection to allow a less reactive group to react
N
Cl
OH
N
Mannich
31
H 2N
O
N
H
+ CH2O +
HN
Now the fun begins! Attempted Mannich reaction on the aminophenol 30 would be dominated by the
more nucleophilic NH 2 group and is no good. Acylation moderates the NH 2 group by delocalisation
30
quinoline
synthesis
OH
HN
b
Cl
a
32
NH2
OH
25a, b
Amopyroquine disconnections
N
HO
+
O

and 33 is a good choice for starting material as it is paracetamol, the common analgesic. Mannich
reaction now chemoselectively gives 34 and alkaline hydrolysis of the amide gives 26.
H 2N
OH Ac2O
AcOH · ·
N
H
pyrrolidine
AcHN
30 33 34
Michael addition of acrylic acid to the chloroamine 32 is straightforward and Friedel-Crafts
cyclisation of 35 gives only 31, presumably because the position next to the chlorine atom is slightly
disfavoured both sterically and electronically. Chlorination and oxidation are conveniently carried
out in the same step and the two halves (26 and 28) of this convergent synthesis are combined to
give amopyroquine 25.
32
CO 2H
Cl
N
H
In the last step we return to the original question of chemoselectivity: Only the primary amine
in 26 reacts because it is more nucleophilic than OH and because the more nucleophilic tertiary
amine adds reversibly – it cannot lose a hydrogen atom as it does not have one. Only the 4-chlorine
atom in the pyridine 28 reacts, presumably because addition to the other position would require
the disruption of both aromatic rings. Though this compound has been succeeded by better antimalarials,
its synthesis illustrates the all-important principle that predictions of chemoselectivity
must be based on sound mechanistic understanding. If doubt remains it is worth trying a model
reaction on simpler compounds or, of course, an alternative strategy.
When Protection is not Needed
OH
O CH 2O
CO2H
PPA
Dianions: wasting reagent to achieve selectivity
In that synthesis we moderated an over-reactive amino group by protection. Sometimes, protection
is not necessary if we are prepared to squander some of our reagents. A trivial example is the
addition of methyl Grignard to the ketoacid 36. We have already seen how acidic protons destroy
Grignard reagents, but if we are prepared to waste one molecule of the Grignard, we get automatic
protection of the carboxylic acid by deprotonation. Nucleophilic MeMgI will not add to the anion
of a carboxylic acid but adds cleanly to the ketone to give, after workup, the alcohol 37.
R
O
R
O
2 When Protection is not Needed 13
Me
35
CO2H
MeMgI
31
R
POCl 3
I 2
Cl
36 36; Mg salt
37; Mg salt
H
CO2 Mg
H2O
2
O
R
OH
Me
Cl
N
28; X = Cl
CO2 Mg MeMgI
2
37
CO 2H
OH
26
N
heat in
aqueous ethanol
25

14 2 Chemoselectivity
At fi rst sight, the synthesis of Z-38 by the Wittig reaction seems too risky. The phosphonium
salt 39 has a more acidic proton (CO 2H) than the one we want to remove to make the ylid, and the
aldehyde 40 not only also has an acidic proton (OH), but it prefers to remain as the cyclic hemiacetal
41 so that there is no carbonyl group at all.
Z-38
HO CO 2H
O
However, simply using a large excess of base makes the reaction work without any protection.
The phosphonium salt 39 does indeed lose its fi rst proton from the CO 2H group 42, but the second
molecule of base forms the ylid 43 as the two anions are far enough apart not to infl uence each
other. 6 Base also catalyses the equilibrium between the anions 44 and 45 so that 43 and 45 can
react to give the target molecule. The transition state for this reaction has three partial negative
charges, but they are well apart from each other and there is obviously not too much electrostatic
repulsion as the reaction goes well. This case is opposite to the previous ones: careful mechanistic
analysis shows that expected chemoselectivity problems do not materialise.
39
41
hemi-acetal
41
Chemoselectivity by Reagent: The Pinacol Rearrangement
So far we have discussed chemoselectivity between different functional groups. The situation gets
more complicated if the functional groups are similar, or even the same. The pinacol rearrangement
is a useful route to carbonyl compounds from diols, the classical example being the rearrangement
of 46 in acid solution to give the t-alkyl ketone 48. There are no chemoselectivity problems here:
the two hydroxyl groups in 46 are the same so it does not matter which gets protonated and, in the
rearrangement step 47, all four potential migrating groups are methyl.
HO OH
46
'pinacol'
Selectivity between secondary and tertiary alcohols by reagent
OH
Wittig
CO 2H
Unsymmetrical diols provide a serious problem of chemoselectivity with an ingenious solution. 7
Treatment of the diol 49 with acid leads to loss of OH from what would be the more stable
t-alkyl cation and hence, by hydrogen shift, to the ketone 51.
Ph 3P
+
HO CHO
base
Ph3P CO2
base
Ph3P 42 43
base
O
O
O CHO
44 45
H
Me
HO OH2
Me
migration
HO O
Wittig
reagent
39
hydroxy-aldehyde
40
CO2
Z-38
47 48
'pinacolone'

H
R
HO OH
The alternative, more interesting rearrangement to give 53 can be initiated by tosylation of
the diol 49 in weak base. It is impossible to tosylate tertiary alcohols under these conditions, as
both the t-alcohol and TsCl are large, so only the secondary alcohol becomes sulfonylated and so
leaves, and the rearranged ketone 53 is the only product.
R
H
HO
Corey’s longifolene synthesis
H
R
H
HO OH2
H
migration
49 50 51
OH
TsCl
pyridine
H
R
TsO
Me
OH
Me
migration
Me
H
R OH
H
R
49 52 53
The question of which group migrates in a pinacol rearrangement is also a question of chemoselectivity,
and usually groups that can participate because they have lone pair or π-electrons migrate
best. In Corey’s longifolene synthesis, 8 the 6/7 fused enone 54 was an important intermediate. Synthesis
from the readily available Robinson annelation product 57 is very attractive, but this demands
a ring expansion step such as the pinacol rearrangement of 55 of unknown selectivity. 1,2-Diols such
as 55 normally come from the hydroxylation of an alkene, in this case the diene 56 which might be
made by a Wittig reaction on the dione 57. Every step in this sequence raises a question of chemoselectivity.
Which of the two ketones in 57 is more reactive? Which of the two double bonds in 56 is
more easily hydroxylated? Which side of the ring migrates in the pinacol rearrangement on 55?
O
54
O
2 Chemoselectivity by Reagent: The Pinacol Rearrangement 15
pinacol
?
HO HO
O
One of the ketones in 57 is conjugated, and one is not. The unconjugated one is less stable and
we can therefore use thermodynamic control if we protect as an acetal, a reversible process. The
unconjugated ketone would also be more kinetically reactive towards the Wittig reagent. Of the
two double bonds in 59, the one outside the ring is more reactive towards electrophilic reagents,
again for both kinetic and thermodynamic reasons. The tosylation route ensures that the right
OH group leaves in the pinacol rearrangement and because the remaining π-bond migrates better
than the simple alkyl group when 60 rearranges with a weak Lewis acid, all is well. The synthesis
therefore follows the route below, with all questions of chemoselectivity neatly solved. The acetal
protecting group was also useful later in the synthesis.
FGI
R
HO
55 56
H
O
R
O
Wittig
? ?
O
H
O
57
O

16 2 Chemoselectivity
57
HO HO
HO OH
TsOH
O
Chemoselectivity in Enol and Enolate Formation
General discussion of enols and enolates
O
O
TsCl
pyridine
O
O
TsO HO
Ph 3P
58 E and Z-59
We have concentrated so far on two functional groups within the same molecule. The chemoselectivity
problem is just as important when we want two molecules to react together in a certain
way, but, because both molecules have similar functional groups, the reaction can occur the other
way round, or one of the molecules may react with itself and ignore the other. This problem is
particularly acute in reactions involving enolisation. The alkylation or acylation of enols or enolates
and the reaction of one carbonyl compound with another, the aldol reaction, are classical
and important examples summarised in the general scheme below. We shall concentrate in this
chapter on the chemoselectivity of these processes, that is we shall look at the enolisation of esters,
aldehydes, and the like.
R 1
R 1
OH
R2 O
H
R2 O
aldol aldol
aldol
H
O
enol
OH
R 2
O
R1 carbonyl compound
R 1
Reaction of an ester 62 with its own alkoxide ion produces a small amount of enolate 63 that
reacts with unenolised ester to give the ketoester 64. This reaction, though useful in its own right,
precludes the direct alkylation of esters under these conditions.
H H EtO
OEt
R
O
O
OH
R
R 2
H
O
O
O
LiClO 4
CaCO 3
THF
O
O
O
OsO4
pyridine
60 61
OEt
R 1
O
R1 enolate
O
H
O
OH
R CO2Et
R 2
R 2
alkylation
RBr
acylation
X
O
R 1
R 1
R 2
O
O
O
R CO2Et
O
62; ester 63; ester enolate 64; β-keto-ester
R
O
O
R 2
R 2

Formation of specifi c enol equivalents
What is needed for the alkylation is rapid conversion of the ester into a reasonably stable enolate,
so rapid in fact that there is no unenolised ester left. In other words the rate of proton
removal must be faster than the rate of combination of enolate and ester. These conditions are
met when lithium enolates are made from esters with lithium amide bases at low temperature,
often 78 C. Hindered bases must be used as otherwise nucleophilic displacement will occur
at the ester carbonyl group to give an amide. Popular bases are LDA (Lithium Di-isopropyl
Amide, 66), lithium hexamethyldisilazide 67, and lithium tetramethylpiperidide 68, the most
hindered of all. These bases are conveniently prepared from the amine, e.g. 65 for LDA, and
BuLi in dry THF solution.
N H
65
Di-isopropylamine
BuLi
THF
N Li
66; LDA
Li Di-isopropyl Amide
Treatment of a simple ester 62 with one of these bases at 78 C leads to a stable lithium
enolate 70 by initial coordination of lithium to the carbonyl group 69 and proton removal via a
six-membered cyclic transition state 69a.
H
R
H
OEt
O
2 Chemoselectivity in Enol and Enolate Formation 17
LDA
–78 °C
THF
R2N
H
Lithium enolates, enamines and silyl enol ethers
H
R
OEt
Li
O
Me 3Si N SiMe 3
Direct alkylation of lithium enolates of esters 9 62 and lactones 73, via the lithium enolates 71 and
74, with alkyl halides is usually successful.
Li
67; LHMDS
Li HexaMethylDiSilyazide
H
R
R2N H
OEt
62; ester 69
69a
70
R 1 CO 2Et
62
1. LDA
Br
R 1
R 2
H
71
Li
O
R
2. R 2 Br
N
Li
68; LTMP
Li TetraMethylPiperidide
H
OEt
O O O OLi O O
1. LDA
73 74
OEt
O
Li
2. RBr
75
OLi
R 2
72
+ R2NH
R 1 CO 2Et
R

18 2 Chemoselectivity
More impressive and more important is the performance of these lithium enolates in aldol
reactions. Ester enolates are awkward things to use in reactions with enolisable aldehydes and
ketones because of the very effi cient self-condensation of the aldehydes and ketones. The traditional
solutions involve such devices as Knoevenagel-style reactions with malonates. 11 Lithium enolates
of esters, e.g. 76, react cleanly with enolisable aldehydes and ketones to give high yields of aldols, 12
e.g. 79 in a single step also involving a six-membered cyclic transition state 77.
MeCO 2Et
OLi
+
OEt
They even react cleanly with formaldehyde, thus solving the problem that the Mannich reaction
is not applicable to esters. The synthesis of the exo-methylene lactone 80 can be accomplished
this way. Enone disconnection 13 reveals formaldehyde as the electrophilic component in a crossed
aldol reaction, realised with a lithium enolate 82. 14 The mono-adduct 83 of formaldehyde and the
lactone 81 can be isolated and the cautious dehydration step is to avoid migration of the double
bond into the ring.
81
OLi
CO2Et
H
H 2O
The same technique can even be applied to carboxylic acids themselves 84 providing two
molecules of base are used. The fi rst removes the acid proton to give the lithium salt 85 and the
second forms the lithium enolate 86.
R
LDA
OH
84
O
LDA
THF
–78 °C
H
O
H
80
LDA
H
H
O
76
O
78
α,β-unsaturated
carbonyl
OLi
CH 2O
These lithium derivatives are also well behaved in alkylations and aldol reactions. Krapcho’s
synthesis 15 of the sesquiterpene α-curcumene 92 starts with the chemoselective condensation of
O
OH
79, 79-90%
H
H
82 83
R
OLi
85
O
LDA
R
O
H
H
OLi
86
77
CO 2Et
81
O
O
OH
OLi
O
OEt
O
Li
O
+ CH 2=O
1. MsCl, Et 3N
2. pyridine
2 x LDA
–78 ˚C, THF
80
84

the dilithium derivative of the acid 87 with the enolisable aldehyde 89. The aldol product 90 is
converted into the β-lactone 91 and hence by heating and loss of CO 2 into α-curcumene 92.
You might be forgiven for thinking that lithium enolates solve all problems of enolate chemoselectivity
at a stroke and wonder why they are not always used. They are very widely used, but
they require strictly anhydrous conditions at low temperatures (usually 78 C, the temperature
of a dry ice/acetone bath) and no-one in their right mind would use these conditions if mixing
the reagents in ethanol at room temperature with a catalytic amount of NaOH did nearly as well.
These are the conditions of many simple aldol reactions and are preferred where practical, particularly
in industrial practice. The intermediate 93 was needed in a synthesis of geiparvirin. The
best aldol disconnection in the middle of the molecule gives a ketone 94, that must be enolised in
the only possible position, and then react with an unenolisable and more electrophilic aldehyde 95.
No selectivity problems arise and an equilibrating aldol reaction between 94 and 95 catalysed by
NaOEt in EtOH gives 93 in 89% yield. 16
Enamines
87
87
HO
CO 2H
2 Chemoselectivity in Enol and Enolate Formation 19
1. 2 x LDA
2. 89
91, 77% yield
O
2 x LDA
93
90
73% yield
O
OLi
O
OLi
88 89
Ph
aldol
140 °C
Lithium enolates do not even solve all problems of chemoselectivity: most notoriously, they fail
when the specifi c enolates of aldehydes are needed. The problem is that aldehydes self-condense
so readily that the rate of the aldol reaction can be comparable with the rate of enolate formation
by proton removal. Fortunately there are good alternatives. Earlier in this chapter we showed
examples of what can go wrong with enamines. Now we can set the record straight by extolling the
virtues of the enamines 96 of aldehydes. 17 They are easily made without excessive aldol reaction as
they are much less reactive than lithium enolates, they take part well in reactions such as Michael
additions, a standard route to 1,5-dicarbonyl compounds, e.g. 97. 18
HO
OH
90, 73% yield
94
CHO
CO2H
PhSO 2Cl
pyridine
92; α-curcumene, 90% yield
O H
+
O
95
Ph

20 2 Chemoselectivity
An impressive example 19 is the Robinson annelation of the unsaturated aldehyde 98 where
neither aldol reaction nor double bond migration in the enamine 99 interferes. The 1,5-dicarbonyl
compound 100 cyclises spontaneously to the enone 101.
Ph
CHO
98
R
+
Silyl enol ethers
CHO R 2NH
N
H
R
R
96
NR2
Ph
NR 2
O
N
For all their usefulness, enamines have now largely been superseded by silyl enol ethers. These
(102-104) can be made directly with Me 3SiCl from the lithium enolates of esters or acids or
from aldehydes under milder conditions with a tertiary amine. The silicon atom is an excellent
electrophile with a strong preference for more electronegative partners and it combines with the
oxygen atom of an enolate so rapidly that no self condensation occurs even with aldehydes.
Silyl Enol Ethers of Esters
R
O
OEt
LDA
R
Silyl Enol Ethers of Acids
O
LDA
R
R
OH
Silyl Enol Ethers of Aldehydes
O Et3N R
R
H
O
OMe
The silyl enol ethers 102 and 104 are shown as single geometrical isomers for convenience:
in fact they are normally formed as mixtures, though this does not usually affect their reactions.
They are thermodynamically stable compounds but are easily hydrolysed with water or methanol
and are usually prepared when they are needed. They are much less reactive than lithium enolates,
or even enamines, and their reactions with electrophiles are best catalysed by Lewis acids, often
O
OHC
Ph
99 100 101
OEt
OLi
H
OLi
OLi
OH
R
Me 3SiCl
Me 3SiCl
Me 3SiCl
NR 2
OMe H
CHO
H2O R CO2Me 97
O
R
R
R
O
OMe
OEt
102
OSiMe3
OSiMe 3
OSiMe3 103
H
104
OSiMe 3
Ph
O

TiCl 4. The aldehydes 105 and 108, the one branched and the other not, are simply converted
into their silyl enol ethers 106 and 109 and combined with two different enolisable aldehydes to
give high yields of aldol products 107 and 110 without any self condensation of any of the four
aldehydes or any cross-condensation the wrong way round. 20
Ph
105
108
CHO
CHO
106
OSiMe3
Ph OSiMe3
The silyl enol ethers of esters, e.g. 111 and lactones, e.g. 114 similarly take part in effi cient aldol
reactions with enolisable aldehydes and ketones with Lewis acid catalysis, again with complete
regioselectivity. Example 113 is particularly impressive as the very enolisable ketone gives a high
yield of an aldol product with two adjacent quaternary centres. 21
CO 2Et
111
O
O
114
2 Chemoselectivity in Enol and Enolate Formation 21
Me 3SiCl
Et 3N
Me3SiCl
1. LDA
Et3N
2. Me 3SiCl
1. LDA
2. Me 3SiCl
Synthesis of the ant alarm pheromone mannicone
Ph CHO
TiCl4 n-PrCHO
Ph CHO
OH
107; 86% yield
The synthesis of the ant alarm pheromone mannicone 117 is a good example. Enone disconnection
reveals that we need a crossed aldol condensation between the symmetrical ketone 118, acting as
the enol component, and the enolisable aldehyde 119.
Mannicone: Analysis
Me 3SiO
O
The ketone gives a mixture of geometrical isomers of the silyl enol ether 120 which condense
with the aldehyde 119 to give the aldol 121 as a mixture of diastereoisomers which dehydrates to
mannicone 117 in acid. 22 It is particularly impressive that the optically active aldehyde 119 has its
TiCl 4
Ph
CHO
OH
109 110; 78% yield
OSiMe3
Ph
O
Ph CO2Et
OEt
OH
112 113, 94% yield
115
TiCl 4
+
O
TiCl4 O
O O H
117
aldol
enone
+
O
O
118 119
116
OH

22 2 Chemoselectivity
stereogenic centre at the enol position and yet optically active mannicone is formed by this route
without racemisation.
Mannicone: Synthesis
118
Me 3SiCl
We shall discuss further aspects of the aldol reaction in the next two chapters where we shall
see how to control the enolisation of unsymmetrical ketones, and how to control the stereochemistry
of aldol products such as 121. We shall return to a more comprehensive survey of specifi c
enol equivalents in chapter 10. In this chapter we are concerned to establish that chemoselective
enolisation of esters, acids, aldehydes, and symmetrical ketones can be accomplished with lithium
enolates, enamines, or silyl enol ethers, and we shall be using all these intermediates extensively
in the rest of the book.
Examples of Chemoselective Reactions in Synthesis
Synthesis of lipstatin
OSiMe 3
120
119
The synthesis of lipstatin 122 is too complex to discuss here in detail but an early stage in one
synthesis uses a clever piece of chemoselectivity. 23 Kocienski planned to make the β-lactone by
a cycloaddition with the ketene 124 and to add the amino acid side chain 123 by a Mitsunobu
reaction involving inversion. They therefore needed Z,Z-125 to join these pieces together. This
was to be made in turn by a Wittig reaction from 126. The problem now is that 126 is symmetrical
and cannot carry stereochemistry and that aldehydes are needed at both ends.
NHCHO
O
O
Et3N TiCl 4
O
H H
O
122; lipstatin
The way they solved the problem was this. (S)-()-Malic acid is available cheaply. Its dimethyl
ester 127 could be chemoselectively reduced by borane to give 128. Normally borane does not
reduce esters and clearly the borane fi rst reacts with the OH group and then delivers hydride to the
nearer carbonyl group. The primary alcohol was chemoselectively tosylated 129 and the remaining
(secondary) OH protected with a silyl group 130 (TBDMS stands for t-butyldimethylsilyl and
is sometimes abbreviated to TBS). Now the remaining ester can be reduced to an aldehyde 131
and protected 132. Displacement of tosylate by cyanide puts in the extra carbon atom 133 and
reduction gives 134, that is the dialdehyde 126 in which one of the two aldehydes is protected.
This compound was used in the successful synthesis of lipstatin.
O
NHCHO
CO 2H
121
OH
OH
Me 3Si
CHO
O
TsOH
TM 117
123 124
OHC
OH
Z,Z-125 126
CHO

MeO 2C
TsO
OH
t-BuMe2SiCl
OTBDMS
CO 2Me
TsO
CH(Oi-Pr) 2
BH3 SMe 2
NaBH 4
THF
OTBDMS
NaCN
DMSO
The synthesis of rubrynolide
HO
CO 2Me
NC
CH 2Cl 2
OTBDMS
CH(Oi-Pr) 2
OTBDMS
The synthesis of the natural product rubrynolide from the Brazilian tree Nectandra rubra presents
rather different problems. When the synthesis was planned it was supposed that rubrynolide was a
trans lactone 135 but the third centre was not defi ned. The synthesis revealed that this structure is
wrong: the lactone is actually cis and the stereochemistry 24 is 2S,4R,2’S 135a.
HO
127; (S)-(–)-malic acid
dimethyl ester
imidazole
2 Examples of Chemoselective Reactions in Synthesis 23
OH
OH
TsCl
CO2Me pyridine
CH2Cl2 TsO
CO2Me 128; 83% yield 129; 75% yield
DIBAL
The synthesis was planned around the reaction of a specifi c enolate of ester 136 with
the epoxide 137. This reaction was expected to give mainly trans 138 and is chemoselective
both because of the usual enolate problem and because 137 contains a terminal alkyne. The
lithium enolate was too basic and the aluminium enolate was used instead. The reaction gave
an 85:15 mixture of trans and cis 138 and also an 85:15 mixture of trans and cis 139 after
cyclisation. Dihydroxylation by osmylation gave a mixture of diols 140: this was deliberate so
that they could determine the stereochemistry at C-2’. To the surprise of the chemists, natural
rubrynolide was identical to one of the minor (i.e. cis) diols in the 15% part of the mixture.
Careful NMR analysis showed that it was 135a.
TsO
130; 92% yield 131; 78% yield
DIBAL
CH 2Cl 2
CHO
OHC
(i-PrO) 3CH
TsOH
OTBDMS
132; 92% yield 133; 83% yield 134; 81% yield
OH O
= 'R'
O
135; supposed rubrynolide
O
N
Me
O
NMO
N-Methylmorpholine
N-oxide
t-BuO
O
HO
2.
O O
O
1. LDA
Et 2AlCl
R
R
OsO 4
NMO
2' 2 4
OH
O
t-BuO
HO
O
135a; rubrynolide
O
OH
OH
136 137 138; 56% yield
139; 95% yield 140; 63% yield
O
R
TsOH
O
R
CH(Oi-Pr) 2

24 2 Chemoselectivity
The synthesis of hirsutene
Tietze’s synthesis of hirsutene 141, an alkaloid from Uncaria rhynchophylla used in Chinese
traditional medicine and with promising activity against infl uenza viruses, uses many chemoselective
reactions of which we shall discuss just three - one at the start, one in the middle, and one
at the end of the synthesis. 25
N
H
H
H
MeO 2C
N
OMe
N
H
H
MeO 2C
The fi rst reaction was the combination of the simple keto-diacid derivative 144 with tryptamine
143. How to make 144 was the problem. The diacid or its diester (the biologist’s ‘oxaloacetate’) is
readily available and they decided to hydrolyse the enolate of the diester 145 with aqueous NaOH.
It seems a strange decision to attack an anion with another anion but the enolate 146 is delocalised
so that one ester group 146b, but not the other, shares the negative charge. The ester that does not
share the negative charge is preferentially attacked by hydroxide ion.
MeO 2C
141; hirsutene
O
145
aldol
The second is an aldol reaction between the enolate 148 of ‘Meldrum’s acid’ 147 and the enolisable
aldehyde 149. Because the enolate 148 is exceptionally stable, it can be made from 147 with
a weak base and chemoselectivity (enolisation of 149) is not a problem. The unsaturated ester 151
is used immediately in a Diels-Alder reaction.
O O
O O
147
Meldrum's acid
CO 2Me
149
base
H 3N NH 3
2 AcO
N
H
MeO
H
O
NH
At the end of the synthesis, the curious alkene, better described as an enol ether, must be
introduced. The anion of the ester in 142 was prepared in base and condensed 152 with ethyl
H
142
N
O
H
OMe
O O
O
MeO
OMe
O
146a 146b
O
O O
O O
148; enolate
N
H
H
NH
O O
150
O
O O
NH2 N
H
143; tryptamine
O
N
H
HO 2C
OMe
H
O
CO2Me
144
NaOH
H2O
NH
O O
144
O O
151

formate. The chemoselectivity required is that ester 142 should react only with ethyl formate and
not with itself. There is a further complication: the fi rst product 153 has a more acidic proton than
that in 142 and will form the enolate 154 under the reaction conditions. The whole system is in
equilibrium and must be driven over by irreversible deprotonation by a strong base. Either LDA
or Na Ph 3C will do. After work-up the stable conjugated enol 155 is formed. Finally the enol is
converted into the enol ether with acidic methanol to give hirsutene itself.
142 H
H H H
O
O
O
O O
base base
References
OMe
H
OMe
2 References 25
OMe
General references are given on page 893
1. K. C. Brannock, R. D. Burpitt, H. E. Davis, H. S. Pridgen, and J. G. Thweatt, J. Org. Chem., 1964, 29, 2579.
2. G. Stork and H. K. Landesman, J. Am. Chem. Soc., 1956, 78, 5129.
3. A. Z. Britten and J. O’Sullivan, Tetrahedron, 1973, 29, 1331.
4. Disconnection Approach, page 158.
5. J. H. Burckhalter, F. H. Tendick, E. M. Jones, P. A. Jones, W. F. Holcomb and A. L. Rawlins, J. Am.
Chem. Soc., 1948, 70, 1363; R. Joly, J. Warnant and B. Goffi net, Roussel-Uclaf, French Patent 1,514,280,
Chem. Abstr., 1969, 70, 68195.
6. H.-J. Bestmann, O. Vostrowsky, H. Paulus, W. Billmann and W. Stransky, Tetrahedron Lett., 1977, 121;
H.-J. Bestmann, J. Süss and O. Vostrowsky, Liebig’s Annalen, 1981, 2117.
7. D. Diederich, Houben-Weyl, 1973, 7/2a, page 958.
8. E. J. Corey, M. Ohno, R. B. Mitra, and P. A. Venkatacherry, J. Am. Chem. Soc., 1964, 88, 478.
9. R. J. Cregge, J. L. Herrmann, C. S. Lee, J. E. Richman and R. H. Schlessinger, Tetrahedron Lett., 1973, 2425.
10. G. Posner and G. L. Loomis, J. Chem. Soc., Chem. Commun., 1972, 892; J. L. Herrmann and R. H.
Schlessinger, J. Chem. Soc., Chem. Commun., 1973, 711.
11. Disconnection Approach, page 160.
12. M. W. Rathke, J. Am. Chem. Soc., 1970, 92, 3222; M. W. Rathke and D. F. Sullivan, J. Am. Chem. Soc.,
1973, 95, 3050; M. W. Rathke, Organic Syntheses, 1973, 53, 66.
13. Disconnection Approach, page 149, 158.
14. P. Grieco, J. Chem. Soc., Chem. Commun., 1972, 1317.
15. A. P. Krapcho and E. G. E. Jahngen, J. Org. Chem., 1974, 39, 1322.
16. P. L. Creger, J. Am. Chem. Soc., 1970, 92, 1397; P. E. Pfeiffer, L. S. Silbert and J. M. Chrinko, J. Org.
Chem., 1972, 37, 451.
17. G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz and R. Terrell, J. Am. Chem. Soc., 1963, 85, 207.
18. Disconnection Approach, chapter 21, page 170.
19. P. Vittorelli, J. Peter-Katalinic, G. Mukherjee-Müller, H.-J. Hansen and H. Schmid, Helv. Chim. Acta,
1975, 58, 1379.
20. T. Mukaiyama, K. Banno, and K. Narasaka, J. Am. Chem. Soc., 1974, 96, 7503.
21. T. Mukaiyama, Angew. Chem., Int. Ed., 1977, 16, 817.
22. T. Mukaiyama, Chem. Lett., 1976, 279.
23. A. Pommier, J.-M. Pons and P. J. Kocienski, J. Org. Chem., 1995, 60, 7334.
24. S. K. Taylor, J. A. Hopkins, K. A. Spangenberg, D. W. McMillen and J. B. Grutzner, J. Org. Chem., 1991,
56, 5951.
25. L. F. Tietze and Y. Zhou, Angew. Chem., Int. Ed., 1999, 38, 2045; L. F. Tietze, Y. Zhou and E. Töpken,
Eur. J. Org. Chem., 2000, 2247.
H
OMe
H
O
O
H
OMe
152 153 154
155
work
-up
H
OH

3
Regioselectivity:
Controlled Aldol Reactions
Defi nition
Introduction and defi nition
Regioselectivity in enol and enolate formation
Regioselectivity by conditions: acid or base
Specifi c Enol Equivalents
Regioselectivity of formation of enamines
Lithium enolates and silyl enol ethers
Regioselective Aldol Reactions
Aldol reactions with specifi c enol equivalents
Contrast with equilibrium methods
Aldols with Lewis acid catalysis: silyl enol ethers
Application to the synthesis of gingerol
Reaction at O or C? Silylation, Acylation and Alkylation
Naked enolates
Alkylation at carbon, problems with enamines
Application to the synthesis of lipoic acid
Alkylation with tertiary alkyl groups
Acylation at Carbon
Lithium enolates of carboxylic acids
Enamines and silyl enol ethers
Reactions with Other Electrophiles
α-Halo carbonyl compounds and epoxides
Michael reactions
A Final Example
Double Michael reactions with enamines
Defi nition
Introduction and defi nition
Regioselectivity means controlling different aspects of the same functional group. Classic examples
are controlling direct (1,2) or conjugate (Michael or 1,4) addition to unsaturated carbonyl
compounds, a subject we shall tackle in chapter 9, or controlling electrophilic substitution on
unsymmetrical alkenes, which we shall meet in chapter 17. In this chapter we shall continue our
study of enolisation by looking at regioselectivity in aldol and related reactions.
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

28 3 Regioselectivity: Controlled Aldol Reactions
Regioselectivity in enol and enolate formation
Reactions in which the enol or enolate (or equivalent) of one carbonyl compound reacts with an electrophilic
carbonyl compound (usually both are aldehydes or ketones) are often loosely called aldol
reactions. In the last chapter we saw how the use of lithium enolates and other specifi c enolate equivalents
conquers the problem of chemoselectivity in enolisation of aldehydes and acid derivatives. In
this chapter, we are going to use the same intermediates to solve the problem of regioselectivity in
crossed aldol reactions in which the enolising component is an unsymmetrical ketone.
R
OH
and/or
R
OH
acid
Regioselectivity by conditions: acid or base
R
1 2
3
4
5
The fundamental mechanistic distinction on which all methods ultimately depend is a precarious
difference between kinetic and thermodynamic enolisation. A ketone 3, in which R is a simple
alkyl group, has protons which are slightly more acidic on the less substituted side, the methyl
group. This is because each alkyl group reduces the number and, by a weak electron donation,
the acidity of the remaining hydrogens. An analogy is that t-BuLi is a stronger base than s-BuLi
which is in turn stronger than n-BuLi. Condensation of 3 with a non-enolisable aldehyde (to avoid
problems of chemoselectivity!) tends to give more aldol from 4 than from 5 when catalysed by
NaOH, but the distinction is often too small to be useful. The ketone 3; R i-Pr does condense
regioselectively at the methyl group with furfuraldehyde 6 and NaOH to give the enone 7 in a
useful 80% yield. 1 Kinetic control favours the less substituted enolate.
+
O O CHO
By contrast, the enol, and also the enolate when in combination with a metal atom, is more
stable when the double bond is more substituted. Our ketone 3 will tend to produce more of
enol 2 than enol 1 in acid solution, particularly if the enols are in equilibrium. Once again the
distinction is usually too small to be useful. One example where it does succeed is the acidcatalysed
Robinson annelation of ketone 8 with butenone 10 where reaction occurs predominantly
on the more substituted enol 9: the yield of 11 is only 50%, but it is at least a one-step operation.
Thermodynamic control favours the more substituted enol. 2
O
base
O
R
O
O
and/or
3; R = i-Pr 6
(E)-7; 80% yield
H
O
H 2SO 4
NaOH
OH O
8 9
10
+
R
11; 50% yield
O
O

An important application of thermodynamic control occurs in the manufacture of Viagra
12, Pfi zer’s treatment for impotence. 3 The NE corner of the molecule comes from the pyrazole
acid 13: removal of the hydrazine portion reveals the one piece of continuous carbon skeleton
14. 1,3-Dicarbonyl disconnection gives an unenolisable diester (an oxalate) and an unsymmetrical
ketone, pentan-2-one 15.
EtO
RO
Condensation of 15 with diethyl oxalate in base without any control gives 14 because the
true product of the reaction is the stable enolate of 14. The enolate 16 at the methyl group
is preferred and the stable enolate of 14 is also preferred to the alternative because it is less
substituted. This product was condensed with hydrazine to give fi rst the pyrazole 13 and then
Viagra.
Specifi c Enol Equivalents
O
2
HN
2
1
O
N
O
3
O
Me
N
N
O
S
N
O
N
Me
12; Sildenafil (Viagra)
1,3-diCO
Claisen
ester
2 x C—N
RO
A survey of the thousands of examples of traditional aldol reactions in the back of Organic
Reactions volume 16 shows how feeble this effect often is. Hardly any compounds are formed in
good yield by chemoselective reactions using catalytic acid or base alone. The situation is different
with modern methods.
RO
O
O
OR
+
O
13
Me
N
N
14 15
O
3 Specifi c Enol Equivalents 29
O O
base
15 16
O O
CO 2Et
O
(CO 2Et) 2
O
2 x C—N
CO2Et
14; R = Et enolate of 14; R = Et

30 3 Regioselectivity: Controlled Aldol Reactions
Regioselectivity of formation of enamines
Enamines show an amplifi ed preference for the less substituted double bond: at fi rst this seems to
contradict what we have just said, but the effect is greatest in cyclic ketones, e.g. 17, with cyclic
amines. 4 † It is steric in origin and arises from the eclipsing of hydrogen atoms (A 1,3 strain) shown
in the more substituted enamine 19. Enamines of acyclic ketones can be persuaded to give only the
less substituted regio-isomer by equilibration of the immonium salt in weak base. 5
17
H
O
Lithium enolates
The most important method 6 for the regioselective synthesis of less substituted enolates is kinetic
enolate formation with strong irreversible bases (LDA etc). Since the lithium enolate 7 20 can be
converted into the silyl enol ether 8 21 directly without isolation, we have access to the two most
valuable specifi c enol equivalents for the less substituted isomer. Alkylation of the lithium enolate
of 23 goes more than 99% on the less substituted side. 9
Silyl enol ethers
N
H
There is no such perfect method for getting enolisation to go on the more substituted side. The best
is thermodynamic control in the formation of the silyl enol ether, 10,11 which gives an approximate
90:10 ratio of 22:25 from 23. Silyl enol ethers can be converted into lithium enolates with MeLi (the
by-product is Me 4Si: useful for NMRs) and hence we can achieve alkylation on the more substituted
side, e.g. 26 is benzylated with PhCH 2Br to give 27; R CH 2Ph in up to 84% yield. 12
† enamine review: Whitesell, Synthesis, 1983, 517
+
R
OSiMe3
22
MeLi
OLi
26
pyrrolidine
3
O
Me 3SiCl
Et 3N
RBr
LDA
R
O
23
R
H
N
18:19
90:10
+
18 19
OLi
Me 3SiCl
R
20 21
O
LDA
THF
–78 °C
27
OLi
O
RBr
N
Me 3SiCl
R
H
H H
OSiMe3
24 25
28
A 1,3
strain
OSiMe 3

Regioselective Aldol Reactions
Aldol reactions with specifi c enol equivalents
Lithium enolates can be used directly in aldol reactions, even with enolisable aldehydes, a simple
example 6 being the synthesis of the enone 32. The ketone 15 forms mostly the less substituted
lithium enolate which condenses 29 with butanal to give aldol 31 in reasonable yield. Elimination
is usually carried out in acid solution.
O
O OH
Contrast with equilibrium methods
Li
O O
Traditional equilibration methods [mix 15, PrCHO and NaOH] would give the enal 33 from
self-condensation of butanal. The aldehyde would ignore the less enolisable and less electrophilic
ketone.
Aldols with Lewis acid catalysis: silyl enol ethers
Silyl enol ethers also combine with aldehydes and ketones in effi cient aldol reactions catalysed by
Lewis acids such as SnCl 4, ZnCl 2, AlCl 3, and TiCl 4, the last being the most popular. 13 Thus each
of the silyl enol ethers 25 and 22 derived from the unsymmetrical ketone 23 gives a different aldol
product 34 and 35 with benzaldehyde. 11,14
O
34
15
work-up
OH
Ph
LDA
CHO
+
The mechanism is a slightly more complicated example of the six-membered cyclic transition
state we met in the last chapter. 13 The titanium atom bonds to both oxygen atoms (of the enolate
and the aldehyde) 36. As the new carbon-carbon bond is formed, one chlorine atom is transferred
TsOH
O
O OLi
29 30
aldol 31 enone 32
O
two molecules of butanal
PhCHO
TiCl4
3 Regioselective Aldol Reactions 31
OSiMe3
O
NaOH
CHO
enal 33
OSiMe 3
PhCHO
TiCl4 Ph
OH
25 23 22
35
O

32 3 Regioselectivity: Controlled Aldol Reactions
from titanium to silicon so that the immediate product is the titanium alkoxide 37. This quickly
combines with Me 3SiCl to give the silylated aldol as the true product 38, and hence the aldol 39
on work-up in a hydroxylic solvent.
R 1
CHO
Me 3SiO
R 1
R 2
TiCl 4
R 1
O SiMe 3
R 1
CHO
Application to the synthesis of gingerol
Cl
Cl Cl
Ti SiMe3 O O
Me3SiCl
R2 R1 H2O R2 CHO
R1 36 37
OH
Mukaiyama’s synthesis 14 of gingerol 40, the pungent fl avouring principle of ginger, illustrates
these methods. 15 The obvious aldol disconnection shows that we require a specifi c enol of an
unsymmetrical ketone 41 on the less substituted side to combine with an enolisable aldehyde 42.
The ketone can be made by the FGA 16 (Functional Group Addition) strategy using another aldol
reaction, this time between acetone and the non-enolisable and readily available aldehyde vanillin
44, the fl avouring principle of vanilla.
MeO
HO
41
FGA
R 2 CHO
O OH
40; gingerol
MeO
HO
38 39
43
aldol
The fi rst aldol can actually be carried out by traditional methods: in acid solution condensation
occurs on both sides of acetone to give 45, but in alkaline solution 43 is formed in 88% yield.
Mukaiyama 15 preferred to use the silyl enol ether of acetone 46 with BF 3 as the Lewis acid, and
this worked as well (89% yield).
MeO
HO
R 2
O MeO
CHO
enone
HO
O O
Ti
Cl
Cl Cl
Me3SiCl 41
44; vanillin
O
+
+ H
O
O
42
Bu

Catalytic reduction with Raney nickel removed the double bond, and the regioselective aldol - now
the silyl enol ether is essential - was carried out by isolating the silyl enol ether 47 and using TiCl 4 as
the Lewis acid. The yield of gingerol 40 was an impressive 92%.
43
MeO
HO
Reaction at Oxygen or Carbon? Silylation, Acylation and Alkylation
Now that you are acquainted with the three main types of regiocontrolled specifi c enol equivalents
(lithium enolates, silyl enol ethers, and enamines) we should consider how well they perform in
the other tasks commonly required of enols. Here we shall face another problem of regioselectivity:
enols, enolates, and their equivalents have two nucleophilic sites, the required carbon atom and a
heteroatom (oxygen in lithium enolates and silyl enol ethers and nitrogen in enamines). We have
seen this regioselectivity in action when lithium enolates reacted with aldehydes and ketones at
carbon, but with Me 3SiCl at oxygen. We normally want reaction at carbon, the site favoured by
frontier orbital 17 and thermodynamic control rather than at the heteroatom, the site favoured by
charge (or Coulombic) and kinetic control.
Ph
Naked enolates
3 Reaction at Oxygen or Carbon? Silylation, Acylation and Alkylation 33
O
45
O Me 3SiCl OSiMe 3
Et 3N Et 2O-BF 3
CH 2Cl 2
46
H2 41
1. LDA MeO
Raney Ni
MeOH
2. Me3SiCl O
Me 3SiCl
Ph
HO
44
“Naked enolates’’ without any complexation can be made from silyl enol ethers using fl uoride ion, a
very selective nucleophile for silicon 49, and a non-metallic cation, usually a tetra- alkylammonium
ion. The commonest reagent is “TBAF’’ (TetraButylAmmonium Fluoride Bu 4N F ). In this way
the “naked enolate’’ 50 was made. It proved to be acylated with acetic anhydride exclusively at
oxygen to give the enol acetate 53 and alkylated with MeI at carbon to give the ketone 51 in 84%
isolated yield. 18
OMe
OH
O SiMe3
44
acid
MeO
HO
47; 69% yield
O
44
base
43; 89% yield
OSiMe 3
42
Et 2O-BF 3
CH 2Cl 2
48 49
50
F
TBAF
Bu4N F
Ph
O
O
43;
88% yield
40; gingerol
92% yield
Bu4N

34 3 Regioselectivity: Controlled Aldol Reactions
Ph
CH3
O
51; alkylated ketone
84% yield
Ph
CH 3
Alkylation at carbon, problems with enamines
I
O
52a; alkylation (left)
of a naked enolate
50
Of our three specifi c enolate equivalents, the lithium enolates are most similar to naked enolates:
most reactive and most basic. The enamines are less reactive, only weakly basic but still nucleophilic
in their own right, while the silyl enol ethers are the least reactive, not basic at all, and are rather
like alkenes with slightly increased nucleophilicity because of an electron-donating substituent.
We have already seen that they usually need a Lewis acid for effi cient reaction, just like an alkene
in, say, the Friedel-Crafts reaction.
Simple alkylation works well with lithium enolates 55, but is a tight S N2 reaction 56 and works
best with methyl, primary alkyl, allyl, and benzylic halides. 9 Halides with acidic hydrogen atoms,
such as α-halocarbonyl compounds may destroy the basic enolate by acting as an acid instead of
an electrophile.
Enamines are inclined to react at nitrogen with alkyl halides, but react particularly well with
α-halo carbonyl compounds 58 to give 1,4-dicarbonyl products 60, and with allylic halides by
reaction at nitrogen followed by a [3,3] sigmatropic rearrangement 61 to give γ,δ-unsaturated
ketones 63.
Silyl enol ethers 64 need Lewis acid catalysis which generates at least a partial positive charge
on the alkyl group so they react best with tertiary, allylic, and benzylic halides, and reasonably
Ph
O
52b; acylation (right)
of a naked enolate
O O
R1 O
R1 OLi
R1 Li
O
R2 Br
R1 O
LDA
R2 C-Alkylation with Lithium Enolates
SN2 CH2Br 54 55 56 57
Br
O
Ph
R 2
O
O
53; enol ester
86% yield
R1 O
R2NH R1 R2N Br
R2 R
O
1
R2N R
O
2 H
H2O R1 C-Alkylation with Enamines
O
54 58 59 60
R1 R2N R1 R2N H
H2O R1 [3,3]
O
61 62 63
S N2 reaction
works well with
R 2 = H, Alkyl,
vinyl, Ph
O
R 2

well with secondary halides. In this way all types of alkyl halide can be added regioselectively to
carbonyl compounds. We have already seen examples of alkylation of the two isomeric lithium
enolates of the ketone 23, giving products 27 or 28 at will with benzyl, methyl, primary alkyl, or
allyl halides.
R1 O
R1 OSiMe3 R
TiCl4
2 C-Alkylation with Silyl Enol Ethers
Br
54
3 Reaction at Oxygen or Carbon? Silylation, Acylation and Alkylation 35
Application to the synthesis of lipoic acid
R 1
O
An example of the use of enamines comes in a synthesis 19 of lipoic acid 67, the primary metabolite
of redox pathways. This is an early synthesis (1957) but it has a simple and direct strategy and
revises aspects of chemoselectivity as well as regioselectivity. The disulfi de linkage comes from
the oxidation of the two thiols in 68, and these will be made by some sort of displacement on
the diol 69. There are 1,3 and 1,6 relationships in this diol acid: the 1,6 offers an opportunity to
use the reconnection strategy 20 via the lactone 70. Seven-membered lactones are usually made
by the Baeyer-Villiger reaction 21 on cyclohexanones, here 71, so we come fi nally to the need to
alkylate cyclohexanone itself with some reagent for an a 2 synthon.
Lipoic Acid: Analysis
S S
OH OH
An epoxide would give the right oxidation level, but the effi cient alkylation of enamines with
α-halo carbonyl compounds evidently appealed and methyl bromoacetate was combined with the
pyrrolidine enamine 72 in good yield. Chemoselective reduction of the ester inevitably required
protection of the more reactive ketone The leaving group selected for eventual displacement by a
sulfur nucleophile was an ester because the Baeyer-Villiger route will provide just such a leaving
group at the other position.
R 2
S N1
64 65 66
67
OH O
69
71
CO 2H
CO 2H
1,4-diCO
FGI
reconnect
SH SH
OH
OH
a 2 reagent
needed
+
O
70
68
O
O
R 1
O
CO 2H
Baeyer-
Villiger
d 2 reagent
S N1 reaction
works well with
R 2 = t-alkyl, allyl,
benzyl, s-alkyl
C–S

36 3 Regioselectivity: Controlled Aldol Reactions
Lipoic Acid: Synthesis
N
H
MeO 2C
76
+
O
O
S
O
1. H2N NH2 The Baeyer-Villiger rearrangement illustrates an important aspect of regioselectivity: which
group migrates? This is not the same as the chemoselective aspect of the pinacol rearrangement
discussed in the last chapter as there is only one leaving group here. The usual rule is followed:
the more highly substituted group migrates. Displacement with a sulfur nucleophile is a classic
problem of chemoselectivity, the problem being to prevent two alkylations at the same sulfur atom.
Thiourea is used here, 22 and the fi nal oxidation is carried out with Fe(III).
Alkylation with tertiary alkyl groups
N
AcO
74; 88% yield 75
2. KOH
FeCl3
MeO2C Br
Alkylation with tertiary halides is the special preserve of silyl enol ethers. Both the familiar
isomers 22 and 25 give regiospecifi c alkylation in good yield with Lewis acid catalysis. 23 The
formation of 78 is remarkable as it puts two quaternary centres next to one another.
OSiMe 3
1. LiAlH 4 (96%)
2. Ac2O (91%)
3. TsOH (90%)
68
80% yield
t-BuCl
TiCl 4
Silyl enol ethers also react well with allylic halides, or with the hemiterpene fragment prenyl
acetate 24 79 or with secondary 25 80 and tertiary 26 81 benzylic halides (Zn salts are used as
catalysts in these examples). In each case, regioselectivity has been demonstrated with the same
two isomers 22 and 25.
O
MeO2C
72 73; 71% yield
S S
TM67; 80% yield
O OSiMe3
MeCO 3H
CO2H
t-BuCl
TiCl4
O
OAc
O
O
76; 65% yield
HO OH
25 77; 67% yield 22
78; 86% yield
Br
OAc
O2N 79 80 81
Br
O
TsOH

Acylation at Carbon
Acylation at carbon is the usual route to 1,3-dicarbonyl compounds 27 and here the regioselectivity
problem is more serious as enolates tend to react with acylating agents on oxygen to give enol
esters. Fortunately all three specifi c enolate equivalents perform well with acid chlorides. The
lithium enolate 83 is on the more substituted side of the ketone 82 and so must be prepared via
the silyl enol ether. Acylation goes in reasonable yield 28 (55%) for the acylation of a basic enolate
The problem is that the acylation products are carbon acids which often “quench unreacted enolate
at a rate that exceeds acylation.’’ The proton marked H in 84 is between two carbonyl groups and
so is easily lost to form a stable enolate. Alternatively, oxidise the corresponding aldol. 29
O 1. Me3SiCl, Et3N OLi
2. MeLi, THF
82 83
Lithium enolates of carboxylic acids
Even the dilithium derivatives 86 of carboxylic acids 85 are acylated at carbon by acid chlorides. 30
When the product 87 is worked up, it loses CO 2 in the usual way, making this a synthesis of
ketones 88. Branched carboxylic acids work well in this sequence so it is the equivalent of the
acylation of a secondary carbanion, i.e. the disconnection 88a is now acceptable.
CO 2H
Enamines and silyl enol ethers
R
H
88a
The best enamines for acylation seem to be those of morpholine. The cyclohexanone 17 forms the
enamine on the less substituted side and this is acylated with a simple enolisable acid chloride in
reasonable yield. 31
O
17
+
85
O
2 x
LDA
N
H
morpholine
3 Acylation at Carbon 37
Cl
O O O
83 H
OLi
RCOCl
R
–CO2 R
OLi
O
CO2H H
86 87 88
O
C–C
acylation
O
N
1.
Cl
H
+
O
Cl
2. H , H 2O
R
enamine 1,3-diketone; 65% yield
O
O
84
O
O

38 3 Regioselectivity: Controlled Aldol Reactions
Silyl enol ethers react with acid chlorides and Lewis acids in what is effectively a Friedel-Crafts
reaction. 32 Both silyl enol ethers 22 and 25 derived from the ketone 23 give regiospecifi c acylation
with MeCOCl and TiCl 4. The yields of the two 1,3-diketones 89 and 90, formed as a mixture of
diastereoisomers, are excellent.
O
O
89; 91% yield
MeCOCl
TiCl4
OSiMe 3
OSiMe 3
MeCOCl
TiCl 4
Acylation at a methyl group in an unsymmetrical ketone, e.g. 15 usually occurs regioselectively
even with traditional methods (ester as acylating agent, corresponding alkoxide as base). We shall
return to this subject in chapter 10 with other specifi c enol equivalents, but you can see already
that virtually any 1,3-diketone can be made by one of these methods.
Reactions with Other Electrophiles
α-Halo carbonyl compounds and epoxides
25
22
Me3SiCl
Et 3N
O O
90; 89% yield
1,4-Dicarbonyl compounds can be made from enolates by alkylation of enamines with α-halocarbonyl
compounds 33 or any specifi c enol equivalent with allylic halides as just discussed,
followed in the latter case by oxidative cleavage of the double bond. 34 The reactions of enolates
with epoxides provides 1,4-difunctionalised compounds 35 at a different oxidation level and so we
should discuss another interesting question of regioselectivity. Unsymmetrical epoxides 91 are
usually opened at the less substituted end 92 by strongly nucleophilic reagents to give 94 via a
tight S N2 mechanism 93.
R
91
O
R
O
92
There has been remarkably little work in this area, but the dilithium derivatives of acids, e.g.
96 do react with unsymmetrical epoxides at the less hindered end. A simple example is styrene
oxide 97 which is attacked at its less substituted end to give the lactone 99 in 84% yield after
cyclisation. 36
CO 2H
95
X
2 x LDA
X
R
O
1. LDA
2. Me 3SiCl
23 25
O(–)
X (–)
R
OH
93 94
OLi
Ph
O
OH CO2H O
O
OLi
97
Ph
Ph
96 98 99
OSiMe 3
X

Spirocyclic lactones of structures such as 100 are interesting because of potential biological
activity, and might be made from available steroids such as oestrone 101.
The sulfur ylid 37 Me 2SCH 2 reacts stereoselectively from the bottom face of the ketone 101 to
give the epoxide 80 which in turn gives the lactone 36 100a with the lithium dienolate 96.
101
MeO
Michael reactions
H
H H
100
Me 2S CH 2 H
O
O
1,5-Dicarbonyl compounds are usually made by Michael (conjugate) addition of enols to α,βunsaturated
carbonyl compounds. Here too is another regioselectivity problem, the one raised
at the start of the chapter concerning direct (1,2) versus conjugate (1,4 or Michael) addition to
such electrophiles. This question will be more fully developed in chapter 9 but it is appropriate
to examine here the performance of our three specifi c enol equivalents in tackling this question
of regioselectivity. In general, direct addition is the kinetically controlled reaction favoured by
more reactive irreversible nucleophiles and more reactive electrophiles (Michael acceptors) such
as α,β-unsaturated aldehydes, while conjugate addition is the thermodynamic process favoured
by less reactive or reversible nucleophiles and less reactive Michael acceptors such as esters of
α,β-unsaturated acids. From this analysis we should expect the less reactive enamines and silyl
enol ethers to be good at Michael additions, and we would be right.
The enamine 103 of our familiar unsymmetrical ketone 23 gives a clean Michael addition
with methyl acrylate on the less substituted side to give the ketoester syn-104 as the only product
providing that the reaction is carried out in MeOH. 38
O
MeO
3 Reactions with Other Electrophiles 39
N
H
102
H H
N
?
O OLi
96
MeO
OLi
CO 2Me
MeOH
MeO
101
H
H H
23 103 syn-104
O
H
H H
100a
O
CO 2Me
O
O

40 3 Regioselectivity: Controlled Aldol Reactions
Just to make the point that chemistry has surprises even for the best informed, the rather similar
Robinson annelation of dihydrocarvone 105 again using the pyrrolidine enamine 106 goes on the
less substituted side 107 when one molecule of enone is used, but on the more substituted side 108
if a large excess (fi vefold) of the enone is used. 38 Both reactions are of course very useful but an
affront to our orderly instincts: we shall meet other examples where only experiment can lay down
the ground rules of selectivity.
O
Silyl enol ethers need Lewis acid catalysis for effi cient Michael reactions, such as the more
substituted (and conjugated) isomer 110 forming a 1,5-diketone 111 from cyclohexenone in good
yield. 39 This product 111 is a mixture of diastereoisomers as have been many of the products in
this chapter. We have also seen some reactions giving single diastereoisomers but without explanation.
It is high time that we addressed the question of stereoselectivity and this is the subject of
the next chapter.
O
A Final Example
Double Michael reactions with enamines
N
H
105 106
Ph
Me 3SiCl
N
But before we go, a special example 40 of double regioselectivity with a doubly nucleophilic enol
equivalent attacking a double electrophile. When the pyrrolidine enamine 112 of cyclohexanone
attacks the unsaturated ester 113, the bicyclic ketone 114 is formed in good yield.
O
1 equivalent
O
O
107
5 equivalents 108
OSiMe3
Ph +
O
TiCl4
Ph
H
O
O
109 110 111
O N
N
H
+
Br
CO 2Et
EtO 2C
112 113
114
O
O

The fi rst step is probably the Michael addition 115 of the enamine 112 to the unsaturated ester
113. The resulting iminium salt 116 loses a proton to regenerate an enamine. But it does so on
the side away from the fi rst reaction to avoid forcing the side chain into the same plane as the
pyrrolidine ring. The new enamine is 117.
N
O
Br
OEt
H
N
H O
N
Now the newly formed enamine 117 can be alkylated by the allylic bromide in the side chain.
To do this reaction, the molecule must put the side chain in an axial position 118. The resulting
iminium salt 119 is hydrolysed on work-up to the bridged bicyclic product 114.
117
The same treatment on 4-methoxycyclohexanone 121 derived from 4-methoxyphenol 120 by
reduction and then oxidation gives compound 123.
OH
OMe
120
This can be cyclised in refl uxing 62% HBr to an adamantane derivative, the dione 125. The
mechanism of this cyclisation is by no means obvious, but with the hint that the alkene 124 is an
intermediate and that the stereochemistry of the ester can change by acid-catalysed enolisation,
you might see what is going on.
O
Br
OEt
115 116 117
N
CO2Et
Br CO 2Et CO2Et
N
hydrolytic
work-up
118 119 114
O
3 A Final Example 41
N
H
N
OMe
OMe
121 122
CO2Et
Br
113
HBr HBr
CO 2Et
OMe
O
O Br
123 124
125
O
O
CO 2Et
123
O
O
Br
OEt
CO 2Et
OMe

42 3 Regioselectivity: Controlled Aldol Reactions
References
General references are given on page 893
1. Y. Terai and T. Tanaka, Bull. Chem. Soc. Jpn., 1956, 29, 822.
2. C. H. Heathcock, J. E. Ellis, J. E. McMurry and A. Coppolino, Tetrahedron Lett., 1971, 4995.
3. D. J. Dale, P. J. Dunn, C. Golightly, M. L. Hughes, P. C. Levett, A. K. Pearce, P. M. Searle, G. Ward and
A. S. Wood, Org. Proc. Res. Dev., 2000, 4, 17.
4. G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz and R. Terrell, J. Am. Chem. Soc., 1963, 85,
207.
5. R. Carlson, L. Nilsson, C. Rappe, A. Babadjamian and J. Metzger, Acta Chem. Scand., 1978, B32, 85,
335, 646.
6. G. Stork, G. A. Kraus, and G. A. Garcia, J. Org. Chem., 1974, 39, 3459.
7. G. Stork, Pure Appl. Chem., 1975, 43, 553; J. d’Angelo, Tetrahedron, 1976, 32, 2979; L. M. Jackman and
B. C. Lange, Tetrahedron, 1977, 33, 2737.
8. J. K. Rasmussen, Synthesis, 1977, 91; P. Brownbridge, Synthesis, 1983, 1.
9. H. O. House, M. Gall and H. D. Olmstead, J. Org. Chem., 1971, 36, 2361; G. H. Rubottom, R. C. Mott
and D. S. Krueger Synth. Commun., 1977, 7, 327.
10. T. Mukaiyama, K. Banno, and K. Narasaka, J. Am. Chem. Soc., 1974, 96, 7503.
11. I. Fleming, Chimia, 1980. 34, 265.
12. M. Gall and H. O. House, Org. Synth., 1972, 52, 39.
13. T. Mukaiyama, Angew. Chem., Int. Ed., 1977, 16, 817.
14. K. Banno and T. Mukaiyama, Bull. Chem. Soc. Jpn., 1976, 49, 1453.
15. P. Denniff and D. A. Whiting, J. Chem. Soc., Chem. Commun., 1976, 712.
16. Disconnection Approach, page 205.
17. Fleming, Orbitals.
18. R. Noyori, I. Nishida and J. Sakata, Tetrahedron Lett., 1980, 21, 2085; R. Noyori, I. Nishida, J. Sakata
and M. Nishizawa, J. Am. Chem. Soc., 1980, 102, 1223.
19. A. Segre, R. Viterbo, and G. Parisi, J. Am. Chem. Soc., 1957, 79, 3503.
20. Disconnection Approach, chapters 26 and 27, particularly page 223.
21. Disconnection Approach, chapters 26 and 27, particularly page 227.
22. Disconnection Approach, page 37.
23. T. H. Chan, I. Paterson, and J. Pinsonnault, Tetrahedron Lett., 1977, 4183; M. T. Reetz and W. F. Maier,
Angew. Chem. Int. Ed. Engl., 1978, 17, 48; M. T. Reetz, W. F. Maier, H. Heimbach, A. Giannis and
G. Anastassious, Chem. Ber., 1980, 113, 3734.
24. M. T. Reetz, S. Hüttenhain, and F. Hübner, Synth. Commun., 1981, 11, 217.
25. I. Paterson, Tetrahedron Lett., 1979, 1519.
26. M. T. Reetz and S. Hüttenhain, Synthesis, 1980, 941.
27. Disconnection Approach, page 144.
28. A. K. Beck, M. S. Hoekstra and D. Seebach, Tetrahedron Lett., 1977, 1187.
29. A. B. Smith and P. A. Levenberg, Synthesis, 1981, 567.
30. A. P. Krapcho, D. S. Kashdan, E. G. E. Jahngen and A. J. Lovey, J. Org. Chem., 1977, 42, 1189.
31. S. Hünig and M. Salzwedel, Chem. Ber., 1966, 99, 823.
32. I. Fleming, J. Iqbal and E.-P. Krebs, Tetrahedron, 1983, 39, 841.
33. Disconnection Approach, page 209.
34. Disconnection Approach, page 217.
35. Disconnection Approach, page 209.
36. P. L. Creger, J. Am. Chem. Soc., 1967, 89, 2500; J. Org. Chem., 1972, 37, 1907.
37. Disconnection Approach, page 253.
38. N. F. Firrell and P. W. Hickmott, J. Chem. Soc., Chem. Commun., 1969, 544; J. W. Huffmann, C. D.
Rowe, and F. J. Matthews, J. Org. Chem., 1982, 47, 1438.
39. K. Narasaka, K. Soai, Y. Aikawa and T. Mukaiyama, Bull Chem. Soc. Jpn., 1976, 49, 779.
40. F. D. Ayres, S. I. Khan, O. L. Chapman and S. N. Kaganove, Tetrahedron Lett., 1994, 35, 7151.

4 Stereoselectivity:
Stereoselective Aldol Reactions
Defi nition
Introduction and defi nitions
Stereoselective and stereospecifi c
Aldol Stereochemistry
Introduction and stereochemical control: syn,anti and E,Z
Relationship between enolate geometry and aldol stereochemistry
The Zimmerman-Traxler transition state
Anti-selective aldols of lithium enolates of hindered aryl esters
Syn-selective aldols of boron enolates of PhS-esters
Stereochemistry of aldols from enols and enolates of ketones
Silyl enol ethers and the open transition state
Syn selective aldols with zirconium enolates
The synthesis of enones
E,Z selectivity in enone formation from aldols
Recent developments in stereoselective aldol reactions
Stereoselectivity outside the Aldol Relationship
A Synthesis of Juvabione
A Note on Stereochemical Nomenclature
Stereoselectivity is at fi rst sight the easiest of the three selectivities to understand and the most
diffi cult to exercise. It simply means control over stereochemistry. More precisely it means the
control over new stereochemistry. In many reactions, whether new carbon-carbon bonds are being
formed or whether some functional group is merely being altered, stereochemistry appears. It
may be that a double bond is formed which can have E or Z geometry, or that a new stereogenic
centre is formed, perhaps by reduction of a ketone, and therefore a relationship develops with other
stereogenic centres in the molecule. If these aspects are controlled then we have stereoselectivity.
One special distinction you should master from now on is that stereospecifi city has a different
meaning. It refers to the specifi c transfer of stereochemistry during a reaction because the
mechanism of the reaction demands this stereochemical outcome. An S N2 reaction goes with
inversion, whether the molecule likes it or not, because an S N2 reaction is stereospecifi c. In the
reduction of a ketone the molecule may select the stereochemistry of the new OH group: this
reaction is not stereospecifi c though it may be stereoselective.
From this chapter onwards stereochemistry will be our constant companion as it is a major
concern of modern organic chemistry. To start with we shall discuss diastereoselectivity alone.
Soon, in chapter 15, we shall discover how to control the geometry of double bonds. Later on,
in chapters 20–21 we shall discuss how to exercise stereoselectivity in general and in chapters
Organic synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

44 4 Stereoselectivity: Stereoselective Aldol Reactions
22–29, there will be a section on asymmetric synthesis, that is the synthesis of optically active
compounds. In this chapter we shall continue the discussion of enolate reactions by exploring
stereoselective aldol reactions.
The Stereochemistry of the Aldol Reaction
Introduction and stereochemical control: syn,anti and E,Z
Aldol reactions typically produce new stereogenic centres at either end of the new carboncarbon
bond. 1 The enolisable ketone 1 might condense with benzaldehyde to give a mixture of
diastereoisomers of the aldol 2 in which the methyl and hydroxyl groups can be either on the
same side (syn-2) or opposite sides (anti-2) of the carbon skeleton. 2 If the aldol is dehydrated to
the enone 3 there is again a question of stereoselectivity as the new double bond can be E or Z.
R
O
PhCHO
Only in modern times has aldol stereochemistry seemed a subject worth studying, or indeed
even accessible to chemists. Formerly it was left to look after itself. Then Dubois carried out some
simple experiments on the condensations between cyclic ketones and aldehydes in base. 3 Though
largely neglected at the time, these results showed that if LiOH (not NaOH) was used as the base,
the anti aldol predominated. Indeed, with cyclopentanone and i-PrCHO, >95% anti-5 was formed,
and syn-5 could not be detected. Later Heathcock 4 showed that the lithium enolate of the open
chain ketone 6 condensed with PhCHO to give >98:2 syn:anti aldol 7.
O
i-PrCHO
LiOH
1
H
base
4 anti-5
R
Relationship between enolate geometry and aldol stereochemistry
O
R
O
These apparently confl icting results can be rationalised if there is a relationship between the
geometry of the enolate and the stereochemistry of the aldol product. Cyclic ketones are forced to
give E enolates, thus cyclopentanone must give 8. Ketone 6 might well prefer to form the Z enolate
9 with the large t-Bu group anti to the methyl group.
O
LiOH
OLi
OH
Ph
and/or
R
O
O Ph
Ph
and/or
R
OH
Ph
racemic (±)-syn-2 racemic (±)-anti-2
O OH O
i-PrCHO
anti-5
E-3 Z-3
O
1. LDA
2. PhCHO
6 syn-7
1. LDA
4 8; E-enolate 6 9; Z-enolate
OLi
O
OH
Ph
2. PhCHO syn-7

The Zimmermann-Traxler transition state
The relationship between enolate geometry and aldol stereochemistry has now been well established
for many aldol reactions. The geometry of lithium enolates expresses itself through the so-called
Zimmerman-Traxler 5 transition state which is nothing more than the six-membered cyclic transition
state that we met in the last chapter. When a lithium enolate reacts with an aldehyde, both the enolate
and aldehyde oxygen atoms coordinate to the lithium atom 10 so that the transition state 11 is a partly
unsaturated six-membered ring.
If we assume that the cyclic transition state 11 adopts an approximate chair conformation 13,
we can explain the results. One carbon atom, marked with a spot, remains trigonal throughout the
reaction and its substituent remains in a plane. All the other carbon atoms have axial and equatorial
substituents. The enolate substituent is forced to occupy one of these positions because of the
confi guration of the enolate. The fi ve-membered ring in 13 is equatorial because it is anti to the
enolate oxygen and it no doubt enjoys this position. So far we have been dealing with stereospecifi
city. The substituent on the aldehyde can occupy either axial or equatorial positions, so it
generally prefers the equatorial. You will see that the i-propyl group in 13 is indeed equatorial. This
is stereoselectivity. The consequences are most easily appreciated by inspecting the marked hydrogen
atoms: in 13: they are clearly anti and this is the relationship found in the aldol product anti-5.
H is forced to occupy
an axial position
because it is cis to
OLi in the enolate 8
H
O
Li
OH
13
H
The i-Pr group comes from
the aldehyde and can
choose an axial or an
equatorial position.
Equatorial is preferred
When the Z-enolate 9 reacts with benzaldehyde, one aspect of the Zimmermann-Traxler transition
state 14 is quite different. The t-butyl group in 14 is forced to be axial because it is syn to the
enolate oxygen even though it will not enjoy this position at all. The only alternative is to abandon
the chair transition state and that would evidently lead to a worse energy penalty. The phenyl group
still has a choice and it will again choose to be equatorial in 14. If we inspect the marked hydrogen
atoms in 14 we can see that they are syn and so they will remain syn in the aldol product syn-7.
t-Bu is forced to occupy
an axial position
because it is cis to
OLi in the enolate 9
4 The Stereochemistry of the Aldol Reaction 45
O Li O O Li Li
O O O
10
11
Zimmerman-Traxler
transition state
O
Li
OH
Ph
H
H
14
12
anti-5
The Ph group comes from
the aldehyde and can
choose an axial or an
equatorial position.
Equatorial is preferred

46 4 Stereoselectivity: Stereoselective Aldol Reactions
This is the basis behind many stereoselective aldol reactions, but in general it is not easy to choose
carbonyl compounds that will reliably give E or Z enolates. We shall restrict our discussion to one
or two of the more reliable. There is a problem in defi ning enolates as E or Z. If we follow the rules
strictly, a series of enolates with the same geometry, such as the four below, would change from
E to Z as we changed the metal on the enolate or as we changed from ketone to ester to thiolester.
When we are discussing enolates, we shall name them E or Z according to the relationship between
the substituent R and the OMetal substituent. This is the generally agreed method and takes no notice
whether the enolates are strictly E or Z alkenes.
R
The fi rst two examples are based on esters, one giving the anti aldol and the other the syn.
Lithium enolates of simple esters like EtCO 2Me give clean aldol reactions with aldehydes but the
products 17 are more or less 50:50 mixtures of syn- and anti- diastereoisomers. 1 Evidently the
lithium enolate 16 is also formed as a 50:50 E:Z mixture and this is hardly surprising as OMe and
OLi must be about the same size.
O
15
OMe
1. LDA
Anti-selective aldols of lithium enolates of hindered aryl esters
OLi
E + Z-16
Hindered aryl esters 6 such as 18 perform very much better. Only the E enolate is formed and very high
ratios of anti:syn aldols 19 are produced, especially with branched aldehydes such as i-PrCHO. 7
O
OLi
Me
E-alkene
E-enolate
O
18; R = H, Me, OMe
OLi
R
OMe
Z-alkene
E-enolate
R
The ester prefers the conformation 20 because of the anomeric effect, the bonding interaction
between one of the lone pairs on the ester oxygen atom and the antibonding orbital of the sigma
bond of the carbonyl group, and normal conjugation with the other lone pair of electrons on the
ester oxygen atom keeps the aryl group in the plane of the carbonyl group. Perhaps this means that
the deprotonation by LDA 21 can take place only when the methyl group is anti to the C=O bond.
R
1. LDA
2. RCHO
OMe
R
OSiMe 3
OMe
E-alkene
E-enolate
2. RCHO
OH
O
R
O
OH
(±)-anti-19
OLi
R
SMe
Z-alkene
E-enolate
O
OMe
syn + anti-17
R

part of
C–O σ*
O
4 The Stereochemistry of the Aldol Reaction 47
lone pair in p-orbital
overlaps with C=O π*
O
lone pair in sp2-orbital overlaps with C–O σ*
Alternatively one could argue that a six-membered chair transition state 23 is again involved
with large axial groups (i–Pr and the THF ligand on Li) and the large aryl group enhancing the
methyl group’s natural preference for an equatorial position.
R2N H
Li
20
Syn-selective aldols of boron enolates of PhS-esters
R
LDA
Li
R2N H
Most esters prefer to form E enolates, and one must turn to a different substituent and a different
“metal” to get good syn selectivity. Evans and Masamune have developed the boron enolates of
phenythio (PhS) esters 24 in this role. 8,9 The boron enolate 25 is prepared with a dialkyl boron
trifl ate and Hünig’s base i-Pr 2NEt. The alkyl groups on boron can be butyl or cyclopentyl or
else 9-BBN (9-borabicyclononane, see chapters 17 and 24) can be used. 10 Trifl ate is trifl uoromethanesulfonate,
one of the best leaving groups known. Only the “Z” enolate 25 is formed,
maybe because of equilibration with this relatively weak base and the lack of an anomeric effect in
PhS esters. Aldol reactions now give high yields of syn aldols 26 helped by the short B–O bonds 9
in the Zimmerman-Traxler transition state, cf. 23.
O
24
O
O
21
O
R
i-Pr
N
i-Pr
H O
Li
O
O
H
Me
O O
S
21 23
R 2B-OTf S
i-Pr 2NEt
O BR 2
25
“Z ” boron enolate
1. RCHO
2. oxidative
work-up
R
R
Li
R
OH
O
O
E-enolate 22
O
S
26
(±)-syn aldol
E-22
R

48 4 Stereoselectivity: Stereoselective Aldol Reactions
Stereochemistry of aldols from enols and enolates of ketones
Other than for the cyclic or t-alkyl ketones we met at the beginning of the chapter, controlling
aldol reactions of ketones has been more diffi cult. Evans’ boron enolates work well in some cases
and it is fortunate that the Z enolates are preferentially formed as these react stereoselectively
with aldehydes to give syn aldols whereas the E enolates show poor stereoselectivity. Thus the
symmetrical ketone 1 gives almost exclusively (>97:3) the Z boron enolate 27 and hence syn aldol
28 with the enolisable aldehyde n-PrCHO. 8
O Bu2B-OTf
1
i-Pr 2NEt
Bu2B
Some unsymmetrical ketones show regioselectivity in favour of the less hindered side: 29
is an impressive example as both sides of the ketone are primary with branching occurring on
one side only at the β carbon atom. 8 You are advised to consult the literature before planning a
stereoselective synthesis with ketone enolates.
Silyl enol ethers and the open transition state
O
27
Z boron enolate
1. n-PrCHO
2. oxidative
work-up
O OH
(±)-syn-28
>97:3 syn:anti
A second kind of stereoselectivity is observed with silyl enol ethers. When made from cyclic
ketones they must have E geometry but often react in a stereorandom fashion, as in the TiCl 4
catalysed reaction of the silyl enol ether E-33 of cyclopentanone with PhCH 2CH 2CHO. This is
totally chemoselective, but gives a 50:50 mixture of stereoisomers 11 of 32. The corresponding
lithium enolate is very stereoselective in the anti sense. The situation is quite different if the
reactions are catalysed by fl uoride ion instead of by a Lewis acid. Now the same silyl enol ether
E-33 reacts stereoselectively, but in the syn sense 12 to give syn-5.
O
H OH
29
O Bu 2B-OTf
O
i-Pr 2NEt
H
TiCl4
Bu2B
Ph
O
30
Z boron enolate
OSiMe 3
O OH
syn and anti-32 E-33
E-34 syn -5
The Z silyl enol ether 35 from the ketone 6 also shows reversed stereoselectivity from the
lithium enolate, giving the anti aldol 7 in high yield. 12 Further study 1 revealed that these reactions,
which take place via an “open” (rather than a chelated) transition state 37, are thermodynamically
F
1. PhCHO
2. oxidative
work-up
O
H
O
O OH
(±)-syn-31
>97:3 syn:anti
Ph

controlled because they are reversible. Both geometrical isomers of many silyl enol ethers favour
the same diastereoisomer of an aldol.
Syn selective aldols with zirconium enolates
Some kinds of metal enolate also give highly stereoselective reactions in the same sense whatever
the geometry of the enolate. At fi rst sight the reactions of zirconium enolates seem like lithium
enolates. Using the pyrrolidine amide 38 as an example, we get the Z-enolate 39 only and this
gives syn aldol products 40 with aldehydes. 13
O
N
However, the t-butylthiol ester 41 gives mostly the E-enolate 42 and yet still favours the syn
aldol 43. Cyclopentanone, which can of course give only the E enolate 44 also favours the syn
aldol 14 45. In short, all zirconium enolates give syn aldols regardless of geometry. This selectivity
is explained in the workbook.
O
41
St-Bu
O ZrCl2Cp 2
St-Bu
O O ZrCl 2Cp 2
4
4 The Stereochemistry of the Aldol Reaction 49
O OSiMe 3 Bu4N F
1. LDA
2. Cp2ZrCl2 1. LDA
2. Cp 2ZrCl 2
1. LDA
2. Cp 2ZrCl 2
N
O
O
H
H
O ZrCl2Cp 2
n-PrCHO
38 Z-39; >95:5 Z:E syn-40; 94:6 syn:anti
O
O
Me
Ph
PhCHO
Ph
O
OH
O
OH
Ph
St-Bu
E-42; 10:90 Z:E syn-43; 93:7 syn:anti
PhCHO
Ph
PhCHO
6 Z-35 36
anti-7
37
OH
E-44 syn-45; 74:26 syn:anti
O
O
N
OH
Ph

50 4 Stereoselectivity: Stereoselective Aldol Reactions
There are many more methods now developed for stereochemical control in the aldol reaction,
as this is an active area of research, but we hope that we have studied enough examples in this
chapter to add to the examples of chemo- and regioselectivity in the last two chapters to convince
you that good control is possible over most of the types of aldol reaction that you might want to
use in a synthesis. We shall leave further diastereoselectivity to chapters 20–22 and the question
of making optically active aldols until chapters 23–30.
The synthesis of enones
The aldol reaction is often used to make enones by dehydration of the aldol itself, a reaction which
often occurs under equilibrating aldol conditions, but has to be induced in a separate step when
lithium enolates or silyl enol ethers are used. In general one has to accept whatever enone geometry
results from the dehydration, and this is usually controlled by thermodynamics, particularly
if enone formation is reversible. Simple enones such as 46 normally form as the E isomer but
the Z isomer is diffi cult to prepare. When the double bond is exo to a ring, e.g. 47, the E isomer is
again favoured, but other trisubstituted double bonds have less certain confi gurations.
O
PhCHO
base
O
E-46
Ph
Yoshikoshi’s synthesis 15 of nootkatone (then supposed to be the fl avouring principle of
grapefruit) uses an optically active enone 52 prepared from β-pinene 48 by ozonolysis to
(+)-nopinone 49 and a chemo- and regioselective aldol condensation using the silyl enol ether 50.
Though the aldol reaction produces a mixture of diastereoisomers of 51, all dehydrate to the same
enone E-52.
Still’s monensin synthesis 16 uses the lactone 55 which inevitably has a Z double bond. This can
again be made by an aldol reaction, this time using the lithium enolate of EtCO 2Et and the optically
active aldehyde 53. A mixture of diastereomeric aldols 54 is again produced, but all dehydrate to
the Z unsaturated lactone without racemising the original stereogenic centre. Cyclisation may
precede dehydration, or the E compound may equilibrate.
O O
53
CHO CO 2Et
O
PhCHO
O3 Me3SiCl SiMe3 MeCHO O
O
Et3N O
TiCl4 Me
OH H
TsOH O
H
Me
(–)-48 (+)-49 50 syn and anti-51 E-52
base
O
E-47
1. LDA
TsOH
THPO
CO
2. 53=
2Et
THPO
OH
O O
CHO
syn and anti-54 55
Ph

Recent Developments in Stereoselective Aldol Reactions
Recent developments tend to focus on the asymmetric aspects of stereoselective aldols but the
diastereoselectivity is just as important. The cyclic ester 56 must of course form an ‘E’ enolate
and when the boron enolate E-57 reacts with aldehydes the anti-aldol products 58 are formed with
good stereoselectivity ranging from 4:1 to >20:1. The predominate isomer is that expected from the
Zimmerman-Traxler transition state. The two benzylic-O bonds can be cleaved by hydrogenation
and the 2,3-dihydroxy acids anti-59 released in good yield. 17
Ph
O
O
A particularly interesting case reported by Denmark 18 reveals several types of selectivity. The
methyl ester 60 of natural (S)-lactic acid forms a Weinreb amide 61 with Me 3Al as catalyst. These
amides are designed to react only once with Grignard reagents and organolithiums thus solving a
classical chemoselectivity problem (chapter 2). Here the starting material 63 for the aldol reaction
is prepared by reaction of ethyl Grignard with 61 and protection of the OH group by silylation.
CO2Me MeHN OMe
OH
Me3Al, CH2Cl2 60; methyl
(S)-lactate
Ph
O
The silyl enol ether 64 is formed from 63 with the Z confi guration because of the enormous
OTBDMS protecting group and reacts with benzaldehyde to give essentially one diastereoisomer
of the syn-aldol 65. The 1,3-stereochemical control across the carbonyl group is discussed in
chapter 21.
Stereoselectivity outside the Aldol Relationship
A Synthesis of Juvabione
4 Stereoselectivity outside the Aldol Relationship 51
R2B-OTf Et3N –78 °C
CH2Cl 2
Ph
R 2B
O
O
Ph
O
RCHO
Ph
N
OH
OMe
O
O
O
EtMgBr
THF
t-BuMe2SiCl
cat. DMAP
Me
OH
THF
OTBDMS
61; 83% yield 62; 91% yield 63; 92% yield
There are of course many kinds of stereoselectivity not involving the aldol reaction and many
will appear in the rest of the book. Just for example, we give a recent synthesis of juvabione,
O
O
Ph
56 ‘E’-57 anti-58
O
OTBDMS
63; 92% yield
Me 3Si OTf
Et3N
OSiMe 3
OTBDMS
64; 96% yield
> 20:1 Z:E
O
PhCHO
15% HMPA
OH
R
H2, Pd/C
HO
O
O OH
OH
anti-59
Ph
TBDMSO
65; 79% yield
30:1 diastereoisomers
OH
R

52 4 Stereoselectivity: Stereoselective Aldol Reactions
a pheromone that controls insect biology. It illustrates two types of pericyclic reaction and an
electrophilic addition to an alkene. We are anticipating many later chapters in giving you this
taste of things to come. 19
Enol ester formation from crotonaldehyde gives the expected E-selectivity 66. Now the silyl
enol ether is formed from this ester, also with the expected double bond geometry. The product 67
has three alkenes: each is conjugated with at least one oxygen atom.
The next stage occurs on heating the triene 67 with ethyl acrylate. First a Diels-Alder reaction
68 with the orientation and endo-stereoselectivity expected of this famous process gives an
adduct with only two alkenes positioned so that it undergoes a [3,3]-sigmatropic (Claisen-Ireland)
rearrangement 69 to give the product 70 with only one alkene.
140 °C, 4 hours
CHO
O
O NaHMDS
t-BuMe2SiCl
Both these reactions are more or less diastereoselective and give more or less one diastereoisomer
of 70. To discover the stereochemistry of the major adduct, the silyl ester (R = SiMet-Bu)
was hydrolysed to the free acid 71 (note the designer chemoselectivity) and this was treated with
buffered iodine in MeCN to give a crystalline iodo-lactone 72. An X-ray of this compound revealed
that the structure of 71 was as shown and that the [3,3]-sigmatropic rearrangement must
have had a boat transition state.
70
H 2SiF 6
KOt-Bu, EtCOCl
THF, –78 °C
OTBDMS
CO 2Me O
HO 2C
Diels-
Alder
H
71; 60% yield
47:29:24 diasts
66; 66% yield
CO 2Me
OTBDMS
CO 2Me CO 2Me
I2, NaHCO3
MeCN, 0 °C
THF/DMPU
–110 °C
Now the synthesis could resume with the elaboration of intermediate 71 into juvabione 76.
Acylation of diazomethane with the acid chloride of 71 gave the diazoketone and hence by rearrangement
the chain extended acid 74. This new acid 74 is still a mixture of three diastereoisomers
but isomerisation to the conjugated ester 75 reduces this to two in an acceptable 78:22 ratio.
O
O
[3,3]
Claisen-
Ireland
O
RO2C
H I
H
O
67; 84% yield
68 69 70
H
CO 2Me
72; 71% yield
major diast crystallises
OTBDMS
CO 2Me

Acylation of the acid chloride of 75 with a Grignard reagent catalysed by Fe(III) completes a
synthesis of juvabione 76 with good stereochemical control.
HO2C
HO 2C
References
H
CO 2Me
71; mixture of diasts
H
CO 2Me
4 References 53
DBU
CH2Cl2
1. (COCl) 2
CH 2Cl 2
cat DMF
2. CH 2N 2
THF, Et 2O
O
HO2C
CO 2Me
General references are given on page 893
1. T. Mukaiyama, Organic Reactions, 1982, 28, 203, C. H. Heathcock in Morrison, Volume 3, 1984,
page 111.
2. S. Masamune, S. K. Ali, D. L. Snitman, and D. S. Garvey, Angew. Chem., Int. Ed., 1980, 19, 557 (see
the footnote on page 558).
3. J. E. Dubois and M. Dubois, Tetrahedron Lett., 1967, 4215; J. Chem. Soc., Chem. Commun., 1968, 1567;
Bull Soc. Chim. Fr., 1969, 3120 and 3553; P. Fellman and J. E. Dubois, Tetrahedron , 1978, 34, 1349.
4. C. H. Heathcock, J. Org. Chem., 1980, 45, 1066.
5. H. E. Zimmerman and M. D. Traxler, J. Am. Chem. Soc., 1957, 79, 1920.
6. C. H. Heathcock, Tetrahedron, 1981, 37, 4087.
7. General Reference for Li Enolates: C. H. Heathcock in Comp. Org. Synth. volume 2, chapter 1.6, pages
181–238.
8. D. A. Evans, J. V. Nelson, E. Vogel, and T. R. Taber, J. Am. Chem. Soc., 1981, 103, 3099.
9. M. Hirama, D. S. Garvey, L. D. Lu and S. Masamune, Tetrahedron Lett., 1979, 3937.
10. General Reference for Boron Enolates: B. M. Kim, S. F. Williams and S. Masamune in Comp. Org.
Synth., volume 2, chapter 1.7, pages 239–275.
11. T. Mukaiyama, K. Banno, and K. Narasaka, J. Am. Chem. Soc., 1974, 96, 7503.
12. W. A. Kleschick, C. T. Buse and C. H. Heathcock, J. Am. Chem. Soc., 1977, 99, 247, 8109; C. H. Heathcock,
C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn and J. Lampe, J. Org. Chem., 1980, 45,
1066.
13. D. A. Evans and L. R. McGee, Tetrahedron Lett., 1980, 21, 3975.
14. Y. Yamamoto and K. Maruyama, Tetrahedron Lett., 1980, 21, 4607.
15. T. Yanami, M. Mayashita and A. Yoshikoshi, J. Org. Chem., 1980, 45, 607.
16. D. B. Collum, J. H. McDonald and W. C. Still, J. Am. Chem. Soc., 1980, 102, 2117, 2118, 2120.
17. M. B. Andrus, B. B. V. S. Sekhar, E. L. Meredith and N. K. Dalley, Org. Lett., 2000, 2, 3035.
N 2
H
O
H
H
73; 80% yield
74; 80% yield 75; 87% yield; 78:22 diasts
76; 75% yield; juvabione
CO 2Me
CO2Me
2.
Ag
H 2O
THF
1. (COCl) 2
MgBr
3. mol% Fe(acac) 3

54 4 Stereoselectivity: Stereoselective Aldol Reactions
18. S. E. Denmark and S. M. Pham, Org. Lett., 2001, 3, 2201.
19. N. Soldermann, J. Velker, O. Vallat, H. Stoeckli-Evans and R. Neier, Helv. Chim. Acta, 2000, 83, 2266.
A Note on Stereochemical Nomenclature
We shall use the terms syn and anti because they have easily understood meanings and because
they must refer to a diagram. Terms like erythro and threo or R*R* and R*S* or worst of all ul and
lk are very diffi cult to understand and we shall not use them. They are of course the terms used by
offi cial bodies such as IUPAC and the Royal Society of Chemistry, probably for that very reason.
Please note that the wiggly line will be used to mean that both isomers are present. It is sometimes
used to mean that the stereochemistry is unknown.
If you think you are interested in stereochemical nomenclature, you should consult the papers
below and then read C. H. Heathcock in Asymmetric Synthesis, ed. J. D. Morrison, Academic
Press, Orlando, Volume 3, 1984, page 112–115 to cheer you up again.
D. Seebach and V. Prelog, Angew. Chem., Int. Ed. Engl., 1982, 21, 654.
F. A. Carey and M. E. Kuehne, J. Org. Chem., 1982, 47, 3811.

5 Alternative Strategies for Enone Synthesis
Introduction
The Seebach nomenclature for synthons: d 2 , a 3 etc.
The Synthesis of Enones by Many Strategies
Introduction to the various strategies
Strategy 4a: The Aldol Route to Enones
When the aldol strategy is ideal
When the aldol strategy is not ideal
Symmetry as a guide
Wittig-style aldol methods
Strategy 4b: Acylation of a Vinyl Anion
Vinyl metal reagents
The aliphatic Friedel-Crafts reaction
Unsaturated Acyl Cations and Anions
Acyl anion equivalents (d 1 reagents)
An example with two enones made by different strategies
Strategic bonds in enone synthesis
Rearrangements of allylic alcohols with Cr(VI)
Looking forward to the chemistry of S and Se
We have already seen how the aldol reaction may be used to prepare enones and other unsaturated
carbonyl compounds. The past three chapters have introduced a lot of new methods without much
analysis of strategy. This chapter and the next will redress the balance by looking at the various
approaches to the synthesis of α, β-unsaturated carbonyl compounds (which we shall often loosely
call enones, a term strictly reserved for α, β-unsaturated ketones) in this chapter, and then choosing
which are most suitable for a particular class of enones, the cyclopentenones, in the next. One aim
of this chapter in particular is to get you to think in terms of strategy. We shall be using words and
phrases descriptive of strategy including a series of terms introduced by Seebach 1 to describe the
electronic nature of synthons.
4 3
O
2 1
1
X
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

56 5 Alternative Strategies for Enone Synthesis
The Seebach nomenclature for synthons: d 2 , a 3 etc.
Any functionalised carbon atom in the target molecule, but most commonly a carbonyl group, is
numbered 1 and the atoms then numbered in turn along the chain so that the position of each relative
to the CO group is clear 1. A disconnection, say 1a will then require a synthon of a particular
type and polarity. Thus 1a requires an alkyl halide and the synthon 3 with a nucleophilic (or donor)
carbon in position 2, so we call this a d 2 synthon. Similarly the disconnection 1b could be realised by
adding an organometallic derivative (MeMetal) to the synthon 2 with an electrophilic (or acceptor)
carbon at position 3. This becomes an a 3 synthon. You will of course see that we could use an
enolate for the d 2 synthon, and an enone for the a 3 synthon. All the enolates, and the other specifi c
enol equivalents we have been discussing so far, are reagents for d 2 synthons. Not everyone is
happy about this labelling, but it is sometimes useful and we shall use it from time to time.
O
X
reagent =
enone
MeMetal +
You will perhaps realise from these particular examples that the d 2 synthon will be represented
in real life by an enolate or its equivalent and the a 3 synthon by an α, β-unsaturated carbonyl
compound, both displaying the natural polarity of these fragments. It is generally true that even
numbered donor synthons (d 2 , d 4 , etc.) and odd numbered acceptor synthons (a 1 , a 3 , etc.) have
natural polarity while the odd numbered donor synthons (d 1 , d 3 , etc.) and the even numbered
acceptor synthons (a 2 , a 4 , etc.) have unnatural polarity or umpolung. This makes the numbering
of such synthons a useful quick check on the type of reagent likely to be needed.
The Synthesis of Enones by Many Strategies
Introduction to the various strategies
O
X
2; a 3 synthon
R 1 R 3
R 2
O
b
1b
Now we start a systematic analysis of most of the possible disconnections which might be used in
planning the synthesis of enones using the generalised structure 4 as our example. The fi rst disconnection
both in importance and in order of discussion is the aldol, that is disconnection of the
enone double bond 4a. You know from previous chapters that we can fi nd a reagent for the enolate
6 when either R 2 or R 3 is hydrogen, providing there is branching on one side, or if R 2 R 3 .
1a
1a,b
O
X
a
EtBr +
R1 R3 O
R2 R1 R3 O
R2 The Aldol Disconnection: d
H
O
2 + a1 Synthons
a
a
aldol
+
4a
5
6
4
General structure for an enone.
The strategies for disconnection
of 4 will be outlined first.
O
X
3; d 2 synthon
R 2
O
6
O
X
reagent =
enolate
R 3

Next we shall tackle the important disconnection 4b between the carbonyl group and the double
bond. In many ways this is theoretically the best strategy as it is right in the centre of the molecule.
This means we shall be examining the reactions between vinyl metals 7 and acylating agents
8 (where X is a leaving group such as Cl or OR). The nature of the metal and the stereochemistry
of the vinyl group may be important here.
An important family of disconnections follows. The alkylations represented by 4c(i), 4c(ii)
and 4c(iii) belong to extended enolate chemistry and you will learn to call the synthons 9, 10 and
11 the α', γ and α extended enolates. Synthons 9 and 11 react in the normal d 2 position but 10 has
d 4 reactivity. There are obvious questions of regioselectivity in this family. This chemistry will not
be discussed further in this chapter as it is the subject of chapter 11.
X R 1
R1 R3 O
R1 R3 Acylation of a Vinyl Anion: another a
O
X
1 Synthon
b
+
The Extended Enolate Family of Disconnections: d 2 and d 4 Synthons
O
R 1 R 3
R 2
O
R2 4b
10; d 4 synthon
R2 4c(i)
R 3
c(i)
The syntheses represented by disconnection 4d belong to a group where the alkene part of the
enone is almost irrelevant: they involve either acylation of an organometallic compound 4d(i) or
alkylation of an acyl anion equivalent (a d 1 reagent) 4d(ii).
Disconnection Outside the Enone: a 1 and d 1 Synthons
R 1
R 2
O
12: a 1 synthon
+
R 3
Metal
5 The Synthesis of Enones by Many Strategies 57
d(i)
i
Another disconnection outside the enone system is 4e which looks at fi rst sight like a conventional
conjugate addition to an a 3 Michael acceptor. However we need to get the alkene back again
after the Michael addition has occurred. The a 3 synthon 14 is unsaturated.
R 1
R 2
R1 R3 c(ii) c(iii)
ii
9
O
R2 iii
7
4c(ii) and 4c(iii)
R 1 R 3
R 2
4d
O
R 2
d(ii)
O
R 1
R 1
R 3 X
8
O
R2 X
11; d2 synthon
R 2
O
13: d 1 synthon
+
R 3
X
R 3
X = leaving
group

58 5 Alternative Strategies for Enone Synthesis
R +
1 R3 O
R1 R3 Michael Addition without loss of the Alkene
O
e
R2 4e
We shall also explore combinations of two disconnections, that is three-component syntheses,
and strategies based on the addition of functional groups (here the double bond and the carbonyl
group). This strategic tour is valuable in its own right as it should give you some useful methods,
but its value also lies in your grasping the possibility of many different approaches to even such
a simple compound as 4. Throughout this chapter and even more so in the next chapter we shall
consider the reasons for choosing one strategy or another from this perhaps rather bewildering
array when faced with the synthesis of a particular compound.
Strategy 4a: The Aldol Route to Enones
We have already seen several examples of this reaction in the synthesis of enones. 2 It is the fi rst
disconnection you should try in planning the synthesis of any enone and you should assess the
likelihood of success by the aldol reaction before going on to any other disconnection, if only to
get inside the skin of the problem. Almost any enone can be made nowadays by the aldol reaction,
but it is worth considering in turn the features which make it specially suitable, and those which
suggest that an alternative strategy should be attempted.
When the aldol strategy is ideal
The most obvious pointer to its success is if the double bond is roughly in the middle of the
molecule, or if it separates two rings. This means that the disconnection will quickly lead to much
simpler starting materials. We obviously want to make the enone 15 from two different aromatic
starting materials and the aldol disconnection gives us an unenolisable aldehyde 16 and a very
enolisable methyl ketone 17 with no problems of selectivity. Simply mixing 16 and 17 with KOH
gives 3 an 87% yield of the enone 15.
OH O OH
15
Cl
Cl
aldol
enone
Metal
14; unsaturated a3 R
synthon
2
OH O OH
The double bond in enone 18 sprouts from a ring and aldol disconnection does indeed simplify
the problem considerably since the starting materials are an unenolisable aldehyde 20 and a cyclic
enolisable ketone 19. There is only one place for enolisation in either molecule. The condensation
between 19 and 20 with HCl in MeCO 2H gives the enone 18 in 75% yield. 4 The stereochemistry
of the enone double bond is under thermodynamic control (chapter 4).
CHO
+
Cl
16 17
Cl

O
When the aldol strategy is not ideal
O
Conversely if the target is a vinyl ketone, then the aldol disconnection removes only one carbon
atom - not much of a simplifi cation! Even so, the aldol and its modifi cations such as the Mannich
reaction are often used for such syntheses. An extreme example comes in Corey’s synthesis of
antheridic acid 5 where an aldol disconnection of an advanced intermediate 21 removes just one
carbon atom but makes the remainder 22 of this complex molecule much easier to synthesise.
If the double bond is embedded in the middle of the molecule there may be no simplifi cation at all,
indeed the proposed starting material might be much harder to make than the target itself! The simple
bicyclic ketone 23 disconnects to the dione 24 which is an unsymmetrical octa-1,4-dione diffi cult to
make and which might cyclise to give 25 if C-5 enolises and attacks C-1 instead of C-8 enolising and
attacking C-4 as we require. We shall see in the next chapter how to make such enones.
Symmetry as a guide
O
O O
RO
18
H
5 Strategy 4a: The Aldol Route to Enones 59
O
O
aldol
enone
Symmetry may guide us. The simple enone 26 disconnects to two molecules of the same
symmetrical ketone 27 and is therefore easily made without selectivity problems. 2 Acid or basecatalysed
self-condensation of cyclopentanone gives the enone 26 in good yield.
O
O
19
O
O
+
OHC
Mannich
O
H O
RO
CO2Me
O
CO2Me
O
21 22
O
aldol
enone
6
7
5
O
1
8
4 3
O
2 =
7
6
8
5
O
1
3
4
O
2
O
23 24
24a 25
O O
aldol
26
enone
+
O
27 27
O
20
O
O

60 5 Alternative Strategies for Enone Synthesis
The bicyclic compound 28 looks a poor subject for the aldol until we realise that the starting
material 29 is symmetrical and as its two carbonyl groups have a 1,6-relationship, it can be made
by the reconnection strategy. 6 The cyclisation to give 28 goes in 96% yield. 2 There is an obvious
contrast with the failed synthesis of 23. There the two ketones in 24 were different so there were
three possible sites for enolisation. In 29 the two ketones are the same and all four sites for enolisation
are the same. There are no selectivity problems.
The complicated heterocyclic compound 32 is symmetrical about a vertical plane and two aldol
disconnections give the symmetrical ketone 34 and two molecules of the unenolisable aldehyde
33. Condensation with KOH gives 7 93% of 32.
O
NMe2
Mechanism may help us. If the required enolate is particularly easy to make, or the electrophile
particularly reactive and/or unable to enolise, these are good points. If there are problems of
chemo- or regioselectivity we cannot solve, then these are bad points. Stereochemistry may be a
problem too. There is not much you can do about the stereochemistry of an enone made by the
aldol reaction as you tend to get the thermodynamically more stable isomer (E or Z) and if you
want the other you should try a different strategy.
Wittig-style aldol methods
O O
aldol
enone
9
8
10
7
1
O
6
2
5
=
28 29
3
4
9
10
N
symmetry
32
6
1
30
O
NMe 2
FGI
reduction
2 x aldol
One version of the aldol is particularly suitable for enones as it uses Wittig-style chemistry and
makes alkenes in one step. As you will see in chapter 15, reactions of stabilised ylids 36 or
8
1
O
31
O
CHO
NMe2
7
2
29a
O
6
3 4
N
34
O
CHO
NMe 2
33 33
5
reconnect
1,6-diCO

phosphonate anions 38 (that is those of the aldol type) with aldehydes give E-alkenes selectively.
Phosphonate anions also react with ketones.
A Wittig-style
'aldol' reaction
A Horner-
Wadsworth-
Emmons
reaction
Ph 3P
O
(RO) 2P
37
O
base O R2CHO R1 Ph3P
R1 35 36; stabilised ylid
O
R 1
base
O
(RO) 2P
R1 O
R2 +
O
In general, the aldol strategy should be your fi rst choice. If you feel that the chemo- and regioselectivity
of the aldol reaction can be controlled and that the stereochemistry is likely to be
correct, you should try the aldol approach. Of course, as in all aspects of synthetic chemistry, a
literature search for precedents might save a lot of time. Even the aldol fails sometimes.
In a recent study of asymmetric conjugate addition, Simon Woodward and co-workers 8 required
a series of enones 43. Some they made with lithium enolates 41 of ketones or esters 40 added to
aldehydes to give the aldols 42 that were dehydrated to the enones 43 with concentrated HCl.
R1 O
R1 OLi
R1 O
R2 R1 O
R2 OH
1. LDA
40; R 42; aldol
1 2. R
= alkyl, OMe 41 43; enone
2CHO HCl
THF
Others they made by Wittig or Horner-Wadsworth-Emmons reactions such as the methoxyketone
45 from the phosphonate ester 44. The 78% yield is of pure E-enone 45.
(MeO) 2P
The search for anti-HIV drugs led workers in New Zealand 9 to potential peptide mimics with
the central amide bond replaced by a trans alkene 47. These compounds would have roughly the
same shape as natural peptides and might inhibit HIV protease. To get the right diastereoisomer
two single enantiomers were coupled by the Horner-Wadsworth-Emmons reaction of phosphonate
46 and the right aldehyde. The slightly odd conditions avoided racemisation of the aldehyde.
O
O
5 Strategy 4a: The Aldol Route to Enones 61
44
Ph
O
OMe
K 2CO 3
n-C5H11CHO
OHC
38
R 2
O
45; 78% yield
Ph O N
H
O
P(OMe) 2
O
i-Pr2NEt, LiCl
MeCN
Ph O N
H
O
46 47
OR
Ph
O
Ph
R 2
O
OMe
R 1
39
O
OR
R 1
Ph

62 5 Alternative Strategies for Enone Synthesis
Strategy 4b: Acylation of a Vinyl Anion
Strategy 4b involves the disconnection 48 of the bond between the double bond and the carbonyl
group of the enone and requires the acylation of a vinyl anion 49 or its synthetic equivalent with
some a 1 reagent 50, an acylating agent, usually an acid derivative.
Vinyl metal reagents
Its most elementary realisation is the reaction of a vinyl Grignard reagent 52 or vinyl lithium,
usually prepared from a vinyl chloride 51 in THF, with an aldehyde followed by oxidation to the
enone 48. The Swern oxidation is particularly useful for the oxidation of allylic alcohols such as
53 to enones.
R 1
51
Cl
1. Mg, THF
OH
R 1
[O]
A more direct version is the treatment of vinyl-lithiums with carboxylic acids. 10 Vinyl-lithium
itself reacts with EtCO 2H in DME (DiMethoxyEthane) to give the enone 56 in high yield. 11 The
fi rst molecule of vinyl-lithium forms the lithium salt 54 and the second molecule adds to give
the di-lithium derivative 55, an intermediate which might remind you of the lithium enolates of
carboxylic acids discussed in the previous three chapters. Hydrolysis during normal work-up gives
the enone 56.
EtCO 2H
Li
MeO OMe
This reaction often gives much poorer yields in other cases, though the cyclic vinyl-lithium
58 prepared from the vinyl chloride 57, gives a moderate yield 12 of 59.
57
O
R1 R2 48
52
MgCl
R1 R2 R1 R2 53 48
O
54
OLi
Li
Cl Li
Li
THF
strategy 4b
R1 R2 +
X
49; vinyl anion
50: acylating agent
O
LiO OLi
PhCO 2H
2. R 2 CHO
H
H2O
O
55 56; 92% yield
58 59; 42% yield
O
O
Ph

The most popular method these days for the acylation of Grignard or organolithium reagents
is the Weinreb amide (also discussed in chapter 8). Acylation of vinyl Grignard with the complex
intermediate 60 was part of a synthesis of ()-fumagillol 13 62.
O
MeO
N
Me
OSiMe3
OPMB
The intramolecular acylation of the vinyl lithium derivative of 63, prepared by exchange of
iodine with lithium (chapter 8) with the Weinreb amide on the side chain gives the fi ve-membered
heterocyclic ring in 64, an intermediate on the way to ()-brunsvigine 65, an alkaloid of the
montanine group. 14
MeO
N
Me
O
I
H
63
OH
The aliphatic Friedel-Crafts reaction
O
O
OMe
MgBr
62; (–)-fumagillol
OSiMe3 OPMB
60 61
O
O
BuLi
In chapter 16 we shall discover that vinyl-copper reagents can be prepared with stereochemical
control over double bond geometry and acylated directly with acid chlorides. We shall also meet
vinyl silanes and see how they too can be acylated with acid chlorides. In this chapter we shall
consider only the acylation of alkenes themselves with acid chlorides, that is the aliphatic Friedel-
Crafts reaction. 15 The normal Friedel-Crafts reaction 66 combines an aromatic compound with an
acid chloride and a Lewis acid to give a cation 67 which loses a proton to give an aryl ketone 68.
O Cl
R
AlCl 3
5 Strategy 4b: Acylation of a Vinyl Anion 63
AlCl3
O
R
O
Ts
N
H
64
An alkene, if it is reactive enough, can give the same sort of intermediate 70 but there is no
longer the same urgency to lose a proton, as there is no aromaticity to regenerate, and a chloride
ion usually adds to give the β-chloroketone 71. Base is needed to give the enone 72. By this
method the enone 72 was made in 40% yield but only after extensive fractionation. 12
O
O
O
R
O
H
O
O N H
65; (–)-brunsvigine
66 67 68
R
O
OH
OH

64 5 Alternative Strategies for Enone Synthesis
O
R
The simple enone 74 was needed for a synthesis of trans chrysanthemic acid 73, a component
of the natural insecticide pyrethrin. 16 An aldol approach would require a cross-condensation
between two enolisable ketones, one of them 75 unsymmetrical, and although this could easily be
done an alternative was sought.
Disconnection between CO and CC with the aliphatic Friedel-Crafts reaction in mind
would require acylation of the unsymmetrical alkene 76 with the acid chloride 77. The alkene 76 is
ideal for acylation as it is tri-substituted and therefore relatively electron-rich and will react at the
required (less substituted) end. The β-chloroketone 78, formed when SnCl 4 was used as the Lewis
acid, was treated with base without isolation to give the enone 74 in 60% overall yield. Lithium
chloride may not look very basic, but in dipolar aprotic solvents like DMF (DiMethylFormamide,
Me 2NCHO), that do not solvate anions, chloride is a good base.
74a
Strategy 4c: Unsaturated Acyl Cations and Anions
Acyl anion equivalents (d 1 reagents)
R
O
Cl
Strategy d(ii) (see 4d) follows logically as similar methods are involved. The same enone 74 can
be made by this strategy 74b if an acyl anion equivalent (a d 1 reagent) for the synthon 79 can be
alkylated at the carbon atom of the carbonyl group.
The point of this is that the proposed starting material 80 can then be made by a simple Wittig
reaction with the stable ylid 81, the equivalent of an enolate of MeCHO, as the extra ylid stabilisation
avoids any regioselectivity problems in enolisation. The cyanohydrin derivative 82 can lose the
marked proton with strong base and alkylation occurs as planned. The product 83 can be hydrolysed
R
O Cl
69 70 71 72
CO 2H
O
H
aldol
enone
73 74 75
O Friedel-
Crafts
O
+
Cl
74b
SnCl 4
Cl
O
base
O
R
+
LiCl
DMF
76 77 78 74
O
4d(ii) X
O
+
X = leaving group 79
80
?
O
O
O
H
O

with anions chemoselective for silicon (fl uoride or chloride) to regenerate the carbonyl group with the
formation of the enone 17 74. We shall meet further examples of acyl anions (d 1 reagents) in chapter 14.
Ph 3P CHO Me2CO
An example with two enones made by different strategies
O
Me 3SiCN
H ZnI2 H
81 80 82
OSiMe 3
CN
Et 3NHF
OSiMe 3
The same strategy, but with the opposite polarity, along with other enone approaches is illustrated
by the bicyclic enone 84 needed for the synthesis of the terpene cadinene. Aldol disconnection
gives the 1,5-diketone 85 which we expect to make by a Michael addition. 18 Hence we require a
specifi c enol equivalent of cyclohexanone to add to the enone 86, and we have rediscovered the
Robinson annelation. 19
O
84
H
5 Strategy 4c: Unsaturated Acyl Cations and Anions 65
aldol
enone
or HCl
83 74
H
O O O
Disconnection of the enone 86 by the strategy we have just used for 74, with the reverse polarity,
gives the unsaturated acid 87 again accessible by a Wittig reaction with the protected reagent 89.
We have in mind using an alkyl-lithium instead of a vinyl-lithium as a nucleophile to make 86.
O O OH
86a
4d(i)
EtLi +
87
85
Wittig
The phosphonate 90 version of the Wittig reaction, often used when there is an anion stabilising
group (here CO 2Me) present, gives 65% of pure E-91, easily hydrolysed to the free acid 87.
Now we need to add EtLi, made from EtBr and Li metal, which gives E-86 in 92% with some
recovered starting material. Finally, the Robinson annelation goes in excellent yield (83%) to give
the required bicyclic enone 84. There is also reasonable selectivity in the Robinson annelation
(7:3 in favour of the required syn isomer), presumably through a transition state such as 93.
This is a Newman projection, often the best way to visualise the simultaneous creation of two
CHO
O
1,5-diCO
Ph3P +
O
86
OH
CN
+
1. LDA
2. i-PrI
O
specific
enolate
needed
Ph 3P
O
88 89
OR

66 5 Alternative Strategies for Enone Synthesis
new stereogenic centres. Note that this is not aldol stereo-selectivity: it is akin to the examples
discussed at the end of chapter 4 and to be discussed in chapters 20–22.
O
O
(MeO) 2P
O OMe
O OMe
O OH
O
90 91 87 86
N
H
1. NaH
2. i-PrCHO
Strategic bonds in enone synthesis
N
92
86
When Fétizon 20 wanted to synthesise members of the cedrene and acorene classes of terpene,
he chose to try the photochemical cyclisation 21 of the dienone 95, hoping to get 94. The best
disconnection strategically is of the bond between the two branchpoints 95. This bond is also roughly
in the middle of the molecule and separates a ring from a chain and so cries out to be disconnected.
We shall call such bonds strategic bonds in future. We might try an organometallic reagent 96
(M metal) and some reagent for the synthon 97. As the enone is cyclic we cannot use the “obvious”
ynone 98.
A more practical strategy uses the chemistry of 1,3-diones 99 which exist as an equilibrium
mixture with the predominant enol form 100. Reaction with an alcohol (MeOH or i-PrOH are
most popular) gives enol ethers such as 101 which react cleanly with organo-metallic reagents
(such as 96; M Li or MgBr). However, attack occurs at the carbonyl group to give 102; and
not at the double bond, so the molecule is turned back to front by this reaction to give the
enone 103.
O
hν
?
K 2CO 3
MeOH
O
H
EtLi
TM84; 83% yield, 7:3syn:anti 93
Analysis:
? ?
+
O
O O O
94 95
96 97
98
HO
i-PrOH
O
O
i-PrO
99 100 101
H
O
RLi or
RMgBr
R
OH
H 2O
H
N
O
R
H
i-PrO
O
102 103

When you have realised, as we hope you did from the way we drew the product 101, that enol
ether formation occurs randomly at either end of the 1,3-dione system, you should also see that
only symmetrical diones are suitable for this reaction. Returning to the original problem, the
synthesis of 95, the ketone 104 is readily made, 22 so this route is suitable using the lithium derivative
made from the chloride 105 and the ethyl vinyl ether 106.
O 1. LiAlH4 2. Ph3P, CCl 4
Cl
1. Li,
hexane Li
2. O
+
104 105
Rearrangements of allylic alcohols with Cr(VI)
EtO OEt
A regiospecifi c version 23 of the same strategy starts with an unsymmetrical enone, such as the
Robinson annelation product 108. An organometallic compound is again added direct to the
carbonyl group, but now the rearrangement is accomplished by oxidation with Cr(VI). The starting
material 109 cannot be oxidised as it is a tertiary alcohol, but the product of allylic rearrangement,
being a secondary alcohol 110, can, and the enone 111 must result.
O
108
This is probably a [3,3] sigmatropic rearrangement 112 of the chromate ester of the tertiary
alcohol so that 109 is oxidised directly to 111 via the chromate ester 113 without any secondary
alcohol 110 actually being formed. An important way to carry out this strategy appears in chapter
18 under the Heck reaction.
R OH
109
5 Strategy 4c: Unsaturated Acyl Cations and Anions 67
Cr(VI)
RMgX
or RLi
R OH
96; M = Li
H
This strategy was recently applied to the synthesis of scopadulcin 24 114. They had already
made the enone 115 and wished to use it as starting material so means had to be found to bolt ring
A onto the bottom left hand side of the enone. Addition of the lithium derivative 117, made from
the chloride 116 with the aid of ultrasound (often a help in heterogeneous reactions) to the enone
115 gave the allylic alcohol 118 and this duly rearranged on Cr(VI) oxidation.
106
R
H
OH
Cr(VI)
OH
107
H
H 2O
109 110 111
O R
R O OH
Cr
O
O O
O Cr OH
112 113 111
R
R
O
O
95
O

68 5 Alternative Strategies for Enone Synthesis
A
H OBz
CO 2H
Looking forward to the chemistry of S and Se
Modern organic chemistry, particularly using the special reactivity of sulfur and selenium
compounds, has developed regiospecifi c reagents for all three synthons 120, 121, and 122, and
the three negative synthons of the same structure, needed for this family of strategies. We shall
postpone a detailed discussion of this chemistry until chapters 16 and 18. The nucleophilic
synthon corresponding to 121 will also appear as extended enolate chemistry, disconnections (7c),
in chapter 11. Finally, there are some further strategies we have not even mentioned which depend
on the late addition of either the carbonyl group or the double bond. These also involve sulphur
and selenium chemistry and will appear in chapter 33 under the heading “FGA strategy”. You will
appreciate that there are many approaches to the synthesis of enones. How you are to decide which
one to adopt in a particular case is the subject of the next chapter.
References
H
114; scopadulcin
115
OH
?
General references are given on page 893
1. D. Seebach, Angew. Chem. Int. Ed., 1979, 18, 238.
2. Review: A. T. Nielsen and W. J. Houlihan, Org. React., 1968, 16, 1.
3. S. S. Tiwari and A. Singh, J. Indian Chem. Soc., 1961, 38, 931.
4. W. H. Perkin, A. Pollard, and R. Robinson, J. Chem. Soc., 1937, 49.
O
O
O
H
H
O
O
O O
117
OH
PCC
NaOAc
O O
Cl
O O
Li, Et 2O
ultrasound
118; 97% yield 119; 72% yield
O O
120
O
O
O O
115 116
117
O
121 122
H
O
Li

5 References 69
5. E. J. Corey and A. G. Myers, J. Am. Chem. Soc., 1985, 107, 5574; E. J. Corey, A. G. Myers, N. Takahashi,
H. Yamane and H. Schraudolf, Tetrahedron Lett., 1986, 27, 5083.
6. Disconnection Approach, chapters 26 and 27, pages 217–228; see page 300 for the synthesis of TM 28.
7. P. I. Ittyerah and F. G. Mann, J. Chem. Soc., 1958, 467.
8. C. Börner, M. R. Dennis, E. Sinn and S. Woodward, Eur J. Org. Chem., 2001, 2435.
9. M. K. Edmonds and A. D. Abell, J. Org. Chem., 2001, 66, 3747.
10. M. J. Jorgenson, Org. React., 1970, 80, 1.
11. J. C. Floyd, Tetrahedron Lett., 1974, 2877.
12. H. E. Zimmermann, J. Org. Chem., 1955, 20, 549.
13. J. Boiteau, P. Van de Weghe and J. Eustache, Org. Lett., 2001, 3, 2737.
14. C.-K. Sha, A.-W. Hong and C.-M. Huang, Org. Lett., 2001, 3, 2177.
15. R. E. Christ and R. C. Fuson, J. Am. Chem. Soc., 1937, 59, 893.
16. J. Ficini and J. d’Angelo, Tetrahedron Lett., 1976, 2441.
17. U. Hertenstein, S. Hünig, and M. Öller, Synthesis, 1976, 416.
18. The Disconnection Approach, chapter 21, page 170.
19. E. Piers and W. M. Phillips-Johnson, Can. J. Chem., 1975, 53, 1281.
20. M. Fétizon, S. Lazare, C. Pascard, and T. Prange, J. Chem. Soc., Perkin Trans, 1, 1979, 1407; D. D. K.
Manh, J. Ecoto, M. Fétizon, H. Colin, and J.-C. Diez-Masa, J. Chem. Soc., Chem. Commun., 1981, 953.
21. Disconnection Approach, chapter 32, page 268.
22. Disconnection Approach, page 1.
23. W. G. Dauben and D. M. Michno, J. Org. Chem., 1977, 42, 682.
24. S. M. A. Rahman, H. Ohno, T. Murata, H. Yoshino, N. Satoh, K. Murakami, D. Patra, C. Iwata,
N. Maezaki and T. Tanaka, J. Org. Chem., 2001, 66, 4831.

6
Choosing a Strategy: The Synthesis
of Cyclopentenones
Strategies Based on an Aldol Reaction
Using the Aliphatic Friedel-Crafts Reaction
The Nazarov Reaction
Cycloadditions of Fe(CO) 4 Complexes of Oxyallyl Cations
The Pauson-Khand Reaction
Recent Developments in the Pauson-Khand Reaction
Oxidative Rearrangement of Tertiary Allylic Alcohols
Other Methods
Strategies Based on an Aldol Reaction
Five-membered rings occur throughout Nature and in many exciting molecules made by man. The
perfumery constituent cis-jasmone 1 might claim to be the molecule synthesised in most different
ways. The prostaglandins, molecules which control human physiology, contain fi ve-membered
rings and some, like PGA 2 2 are cyclopentenones. Dodecahedrane 3, the highly symmetrical
(CH) 20 hydrocarbon, consists of nothing but fi ve-membered rings, twelve of them in all, and has
been approached from various cyclopentenones.
O
1; cis-jasmone
O
We shall look at the many different strategies used to make cyclopentenones: some will be
similar to the methods explored in the last chapter, some will be totally different. Some will introduce
more advanced chemistry that we shall meet later in the book, but the point of this chapter is
the strategy: in each case we hope you will ask yourself why that particular route was followed.
When Stork 1 wished to synthesise cis-jasmone 1, he considered how helpful it would be if there
were an equivalent to the famous Robinson annelation 2 which would make fi ve-membered instead
of six-membered rings. Analysis would start in the same way (cf. chapter 5) 1a but the starting
material 4 for cyclisation would be a 1,4-diketone instead of a 1,5-diketone.
OH
2; PGA2
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd
CO 2H
3; C20H 20
dodecahedrane

72 6 Choosing a Strategy: The Synthesis of Cyclopentenones
Disconnection 4a to an enone 5 is still possible, but we should have to add a d 1 reagent, or acyl
anion equivalent 6 instead of an enolate. At the time of Stork’s work, there were no d 1 reagents
which reliably added Michael fashion, so he invented one. It would obviously be convenient if the
d 1 reagent would also act as an alkylating agent in the synthesis of 6, that is if it would act as the
doubly nucleophilic synthon 7.
cis-jasmone: Analysis II
O
O
4a
O
1,4-diCO
O +
?
5
d 1 synthon 6
The amino nitrile 9 fulfi ls all these hopes. It is easily made, it can be alkylated to give 10, and
the anion from removal of its second proton gives a clean Michael reaction to form 11. Finally,
the amino-nitrile functionality is easily hydrolysed at room temperature and neutral pH ( unlike
so many such compounds: see chapter 14) with Cu(II) catalysis to give the ene-dione 4 and
hence cis-jasmone 1 by thermodynamically controlled cyclisation in weak base. 1 This process of
adding a new fi ve-membered ring, not necessarily to give a cyclopentenone, is often called cyclopentannelation
and there are now many such methods. 3
Et2N CN
O
HCN
CH 2O Et2NH
11
cis-jasmone: Analysis I
O
1a
CN
CN
Et2N
1. LDA
2. 8; X = I Et2N 9 10
CuSO4
H 2O
EtOH
O
O
aldol
4; 72% yield from 9 1; cis-jasmone, 91% yield
This fi rst approach kept the Michael acceptor half 5 of the Robinson annelation. The alternative
would be to keep the enolate half and replace the Michael acceptor by an a 2 synthon. An example
is the synthesis of the cyclopentenone 12 by Yoshikoshi. 4 As before, aldol disconnection gives
a 1,4-diketone 13, but this time there is a strategic bond for disconnection leading logically to a
regiospecifi c enolate 14 and a regiospecifi c a 2 synthon 15. From chapter 3 we know that a silyl
enol ether is the best choice for a more substituted enol. It is less obvious to choose an unsaturated
nitro compound 16 as the a 2 reagent, but you should be aware that aliphatic nitro compounds can
be converted into ketones, and that the great anion stabilising ability of the nitro group makes the
synthesis of unsaturated nitro compounds a simple matter. 5 Putting these two ideas together makes
O
O
4
1% NaOH
H 2O, Et 2O
O
C
7
O
+
X
1. LDA
2. 5
8

this a good strategy, particularly as the same anion-stabilisation will make the Michael addition
a good reaction too.
12
O
aldol
2
1
3
4
O
1,4-diCO
O O
13 14; regiospecific
enolate
Nitropropane 17 can be condensed directly with CH 2O to give the alcohol 18 which is de hydrated
with phthalic anhydride to give nitroalkene 16. The silyl enol ether 20 can be made directly from
the unsymmetrical ketone 19 under equilibrating conditions and reacts with the nitroalkene under
Lewis acid (TiCl 4 as usual) catalysis to give the adduct 21. Normally one needs quite vigorous
conditions to convert nitroalkanes to ketones, and the very mild hydrolysis used in this example
suggests that 21 hydrolyses unusually easily. The result is another effi cient cyclopentannelation by
a different strategy. 4
NO 2
CH 2O HO
NaOH
Me 3SiCl
NO2
O
Et3N
OSiMe3 TiCl4
O
19 20 21
The fi rst strategy one normally considers is the one which is already in the literature. In the case of
the cyclopentenone 22, widely used in natural product synthesis, 6 the near symmetry led to an unusual
strategy via the acyloin product 23 and hence to the symmetrical diester 24 as starting material. 7
This synthesis works well, using the silicon modifi cation 25 of the acyloin reaction, but the fi nal
dehydration leads to a mixture of enone 22 with the rearranged enone 26. This problem was not
realised until chemists 8 began to use this published procedure, 9 and is a warning to all chemists
involved in synthesis to check the structure of their intermediates carefully by NMR.
24
17 18 16
O
Na
Me 3SiCl
22
Me 3SiO
Me3SiO 25
6 Strategies Based on an Aldol Reaction 73
FGI
dehydration
H
+
O
FGI
NO 2
15; a 2 synthon 16; a 2 reagent
phthalic
NO2 anhydride phthalic
O
anhydride
O
16
NO 2
MeO 2C
HO MeO 2C
H2O
23
O
HO
acyloin
H
23 22
O
O
24
H 2O
reflux
O O
+
TM 12
87% yield
26

74 6 Choosing a Strategy: The Synthesis of Cyclopentenones
A more conventional analysis, using the aldol disconnection 22a, leads to a strategy similar
to that used for 12 and we must decide which half of the 1,4-keto-aldehyde 27 should have the
natural, and which the unnatural polarity. The two methyl groups help as they do not hinder
chemoselective enol formation from Me 2CH.CHO, but would make the a 2 reagent sterically less
reactive towards an S N2 reaction.
O aldol O
22a
1,4-di-CO O
CHO
CHO
27 28; a2 +
synthon 29
The choice for a specifi c enol equivalent is easily made: we used aldehyde enamines for just
these sorts of reactions in chapter 3. You may wonder why a simple α-haloketone was not chosen
for the a 2 reagent. This was a matter for personal preference dictated by the need to make large
quantities of 22. Stevens 10 and his group preferred the propargyl halide 31 even though this meant
using an Hg(II) salt to catalyse the hydration of the triple bond 11 to give 27. Aldol cyclisation
completed the synthesis.
CHO
R 2NH
R2N 30
Br
Sometimes even the aldol reaction fails to perform with its usual reliability and we must give it
some help. The bicyclic enone 33 continues the contrast with Robinson annelation as it resembles
the Wieland-Miescher ketone, used as a starting material for steroid syntheses, 12 but with two fi vemembered
instead of two six-membered rings. Aldol disconnection reveals the 1,4-diketone 34
but it turns out that closing the second fi ve-membered ring this way works rather badly.
The solution is to make the intramolecular aldol into a Wittig reaction. There are many ways to
do this using reagents such as 38 on the stable enolate 37. Note that this reagent 38 is an ylid not a
phosphonium salt, so there are no acidic protons to destroy the enolate of the dione 37. This is one
example of a family of reagents 3 that act fi rst as electrophiles and then as enolate equivalents. This
bicyclic enone 33 has been used in the synthesis of coriolin. 13
O
35
O
H
O
33
1. base
O
O
aldol
31
O
O
34
32
O
CHO
2. O
+
Br PPh3
O
37 38
1,4-diCO
Hg(OAc) 2
H 2SO 4
O
O
O
35
H
O
27
O
39
+
CHO
O
36
PPh 3
base
O
22
33

Modern versions of these strategies were needed for Robertson’s synthesis 14 of the heterocyclic
core of roseophilin 40. He decided to use the cyclopentenones 41 or 42 as starting materials.
Cl
NH
40; R = i-Pr
roseophilin
O
OMe
The standard aldol disconnection on enone 42a reveals the ketoaldehyde 43 best disconnected
at the branchpoint to the simple aldehyde 44 and some a 2 reagent derived from acetone.
The synthesis involved the formation of an enamine 46 from the aldehyde 45 and alkylation
with chloroacetone to give the ketoaldehyde 43. Then events took a twist. Aldol reaction under
equilibrating conditions (KOH, THF, H 2O) gave 41 rather than 42.
OHC
O
Though milder conditions (NaOH, Et 2O) gave 42 in 86% yield, this was of course racemic.
The single enantiomer was made from tartaric acid 47 by conversion into the enone 48, conjugate
addition of a lithium cuprate with excellent anti-selectivity 49 and elimination with DBU. 14
HO
42a
Using the Aliphatic Friedel-Crafts Reaction
N
aldol
R
CHO
Cl O Cl
Cl
i-Bu2N Cl
45 46; enamine
CO2H
6 Using the Aliphatic Friedel-Crafts Reaction 75
i-Bu 2NH
K2CO 3
Strategy B of chapter 5, disconnection between the double bond and the carbonyl group 50, looks
at fi rst sight to be of little use as it would require an intramolecular aliphatic Friedel-Crafts reaction
O
Cl
or
O
41 42
1,4-diCO
O
Cl
CHO
43 44
Cl
O
NaI
18-crown-6
OSiMe2t-Bu I(CH2)6Cl
43
58% yield
from 45
(CH 2) 6Cl
HO CO2H O
t-BuLi, CuI
O
47; tartaric acid 48 anti-49; 88% yield
KOH
Cl
THF
H2O O
Cl
41; 100% yield
OSiMe2t-Bu
DBU
42

76 6 Choosing a Strategy: The Synthesis of Cyclopentenones
on a compound of equal size. It is of value because the starting material 51 comes from some acid
derivative 52 that can be made by allylation of an enolate. The Friedel-Crafts should be regioselective
as cyclisation of the other end of the alkene would give a four-membered ring.
O
R
O
Friedel-Crafts FGI
Cl
R
50 51
52
This strategy has been used to make the simple cyclopentenone 54 from the unsaturated carboxylic
acid 53 presumably by intramolecular aliphatic Friedel-Crafts reaction 56 and loss of
a proton from the resulting cation 55. This strategy was used because 53 was available by the
telomerisation of butadiene, but it would be simple to make such unsaturated acids in other ways.
O
OH
53
1. SOCl 2
2. AlCl3
O
54
A more exciting version 15 adds a three carbon unit (the d 3 reagent 57) twice to the symmetrical
diketone 58, oxidises the resulting tetraol 59 to a diacid which spontaneously cyclises to the
dilactone 60, and generates the acylating agent and the double bond needed for the Friedel-Crafts
reaction by acid-catalysed dehydration. The resulting curved row of cyclopentane rings 61 is
clearly one possible starting point for the synthesis of dodecahedrane 3.
O
The fi rst disconnection 50 or 62 is the same for both these approaches, giving in each case an
unsaturated acid as the intermediate. In the open chain case 52, we could proceed by a Wittig disconnection
of the double bond or a simple alkylation with an allylic halide 53. For the cyclic case
(using a six-membered ring as the second ring) 63 these are much less attractive. The bond joining
the ring to the chain is a strategic bond and we can disconnect it after FGI to the alcohol 64 reveals
the need for a d 3 reagent or homoenolate. Further examples of these reagents appear in chapter 13.
O
OR
R
allylation
of enolate
O
H
R
X
O
OR
55 56
1. 2 x 57
Cr(VI)
PPA O
O
2. H , H2O HO
OH OH
OH
O O MsOH
O O
58 59 60 61
O
Friedel-
Crafts CO2H FGI
62 63
Li O OEt
57; d 3 reagent
dehydration
CO2H
CO 2H
OH
64 d3 reagent
+
O
R
O
R
O

The Nazarov Reaction
In addition to the application of known and established strategies, each structural type of target
molecule may have special methods developed for, in this case, cyclopentenones alone. The
Nazarov reaction is historically important as one of the few unexplained reactions which led
Woodward towards the Woodward-Hofmann rules for pericyclic reactions. 16 Treatment of a crossconjugated
dienone, 65 being a minimalist example, with acid or Lewis acid leads to a cyclisation
in which two electrophilic atoms react with each other to give a cyclopentenone 69. Seen as an
ionic reaction, it makes no sense, but as a conrotatory 4n electrocyclic reaction 17 it is entirely
reasonable. Protonation gives a pentadienyl cation 66 which cyclises to a cyclopentenyl cation
67, the driving force being formation of a new σ-bond that more than compensates for the loss of
conjugation. Loss of a proton and enol-keto tautomerism complete the reaction.
Inspection of the starting material and the product reveal that the disconnection is of the bond in
the ring opposite the carbonyl group. Applying this to the molecule 70 we discussed in chapter 5, and
for which we rejected the aldol strategy, we discover that we need the dienone 71. An attractive
disconnection corresponds to the Friedel-Crafts reaction we have just been discussing and requires
in this instance cyclopentene and the unsaturated acid chloride 72.
70
O OH OH OH
4n conrotatory
electrocyclic
reaction
65 66 67 68 69
Oppolzer, 18 who wanted this cyclopentenone for the synthesis of modhephene 75 followed this
strategy and found that the Friedel-Crafts went well with AlCl 3 as catalyst and the Nazarov cyclisation
with another Lewis acid, SnCl 4. You will notice the position of the double bond in the fi nal
product: there are no protons on one side of the cation 73 so one must be lost from the other side.
In cases where there is a choice, the more substituted alkene results, as here. The product is ideally
functionalised for development into modhephene 75.
72
AlCl 3
H
O O O
Nazarov
71
79% yield
SnCl 4
6 The Nazarov Reaction 77
71
Friedel-
Crafts
OSnCl 3
In chapter 16 we shall see how the use of vinyl silanes has solved some of the regioselectivity
problems inherent in the Nazarov reaction. 19 Meanwhile we look at some recent developments on
–H
+
Cl
H
73 74
72
OSnCl 3
H 2O
O
H
75
modhephene
70
60% overall
yield from
cyclopentene

78 6 Choosing a Strategy: The Synthesis of Cyclopentenones
the effects of substituents on the reaction. The introduction of fl uorine into organic molecules is of
the greatest importance for the synthesis of new drugs. The synthesis of the trifl uromethyldienone
78 gives you a preview of methods we shall see later involving Sn and Pd. For the moment accept
that this is a way to produce a potential substrate for a Nazarov cyclisation. 20
ClOC
CF3 Br CuI, Bu3SnLi CF3 SnBu3 +
The Nazarov reaction is carried out with Me 3SiOTf as Lewis acid through intermediates 79 and
80. Elimination occurs exclusively away from the CF 3 group to give 81 in excellent yield.
78
76 76
Me 3SiOTf
CH2Cl 2
CF 3
OSiMe 3
Me 3SiO
A silyl group, on the other hand, attracts the alkene in the product. The dienone 82 cyclises
easily in acid to give only the less substituted cyclopentenone 84 in excellent yield. 21 We shall
discuss the stabilisation of cations such as 83 and allyl silanes such as 84 in chapter 12.
Cycloadditions of Fe(CO) 4 Complexes of Oxyallyl cations
CF 3
79 80
These Nazarov approaches add three extra carbon atoms (usually CH 2CH 2CO) onto a ketone to
form the fi ve-membered ring. It is also possible to add the three atoms CH 2CO.CH 2 onto an alkene
to form a cyclopentenone of different structure. The oxyallyl cation 87, which can be made by the
action of a metal, often zinc, to α,α-dibromoketones 85, might provide the three carbon atoms.
Unfortunately it is a two electron system and so adds to dienes 88 rather than mono-enes giving
cycloheptenones 89 in good yield. 22
O O
85
O
metal
SiPh 2t-Bu
Br Br Br
86
CF 3CO 2H
THF, 60 °C
H
82 83
O
87; the oxyallylcation
OH
O
Pd(0)
Cu(I)
CF 3
77 78; 75% yield
SiPh2t-Bu
π4σ + π2σ
cycloaddition
CF3
O
88 89a
O
O
81; 95% yield
H
O
H
84; 85% yield
SiPh2t-Bu
O
89b

If iron carbonyl is used to generate the oxyallyl cation, the iron supplies two extra electrons
in the complex 90 which now adds 23 to mono-enes to give cyclopentanones 91. We shall see
more examples of transition metal complexes altering selectivity later in the book. To get a cyclopentenone
92 we need an extra degree of unsaturation, best provided by using the enamine of a
ketone instead of a simple alkene.
O
Fe(CO) 5
Br Br
Fe(CO) 4
R
85 90 91
This cycloaddition works best with substituted oxyallyl cations, like the one from the dibromoketone
93 which reacts with the morpholine enamine of cyclohexanone 95 to give the cyclopentenone
96 in excellent yield. 24 You should mark the difference in structure between the Nazarov products,
e.g. 70, formed in an electrocyclic reaction, and these cycloadducts, e.g. 96. Each strategy has its
part to play and must be chosen according to the structure of the target molecule.
O
Br Br
1. Fe(CO)5
The Pauson-Khand Reaction
O
93 94
6 The Pauson-Khand Reaction 79
×
O
R
Fe(CO) 4
+
The typical Nazarov strategy 51 followed by 53 disconnects the rest of the ring from the double
bond, but you cannot be quite sure where the double bond will end up in the ring. Another special
method, the Pauson-Khand reaction, 24, 25 differs in both respects. It adds the enone portion of
the ring to the rest of the molecule and you can be quite certain where the new double bond will
be. The reaction is between an alkene, say cyclopentene 97, an alkyne, and Co 2(CO) 8 to form a
cyclopentenone 26 98 in one step. A complex 99 is fi rst formed between the alkyne and the cobalt
atoms with the two π-bonds replacing two CO molecules (both are two-electron donors). You may
see this complex drawn as 99a but it really has a tricyclic ‘tetrahedrane’ structure 99b composed
of three-membered rings and with a Co–Co bond.
The π-bond of the alkene then replaces another CO on one Co atom (we hope you are alert to
the difference between Co and CO!) to give the π-complex 100. A returning molecule of CO displaces
the alkene from the π-complex and forces it to make the fi rst new σ-bond, between one end
O
N
O
90
R
NR2
R
O
92
95 96
H H
O
H
Co2(CO) 8
H
H
Co(CO) 3
Co2(CO) 8
H
H
Co2(CO) 6
H
Co(CO) 3
97 98
99a 99b
O

80 6 Choosing a Strategy: The Synthesis of Cyclopentenones
on the alkene and one end of the alkyne, sacrifi cing one C-Co σ-bond to give the σ-complex 101.
Another molecule of CO returning to the Co atom forces one of the other CO molecules to insert
into the Co-C bond to give the acyl σ-complex 102. This is a standard reaction of organometallic
compounds which we shall meet again later.
97 + 99
Co(CO) 3
Co(CO) 2
+CO
Co(CO) 3
Co(CO) 3
The cobalt-acyl σ-complex 102 is unstable and forms the third and last C–C σ-bond by addition
of the carbon end (marked with a blob) of a C–Co bond to the carbonyl group 102a and decomposition
of the adduct 103 with loss of another Co–C bond. The product 104 is an unstable
cobalt complex of an alkene so the cobalt atoms drop out of the molecule altogether, leaving a
π-bond 98 where the old alkyne used to be. Cobalt carbonyl complexes of alkynes are stable: those
of alkenes are unstable. The mechanism 102a to 103 to 104 is very much an organic chemist’s
view of things: inorganic chemists may well be sceptical.
Co(CO) 3
Co(CO) 3
O
–CO
There is good regioselectivity with unsymmetrical alkynes, e.g. 1-heptyne 105; R n-pentyl
forms the 2-substituted cyclopentenone 106 in excellent yield 26 but unsymmetrical alkenes give
much poorer selectivity, e.g. 1-octene gives 21% each of the cyclopentenones 108 and 109; R 1
n-pentyl R 2 n-hexyl. 27 It must be admitted that this combined yield of 40–50% yield is more
typical than the 80–85% of 106, but this can be forgiven in a three-component reaction that
accomplishes so much. In the formation of the fi rst σ-bond a substituent on the alkyne evidently
prefers the blobby position in 102 while substituents on the alkene are indifferent about remaining
on the atom joined to cobalt.
The disconnections are simple 110 but one must look for a symmetrical alkene and make sure
that the substituent on the alkyne is next to the ketone.
+CO
Co(CO) 3
Co(CO) 3
100; π-complex 101; σ-complex 102; acyl σ-complex
(CO) 3Co
Co(CO)3
O
(OC)3Co
102a 103 104
R
R
O
R1 Co2(CO) 8
CH2=CH2
106; 80-85%
105 107
Co2(CO) 8
R 2
Co(CO)3
R 1
O
O
108
–Co 2(CO) 6
R 2
+
R 1
O
O
109
98
R 2
O

Intramolecular Pauson-Khand reactions are often regioselective because it is physically
impossible for the molecule to cyclise any other way. Pauson-Khand disconnection of bicyclic 111
reveals an allyl ether 112 of the alcohol 113, easy to make from acetylene and cyclohexanone. In
the cobalt-catalysed cyclisation, only one regioisomer is possible and this, the TM111, is formed
in an excellent 80% yield. 28
O O
Pauson-Khand
O
112 113
+ Br
The synthesis of the antibiotic methylenomycin A 114 is instructive on the choice between
modern and traditional methods. The key intermediate 116 has been converted into methylenomycin
by several groups whose strategy differs only in the synthesis of 116. The Pauson-
Khand disconnection is simplicity itself, requiring the symmetrical unsaturated ether 117 and
symmetrical butyne.
O
O
111
CO2H
114
methylenomycin A
O
R
Pauson-Khand
The traditional aldol analysis requires a 1,4-diketone 117 whose stereochemistry suggests a
2 2 photochemical cycloaddition 29 also on 117 and oxidative cleavage of the product 118.
O
H
H
O
reconnection
aldol
6 The Pauson-Khand Reaction 81
110
O
H
O O
O
O
H
115
H
H
O
O
FGI
reconnection
This approach was used by Amos Smith 30 starting with maleic anhydride to get an effi cient
photochemical reaction. Every step goes in good yield and can be carried out on a large scale, but
there are fi ve separate steps and only a 42% overall yield.
C–O
O
H
116
H
O
C
HO
116 117 118
H
H
O
R
Pauson-
Khand
O
2+2
+
H
H
117
O
+ 117

82 6 Choosing a Strategy: The Synthesis of Cyclopentenones
O
O
O
hν
MeCN
H O
H
In contrast the Pauson-Khand approach used by Billington 31 is only one step, but gave less than
20% yield when fi rst attempted. Gradually this was pushed up until it was claimed as a 70% yield,
but there is a lot of recovered starting material and the conversion is lower. You must make your
own choice!
Improvements in the Pauson-Khand procedure using silica support, 28 ultrasound, 26,32 and, best
of all, reaction in the presence of promoters such as N-methylmorpholine N-oxide 33 (NMO) 119
have led to increased yields. Probably most of the yields quoted so far could be improved if this
last method were used.
Recent Developments in the Pauson-Khand Reaction
O
O
1. LiAlH 4
(96% yield)
2. TsCl, pyr
(86% yield)
118
1. O3, MeOH
2. Ph3P, 117
75% yield
2% NaOH
H2O 116
MeOH
(85% yield)
Asymmetry as well as improved procedures has been a high priority recently. The heterocyclic
enyne 122 prepared from natural proline 120 gave initially only a 6% yield of the tricyclic amine
123. Addition of NMO 119 increased this to 72% but DMSO (Me 2SO) was the best promoter
raising the yield of a single diastereoisomer of 123 to near quantitative. 34
N
CO 2Me
NH
CO 2H
Since the intramolecular reactions are so much the best, others have linked the alkene and the
alkyne by a weak bond that can later be sacrifi ced. This is the ‘tether’ strategy you will meet in
chapter 36. An N–O bond is ideal and with the alkyne additionally blocked with a silyl group 124,
good yields of Pauson-Khand product 125 and of the amino alcohol 126 could be achieved even
with an amine N-oxide as promoter. Samarium(II) iodide was used as the reducing agent. 35
Me3Si
O
N
Me
119; NMO
124
O
N Boc
O
NH 2
CO 2Me
120; (S)-proline 121
122; 96% yield
1. Co 2(CO) 8
CH 2Cl 2
2. Me 3N + –O –
1. Co 2(CO) 8
THF, 2 hours
2. 6 x DMSO
50 °C, 26 hours
N
CO2Me
Cl
123; 94% yield
Br
NaHCO 3, LiI
MeCN, 60 °C
N
O
Boc
O
SmI2 THF
O
N
H
Boc
Me3Si
EtOH
Me3Si OH
125; 76% yield 126; 83% yield
O

Other recent developments include a high yielding and totally regioselective intermolecular
reaction between an unsymmetrical alkyne 127 and propene. The cobalt complex 128 was
isolated and treated with propene using NMO hydrate as promoter to give a high yield of the cyclopentenone
129. The methyl group from propene ends up next to the ketone as expected but the
regioselectivity of the alkyne, evidently due to the conjugating ester group, is remarkable. 36
CO 2Et
OTBDMS
127
Co 2(CO) 8
petrol, 0 °C
CO 2Et
OTBDMS
Co2(CO) 6
NMO.H 2O
CH2Cl 2
Other catalysts have been developed. Cobalt deposited on charcoal is effective in a range of
regioselective intramolecular reactions, though a 20 atmosphere pressure of CO must be used. 37
MeO2C MeO2C
6 Oxidative Rearrangement of Tertiary Allylic Alcohols 83
In chapter 19 you will meet palladium allyl cations as useful reagents and Evans and Robinson 38
have combined the Pauson-Khand reaction with allyl cation complexes using rhodium as a
compromise between Pd and Co. The enolate 132 combines with the Rh(I) cation complex from
the allylic carbonate 133 to give the enyne 134 that gives the Pauson-Khand product 135 in 87%
yield with the same catalyst but at higher temperatures.
Oxidative Rearrangement of Tertiary Allylic Alcohols
CO 2Et
128; 100% yield 129; 92% yield
20 atmospheres CO MeO2C 12 weight % Co/C
130 °C, THF
MeO2C
130 131; 98% yield
MeO2C MeO2C +
OCO2Me
132 133
cat Rh(I)
MeCN, 30 °C
MeO2C CO
cat Rh(I)
MeO2C MeO2C MeCN, reflux
MeO2C Me
H
134; 88% yield 135; 87% yield
OTBDMS
The oxidative rearrangement route (chapter 5) has been used in many syntheses of cyclopentenones.
Büchi’s route 39 to cis jasmone 1 simply involves treating the cyclopentenone 136 with
MeLi and oxidatively rearranging the product 137 directly to cis jasmone 1.
O
O
O

84 6 Choosing a Strategy: The Synthesis of Cyclopentenones
The natural prostaglandins, like PGA 2 2 are usually made by the oxidation of an allylic
alcohol. 40 This apparently trivial strategy is used because the stereochemistry around the fi vemembered
ring is easily derived from the bicyclic enone 138 by Baeyer-Villiger rearrangement. 41
Interesting principles of chemoselective oxidation are involved both in the formation of 139 and in
the synthesis of the starting material 138.
RO
138
In the PGA synthesis, a Wittig-style reaction puts in one side chain to give 142 which has the
wrong arrangement of double bond and OH group. This time oxidation cannot be used to force the
rearrangement as the alcohol is secondary, so a displacement is used 143. This is stereospecifi c
because the incoming CO 2H group is physically constrained to approach from underneath to give
the cis fused lactone 144. A reduction and another Wittig reaction complete the synthesis. PGAs
are so easily made that they are now used as large scale intermediates in the synthesis of other
PGs. 42
O O
(MeO) 2P
R
142
Other Methods
RCO 2
O
1. NaH
2. 140
O
MeLi
O
Me
OH
136 137 1; cis-jasmone
1. H 2O 2, KOH
2. NH3, Et 2O
RO
141; R = n-pentyl 142
O
R
HO
CO2Me
O
143 144
CO2H
CO2Me OR
CHO
RO
139 140
O
The recent discovery that unsaturated fi ve-membered carbonyl compounds bearing two aromatic
rings such as Merck’s MK-0966 145 are new generation anti-infl ammatory compounds led
O
R
O
O
O
CrO 3
R
1. DIBAL
2. Wittig
3. Cr (VI)
4. H
O
OH
2; PGA2 2; PGA2
CO2H

medicinal chemists 43 to make analogues such as 146. Ideal disconnections would be the removal
of the two aromatic rings with the idea that they could be added as organometallic compounds
to the two electrophilic sites in 147. A similar idea was used for a cyclohexenone, compound 95
in chapter 5.
O
O
145; MK-0966
O O
S Me
O
O O
S Me
O
N
N
146 147 148
The enol ether 150 was reacted with the lithium derivative of the thioether 149 to give the intermediate
151 after oxidation. A Suzuki coupling, as you will learn to call it, linked the boronic acid
derivative of the pyridine to the bromoenone to give the cyclopentenone 146 in just two steps.
SMe
O O
149
Br
O
1. BuLi, THF
2. 150
3. HCl, H2O
4. [O]
S
Me
Pd(0), Ph3P (i-PrO) 3B
146
73% yield
150
N
EtO
Br
O
Br
151; 71%
Among the many new methods, one deserves special attention because it is so simple to carry
out and yet includes such remarkable reactions. 44 The ynoate 152 reacts with ketones to give
four membered cyclic ester enolates that can cyclise 153 onto neighbouring ester groups to give
bi cyclic keto-lactones 154 that readily lose CO 2 to give cyclopentenones 155. The origin of 152
and the mechanistic implications of each step are explored in the workbook.
CO 2Et
6 Other Methods 85
Finally another extraordinary route to nitrogen-containing cyclopentenones using interesting
chemistry. de Meijere 45 used chromium carbonyl complexes 160 formed from terminal alkynes
156 via addition to Cr(CO) 6, insertion of the alkyne into one of the CO ligands to give the
carbene complex 158, alkylation on oxygen to give 159 and conjugate addition of a secondary
amine.
?
X
Br
Br
O O
S Me
+
O
'2 + 2'
EtO O
R
O
intramolecular
Dieckmann
O
R
O
–CO2 O
R
O
R
O
O
152 153
154 155

86 6 Choosing a Strategy: The Synthesis of Cyclopentenones
H
These complexes reacted with a second alkyne 161 without carbonyl insertion to give the
cyclopentadiene 161. This intermediate is also the enol ether of a cyclopentenone and hydrolyses
in strong aqueous acid to give a bicyclic compound 162.
Old and new chemistry provides many ways to make cyclopentenones. This chapter only hints
at the richness of modern organic chemistry. As we progress through the book most of these
methods will be explained in more detail.
References
O
Et 3O BF 4
O
1. BuLi
2. Cr(CO)6
(CO) 5Cr
(CO)5Cr
OEt
CO
O
General references are given on page 893
1. G. Stork, A. A. Ozorio, and A. Y. W. Leong, Tetrahedron Lett., 1978, 5175.
2. Disconnection Approach, page 170.
3. M. Ramaiah, Synthesis, 1984, 529.
4. A. Yoshikoshi and group, J. Am. Chem. Soc., 1976, 98, 4679.
5. Disconnection Approach, chapter 22, page 179.
6. S. Danishefsky, K. Vaughan, R. C. Gadwood and K. Tsuzuki, J. Am. Chem. Soc., 1980, 102, 4262; 1981,
103, 4136. T. Hudlicky, T. M. Kutchan, S. R. Wilson and D. T. Mao, J. Am. Chem. Soc., 1980, 102, 6351;
W. K. Bornack, S. S. Bhagwat, J. Ponton and P. Helquist, J. Am. Chem. Soc., 1981, 103, 4647.
7. Disconnection Approach, page 202.
8. S. Wolff, W. L. Schreiber, A. B. Smith and W. C. Agosta, J. Am. Chem. Soc., 1972, 94, 7797.
9. A. J. Bellamy, J. Chem. Soc. (B), 1969, 449.
10. R. V. Stevens, R. E. Cherpeck, B. L. Harrison, J. Lai and R. Lapalme, J. Am. Chem. Soc., 1976, 98,
6317.
11. Disconnection Approach, chapter 16, page 126.
12. Disconnection Approach, page 175.
13. B. M. Trost and D. P. Curran, J. Am. Chem. Soc., 1980, 102, 5699; 1981, 103, 7380.
14. J. Robertson, R. J. D. Hatley, and D. J. Watkin, J. Chem. Soc., Perkin Trans. 1, 2000, 3389; K. Ogura,
M. Yamashita and G. Tsuchihashi, Tetrahedron Lett., 1976, 759; A. G. Myers, M. Hammond and Y. Wu,
Tetrahedron Lett., 1996, 37, 3083.
O
O
O
Me 2NH
(CO)5Cr
156 157 158
+
(CO) 5Cr
OEt
O
(CO) 5Cr
OEt
Me2N
159 160; 68% yield
O
pyridine
80 °C
EtO
O
O
conc HCl
SiMe3 Me2N
Me3Si
NMe2 Me3Si
NMe2 161 160 161; 40% yield 162
THF
O
O
O
O
O
O
OH

6 References 87
15. P. E. Eaton and R. H. Mueller, J. Am. Chem. Soc., 1972, 94, 1014.
16. R. B. Woodward and R. Hoffmann, Angew. Chem., Int. Edn., 1969, 8, 781.
17. I. Fleming, Orbitals, page 103.
18. W. Oppolzer and K. Bättig, Helv. Chim. Acta, 1981, 64, 2489.
19. J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, and H.-U. Reissig, Organic Synthesis Highlights, VCH,
Weinheim, 1990, page 137.
20. J. Ichikawa, M. Fujiwara, T. Okauchi and T. Minami, Synlett., 1998, 927.
21. A. Barbero, P. Castreño, C. Garcia and F. J. Pulido, J. Org. Chem., 2001, 66, 7723.
22. H. M. R. Hoffman, Angew. Chem., Int. Ed., 1973, 12, 819.
23. Y. Hayakawa, K. Yokoyama and R. Noyori, J. Am. Chem. Soc., 1978, 100, 1799.
24. N. E. Schore, Org. React., 1991, 40, 1.
25. P. L. Pauson, Tetrahedron, 1985, 41, 5855.
26. D. C. Billington, I. M. Helps, P. L. Pauson, W. Thompson and D. Willison, J. Organomet. Chem., 1988,
354, 233.
27. M. E. Kraft, Tetrahedron Lett., 1988, 29, 999.
28. W. A. Smit, A. S. Gybin, A. S. Shashkov, Y. T. Strychkov, L. G. Kyz'mina, G. S. Mikaelian, R. Caple and
E. D. Swanson, Tetrahedron Lett., 1986, 27, 1241.
29. Disconnection Approach, chapter 32, page 268.
30. R. M. Scarborough, B. H. Toder and A. B. Smith, J. Am. Chem. Soc., 1980, 102, 3904.
31. D. C. Billington, Tetrahedron Lett., 1983, 24, 2905.
32. P. Blaydon, P. L. Pauson, H. Brunner and R. Eder, J. Organomet. Chem., 1988, 355, 449.
33. S. Shambayati, W. E. Crowe and S. L. Schreiber, Tetrahedron Lett., 1990, 31, 5289.
34. S. Tanimori, K. Fukubayashi and M. Kirihata, Tetrahedron Lett., 2001, 42, 4013.
35. S. G. Koenig, K. A. Leonard, R. S. Löwe and D. J. Austin, Tetrahedron Lett., 2000, 41, 9393.
36. M. E. Krafft, Y. Y. Cheung and K. A. Abboud, J. Org. Chem., 2001, 66, 7443.
37. S. U. Son, S. I. Lee and Y. K. Chung, Angew. Chem., Int. Ed., 2000, 39, 4158.
38. P. A. Evans and J. E. Robinson, J. Am. Chem. Soc., 2001, 123, 4609.
39. G. Büchi and B. Egger, J. Org. Chem., 1971, 36, 2021.
40. E. J. Corey and G. Moinet, J. Am. Chem. Soc., 1973, 95, 6831.
41. Disconnection Approach, page 226.
42. E. J. Corey and X-M. Cheng, The Logic of Chemical Synthesis, chapter 11, page 250.
43. W. C. Black, C. Brideau, C.-C. Chan, S. Charleson, N. Chauret, D. Claveau, D. Ethier, R. Gordon,
G. Greig, J. Guay, G. Hughes, P. Jolicoeur, Y. Leblanc, D. Nicoll-Griffi th, N. Ouimet, D. Riendeau,
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1999, 2025.

Section B:
Making Carbon–Carbon Bonds
7. The Ortho Strategy for Aromatic Compounds .................................................................. 91
8. σ-Complexes of Metals ....................................................................................................... 113
9. Controlling the Michael Reaction ..................................................................................... 127
10. Specifi c Enol Equivalents ................................................................................................... 139
11. Extended Enolates............................................................................................................... 155
12. Allyl Anions ......................................................................................................................... 173
13. Homoenolates ...................................................................................................................... 189
14. Acyl Anion Equivalents ..................................................................................................... 203

7
The Ortho Strategy for Aromatic
Compounds
Introduction
PART I – TRADITIONAL METHODS
Friedel-Crafts Reaction and Fries Rearrangement
The Claisen Rearrangement
PART II – USING LITHIUM
Ortho-lithiation
Anisole
Regioselectivity I – The ortho versus para question
Directing groups
Directing groups containing oxygen
Directing groups containing nitrogen
Regioselectivity II — ortho versus ortho
Choice in ortho-lithiation
Several lithiations
One ortho-director leads to another
Dilithiations
One ortho-director rearranges into another – the anionic Fries reaction
Halogens
Benzyne Formation
α-Lithiation
Lateral Lithiation
Chemoselectivity
Summary
Introduction
Most of this chapter is dedicated to ortho-lithiation—a powerful synthetic technique.
Part I looks at more traditional methods that do not include lithiation.
Building aromatic compounds by electrophilic substitution using ortho and para or meta directing
effects is part of the early training of all organic chemists. Reactions such as the Friedel-Crafts
acylation, that effi ciently build carbon-carbon bonds between aromatic rings and aliphatic side
chains are well known and have been assumed so far in this book. It is usually assumed that the
ortho and para mixtures, that arise when such reactions are applied to activated aromatic rings,
are acceptable because they can be carried out on a large scale and separation is usually simple.
This may be true for very simple compounds as uses can often be found for the unwanted isomer,
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

92 7 The Ortho Strategy for Aromatic Compounds
but the modern organic chemist needs ways to control or divert such mixtures into high yields of
single compounds. Making the para substituted compound is not usually diffi cult as large substituents
direct para. Making high yields of ortho compounds regardless of the size or electronic
nature of the substituents is no such easy matter and is the subject of this chapter.
PART I
OMe OMe
RCOCl
1
R
2
AlCl 3
Friedel-Crafts Reaction and Fries Rearrangement
The Friedel-Crafts acylation 1 on simple aryl ethers such as anisole PhOMe 1 usually gives almost
quantitative yields of the para ketone 2. If the acid chloride is attached to the oxygen atom by a
short chain of carbon atoms (a ‘tether’) 3 the resulting intramolecular reaction is forced to give the
ortho product 4, and these reactions also go in good yield. 2
O Cl
O
3 4
O
If the acid group is joined directly to the oxygen atom as an ester 6 we have the Fries rearrangement
3 which can be controlled to give either the para or ortho products. In polar solutions such as
nitrobenzene, 4 the para product 5 is formed in high yield, e.g. R Me, 75%, while in non-polar solvents
or in the absence of solvent, the ortho product 7 is formed in similar yield, e.g. R Me, 70%.
R
O
5
OH
This is not a concerted rearrangement mechanism of the usual cationic sort, like the pinacol
(Chapter 2), but a normal ionic reaction. The Lewis acid catalyses the breakdown of the ester 8
into an acylium ion and a metal complex of the phenol which remain associated as an ion pair 9 in
non-polar solvents. This naturally tends to give the ortho product as the acylium ion is held close
to the ortho position by electrostatic interactions. In polar solvents, the ion pair is separated into
two independent ions which show the normal Friedel-Crafts selectivity, that is high preference for
the para product.
O R
O
AlCl3
AlCl3
PhNO 2
AlCl3 O R
6
AlCl 3
O
O R
O
AlCl 3
165 °C
6 8 9
O
O
7
AlCl 3 R
O
O
OH
O
R
7

Derivatives of meta cresol 10 are even more complicated. Three different sites are activated
(arrows on 10), but Friedel-Crafts acylation of simple ethers 11 favours the position para to the
ether group almost exclusively, anhydrides being the best acylating agents. 3
Me OH Me
OMe
The Fries rearrangement on simple esters 13 by contrast favours one of the ortho positions
equally exclusively, a very high yield of the ketone 14 being obtained in the absence of solvent. 3,4
In nitrobenzene, 28% of 14 and 64% of 15 are formed. 5
When Rao 6 wanted to make sydowic acid 16, a sesquiterpene from Aspergillus sydowi, he
chose to disconnect the ether fi rst and to make the triol 17 by addition of three methyl groups to
the keto-ester 18. This is clearly a Friedel-Crafts product but how are we to get the correct position
on the aromatic ring?
Knowing more about the behaviour of meta cresol 10 than of the hydroxy-acid 19 with the same
substitution pattern, Rao chose to work at the ‘wrong’ oxidation level through the Fries, using
the cyclic anhydride 20 as the acylating agent. This gave the right isomer 21, and, by addition
of four molecules of methyl Grignard (one is used up by the free OH group), and acid-catalysed
cyclisation, the intermediate 23. Sadly, direct oxidation destroys the phenol, so it must be protected
as an ester. This short synthesis involves regioselectivity twice: the obvious ortho Fries selectivity
and regioselectivity again in the formation of a six- instead of a four- or eight-membered ring in
the cyclisation of 22.
Ac 2O
AlCl 3
O
10 11 12; 87% yield
Me O Me
13
OH
O
O
HO2C 16; sydowic acid
HO2C
7 Friedel-Crafts Reaction and Fries Rearrangement 93
OH
18
O
AlCl3 165 °C
CO 2R
C–O
ether
Me
Me
OMe
Me OH
Me
OH
O
14; 95% yield
HO 2C
Friedel-
Crafts
OH
HO 2C
Me
+
OH
17
OH
Me
+
O
OH
15
C–C
4 x Me
(Grignard)
O O O
19 20

94 7 The Ortho Strategy for Aromatic Compounds
Me
m-cresol
10
OH
22
1. 20, AlCl 3
2. MeOH, H
OH
OH
Me
H2SO4
OH
Me
The remaining site in meta cresol 10, between the OH and Me groups, is very diffi cult to get into,
as is commonly the case when one tries to insert a largish substituent between two others which
are already there. A better strategy is usually to put two next to each other and add an outside substituent
last. When Wiesner 7 was planning the synthesis of some delphinine alkaloids, he required
the indanone 25 as a starting material in large amounts (150 g scale). The Friedel-Crafts disconnection
of 25 would require an acylation of 24 between two substituents and will not give 25.
Me
Indanones are an aromatic variety of the cyclopentenones we were considering in Chapter 6,
and the Nazarov strategy looks appealing as it becomes a Friedel-Crafts reaction on ortho cresol
27 with the acid chloride of acrylic acid. The problem is to make the reaction give just that isomer,
that is the one having four adjacent substituents. The Fries rearrangement is the answer as it
transfers the acyl group to the next carbon atom round the ring and the alkylation step has to
occur at the next ortho atom in turn. The unsaturated acid chloride is too reactive, but either of the
halides 28 or 31 will do the trick. 7,8
Cl
Br
O
28
O
31
The yields are not wonderful, but this is the fi rst step and it accomplishes a lot in one reaction.
Presumably either haloester or the haloketones 30 or 33 derived from them can form the double
21
O
OH
23
CO2Me
O
4 x
MeMgI
1. Ac 2O
2. KMnO4
3. NaOH
TM16
Friedel
b
X
-Crafts
Nazarov
Fries
CO2R a Me a
b Me
a Me
OH
OH
O
OH O
OH
24 25 26 27; o-cresol
Br
Cl
AlCl 3
27
AlCl 3
27
ArO
Fries
Me
O Cl
OH O
29 30
ArO
Br
Fries
Me
O
OH O
32 33
Cl
Br
Me
OH
34
O
24
23%
yield
24
35%
yield

ond under the reaction conditions so that the Nazarov intermediate 34 is formed and cyclised by
the same Lewis acid.
The Claisen Rearrangement
One reaction much used to produce the ortho relationship is the Claisen rearrangement. 9 An allyl
ether 36 from a phenol and an allylic halide 35 undergoes [3,3] sigmatropic rearrangement to give
an intermediate 37 that is the “keto form” of a new phenol 38 with the allyl group now in the ortho
position.
phenol
OH Br O
O
+
base
[3,3]
35
The rearrangement is regiospecifi c with regard to the allyl portion, substituents starting next
to the oxygen atom 39 fi nishing at the far end of the double bond 40. This example is particularly
favourable as the double bond becomes more highly substituted as the reaction proceeds.
Substituents in the middle of the allyl system 41 produce no regioselectivity problem, but the
products 42 are rather inclined to cyclise to ethers 43 by protonation of the double bond. 10
O
7 The Claisen Rearrangement 95
O
Substituents which start at the end of the double bond should fi nish next to the ring: the formation
of 45 is a particularly impressive example as the double bond moves out of conjugation. These are
the most tricky type of Claisen rearrangement and other products can be formed if conditions are
not carefully controlled. 9
There can be some regioselectivity if there are two different ortho positions. This is usually
attributed to ‘double bond fi xation’ as in the naphthalene 46 where the structure drawn represents
H
36 37 38
reflux
Et 2NPh
OH
39 40
OH O
heat H
41 42
43
OH
44
O Ph
heat
45
H
Ph
OH

96 7 The Ortho Strategy for Aromatic Compounds
more than just a Kekulé form. The bonds marked double are shorter than those marked single and
the products are 9:1 in favour of migration to the ‘better’ ring double bond in 47.
The side chain produced by the Claisen rearrangement contains a useful alkene that can be
elaborated by epoxidation, for example, and the reaction is slightly more versatile than it appears
at fi rst sight.
PART II
Using Lithium
So far, the only metal in sight to help us form aromatic compounds has been aluminium. Now
we look at a metal that activates aromatics in an entirely different way—lithium. Lithium is
introduced ortho to a ring substituent that already exists 50 and the process itself called ortho- or
directed lithiation.
Ortho-lithiation
Before we go any further we should be clear that ortho-lithiation is a proton-lithium exchange
reaction and is not to be confused with halogen-lithium exchange. For instance, the exchange of
bromine for lithium in 52 occurs, it just so happens, next to another substituent. But to call that
reaction an ortho-lithiation would be misleading because we would not want to imply that the
methylsulfanyl group had anything to do with it – the bromine will exchange whether the sulfi de
is there or not.
Anisole
O OH
OH
heat
+
46 47
XR XR
BuLi
9:1 48
[an electrophile]
Li
49 50 51
We have already seen how anisole 1 may be functionalised by using a Friedel-Crafts reaction.
Anisole is a simple, perhaps the most simple, functionalised benzene ring that can be lithiated by
ortho-lithiation. We use it here to introduce the reaction.
SMe SMe
BuLi
Br
not ortho
lithiation
52 53
Li
E
XR
OMe OMe
1. BuLi
2. CO2
CO2H 1 54; 50% yield
E

Firstly, let us consider the substituent ortho to the newly introduced lithium. The ortho directing
group here is a methoxy group and within it is the oxygen atom that is doing the work. Without concerning
ourselves with the mechanism of the reaction too much at this stage, the lone pair on the
oxygen atom coordinates to the organolithium reagent. Notice that the oxygen is attached directly
to the ring – anisole is a phenyl ether. We shall see examples later where the heteroatom is more
remote. The group which directs the lithiation we shall refer to as the ‘ortho-director’ although it is
called other things by different authors (DMG for Directed Metallation Group for instance). 11
Regioselectivity I—The ortho versus para question
Even without lithium, the reactivity of aromatic rings is nucleophilic. But the source of that nucleophilicity
is very different when a lithium atom is in place. The lithium atom does more than
dramatically increase the reactivity of the benzene ring, it alters its character entirely.
When benzene reacts with an electrophile like NO 2 , it is the π electrons of the ring that attack
the electrophile and the aromaticity of the benzene ring is necessarily disrupted. Any one of six
carbon atoms may be the focus for the attack on NO 2 , it makes no difference. With a substituted
benzene ring, we know that some sites are more reactive than others due to the infl uence of the
substituent – usually the ortho and para positions. But with a lithiated benzene ring the situation
is different. Now the attacking electrons are not π but σ. They are localised and have no choice
as to which carbon atom they attack from. And it doesn’t matter if the substituent increases the
π-electron density a little at this or that carbon because it will not compete with the full negative
charge from the C-Li bond. A ‘full negative charge’ would imply that we have an anion. This is
not the case but organolithium reagents are carbanion σ-complexes (chapter 8). Once the lithium
atom is in place the reaction with electrophile is regiospecifi c.
OMe
MeO MeO
But what about where the lithium atom goes in the fi rst place? If, as is usually the case, the
directing substituent coordinates to the organolithium reagent, then the reaction is directed to the
ortho position and the introduction of lithium is regiospecifi c. The organolithium reagent cannot
reach any further round the ring. We shall deal with two competing ortho positions and more
exceptional cases later but for now ortho-lithiation means what it says.
Directing groups
Anisole reacts at ortho or para positions
with π-electrons
E +
or
7 Ortho-lithiation 97
OMe
Li
E +
Lithiated anisole reacts at ortho position
with σ-electrons
The Fries and Claisen rearrangements need an oxygen atom next to the site where the new bond is
to be formed. From a strategy point of view, it’s good to start with your oxygen in place because
it can be diffi cult to introduce. 12 Ortho-lithiation strategy can make use of an oxygen substituent
too, but it also works extremely well with other directing groups. The nature and diversity of these
other directing groups gives ortho-lithiation very broad scope and makes it a powerful reaction.
After all, not all aromatic target molecules have C–O bonds of any kind, let alone Ar–O bonds
next to another substituted position.
E +
MeO
Li

98 7 The Ortho Strategy for Aromatic Compounds
As we now discuss these other directing groups, it would be a good time to consider the
mechanism of the reaction more closely. We should then understand why some groups work better
than others and be able to predict which ones will make a successful synthesis.
There are two basic aspects to the function of any directing group. It may—
i) coordinate to the lithium reagent
ii) increase the acidity of its neighbouring hydrogen atoms.
Both aspects may be operative, as they are in the case of anisole for instance, but they need
not both be present in the director. A director which does not coordinate to lithium must acidify
the positions next to it considerably if it is to be effective. We shall see that fl uorine is such a
substituent. Conversely, if the hydrogen atoms are not activated in any way by the director then it
must compensate by being a very effective donor to lithium.
The consequences of having two different directing groups, one which relies upon mostly
coordination and the other which relies upon mostly increased acidity, are discussed in Regioselectivity
II later.
Directing groups containing oxygen
We have already seen that oxygen directs lithiation in anisole 1 very effectively. Here are two more
examples of aromatic compounds 55 and 56 with an oxygen substituent that can be lithiated at the
marked atoms. But oxygen (unaccompanied by any other heteroatom) is a very poor director of
lithiation when it is any further away from the ring. Attempts, for instance, to direct a lithiation
within methoxybenzyl ether 57, fail. Deprotonation at the benzylic position occurs instead and the
molecule undergoes a Wittig rearrangement. Utilising a benzyl oxygen atom alone is bad strategy –
if it is used it must be done in conjunction with another directing group.
O
OH
OH
OH
O Me O
O
O
OMe
O
1. BuLi, 2. E
There are plenty of other groups which are known to be ortho-directors. The halogens can
behave as ortho-directors and fl uorine is perhaps the best (which is why it is in a box in the fi gure).
However, if you were attempting to use either bromine or iodine as an ortho-director then you’d
better watch out. It would be essential not to use butyl lithium as the lithiating reagent—they
Fries
Claisen
ortho-lithiation
OMe BuLi
OH
O
OH
OMe
55 56 57 58; 26% yield
E
Me
OH

would simply undergo a lithium – halogen exchange instead. Sulfones 64 and phosphates 65 are
also known as ortho-directors but then anything which either acidifi es protons at the ortho position
or would bind to an alkyl lithium reagent placing it next to an ortho proton has . . . well, at least
the potential to behave as an ortho-director.
Halogens, sulfones and phosphates
59
F
60
CF 3
61
Directing groups containing nitrogen
Cl
Br I
62 [not with BuLi] 63
O O
S t-Bu
Oxazolines 66, amides 67 and carbamates 68 are the three kings of the ortho-director world.
These are the most widely used ortho directing groups and among the best. Best means that they
not only give high yields but that their action is reliable. We shall also see that they are usually
easy to introduce and versatile in subsequent reactions. Be careful to note the difference between
an amide and a carbamate – they look very similar when their structures are not drawn out in full
(CONR 2 vs. OCONR 2). Although benzylic ethers often fail in ortho-lithiation reactions due to the
Wittig rearrangement, benzylic amines 69 are fi ne. They do not, however, approach the generality
of the ‘three kings’.
O
N
66; oxazoline
Oxazoline 71 is an intermediate in the synthesis of the azirine 70 which was used in
investigations into cycloaddition reactions. 13 Let’s consider how we would make the oxazoline.
Clearly we can disconnect the bond between the aromatic ring and the side chain to reveal 72, the
lithium derivative of oxazoline 75, which can be coupled with an electrophilic side-chain. 14
N
7 Ortho-lithiation 99
NR 2
67; amide
O
O
The synthesis is straightforward. The oxazoline 66 directs the ortho-lithiation and then the
lithium derivative is reacted with an allyl bromide. One thing we did not consider in the analysis
was the synthesis of the oxazoline itself and perhaps we should. One way to make oxazolines
(and there are many) is to react an acid chloride with an amino alcohol 74 followed by thionyl
chloride.
O
O
68; carbamate
N
N
+
R R
Li Br
70 71
72
NR 2
64
O
69
O P(OR)2
65
NR 2
73
O
R

100 7 The Ortho Strategy for Aromatic Compounds
HO
H 2N
1. PhCOCl
2. SOCl2
74 66
Oxazolines are versatile functional groups. It is entirely possible for one ortho-director to
direct the introduction of a new group that is then an ortho-director in its own right. This leads to
all sorts of interesting possibilities and is discussed in Several Lithiations.
Regioselectivity II—ortho versus ortho
O
N
What happens when there is more than one directing group on the same ring? There are of course
two fundamental possibilities – either they compete or they work together. There are three basic substitution
patterns because the second directing group can either be ortho, meta or para to the fi rst.
X
Y
X and Y ortho X and Y meta
1. BuLi
2. 73
There are two ‘ortho’ positions in the fi rst case, three in the second, and four in the third. We
notice, of course, that although all four sites in the para case can react, there are only two different
sorts of proton due to the plane of symmetry. The para substitution pattern is the example we look
at fi rst. Oxazoline 75 has two para related ortho-directors and two possible sites for lithiation on
the ring. We can clearly see from the result that the oxazoline ring was the more potent director
because the product 76 has the new methyl group ortho to it rather than ortho to the methoxy
group.
MeO
75
O
N
X
Y
1. BuLi
2. MeI
In general, if one of the directing groups is much more potent than the other, we would expect
that directing group to direct lithiation ortho to itself. And that is indeed what we see although the
situation is, in fact, more complicated than this because in some cases we can choose which group
we would like to lithiate next to. This issue is discussed later. Direct comparison between an amide
and other ortho-directing groups in compounds such as 77 to 80 reveal that only a carbamate is
a more powerful director than an amide while oxazoline, sulfonamide and benzylamine etc. are
less powerful. 11,15
X
Y
X and Y para
MeO
76
O
Me
O
71
N
N
R
X and Y
are orthodirecting
groups

Et2N
O
O
In the same way, direct comparison with other groups 15 shows that the simple methoxy director
is less powerful than a sulfonamide 81 or a benzylic amine 82, but more powerful than F, CF 3,
NR 2, or (CH 2) 2NR 2.
Multiple Directed Lithiations
O
NEt2
N
O
O
NEt 2
Et2N S
O O
Let’s consider how we might make compound 85. For a start three of the four groups on the
aromatic core are good ortho-directors. We have just seen that an amide is a more powerful
directing group than a methoxy group so we can safely disconnect the methyl group 85a in the
knowledge that the lithiation of 86 will go where we want it to. The synthesis is really very easy.
The reaction of 86 with sec-BuLi and TMEDA followed by methyl iodide yields the compound
we want.
Further, a carbamate – the most potent ortho-director of the three – sits in between the other
two. This can be used. We will come back and look at this compound again in the next section and
disconnect it further but apply another concept to its analysis – that of multiple ortho-lithiation.
For now we restrict ourselves to the one disconnection.
The amide 87 contains two ortho-directing groups—the amide and the fl uoride. The methyl
group could be introduced by reacting a lithium derivative with methyl iodide. However, this is
where we run into trouble because the lithium atom will not be introduced where we want it to
be. Since both fl uoride and the amide are ortho-directors and since they are meta substituted
then they can cooperate with one another. This was illustrated with a reaction done with
benzaldehyde.
O
NEt 2
Et2N
77 78
79 80
OMe
OMe
OMe
Et2N S
Et2N F
F3C
O O
81 82 83 84
MeO
Me
O
O
O
NEt 2
NEt 2
7 Multiple Directed Lithiations 101
MeO
Me
O
O
O
85 85a
NEt 2
NEt 2
C–C
MeI +
MeO
O
86
O
O
NEt 2
NEt2
OMe
O
NEt 2

102 7 The Ortho Strategy for Aromatic Compounds
Me
F
87
O
NEt 2
C–C
We could, of course, use a protecting group to block the position between the two ortho- directors.
There is now just one thing to consider – which of the two remaining ortho positions with be
lithiated. The amide is a better director than the fl uoride so there is no problem – the lithiation goes
the way we want it to. 16 The protecting group that we use is trimethylsilyl. The lithiation is then
achieved using sec-BuLi and TMEDA and the lithium derivative reacted with MeI. Deprotection
of the silyl group is done using a source of fl uoride which is CsF in this case.
H
F
88
O
NEt 2
The fact that the two groups cooperate with one another needs to be emphasised. From our experience
of chemistry we might expect a proton between two other groups to be more diffi cult to get at.
This is not true with ortho-lithiation and with a meta substitution pattern you can expect cooperation.
Quinolines such as 92 have been widely used in the synthesis of alkaloids. We might imagine
that almost any position in 92 could be lithiated, but the position between the two MeO groups is
preferred. When the electrophile is Me 2CCH.CH 2Br the product is 94, and when it is R 2N.CHO
the aldehyde 93 is produced. Each of these compounds was developed into γ-fagarine, from 94
starting with ozonolysis, 17 and from 93 by a Wittig reaction. 18
OMe
OMe
N
92
Choice in ortho-lithiation
In some cases we can choose which group we would like to lithiate next to. This choice arises
from the two mechanisms that directing groups use and is one of the more subtle aspects of
directed lithiation. Perhaps the best evidence for these different mechanisms is the change in
regioselectivity with competing directing groups when the reaction conditions are changed.
Reactions of Fluoroanisoles
MeI +
H
F
Fluoroanisoles 95 and 97 each have two different sites that could be lithiated. 19 In each case, the
site next to oxygen can be lithiated if a coordination mechanism is operative and the site next
to fl uorine can be lithiated if an acid-base mechanism is operative. If ortho-fl uoroanisole 97 is
O
NEt2
1. s-BuLi
TMEDA
2. PhCHO
F OH
88 89
H
O
NEt2
Protect
H O
Me O
Deprotect
1. BuLi
1. s-BuLi
NEt2 TMEDA
NEt2 CsF
2. Me3SiCl 2. MeI
DMF
SiMe3 SiMe3 1. BuLi
2. E
OMe N
OMe
93
F
F
90 91
OMe
CHO
OMe
or
OMe
OMe
N
94
OMe
Ph
88

eacted with BuLi followed by solid CO 2, the product is exclusively the carboxylic acid 98.
However, if it is reacted with a mixture of BuLi and potassium tert-butoxide followed by solid
CO 2 then the product is – again exclusively – the regioisomer 96.
OMe
The situation is, however, even more subtle than this. Not only is it possible to exploit the
difference between an acid-base mechanism and a coordination mechanism, it is also possible to
choose between one coordinating director and another coordinating director. 20 This is the case
with 100. Both the nitrogen and oxygen atoms have the potential to coordinate to lithium. In
a ‘superbasic’ mixture BuLi and KOBu t , the lithiation proceeds next to the most electronegative
atom – oxygen 99. The reagent is not bothered about coordination but just plucks off the most
acidic proton – the one next to the most electronegative atom. When BuLi is used on its own, the
lithiation proceeds next to the nitrogen atom 101. Nitrogen coordinates lithium better than oxygen
and so in this case the reaction goes via a coordination mechanism. 20
MeO 2C
MeO
99
Several lithiations
OMe
F
2. CO2 F CO2H 3. H
95 96
97
H
N Ot-Bu
O
1. t-BuLi,
t-BuOK
2. CO2
3. HCl
MeO
4. CH2N2
1. BuLi,
t-BuOK
One powerful aspect of ortho-lithiation strategy is the ability to do more than one lithiation on the
same ring. Exactly how this is done varies. One might imagine a situation where – i) The new
group introduced by ortho-lithiation to give 103 can itself direct a further ortho-lithiation. ii)
There could be two directing groups on the ring in the fi rst place 105 and they may be able to
direct two lithiations to make a dilithiated ring. And iii) the lithium derivative reacts intramolecularly
with its own directing group to yield a product 108 with a different directing group
and new functionality at the position of the original directing group (W). If the last example
sounds a bit complicated, all will become clear with examples of the three types. 15
Case (i): R 1 and R 2 are directing groups
OR 1 OR 1
102
1. BuLi
2. R 2 X
R2 1. BuLi
2. E
OR 1
103 104
Case (iii): R 1 and R 2 are directing groups
7 Several lithiations 103
100
R 2
E
OR 1
OMe
F
H
N Ot-Bu
O
RO
BuLi
W
1. BuLi
2. CO2
3. H
1. t-BuLi,
2. CO2
3. HCl
4. CH2N2
OR
R 2
2. E
MeO
Case (i): R is a directing group
1. BuLi
2. E
E
RO
105 106
1. BuLi
CO 2H
W
98
107 108 109
OMe
F
H
N Ot-Bu
O
CO2Me
101
OR
E
R 2
E

104 7 The Ortho Strategy for Aromatic Compounds
Case (i) One ortho-director leads to another
The carbamate 110 reacts with sec-butyl lithium followed by Et 2NCOCl to yield the new amide
86. This reacts with sec-butyl lithium and methyl iodide to give the tetra-substituted aromatic
compound 21 85.
OMe
O NEt 2
110
O
1. s-BuLi
2. ClCONEt2
OMe
O
86
OCONEt 2
The tetrasubstituted benzene 112 was synthesised by multiple ortho-lithiations. Three of the
four groups are ortho-directors themselves. The question of which group to disconnect fi rst is not
simplifi ed in this case by the knowledge that the group must be introduced by an adjacent orthodirector
because all the groups are adjacent to at least one other. Let’s consider disconnection
a. The forwards reaction from 111 would not lead to a problem of regioselectivity because the
two ortho-directors direct lithiation to this site. The problem is which ortho-directing do we
disconnect next? We do not have two adjacent directing groups so we cannot use one to introduce
the other. This forces us to adopt an alternative strategy sometimes referred to as a ‘walk around
the ring’.
SiMe3 OCONEt2 CONEt2 111
We start b at one end of the three ortho-directors and disconnect them successively. After
two disconnections we are left with the carbamate 114. The silyl group will be introduced by
ortho-lithiation too. The introduction of the silyl group stops the sequence of ortho-lithiations
proceeding in an anti-clockwise manner and hence prevents any competition that might otherwise
arise after the between the carbamate and the amide in subsequent ortho-lithiations.
c
SiMe 3
OCONEt 2
114c
The three lithiation reactions use sec-BuLi and TMEDA. Trimethylsilyl chloride is the fi rst
electrophile and diethyl carbamoyl chloride is used twice to give our target material 112.
NEt 2
1. s-BuLi
2. MeI
OMe
Me O
85
OCONEt 2
NEt 2
SiMe3 SiMe3 SiMe3 a OCONEt2 b
OCONEt2 a
OCONEt2 a
a
CONEt2 CONEt2 b
CONEt2 112 113 114
c
OCONEt 2
SiMe3
OCONEt 2
CONEt 2
OCONEt 2
CONEt 2
CONEt2
CONEt2
115 112; no competition competition

115
ii) Dilithiations
OCONEt 2
1. s-BuLi
TMEDA
2. Me3SiCl SiMe3 OCONEt2 True dilithiated species generated by ortho-lithiation in which there are two lithium atoms on the
same ring are very rare (with dilithiated species formed by halogen/lithium exchange being more
common). It is not a surprise that in those examples where dilithiated species do exist 22 the lithium
atoms are usually para to one another 117.
Et2N
O
O
O
O
NEt 2
Putting two lithium atoms closer together is more diffi cult and while the 2,6-dilithium derivative
118 can be made, it cannot be made by double ortho-lithiation of 67; R Et. Instead it must be
made from dibromide 119 and tert-BuLi.
H
116
CONEt 2
H
BuLi
Li
iii) One ortho-director rearranges into another – the anionic Fries reaction
114
1. 2 x s-BuLi
TMEDA
2. Me3SiCl
CONEt 2
1. s-BuLi, TMEDA
2. ClCONEt2
3. s-BuLi, TMEDA
4. ClCONEt2 SiMe3 OCONEt2 CONEt2 112
CONEt 2
Et2N O
SiMe3 O
O
Me3Si O NEt2 117; 67% yield
We have come across the Fries rearrangement previously in this chapter before lithium had even
made its entrance. A similar rearrangement can occur in the realm of ortho-lithiated species and
is sometimes call the anionic Fries rearrangement. Compare the two.
The Fries
Rearrangement
The Anionic Fries
Rearrangement
7 Several lithiations 105
Li
t-BuLi
67; R = Et 118 119
O R
O
O NMe2
Lewis acid
s-BuLi
OH
O
R
Br
R
O NMe2
O
CONEt 2
O
TMEDA
Li
O
O
NMe2
120 121 122
+
Br
OH
OH

106 7 The Ortho Strategy for Aromatic Compounds
The carbamate 120 is lithiated with sec–butyl lithium to form the intermediate 121 that reacts
further to form the amide 122. From the ortho-lithiation point of view we now have a different
ortho-director in the molecule and, if we protect the phenol group, we can continue lithiation
around the ring. This chemistry was used in the synthesis of the diene 124 needed for the antitumour
compound pancratistatin 23 123.
Disconnection of 124 across the double bond closest to the ring reveals the aldehyde 125. This
aldehyde can be introduced by the action of an ortho–lithium species (as the dialkylamide in 126
is a good ortho-director) on a formylating reagent.
O
O
OH O
O
O
H
NH
H
OH O
OH
CHO
NEt 2
The amide is a good ortho–director but so is the acetal function. The regioselectivity ( actually
there is the issue of chemoselectivity here too) of the lithiation reaction will depend upon which
of the two is the more potent. Amides were one of our ‘three kings’ of the ortho-directors and are
more powerful than acetals. Now it is time for an anionic Fries rearrangement (in the retrosynthetic
direction) to give the starting material 127.
We ortho-lithiate 127 using sec-BuLi and TMEDA. The lithiation goes where we want it –
ortho to the carbamate rather than ortho to the acetal. The lithiated intermediate is then allowed
to warm up – we will come back to this in a moment – to yield phenol 126. This is reacted with
TBDMSCl and imidazole to give the protected phenol 128. Once again, the acetal loses out and
the amide does the directing during the second lithiation. Formylation is achieved using DMF.
127
O
O
activated
by acetal
1. s-BuLi
TMEDA
2. warm to room
temperature
123 HO OH
pancratistatin
OH
OH O
NEt 2
O
O
O
O
OH O
124
OH O
125 126
O
OH O
NEt2
anionic
Fries
NEt 2
NEt2
activated
by amide
O
O
126 126a 127
126
t-BuMe 2SiCl
(TBDMSCl)
imidazole
O
O
OTBDMS
128
CONEt 2
1. s-BuLi
TMEDA
2. DMF
O
O
O
OCONEt 2
OTBDMS
129
CONEt2
CHO

The aldehyde 129 is attacked using allyl Grignard. The alcohol 130 is converted to the mesylate
and then an elimination reaction using DBU as the base gives diene 131. The protecting silyl group
can easily be removed to give 124 but in fact it was retained for protection during the rest of the
synthesis.
129
It is important to recognise the element of choice that exists in the anionic Fries rearrangement.
After the initial lithiation of 127 we can either let it warm up and do the rearrangement or, if we
are careful, we can keep it cold so that the rearrangement does not take place and we can introduce
another electrophile to react with the intermediate lithiated compound instead. 11
Halogens
BrMg
Fluorine as an ortho-director
O
O
Fluorine is a good ortho-director. 24 It directs the lithiation of fl uorobiphenyl without the assistance
of another directing group and does so very effi ciently.
Fluorine as a leaving group
OTBDMS
CONEt 2
OH
130 131
CONEt 2
Fluorine can also function as a leaving group from aromatic rings. 25 The C!F bond is very strong
and it would be misleading to describe fl uorine as a good leaving group (even though many of
the reactions in which it leaves are good). Nucleophiles attack because the ipso carbon is made
electrophilic by the strongly electronegative fl uorine. In compound 134 there are four fl uorine atoms
on the benzene ring: one is displaced by nucleophiles to yield the quinolone antibiotic 25 135.
F
F
F
F
O
N
134
132
CO 2H
7 Halogens 107
1. MsCl, Et 3N
The electron-withdrawing group on the aromatic ring is essential. Since direct S N2 displacement
reactions on sp 2 centres do not occur, the electron-withdrawing group gives the electrons somewhere
2. DBU
F F
1.
Me
1. s-BuLi, TMEDA
2. CO 2
N
NH
2. NaOMe, MeOH
Me
N
O
O
133; 79% yield
F
N
F
F
135
OTBDMS
CO2H
O
N
CO 2H

108 7 The Ortho Strategy for Aromatic Compounds
to go in the intermediate before expulsion of fl uoride. The same process occurs when a nucleophile
reacts with an acid chloride.
Nu
F
F
F
F
O
N
CO 2H
Fluoride as ortho-director and leaving group
F
F
Nu
F
F
A method developed by Bridges 24 enables the synthesis of the benzothiophene 139 and other
similar derivatives using a combination of fl uorine as both an ortho-director and a leaving group.
Disconnection of the acetal will not get us very far but the double bonds of the thiophene ring also
forms part of an α,β-unsaturated ester. A simple aldol disconnection here gives us aldehyde 140.
The next disconnection relies on our knowledge that fl uorine can behave as a leaving group from
aromatic rings. The aldehyde is the necessary electron withdrawing group. We now 141 have three
substituents round the ring. The acetal, although a poor ortho-director in its own right, will assist
the fl uorine in a lithiation. We can remove the formyl group with an ortho-lithiation in mind.
O
O
The acetal 142 is lithiated with sec-BuLi and TMEDA and formylated with DMF to give,
after workup, the aldehyde 141. The next couple of reactions happen in one pot under the same
set of reaction conditions. The thiol is reacted with NaH and the anion added to a solution of the
aldehyde 141. After workup the product is the target material. 24
O
S
136
CO 2Me
ratedetermiming
step
aldol
O
O
CHO
139 140
O
142
F
1. s-BuLi
TMEDA
2. DMF
3. H
O
O
The next three sections – Benzyne Formation, α-Lithiations and Lateral Lithiations – are just a
brief look at some of the other lithiation reactions that are available to the synthetic organic chemist.
They are also words of warning. They show what other reactions can take place in the frame of
lithiation of aromatic substrates and are intended to prime you for potential traps.
O
N
S CO2Me
CO 2H
fast
F
Nu
137 138
nucleophilic
aromatic
substitution
O
O
F
F
CHO
O
N
O
F
141 142
CHO
HS CO2Me
NaH
CO2Me F
S
141; 91% yield 139; 56% yield
O
O
CO 2H
O
F

Benzyne Formation—A different aromatic strategy
Benzynes are readily formed when we have a leaving group ortho to a lithium atom. Thus when
ortho-bromofl uorobenzene 143 is reacted with butyl lithium, the intermediate formed is ortholithiofl
uorobenzene 144. Lithium fl uoride can eliminate from this to yield benzyne 145. Benzynes
are reactive species and do not hang about. Here, ortho-bromofl uorobenzene is treated with butyl
lithium in the presence of furan. When the benzyne forms it rapidly reacts with furan in a cycloaddition
reaction to form the adduct 146 in a 68% yield.
Br
BuLi, Et2O Li
F
–30 to –25 °C
F
O O
143 144 145; benzyne 146
Note the ortho relationship between the lithium and fl uorine atoms on the benzene ring. We
have previously seen lithium next to the fl uorine without benzyne formation and yet here the very
same species forms benzyne! The crucial difference between the two cases is temperature. The
ortho-fl uoro-aryllithium is stable at 78 C and the benzyne does not form until the temperature
reaches 40 C to 50 C. Aromatic rings with lithium adjacent to other halogens (such as
bromine) are less stable and form benzynes at lower temperatures.
An ortho relationship between a trifl ate and a silyl group is another way to generate benzynes. 26
The benzyne 149 is formed when the silyl group is removed 11,27 using the fl uoride ion 148.
OCONEt2
147
α-Lithiation
SiMe 3
OH
1. Tf 2O
OCONEt2
148
SiMe 3
OTf
F
OCONEt2
OCONEt2
An α-lithiation reaction is characterised by a lithiation occurring at an sp 2 centre and α to a
heteroatom 28 152. Lithiation of furan with BuLi and reaction with benzaldehyde gives alcohol 154
in 98% yield.
We might expect that the sulfonamide group in 155 would direct lithiation of the thiophene ring
to its adjacent site in an ‘ortho’-lithiation. It doesn’t. An α-lithiation to give 156 occurs instead.
2. CsF
H
X
BuLi Li
X O
BuLi
–20 °C to room
temperature
O
Li
PhCHO
–20 °C
O
Ph
OH
151 152 furan 153 154; 98% yield
S S NEt 2
O O
1. BuLi
0 °C
Li
7 α-Lithiation 109
furan
S S NEt 2
O O
2. CO2
–78 °C
149
HO2C
150
O
S S NEt 2
O O
155 156 157; 82% yield

110 7 The Ortho Strategy for Aromatic Compounds
One last word of warning with regard to α-lithiations. The benzofuran 158 has a methoxy
group on the benzene ring and we might expect this to direct an ortho-lithiation. It would be easy
to overlook the α-lithiation of the furan ring: this, in fact, happens instead.
MeO
155
Lateral Lithiation
A lateral lithiation occurs at a benzylic position 29 (161 reacting to 162) rather than on the benzene ring
itself. These reactions are quite common so we must discuss them briefl y here as the same functional
groups that behave as ortho-directors are also lateral lithiation directors as in the case of the amide
161 below. The lithiated species can be represented as a lithium enolate 163 or even with chelation
164. This is not possible with an ortho-lithiation where the ‘charge’ is localised in a C-Li σ-bond.
O
Chemoselectivity
O
1. BuLi
MeO
156
O
O
Lateral lithiations do not necessarily need an adjacent (ortho) director. So LDA will happily deprotonate
the para methyl group of the amide 166 in THF at 0 C. Once again the ‘charge’ can delocalise
into the electron withdrawing group. But reaction with a much stronger base at low temperature, sec-
BuLi at 78 C, gives the ortho-lithiation 165 we have come to expect. The lateral lithiation gives
the thermodynamically more stable lithiated product whereas the ortho-product 165 is the kinetic
product as complexation of the alkyl lithium reagent with the amide accelerates the lithiation. 30
Me
Here is an example 168 of a reaction in which both benzyne formation and lateral lithiation are
involved. What’s going on here? Try to work out the mechanism before reading the explanation. You
have the clues you need – the reaction involves the formation of a benzyne and a lateral lithiation. 31
MeO
Li
2.
O
MeO
O
157; 62% yield
NEt2 LDA
NEt2
Li
NEt2 Me
161 162 163 164
O
NEt 2
s-BuLi NEt 2
Li
TMEDA,
–78 °C Me
H
THF, 0 °C Li
165 166
167
OMe
O
O
1. 3 x
LiTMP
2. 171
3. [O]
MeO
OMe
O
O
O
OMe
Me
OMe
168 169; 66% yield 170
LiTMP
171
LDA
OLi
N
Li
Br
NEt 2
O
Li
O
H
OMe
OH
NEt 2
Me
OMe

The lactone 168 is lithiated at the benzylic site by lithium tetramethyl piperidide (LiTMP)
167 to give 172. Notice that this ‘charge’ can delocalise into the carbonyl group and that ortholithiation
between the two methoxy groups does not occur. One of the reactive species then is 172.
The aromatic bromide 171 is lithiated ortho to the bromide 174, eliminates lithium bromide, and
generates a benzyne 173. These two species then combine.
The benzyne 173 is attacked regioselectively. By attacking meta to the methoxy group, the
lithium atom ends up ortho to the methoxy group (175). The C-Li bond can then attack the lactone
and spring it open to give 176. We are now very close, and a little oxidation will take 176 to the
anthraquinone 31 169.
Summary
In this chapter we have introduced many powerful reactions. We have seen that—
•
•
•
•
168
LiTMP
MeO
MeO
OMe
172
MeO
Ortho-lithiation turns aromatic compounds into much more powerful nucleophiles.
The range of groups that direct lithiation is extensive though some are better than others.
More than one ortho-director can lead to competition or cooperation. In some cases there is
a choice over the ortho-lithiation site.
We have also seen that ortho-lithiation can be used in conjunction with other reactions – such
as fl uoride displacement or an anionic Fries rearrangement – that make ortho-lithiation a
particularly versatile strategy.
Summary of Reagents
7 Summary of Reagents 111
O
O
Li
O
OMe
OMe
BuLi BuLi is often suffi ciently reactive to bring about an ortho-lithiation on its own. It
coordinates to electronegative groups before it deprotonates in the ortho position.
With tert-BuOK it forms a ‘super’ base. However, halogens will often undergo
halogen/lithium exchange with BuLi. A nitrogen base (like LDA) is more appropriate
in such cases.
sec-BuLi sec-BuLi is a stronger base than BuLi. It is often used in conjunction with TMEDA
to ortho-lithiate.
LDA LDA prefers to deprotonate rather than react with a halogen. When an aromatic
bromide reacts with BuLi a by-product is BuBr (a carbon – bromine bond). If LDA
Me
OMe
Br
Li
OMe
173 174
Li
Me
Me
[O]
172 + 173 O
169
OMe
MeO
OMe
OH
175 176
O
Me
OMe
OMe
LiTMP
OMe
171

112 7 The Ortho Strategy for Aromatic Compounds
were to lithiate an aromatic bromide the by-product would contain a week nitrogen –
bromine bond and so the reaction does not occur.
LTMP Lithium tetramethylpiperidide is a stronger, more hindered, and more expensive
version of LDA.
• Notice that ortho-lithiations frequently use BuLi or sec-BuLi but that the lateral lithiations
frequently use lithium amide bases like LDA and LiTMP instead. This is not insignifi cant.
References
General references are given on page 893
1. P. H. Gore in Friedel-Crafts and Related Reactions, Interscience, New York, 1964, Vol III, Part I, page 1.
2. F. Arndt and G. Källner, Chem. Ber., 1924, 57, 202; J. D. Loudon and R. K. Razdan, J. Chem. Soc.,
1954, 4299.
3. A. H. Blatt, Chem. Rev., 1940, 27, 413; Org. React., 1942, 1, 342.
4. K. W. Rosenmund and W. Schnurr, Liebig’s Ann., 1928, 460, 56.
5. R. Baltzly, W. S. Ide and A. P. Phillips, J. Am. Chem. Soc., 1955, 77, 2523.
6. P. R. Vijayasarathy, R. B. Mane and G. S. Krishna Rao, J. Chem. Soc., Perkin Trans. 1, 1977, 34.
7. T. Y. R. Tsai, K. P. Nambiar, D. Krikorjan, M. Botta, R. Martini-Bettolo and K. Wiesner, Can. J. Chem.,
1979, 57, 2124; K. Wiesner, Pure Appl. Chem., 1979, 51, 689.
8. R. E. Dean, A. Midgley, E. N. White and D. McNiel, J. Chem. Soc., 1961, 2773.
9. S. J. Rhoads and N. R. Raulins, Org. React., 1975, 22, 1.
10. A. T. Shulgin and A. W. Baker, J. Org. Chem., 1963, 28, 2468.
11. V. Snieckus, Chem. Rev., 1990, 90, 879.
12. Disconnection Approach, p.21; but see Chapter 33 below.
13. A. Padwa and H. Ku, J. Am. Chem. Soc., 1978, 100, 2181.
14. H. Reuman and A. I. Meyers, Tetrahedron, 1985, 41, 837: see page 853 in particular.
15. Clayden, Lithium, pages 28–72 and 90–96.
16. R. J. Mills, N. J. Taylor and V. Snieckus, J. Org. Chem., 1989, 54, 4372,
17. N. S. Narasimhan and R. S. Mali, Tetrahedron, 1974, 30, 4153.
18. J. F. Collins, G. A. Gray, M. F. Grundon, D. M. Harrison and C. G. Spyropoulos, J. Chem. Soc., Perkin
Trans. 1, 1973, 94.
19. G. Katsoulos, S. Takagishi and M. Schlosser, Synlett, 1991, 731; M. Schlosser, F. Faigl, L. Franzini,
H. Geneste, G. Katsoulos and G-F. Zhong, Pure Appl. Chem., 1994, 66, 1439.
20. R. Maggi and M. Schlosser, J. Org. Chem., 1996, 61, 5430.
21. P. Beak, A. Tse, J. Hawkins, C.-W. Chen and S. Mills, Tetrahedron, 1983, 39, 1983; Ref 11, page 895,
table 12, entry 33.
22. R. J. Mills, R. F. Horvath, M. P. Sibi and V. Snieckus, Tetrahedron Lett., 1985, 24, 1145.
23. S. Danishefsky and J. Y. Lee, J. Am. Chem. Soc., 1989, 111, 4829.
24. A. J. Bridges, A. Lee, E. C. Maduakor and C. E. Schwartz, Tetrahedron Lett., 1992, 33, 7495; 7499.
25. T. Miyamoto, J. Matsumoto, K. Chiba, H. Egawa, K. Shibamori, A. Minamida, Y. Nishimura, H. Okada,
M. Kataoka, M. Fujita, T. Hirose and J. Nakano, J. Med. Chem., 1990, 33, 1645.
26. Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983, 1211.
27. K. Shankaran and V. Snieckus, Tetrahedron Lett., 1984, 25, 2827.
28. H. W. Gschwend and H. R. Rodriguez, Org. React., 1979, 26, 1.
29. R. D. Clark and A. Jahangir, Org. React., 1995, 47, 1; Clayden, Lithium, pp 73–83.
30. P. Beak and R. A. Brown, J. Org. Chem., 1982, 47, 34.
31. C. A. Townsend, S. G. Davis, S. B. Christensen, J. C. Link and C. P. Lewis, J. Am. Chem. Soc., 1981,
103, 6885.

8
σ-Complexes of Metals
Introduction The structure of organo-lithium compounds
Lithium and Magnesium Complexes
Making organo-metallic σ-complexes by oxidative insertion
Structures of organo-lithium and magnesium reagents
Reactions of organo-lithium and organo-magnesium reagents
Chiral Grignard reagents
Acylation at carbon with Grignard and organo-lithium reagents
Transition Metal Complexes
Acylation with acid chlorides
Hydrometallation
Carbonylation of organometallic complexes
Palladium σ-complexes
Recent results with Cu(I) and Pd σ-complexes
Introduction The structure of organo-lithium compounds
Every reader of this book is familiar with Grignard reagents, the fi rst useful organometallic compounds,
and with lithium derivatives of organic compounds as we have already discussed these
at some length in the fi rst seven chapters. We must now widen our discussion to include all compounds
with a direct metal–carbon bond and we shall call these σ-complexes in contrast to the
more common η and π complexes that we shall meet in later chapters. A saturated carbon atom has
no lone pair electrons or accessible empty orbitals and we can treat the metal–carbon σ-bond like
the boron-carbon or silicon-carbon bond without discussing back-bonding or invoking d-orbitals.
We should still recognise that the apparently simple compound MeLi actually exists as trimers and
tetramers 1 such as 1. In this chapter we shall be concerned with the synthesis of σ-complexes of
metals such as Li, Mg, Cu, and Zr. We shall see how far simple-minded organic mechanistic ideas
can be extended to these undoubtedly more complex structures, and that we need not in general
worry about their polymeric nature as they often react in solution as monomers 2 1b.
Li
Li
Li
Li
1a
Li atoms in MeLi
add Me group to
centre of each triangle
Me
Me
Li
Li
Li
Me
Me
Li
1; MeLi
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd
OR2
Me Li
OR2 OR2 1b; MeLi
in solution

114 8 σ-Complexes of Metals
We have just been considering the formation of aryl-lithiums by deprotonation with the more
basic alkyl-lithiums, normally BuLi, and you are also aware that protons may be removed from
many molecules to give lithium derivatives. We shall not discuss this further in this chapter, but
concentrate instead on three other approaches, oxidative addition (insertion), transmetallation,
and hydrometallation.
Making organo-metallic σ-complexes by oxidative insertion
You are familiar with the normal method of making a Grignard reagent: an alkyl halide 2 reacts
with magnesium metal in ether solution to give something we normally write as RMgBr, but
which certainly contains a tetrahedral Mg atom, the remaining sites being occupied by ether
molecules 4a. This is at least one of the species present in such solutions. In making these new
bonds, magnesium has accepted electrons from the ether ligands. In a simple organic structure
formed like this we should put charges on the atoms 4c, or draw the bonds as arrows 4b. Structure
4c is most unattractive for a metal complex as the metal ends up with a double negative charge.
The best compromise is just to draw all bonds as lines 4d and leave out the charges.
R Br R Br R Br R Br
R Br
Mg(0)
R
Mg
Br Mg
Et2O OEt2 Mg
Et2O OEt2 Mg
Et2O OEt2 Mg
Et2O OEt2 2 3 4a 4b 4c 4d
We shall call this reaction oxidative insertion (or oxidative addition) because the metal atom
inserts itself between the carbon and halogen atoms and simultaneously undergoes oxidation from
Mg(0) to Mg(II). If you are unhappy at assigning an oxidation state to a metal in a complex, then
the quickest way is to remove the ligands from the metal. First remove all the real molecules (two
of Et 2O in this case) as you can obviously do this without changing the oxidation state of the metal.
Then remove the remaining ligands as anions 3a (two in this case), leaving the same number of
positive charges on the electropositive metal. The number of charges gives the oxidation state of
the metal. We therefore describe 4 as a sigma complex of a carbanion with Mg(II).
R Br
Mg
remove molecular
ligands
Et2O OEt2 [2 x Et2O]
4d 3
R Br remove remaining R
Mg
ligands
Mg
as anions
In detail, the oxidative insertion probably begins with an interaction between the electron-rich
halogen atom and the electron-poor metal 5. Back-bonding from the metal also builds up in the
intermediate 6, weakening the carbon-halogen bond. The electrons of the C-Br bond then abandon
the halogen atom and form a bond to the metal 6c. The carbon atom has undergone electrophilic
substitution, while the metal has made two new bonds, using an empty orbital for one and a lone
pair for the other. You may object that if the metal has been oxidised, then something must have
been reduced, and this is the carbon atom which is like R in RBr and is now like R – in the complex.
Words like might, probably, and could are used a lot in this area and question marks litter
both the structures of the intermediates and the reaction pathways. We should still take pride in
attempting to understand these reactions even if the details of the mechanisms are uncertain.
3a
Br

R Br
5
8 Introduction The structure of organo-lithium compounds 115
Mg
R Br
Mg
(–)
R Br
(+)
Mg
6a? 6b?
R Br R
Mg
Mg
Br
7?
3
Magnesium probably undergoes oxidative insertion more easily than the other metals we use,
but lithium, used as wire, hammered-out sheets, or even slices 3 inserts quite easily into alkyl or
aryl halides, particularly in THF solution. 4 A one-electron donor like lithium probably follows a
similar pathway to Mg but with single electron arrows. Palladium forms aryl Pd(II) derivatives
in the same way, 5 but the Pd must be added as a soluble complex like Pd(Ph 3P) 4. Other transition
metals are much less successful.
Structures of organo-lithium and magnesium reagents
We may describe these species as σ-complexes of carbanions with metals but they are not
carbanions. As normally prepared from alkyl halides and Mg(0) or Li(0) in ether solvents (Et 2O
or THF), they are soluble in organic solvents as tetrahedral complexes and are not salts. Chemists
are happy to draw the monomeric species RLi or RMgX and it is likely these are the reactive
entities in many reactions.
Reactions of organo-lithium and organo-magnesium reagents
?
R Br
Mg
Grignard reagents and alkyl-lithiums, organometallic reagents of very electropositive metals
with a strong affi nity for oxygen, are useful reagents, as you are aware. They are very reactive,
basic nucleophiles, combining well with hard electrophiles such as carbonyl compounds, but less
successfully with softer electrophiles such as alkyl halides. A brief exploration of these reactions
will make it clear why other organometallic σ-complexes are needed. When Cram 6 was studying
the stereochemistry of addition to chiral aldehydes, he compared the behaviour of i-propyl
Grignard (i-PrMgBr) with i-PrLi in nucleophilic attack on the aldehyde 8. He was interested in
the diastereomer ratio in the product 9, but we can note the almost identical yields from the two
reagents.
OH
CHO
1. Mg, Et2O Br 2. 8
Ph
Ph
8 84% yield
9
Additions of either RLi and RMgBr to most aldehydes and ketones give good yields, and
there are many examples known. 7,8 The only problems likely to arise are enolisation by RLi or
reduction by RMgX. The latter is more serious, especially with branched Grignard reagents
10. It appears erratically 8 - the very unreactive ketone Ph 2CO gives 9 mostly addition 13 with
t-BuMgCl, but only reduction 11 with iso-butyl Grignard 12, quite the reverse of what we might
expect.
6c?
1. Li ribbon
pentane
2. 8
88% yield
Br

116 8 σ-Complexes of Metals
BrMg
OH
Ph Ph
RCHO
H
H H
Mg
Br O R Br Mg O R
ClMg
10
+
O BrMg
+
Ph Ph
H H
+
HO R
11; 91% yield 12 13; 63% yield
Reaction with epoxides are generally excellent with RLi, but deprotonation leading to
rearrangement can be a problem. 10 Grignard reagents react well with ethylene oxide itself, but with
other epoxides rearrangement can occur because of the Lewis acid effects of Mg(II). Cyclohexene
oxide 14 reacts as expected with RLi to give 15, but can give the surprising product 16 with Grignard
reagents, by rearrangement to the aldehyde 17 before addition. A famous example is Robinson’s
reported synthesis of 15; R PhCH 2CH 2- in 92% yield, later corrected to 16; R PhCH 2CH 2-,
and hence useless for the synthesis of steroids. 11
O
R
Reaction with alkyl halides is generally thwarted by the rapid exchange of Mg or Li between
the two species. This can be used to advantage if the new organo-lithium reagent is more stable
than the old, as in the synthesis of aryl-lithiums from aryl halides and BuLi. Direct lithiation
by replacement of hydrogen generally occurs in positions ortho to heteroatoms (chapter 7) but
a halogen, as in the bromo-pyrimidine 20 directs the lithium atom to that same site giving 21.
Addition to the unreactive dichloro-diarylketone 22 gives the fungicide fenarimol 12 23.
Br
N
N
14
14
O
BuLi
Many alkynyl, alkenyl, aryl, and functionalised alkyl-lithiums behave well in alkylation
reactions because they are more stable anions than those derived from the simple unfunctionalised
alkyl halides with which they are to react. Examples are 24, 25, and 26 and these will be treated
in later chapters with the reactions of Grignard reagents with allyl halides.
H
H2O
OH
OH
RLi RMgBr
RMgBr
or MgBr 2
Li
20 21
N
N
15
O MgR
Ph
Ph
R
16 17
O MgBr
18 19
O
HO
OH
CHO
Cl Cl Cl Cl
22 23
21
N
N

Chiral Grignard reagents
It has long been supposed that enantiomerically pure Grignard reagents cannot be made. Certainly
13 ‘enantiomerically pure Grignard reagents…are not accessible from enantiomerically pure
secondary alkyl halides by reaction with magnesium metal since electron transfer processes and
the intervention of radicals annihilates the stereochemical information.’ Hoffmann’s recent success
in this diffi cult area 13,14 also illustrates the reactions of a simple Grignard reagent, EtMgBr.
Ar S
Ar S
O
O
Ph
ClMg
The enantiomerically pure sulfoxide 27 is chlorinated with NCS (N-chlorosuccinimide) to give
the enantiomerically pure 28 easily separated from its diastereoisomer. Reaction with EtMgCl
occurs in two stages. Nucleophilic attack at the sulfoxide with inversion to give 29 expels a single
enantiomer of the chloro-Grignard 30. Still at low temperature an excess of EtMgCl displaces
chloride with inversion from 30 to give the simple secondary Grignard reagent 31. This compound
maintains its stereochemical integrity at 78 C. If the Grignard reagent 31 is prepared and
immediately reacted with an electrophile compatible with the conditions a product 33 can be
isolated in good yield and high ee showing that 31 reacts with retention.
27
5 x EtMgCl
THF
–78 to –30 °C
8 Introduction The structure of organo-lithium compounds 117
S
S Li O Li N
24 25 26
27; 99% ee
Ar = p-chlorophenyl
29; 99% yield
96% ee
MgCl
Ph
31; not isolated
stable at –78 °C
+
1. N3 2. Ac 2O
Acylation at carbon with Grignard and organo-lithium reagents
NCS
Cl
30; stable
at –78 °C
SPh
Ar S
Acylation at carbon is always a diffi cult problem because the product (usually an aldehyde or
ketone) may be more reactive than the acylating agents in two ways: more electrophilic at the
carbonyl group and more acidic because of enolisation. Nitriles often perform well in the acylation
of RLi or RMgBr, and the reaction of lithium salts of carboxylic acids with RLi is a strategy
already discussed in chapter 2. Both these methods rely on the product being released during
the work-up after all RLi is quenched. One example is the cyclopropyl ketone 34 needed by
Ph
O
Cl
28; 97% ee
EtMgCl
THF
–78 °C
Ph
ClMg
EtMgCl
THF
–78 °C
PhS N
N
NAc
32; not isolated
31; stable
at –78 °C
Ph
Li
Ph
KOH
Ph
NHAc
33; 82% yield
from 27, 92% ee

118 8 σ-Complexes of Metals
Masamune as an intermediate in his amphotericin synthesis. 15 Disconnection to the hydroxyacid
36 was particularly attractive as optically active 36 was available. Cyclopropyl-lithium 35; MLi
is actually easier to make than other s-alkyl-lithiums as the three-membered ring stabilises the
anion in the σ-complex. 16 Acylation with 36 needed three molecules of 35; R Li as two are
consumed by the acidic OHs, but the reaction is an effi cient acylation at carbon.
OH
OH
O
C–C
M
+
HO
O
Br
Li
THF
Li
36
34 35 36 37 35; M=Li
More commonly, acylating agents are based on tertiary amides because they are much less
reactive than ketones, or on lactones because they are about as reactive than ketones. This paradox
arises because tertiary amides RCONMe 2 add alkyl-lithiums but the tetrahedral intermediate does
not decompose while RLi is present. Hence 26 gives good yields of the ketones 17 39.
BuLi
N N
38 26
Li
1. RCONMe 2
2. H + , H 2O
The “Weinreb amides” 40 are particularly effi cient in acylating reactive carbon nucleophiles. 18
An alkyl-lithium adds to form the chelated lithium derivative 41 which decomposes on work-up to
give the ketone 42. Compounds 60 and 63 in chapter 5 are examples of Weinreb amides.
O
R 1 N O Me
Me
40
Lactones have similar reactivity to ketones and at low temperature one molecule of an alkyllithium
may give the ketone in good yield. In his synthesis of the pine saw fl y sex attractant 43,
Magnusson 19 chose to replace the more-or-less central methyl group by a double bond 44 so that
disconnection to a ketone 45 was possible.
Reconnection to the lactone 46 then provides a means of controlling the stereochemistry
using the Baeyer-Villiger rearrangement of the cyclohexanone 47. Acylation of the lactone 46 with
n-octyl-lithium at low temperatures gives a 70% yield of the hydroxyketone 48, which in turn
gives the pheromone 43.
N
39
R1 O
Li
O
R
N
41 42
2
Me
Me
R1 R2 R
O
2Li H
H2O
43
OAc
O
R
34

43
Me
R
FGA
Transition Metal Complexes
Acylation with acid chlorides
R
O
O
Me
O
48; 70% yield
44; R = n-octyl
Baeyer-
Villiger
OH
OAc
46 47
O
2 equivs
Ph 3P=CH 2
Wittig
R
These methods of acylation are devices to solve the problem that acid chlorides and organolithium
or magnesium derivatives are not good partners. To get good acylation with acid chlorides,
as well as good alkylation with alkyl halides, we need to turn to other metals which provide softer
carbanion complexes, less basic compounds with metals showing a lower affi nity for oxygen. The
most important is copper.
The diffi culties of direct oxidative insertion with metals other than Mg or Li mean that
σ- complexes are often made from organo-lithium or Grignard reagents by metal exchange. This
reaction amounts to a nucleophilic substitution at the metal without a change of oxidation state
so the metal is used in whatever oxidation state is fi nally needed. Attack of methyl lithium on
a Cu(I) halide gives methyl copper 50, a σ-complex of Me and Cu(I). If an excess of MeLi is
present an “ate” complex is formed, lithium dimethylcuprate 51. This is formally a compound of a
copper anion 51a, just as BF 4 is a borate. The term “ate complex” refers to such formally anionic
complex in which the metal has one extra anionic ligand. Its true structure is dimeric 51b and it
exists as an equilibrium with 52 in solution. 20
MeLi
Cu(I)Br
LiBr +
Cuprates couple effi ciently with alkyl halides, as in the simple synthesis of n-undecane 21 via the
cuprate prepared from BuLi. When a Grignard reagent is involved, a Cu(I) compound is usually
added in catalytic amounts for coupling with an alkyl halide.
BuLi
Cu(I)I
THF
8 Transition Metal Complexes 119
MeCu
50
MeLi
Bu 2CuLi
R
O
45; R = n-octyl
47
CH2Cl2 mCPBA 46
69% yield
49; 66% yield
OH
OAc
n-octyl
lithium
acylation
of RLi
Et 2O, –78 °C
1. H 2, Pd/C
100% yield
2. Ac 2O
pyridine
Me Me
Me Cu Me
Cu Li Cu Li Li Li
Me Me
Me Cu Me
51 51a
51b
n-C 7H 15-I
n-C 11H 24 = n-undecane
43
Me3Cu2Li 52

120 8 σ-Complexes of Metals
The acetoxy-aldehyde 53 has a 1,7-relationship between the functional groups and there is no
well established approach for this relationship. Disconnection to the alkyl halide 55 is appealing
as it can be made from THF in one step. It might be coupled to the Grignard reagent 54 provided
we protect the CHO group and exchange Mg for Cu.
O OAc
C–C
O MgBr
+ I
OAc
H
H
53 54 55
The coupling actually needs only 0.06 moles of Cu(I) per mole of Grignard reagent from 57
and gives the product in two simple steps. 22 Cuprates are often further complexed with Me 2S,
cyanide, or BR 3 and couple well with tosylates as well as halides. 23
O
H
Acylation of copper derivatives with acid chlorides works well, but they do not react with free
carboxylic acids, unlike the more basic alkyl-lithiums. A dramatic illustration of chemoselectivity
comes in the interaction of Bu 2CuLi with the free acid 59 and its acid chloride 61. Reaction
occurs 24 at the alkyl iodide with the one to give 60 and at the acid chloride with the other to give
the ketone 62. Acylation can also be achieved by many other metal complexes, from Al to Zr, but
to make those we need hydrometallation, the subject of the next section.
I
I
56
57
Hydrometallation
O
Br HO
cat H
OH
O
H
Br
I
OAc
Ac2O, HI
Zn dust
O
57 55; 80% yield
1. Mg, THF
2. 0.06 equivs Cu(I)I, 48
O
O
H
58; 77% yield
HCl, MeOH
AcOH, H2O
53
90% yield
Hydrometallation is the addition of a metal hydride across a double or triple bond. It might be
familiar to you through hydroboration (see chapter 17) while that other not-very-metallic metal,
silicon, can be added through hydrosilylation. We shall concentrate here on hydrozirconation.
Zirconium is a fairly abundant transition metal in the same group as that very useful metal
titanium (see chapters 2–5) with stable oxidation states of 2 and 4. It is normally used in
organic synthesis as bis cyclopentadienyl complexes such as Cp 2ZrCl 2 63 or Cp 2ZrHCl 64. We
met complexes like these in chapter 4 where zirconium enolates gave syn-selective aldol reactions.
Hydrometallation with 64 and an alkene involves the formation 65 of an unstable 18-electron
OAc
Bu
CO2H 2CuLi
CO2H 59 60; n-C14H 29CO 2H, 60% yield
COCl
Bu2CuLi
I
61 62
O

complex with the two π-electrons of the double bond and the reorganisation of this back to a 16electron
σ-complex by a hydride transfer from Zr to carbon 66. The result is a carbanion-Zr(II)
complex 67.
Cl
Zr
Cl
63; ZrCp2Cl 2
16 electrons
Zr H
Cl
Cp2Zr H
Cl
Cp2Zr
This is a good point to address an irritating problem with σ-complexes: their tendency to decompose
by β-elimination of metal hydrides. We have already met the tendency of crowded Grignard
reagents to donate β-hydrogen atoms 10 and act as reducing agents. Alkyl zirconium complexes
prefer to lose the same hydrogen atom by transferring it to the metal in a β-elimination. Complex
69, formed by hydrozirconation of E-hex-3-ene 68 could go back to starting material, or on, via
complex 70 to a π-complex of hex-2-ene 71 and hence via 72, to the terminal σ-complex 73.
E-68
H
71
This means that any positional 74 or geometrical Z-68 isomer, or a mixture such as might be
formed in a dehydration or Wittig reaction, gives the same terminal Zr σ-complex 73.
Z-68
64; ZrCp2HCl
16 electrons
ZrCp2Cl
72
These organo-zirconium derivatives give good acylations with simple acid chlorides 25 (and even
better yields if treated with AlCl 3). Thus any linear hexene gives 2-octanone 75 by zirconation
and acetylation, and even branched chain alkenes such as 76 are acylated at the terminus 78 by
this method.
76
Cp2ZrHCl
H
Cp 2ZrHCl
8 Transition Metal Complexes 121
73
Cp 2ZrHCl
MeCOCl
PhH
Cl
H
Cp2Zr
65 66; π-complex 67; σ-complex
ZrClCp2
H H
69
77
73
–Cp 2ZrHCl
ZrCp2Cl
H
ZrCp 2Cl
75; 80% yield
ZrClCp 2
MeCOCl
PhH
O
Cp 2ZrHCl
70
H
O
78; 72% yield
73
Cl
H
ZrCp2Cl
74
ZrCp2Cl

(+)
Cp2Zr
Cl
122 8 σ-Complexes of Metals
Carbonylation of organometallic complexes
Formylation (addition of an electrophilic CHO group) has always been a diffi cult operation. It cannot
be accomplished with HCOCl as this decomposes to HCl and CO. Some metal complexes will
react with CO and this gives us another approach to acylation at carbon. The tendency of transition
metal σ-complexes to lose an H atom by β-elimination is just one symptom of the poor performance
of alkyl groups as ligands. A simple σ-bond gives nowhere near the stability conferred by ligands
that can simultaneously donate and accept electrons. The outstanding examples that we shall meet
again and again are the phosphines, such as Ph 3P, and CO. Phosphines donate their lone pair
electrons and accept electrons from the metal into empty d-orbitals. On balance they are electron
donors. Carbon monoxide donates its lone pair (from carbon) 79 and accepts electrons into the π*
orbital 80. On balance CO is an electron acceptor: though the resulting complex can be represented
with a metal-carbon double bond 81, two of these electrons come from the metal and CO is a two
electron donor and two electron acceptor.
Alkyl zirconium complexes such as 67 react with CO to give an unstable 18e complex 82 that
transfers the alkyl group from the metal to the CO π* orbital to give the metal acyl complex 83.
This is a Zr(IV) complex of an acyl anion 83a and can be protonated to give the aldehyde 84 in
excellent yield. These zirconium complexes are usually made from alkenes so that any hexene or
mixture of hexenes gives 85 again in excellent yield. 26
1. Cp 2ZrHCl
O
(–)
83a
σ-complex of acyl anion
R4Zr
Cp 2Zr
Cl
67
linear
hexenes
Palladium σ-complexes
C O R4Zr C O R4Zr C O
79 80
81
2. CO
1. Cp 2ZrHCl
Cp 2Zr
Cl
O
C
82
Cp 2Zr
ZrCp 2Cl
The metal for carbonylation reactions, and for many other extraordinary transformations is
palladium. You will be familiar with this metal’s excellent performance in hydrogenation reactions,
usually as a fi nely divided powder on charcoal, and so you are aware that Pd(0) is stable. It also
has a stable Pd(II) state, and there is little to choose between them in stability or in importance to
organic chemists. Soluble reagents such as Pd(PPh 3) 4, PdCl 2, or Pd(OAc) 2 are often used in
reactions. Palladium is expensive and catalytic reactions are preferred. Mg(II), as in RMgBr, is
73
Cl
O
83
2. CO
3. H, H 2O
3. H , H2O
H
O
84; 97% yield
85; 99% yield
CHO

more stable than Mg(0), as in the metal, by 2.4 eV but Pd(II) is more stable than Pd(0) by only 0.2
eV. Once Mg has been oxidised to Mg(II) it will not return to the metal without serious reduction.
On the other hand, Pd(II) can easily return to Pd(0) during a chemical reaction. Pd can be used
catalytically: Mg cannot.
Hydrogenation works in solution because Pd forms stable π-complexes 87 with alkenes 86,
easily inserts into a hydrogen molecule to give 88 and transfers H atoms one at a time to the alkene
to give a σ-complex 89 and eventually the alkane 90.
PdL4
R R
PdL 3 H2
This well known reaction can deceive us into thinking that σ-complexes of Pd are stable. They
are not. All the steps between 86 and 89 are reversible and in the absence of hydrogen, the reaction
runs backwards. Palladium readily does the oxidative insertion into an alkyl halide to give the
σ-complex 92, a carbanion complex of Pd(II), but this immediately loses hydrogen by β-elimination
and the alkene 86 is formed with the loss of a PdHBr complex. Notice that this Pd(II) complex
immediately reverts 93 to Pd(0).
R
86
91
R
86
R
8 Transition Metal Complexes 123
Br
H H
+
89
PdL 3
Pd(PPh 3) 4
oxidative
insertion
Br
H
87
L
R
Pd(PPh 3) 3
93
H
Pd is very widely used in organic synthesis 27 and we shall meet η 2 alkene and η 3 allyl complexes
later. This chapter will end with a brief description of Pd σ-complexes. Stable Pd σ-complexes can
be formed from ArX, MeX, and a few blocked alkyl compounds with no β-hydrogens. They react
well with alkyl and acyl halides, but a major application is in carbonylation reactions. 28
A simple example is the oxidative insertion of Pd(0) into PhI and its reaction with CO
to give the complex 96. This illustrates several important points though the reaction is no
great news as a synthesis. First, soluble Pd often comes quite exotically wrapped, here as the
“diphos” complex 94, chiral versions of which we shall meet in chapters 25 and 26. Then the
decomposition of the acyl-Pd complex 96 by a nucleophile rather than acid leads to the loss of
the metal as leaving group since it reverts to Pd(0) as it goes 97. In the corresponding reaction
with zirconium, the Zr left as Zr(IV) as it has no tendency to drop down to Zr(II), let alone
Zr(0). Finally, the reaction is modestly catalytic in Pd, only 0.2 equivalents being required
(20 mol%).
R
Ph 3P
92
H
90
Br
R
H
PdL2 H
88
Pd(PPh 3) 3
H + PdL4 HBr + Pd(PPh 3) 4
L
β-elimination

124 8 σ-Complexes of Metals
Much more impressive examples come in intramolecular reactions where the nucleophile
( usually an OH group, but it can be NH) is built into the starting material before carbonylation. In
these examples, Pd is often added as PdCl 2 or Pd(OAc) 2 for convenience and reduced to Pd(0) (by
Ph 3P?) in situ. The alcohol 99 gives an excellent yield (82%) of the lactone 29 102 via the complexes
100 and 101. The yield falls off when the lactone size is increased to six (70%) or seven (42%).
The natural product pseudomeconin 98 has been made by this method. 30
Br
Pd(PPh3) 2
Br
Pd(PPh3) 2
O
Br
OH
Pd(OAc)2, Ph3P CO, Bu3N O
OH
Bu3N O
O
O
Pd(0)
99 100 101 102
Adaption to the synthesis of alkaloids such as 103 requires as the disconnection simply the
removal of the CO group! This is good strategy as disconnecting one bond in the middle ring
allows a second disconnection (Mannich or Pictet-Spengler 31 ) to two simple starting materials
105 and 106. The Pd-catalysed carbonylation needs 5% Pd and uses a nitrogen nucleophile to
decompose the intermediate Pd-acyl complex.
MeO
MeO
MeO
MeO
Ph2P PPh2 Pd
Ph 3P PPh 3
Ph2P PPh2
Pd MeOH
Ph
I
O
105
N
MeO
O –CO
NH
MeO
Br
O
103 O
104
NH 2
CHO Br
106
Ph-I Ph2P PPh2 Pd
O
O
Ph I
94 95
K2CO 3
Ph2P PPh2
Pd
Ph
MeO
O
96 97
I
CO
94 +
PhCO 2Me
O
MeO
O
Mannich
OMe
98
105 + 106 104
5% Pd(OAc)2
Ph3P, Bu3N, CO
103
O
O

Just occasionally a Pd reaction with an alkyl σ-complex is successful. One instance is the remarkable
synthesis of four-membered ring lactones 109 from styrene oxide 107 with 1.6% Pd in 63%
yield. 30 Probably the OH group on the same carbon as the β-Hs in 108 inhibits β-elimination.
Recent results with Cu(I) and Pd σ-complexes
The displacement of halides from benzene rings by nucleophiles is traditionally a reaction that
requires strongly electron-withdrawing groups, such as nitro, in the ortho- or para-positions. A
highly signifi cant recent discovery is that Pd(0) and Cu(I) can catalyse such reactions in simple
unactivated aryl halides with, for example, amine nucleophiles. Even aryl chlorides with electrondonating
substituents such as 110 combine with simple amines providing a trace of the palladium
catalyst 112 is present giving excellent yields 32 of amines 111.
The copper-catalysed reactions are not so well developed but aryl bromides combine with
primary amines catalysed by Cu(I) using the salicylamide ligand 115. Free OH groups are
tolerated in either partner: the amine or the aryl halide. 33
Me
References
Ph
107
O
HBr
8 References 125
Ph
Br
OH
1.6% PdCl2 (PPh3)2
CO, DMF
General references are given on page 893
1. T. L. Brown, Adv. Organomet. Chem., 1966, 3, 365.
2. P. G. Willard in Comp. Org. Synth., Vol 1, Chapter 1.1, page 1; W. Setzer and P. von R. Schleyer, Adv.
Inorg. Chem., 1985, 24, 353.
3. M. J. Pearce, D. H. Richards and N. F. Scilly, J. Chem. Soc., Perkin Trans. 1, 1972, 1655.
Ph
108 109
O
Cl
OMe
+
HN
O
1 mole % catalyst
t-BuONa
toluene, 80 °C
N
OMe
Pd
AcO
t-Bu
t-Bu
110 morpholine 111; 95% yield 112; catalyst
Me
113
Br
H 2N
116
Br
ligand 115
OH
5 mol% CuI, K3PO4
DMF, 90 °C
OH
Me
HexNH 2, ligand 115
5 mol% CuI, K3PO4 DMF, 90 °C
H
N
Me
114; 91% yield
H
N
OH
OH
117; 81% yield
O
O
NEt 2
O
OH
115; salicylamide
ligand
Me

126 8 σ-Complexes of Metals
4. Clayden, Lithium.
5. L. S. Hegedus, Organopalladium Chemistry in Organometallics in Synthesis II: A Manual, ed.
M. Schlosser, Wiley, Chichester, 2002, pages 1125–1217; V. Farina, Transition Metal Alkyl Complexes:
Oxidative Addition and Transmetallation in Comprehensive Organometallic Chemistry II, eds E. W.
Abel, F. G. A. Stone and G. Wilkinson, Pergamon, Oxford, 1995, volume 12, pages 162–241.
6. D. J. Cram, F. A. A. Elhafez and H. L. Nyquist, J. Am. Chem. Soc., 1954, 76, 22.
7. H. Kropf in Houben-Weyl, VI/1a, volume 2, Alkohole II, pp 928-1304; Patai, ed, Organo-Metallic, vols
2 and 4; B. J. Wakefi eld in Comprehensive Organo-Metallic Chemistry, ed G. Wilkinson, Pergamon,
Oxford, vol 7, 1982, chapter 44, pages 1-110; B. J. Wakefi eld, The Chemistry of Organolithium Compounds,
Pergamon, Oxford, 1974.
8. M. S. Kharasch and O. Reinmuth, Grignard Reactions of Non-metallic Substances, Prentice-Hall, New
York, 1954, pp 147-166.
9. M. S. Kharasch and S. Weinhouse, J. Org. Chem., 1936, 1, 209.
10. J. K. Crandall and M. Apparu, Organic React., 1983, 29, 345.
11. J. D. Fulton and R. Robinson, J. Chem. Soc., 1933, 1463; 1936, 71, and note on page 80.
12. H. Bredereck, F. Effenberger and E. H. Schweizer, Chem. Ber., 1962, 95, 804; J. D. Davenport, R. E.
Hackler and H. M. Taylor, Eli Lilley, 1969, French Patent 1,569,940, Chem. Abstr., 1970, 72, 100745.
13. R. W. Hoffmann, B. Hälzer, O. Knopff and K. Harms, Angew Chem., Int. Ed., 2000, 39, 3072.
14. R. W. Hoffmann and P. G. Nell, Angew Chem., Int. Ed., 1999, 38, 338; R. W. Hoffmann, B. Hälzer and
O. Knopff, Org. Lett., 2001, 3, 1945.
15. S. Masamune, T. Kaiho and D. S. Garvey, J. Am. Chem. Soc., 1982, 104, 5521.
16. D. Seyferth and H. M. Cohen, J. Organomet. Chem., 1963, 1, 15.
17. R. P. Cassity, L. T. Taylor and J. F. Wolfe, J. Org. Chem., 1978, 43, 2286.
18. S. Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22, 3815.
19. G. Magnusson, Tetrahedron Lett., 1977, 2713.
20. R. G. Pearson and C. D. Gregory, J. Am. Chem. Soc., 1976, 98, 4098; B. H. Lipshutz, J. A. Kozlowski
and C. M. Breneman, J. Am. Chem. Soc., 1985, 107, 3197.
21. Vogel, page 480.
22. J. C. Stowell and B. T. King, Synthesis, 1984, 278.
23. B. H. Lipshutz, R. S. Wilhelm and J. A. Kozlowski, Tetrahedron, 1984, 40, 5005.
24. G. H. Posner and C. E. Whitten, Tetrahedron Lett., 1970, 4647; G. H. Posner, C. E. Whitten and P. E.
McFarland, J. Am. Chem. Soc., 1972, 94, 5106.
25. For reviews, see D. J. Cardin, M. F. Lappert, C. L. Raston, and P. I. Riley in Comprehensive Organometallic
Chemistry, eds G. Wilkinson, F. G. A. Stone, and E. W. Abel, Pergamon, Oxford, 1982, vol 3,
pp 549-646; E-i Negishi, and T. Takahashi, Aldrichimica Acta, 1995, 18, 31-47.
26. C. A. Bertelo and J. Schwartz, J. Am. Chem. Soc., 1975, 97, 228.
27. A. D. Ryabov, Synthesis, 1985, 233.
28. B. M. Trost, Comprehensive Organo-Metallic Chemistry, ed G. Wilkinson, Pergamon, Oxford, vol 8,
chapter 57, page 800.
29. M. Mori, K. Chiba, N. Inotsume and Y. Ban, Heterocycles, 1979, 12, 921.
30. A. Cowell and J. K. Stille, J. Am. Chem. Soc., 1980, 102, 4193.
31. Disconnection Approach p. 337.
32. D. Zim and S. L. Buchwald, Org. Lett., 2002, 5, 2413.
33. F. Y. Kwong and S. L. Buchwald, Org. Lett., 2002, 5, 793.

9
Controlling the Michael Reaction
Introduction: Conjugate, 1,4- or Michael addition vs direct or 1,2-addition
Sulfur and phosphorus ylids
Where direct (1,2-) addition is necessary
Using Copper (I) to Achieve Michael Addition
Stereoselectivity in Michael additions of organo-copper(I) compounds
Trapping the enolate intermediate by silylation
Michael Addition followed by Reaction with Electrophiles
Tandem Michael/aldol reactions
A Double Nucleophile: An Interlude without Copper
A Michael Reaction Coupled to a Photochemical Cyclisation: Copper Again
Michael Additions of Heteroatom Nucleophiles
Michael Additions with and without Copper: Functionalised Michael Donors
Introduction: Conjugate, 1,4- or Michael addition vs direct or 1,2-addition
HO Nu HNu
R
Direct or 1,2-
Addition
The Michael reaction (also known as conjugate or 1,4-addition) is at its simplest the addition of
a nucleophile to an electrophilic alkene, usually an unsaturated carbonyl compound 2, to give
the product of 1,4-addition 3 rather than direct addition at the carbonyl group 1. It is a useful
reaction in synthesis since the nucleophile can be a heteroatom (O, N, S etc) or a variety of carbon
compounds (organometallic compounds, enolates, aromatic rings etc). It has been extensively
reviewed 1 and the ground rules 2 are:
Direct (1,2) attack at the CO group is dominated by charge interactions and the allylic alcohol
1 is the kinetic product.
Conjugate, Michael, or 1,4-addition is dominated by frontier orbital interactions and the
saturated CO compound 3 is the thermodynamic product.
The most reactive Michael acceptors tend to give 1,2-addition (roughly
CHOAlkCOArCOCO 2RCN) while the least reactive tend to give 1,4-addition
( reverse order).
The most reactive, most basic or hard, nucleophiles tend to give 1,2-addition: the least reactive,
least basic or soft nucleophiles tend to give 1,4-addition.
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd
O
R
HNu
Conjugate or
Michael or 1,4-
Addition
1; allylic alcohol 2; enone 3; ketone
Nu
O
R

128 9 Controlling the Michael Reaction
Steric effects matter: large groups next to the CO end (a 1 ) or at the a 3 position can defl ect
addition to the other end.
Sulfur and phosphorus ylids
Sulfur and phosphorus ylids provide good illustrations. Simple sulfur ylids 5 react with aldehydes
and ketones to give epoxides. 3 But what if the electrophile is a conjugated aldehyde or ketone?
Two reactions are possible: direct addition 6 to give the epoxide 8 and 1,4-addition 11 to give the
cyclopropyl ketone 4 13. The structure of the acceptor cannot generally be altered so that of the ylid
must. The least stabilised, least reversible, and hardest ylids are those 5 derived from Me 3S 4 and
these give epoxides, while the extra anion-stabilising ability of an SO bond in the sulfoxonium
ylids 10 makes them softer and more reversible, and they give the cyclopropyl ketones.
Me
S Me
Me
Me
S CH2
Me
O
Me2S CH3 O
Me2S CH2 R1 R
O
2
R1 O
R2 R1 O
R2 R
O
Me2S 1 R2 Me2S O
R1 R
O
2
R1 O
R2 base
4; sulfonium 5; sulfonium 6; direct
salt
ylid addition 7 8; epoxide
base
9; sulfoxonium
salt
10; sulfoxonium
ylid
11; Michael
addition
12
13; cyclopropane
A good example is the natural product eucarvone 16 mentioned in the original Corey papers. 5
The simple sulfonium ylid 5 gives the epoxide 16 in 93% yield by direct addition while the
sulfoxonium ylid 10 gives the cyclopropane 14 in 88% yield by conjugate addition to the nearer
alkene. In an extended conjugated system the alkene nearest to the carbonyl group is normally the
most electrophilic.
That sulfonium ylids can add in a Michael fashion is neatly shown by an intramolecular
reaction of the ylid 17. Direct attack would form an awkward 7-membered ring but conjugate attack
17 gives a fi ve-membered ring intermediate with both new CC bonds necessarily formed cis to
the ylid. 6 Here is regio- and stereoselectivity.
H 2C
O
O
O
Me 2S CH 3
14 15 16
Me
S
17
t-BuOK
O
Me
S
O
Me 3S
t-BuOK
O
MeS
18
O

Where direct (1,2-) addition is necessary
For some reactions, 1,2-addition is essential. The synthesis of allylic alcohols by reduction of
enones, enals, or enoate esters requires a hard reducing agent and LiAlH 4 is usually suitable
( chapter 19). The Wittig reaction 7 also requires 1,2-addition otherwise the usual four-centred
elimination of a phosphine oxide is impossible. In fact 1,2 addition is generally preferred with
hard unstabilised ylids, and if the ylid is stabilised, Michael addition may be reversible. In the
synthesis of α-eleostearic acid 8 19 any of the double bonds could have been disconnected. The cis
double bond was preferred both because unstabilised ylids usually give Z-alkenes, and because
both starting materials, the dienal 20 and the ylid 21 are easily made.
Bu CO 2H
Bu
CHO
You may guess that Grignard reagents and alkyl-lithiums are also very likely to give 1,2-addition,
especially with aldehydes. A classic example is the addition of methyl Grignard to crotonaldehyde
22 to give the allylic alcohol 23 in high yield. 9
Using Copper (I) to Achieve Michael Addition
That was a useful synthesis of allylic alcohols, but the greater need is to accomplish 1,4-addition
reliably with hard or soft nucleophiles and reactive or unreactive Michael acceptors. The organocopper
σ-complexes we met in the previous chapter are the answer. There is some discussion 10
over the exact mechanism of addition of organo-copper compounds to enones, but we shall present
the simplest possibility. Organo-copper reagents may add to enones by fi rst making an η 2 -complex
24 with the alkene. Transfer of the ligand R from copper to the enone forms the η 3 allyl (enolate)
complex 25 which gives the Michael adduct 26 on protonation.
R 2
22
crotonaldehyde
O
R 1
9 Using Copper (I) to Achieve Michael Addition 129
R Cu
R 2
19; α-eleostearic acid
+
PPh3 20 21
R
O
Cu
H
O
R 1
MeMgCl
HO Me
The addition 11 may be carried out using a Cu(I) catalysed Grignard reaction, a discrete RCu
species with or without other ligands such as Me 2S, or with the R 2CuLi complexes described in
chapter 8. A typical (and very early!) result 12 is the addition of MeMgBr to the enone 27 giving
mostly the allylic alcohol 28 by 1,2-addition. The same reagent with catalytic Cu 2Cl 2 reverses the
regioselectivity to a reasonable degree.
R 2
R Cu
O
H
R 1
Wittig
CO 2
23; pent-3-en-2-ol
81-86% yield
24; η 2 alkene complex 25; η 3 enolate complex 26
H
R 2
R
O
R 1

130 9 Controlling the Michael Reaction
O
Me Metal
Me OH
27 28; allylic alcohol 29; saturated ketone
Me Metal = MeMgBr 98.5: :1.5
Me Metal = MeMgBr + cat. Cu2Cl2 17.5: :82.5
Stereoselectivity in Michael additions of organo-copper(I) compounds
Better results are achieved with stoichiometric copper reagents, either RCu [alone or as a complex
with sulfi des Me 2S, phosphines Bu 3P, or phosphites (MeO) 3P] or cuprates R 2CuLi. Thus Me 2CuLi
adds exclusively 13 1,4 to the diffi cult enone 30, while the Cu-catalysed Grignard reaction gives mostly
allylic alcohol 31. The syn stereochemistry of the 1,4-product 32 is thermodynamically controlled
and appears on protonation during the acidic work-up to give the more stable cis ring junction.
Me Metal
Me OH O
100%
H
O
30 31; allylic alcohol 32; saturated ketone
Me Metal = MeMgI, Cu2(OAc) 2 56% 34%
Me Metal = Me2CuLi 0%
In other cases anti stereochemistry is preferred. An ingenious synthesis of the trans di-t-butyl
cyclobutanone 34 uses Michael addition to the enone 33. Here a Cu-catalysed Grignard reaction
gives total regio- and stereoselectivity as well as a quantitative yield. 14 The stereochemistry again
comes from protonation of an enolate during work-up, but this time it is better to have the two large
groups anti on the rigid four-membered ring.
O
MeMgI
Cu2Cl 2
Similar stereoselectivities are found when the new chiral centre is formed during the addition
rather than in the work-up, but the stoichiometric reagents generally perform better. Thus PhCu
adds to the enone 35 to give anti-36 in both a better yield and a better stereoselectivity than a
copper-catalysed Grignard reagent. 15 The 1,3-stereoselection in Me 2CuLi addition to 37 is also
excellent, 16 and results largely from axial addition rather than a preference for anti addition. These
conformational aspects of stereoselectivity are discussed in chapters 20–21.
O
33 34
O
Me

9 Using Copper (I) to Achieve Michael Addition 131
O
O
PhMgBr
cat Cu2Cl2 35
35
75% yield
87:13 anti:syn
Ph
36
37
98% yield
Open chain compounds often give good regioselectivity too. 11 The simple enone 39 adds a
variety of organo-copper compounds 17 in up to 95% yield of the 1,4-adduct 40. Unsaturated esters
generally give good results too.
Unsaturated aldehydes and enones with heavy β-substitution in particular often give poor
results either by competing 1,2-addition or by aldol condensation of the enolate products. Thus
the enone 18 42 and most aldehydes give predominantly 1,2-adducts 44 even with Me 2CuLi. These
problems can be avoided if the reaction is carried out in the presence of Me 3SiCl.
Cinnamaldehyde 45 gives mostly the alcohol 47 with Me 2CuLi but if Me 3SiCl is added before
the organo cuprate, the less reactive cyanocuprate Me(CN)CuLi can be used and the 1,4-adduct
46 isolated in 98% yield.
Trapping the enolate intermediate by silylation
O
Me2CuLi
100% yield
96:4 anti:syn
anti-38, 98:
Cuprates react only very slowly with Me 3SiCl so it can be present during the Michael addition
reaction, enhancing the rate of the reaction and the proportion of 1,4-addition, and trapping the
enolate product as the silyl enol ether. 18–22 Thus the troublesome enone 42 gives good yields of
O
+
PhCu
:2 syn-38
O O Me OH
Me-Metal
+
39 40 41
Me2CuLi + HO
O O
Me
42 43 44
O
Ph H
Ph H
Cu 2I 2
45
46
47
minor major
1. Me3SiCl, 2. Me(CN)CuLi, 3. H + Me2CuLi
, H2O 98% yield not detected
Me
O
+
O
OH
PhLi
Ph Me

132 9 Controlling the Michael Reaction
48 under a variety of conditions, and the 1,4-product 43 released by acid- or fl uoride-catalysed
hydrolysis.
Me2CuLi
Me3SiCl or Bu4NF, MeOH
O Me3SiO O
Cuprates generally perform better than RCu in additions to aldehydes. Acrolein itself 49
gives the 1,4-product 50 in 88% yield with Bu 2CuLi, and even β-substitution in the crowded enal
51 does not prevent Ph 2CuLi adding 1,4 to give 52 in 99% yield. 20
Michael Addition followed by Reaction with Electrophiles
Both these silyl enol ethers 50 and 52 could of course be hydrolysed to the saturated aldehydes, but
that would be to sacrifi ce the useful reactivity of these intermediates in aldol and other reactions
explored in chapters 2-6. A more productive development is to react the silyl enol ether with an
electrophile and hence develop a synthesis from three components in two consecutive reactions. 23
This approach has formed the basis of many modern syntheses as it develops the target molecule
so quickly and is discussed in chapter 37 under ‘tandem reactions’. It is not necessary to trap
the enolate with Me 3SiCl when lithium cuprates are used with ketones as the lithium enolate is the
product of 1,4-addition. You may choose the lithium enolate or the silyl enol ether, whichever is
more appropriate for the next step.
Cyclohexenone adds Bu 2CuLi to give the lithium enolate 54 which is quenched with methyl
iodide to give the anti disubstituted 24 ketone 55. This could in principle be made from the ketone
56, but whatever regioselectivity 56 might show with LDA cannot be expected to favour 54.
Tandem Michael/aldol reactions
H , MeOH
42 48 43
CHO
Bu2CuLi Me3SiCl OSiMe3 CHO
Ph2CuLi Me3SiCl
OSiMe3 49 50; 88% yield 51
Ph
52; 99% yield
O Bu OLi Bu O Bu
O
Bu2CuLi
MeI
53 54
55 56
Aldol reactions with lithium enolates are improved if zinc(II) salts are present, or, if silyl enol
ethers are used, TiCl 4 is also helpful. We have chosen the example of Me 2CuLi addition to the
enone 57 as the examples in the literature 23 are overwhelmingly of cyclic enones, and we wanted
an acyclic example. The aldols (mixed diastereoisomers) 59 are formed in 96% yield. 25
Me

O OLi
Me2CuLi 57 58
PhCHO
59;
1:2
syn:anti
Before looking further at syntheses developed with this strategy, we must deal with an annoying
feature of cuprates of the type R 2CuLi. Only one of the two R groups is transferred to the enone
from the copper: the other is lost during the work-up. If this is simply Me, Bu, or Ph there is
no problem, and that is why all our examples have been selected from these cuprates. Where
the group attached to copper has itself been synthesised, perhaps including some stereochemical
features, it is not acceptable to waste half of one’s labours. Copper prefers to retain the better
complexing group, that is the one with more π-bonds, or the one which forms the more stable
anion. 26 There is particularly good selectivity between alkynes (retained) and alkanes (donated)
so complexes such as 62 donate the alkyl group to enones and then alkynyl copper 61 can be
recycled. Pent-1-yne 60 is commonly used for this sequence as it is the smallest liquid terminal
alkyne (only just liquid - b.p. 40 C).
The disconnection for these three-component syntheses is to remove the trans substituents
from the α and β positions. Thus the ketone 65 disconnects to the enone 66, a vinyl-Cu derivative
and an electrophilic bromoester. In the event, a Cu 2I 2 catalysed Grignard addition followed by
alkylation of the magnesium enolate gives pure trans-65 in 91% yield. 27
Functionalised nucleophiles normally need to be protected, as in the synthesis of the bicyclic
enone 67 which requires the addition of a d 3 reagent to cycloheptenone 69. The Me 2S complex of
the Cu(I) derivative of 70 fi lls this role; deprotection and cyclisation being accomplished in acid
solution. 28 This synthesis also illustrates that tandem Michael-aldol sequences of this kind with an
intramolecular aldol are perfectly satisfactory.
Br
ZnCl 2
Ph
OH O
Pr H
1. BuLi
2. Cu(I)X
Pr Cu
RLi
Pr CuRLi
60
61 62
R 2
O
O
67
9 Michael Addition followed by Reaction with Electrophiles 133
O
R 1
CO 2Et
62
R 2
65 65a
O
O
aldol
R
OLi
Me3SiCl
R1 R2 63 64
R
OSiMe 3
O O Br
CO2Et disconnect
trans groups
+ CO2Et
Cu
O
CHO
1,6-diCO
68 69 69; d
OMgBr
O
1. Mg, Et2O 2. Cu2Br2, Me2S 69, THF
O O HCl
3 reagent
66
O
+
Cu
R 1
CHO
70 71 67; 70% yield

134 9 Controlling the Michael Reaction
A Double Nucleophile: An Interlude without Copper
The Erythrina alkaloids such as dihydroerythramine 72 have an awkward junction of three rings
at one carbon atom. The amide 73 offers the opportunity of disconnection of one ring but this still
leaves the quaternary carbon atom intact 74.
O
O
N
O
O
FGA N
2 x C–C
O
MeO
MeO
MeO
72 73 74
One successful approach imagines two CC disconnections around that carbon atom 75 using
a nitro group to stabilise the anion 76 and a double electrophile 77 with a Michael acceptor on one
side and some suitable a 2 reagent, perhaps an epoxide, on the other. 29
O
O
A palladium-catalysed reaction of an allylic acetate (chapter 19) was used for the fi rst CC
bond formation and the planned Michael addition for the second though the intermediate 79 was
not isolated. The conformational diagram of 80 should help you to see why that diastereoisomer
was favoured.
O
O
O
O
MeO
74a
H
N
NO 2
O
C–N
amide
and FGI
Cs 2CO 3
O
O
O
O
MeO
75
A Michael Reaction Coupled to a Photochemical Cyclisation: Copper Again
An intermolecular three-component step may be followed by other intramolecular reactions. In the
synthesis 30 of β-panasinene 81, a principal component of ginseng oil, the obvious Wittig disconnection
leads to an equally obvious 22 photochemical cycloaddition 31 from dienone 83. Either
group may be disconnected from the β-position of 83 so it makes sense to remove the larger 84.
NO 2
O
N
O
CO2R
2 x C–C
AcO
78 76 78
79
NO 2
CO 2Me
Cs 2CO 3
O
O
+
NO 2
O
O
CO 2Me
O
O
MeO
CO 2Me
76
H
N
NO 2
77
(Ph 3P) 4Pd
Ph3P, THF
60 °C
Ar
NO 2
O
CO2R
CO 2Me
80; 79% yield, 4:1 diastereoisomers major diastereoisomer of 80

81; β-panasinene
Wittig 2 + 2
O O
82 83
Copper-catalysed Michael addition followed by an aldol reaction with formaldehyde, gives a 1:1
mixture of diastereoisomers of the aldol 86 that can be eliminated to the enone 83. The resulting
effi cient photochemical cycloaddition gives ketone 82 with total regioselectivity probably because
it is intramolecular.
Michael Additions of Heteroatom Nucleophiles
Michael
-Aldol
Michael additions of heteroatoms (O, N, S etc.) have been developed in modern chemistry to
a high degree of regio- and stereoselectivity. Intramolecular Michael addition is particularly
favoured and contributes a key reaction in Mulzer’s synthesis of the antibiotic kedomycin 32 89.
The intermediate 90 contains all the stereochemistry of the left hand side of kendomycin, the
awkward quinone methide ring is replaced by a benzene ring, and, most signifi cantly, a ketone has
been introduced to allow Michael disconnection of a strategic CO bond.
84
Cu
CH 2O
Then came a nasty surprise. The ketone 82 is rather crowded and would not undergo a Wittig
reaction with Ph3PCH2, but Johnson turned this to advantage by using his asymmetric reagent
87 to resolve the compound and do the methylenation in one step. Optically active 88 can be
isolated in 42% yield (out of a maximum of 50%) and gives natural ()-panasinene 81.
Ph O
O
S
Ph O
NMe
OH
Li S
NMe
Al/Hg
HO
O
85
O
HO
1.
82
O
89; kendomycin
9 Michael Additions of Heteroatom Nucleophiles 135
5% Cu 2Br 2, Me 2S
2. CH 2O
OH
O
MgBr
87
O
HO
(+)-88; 42% yield
OR
O
MeO
OH
O
86; 90% yield, 1:1 syn:anti
OMe
1. TsCl, pyridine
(82% yield)
2. t-BuOK
(78% yield)
HOAc
THF
Michael
+
(–)-81; β-panasinene
92% yield
HO
83
OH
OMe
90 91
hν
O
MeO
OR
OMe
85
O
82
67% yield
OMe

136 9 Controlling the Michael Reaction
The enone 91 was made by a Horner-Wadsworth-Emmons reaction (chapter 15) and so has the
E-confi guration. The cyclisation to 90 in dilute methanolic acid in 92% yield occurs with remarkable
selectivity. Only one of the two free OH groups reacts, only conjugate addition occurs, and
the stereoselectivity is 97:3 in favour of the isomer shown.
Michael additions of heteroatoms can be coupled to reactions of the specifi c enolate produced.
The synthesis of the modifi ed carbonucleoside ()-neoplanocin A 92 required some cyclopentane
to which the heterocyclic purine could be joined. The decision was taken to close the cyclopentane
by an aldol reaction. This required an aldehyde and an ester in a compound such as 94 to combine
regio- and stereo-selectively without epimerisation of any chiral centres. The aldehyde is enolisable
so there are serious problems. 33
HO
N
N
H
NH 2
N
HO OH
92; (–)-neoplanocin A
N
EtO2C
HO OH
93
A sulfur atom was introduced to supply the control. Michael addition of a thiol (PhCH 2SH was
actually used) to the unsaturated ester 95 would give a specifi c enolate that might cyclise onto the
aldol fast enough to prevent enol exchange. In practice the hydroxyl groups had to be protected
and the lithium thiolate was added to 96 to give the specifi c enolate 97 that cyclised with good
stereoselectivity to give mainly 98. Elimination of the SBn group by oxidation (chapter 15) gave
99, used to complete the synthesis.
EtO 2C
OR
LiS Ph
Michael Additions with and without Copper:
Functionalised Michael Donors
O
OEt
SR
S Bn
OR
OH
EtO2C SR
O OH
O OH
94 95
Perhaps the major disadvantage of the copper-catalysed Michael reaction is the need to protect
functional groups. Michael reactions with heteroatom nucleophiles or functionalised carbon
nucleophiles are usually carried out without copper. Many such nucleophiles, particularly enol
equivalents, are excellent at Michael reactions, and are often to be preferred for ease of working.
Silyl enol ethers, enamines, and stabilised enolates all carry out Michael reactions. In the next
chapter we shall look at specifi c enol equivalents in more detail and note which ones are good at
Michael additions.
aldol
EtO 2C
OH
Michael
EtO 2C
O OR
O OR
HO OR
RO OR
96 97 98 99
SBn
OR EtO 2C
OH
OH

Do not suppose that the regioselectivity problem is now trivial. In a study mainly aimed at
achieving asymmetric reactions, Braun 34 showed just how narrow is the gap between 1,2 and 1,4
addition. The silyl enol ether 101, easily made from the enantiomerically pure ester 100, gave
mainly (95:5) direct (1,2) addition to a simple enone under the usual conditions (TiCl 4 catalysis)
for Michael addition.
O
O Ph
100
Ph Ph
A minor change in the structure of the enone: the addition of an α-methyl group to give 103,
led to an almost complete reversal of the regioselectivity: the Michael (1,4) adduct 104 was formed
in a 95:5 ratio to the 1,2 adducts. The only difference is a slight increase in steric hindrance for
direct addition but the switch from one reaction to the other is remarkable and a warning not to be
complacent about our understanding of selectivity.
References
OH
1. LDA
2. Me3SiCl
Ph Ph
Me3SiO O
Ph
OSiMe3 O
TiCl4 HO Me O
O
Ph
101 102
103
O
9 References 137
101
TiCl 4
O
Ph Ph
General references are given on page 893
1. E. D. Bergmann, D. Ginsburg, and R. Pappo, Org. React., 1959, 10, 179; J. P. Schaffer and J. J.
Bloomfi eld, Org. React., 1967, 15, 1; the Dieckmann reaction, see table 5; G. Jones, Org. React., 1967, 15,
204; the Knoevenagel reaction, unsaturated carbonyl compounds scattered throughout the tables; G. H.
Posner, Org. React., 1972, 19, 1; organo-copper reagents; E. Erdik, Tetrahedron, 1984, 40, 641; Copper
(I) catalysed reactions or organolithiums and Grignard reagents; A. G. Cook, Enamines, Marcel Dekker,
New York, second edition, 1988, pages 190-194 and 353-380; I. Fleming, J. Dunogues, and R. Smithers,
Org. React., 1989, 37, 1; M. J. Chapdelaine and M. Hulce, Org. React., 1989, 38, 225 “tandem vicinal difunctionalisation”;
D. Duval and S. Géribaldi in The Chemistry of Enones, ed S. Patai and Z. Rappoport,
Wiley, Chichester, 1989, chapter 10, pages 355–469.
2. Fleming, Orbitals, pages 70-73; Disconnection Approach, page 116.
3. Disconnection Approach, page 252.
4. B. M. Trost and L. S. Melvin, Sulfur Ylids: Emerging Synthetic Intermediates, Academic Press, London,
1975.
5. E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1962, 84, 3782; 1965, 87, 1353.
6. R. S. Matthews and T. E. Meteyer, Chem. Comm., 1971, 1576.
7. Disconnection Approach, page 120.
8. L. D. Bergelson and M. M. Shemyakin, Angew. Chem., Int. Ed., 1964, 3, 250 (see p. 255).
9. E. R. Coburn, Org. Synth. Coll., 1955, III, 676.
10. S. Woodward, Chem. Soc. Rev., 2000, 29, 393; see also E. J. Corey and N. W. Boaz, Tetrahedron Lett.,
1985, 26, 6015; S. R. Kraus and S. G. Smith, J. Am. Chem. Soc., 1981, 103, 141; G. Hallnemo, T. Olsson
and C. Ullenius, J. Organomet. Chem., 1985, 282, 133; H. O. House, Acc. Chem. Res., 1976, 9, 59.
11. G. H. Posner, Org. React., 1972, 19, 1.
12. M. S. Kharasch and P. O. Tawney, J. Am. Chem. Soc., 1941, 63, 2308.
O
O Ph
104
Ph Ph
OH
OH

138 9 Controlling the Michael Reaction
13. W. E. Parham and L. J. Czuba, J. Org. Chem., 1969, 34, 1899.
14. J. Salaün and J. M. Conia, Bull. Soc. Chim. France, 1968, 3730.
15. N. T. Luong-Thi and H. Riviere, Compt. Rend., 1968, 267, 776.
16. H. O. House and W. F. Fischer, J. Org. Chem., 1968, 33, 949.
17. see reference 11, table I, pages 67–68.
18. E. J. Corey and N. W. Boaz, Tetrahedron Lett., 1985, 26, 6019.
19. A. Alexakis, J. Berlan, and Y. Besace, Tetrahedron Lett., 1986, 27, 1047.
20. E. Nakamura, S. Matsuzawa, Y. Horiguchi, and I. Kuwajima, Tetrahedron Lett., 1986, 27, 4029.
21. M. Bergdahl, E.-L. Lindstedt, M. Nilsson, and T. Olsson, Tetrahedron, 1988, 44, 2055.
22. S. H. Bertz and R. A. J. Smith, Tetrahedron Lett., 1990, 31, 4091.
23. M. J. Chapdelaine and M. Hulce, Org. React., 1989, 38, 225; R. J. K. Taylor, Synthesis, 1985, 364.
24. G. H. Posner, J. Am. Chem. Soc., 1975, 97, 101.
25. K. K. Heng and R. A. J. Smith, J. Org. Chem., 1981, 46, 2932.
26. The details are more complicated: see P. A. Bartlett, J. D. Meadows and E. Ottow, J. Am. Chem. Soc.,
1984, 106, 5304.
27. K. C. Nicolaou and W. E. Barnette, J. Chem. Soc., Chem. Commun., 1979, 1119.
28. A. Marfat and P. Helquist, Tetrahedron Lett., 1978, 4217.
29. C. Jousse-Karinthi, C. Riche, A. Chiaroni and D. Desmaële, Eur. J. Org. Chem., 2001, 3631.
30. C. R. Johnson and N. A. Meanwell, J. Am. Chem. Soc., 1981, 103, 7667.
31. Disconnection Approach, page 268.
32. H. J. Martin, M. Drescher, H. Kählig, S. Schneider and J. Mulzer, Angew. Chem., Int. Ed., 2001,
40, 3186.
33. M. Ono, K. Nishimura, H. Tsubouchi, Y. Nagaoka and K. Tomioka, J. Org. Chem., 2001, 66, 8199.
34. M. Braun, B. Mai, and D. Ridder, Eur. J. Org. Chem., 2001, 3155.

10
Specifi c Enol Equivalents
Introduction: Equilibrium and specifi c enolates
Enolates from 1,3-di-Carbonyl Compounds
Enamines and Aza-Enolates
The synthesis of multistriatin
Metallated hydrazones
Lithium Enolates and Silyl Enol Ethers
Specifi c enolates by conjugate (Michael) addition
An intermediate in Corey’s ginkgolide synthesis
A synthesis of jasmine ketolactone
Tables of Enol Equivalents and Specifi c Enolates
Modern Use of Specifi c Enolate Equivalents
Malonates, lithium enolates and silyl enol ethers in one synthesis
Other metal enolates
Coupling large fragments with metal enolates
Introduction: Equilibrium and Specifi c Enolates
Almost every chapter so far has mentioned enolates in one form or another and their chemistry is
central to organic synthesis. Now it is time to take stock of the various d 2 reagents developed to
play the role of enolates, to see what reactions they are particularly suited for, what chemo- regio-
and stereo-selectivity they show, and some examples of their use in total synthesis.
This is only a very brief summary of simple enolates. They are discussed more fully in The
Disconnection Approach, chapters 18-28, pages 140-239. Originally enolates were generated by
treating carbonyl compounds with weak bases, that is bases too weak to convert the carbonyl
compound entirely into its enolate. Under these conditions, self-condensation with unenolised
carbonyl compound is always a risk. With aldehydes it is unavoidable. Treating an aldehyde 1 with
an alkoxide produces a small amount of enolate 2 that reacts rapidly with unenolised 1 to give
aldols 3, enals 4, and further condensation products.
R
O
EtO
R
O
H
H
1 2
R CHO
OH
3; aldol
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd
1
R
–H 2O
R
R CHO
4; enal

140 10 Specifi c Enol Equivalents
The less reactive ketones can be persuaded to react with other, usually non-enolisable, carbonyl
compounds as in the reaction of cyclohexanone 5 with diethyl carbonate to give the β-keto-ester
7. This reaction is really under thermodynamic control as the favourable equilibrium between
the product 7 and its stable enolate 8 more than compensates for the unfavourable equilibrium
between 5 and its unstable enolate 6. This stable enolate 8 is a specifi c enolate.
O O
O O
H
O
EtO EtO OEt
OEt
EtO
5 6 7 8
This product can be used to make 2,2,6-trimethylcyclohexanone 10 by methylation under forcing
conditions to replace all the enolisable hydrogen atoms in 7a and give 9. In this reaction both the
stable enolate 8 and the unstable enolates on the other side of the ketone must be methylated. The
reaction 1 is completed by hydrolysis and decarboxylation of the CO 2Et group and the overall yield
is a reasonable 41%.
H
H
O
H
7a
O
OEt
1. NaH
2. MeI
Me
Me
Enolates from 1,3-di-Carbonyl Compounds
O
O
Me
A simple example 2 should remind you of these useful reagents. Condensation of the stable enolate
12 of the 1,3-diketone 11 with the enone 13 gives the Michael adduct 14. Elimination generates a
new enone 15.
H
O
Cl
11
O
O
NaOH
EtOH
Et 2O
O
O
The new enone 15 condenses in turn in a second Michael addition with the keto-ester 16 under
equilibrating conditions to form, presumably, intermediates like 17a and/or 17b. This gum is not
isolated but hydrolysed and decarboxylated to give the steroid intermediate 18.
9
O
OEt
O
Cl
12 13
base
TsOH
AcOH
O
O
14 15
+
O
Me
Me
O
O
O
10
O
Me
H
OEt

O
16
CO2t-Bu
15
cat t-BuOK
t-BuOH
O
O
O
O
? TsOH
AcOH
O
CO2t-Bu 17a
CO2t-Bu
17b
O
18
This sequence illustrates the use of enolates from 1,3-dicarbonyl compounds in Michael
reactions: they are useful too in alkylations, aldol condensations (Knoevenagel conditions),
and reactions with epoxides, as in the synthesis 3 of 20. Nowadays they tend to be used if they
are readily available, or if the disconnections suggest their use, as in the building of 11 into 18.
Examples include the diketone 11 and the six-membered equivalent both used in steroid synthesis,
acetoacetates 16 and 19 and the keto-lactones 20, malonic acid 21 and its esters, “Meldrum’s acid”
22, a very enolisable malonate derivative, 4 and the keto-ester 25 formed via its stable enolate 24,
by the cyclisation of the diester 23, an intermediate in nylon manufacture. The compounds 11, 16,
19, 20; RH, 21, 22, and 25 are all available commercially.
O
CO 2Et
O
R
O
O
R
19 20
21 22
EtO 2C
O
The 1,3-dicarbonyl approach is not suitable for aldehydes as the fi nal destruction of the
dicarbonyl relationship usually means that the aldehyde itself is sacrifi ced, as in the sequence 26
to 30 used in the alkylation of ketones. 5
O
HCO2Et
EtO
10 Enolates from 1,3-di-Carbonyl Compounds 141
23
EtO
O
CO2Et
O
EtO
EtOH
OH OH
When the position between two carbonyl groups is blocked, attack by a nucleophile 31 occurs at
the more electrophilic of the two (an aldehyde if there is one) cleaving 32 the 1,3-dicarbonyl system.
O
O
24
O O H O
R
H
O
H
NaOH
CO 2Et
O
O
base
O
Me 2CO
Ac2O
H 2SO 4
O
O
O O
5 26 27 28
29 30
R
O O
25
CO 2Et
RX
O
O

142 10 Specifi c Enol Equivalents
Enamines and Aza-Enolates
One specifi c enol equivalent that works very well for aldehydes is an enamine. Secondary amines
such as Me 2NH, Et 2NH, pyrrolidine, piperidine, or morpholine 34 add cleanly to aldehydes to give
enamines 36. These relatively stable nitrogen analogues of enols react well with reactive alkyl
halides, such as α-carbonyl halides, and in Michael additions. They were considered in chapter 2
and only a few extra examples will be given here.
R CHO +
HN
O
R
N
O
R
N
34 35
36
The diketo-aldehyde 37 has four electrophilic carbon atoms (A-D) and three positions for
enolisation (1-3). Cyclisation could occur in twelve different ways. Three can be regioselectively
realised by different conditions. 6 With morpholine catalysis, the aldehyde forms an enamine which
does a Michael addition on the enone (B) to give 39. Enamine formation with PhNHMe also gives
the aldehyde enamine, but this time it does an aldol condensation with the simple ketone (D) to
give 38.
O
O
R
31
O
38
enamine at 1
adds to D
H
CHO
OH
O
Finally, acid catalysed reaction gives the expected thermodynamic product 40. All three products
involve the aldehyde: the enamines select for d 2 behaviour of the aldehyde while acid catalysis
brings it in as an electrophile (a 1 ). You cannot expect to achieve such control in all examples, but it
is clear that enamines have something special to offer as aldehyde specifi c enol equivalents.
37
PhNHMe
TiCl 4
CF 3CO 2H
TsOH
reflux
benzene
O
C
R
H
O OH O
32
B
1
O
D
3
2
37; a diketoaldehyde
O
O
CHO HN
A
33
R
TsOH
40
enol at 2
adds to A
H 2O
O
O
30 + HCO 2
OHC
H
O
O
39
enamine at 1
adds to B

Alkylation with simple alkyl halides is generally a poor reaction with enamines. Alkylation
often takes place on nitrogen instead of carbon, and Stork and others 7 have developed the
aza-enolates to remedy this defi ciency. A primary amine, usually cyclohexylamine, combines with
an aldehyde to form an imine 42. Treatment with LDA 43 gives the lithium derivative, the analogue
of a lithium enolate, known as an azaenolate 44. These intermediates are alkylated reliably
at carbon 45 with most primary, and even with secondary alkyl halides, to give the alkylated
aldehyde 47 after hydrolysis of the imine 46.
H 2N
R 1
R 1 CHO
R 2
The synthesis of multistriatin
N
R 1
H
H 2O
N
Br
R 1
Dutch elm disease is a fungal disease, carried by elm bark beetles, which devastated the elm populations
of many parts of the world in the 1970s. The beetles assemble at a suitable elm tree on the
call of a pheromone containing, among compounds derived from the tree, one charactacteristic
of the beetle itself, multistriatin 48. The stereochemistry of this compound was deduced by the
synthesis of the various possible isomers as so little natural product was available. 8 We shall use
three of these syntheses to illustrate the application of aza-enolates to alkylation reactions.
Multistriatin 48 is an acetal formed from the keto-diol 49. Disconnection 49a next to one of
the branchpoints reveals the enolate of a symmetrical ketone (Et 2CO). This will have to react with
an alkylating agent 50 whose 1,2-diol could be masked if it were made from an alkene 51. This is
doubly attractive as the alkene 51 is available by known chemistry from 52.
O
41
R 1
O
48; multistriatin
HO
OH
50
Li
N
44; aza-enolate
R 2
R 1
LDA
Li
N
R 2
H
R 1
O
R2N
H
42; imine 43
R 2 Br
46; alkylated imine 47; alkylated aldehyde
1,1-diO
acetal
10 Enamines and Aza-Enolates 143
FGI
OH
O
OH
49
45
=
HO
dihydroxylation
X X OTs
51 51; X = OTs
OH
49a
Li
N
1. Mg, Et2O 2. CO2
O
3. LiAlH4
4. TsCl, pyridine
Br
alkylation
of enolate
52

144 10 Specifi c Enol Equivalents
For the alkylation step, Silverstein 9 chose the magnesium derivative 55 of the aza-enolate of 53
and cyclohexylamine 41. Reaction with the toluene sulfonate 51; XOTs gave inevitably a mixture
of diastereoisomers of the enone 56. It turned out not to be necessary to make the diol as the
epoxide 57 could be directly transformed into multistriatin 48 with a Lewis acid catalyst (48 and
57 are isomers). This method produced all four diastereoisomers and the all equatorial compound
48 was identical with natural multistriatin.
41
O
TsOH
benzene
Dean-Stark
N
R
53
54; R = Cy
mCPBA
O
57
O
EtMgBr
SnCl 4
N
BrMg R
55; R = Cy
1. 51; R = OTs
2. HCl, H 2O
O
+
O
O
O
48; 34 parts 48a, b, c; 1, 7, and 58 parts
Synthetic optically active compound was needed to check the absolute confi guration of the
natural product, and disconnection of the intermediate 56a to the aldehyde 58 was chosen as 59
could be made from natural ()-citronellol.
C–C
O
O
56a 58
59
For the alkylation step, the lithium derivative of the t-butyl imine 60 gave a good yield, but
of course a mixture of diastereoisomers. The rest of the synthesis 10 is straightforward and gave
a mixture of compounds from which the correct enantiomer of multistriatin was isolated in 53%
yield. It emerged from this synthesis that the chiral centre next to the ketone could be epimerised
to the correct confi guration during acid-catalysed cyclisation of the fi nal intermediates.
58a
H
All that is needed is a more controlled synthesis of the two other chiral centres, and one such
started from the available cis butenediol 61. Protection as an acetal 63, epoxidation 64, and epoxide
opening with a cuprate (chapter 8) gave the correct diastereoisomer of 65. This undergoes an
acid-catalysed acetal rearrangement from the less stable seven to the more stable fi ve-membered
ring 66, and a suitable leaving group (iodide) is introduced 67. Every step goes in very high yield.
H
C–C
t-BuNH 2 H
1. LDA
2. MeI
59
O
1. EtMgBr
60
N
t-Bu
3. H , H2O
H
2. H , H2O SnCl4 O
O
3. Cr(VI)
4. mCPBA
O
O
56b (–)-48; multistriatin
56
O
H
O

HO
+
OMe
HO
OMe
This time the lithium enolate 68 of 53 was used to give, after equilibration of the centre next
to the ketone, a stereoselective synthesis of racemic multistriatin. 11 The yield in the fi nal step was
98% of an 85:15 mixture of 48 and 70 separated by chromatography.
53
61 62
O
O
65; 94% yield
OH
LDA 67
OLi
68
It would be a fair summary of the present situation to say that lithium enolates of ketones or esters
are now usually preferred to aza-enolates for nucleophilic alkylation, but that lithium derivatives
of cyclohexyl or t-butyl imines are preferred for the nucleophilic alkylation of aldehydes. We shall
treat lithium enolates later, along with the equally popular silyl enol ethers, but there is one more
nitrogen derivative which should come fi rst.
Metallated hydrazones
O
TsOH CH2Cl2 O
1. two drops
conc. HCl
63; 89% yield
O
O
mCPBA
Various derivatives of aldehydes and ketones are used to make stable crystalline compounds for
purifi cation and identifi cation, chiefl y oximes and substituted hydrazones, and it was inevitable
that they should also be tried out as sources of d 2 reagents. Only the N,N-dimethylhydrazones
have emerged as important reagents. Dimethyl hydrazine gives E-hydrazones, e.g. 72 from
unsymmetrical ketones 71 with the NMe 2 group cis to the methyl group. 12 Lithium derivatives
73 can be made with LDA or BuLi and these react with electrophiles (E ) to give a new bond to
the methyl group 74. The products are formed as stable hydrazones and must be worked up under
oxidative conditions, or by alkylation and hydrolysis, to restore the carbonyl group 75.
R
O
O
O O
OH
O
O
64; 99% yield
3. NaI, Me2CO
(99% yield)
O
2. TsCl, pyridine
(98% yield)
1. Me2CuLi
2. NH4Cl, MeOH
66; 98% yield 67
10% HCl
(aqueous)
69; 84% yield, 85:15 mixture 48; multistriatin 70; epi-multistriatin
H 2N NMe 2
R
10 Enamines and Aza-Enolates 145
R
N NMe2
71 72; hydrazone
LDA
N NMe2
NaIO4, pH7
E R
or 1. MeI
2. H , H2O 74
R
O
Li
O
O
N NMe2
73; aza-enolate
75
E
+
O
E
O
O
O
I

146 10 Specifi c Enol Equivalents
Clean reaction occurs with enolisable aldehydes or ketones to give aldol products, e.g. 76 and
with epoxides to give products 77 with a 1,4-relationship between the functional groups. The
oxidative work-up affects neither secondary alcohol, but these can of course be oxidised with
Cr(VI) if a diketone 78 is wanted.
O
71; R = Et
72; R = Et
H2N NMe2
2.
N NMe2
Alkylation and Michael addition also occur, and these are illustrated together in Heathcock’s
synthesis of lycodine intermediates. The dimethylhydrazone of acetone 79 can be alkylated to
give 80. The hydrazone is retained while the lithium derivative is again formed. Though the new
hydrazone 80 must intially have the Z confi guration, its lithium derivative 81 can rotate to the E
confi guration while lithium is exchanged for copper so that a Michael addition to the enone 82 can
be carried out. The product 83 has the expected anti-1,3 relationship due to axial attack, but no
stereoselectivity was found on protonation next to the ketone. 13
Me 2N
N NMe2
N Li
1. BuLi
2.
Br
1. LDA
O
3. NaIO4, pH 7
72; R = Et
N NMe2
79 80
81-Cu +
Lithium Enolates and Silyl Enol Ethers
O
77
Lithium enolates 85 and silyl enol ethers 86 are probably widest in application in modern organic
synthesis. The basic rules of selectivity were laid down in chapters 2-4 where many examples
were given. We shall simply summarise the position and add some extra versatility from chapters
5-9. These two methods must be taken together because easy interconversion means that a way
of making one is a way of making another. In addition, the silyl enol ethers 86 are a source of
“naked” enolates 87 when fl uoride is used to remove silicon in the absence of a metal cation. Tetraalkyl
ammonium fl uorides such as TBAF (Bu 4N F ) are usually used.
R
81
O
LDA
1. PhSCu
O Li
Me 3SiCl
1. LDA
2. MeCHO
3. NaIO4, pH 7
OH
BuLi
PCC
CN
O
O OH
76; 99% yield
78
O
O
82 83
O SiMe3
Bu 4N F
THF
–78 °C
R
MeLi R
(TBAF) R
84 85
86 87
O
O
O
NBu 4
CN

Aldehydes 88 do not form stable lithium enolates as the aldol reaction is too fast, but they
form stable silyl enol ethers 89 under equilibrium conditions. Acids 90 can be transformed into
either type of derivative: the dilithium enolate 91 or the ketene silyl acetals 92. Esters give predominantly
E-lithium enolates and silyl enol ethers, e.g. 65:15 E:Z -95; RMe. Amides rarely give
satisfactory enolates.
R CO 2H
90
R CO2Et
93
2 x LDA
LDA
With ketones we come to the problem of regioselectivity, and the situation from chapter 3 is that
methyl ketones 98 and ketones with one primary and one secondary alkyl group, particularly cyclic
ketones such as 103 give the less substituted lithium enolate 97 or 102 by kinetically controlled
deprotonation with LDA, and the more substituted silyl enol ether 99 or 104 on silylation under
equilibrium conditions. Either derivative (lithium enolate or silyl enol ether) may be used to make
the other, e.g. 96 and 100.
R
R
OLi
Specifi c enolates by conjugate (Michael) addition
R
O
Me3SiCl Et3N R
OSiMe3
88 89
R
OLi Me3SiCl
R
OSiMe3
OLi
OSiMe3 91 92
R
OLi Me3SiCl
R
OSiMe3 OEt
OEt
E-94 E-95
OSiMe3 Me3SiCl R
OLi
LDA
R
O
Me3SiCl Et3N R
OSiMe3 MeLi
R
OLi
96 97 98 99 100
OSiMe3
Me R
R
3SiCl LDA
Me3SiCl After our discovery of Michael additions of lithium cuprates to enones in chapter 9, we are also
now able to make specifi c enolates 106 and 108 of unsymmetrical ketones whose branchpoint is
the β rather than the α atom, such as 3-alkyl cyclohexanones 107. That is, providing we don’t try
and make them from the ketone itself.
O
Et 3N
R
OSiMe3
101 102 103 104 105
R
10 Lithium Enolates and Silyl Enol Ethers 147
O
106
?
R
O
?
O
R
107 108
MeLi
R
OLi

148 10 Specifi c Enol Equivalents
Addition of R 2CuLi to cyclohexenone 109 gives the lithium enolate 110 and hence the silyl
enol ether 14 111. It is not so obvious how to make the alternative enolates, but reduction of enones
with Li in liquid ammonia or in a simple amine such as Et 2NH gives the lithium enolate by
the Michael addition of hydrogen. 15 Two electrons are added to the enone to give the unstable
dilithium derivative 114. One molecule of a weak acid (usually t-BuOH or water) is present which
protonates the more unstable of the two anions to give the lithium enolate 115. This means that
enone 112 is an alternative source of 110 and 111.
R
O
113
EtNH 2
or NH3(l)
114
Since we know many methods to make enones with complete regioselectivity (chapter 5) we are
equipped to make both specifi c enolates of any unsymmetrical ketone, though not necessarily from
the ketone itself. It is of course a strategic advantage to have methods which make carbon-carbon
bonds on the way to specifi c enolates as these methods are more versatile and more likely to be
convergent. 16
An intermediate in Corey’s ginkgolide synthesis
A few examples should make modern approaches plain. In Corey’s ginkgolide synthesis he
needed the intermediate 117 and decided to make it by coupling two vinyl derivatives (see chapters
11 and 20), the one derived from a triple bond 118 and the other an enol derivative of a cyclic
ketone 119.
The fi rst 118 was made by alkylation of a malonate ester followed by hydrolysis and decarboxylation
in the traditional way. With no problems of regio- or stereo-selectivity there is something to
be said for methods easily carried out on a large scale.
EtO 2C
109
O
HO2C
EtO2C
NaOEt
EtOH
R
OLi
110
R
OSiMe 3
R 2CuLi Me3SiCl Li
Li
OHC
R
OH
OLi
t-Bu
ROH
vinyl
coupling
R
111
OLi
115
HO2C
R
O
112
Me 3SiCl
OHC
RO
R
EtNH 2
or NH 3(l)
117 118 119
EtO 2C
EtO2C
+
Cl
EtO 2C
CO2Et
+
1. KOH, EtOH
2. 150–175 °C
116
110
OSiMe3
OH
t-Bu
HO 2C
118

The second 119 clearly came from the ketone 121 and this looks like an aldol product from
CH 2O and a specifi c enolate of the ketone 121. This ketone is substituted at only one α-atom, so
regioselective enolisation would be possible. But there are problems of chemoselectivity (the other
CHO group) and stereoselectivity and a Michael addition approach on the enone 122 looked more
promising. Aldol disconnection of 122 seems to have uncovered an excellent symmetrical intermediate
123 which can cyclise only to give 122.
119
OHC
OH
FGI
O
t-Bu
aldol
O
t-Bu
Michael
+CH2O + t-BuM
Corey evidently did not want to work with a keto-dialdehyde 123 and preferred to consider the
aldol disconnection on the alternative enone 124 (the double bond will readily move into the ring).
This reveals a symmetrical dialdehyde 125, but this is too reactive to be used and Corey preferred
the half-protected compound 126.
OHC
O
120
OHC
The morpholine enamine 127 of cyclopentanone ensured a clean aldol reaction and strong HCl
put the double bond into the ring to give 128. Cuprate addition and trapping by silylation gave the
specifi c enol equivalent 129 which reacted with formaldehyde polymer under the usual Lewis acid
catalysis to give 130, which is 120 protected as an internal acetal. The electrophile (CH 2O) added
to the opposite face of the enol to the one occupied by the t-butyl group. 17
A synthesis of jasmine ketolactone
O
OHC
121
The synthesis of the macrocyclic lactone 131 found in jasmine fl owers illustrates the use of
“naked” enolates. Lactone disconnection to 132 and the usual Michael-based three-component
O
OHC
O
CHO
CHO
122 124
125
O
10 Lithium Enolates and Silyl Enol Ethers 149
FGI
N
MeO
Me3SiO
OMe
1. 126
2. 6M HCl
aldol
MeO
O
OMe
127 128
129
t-Bu
1. (CH 2O) 3
TiCl 4
CH2Cl2
2. MeOH
+
MeO
O
122
O
MeO
1. t-Bu 2Cu(CN)Li 2
2. Me 3SiCl
130
t-Bu
aldol
CHO
126
OHC
O
OMe
123
CHO

150 10 Specifi c Enol Equivalents
disconnection reveals cyclopentenone, an acetate enolate equivalent, and a Z allylic halide 133
with an OH group which will have to be protected.
H
O
O
H
O
131; jasmine ketolactone
The t-butylthiolester 134 provides the silyl enol ether 135 as the acetate enolate equivalent and
adds to cyclopentenone with fl uoride catalysis to give the silyl enol ether 136. Release of the naked
enolate and alkylation with the alkyne 137 gives 138 which has the correct anti stereochemistry
and can simply be transformed into the hydroxy acid. 18 The fi nal cyclisation demands special
methods we shall meet in chapter 43.
O
1. LDA
2. Me 3SiCl
C–O
lactone
When the enolate is formed by reduction of an enone, the fi rst chiral centre is created by protonation
and is often under thermodynamic control. Thus the steroid intermediate 139 is reduced to
the trans decalin 140. Reaction with an electrophile (here CH 2O) occurs on the same side as the
added proton as the group that was already there (the other ring in 140) is bigger than the added
hydrogen atom. The conformational drawing 141a shows that the CH 2OH group is equatorial and
may also have equilibrated by enolisation. 15
Tables of Enol Equivalents and Specifi c Enolates
H
O
OH
H
O
132
OH
1. Bu 4N F
Michael
disconnect
trans groups
134 135
136
H
St-Bu
COSt-Bu
O
H
138
Li, PhNH2
OSiMe 3
OTHP
liquid NH 3
O LiO
139
St-Bu
2. cyclopentenone
1. TsOH, MeOH, H 2O
2. H2, Pd/C, Lindlar
3. Hg(II), H2O
140
H
CH2O
COSt-Bu
OSiMe3
CO 2R
Table 1 lists the simplest enolates. The less reactive enol-like compounds on the left and the more
reactive enolate like compounds on the right. The headings refl ect this but you should be aware by
132
O
HO
O
macrolactonisation
H
2.
Br
+
1. Bu 4N F
H
O
O
X
137
O
H
133
O
131
H
OH
141 141a
OR
OTHP

now that the simple enols and enolate anions shown there cannot be prepared and isolated but are
normally used in equilibrium with the carbonyl compound.
In general terms the reagents on the left are good at conjugate addition while those on the
right are reactive enough to be alkylated. All react with simple carbonyl compounds in aldol and
Claisen ester reactions.
R
R
Ph 3P
OH
O SiMe 3
O
R
R OEt
R OEt
R OEt
Enol 1,3-Dicarbonyl Compound Enolate anion
Modern Use of Specifi c Enolate Equivalents
So which specifi c enolates are in normal use today? The answer is simple - all of them! We shall
end this chapter with a few examples to make the point.
Malonates, lithium enolates and silyl enol ethers in one synthesis
R
O
In a study of ring closure by metathesis (chapter 15) to produce specifi c enol equivalents from
cyclic ketones, Shibasaki 19 decided to use enolates from malonates to make the many starting
materials quickly. For example, alkylation followed by conjugate addition gave starting material
143 in two steps.
MeO2C CO2Me
Enol Carbonyl compound Enolate anion
R
R
O Li
N N Li
Nitrogen Derivatives
R
Enamine Aza-enolate
H
O O
10 Modern Use of Specifi c Enolate Equivalents 151
Oxygen Derivatives
Silyl enol ether Lithium enolate
Conjugated ylide
1. MeO
2.
Br
Phosphorus Derivatives
O O
O
O O
(RO)2P
R
Phosphonate ester
anion
1. MeO
O O
RO
O ZnBr
Reformatsky
2. O
MeO2C CO2Me MeO2C CO2Me
142 143
O

152 10 Specifi c Enol Equivalents
This was converted into the kinetic lithium enolate and then into the silyl enol ether 144.
Metathesis with the Grubbs catalyst (you will meet this properly in chapter 15) gave the cyclic silyl
enol ether 145 in 99% yield.
O
MeO2C CO 2Me
143
If the unsymmetrical cyclic ketone 146 was treated with LDA and Me 3SiCl, some of the same
silyl enol ether 145 was formed but as 30% of a mixture with the alternative 147. This could also be
prepared by metathesis from the unsaturated compound 148, prepared in a similar way. This is surely
the best way to produce specifi c enolates of (though not from) unsymmetrical cyclic ketones. This
study shows how an old method (malonate), modern methods (lithium enolates and silyl enol ethers)
and very modern methods (metathesis) can be used in cooperation to produce excellent results.
O
MeO 2C CO 2Me
146
Other metal enolates
1. LDA
2. Me 3SiCl
OSiMe 3
Later in the book, when we deal with asymmetric enolate reactions, boron enolates will be very
important. A simple example 20 of an aldol reaction with a boron enolate, prepared from the ester
149 and a boron trifl ate using an amine as base, shows why. The boron enolate 150 could be
prepared with a weak base and reacts with the aldehyde without catalysis to give essentially one
diastereoisomer of the aldol 151 in good yield. If the titanium enolate (prepared with TiCl 4 and
an amine) was used, both the yield and the stereoselectivity were worse. In other circumstances
enolates of titanium and other metals are very successful.
Ph
O
1. LDA
2. Me3SiCl
O
Ph
149
O
Me3SiO
Coupling large fragments with metal enolates
Grubbs
catalyst
Me 3SiO
MeO2C CO2Me MeO2C CO2Me 144 145
O
Et3N
O
R2BOTf Ph
O
R = cyclohexyl
Ph
150
+
MeO2C CO2Me 145 (30%)
Me3SiO
MeO 2C CO 2Me
147 (70%)
Even reactive lithium enolates can be used to couple complex fragments burdened with extensive
functionality and stereochemistry. Mulzer’s work on epothilones 21 combined the lithium enolate
BR2
147 only
88% yield
i-PrCHO
Ph
Grubbs
catalyst
O
Me3SiO
O
O
OH
Ph
151; 86% yield
MeO 2C CO 2Me
148

of the ketone 152 with an aldehyde in an aldol reaction to give a 70% yield of the epothilone
analogue 153.
The product 153 is formed in good yield and stereoselectivity though the aldehyde (whose
structure you can easily deduce from that of 153) has an enolisable chiral centre and various
other functional groups and stereogenic centres. Specifi c enolates are vital reagents for the 21st
century.
References
R = SiMe 2Bu-t
O OR
152
OR
10 References 153
1. LDA
2. R*CHO
HO
O OR
General references are given on page 893
1. C. L. Stevens and A. J. Weinheimer, J. Am. Chem. Soc., 1958, 80, 4072; H. R. Snyder, L. A. Brooks and
S. H. Shapiro, Org. Synth. Coll., 1943, 2, 531.
2. S. Danishefsky and B. H. Migdalof, J. Am. Chem. Soc., 1969, 91, 2806.
3. W. L. Johnson, U. S. Patent 2,443,827 (1948); Chem. Abstr., 1949, 43, 677; G. W. Cannon, R. C. Ellis and
J. R. Leal, Org. Synth. Coll., 19, 4, 597.
4. K. Pihlaja and M. Seilo, Acta Chem. Scand., 1968, 22, 3053; 1969, 23, 3003.
5. House, Modern Synthetic Reactions, chapter 9, page 492.
6. S. D. Burke, C. W. Murtiashaw and M. S. Dike, J. Org. Chem., 1982, 47, 1349.
7. G. Stork and S. R. Dowd, J. Am. Chem. Soc., 1963, 85, 2178; G. Wittig and H. Reiff, Angew. Chem. Int.
Ed, 1968, 7, 7; J. K. Whitesell and M. A. Whitesell, Synthesis, 1983, 517; D. Caine in Comp. Org. Synth.,
vol 3, chapter 1.1.
8. W. E. Gore, G. T. Pearce and R. M. Silverstein, J. Org. Chem., 1975, 40, 1705.
9. W. E. Gore, G. T. Pearce and R. M. Silverstein, J. Org. Chem., 1976, 41, 2797.
10. G. J. Cernigliaro and P. J. Kocienski, J. Org. Chem., 1977, 42, 3622; multistriatin has also been made
from glucose, K. Mori, Tetrahedron, 1976, 32, 1979; 1977, 33, 289.
11. W. J. Elliott and J. Fried, J. Org. Chem., 1976, 41, 2475.
12. E. J. Corey and D. Enders, Tetrahedron Lett., 1976, 3, 11; E. J. Corey, D. Enders and M. G. Bock, Tetrahedron
Lett., 1976, 7; E. J. Corey and D. L. Boger, Tetrahedron Lett., 1978, 4597; D. Enders and P.
Wenster, Tetrahedron Lett., 1978, 2853.
13. E. Kleinman and C. H. Heathcock, Tetrahedron Lett., 1979, 4125.
14. G. Posner, J. J. Sterling, C. E. Whitten, C. M. Lenz and D. J. Brunelle, J. Am. Chem. Soc., 1975, 97, 107.
15. G. Stork and J. d’Angelo, J. Am. Chem. Soc., 1974, 96, 7114.
16. Disconnection Approach, page 346.
17. E. J. Corey, M. Kang, M. C. Desai, A. K. Ghosh and I. N. Houpis, J. Am. Chem. Soc., 1988, 110, 649.
18. K. Gerlach and P. Kunzler, Helv. Chim. Acta, 1978, 61, 2505.
19. A. Okada, T. Ohshima and M. Shibasaki, Tetrahedron Lett., 2001, 42, 8023.
20. M. B. Andrus, B. B. V. S. Sekhar, E. L. Meredith and N. K. Dalley, Org. Lett., 2000, 2, 3035.
21. J. Mulzer, G. Karig and P. Pojarliev, Tetrahedron Lett., 2000, 41, 7635.
O
OR
O
OR
S
N
153
70% yield

11
Extended Enolates
Introduction: The extended enolate problem
Kinetic and thermodynamic control
Wittig and Horner-Wadsworth-Emmons Reactions
Extended Aza-Enolates
Extended Lithium Enolates of Aldehydes
Summary: α-Alkylation of Extended Enolates
Reaction in the γ-Position
Extended Enolates from Unsaturated Ketones
Diels-Alder Reactions
Extended Enolates from Birch Reductions
The Baylis-Hillman Reaction
The Synthesis of Mniopetal F
A Synthesis of Vertinolide Using α´-and γ-Extended Enolates
Conclusion: Extended Enolate or Allyl Anion?
Introduction: The extended enolate problem
The extended enolate problem 1 is easily stated but not so easily solved. If an unsaturated ester
1 is treated with base, a conjugated enolate 2 is formed. The conjugated ester 3 can form the
same enolate 2 by loss of one of the marked protons. This intermediate 2 is an extended enolate,
extended by conjugation into a double bond and interesting because a new dimension of versatility
is added to its reactions. Enolates normally have to choose between reaction at oxygen or carbon,
but the extended enolate may also choose at which carbon to react. This chapter is about the
reasons for that choice.
R
H H
1
O
OEt
O
base
R
γ α
OEt
base
2; extended enolate
H H
The two possibilities are traditionally known as α and γ. Reaction in the α position 4 as a d 2
reagent gives unconjugated ester 5 which may become conjugated 1 by α to γ proton transfer via
extended enolate 6. Reaction in the γ position 9 as a d 4 reagent gives conjugated 10 directly. The
remaining possibility – reaction at oxygen – is realised by silylation to give the extended silyl enol
ether 8.
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd
R
3
O
OEt

156 11 Extended Enolates
R
O
O
O
O
α or d
OEt
R
OEt
R
OEt
R
E H
E
2
E E
4 5
6 7
Kinetic and thermodynamic control
8
R
E
9
O
The kinetic site for reactivity is the α position, where the coeffi cient of the HOMO is larger, 2,3 but
reaction at the γ position gives the more stable conjugated product. Ester 5 is the kinetic product
and 7 and 10 are thermodynamic products. Early experiments 4 soon revealed that reactive lithium
enolates such as 12 were alkylated almost exclusively with kinetic control at the α position, making
synthesis of rings 14 possible by double alkylation. 5
Even Michael addition occurred at the same (α) site and the resulting specifi c enolate 15 can be
alkylated with the stereoselectivity expected for three-component reactions from chapter 9 (anti
addition of the new groups). The product 16 was used by Oppolzer in his synthesis of khusimone. 6
The dilithium derivatives 19 of carboxylic acids 17 are much more inclined to alkylation at the
γ position 7 to give 20 though α-alkylation is by no means uncommon, 8 while extended enolates
22 of amides such as 21 occupy a midway position, ratios of 23:24 varying from 67:33 to 98:2
for different R groups. In both these last two examples the metal can be exchanged for copper to
improve γ-selectivity, as it seems copper favours conjugate addition both for nucleophiles and for
electrophiles. 9
17
21
R
11
O
O
O
OH
OEt
NR 2
11
OSiMe 3
LDA
O
LDA
LDA
OEt
OEt
H
Me 3SiCl
12
OLi
1. LDA
OEt
2. cyclopentenone
18
22
O
OLi
RBr
OLi
NR 2
OEt
O
R
13
OLi
15
LDA
RBr
OEt
γ or d 4
O
R
OEt
Br
E H
19
R
23
O
11
OLi
10
O
OEt
1. LDA
2. Br(CH2) 4Br
3. LDA
OLi
NR 2
+
RBr
R
O
O
16
OEt
R
24
14
OEt
O
20
O
OEt
O
NR 2
OH

Alkylation is essentially irreversible, so thermodynamic products are diffi cult to make, but the aldol
reaction is reversible, and the proportion of reaction at the γ position of ester 11 and acid 17 derivatives
in aldol reactions increases both with temperature and time. Hence the α-aldol 27 is the product with
the extended enolate of ester 11 if the reaction is worked up at low temperatures. At higher temperatures
the γ-aldols 25 and E-26 are the only products, 10 the lactone 25 coming from cyclisation of Z-26.
R
Z-25
O
O
Wittig and Horner-Wadsworth-Emmons Reactions
A device for getting extended enolates of esters to combine with aldehydes and ketones in the γ
position is to use a Wittig approach. The bromo-ester 28 is commercially available. Reaction with
a trialkyl phosphite gives the phosphonate ester 29 that gives dienes such as 30 with aldehydes. 11
Phosphonium salts can also be used. 12
28
Other γ-bromoesters such as 31 can be made by radical bromination 13 with NBS (this too is a
γ reaction!) and used in similar Horner-Wadsworth-Emmons reactions. It does not matter if some
reaction occurs at the γ position of 29 or 33 as the Wittig elimination cannot occur on such an
intermediate and it reverses. The products of these ‘aldol’ reactions are dienes 30 and 34 and are
usually made for use in Diels-Alder reactions. We shall return to this subject later in this chapter.
Extended Aza-Enolates
+
Br CO2Me
E-26
(EtO) 3P
O
OEt
1. LDA
2. RCHO
work up
at –15 °C
(EtO) 2P CO 2Me
Br O
NBS NaOH (EtO) 3P O
11
O
Br CO2Et Br
(EtO)2P
31 32
Aldehydes present special problems as usual. For alkylations in the α-position, the aza-enolates
discussed in chapter 10 are the best. The cyclohexylimine 37 can be made in 82% yield from
crotonaldehyde 14 and its lithium derivative 38 reacts cleanly at the α-position with alkyl halides 15
to give the non-conjugated imine 39.
35
CHO
N
Li
11 Extended Aza-Enolates 157
+
H 2N
11
O
OEt
1. LDA
2. RCHO
work up
at –78 °C
O
R OH
27
OEt
O 1. (Me3Si) 2NLi
CO2Me
36
29
K 2CO3
benzene
38; aza-enolate 39
2. i-PrCHO
30; 97:3 E.E:Z,E
O
O
base
RCHO
R
33 34
N
37; imine
RBr H
N
H2O
R
R
40
LDA
CHO
O
O

158 11 Extended Enolates
There is naturally a problem in hydrolysing 39 to the unconjugated aldehyde as the double
bond tends to move into conjugation to give 40 unless the α-position is blocked 42 by two
alkylations. 15
R 1
39
N
1. LDA
2. R 2 Br
R 1 R 2
Aldol reactions also occur with these intermediates 38 though α,γ mixtures are often formed. 16
Silylation of t-butyl imines occurs reliably in the γ-position and this is one of the best ways to
control aldol reactions with extended enolates. 17
Treatment of 45 with an aldehyde RCHO at room temperature with catalytic CsF to remove the
silyl group creates low concentrations of free extended enolate that react in the γ-position with the
new aldehyde to give the imine 46. This can be converted into the true γ-aldol 48 by hydrolysis
and removal of the silyl group.
45
Under more vigorous conditions (100 C) the dienal is formed in good yield and it is even
possible to combine two enals to form a trienal, e.g. 50, regiospecifi cally.
45
Extended Lithium Enolates of Aldehydes
Extended lithium enolates of conjugated aldehydes are more stable than those of simple unconjugated
aldehydes, and can be used particularly where there is a branch at the α-position as in
the vernolepin intermediate 53 which can be made by alkylation of the lithium derivative 18 52. You
will notice that the ketone in 51 is protected, an obvious precaution against enolisation, and it is
impressive that the enolate-acetal in 52 does not fragment.
N
H
H2O
R 1 R 2
41 42
CHO
CHO +
H2N
35 43
molecular
sieves
0°C
pentane
N
44; imine
1. LDA
2. Me3SiCl
Me3Si N
45; γ-silylated imine
CsF, RCHO
DMSO R
OSiMe3 N
ZnCl2 H2O R
OSiMe3 CHO
TBAF
MeOH R
OH
46 47 48
catalytic CsF
PhCH=CHCHO
DMSO, 100°C
H
O
51
O
Ph
O
LDA
N
ZnCl2
H2O Ph
49 50; 92% yield
H
OLi
O
O
Br
CHO
52 53
O
O
CHO
CHO

Summary: α-Alkylation of Extended Enolates
To summarise: α-alkylation of extended enolates of esters, acids, and aldehydes with alkyl halides
or Michael acceptors can be accomplished reliably by kinetic methods. These reactions are
particularly suited to producing quaternary centres between CO and CC functional groups.
Aldol reactions are not so reliable, but can be controlled by temperature in some cases, and by
Wittig approaches in others. We now need to look at ways of getting reaction at the γ-position.
Reaction in the γ-Position
The most obvious methods of activating the γ-position would involve enamines 19 and silyl enol ethers. 20
These are the more stable of the various specifi c enol equivalents (chapter 10) and thus are more suited
to thermodynamic control. Extended enamines 55 are easy to make and are excellent electron-rich
dienes for the Diels-Alder reaction but react in the α-position with most alkylating agents.
OSiMe3
Me3SiCl
Et3N
CHO +
HN
54 35 55
Silyl enol ethers from aldehydes 54 and esters 57 are reagents that give clean reaction at the
γ-position with a variety of electrophiles 58. Acylation occurs under Friedel-Crafts conditions,
and the crowded esterifying group (i-Pr) 2CH in 59 ensures that reaction occurs entirely at the
γ-position. The product is a mixture of double bond positional isomers 61 as both are conjugated
with one of the carbonyl groups.
OMe
56 (cf. 11)
O
59
O
O
1. LDA
2. Me3SiCl 1. LDA
2. Me3SiCl OMe
OSiMe3 57; 93% yield
OSiMe3
60
It is more diffi cult to make alkylation reversible but Fleming and Paterson achieved this by
using a PhS group to stabilise even a primary cation. 21 An alkyl halide is converted into a sulfi de
62 and then into a chlorosulfi de 63 with N-chlorosuccinnimide (NCS) by the Pummerer reaction.
These compounds 63 react with Lewis acids to give sulfur-stabilised cations that react in the
γ-position 64 with silyl enol ethers 65 to give 66.
O
N Cl
O
NCS
N-chlorosuccinimide
R
Cl
PhSH
11 Reaction in the γ-Position 159
NaOH R
SPh
NCS
E
Lewis
acid
OCHi-Pr2
SPh
R Cl
E
MeCOCl
ZnBr2
ZnCl2
58
O
OMe
O
61
O
N
OCHi-Pr2
OR
63
SPh
Raney
nickel
OSiMe3 ZnCl2 R
CO2R R
65 66 67
R
SPh
62 63 64
OR
OSiMe 3
CO2R

160 11 Extended Enolates
The PhS group may be removed in two ways: reductively with Raney nickel to give 67, the
product of γ-alkylation of 65 with the alkyl halide, or oxidatively by thermal decomposition of
the sulfoxide 68 (chapter 32) to give the new double bond in 69, the product of an extended aldol
reaction, like the ester 30.
R
SPh
[O]
Ph
S
O
CO2R
e.g. NaIO4 R
66 68
CO2R
The true extended aldol reaction, the combination of an extended enolate in the γ-position,
with an aldehyde or ketone, can best be realised by combining a silyl enol ether 54 with an acetal
70 under Lewis acid catalysis. 20 The Lewis acid, usually TiCl 4, catalyses the formation of the
oxonium ion 71 which adds in the γ-position to the silyl enol ether [cf. 64] to give the adduct
72 from which the remaining OMe group can be removed with base to give the dienal 73, the
extended aldol product.
OMe TiCl 4
R OMe
R
70 71
OMe
54
OSiMe 3
An excellent example is the synthesis of the visual pigment retinal 74. An aldol disconnection 74a
is possible but four sequential aldols would be needed. But only two extended aldol disconnections
74b and 75 are needed and both require the same extended enolate 22 77.
The starting material is natural β-cyclocitral 76, converted to its methyl acetal 78. The extended
enolate 77 is best realised as the silyl enol ether 79 and reaction with 78 followed by base gives the
trienal 75. Repetition of the three steps gives all E retinal 74. The two extended aldol reactions go
in excellent yield with total regioselectivity, only the base-catalysed eliminations with DBU are
disappointing.
76
80
HC(OMe)3
MeOH
DBU
b
74; retinal
R
OMe
heat
CHO
R
base
R
69
72 73
a
b
CHO CHO CHO
OMe
OMe
TiCl 4
75 76
OSiMe 3
OMe
78; 100% yield 80
75
56% yield
from 78
HC(OMe)3
MeOH
OMe
OMe
1. 79, TiCl 4 (80% yield)
2. DBU (59% yield)
79
81; 95% yield
CO2R
CHO
CHO
77
γ-extended
enolate
CHO
TM 74
retinal

Recent developments include an asymmetric version of the aldol reaction in the γ-position.
The silyl enol ether 82 from ethyl crotonate reacts with aldehydes in the presence of the Lewis
acid SiCl 4 and an asymmetric catalyst (see the paper if you are interested in the structure of this
complex catalyst) to give a high yield of the ‘aldol’ product 83. The γ:α ratio is 99:1 and the
product 83 is virtually enantiomerically pure. 23
O
OEt
OSiMe2t-Bu
OEt
Extended Enolates from Unsaturated Ketones
PhCHO, SiCl 4
catalyst
ethyl crotonate 82 83; 89% yield
With ketones 82 a further dimension of regioselectivity is present. The extended enolate 83 can
be formed in the same way by the loss of the γ-proton, and it can react in either the α or the γ
positions to give conjugated 87 or 88, or unconjugated 84 products. But the ketone may also be
able to enolise on the other side of the carbonyl group, usually called the α´ position, to give a new
enolate 85 which can react at the α´ position to give another conjugated product 86. There are four
possible products in all. The kinetic and thermodynamic factors governing the regioselectivity of
the reactions of the extended enolate are as before, but the enolisation itself is now also subject
to such factors. The protons in the α´ position are more acidic than those in the γ position and so
85 is the kinetic enolate, while the linearly conjugated extended enolate 83 is the thermodynamic
enolate rather than the cross-conjugated and therefore less stable enolate 85.
O
H H
γ
O
α
82
α′
O
Kinetic enolisation and reaction at the α´ position are easy to control by lithium enolates. Hence
cyclohexenone reacts with LDA to give the enolate 90 which is alkylated at the α´ position to give
91 but silylated on oxygen 24 to give 92, much as expected for simple lithium enolates (chapter 2).
α'
removal of α′-proton
11 Extended Enolates from Unsaturated Ketones 161
removal of γ-proton
E E
α′ α′
E
85 86; α′ product 87; γ product 88; α product
O OLi O
R
LDA
RX
89
A spectacular example is the synthesis of the bicyclic keto-ester 93. Two consecutive Michael
disconnections reveal the α´ extended enolate of cyclohexanone 95 and methyl acrylate. The
synthesis is even easier: kinetic enolisation of cyclohexenone with LDA and reaction with methyl
γ
α
83
E
O
γ
O
Ph
E
α
OH
E
O
O
84; α product
90 91
90
92
O
OLi OSiMe3
Me 3SiCl
OEt

162 11 Extended Enolates
acrylate gives the cage ketone 93 directly in 90% yield. 25 Reaction of cross-conjugated lithium
dienolates such as 95 with Michael acceptors tends to give Diels-Alder adducts (see below) and
this may be the mechanism of the addition.
2 3 4
1 CO2Me 5
O
1,5-diCO
CO 2Me
Extra selectivity is needed in the synthesis of the open chain compound 96. This is clearly an
aldol, but analysis reveals the need for two forms of regioselectivity in that an α´ extended enolate
97 is required to add 1,2 to a conjugated aldehyde 35. Fortunately aldehydes tend to prefer 1,2
to 1,4-addition (chapter 9), especially with hard nucleophiles such as lithium enolates, and this
synthesis works as planned. 26
Under more equilibrating conditions such as alkoxide bases in alcohol solution or amide bases
in liquid ammonia, enolisation occurs to give the extended enolate 83 which is then alkylated
in the α-position by alkyl halides. At fi rst this seems the most diffi cult combination to achieve:
thermodynamic enolisation followed by kinetically controlled addition of an electrophile, but it
is in fact a common result achieved with a variety of bases. Examples include the synthesis of
pentethylcyclanone 100, an anti-tussive drug, by alkylation of the enone 103, the aldol dimer
of cyclopentanone. Disconnection at the branchpoint to the available alkyl halide 102; X Cl
requires α-alkylation of the extended enolate 101 derived from the cyclopentanone aldol dimer 27
103. This is easily achieved by sodium amide in toluene. 28
O
O
O
O 3
= MeO2C 4
1
5
2
1,5-diCO
MeO 2C
93 94 94a 95
98
1 2
96
3
1,3-diO
aldol
O OH O O
O
O
LDA H
+
99
alkylation
of enolate
N
O
100 101
base
or acid
C–C
H
O
NaNH2
toluene
OLi
O
97
O
35
+
H
35
TM 96
X
1,2-diX
HN
+ O +
N
O
102
Cl
+
O
+
N
TM 100
O
103 101 102; X = Cl
O

Reaction in the α- or γ-positions (i.e. from the extended enolate) is again best controlled by
enamines or silyl enol ethers, both being formed under equilibrating conditions. 20,29 Enones such
as 104 give the enamine 105 and the silyl enol ether 107 from which the lithium enolate 108 can
be made. Both these intermediates give α-alkylated products 106 or 109. Direct reaction of 104
with LDA would of course give the α´ lithium enolate.
O
Me 3SiCl
104
Et 3N, ZnCl 2
NH
H, reflux
Alkylation of the lithium enolate 108 occurs in the α-position to give 109. This may remain
unconjugated, but in the next example 113, became conjugated. 30 Aza-enolates and hydrazones
achieve α-alkylation too. 31 Reaction in the γ-position of silyl enol ethers requires the same methods
as were used for aldehydes and esters above.
O
A good example of enolate control comes in Stork’s synthesis of abietic acid. 32 The fi rst two
reactions each involve regioselectivity of enolates in the formation of 115 and 117.
O
11 Extended Enolates from Unsaturated Ketones 163
The next stage requires formation of an extended enolate 118 and its reaction with ethyl
bromoacetate. Reactions of enolates with α-bromoesters are not normally recommended as the
basic enolates may remove the rather acidic proton between the ester and the bromine atom. The
extra conjugation in the extended enolate makes it signifi cantly less basic and this reaction goes
105
Me 3SiO LiO O
107 108
N
1. RHal
2. H 3O
MeLi RX
Ot-Bu
Ot-Bu
NaH
DMSO
+
MeO2C
O
110 111
1.
N
H
2. MeI
3. H, H2O
O
R
106
R
109
Ot-Bu
O O
Br
O
112 113
MeO 2C
O NEt2 O
O
NaOEt
114 115 116
117
O
O

164 11 Extended Enolates
cleanly in the α-position and on the opposite face to the axial methyl group. The rest of the synthesis
is described in Fleming, Selected Organic Syntheses. 33
EtO2C Br
O O
O
EtO2C
117 118 119
Diels-Alder Reactions
The extended enolates themselves as well as the enamines and the silyl enol ethers derived from
them are all good electron-rich Diels-Alder dienes showing excellent regioselectivity in reactions
with electron-defi cient dienophiles. Thus extended silyl enol ethers such as 54, 60, and 92 are also
1-substituted butadienes. 34 A typical reaction is the cycloaddition of 120 with the alkyne 121 to give
a single regioisomer of the adduct 122 in high yield. This compound was used by Schlessinger 35 in
his synthesis of senepoxide 123.
+
KOt-Bu
OSiEt 3
CO 2Et
122; 87% yield 123; senepoxide
Enamines such as 55 are even more reactive 19 and 124 reacts regiospecifi cally with the
unsaturated ester 125 to give a single regio- and stereo-isomer of 126 while no 1-RO butadiene
will do so.
The 2-silyloxybutadienes derived from the α´ enolates such as 127 are in some ways even more
interesting. 20 They add equally well to dienophiles such as 128 with the expected “para” regioselectivity,
but the products are now specifi c enol equivalents of cyclic ketones: it would be diffi cult
to make 129 from 130 in any other way.
Me 3SiO
OSiEt 3 CO 2Et
120 (cf. 54) 121
NEt 2
124
+
+
127 128
80 °C
CO 2Me
CO 2Me
NEt2
PhCO 2
125 126
Me3SiO
129
CO 2Me
O
OAc
CO2Me
O
130
OAc
CO 2Me

Extended Enolates from Birch Reductions
Simple Birch reduction of benzoic acid 131 gives initially an intermediate that can be represented
as dianion 132. Proton transfer from CO 2H to the less stable of the two anions gives the enolate
133 that you will recognise as a (doubly) extended enolate with one α- and two γ-positions.
Alkylation occurs at the α-position to give 134. This is a useful way to construct a quaternary
centre on a six-membered ring: the two remaining alkenes can be further developed in many
ways. 36
O
R
CO2H Li, EtNH2 or Na, NH3(l) CO2H γ
α O RX
CO2 γ
131 132 133 134
Functionalised alkyl halides can be used and substitution on the benzene ring is all right. Here
are two examples giving the protected ketone 136 and the diacid 137 in good yields. 37
135
CO 2H
Br
O
O
CO2H O
Birch reduction of aromatic heterocycles is equally rewarding if more challenging mechanistically.
The pyridine diester 138 is reduced to an intermediate that could be drawn as 139. Both
anions are extended enolates but one has the charge delocalised onto the nitrogen atom and so is
less reactive than the other. Alkylation occurs at the α-position 38 to give 140.
i-PrO 2C
Li, NH 3(l)
136; 94% yield
Asymmetric versions of the Birch reduction are now appearing (chapter 28) and a C 2 auxiliary
attached to the furoic acid 141 allows Birch reduction and alkylation between the ring oxygen
atom and the carbonyl group to give, after hydrolysis, enantiomerically pure acids 39 144.
O
N
138
CO 2H
11 Extended Enolates from Birch Reductions 165
CO2i-Pr
1. Na, NH3(l) O
OMe
O
N
O
Oi-Pr
OMe
N
139
1. Na, NH3
2. RX
O
CO 2i-Pr
O
R
131
Li, NH 3(l)
Br CO 2H
2. RX
3. NH4Cl i-PrO2C OMe
O
N
R
CO 2H
CO 2H
137; 79% yield
N
H
140; 90-99% yield
6M HCl
H2O OMe
O R
CO2i-Pr
141 142 143; 57-98% yield 144; >96% ee
CO 2H

166 11 Extended Enolates
The Baylis-Hillman Reaction
The disconnections for the aldol reaction in the α-position on an extended enolate would be something
like this: fi rst move the alkene from conjugated 145 to unconjugated 146 so that aldol disconnection
gives the extended enolate 147 derived from the enone 89. This chemistry demands at least
one hydrogen atom in the γ-position of the enone 89 so that formation of the extended enolate 147 is
possible. That hydrogen is of course replaced when the conjugated product 145 is formed from 146.
R
OH
145
O
FGI
R
OH
O
aldol
We might prefer the simpler disconnection 145a as this gives the starting materials directly. But
supposing the aldol product 148 has no γ-hydrogens? No extended enolate can be formed from the
enone 149, the reaction is impossible and it appears that the disconnection is meaningless.
O OH
R
aldol
145a 89
O O
+
Fortunately this is not so and the Baylis-Hillman reaction 40 allows an escape from these
problems. The enone is mixed with the aldehyde and a catalyst, usually a tertiary amine or
phosphine, is added. The catalyst need not be basic as its role is reversible conjugate addition 150.
This gives the enolate, as we saw in chapter 10, that does the aldol addition 151. The product 152
forms a new enolate that eliminates 153 (E1cB) the catalyst to give the product 148.
R 1
O
150
NR 3
R 1
O
O
NR 3
R 2
The best catalysts are usually DABCO 154 or hydroxyquinuclidine 155 among amines and
tricyclohexylphosphine 156. Efforts continue to fi nd effective asymmetric catalysts. 41 Examples
with acrylates, enolisable aldehydes, and the amine catalysts are 158 and 159.
N
N
151
R
146 147
O
H R R1 R2 R 1
O
H
152
O
NR 3
OH
= N
=
R 2
N N
N
H
+
O OH
O
?
aldol
148 149
R 1
OH
154; DABCO 155; 3-hydroxyquinuclidine
O O
O OH
MeO
+
H
155
MeO
157 158; 90% yield
O
153
OH
NR 3
O
89
O O
R1 R2 + H
R 2
3 P
156 tricyclohexylphosphine
O OH
R 1 R 2
O
O OH
157 +
H Pr
154
MeO Pr
159; 87% yield
148

Recent developments to make the reaction more effi cient have included using stoichiometric
amine in mixed organic aqueous solvents and a notable success was achieved with aromatic
aldehydes to give e.g. 161 and enolisable aldehydes to give e.g. 162 in high yields under mild
conditions. 42
157
OHC
+
N
1 equivalent 154
1:1 dioxan:water
MeO
O OH
N MeO2C OH
NHBoc
160
1 hour, room
temperature
Though some of these reactions use enolisable aldehydes, none uses enolisable Michael
acceptors so the question of competition of this α´ reaction with extended enolisation proper has
not arisen. One alternative approach uses an indium-mediated reaction of the γ-brominated ester
163 with aldehydes to give either non-conjugated 165 or conjugated 166 α´-products. 43
MeO 2C
In(0)
THF/H2O
MeO 2C
One genuine case where the enone can form both normal (α´) and extended enol(ate)s is cyclohexenone
89, the compound we used to introduce this section. Recent results show that Baylis-
Hillman reaction with this enone gives good yields of Baylis-Hillman products 167 providing stoichiometric
155 is used in solution in water or formamide (NH 2CHO) with Yb(OTf) 3 catalyst. The
aldehydes can be aromatic 167a, aliphatic 167b or even formaldehyde 167c most easily used in
aqueous solution. Under these conditions the reaction is quite fast. 44
The Synthesis of Mniopetal F
161; 100% yield
MeCHO MeO 2C
162; 99% yield
Br
InBr
163 164 165 166
O OH O OH O
RCHO
1 equiv 155 R
Ph
89
Yb(OTf)3
NH2CHO or H2O We conclude with two synthesis that include both γ- and α´-selective extended enolate
chemistry. 45 The first is of of mniopetal F. The Horner-Wadsworth-Emmons reaction of 168
(cf. 29) prepared by γ-bromination of an extended enol with the appropriate aldehyde gives
the triene 169 with good (20:1) E:Z selectivity and of course total γ-selectivity. This is
converted into 170.
O
(MeO)2P
CO2Me
11 The Synthesis of Mniopetal F 167
2.
167 167a; 82% yield
1. LiHDMS
CHO
OH
OH
DBU MeO 2C
O
OH
O
OH
167b; 59% yield 167c; 99% yield
CO2Me CHO
168 169; 85% yield 170; R = SiPh2t-Bu
OR

168 11 Extended Enolates
A Baylis-Hillman reaction with the chiral butenolide 171 goes in excellent yield and stereoselectivity
with LiSPh as the catalyst. Sulfur is of course good at conjugate additions. The product
172 is clearly destined for a Diels-Alder reaction and the product 173 is nearly ideal for conversion
into mniopetal F 174.
O
O
171; R* =
(+)-menthyl
OR*
O
170
O
OR*
PhSLi OH OR xylene
OR
A Synthesis of Vertinolide Using α ´ and γ-Extended Enolates
A recent synthesis of the natural tetronic acid vertinolide 175 illutrates several aspects of extended
enolate chemistry. An enone disconnection suggests an aldol reaction between the methyl ketone
176 and crotonaldehyde 35. The ketone 167 might be made by conjugate addition of a reagent for
the γ-extended enolate 178 to butenone 46 177.
O
HO
175; vertinolide
The tetronic acid 181 is easily made by bromination of the ketoester 179 and treatment of
180 with KOH. Protection with the MOM group (MeOCH 2-) gives 182 from which an extended
enolate might be made.
O
CO2Et
172; 88% yield
O
1. Br2, CHCl3
2. air
O
aldol
[+ 35]
Br
O
140 °C
Treatment of 182 with LDA gives the lithium enolate 183. This is an unusually interesting
extended enolate. It has an obvious α-position at C2 but we want reaction to occur at the γ-position
C4. The complexity arises from the other two oxygen atoms. The ring oxygen makes C2 and C3
both nucleophilic and the MOMO group makes C4 nucleophilic as all these connections are enol
ethers. Finally the ring is a furan. The enolate is therefore very stable and thermodynamic control
a possibility. In the event, conjugate addition occurred with butenone 177 at C4 as hoped and in
good yield to give 184.
O
HO
protect HO
O
CO2Et
KOH
176
O
H
OR*
H
O
HO
O
H
OH
H
CHO
173; 68% yield 174; mniopetal F
O
HO
O
O
O
O
MOMCl
i-Pr 2NEt
+
RO
O
O
177 178; d 3 synthon
γ-homoenolate
MOMO
179 180 181; 67% from 167 182; 99% yield
O
O

MOMO
H
O
O
MOMO
O
The aldol reaction of 184 with crotonaldehyde 35 was rather unsatifactory as a mixture of aldol
185 and dienone 186 was formed. The aldol could be converted into the enone with basic alumina
but the yield was only 61%. An alternative was needed.
184
2.
182
1. LDA
35
CHO
LDA
3
4
183
2
1
Since the conjugate addition of the extended enolate 183 works so well, an attractive alternative
is to disconnect the whole side chain and attempt conjugate addition of 183 to the trienone 187.
There is an obvious problem of regioselectivity with 187.
O
HO
175a; vertinolide
O
OH
The trienone 187 could be made by Lewis acid catalysed addition of the α´ silyl enol ether 188
from butenone 177 to the diethyl acetal of crotonaldehyde and elimination with basic alumina.
O
OSiMe3 177 188
O
MOMO
Conjugate addition of the γ-extended enolate 183 to the trienone 187 went in excellent yield and
gave the complete skeleton of vertinolide in one step. Deprotection gave the natural product in a
remarkably short and effi cient way.
MOMO
11 A Synthesis of Vertinolide Using α´ and γ-Extended Enolates 169
O
183
Me3SiCl
OLi
α′
187
185; 63% yield
O
O
OEt
TiCl4
OLi
O
OEt
O
O
O
177
+
187
MOMO
186; 97% yield
O
OEt
O
189
O
MOMO
O
184; 75% yield
O
MOMO
186; 24% yield
O
+
O HCl
AcOH
MOMO
O
O
183
basic
alumina
O
O
187
175; 94%
vertinolide
OLi

170 11 Extended Enolates
Conclusion: Extended Enolate or Allyl Anion?
We have considered a variety of related intermediates in this chapter as extended versions of
enolate ions 191 and as dienes. Another legitimate way to consider them is as acylated allyl
anions 191c, and this leads us to the next chapter where we consider how to use allyl anions in
synthesis.
References
O O O O
base
190 191a
General references are given on page 893
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2. Fleming; Orbitals.
3. R. Gompper and H.-U. Wagner, Angew. Chem., Int. Edn. Engl., 1976, 15, 321.
4. M. W. Rathke and D. Sullivan, Tetrahedron Lett., 1972, 4249; J. L. Herrmann, G. R. Kieczykowski, and
R. H. Schlessinger, Tetrahedron Lett., 1973, 2433; A. Kajikawa, M. Morisaki, and N. Ikegawa, Tetrahedron
Lett., 1975, 4135.
5. A. B. Smith, S. J. Branca, and B. H. Toder, Tetrahedron Lett., 1975, 4225; T. J. Brocksom, M.. Constantino,
and H. M. G. Ferraz, Tetrahedron Lett., 1977, 483.
6. W. Oppolzer and R. Pitteloud, J. Am. Chem. Soc., 1982, 104, 6478.
7. P. M. Savu and J. A. Katzenellenbogen, J. Org. Chem., 1981, 46, 239; W. Oppolzer, Tetrahedron Lett.,
1982, 23, 4673.
8. S. Johnson and L. A. Bunes, J. Am. Chem. Soc., 1976, 98, 5597; M. B. Gravestock, W. S. Johnson, R. F.
Myers, T. A. Bryson, D. H. Miles and B. E. Ratcliffe, J. Am. Chem. Soc., 1978, 100, 4268, W. S. Johnson,
B. E. McCarry, R. L. Markezich and S. G. Boots, J. Am. Chem. Soc., 1980, 102, 352; E. J. Corey and T.
Hase, Tetrahedron Lett., 1979, 335.
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10. R. W. Dugger and C. H. Heathcock, J. Org. Chem., 1980, 45, 1181; G. Cainelli, G. Cardillo, and M.
Orena, J. Chem. Soc., Perkin Trans.1, 1979, 1597; G. Cardillo, M. Orena, G. Porzi and S. Sandri, J. Org.
Chem., 1981, 46, 2439.
11. W. R. Roush, J. Am. Chem. Soc., 1978, 100, 3599; W. Gärtner, D. Oesterhelt, P. Towner, H. Hopf and L.
Ernst, J. Am. Chem. Soc., 1987, 103, 7642; P. J. Reider, P. Davis, D. L. Hughes and E. J. J. Grabowski,
Tetrahedron Lett., 1976, 955; W. R. Roush, H. R. Gillis and S. E. Hall, Tetrahedron Lett., 1980, 21,
1023.
12. E. J. Corey and B. W. Ericson, J. Org. Chem., 1974, 39, 821.
13. R. K. Boeckmann and S. S. Ko, J. Am. Chem. Soc., 1982, 104, 1033.
14. J. K. Whitesell and M. A. Whitesell, Synthesis, 1983, 517 (see page 528).
15. G. R. Kieczykowshi, R. H. Schlessinger and R. B. Sulsky, Tetrahedron Lett., 1976, 597.
16. E. Vedejs and D. M. Gapinski, Tetrahedron Lett., 1981, 22, 4913.
17. M. Bellasoued and M. Salemkour, Tetrahedron, 1996, 52, 4607.
18. H. Ido, M. Isobe, T. Kawai and T. Goto, Tetrahedron, 1979, 35, 941.
19. P. W. Hickmott, Tetrahedron, 1984, 40, 2989.
20. P. Brownbridge, Synthesis, 1983, 85.
21. I. Fleming, J. Goldhill, and I. Paterson, Tetrahedron Lett., 1979, 3209; I. Paterson and L. G. Price, Tetrahedron
Lett., 1981, 22, 2829, 2833.
22. T. Mukaiyama and A. Ishida, Chem. Lett., 1975, 1201.
23. S. E. Denmark and G. L. Beutner, J. Am. Chem. Soc., 2003, 125, 7800.
24. K. B. White and W. Reusch, Tetrahedron , 1978, 34, 2439.
191b
191c

11 References 171
25. R. A. Lee, Tetrahedron Lett., 1973, 3333.
26. G. Stork, G. A. Kraus and G. A. Garcia, J. Org. Chem., 1974, 39, 3459.
27. A. T. Nielsen and W. J. Houlihan, Org. React., 1968, 16, 1: see table on page 114.
28. H. Ueberwasser, CIBA, Ger. Pat., 1,059,901, (1959), Chem. Abstr., 1962, 56, 355f.
29. G. Stork, A. Brizzolara, H. Landesman and J. Szmuszkovicz, J. Am. Chem. Soc., 1963, 85, 207.
30. Z. J. Hajos, R. A. Micheli, D. R. Parrish and E. P. Oliveto, J. Org. Chem., 1967, 32, 3008; W. Nagata,
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Schwatzel and M. Yoshioko, J. Am. Chem. Soc., 1972, 94, 8593; W. Oppolzer, Helv. Chim. Acta, 1979,
62, 1493.
31. G. Stork and J. Benaim, J. Am. Chem. Soc., 1971, 93, 5939.
32. G. Stork and W. Schlulenberg, J. Am. Chem. Soc., 1962, 84, 284.
33. Ian Fleming, Syntheses, pp 76–79.
34. R. H. Schlessinger and A. Lopes, J. Org. Chem., 1981, 46, 5252.
35. G. A. Berchtold, J. Ciabattoni and A. A. Tunick, J. Org. Chem., 1965, 30, 3679.
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2002, 500.

12
Allyl Anions
Introduction: Allyl Grignard Reagents
The [1,3] allylic shift
Allylic Lithiums and Grignard Reagents
Allylic lithiums with C-2 substituents
Allyl Nickel Complexes
Alkylation and a cyclopentenone synthesis
Allyl Silanes
Synthesis: silylation, Wittig, and cycloaddition reactions
The stabilisation of cations by silicon
Reactions: alkylations, reactions with epoxides and aldehydes, conjugate additions
Heterocyclic synthesis with allyl silanes
Reactions with Co-stabilised cations
An Allyl Dianion? The Role of Tin in Anion Formation
Halide Exchange with Chelation: Indium Allyls
Allyl Anions by Deprotonation
The synthesis of all-trans dienes
The synthesis of all-trans retinol
Introduction: Allyl Grignard Reagents
A Grignard reagent 2 can be made from allyl bromide 1 and it reacts cleanly with electrophiles
such as carbon dioxide to give the unconjugated acid 4. So also do vinyl halides such as propenyl
bromide 5, giving the conjugated acid 8. It is important that you understand the difference between
these two series. When the halide is directly attached to a double bond 5 we have a very unreactive
vinylic halide and a well-behaved Grignard reagent 6. We have already used these intermediates
in chapter 5 and we shall meet them in more detail in chapter 16. When the halide is joined, not
directly to the double bond, but to the atom next door we have a reactive allylic halide 1 and a
badly behaved Grignard reagent 2. Controlling the behaviour of allyl anions and metal derivatives
is the subject of this chapter.
Br
Mg
MgBr
CO2 CO2MgBr H
CO2H 1
Et2O 2 3
H2O
4
Br
Mg
MgBr
CO2
CO2MgBr
H
CO2H
5
Et2O
6 7
H2O 8
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

174 12 Allyl Anions
So what exactly is wrong with allyl Grignard reagents? Even if they are symmetrical 2, yields
tend to be low as the allyl metal bond cleaves easily to give relatively stable allyl radicals that may
dimerise or polymerise. When the allyl group is unsymmetrical 9 reaction often occurs at the
“wrong” end of the allyl system, here to give the acid 10 and eventually the tosylate 11 needed in
chapter 10 for the synthesis of multistriatin.
The reaction may occur through a six-membered cyclic transition state 12 that directs the electrophile
to the other end of the allylic system. This is bad enough, but worse is to come.
9
The [1,3] allylic shift
Br
1. Mg, Et2O
1. LiAlH4 2. CO2 CO2H 2. TsCl, pyridine
OTs
9 10
11
1. Mg, Et2O 2. CO2H O
C
O
Mg
Br
O O
Mg
Br
H2O O OH
12 13 10
Very few allylic derivatives are stable: only H, C, O, N, Si, and F are secure from a [1,3] shift.
Halogens may move from one end to the other of the allylic system by an ionic pathway via the
delocalised allylic cation 15 or by a radical chain pathway via the dibromoalkyl radical 19. These
are both equilibrium reactions and the dominant component is the one with the more heavily
substituted double bond 16 or 20.
R
Br
17
Br Br
14
hν
R
Br
18
15
Metals such as Li or Mg may move by way of the η 3 allyl complex 22 from one end 21 to the
other 23 of an allylic system. This η 3 allyl complex has the metal sitting roughly at the middle
of the triangle formed by the three carbon atoms of the allyl system, and at right angles to them,
so that the orbitals of the metal may overlap with all three p-orbitals of the allyl group 24. This
becomes a stable compound rather than an intermediate when M is a transition metal.
R
MgBr
R
MgBr
21 22
23
Br
R
Br
Br
16
R Br
Br
19 20
R MgBr
M
24
R

If neither the halides nor their metal derivatives have a stable structure, how can we expect to
control their reactions? Things are not quite as bad as that. The bromides and chlorides are stable
at low temperatures in the absence of Lewis acid catalysts or radical generators. The Grignard
reagents often react cleanly to give the less substituted double bond isomer, presumably by the
type of process shown in 12. We shall be seeing methods to control transition metal allyls and allyl
silanes which make these intermediates valuable reagents in synthesis, and you should fi nish this
chapter in a confi dent mood without fear of fl uxional allyl compounds.
Allylic Lithiums and Grignard Reagents
Before looking at alternative solutions, let us review the situation with allyl Grignards and allyl
lithiums. Allyl Grignard 2 has a lower basicity than propyl Grignard and it reacts well with aromatic
ketones to give tertiary alcohols 26 without much enolisation. 1 Reactions with conjugated
enones and enals occur by direct (1,2) rather than Michael (1,4) addition, as in the reaction with
acrolein 2 to give 25. Allyl-lithium 28 also gives reasonable yields with enolisable ketones, as in the
adduct 3 31. The reaction of allyl-lithium with the epoxide 29 to give the anti adduct 27 illustrates
regioselectivity as well as stereospecifi city. 4 Reaction at the allylic end of the epoxide occurs
because of the superior reactivity of allylic electrophiles in the S N2 reaction.
OH
25; 57-59% yield
27
OH Li
12 Allylic Lithiums and Grignard Reagents 175
1. Mg, Et2O Br
1. Mg, Et2O 2. OHC
2. ArCO.Me
28
29
1
O
Turning to unsymmetrical allyl derivatives, the halides 9 and 32 are usually used as an 80:20
mixture. Both give the same Grignard reagent that reacts with CO 2 to give 10 and with aldehydes
and ketones with the same regioselectivity 5 to give alcohols such as 33. Another unsymmetrical
allylic halide, existing only in the form 35 with the trisubstituted double bond inside the sixmembered
ring, reacts with ethylene oxide at the more substituted end to give the alcohol 36.
Presumably these unsymmetrical allylic Grignard reagents prefer the form with the more highly
substituted double bond and react via a six-membered cyclic transition state such as 12. In some
cases the regioselectivity can be reversed by exchanging Li or Mg for copper. The allylic Grignard
derived from 35 gives only the alternative alcohol 34 when Cu(I) salts are added before the
epoxide. 6
Br
Br
9 (80 parts) 32 (20 parts)
OH
1. Mg, Et2O
2. Cu(I)
O
30
1. Mg, Et 2O
2. Me 2CO
1. Mg, Et 2O
3.
2.
34
O
35
O
36
Br
28
HO
Li
33
26
OH
Ar
31
OH
OH

176 12 Allyl Anions
The unsymmetrical copper allyl derived from prenyl halides 38 and 39, the basic unit from
which terpenes are constructed, can be alkylated at the less substituted end to give unrearranged
37, though the corresponding Grignard reagent gives a mixture of products. 7 The corresponding
lithium derivative, made from prenyl bromide 39, reacts with aldehydes with the reverse regioselectivity.
8 The copper derivatives are probably η 3 allyls and react at the less hindered end, as do
the nickel allyls soon to be discussed.
1. Mg
R 2. Cu(I)I
Cl
Br 2. t-BuCHO
3. RX
OH
37 38 39 40
The extra delocalisation in an allyl anion might tempt one to make lithium allyls by removal of
a proton from an alkene. This approach is not generally very successful. Either E or Z-but-2-ene 41
can be deprotonated, but t-BuLi is needed as well as the lithium chelating agent TMEDA (Me 2NCH 2-
CH 2NMe 2). The lithium allyl prefers the Z confi guration 42 but gives a mixture of regio and stereoisomers
43 and 44 on alkylation. 9 Nor is it possible to make useful lithium allyls by addition of, say
BuLi, to butadiene 45 as the resulting allyl lithium 46 adds to another molecule of butadiene to give
another allyl lithium 47 and polymers are formed. 10
E-41
45
or
Z-41
RLi
Allylic lithiums with C-2 substituents
1. Li, THF
t-BuLi, hexane RX
R
Me2N NMe2 Li
42; 85:15 E:Z
+
R
Z-44; 46% yield
43; 46% yield
(+ 8% E-44)
R
Li
45
R
Li
46 47
One way in which allyl lithiums can be made by direct deprotonation is when the allyl system has
a substituent not at one end but in the middle, and when the substituent is of the kind we used in
chapter 7 for directing aromatic lithiation. The simplest examples are amides such as 48 that react
with two molecules of BuLi to give a dilithium derivative 11 often represented as an allyl complex
50b though it is probably a lithium σ-complex 50a. These amide derivatives react with aldehydes
and ketones to give lactones, 12 e.g. 53 via adducts such as 52.
Me
H
N
N R
O
H
BuLi
N R
Li
O
H
BuLi
N R
Li
O
Li
N R
Li
O
or
Li
48 49 50a 50b
O
1. two equivalents
s-BuLi
2. Me 2CO
Me
Li
N
O OLi
51 52 53
H
H 2O
O
O

Similar compounds 56 can be made 13 from zinc derivatives of bromoesters 54 and even the
simple alcohol 14 57 gives the diol 59 and hence another exo-methylene lactone 60 by oxidation.
H
Br
OH
OEt
O
t-BuOK
t-BuLi
Allyl Nickel Complexes
1. Zn
54 55
57 58
OEt
O Li
Li
O
Zn
Me 2CO
2. RCHO
Perhaps the most useful of the η 3 allyl complexes (cf. 24) are the π-allyls of nickel. 15 The simplest
type 61 are rather unstable and form the bromide-bridged complex 62 on treatment with HBr.
These are stable compounds offi cially complexes of Ni(I) but better regarded for our purpose
as dimers of η 3 complexes of allyl anions and Ni(II), much as allyl Grignard reagents 2 can be
regarded as σ-complexes of allyl anions and Mg(II). Direct exchange of Mg(II) for Ni(II) gives
the unstable complexes 61, but the stable dimer 62 can be made by oxidative insertion of Ni(0), as
its cyclo-octa-1,5-diene (COD) complex, into allyl bromide 1.
These π-allyls of nickel are prone to give allyl dimers, but the more stable complexes 62 are useful
for coupling with alkyl halides, the allyl group of 62 acting as an allyl anion equivalent. That
this is not an S N2 reaction, but a coupling on the nickel atom, is clear because even aryl halides
react successfully. Almost all the published examples involve substituted allyl groups, particularly
in the 2-position. Thus the 2-methylallyl complex 64 couples with alkyl iodides or iodobenzene to
give adducts, e.g. 65 in excellent yield. There is good selectivity for iodides against other halogens:
thus the complex 66, derived from 54, displaces only iodide from 67, again in excellent yield. 15
CO 2Et
54
Br
Unsymmetrical allyl complexes react almost exclusively at the less substituted end of the allylic
system. Santalene 71 has been prepared from 69 and 16 in two ways. Coupling the Grignard
reagent 70; MX MgBr with 16 gives 20% yield 16 while the allyl nickel complex 70; MX NiI
couples with 16 in 95% yield. 17 This is a major development from the allyl derivatives of Mg and
Li, which tend to react at the more substituted end of the allyl system, and are in any case less well
behaved than the nickel complexes.
OH
OH
O
O
R
56
O
[O] O
59 60
MgBr
NiBr2
Ni
HBr
Ni
Br
Ni
Br
Ni(0)
COD
2 61 62 1
63
Ni(0)
COD
Br
Ni(0)
COD
12 Allyl Nickel Complexes 177
EtO 2C Ni
Ni
Br
Ni
Br
66
Br
Ni
Br
PhI
Ph
64 65; 98% yield
CO 2Et
I Br
67
CO2Et
Br
68; 96% yield
Cl

178 12 Allyl Anions
Alkylation and a cyclopentenone synthesis
Modern developments have included allyl groups functionalised at the ends, particularly those derived
from silylated enals such as 72. The application shown here creates a cyclopentenone 74 by
combination of the allyl nickel 73 with an alkyne and CO rather in the style of the Pauson-Khand
reaction (chapter 6). 18
O
72
acrolein
This last example succeeds partly because nickel catalyses the union of the three reagents in
the second step. Similar things happen in the combination of nickel allyls with zinc borates 76.
The allyls are derived from unsymmetrical allylic acetates 75 and react at the end remote from the
phenyl group (R 1 is an alkyl group and R 2 is an aryl or alkyl group). 19
Allyl Silanes
X MX
metal
Br
+
69 70 16 71
Ni(COD) 2
Me 3SiCl
Me3SiO
Ph OAc
R1 Me
+
Me
O
B
O
Me
75 76
Cl
Ni Ni
Cl
OSiMe3
The most useful of all allyl anion equivalents are the allyl silanes. 20 This is because it is easy to
make them regioselectively, because they do not undergo allylic rearrangement (silicon does not
do a [1,3] shift) and because their reactions with electrophiles are very well controlled: addition
always occurring at the opposite end to the silicon atom. Symmetrical allyl silanes can be made
from allyl-lithiums or Grignards by displacement of chloride from silicon. A useful variant is to
mix the halide with a metal, e.g. sodium, and Me 3SiCl in the same reaction, rather after the style
of the silicon acyloin reaction, 21 as in the synthesis of the acetal 80.
MeO
OMe
79
Synthesis: silylation, Wittig, and cycloaddition reactions
Cl
73
R 2
NiCl 2(PPh 3) 2 Ph
77; NMI
Na, Me 3SiCl
Et 2O
CO2Me
Syntheses of unsymmetrical allyl silanes from Grignard reagents are subject to the usual
regioselectivity problems. The mixture of halides 81 and 82 gives a mixture of Grignard reagents,
1. CO,
2. MeOH
MeO
MeO
O
R1 78; 76-98% yield
OMe
80
R 2
OMe
74
Me
SiMe3
CO 2Me
N
O
N
77; NMI
Me

see 21 and 23, from which a mixture of allyl silanes 83 and 84 can be made. 22 However, this mixture
can be converted 23 into the thermodynamic product (83, as a mixture of E and Z isomers) by
TBAF (Bu 4NF) at 100 C as the fl uoride ion is a nucleophilic catalyst, attacking the silicon atom
with excellent chemoselectivity. More highly substituted allyl halides like 38 give only the less substituted
allyl silane 24 85. This may seem a disadvantage, but it is quite the reverse as you will see.
Cl
One reliable method for getting the silicon on the less substituted end of the allylic system
is the Wittig approach of Seyferth. 25 The unsubstituted reagent 86 reacts well with ketones to
give allyl silanes of the type 87. Alternatives depend on cycloaddition reactions: 1-trimethylsiclylbutadiene
88 gives Diels-Alder adducts, e.g. 89 with maleic anhydride. Direct silylation of the
cyclopentadienyl anion 91 gives 92, one of the few substituted cyclopentadienes which is useful in
cycloadditions. A 22 cycloaddition with dichloroketene 26 gives the cyclobutanone 93 which can
be dechlorinated with zinc. Both 93 and 94 are allyl silanes. 27
Ph 3P
90
86
The stabilisation of cations by silicon
+
Cl
81 82
1. base
SiMe3 2. cyclohexanone
38
1. base 2. Me 3SiCl
91
1. Mg, Et 2O
2. Me3SiCl
SiMe3 SiMe3 +
83; 25% yield, 3:2 Z:E 84; 75% yield
Cl
1. Mg, Et2O
2. Me3SiCl
85
SiMe3 SiMe 3
SiMe 3
H
Me 3Si
87 88 O
89
92
Cl COCl
Even if silicon chemistry is new to you, you should by now have a picture of stable compounds with
C-Si bonds and selective reaction with fl uoride. You are already familiar with silyl enol ethers as
nucleophilic enolate equivalents and allyl silanes resemble these in many ways. The missing link
is the β-silyl effect. A Si atom stabilises a cation in the β-position by overlap of the populated and
relatively high energy C-Si σ-orbital with the empty p orbital of the cation. This overlap is already
present in the preferred conformation 95a of the allyl silane 95 as an anti-bonding interaction 95b
between the C-Si σ-orbital and the π orbital of the double bond. The resultant molecular orbital
(the new HOMO) 95c increases the nucleophilic reactivity of the carbon atom in the γ-position.
α
Me3Si Me3Si
β
γ
H
H
95; allyl silane 95a; preferred
conformation
12 Allyl Silanes 179
Cl
Et 3N
Me 3Si
H
Me 3Si
H
H
93
H
95b; σ and π
bond HOMOs
O
O
O
Cl
Cl
σ + π
Me 3Si
Zn
Me3Si
H
H
Me 3Si
H
H
94
95c; HOMO
of molecule
H
H
O
O
O
O

180 12 Allyl Anions
Electrophilic attack on an allyl silane therefore occurs 96 away from the silicon to give the
stabilised cation. A nucleophile, particularly an oxygen or halogen nucleophile such as MeOH or
Cl , attacks the silicon atom selectively 97 and removes it to give the allylic product 98 in which
the electrophile has added regiospecifi cally to the far end (from Si) of the allyl silane. The β cation
97a is stabilised by a bonding overlap between the fi lled C–Si σ-orbital and the empty p-orbital of
the cation. This is σ-conjugation or hyperconjugation.
Me 3Si
E
X
β
Me3Si E E
Me3Si
96 97 98
97a
Reactions: alkylations, reactions with epoxides and aldehydes, conjugate additions
The range of electrophiles is very large. 20 Alkylation with tertiary alkyl halides, e.g. 99, and Lewis
acid catalysts allows the synthesis of molecules with two adjacent quaternary centres, 28 such as
100 from 87.
The best alkylating agents are those which give the most stable cations: only the halide next
to oxygen in 101, which can give 101a the oxonium ion 102, reacts with allyl silane 29 to give 103.
That the reaction involves regiospecifi c attack at the end of the allyl system away from silicon
is shown by the oxonium ion 105 and 93 which also react stereoselectively on the outside of the
folded bicyclic structure. 30
Cl
Cl
101
O
SiMe3
+
Cl
87 99 100; 98% yield
Cl
Cl
O
MeO Cl MeO CH 2
104 105
101a
Me3Si
Cl
Epoxides generally react at the more substituted end, even in intramolecular endo-like reactions
such as the cyclisation of 107, as this gives the more stable cation. 31 The allyl silane must capture
the epoxide in 107 as it opens and it must do so faster than the familiar rearrangement of epoxides
under the same conditions (BF 3).
O
TiCl 4
Me 3Si
102 103; 90% yield
H
H
93
O
Cl
Cl
Me 3SiI
MeO Cl
SnCl 4
H
H
Cl
H
O
O
E
Cl
H Cl
MeO
106; 78% yield

Me 3Si
Et 2O.BF 3
There are many regiospecifi c reactions with aldehydes and ketones, such as the four- membered
ring example 110 which gives an addition to the aldehyde 111 very like the aldol reaction with
a silyl enol ether (and even uses the same catalyst, TiCl 4) to give the unsaturated alcohol 32
112 - presumably the key step is 113.
Me 3Si
110
Additions to enones, e.g. 115 generally occur in the Michael sense giving δ,ε-unsaturated
enones 33 such as 116. Acetals 118 can replace aldehydes in additions with allylic transposition 34 as
in 117 to 119 and acylation occurs with acid chlorides as in the synthesis of the terpene artemisia
ketone 122 from two C 5 units with at least a passing resemblance to the biosynthesis of this
irregular terpene. 20,35
Me 3Si
Heterocyclic synthesis with allyl silanes
Me 3Si
O O
OH
BF3 107
108 109; 71% yield
Me3Si
+ OHC
TiCl4 Me3Si OH
O
111 112; 86% yield
113
120
+
+
O
Two aspects of allyl anion chemistry are combined in the synthesis of bicyclic lactams by Gramain
and Remuson. 36 Treatment of the unsaturated alcohol 123 with BuLi initially forms the lithium
alkoxide 124 and then the allyl lithium 125, possibly better represented as 125a. The proton is
removed only from the methyl group rather then the internal CH 2 group. Reaction with Me 3SiCl
and careful acidic workup gives the allyl silane 126.
O
TiCl3
114
115 116; 78% yield
CO2Me
CO2Me
+
Ph
OEt
OEt
TiCl4
Ph
OEt
CO2Me CO2Me
117 118 119; 100% yield
SiMe3
12 Allyl Silanes 181
O O
Cl
TiCl 4
AlCl 3
121 122; 90% yield

182 12 Allyl Anions
BuLi
BuLi
1. Me3SiCl Li
123
OH
124
OLi
125
OLi
Li
O
Li
The allyl silane 126 is coupled with the imide 127 by a Mitsunobu procedure and one of the
carbonyl groups is reduced to give the alcohol 129. Treatment with CF 3CO 2H now cyclises the
allyl silane to give a new heterocyclic ring 130.
126, Ph3P
DEAD
O N
H
O THF O N O
127 128
More recent developments with allyl silanes have included the use of single enantiomers
such as (R)-133 that adds in a Mannich-style reaction to give (S)-134 with about 95% enantioselectivity.
37
N
Reactions with Co-stabilised cations
SiMe3
125a
Me3Si
2. 10%
H 2SO 4 126
NaBH4 MeOH
CF3CO2H 0 ˚C O N OH
O N
ClCO2Ph SiMe3 AgOTf
+
N
CO2Ph Ph H
SiMe 3
More exotic electrophiles include cobalt-stabilised cations derived the alcohol (S)-138 made by
a sequence of reactions that shows the stability of allyl silanes to bases. The cuprate from Z-135
adds to a single enantiomer of the epoxide (S)-136 and the tosylate in the product (S)-137 is displaced
by a Co(I) anion to give the intermediate (S)-138 as a stable orange solid. 38
In acid solution, cobalt creates a π-stabilised cation at the site of the OH group that cyclises onto
the allyl silane with the expected regioselectivity and excellent enantioselectivity. The nature of
the cation stabilisation and the removal of the cobalt are discussed in the workbook. The structure
of this group ‘Co(dmgH) 2py’ is explained in the workbook.
OH
129 130; 94% yield
131; quinoline 132 (R)-133 (S)-134
Cl
1. Mg, THF
2. Li2CuCl 4
OH
OTs
Co(dmgH) 2py
3. O
SiMe3
OTs
SiMe3 SiMe3 Z-135 (S)-136 (S)-137 (S)-138
OH
N CO2Ph
Co(dmgH) 2py
Ph

OH
Co(dmgH) 2py
SiMe3 (S)-138
0.3 equivs TsOH Co(dmgH)2py
OH
An Allyl Dianion? The Role of Tin in Anion Formation
The prospects of inventing a reagent for the dianion synthon 141 might look remote but the
reagent 142, both an allyl silane and an allyl stannane, does the job. 39 Reaction with one
aldehyde occurs at the end occupied by tin and the second, using a different Lewis acid, at the
end occupied by silicon. The result is a tetrahydropyran 144 with 2,6-syn substituents, both
being equatorial.
141
12 Halide Exchange with Chelation: Indium Allyls 183
A commoner role for tin is to sacrifi ce itself in the formation of allyl anions (or allyl lithiums)
with BuLi. The ‘allyl’ (it has a nitrogen atom in the backbone, so strictly an ‘aza-allyl’) tin 145
reacts with BuLi to form Bu 4Sn and the allyl anion 146 that adds to the styrene 147 in a 1,3-dipolar
cycloaddition to give the amide ion 148 that eliminates pyrrolidine to give the imine 149. The
imine 149 is formed as a 10:1 mixture of positional isomers. 40
Halide Exchange with Chelation: Indium Allyls
THF
Bu3Sn SiMe3 SiMe3 R1 OH
R1CHO 142
SnBu3
Ti(OPr i ) 4
i PrSBEt2
139 140
R O 1 R2 144
The problem with forming allyl metal derivatives by exchange of zerovalent metal with halide ions
is that we often cannot be sure where the halide ion is and never sure where the metal is because
of rapid [1,3] shifts, cf. compounds 21 and 23. If the allylic system has a substituent that chelates
with the metal then only one derivative is likely to be formed. We need a halide at one end of the
allyl group and a chelating substituent at the other. Just such compounds can be made by acylation
of acrolein 72 in the presence of zinc chloride. No [1,3] shift of Br will occur as the alkene
much prefers to be disubstituted and conjugated with oxygen 151 rather than unconjugated and
terminal 152.
143
BuLi
N N N N
N N
147
Bu 4Sn
145 146
Ph
Ph
148
R 2 CHO
Me 3SiNTf 2
Ph
N
149; 88% yield
10:1 isomers

184 12 Allyl Anions
H
O
O ZnCl 2
Br Me
Whichever isomer (positional or geometrical) of the indium allyl is fi rst formed (e.g. 153) is
unimportant as equilibration leads to the stable chelated version 154 that reacts with aldehydes to
give, as expected, reaction at the other end of the allyl system from the metal. 41 The product 155 is
formed as a syn/anti mixture but the syn isomer can predominate by as much as 90:10. You may
wonder why indium was used. The usual reason for indium is that its organic derivatives are stable
in water but here the more important point is the low reactivity of allyl indiums.
151
In(0)
Allyl Anions by Deprotonation
In the next chapter we shall see that allyl anions made from allyl silanes 95 by the removal of a
proton still react in the γ-position 156 but retain the silyl group in the form of a vinyl silane 157
and are reagents for the d 3 synthon, the homoenolate ion. Though the Me 3Si group is electrondonating
it is also anion stabilising. Other electron-rich but anion-stabilising groups such as
amines 158 also form anions that react in the γ-position.
Allyl anions with electron-withdrawing and anion-stabilising functional groups form anions
much more easily and then react (mostly) in the α-position. There are many examples of this sort
of substituent including extended enolates (chapter 11), and allyl anions stabilised by phosphonium
159, phosphonate 160, sulfone 161, and cyanide 162 functional groups. All of these prefer to
react in the α-position (at least kinetically) and we shall explore some of these.
The synthesis of all-trans dienes
+
Br
72 150 151 152
InLn O
RCHO
OH
OH
O
LnIn O O
OAc
R +
OAc
R
153 154
syn-155 anti-155
Me3Si BuLi
Me3Si E Me3Si E R2N α γ
95: allyl silane 156; reaction at C-γ 157: a vinyl silane 158: allylic amine
Ph 3P Ph 2P
159: allyl phosphonium
ylid
O
160: allyl phosphonate
anion
We shall fi nish this chapter by considering two ways to achieve condensation between an allyl
anion and an aldehyde (or ketone) in the synthesis of dienes 163. The reagent 165 is an allyl anion
stabilised by a heteroatom (Z) that can be lost with the OH group after addition to R 1 CHO.
O
O
O O
S
Ph
161: allyl sulfone
anion
NC
Br
O
O
162: allyl cyanide
anion

R 1
The best candidates are phosphonium salts (Z Ph 3P ) 167, using the Wittig reaction, and
sulfones (Z PhSO 2) 168, using the Julia reaction, 42 as we shall see in chapter 15. Wittig reagents
are easily made from allylic halides, substitution usually occurring at the less hindered end, and
react with aldehydes at the site next to the Ph 3P group since elimination of Ph 3PO can occur only
if this regioselectivity is observed (c.f. the similar solution to the γ-extended enolate problem,
chapter 11).
Ph
O O
S
These ylids are classifi ed as “semi-stabilised” or of “intermediate” reactivity, and their stereoselectivity
may be poor. 43 If the stereochemistry of the double bond in the ylid (from 167) is
E, this is generally retained in the product, but if it is Z, as in the ylid derived from 170, low
temperatures are needed to stop rotation at the allyl ylid stage. At 25 C less than 5% E-171
is formed in the synthesis of vitamin D metabolites. 44 The stereochemistry of the new double
bond is generally not well controlled, 1:1 ratios of E:Z are not uncommon, but Vedejs fi nds
that phosphonium salts such as 172 with two phenyl and two allyl groups give good yields of
E-dienes 45 such as 173.
The synthesis of all-trans retinol
R2 R1 CHO R2 + Z
E,E-163 164 E-165
R2 Br R2 Ph3P 1. base
166 167
2. R1 Ph3P
CHO
168
12 Allyl Anions by Deprotonation 185
OH
R 2
1. base
2. R 1 CHO
R 1
OH
SO 2Ph
If E,E dienes like 163 are wanted, then such Wittig reactions are ideal as the mixed products
can be equilibrated to the E,E diene by addition of small amounts of radical generators such as
iodine or PhSH. The commercial (BASF) synthesis of Vitamin A involves all trans retinol 174
that can be made from two different allylic ylids derived from 175 and 178 with the appropriate
aldehydes 176 and 177. In both cases E,Z mixtures are formed, but equilibration with iodine
gives 174 with an all E side chain. 46 A different synthesis of such compounds appeared in
chapter 11.
169
1. two equivalents BuLi, –25 ˚C
R 2
R 1
1. Ac2O
pyridine
2. Na/Hg
PPh3 2. cyclohexanone
Z-170 Z-171
PPh2 2
172
1. BuLi
2. PhCHO
E-173
E,E-163
OH
E,E-163
Ph
R 2

186 12 Allyl Anions
Direct α-alkylation of anions of allylic sulfones 179 gives products 180 from which PhSO 2
can be eliminated with mild base (MeONa) to give E-dienes 181. The more usual condensation
of sulfones with aldehydes is not necessary and those adducts 169 may eliminate to give vinyl
sulfones instead of alkenes. 47
As part of a synthesis of sesquiterpenes, the sulfone 182 and the allylic halide 183 were coupled
(allylic electrophile as well as allylic nucleophile!) to give a mixture of diastereoisomers of 184
that gave the triene 185 on elimination. 48 Note that the new double bond is exclusively E.
OH
182
175
References
174; all trans- (E) retinol acetate
PPh3
SO 2Ph
2.
SO2Ph 1. BuLi
2. RCH2Br SO2Ph
R
base
179 180 E-181
1. two equivalents BuLi
2.
Br CO2Me 183
1. PhLi
OHC OAc
176
OH
OAc
174
OHC OAc
177
CO2Me
MeONa
SO2Ph 184 E-185
General references are given on page 893
1. M. S. Kharasch and O. Reinmuth, Grignard Reactions of Non-Metallic Substances, Prentice-Hall,
New York, 1954, Table VI-XVIII; J. Mazurewitsch, J. Russ. Phys. Chem. Soc., 1911, 43, 973.
2. A. J. Sisti, Org. Synth. Coll., 1973, V, 46.
3. D. Seyferth and M. A. Weiner, Org. Synth. Coll., 1973, V, 452.
4. M. Apparu and M. Barrelle, Bull. Soc. Chim. Fr., 1977, 947.
5. J. F. Lane, J. D. Roberts and W. G. Young, J. Am. Chem. Soc., 1944, 66, 543; J. D. Roberts and W. G.
Young, J. Am. Chem. Soc., 1945, 67, 148.
6. G. Linstrumelle, R. Lorne and H. P. Dang, Tetrahedron Lett., 1978, 4069.
7. F. Derguini-Boumechal, R. Lorne and G. Linstrumelle, Tetrahedron Lett., 1977, 1181.
8. T. E. Stanberry, M. J. Darmon, H. A. Fry and R. S. Lenox, J. Org. Chem., 1976, 41, 2052.
9. R. B. Bates and W. A. Beavers, J. Am. Chem. Soc., 1974, 96, 5001.
10. B. J. Wakefi eld in Comprehensive Organometallic Chemistry, chapter 44, vol VII, page 1 (see page 8).
11. J. J. Fitt and H. W. Gschwend, J. Org. Chem., 1980, 45, 4257.
12. P. Beak and D. J. Kempf, J. Am. Chem. Soc., 1980, 102, 4550.
2.
1. PhLi
8
174a; Wittig disconnections
4
OH
178
R
OAc
PPh 3
CO 2Me

12 References 187
13. H. Mattes and C. Benezra, Tetrahedron Lett., 1985, 26, 5697.
14. R. M. Carlson, Tetrahedron Lett., 1978, 111.
15. M. F. Semmelhack, Org. React., 1972, 19, 115.
16. E. J. Corey, S. W. Chow, and R. A. Scherrer, J. Am. Chem. Soc., 1957, 79, 5773.
17. E. J. Corey and M. F. Semmelhack, J. Am. Chem. Soc., 1967, 89, 2755.
18. G. García-Gómez and J. M. Moretó, J. Am. Chem. Soc., 1999, 121, 878; Eur J. Org. Chem., 2001, 1359.
19. Y. Kobayashi, Y. Tokoro and K. Watatani., Eur J. Org. Chem., 2000, 3825.
20. I. Fleming, Comp. Org. Chem. vol 3, chapter 13, page 542; P. D. Magnus, T. Sarkar, and S. Djuric,
Comprehensive Organometallic Chemistry, vol 7, chapter 48, page 515; E. Colvin, chapter 9, page 97;
T. Chan and I. Fleming, Synthesis, 1978, 761; I. Fleming, J. Dunogues, and R. Smithers, Org. React.,
1989, 37, 60.
21. I. Fleming, R. Snowden and A. Pearce, J. Chem. Soc., Chem. Commun,, 1976, 182; Disconnection Approach
page 202.
22. J. Slutsky and H Kwart, J. Am. Chem. Soc., 1973, 95, 8678.
23. A. Hosomi, A. Shirahata and H. Sakurai, Chem. Lett., 1978, 901.
24. J.-P. Pillot, J. Dunogues, and R. Calas, Tetrahedron Lett., 1976, 1871.
25. D. Seyferth, K. R. Wursthorn and R. E. Mammarella, J. Org. Chem., 1977, 42, 3104.
26. Disconnection Approach, chapter 33, page 274.
27. B.-W. Au-Yeung and I. Fleming, J. Chem. Soc., Chem. Commun., 1977, 79.
28. I. Fleming and I. Paterson, Synthesis, 1979, 446.
29. H. Sakurai, Y. Sakata, and A. Hosomi, Chem. Lett., 1983, 409.
30. I. Fleming and B.-W. Au-Yeung, Tetrahedron, 1981, 37, supplement no 1, 13.
31. D. Wang and T.-H. Chan, J. Chem. Soc., Chem. Commun., 1984, 1273.
32. S. R. Wilson, L. R. Phillips, and K. J. Natalie, J. Am. Chem. Soc., 1979, 101, 3340.
33. I. Ojima, M. Kumagai, and Y. Miyazawa, Tetrahedron Lett., 1977, 1385.
34. A. Hosomi, M. Saito, and H. Sakurai, Tetrahedron Lett., 1980, 21, 355.
35. G. Déléris, J.-P. Pilot, and J.-C. Rayez, Tetrahedron, 1980, 36, 2215.
36. J.-C. Gramain and R. Remuson, Tetrahedron Lett., 1985, 26, 327.
37. R. Yamaguchi, M. Tanaka, T. Matsuda and K. Fujita, Chem. Commun., 1999, 2213.
38. G. Kettschau and G. Pattenden, Tetrahedron Lett., 1998, 39, 2027.
39. C.-M. Yu, J.-Y. Lee, B. So and J. Hong, Angew. Chem., Int. Ed., 2002, 41, 161.
40. W. H. Pearson, E. P. Stevens and A. Aponick, Tetrahedron Lett., 2001, 42, 7361.
41. M. Lombardo, R. Girotti, S. Morganti and C. Trombini, Org. Lett., 2001, 3, 2981.
42. M. Julia, Pure Appl. Chem., 1985, 57, 763.
43. B. Maryanoff and Reitz, Chem. Rev., 1989, 89, 863; I. Gosney and A. G. Rowley in Organophosphorus
Reagents in Organic Synthesis, ed J. I. G. Cadogan, Academic Press, London, 1979, pages 63–77.
44. I. T. Harrison and B. Lythgoe, J. Chem. Soc., 1958, 843.
45. E. Vedejs and H. W. Fang, J. Org. Chem., 1984, 49, 210.
46. H. Pommer, Angew. Chem., 1960, 72, 811.
47. J.-L. Fabre and M. Julia, Tetrahedron Lett., 1983, 24, 4311; T. Cuvigny, C. Hervé de Penhoat and M. Julia,
Tetrahedron Lett., 1983, 24, 4315; T. Cuvigny, J. L. Fabre, C. Hervé de Penhoat and M. Julia, Tetrahedron
Lett., 1983, 24, 4319.
48. K. Uneyama and S. Torii, Tetrahedron Lett., 1976, 443.

13
Homoenolates
Introduction: Homoenolisation and homoenolates
Summary of strategies
Three-Membered Ring Homoenolate Equivalents (The ‘Direct’ Strategy)
Unsymmetrical cyclopropane homoenolates
Conjugate addition of zinc homoenolates
Zirconium homoenolates
Enantioselective cyclopropane homoenolates
An enantioselective amino acid homoenolate
Homoenolate equivalents from three-membered rings
The Defensive Strategy: d 3 Reagents with Protected Carbonyl Groups
Acetals
Sulfones
Phosphonium salts
The Offensive Strategy: Heteroatom-Substituted Allyl Anions
Regioselectivity
Anions of allyl silanes
Anions of allyl sulfi des
Anions of allyl ethers
Anions of allyl amines
Asymmetric allylic amines
Allyl Carbamates
Stereoselectivity in the homoaldol reaction
Introduction: Homoenolisation and homoenolates
Enolisation 1 involves the removal of the α-proton from a carbonyl compound to form an enolate
ion 2. Homoenolisation involves the removal of a β-proton 3 to form the homoenolate ion 4 or 5.
Both the enolate and the homoenolate can be represented as carbanions, but whereas the enolate
version 2b is merely a different way of representing a single delocalised structure, the homoenolate
5 is a different compound from the cyclopropane 4. No literal examples of homoenolates
5 are known so they have the status of synthons which may be represented in real life by reagents
derived from cyclopropanols 4 among many other possibilities. 1
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

190 13 Homoenolates
B
B
Direct homoenolisation of a carbonyl compound with base is not of much practical use. Ketones
blocked in the α-position do exchange with deuterium in base, but after fi ve weeks in t-BuOK/
t-BuOD at 185 C only 3.18 atoms of deuterium had been incorporated into camphor 6 with the
distribution shown. The two sites for homoenolisation were responsible for only 0.65 and 0.45
atoms, in contrast to 1.27 atoms at the α and 0.81 at the γ atoms. 2
Summary of strategies
6
O
O
O
H
base
R
R
R
1 2a 2b
O
base
H R
R
3 4 5
Useful synthetic methods therefore rely on reagents which have been devised to represent the
d 3 synthon or homoenolate 5 in reactions and there are three important classes of these. The
cyclopropane or direct approach uses reagents such as 4. Hoppe’s ‘defensive strategy’ uses a
nucleophile created at C3 that is neither stabilised nor destabilised by a protected carbonyl
group as in the Grignard reagent 8. Hoppe’s ‘offensive strategy’ uses an allyl anion with a
heteroatom (X in 9) at one end. 1 This strategy has ‘many problems’ or rather many conditions
that must be fulfi lled. The heteroatom must help to stabilise the anion, the anion must react in
the γ-position 10 (chapter 12), and it must be possible to hydrolyse the product 11 to a carbonyl
compound.
Br
Three-Membered Ring Homoenolate Equivalents (The ‘Direct’ Strategy)
Perhaps the only true homoenolates used in synthesis are derived by metallation of derivatives of
3-haloacids. The acids themselves 12 give lithium 3-halocarboxylates 13 and hence by metallation
the homoenolate which probably exists as 15, an analogue of the dilithium enolates of carboxylic
acids (chapter 2). Reaction 16 with aldehydes or ketones gives γ-lactones 19, by a ‘homoaldol’
reaction via γ-hydroxyacids 18, common products from addition of acid homoenolates to carbonyl
compounds. 3
O
?
O
R
0.81
t-BuOK, t-BuOH
1.27
5 weeks, 185 ˚C
0.45
O O 0.65
O
d3-6 (3.18 atoms D) D distribution in d3-6 O
R BrMg
O O
R
X
H
R
base
E
X
R E
X
7 8 9 10
11
R

O
BuLi
O
BuLi
O
OLi
Br OH Br OLi Li OLi
OLi
12 13 14 15
R
O
O Li
OLi
R
O
OLi
H
H2O
R
O
OH
O
O
16
OLi
17
OH
18
R
19
Ester homoenolates can be made from 3-chloroesters 20 with sodium in the presence of
Me 3SiCl which traps them as the cyclopropyl silyl ethers 4 21, analogues of silyl enol ethers, in a
step reminiscent of the acyloin condensation. 5 Reaction with aldehydes and ketones again gives
γ-lactones 19 and Kuwajima has shown that the titanium homoenolate 22 is a true intermediate in
this reaction. 6
O
Na
OSiMe3 TiCl4
Cl3Ti
RCHO
Cl OEt Me3SiCl OEt
O OEt
20 21
22
Addition of this homoenolate to the ketone 23, a single enantiomer derived from natural
proline, gives the tertiary alcohol 24 with high stereoselectivity. 7 Removal of the Cbz protecting
group leads to spontaneous cyclisation to give 25, an intermediate on the way to the neurotoxin
pumiliotoxin 251D 26.
H
N
O
Cbz
Unsymmetrical cyclopropane homoenolates
H
N
OH
Cbz
CO 2Et
There is an obvious diffi culty if the cyclopropane ring is unsymmetrically substituted and our best
guideline here is the last stage of the Favorskii reaction, 8 e.g. 27 to 31, where a cyclopropoxide ion
is protonated 30 at the carbon atom giving the better anion, usually at the less substituted carbon.
O
23
13 Three-Membered Ring Homoenolate Equivalents (The ‘Direct’ Strategy) 191
Br
21
TiCl 4
MeO
MeOH
24; 49% yield
O
Br
H 2, Pd/C
Opening the corresponding silyl ethers 32 with TiCl 4 also usually occurs at the less substituted
atom to give the homoenolates 6 33 and hence the lactones 34. This regioselectivity means that a
chiral centre next to the carbonyl group 35 can be preserved during the formation of esters 37 by
alkylation of a zinc homoenolate 9 which may have the structure 36.
O
H
N
OH
19
O
Bu
25; 100% yield 26; Pumiliotoxin 251D
MeO O
H OMe
27 28 29 30
31
MeO
MeOH
H
N
OH
CO2Me

192 13 Homoenolates
MeO OSiMe 3
Conjugate addition of zinc homoenolates
The simple zinc homoenolate 39, derived from 21 with ZnCl 2 and ultrasound, does a conjugate
addition to the acetylenic ester with Cu(I) catalysis to give a new cyclopentenone 40, an
intermediate 10 on the way to gingkolide B. The stereochemistry of 38 is not affected by the
reagent.
EtO2C
Zirconium homoenolates
X
TiCl4 Cl3Ti RCHO
R
O OMe O O
32 33
34
H
H
CO2Me
Zn
Zn
O OMe
RHal
R
H
CO2Me
(+)-35 36 37
Et3SiO t-Bu
38 39
O
+
Zn
O OEt
CuBr.SMe 2
HMPA
Et 2O, THF
CO 2Et
Et3SiO t-Bu
40
Zirconium ester homoenolates 43 or 44 can be prepared from the triethyl orthoacrylate 42 with the
zirconocene complex of but-1-ene 41 (Cp means cyclopentadiene). These resemble the zinc and
titanium species we have been discussing but are not derived from cyclopropanes. 11
Et OEt
Cp2Zr
OEt OEt
OEt
+
Cp2Zr OEt
OEt
41 42 43
In the presence of CuCN, these homoenolates react with acid chlorides to make γ-ketoesters but
their forte is reaction with allylic phosphates. Prenyl diethylphosphate gives 45 in good yield and
the more highly substituted product 46 is formed in near quantitative yield. These are impressive
results: both reagents react through the γ-carbon: the homoenolate 43 where the Zr is and the
allylic phosphate where the phosphate isn’t.
γ
Cp 2Zr
OEt
43
OEt
OEt
γ
O
CuCN
O OEt
P
OEt
O
Cp 2Zr
OEt
44
OEt
O
OEt
CO 2Et CO 2Et
Ph
45; 81% yield 46; 96% yield

Enantioselective cyclopropane homoenolates
Recent developments in the cyclopropane approach to homoenolates have emphasised enantioselectivity.
12 Racemic mixtures of acetals of cyclopropanones can be prepared by Simmons-
Smith cyclopropanation of silyl ketene acetals. Silicon-promoted conjugate addition (chapter 9) of
Grignard reagents to acrylate esters 47 gives mixtures of E/Z isomers of the silyl ketene acetals
48. Cyclopropanation and exchange of the silyl group for an acetate gives a roughly 1:1 mixture of
syn and anti cyclopropanes 49 and 50, easily separated by chromatography.
O
OEt
RMgBr
Me3SiCl
Me3SiO
47 48
OEt
Kinetic resolution (chapter 28) of each diastereoisomer with a lipase gives single enantiomers
of the hemiacetals 51 and hence the zinc homoenolates 52. Various electrophiles (E in 53) gave
enantiomerically pure (99% ee) adducts where E = H, allyl or imine. 13
R
OEt
AcO
(±)-50
1. lipase from
Candida antarctica
2. LiAlH 4
An enantioselective amino acid homoenolate
R
OEt
HO
(–)-51
1. CH 2I 2, Zn
2. MeOH
3. Ac2O, pyridine
R
1. Me 3SiOTf
2. ZnCl2
OEt
AcO
(±)-49
An important use of enantiomerically pure homoenolate equivalents is the synthesis of other
α-amino acids from serine. Natural (S)-()-serine 54 is protected on both its amino and carboxyl
groups and the OH group turned into a leaving group 55. Displacement with iodide gives the
starting material 56 with no loss of optical activity. 14
HO
NH 2
CO 2H
54; (S)-(+)-serine
Treatment with zinc/copper couple activated by ultrasound in dimethylacetamide gave the zinc
homoenolate 57 stabilised by chelation to either the ester or the carbamate. Acylation with acid
chlorides and Pd(0) catalysis gave the enantiomerically pure γ-oxo-amino acids 58 in good yield.
I
13 Three-Membered Ring Homoenolate Equivalents (The ‘Direct’ Strategy) 193
NHBoc
CO2Bn
56
1. PhCH2OH, PhSO 2OH, CCl 4 (74%)
2. (Boc) 2O, NaOH, H 2O, THF (81%)
3. TsCl, pyridine (84%)
Zn/Cu
Me 2NAc
ultrasound
IZn
Arylation with ArI and palladium catalysis is also possible and forms the key step in an
asymmetric synthesis of the antibiotic azatyrosine. 15 This differentiating antibiotic has anti-cancer
potential. Coupling 57 with the pyridine 59 gave 60 and removal of the methyl protecting group
gave azatyrosine 61.
TsO
NHBoc
CO2Bn
57
R
R
+
OEt
AcO
~1:1 (±)-50
H
E
Zn
R E
R
O OEt
CO2Et (–)-52 (–)-53
NHBoc NaI
CO2Bn 55
Me2CO RCOCl
catalytic
PdCl 2(PPh3)2
R
O
I
NHBoc
CO2Bn 56
NHBoc
CO2Bn
58

194 13 Homoenolates
MeO
I
57
NHBoc
N catalytic
N CO2Bn CH2Cl2
N CO2H PdCl2(PPh3)2 MeO
HO
59 60; 74% yield
61; 90% yield
Homoenolate equivalents from three-membered rings
Other three-membered ring compounds have been used to achieve the result of homoenolate attack
on ketones, the most important being Trost’s cyclopropyl sulfur compounds and Corey’s
cyclopropyl ethers. Attack of the sulfonium ylid 16 63 on a ketone gives the usual epoxide 17 even
though it is an oxaspiropentane 64: this rearranges to the cyclobutanone 65 in acid. Baeyer-
Villiger rearrangement involves migration of the more highly substituted carbon atom 18 to give the
lactone 19 66, the result of ester homoenolate addition to the ketone R 2CO.
H
Ph2S BuLi
Li
Ph2S R2C=O
R
O
R
HBF4
R
R
O RCO3H
R
R
O
62 63 64 65 66
Corey’s method 20 relies on metal exchange with the bromocyclopropane 69 prepared by
carbene addition. The extra stabilisation of cyclopropyl anions (chapter 8) makes both this lithium
derivative and the ylid 63 more easily handled. Addition to aldehydes or ketones gives mixtures
of adducts 70 [it turns out that none of the stereochemistry of 69 or 70 matters] which fragment
under Lewis acid catalysis to give the thioacetal 71. Careful hydrolysis releases the 3,4-enal E-72,
the product of a homoaldol reaction with an aldehyde homoenolate and RCHO and a diffi cult
compound to make as the double bond moves into conjugation very easily.
Br
67
CHOMe
68
R
The disconnections for this homoaldol are not obvious. Just as a conjugated (α,β-unsaturated)
enal is derived from an aldol, we can consider deriving this unconjugated (β,γ-unsaturated) enal
72 from a hydroxyaldehyde. We might initially prefer FGI to 73 as the 1,3-relationship is easy to
make. But 73 will dehydrate to the conjugated (α,β-unsaturated) enal. Instead we must set up a
1,4-diO relationship 74 so that we can disconnect to an aldehyde RCHO and the homoenolate 75
of propanal.
R
3
OH
2
1
CHO
73
FGI
BBr3
OH
Br OMe 1. t-BuLi
R
OMe HO SH
2. RCHO
BF3 69
S
R CHO
72
O
Hg(II)
MeCN
H2O
CaCO 3
70
R CHO
71 72
FGI
NH2
OH
1,4-diO O
2
1
CHO
R 4 CHO homo-
3
R
aldol
74 75; d3 synthon
O

The Defensive Strategy: d 3 Reagents with Protected Carbonyl Groups
Acetals
Conceptually the simplest of all the homoenolate equivalents, organometallic reagents such as
the Grignard 8 could be regarded as avoiding the problem. This is unfair and a better way to look
at them is to regard their synthesis as reversing the polarity of unsaturated carbonyl compounds.
Unsaturated aldehydes and ketones can be converted into bromoacetals such as 77, and Büchi and
Wuest 21 used the Grignard reagent derived from 77, that may have the chelated structure 78, in
their synthesis of nuciferal as long ago as 1969.
O
Br
Mg O
R CHO
HO OH
1. Mg 2. RCHO
CHO
Br
O
HBr
O
OH
76 77 78 3. H, H2O
79
Roush used this reagent in his synthesis of dendrobine 22 for which he needed the unsaturated
hydroxyaldehyde 80. Disconnection next to the OH group reveals the dienal 81 and the homoenolate
synthon 75. The dienal can be made by consecutive aldol reactions or using extended
enolate chemistry (chapter 11). Reaction between the Grignard reagent from 77 and the aldehyde
81 in THF gave 95% of 80. Similar reagents are available at the ketone oxidation level. 23
OH
1,4-diO
O
CHO homoaldol
H
+
CHO
80 81 75
For both the alcohol and the carboxylic acid oxidation levels, the best organometallic reagent is
probably the very simple protected lithium derivative 84 introduced by Eaton. 24 Easily made from
available bromopropanol 82, the acetal 83 gives the stable (because of chelation by one or both
acetal oxygen atoms?) lithium derivative 84 by oxidative insertion.
OEt
OEt
O
Li
Br
82
OH
Cl2CH.CO2H Br
83
O
Et2O Li
84
O
Addition to aldehydes, ketones, and enones occurs cleanly at the carbonyl group, e.g. to
give 86, but the copper derivative adds to enones in the expected Michael sense (chapter 9) to
give 1,6-dicarbonyl compounds such as 88 after oxidation. Cyclisation to 89 completes a cyclopentannelation
sequence (chapter 6).
Li O
O
13 The Defensive Strategy: d 3 Reagents with Protected Carbonyl Groups 195
CuI
84
OEt
+
85
O
85
1. H, H2O
O
O O
O
2. RuO4/NaIO4
3. H, MeOH
CO2Me base
87
OEt
88 89
OH
86
O
OEt

196 13 Homoenolates
Sulfones
Possibly more popular are the protected sulfones 25,26 such as 94, again easily made by Michael addition
at either the sulfi de or sulfone 27 oxidation state as sulfur nucleophiles are excellent Michael donors.
CHO
Lithium derivatives of these sulfones can be alkylated with alkyl halides or epoxides, 28 and acylated
with esters to give the ketones 95 from which the sulfonyl group can be removed with aluminium
amalgam. Deprotection and cyclisation provides a synthesis of cyclopentenones 98 (cf. chapter 6). 26
94
O
Ph S 92
Li
1. BuLi
76
O
2. RCH 2CO 2Me
Phosphonium salts
The corresponding phosphonium salts 29 99, 100, and 101, made from the bromoacetals, can be
used in Wittig reactions to give Z-acetals such as 102. It is diffi cult to hydrolyse the acetal without
isomerising the geometry or the position of the double bond, but non-cyclic acetals such as 101
satisfactorily give Z-alk-3-enals 30 103.
The Offensive Strategy: Heteroatom-Substituted Allyl Anions
Regioselectivity
O
PhO 2S
PhSH
CHO
PhS
PhO2S
O
Ph3P O
99
101
90
93
CHO
CHO
O
HO OH
HO OH
Allyl anions with a heteroatom at one end 106; Z = OR, NR 2, etc, can act as homoenolates
providing certain conditions are met. The anion must be easy to make from 104 or 105, it must
react reliably at the γ-position with a range of electrophiles E to give only the vinyl derivative
H
O
H
PhS
PhO 2S
R R R
Al/Hg
O
O
mCPBA
O
O
CHO
95 96
97
O
Oi-Pr
Ph3P Oi-Pr
1. BuLi
2. RCHO
Ph 3P
R
100
O
Z-102
O
Oi-Pr
Oi-Pr
H
O
O
Oi-Pr
91
O
base
Ph3P Oi-Pr
101
H
H2O
R
Z-103
CHO
94
O
98
R

107, and that vinyl derivative must be easily hydrolysed to a carbonyl compound. It turns out 1 that
these conditions are generally fulfi lled when Z = NR 2, SiR 3, OR, or SR, though the substituent(s)
R do also matter. If M is a transition metal, the π-allyl complex 106c may be the best representation
of the allyl ‘anion.’
H
base
R Z R γ α Z
104
106a
H
base
α
R Z R γ Z
105
106b
Anions of allyl silanes
Lithium derivatives of allyl silanes react in the γ-position with alkyl halides, epoxides, and
carbonyl compounds. The lithium derivative 110 of allyl silane 109 gives only the γ-adduct 111
with ketones. 31 Vinyl silanes such as 111 are usually converted into carbonyl compounds via
epoxides which rearrange with Lewis acid catalysis and loss of silicon to give protected versions
of ketones or aldehydes 112.
The reaction may involve the formation of the β-silyl cation 114 (chapter 12) or in this case
participation by the OH group may be involved. In any case the fi nal product is a protected version
112 of the 3-hydroxyaldehyde 116.
Anions of allyl sulfi des
E
E
R
E
E
M
Z R
CHO
R
Z
107 108 106c
Li OH
SiMe3 BuLi
SiMe3 cyclo-
SiMe3 1. RCO3H
2. BF3
O
hexanone
MeOH
109 110 111
112
111
OH
13 The Offensive Strategy: Heteroatom-Substituted Allyl Anions 197
OH O OH
RCO3H
SiMe3
BF3 115
OH
113
OH
116
CHO
OBF 3
Anions of allyl sulfi des have been quite widely used but their regioselectivity is unpredictable and
the vinyl sulfi des 107; Z = SR resulting from γ-addition are diffi cult to hydrolyse. 32 Anions of allyl
ethers are more diffi cult to prepare, but generally better behaved. 33 A study of such anions led Still
to propose that allyl anions with very anion stabilising substituents Z = COR 118, SO 2Ph 119,
PPh3 120 etc, react α with all electrophiles, those with moderately anion-stabilising substituents
114
O
117
SiMe3 MeOH
OH
MeOH
112
OMe

198 13 Homoenolates
react α (or where the metal is) with alkyl halides but γ (or where the metal isn’t) with carbonyl
compounds, and those with anion destabilising substitutents Z = OR 121, NR 2 122, or SiMe 3 123,
react γ with all electrophiles. 34 A wide selection of these anions appears in Hoppe’s review. 1
E
Anions of allyl ethers
Allyl ethers 124 clearly belong in the last category and their lithium derivatives 125 react both
with alkyl halides, to give 126, and carbonyl compounds, to give 128, with the correct regioselectivity
for them to act as homoenolate equivalents. The Z-alkene in both products 126 and 128
suggests the chelated structure 125 for the allyl-lithium. Acidic hydrolysis releases the carbonyl
group 117b, in the form of a hemiacetal 117a from the carbonyl adduct 128. These allyl ethers 124
need strong base to remove the not very acidic proton and must be lithiated at low temperature to
avoid the Wittig rearrangement. 33
124
118
124
COR
R
OMe
1. s-BuLi, –65 ˚C
Anions of allyl amines
SO 2R
R
PR 3
R
OR
NR2 E
R
E
R
E
121 122
s-BuLi RHal R
H
R
Li O CHO
–65 ˚C
Me
OMe H2O 125 126
127
H
2. cyclohexanone H2O
OH
O
CHO
OMe
OH
OH
128 117a
117b
Anions derived from enamines or allyl amines have been widely explored and are among the best
homoenolate equivalents. Enamines 130 from PhNHMe and aldehydes 35 or aryl ketones 36 129 can
be deprotonated with BuLi to give lithium allyls 131, as can the corresponding allyl amines. 37 The
anion of carbazole 132 reacts on nitrogen with allyl halides and the products 133 can be converted
to lithium derivatives 134 with BuLi in the presence of chelating agents such as TMEDA. The
representations 131a, 131b and 134 are alternatives. 38
Ph
O
129
E
N
H
132
119
PhNHMe
TiCl4
Br
E
Ph
Ph
base
120
N
130
Me
BuLi
Ph
Ph
Me
N
131a
Li
BuLi
or
Ph
Ph
Me
133 134
N
131b
Li
TMEDA
N N
123
SiR 3
R

Amino-nitriles 39 136 can be made directly from unsaturated aldehydes in the fi rst stage of the
Strecker reaction and deprotonated with LDA. The same allyl-lithium derivatives 137 can be made
from saturated amides 40 139 via the vinyl isomer 140 of 136. All these lithium allyls, maybe 138
is the best representation, react as homoenolates.
NR2 CHO
R2NH HCN
CN
135 136
139
CONR 2
The lithium derivative from the unsymmetrical allylic carbazole 141 reacts with the unsymmetrical
allyl chloride 142 to give 143. The starting material was made from carbazole 132 and
142 so this allyl electrophile has reacted twice at its less substituted end, but the nucleophilic
homoenolate from 141 has reacted at its more substituted end, because that is γ-addition relative to
the nitrogen atom. 38,39 Hydrolysis of the resulting enamine E-143 gives the aldehyde 144.
We shall see in chapter 14 that saturated amino nitriles are good d 1 reagents and the unsaturated
versions 140 are good d 3 reagents, particularly effective at Michael addition. The lithium derivative
from 140; R = Et gives conjugate addition to cyclohexenone and hence the keto-acid 146 with
a 1,6 relationship between the two carbonyl groups. The reconnection strategy 41 is not suitable for
this compound as it is impossible to put a double bond between the two carbonyl groups. Lithium
derivatives of allyl amines are homoenolates of aldehydes or ketones while lithium derivatives of
unsaturated amino-nitriles are homoenolates of acids.
Asymmetric allylic amines
13 The Offensive Strategy: Heteroatom-Substituted Allyl Anions 199
1. COCl 2
2. Zn(CN) 2
3. Et 3N
1. BuLi, TMEDA
140
NR 2
CN
LDA
In this style too, asymmetry has become a major concern. 42 An asymmetric version 147 of this
homoenolate was made from natural nor-ephedrine and could be alkylated stereoselectively using
lithium tetramethylpiperidide (LiTMP) as base. The product could be hydrolysed to the bicyclic
amide 43 149.
LDA
137a
NR 2
137b
CN
NR2
N 2. Cl
N H2O
OHC
141 142
143 144
NEt 2
140; R = Et
CN
1. LDA
2. cyclohexenone
O
CN
H
H2O
CN
O
Li
NEt2 145 146
138
NR2
CO 2H
CN

200 13 Homoenolates
N
Li
An open chain example 44 153 of asymmetric homoenolates from allylic amines uses the proline
derivative 152 and the β-stannyl ketone 153 made by conjugate addition of Bu 3SnLi to the enone 150.
The lithium derivative of 153 can equilibrate to the chelated isomer Z-154 that reacts cleanly in
the γ-position with alkyl and allyl halides to give, after hydrolysis of the initially formed enamine
155, the ketones 156 with generally good enantiomeric excess. Structure Z-154a shows the
chelation in the lithiated intermediate best.
153
LiTMP
O
150
Allyl Carbamates
O
N
147
CN
Ph
Me
1. LiTMP
2. MeI
Me
The most sophisticated homoenolate equivalents, and the fi rst to allow some control over
stereochemistry, are the lithium derivatives 160 of allyl carbamates 159 introduced by Hoppe. 1
They are particularly valuable for reaction with an aldehyde or a ketone in a homoaldol reaction.
R
BuLi
THF
–78 ˚C
O
O
N
CN
Ph
Me
H
H2O
Me
O
148 149
O
Bu3SnLi THF, –78 ˚C
+
N
H
OMe
TsOH N
Bu3Sn
151 152
Bu3Sn 153
N
OMe
N
OMe
E-154 Z-154
Z-155
N
RX
Li
Z-154a
OMe
N
OMe
1. HCl
2. NaOH
O
O
Li O
+
OH Cl NR2
O NR2 LDA
O
RCHO
NR2
157 158 159
160
Li
O
O NR2
161
R
O
Li
O
R
OCONR 2
O NR2OH
OH
162 163 164
N
O
Ph
OMe
Me
O R
156
R CHO

Though anions of allyl ethers, the extra functionality allows regiospecifi c heteroatom-directed
lithiation 160 in the manner of chapter 7. Hence reaction of 160 with an aldehyde goes
through a six-membered cyclic transition state 161 to give the enol derivative 163 and hence the
γ-hydroxyaldehyde 164.
We described some anions of allylic amines as γ-lithiated species 131a and 154 that reacted in
the γ-position. Here the position of lithiation is α 160 but that too ensures good γ-selectivity even
when the γ-position is disubstituted 165 and the aldehyde is branched. Both the yield of 167 and
the selectivity are excellent. 40
Stereoselectivity in the homoaldol reaction
Because of the cyclic transition state, stereoselectivity in the manner of stereoselective aldol
reactions (chapter 4) is found, that is the geometry of the double bond in 168 determines the
stereochemistry of the homoaldol product 169, providing that lithium is exchanged for titanium or
aluminium. That E-168 gives anti-169 and Z-168 gives syn-169 is not surprising, but the geometry
of the resulting enol derivatives is. Fortunately it is irrelevant to the fi nal product.
The fi nal hydrolysis is not trivial: an Hg(II) catalyst is necessary to give acetals 170 that can
be oxidised to lactones 171. By this means both syn and anti-172, the quercus lactones from oak
bark, 45 can be made stereoselectively in 87% and 90% yields respectively.
References
O
O NR2 165
1. BuLi
TMEDA
1. BuLi
TMEDA
OCONR2 2. (Et2N) 3TiCl
3. MeCHO
E-168; R = i-Pr
13 References 201
OH
Li
O
O NR2
166
OCONR 2
anti-Z-169; R = i-Pr
2. i -PrCHO
O NR2
General references are given on page 893
1. N. H. Werstiuk, Tetrahedron, 1983, 39, 205; D. Hoppe, Angew. Chem., Int. Edn., 1984, 23, 932.
2. A. Nickon, J. L. Lambert, J. E. Oliver, D. F. Covey and J. Morgan, J. Am. Chem. Soc., 1978, 98, 2593.
3. D. Caine and A. S. Frobese, Tetrahedron Lett., 1978, 883.
4. K. Rühlmann, Synthesis, 1971, 236.
O
OH
167; 87% yield, >97% γ-addition
OH
OCONR2 1. BuLi
TMEDA
2. (Et2N) 3TiCl
3. MeCHO
OCONR2 syn-E-169; R = i-Pr Z-168; R = i-Pr
Me
163
MeOH
MsOH
cat Hg(II) R
O
OMe
RCO3H BF3
R
O
O Bu
O
170 171 anti-172
O
Bu
Me
O
syn-173
O

202 13 Homoenolates
5. Disconnection Approach, page 202.
6. E. Nakamura and I. Kuwajima, J. Am. Chem. Soc., 1977, 99, 7360; 1983, 105, 651; 1984, 106, 3368.
7. A. G. M. Barrett and F. Damiani, J. Org. Chem., 1999, 64, 1410.
8. Clayden, Organic Chemistry, p. 990.
9. E. Nakamura, K. Sekiya and I. Kuwajima, Tetrahedron Lett., 1987, 28, 337.
10. M. T. Crimmins, J. M. Pace, P. G. Nantermet, A. S. Kim-Meade, J. B. Thomas, S. H. Watterson and
A. S. Wagman, J. Am. Chem. Soc., 2000, 122, 8453.
11. A. Sato, H. Ito, Y. Yamaguchi and T. Taguchi, Tetrahedron Lett., 2000, 41, 10239.
12. H. Ahlbrecht and U. Beyer, Synthesis, 1999, 365.
13. B. Westermann and B. Krebs, Org. Lett., 2001, 3, 189.
14. R. F. W. Jackson, N. Wishart, A. Wood, K. James and M. J. Wythes, J. Org. Chem., 1992, 57, 3397;
R. F. W. Jackson and M. Perez-Gonzalez, Org. Synth., 2005, 81, 77.
15. B. Ye and T. R. Burke, J. Org. Chem., 1995, 60, 2640.
16. B. M. Trost, Acc. Chem. Res., 1974, 7, 85.
17. Disconnection Approach, page 253.
18. Disconnection Approach, page 227.
19. B. M. Trost and M. J. Bogdanowicz, J. Am. Chem. Soc., 1972, 94, 4777; 1973, 95, 5321.
20. E. J. Corey and P. Ulrich, Tetrahedron Lett., 1975, 3685.
21. G. Büchi and H. Wuest, J. Org. Chem., 1969, 34, 1122.
22. W. R. Roush, J. Am. Chem. Soc., 1980, 102, 1390.
23. A. A. Ponaras, Tetrahedron Lett., 1976, 3105; S. A. Monti and Y.-L. Yang, J. Org. Chem., 1979, 44,
897.
24. P. E. Eaton, G. F. Cooper, R. C. Johnson and R. H. Mueller, J. Org. Chem., 1972, 37, 1947.
25. M. Julia and B. Badet, Bull. Soc. Chim. Fr., 1975, 1363.
26. K. Kondo and D. Tunemoto, Tetrahedron Lett., 1975, 1007; 1397.
27. H. W. Pinnick and M. A. Reynolds, J. Org. Chem., 1979, 44, 160.
28. K. Kondo, D. Tunemoto, and E. Saito, Tetrahedron Lett., 1975, 2275.
29. J. C. Stowell and J. R. Keith, Synthesis, 1979, 132; S. W. Baldwin and M. T. Crimmins, J. Am. Chem.
Soc., 1982, 104, 1132.
30. A. R. Battersby, D. G. Buckley, J. Staunton and P. J. Williams, J. Chem. Soc., Perkin Trans. 1, 1979,
2550.
31. R. Corriu and J. Masse, J. Organomet. Chem., 1973, 57, C5; D. Ayalon-Chass, E. Ehlinger and P. Magnus,
J. Chem. Soc., Chem. Commun., 1977, 772; E. Ehlinger and P. Magnus, J. Am. Chem. Soc., 1980, 102,
5004; Tetrahedron Lett., 1980, 21, 11.
32. J. F. Biellmann and J. B. Ducep, Org. React., 1982, 27, 1.
33. D. A. Evans, G. C. Andrews, and B. Buckwalter, J. Am. Chem. Soc., 1974, 96, 5560.
34. W. C. Still and T. L. Macdonald, J. Am. Chem. Soc., 1974, 96, 5561; J. Org. Chem., 1976, 41, 3620.
35. G. Rauchschwalbe and H. Ahlbrecht, Synthesis, 1974, 663.
36. H. Ahlbrecht and G. Rauchschwalbe, Synthesis, 1973, 417.
37. H. Ahlbrecht and J. Eichler, Synthesis, 1974, 672.
38. M. Julia, A. Schouteeten and M. Baillage Tetrahedron Lett., 1974, 3433; M. Julia, F. Le Goffi é, and L.
de Matos, Compt. Rend., 1970, 270C, 954.
39. H. Ahlbrecht and C. Vonderheid, Synthesis, 1975, 512.
40. B. Lesur, J. Toye, M. Chantrenne and L. Ghosez, Tetrahedron Lett., 1979, 2835; D. S. Grierson, M.
Harris, and H.-P. Husson, J. Am. Chem. Soc., 1980, 102, 1064; B. Costisella and H. Gross, Tetrahedron,
1982, 38, 139.
41. Disconnection Approach, chapters 26 and 27, page 217.
42. H. Ahlbrecht and U. Beyer, Synthesis, 1999, 365.
43. J. B. Schwarz and A. I. Meyers, J. Org. Chem., 1998, 63, 1732; A. G. Waterson and A. I. Meyers, J. Org.
Chem., 2000, 65, 7240.
44. H. Ahlbrecht, R. Schmidt, and U. Beyer, Eur. J. Org. Chem., 1998, 1371.
45. D. Hoppe and F. Lichtenberg, Angew. Chem., Int. Edn., 1984, 23, 239; D. Hoppe and A. Brönneke,
Tetrahedron Lett., 1983, 24, 1687.

14 Acyl Anion Equivalents
Introduction: Acyl Anions?
Acyl Anion Equivalents: d 1 Reagents
Modifi ed Acetals as Acyl Anion Equivalents
An asymmetric synthesis of pyrenophorin
The synthesis of a drug using a dithian as an acyl anion equivalent
Dithioacetal monoxides
Protected Cyanohydrins of Aldehydes
Amino nitriles are useful for conjugate addition
Acyl anion equivalents of the ester d 1 synthon – CO 2R
Methods Based on Vinyl (Enol) Ethers and Enamines
Lithium derivatives of cyclic vinyl ethers
The synthesis of pederin and related anti-tumour agents
Lithium derivatives of allenyl ethers
Oxidative Cleavage of Allenes
Vinyl Ethers and Enamines from Wittig-Style Reactions
Vinyl ethers
Enamines
A synthesis of O-methyljoubertiamine
Synthesis of enals by functionalised Wittig reagents
Nitroalkanes
A synthesis of strigol using nitroalkanes
Synthesis of mono-protected diketones
Catalytic Methods: The Stetter Reaction
Introduction: Acyl Anions?
The acyl cation 2a or acylium ion 2b is a familiar intermediate in the Friedel-Crafts reaction. It
is easy to make (acid chloride Lewis acid 1) and it can be observed by NMR as it expresses the
natural reactivity pattern of the acyl group. The acyl anion by contrast has umpolung or reverse
polarity. 1 One might imagine making it from an aldehyde by deprotonation 3 and that it would be
trigonal 4a or possibly an oxy-carbene 4b. Such species are (probably) unknown and their rarity as
well as their potential in synthesis has led to many synthetic equivalents for this elusive synthon.
The acyl anion, the d 1 synthon, is the parent of all synthons with umpolung 2 and should perhaps
have been treated before the homoenolates dealt with in the previous chapter.
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

204 14 Acyl Anion Equivalents
O
R Cl AlCl3 R
R
1 2a 2b
There are a few examples of carbonyl compounds losing a proton from the CHO group in
strong base, though they are not aldehydes. The tertiary amide 5 gives a lithium derivative with
t-BuLi, perhaps 6, that adds to aldehydes to give 7, the result of addition of an acyl anion to the
aldehyde. 3
There are two approaches to lithium derivatives of aldehydes, though neither starts from the
aldehydes themselves. Carbonylation of primary alkyl-lithiums gives an intermediate, 4 probably
8, that adds to aldehydes or ketones, e.g. 9, to give hydroxyketones 10 and can be silylated to give
the acyl silane 11.
Alternatively the Me 3Si group may in turn be removed from the acyl silanes 11, 12 or 14 with
CsF to give possibly the acyl anion itself, or at any rate a species which adds to aldehydes and
ketones in the same way, 5 and even does Michael reactions to give e.g. 15.
O
BuLi
O
12
CO
SiMe 3
i-Pr 2N H
Acyl Anion Equivalents: d 1 Reagents
O
O
t-BuLi
O
R H
O
The yields in these reactions are not wonderful and most syntheses planned with acyl anion or
d 1 synthons are realised with one of the reagents we are about to describe rather than with acyllithiums.
Things may change as understanding of these rather reactive intermediates develops.
There are three main types of acyl anion equivalent: reagents which can be considered as modifi ed
acetals, that is protected aldehydes, masked carbonyl compounds such a nitroalkanes, and substituted
vinyl-lithiums. The rest of this chapter will be devoted to these reagents.
O
3
i-Pr 2N Li
B
RCHO
?
R
i-Pr 2N
5 6? 7
O
+
Bu Li
8
PhCHO
CsF
O
Bu
O
O
OH
9 10
O
13
OH
Ph
N
Me
8
O
R
O
4a 4b
O
Me3SiCl
OH
R
O
Bu SiMe 3
11
SiMe3 CsF
cyclo- N
O
hexenone
Me O
14 15
O

Modifi ed Acetals as Acyl Anion Equivalents
Any acetal-like derivative 16 of an aldehyde can be used as an acyl anion equivalent providing the
atoms X and Y stabilise an anion so that the lithium derivative 17 (or even the anion itself) can be
formed, and providing that the product 18 of addition to an electrophile can be hydrolysed to a carbonyl
compound. There is usually a confl ict between these two requirements: thus acetals 16; X = Y =
O are very easily hydrolysed but do not in general form lithium derivatives. Often one substituent is
chosen to stabilise the anion (S, CN, etc) while the other is chosen to help the hydrolysis (O, N, etc).
RCHO
RX YR BuLi
Dithians 20 illustrate this approach and have been remarkably popular considering the problems
in their use. They can be made from aldehydes with propane-1,3-dithiol and Lewis acid
catalysis. They are deprotonated with BuLi and react with alkyl halides, epoxides, and carbonyl
compounds (E ) to give 22 and hence 19 after hydrolysis. The hydrolysis is by no means easy:
there are many methods and this alone should warn us that none is very good. 6
RCHO
SH
BF3
SH
An asymmetric synthesis of pyrenophorin
RX YR
RX YR
R H
R Li
R E H2O R E
16 17 18 19
A synthesis of pyrenophorin using dithian shows how it works. The target 23 is a macrocyclic (16membered
ring) dilactone and disconnection of the ester linkages reveals two identical halves 24:
pyrenophorin has C 2 symmetry. 7
O
O
The enone 24 could be made by an aldol or Wittig approach from 25. This contains unhelpful
1,2 and 1,4 relationships and the strategy is to ignore these and disconnect either side of the ketone,
imagining it as a d 1 reagent used twice. The electrophiles would be one enantiomer of an alkylating
agent 26, probably with the OH group protected, and a reagent for the formyl cation 28.
OH
O
14 Modifi ed Acetals as Acyl Anion Equivalents 205
E
O
S S BuLi S S E S S Hg(II)
R
20
H
R
21
Li
R
22
E BF3
R
19
E
O
O
23; pyrenophorin
O
O
2 x C–O
lactones
O
OH
HO2C O
O
24
H
CO2H
OH
CO2H
OH
CHO
OH X
S S CHO +
aldol 2 × d
+
24a 25
26 27 28
1
O

206 14 Acyl Anion Equivalents
An optically active reagent 32 for the left hand fragment can be made by asymmetric reduction
of ethyl acetoacetate with ordinary baker’s yeast (see chapter 29), protection of the OH group as a
mixed acetal 31, reduction of the ester and conversion of the new OH group into an iodide 32.
O
CO 2Et
CO2Et OH
30
Alkylation of dithian itself 27 with the iodide 32 establishes the 1,4-diO relationship in 34 and
this new dithian can be acylated with DMF (Me 2NCHO). The carbon skeleton of half pyrenophorin
35 is completed by an E-selective Wittig reaction with a stabilised ylid.
Removal of the two protecting groups leaves the dithian in place and it is left there while the
macrocyclisation is completed with a Mitsunobu reaction. Notice that this esterifi cation occurs
with inversion so only now is the correct stereochemistry in place. Finally the dithian is hydrolysed
with Hg(II) and BF 3.
35
29
27
1. H, H2O
2. LiOH
MeOH
1. BuLi
2. 32
baker's
yeast
OH
DEAD = DiEthyl
AzoDicarboxylate
O
S S
OMe
33
S S
24
The synthesis of a drug using a dithian as an acyl anion equivalent
H
The anti-antihyperlipoproteinemic drug acifran 37 is a simple heterocycle whose structure can
best be understood after disconnection of the enol ether. 8 The carbon framework 38 contains a
OMe
CF 3CO 2H
1. BuLi
2. DMF
S S
O OMe
CO 2H
EtO2C N N CO 2Et
35
DEAD
Ph 3P
O
O
CO2Et OMe
1. LiAlH4 2. TsCl,
pyridine
3. NaI,
O
I
OMe
acetone
31
32
CO 2Me
O
O
S S
OMe
34
S
S
CHO
36
S
S
PPh 3
O
CO 2Me
O
HgO
BF3
23

emarkable number of relationships: two 1,2- and one 1,3-diCO relationships 38a as well as two
1,4-diCO and a 1,5-diCO.
Ph
O
O
37; Acifran
CO 2H
C–O
enol
ether
Ph
O
HO
O
38
CO2H
We prefer odd-numbered to even-numbered disconnections and of the two possible 1,3-diCO
38b is better as it gives an enolisable ketone 39 and the unenolisable, symmetrical and very
electrophilic diethyl oxalate 41.
Ph
O O O
a
HO
b
CO2H
1,3-diCO
b
Ph
HO
38b
39
The α-hydroxyketone 39 could be made from attack of a d 1 reagent on the rather enolisable
ketone PhCOMe 42. The reagent chosen for the d 1 synthon 43 was again a dithian 44.
Ph
HO
39
O
1,2-diCO
The synthesis starts simply with the coupling of the lithium derivative of 44 with 39 but takes a
novel turn when a dithian exchange with pyruvic acid is used to remove the dithian from 45. The
keto group in pyruvic acid is unstable, being next to another carbonyl group, while that in 39 is
stable. Dithian exchange removes this instability by forming the pyruvic acid derivative 46.
The rest of the synthesis is straightforward: no protection is needed in the favourable Claisen
ester condensation to give 47 and the formation of the enol ether, being intramolecular, requires
only heating with acid. This treatment also hydrolyses the remaining ester.
Ph
44
HO
39
1. BuLi
O
2. 39
14 Modifi ed Acetals as Acyl Anion Equivalents 207
Ph
(CO 2Et) 2
base
+
=
X
1,2-diCO
O
Ph
40
HO
CO 2H
O
38a
O
1,3-diCO
FGI
1,2-diCO
CO 2H
O
OEt
EtO
O
41; diethyl oxatale
Ph
O
S S
O
H
42; a1 +
reagent 43; d1 synthon 44; d1 reagent
O
O
S S
CO2H Ph + S S
OH
H
HO
CO2H 45 39
46
Ph
O
O
H
CO2Et
HO
Ph
O CO2H 47; not isolated 37; Acifran, 92% yield
O

208 14 Acyl Anion Equivalents
Dithioacetal monoxides
Recent developments have tried to remedy the diffi cult hydrolysis of the dithian. The
monosulfoxides of dithioacetals are better at stabilising anions and more easily hydrolysed. They
can be prepared by alkylation of the parent compound 50 with a suitable alkyl halide, e.g. to
give 51. 9
O
48
O
Ph
1. LiAlH 4
2. Ph 3P, I 2
imidazole
OBn
The lithium derivatives are prepared with LDA and add to most electrophiles. Only direct
addition occurs to the sensitive Z-enal 52 to give a mixture of diastereoisomers 53 from which the
dithioacetal is easily removed under mild conditions to give the ketone 54. The product 54 was
converted into the symmetrical triether 10 55.
51
1. 2 x LDA
Protected Cyanohydrins of Aldehydes
I
MeS
SMe
O
BnO
MeS
SMe
49 50
SMe
51
Unsymmetrical d 1 reagents of this kind, i.e. 16; X ≠ Y, are best represented by the various cyanohydrin
derivatives. Cyanohydrins themselves have an acidic H on the free OH group, but silylated
cyanohydrins 11 57, formed with Lewis acid 12 or crown ether 1 catalysis, lack this acidic proton and
give lithium derivatives 58 with LDA.
These lithium derivatives 58 react with many electrophiles but are particularly suited to
aldehydes and ketones as the developing oxyanion captures the Me 3Si group 59 with loss of
the CN group making this a much easier hydrolysis than that of a dithian. Treatment with
fl uoride then gives the hydroxy-ketone 61. An example is the coupling of the d 1 reagent 62 from
benzaldehyde with cyclopentanone to give the α-hydroxyketone 64 in a respectable 78% yield
from benzaldehyde.
O
TFA:THF:H2O
1. BuLi
2. 49
O
MeS
2. 52 1:10:10
BnO HO
H
O 20 ˚C, 2 hours BnO HO
53 54
OBn
CHO
54
H H
O
O
O
H
O
H
52 55
O
R H
catalytic
CN
NC O Me 3SiCN
NC OSiMe 3
R H
R H
56 57
LDA
O
NC OSiMe 3
R Li
58
BnO
OBn
H
O

O
58
2. LDA
NC
O SiMe3
R
59 60 61
NC OSiMe3
+
Ph Li
Amino nitriles are useful for conjugate addition
For d 1 reagents which will add Michael fashion to any unsaturated carbonyl compound,
amino-nitriles are best. They were invented by Stork 13 for this very purpose and used in his cis
jasmone 65 synthesis. This TM has perhaps been more synthesised than any other, though its
simple structure and obvious enone disconnection to 66 make it a rather uninspiring choice these
days. The 1,4-diketone 66 does indeed cyclise to 65 presumably under thermodynamic control,
and the double disconnection 66 [cf. the disconnection of pyrenophorin 23] requires a d 1 reagent
that will react with enones 67 in the Michael sense and with alkyl halides 69.
O
The amino nitrile 70 is simply and cheaply made (90% yield) and does react with alkyl halides. 14
Aldehydes are easily released from 71 with aqueous oxalic acid. After a second alkylation or
Michael addition an even milder method of hydrolysis, aqueous Cu(II) salts at near neutrality,
releases diketones such as 57. Cyclisation in base gives cis-jasmone 13 65.
70
PhCHO
1. Me 3SiCN
65; cis-jasmone
1. LDA
2. 69; R=I
CH 2O
H
aldol
NaCN
Et 2NH
NaHSO 3
Et 2N CN
14 Protected Cyanohydrins of Aldehydes 209
72
62
Acyl anion equivalents of the ester d 1 synthon – CO 2R
O
O
O
Et2N CN
70
66
R
O
1. LDA
2. 67
O
1. LDA
2. RI
OSiMe3
64; 78% yield
At the ester oxidation level the best d 1 reagent is probably Yamamoto’s ROCH(CN) 2. This reagent
74 (EE = EthoxyEthoxy) is easily prepared and reacts with alkyl halides using only the mild base
K 2CO 3. Hydrolysis of the protecting group and displacement with a secondary amine gives the
amides 15 77. Reaction with tosylimines gives amino acids.
Ph
1,4-diCO
O
O
63
Et 3N.HF
OSiMe3
Et 2N CN
R
71
Et 2N CN
73
R
O
Et 3N.HF
(CO2H)2
H2O
OH
Ph
O
O
X
67
68; double
d1 + +
synthon 69
RCHO
O
Cu(II)SO 4
pH 5
MeOH/H 2O
OH
66

210 14 Acyl Anion Equivalents
EEO
CN
CN
K2CO3 RX
EEO
R
CN
CN
TFA
CH2Cl2 HO
R
CN
CN
+
N
H
R
O
N
74 75 76 77
Since the anion is so stable, it reliably does conjugate additions and provides a simple route to
γ-keto acid derivatives. 16 The initial adducts 78 can be worked up with either alcohols or amines
to give γ-keto-esters 79 or γ-keto-amides 80.
O O
74
K 2CO 3
NC CN
OEE
Methods Based on Vinyl (Enol) Ethers and Enamines
Just as anions of allyl derivatives can be homoenolate equivalents (chapter 13) so anions
of vinyl derivatives can be acyl anion equivalents. Vinyl (or enol) ethers can be lithiated
reasonably easily, especially when there is no possibility of forming an allyl derivative, as with
the simplest compound 81. The most acidic proton is the one marked and the vinyl-lithium
derivative 82 reacts with electrophiles to give the enol ether of the product 17 84. However,
tertiary butyl lithium is needed and compounds with γ-CHs usually end up as the chelated
allyl-lithium 85. These vinyl-lithium compounds add directly to conjugated systems but the
cuprates will do conjugate addition. 18
Lithium derivatives of cyclic vinyl ethers
1. TFA, CH 2Cl 2
2. ROH or R 2NH
Cyclic vinyl ethers such a dihydropyran 86 form stable lithium derivatives 87 probably because
isomerisation to structures like 85 is impossible. Reaction with electrophiles such as alkyl halides
gives adducts, e.g. 88, and hydrolysis under very mild conditions reveals the carbonyl group 19 89.
These reagents, usually with further functionalisation, have been widely used. Smith’s synthesis
of phyllanthoside involved the coupling of the lithium derivative of 90 with the aldehyde 92 and
the exposure of one protected ketone to give 93 having two exposed ketones and one concealed
as an enol ether. 20
O
O
O
OR or
78 79 80
H
t-BuLi
Li
E
E
H
E
OMe
OMe
OMe H2O O
Li OR
81 82 83 84 85
O
86
t-BuLi
THF, 0 ˚C
RX
7.5% HCl/H 2O
O Li
O R
THF, 25 ˚C
HO O R
87 88
89
O
NR 2

O O t-BuLi
O
90
O
O
O
The hidden carbonyl group is more apparent after the removal of the MEM protecting group 94
and formation of the acetal 95 in acid solution. One diastereoisomer of the spirocyclic compound
95 is formed in 71% yield.
93
THF, 0 ˚C
ZnBr 2
CH 2Cl 2
The synthesis of pederin and related anti-tumour agents
Li
+
OHC
OMEM
H OBn
H, H 2O
91 92
93
The group of antitumour agents related to pederin have a common structural feature 96 of a functionalised
tetrahydropyran attached through an amide linkage to a variety of complex amines. In
his successful syntheses of these compounds, Kocienski 21 chose to disconnect next to the ring and
use a reagent 99 for the d 1 synthon 97 that would be acylated by the oxalyl derivative 98.
O
OMe O
OH
O
O
NHR
96; pederin antitumour agents
H
O OH
H
OBn
The lithium reagent 99 was prepared from the stannane 100 - one advantage being that n-BuLi
is strong enough to do the job. Addition to the ester 98 gave the ketone 101 and reduction and
acetal formation gave the complete structure 102 from which the alkene 96 could be revealed by
oxidation and selenoxide elimination (chapter 33). This synthesis looks very easy but the complicated
amines ‘RNH 2’ were very diffi cult to make.
O SnMe3
BuLi
SePh
100
14 Methods Based on Vinyl (Enol) Ethers and Enamines 211
–80 ˚C
THF
99
98
94
O
cat. H
+
MeO
then
Swern
O
O
97 98
O
O NHR
SePh
101
O
O
O
1. LiBH(s-Bu)3
2. H, MeOH
O
O
O
O
H
H
H
O OMEM
H
95; 71% yield
NHR
O
O
99
OBn
OBn
Li
SePh
OMe O
OH
SePh
102
NHR

212 14 Acyl Anion Equivalents
Lithium derivatives of allenyl ethers
Allenyl ethers similarly have no γ-protons so allyl anions cannot be formed. The allenyl ethers
104 are readily made from propargyl ethers 103 and are lithiated next to oxygen 105. Reaction
with lactones gives adducts 106 that decompose in acid to the hemiacetal 107a of the 1,2-diketone
107b. The conjugated alkene has the Z-confi guration as the enol ether in 106 prefers protonation
on the side away from the R group. The allenyl lithium 105 is a reagent for the synthon 22 108.
R
Oxidative Cleavage of Allenes
Another way that allenes can be used to provide an acyl anion equivalent is by the Lewis acid
catalysed addition of propargyl silanes to electrophiles 109 followed by oxidative cleavage of the
allene. The intermediate vinyl cation 110 is stabilised by the silicon β-effect (chapter 12) and loss
of the Me 3Si group gives the allene 111. Oxidative cleavage of the sensitive allene reveals that it
has acted as a reagent for the formyl anion.
Me3Si
In their synthesis of hemibrevetoxin, Nelson 23 converted the centro-symmetric acetal 113 into
the dialdehyde 115 by this method. Yields of the bis-allene 114 and of the fi nal product were
excellent. Note that the acetal 113 acts as a suitable electrophile as the Lewis acid (Me 3SiOTf)
removes the OMe group to give an oxonium ion intermediate.
H
MeO O
Me
Vinyl Ethers and Enamines from Wittig-Style Reactions
Vinyl ethers
t-BuOK
R
H BuLi
OMe
OMe
OMe
OMe
103 104 105 106
H
H 2SO 4
R1 109
O
R 2
R
O LA
Me 3Si
HO
Me3Si OTf
OMe
Me
O
More general methods depend on Wittig reactions with functionalised ylids. The ylid 24 from 116
and the lithium derivatives of 117-120 all react with aldehydes and ketones to give enol ethers
that can be hydrolysed to chain-extended aldehydes. Yields with the ylid from 116 are not always
wonderful and the phosphonate ester 120a with a chelating substituent generally does better. 25
R
R O
Li O
O
O
O OH
Z-107a Z-107b 108
Me3Si
R 2
R 1 OLA
R
R 2
R 1 OH
R
1. O3
2. Me 2S
HO
110 111 112
Me H
O
H
O
Me
O
O
H
OHC O
Me
1. O3 2. Me 2S
113 114; 92% yield 115; 98% yield
H
O
H
O
R 2
R 1 OH
CHO
Me

In very crowded cases the lithium derivative of the phosphine 118, though it must be made with
s-BuLi, is the most reactive. 26
Enamines
Ph 3P OMe
O
Ph 2P OMe
Lithium derivatives of amino substituted phosphine oxides, such as the morpholine 121, give
adducts 122 on reaction with aldehydes that eliminate with a potassium base to give enamines 123
in excellent yields: 90–99% for R = Ar and 63–83% for R = alkyl. These are easily hydrolysed to
the homologous aldehydes 27 124.
The pyrrolidine phosphonate 125 does much the same thing in one step but the real virtue
of these methods is that the enamines 123 and 126 are reactive enough to combine with various
electrophiles, particularly allylic halides, α-halo-carbonyl compounds and Michael acceptors (see
chapter 10) to give substituted homologous aldehydes or ketones 28 127.
A synthesis of O-methyljoubertiamine
O
OMe
Ph 2P OMe
H 2O
(Me 2N) 2P OEt
This method has been applied to a synthesis of the alkaloid O-methyljoubertiamine. Reaction
of the lithium derivative of 125 with the part-protected diketone 128 gave an enamine 129 that
was immediately allylated to create the quaternary centre in 130. Deprotection and cyclisation
completed the cyclohexenone 28 131. A discussion of the strategy and further details of this
synthesis are in the workbook.
O
H
O
O
(EtO) 2P O
O
(RO)2P OR
116 117 118 119 120
116
base
O O
O O 1. BuLi Ph2P N
Ph2P N
2. RCHO
3. NH4Cl H2O/THF R OH
121
122; intermediate
OMe
(EtO) 2P N
O
O O
14 Vinyl Ethers and Enamines from Wittig-Style Reactions 213
O
125
OMe
O O
1. LDA
2. RCHO
H
1.
R
KH
THF
N
N
O
R
123; enamine
1. E
2. H 2O
120a
H
H 2O
126; enamine 127
OMe
125
LDA
N
Br
2. H2O CHO
1. H, H2O 2. KOH
MeOH/H2O O O
R
O
E
R
OMe
CHO
124; homologous
aldehyde
CHO
128 129 130 131
OMe

214 14 Acyl Anion Equivalents
Synthesis of enals by functionalised Wittig reagents
If there is a leaving group in the β-position of the carbonyl starting material 132 during homologation
by the methoxymethyl reagents 116 or 117, it is lost during the hydrolysis of the enol ether
product 133 to form an enal 134.
The leaving group X may be only an OH group, inserted by hydroxylation of a silyl enol ether
136 (chapter 33) formed by conjugate addition of a silyl cuprate (chapters 9 and 10) to an enone
135 and protected by the robust silyl group TBDMS (t-BuMe 2Si-) 137 for reaction with the lithium
derivative of 117.
The lithium derivative of 117 gives an adduct from which the phosphinate can be removed with
NaH. Hydrolysis of the enol ether 138 with HF in aqueous acetonitrile gave the enal, e.g. 139 in
around 50% overall yield. 29 The overall strategy is conjugate addition of a nucleophilic alkyl group
followed by direct addition of a nucleophilic CHO group. An alternative uses a sulfur leaving
group (X = SPh in 132) and the ylid from 116 to achieve the same result. The fi nal hydrolysis
requires Hg(II) to remove the sulfur. 30
Nitroalkanes
O
116 or 117
X X
132 133 134
The problem with many acetal-style d 1 reagents is often that there is barely enough stabilisation for
the “anion”. This problem is easily solved with the nitro group as it has enough anion-stabilising
ability by itself, about the same as two carbonyl groups in fact. Using only weak bases such as
tertiary amines (Hünig’s base i-Pr 2NEt is popular) nitroalkanes react 141 with many electrophiles
such as alkyl halides, aldehydes or ketones, and unsaturated carbonyl compounds to give products
such as 142, 144, 145 or 147. For a long time the problem with the nitro group was rather the
eventual conversion to a carbonyl group, e.g. 142 to 143, but there are now many reagents for this
reaction at the aldehyde, ketone, or acid oxidation levels. 31 The examples which follow illustrate
some of these.
OMe
enol ether
hydrolysis
CHO
O OSiMe3 O
1. Me2CuLi 1. mCPBA
2. Me3SiCl
2. Et3NHF
3. t-BuMe2SiCl
imidazole
OTBDMS
135 136 137
O
Ph2P OMe
117
1. LDA
2. 137
3. NaH
138
OMe
OTBDMS
HF, H 2O
MeCN
139
CHO

O O
N
R 1
O O
N
R1 H NR3 H
X
140 141
R 1
R3N
NO2 R2 +
O
146
R 1
NO 2
base
R 2
R 2 CHO
base
R 1
Alkylation solves the awkward problem of how to make aryl ketones of the pattern 151, awkward
because the Friedel-Crafts reaction doesn’t work with this substitution pattern. Alkylation of a
nitroalkane with the benzylic halide 149 does work well and the product 150 can be oxidised to
the ketone 32 151. Reactions with aldehydes work even with masked aldehydes 33 like dihydropyran
to give 154 and hence the ketone 155 with a 1,2-substitution pattern after hydrolysis. 34 More
vigorous conditions give nitroalkenes 145 from aldehydes and these will be very useful later as
a 2 reagents.
Cl
Cl
Michael additions go particularly well with nitroalkanes with catalytic base because the
fi rst formed enolate is more basic than the nitroalkane. Diketones, e.g. 159, keto-aldehydes
and keto-acids can all be made by this route and the two steps can be combined in one using
alumina to catalyse the Michael addition (158 is not isolated) and an oxidative work-up to
release the ketone. 34
R 1
NO 2
R 1
147
NO 2
O
R2 R1 142 143
NO 2
R 2
NO 2
OH
R1 144 145
O
NO2
Cl
NO2 2. mCPBA
Cl
149 150 151
O OH
152
+
+
NO 2
base
base
14 Nitroalkanes 215
O
R 2
1. DBU
Me3SiCl
R 1
1. Me 2NH
148
OH
NO2 O
NO2 2. HCl
H2O
O
O
153 154 155
Bu
NO2
+
O
Al2O3 NO2
H2O2 K2CO3
O
O
O
156 157 158 159; 90% yield
O
R 2
R 2
O
R 2

216 14 Acyl Anion Equivalents
A synthesis of strigol using nitroalkanes
When Raphael wanted the key intermediate 162 for his synthesis of strigol 160, the aldol disconnection
162a revealed the need for the diketone 163 and hence by disconnection of a very strategic
bond, the d 1 synthon 164.
H
O
H
OR
OH
OH
OR
160; strigol 161 162
OR
aldol
The nitroketone 166, though at the wrong oxidation level, is an ideal reagent for this purpose
as it is not necessary to protect its ketone during the Michael addition. Conversion of the nitrocompound
168 into the ketone 169 with TiCl 3 illustrates the generally preferred method for this
reaction. 35
O
O
Synthesis of mono-protected diketones
O
O
OR
162a 163
NO2 166
O
strategic bond
disconnection
The nitro group can solve the problem of making a diketone with one of the ketones protected.
When Hewson wished to make a series of natural products from the key intermediate 170 using
his reagent 171 he needed the diketoester 172. Disconnection of a strategic bond reveals the
possibility of adding a d 1 reagent to the unsaturated ketoester 36 174.
MeO 2C
H
O
165
base
O
MeS MeS
NO2
167
PPh 3
O
O
H
MeO 2C
170 171
172
+
O
CO2R
O
OR
+
164; d 1 reagent?
O
TiCl 3
H 2O
O
O
165
natural
a 3 reagent
NO2
O
168 169
O
O
Me
173
+
MeO 2C
O
174
O

O
MeS
SMe
175; cf. 50
Me
Attempts with various reagents showed that the ketoester was inclined to polymerise unless it
was used as its acetal 176 and that acetal style reagents for the d 1 synthon 173 such as 175 gave
poor results. The solution was to use nitroethane to give 177 having each keto group masked in
a different form. Conversion of nitro group to ketone was better with TiCl 3 than other reagents.
The diketoester was formed as a single (trans) isomer which gave an excellent yield of 170 with
the reagent 171.
MeO 2C
O
176
O
O
EtNO2 MeO2C O
base
O2N
O
TiCl3 MeO2C O
Alternative and more general approaches to partly protected diketones include the Michael
addition, protection, Michael addition sequence 179 to 182 and the Michael addition reduction
sequence 183 to 186. The fi rst provides a molecule 182 containing three ketones: one free, one
protected as an acetal, and one masked as a nitro group. The acetal can be removed in dilute acid
without hydrolysing the nitro group and the nitro group can be converted to a ketone without disturbing
the acetal, 31,34 e.g. with H 2O 2 and K 2CO 3.
R 1
The second has been used to make prostaglandins from the intermediate aldehyde 186. Note
the stereochemistry: the obvious trans arrangement of the two substituents in 184 after the
Michael addition and the approach of the bulky reducing agent L-selectride® Li(s-Bu 3BH) from
the opposite face to the nearer and larger of the two substituents. Finally, a reductive workup
(Me 2S) is needed after the oxidation of nitro to ketone with ozone. 37
O
HO
O
177 178
CF 3CO 2H
H 2O
172 171
O
MeNO2 R1 O
HO OH
R
NO2
1
O O
R
NO2 2
base
H
base
179 180 181
NO 2
14 Nitroalkanes 217
O
R 1
CO 2Et
O
NO 2
182
base
NO2 183 184
185
CO2Et
MeNO2
O
1. t-BuMe 2SiCl
imidazole, DMF
2. NaOMe, MeOH
3. O3, MeOH
4. Me2S
O
R 2
TBDMSO
CO 2Et
CHO
186
O
LiBH(s-Bu) 3
170
97% yield
CO2Et

218 14 Acyl Anion Equivalents
Catalytic Methods: The Stetter Reaction
The useful Stetter reaction 38 is biomimetic - the idea and the reagent came from the coenzyme
thiamine pyrophosphate 187. Removing unnecessary substituents left the core of the thiazolium
species 188 where R is usually benzyl (catalyst a) but can be various other primary alkyl groups.
Reaction with an aldehyde starts by the removal of a proton with quite a weak base (usually a
tertiary amine) to give the ylid 189 in which the negative charge is stabilised partly by electrostatic
interaction (the ylid) and partly by the sulfur atom. Nucleophilic attack on the aldehyde gives 190
which can transfer a proton from C to O to give uncharged 191.
Bn
This is a strange compound. The exocyclic (arrowed) alkene is an enol at one end but an
enamine and a vinyl sulfi de at the other. All three atoms, O, N, and S, have lone pairs making
this a very electron rich alkene. The nitrogen atom dominates so that conjugate addition 192 to
enones works well. The product 194 loses the catalyst 189 to give a 1,4-diketone 195. The reaction
is simplicity itself: the aldehyde, enone, catalyst and weak base (usually amine or sodium acetate)
are heated in ethanol.
R 1
HO
188
R = Bn
S
O O O O
N
P
Bn
Et 3N
OH
R 2
P
R 2
192
O
O
N
R S
1
N
R S
1
R2 O
189; ylid 190
H
O
+
R 3
S
N
O
R 1
R 3
NH2
N
S
N
N
187; thiamine pyrophosphate 188; Stetter thiazolium salts
Bn
R 2 OH
cat. 188
Examples include enolisable aldehydes adding to enolisable enones to give e.g. 197, and an
impressive range of aromatic and heterocyclic compounds as either component. The pyridine 200
is formed in only 12% yield if sodium cyanide is used as catalyst. 38
O
R 2
Bn
R 3
O
R 2
O H
R 1
O
R 1
R 3
S
N
S
N
191
Bn
Bn
R 2 O
193 194
Et3N
HO
195
S
N
R
catalyst a:
R = CH 2Ph
(benzyl)
others (b-d)
R = Me, Et
(CH 2) 2OEt
OH
R 2
189
O
R 3

Me
References
O
H
+
O
196
14 References 219
OMe
cat. 188; R = Bn
Et3N, dioxane
General references are given on page 893
1. O. W. Lever, Tetrahedron, 1976, 32, 1943.
2. T. A. Hase, Umpoled Synthons, Wiley, New York, 1987.
3. A. S. Fletcher, K. Smith and K. Swaminathan, J. Chem. Soc., Perkin Trans. 1, 1977, 1881.
4. D. Seyferth and R. M. Weinstein, J. Am. Chem. Soc., 1982, 104, 5534; D. Seyferth, R. M. Weinstein and
W.-L. Wang, J. Org. Chem., 1983, 48, 1144.
5. A. Ricci, M. Fiorenza, A. Degl’Innocenti, G. Seconi, P. Dembech, K. Witzgall and H.-J. Bestmann,
Angew. Chem., Int. Ed., 1985, 24, 1068; A. Ricci, A. Degl’Innocenti, S. Chimichi, M. Fiorenza, G. Rossini
and H.-J. Bestmann, J. Org. Chem., 1988, 50, 130.
6. P. C. B. Page, N. B. van Niel, and J. C. Prodger, Tetrahedron, 1989, 45, 7643.
7. D. Seebach, B. Seuring, H.-O. Kalinowski, W. Lubosch and B. Renger, Angew. Chem., Int. Ed., 1977, 16,
264; B. Seuring and D. Seebach, Helv. Chim. Acta, 1977, 60, 1175.
8. I. Jirkovsky and M. N. Cayen, J. Med. Chem., 1982, 25, 1154.
9. K. Fujiwara, K. Saka, D. Takaoka and A. Murai, Synlett., 1999, 1037.
10. K. Fujiwara, D. Takaoka, K. Kusumi, K. Kawai and A. Murai, Synlett., 2001, 691.
11. S. Hünig and G. Wehner, Synthesis, 1975, 391.
12. D. A. Evans, L. K. Truesdale and G. L. Carroll, J. Chem. Soc., Chem. Commun., 1973, 55.
13. G. Stork, A. A. Ozorio and A. Y. W. Leong, Tetrahedron Lett., 1978, 5175.
14. G. Büchi, P. H. Liang and H. Wüest, Tetrahedron Lett., 1978, 2763.
15. H. Nemoto, Y. Kubota and Y. Yamamoto, J. Org. Chem., 1990, 55, 4515.
16. Y. Kubota, H. Nemoto and Y. Yamamoto, J. Org. Chem., 1991, 56, 7195.
17. J. E. Baldwin, G. A. Höfl e and O. W. Lever, J. Am. Chem. Soc., 1974, 96, 7125.
18. R. K. Boeckman, K. J. Bruza, J. E. Baldwin and O. W. Lever, J. Chem. Soc., Chem. Commun., 1975, 519;
C. G. Chavdarian and C. H. Heathcock, J. Am. Chem. Soc., 1975, 97, 3822.
19. R. K. Boeckman and K. J. Bruza, Tetrahedron Lett., 1977, 4187.
20. A. B. Smith and R. A. Rivero, J. Am. Chem. Soc., 1978, 109, 1272.
21. P. Kocienski, R. Narquizian, P. Raubo, C. Smith, L. J. Farrugia, K. Muir and F. T. Boyle, J. Chem. Soc.,
Perkin Trans. 1, 2000, 2357.
22. P. Kocienski, R. C. D. Brown, A. Pommier, M. Procter and B. Schmidt, J. Chem. Soc., Perkin Trans. 1,
1998, 9.
23. J. M. Holland, M. Lewis and A. Nelson, Angew. Chem., Int. Ed., 2001, 40, 4082.
24. S. G. Levine, J. Am. Chem. Soc., 1958, 80, 6150; G. Wittig and M. Schlosser, Chem. Ber., 1961, 94, 1373;
G. Wittig, W. Böll and K.-H. Krück, Chem. Ber., 1962, 95, 2514.
25. A. F. Kluge and I. S. Cloudsdale, J. Org. Chem., 1979, 44, 4847.
26. E. J. Corey and M. A. Tius, Tetrahedron Lett., 1980, 21, 3535.
27. N. L. J. M. Broekhof, F. L. Jonkers and A. van der Gen, Tetrahedron Lett., 1978, 2433.
28. S. F. Martin and T. A. Puckette, Tetrahedron Lett., 1978, 4229; S. F. Martin, G. W. Phillips, T. A. Puckette
and J. A. Colapret, J. Am. Chem. Soc., 1980, 102, 5866.
29. T. K. Jones and S. E. Denmark, J. Org. Chem., 1985, 50, 4037.
O
O
197; 80% yield
+
O cat. 188; R = Et
O
N CHO
Et3N, dioxane N
198 199
O
200; 75% yield
OMe

220 14 Acyl Anion Equivalents
30. J. W. Huffman, M.-J. Wu and H. H. Joyner, J. Org. Chem., 1991, 56, 5224.
31. H. W. Pinnick, Org. React., 1990, 38, 655.
32. J. M. Aizpurua, M. Oiarbide and C. Palomo, Tetrahedron Lett., 1987, 28, 5361.
33. M. Lagrenée, Compt. Rend., 1977, 284C, 153.
34. R. Ballini, M. Petrini, E. Marcantoni and G. Rosini, Synthesis, 1988, 231.
35. G. MacAlpine, R. A. Raphael, A. Shaw, A. W. Taylor, and H.-J. Wild, J. Chem. Soc., Chem. Commun.,
1974, 834; J. Chem. Soc., Perkin Trans. 1, 1976, 410.
36. A. T. Hewson and D. T. MacPherson, J. Chem. Soc., Perkin Trans. 1, 1985, 2625.
37. B. P. Cho, V. K. Chadha, G. C. LeBreton, and D. L. Venton, J. Org. Chem., 1986, 51, 4279.
38. H. Stetter and H. Kuhlmann, Org. React., 1991, 40, 407.

Section C:
Carbon–Carbon Double Bonds
15. Synthesis of Double Bonds of Defi ned Stereochemistry ................................................. 223
16. Stereo-Controlled Vinyl Anion Equivalents .................................................................... 255
17. Electrophilic Attack on Alkenes ........................................................................................ 277
18. Vinyl Cations: Palladium–Catalysed C–C Coupling ..................................................... 307
19. Allyl Alcohols: Allyl Cation Equivalents (and More) ...................................................... 339

15
Synthesis of Double Bonds of Defi ned
Stereochemistry
Introduction: Alkenes: framework or functional groups?
Control of Alkene Geometry by Equilibrium Methods
Some examples from other chapters
A More Detailed Look at The Principles
Case 1: Only one alkene is possible. This is usually a cyclic cis alkene
Case 2: The two alkenes are in equilibrium and the trans alkene is formed
Case 3: The cis alkene is formed stereoselectively
The Wittig Reaction
The last step of the Wittig reaction is stereospecifi c
The Z-selective Wittig reaction with simple ylids
Case 4: The trans alkene is formed stereoselectively
The trans-Selective Wittig Reaction
Crossing the Stereochemical Divide in the Wittig Reaction
The Schlosser modifi cation
Conjugated Z-alkenes
Stereocontrolled Reactions
The Horner-Wittig reaction with phosphine oxides
The Peterson reaction
Stereoselective Methods for E-Alkenes: The Julia Reaction
Modifi ed Julia reactions
The Kocienski modifi cation of the Julia reaction
Direct Coupling of Carbonyl Compounds and Alkenes
Carbonyl compounds: the McMurry reaction
Alkenes: olefi n metathesis
Stereoselective Methods for E-Alkenes
[3,3]-Sigmatropic rearrangements
[2,3]-Sigmatropic rearrangements: the Wittig rearrangement
Reduction of Alkynes
Stereospecifi c Methods for Z-Alkenes
Using cyclic compounds
Interconversion of E and Z Alkenes
Photochemical isomerisation to the Z-isomer
A synthesis of methoxatin
Radical isomerisation to the E-isomer
Stereospecifi c Interconversion of E and Z-isomers
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

224 15 Synthesis of Double Bonds of Defi ned Stereochemistry
Introduction: Alkenes: framework or functional groups?
The carbon-carbon double bond (olefi n or alkene) is a structural feature on the border of framework
and functionality. Unlike the carboxylic acid in 1 it is inside the skeleton of the molecule
and involves no atoms except carbon and hydrogen. It has no polarity and yet it has the potential
of producing highly polar functionality at two carbon atoms in a single reaction, as in the
iodol actonisation to give 2 from 1.
CO 2H
1 2
In the same reaction stereochemistry may be generated: two stereogenic centres are in fact
produced in this reaction and in the epoxidation of 3. The sense of the stereochemistry produced
in these reactions depends critically on two factors: the inherent stereoselectivity of the reactions
(anti in the iodolactonisation and syn in the epoxidation) and the geometry of the alkene. Inside a
six-membered ring of 1 the alkene must of course by cis or Z. In the open chain allylic alcohol 3
it can be E or Z depending on the method of synthesis. This chapter explores ways to control the
stereochemistry of alkenes as an essential preliminary to the control of three-dimensional stereochemistry
in chapter 25 where you will meet a method to make single enantiomers of 4 from the
alkenes in E- and Z-3.
Control of Alkene Geometry by Equilibrium Methods
In many reactions there is an equilibrium between reactants and products so that only the more
stable of the two alkenes is produced. In the Claisen ester condensation of cyclohexanone 8 with
ethyl formate, the true product under the conditions of the reaction is the stable enolate 9 and this
is reversibly protonated on workup to give the more stable H-bonded enol of the ketoaldehyde
Z-10. In the aldol reaction between the same ketone and benzaldehyde, the initial product 7 gives
the enolate 6 and dehydration is reversible: only the more sterically favourable E isomer of 5
is formed. Note that it is irrelevant that the aldol 7 is a mixture of diastereoisomers: all stereochemistry
is lost in the formation of the enolate 6. In later parts of this chapter a more specifi c
relationship between 3D and 2D stereochemistry will be established.
I 2
NaHCO 3
mCPBA
O
R
mCPBA
R
O
R OH R OH H OH
H OH
E-3 anti-4 Z-3 syn-4
O
Ph
O
HO O
Ph
O
Ph
I
PhCHO
NaOH
O
O
O
HCO 2Et
H
O O O O
E-5 6 7 8 9
Z-10
EtO
EtOH

15 Control of Alkene Geometry by Equilibrium Methods 225
Some examples from other chapters
There are very many reactions which routinely give E-alkenes as the more stable product. You
will already be aware of many of them and there are many scattered around the other chapters in
this book. We shall simply give a few more examples here and a list of cross references to other
examples.
1. Aldol reactions followed by dehydration, e.g. enones E-11 and E,E-12. We shall meet E,
E-12; Ar Ph later as a useful ligand for palladium. 1
O
O
O
ArCHO
ArCHO
NaOH
Ar NaOH Ar
acetone E-11 E,E-12
2. The base-catalysed condensation of nitromethane with aldehydes to give nitroalkenes E-13
(the Henry reaction). One example E-14 was used in a Corey prostaglandin synthesis. 2
RCHO, base
CH
NO2 3NO2 R
NC
nitromethane E-13 E-14
3. Dehydration of tertiary alcohols 16 formed by the addition of organo-metallic species to
ketones 15. An example is from Corey’s erythronolide synthesis where dehydration of 18 gives
only the E-enyne 3 19.
R 1
R
O
1
R1 R2 OH
or R2 R
Li
2MgX cat H (TsOH etc)
or SOCl2, pyridine
15 16 E-17
O
4. The Heck reaction with α,β-unsaturated carbonyl compounds. The intermediate Pd(II)
σ-complex 20 eliminates PdHI in a cis fashion and prefers to give the E-alkene 21.
CO 2Et
Li
ArI
Pd(0)
Ar
PdI
syn-elimination
CO2Et 20
of PdHI Ar
CO2Et E-21
5. Nucleophilic addition to α,β-unsaturated alkynes under equilibrating conditions. This
example comes from a recipe in Organic Syntheses where a good yield of crystalline E-22 is
reported. 4
OH
cat TsOH
15; R 1 = Et 18 E-19
CO 2Et
25% aqueous Me3N
40:1 water : CH2Cl 2
Me3N CO2
E-22; 76-82% yield
Ar
R 2
NO 2

226 15 Synthesis of Double Bonds of Defi ned Stereochemistry
6. Equilibration of allylic alcohols, halides etc via an allyl cation. Whichever alcohol 23 or 26
is used as starting material, treatment with HBr gives the same equilibrium mixture of all E-24
and 25. No doubt any Z-24 has also equilibrated to E-24.
OH
HBr
Br
+
HBr
E-23 E-24; 80-87% 25; 13-20%
26
7. Formation and equilibration of allylic metal derivatives such as those from the allylic
bromides 24 and 25 we have just made. Reaction of the Grignard reagent with CO 2 gives only 27
but displacement of bromide with cyanide leads to the isomeric acid E-28 both in good yield. 5
CO2H 1. Mg, Et2O 2. conc. HCl
E-24 + 25
1. CuCN
2. conc. HCl
CO2H
28; 8.5 parts
+
CN
27; 75% yield 70% yield 29; 8.5 parts
A More Detailed Look at The Principles
This simple picture hides a number of principles which we shall need to explore in this chapter. In
outline we can distinguish these cases:
1. Only one alkene is possible. This is usually a cyclic cis alkene.
2. The two alkenes are in equilibrium and the trans alkene is formed.
3. The cis alkene is formed stereoselectively.
4. The trans alkene is formed stereoselectively.
5. The reaction is stereospecifi c. The geometry of the alkene depends on the mechanism of the
reaction and the stereochemistry of the starting material.
Case 1: Only one alkene is possible. This is usually a cyclic cis alkene
We shall deal with all the cases and explain the principles behind them. We need spend no time
on case 1. Alkenes in 3- to 7-membered rings must be cis as the trans alkenes cannot be formed.
Medium rings from 8-membered upwards can form trans alkenes but they are less stable. Only
from (about) 12-membered rings upwards is the trans alkene the more stable isomer.
This simple Robinson annelation (chapter 5) produces a cis cyclohexene 33 because that alone
is possible. The step in which the double bond appears is the E1cB elimination 32 at the end. The
enolate will always have one lobe of the p-orbital shown in the conformational diagram correctly
aligned to expel the hydroxide leaving group and form the cis alkene.
O
OHC OHC
O O
HO
HO
30 31 32 33
Br
O
O
HO
OH
O
conformation
of E1cB on 32

Each of the following reactions gives exclusively the cis (actually E or Z as shown) alkenes
35, 36, and 38 for the same simple reason: trans alkenes cannot exist in four-, fi ve- or sevenmembered
rings. The reactions are from other chapters of the book.
CO2Me Na
OSiMe3 O HN
N
Ph
OH H
CO2Me Me3SiCl
OSiMe3 34 Z-35 E-36
37 E-38
The fi rst reaction is the silicon-directed acyloin the second is simple enamine formation from
chapter 2 and the third reaction is a simple E1 elimination. The same reaction will start off our
next section concerning alkenes in equilibrium.
Case 2: The two alkenes are in equilibrium and the trans alkene is formed
We can go back in time to some very famous work by Cram which led him to deduce his famous
rule. 6 Reaction of either diastereoisomer of the (racemic) tertiary alcohol 39 with acid gives the
same mixture of alkenes in which the trans alkene E-40 predominates (50:1) to a very great
extent. The elimination is E1 via the tertiary carbocation 43.
Ph
Me
Ph
OH
H
OH
39; syn alcohol 40; trans E-alkene
41; anti alcohol
Ph
H H
Me
Ph
H
Ph
Me
Ph
Ph
Me
OH 2
cat. TsOH
AcOH, 75 °C
Ph
Me
42 43 44
Each alkene can be made stereospecifi cally (the synthesis of the Z-isomer 45 is given later in
this chapter) and treatment of the cis alkene 45 under the same acidic conditions also gives the
trans alkene 40. The alkenes are in equilibrium via the stable tertiary carbocation 43. The cation
has two conformations 43a and 43b that can eliminate to give the E-alkene 40 and free rotation
about the central σ-bond in this relatively long-lived intermediate 43 ensures that one of these
conformations is accessible from all possible starting materials.
Me
15 A More Detailed Look at The Principles 227
H
Ph
cat. TsOH
AcOH, 75 °C
Ph
Ph
OH
39; syn alcohol
H
H2O
H
Ph
Me
Ph
H
H2O Ph
Ph
OH
41; anti alcohol
Ph
Ph
Me H
43a; conformation
of cation 43
Me
H
Ph
Ph
45; cis Z-alkene
H
–H
H
43
H
–H
Me
Ph
Ph
H
40; trans E-alkene
Me
Ph
Ph
H H
43b; conformation
of cation 43
Me
Ph
Me
H
OH2
Ph
Ph
Ph

228 15 Synthesis of Double Bonds of Defi ned Stereochemistry
Such perfect cases of equilibration are rare. Another important one concerns equilibration
by Michael addition to conjugated alkenes. A classic case is the preparation of maleate 47 and
fumarate 48 esters from (the necessarily Z-) maleic anhydride 46. Simple treatment with methanol
in acidic solution gives the liquid maleate 47 as expected. It is unusual for cis and trans alkenes
to be given different names: maleic and fumaric acids were named before their relationship was
understood.
O
O
O
46; maleic
anhydride
MeOH
CO 2Me
Slowly in solution crystals are formed and these are the more stable fumarate ester. The process
is enormously accelerated by adding a trace of an amine and must occur by reversible Michael
addition of the amine or even of traces of methanol or any other stray nucleophile. 7
Nu
O
OMe
CO 2Me
H
Once again a long-lived intermediate - the enolate ion 50 - allows free rotation about the central
σ-bond and the elimination of the catalyst from a more favourable conformation 51 leading to the
E-alkene 48. The same process occurs during the dehydration step following aldol reactions which
occurs by an E1cB mechanism with the same sort of intermediate (e.g. formation of E-5, E-11 and
E,E-12). This process is so easy that it is actually very diffi cult to make cis alkenes conjugated to
the more reactive electrophilic groups such as aldehydes.
Case 3: The cis alkene is formed stereoselectively
CO2Me CO2Me cat. R2NH 47; dimethyl maleate
b.p. 204-205 ˚C
O
OMe
180°
rotation
Nu CO2Me MeO2C Nu
MeO 2C
48; dimethyl fumarate
m.p. 103-104 ˚C
You might think that this case would be very rare. Why should any reaction choose to form the less
stable cis alkene? There are only a few simple cases, it is true, but there is one extremely important
more complex case too. So important is this case that it is the fi rst choice alkene synthesis in most
people’s mind. We shall look fi rst at the simple Z-selective reactions.
We can start with a Michael addition. This sounds crazy as we have just explained that Michael
addition leads to rapid equilibration. However, Michael addition to triple bonds may not. One
remarkably simple case is the addition of LiBr in weakly acidic solution to a triple bond conjugated
to an ester 52.
Only the Z-alkene 53 is formed. The difference here is in the structure of the enol intermediate
55. There is no free rotation. Instead the two cumulated (allene style) double bonds are held rigidly
O
OMe
MeO 2C
49 50 51 48
LiBr Br CO2Et CO2Et
HOAc, MeCN
52 Z-53
85% yield
Z-isomer only
no trace of E-53
CO2Me

at right angles to each other. Protonation occurs on the lobe of the p-orbital away from the bromine
atom 55 and the Z-alkene 53 results. This is clearly kinetic control. 8
Br
O Br
OH Br CO2Et
OEt
OEt
H
H
54 55 Z-53
A more remarkable case is the formation of predominantly Z-enediyne 57 during the base
catalysed dimerisation of the propargyl bromide 56. This is important as well as remarkable as the
enediyne antibiotics contain this structural feature which has to be Z for biological activity. 9
Br
SiMe 3
15 A More Detailed Look at The Principles 229
LiHMDS 58
HMPA 59
SiMe3 56 Z-57; 94% yield, 2:1 Z:E
SiMe 3 Me 3Si N SiMe 3
You might say that the selectivity is “only” 2:1 but in truth it is remarkable that the reaction
is Z-selective at all. In practice 60% Z-57 can be isolated by chromatography. The obvious
mechanism is the formation of a lithium derivative, S N2 coupling 60, and base-catalysed E2
elimination 62.
For this mechanism to deliver Z-57 the conformation (or even confi guration?) of the inter mediate
must favour 62 which looks rather unlikely. However, the reaction does give predominantly Z-57.
Maybe the two long thin alkynes actually attract rather than repel one another 62a. The original
authors offer a different (carbenoid) explanation but without much conviction.
These examples both concern triple bonds. But please do not think that all reactions of
alkynes are Z-selective. A salutary lesson is hidden in another volume of Organic Syntheses in
a nucleophilic addition to the same alkyne as in our fi rst example. Evidently under these polar
hydrophilic conditions equilibration occurs by reversible protonation. 10
Li
58; LiHMDS
Lithium
HexaMethyl
DiSilazide
SiMe3 SiMe3 SiMe3 LiHMDS Br
56
Br
LiHMDS
Br
57
Li
Br
60
H
SiMe3
SiMe3 61
Li
62
SiMe3 CO 2Et
25% aqueous Me 3N
40:1 water : CH 2Cl2
Me3N
CO2
E-22; 76-82% yield
Me2N Me2N P
Me2N
O
59; HMPA
HexaMethyl
PhosphorAmide

230 15 Synthesis of Double Bonds of Defi ned Stereochemistry
The Wittig Reaction
Now to the great Z-selective alkene synthesis. The Wittig reaction. Along with the Diels-Alder
and the aldol reactions this is one of the most important reactions of all time. You probably have
an idea of the basic reaction:
O Wittig
CH3I
base
Ph3P Ph3P CH3 phosphine phosphonium salt
Ph3P CH2 63; ylid(e)
+
reaction
+ Ph3P O
phosphine
64; alkene oxide
We have chosen this example to illustrate the fi rst virtue of the Wittig reaction: you know where
the alkene will be in the product 64. Even if, as here, it is less stable than some other possibility
(the endocyclic alkene 66 that would be formed by dehydration of the tertiary alcohol 67), the
new alkene must be between the carbon atoms formerly occupied by the phosphonium ylid and
the carbonyl group. This is because the last step is the regiospecifi c decomposition of a fourmembered
ring (an oxaphosphetane) 65.
O
Ph3P CH2
PPh3 O
H
63; ylid(e)
65; oxaphosphetane 64; alkene 66; alkene 67; t-alcohol
The last step of the Wittig reaction is stereospecifi c
This regiospecifi city has stereochemical consequences too. The geometry of the alkene product 70
is not decided in the elimination of Ph 3PO from the oxaphosphetane 69. If this step is a concerted
cis elimination then the stereochemistry of the oxaphosphetane is faithfully reproduced in the
alkene product. Here is an example:
R2 R
2.
O
1 PPh3 R
PPh3 O
1
R2 R2 R1 1. base
+
68; phosphonium salt 69; oxaphosphetane 70; Z-alkene
The Z-selective Wittig reaction with simple ylids
If the syn oxaphosphetane 69 is favoured, the Z-alkene 70 must be formed. And it is! The formation
of the oxaphosphetane is syn selective and the elimination step is stereospecifi c. The selectivity
varies, but with RAlkyl it is usually quite good. Here is an example - the synthesis of the sex
attractant 75 of the Gypsy moth. This is the epoxide of a long chain cis alkene Z-74 easily made
by a Wittig reaction with excellent Z-selectivity. 11
OH
PPh 3
O

RCHO
Br
Ph3P MeCN
PPh3 BuLi
DMSO
71 72; 86% yield 73
74; 91% yield Z-alkene isolated
O
75; disparlure: sex attractant for the gypsy moth
mCPBA
This reaction is obviously of the greatest signifi cance. Yet the detailed mechanism of the formation
of the oxaphosphetane is not agreed. No previous intermediates have been isolated and one
of the two main contenders is a one-step mechanism 76. This mechanism has the advantage of
a believable explanation for the stereoselectivity. A 22 cycloaddition must have an antarafacial
component - it must be a π2 s π2 a reaction 76a.
Ph 3P
R 1
As the two components approach each other at 90 76a, the two substituents keep out of
each other’s way 77 and so, when you fl atten out the four-membered ring 69a, they end up on
the same side 69. Part of the evidence for this mechanism is that salt-free ylids give the highest
Z-selectivity. 12 Normal preparations of ylids by treatment of, say, a phosphonium bromide with
BuLi, have a molecule of salt (here LiBr) inevitably present. But not this way:
This procedure was used in the synthesis of the upper chain of a prostaglandin 82 (see chapter
6) where the stereochemistry is related to the biological activity. 13 Note that the aldehyde is tied up
as a hemiacetal in the starting material 81 (see chemoselectivity chapter) and that the “salt-free”
ylid is actually a carboxylate anion made with sodium derivative of DMSO in DMSO. As you will
see in the next section, not all Wittig reactions are cis selective - those of stabilised ylids are trans
selective.
O
THPO
PPh 3
O
R2 Ph3P O
R2 R1 P
R1 Ph Ph O
Ph
R2 H
P
H R1 Ph Ph O
Ph
R2 H
P
H R1 Ph Ph O
Ph
R2 2 + 2
cycloaddition
flatten
out
76 69 69a 77 76a
Ph 3P
OH
78
OTHP
1. NaNH 2, NH 3(l)
2. extract ylid
with benzene
15 The Wittig Reaction 231
Ph3P
Ph 3P
EtCHO
79; pure ylid - no NaBr 80; 97:3 E:Z
ylid made with
O
Me S CH 2
CO 2
HO
THPO OTHP
81 82; 80% yield, all Z
CO 2Li

232 15 Synthesis of Double Bonds of Defi ned Stereochemistry
Case 4: The trans alkene is formed stereoselectively
Many E2 reactions fi t into this category. A simple base-catalysed elimination of an alkyl bromide will
normally give the E-alkene because there are two diastereotopic hydrogen atoms which could be lost
and the one which gives the E-alkene is lost more quickly because that transition state has the lower
energy. This is a kinetic effect on a reaction in which the transition state resembles the product.
Ph
H H
Ph
base
Ph
Br
Br
83 E-84; trans-stilbene 83a
Ph
The same arguments apply to most E1cB reactions (see 32) where there are two conformations
of the enolate during elimination - one leading to the Z- and the other to the E-alkene. The second
is preferred in acyclic compounds as it gives the more stable transition state.
The trans-Selective Wittig Reaction
H A H B
Simple phosphonium ylids give Z-selective olefi nation. Ylids in which the carbanion is stabilised not
only by the P atom but also by a conjugating group, particularly a carbonyl group, give E-selective
reactions. The extra stabilisation is delocalisation of the enolate kind 85b. This simple example 85
with an aldehyde group is a stable ylid which can be prepared in and even recrystallised from water
and is available from Aldrich. It reacts with aldehydes and ketones to give E-enals 14 86.
A sequence using this reagent 85 followed by a Wittig reaction with an unstabilised ylid is a
good route to E,Z-dienes that are often found as insect pheromones. This sequence was used in the
synthesis of bombykol 90, the pheromone of the silk worm moth 15 Bombyx mori. The fi rst Wittig
gives less than 5% Z-88 and the second, using a salt-free ylid, less than 3.5% E,E-89.
OHC
The extra stabilisation makes the ylid rather unreactive and phosphonate esters 91 are often used
instead of phosphonium salts in these reactions. Treatment with a base (NaH or RO is often used,
BuLi will certainly not do) gives an inherently more reactive enolate anion 92 rather than an ylid.
These Horner-Wadsworth-Emmons reagents (HWE as we shall call them, though they go under many
other names) react with ketones as well as aldehydes and the product is normally the E-alkene 16 93.
Ph
Ph
B
E2
antielimination
Ph
Ph
E-84; trans-stilbene
H
H
Ph3P O
Ph3P
O
PhCHO
Ph
CHO
85a; ylid 85b; enolate 86; 99% yield, all E
85 OHC
CO2Me 87 E-88;
PPh 3
Z, E-89
1. (Me3Si)2N
2. E-88 Z, E-89
LiAlH4 OH
Z, E-90; bombykol, 92% yield
CO 2Me
CO2Me

O
(EtO) 2P
O
OEt
EtO
or NaH
O
(EtO) 2P
O
OEt
O
(EtO) 2P
O
OEt
RCHO
R
CO2Et 91 92a 92b E-93
Here are two examples - one with an ylid and an aldehyde and one with a phosphonate ester
and a ketone. Both give esters of conjugated unsaturated acids and both give the E-isomer. The
fi rst gave an excellent yield of E-95 with good selectivity (15:1) even though the new alkene is
trisubstituted. It was used in the synthesis of the terpene eremophilone. 17
O
O
CHO
Ph3P CO2Me
O
O
CO 2Me
94 E-95; 91% yield (15:1 E:Z) eremophilone
The second gave the trisubstituted alkene E-98 (together with 9% of the Z-isomer) and this was
used to make the interesting millipede compound polyzonimine. 18
O
91
NaH, DME
CO2Et +
CO2Et 96 97 E-98 (9% Z-98 also formed) polyzonimine
So what makes the dramatic difference between these reactions and those of the unstabilised
ylids? Well, again there is no agreement, but we offer one explanation. Supposing the reaction
is again stereoselective in favour of the syn oxaphosphetane 101, but this time the reaction can
reverse as the starting ylid (or carbanion) is so much more stable. The more abundant syn-100
cyclises to syn-101 more slowly than does the less abundant anti-100 to anti-101 and, in turn, anti-
101 eliminates more rapidly than syn-101.
Ph3P CO 2Me
O
99
R
15 The trans-Selective Wittig Reaction 233
Ph3P CO 2Me
Ph3P CO 2Me
slow
CO2Me
O R
cyclisation O
R
syn-100; major adduct syn-101; less stable
or betaine
oxaphosphetane
fast
This is more than just an explanation of the trans selectivity. It is an alternative (many would
say the correct!) mechanism for the Wittig reaction. We shall not enter the debate about whether
the “adduct” (or betaine) 100 is a true intermediate. There is no doubt that the oxaphosphetane 101
is a true intermediate. This explanation is more convincing because it also allows us to explain the
reactions in the next section.
Ph3P
Ph3P
CO2Me
O
N
CO2Me
elimination
H R
Z-102; less stable
cis-alkene
CO2Me
cyclisation O
elimination
O R
R
R H
anti-100; minor adduct anti-101; more stable E-102; more stable
or betaine
oxaphosphetane
trans-alkene
slow
fast

234 15 Synthesis of Double Bonds of Defi ned Stereochemistry
Crossing the Stereochemical Divide in the Wittig Reaction
The Schlosser modifi cation
The Wittig reaction is so powerful that we should like to cross into the forbidden zones - to
make E-alkenes from non-stabilised ylids and to make Z-alkenes from stabilised ylids. Both are
possible. The stability of the two oxaphosphetanes just considered gives us a clue as to how to
accomplish the fi rst of these. Schlosser argued that if we could equilibrate the two series without
going back to the starting materials we could cross from the kinetically favoured syn betaine
or oxaphosphetane to the more stable anti series. He did this by carrying out the reaction at low
temperature and treating with a second molecule of base before the elimination occurred. The
oxido-ylid 107 can be formed from both diastereoisomers of either the betaine 104 (if it is an
intermediate) or oxaphosphetane 105. Reprotonation preferentially gives the more stable anti-104
or 105 and hence the E-alkene 106 on warming.
Ph 3P Alk
O
103
R
H
Ph3P Alk
H
Ph3P Alk
slow
Ph3P Alk
O R
As an example, the synthesis of oct-2-ene by the normal Wittig procedure gives an 80:20 Z:E
mixture. By the Schlosser modifi cation, set out in detail below, virtually pure (99:1) E-oct-2-ene
is formed in good yield in a one-pot process. Notice the low temperature used when the aldehyde
is added. This is necessary to avoid completion of the Wittig. After epimerisation with a second
molecule of PhLi, the oxido ylid 107 is acidifi ed to give the alcohol syn-109 that eliminates quickly
with a potassium base. 19
Ph 3P Alk
PhLi
Ph 3P
Alk
O R
cyclisation O
R
elimination
syn-104; major adduct syn-105; less stable
or betaine
oxaphosphetane
fast
Ph3P
H
107; oxido-ylid
formed reversibly
with a second
molecule of base
H
Alk
Alk
H R
Z-106; less stable
cis-alkene
cyclisation
O R
anti-104; minor adduct
O
elimination
R
anti-105; more stable
R H
E-106; more stable
or betaine
oxaphosphetane
trans-alkene
The Schlosser-Wittig Sequence for making simple E-Alkenes
THF/Et2O
Ph 3P Alk
PhLi
RCHO
Ph3P Alk
THF/Et2O –78 °C
LiO R
107; oxido-ylid
HCl
Et 2O
108; ylid
H
Ph3P Alk
t-BuOK
t-BuOH
H
Ph3P Alk
LiO R
syn-104
Alk
LiO R
R
anti-109 E-106
slow
fast
warm
example:
Alk
Alk
R
Z-106
70% yield, 99:1 E:Z

A more serious example is from Johnson’s biomimetic polyolefi n cyclisation. He wished to
make the polyene 111 for potential cyclisation to 110, a 5-6-6-5 ring system analogous to the
natural steroids. After the obvious aldol disconnection, it is best to disconnect the trans-alkene
112 in the middle of the molecule.
H
H
H
O
?
O
H
O O
110 111
This requires a Schlosser modifi cation of the Wittig reaction and in theory the CHO and PPh 3
groups could be placed on either fragment. There is, as we shall soon see, a strong reason for
wishing to make the trisubstituted E-alkene by a [3,3]-sigmatropic rearrangement that gives an
alk-4-enal and so this is the preferred analysis:
The Wittig reaction was carried out by the Schlosser method - the ylid was generated with PhLi
and the aldehyde added at low temperature (70 C). A second equivalent of PhLi was added and
the intermediates allowed to equilibrate at 30 C. Elimination of Ph 3PO occurred under these
conditions to give the E-alkene. Deprotection and aldol condensation gave the cyclopentenone in
a very impressive 46% yield over the fi ve steps from the original aldehyde.
O
O
O O
O
O
115
15 Crossing the Stereochemical Divide in the Wittig Reaction 235
112
PPh 3
Wittig
1. PhLi, –70 °C
2. RCHO, –70 °C
3. PhLi, –30 °C
O
O
O
Notice the control inherent in the aldol cyclisation. One from four possible enolates attack one
of two carbonyl compounds. This is clearly thermodynamic control under these weakly basic
conditions (chapter 5?). The more highly substituted alkene (here tetra-substituted) and the most
stable possible ring (i.e. 5- not 3- or 4-membered) is formed. The geometry of the alkene is of
course controlled by the ring. 20
aldol
PPh 3
113; protect ketones
O
O O
E-116
+
O
112
CHO
114; γ,δ-unsaturated
aldehyde containing
E-trisubstituted alkene
1. HCl, H2O MeOH
2. 2% NaOH
in water
Wittig
111
46% yield
from RCHO
?

236 15 Synthesis of Double Bonds of Defi ned Stereochemistry
Conjugated Z-alkenes
A typical Horner-Wadsworth-Emmons synthesis of a conjugated alkene would involve a phosphonate
ester 92 and an aldehyde and would be extremely E-selective for E-93. This selectivity relies
on the reversal of the reaction leading to the major adduct 100, so if we want to make this reaction
Z-selective, we have to make the cyclisation of the major adduct faster. The black spot marks
where the acceleration is needed. Once the syn-oxaphosphetane 101 is the major (or only) product,
the Z-alkene 102 must be formed as the elimination is stereospecifi c.
Ph 3P CO 2Me Ph3P CO 2Me
O R
99
This problem was solved by Still and Gennari with strongly electron-withdrawing groups
(CF 3CH 2O-) on the phosphorus atom. Nucleophilic attack at phosphorus is speeded up and the
reaction becomes Z-selective. Conditions have been chosen to get the best Z-selectivity and we can
contrast the two results with the same aldehyde. 21
Ph
CO2Me
O
(MeO) 2P CO2Me E-117; >95% yield
>50:1 E:Z
MeO, MeOH
Amazingly, this reaction works well when trisubstituted alkenes are needed - one of the few
methods which does - and we can summarise that situation in a similar picture.
Ph
Me
CO2Me
E-118; 83% yield
22:1 E:Z
Stereocontrolled Reactions
slow
O R
cyclisation O
R
syn-100; major adduct syn-101; less stable
or betaine
oxaphosphetane
O
Me
(MeO) 2P CO2Me MeO, MeOH
PhCHO
PhCHO
These two versions of the HWE are close to stereochemical control: the formation of either isomer
(E or Z) at will from (more or less) the same starting materials. The next two reactions achieve
this aim. By purifi cation of Wittig-type intermediates the stereospecifi c elimination gives a single
isomer of the alkene.
The Horner-Wittig reaction with phosphine oxides
CO 2Me
Treatment of a phosphonium salt 68 with aqueous base instead of the anhydrous bases used in
the Wittig reaction leads to a stable phosphine oxide 119. The lithium derivative 120 contains a
genuine C–Li bond and reacts stereoselectively with aldehydes to give stable adducts 121 that in
turn gives the highly crystalline alcohols syn-122, easily purifi ed by crystallisation and, if necessary,
chromatography. 22
Ph3P
O
slow
CO2Me
elimination
H R
Z-102; less stable
cis-alkene
(CF3CH2O) 2P CO2Me Ph CO2Me (Me3Si) 2NK, 18-crown-6, THF Z-117; >95% yield
>50:1 Z:E
O
Me
(CF3CH2O) 2P CO2Me (Me 3Si) 2NK, 18-crown-6, THF
Me
Ph CO 2Me
Z-118; >95% yield
30:1 Z:E

Ph3P R1 NaOH
Ph2P R1 O
BuLi
Ph2P R1 H2O THF
O
Li
Ph2P R1 R2 LiO
NH4Cl H2O Ph2P R1 R2 R
HO
2 68; phosph-
119
CHO
onium salt phosphine oxide 120 121 syn-122
When one pure diastereoisomer of 122 is treated with a sodium or potassium base, a Wittigstyle
elimination occurs on the anion 123 via the four-membered ring 124. The stereochemistry
of 122 is not affected by this reaction so syn-122 must give Z-alkene 122. The by-product is
water-soluble Ph 2PO 2 rather than the sometimes diffi cult to remove Ph 3PO formed in the Wittig
reaction.
Ph2P R1 O
R2 HO
Ph2P R1 O
R2 O
R1 R2 O
Ph2P O
O
Ph2P O
R1 R2 NaH, DMF
or KOH, DMSO 125; watersoluble
+
syn-122 123 124 by-product Z-126
If the E-alkene is required, reduction of the ketones 127, prepared by acylation of 119 or
by oxidation of mixtures of isomers of 122, with NaBH 4 in alcoholic solution gives anti-122
selectively. Stereospecifi c elimination then gives exclusively E-126. The reduction is controlled by
Felkin-Anh selectivity (see chapter 21).
Ph2P R1 O
R2 O
NaBH4 Ph2P R1 O
R2 HO
R1 R2 119
1. BuLi
2. R2 O
Ph2P 122
CO2R
[O], e.g. PDC
NaH, DMF
or KOH, DMSO
125 +
127 anti-122
E-126
R2
O
H
R1 [H]
Felkin-Anh selectivity
A simple example is the stereochemically controlled synthesis of the two isomers of isosaffrole
130 from the phosphine oxide 128. Two steps give Z-130 in 64% yield while three steps give
E-130 in 70% yield. It is a matter of judgement whether the inevitable sacrifi ce of yield in a two-
or three-step process is worth the formation of single geometrical isomer rather than the mixture
obtained from the one-step Wittig or HWE reaction. 23 More complex molecules formed by the
Horner-Wittig reaction include brevetoxin 24 A and the immunosuppressant 25 FK506.
O
Ph 2P
O
Ph2P
O
128
1. BuLi
2. ArCHO
O
O
131; 85% yield
15 Stereocontrolled Reactions 237
NaBH4
O
Ph 2P
HO
1. BuLi
O
2. ArCO2Me syn-129; 76% yield
O
Ph 2P
HO
O
O
O
O
anti-129; 91% yield E-130; 91% yield
O
NaH
DMF
NaH
DMF
O
O
O
Z-130; 84% yield
O

238 15 Synthesis of Double Bonds of Defi ned Stereochemistry
The intermediate 122 is a stable compound and can be made by any chemistry that gives simple
alcohols. Acylation of 128 with a lactone gives the hydroxy ketone 132 and reduction gives the
anti-diol 133 in excellent yield. Elimination gives pure E-134, a pheromone of the Mediterranean
fruit fl y.
O
O
128
BuLi
The γ-ketone 135 can be made by reaction of 128 with cyclohexene oxide followed by
oxidation. Baeyer-Villiger rearrangement gives mostly (24:1) the lactone 136 with the right regiochemistry
for elimination after hydrolysis to give 26 only Z-137.
O
Ph 2P
O
The Peterson reaction
O
Ph 2P Me
NaH
DMF
O
CF 3CO 3H
This silicon analogue of the Wittig reaction has the advantage of two alternative stereospecifi c
elimination mechanisms. 27 Providing you can make the silicon-containing alcohols (and there’s
the problem!) as single diastereoisomers, you can get either E- or Z-alkene from either one. The
best example is probably Barrett’s synthesis of trisubstituted alkenes 28 The silyl-lithium derived
from 138 is converted into the ketone 141 by straightforward steps. Reaction with MeLi is stereoselective
(see Felkin-Anh explanation) to give the alcohol 142 with the silyl and OH groups syn.
Elimination in base goes through the Wittig-style intermediates 143 and 144 and is syn-specifi c
to give E-145 while elimination in acid follows an E2 mechanism with an anti arrangement of silyl
and OH groups to give E-145.
NaBH 4
OH
O
Ph2P Me
OH
HO
132, 81% yield 133, 85% yield
O
E-134, 98% yield
CH2Cl2 Ph2P H
Me
H
Me
135 136; 89% yield
Cl Si Ph
Me Me
R 1
PhSiMe 2
1. Li, THF
2. R 1 CHO
R 2
R 1
OH
138 139
MeLi
O
O
Si Ph
Me Me
R 1
PhSiMe 2
R 2
O
Me OH
141 142
Ph3P
CCl 4
1. 2 x KOH
H 2O
2. DMSO
50 ˚C
Cl
OH
CO 2H
Z-137; 91% yield, Z only
Si Ph
R
Me Me
1
1. Mg, CuBr.SMe 2
2. R
140; 71-75% yield
2COCl R 2
H
MeLi
PhMe2Si
R
O
1
Felkin-Anh selectivity

R2 R1 PhSiMe2 Me OH
142
KH
18-crown-6
R2 R1 PhSiMe2 Me OH
142
PhSi
R 1
TsOH
THF
Me Me
Stereoselective Methods for E-Alkenes: The Julia Reaction
O
R2 Me
R2 Me
143 144
Nu
R 1
PhSiMe 2
The Julia olefi n synthesis is rather like the Wittig reaction with a sulfone instead of a phosphonium
salt but with one other important difference: the elimination step is stereoselective and both diastereoisomers
of the intermediate can give the same isomer of the alkene. Treatment of the sulfone
147 with a strong base gives the anion 148 (or a metal derivative) that combines with an aldehyde
to give a diastereomeric mixture of adducts 149. Elimination by various methods gives, in open
chain compounds, mostly E-150 but, in cyclic compounds, mostly the Z-alkene. 29
Originally the phenylsulfone 147; ArPh was used and the adduct was acylated then treated
with dissolving metal (e.g. sodium amalgam) to bring about a reductive elimination by electron
transfer. Addition of two electrons to 151 gives the dianion 152 that breaks down to the carbanion
153 or something like it - at any rate without stereochemistry - and so to the alkene.
Ph
An advanced example of this simple approach was used by Danishefsky in the synthesis of
the antibiotic indolizomycin. 30 This example illustrates the compatibility of the Julia olefi nation
with many sensitive functional groups. The enal 154 was combined with the lithium derivative
of an allylic sulfone and the adduct acylated to give a mixture of isomers of the adduct 155.
Elimination with sodium amalgam gave a good yield of the E,E,E-triene 156. [The ‘R’s are
protecting groups.]
R 1
Me Me
PhSi
O
R 2
Me OH 2
146
O O
O O
S
Ar
R1
O O
S
Ar
R1
S
Ar
HO
R1
R2 base R2CHO 147 148
149
O O
S R1
147; Ar=Ph
15 Stereoselective Methods for E-Alkenes: The Julia Reaction 239
1. base
2. R2CHO 3. R3COCl Ph
O O
S R1
O R 2
Na/Hg
Ph
O O
S R1
O R 2
E2
R 1
R 1
R 2
R 2
E-alkene 145; 95:5 E:Z
50-55% yield from 138
Z-alkene 145; 92:8 Z:E
50-55% yield from 138
elimination
R3 O
R3 O R3 O
151 152 153
R2 E-150
R 1
O R 2
R 1
E-150

240 15 Synthesis of Double Bonds of Defi ned Stereochemistry
O OR
N
R H
154
CHO
1. Li
Modifi ed Julia reactions
2. Ac 2O
SO 2Ph
O OR
N
R H
AcO
155; 86% yield
mixture of
diastereoisomers
SO 2Ph
THF
MeOH
O OR
Recent developments emphasise the convenience of replacing the three step (Marc) Julia reaction
by one-step procedures using reagents 147 in which Ar is a heterocycle. Thus (Sylvestre) Julia
used a benzothiazole 157. The adduct 158 with an aldehyde decomposes by fragmentation of the
spiro compound 159 without the need for any further reagents to give SO 2, the alkene 150 and the
benzothiazole 169. The benzene rings are omitted from 158–160 for clarity. 31
S
S R1 O O
N
1. base
2. R 2 CHO
S
O O
S
S R 1
N R 2
O
O O
S R 1
N O R 2
This method was greatly improved by Charette’s observation that the hexamethyldisilazide
bases (Li, Na or K) and careful choice of solvent made either E- or Z-selective alkene synthesis
possible without the side reactions found in the original method. 32 Starting from the benzothiazole
164, either E- or Z-162 could be made in high yield and good selectivity by choice of solvent alone.
Both partners in this modifi ed Julia reaction are enantiomerically pure cyclopropanes and this
method led to no destruction of either stereochemistry or the three-membered rings. This method
was used to make a single enantiomer of a natural product containing six cyclopropane rings:
details are given in the workbook.
SO 2
R 1
S
N
161
Na/Hg
157 158 159
160
O O
O
S
R2 E-150
O
N
R H
156; 89% yield
E,E,E-isomer
only
1. (Me3Si) 2NNa
DMF S
S
1. (Me3Si) 2NNa
toluene or CH2Cl2 OR
2.
162; 100% yield, OHC
3.4:1 E:Z, R = Sii-Pr3
163
OR
N
164
2.
OHC
163
OR
OR
162; 100% yield,
10:1 Z:E, R = Sii-Pr3 O
S
N
O
R 1
R 2

The Kocienski modifi cation of the Julia reaction
The best version of the Julia olefi n synthesis (so far) is probably that introduced by Kocienski. 33 It
uses N-phenyl tetrazolyl sulfones 167 easily prepared from the available thiol 165 by a Mitsunobu
reaction with a simple alcohol followed by oxidation.
N
SH
N
N N
Ph
HO R1 S R1 N
N
N N
Ph
S R
NaHCO3
CH2Cl2 1
O O
N
N
N N
Ph
mCPBA
DIAD, Ph3P THF
165 166 167
The reaction uses hexamethyldisilazide bases and is again sensitive to solvent. Polar solvents
(dimethoxyethane, DME, is the best) and (Me 3Si) 2NK give high E-selectivity (usually 95:5 E:Z)
while non-polar solvents (toluene is the best) with (Me 3Si) 2NLi give moderate Z-selectivity.
R 1
Z-150
R 2
1. (Me 3Si) 2NLi
toluene
2. R 2 CHO
S R1 O O
N
N
N N
Ph
167
1. (Me 3Si) 2NK
DME
2. R 2 CHO
A recent application is the synthesis of the anti-parasitic agent nafuredin 168 by Omura’s
group. 34 Nafuredin has four alkenes in the side chain but disconnection near the middle of the
molecule is strategically best. As with the Wittig, there is a choice where to put the sulfone and
the aldehyde. The sulfone 169 can be easily made from an allylic alcohol. No doubt some of the
functional groups in 169 will have to be protected.
HO
O
15 Stereoselective Methods for E-Alkenes: The Julia Reaction 241
O
H
O
168; nafuredin
OHC
The asymmetric aspects of the syntheses of 169 and 170 appear in the workbook. The other
three alkenes were made by E-selective Wittigs with stabilised ylids or HWE reactions. The sulfone
172 for the Julia reaction was prepared from 171, in turn prepared from glucose and gave the
corresponding E-alkene (a modifi ed version of 168) in excellent yield and perfect E-selectivity.
170
Julia
HO
O
O
R 1
N
N
N
H
O
169
E-150
N
R 2
Ph
O
S O

242 15 Synthesis of Double Bonds of Defi ned Stereochemistry
HO
MsO
BnO
N
H
OH 1. 165
DEAD
Bu3P HO
MsO
N
H
N
O
2. H2O2 Mo(VI)
BnO
O
OTIPS
OTIPS
171 172
Direct Coupling of Carbonyl Compounds and Alkenes
Carbonyl compounds: the McMurry reaction
The disconnections for the Wittig, HWE, and Julia reactions are at the double bond with the
starting materials being a carbonyl compound and a P or S functionalised alkyl group. There is a
choice about which component has which functional group.
R 1
We now turn to two reactions, the McMurry and metathesis, that have the same disconnection
but both reagents have identical functional groups: carbonyls for the McMurry and alkenes for
metathesis. These methods have the advantage of simplicity but there are obvious problems of
selectivity.
R 1
R 2
CHO
R1 The McMurry 35 uses low-valent titanium to couple two carbonyl groups together and works
very well when the two compounds are the same: the symmetrical stilbene E-174 can be made in
95% yield and in almost perfect (99.92:0.04 E:Z) E-selectivity from 3-fl uorobenzaldehyde 173.
The low-valent titanium is produced by reduction of Ti(III) with lithium metal. 36
F
+
Wittig, HWE
or Julia
173
R 2
CHO
metathesis
If the reaction is intramolecular two different carbonyl groups can be coupled unambiguously
and these two examples show that esters 37 175 and amides 38 177 can be used to make benzofurans
176 and indoles 178.
N
Ph
O
S O
R2 Z
R1 Z
+ or
+
R 1
TiCl 3, Li
DME, reflux 18 hours
R 2
F
McMurry
1. (Me 3Si) 2NK
THF
2. 170
OHC R2
CHO
R1 E-174; 95% yield
E-alkene
79% yield
E only
Z = PPh 3
or P(O)(OR) 2
or SO 2Ar
OHC R2 +
F

MeO
Ph
O
O TiCl3, Li MeO
O
naphthalene
THF, 25 ˚C
Alkenes: olefi n metathesis
O
CF3 175 176 177 178
Metathesis is now one of the most important ways to make alkenes. And yet practical catalysts
for metathesis were reported only in the 1990s and the reaction 39 was largely limited to cyclic
alkenes such as 180. Though there are many metathesis catalysts, by far the most important
are the two Grubbs ruthenium carbene complexes 181 and 182. They are not the most active
catalysts but they are stable and easy to use and compatible with a wide range of functional
groups. The simpler 181 is obviously a carbene complex and is usually called ‘Grubbs’
catalyst’. The more active complex 182 (‘second generation Grubbs’) replaces one of the
tricyclohexyl phosphines with a heterocycle. In these diagrams the dotted line shows that
there may or may not be a double bond on the other side of the ring. Otherwise the diagrams
182a-c show three different ways of drawing the same compound. The fi rst 182a has the
advantage of simplicity but wrongly suggests that there is a hydrogen atom on the ring where
the Ru atom bonds. The other two 182b,c show more clearly that the heterocyclic ring is also
a carbene-like ligand.
The mechanism of the reaction involves a series of [2 2] cycloadditions 183 and 185 and
cycloreversions 184 and 186. The fi rst cycle (183 to 185) is different from the main reaction in
that the other product is styrene and the catalyst then changes to the methylene complex 187. The
reaction goes from left to right as the other product is gaseous ethylene.
183
metathesis
catalyst
+ CH2=CH2
179 180
Ph
Ru
147
15 Direct Coupling of Carbonyl Compounds and Alkenes 243
Ru
Ph Ph
Ph
Ru
N
Ph
NH
O
O
O
184 185 186
TiCl 3, Zn
DME
Ru
N
H
O
F 3C
PCy3 N N
Cl
R
R N N
R
R N N
R
R
Ru
Cl Ph Cl
Ru
Cl
Ru
Cl
Ru
PCy3 Cl Ph Cl Ph Cl Ph
181
PCy3 PCy3 PCy3
Grubbs' catalyst 182a
182b 182c
Ph
N
PCy3
Cl
Ru CH2 180 + Cl
PCy3
187; catalyst
for rest
of reaction

244 15 Synthesis of Double Bonds of Defi ned Stereochemistry
A simple example is the synthesis of analogues of the antibiotic and antifungal streptazolin by
Cossy. 40 Enantiomerically pure diene carbamate 188, prepared from the chiral pool (see chapter 23 and
the workbook for this chapter) was treated with the Grubbs’ catalyst to form the six-membered ring 189
required for ()-4,5-dihydrostreptazolin 190. This metathesis product inevitably contains a Z-alkene.
OHC
O
O
protected
glyceraldehyde
3 mol% 181
N
H
O
OH 60 ˚C N
H
O
OH
N
H
O
O
188
O
189; 90% yield
O
190
Metathesis is excellent for the formation of medium- and large rings. In the synthesis of epothilones
K. C. Nicolaou 41 used the Grubbs catalyst to close the 16-membered ring lactone 192 from
the open chain ester 191 in good yield under mild conditions. The most obvious way to prepare
192 is to make an open chain hydroxy-acid and cyclise by lactone formation. The metathesis
cyclisation generally works better.
HO
O
O
OTIPS
0.1 equivs 181
25 ˚C, CH 2Cl 2
O
O
191 192; 80% yield
The very complex natural product ircinal A Z-196 has diffi cult Z-alkenes in the eight- membered
ring and in the ‘frill’ round the molecule’s waist. Both have been inserted by metathesis with good
Z-selectivity. 42 The starting material 193 has three alkenes but only two metathesise to give the
13-membered cyclic frill 194. The fi nal metathesis to close the eight-membered ring is obviously
diffi cult and the yield is poor.
N
H
CH(OMe)2
N
193
N
O
O
H
H
HO
CH(OMe)2
181 N
1. KOH
N
O
2. COCl
CH(OMe) 2
N
OH
O
194; 67% yield
8:1 Z:E
1. 181
2. HCl
water
O
N
O
H
H
N
O
CHO
195; 75% yield Z-196; 26% yield
OH
O
H
OTIPS

A much simpler heterocyclic eight-membered ring 43 198 was successfully closed in 95% yield
with the second generation Grubbs catalyst 182; R mesityl [this is the catalyst with the double
bond]. This example shows that trisubstituted alkenes can be made by metathesis too.
O
O
H
N
O
197 198; 95% yield
Stereoselective Methods for E-Alkenes
[3,3]-Sigmatropic rearrangements
182; R = mesityl
O
H N
We said a few pages back that there was a strong reason for making a trisubstituted E-γ,δ-unsaturated
carbonyl compound 111 by a [3,3]-sigmatropic rearrangement and we have come now
to the section of the book where we look at this reaction more closely. The disconnection is of the
α,β bond in a γ,δ-unsaturated carbonyl compound 199.
O
15 Stereoselective Methods for E-Alkenes 245
X R
199
enolate
allylation
We call this disconnection “enolate allylation” because we want to alkylate an enolate ion with
an allyl halide. We have already discussed (chapter 19) the regioselectivity problems inherent in
reactions of allyl derivatives and you should recall that we want to react at the correct (less substituted)
end of the allyl system and we want to make an E-alkene. The solution is to use a [3,3]sigmatropic
rearrangement. This is the reaction sequence:
R MeO
+
OMe RCO2H O [3,3]
200
OH
X
201 202
R
X
Instead of an allylic halide, which can equilibrate all by itself, we use a regiochemically stable
allylic alcohol 200. This is combined with an acetal 201 under proton catalysis or with a vinyl (enol)
ether 203 under Hg(II) catalysis to give the key vinyl allyl ether 202. These compounds rearrange
on heating as the mechanism shows 202 to give the E-γ,δ-unsaturated carbonyl compound 199.
A C–C single bond replaces a C–O single bond (a bad bargain this) and the reaction is driven by
the replacement of a CC double bond by the more stable carbonyl group. These reactions can
be carried out at the aldehyde (XH), ketone (XR), ester (XOR) or amide (XNR 2) oxidation
level just by choosing the correct starting material.
N
O
Me
Me
+
X Br
R
X
O
199
R
[3,3]
202
Me
the
N-mesityl
group
Hg(II)
200
OMe
X
203
R
OH
X
O
X
O
R
X
O
X
O
R
R
R
200 202 204 E-199 E-alkene in 204

246 15 Synthesis of Double Bonds of Defi ned Stereochemistry
Because the [3,3] sigmatropic rearrangement turns the allylic system inside out we must use the
‘wrong’ allyl alcohol 200 to make 199. The E-selectivity is a result of a chair-like transition state
204 in which the substituent R prefers an equatorial position. The second diagram of the transition
state marks the trans arrangement of the three bonds involved. These rearrangements are among
the most E-selective reactions known. 44 The selectivity is still good even when a tri-substituted
alkene 208 is being made, providing that a large substituent is in the equatorial position 207.
R
205
OH
X
O
206
R
X
O
R
207; R > Me
E-208
An excellent illustration is Johnson’s synthesis of squalene 45 by a series of double [3,3]
rearrangements. Reaction of a dialdehyde 209 with propenyl lithium 210 gives a double allylic
alcohol 211 that undergoes a double rearrangement at the ester oxidation level with an orthoacetate
[MeC(OEt) 3].
OHC
OH
Li
CHO
210
MeC(OEt) 3
EtCO2H EtO2C CO2Et 209 211
OH
E,E-212
Reduction of the esters in the product 212 to aldehydes allows the whole process to be repeated
twice more. The complete skeleton 214 has four new alkenes and yet contains over 90% of the
E,E,E,E isomer.
E,E-212
MeC(OEt) 3
EtCO 2H
1. LiAlH 4, 2. CrO 3
3. 210
EtO 2C
OH
E,E-213
E,E,E,E-214
This method too gives Z-alkenes if they are in a ring. The β-lactam 215 can be converted into
the E-alkene 216 by a Wittig reaction and hence by a [3,3] sigmatropic rearrangement into the eightmembered
heterocycle 217 containing two new Z-alkenes. 46 The discerning reader will notice that
this is quite a different reaction from the last. That was an oxy-Cope (or Claisen-Cope) driven by the
formation of a carbonyl group. This is the Cope itself with all carbon atoms in the (necessarily boat
shaped) cyclic transition state. The driving force is the loss of the strained four-membered ring.
CHO
Ph 3P CO 2Me
CO2Me
toluene
O
OH
X
CO 2Me
CO 2Et
N
N
reflux
N
O R
O R
O R
215 E-216; 82% yield Z,Z-217; 86% yield
R

[2,3]-Sigmatropic rearrangements: The Wittig rearrangement
Derivatives of allylic alcohols such as 219 may rearrange in base to the homoallylic alcohols 222
with the creation of a new alkene. The reaction is a [2,3]-sigmatropic rearrangement of the anion
220 and works best when the group Z is anion-stabilising otherwise there may be competition with
the original Wittig rearrangement to give the alcohol derived from 218. Both these products are
more stable than the carbanion 220 because they are oxyanions. The reaction of 220 to give 221
is best called the [2,3]-Wittig rearrangement and is E-selective as the group R prefers a (pseudo-)
equatorial position in the half-chair transition state. 47
R
O
218
Z
[1,2]
R
O
Z
219
base
R
O
Z
220
The problem of what to do with the usually unwanted anion-stabilising group Z is solved in
the Wittig-Still rearrangement by using the R 3Sn group that sacrifi ces itself to form the anion.
Alkylation of the allylic alcohol 223 and treatment with BuLi initiate the rearrangement 225 to
give the unsubstituted E-allylic alcohol 226. There are many examples. 48
R
OH
223
2. I
1. KH
SnBu 3
R
O
BuLi R
Most of the examples in this chapter have been disubstituted alkenes, a few have been
trisubstituted, but none so far has been tetrasubstituted (except cyclic alkenes) as this is the most
diffi cult case of all. One solution 49 starts with ethyl lactate 228 and uses a HWE reaction on
the enantiomerically pure phosphonate 229 to make the E-enone 230 with very high selectivity.
Chelation-controlled addition of a Grignard reagent gives the stereochemically pure allylic alcohol
231. Chelation control is explained in chapter 21.
EtO 2C
OH
228; ethyl
lactate
(EtO) 2P
Alkylation of the free OH provides the substrate 232 for the Wittig-Still rearrangement 233.
The new tetrasubstituted alkene 234 is almost entirely E (95:5 in most cases) and the migrating
CH 2O group is transferred across the top face of the allylic system as drawn. The [2,3]-sigmatropic
rearrangement is suprafacial.
1. KH
E-231
2. I SnBu3 15 Stereoselective Methods for E-Alkenes 247
[2,3]
R
[2,3]
O Z
221
R
R
HO Z
E-222
SnBu3 O
O
HO
224 225 226 E-227
O O
O
OR
229; R = BnOCH2 Bu 3Sn
R 1
O
R2 R1CHO LiOH,H2O
BuLi
R 1
OR
E-230; >95:5 E:Z
R 1
O
R2 R 2 MgBr
R 1
R
HO
E-231
OR
OR
OR
E-232 E-233
E-anti-234
[2,3]
HO
R 1
R 2
OR

248 15 Synthesis of Double Bonds of Defi ned Stereochemistry
There are many sigmatropic rearrangements and all are E-selective in open chain compounds
but can give Z-alkenes if the structure of the compound demands it. In this way they resemble
the McMurry reaction and olefi n metathesis. Many such reactions are used to transmit threedimensional
stereochemistry rather than for E/Z control in alkenes.
Reduction of Alkynes
You will already be aware that cis-alkenes can be formed by catalytic hydrogenation of alkynes.
This example illustrates how acetylene, a double-ended nucleophile, can be used to build the skeleton
of a Z-allyl silane 235 of the type used in chapter 12. The disconnection 236 is next to the
‘alkene’ (now an alkyne) rather than across it.
EtO
OEt
SiMe3 FGI
EtO
SiMe3 EtO
Cl
235
reduction
OEt
236
OEt
237
Cl SiMe3
238
The synthesis is straightforward except that the normal Lindlar catalyst is not used, Raney
nickel being preferred in this case. 50
1. BuLi
2. 237
EtO
OEt
H
Reduction of alkynes with sodium in liquid ammonia produces E-alkenes as you will be aware
though the reduction of functionalised alkynes with LiAlH 4 is perhaps more common nowadays.
Here are simple examples of both methods: the LiAlH 4 reduction will be discussed in the next
chapter.
In an important paper making enantiomerically enriched amines by 1,3-dipolar cycloadditions,
Denmark 51 made both isomers of the vinyl ether 243 from the alkyne 244. Lindlar reduction gave
pure Z-243 while LiAlH 4 reduction gave pure E-243.
Ph
O
1. Na, NH 3(l)
OH LiAlH4
1. NaNH2
2. 238
236
H 2N
H2, Raney Ni
NH2
OH
235
2. NH 3, H 2O
239 240; 80-90% yield, all E-dec-5-ene
Ph
241 E-242
LiAlH4
THF
Ph
O
Ph
H2, Pd/BaSO4
quinoline
E-243 244
Z-243
Ph
O
Ph

Stereospecifi c Methods for Z-Alkenes
Using cyclic compounds
In a smaller ring (8 membered) an alkene must have the Z-confi guration. Cleavage of another bond
in such a ring must leave the Z-alkene intact. We shall look at oxidative cleavage of Birch reduction
products, elimination in a nitrogen heterocycle and hydrolysis of lactones. Birch reduction of aryl
ethers 245 leaves two non-conjugated alkenes 246: the enol ether is much more nucleophilic and so
is more easily cleaved by ozone. Corey 52 used this strategy to make trisubstituted alkene 247.
OMe
Li, THF
OMe 1. ozone
MeOH, Me2S HO
CO2Me t-BuOH, NH3(l) 2. NaBH4 245 246 Z-247
Simple pyridines, such as 2-methylpyridine 248, can be alkylated and reduced to leave just one
necessarily Z-alkene 251 not conjugated with nitrogen.
1. BuLi
MeI
N
2. RCl
N
R MeOH
N
R
N
248
Me
Me
2-methylpyridine 249 250 Z-251
Further alkylation and elimination 253 gives an open chain diene 254. The second alkene is
formed stereoselectively with E geometry. 53
Z-251
MeI
MeOH
White needed the diacid ester Z,E,Z-255 for his synthesis of the anti-leukaemia compound verrucarin.
54 It must clearly be made from the components Z-256 and E,Z-257 though there are obvious
selectivity problems in getting the right ester from compounds with three different CO 2H groups.
CO 2H
15 Stereospecifi c Methods for Z-Alkenes 249
The Z-acid 256 was made from a lactone. Dehydration of the tertiary alcohol in the open chain
compound 258 would give the E-alkene but after cyclisation to the lactone 259 dehydration with
polyphosphoric acid (PPA) must give Z-260. Careful hydrolysis and methylation gives Z-261, the
methyl ester of Z-261.
NaBH 4
H OH
R
KOH
N
Me Me
R
N
Me Me
R
Me2N
Z-252 Z-253 Z,E-254; 57% yield
O CO2H O
OH +
HO2C Z,E,Z-255
CO2H Z-256 E,Z-257
CO 2H
R

250 15 Synthesis of Double Bonds of Defi ned Stereochemistry
EtO 2C
HO
HCl
HO
OTHP EtOH
O O
258 259
The Z-alkene in the other half 257 was made from a furan 262. Cycloaddition with singlet
oxygen (rose Bengal is a dye that sensitises the conversion of normal triplet oxygen to the singlet)
leaves one necessarily Z-alkene in the fi ve-membered ring 264. One possible mechanism for the
decarboxylation of the cycloadduct 263 is given 265.
O
O
CO2H O2, hν
rose Bengal O
O O
CO2H HO
O
O O
O O O H
262 263 264 265
The two halves are coupled by an HWE reaction to put in the easiest double bond - the conjugated
E-alkene. The alcohol Z-261 is converted into an ester Z-266 that reacts directly with the
hemiacetal 264 using two equivalents of base to give the ester of Z,E,Z-255 in 84% yield. Note
that this method also keeps the acids distinct.
OH
O
CO2Me
CO2Me Z-261 Z-266
Interconversion of E and Z Alkenes
Photochemical isomerisation to the Z-isomer
A simple approach to a diffi cult alkene might be to make whatever mixture results from the easiest
synthesis and convert it stereoselectively into one isomer or, with more precise control, to make
the wrong isomer, if that is easier to make, and convert that stereospecifi cally into the other. A
simple example is the enone E-5 made by an aldol condensation. It is easy to see why E-5 is the
thermodynamic product: there is a steric clash in the Z-isomer between the carbonyl oxygen and
one of the ortho-Hs on the benzene ring.
O
PhCHO
NaOH
H2O O
E-5 only
O O
Ph
Shining light on the pure E-5 isomerises it completely 55 into Z-5. The excited π,π* state of the
enone 5 has one electron in the π* orbital allowing free rotation about the alkene. But why should it
prefer the less stable Z-isomer? Photochemical reactions are determined not by thermodynamic stability
but by light absorption. More stable E-5 is planar and conjugated and absorbs light more effi
ciently and at higher wavelength but Z-5 cannot be planar and absorbs light less effi ciently and at
a shorter wavelength than does E-5. Irradiation at a higher wavelength converts all E-5 into Z-5.
PPA
P(OEt) 2
hν
O
1. NaOMe
2. 264
O
260
O Ph
1. NaOH
H 2O
2. CH 2N 2
CO2Me
Z-261
OH
O CO2H
O
CO2Me
Z,E,Z-255 (mono methyl ester)
O H
Z-5 85% yield Z-5; steric clash

A synthesis of methoxatin
Methoxatin 267 is a bacterial co-enzyme that allows the oxidation of methane to more useful
one-carbon compounds. The 1,2-dione in the middle ring is the powerhouse of the molecule and
can be made from the simpler aromatic compound 268 by oxidation. Oxidative cyclisation of the
Z-alkene 269 might give 268.
HO 2C
O
NH
CO 2H
N
O
267; methoxatin
CO 2H
FGI
oxidation
HO 2C
Making 272 from the aldehyde 270 and the Wittig reagent 271 proved easy once all the carboxylic
acids were protected as methyl esters but gave mainly E-272 as either of the possible ylids
is stabilised. Clearly this isomer cannot cyclise so isomerisation to Z-272 was necessary. 56
Brief irradiation with UV light through a pyrex fi lter (to remove short wavelength light) in the
presence of diphenyldiselenide (PhSe – SePh) gave the trimethyl ester of 268 by isomerisation to
Z-272 and oxidative cyclisation.
Radical isomerisation to the E-isomer
NH CO 2H
268
Relatively stable radicals such as I • , PhS • or Bu 3Sn • add to alkenes 274 and then drop out again.
PhS• radicals are easily made by AIBN treatment of thiophenol (PhSH) or simply by refl uxing the
alkene with PhSH without any precautions to remove oxygen. If the intermediate 275 has a long
enough life it can rotate and equilibrate thermally to the E-alkene 277.
N
CO 2H
C–C
oxidation
HO 2C
NH
Z-269
CO2H
MeO2C CO2Me CO2Me NH
+
NaH MeO2C CHO
PPh3 N CO2Me DMF
N
H
N CO2Me
270 271 E-272; 84% yield, >95% E
E-272
R 1
hν
pyrex
filter
MeO 2C
15 Interconversion of E and Z Alkenes 251
NH
CO 2Me
N CO2Me
Z-272; 100% yield, 100% Z
hν
PhSe SePh
MeO 2C
NH
N
273
N
CO 2Me
CO2Me
R2 SPh R1 R2 SPh
R1 R
SPh
2
R1 R2 274 275 276 E-277
CO 2H

252 15 Synthesis of Double Bonds of Defi ned Stereochemistry
Stilbene formation by the Wittig reaction usually gives a mixture (here 7:3 Z:E) of E- and
Z-isomers 280. Irradiation of a heptane solution containing a small amount of iodine in sunlight
isomerises the mixture to the E-stilbene 280 which crystallises from solution in 68%
yield. 57
Br
278
PPh 3
2. Br
1. base
OHC
279
E- and Z-280
The mechanism is the same: iodine absorbs the sunlight (the solution is purple) to give I •
radicals that add to the alkene 281 to give a long lived radical 282 that rotates before ejecting the
I • radical. There is an example of the use of the Bu 3Sn • radical in the next chapter.
Stereospecifi c Interconversion of E and Z-isomers
Some isomers of alkenes are particularly diffi cult to make and a stereospecifi c method is required.
Fortunately there is a good one. Cis-cyclo-octene Z-284 is easy to make by elimination and is
available commercially. The epoxide 285 is made without change of stereochemistry and opening
this epoxide with the very nucleophilic Ph 2PLi ensures one inversion in the formation of the
phosphine 286.
The phosphine 286 is easily alkylated to provide the Wittig intermediate 287 that eliminates in
the usual stereospecifi c manner via the oxaphosphetane 288 and must therefore give the strained
trans-cyclo-octene E-284, the smallest trans cycloalkene that is stable. It is also chiral. 58
I 2, hν
heptane
Br
E-280
Ar1 Ar2 Ar1 Ar2 I
Ar1 Ar
I
2
Ar1 Ar2 I
Z-281 282 283
E-281
H
OH
mCPBA
H
O
Ph 2PLi
H
H
PPh2
Z-284 285 286
MeI
OH
PPh2 PPh2 H
H
Me
286 287
H
base
H
O
H
OH
Br
PPh2
PPh2 H
H Me
H
Me
288 289 E-284
H
O
H

References
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16
Stereo-Controlled Vinyl Anion Equivalents
Introduction: Reagents for the Vinyl Anion Synthon
Vinyl-Lithiums
Vinyl-Lithiums from Ketones: The Shapiro Reaction
The Aliphatic Friedel-Crafts Reaction
Hydrometallation of Alkynes
Hydrostannylation of terminal alkynes
Hydroboration and Hydroalumination of Alkynes
Hydroboration of alkynes
Hydroalumination of alkynes
Hydroalumination of propargyl alcohols
Hydrosilylation
Hydrosilylation of alkynes catalysed by Lewis acids
Hydrosilylation of alkynes catalysed by transition metals
Hydrozirconation
Carbo-Metallation
Carboalumination
Carbocupration
Reactions of Vinyl Sn, B, Al, Si, and Zr Reagents with Electrophiles
Reactivity of vinyl alanes
Preparation of vinyl silanes
Reactions of vinyl silanes
‘Ate’ complexes from vinyl silanes
Introduction: Reagents for the Vinyl Anion Synthon
Fresh from the discussion in chapter 15 on stereo-controlled alkene synthesis, did you notice that
we avoided one disconnection entirely? We never considered combining a vinyl anion 2 with a
carbon electrophile. This chapter concerns reagents for the vinyl anion synthon and particularly
those that allow control over the stereochemistry of the double bond in the product. Please notice
from the start that we mean vinyl anions where the nucleophilic group is in the plane of the alkene
3. This means that we shall chiefl y be discussing vinyl metals such as vinyl-lithiums. These are
metal σ-complexes 4 with the metal atom also in the plane of the alkene.
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

256 16 Stereo-Controlled Vinyl Anion Equivalents
R 2
R 1
R 3
We shall not be using metal π-complexes 5 where the metal sits at right angles to the alkene
plane 6. These are very important compounds and have their role to play in synthesis but they
do not have the right properties to act as reagents for the vinyl anion synthon. Nor shall we be
using the familiar organic reagents such as enamines 8 that act as π-donors at the same atom.
The problem here is the same - though electrophilic attack occurs at the correct atom, it occurs
at right angles to the alkene plane and stereochemistry is diffi cult to control. Instead we shall be
describing vinyl metal σ-complexes 7.
Stereochemical information is built into reagents 9 that have a nucleophilic vinyl-metal bond in
the plane of the alkene. This bond already has a stereochemistry - it is cis to R 1 and trans to R 2 -
and this information can be passed to the products providing that the reaction with electrophiles
is stereospecifi c. In most of the methods in this chapter vinyl metals 9; M Li, Mg, Cu, Sn, Al,
Zr, or compounds closely related to them such as vinyl boranes 10 or vinyl silanes 11, react with
electrophiles E with retention of confi guration 12.
R 2
R 2
R 1
This reaction will be useful only if we are able to prepare these compounds with a fi xed (E or Z)
confi guration. The fi rst part of the chapter concerns the preparation and reactions of simple vinyl
metal derivatives and we shall then progress to a study of stereochemistry.
Vinyl-Lithiums
R 2
R 1
+
R 3 X
H H
H
H
1 2
3 4
R1 M
H
5; M = metal
M
R 2
R 1
BR 2
R 2
R 1
H
H
H
9 10 11
Unsubstituted vinyl-lithium and vinyl Grignard 14 reagents can be made directly from the halide
by oxidative insertion of Li(0) and Mg(0). Vinyl-lithium is available as a 2M solution in THF
from Alfa and vinyl magnesium bromide, which must be prepared in THF, is available in THF
from Aldrich. These are quite stable σ-complexes because alkenyl anions are more stable than
saturated alkyl anions. They add as nucleophiles to carbonyl groups, e.g. cyclobutanone to give 15
and prefer direct to conjugate addition with enones to give e.g. 13. We have already used them in
enone synthesis (chapter 5).
OH
M
R2 R1 6; metal π-complex
O
R 2
SiR 3
MgBr
R 2
R 1
9, 10, 11
13 14 15
R 1
H
Li
7; metal σ-complex
O
R2N
E
R 2
R 1
R 2
R 1
OH
H
H
8; organic π-donor
R 1
H
12
Li
E

Both the Grignard reagent 14 and vinyl-lithium can be converted into copper derivatives by
exchange with Cu(I) halides. Two Cu(I)-catalysed conjugate additions of vinyl Grignard to enones
start one of Corey’s gibberellin syntheses. 1 In the absence of Cu(I) the vinyl Grignard reagent 14
adds directly to the carbonyl groups of 17 and 20.
BnO
O O O
(EtO) 2P
KOH, EtOH/H2O BnO
O
14
Cu(I) BnO
16 17 18
OsO4 CHO
NaIO4 NaOH
pyridine
t-BuOH/H2O BnO
O
EtOH
BnO
19
The extra stability of vinyl Grignard reagents is clearly shown by Knochel’s preparation of 22
by exchange with i-Pr 2Mg. Notice that the alkenyl group is transferred rather than the alkyl group
to benzaldehyde and that both metallation and reaction with the aldehyde occur with retention of
confi guration. 2
I
i-Pr 2Mg
–20 ˚C, THF
Hex
A few substituted vinyl halides are available, such as E- and Z-1-bromopropene, and a few can
be made with stereochemistry. Both E- and Z-1-bromostyrene have been used in stereospecifi c
additions to benzaldehyde with Cr(II) and catalytic Ni(II) as the metals. 3 The synthesis of these
isomers from cinnamic acid is described in the workbook.
Ph
Br
CrCl2, cat NiCl2
E-24
PhCHO, DMF
Ph
E-25
OH
A few more vinyl halides can be made stereospecifi cally by halogenation and base-catalysed
elimination. One example is the vinyl bromide E-28 available by stereospecifi c trans bromination of
crotyl alcohol 26 followed by stereospecifi c elimination. 4 Various regioselectivities are available in
the elimination reaction so the formation of that particular alkene is in a way more surprising than
the stereopecifi city of the reaction. Presumably the bromine atoms increase the acidity of nearby Hs
(H-2 and H-3 in anti-27) so that one or other of the vinyl bromides will be formed. One explanation
is an intramolecular elimination through an anti-peri-planar transition state in a chair like
conformation using OLi as an internal base 26. It can reach H-3 in a fi ve-membered cyclic array.
Br 2
Br
OH
CCl4 OH
26; crotyl alcohol
Br
anti-27
16 Vinyl-Lithiums 257
LDA
Ph
THF
HMPA
O
14
Cu(I)
BnO
20 21
OH
Mgi-Pr PhCHO
Hex Ph
22 23; 60% yield
Ph
Ph OH
Br
CrCl2, cat NiCl2
Z-24
PhCHO, DMF
Z-25
Ph
Br OH
Br
H Br
Me
E-28 29
O
H
O
Li
O

258 16 Stereo-Controlled Vinyl Anion Equivalents
This type of approach is inevitably limited and we need to look at more general methods of
making alkenyl-lithiums since these can be converted into all the other reagents we might need.
Vinyl-Lithiums from Ketones: The Shapiro Reaction
This extraordinary reaction converts a ketone into a vinyl-lithium 32. First an aryl sulfonyl hydrazone
31 is made by the obvious condensation with the aryl sulfonyl hydrazine 30. Treatment with
two equivalents of butyl-lithium gives the vinyl-lithium. 5
O
H
N
H
N
S
Ar
Li
+ H2N N
S
Ar
O O 2 x BuLi
+ N2 + ArSO2 O O
30
31; arylsulfonylhydrazone
32; vinyl lithium
The fi rst equivalent of butyl-lithium removes the rather acidic NH proton to give 33 and
the second forms an aza-enolate 34. It may sound diffi cult to get two lithium atoms into the
same functional group but the necessary sulfonyl group is very electron-withdrawing. Two
β-eliminations now occur. The more reactive aza-enolate NLi bond expels arylsulfi nate anion to
create an NN double bond 35. Note that this is not the usual arylsulfonate (ArSO 3 ) containing
S(VI) but the lower oxidation state aryl sulfinate (ArSO 2 ) containing S(IV). Though not such
a good leaving group as sulfonate, it is still good. The remaining NLi bond now lacks any
stabilisation from sulfur and so can initiate the second β-elimination. The main driving force for
this reaction is the formation of a molecule of nitrogen. The lithium atom is forced to migrate from
nitrogen to carbon to form a vinyl-lithium 32.
31
S Ar
O
O
S Ar
O
O
N N
Li N N Li
BuLi BuLi
Practically, it is important that the aryl group has no ortho hydrogen atoms as competing ortholithiation
(chapter 7) may interfere with the reaction. The favoured aryl group is 2,4,6-tri-isopropylphenyl
or ‘trisyl’ shown in the hydrazone 36. Hydrocarbon solvents such as hexane and addition of
ligands for lithium such as TMEDA allow the reaction to go with maximum effi ciency.
O
+
H2N
33 34
H
N S Tr
O O
N
H
N
S
O O
Li
36;'trisyl' hydrazone
ArSO2
hexane
Li
N N
35
2 x BuLi
TMEDA
32 + N 2
32 + N2 + TrSO 2

The vinyl-lithium may be combined directly with the carbon electrophile such as an alkyl
halide or a carbonyl compound, or converted into another vinyl derivative such as the silane for
later development. Many common examples use cyclic ketones. Cyclohexanone gives the Z-vinyllithium
6 38 (Li has a lower priority than C) and hence the E-vinyl silane 39 (Si has a higher
priority than C) in good yield on trapping with Me 3SiCl.
O
H2N NHTr
N NHTr
This example has stereochemistry of a sort, but the other isomer is impossible. If the ketone
is unsymmetrical, the double bond prefers to go into a methyl group 49, as one would expect for
kinetically controlled aza-enolate formation (chapter 3), so no stereochemistry can be developed
there. With symmetrical open-chain ketones, the lithium atom prefers to sit trans to the chain
giving the Z-vinyl-lithium 6 41. Reaction with an electrophile, such as DMF, occurs with retention
of confi guration giving the trans product E-42 (this is usually the E isomer as the electrophile
usually has higher priority than saturated C!).
This process is obviously of limited value as the two side chains in the product will always
differ by only one carbon atom. There is a way round this diffi culty. If acetone trisylhydrazone 43
is converted to the dilithio derivative 44 and alkylated at low temperature, the monolithio-product
45; R Li is stable. You may have noticed that we have always drawn the hydrazone with the NTr
group on the same side as the double bond. This is no coincidence. When alkylation occurs this
confi guration of the CN bond is maintained.
O
O
16 Vinyl-Lithiums from Ketones: The Shapiro Reaction 259
H 2N NHTr
37
N NHTr
40
H
H 2N NHTr N N Tr
43
2 x BuLi
TMEDA
hexane
2 x BuLi
TMEDA
hexane
2 x BuLi
TMEDA
hexane
It appears that the lithiation site is determined by the geometry of the CN bond. When a
second (third?) lithiation is induced, it occurs on the same side as the fi rst - and this is now
the more crowded side 46. The regiochemistry is determined by the CN bond but the stereochemistry
remains as before. When the Shapiro reaction is allowed to go to completion, by warming
to 0 C, the unsymmetrical Z-vinyl lithium Z-47 is produced. This is the isomer that cannot be
made by the Shapiro reaction from the methyl ketone 48.
Li
Li
Me3SiCl
SiMe 3
Z-38 E-39; 83% yield
Li
Me 2NCHO
CHO
Z-41 E-42; 70% yield
Li
N N Tr
44
R 1 CH2I
–78 ˚C
R
N N Tr
R1 45; R=Li

260 16 Stereo-Controlled Vinyl Anion Equivalents
45
R=H
It can be quenched with electrophiles in the usual way. In this example prenyl bromide is
the fi rst electrophile giving the stable lithiated hydrazone 50: the Shapiro reaction gives Z-51
trapped as the vinyl stannane 7 E-52. The vinyl silane 39 and stannane 52 products from these
reactions can be used to make more elaborate alkenes with control over geometry as we shall
see later.
43
2.
1. 2 x BuLi
Br
Li
N Tr
N Li SnBu3
1. s-BuLi
2. Bu3SnCl 50
One recent application (that also introduces the next section) is to quench the vinyl-lithium Z-
54 with iodine and use the vinyl iodide E-55 in a Suzuki coupling 8 (chapter 18) with a vinyl borane
made by hydroboration of an acetylene. 9
43
2 x BuLi
TMEDA
hexane
1. 2 x BuLi
DME
2. ArCH 2CH 2I
Li
Li
N N Tr
R1 46
Li
N
N
Tr OMe
53
0 ˚C
Li
1. 2 x BuLi
TMEDA
2. 0 ˚C
1. H 2N.NHTr
R1 R1 Z-47 48 49
A recent application involving a kinetic resolution (chapter 28) led to an asymmetric synthesis
of the cotton boll weevil pheromone grandisol. Photochemical addition of ethylene to the cyclopentenone
58 gives the racemic ketone 59. The Shapiro reaction using simply tosylhydrazine
works well and is completely regioselective in favour of the alkene not at the bridge. Trapping
with DMF and Luche reduction gives the allylic alcohol 61. Attempts to make 61 by other methods
gave much worse yields. 10
Z-51
Li OMe
Hex
1. 9-BBN, THF, 23 ˚C
2. E-55, NaOH
56; 1-octene
PdCl2(dppf), 0 ˚C
E-57; 99% yield
×
2. 2xBuLi
O
1. H 2N.NHTr
2. 2xBuLi
I 2
Li
E-52; 90% yield
I OMe
Z-54 E-55; 77% yield
OMe
R 1

hν
Me
H 2N NHTs
CH2 CH2 MeOH
2. DMF
O
H
O
H
N
NHTs
3. CeCl3 NaBH4 58 (±)-cis-59; 77% yield (±)-cis-60; 89% yield
Kinetic resolution (chapter 28) using the Sharpless asymmetric epoxidation with L-()di-isopropyl
tartrate (chapter 25) removed the unwanted enantiomer as the epoxide 62 and left the
required enantiomer ()-61 for transformation into ()-grandisol 63.
Me
t-BuOOH
Ti(OPri ) 4
Me
(+)-DIPT
H
OH
H
(±)-cis-61 62
OH
The Shapiro reaction is important and useful but it is limited. We need to explore next a method
with a wider scope - vinyl metals made from alkynes. The trick here is to add two things on the
same side of the triple bond - typically one is a metal and the other a hydrogen atom or an organic
fragment such as an alkyl group.
The Aliphatic Friedel-Crafts Reaction
O
The application of the aliphatic Friedel-Crafts reaction (chapter 5) to alkynes is a stereoselective
approach to vinyl-lithiums that forms a bridge between the Shapiro reaction and the next section-
hydrometallation. Acid chlorides 64 react with alkynes under Lewis acid catalysis to give
E-β-chloroenones E-65 stereoselectively. The chlorine can be replaced by more reactive iodine by
conjugate substitution. 11
Cl
+
Both these reactions are stereoselective. Chloride prefers to add anti to the ketone in the linear
vinyl cation intermediate 67. Rotation of the σ-bond in the enolate intermediate 69 in the conjugate
substitution allows loss of chloride to give either the E- or the Z-vinyl iodide 66.
This compound E-66 could be metallated with lithium directly but it would then destroy itself
by reaction with its own keto group so reduction and protection fi rst gives the silyl ether E-70.
This vinyl iodide was converted into a vinyl-lithium E-71 and then into a vinyl cuprate E-72 for
Me
Me
H
OH
(–)-cis-61; 94% ee
31% yield
1. BuLi
TMEDA
Me
H
OH
(±)-cis-61; 83% yield
Me
H
OH
63; (+)-grandisol
Cl NaI I
AlCl3 acetone
O O
O
64 E-65 E-66
Cl
H
67
O
16 The Aliphatic Friedel-Crafts Reaction 261
R
E-65
Cl R I
R
I
68
O
Cl O
69
E-66

262 16 Stereo-Controlled Vinyl Anion Equivalents
conjugate addition. We shall have more to say about these reactions below but note at this stage
that both occur with retention of confi guration at the alkene.
E-66
Conjugate addition to cyclohexenone occurred very effi ciently to give E-73 in 80% yield. It can
be argued that both ends of the alkene in this product were linked to the rest of the molecule by
vinyl anion additions to electrophiles. 12
O
E-72
Hydrometallation of Alkynes
There are broadly three groups of metals that do this reaction. Some such as tin hydrides do so by a
radical mechanism, boron and silicon by hydroboration-style reactions, and transition metals such
as zirconium by π-complex formation. We shall take them in that order.
Hydrostannylation of terminal alkynes
O
OTBDMS
Tin hydrides readily form radicals. Typically Bu 3SnH reacts with AIBN to give tin radicals that
add to alkynes at the unsubstituted end to give the more substituted vinyl radical. The vinyl radical
captures a hydrogen atom 74 from another molecule of Bu 3SnH to produce another tin radical and
complete the chain. The other product is a vinyl stannane Z-75. Here is the complete scheme:
Bu3Sn H AIBN
Bu3Sn R
Bu3Sn
R
H H SnBu3
Bu3Sn
This reaction shows a remarkable stereoselectivity. The kinetic product is the Z-alkenyl
stannane Z-75. This is easily explained by arguments similar to those we used in chapter 15. The
vinyl radical is on a linear (sp hybridised) carbon and reaction with a large reagent like Bu 3SnH
occurs preferentially on the less hindered side 74. This gives the Z-alkene Z-75. If the reaction
is carried out at higher temperatures or with an excess of Bu 3SnH the E-alkenyl stannane E-75
becomes the product. This is obviously the thermodynamic product and equilibration occurs by
repeated addition 76 and loss 77 of Bu 3Sn• radicals to the vinyl stannane.
Bu 3Sn
1. NaBH 4
2. t-BuMe 2SiCl
Pr Cu
Bu3Sn R
I
(Me 2N)3P
Li
t-BuLi
OTBDMS
OTBDMS
E-70 E-71
Pr
Li
Cu
74
Bu3Sn R
H
OTBDMS
E-72
E-73
H H
Bu3Sn H
Bu3Sn H
76 77
E-75
+
Bu3Sn R
H R
H H
Z-75

This example of the commoner thermodynamic route was used by Corey 13 in the synthesis of
prostaglandins as described below.
OSiMe 2t-Bu
Hydroboration and Hydroalumination of Alkynes
Boron and aluminium are group three (13) elements so their hydrides R 2BH and R 2AlH are dimers
e.g. 81 linked by hydrogen bonds. Two useful compounds are 9-BBN 80 (9-BoraBicyclo[3.3.1]nonane)
and DIBAL 82 (Di-IsoButylALuminium hydride, also known as DIBAH). Because
of their large alkyl substituents these compounds are reasonably stable and can be bought. In
solution they are in equilibrium with their monomeric forms which are active hydro-boration
and -alumination reagents for triple bonds. The monomers 80 and 82 are trigonal with an empty
p-orbital on the B or Al atom.
Hydroboration of alkynes
Bu 3Sn H
AIBN
Bu 3Sn
78 E-79
OSiMe 2t-Bu
H
B H B B
Al
H
H
80; 9-BBN monomer 81; 9-BBN dimer
82; DIBAL monomer
They react with terminal alkynes by electrophilic addition of the empty p-orbital to the unsubstituted
end of the triple bond 83. The intermediate would then be the more substituted vinyl cation
84. It is easier to draw this mechanism with R 2BH than with the full structure for 9-BBN. The
intermediate 84 is not fully formed before hydride transfer begins so that the reaction is semiconcerted
and the transition state is something like 86. The result is a regioselective and
stereospecifi c cis hydroboration of the triple bond to give the E-vinyl borane 85. The intermediate
84 is quite like the radical intermediate in hydrostannylation but the difference is that hydrogen
transfer is intramolecular and stereospecifi c in hydroboration.
R
R 2BH
16 Hydroboration and Hydroalumination of Alkynes 263
R2B H
R
R2B H
H
R
R2B
H
H
R
R2B H (–)
H
(+)
R
83 84 85 86
Here is a simple example in the fi eld of prostaglandin synthesis where 9-BBN was used on a
protected optically active propargyl alcohol. 12 The starting material is identical to the alkyne 78
that we reacted with Bu 3SnH above and the result is the same - cis hydrometallation with the metal
atom at the terminus. However that was a thermodynamically controlled stereoselective radical
chain reaction while this is a kinetically controlled stereospecifi c electrophilic addition to give the
vinyl borane E-87.
OSiMe 2t-Bu
9-BBN
R 2B
78 E-87
OSiMe 2t-Bu

264 16 Stereo-Controlled Vinyl Anion Equivalents
Of recent years, boronic acids RB(OH) 2 have become important in Suzuki couplings (chapter
18) and they too can be made by hydroboration of alkynes. Catechol borane 14 89 is prepared from
catechol 88 and diborane - a typical reaction of boranes with acidic OH groups to give stable B–O
bonds - and is available commercially as a solution in THF. Hydroboration of an alkyne with
catechol borane shows the usual regioselectivity and stereospecifi city to give a terminal E-vinyl
boronate ester 15 90 and hydrolysis of the ester under very mild conditions 14 (room temperature,
no acid or base) gives the boronic acid 16 91. We shall see later that you can argue whether these
compounds can be considered as vinyl anion equivalents, but it seems sensible to discuss their
preparation at this point.
OH
B2H6 O
B H
R
O
B
OH
O
O
88; catechol 89; catechol borane E-90
Treatment with iodine gives the E-vinyl iodides 93 stereospecifi cally and quantitatively. There
is no doubt that these intermediates act as vinyl anion equivalents after exchange of the iodine for
a metal. With bromine in methanol, protected 2-bromo aldehydes 92 are formed in good yield. 16
A dramatic example of this technique is the last step of Heathcock’s synthesis of myxalamide
A 96. Hydroboration of the alkyne 94 with catechol borane gives the E-vinyl borane and this is
combined with the Z-vinyl iodide 95 in a palladium-catalysed Suzuki coupling to give the natural
product 96 with every alkene correct. 17
I
MeO
Br
Hydroalumination of alkynes
R
OMe
92; 90-94% yield
95
OH
94
O
N
H
HO
OH
B
Reactions of terminal alkynes with DIBAL are very similar - syn addition leads to the E-vinyl
alane and hence, by exchange with iodine or bromine, to E-vinyl halides. 18
1. i-Bu2AlH
2. I2, THF
Br 2, NaOMe
MeOH, –78˚C
OH
97 E-98; 94% yield
R
E-91; boronic acid
1. 89, PhNEt 2
2. 95, Pd(OAc) 2
i-Pr2NH, MeCN, H2O
I
OH
I 2, NaOH
H2O, 0˚C
96
44% yield
96
R
H2O
25 ˚C
no acid
or base
I
HO
OH
B
R
E-91; boronic acid
R
E-93; 100% yield
1. i-Bu2AlH
2. I2, THF
O
N
OH
99 E-100; 72% yield
H
I

Hydroalumination of propargyl alcohols
Reduction of acetylenes does not usually occur with LiAlH 4 but reduction of propargyl alcohols
101 with LiAlH 4 occurs through a cyclic aluminium σ-complex 103 and is well controlled stereochemically.
If the σ-complex 104 is trapped with an electrophile such as halogens or Bu 3SnOTf, a
simple Z-vinyl derivative, e.g. 105 results with a useful OH group for further development. 19 The
kinetic route to Z-vinyl stannanes above is a radical reaction and more diffi cult to control so it is
just as well that there is a good route to a simple Z-vinyl stannane by a non-radical reaction.
OH LiAlH 4
A similar process occurs with Grignard reagents. 20 Though this is strictly carbometallation, the
subject of the next section, it is very similar mechanistically to the reduction with LiAlH 4. One
magnesium atom guides a second Grignard reagent into the alkyne 106 to form the metallocycle
108 and hence, by reaction with, say, halogens, derivatives 109 with R 1 and R 2 cis (E or Z depending
on priorities!). Two molecules of LiAlH 4 or R 2 MgBr are needed and the intermediates 103 and
108 are vinyl anion equivalents.
R 1
Hydrosilylation
H 3Al H
H 2Al
The reaction of alkynes with R 3SiH can take place by three different mechanisms: radical, ionic
catalysed by Lewis acids, and ionic catalysed by transition metals. 21 The radical method is best
with tris(trimethylsilyl) silane, a reagent introduced originally to take toxic tin out of radical chemistry.
Promoted by Et 3B in the presence of oxygen the stable radical 110 adds to the alkyne to give
the linear radical 111 that collects a hydrogen atom from another molecule of tris(trimethylsilyl)
silane to complete the cycle. As in the formation of vinyl stannanes 75 the large reagent delivers
hydrogen anti to the large Si(SiMe 3) 3 substituent. 22 Typical Z:E selectivity is 20:1. The products
112 can be converted into Z-vinyl bromides by reaction with bromine in CH 2Cl 2 at 25 C.
Et 3B
Hydrosilylation of alkynes catalysed by Lewis acids
O
H
H
Al
H
Lewis acid-catalysed addition of Et 3SiH (Me 3SiH cannot be used as it is unstable) also gives the
Z-vinyl silane 115. This is trans addition to the alkyne and probably occurs by ‘H – ’ transfer to the
O
H
TfO
H
H
Al
O
SnBu 3
Bu 3Sn
101 102 103 104 105
O 2
R
106
Et
OH
R 2 MgBr
R 1
H Si(SiMe 3) 3
Si(SiMe3) 3
110
16 Hydrosilylation 265
BrMg R2 107
Cl
Mg
O
EtH
(Me 3Si) 3Si H
R
111
Mg
O
E
HO
R2 R1 R1 R2 108 109
Si(SiMe 3) 3
H
R
H
E
HO
Si(SiMe3) 3
H
Z-112

266 16 Stereo-Controlled Vinyl Anion Equivalents
π-complex 113 followed by electrophilic substitution of the ‘ate’ complex 114 with retention of
confi guration. The substituent R can be alkyl or aryl and can have an alkyloxy functionality. 23
R
Hydrosilylation of alkynes catalysed by transition metals
The commonest combination here is trichlorosilane with H 2PtCl 6 as catalyst. Cis addition of the
silane is preferred, probably via a metal complex such as 116, giving the E-vinyl silane 117. The
SiCl 3 group is not easily replaced but the dianion 118 formed with KF reacts cleanly with NBS to
give the E-vinyl bromide 119 with retention of confi guration. 24
R
R can be alkyl or aryl and can carry various functional groups such as the ester in 120. The
vinyl bromide E-121 is formed in 68% yield and is 95:5 E:Z. However other transition metals
may give the Z-vinyl silane as is the case with Et 3SiH and an Ir(I) catalyst. 25 Yet other transition
metals give the opposite regioselectivity as with Et 3SiH and a Ru(I) catalyst. 26 The best advice is
to use conditions already determined by reliable workers.
MeO 2C
Hydrozirconation
AlCl3 R
Cl3SiH R
cat H2PtCl6
H
Et3SiH H H Et3SiCl H H
+ AlCl3 AlCl3 113
R AlCl3 114
R SiEt3 Z-115
Pt SiCl 3
R H
H
Among transition metals, zirconium is the most important for hydrometallation of alkynes.
The available 16 electron complex Cp 2ZrHCl (Cp cyclopentadienyl) 122 (zirconocene hydrochloride)
adds stereoselectively syn to alkynes to give the E-vinyl zirconium species 126. The
initial interaction is the donation of two electrons by the triple bond 123 to make the reasonably
stable 18-electron π-complex (or η 2 -complex) 124. Typically for a transition metal π-complex, a
ligand is now transferred from the metal to one end of the π-bond 125 while the metal itself forms
a stable 16-electron σ-complex at the other 126. The H transfer is intramolecular so the metal and
H atoms must add to the same side of the triple bond. The zirconium atom transfers the least stable
anion among its ligands. This is obviously H – as Cl – is much more stable. The metal prefers to
take the terminal position because the resulting σ-complex is more stable as it is a σ-complex of
the less-substituted carbanion. 27
Zr H
Cl
122; Cp 2ZrHCl
16 electrons
120
116
Cp2Zr
R
Cl
H
123
E-117
SiCl 3
1. Cl 3SiH, H 2PtCl 6
2. KF, 3. NBS
Cp2Zr Cl
H
R
124; π-complex
18 electrons
KF
R H
H
MeO 2C
SiF 5
Cp2Zr R
Cl
H
125; hydrozirconation
2K NBS
R H
H
E-118 E-119
E-121
Cp2Zr
Cl H
R
126; σ-complex
16 electrons
Br
Br

Here is an example from the McMurry fl exibilene synthesis quoted in chapter 1. An alkyne
127 with a protected aldehyde group reacts with Cp 2ZrHCl to give a vinyl zirconium complex 128
which is coupled to a palladium-allyl complex in the next step. The E double bond so produced is
present with the same E confi guration in the fi nal product. It is marked 129 with an arrow in the
diagram. 28
MeO
OMe
127
Exchange of the zirconium for zinc allows addition to carbonyl compounds. A free alcohol
group, as in 130, must be protected and the zirconium in the initial product 132 replaced by zinc
before the aldehyde is added to give the allylic alcohol 134. Both reactions occur with retention
of confi guration. 29
Carbo-Metallation
Some of the metals we have been discussing can be used for the simultaneous cis-addition of
an alkyl or aryl group and a metal to an alkyne. 30 This process is called carbometallation and
involves particularly Li, Mg, Al, Cu, and Zn.
Carboalumination
Cp 2ZrHCl
MeO
OMe
HO t-BuPh2SiCl imidazole
RO
130
DMAP, CH 2Cl2 131; 96% yield
ZrCp2Cl
128 129
Cp 2ZrHCl
Me2Zn –60 ˚C
RO
ZnMe
RCHO
0 ˚C, CH 2Cl2 t-Bu O
Si
Ph Ph
OH
133 E-134; 66% yield
ZrCp2Cl
Trialkyl aluminiums are not reactive enough to add to alkynes but do with catalysis particularly
from Cp 2ZrCl 2. In reaction with Me 3Al, the methyl and the AlMe 2 groups are added to the same
side of the triple bond to give an unstable alkenyl aluminium E-136 that is reacted immediately
with an electrophile to give the product E-137 with retention of confi guration. 31 The mechanism is
uncertain but almost certainly involves transfer of a methyl group from zirconium in a π-complex
such as 135 with a number of chloride ligands on one or both metals, or even between them. 32
R
Me 3Al
0.4 equivs
Cp 2ZrCl 2
16 Carbo-Metallation 267
Palladium-catalysed coupling of such an intermediate E-139 with benzyl chloride gives the
trisubstituted alkene E-140 as the only product in high yield. 33
RO
132
R
Me Zr AlMe2 carboalumination
R
Me
AlMe2 E
R
Me
E
135 E-136 E-137

268 16 Stereo-Controlled Vinyl Anion Equivalents
138
A recent application to the synthesis of the macrolide antibiotic concanamycin used carbometallation
of the alkyne 141 to give the vinyl iodide E-142 followed by a palladium-catalysed
coupling with a vinyl stannane, also created from an alkyne, to give the diene 34 E,E-143.
OR 1
R 1 O OR 2
Carbocupration
Me3Al
0.4 equivs
Cp 2ZrCl 2
1. Me3Al
Cp 2ZrCl 2
2. I 2
R
AlMe2
5 mol% Pd(0)
Me Ph Cl Me
E-139 E-140; 92% yield
OR 1
R 1 O OR 2
Various organo-copper compounds carry out carbocupration of alkynes without any extra catalyst.
The reagents may be RCu (usually with some ligand such as Me 2S), Grignard reagents with added
Cu(I), or any of the more complex cuprates also used in conjugate addition (chapter 9). Cis addition
is the rule with the metal ending up on the terminal carbon atom 35 E-145.
R 1
The electrophile (E in E-146) can be an alkyl halide, acid chloride, conjugated carbonyl
compound and so on. A simple example illustrating the use of a functionalised alkyl halide,
produces the Z-alkene 148 as the larger group is added by carbocupration. 36 Addition in the reverse
order would have given E-148.
EtMgBr
We expect vinyl copper derivatives to be best at conjugate addition but we are disappointed at
the few enones that react satisfactorily. Carbocupration of propyne with n-hexylcopper gives the
intermediate 149 that adds to cyclohexenone with retention of the Z-confi guration to give the conjugate
addition product 37 150. With open chain enones results are not so good.
I
OR 1
R 1 O OR 2
141 E-142; 88% yield E,E-143; 72% yield
2.
n-HexMgBr
Me
R 2 Cu
L = ligand
1. Cu 2Br 2, LiBr
Et 2O, –15 ˚C
1. Cu 2Br 2.SMe 2
2. Me
Me
R1 R
2 R
Cu
L
1
Cu
R2 R1 R2 carbometallation
E
144 145 E-146
Et
O
O
E
Ph
OMe
Cu.MgBr2
I CO2Me Me
CO2Me Et
147 Z-148; 56% yield
n-Hex
Cu.MgBr 2
cyclohexenone
O
149 Z-150; 73% yield

Reactions of Vinyl Sn, B, Al, Si, and Zr Reagents with Electrophiles
So far we have given an assortment of ways these vinyl metals might be used in synthesis as vinyl
anion equivalents. Now it is time to consider their reactions in more detail. One of the commonest
ways, and certainly the most obvious way in which they act as vinyl anions, is to transform them
into vinyl-lithium reagents. This can be done directly or via halogenation. After carbocupration,
exchange with iodine and then lithium gives a vinyl-lithium that reacts cleanly with enolisable
aldehydes and ketones to give allylic alcohols, e.g. E-152, all with retention of confi guration. 38
EtMgBr
1. Cu 2Br 2.SMe 2
2. Bu
[Cu]
1. I2, Et2O, 0 ˚C
2. BuLi, Et2O
–70 ˚C
OH
151
3. Me2CO E-152; 87% yield
Treatment of vinyl Sn, B, or Al compounds with BuLi results in effective addition of Bu to the
metal to form a hypervalent anion such as 154. These are often referred to as “ate” complexes. The
analogy is with the names of anions such as sulfate or carbonate. You are already familiar with
the copper analogues, usually called cuprates. Lithium now replaces tin at the vinyl group 155 to
form a vinyl-lithium derivative E-156. The reaction is an electrophilic substitution at carbon - the
lithium atom attacks the C-Sn bond and does so with retention of confi guration.
Bu3Sn R
BuLi
Bu4Sn E-153 E-154
R
Vinyl copper derivatives such as 157 do not react with epoxides but transformation of the vinyl
copper into a cuprate by the addition of pentynyl lithium gives a cuprate that preferentially transfers
the vinyl group (the less stable anion is transferred from copper) to ethylene oxide to give the
homoallylic alcohol 39 E-159. Note that 157 has the opposite stereochemistry to 149.
MeMgBr
2.
R
Cu
A lithium atom may also be replaced by copper to make a cuprate 161. As in the previous
example, using pentynyl copper ensures that no vinyl group is wasted. Such cuprates are superior
to simple copper derivatives in conjugate addition to give 162 with enones. All these reactions
happen with retention at the vinylic carbon.
Li
16 Reactions of Vinyl Sn, B, Al, Si, and Zr Reagents with Electrophiles 269
1. Cu2Br2.SMe2
Li
Li
Bu4Sn R
Li
R
155 E-156
157
O
[Cu] Pr Li
158 Pr
E-159; 75% yield
R
Pr Cu Li
Pr
Cu
R +
160 161 162
O
O
+ Bu4Sn
OH
R

270 16 Stereo-Controlled Vinyl Anion Equivalents
An excellent illustration of both these types of vinyl anion equivalent appears in Corey and
Wollenberg’s synthesis 40 of the antibiotic brefeldin A 163. This interesting molecule has two
E-alkenes, one attached to a hydroxyl group as an allylic alcohol, and so accessible by direct
addition of a vinyl lithium 165 to an aldehyde, and one in a 1,3-relationship with an alcohol and so
accessible in theory by conjugate addition of a vinyl copper (or cuprate) 166 to the simple double
electrophile 164. Each OH group must be protected.
HO
H
H
OH
O
O
163; brefeldin A 164
H
O
Each vinyl metal reagent was prepared by thermodynamic hydrostannylation of the corresponding
alkyne. 41,42 The simpler lithium derivative 165; R CH 2SMe came from the protected
propargyl alcohol 167.
OH O
SMe
Bu 3SnH
The vinyl stannane 170 for the copper derivative came from another protected alcohol 169 by
a similar route but the protecting groups were made quite different so that they could be removed
selectively.
The vinyl stannane 170 was converted into the vinyl-lithium and then the vinyl cuprate as
described for 161 and added to the enolate anion of 171. Notice the protection of the malonate
ester group in 162 by deprotonation with sodium hydride. The product 172 is all anti across the
fi ve-membered ring and all E, but there is of course no control at the remote stereogenic centre on
the side chain.
170
101 167
AIBN
Functional group manipulation now gives the aldehyde 173 ready for addition to the vinyllithium
reagent 165. The product was trapped as the MEM (methoxy-ethoxy-methyl-) derivative
174 in a very high yield but without any stereoselectivity. Fortunately, Corey already knew how
to control the stereochemistry at the two OH groups by oxidation to ketones and stereoselective
reduction so the synthesis could be completed.
O
Li
Cu
OR
165: vinyl-lithium
for direct addition
OR
166; vinyl-copper for conjugate addition
Bu 3Sn O SMe
BuLi
THF
–78 ˚C
168
Li O SMe
165; R = CH 2SMe
Bu3Sn OSiMe2t-Bu Bu3SnH
OSiMe2t-Bu AIBN
Bu3Sn 169 170; 94% yield
1. BuLi pentynyl
cuprate
+
2. Pr Cu
O
of 170
CO2Et
CO2Et O
CO 2Et
166
CO2Et OSiMe2t-Bu
171 172; 84% yield from 170

O
CHO
173
Reactivity of vinyl alanes
Vinyl aluminium compounds also carry out conjugate additions and illustrate well the difference
in reactivity between vinyl alanes and the related “ate” complexes. If the enone can adopt the s-cis
conformation, as in 175, a cyclic mechanism is possible in which aluminium both acts as a Lewis
acid and delivers the vinyl nucleophile. Notice that the E-vinyl alane leads to the E-γ,δ-unsaturated
ketone 178 as this is again an S E2 reaction at the vinyl carbon. 32
i-Bu2Al O
If the enone cannot adopt the s-cis conformation, it is necessary to convert the vinyl alane
into an “ate” complex 179 before conjugate addition. Conjugate addition now occurs to s-trans
enones, such as cyclic enones, to give the E-γ,δ-unsaturated ketone 180 after aqueous work-up.
Notice that this time the most stable anion is transferred - the choice is between Me, i-Bu, or vinyl.
Aluminium is not a transition metal and simply releases the most stable anion as there must be
some negative charge on the group being transferred.
i-Bu 2Al
We have already seen examples of cuprates being used in stereochemically controlled conjugate
additions to cyclopentenones and similar results can be achieved with ate complexes of vinyl
alanes prepared by hydroalumination of alkynes to give e.g. 179; R hexyl and hence the anti-
E-product 43 182.
Hex
16 Reactions of Vinyl Sn, B, Al, Si, and Zr Reagents with Electrophiles 271
Preparation of vinyl silanes
R
OSiMe 2t-Bu
i-Bu i-Bu
O
Al
1. 165;
R = CH 2SMe
R
2. MEMCl
i-Bu 2Al
We have seen that vinyl silanes can be prepared by hydrosilylation of alkynes by three different
mechanisms giving good control over geometry of these inevitably terminal vinyl silanes. Vinyl
silanes are stable compounds and can be isolated, unlike most of the vinyl metals we have seen so
far, and other ways of making vinyl silanes allow the more-or-less controlled synthesis of mono-
or trisubstituted compounds with reasonable control over selectivity. These include the Peterson
reaction with two SiMe 3 groups on the same carbon atom 183 and, more relevant to this chapter,
reactions of vinyl lithiums with silyl chlorides. 44
O
O
H
H
R
OMEM
174; 82% yield
175 176 177 178
R
MeLi
H
H 2O
O
OR
OSiMe2t-Bu Me
i-Bu2Al 179
R
+
O O
180
R
1. i-Bu2AlH 2. MeLi
Me
i-Bu2Al Hex
+
179; R = n-hexyl
O
R
O
181 182; 76% yield
R
CO2Et

272 16 Stereo-Controlled Vinyl Anion Equivalents
R
Me3Si SiMe3 1. base
2. RCHO
Me3Si O
Me3Si 183
SiMe3
184 185
Hydrometallation or carbometallation of alkynyl silanes 186 is easier because of the presence
of the silicon atom as the metal prefers to be at the silylated end of the resulting alkene 187. Trapping
these intermediates with electrophiles allows the stereochemically controlled synthesis of
almost any vinyl silane 188. The metal can be Li, Mg, Al, or Cu and both 187 and 188 are single
geometrical isomers (whether E or Z depends on priorities of M and the various R groups). 30
R 1 SiMe 3
Reactions of vinyl silanes
R1 R
[M]
2
R2 [M] R3X SiMe3 SiMe3 186 187 188
Vinyl silanes resemble alkenes in reactivity: they combine with reactive electrophiles such as
bromine without catalysis but need Lewis acid catalysis for reaction with carbon electrophiles.
Reaction usually occurs 189 at the silyl end of the alkene so that the intermediate 190 enjoys the
β-silyl stabilisation of the carbocation. The silyl group is removed by a nucleophile, usually a
halide ion. 45
Me 3Si
E
189
R
If the electrophile also benefi ts from Lewis acid catalysis, as in the aliphatic Friedel-Crafts
reaction, good yields of products are generally found. The anion of the allyl phosphonate 192 can
be silylated to give the vinyl silane 193 and this reacts in turn with the classical combination of
acetyl chloride and AlCl 3 to give the enone E-194 that can be used in HWE reactions to make
dienones 46 (chapter 15).
The conversion of 193 to 194 occurs with retention of confi guration. Many such reactions give
only the more stable of the two possible products, depending on the lifetime of the β-silyl cation
190. In favourable circumstances the reaction is stereospecifi c with retention. The initial attack
of the electrophile occurs on either face of the alkene by interaction with the π-bond. As the new
CE bond is formed the Me 3Si group starts to rotate away from the electrophile as the C-atom
becomes tetrahedral. This rotation continues until the CSi bond is parallel with the empty porbital
on the other carbon atom and then stops. Loss of the Me 3Si group gives the product with
retention of alkene geometry.
R 1
R 2
X Me3Si
R
E
E
190 191
O
O
O O
(EtO) 2P
192
1. 2 x LDA
2. Me3SiCl (EtO) 2P
SiMe3 E-193; 96% yield
MeCOCl
AlCl3, 0 ˚C
CH2Cl2 (EtO) 2P
E-194; 89% yield
R 3
R
R

Me 3Si
E
electrophilic
attack
O SiMe3
R
E
Me 3Si R
H
Me 3Si starts to
rotate downwards
E
SiMe3
R
Me 3Si rotation
complete
SiMe 3
Of course, if the intermediate cation, stabilised by the β-silyl cation effect, has
a lifetime long enough to allow rotation about the CC bond, the stereochemical
information is lost. Clear-cut examples with retention are often intramolecular and
the most valuable are those that create an exocyclic alkene. A famous example is
the cyclisation of the two acetals E- and Z-195 with SnCl 4 as the Lewis acid to give
reasonable yields of the oxepanes 196 with complete retention of confi guration at the
exocyclic alkene. 47
t-Bu
SnCl4
t-Bu
CH2Cl2
O
O SiMe3
CH2Cl2
t-Bu
–15 °C –15 °C
OMe
E-195 O
E-196; 57% yield, >98% E Z-195
O
S
N
H
O
The lifetime of the key intermediate can sometimes be controlled by choice of
Lewis acid. Copper-catalysed conjugate addition of the vinyl Grignard reagent 198
to the enone 197 gives the anti adduct 199 as expected. Intramolecular Friedel-
Crafts reaction of the corresponding acid chloride with AgBF 4 as this Lewis acid
gave only the less stable Z-enone 200 but other Lewis acids such as TiCl 4 gave E/Z
mixtures. 48
BrMg SiMe3
CO2t-Bu 197 198
H
199
O
16 Reactions of Vinyl Sn, B, Al, Si, and Zr Reagents with Electrophiles 273
H
Even replacement of silicon by a humble halide can be important in complex syntheses.
The epothilones, e.g. 201, are anti-cancer compounds of some promise. Chemoselective
epoxidation of intermediate 202 is possible and Shibasaki decided to disconnect
at the obvious ester and the far less obvious diene requiring a CC bond to be made
stereoselectively between two alkenes 49 203 and 204.
H
+
O
O
OH
OH
O
S
N
1. Cu(I)
2. NaI
Me 3SiCl
H
O
O
O
OH
OH
O
Cl
OMe
SiMe 3
CO 2H
S
N
E
R
Me 3Si lost
SnCl4
O
E
R
product formed
with retention
t-Bu
Z-196; 71% yield, >98% Z
1. (COCl) 2
2. AgBF 4
MeNO2
I
diene
linkage
O
H
Z-200; 71% yield
ester
linkage
H
OAc
PhO2C 201; epothilone A 202 203 204
OH
O
O
OTBDMS

274 16 Stereo-Controlled Vinyl Anion Equivalents
Each half of the molecule was made as a single enantiomer by catalytic asymmetric synthesis.
We are concerned with the vinyl iodide 203. The obvious reduction of 205 with DIBAL failed and
instead hydrotitanation gave the Z-vinyl silane 206. Replacement of Me 3Si with iodine was regio-
and stereospecifi c giving only the Z-vinyl iodide in 59% yield.
S
N
Me3Si
205
OTBDMS
‘Ate’ complexes from vinyl silanes
H
Ti(OPr i ) 4
i-PrMgBr
Et2O
–78 °C
S
N
As we have seen with E-118, ‘ate’ complexes with two negative charges on silicon are possible and
so it should come as no surprise that one fl uoride ion can be added to most silyl groups to give an
‘ate’ complex with just one negative charge. These complexes now have a CSi bond of greater
nucleophilicity than the π-bond and so behave like the other vinyl metals in this chapter. Silylation
of the alcohol 207 with a silyl halide having a SiH bond opens the way for Pt-catalysed intramolecular
hydrosilylation (cf. above) to give only the E-vinyl silane 50 209.
Addition of fl uoride (as TBAF, the salt Bu 4NF) gives the ‘ate’ complex 210 that couples with
aryl and alkenyl halides to give a single isomer of a trisubstituted unsaturated alcohol, e.g. 202,
with retention at the alkene.
209
The scope of vinyl metals as sources of nucleophilic vinyl groups is very great. As well as the
expected electrophiles such as halogens, alkyl and acyl halides, aldehydes and ketones, unsaturated
carbonyl compounds and epoxides, they also combine with aryl and alkenyl halides with palladium
catalysis. The usual stereochemical course is retention at the vinyl group. It is necessary to decide
whether the vinyl metal is reactive enough or whether it must fi rst be transformed into an ‘ate’
complex. Since most of these vinyl metals can be converted into each other with retention, this is
an unusually versatile group of reagents.
H
OH
1. I2,
CH2Cl 2
2. Ac2O
Et3N
DMAP
CH2Cl 2
SiMe3
I
206 203
OH
H
i-Pr2Si Cl
O Si Et3N, DMAP
i-Pr i-Pr
H
H2PtCl6.6H2O CH2Cl2 O
Si
i-Pr i-Pr
207 208 209
2 x TBAF
Si
O
F
i-Pr i-Pr
210
PhI, 5 mol% Pd(dba)2
THF, –45 ˚C
S
N
OH
E-211; 88% yield
H
OAc

References
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276 16 Stereo-Controlled Vinyl Anion Equivalents
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17
Electrophilic Attack on Alkenes
Introduction: Chemo-, Regio-, and Stereoselectivity
Chemoselectivity
Controlling Chemoselectivity
Regioselectivity
‘Markovnikov’ Hydration
Mercuration-reduction
Wacker oxidation
Hydroboration: ‘Anti-Markovnikov’ Hydration of Alkenes
Mechanism, regio- and stereoselectivity of hydroboration
Alternative Approaches to the Synthesis of Alcohols from Alkenes
Regioselective reduction of epoxides
Intramolecular hydrosilylation
Stereoselectivity
Selectivity by Intramolecular Interactions
Halolactonisation
The synthesis of vernolepin
Halolactonisation in the synthesis of erythronolides
Sulfenyl- and Selenenyl-Lactonisation
The Prins Reaction
The original Prins reaction
The formation of tetrahydropyrans by the Prins reaction
The oxo-ene mechanism
Stereoselectivity in the Prins reaction
Double Prins reactions: use of Sn and Si to control cation formation
Hydroboration as a Way to Make Carbon-Carbon Bonds
Carbonylation of Alkyl Boranes
Carbon monoxide
Ketone synthesis using cyanide ion
Reactions with α-halo-carbonyl compounds
Polyene Cyclisations
Looking Forwards
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

278 17 Electrophilic Attack on Alkenes
Introduction: Chemo-, Regio-, and Stereoselectivity
The last two chapters have been concerned with making alkenes of known stereochemistry. An
important reason for wanting to do this is that alkenes have unusual potential as starting materials
for making polyfunctional compounds with control over all aspects of selectivity.
Chemoselectivity is often easy to control in alkenes because the alkene is a “weak” functional
group. It does have inherent reactivity with electrophiles such as bromine but when another
functional group, whether electron-donating or electron-withdrawing, is conjugated to the alkene,
the reactivity is normally dominated by the other functional group. Compounds 2–4 would
normally not be described as alkenes but as benzene, an enone, and an enol ether. But they are all
alkenes. You will already know many reactions that would happen with one of these compounds
and not at all with another. The triene 5 has three alkenes in the same molecule and we shall want
to react just one and not the others. Chemoselectivity.
Regioselectivity usually arises when an unsymmetrical electrophile attacks an unsymmetrical
alkene. Familiar examples would be the action of bromine water or peroxyacids on a terminal
alkene 8. The intermediate bromonium ion would be attacked by water at the more substituted end
9 and the epoxide by a nucleophile at the less substituted end 7.
OH
X
X
O
mCPBA
Br2 H2O
Br
11 12 1
13 14
Stereoselectivity comes from a stereospecifi c syn or anti addition to an alkene of fi xed and
known geometry. These last reactions, applied to cyclohexene, lead to anti bromohydrin 14 while
epoxidation occurs stereospecifi cally and syn. It doesn’t matter which end of the epoxide 12
or bromonium ion 13 is attacked by the nucleophile: anti addition occurs in both cases since
inversion is demanded by the mechanism of the S N2 reaction. Cyclohexene must be Z but in open
chain compounds syn addition to the E-isomer would lead to the same diastereoisomer of the
product as anti addition to the Z-isomer. In this chapter we explore more advanced versions of
these reactions in which usually several types of selectivity will be combined and show how they
are used in synthesis.
R
OH
OH
R
OsO 4
R
R
Br2
H 2O
O
1 2 3 4 5; Cecropia juvenile hormone
OH
O
Br
mCPBA
Br
X
2
R
R R
R
X
H2O 6 7 8
9
R
Br
OH
O
R
syn-15 E-16 anti-17 anti-15 Z-16 syn-17
R
OH
OH
R
OsO4
R
R
R
Br2
H 2O
OH
10
R
CO2Me
OH
Br
Br
Br
OH
R

Chemoselectivity
The commonest form of chemoselectivity involves the preferential attack of electrophiles on
electron-rich alkenes as in the ozonation of a Birch reduction product 19 used in chapter 15 to
make a Z-alkene Z-20; RMe and hence Cecropia juvenile hormone 5.
R
OMe
Birch
reduction
R
18 19
OMe
CO2Me
R OH
20
The alkene that is attacked is an enol ether and is much more nucleophilic than the other simple
alkene. Similarly nucleophilic reagents attack only alkenes that are conjugated with an electronwithdrawing
group. Chemoselective epoxidation is usually straightforward. The peracid epoxidation
is stereospecifi c: the alkene 22 is E and so the epoxide 23 is trans (or anti). The other epoxidation
is stereoselective as it is a two stage process and gives the more stable trans (or anti) epoxide 21 by
choice. There is an example later in the synthesis of vernolepin.
O
O
There is often no diffi culty either if the two alkenes are the same, whether conjugated or not,
as some reactions will stop cleanly after one alkene has reacted. A conjugated diene is more
nucleophilic (higher energy HOMO) than a simple alkene so the fi rst product, e.g. 25 is a less
nucleophilic alkene than the starting material. The monoepoxide of cyclopentadiene 25 can be
made by direct epoxidation of cyclopentadiene itself 24 provided that the solution is buffered
with sodium carbonate to prevent the acid by-product (MeCO 2H) from decomposing 25. Cycloocta-1,5-diene
26 can also give the mono-epoxide 27 cleanly. The difference in reactivity is less
here - probably only about a factor of two - there are two equal double bonds in the diene and only
one in the epoxide - and this approach is less reliable. 1
MeCO 3H
Na 2CO 3
Even if the only difference between the two alkenes is the number of substituents, that can be
enough for some reactions. If the substituents are simple alkyl or aryl groups, then the more highly
substituted alkene will be the more nucleophilic. This is enough to allow the epoxidation of the
trisubstituted alkene in citronellene 2 28 while leaving the monosubstituted alkene intact and provide
a source of the optically active acid 31 for Nicolaou’s synthesis of rapamycin. 3
1. O3
2. NaBH 4
H2O2 NaOH
RCO3H 21
O
E,E-22
O
23
MeCO 3H
O Na 2CO 3
24 25 26 27
28; (+)-β-citronellene
mCPBA
17 Chemoselectivity 279
O
HO 2C
H2O OH
29 OH 30
31; 75% yield from 28
HClO 4
O
5
O
1. NaIO 4
2. CrO3
H 2SO 4

280 17 Electrophilic Attack on Alkenes
The synthesis of the aglycone (the bit without the sugar) fortamine 44 of the antibiotic fortimicin
A illustrates this sort of chemistry perfectly. Selective epoxidation of cyclohexadiene 32 gives a
good yield of monoepoxide 33 if the reagent is buffered. Nucleophiles, such as MeNH 2 attack at
the allylic centre as the S N2 reaction is accelerated by the alkene to give the anti-amino alcohol 34.
The amino group is acylated and the OH group methylated ready for the next step.
32
1. ClCO2Me MeCO3H
MeNH2 MeOH, Na2CO3 Na2CO3 MeOH MeHN
2. NaH
MeO2C
N
O
70 ˚C
OH
3. MeI
Me OMe
33; 84% yield 34; 99% yield 35; 88% yield
We shall discuss the conversion of 35 into 36 later in the chapter. Elimination and epoxidation
stereoselectively produces the epoxide 37 on the outside (exo-face) of the folded alkene. Nucleophilic
opening with PhSe gives the trans-diaxial product (chapter 21).
35
Br
H
H O
O
1. DBU, 85 ˚C O
O
toluene
O
N
Me
H
OMe
2. (CF3CO) 2O
H2O2, 0 ˚C
CH2Cl2 N
Me
H
OMe
36; 86% yield
37; 89% yield
PhSeNa
EtOH
H
OMe
38
Oxidation to the selenoxide 39 and thermal elimination (chapter 32) produces a new alkene
40 that forms an epoxide 41 on the outside face again. At this point every carbon atom in the sixmembered
ring is functionalised, fi ve oxygen-based and one nitrogen, and this all started with
symmetrical cyclohexadiene. Each functional group was selectively introduced from an alkene.
38
mCPBA
i-Pr2NH O
O
N
H
OH O
SePh
O
O
N
H
OH
(CF3CO) 2O
H2O2, 0 ˚C
CH2Cl2 Me
H
OMe
Me
H
OMe
39
40; 94% from 37
Now the epoxide 41 was opened regioselectively and stereospecifi cally with azide ion to give
the trans di-axial product 42 that was reduced to the amine 43. The synthesis of fortamine 44 was
completed by the removal of the protecting carbamate. 4
41 NaN 3, MeOH
NH4Cl, 65 ˚C
O
Me
O
N
O
Me
O
N
H
OH
N
Me
H
OMe
41; 62% yield
SePh
H
OH
N3
H2
O
O
H
OH
NH2
HCl
HO
OH
NH2
H
OMe
OH
Pd/C
N
Me
H
OMe
OH
H2O
MeHN
OMe
OH
42 43; 92% yield
44; 99% yield
O
O
H
OH
O

HO
Controlling Chemoselectivity
17 Controlling Chemoselectivity 281
In view of the last example, you should not be surprised that the non-conjugated diene 45
reacts with mCPBA at the more highly (tri-) substituted alkene to give the epoxide 33 in good yield. 5
mCPBA
HO CH2Cl2 HO
45 46; 75% yield
Chemoselective reaction at the cis-disubstituted alkene is more diffi cult. One solution is to
deliver the reagent intramolecularly through a favourable 5/6 membered ring. The alcohol 45
is converted into the aldehyde 47. Oxidation of the derived imine with the commercial reagent
Oxone® (KHSO 5.KHSO 4.K 2SO 4) gives the oxaziridine 48 in yet another chemoselective oxidation.
Methylation at nitrogen makes the oxaziridine electrophilic at oxygen and intramolecular
epoxidation takes place.
BnN
2. Oxone®
OHC NaHCO3 H
OHC
1. BnNH 2
mol sieves
47 48; 47% yield
It is not necessary for the reagent to be covalently bound to the substrate for intramolecular
epoxidation. Hydrogen bonding of peroxy acids or hydroperoxides, often with a co-ordinating metal
such as VO(acac) 2, delivers the reagent to well situated alkenes. 6 This can achieve chemo- and
stereoselectivity. Epoxidation of the dienol 50 with mCPBA gives a good yield of the epoxide 51
with only 15% of the bis-epoxide. They tried VO(acac) 2/t-BuOOH fi rst but it gave mainly enone. 7
O
H
50
mCPBA
–20 ˚C
CH2Cl2
HO
O
O
H
51; 73% yield
53
The intramolecular delivery of the reagent by some intramolecular mechanism such as the
one in the margin is confi rmed by the exclusive syn relationship between the OH group and the
epoxide in 52. The hydrogen bond between the OH group and the peracid makes the electrophilic
oxygen atom of mCPBA more reactive and guides it in to the bottom face of the molecule as
O
O
49; 48% yield
1. MsCl, DMAP
Et 3N, CH2Cl2
2. CsOAc, DMAP
3. K2CO3 NaHCO3, MeOH
HO
O
O
H
52; 83% yield
O
1. MeOTf
CH 2Cl 2
2. H 2O
NaHCO 3
H
O
Ar
O
O H
O
O R

282 17 Electrophilic Attack on Alkenes
drawn. Epoxidation of the other alkene would involve an unfavourable medium-ring transition
state. In fact the trans relationship 53 was required so the OH group was inverted.
Regiospecifi c opening of the epoxide was also achieved by intramolecular delivery of
the nucleophile. The alcohol 52 was converted into the reactive intermediate 53 with methyl
isocyanate. Cyclisation can occur only to the nearer end of the epoxide (5-exo-tet) to give 54. The
stereochemistry is already correct for the S N2 inversion on the epoxide 53. The free OH group is
turned into a good leaving group by mesylation without isolation of 54.
52
Me
1. NaH, THF
MeNCO
O
O
N
O
O
O
Me
N
OH
2. MsCl
Finally the remaining alkene is dihydroxylated with catalytic OsO 4 and stoichiometric N-methylmorpholine
(NMO) as oxidant to give the diol 56 that cyclises to the THF 57 stereospecifi cally.
The aldehyde 58 was used to make ()-dysiherbane.
55
OsO 4
NMO
O
H2O
acetone
O
O H
Regioselectivity
Me
N
OMs
OH
O
53
H
OH
O
O
Epoxidation and dihydroxylation have become even more important in recent times as asymmetric
versions have been developed and widely used. These are the subject of a special
chapter (chapter 27) and do not have intrinsic regioselectivity. In this section we shall discuss
the hydration of alkenes and how to reverse the normal regioselectivity of the reaction by
hydroboration. These reactions do have regioselectivity and are used in organic synthesis
as is a related electrophilic addition, iodolactonisation, that we shall deal with later in this
chapter. The hydration of an alkene 8 - literally the addition of water - might occur with either
regioselectivity to give the primary 59 or secondary 62 alcohol. If the reaction were a simple
acid-catalysed addition, the secondary alcohol 62 would be expected as the secondary cation
60 would be an intermediate and the alcohol 62 is sometimes called the Markovnikov product.
In fact the reaction does not usually occur just by treating alkenes with acidic water and
special methods must be developed for both regioselectivities.
R
56
pyridine
O H
Me
N
H
54
O
H
57
O
OH
Et 3N
Dess-
Martin
O
O
O
O
Me
N
OMs
O H
55; 67% yield
Me
N
H
OH2 OH
OH
R R
R
R
?
H H2O 59 8 60
61
62
O
O
H
58; 78% yield
CHO

‘Markovnikov’ Hydration
Mercuration-reduction
The proton is not a good electrophile for an alkene - it is too hard. Some metal ions are much better
soft electrophiles and mercury, as Hg(II), is outstandingly good. Addition of mercury (II) salts, usually
the acetate but the oxide and sulfate are also used, to alkenes 8 gives regioselective addition via the
cation 63 with the mercury adding to the less substituted end of the alkene. This stage, the formation
of 64, is oxymercuration. Reduction in alkaline solution removes the mercury, hydrolyses the ester and
releases the secondary alcohol 62. The complete process is Brown’s mercuration-reduction method
(Vogel, page 545, calls it oxymercuration-demercuration, take your choice) for the hydration
of alkenes. 8 The radical mechanism for the removal of mercury is discussed in the workbook.
R
OAc
Hg
R
HgOAc
AcO
R
OAc
HgOAc
NaBH4 NaOH, H2O R
OH
8 OAc
63 64
62
The reaction is surprisingly tolerant of other functional groups. The tertiary alcohol 66 is
formed in 100% yield on a 5 gram scale by this method 9 and the electron-withdrawing triazine
ring in 67 makes the secondary alkyl cation more stable than the alternative. 10 In spite of these
virtues, this method has fallen out of favour as it requires stoichiometric toxic mercury.
O
Ph 2P
1. Hg(OAc) 2
THF, H 2O
2. NaBH4 NaOH, H2O O
Ph2P OH
65 66; 100% yield
Wacker oxidation
N
N
N N
1. Hg(OAc) 2
THF, H 2O
2. NaBH4 NaOH, H2O N N OH
67 68; 78% yield
Wacker oxidation 11 provides a way to add water to an alkene 8 and oxidise the product to a
ketone 72 all in the one step using oxygen under palladium (II) catalysis. The key to the difference
between these two superfi cially rather similar sequences lies in the great tendency for palladium to
undergo β-elimination 70. Oxypalladation 69 gives an unstable alkyl-palladium σ-complex which
decomposes at once to regenerate the double bond.
R
PdCl 2
H 2O
Cl
Pd
R
8 69; oxypalladation
17 ‘Markovnikov’ Hydration 283
Cl
HO
H
PdCl
R
70; βelimination
HPdCl
The palladium is released as HPdCl - still Pd(II)- but this decomposes rapidly to Pd(0) to
end the cycle. In practice Pd(0) is reoxidised to Pd(II) with catalytic Cu(II) and the stoichiometric
oxidant, O 2, oxygen itself, regenerates the Cu(II). The Wacker process is run on a large
scale in industry to make simple carbonyl compounds but does fi nd some use in the laboratory.
R
OH
R
O
71; enol 72; ketone

284 17 Electrophilic Attack on Alkenes
It obviously has no stereoselectivity but the regioselectivity is as expected for oxymetallation:
water adds to the more substituted centre.
This reaction is part of a useful cyclopentannelation sequence. Allylation of ketones is among the
easiest alkylations: subsequent Wacker oxidation and cyclisation creates a new fi ve-membered ring 76.
This is the α-acyl cation strategy discussed in chapter 6, though this version of it was not mentioned.
O X O O
allylation
of enol(ate)
cat. PdCl2 cat. CuCl2 O
aldol
73 74 75 76
An illustration that demonstrates stereoselectivity as well comes in Ikegama’s synthesis of
coriolin. 12 Allylation of the sodium enolate of cyclopentanone 77 gives one diastereoisomer of the
precursor 78 for a Wacker oxidation and cyclisation to give the tricyclic intermediate 79.
THPO
H
H
77
O
1. NaH, DME
2.
Br
THPO
Hydroboration: ‘Anti-Markovnikov’ Hydration of Alkenes
Mechanism, regio- and stereoselectivity of hydroboration
H
O2
1. O 2
PdCl 2
CuCl 2
Reversing the Markovnikov regioselectivity calls for hydroboration. 13 We discussed hydroboration
of alkynes in the last chapter and many of the same principles apply here. The reaction is a syn
addition of R 2BH to an alkene in which the boron bonds to the less substituted end of the alkene.
The same sort of hydroborating agents are used – such as 9-BBN –and the mechanism is similar.
The most important interaction is between the full π orbital of the alkene (HOMO) and the empty
p-orbital on boron (LUMO) 80, but the reverse interaction between σ(BH) and π*(alkene) also
comes into play as the reaction proceeds. The result is syn addition via a transition state 81 with
some positive charge on carbon and some negative charge on boron.
R
These alkyl boranes are not used as precursors for alkyl-lithiums but more usually oxidised to
alcohols 59 with alkaline H 2O 2. This reaction involves nucleophilic attack by HOO anion on
boron 83 followed by alkyl migration from boron to oxygen 85.
R
base
THPO
2. base
O
H
H
78; 94% yield 79; 77% yield
R2BH R
H
BR2 (+)
R
H
BR2 (–) R
BR2
H2O2
NaOH R
8 80 81
82
59
R R
BR2
B
O OH
R
O OH
O HO
R
BR2 R
H2O 83 84 85 59
H
O
OH
OH
O

The stereochemistry of all these steps is important. The hydroboration is a cis addition of H
and BR 2 displayed clearly by the product 87 from the cyclic alkene 86. The addition of HOO to
boron obviously involves no change in stereochemistry at carbon. The migration step 88 goes with
retention of confi guration as the fi lled s orbital of the CB bond is used and the last step involves
nucleophilic attack by HO on boron so there is again no change in stereochemistry at carbon. The
overall result is retention at the stereogenic centre during the oxidation to give 89.
R' R2BH
H
R'
H 2O 2
BR2
NaOH
B O R R
OH
86 87 88 89
A simple example is the oxidation of an alkene to a carboxylic acid 93 in Evans’ synthesis of
cytovaricin. The alkene had been put in by allylation and the optically active unsaturated alcohol
90 was fi rst protected 91 and then subjected to hydroboration and oxidation. Protection before the
second alcohol appeared prevented impossible chemoselectivity problems. 14
RO RO OH RuCl 1. 9-BBN
3.3H2O RO
CO2H 90; R = H
2. H2O2 NaOH
K2S2O8.H2O 91; R = t-BuMe2Si 92; R = t-BuMe2Si 93; R = t-BuMe2Si If the alkene has diastereotopic faces, the less hindered is normally attacked by the borane. A
simple example occurs in Grieco’s recent synthesis of the alkaloid ibogamine. The alkene 94 is a
trisubstituted cyclohexene with two stereogenic centres in the ring. Hydroboration occurred with
the expected regioselectivity on the top face of the alkene. This is the same face as the CO 2Me
group, but the opposite face to the nearer and larger indole substituent. The alcohol 95 was the
only product formed and was isolated in 68% yield. Simple reactions led to ibogamine. 15
N
H
H
NHCbz
1. B2H6, THF
2. H2O2, NaOH
94
CO2Me N
H
95
A more complex example with stereochemistry comes from Schreiber’s asteltoxin synthesis. 16
Hydroboration of the bicyclic acetal 96 with borane itself occurs on the underside of the folded
bicyclic molecule to give 97. But this is not the end of the story. The product of the hydroboration
is the THF 98.
Me
17 Hydroboration: ‘Anti-Markovnikov’ Hydration of Alkenes 285
H
H
O
O
Me
96
Ph
BH 3.THF
hydroboration
H
R'
NHCbz
HO
H
H
H
CO 2Me
R'
OH
R2B H
Me
O
H H
O
Me
Ph
R2B
H
Me
O
H
O
Me
BR2
Ph
H
97 98

286 17 Electrophilic Attack on Alkenes
Borane was used to achieve a cunning reduction of the acetal in the same reaction mixture by
acetal opening 99 followed by intramolecular hydride transfer 100 so that a single diastereoisomer
of the borane/borate 98 was formed. Only now is the borane oxidised with alkaline hydrogen
peroxide and the new alcohol 101 is formed as expected with retention of confi guration. Three
new stereogenic centres (the old acetal centre could not be counted as a permanent stereogenic
centre) are formed in this sequence. We shall return to hydroboration later as a way of making
carbon-carbon bonds.
97
BH3.THF borane
as Lewis
acid
R2B H
Me
O
H H
O
Me
Ph
BH2 R2B
H
Me
O
Ph
H
O
B
H
H
Me H
98
H2O2 NaOH
99
100
Alternative Approaches to the Synthesis of Alcohols from Alkenes
Regioselective reduction of epoxides
In view of the diffi culties inherent in all these methods, others have been developed from epoxides
and by intramolecular delivery of reagents. These methods are not so general as those we have
described so far and we shall quote just two approaches. The unsymmetrical diaryl epoxide 103,
easily made by the sulfonium ylid method [details in workbook] reacts with nucleophiles as the
benzylic centre rather than the centre next to the pyridine ring. Reduction with LiAlH 4 gives just
the alcohol 104 while reaction with MgBr 2 gives just one bromohydrin 102 both in quantitative
yield. It is possible that metals such as Mg, Al, or Li coordinate the pyridine nitrogen and epoxide
oxygen atoms. 17
N
OH
Br
102; 100% yield
MgBr 2.2Et 2O
Et 2O, 0 ˚C
Intramolecular hydrosilylation
N
O
H
Me
A hydrosilylation approach with the silicon being delivered intramolecularly from an OH group
in 106 is also regioselective. 18 Catalysis by H 2PtCl 6 effi ciently gave the heterocycle 107 and an
oxidation of the CSi bond (cf. the similar reaction on boranes above) gave one regioisomer of
the diol 108.
LiAlH 4
N
HO
H
Ph
O H
Me
101
OH
103 104; 100% yield
OH
Me Me
Si
H O
Me
Si O
Me
0.1 mol %
(HMe2Si) 2NH H2PtCl6.6H2O H2O2 60 ˚C. 10 min
Na2CO3
105 106 107 108; 69% from 105
OH
OH
OH

There is good stereoselectivity with cyclic chiral alcohols such as 109 (100:1) but the more
fl exible achiral compounds such as 111 are not so good. In both cases the OH group delivers the
SiH from the same face but 111 can adopt a different conformation. 19
OH
1. (HMe2Si) 2NH
OH
R
1. (HMe2Si) 2NH
R
2. 0.1 mol %
2. 0.1 mol %
H2PtCl6.6H2O 3. H2O2, NaHCO3 OH
OH
H2PtCl6.6H2O 3. H2O2, NaHCO3 OH OH
109 110; 73% yield 111; R = n-C5H11 112; 72% yield
Stereoselectivity
Electrophilic attack on alkenes is normally stereospecifi cally syn (as in hydroboration) or anti
(as in bromination). In this section we consider stereoselective aspects of these reactions. In
the simplest cases, the two faces of the alkene are diastereotopic because of some stereogenic
centre elsewhere in the molecule. Reaction will then occur on the less hindered face opposite the
substituent already present. In favourable cases, where the substituent is large and close to the
alkene, the selectivity may be high.
O
113 114
OH
115
Corey took advantage of the availability of specifi c syn and anti additions to make the two
possible diastereoisomers of a bromohydrin by different methods. In each case the initial attack
occurs anti to the t-butyl group and the second reagent, the nucleophile, adds from the other face.
The order of events decides which product is formed. 20
t-Bu
t-Bu
116
HBr
O
OH
Br
17 Stereoselectivity 287
mCPBA
mCPBA
t-Bu
OsO 4 etc
For a more complex example, we turn to Whitesell’s synthesis of iridomyrmecin 21 121, a
compound from the Argentine ant Iridomyrmex humilis. This compound is a bicyclic lactone
with four stereogenic centres. Opening the lactone reveals the basic skeleton 122. This skeleton
has a 1,5-diO relationship and one might consider Michael additions at this point, but Whitesell
noticed something more fundamental. If the two functionalised atoms were reconnected, the
skeleton 123 has some symmetry. The substitution pattern of the two methyl groups in the two
fi ve-membered rings is the same, though the stereochemistry is different and an oxidisable double
bond is required in one ring but not the other. It might be possible to make the compound from a
symmetrical cyclo-octadiene 124.
NBS
H2O
t-Bu
117 118 119
t-Bu
H 2O
120
Br
OH
OH
Br

288 17 Electrophilic Attack on Alkenes
O
O
H
C–O
lactone
HO2C
HO
H
H
121; iridomyrmecin 122
H
reconnect
The synthesis of such eight-membered rings by the nickel-catalysed dimerisation of butadienes,
is used here with 2-methylbutadiene. The regio-selectivity and stereo-specifi city of the hydroboration
of symmetrical 124 are as expected for a trisubstituted alkene. Conversion of the alcohol
125 into a good leaving group 126 made it reactive enough to carry out electrophilic addition on
the other alkene. In aqueous solution, the fi nal nucleophile was water and the product a mixture of
diastereoisomers of the tertiary alcohol 127.
Ni(0)
124
1. 9-BBN
2. H2O2 NaOH
HO
H
MsO
H
125 126
For the transannular reaction to occur, the molecule must fold inwards. In fact medium
rings are normally folded like this anyway. The regioselectivity of the electrophilic cyclisation
of the alkene gives as normal the more substituted cation. Inversion of course occurs at the
mesylate centre and the ring junction has to be cis as 5/5 ring fusion would be very strained
it were trans. The third stereogenic centre does not matter. Elimination of the tertiary alcohol
127 (TsCl, pyridine) preferentially gives the alkene 128 away from the ring junction. This is
mainly to avoid fl attening out the stable folded fused fi ve-membered rings, but the tri-substituted
alkene 128 may also be preferred to the alternative tetra-substituted alkene 130. Now a
second hydroboration introduces the required oxygen functionality in the left hand ring 129.
The regiospecifi city is as expected and the borane (9-BBN again) adds stereoselectively to the
less hindered lower face of the molecule. This is because of the folded rings. They are folded
upwards (the ring junction hydrogens are down) and so the lower surface is outside the fold.
It is very diffi cult to get inside these folded molecules, particularly with a large reagent like
9-BBN.
HO
H
H
127
TsCl
pyridine
H
H
128
1. 9-BBN
2. H2O2 NaOH
The left hand ring must now be cleaved and so the alcohol is converted to a ketone 131. The
obvious Baeyer-Villiger reaction will give the wrong cleavage product 133 as the more substituted
group migrates from carbon to oxygen in these rearrangements. Stereospecifi city is fi ne - the
rearrangement goes with retention- but the regio selectivity is wrong. The problem is solved by
ozonolysis of an enol derivative. Kinetic lithium enolate formation (chapter 3) and trapping with
MsCl
Et3N HO
H
H
H
129
H
H
123
?
Na2CO3 H2O dioxane
HO
124
H
H
127
H
130: not formed
in elimination

Me 3SiCl gives a stable silyl enol ether 132. Silyl enol ethers are of course alkenes too and can be
oxidised by ozone. Reductive work-up is necessary not only to prevent the H 2O 2 by-product from
oxidising the aldehyde but also to reduce it to the alcohol in situ. Acid-catalysed lactonisation of
122 fi nally gives iridomyrmecin 121.
CrO 3
H2SO4
129 acetone
(Jones)
O
H
131
H
H
This synthesis involves four electrophilic attacks on alkenes - two hydroborations, one
alkylation by a mesylate, and one ozonolysis. This is possible - even though the starting material
had only two alkenes - because one of the alkenes is recreated three times. You will have noticed
that each time it reappears, it moves round the structure so that electrophilic attack followed by
double bond (re-)creation enables the formation of several new bonds as well as the introduction
of new functionality.
Now that we have introduced all three kinds of selectivity in the context of electrophilic attack on
alkenes, we shall look at some ways to control selectivity by special devices. In the examples which
follow it is more convenient to treat the three selectivities together as they are often interdependent.
Selectivity by Intramolecular Interactions
Halolactonisation
1. LDA
2. Me 3SiCl
H H
H
Me3SiO
1. O3 2. NaBH4 122
H
121
O
H
O
H
132
133; Baeyer-Villiger
product from 131
We have seen several instances of regio- and stereochemical control by intramolecular delivery
of a reagent. This approach reaches its apogee when the reagent is tethered with a covalent bond
to the alkene. The most important of these reactions is iodolactonisation or, more generally, halolactonisation.
22 Reaction of an unsaturated acid 134 with iodine in aqueous NaHCO 3, to ensure
that the acid is present as its anion 135, gives an iodolactone 137 with virtually complete control.
Iodine attacks the double bond and the regioselectivity is normal - the nucleophile, the carboxylate
anion, attacks the more highly substituted end of the iodonium ion 136.
CO 2H
I 2
NaHCO 3
H 2O/MeCN
134 135
17 Halolactonisation 289
CO2
O O
O
I
I
136 137
However, if the alkene is symmetrically substituted, the nucleophile attacks the nearer end
of the iodonium ion as it is easier for it to achieve the 180 angle necessary for the S N2 reaction.
This automatically leads to stereoselectivity as well. Perhaps the most famous examples
come from Diels-Alder adducts such as 139. The carboxylate anion can reach only the
same face of the six-membered ring to which it is already attached (a trans ring junction is
impossible with this bridged ring). This means that only the anti iodonium ion 140 can cyclise
and the syn iodonium ion 138 must revert to starting materials. The iodolactone 141 has a
1,3-diaxial bridge 141a.
I 2
O

290 17 Electrophilic Attack on Alkenes
O
O I
O
I
CO2 CO2H I
O
O
138
139 140
I
141
O
141a
This result has further implications. An elimination using the bicyclic amidine DBU can occur
only on one side of the iodine atom 142 as this is the only way to get H and I anti-peri-planar for
the E2 reaction. The alternative H atom is equatorial. Electrophilic attack on this new alkene 143
must occur from the side opposite to the lactone bridge which, because it is diaxial, effectively
blocks the alkene on one side 145. Epoxidation 144 again provides a good illustration.
B
H
I
142
O
H
O
O
DBU
O
RCO3H E2
143
O
O
If the lactone produced might be either four- or fi ve-membered, then the fi ve-membered ring
is usually preferred as this reaction is under thermodynamic control. 23 A series of aryl lactones
was prepared in this way using KI and an oxidising agent as the source of iodine. Attack on either
enantiotopic face of the alkene E-146 gives an iodonium ion which cyclises by the rather awkward
mechanism 147 needed to make the fi ve membered ring 148. Note that the stereochemistry of the
alkene survives the one inversion. Preparation of the starting materials involves chemistry we met
in the last chapter so it is reviewed in the workbook.
If the choice is between a seven- and an eight-membered lactone, the seven-membered ring 151
is preferred to the medium sized ring as in a recent series of experiments 24 using the collidine-Br
reagent 150.
We can now return to the conversion of 35 to 36 mentioned earlier in the chapter. This is a bromolactonisation
using a carbamate ester as the free acid would be unstable. The reagent is nearly the
same as 150; only the perchlorate salt is used instead in aqueous base. The ester group attacks the
bromonium ion 152 to give the oxonium ion 153 that is hydrolysed under the conditions. 4
O
easy attack
from above
× O
no attack
from below O
144 145
I
I
I
Ar CO2H KI, NaHCO3, H2O Ar
=
E-146
Na2S2O8, H2O O
147
O
Ar
O
H
148a
O Ar
O
148b
CO 2H
149
+
N
Br
PF6 150 151; 95% yield
O
O
Br
H
O

MeO2C
Br
H2O H
Br
H
150
O
MeO
O
O
O
N
Me
35
ClO4
H2O
OMe
Na2CO3 MeO N
Me
152
OMe
N
Me
H
153
OMe
etc. N
Me
H
36
The synthesis of vernolepin
In his synthesis of the anti-tumour compound vernolepin, Danishefsky 25 used this very style of
chemistry to great effect. Vernolepin 154 has just one carbocyclic ring and two lactone rings, but
the synthesis was planned around an intermediate with two carbocyclic rings 155 so that all the
stereochemistry could be controlled. You can see that the three stereogenic centres in the intermediate
are correct, that there is a double bond in ring A 156 that might be cleaved oxidatively and
another in ring B where the third ring is to be added.
O
O
H H
H
O
O
154; vernolepin
O
OH O
O
H
155; bicyclic
intermediate
cleave ring
A here
We shall discuss the synthesis of the intermediate 155. The combination of a double bond and
a lactone in ring B looks as though it could come from an iodolactonisation and elimination. We
can draw the disconnections for these steps to reveal a possible starting material 158.
O
O
O
O
O
H
H
155 157
This unsaturated acid was made by a Diels-Alder reaction, but not the one you might have
expected. Danishefsky invented a special diene ‘Danishefsky’s diene’ 159 for the introduction of
enone functionality in the Diels-Alder reaction and here you see an application. The Diels-Alder
adduct 161 is a silyl enol ether with a leaving group in the β-position and it hydrolyses easily to
the enone 162.
OMe
FGI
17 Halolactonisation 291
OMe
CO2Me CO2Me O
I
iodolactonisation
O
O
O
A B
H
156
O
H
158
CO 2Me
H2O H2O
Me3SiO
Me3SiO H
O
H
159 160 161
162; about 60% yield
H
O
OH
Br
add ring
C here
HO
OMe
158
100%
yield

292 17 Electrophilic Attack on Alkenes
Note the chemoselectivity between the two alkenes in the cyclohexadiene 160. This is the
expected selectivity as Danishefsky’s diene, with two electron-donating substituents is obviously
electron rich and prefers to react with the electron-defi cient alkene. The next two steps are the
planned iodolactonisation and elimination with the usual reagents. There is chemoselectivity here
too as iodine will attack the more nucleophilic double bond in 158, regioselectivity in that the
carboxylate anion attacks the nearer end of the alkene 163, and stereoselectivity in that the anion
can reach only the bottom face of the alkene.
158
I 2, KI
NaHCO3
H2O
O
O
H
163
O
Now the time has come to react one of the alkenes and not the other. The reaction chosen was
epoxidation as we could expect only the more nucleophilic non-conjugated alkene to be attacked
by mCPBA. Direct epoxidation of the lactone 155 gave only the epoxide 164 with the correct
chemoselectivity but the wrong stereoselectivity. The lactone bridge directs the peracid to the top
face of the alkene.
But if the lactone is fi rst hydrolysed, there is an OH (and CO 2H) group on the lower face of
the molecule to deliver the peracid to the same face. This is a clear demonstration of the positive
nature of this type of stereoselectivity as the lower face of the molecule is the more crowded. The
last step closes the lactone again.
1. NaOH
H2O, THF
155
2. HCl, H2O O
O
H
165; 99% yield
Now that the more nucleophilic alkene is no more, the less nucleophilic one can be oxidised
and ring A converted into a lactone 169. The rest of this synthesis is equally interesting but is
outside the scope of this chapter. It has to start with some chemoselective reaction on the two
lactones in 169 as described in the workbook.
167
1. OsO 4
2. Pb(OAc) 4
MeOH
benzene
MeO 2C
Halolactonisation in the synthesis of erythronolides
I
OH
O
O
157
88% yield
DBU
24 hours
room
temperature
O
H
155; 87% yield
OH O
O
OHC
mCPBA
dioxane
O
H O
168; 86% yield
O
1. LiAlH(OBu t ) 3
2. H + resin
A remarkably clever combination of hydroboration and successive halolactonisations gave a vital
intermediate in Corey’s synthesis 26 of erythronolide B. Compound 170 was required with its fi ve
H
166
O
OH
O
OH
Ac 2O
O
O
O
O
H O
164
O
NaOAc
O
H O
167; 76% from 155
O
O
H O
169; 100% yield
154
vernolepin
O

stereogenic centres around a six-membered ring. Corey realised that both sides of the ring could be
developed by halolactonisations with the same carboxylic acid, used twice, once on each alkene.
O
O
170
O
O
FGA
iodolactonisation
O
O
171
The starting material 173 is drawn without stereochemistry because it is not chiral! The
symmetry in this dienone means that it does not matter which alkene reacts fi rst as they are the
same. You may also have noticed that the stereochemistry of the methyl groups on the double
bonds comes out wrong in both reactions, but, as we shall see, this does not matter. The starting
material can be made from a simple phenol 174 by ipso-allylation and then hydroboration. The
hydroboration is of course regioselective and attacks the electron-rich alkene rather than the enone
system. The alcohol produced was further oxidised by Jones reagent without isolation. Now we are
ready for the fi rst bromolactonisation.
OH
Br
174 175
This reaction goes in a wonderful yield in spite of the rather unreactive enone. Maybe this
is why the more aggressive bromine was preferred to iodine. The acid can be delivered only to
the bottom face of the ring as it is tethered to that face and the bromine must therefore add to
the top face. The next stage was to hydrolyse the lactone in base. The oxyanion released closed
spontaneously onto the neighbouring bromide 177 to form an epoxide 178 with inversion. With
that inversion, the stereochemistry is correct. This sequence of halolactonisation, hydrolysis and
closure to an epoxide has been used in many syntheses to get one particular diastereoisomer of an
epoxide. Now that the molecule is unsymmetrical and while it has a free carboxylic acid, it was
resolved so all future diagrams show a single enantiomer. The next step was bromolactonisation
on the other side to give 170.
KOH
176
H2O
THF
Br
O
O2C
NaOMe
O
17 Halolactonisation 293
This also worked very well with all the usual selectivities and the bromine atom was removed
with Bu 3SnH to give mostly the correct diastereoisomer as the hydride approaches the enolate
O
I
OH
FGI
C–I O
iodo
lacton-
OH
O O
isation
O
172
173
O O
171
98% yield
1. BH 3.THF
2. H 2O 2, NaOH
3. CrO 3, H 2SO 4
(Jones)
Br2
KBr
O
HO2C
O
Br2
KBr
H2O
Br
O
173 176; 96% yield
H2O O AIBN O
O
O
177 178; 91% yield
170; 93% yield
Br
Bu 3SnH
O
O
O
O
O

294 17 Electrophilic Attack on Alkenes
radical intermediate to give mostly an equatorial methyl group. We shall stop our analysis here but
the full story is told in Classics in Total Synthesis, page 173 ff.
Sulfenyl- and Selenenyl-Lactonisation
Halolactonisation works well because bromine and iodine form three-membered ring intermediates
when they attack an alkene. Sulfur (II) and selenium (II) electrophiles form even better
defi ned intermediates of this kind and similar cyclisation reactions occur with impressive control
over selectivity. 27 A simple example would be the formation of the bicyclic lactone 181. As the
carboxylic acid is tethered to the fi ve-membered ring, it can cyclise only to the intermediate
with S(e) on the other face 180. The mechanism is similar to that of iodolactonisation and the
stereochemical points are the same. The products are useful for the generation of radicals as
Bu 3SnH removes a PhSe group and leaves a radical behind while oxidation and elimination leaves
a new alkene (chapter 33).
Ph
S(e)
PhS(e)
H
O
PhS(e)Cl
O
CO2H OH
H
179 180 181
We can use sulfenyl-lactonisation to illustrate the stereospecifi city of the process when the alkene
differs in geometry. Rokach 28 has shown that the geometrical isomers of the unsaturated acid E-
and Z-182 give the correct diastereoisomers of the lactones from anti addition of Cl and R’S.
R CO 2H
E-182
R
R'S
Et3N O
O
Et3N O
anti-183
Returning to a reaction we met right at the start of this chapter will illustrate that the regio-
and stereochemistry of many different electrophilic reactions with alkenes can be controlled
by intramolecular nucleophiles. The mercuration of the cis alkene Z-184 leads to a 6:1 ratio of
diastereoisomers of a cyclic ether 185 by a related trapping of the intermediate by the internal OH
group.
CONR 2
OH
Z-184
R'SCl
OR
1. Hg(OAc)2
MeCN
2. NaCl
H2O This is impressive because attack on the cis alkene 186 has to occur on the bottom face to lead to
the product 185 and this line is hindered by the allylic OR group. Notice that the regiochemistry is
R
R'S
O
syn-183
R 2NOC
R'SCl
R
OR
O
H H
HgCl
185
O
Z-182
CO 2H

determined by the proximity of the OH group to one end of the alkene and that the stereochemistry
of the alkene survives (with an inversion) in the product. The HgCl group is removed by reduction
and the product converted into a building block 187 for the pammamycins, naturally occurring
macrolides. 29
CONR2
HO
OR
185
MeO2C
H
O
H
Hg
AcO 186
187
We shall end this chapter with three ways to make carbon–carbon bonds by electrophilic attack
on alkenes. Though useful, they are not as important as the functionalisation reactions we have
discussed so far, but they are each special in their own way. The fi rst two, the Prins reaction and
hydroboration revisited, use one-carbon electrophiles.
The Prins Reaction
The original Prins reaction
This is a “forgotten” reaction of remarkable scope which can sometimes give useful molecules very
diffi cult to make by any other means. 30 The electrophile is formaldehyde (or occasionally another
reactive aldehyde) in acid solution and the fi rst step is straightforward - normal “Markovnikov”
addition 188 gives the more stable cation 189, the key intermediate in a Prins reaction.
O
H
H
H
HO
H
H
R HO
R
188 189
A number of things can happen now depending on the structure of the alkene and counterion
of the acid. Direct cyclisation is not usually one of them as that would give an oxetane, a fourmembered
cyclic ether. Formaldehyde is often used as the 37% aqueous solution “formalin” (used
to preserve biological specimens) and then there is then plenty of water around.
One good example is the reaction of styrene with two molecules of formaldehyde to give an
acetal 190 in 100% yield with a solid acidic resin as catalyst. 31 Resuming the mechanism where we
left off, presumably water adds to the cation to give a diol 191 which cyclises with another molecule
of formaldehyde. There are other possibilities as this reaction gives a stable six- membered ring
with an equatorial phenyl group and is probably under thermodynamic control.
Ph
styrene
CH 2O
H 2O
Ph
17 The Prins Reaction 295
O O
189; R = Ph
H2O OH
190
Ph
191
The true product is the 1,3-diol 191, of which the product actually formed 190 is the formaldehyde
acetal, and the disconnection should be contrasted with the aldol route 192 to the same product as
a different carbon-carbon bond is formed.
OH
CH 2O
OH
products
190

296 17 Electrophilic Attack on Alkenes
Ph
O
O
OH
OH OH
Aldol
FGI
Prins
CH
+ CO2Me
Ph +
2O
OMe
Ph
Ph
H2O
192
191a
The formation of tetrahydropyrans by the Prins reaction
Aliphatic alkenes also undergo the Prins reaction and a well-conducted example is with propene,
formaldehyde and HCl. The product is 4-chloro-tetrahydropyran in good yield. 32 This compound
presumably arises from the cyclisation of another diol 194 and that clearly comes from one
molecule of propene and two of formaldehyde. What is different from the last example is that the
two molecules of formaldehyde must have been added to opposite ends of the original propene.
Cl Cl
CH2O 193
FGI
Prins
HCl
O
HO OH CH2O CH2O 193
194
We can now reconstruct the reaction mechanism. The fi rst cation 189; RMe is formed as
before, but in the absence of water elimination must reform an alkene 195 on the other side before
a second molecule of formaldehyde is added. The HCl used provides a chloride ion to intercept
the second cation 196.
CH2O HCl
–H
CH2O Cl
HO
189; R = Me
HO
195
HO
196
OH
194 193
This product (4-chlorotetrahydropyran, 4-Cl-THP) 193 may not look very useful but the
chlorine atom can be converted into a nucleophilic Grignard reagent or used in a Friedel-Crafts
reaction to give 197 while the ether ring may be cleaved to give a doubly electrophilic unit 198.
One useful application is the synthesis of 4-phenyl piperidine 199, a structural unit found in
medicinal compounds.
Cl
O
193
benzene
AlCl 3
Ph
O
197; 91% yield
48% HBr
Br
The disconnections corresponding to this chemistry are remarkable as the molecule is built up
quickly from very simple starting materials. In this application, 193 acts as a pentyl 1,3,5-trication
synthon!
A more modern version 33 of these reactions uses a Lewis acid (TiX 4) and a pre-formed acetal
200 of a homoallylic alcohol to make the same products. Asymmetric reduction (chapter 26) of
ethyl acetoacetate gives the starting hydroxyester as either enantiomer. Yields are much higher and
control is exerted in making the protected homoallylic alcohol 200.
Ph
Br
NH 3
i-PrOH
Ph
N
H
198; 64% yield 199; 87% yield

OH O
CO2Et
from ethyl acetoacetate
by asymmetric reduction
The oxo-ene mechanism
O OMe
200
OTBDMS
TiBr4
CH2Cl2 Br
87% yield
Returning to the mechanism of 4-Cl-THP 193 formation. When the cation 189 loses a proton to
form an alkene, why should it lose that proton to make a terminal alkene? Surely the proton from
the other side would be lost preferentially to give the more stable alkene 201? One solution to this
dilemma is to make the loss of the proton and the addition of formaldehyde concerted 202.
?
?
HO
–H
HO
CH2O
H
CH2O H
O
CH2 HO
201 189; R = Me propene
202
195
The fi rst step 202 is now a pericyclic reaction. It looks like a cycloaddition, though it involves a
hydrogen transfer as well. It is in fact a carbonyl (or ‘oxo-’) “ene” reaction. It is like a Diels-Alder
cycloaddition in which a C–H bond has replaced one of the double bonds in the diene and a CO
group is the dienophile. Many Prins reactions are probably carbonyl ene reactions. In his excellent
review 30 in Comprehensive Organic Synthesis, B. J. Snider says “The (carbonyl) ene reaction and
the Prins reaction are not mechanistically distinct”. Though this step is pericyclic, it is very polar
and the transition state 203 no doubt contains partial charges. It is therefore stabilised and the
reaction accelerated by protic acids 205 and Lewis acids 207.
H
O
202
CH 2
(+)
H
O
(–)
195
H
CH2
O
H
204
Snider has found dialkyl aluminium halides to be excellent catalysts for this reaction and they
can be used to stop the reaction after the fi rst step. This is a real advance in the Prins reaction
that otherwise tends to give a mixture of products by multiple addition of the aldehyde and intervention
by various nucleophiles. A simple example is the addition of formaldehyde to the terpene
limonene 208 catalysed by BF 3. A single monoadduct 210 is formed in good yield. 34 This must be
a Lewis acid catalysed carbonyl ene reaction on the external double bond 209. Notice the excellent
chemoselectivity in that the internal alkene is not attacked and the excellent regioselectivity in that
hydrogen atoms at four other sites might have taken part in the reaction, but do not.
H
203
CH 2O, BF 3
Ac 2O, CH 2Cl 2
208 209
17 The Prins Reaction 297
H
(+)
O
OTBDMS
(+)
H (+)
O
H
O
CH2 H (+)
O
H
AlR2 AlR2
205 206 207
O
CH2
BF3
210
OH

298 17 Electrophilic Attack on Alkenes
Stereoselectivity in the Prins reaction
Snider’s synthesis of the aryl lignan skeleton is an example with stereochemistry. 35 Either geometrical
isomer (E or Z) of the starting material (1,4-diphenylbut-2-ene) was combined with formaldehyde
and a mixed catalyst of MeAlCl 2 and Me 2AlCl. The all anti cyclised product 214 was formed
in 40-50% yield. The fi rst step must be a carbonyl ene reaction 212. It doesn’t matter which way we
write this as the molecule is symmetrical and we know that the stereochemistry is irrelevant.
Ph
CH2O
Me 2AlCl
MeAlCl2
CH 2Cl 2
Ph
CH2 O AlR3
Ph
Ph
Ph
Ph
211 212 213
214
The next step is a simple electrophilic attack by another molecule of formaldehyde on the
alkene - in other words a simple Prins reaction 215 - showing the regioselectivity we expect to
produce the secondary benzylic cation 216. The second molecule of formaldehyde has added
onto the opposite side from the fi rst. The resulting cation is perfectly placed for an intramolecular
Friedel-Crafts alkylation 216 of the benzene ring. This is again a stereoselective reaction giving
the more stable anti diastereoisomer 214. This sequence involves three successive CC bondforming
reactions and the stereochemistry is simply controlled by the preference for the more
stable anti product.
Double Prins reactions: use of Sn and Si to control cation formation
H
Ph OH
OH
Ph
CH2 O
AlR3
Ph
OH
H
Ph
215 216 217
One problem with the original Prins reaction was uncertainty in the fate of the cation 189. Recent
advances have used the chemistry of allyl tins and silanes explored in chapter 12. For example
addition of aldehydes to reagent 218 with a chiral catalyst formed from BINOL (chapter 26)
and Ti(Oi-Pr) 4 gave the allyl silane 219. This in turn reacted with a second aldehyde using an
achiral Lewis acid to give the THPs 220. Yields are very high, enantiomeric excess almost perfect
(90-96%) and various aromatic, enolisable aliphatic and functionalised aldehydes can be used in
both steps. Control expressed in the isolation of the stable intermediate 219 means that the two
aldehydes need not be the same. 36
Bu3Sn SiMe3 SiMe3 R1 OH
R O 1 R2 R1 218
CHO
BINOL-Ti
catalyst
219; 74-96% yield
R
220; 95-98% yield
2CHO Me3SiOTf
The fi rst step 221, whether you call it a Prins reaction or not, gives a cation 222 stabilised by
both silicon and tin (chapter 12). Nucleophilic attack on tin is preferred (tin is lower down the
Ph
OH
OH
OH
OH
OH
214

periodic table) and that gives the product. The presence of both silicon and tin stabilise the cation
while the tin decides its fate. There is no need to invoke an oxo-ene mechanism. The absolute
stereochemistry is decided by the chiral catalyst: you are not expected to see how.
218
R 1 CHO
BINOL-Ti
catalyst
L4Ti SnBu3
O
R 1
The second Prins reaction goes through the oxonium ion 223 to give the fi nal product. Again
the nucleophile is an allyl silane 223 and the second intermediate is a cation stabilised by the
silicon β-effect. The relative stereochemistry is decided in the second reaction and 220 has the
favoured diequatorial conformation.
Me 3SiOTf
221
Me 3Si
Hydroboration as a Way to Make Carbon-Carbon Bonds
Carbonylation of Alkyl Boranes
SiMe 3
R O 1 R2 L4Ti SnBu3 O
SiMe 3
Earlier in this chapter we discussed the oxidation of boranes with hydrogen peroxide. When
borane itself was used, the reaction was quite unambiguous. The trialkylborane 225 is the fi rst
product and when it is oxidised any of the three identical alkyl groups may migrate fi rst to oxygen.
Eventually all three will migrate and three molecules of alcohol will be formed.
Borane is supplied as its THF, R 3N, or Me 2S complex or generated in situ from BF 3 and NaBH 4.
But substituted boranes must be prepared. We met 9-BBN, the most popular dialkyl borane, in
chapter 16 and used it earlier in this chapter. The most popular monoalkyl borane is “thexyl”
borane whose pet name simply means t-hexyl borane and whose t-hexyl group is often represented
as a large letter H. These are obviously bulky boranes and give sterically enhanced regioselectivity
in hydroboration of mono substituted alkenes 8. They are both used in the synthesis of alcohols
59. These reactions will be successful providing that the newly introduced alkyl group migrates to
oxygen in preference to the t-alkyl group in 228 here or the cage structure in 9-BBN adducts.
226
219
R 2 CHO
17 Carbonylation of Alkyl Boranes 299
BH 3
R R
8
B 2H 6 BH 2
X
R 1
Me 3Si
222
R O 1 R2 223 224
B
3
225
H 2O 2
NaOH
R
BH 2
59
OH
+ B(OH)3
227 227 228
8
B
X
R
R
220
H 2O 2
NaOH
219
59

300 17 Electrophilic Attack on Alkenes
The rule most people know is that “the group best able to support a positive charge” migrates
best. This rule applies to cationic rearrangements like the Baeyer-Villiger where the transition
state for the migration has a positive charge. In these boron “ate” complex rearrangements, the
transition state has a negative charge and the rule is reversed. 37 It might be an exaggeration to
say that the group “best able to support a negative charge” migrates as alkyl groups destabilise
negative charges, but the migration order is primarysecondarytertiary. The group which
destabilises the negative charge least migrates best. In the case of 9-BBN, other secondary
alkyl groups migrate better than the bicyclononane group because bridgehead atoms migrate
worse than ordinary groups. If a bridgehead atom migrates, the whole cage must distort.
Carbon monoxide
Armed with this essential information, we can look at CC bond-forming processes. A famous
example is the formation of ketones with carbon monoxide. 38 The fi rst step is addition of CO 229
and then boron to carbon migration 230 of the primary alkyl group. For the transfer of the second
alkyl group an “ate” complex 231 must be formed again, and a nucleophile, usually based on
oxygen, is added to the very unstable ketoborane 230 and a second alkyl group is driven across
231 to give a more stable hydroxyborane 232, the product at this stage.
R
t-HexB
O C
t-Hex
229
B
232
O
R
R
R
t-Hex
O
R
t-Hex
B
230
2
B
O
The fi nal step is the usual oxidation with alkaline hydrogen peroxide. Both groups on the boron
232 are now tertiary so an excess of oxidant must be used to drive both across to oxygen. The
products are t-hexanol and the hydrate of the ketone 234. This doesn’t affect the ketone synthesis,
only the by-product.
If all three groups on borane can migrate, as in normal trialkyl borane, tertiary alcohols are the
products. Three migrations from boron to carbon go via the unstable ketone 236 and epoxide 238
to the relatively stable t-alkyl boron derivative 239 that is oxidised to the t-alcohol 240. A t-alkyl
group must migrate here as there is no alternative.
R
R
O B
232a
Hex-t
R
t-Hex
R
2
B
231
R
O
t-Hex
R
X
B
O
231a
t-Hex
R
B
O
R
H2O2 NaOH
R
OH
OH
R R
O
233 234
R
R

225
second
CO
migrationR
R
first
B O
3
R
migration
235
R
A dramatic example is the synthesis of the alcohol 244 by the literal insertion of a CO unit
into the triene 241. Heating 242 at 200 C for six hours after hydroboration equilibrates positional
and stereochemical isomers and shows how stable the trialkyl borane is. Glycol is added as the
nucleophile so that the stable heterocycle 243 equivalent of 239 can be purifi ed as a crystalline
compound. All three B to C migrations go with retention of confi guration. 38
Ketone synthesis using cyanide ion
B
O
238
H
R
third
migration
R
B
H
OB
B
2
O
236
239
HO OH
Not everyone wants to use carbon monoxide and a more convenient, though equally deadly, onecarbon
reagent is cyanide ion. This does not require the high pressures often needed to make CO
react. 39 Cyanide forms stable “ate” complexes 247 with boranes and we shall use two different
alkenes to illustrate this possibility. Thexyl borane 227 is essential for reaction with two different
alkenes and it is better to use the more hindered alkene fi rst. These precautions lead to a more
selective reaction with the fi rst alkene.
The “ate” complex 247 has an obvious resemblance to the CO complex 230 but the nitrogen
atom is less electron-withdrawing than the oxygen atom as it lacks the positive charge so the
cyanide complex is less prone to rearrangement. Acylation with trifl uoroacetic anhydride leads to
B to C migration of the primary alkyl group 248. This new borane 249 looks stable but the amide
group can cyclise onto the boron to regenerate an “ate” complex 250 and initiate migration of the
secondary alkyl group. Oxidation of this quite stable heterocycle 251 causes the usual migrations
and replaces all BC bonds by BO bonds. The fi nal organic product is a ketone 252. Notice that
the fi rst formed borane had primary, secondary and tertiary alkyl groups on it so this sequence
illustrates well the order of rearrangements.
R
R
R
H2O 2
NaOH
R
R
HO
O O
CO H
B
H H2O2 240
O
B R
2
H
H
H
241 242 243 244; 72% yield
227
BH3.NEt3
17 Carbonylation of Alkyl Boranes 301
t-Hex
B H
R
R = n-hexyl
t-Hex
B
R
NaCN
NaOH
237
R
R
H OH
t-Hex
245 246 247
B
CN
H
R

302 17 Electrophilic Attack on Alkenes
TFAA
247
–78 ˚C
Reactions with α-halo-carbonyl compounds
Any nucleophile that contains a leaving group on its α-atom could in principle be used to initiate
rearrangement of alkyl boranes. A simple way to make CC bonds is to use the enolate of an
α-halo-carbonyl compound. 40 The favoured reagent is 9-BBN (R 2BH) and primary or secondary
groups can be migrated in preference to that cage structure. The best base for creating the enolate
is the very hindered 2,6-di-t-butylphenoxide and B to C migration occurs on the ‘ate’ complex
with displacement of bromide 254. The 9-BBN is removed from the product simply with ethanol.
R2BH
9-BBN
t-Hex
B
second
migration
BR 2
Polyene Cyclisations
N CF3
O
R
O
R
R
248 249 250
R
Br
first
migration
t-Hex
B
N
251
O
CF3
R R
O CF3 t-Hex
B N
B Br
ArO
O
253 254 255
O
256; 73% yield
In these remarkable reactions, a series of electrophilic attacks on a bank of alkenes e.g. 257 is
initiated by an electrophile. Each alkene adds to its neighbour until the bank is exhausted and
essentially complete chemo-, regio- and stereo-selectivity is achieved. These reactions were
discovered by W. S. Johnson 41 and the idea came from nature where steroid synthesis is
accomplished by very similar reactions. The main problem is terminating the sequence
regioselectively and here allyl silanes (chapter 12) are most effective.
OH
SiEt 3
CO 2R
The mechanism involves the formation of an allylic cation 259 from the tertiary alcohol 257
and the electrophilic attack on each alkene in turn until the allyl silane is reached when loss of the
Et 3Si group to the β-silyl cation terminates the reaction. Chemoselectivity is determined simply
H2O 2
NaOH
CF 3CO 2H
CH2Cl2
–20 ˚C
3.5 hours
R
O
252; R = n-hexyl
83% yield
BR 2
O
H 7
4 6
H
5
H
t-Hex
EtOH
257 258; 68-75% yield
1
3
2
8
B
O
CO 2R
N
CF 3

y the proximity of the right alkene. Regioselectivity comes from the way the molecule folds up
260 so that each new ring is already in a chair as it is formed. Stereospecifi city - the relationship
between centres 4 and 5 and between centres 6 and 7 - comes from the two central alkenes reacting
in a concerted fashion so that their trans geometry becomes trans 3D stereochemistry in the
product. Stereoselectivity - the relationship between centres 3 and 4 and between centres 5 and
6 - is again determined by the way the molecule folds.
257
H
259
X
SiEt 3
CO 2R CO2R
This may look like a rather specialised method but the biomimetic inspiration applies to much
simpler compounds. Taxodione 261 is an antitumour compound from the swamp cypress Taxodium
distichum. It has an extended quinone-like enone system and two trans fused six-membered
rings. Livinghouse 42 realised that the extended quinone might be derived by oxidation of a simpler
aromatic compound 262 where “X” is an oxidisable group. He then saw a possible polyolefi n
cyclisation in which a tertiary cation derived from a simple alkene 263 starts the reaction and the
aromatic ring terminates the sequence.
HO
O
HO
H
O
H
X
261; taxodione 262
The unknown “X” now assumes a different role. If it is both oxidisable and anion stabilising, it
can be used to build the molecule by a simple alkylation reaction. This disconnection is more or
less in the middle of the molecule, both starting materials 264 and 265 will have to be prepared,
and so the synthesis will be very convergent. The choice for “X” was cyanide and the phenolic
OH groups were protected as OMe groups. The cyclisation was accomplished with BF 3 in MeNO 2
and gave a very good yield indeed of 267 with complete control over stereochemistry - even the
cyanide centre was controlled as the CN group goes equatorial.
MeO
264
OMe
Cl
CN
17 Polyene Cyclisations 303
FGI
oxidation
265
LDA
OH
MeO
OMe
polyene
cyclisation
CN
266; 88% yield
260
BF 3
MeNO 2
Et 3Si
HO
X
263
MeO
OH
OMe
258
H
CN
267; 83% yield

304 17 Electrophilic Attack on Alkenes
The remaining steps are trivial except for the conversion of the cyanide to a ketone. This was
achieved by oxidising the lithium “enolate” of the cyanide. The methyl groups were removed from
the phenols with BBr 3 and the fi nal oxidation to the extended quinone was done with oxygen adsorbed
onto silica. The whole synthesis took only seven steps and gave a remarkable overall 21% yield.
Recent developments include asymmetric polyene cyclisations but also include new ways to initiate
cyclisations. Iron tricarbonyl stabilises pentadienyl cations and its complexes with dienes are chiral.
Addition of the achiral lithium derivative 268 to the chiral complex 269 gives the polyene precursor
270 that cyclises with Lewis acid to give a single diastereoisomer of the bicyclic compound 43 271.
Li
The Lewis acid removes the OH group from the alcohol 270 to give the Fe(CO) 3-stabilised
cation 272 that initiates the cyclisation. The product is formed with the large iron diene complex
in the equatorial position.
270
Looking Forwards
We have spent some time in this chapter looking at the diastereoselectivity of some very important
reactions. We shall be returning to the most important of these in chapter 25 where we discuss
two of the most important reactions of the century - asymmetric versions of epoxidation and
dihydroxylation by osmium. These developments were possible only because of the selectivities
already established by the work described in this chapter and the selectivities we have discussed
will be important in many syntheses.
References
OMe
O
Fe(CO)3
Fe(CO)3
General references are given on page 893
1. J. K. Crandall, D. B. Banks, R. A. Colyer, R. J. Watkins and J. P. Arrington., J. Org. Chem., 1968, 33, 423.
2. D. R. Williams, B. A. Barner, K. Nishitani and J. G. Phillips, J. Am. Chem. Soc., 1982, 104, 4708.
3. Nicolaou and Sorensen, chapter 31.
4. S. Knapp, M. J. Sebastian and H. Ramanathan, J. Org. Chem., 1983, 48, 4786; S. Knapp, M. J. Sebastian,
H. Ramanathan, P. Bharadwaj and J. A. Potenza, Tetrahedron, 1986, 42, 3405; S. Knapp, Chem. Soc.
Rev., 1999, 28, 61.
OH
OMe
BF3.Et2O CH2Cl2 Fe(CO)3
268 269 270 271; 79% yield
BF3.Et2O CH2Cl2 Fe(CO)3
OMe
(OC)3Fe
272 271
H
H
Ar
OMe

17 References 305
5. A. Armstrong and A. G. Draffan, J. Chem. Soc., Perkin Trans. 1, 2001, 2861.
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Fu, Chem. Rev., 1993, 93, 1307.
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10. H. L. Nyquist, E. A. Beeloo, L. S. Hurlbut, R. Watson-Clark and D. E. Harwell, J. Org. Chem., 2002,
67, 3202.
11. J. Tsuji, Synthesis, 1984, 369; Comp. Org. Synth., 7, 449.
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Shibasaki and S. Ikegami, Tetrahedron, 1981, 37, 4411.
13. G. Zweifel and H. C. Brown, Org React., 1963, 13, 1; K. Smith and A. Pelter, Comp. Org. Synth., 8,
chapter 3.10, page 703.
14. Nicolaou and Sorensen, page 491.
15. K. J. Henry, P. A. Grieco and W. J. DuBay, Tetrahedron Lett., 1996, 37, 8289.
16. Nicolaou and Sorensen, page 317; G. Zweifel and J. Plamoden, J. Org. Chem., 1970, 35, 898; S. L. Schreiber
and K. Satake, J. Am. Chem. Soc., 1983, 105, 6723; 1984, 106, 4186.
17. A. Solladié-Cavallo, P. Lupatelli, C. Marsol, T. Isarno, C. Bonini, L. Caruso and A. Maiorella, Eur. J.
Org. Chem., 2002, 1439.
18. K. Tamao, T. Tanaka, T. Nakajima, R. Sumiya, H. Arai and Y. Ito, Tetrahedron Lett., 1986, 27, 3377.
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6090.
20. E. J. Corey and J. Das, Tetrahedron Lett., 1982, 23, 4217.
21. R. S. Matthews and J. K. Whitesell, J. Org. Chem., 1975, 40, 3312.
22. M. D. Dowle and D. Davies, Chem. Soc. Rev., 1979, 8, 171.
23. J. Thibonnet, M. Abarbri, J-L. Parrain and A. Duchêne, Tetrahedron Lett., 1996, 37, 7507.
24. M.-C. Roux, R. Paugam and G. Rousseau, J. Org. Chem., 2001, 66, 4304.
25. S. Danishefsky, P. F. Schuda, T. Kitahara and S. J. Etheredge, J. Am., Chem. Soc., 1977, 99, 6066.
26. Nicolaou and Sorensen, page 173.
27. S. D. Burke, W. F. Fobare and D. M. Armistead, J. Org. Chem., 1982, 47, 3348.
28. R. N. Young, W. Coombs, Y. Guindon and J. Rokach, Tetrahedron Lett., 1981, 22, 4933.
29. I. Mavropoulos and P. Perlmutter, Tetrahedron Lett., 1996, 37, 3751.
30. B. J. Snider, Comp. Org. Synth., vol 2, p. 527.
31. M. Delmas and A. Gaset, Synthesis, 1980, 871; R. El Gharbi, M. Delmas and A. Gaset, Synthesis, 1981,
361.
32. P. R. Stapp and C. A. Drake, J. Org. Chem., 1971, 36, 522; P. R. Stapp, J. Org. Chem., 1971, 36, 2505.
33. K. Al Mutairi, S. R. Crosby, J. Darzi, J. R. Harding, R. A. Hughes, C. D. King, T. J. Simpson, R. W. Smith
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C. L. Willis, Org. Lett., 2002, 4, 577.
34. A. T. Blomquist and R. J. Himics, J. Org. Chem., 1968, 33, 1156.
35. B. B. Snider and A. C. Jackson, J. Org. Chem, 1983, 48, 1471.
36. G. E. Keck, J. A. Covel, T. Schiff and T. Yu, Org. Lett., 2002, 4, 1189.
37. A. Pelter, K. Smith and H. C. Brown, Borane Reagents, Academic Press, London, 1988.
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18
Vinyl Cations:
Palladium-Catalysed CC Coupling
Introduction: Nucleophilic Substitution at sp 2 Carbon does NOT Occur
Stereospecifi city in the addition-elimination mechanism
Towards Carbon Nucleophiles and Vinyl Cation Equivalents
Vinyl cation equivalents
Conjugate Substitution
Unsymmetrical 1,3-dicarbonyl compound derivatives
Unsymmetrical enaminones
Conjugate Addition to Alkynes
Sulfur-based leaving groups
Sulfoxides and sulfones
The Diels-Alder Reaction on β-Bromo and β-Sulfonyl Alkynes
Choice of leaving group
Modifi ed Conjugate Addition
The Heck Reaction
General description
Scope and limitations of the Heck reaction: synthesis of dienes
The Heck reaction with electron-rich alkenes
A synthesis of strychnine
Recent developments in the Heck reaction
Sp 2 –sp 2 Cross-Coupling Reactions by Transmetallation
Stille coupling
Recent developments in Stille coupling
Variations in Stille coupling
Suzuki coupling
Recent developments in Suzuki coupling
Summary
Introduction: Nucleophilic Substitution at sp 2 Carbon does NOT Occur
If you want to make a diene one obvious place to disconnect is between the two alkenes 1. Though
this has a pleasing symmetry, one of the synthons must be a vinyl cation 2 and the other a vinyl
anion 3. We have already met stereochemically controlled reagents for the vinyl anion synthon
such as vinyl metals 4 (chapter 16) and all we now need is a good reagent for the vinyl cation. That
is the subject of this chapter. First we need to examine why you can’t just use a vinyl halide and
expect to get substitution of the halide ion.
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

308 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
R 1
R2 R1 R2
Metal
R2 +
=
1 2; vinyl cation 3; vinyl anion 4; vinyl metal
Nucleophilic substitution of unactivated vinyl halides is a rare reaction. 1 The S N2 reaction
at a trigonal sp 2 carbon atom 5 is generally thought to be unknown. It is puzzling that this
innocent looking reaction should be impossible: could it be that the transition state, which
would have to contain square co-planar carbon 6, is too high in energy? Recent work 2 suggests
the PhI may be displaced from vinyl iodonium salts 8 by halide nucleophiles with inversion of
confi guration (E-8 gives Z-9 with inversion) but it remains to be seen if this is a useful reaction
in synthesis.
R 1
Nu
5
X
R 1
Nucleophilic substitution at trigonal carbon is known by the addition-elimination mechanism
10 where an enolate intermediate 11 is formed and the negative charge is deposited on an electronegative
atom such as oxygen. This is conjugate substitution and you will see the analogy with
nucleophilic aromatic substitution. There is no need for stereospecifi city in the two-step process
and we might expect Z-alkenyl halides 10 to give E-enone products 12.
The third possibility is an S N1 reaction with a vinyl cation as intermediate. This is unlikely
when we are dealing with vinyl bromide itself 13 as the cation 14 would be very unstable. Notice
that the vinyl cation would be a linear species with an empty p-orbital. Such cations are known
when they are stabilised by conjugation 17 and the leaving group is excellent, such as trifl ate
(OTf CF 3SO 2O in 16) but these S N1 reactions are rarely used in synthesis.
H
R
Br
O Br
×
Nu
Stereospecifi city in the addition-elimination mechanism
X
H
6; square planar
transition state
Nu
13 14; vinyl cation
conjugate
addition
R
R 1
O Br
By far the most important of all these mechanisms is addition-elimination. The carbanion intermediate
must be stabilised by a group Z such as Ar, COR, CN, RSO, or RSO 2. The reaction then
becomes a conjugate substitution as 10 to 12. It appears there that, if the intermediate 11 has a
lifetime longer than bond rotation, only the more stable of the two products (E in this case) will
be formed. However, there are quite a few cases where the fi rst step is rate-determining and the
intermediate has a very short lifetime indeed. These reactions go with retention of confi guration.
An important example is the replacement of halides by thiolate nucleophiles 3 in 2-bromo
styrenes 19.
H
Nu R 1
IPh
Bu 4N
R 1
7 8 9
conjugate
elimination
Nu R
10 11
12
H
Nu
Ar
Nu OTf
15 16 17 18
O
Ar
X
Nu
Ar
Nu
X

Ar
E-19
Br
AlkS
Ar
SAlk
The explanation resembles that for the retention of stereochemistry in the reaction of vinyl
silanes with electrophiles (chapter 16). To make this clearer, we have drawn the diagrams as
nearly the same as those in that chapter as possible. It does not matter which surface of the alkene
is attacked by the nucleophile as long the bromine atom continues to rotate in the same direction.
Once it reaches the vertical it can be eliminated by the carbanion and the result is retention (5%
of the other isomer).
Nu
Br
Ar
nucleophilic
attack
Nu
Br Ar
H
The reaction even goes twice if there are two leaving groups (chloride in this case 21) and the
products can be oxidised to the more stable sulfones 24. It is more impressive with the Z-isomer.
Other systems that allow stereospecifi c substitution with retention include ester-activated
chloride displacement by an amine (25 to 26) and sulfone-activated chloride displacement by
azide (27 to 28). The choice of E- or Z-isomers is arbitrary as each gives 98% retention. 1 The
reactions shown so far do not include carbon nucleophiles.
Cl
Cl
Towards Carbon Nucleophiles and Vinyl Cation Equivalents
The subject of this chapter is how we can achieve reaction of nucleophiles with vinyl electrophiles
such as vinyl halides. We cannot easily make S N1 or S N2 reactions happen at sp 2 carbon atoms but
we can make the products of those unfavourable reactions by other reactions in which the same
bond is formed. We want to be able to use carbon nucleophiles. We also want to control the stereochemistry
of the double bond in the product. This is the disconnection we want to achieve 29:
Z
18 Towards Carbon Nucleophiles and Vinyl Cation Equivalents 309
Cl
Br starts to
rotate downwards
AlkS
Cl
Z-21 Z-22
CO2Et
NH
You may think that we already know how to do this by conjugate or Michael addition where
Z is an anion-stabilising group. These reactions do add nucleophiles to double bonds but the
Ar
Br
AlkS
E-20 Z-19 Z-20
SAlk
N
Nu
AlkS
Br
Br rotation
complete
AlkS
CO 2Et
Ar
SAlk
Nu
[O]
Br
Br lost
Ar
Ar
SAlk
Nu
O Alk
O O S
S
Alk
O
Z-23 Z-24
SO 2Ar
E-25 E-26
Z-27
Z-28
Nu
Z
Nu
Z
Nu
Z
29 30 31 32
Cl
N3
N 3
Ar
product formed
with retention
SO 2Ar
Nu

310 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
intermediate is an enolate and the double bond disappears in the product so that the disconnection
is 31 and the alkene 32 is a reagent and not a synthon. We would be happy with conjugate
addition as a solution to the problem if the double bond could be restored in the product. We
shall fi rst consider some conventional solutions to the problem such as conjugate substitution and
conjugate addition with the restoration of the double bond and then move on to more important
modern solutions mostly based on palladium chemistry.
Vinyl cation equivalents
We shall start with a pharmaceutical example, the Wyeth analgesic Meptazinol 4 33. This
compound has a seven-membered ring amine attached through a quaternary carbon atom to a
meta-hydroxy benzene ring. The greatest simplifi cation would undoubtedly arise by disconnection
of the strategic bond joining the two rings. But the functionality is all wrong for this. Hydroxy
groups direct ortho and para and the nitrogen cannot help to activate the required carbon on the
seven-membered ring. Changing the functionality of the amine to an amide makes a lot of sense
as a correctly placed carbonyl group activates the right carbon atom and amides can be converted
into amines by reduction. However this will require the use of a nucleophilic enolate 34 at what
is to become the quaternary carbon atom and so forces us to use an equivalent of an aryl cation
35: this route was beautifully realised by the use of benzyne chemistry and this is described in
the workbook.
OH
N
Me
33; meptazinol
Conjugate Substitution
?
? ?
+
N
Me
More relevant to this chapter is the realisation of a vinyl cation strategy which was in fact chosen
as the development route for the product. Adjusting the oxidation state of the benzene ring reveals
a promising enone 37 and requires a reagent for the vinyl cation synthon 38.
33 reduction
O
NMe
36
OH
FGI FGI
oxidation
The best way to derive a reagent for the synthon 38 is to insert a leaving group at the vinylic
position. The enol ether 40, easily prepared from the 1,3-diketone 39 turns out to be ideal as we
can envisage conjugate substitution by the amide enolate 34.
OH
FGI
O
NMe
37
O
O
N
Me
34; amide
enolate
?
+
34; amide
enolate
OH
35; benzyne
chemistry?
O
38; vinyl
cation
synthon?

O
O
i-PrOH
toluene
39
i-PrO
40; enol ether
i-PrO
R
41
O
RLi?
Addition of the magnesium enolate of the amide followed by acidic work-up gave the amidoenone
in one step with the double bond still present in the ring. Notice that direct addition of the
enolate to the carbonyl group 41, rather than the conjugate addition envisaged, actually occurred.
This doesn’t matter as the enol ether 40 has a symmetrical carbon skeleton. The synthesis was
completed by an oxidation of the enone ring with bromine to give the benzene ring in 36 and a
reduction of the amide to give meptazinol itself.
NMe
43
O
1. i-Pr2NMgBr 2. 40
NMe
44
i-PrO
OH
O
The nucleophile does not have to be an enolate: ortho-lithiated aromatics (chapter 7) work well
as in this sequence used in the synthesis of sesquiterpene lactones. 2-Methyl furan 45 is lithiated
in the one remaining α-position 46 and it adds to the ethyl equivalent of 40 to give the enone 48
in quantitative yield. 5
O
BuLi
Et2O
O
45 46
The further development of 48 is interesting. Conjugate addition of Me 2CuLi creates a
quaternary centre 49 and acid hydrolysis of the furan releases the triketone 50 used to make sesquiterpene
lactones. The yields in these three steps are amazingly good.
Me2CuLi 48
Et2O, 0 °C
O
18 Conjugate Substitution 311
Li
+
Substituted versions of these reagents retain the symmetry of 40 and 47. One interesting type is
prepared by a Prins reaction of the diketone 51 with trioxan 52, the trimer of formaldehyde. 6 The
six- 54 and seven-membered 55 compounds are easily made in the same way.
H
H2O O OEt
47; enol ether
O
Br2
37 36
CHCl3 80% yield
O
R
42
LiAlH 4
O
48; 100% yield
33
90% yield
O
O HCl, MeOH
room
O
temperature O
49; 100% yield 50; 100% yield
O

312 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
O
O
O
+
OH
O
O
O BF3.Et2O CH2Cl2 O
O
O
O
O
O
51 51a 52
53; 72% yield 54; 84% yield 55; 72% yield
Reaction with organo-lithium compounds works well with all three examples: one molecule of
formaldehyde is lost but a CH 2OH group is retained in the products 56, 57, and 58 from addition
of vinyl, phenyl, and butyl lithium. This chemistry was used to make bertyodionol. 7
53
Li
O
Unsymmetrical 1,3-dicarbonyl compound derivatives
For unsymmetrical versions do not start from the diketone. One way is to start from a monoketone
and react with an amide acetal (like those used in Claisen rearrangements, chapter 15). Thus
cyclopentanone gave the enaminoketone 59 that reacts with BuLi to give the enone 60. There is no
doubt here that the nucleophile has added in a conjugate fashion. 8
The same intermediates 62 can be formed from diketones and amines, particularly pyrrolidine,
and react well with organolithium compounds. The newly added RLi replaces pyrrolidine in good
yield providing that a hydrocarbon solvent is used. The yields of dienyl ketones such as 63 are
very good. 9
t-Bu
THF, –78 °C
O O
61
O
Unsymmetrical enaminones
It is obviously easier to prepare symmetrical enaminones such as 64 by this method but these can
be ‘desymmetrised’ by enolate alkylation to give, say, 65 before conjugate substitution leads to the
fi nal product 66. The yields are reasonable for a three-step process and the middle step gives the
product 65 of γ-alkylation of an extended enolate (see chapter 11).
O
O
OH
54
PhLi
OH
55
BuLi
OH
Ph
Bu
56; 94% yield 57; 93% yield 58; 89% yield
OMe
MeO NMe2 110 °C, 12 hours
N
H
t-Bu
O
NMe 2
59; 68% yield
O N
BuLi
THF, –30 ˚C
O
O
Bu
60; 75% yield
62
Li
hexane t-Bu
63; 84% yield
O
O
O

O
51
O
N
H
The reverse regioselectivity is realised by cerium-catalysed addition of Grignard reagents to
enamino ketones 68 formed with primary amines. 10 The structure of the product shows that direct
addition to the carbonyl group has occurred: the Ce atom presumably delivers the butyl group
through chelation to nitrogen. There is reasonable stereochemical control: the newly introduced
group goes trans to the carbonyl group in the product 70.
Ph
Conjugate Addition to Alkynes
O
N
1. LDA
2. EtI
Conjugate addition alone gives a vinyl derivative if the electrophile is an alkyne. We have seen
examples of this in chapter 15 where, for example, halides and thiolate nucleophiles gave substituted
alkenes such as 71 and 73 from 72 as the E-isomers under equilibrating conditions. The
bromoester 73 is easily made from the acetylenic acid 72b and esterifi ed afterwards. 11 These compounds
will now prove useful as vinyl cation equivalents as conjugate substitution on 71 and 73
is generally more successful than conjugate addition to 72, at least with carbon nucleophiles. We
are not concerned here with the related carbometallation of alkynes described in chapter 16 as the
products are formally vinyl anion equivalents. However, as we shall see later in this chapter, the
distinction is blurred in Pd-catalysed couplings.
RS
So lithium enolates react with the halide 73 by conjugate substitution. The lithium enolate of
the enantiomerically pure heterocycle 74 prepared from natural alanine gives one diastereoisomer
of E-75 in reasonable yield. After further manipulation the heterocycle was hydrolysed to give
cyclopropanes that are glutamate antagonists. 12
The corresponding ketones 76 can be made by aliphatic Friedel-Crafts reactions between an
acid chloride and acetylene using AlCl 3 as catalyst. Under these conditions chloride adds to the
acetylenic ketone to give the β-chloroenone 77 directly. These compounds are converted into the
sulfi des 78 by conjugate substitution 13 and are used as vinyl cation equivalents in the next section.
O
Et
N
BuLi
petrol
ether
O
Et
Bu
64 65 66; 56% yield
O O
MeNH2 O NHMe
BuMgCl
Ph NMe
HOAc
Ph O
Ph
CeCl3 Bu
H2O
Bu
67 68 69 70; 65% yield
RSH
MeOH
1. HBr
CO2Me CO CO
2Me
CO2H 2Me
base
Br
H
2. MeOH,H
71 72a 72b
73
H2N
CO 2H
L-alanine
18 Conjugate Addition to Alkynes 313
Ph
O
N
Bz
74
O
Me
1. LiN(SiMe3)2
2. 73
O O
Ph
N
Bz
Me
75; 65% yield
CO 2Me

314 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
H H
Sulfur-based leaving groups
The sulfur compounds like 71 can be made by conjugate addition not only to alkynes but also to
enones, e.g. 79, by using the Pummerer oxidation of the products 80 with N-chlorosuccinimide
(NCS) 82 to give a β-thio-enone 81 not accessible by conjugate addition to an alkyne.
Me 3Si
79
O
While organo-lithium compounds add directly to the carbonyl group of 81, cuprates carry out
a conjugate substitution to give the enone 83. Now a conjugate addition gives the ketone 85. It is
necessary to use Cu(I) catalysis and silyl trapping (see chapter 9) to make this conjugate addition
work but it gives good yields. The group added second (here p-tolyl) ends up trans to the Me 3Si
group on the other side of the ring. 14 And what is the Me 3Si group there for? That is explained in
the workbook.
81
Me 2CuLi
RCOCI
AICL 3
Sulfoxides and sulfones
O
ArSH NCS
Me3Si SAr
CCl4
Me3Si SAr
80 81; Ar = p-Tolyl
O
Me 3Si Me
83
ArMgBr
cat. Cu(I)
Me 3SiCl
OSiMe 3
One advantage of sulfur chemistry is that reagents can be used at three oxidations levels: sulfi de
80, sulfoxide and sulfone. The enones with the more highly oxidised sulfur atoms are more
electrophilic and need less reactive nucleophiles. Thus the sulfoxide 87 reacts with unactivated
pyrroles and furans, e.g. 86 with or without acid catalysis. 15
O
+ Ph
86; 10-fold excess
O
S
76
O
R
HCI
The nucleophiles 89; Z O or NR react by normal electrophilic aromatic substitution: both the
addition 89 and the expulsion of the leaving group 91 are faster with PhSO instead of PhS. In the
acid catalysed reactions the intermediates 90 and 91 would be enols rather than enolates.
Cl
O
KF
O
O
N
Cl
82; NCS
N-Chloro-
Succinimide
Ar
MeOH
Ar
Me3Si Me
Me3Si
Me
84; Ar = p-Tolyl 85; 90% yield
25 ˚C, 6 days, 91% yield
TsOH catalyst
O
87
O
25 ˚C, 1 hour, 86% yield
88
77
O
R
PhSH
Et 3N
CH 2Cl 2
PhS
O
78
O
O
R

Z
O
PhS
O
Z
H
O
S
Ph
89 90
vThe more reactive pyrrole 92 needs a shorter time while imidazole and pyrazole 94 react much
faster but through nitrogen. All these reactions go in remarkably high yield.
The sulfone 98 allows a tandem (chapter 36) sequence of remarkable selectivity. The lithium
derivative of the allylic phosphine oxide 96 (see chapter 12) adds to the enone 97 to give the
lithium enolate 99 trapped by the sulfone 98 to give the complex product 100 in 96% yield: the
only imperfection in stereochemical control is 3% of the Z-vinyl phosphine oxide. 16
The Diels-Alder Reaction on β-Bromo and β-Sulfonyl Alkynes
An alternative to conjugate addition to alkynes is the Diels-Alder reaction that gives the required
β-substituted alkenes without conjugate addition. Thus the deactivated pyrrole 101 reacts quite
well with the activated haloalkyne ester 102 to give the bicyclic compound 103 having the right
arrangement of Br and CO 2Me to allow conjugate substitution. Alkyl copper reagents are best and
give good yields of compounds such as 104 used in a synthesis of epibatidine. 17
The more elaborate diene 105, prepared by enantioselective reduction of the corresponding
ketone, (chapter 26) reacts with the β-tosyl alkyne acid 106 to give a good yield of one regio- and
O
Z
O
S Ph
N
87
25 ˚C,14 hours
N
N
N
87
25 ˚C, 8 days
MeCN
H
H O H
92; 10-fold excess 93; 98% yield 94; 1.2 equivs
93
1. BuLi
2. 97
18 The Diels-Alder Reaction on β-Bromo and β-Sulfonyl Alkynes 315
96
O
PPh2 O
97
LiO
H
99
O
PPh 2
3. 98
O
O
O
O
O
91
O
98
O
N
O
100; 76% yield
N
product, e.g.
88 + PhSO
O
95; 92% yield
Ph
S
O O
Br
MeO2C
MeO2C
N
N
N +
90-95 ˚C
30 minutes
Br
BuCu
Bu
CO2Me CO2Me
no solvent
CO2Me CO2Me 101 102 103; 56% yield 104; 78% yield
H
O
PPh 2

316 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
stereo-isomer of the lactone 107 having the leaving group in the right position for replacement
with a nucleophile. A methyl group was needed for the synthesis of forskolin and Me 2CuLi was
the best reagent. 18
OH HO2C O
Choice of leaving group
S Tol
O O
You will notice that simple organo-lithium and copper compounds as well as lithium enolates are
used in these conjugate substitution reactions. If the leaving group is a halide, there is a danger of
transmetallation with RLi (though not with lithium enolates) and organo-copper compounds are
safer. With leaving groups such as NR 2, OR, or sulfur in various oxidation states, there is essentially
no danger of transmetallation as oxidative insertion into the strong C-N, C-O, or C-S bonds
is rare, and simple RLi can be used.
Modifi ed Conjugate Addition
23 ˚C
30 hours
CHCl 3
105 106 107; 72% yield 108; >95% yield
The double bond can be restored after a conjugate addition to an electrophilic alkene if the enolate
intermediate 110 is trapped as a silyl enol ether 111 and then combined with a sulfur or selenium
electrophile which is later eliminated. Organocuprates are ideal nucleophiles for this process as
the intermediate enolate can be trapped as a silyl enol ether and reacted directly with PhSCl or
PhSeCl.
This method of making specifi c enolate equivalents we met in chapter 9. Reactive electrophiles
like PhSCl and PhSeCl react rapidly with the silyl enol ether 111 to give the 2-PhS(e)-ketone 114.
Addition is to the face of the ketone not blocked by the alkyl group on C-2.
111 PhS(e)Cl
Oxidation of the sulfur or selenium atom to the sulfoxide or selenoxide stage allows thermal
elimination to take place by a cyclic mechanism 115. Because the PhS(e) group is trans to the
alkyl group it must be cis to the hydrogen atom at C-2 and so cis elimination is possible. The
selenoxides are unstable and decompose spontaneously but the sulfoxides usually need heating.
The double bond is put back in its original position 116 so the strategy of the sequence is addition
O
Ts
Me2CuLi BF3.OEt2 O R2CuLi R OLi Me3SiCl R
OSiMe3 109 110
111
R
Cl
S(e)Ph
112
OSiMe 3
R
S(e)Ph
O
SiMe3
Cl
113 114
O
R
O
Me
S(e)Ph
O

of an alkyl anion to a β-enone cation synthon 117. This chemistry is discussed in more detail in
chapter 33 under ‘oxidation of enolates’.
R
S(e)Ph
O
A more general solution to the problem is to change the nucleophile from an organo-lithium or
copper species to an organo-palladium compound and this leads on to the Heck reaction.
The Heck Reaction
General description
[O]
O
H
R
Ph
S(e)
O
R
PhS(e)OH +
114 115 116
We have discussed palladium chemistry in chapter 8 where there was a brief description of
palladium σ-complexes. In this chapter we shall see the results of adding palladium σ-complexes
to unsaturated carbonyl compounds. Michael addition occurs but the palladium leaves the intermediate
in such a way that the original alkene is restored. 19 We shall take a simple example fi rst –
the addition of iodobenzene to methyl acrylate.
PhI +
cat. Pd(PPh3) 4 Ph
CO2Me CO2Me 118 119
The fi rst step is oxidative addition of the Pd(0) species to iodobenzene. This is called oxidative
addition because the Pd atom adds between the benzene ring and the iodine atom and is oxidised
from Pd(0) to Pd(II) 120. The mechanism is described in chapter 8. Next the alkene forms a
π-complex 121 with the palladium atom. The π-bond is a two-electron ligand and it makes sense
for it to displace one of the two-electron phosphine ligands. However, we should emphasise that it
is not always possible to be precise about which other ligands are present on the palladium atom
in these reactions. Now the nucleophilic attack occurs. The palladium atom transfers its phenyl
ligand to one end of the double bond and attaches itself to the other as a σ-complex 122. This
is like a phenyl anion doing a Michael addition to the alkene which is made even more electron
defi cient by complexation to Pd(II). This view explains the regioselectivity of the addition as
“Ph ” would certainly attack the more electron-defi cient end of the alkene and the Pd would prefer
to form a σ-complex to the more carbanion-like enolate position. However, you can view it as a
coupling reaction on the surface of the metal if you like.
PhI
18 The Heck Reaction 317
Palladium alkyl complexes are inherently unstable because of β-elimination. We saw this in
action in the discussion on hydrogenation in chapter 8. The palladium atom leaves with a hydrogen
O
O
117
vinyl cation
synthon
I PPh3 Pd(0) I PPh3 CO2Me I PPh3 Ph Pd
Pd
Pd
oxidative
carbo-
PPh3
insertion Ph PPh3
Ph CO palladation
2Me
CO2Me 120
121 122

318 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
atom from C-3 of the ester 123 and the σ-complex 122 reverts to a π-complex 124 with the product.
The product is freed if the palladium (II) atom drops out of the π-complex as 125: it can lose HI
and revert to Pd(0) ready for the next cycle. During the reactions Pd is present in all the complexes
as Pd(II) but it enters and leaves the cycle as Pd(0).
I PPh3 Ph H Pd
I PPh3
PPh3
Pd
CO
H
2Me
reductive
CO2Me elimination Ph
123
124
I PPh3 115 + Pd
H PPh3 125; Pd(II)
The stereochemistry of the double bond in the product is a result of the stereoselective
β-elimination of palladium - this reaction could give either the E- or the Z-cinnamate but the
reaction is reversible and the E-cinnamate is more stable.
This sort of Heck reaction is normally done in a more convenient way. Though Pd(0) really
starts off the cycle, Pd(II) is involved and Pd(OAc) 2 [or (Ph 3P) 2Pd(OAc) 2] is a more convenient
reagent than Pd(PPh 3) 4. This same product can be made in excellent yield under very mild
conditions without any phosphine at all. 20 An explanation of the necessary reduction of Pd(II) to
Pd(0) is in the workbook.
PhI +
cat. Pd(OAc) 2 Bu4NCl Ph
CO2Me CO2Me
K2CO3, DMF, 27 ˚C
118
119; 91% yield
Scope and limitations of the Heck reaction: synthesis of dienes
Ph3P PPh3 Pd
Ph3P PPh3 126; Pd(0)
Because of β-elimination of palladium, this reaction cannot be used with most alkyl halides. However,
vinyl halides are fi ne as their palladium σ-complexes do not undergo β-elimination to give
alkynes. Here is a simple example.
I CO2Me CO2Me +
cat. Pd(OAc) 2
127 118 E-128
The mechanism is the same as before with vinylPdI replacing PhPdI. The E-alkene is again
produced under thermodynamic control. But what happens if the vinyl iodide has some stereochemistry?
Then there is stereospecifi city in the formation of this alkene: Z-vinyl iodides 129 give
Z-alkenes and E-vinyl iodides give E-alkenes stereospecifi cally with retention. In chapter 16 we
discussed this sort of reaction - replacement of halide by metal or of metal by metal at a trigonal
carbon atom normally occurs with retention. This reaction can give E,E- or Z,E- dienes 130 but
not E, Z- or Z,Z-dienes. 20
R
118
CO2Me R
R = Bu; 90% yield,
R
Z-129 95:5 Z,E:E,E-130 E-129
I cat. Pd(OAc) 2
cat. Pd(OAc) 2
R
CO2Me R = Bu; 96% yield,
99:1 E,E:Z,E-130
As we have drawn the products, the right hand double bond is formed stereoselectively under
thermodynamic control, and can be E only, while the left hand double bond is formed stereospecifi
cally with retention from the original vinyl halide and can be E or Z.
I
118

The Heck reaction with electron-rich alkenes
The obvious limitation of this reaction so far is in the electrophile as we have suggested
naturally electrophilic enones as ideal partners for aryl or vinyl palladium σ-complexes. In fact,
complexation with palladium makes all alkenes electrophilic and nucleophilic addition can in
principle occur to a simple alkene while it and the nucleophile are both bound to the palladium
atom. Such reactions are known for aryl halides. Even ethylene itself does satisfactory Heck
reactions and its reaction with the bromopyridine 132 is the basis for a large scale process
leading to a drug. 21
Br 2
H2N N
Ac2O
AcHN N
131 132
18 The Heck Reaction 319
Br
50 psi ethylene
Pd(OAc)2, (o-Tol) 3P
MeCN, Et3N, 90 ˚C
AcHN N
133; 72% yield
10 kg scale
In practice, with vinyl halides, three regioselective problems arise - which alkene is to act as
the electrophile, which end of the alkene is attacked by the nucleophile, and which way does the
β-elimination occur?
I +
Pd(0) ?
R R
These problems may be avoided by making an organometallic compound [often of Cu(I) or
Mg(II)] from the halide intended to become the palladium σ-complex and to use another vinyl
halide as the electrophile. Palladium prefers to take out a halide rather than a hydrogen atom
in the β-elimination step and all three problems disappear. In the synthesis of this E,Z-diene
134, we prefer to use a Pd σ-complex for the Z-alkene part 136 and a vinyl iodide 135 for the
E-alkene.
134
E
+ Br
The Grignard reagent from Z-1-bromopropene combines with E-1-iodo-octene with catalytic
Pd(PPh 3) 4 to give the pure E,Z-diene in 87% yield. The Mg and Pd exchange by transmetallation
as Mg forms stronger bonds to oxygen. 22
Br 1. Mg
2.
BrMg Hex
Z-136
Et2O
Z
Z-137
135; electrophilic vinyl group
cat. Pd(PPh3)4
This solution takes the method outside the scope of the Heck reaction which is better realised
with vinyl trifl ates 138 [Trifl ate OTf OSO 2CF 3]. These can be made into palladium σcomplexes
but do not function as electrophiles since the β-elimination of Pd and OTf is a poor
reaction. The small amount of Pd σ-complex 139 formed in solution adds both to the alkene and
the remaining vinyl trifl ate but β-elimination leads rapidly to product, releasing Pd(0) for the next
cycle, from only intermediate 141.
I
I
Z-136
E,Z-134; 87% yield
to be used
as an organo
-Mg or organo-
Cu reagent

320 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
OTf
138
Pd(0)
Vinyl trifl ates, which are of course enol trifl ates, such as 144 and 147, can be made directly
from ketones 143 and 146, and react with electron-defi cient, conjugated, and electron-rich alkenes.
Here are just two examples giving dienes 145 and 148 in good yield.
A synthesis of strychnine
Pd OTf
L L
139
intermediate
σ-complex
1. base
OTf
R
OTf
140
PdL2OTf
PdL 2OTf
Rapid development in the Heck reaction has made it one of the most important of all modern
methods. A dramatic example is a recent synthesis of strychnine by M. Nakanishi and M. Mori. 23
This synthesis illustrates the intramolecular Heck reaction particularly well, showing examples of
regioselectivity in attack on the alkene and in formation of the new alkene. The synthesis starts
with a Heck reaction on enantiomerically pure 149. Attack occurs on the nearer end of the alkene
to give 150 that cannot eliminate to reform the same alkene as there are no H atoms left and the
alkene 151 must be formed. The stereochemistry is controlled by the short tether linking the aryl
bromide and the alkene.
The second ring is closed by an amido-palladation reaction. The nitrile in 151 is reduced to a
primary amine and protected with a Boc group. Reaction with Pd(II) allows nucleophilic attack
by the amide on the nearer end of the alkene and β-elimination again pushes the alkene round the
ring 153, this time because there is no syn H atom in the intermediate 154 at the site of addition.
Palladium is released as Pd(0) but this reaction needs Pd(II) so the quinone and MnO 2 are there
to carry out the required oxidation.
H
141
R
β-elimination
of Pd and OTf
FAST
SLOW
β-elimination
of Pd and H
O
2. Tf 2NPh
TfO
(Ph3P) 2Pd(OAc) 2
Ph
143; steroid 144
145; 77% yield
t-Bu
O
1. LDA
2. Tf 2NPh
t-Bu
146 147
CN
Br
N
H
Ts
149
2 mol% Pd(OAc) 2
PMe2Ph, Ag2CO3
DMSO, 90 ˚C
OTf
Ph
CHO
(Ph 3P) 2Pd(OAc) 2
NC
N
Ts H
150
PdL 2
t-Bu
148; 86% yield
no product
R
142; product
N
Ts H
CHO
CN
151; 87% yield

151
1. LiAlH 4
NHBoc
Pd(OAc) 2
N
Ts H
2. (Boc)2O quinone
152; 74% yield
MnO2 NBoc
NBoc
H
N
H
Ts
H
153; 87% yield 154
Now the alkene must be moved yet one more time around the ring to prepare the way for another
intramolecular Heck reaction. Hydroboration (chapter 17) of 153 is regioselective because of
the large N-Boc group and Swern oxidation completes the insertion of the ketone 155. Reduction
and elimination use another palladium-catalysed reaction. Conversion to the trifl ate 157 is followed
by Pd-catalysed transfer hydrogenation, the H atom coming from formic acid HCO 2H.
1. 9-BBN
2. H2O2 NaOH
153
3. (COCl)2
DMSO, Et3N NBoc
H
N
H
Ts
155; 70% yield
NBoc
NBoc
1. PhNTf2 (Me3Si)2NK
H
H
O
2. Pd(OAc) 2
HCO2H, Ph3P
i-Pr2NEt N
H
Ts
H
156; 64% yield 157
The molecule is now prepared for the next Heck reaction by reductive removal of the Ts group
from nitrogen and acylation with Z-3-bromoacryloyl chloride to give 158. Intramolecular Heck
reaction closes the ring 159 in reasonable yield and with the correct and expected regioselectivity.
The stereochemistry of the new centre is irrelevant as it will disappear. The double bond is moved
back round the ring one place! In this reaction we see a β-bromo unsaturated acid derivative providing
the nucleophile for the Heck reaction rather then the electrophile for conjugate substitution.
156
1. Na
naphthalene
2. RCOCl
K 2CO 3
NBoc
H
Pd(OAc) 2, Ph3P H
O
N
H
Br
i-Pr2NEt, DMSO
O
N
H
158; 56% yield 159; 46% yield
NBoc
The double bond is moved into conjugation 160 with base and the side chain for the last Heck
reaction is added by deprotection at nitrogen and alkylation with an allylic bromide to give 161.
Notice that the allylic bromide reacts rather than the vinylic iodide as this reaction is not catalysed
by palladium.
159
i-PrO
i-PrOH
O
N
160
H
18 The Heck Reaction 321
NBoc
H
Br
1. CF 3CO 2H
2. Li 2CO 3, DMF
I
OTBDMS
O
N
H
N
H
161; 53% yield
I
PdL2
OTf
OTBDMS

322 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
Now the Heck reaction can be induced to close the ring 162. In this case the vinyl iodide forms
the palladium derivative and the regioselectivity of the attack is at the δ-position of the dienone
mainly because of the tether. The closure of the last ring was already known and the synthesis
of strychnine 164 complete. This synthesis uses three Heck reactions and two other palladiumcatalysed
reactions.
161
Pd(OAc) 2
Bu4NCl K2CO3 DMF
162; R = TBDMS, 48% yield
Recent developments in the Heck reaction
O
N
N
H
H
RO
1. LiAlH 4
The big difference between the Heck reaction and those couplings to follow in the next section
is that only one of the alkenes is marked with functionality (halide, trifl ate): the other is a simple
alkene and loses a hydrogen atom during the Heck process. This sounds like a disadvantage
where regioselectivity is concerned but some recent examples should convince you that the Heck
reaction is very important indeed. So the Heck reaction can be combined with a Pd-catalysed
ortho alkylation of an aromatic halide 165 to give benzoxepines 166 in excellent yield even with
an unprotected amide on the ring. 24
A bonanza of Heck reactions was used by Tietze 25 in the synthesis of cephalostatin analogues.
Corey-Fuchs reaction on the aldehyde 167 gives the alkene 168 from which the trans Br atom is
stereoselectively removed by Pd-catalysed tin hydride reduction to give the Z-vinyl bromide 169.
This reaction is discussed below under Stille coupling.
O
O
I
Br
2. HCl
N
H
N
H H
O
H
O
H
164; strychnine
O CO2Et
MeCN, reflux
AcNH AcNH
Br
165
Br CHO
167
Ph3P, CBr 4
CH2Cl2, 0 ˚C
Pd(OAc) 2, TFP, Cs 2CO 3
O
O
Br
Br
O
N
H
N
H
163; 44% yield
Bu3SnH
166
H
HO
CO 2Et
O
KOH
EtOH
Pd(PPh3) 4
Br
Br
Br
168; 80% yield 169; 98% yield
O
O
Br
Br

Heck reaction with the enantiomerically pure bicyclic alkene 170 gives the new C–C bond 171
with retention at the vinyl bromide, stereoselective introduction of two new stereogenic centres,
and relocation of the alkene since cis elimination of palladium is required. Repetition of the fi rst
two reactions after deprotection of the other aldehyde gives a new Z-vinyl bromide 172 ready for
the next Heck reaction.
Ot-Bu
169
O
O
Br
Ot-Bu
Now a second Heck reaction between the newly formed vinyl bromide 172 and the same
alkene 169 gives the C 2-symmetric compound 173 with all the same selectivity. Notice that vinyl
bromides are more active in the Heck reactions than the aryl bromides present 169 and 172.
However, when there are no more vinyl bromides left, the two aryl bromides do take part in a
double intramolecular Heck reaction. Two more stereogenic centres are introduced and the alkene
moves one place further round the ring. A special catalyst 175 is needed for this reaction that goes
in excellent yield.
170
170
169
Pd(OAc) 2
PPh3 Bu 4NOAc
K2CO 3
t-BuO
18 Sp 2 –sp 2 Cross-Coupling Reactions by Transmetallation 323
Pd(OAc) 2
PPh3
Bu4NOAc
H
H
Br
This synthesis involves two Pd-catalysed reductions and four Heck reactions all using Pd(OAc) 2
except the last. The yields are not always wonderful, but the synthesis is made very short and
selective by the repeated Heck requirements.
Sp 2 –sp 2 Cross-Coupling Reactions by Transmetallation
Br
H
171; 41% yield
Br
H
H
H
Ot-Bu
175
Bu4NOAc 1. HOAc
2. Ph3P CBr4 3. Bu 3SnH
Pd(PPh 3) 4
Br
Br
Ot-Bu
Halide and trifl ate leaving groups are also involved with palladium catalysis in the most general
of all these reactions with vinyl electrophiles. These use a main group rather than transition metal,
chiefl y boron or tin, in stoichiometric amounts to mark one molecule as nucleophilic and then
Br
H
172; 59% yield
H H H
173; 47% yield t-BuO 174; 80% yield
Ar
O O
Pd
P
Ar Ar
O O
P
Pd
175; Ar = o-Tolyl
Ar
H
H
H
H
Ot-Bu

324 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
transfer that group to the palladium atom by a transmetallation. Combination with an aryl or vinyl
halide or trifl ate completes the synthesis.
We can write a general scheme for this class of reaction in four stages:
1. Preparing the organometallic (usually boron 176 or tin 177) compound by various methods
from the intended nucleophile.
reagents
usually or
X Metal B(OH) 2 SnBu3 176 177
2. Oxidative addition of catalytic palladium (0) to the aryl or vinyl halide or trifl ate.
L L
Br Pd
Pd(0)
Br
L L
Pd(0)
Br Pd
Br
178; Pd(II) 179; Pd(II)
3. Transmetallation to give a Pd-C bond 180 and a B-(or Sn-) halide (shown with an aryl
‘nucleophile’ and vinyl ‘electrophile’).
Metal
L L
L L
Pd
Br
transmetallation
Pd
180; Pd(II)
The arrows on the transmetallation step are intended to indicate which group joins to which
rather than a mechanism. We have seen other transmetallation reactions of this sort - Li exchanged
for Cu or boron or tin for example in chapter 16 in particular. They may well go through a fourcentred
transition state in which the aryl group (in this case) is bonded to both metals and the
halide also. Organometallic mechanisms are not always known in detail.
4. Coupling on Pd to make the new CC bond and to release the Pd(0) for the next cycle.
L L
Pd
181; Pd(II)
reductive
coupling
L L
Pd
182
183; product
L L
Pd
We have described the two components in the coupling as “nucleophilic’’ and “electrophilic’’.
These words are intended to help you make sense of the reactions and should not be taken literally.
Of course, when the two groups, vinyl, aryl or whatever, are both bound to the palladium atom,
neither is nucleophilic or electrophilic (unless one of them is an unsaturated carbonyl compound)
and their combination is a coupling reaction. The coupling occurs through a three-membered
transition state 182 and there may be some involvement of the p-orbitals on the carbon atoms
joined to palladium.
+
Pd(0) for next cycle

The designation “intended as the nucleophile” is helpful when considering the origin of the
fragments. When making a disconnection with an sp 2 -sp 2 cross-coupling in mind, one has to decide
which molecule is to form the palladium σ-complex and that one is “intended as the electrophile”.
If these labels do not help, discard them.
Stille coupling
When an organotin compound is the nucleophile, the coupling is called Stille coupling after
J. K. Stille of Colorado State University, the inventor. 26 In chapter 15 we saw how organo-tin
compounds are sources of radicals, but with palladium catalysis the reaction changes. We shall
start with an example which may look trivial but is very important for this chapter. Reaction
of readily prepared 1,1-dibromoalkenes 184 with tributyltin hydride under Pd(0) catalysis gives
Z-1-bromoalkenes 185 with high stereoselectivity. 27
Ph 3P, CBr 4
RCHO CH2Cl 2
R
Br
184
Br
Bu 3SnH, 4 mol% Pd(PPh 3) 4
room temperature
15 minutes
The reaction starts with stage 2 (stage 1 is already done as we can buy the ‘organometallic’
Bu 3SnH): oxidative insertion of Pd(0) into the less hindered of the two C-Br bonds of the dibromoalkene,
that is the one trans to R to give the Pd(II) σ-complex 186. Notice that palladium
is again strongly infl uenced by steric hindrance. Stage 3 is transmetallation – the palladium gets
the H atom and the tin gets the Br atom 187. Most reactions of Bu 3SnH end up with tin exchanging
the weak SnH bond (∼310 kJ/mol) for the much stronger SnBr bond (∼380 kJ/mol). Stage 4 is
the coupling of the vinyl group and the H atom - stereospecifi cally with retention.
184
oxidative
insertion
R
L L
Pd
Br
186
Br
Bu3SnH transmetallation
R
Bu3SnBr +
Palladium is released as Pd(0), ready for the next cycle. The relevance of this reaction to the
subject of this chapter is that we have already used, and will use again, Z-bromoalkenes for the
stereospecifi c synthesis of dienes. This is one way to make them.
Carbon-carbon bonds can be made from palladium-catalysed reactions of vinyl bromides,
iodides 189 or trifl ates with any organotin compounds which cannot undergo β-elimination after
transfer to palladium. These include vinyl, methyl, allyl, benzyl, and aryl groups. This raises the
question of which group is transferred from a tin atom in such reactions. With tetramethyl tin
there is no choice, the methyl group being transferred to give 190 but aryl groups are transferred
in preference to alkyl, giving 188.
Bu 3SnI +
18 Sp 2 –sp 2 Cross-Coupling Reactions by Transmetallation 325
R
When we want to transfer a group from tin we do not want to waste three of them. The rule is
that tin transfers the best anion to palladium (strengthening our view that the organotin compound
is the nucleophile). Alkynyl groups are transferred best and the order for other groups is roughly
as below.
R
H
+ Bu3SnBr Br
Z-185
L L
Pd
H
Br
187
coupling
Z-185
Ar SnBu Me4Sn
3
Ar
I
Me
cat. Pd(0) R
cat. Pd(0) R
+ Me3SnI 188 189 190

326 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
alkynyl
alkyl
vinyl (alkenyl), aryl allyl, benzyl
R R
R
Me, Bu etc
most easily transferred
Ar
Ar
least easily transferred
The exact order doesn’t matter. What is important is that aryl, vinyl, allyl and benzyl are all
transferred more easily (and that means much more easily) than butyl or methyl. If we use a
Bu 3Sn– or an Me 3Sn– group, we can be sure that no butyl or methyl groups will be transferred. A
neat example is the preparation of aryl tin compounds 192 from aryl halides by Stille coupling.
How is that possible? If one tin is to be transferred to carbon, another must pick up the halide so
we need two tin atoms joined together – hexamethylditin 191 is the reagent.
Ar Br + Me3Sn SnMe3 Ar SnMe3 + Me3Sn Br
191 cat. Pd(0) 192
If the electrophile is a vinyl trifl ate, it is essential to add LiCl to the reaction so that the chloride
may displace trifl ate from the palladium σ-complex. Transmetallation takes place with chloride
on palladium but not with trifl ate. This famous example illustrates the similar regioselectivity of
enol trifl ate formation from ketones to that of silyl enol ether formation discussed in chapter 3.
Kinetic conditions give the less 198 and thermodynamic conditions the more highly substituted
195 trifl ate.
thermodynamic control
O
1. i-Pr2NMgBr 2. Tf 2NPh
OTf
193
Me 3Sn
kinetic control
O
1. i-Pr2NLi (LDA)
2. Tf 2NPh
OTf
196
Pd(PPh 3) 4, LiCl
195; 90% yield; 98:2 regio
198; 100% yield; 95:5 regio
Now let us look at a complete synthesis. 28 The natural product pleraplysillin-1 199 is found
in a marine sponge and in the nudibranch (a kind of apparently defenceless shell-less mollusc)
that eats it. It has a defensive role - the nudibranch is “rapidly rejected as a food source by
carnivorous fi sh”. 29 Pleraplysilin-1 has a diene joined to a furan at the diffi cult 3-position.
Disconnection between the two double bonds suggests a vinyl trifl ate 201 from a cyclic alkene,
as we can make that regioselectively from the corresponding ketone, and a vinyl stannane from
the furan half 200.
O
199; pleraplysillin-1
194
197
Stille
Pd(PPh3) 4, LiCl
O
The enol trifl ate comes from regiospecifi c reduction of the enone (chapter 3) which can be
made by a Robinson annelation.
Me 3Sn
SiMe3
SiMe 3
SnBu3
+
TfO
SiMe 3
200 201
SiMe 3

201
O O
FGA
202
3-Substituted furans are awkward to make but 3-hydroxymethylfuran 207 is available commercially
and is converted into the corresponding bromide 205 with PBr 3 in pyridine. Alkylation
of a vinyl cuprate with this reactive alkyl bromide was used here.
O
18 Sp 2 –sp 2 Cross-Coupling Reactions by Transmetallation 327
200a
SnBu 3
The synthesis is summarised below. Note the use of a hexynyl group on the cuprate 208 - the
rule for cuprates is the opposite of the rule for stannanes - the less stable anion is transferred fi rst.
The coupling requires LiCl and is then very effi cient.
208
Cu
SnBu3
The synthesis is convergent, very short, and gives just the one regiochemical and geometrical
isomer of the diene. Another peraplysillin-1 synthesis is described in the workbook.
Recent developments in Stille coupling
O
203
Because Stille coupling uses stoichiometric tin to control the regioselectivity, one might expect
it to become rather less popular as concern over the environmental effects of toxic tin grows. In
fact it is as popular as ever, particularly in laboratory syntheses. Two recent syntheses of crocacins
both use the reaction to make the diene system. Crocacin C is a primary amide 210 while crocacin
D has the more complicated side chain 211. The rest is the same.
Me
200 + 201
Me
Both syntheses made the bond between the two alkenes by a Stille coupling. One put the tin
on the amide part by a Cu(I) catalysed conjugate addition of Bu 3SnLi to the acetylenic ester 212
and Weinreb amide formation. Coupling this vinyl stannane with a single enantiomer of the iodide
derived from the rest of the molecule gave crocacin C in good yield. The synthesis of the iodide
uses an asymmetric aldol reaction and is described in the workbook. 30
aldol
O
204
CHO
1,5-di-CO
etc
Br
+ Br
SnBu3 O
205 206 207
205
Pd(PPh 3) 4, LiCl
200 203 L-selectride
LiO
209
199, peraplysillin, 75% yield
Tf 2NPh
OMe OMe Me
CONHR
NH
N
H
CO2Me 210; Crocacin C: R = H 211; NHR group for Crocacin D
O
OH
201

328 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
Me CO 2Et
212
The other synthesis 31 had the tin on the larger part of the molecule 215. This starting material
was also made by an asymmetric aldol reaction and the vinyl stannane was introduced by a special
reaction described in the workbook. This is perhaps the more obvious way to do the coupling with
the electrophilic halide combining with the vinyl stannane but these syntheses show that the Stille
coupling is versatile.
Variations in Stille coupling
1. Bu3SnLi
CuBr.SMe2 Bu3Sn CO2Et Me3Al Bu3Sn
CONH2 2. 1.7 equiv.
MeOH
Me
213; 70% yield, 87:13 E:Z
NH4Cl Me
214; 72% yield, E only
Me
Me
OMe OMe
215
OMe
Me
OMe
Me
216; 80% yield
SnBu 3
I
CO2Me Me
cat. Pd2(dba) 2
CO 2Me
Other reasons for the continuing popularity of the Stille are the range of functional groups compatible
with the reaction and the variety of structures that can be incorporated into either component.
The allyl isoxazole 218 can be made either from vinyl or allyl-tributyltin using either 217 or
219 It turns out that vinylation of 217 gives a better yield. 32
N
Br
Ph Ph
O
Bu3Sn
N
The ‘electrophile’ can include reagents such as acid chlorides, leading to acylation 221 and
cyclisation to pyrones 33 222 or bromo-quinones with similar reagents 220 leading eventually to
chromenes. 34
Double Stille couplings are valuable for symmetrical compounds like β-carotene 226. The
symmetrical bis-tributylstannyl-pentaene 224 is coupled at both ends to the iodo-triene 223 in
one step with catalyst 225 to give an excellent yield of β-carotene 226 with full control over E/Z
stereochemistry. 35
Me
Bu3Sn
Ph 3As
2.5 mol% Pd2(dba) 3
2.5 mol% Pd2(dba) 3
(Furyl) 3P Ph Ph (Furyl) 3P
O
217 98% yield
49% yield
218
219
O
RCOCl
Bu 5 mol% Pd(PPh3)4
3Sn
OSnBu3 dioxane, 50 ˚C
220; 85:15 E:Z
R
O
221
O
OSnBu 3
N
Br
Ph Ph
O
R O
222
O

(PhCN)2PdCl2
225
i-Pr 2NEt, 25 ˚C
The synthesis of the complex anti-leukemia compound asperazine 231 uses a series of
palladium-catalysed reactions including a Stille coupling and a Heck reaction as well as a
palladium-catalysed hydrostannylation. This is an asymmetric synthesis as the starting materials
are made from serine and tryptophan. We summarise only the key steps but the full description
is worth reading. 36
I
Suzuki coupling
I
SnBu3
+
Bu
+
3Sn
I
223 224
223
R
N
O
H
226; β-carotene, 73% yield
+ H
R
CO Stille
2Me
N
RN
coupling
RN
O
Pd2(dba) 3.CHCl3 SnBu3 (Furyl) 3P, CuI
H
H
227 228
229; >84% yield
NR
HN
O
R
N
I
RN
O
O
NR
230 H
231; 66% yield
In the Suzuki coupling 37 the trialkyltin functional group on the “nucleophilic” partner in the
coupling reaction is replaced by a boronic acid 234. These stable compounds are easily made from
simple organometallic compounds and boronic esters 233 followed by hydrolysis.
R
18 Sp 2 –sp 2 Cross-Coupling Reactions by Transmetallation 329
Br
1. Li or Mg
Heck Reaction
Pd 2(dba) 3.CHCl 3
(Furyl) 3P, CuI
Oi-Pr
O
N
R
O
H
NR
O
CO 2Me
2. (i-PrO) 3B
R
R
232 233 234
B
Oi-Pr
HCl
R
N
R
N
OH
B
OH
RN
H
O
O

330 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
A standard way to make vinyl boronic acids 237 is to hydroborate an alkyne with catechol
borane 38 235 and again hydrolyse the ester products 236. The empty orbital of the boron atom
attacks the electron-rich terminus of the alkyne where is the larger HOMO of the π-bond. One
detailed example 39 includes Suzuki coupling to Z-styryl bromide. Another diester group commonly
used in the Suzuki coupling is derived from pinacol - examples appear later.
R
syn
O
OH
O
hydroboration
B
B
H B
R O
R OH
O
235; catechol borane 236; vinyl boronic ester 237; vinyl boronic acid
There are many other ways of making boronic acids and you are referred to Suzuki’s review 37
for a full discussion. A Suzuki coupling would occur if one of these boron compounds 236 was
combined with an aryl or vinyl halide or trifl ate in the presence of Pd(0) and an oxy-anion.
O
B
+
R O
236; vinyl boronic ester
I
238
catalytic
Pd(PPh 3) 4 +
RO
O
B
O
The fi rst step in a Suzuki coupling is the formation of the vinyl or aryl boron derivative and
this we have already discussed. The second step is the oxidative insertion of Pd(0) into the other
partner in the coupling reaction, here iodobenzene 238. This σ-complex 241 forms without the
oxyanion. It is in the third step, the transmetallation reaction 243, that the oxyanion is necessary.
Boron is barely a metal and it forms strong BO bonds. It will not exchange its organic group with
the palladium atom unless it gets an oxygen atom in return.
The dotted arrows on the transmetallation step 243 show only what joins to what and are not
intended as a serious mechanism. Indeed a better mechanism might involve addition of RO to
the boron atom before transmetallation. This process can be used to couple aryl to aryl, vinyl to
vinyl, and aryl to vinyl (either way round!). As boron compounds are much less toxic than tin compounds,
the Suzuki coupling is often preferred industrially. Because each partner in the coupling
reaction is marked in a different way – one with a boron atom and one with a halide – we can be
sure that we shall get cross coupling reactions only.
When the bond between the two sp 2 centres is in the middle of the molecule, the disconnection
becomes very attractive strategically. Markós milbemycin synthesis 40 illustrates this point well.
Milbemycins belong to a family of anti-parasitic agents and milbemycin β3 244 is one of the
simplest. Disconnection of the macrocyclic lactone a reveals a continuous carbon skeleton with an
aromatic ring conjugated to a diene and one isolated alkene. Markó next decided to disconnect the
isolated alkene b, having in mind a Wittig reaction with 246 on the ketone 245 and it is this ketone
we are going to analyse in detail.
R
RO
239 240
O R
Pd(PPh3) 4
238
I
oxidative Pd
insertion
Ph3P PPh3 241
RO
RO
Pd
Ph3P PPh3 242
B
O RO
Pd
Ph3P PPh3 243
transmetallation
Pd(PPh 3) 2
239

O
O O
a
O
OH
244; Milbemycin β3
a
C–O
b
Wittig
CO 2H
Removing the aromatic ring from the diene makes good sense once we know about Suzuki
coupling as it allows us to build the two halves of the molecule separately. There is a free choice
as to whether we put the boron atom on the diene or on the aromatic ring, but Markó put it on the
diene because he planned to make the vinyl boronate 248 by hydroboration of an alkyne 249. Note
the protection of the phenol and the carboxylic acid as methyl ether and ester respectively.
O
lactone
OH
OH
245a 247
No doubt joining the alkyne to the alkene could also have been done by a coupling reaction
in the coordination sphere of a metal but an alternative is to imagine the alkene as coming from
the dehydration of an alcohol 251. This allows disconnection to the known lactone 250. The synthesis
of the alkyne uses DIBAL for partial reduction and the differential protection of the two
OH groups by more or less hindered silyl groups.
O
CO 2H
O
250
known lactone
18 Sp 2 –sp 2 Cross-Coupling Reactions by Transmetallation 331
Suzuki
coupling
1. DIBAL
2. BrMg
X
HO
CO 2H
OH
Hydroboration of the alkyne 252 with catechol borane 235 is regioselective for steric reasons and
the resulting E-vinyl boronate 253 couples with the iodo-benzene 254 under palladium catalysis.
+
251; 85% yield
O
245
O
OH
H
+
hydroboration
PPh 3
O
OH
246
O
O
B(OR) 2
248 249
1. TBDPSiCl
Et3N, DMAP
2. TBDMSiCl
Et3N, DMAP
TBDPSO
OTBDMS
252; 70% yield

332 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
The coupling was followed, without isolation, by a Jones oxidation to give the required protected
hydroxyketone. Half of milbemycin β3 had been assembled with good stereochemical control
thanks to Suzuki coupling.
252 235
TBDPSO
OTBDMS
H
B(OR)2
CO 2Me
I TBDPSO CO 2Me
OMe
253; 100% yield 254
+
1. Pd(OAc) 2
Ph3P, Tl 2CO3
2. KF, H 2O
CrO 3, H 2SO 4
All the examples we have chosen so far have been of aryl and vinyl nucleophiles with no
possibility of β-elimination when they are transferred to palladium before coupling. With Suzuki
coupling it is possible to use saturated alkyl boranes in combination with vinyl halides and get
coupling products in good yield. An example is the preparation 41 of exo-brevicomin 256, the aggregation
pheromone of the Western pine beetle Dendroctonus brevicomis. Almost all syntheses,
including this one start with the unravelling of the acetal to reveal a ketodiol 257. The 1,2-diol
is syn as drawn and can be made diastereoselectively by cis dihydroxylation of an alkene of the
same confi guration, that is E-258. The reagent normally used in this reaction is OsO 4 with various
catalysts. In chapter 25 you will see that this reaction can be made to produce just one enantiomer
of the syn diol.
O
O
H
256; (+)-brevicomin
H
HO H
OH
Using a Suzuki disconnection, we intend to add an alkyl boronic acid 260 to an E-vinyl bromide
259 (from but-1-yne) and the boronic acid will come from hydroboration of a simple alkene 261
rather than an alkyne.
H
H
E-258a
O
1,1-diO
acetal
Suzuki
257
Each stage of this synthesis uses interesting reactions. The unsaturated ketone was made by
allylation of a d 1 equivalent – a methoxyvinylcuprate from 263 and it was necessary to protect the
ketone as the acetal 265 during the rest of the reactions.
H
O
H Br
E-259 from alkyne
+
1,2-diO
functionalisation
O
O
OMe
255; 68% yield from 253
H
H
E-258
B(OH) 2
260 261
O
O

MeO MeO
1. BuLi
2. Cu(I)
3.
Li
Br
H
262 263 264 265
The E-butenyl bromide 259 was made by hydroalumination and bromination of but-1-yne 266.
Hydroalumination occurs stereospecifi cally cis (chapter 16) 267 and electrophilic replacement of
aluminium by bromine occurs with retention at the sp 2 centre. 42
Hydroboration of the unsaturated ketone was carried out with the very hindered borane 9-
BBN and the alkyl borane 268 was coupled with the vinyl bromide 259 without isolation using
Pd(0) as catalyst and NaOH to force the transfer of the alkyl group from boron to palladium. The
pure trans (E-) coupled product 269 is formed in 85% yield so coupling must be faster than βelimination
in this case.
Asymmetric dihydroxylation with OsO 4 gave the syn diol 270 which was deprotected and
cyclised with toluene-p-sulfonic acid (TsOH) catalysis in over 90% yield to complete this short
and interesting stereochemically controlled synthesis of exo-brevicomin 256 in 65% yield from
allyl bromide.
H
18 Sp 2 –sp 2 Cross-Coupling Reactions by Transmetallation 333
H
Recent developments in Suzuki coupling
You will have realised that the Suzuki coupling is the best of those we have mentioned. It is
regiospecifi c as the positions for coupling are marked, one with a boronic acid and one with a
halide. It does not use toxic tin. It can be used for all the aryl, heteroaryl, vinyl, benzyl and other
groups that Heck and Stille use and in addition it can be used for saturated alkyl boronic acids
with β-hydrogen atoms without β-elimination. It is not surprising that it is very widely used and
we give a few representative examples.
Direct coupling of aryl with heteroaryl compounds works well with o-Cl and o-MeO groups
on the phenylboronic acid in coupling with isoquinolines or coumarins. In the fi rst case 271 it was
OMe
i-Bu 2AlH Br 2
HO OH
[DIBAL]
H H Ali-Bu2 H Br
266; but-1-yne
E-267 E-259
9-BBN
O O O O
R2B 265 268
E-269
O O
OsO 4
HO
H
H
OH
H
E-259
Pd(PPh3) 4
NaOH
O O
H
H
O O
H
E-269; 85% yield
TsOH
O
O
H
O O
syn-270 256; (+)-brevicomin

334 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
necessary to have a bromine (rather than a chlorine) atom on the isoquinoline to ensure chemoselectivity
as there is a chlorine atom on the boronic acid. 43 In the second 272 a chlorine is all right
but this is an easier reaction as it is like conjugate substitution. 44
Br
N
B(OH) 2
CO 2Me
Cl
Pd(PPh 3) 4
K 3PO 4
N
CO 2Me
Cl
B(OH) 2
271; 90% yield O
272; 98% yield
Heterocycles are also coupled to vinyl boronic acids and these can be made by hydro boration
of alkynes. This example 45 shows the compatibility with functionality such as the NHBoc
group in 273.
Direct coupling of two vinyl groups remains an important job for the Suzuki reaction. In their
synthesis of the antibiotic ()-fostriecin, Reddy and Falck 46 coupled the Z-vinyl bromide 276 with
the Z-boronic ester 277 to make the triene 278 with Z,Z,E-alkenes. Free OH groups obviously do
not interfere.
The most distinctive contribution of the Suzuki to modern methodology is the coupling
of alkyl boronic acids, formed by hydroboration of alkenes, to vinyl and aryl halides. 47 The
simple mono-substituted alkene 279 reacts with 9-BBN followed by Suzuki coupling with
aryl iodides to give products 281 in good yield regardless of the nature or the position of the
substituents. 48
MeO
Cl
CHO
Pd(PPh 3) 4
Ipc2BH
1.
NHBoc
2. 30 x MeCHO
O
B
O
NHBoc
+
N
N
I
Pd(OAc)2
(o-Tol)3P
N
N
NHBoc
3. pinacol
273
Tr
274
K2CO3 Tr
275; 51% yield
O
O
O
OH OR Br
+
OH
B
O O
276 277
O
OH OR
OH
278; 74% yield
K 2CO 3
OR
OR
MeO
Pd(PPh 3) 4
Ag2O
O
CHO

BocN
O
BR 2
ArI, 5 mol%
2 equivs
9-BBN-H
PdCl2(dppf).CHCl3 BocN
THF 3M K3PO4 O
THF-DMF
279 280
BocN
Intramolecular coupling of a Z-vinyl iodide and a saturated alkyl chain in 282 creates a new
11-membered ring 283 providing the ‘ansa’ bridge in Danishefsky’s synthesis 49 of xestocyclamine
A. The yield in the formation of this diffi cult medium ring and the toleration of functionality are
both impressive.
Ts
N
O
HO
OR
N
The coupling of two enantiomerically pure fragments to form an alkene of fi xed geometry in
the centre of ebelactone allows a convergent synthesis. 50 One fragment, the vinyl iodide 285 is
ultimately derived from a coupling between a chiral aldehyde and a chiral allyl boronate but more
immediately by silyl-cupration of an alkyne 284 and iodination.
The other fragment, the alkene 286 originates in an Evans’ aldol reaction (chapter 27) and
is coupled to 285 by hydroboration and Suzuki reaction. The yield is very impressive, as is the
stereocontrol over the new centre next to the acetal. The full synthesis appears in the workbook
together with some stereochemical explanations.
BnO
O O
286
18 Sp 2 –sp 2 Cross-Coupling Reactions by Transmetallation 335
1. 9-BBN
2. H2O 3. Pd(dppf)Cl2 TlCO3, Ph3As N
O
281
HO
OR
282
I
283; 60% yield
OR2 OR1 OR2 OR1 1. PhMe2SiLi, CuCN
2. N-I-succinimide I
284 285; 90% yield
1. 9-BBN, THF
room temperature
2. 285
Pd(dppf)Cl2 NaOH, H2O room temperature
BnO
Ts
O O
O
Ar
N
287; 70% yield
Ar = phenyl
substituted:
p-OMe, 71% yield
m-NO 2, 69% yield
o-F, 77% yield
OR 1
OR 2

336 18 Vinyl Cations: Palladium-Catalysed C–C Coupling
Summary
The palladium-catalysed reactions with alkenyl, aryl, and heteroaryl halides or trifl ates as one
partner (‘electrophilic’) and alkenes (Heck), aryl or vinyl stannanes (Stille) or aryl, vinyl and even
alkyl boronic acids (Suzuki) as the other (‘nucleophilic’) partner provide a synthetic method of
astonishing power and versatility. These reactions are only just starting to be explored and great
things are expected of them.
References
General references are given on page 893
1. Z. Rappoport, Acc. Chem. Res., 1981, 14, 7.
2. M. Ochiai, S. Yamamoto and K. Sato, Chem. Commun., 1999, 1363.
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5. F. J. Moreno-Dorado, F. M. Guerra, F. J. Aladro, J. M. Bustamante, Z. D. Jorge and G. M. Massanet,
Tetrahedron, 1999, 55, 6997.
6. K. Chen, C. S. Brook and A. B. Smith, Org. Synth., 1998, 75, 189; A. B. Smith, B. D. Dorsey, M. Ohba,
A. T. Lupo and M. S. Malamas, J. Org. Chem., 1988, 53, 4314.
7. A. B. Smith, B. D. Dorsey, M. Visnick, T. Maeda and M. S. Malamas, J. Am. Chem. Soc., 1986, 108,
3110.
8. R. F. Abdulla and K. H. Fuhr, J. Org. Chem., 1978, 43, 4248.
9. T. Mukaiyama and T. Ohsumi, Chem. Lett., 1983, 875.
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12. D. Ma, Z. Ma, J. Jiang and C. Zheng, Tetrahedron: Asymmetry, 1997, 8, 889.
13. R. K. Haynes, S. C. Vonwiller, J. P. Stokes and L. M. Merlino, Austr. J. Chem., 1988, 41, 881.
14. M. Asaoka, K. Takenouchi and H. Takei, Tetrahedron Lett., 1988, 29, 325.
15. K. Hayakawa, M. Yodo, S. Ohsuki and K. Kanematsu, J. Am. Chem. Soc., 1984, 106, 6735.
16. R. K. Haynes, S. C. Vonwiller and T. W. Hambley, J. Org. Chem., 1989, 54, 5162.
17. C. Zhang and M. L. Trudell, Tetrahedron, 1998, 54, 8349.
18. E. J. Corey, P. D. S. Jardine and J. C. Rohloff, J. Am. Chem. Soc., 1988, 110, 3672; E. J. Corey and P. D.
S. Jardine, Tetrahedron Lett., 1989, 30, 7297.
19. R. F. Heck, Org. React., 1982, 27, 345; R. F. Heck, Palladium Reagents in Organic Syntheses, Academic
Press, London, 1985; J. T. Link, Org. React., 2002, 60, 157.
20. T. Jeffery, Tetrahedron Lett., 1985, 26, 2667.
21. J. W. Raggon and W. M. Snyder, Org. Process Res. Dev., 2002, 6, 67.
22. H. P. Dang and G. Linstrumelle, Tetrahedron Lett., 1978, 191; D. Michelot, Synthesis, 1983, 130.
23. M. Nakanishi and M. Mori, Angew. Chem., Int. Ed., 2002, 41, 1934.
24. M. Lautens, J.-F. Paquin and S. Piguel, J. Org. Chem., 2002, 67, 3972.
25. L. F. Tietze and W.-R. Krahnert, Chem. Eur. J., 2002, 8, 2116.
26. J. K. Stille, Angew. Chem., Int. Ed., 1986, 25, 508; V. Farina, V. Krishnamurthy and W. J. Scott, Org.
React., 1997, 50, 1.
27. J. Uenishi, R. Kawahama, Y. Shiga and O. Yonemitsu, Tetrahedron Lett., 1996, 37, 6759.
28. W. J. Scott, G. T. Crisp and J. K. Stille, J. Am. Chem. Soc., 1984, 106, 4630.
29. J. E. Thompson, R. P. Walker, S. J. Wratten and D. J. Faulkner, Tetrahedron, 1982, 38, 1865.
30. L. C. Dias and L. G. de Oliveira, Org. Lett., 2001, 3, 3951.
31. J. T. Feutrill, M. J. Lilly and M. A. Rizzacasa, Org. Lett., 2002, 4, 525.
32. B. Clapham and A. J. Sutherland, J. Org. Chem., 2001, 66, 9033.
33. J. Thibonnet, M. Abarbri, J.-L. Parrain and A. Duchêne, J. Org. Chem., 2002, 67, 3941.

18 References 337
34. K. A. Parker and T. L. Mindt, Org. Lett., 2001, 3, 3875.
35. B. Vaz, R. Alvarez and A. R. de Lera, J. Org. Chem., 2002, 67, 5040.
36. S. P. Govek and L. E. Overman, J. Am. Chem. Soc., 2001, 123, 9468.
37. N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
38. H. C. Brown and S. K. Gupta, J. Am. Chem. Soc., 1972, 94, 4370.
39. N. Miyaura and A. Suzuki, Org. Synth., 1989, 68, 130.
40. I. E. Markó, F. Murphy and S. Dolan, Tetrahedron Lett., 1996, 37, 2507.
41. J. A. Soderquist and A. M. Rane, Tetrahedron Lett., 1993, 34, 5031.
42. G. Zweifel and W. Lewis, J. Org. Chem., 1978, 43, 2739.
43. Y. L. Janin, E. Roulland, A. Beurdeley-Thomas, D. Decaudin, C. Monneret and M.-F. Poupon, J. Chem.
Soc., Perkin Trans. 1, 2002, 529.
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46. Y. K. Reddy and J. R. Falck, Org. Lett., 2002, 4, 969.
47. S. R. Chemler, D. Trauner and S. J. Danishefsky, Angew. Chem., Int. Ed., 2001, 40, 4544.
48. P. N. Collier, A. D. Campbell, I. Patel, T. M. Raynham and R. J. K. Taylor, J. Org. Chem., 2002, 67,
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50. A. K. Mandal, Org. Lett., 2002, 4, 2043.

19
Allyl Alcohols: Allyl Cation Equivalents
(and More)
This chapter analyses the problems associated with allylic electrophiles and the unique
usefulness of allylic alcohols in their solution. The preparation and other chemistry
of allylic alcohols is here too.
PART I – INTRODUCTION
The Problem of the [1,3]-Shift
Nucleophilic attack on unsymmetrical allylic halides
Rearrangement and stability of allylic alcohols
PART II – PREPARATION OF ALLYLIC ALCOHOLS
Traditional Methods
Reduction of enones prepared by the aldol or Wittig reactions
Elimination on or reduction of iodolactonisation products
Addition of vinyl metals to aldehydes and ketones
Reduction of acetylenic alcohols made by addition of alkynes to aldehydes or ketones
Wittig examples
Allylic Alcohols by [2,3] Sigmatropic Shifts
Sulfoxides and sulfonium ylids: Regio- and stereochemical control
[2,3] Sigmatropic shifts in the allylation of ketones
Recent applications
PART III – REACTIONS OF ALLYLIC ALCOHOLS
[2,3] Sigmatropic Rearrangements
Reminder of the conversion to allylic sulfoxides
The [2,3] Wittig rearrangement
Reactions with Electrophiles
The Simmons-Smith cyclopropanation reaction
Stereochemically controlled epoxidations
Regio- and Stereocontrolled Reactions with Nucleophiles
Claisen-Cope rearrangements
Stereochemistry in the Claisen-Cope rearrangement
The Claisen-Ireland rearrangement
Pd-catalysed reactions of allylic alcohols
Pd-allyl acetate complexes
Stereochemistry of Pd-allyl cation complexes
Pd and monoepoxides of dienes
The control of remote chirality
Recent developments
Summary
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

340 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
PART I – INTRODUCTION
The Problem of the [1,3]-Shift
Nucleophilic attack on unsymmetrical allylic halides
At the start of chapter 12 (Allyl Anions) we discussed briefl y the general problem that faces any
use of allylic derivatives in synthesis. Many of them are not stable with respect to the [1,3]-shift
or allylic rearrangement. The bromides 1 and 3 are in equilibrium under most conditions: in polar
solvents they equilibrate via the allylic cation 2 to give mostly the compound 3 with the more
highly substituted alkene. 1
Br
This does not prevent the use of allylic bromides in synthesis. As nucleophiles may attack an
allylic derivative from either end of the allylic system, there is a further opportunity to get the
product with the more highly substituted double bond. You will probably know that prenylation
of nucleophiles, particularly enolates, gives overwhelmingly the prenyl derivative 5. The primary
allylic halide 6 (prenyl bromide) reacts by the S N2 reaction while the tertiary halide 4 reacts by
the S N2’ reaction.
Br
1; 13-20% 3; 80-87%
2
Nu
This chapter is about ways to get greater control over processes like these. It concerns ways
to make allylic derivatives react at the more substituted end to give the less stable product, ways
to control allylic substitution when both possible products have equal numbers of substituents on
the alkene and ways to control the stereochemistry. The key reagents in this chapter are allylic
alcohols. Though these do equilibrate in acid solution, under other conditions they are stable and
they are easily prepared regio- and stereospecifi cally by many ways. Strictly ‘allyl’ refers to the
prop-2-enyl group CH 2=CH-CH 2- though nowadays it usually means any group next to an alkene
but not directly attached to it. We shall use ‘allylic’ rather than ‘allyl’ for that meaning though the
distinction is on the way out.
Rearrangement and stability of allylic alcohols
The mixture of 1 and 3 can be made by treatment of either alcohol 7 or 8 with HBr. Under
these strongly acidic conditions equilibration between the alcohols as well as between the allylic
bromides occurs through the allylic cation 2.
1; 13-20%
+3; 80-87%
SN2' SN2
4 5 6
Nu
OH
HBr H H
7
2
8
OH
Br
HBr
Nu
Br
1; 13-20%
+3; 80-87%

This can be useful when oxidation of an equilibrating alcohol is carried out in acidic conditions,
say with a Cr(VI) reagent. The fi rst formed alcohol 10 cannot be oxidised but the rearranged
alcohol 11 can. This rearranged alcohol might be formed via an allylic cation or it might be by
[3,3]-sigmatropic rearrangement of the chromate esters 13.
O R OH R
9
RMgX
or RLi
Under other conditions such as base or ionic solvents or radical formation, 1,3-shifts do not occur
either with the alcohols themselves nor with simple derivatives like carboxylate esters. They are therefore
ideal for use as specifi c allylic electrophiles except for the fact that OH – is a terrible leaving group and
simple nucleophilic displacements on allylic alcohols are unknown. Special chemistry will be needed.
PART II – PREPARATION OF ALLYLIC ALCOHOLS
Traditional Methods
OH
O
10 11 12 13
Reduction of enones prepared by the aldol or Wittig reactions
Types of reactions we meet elsewhere in the book include the reduction of α,β-unsaturated
carbonyl compounds prepared by the aldol or Wittig reactions. The cyclic enone 14, prepared by
a Robinson annelation is reduced regio- and stereo-selectively by LiAlH 4 to the allylic alcohol 2
15. The reduction of acetylenic alcohols 16, prepared by addition of metallo-alkynes to aldehydes,
also with LiAlH 4 is E-selective (chapter 15) giving the allylic alcohol 3 E-17.
Elimination on or reduction of iodolactonisation product
H
Slightly more unusual is the elimination and hydrolysis or reduction of iodolactonisation products
20 (chapter 17). Elimination replaces the alkene but in a different position 20 and cleavage of the
lactone bridge 4 by methanolysis gives 21 or by reduction gives 22. As we get on to the reactions of
allyl alcohols you will see how these and other methods are used to make particular compounds.
Cr(VI)
R
R O
OH
Cr O
O
O
LiAlH4 OH
R2 R
OH
1
LiAlH4 R2 R
OH
1
–20 ˚C
14 15 16 E-17
CO 2H
I 2
NaHCO 3
O
19 Traditional Methods 341
O
DBU
O
I
18 19 20 21
22
O
HO CO 2Me HO
OH

342 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
Addition of vinyl metals to aldehydes and ketones
Addition of vinyl metals to aldehydes and ketones (chapter 16) also allows control over
stereochemistry. The stereospecifi c vinyl anion equivalent 24 is one we made in chapter 16 by the
Shapiro reaction. We repeat this scheme because it uses prenylation of a hydrazone aza-enolate to
make the starting material for the vinyl-tin compound 25.
N
Conversion of the vinyl tin 25 to the vinyl lithium 26 and coupling with the keto-epoxide 27
gives one diastereoisomer of the allylic alcohol 28 (17:1), used in a synthesis of ovalicin. 5 Notice
that the vinyl-lithium 26 is one geometrical isomer and that it attacks the carbonyl group of 27 on
the same face as the oxygen atom of the epoxide. This looks like chelation control.
Reduction of acetylenic alcohols made by addition of alkynes to aldehydes or ketones
Conjugate addition of the complete allylic alcohol fragment is possible with the mixed cuprate
reagents 33 prepared by asymmetric reduction (chapter 26) of acetylenic ketones 29 to give the
alcohols 30, protection as a silyl ether 31 and hydroboration-iodination. Lithiation and reaction
with hexynyl copper (I) gives the mixed cuprate 33 from which the less stable anion is transferred
selectively to an enone. 3 This approach has been widely used in the synthesis of prostaglandins.
I
O
25
Wittig examples
NHTr N
NTr
1. 2 x BuLi 1. s-BuLi
2.
Br
23 24
BuLi
Li
2. Bu
OTBDMS
32
R
+
Li
2. Bu 3SnCl
O O OH
O
OMe
OMe
26 27 28
Cu
Bu
Cu
SnBu 3
25; 90% yield
asymmetric
reduction
R
TBDMSCl
DMAP, DMF R
1. 9-BBN
OH
OTBDMS
2. I2, Me3NO 29 30 31
O
1. 2 x t-BuLi, Et 2O
Two simple examples of an E-selective Wittig reaction followed by reduction of the carbonyl group
giving allylic alcohols with full control over double bond geometry are given in chapter 15 and the
following section in that chapter on Z-selective Wittig variants shows how Wittig-style reactions
followed by reduction can be used to give Z-allylic alcohols. The methods used to make enones
R
OTBDMS
cyclohexenone
33 34
R
OTBDMS

in chapters 2-4 and summarised in chapters 5 and 6 are also methods to make allylic alcohols as
reduction with anionic reducing agents (e.g. NaBH 4 or LiAlH 4) is usually regioselective.
One special case with a non-stabilised Wittig reaction is the remarkably Z-selective reaction 6 with
THP-protected α-hydroxyketones 37. These are among the most Z-selective Wittig reactions known and
it is the infl uence of the α-OTHP group that is decisive. The product 38 is of course a protected allylic
alcohol. In chapter 33 we shall see how to make these α-hydroxyketones stereo- and regiospecifi cally.
Ph3P (Me3Si) 2NK Ph3P +
OTHP
Me
Me
35 36 37
All these methods give allylic alcohols regiospecifi cally, that is with the OH group and the
alkene in predictable positions. They are often stereoselective for the alkene and may also be
enantioselective as we shall see later. Provided the allylic alcohol is kept away from strong acid,
its structure is more secure than that of most allylic compounds.
Allylic Alcohols by [2,3] Sigmatropic Shifts
Sulfoxide and sulfonium ylids: Regio- and stereochemical control
O
O O
38; 95% yield, >200:1 Z:E
We shall be using [2,3] sigmatropic shifts in the reactions of allylic alcohols so this section is an
introduction to that as well as describing perhaps the most tightly controlled method for making
allylic alcohols. Allylic sulfi des 40 are easily oxidised chemoselectively with reagents such as
sodium periodate to the corresponding sulfoxides 41. More powerful oxidants tend to form the
sulfone 42.
Br R
PhSH
NaOH
PhS R
NaIO4 O
PhS R
O O
S
Ph
R
39 40 41 42
These allylic sulfoxides 41 are in equilibrium with a sulfenate ester 43 by a [2,3]-sigmatropic
rearrangement 41a. It is not usually possible to detect the sulfenate ester by NMR so there must
be less than about 3% of it, but it can be trapped by various nucleophiles that like to attack
sulfur. These ‘thiophiles’ include secondary amines, thiolate anions and, most important, phosphite
esters. The reaction is carried out in a protic solvent (usually the alcohol already present in the
phosphite ester) and a rearranged allylic alcohol 45 is formed.
Ph
O
S
41a
R
19 Allylic Alcohols by [2,3] Sigmatropic Shifts 343
[2,3]
(MeO)3P
Ph O R O R
S
Since the original preparation of the allylic sulfi de involved nucleophilic attack on an allylic
halide 39, the more stable allylic sulfi de - the one with the more highly substituted alkene 40 - is
formed and this is inevitably and usefully transformed into the less stable allylic alcohol 45. The
reaction is more useful still because the intermediate allylic sulfoxide 41 may be alkylated before
rearrangement and this gives the unsymmetrically substituted E-allylic alcohols 47. These reactions
MeOH
HO R
43 44
45

344 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
are exceptionally E-selective and we shall delay an explanation of this stereoselectivity until we have
discussed the use of such allylic alcohols in [3,3] sigmatropic rearrangements later in the chapter.
An example is the synthesis of nuciferal by David Evans and group. 7 Symmetrical allylic halides
like ‘methallyl’ bromide 48 can give only one product on reaction with nucleophiles. Alkylation
of the sulfoxide with a large alkyl iodide gives the allylic sulfoxide 49. The [2,3] sigmatropic
rearrangement gives a single geometrical isomer of the primary allylic alcohol 50: the corresponding
aldehyde, formed in 99% yield on oxidation of 50 with MnO 2 is the natural product nuciferal. Both
regio- and stereochemical control are complete.
Br
48
1. PhSH, NaOH
2. NaIO4 3. BuLi
4. RI
Ph
S
O
(MeO)3P
These [2,3] sigmatropic rearrangements on sulfur compounds are not restricted to sulfoxides as they
occur equally with sulfonium ylids. A good example showing both is the synthesis of yomogi alcohol
51, an irregular monoterpene. Reversing the [2,3] sulfoxide rearrangement gives an allylic sulfi de 52
that we should like to make by alkylation of the simple prenyl sulfi de 54 with the allylic halide 53. However,
we know that won’t work: the alkylation will occur at the less hindered end of the allylic halide.
OH
51; yomogi alcohol
The solution is surprising. Evans deliberately made the wrong doubly allylic sulfi de 55 and
rearranged it twice to give yomogi alcohol. At fi rst the sulfur atom must be alkylated (therefore adding
a phenyl group is not suitable and a methyl group is used instead). Then the fi rst [2,3] rearrangement
(on the sulfonium ylid) 56 gives the right skeleton 57 and the second (on the sulfoxide 58) gives the
target molecule. In this reaction, the older thiophile EtNH 2 was used. 8
Br
PhS R1 O
PhS R1 O
R2 (MeO)3P
MeOH
R2 R1 1. BuLi
2. R
OH
41 46 47
2Br Na 2S
6; prenyl bromide 55
MeOH
49 50
[2,3] ?
+
Br
PhS
PhS
52 53 54
NaIO4
SMe
Me
S
O
57 58
S
1. MeI
2. BuLi
EtNH2
MeOH
S
Me
56; sulfonium ylid
51; 69% yield
[2,3]
OH
OH

[2,3] Sigmatropic shifts in the allylation of ketones
The allylation of ketones is a simple reaction. Most of the specifi c enol equivalents described in
chapters 2-6 react well with allylic halides. Disconnection of the γ,δ-unsaturated ketone 59 to the
enolate 61 and the allylic halide 60 is trivial and the reaction of, say, an enamine will occur at the
less hindered primary centre to give 59. However, supposing the target molecule is the isomeric
ketone 63. The same disconnection gives the isomeric allylic bromide 62 which will almost
certainly give the alternative product 59 by reaction at the less hindered end of the alkene.
R 1
O
One solution is a [2,3] sigmatropic rearrangement of a sulfonium ylid. A stable allylic thiol
reacts cleanly with an α-haloketone 64 to give a sulfi de and hence the sulfonium salt after
ethylation. Only a weak base is need to make the ylid 65 as this is also an enolate. Notice the
regioselectivity here: the alternative ylid would also be stabilised but only by an alkene. The [2,3]
shift joins the allylic fragment to the enolate of the ketone and at the same time turns it inside out.
This automatically produces the more diffi cult product 63 after desulfurisation with Raney nickel.
We shall see alternative solutions to this problem later in the chapter. 9
Ph
O
Recent applications
Br
O R 2
+
R1 R2 R1 R2 +
Br
59 60
61 62 63
1.
HS Ph
Ph
O
2. Et3O S
Br
Et
O
64 65 66
+ BF –
4
3. K2CO3, EtOH
The preparation of the allylic alcohol 68 by Horner-Wadsworth-Emmons reaction followed
by reduction illustrate how this method is compatible with varied functionality and
stereochemistry.
BnO
Me
N
O
67
19 Allylic Alcohols by [2,3] Sigmatropic Shifts 345
CHO
O
The diene alcohol derivative 68 is used to prepare the starting material 69 for an intramolecular
hetero-Diels-Alder reaction to give a new heterocyclic ring 70 that can be cleaved with phenyl
Grignard to release a sulfoxide 71 for the preparation of a new allylic alcohol 72. Notice that
the stereochemistry of the sulfoxide is shown and that there is complete control over 2D and 3D
stereochemistry. The allylic alcohol 72 was used in Weinreb’s synthesis of toxins 10 produced by
fresh water blue-green algae.
O
Ph
1. O
base
(EtO) 2P CO2Me 2. DIBAL
3. RCl, NaH
[2,3]
R 2
Ph
BnO
Me
SEt
N
O
68
Ph
O
Raney Ni
EtOH
OR
63

346 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
PART III – REACTIONS OF ALLYLIC ALCOHOLS
[2,3] Sigmatropic Rearrangements
Reminder of the conversion to allylic sulfoxides
You saw in the last section that the preparation of allylic sulfi des by displacement of, say, a halide
from an allylic system is likely to give the more stable allylic sulfi de whichever allylic halide is
used and that the corresponding allylic sulfoxides are made by oxidation of the sulfi de. The same
is true of phosphorus compounds 73 used in chapter 15 to make dienes of fi xed confi guration. If
R = OR, 73 is an allylic phosphonate for the Horner-Wadsworth-Emmons reaction but if R = Ph,
73 is a phosphine oxide for the Wittig-Horner reaction.
Br
R2P OMe R1 R2P R 2P OMe
R1 O
Br
39 73 74
The specifi c preparation of either phosphine oxide 73 or 80 can easily be carried out from the
appropriate allylic alcohol. The reaction is like the one we saw for the preparation of allylic alcohols
from allylic sulfoxides but the [2,3]-sigmatropic rearrangements 76 and 78 run only in this direction
with phosphorus. 11 It is also the preferred direction with sulfur. Since allylic alcohols 75 and 78 are
stable to the allylic rearrangement, each alcohol gives specifi cally one allylic phosphine oxide 73 or
80 or allylic sulfoxide 41 or 77. This is the theme for most of the rest of the chapter.
R 1
68
PhMgBr
O
41
R 1
77
O
SPh
SPh
BnO
Me
BnO
Me
BnO
BnO
1. PhSCl
pyridine
2. heat
1. PhSCl
pyridine
2. heat
N
H H
R 1
OH
N
O O OR
O
BnO
69 70
OH
R 1
Ph 2PCl
R2 R1 pyridine
75 76 73
78
S
Ph 2PCl
pyridine
(MeO) 3P
BnO
Me
O
BnO
O PPh 2
PPh 2
H H
N
[2,3]
[2,3]
N
S
O
H H
N NH
PhS
MeOH
Me
N NH
O
71
O OR
BnO
O
72
R 1
OH
OR
O
R 1
OR
PPh 2
R1 PPh2 79 80
O

The [2,3] Wittig rearrangement
Ethers of allylic alcohols also undergo a [2,3] sigmatropic rearrangement. The driving force is
the conversion of an unstable C-Li compound into a stable O-Li compound. These intermediates
are often described as anions and in some cases may be so - it is certainly easier to draw the
mechanism of the [2,3] shift that way. The commonest ethers used are benzylic 81 and 85 so that
the proton to be removed has some acidity. Again a specifi c product 84 or 88 is formed from each
isomer of the allylic alcohol 75 or 78. The original allylic alcohols are transformed into homoallylic
alcohols. This rearrangement 82 and 86 is often called the [2,3]-Wittig rearrangement. 12
R
OH
OH
BnCl
NaH R
R
R
R
75 81
82
83 84
BnCl
O
O
Ph
Ph
BuLi
BuLi
R
NaH
R
78 85
86
O
O
There is good, if somewhat substrate-dependent, stereoselectivity when there is a substituent at
the end of the alkene in the starting material. The E-ether 90 gives almost exclusively (98%) the
stereochemistry shown in the product. 13 The transition state has a ’half-chair’ conformation. 14
In this form the reaction is limited as an anion-directing substituent such as phenyl is needed
and this group is incorporated into the structure. A more general approach is to provide an R 3Sn
group 93 that can be replaced by lithium even if there is no other substituent at all on the carbon
atom. This variation is often known as the Wittig-Still rearrangement. 15
75
R
O
Ph
I SnBu 3
BuLi
O
Ph
[2,3]
This approach has been applied to the synthesis of peptide isosteres, compounds that have the
same shape as peptides but lack the amide link. In this case 99 it is replaced by an E-alkene. The
starting material 97 is made from the natural amino acid leucine and the Wittig-Still [2,3] shift on
98 rearranges this into an E-alkene fl anked by two chiral centres 99.
Ph
Ph
R
[2,3]
[2,3]
O Ph
O
O
Ph
Ph
HO
HO
R
87 88
R
R
R
89 90 91
92
R
19 [2,3] Sigmatropic Rearrangements 347
HO Ph
LiO
O SnBu3BuLi O Li [2,3]
R
R
R
93 94 95 96
Ph
R
Ph
OH

348 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
Me
BocN
OH
The migrating group passes suprafacially across the Z-alkene but appears to invert because the
skeleton must be redrawn to show the E-alkene. This is an elegant way of transforming relatively
easy to control 1,2 stereochemistry into more remote 1,4 stereochemistry. 16 There is another example
of the conversion of 1,2- into 1,4-stereochemistry at the end of this chapter. Not everyone is happy
with stoichiometric toxic tin, but an alternative is available in the silicon compounds such as 101
Alkylation of the allylic alcohol 100 with the silyl alkyl trifl ate gives an ether 101 from which
the Me 3Si group can be removed with BuLi. The new substituent (CH 2OH) in 103 must be axial
as it has to overlap with the p-orbitals of the alkene as it moves. 17
Reactions with Electrophiles
This section is mainly about the role of the OH group in directing reagents (mostly electrophiles)
to one face or other of the alkene. This does not strictly fi t with the title of the chapter but these
reactions are important and this seems to be the logical place for them.
The Simmons-Smith cyclopropanation reaction
In its most general form the Simmons Smith reaction 18 is the addition of a carbenoid to an alkene
to form a cyclopropane. The reagent is an organometallic compound made from a gem-dihalide
and zinc usually with catalysis from a more active metal such as copper or silver, and probably has
a structure such as ICH 2ZnI. It is best known with allylic alcohols as the OH group directs both the
regio- and stereochemical outcome. In the simple diene Z,Z-104, only the allylic alcohol forms a
three-membered ring even with an excess of the reagent and does so stereospecifi cally. 19
HO
KH
Bu3SnCH2I 18-crown-6
Z,Z-104
Me
BocN
CH 2I 2, Zn
cat Cu
O SnBu 3
When the OH group is on a chiral centre the faces of the alkene become diastereotopic and
the face syn to the OH group is preferred. These two diastereoisomers anti-106 and syn-108 show
clearly that this is chelation control and not mere steric hindrance as the cyclopropane ring is
formed on the same side as the OH group regardless of the position of the benzene ring. 20
HO
BuLi BocN OH
97 98 99
2.
Me 3Si
HO
100; natural
(R)-(+)-perilla alcohol
1. BuLi
OTf
Me 3Si
O
BuLi
Li
O
H H
105
Me
[2,3]
OH
101 102 103

Ph
Ph
CH 2I 2, Zn
Ph
Ph
cat Cu
cat Cu
H
H
OH
OH
OH
OH
anti-106 107 syn-108 109
The zinc atom probably coordinates to the OH group and delivers the CH 2 group in a mechanism
such as 111. It appears that the iodine atom is simultaneously transferred to the metal so that the
transition state is something like 112. At all events, the new ring is formed on the syn face to the
OH group 113. These diagrams have been stripped of the benzene rings for clarity.
The many recent publications affi rm the importance of this reaction in modern synthesis. Tanaka
and Takemoto’s synthesis of the marine metabolite halicholactone uses a sulfoxide route to the
allylic alcohol 115. Notice the suprafacial [2,3]-sigmatropic rearrangement and that the OH group
ends up in the middle of the diene. Attempted cyclopropanation of 115 gave a poor yield of a
mixture of products. 21
PivO
It was necessary to exchange protecting groups so that there was only one allylic alcohol 116
and to use a modifi cation of the Simmons-Smith reaction with Et 2Zn and CH 2I 2 to get a good yield
of one diastereoisomer of the cyclopropane 117.
PivO
Further transformations gave a precursor 118 for a ring-closing olefi n metathesis using the Grubbs
catalyst described in chapter 15. This gave the unsaturated nine-membered lactone required and
deprotection revealed halicholactone 119. The solution to the regioselectivity problem of cyclo-propanation
with three OH groups and three alkenes embedded in the skeleton of 119 is elegant.
Ph
Ph
CH2I 2, Zn
I I
CH2I2, Zn
I Zn
OH
I Zn
CH2 OH
H
cat Cu
OH
H
OH
110 111 112 113
Ph
S O
O O
OH
O
R
OTBDMS
(MeO)3P
MeOH
PivO
O O
CHCl2
CHCl2
114 115; 88% yield
O
OSEM
19 Reactions with Electrophiles 349
R
OTBDMS
Et 2Zn, CH 2I 2
–20 ˚C, CH 2Cl 2
PivO
OH
OH
Ph
OSEM
116 117; 69% yield
OSEM
R
1. Grubbs
catalyst
72% yield
OTBDMS 2. K2CO3
MeOH
O
118
61% yield O
119; R = n-C5H11 OH
R
Ph
OTBDMS
R
OTBDMS
OH
R

350 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
Stereochemically controlled epoxidations
Many epoxidising agents, notably mCPBA and t-BuOOH/VO(acac) 2, are capable of bonding to
the OH group of an allylic alcohol. Epoxidation then occurs more readily on allylic alcohols and
on the same side of the alkene as the OH groups, rather in the style of the Simmons-Smith reaction.
The stereochemical outcome is easiest to see in cyclic allylic alcohols. Thus the cyclohexenol 120
gives the syn epoxide 121 cleanly with mCPBA via the conformation 122 in which the axial OH
delivers the reagent to the same face of the alkene.
A good illustration of many aspects of this chemistry comes from Koreeda’s synthesis of
shikimic acid. 22 The silyl diene 123 adds cleanly to methyl acrylate to give essentially one isomer
of the adduct 124 (9:1). Dihydroxylation with catalytic OsO 4 and the stoichiometric oxidant NMO
(N-methylmorpholine-N-oxide) occurs on the opposite face to all three substituents. The alkene
124 is an allylic acetate but this group has no attractive interaction with the reagent.
OAc
+
SiMe3 123
CO2Me
OAc
CO2Me
SiMe3
124; 72% yield
cat OsO 4
A Peterson elimination, necessarily in acid solution as the OH and SiMe 3 groups are anti
(see chapter 15) gives a new alkene 126 that is allylic to the remaining OH group. Now epoxidation
with mCPBA occurs on the face of the alkene syn to the OH group to give 127.
125
TsOH
HO
OAc
CO 2Me
CH 2Cl 2
HO
An example showing both regio- and stereoselectivity occurs in Ogawa’s synthesis of pipoxide. 23
Epoxidation of the diene 128, with no free OH groups, gave a mixture of epoxides in low yield
with very poor regio- and stereoselectivity.
OBz
128
OAc
OAc
OH
mCPBA
O
H
120 121
mCPBA
NMMO
OAc
HO
HO
OAc
CO 2Me
SiMe3
125; 96% yield
CO 2Me
O
N
Me O
NMO
O
OH
126; 98% yield 127; 91% yield shikimic acid
mCPBA
pH 8 buffer
O
OBz
OH
H
OAc
O
H
O
O H
O
OBz
OAc
+ +
HO
HO
OBz
CO 2H
OAc
OAc
O
OAc
O
OAc
129; 19% yield 130; 24% yield 131; 14% yield
Ar
122; possible
arrangement
of peracid and
allylic alcohol

By contrast, the diene 132 with one free OH group gave a single epoxide in excellent yield.
Epoxidation has occurred only at the allylic alcohol and only on the same side as the OH group
despite the crowded nature of the alkene. This product 133 is the plant metabolite pipoxide.
132
OBz
OH
OBz
mCPBA
pH 8 buffer
The stereoselectivity with non-cyclic allylic alcohols is more complicated. The molecules
tend to adopt a Houk conformation (chapter 21) with a hydrogen atom in the alkene plane
and the OH group above or below. If the reagent is guided in by bonding to the OH group,
syn epoxidation results. This is the case with allylic alcohols with a trisubstituted or a
cis-disubstituted alkene 134 since there is then a group in the plane of the alkene favouring
the Houk conformation 134b since whichever group on the chiral centre sits in the alkene
plane must eclipse the cis substituent. 24
Me
=
OH
Me
Me OH Me H
134a 134b
However, trans-disubstituted alkenes are in general not epoxidised so selectively. In the simplest
case with two methyl groups 136, the selectivity is about 2:1 syn:anti as the three conformations
136a, 136b, and 136c are about equally favourable since whichever group on the chiral centre sits
in the alkene plane needs eclipse only the cis hydrogen atom.
Me
OH
136
Me
OH
Me
mCPBA
Me
Even mono-substituted allylic alcohols 139 that generally give very poor diastereoselectivity
can give good results if the steric interactions are boosted by a Me 3Si group 143. The Me 3Si
group pushes the Ph and OH groups out of the plane and favours the Houk conformation so that
stereoselectivity is complete 25 142. The Me 3Si group can be removed with retention of confi guration
by fl uoride ion. These more complex cases really fi t into chapter 21 where you will see other
examples of the Houk conformation in action. 26
Ph
19 Reactions with Electrophiles 351
O
mCPBA
OH
H
OBz
OH
OBz
O
133
87% yield
(+)-pipoxide
OH
Me
Me H
135; >95:5 syn:anti
Me
OH
Me
H H
O Me
OH
Me
H H
O
+
137 64:36 138
H H
H Me
H OH
136a 136b 136c
O
O
O
Ph
Ph Bu4NF
Ph
SiMe3
mCPBA mCPBA
+
Me
H
Me
SiMe3
OH
OH
OH
OH
OH
139 140 35:65 141 142; 100% yield 143
Ph

352 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
Fortunately the synthesis of complex molecules is likely to involve the epoxidation of more
rather than less crowded allylic alcohols. An outstanding recent example is Isobe’s synthesis 27
of 11-deoxytetrodotoxin 146, one of the metabolites of the notoriously poisonous Japanese fugu
(puffer fi sh). Epoxidation of the allylic alcohol 144 gave an almost quantitative yield of one
regio- and stereo-isomer of the epoxide 145. The mCPBA reagent was buffered with phosphate
but that explains only the survival of the acetal: the lack of epoxidation at the other alkene is
remarkable as it has an allylic relationship with the rather acidic NH group.
Regio- and Stereocontrolled Reactions with Nucleophiles
We now return (at last!) to the original theme of the chapter: how can we add allylic electrophiles
to other molecules with control over all the aspects of allylic systems we have been considering?
We need to control:
•
•
•
H
O
O
HN COCCl3
Which end of the allylic system is attacked (regioselectivity)
Which face of the allylic system is attacked (stereoselectivity)
The geometry of the alkene in the product (stereoselectivity)
Among the methods available for these reactions, two have gained prominence: the use of
Claisen-style [3,3]-sigmatropic rearrangements for the selective allylation of enolates and the
more general reactions of palladium allyl cation complexes.
Claisen-Cope rearrangements
The Cope rearrangement is a [3,3]-sigmatropic reaction of a 1,5-diene to give another 1,5-diene.
The reaction may be degenerate or there may be some reason for the reaction to go one way or
the other such as relief of strain or development of conjugation. The Claisen version of the Cope
rearrangement has a built-in direction fi nder. An oxygen atom in the carbon chain becomes a
carbonyl group in the product and a CO bond is signifi cantly more stable than a CC bond. 28
The Cope
Rearrangement:
mCPBA
Na 2HPO 4
CH2Cl2
[3,3]
H
O
The Claisen-Cope
Rearrangement:
H
N
HN
HO
O
O
OH
O [3,3]
O
Corey 29 used a Cope rearrangement 147 in one of his syntheses of gibberellic acid. This reaction
is driven both by the release of strain (the fused bicyclic product 148 is less strained than the
bridged bicyclic starting material) and by development of conjugation. But the Cope is diffi cult to
use and there is no general synthesis of appropriate starting materials.
O
HN COCCl3
OH
O
OH
OH
144 145; 96% yield 146; 11-deoxytetrodotoxin
H2N
HO
O

6
R
5
4
CO2Me 3
[3,3]
CO 2Me
1
2 OSiMe3 R
OSiMe3 R
147 148 148
The Claisen-Cope rearrangement is much easier to use. The starting material is an allyl vinyl
ether 149 that can be made from an allylic alcohol. The product looks as though it might have been
made by the allylation of an enol(ate) and the same disconnection 150 does for both. In this simple
case, the product could equally well be made from an enamine of acetaldehyde and allyl bromide
but you should by now realise that more complicated examples need a lot of control.
OH OR H O [3,3] O
+
The starting materials are made from the allylic alcohol 75 by exchange with either an acetal
151 or a vinyl ether. Though acid catalysis is needed for this reaction, it must not be strong enough
to cause isomerisation of the allylic alcohol so carboxylic acids such as propionic (EtCO 2H) are
strong enough. Derivatives of aldehydes 152, ketones, acids, and amides 155 can all be used. Here
are examples of an aldehyde 153 and an amide 156.
R
R
OH
75
OH
75
19 Regio- and Stereocontrolled Reactions with Nucleophiles 353
OMe
151
149 150
MeO EtCO 2H
Regiocontrol is easy to explain: the allyl part of the molecule is turned inside out (or back to
front if you prefer) with the new C–C bond being formed at the other end of the alkene from the
OH group 158. Since the easier allylic alcohol to make is the one with the more highly substituted
alkene (e.g. geraniol 157) it is actually easier to make the more ‘diffi cult’ allylated product. 30
157; geraniol
+
+
MeO
Me2N OH
154
MeO
OMe
dry HCl
EtCO 2H
R
The stereochemistry of the alkene needs a little more explanation. The transition state for the
reaction is a six-membered ring and it prefers a chair-like conformation with the substituent R in
an equatorial position 161. This gives an E alkene in the product and these reactions, like the [2,3]
158
R
R
O
O
O
=
152
NMe2 155
188 ˚C
90 minutes
O
heat
heat
H
R
R
Br
O
CO 2Me
OSiMe3
use enamine
OHC
153
156
NMe2
159; 70% yield
CHO

354 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
shifts we have already seen, are very E-selective. The heavy bonds in the transition state 161 show
the trans arrangement of the alkene that is being formed.
R
O
An example of the formation of an ester of an E-4,5-alkenoic acid 164 comes in a synthesis of
chrysanthemic acid by Ficini and her group. 31 Reduction gives the allylic alcohol 163 and [3,3]
Claisen rearrangement with triethyl ortho-acetate gives the product 164 in one step.
Stereochemistry in the Claisen-Cope rearrangement
Control over the geometry of the allylic ether portion of the starting material is easy - just use the
appropriate allylic alcohol. Control over the vinyl ether is more diffi cult as that alkene is created
in the exchange reaction. If the vinyl ether is cyclic, the problem disappears. The allyl vinyl ether
165, made from cyclopentanone and the allylic alcohol but-2-en-1-ol 8 rearranges with catalysis by
2,6-dimethylphenol into one diastereoisomer of the allylated product 32 168. The stereoselectivity
is easily predicted by the chair transition state 167.
O
R O
R O
R
152 160 161 153
120 ˚C
NaBH 4
O
MeC(OEt) 3
If a Pd(II) catalyst is used instead the other diastereoisomer 170 is formed. Presumably Pd coordinates
to both alkenes and holds the molecule in a boat conformation 169 during the reaction. In both cases
the more diffi cult regiochemistry is achieved with the bonus of stereochemical control.
The easiest way to fi nd the Claisen-Cope disconnection is to reverse the reaction. First you
must recognise that this is worth doing and the simplest clue is to look for a piece of skeleton
with two terminal π-bonds (alkene or carbonyl), the ends being 1,6-related. Here is a diffi cult
example that makes an eight-membered ring 171 and also illustrates a different way to make the
enol ether. 33 Reversing the [3,3] looks awkward 173a, but redrawing the structure 173 makes it
look much better.
H
O
ArOH
Me
Me
H
Me
H
165 166 167 168
Me
Pd
O
H H
O
room
temperature
[3,3]
H
O
PdCl2(MeCN) 2
Me
H
165 169 170
OHC
CO2Et O
OH
H
162 163; 100% yield 164; 70% yield
H
O

3 O
1
O
2
O OR
O O OR
O
O OR
O
4
5
6
recognise
1,6-link
reverse
[3,3]
=
171 172 173a 173
This particular enol ether is also an acetal (a ketene acetal) so we should be able to make it from
the diol 174. This has 1,2- and 1,3-diO relationships and we much prefer to disconnect the 1,3 as
we can then use some sort of aldol reaction.
O
O
173
OR
1,1-diX HO
FGI
OR
HO
There are also stereochemical considerations here and Holmes used the Evans asymmetric
aldol reaction (chapter 27) to make the starting material 174; RBn. The formation of any allyl
vinyl ether reagent involves no change in the stereochemistry of the allyl alcohol - this is acetal
exchange at the vinyl ether or acetal centre. The enol ether was added in masked form as a selenium
compound 175 (chapter 32) as selenoxides eliminate at room temperature. The stereochemistry is
developed directly from that in 177 as it transforms during the [3,3] shift.
The Claisen-Ireland rearrangement
174
One special application comes when silyl enol ethers of allylic esters provide the starting
material: this is known as the Claisen-Ireland reaction. Esters normally form E-enolates 181
with LDA at low temperature. Because the E/Z nomenclature depends on the hierarchy of the
substituents it is particularly ridiculous when applied to enol derivatives of esters. A lithium
enolate (Li C) would have the opposite stereochemical label from a silyl enol ether (Si C)
so a uniform scheme is adopted whereby the metal – O bond always has priority over the other.
The mechanism 180 may remind you of the reasons for this - they are discussed in more detail
in chapter 4.
HO
HO2C 1
3 aldol
2 OR
O
HO 2C
PhSe OEt HO
cat. TsOH
PhSe O
NaIO4 OEt HO
OBn
O
OBn
NaHCO3 MeOH, H2O 175
174; R=Bn 176; 70% yield
O
PhSe
19 Regio- and Stereocontrolled Reactions with Nucleophiles 355
O
OBn
O
O
177 178
O
OBn
[3,3]
O
O
179; 73% yield
OBn
OR
OR

356 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
This is true also of allylic esters 182 so that the geometry of both alkenes involved in the
Claisen-Cope rearrangement can be controlled if the lithium enolate is trapped by silylation to
give 183. Drawing the rearrangement in the chair conformation 183a → 184 gives a predictable
diastereoisomer of the product 185.
Ireland also discovered a remarkable way to form the Z-enolate. 34 All that was necessary was to
add HMPA (HexaMethylPhosphorAmide 189) to the solvent in making the lithium enolate. This
excellent (though also dangerously carcinogenic) ligand for Li reverses the stereochemistry to give
the more stable Z-silyl enol ether 186 and hence the opposite stereochemistry of the product 188.
182
1. LDA, HMPA,
THF, –78 ˚C
2. Me 3SiCl
R 1
R 2
OSiMe3 [3,3]
O
R 2
H
O
H
R1 OSiMe3 H2O
186 187 188
CO 2H
Most of the complex polyether antibiotics made using this reaction have actually used cyclic allylic
alcohols and with them a boat-like conformation is preferred in the Claisen-Ireland rearrangement.
A simple example is the dihydrofuran 190, prepared as a single enantiomer from a sugar (in chapter
23 we shall call this a ‘chiral pool’ strategy). Acylation and E-selective silyl enol ether formation 191
followed by Claisen-Ireland rearrangement gives one diastereoisomer of the product 35 192.
O
R 1
O
OH
R
O
OMOM
O R
1. EtCOCl
2. LDA, THF
–78 ˚C
3. Me3SiCl
LDA
– 78 ˚C
THF
R2N
H
OSiMe 3
O
Li
O
R
180
OMOM
1. room
temperature
2. CH 2N 2
O
190 191 192
The observed stereochemistry requires the enol ether to be transferred suprafacially across
the top face of the fi ve-membered ring 193 (this fi xes the stereochemistry at the new centre on
O R
Li
O
R
R
181; 'E'-Li-enolate
O
R2 O
H
R2 H OSiMe3 R1 R
H2O
1
OSiMe3 O
R2 CO2H R1 R2 O
H
R1 R2 OSiMe3 182
1. LDA, THF
– 78 ˚C
2. Me3SiCl
183 183a
[3,3]
184 185
R 2
MeO 2C
O
R 1
H
O
Me2N Me2N
Me2N P O
189
HMPA
OMOM

the ring) with the bulk of the side chain away from the ring in a boat-like arrangement. The
stereochemistry of the centre on the side chain is determined by the geometry of the enolate: this
E-enol ether has the methyl group over the heterocyclic ring 194.
Me3SiO Me3SiO
191
H O
OMOM
H
H
O
Me
OMOM 192
O
O
193 194
This result in particular should warn you that the choice between a chair- and boat-like transition
state is narrow. In general open-chain compounds prefer the chair and cyclic compounds the boat but do
not rely on it! In spite of this apparent disadvantage the Ireland version of the Claisen rearrangement is
one of the most widely used ways to set up complicated molecules. Ireland himself has used it to make
a catalogue of polyether antibiotics with the monensin synthesis being perhaps the most remarkable.
These syntheses are beyond the scope of this book but are worth reading. 36
When both alkenes (allyl and vinyl ether) are inside a ring the stereochemical problems are
much simplifi ed. The reaction inevitably leads to ring contraction and a simple example is Funk’s
synthesis 37 of chrysanthemic acid 197 from the seven-membered lactone 195. The silyl enol ether
196 rearranges to cis-chrysanthemic acid in very high yield. A chair transition state is impossible
in this restricted molecule.
O
195
O
1. LDA
2. t-BuMe2SiCl
O
196; 97% yield
1. 65 ˚C
OTBDMS 2. HF, MeCN
CO2H
197; 94% yield
Knight’s synthesis of ()-α-kainic acid provides a heterocyclic example. 38 The starting material
for the Claisen rearrangement is made from natural aspartic acid coupled to an allylic chloride
198 with a protected allylic alcohol 200 also present. Deprotection and lactonisation gives the
nine-membered nitrogen-containing lactone 201.
OTHP
Cl
198
+
19 Regio- and Stereocontrolled Reactions with Nucleophiles 357
HN
CO2Et
CO 2H
199
OTIPS
OTHP
CO2H
1. H , MeOH
O
2.
N
EtO2C OTIPS N
Me
Cl
N
EtO2C OTIPS
200 201
Formation and trapping of the lithium enolate gave only the E silyl enol ether 202
(that is with a cis alkene in the ring). As this is a cyclic enol ether, a boat-like transition
state is expected and the formation of a single diastereoisomer of 203 confi rms that this is
true. Diagrams 204 and 205 should clarify the conformation of the molecule as it reacts, the
mechanism, and the stereochemistry of the product. The product was converted into kainic
acid 206 in a few steps.
O

358 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
Recent developments in this important reaction have helped to reveal the relationship between
2D and 3D stereochemistry. The synthesis of the phospholipase inhibitor cinatrin B 207 illustrates
a serious stereochemical problem. 39 Cinatrins have spiro-fused lactones. Each ring contains chiral
centres and the spiro C-atom is also chiral. It is very diffi cult to relate stereochemistry between such
orthogonal rings. The second lactone might be added by cyclisation onto an alkene such as 208 and
that could arise from allylation of an enolate 209. Clearly some protection will be needed.
The starting material 212 was chosen as it was available from natural arabinose and contains
enough functionality for the purpose. Esterifi cation with racemic alcohol 211 gave a mixture of esters
213. This does not seem to matter as that centre is destroyed in the Claisen-Ireland rearrangement giving
214 but this compound was formed as a 43:57 mixture of diastereoisomers.
BnO OBn BnO OBn
1. LDA, Me 3SiCl
THF, HMPA
HO OBn
MeO
O
212
CO2H MeO
O
O
213
O
R
–100 ˚C
2. NaOH
3. CH2N2 HO
O
CO2Me
214
R
Use of the enantiomerically pure alcohol 211 revealed a surprising stereospecifi city. One enantiomer
215 gave (mostly) the required diastereoisomer 216 and hence the iodolactone 217 having the right
stereochemistry at the spiro centre and at the lactone centre in the new ring. Removal of iodine,
selective oxidation and addition of a d 1 reagent gave ()-cinatrin B.
BnO
MeO
201
TBDMSO
Me
O
LDA
t-BuMe 2SiCl
–100 ˚C
HO HO CO2H
O
TIPSO
O
O
O
207; R = n-C9H19 (–)-cinatrin B
NCO2Et
OBn
1. LDA, Me 3SiCl
THF, HMPA
BnO OBn
O
–100 ˚C
O
O
215
R
2. NaOH
3. CH2N2 MeO
O
CO2Me
216
O
OTBDMS
CO2H
N
OTIPS
1. room
temperature
2. K2CO3 N
OTIPS
CO2Et
H2O, MeOH
CO2Et 202 203
TBDMSO
Me
TIPSO
H O H
204 205
R
HO HO CO2H
O
O CO2H
R
enolate
allylation
NCO2Et
HO HO CO2H
O
208 209
R
O CO2H
1. H2O NaOH
2. I2, NaHCO3 N CO2H
H
206; (–)-a-kainic acid
+
BnO OBn I
MeO
X
HO
R
O
O
217
CO 2H
R
O
210
211
R

The scope of the Claisen-Cope rearrangement is very great but you have been given enough
mechanistic and stereochemical detail to unravel all but the most diffi cult. The disconnection is
always simple - the reaction corresponds to an allylation of an enolate and, providing you remember
to turn the allylic system inside out, you will fi nd the starting materials. All that remains is to
identify which method to use and how to control the stereochemistry. Oh, and you also have to
make the starting materials!
Pd-catalysed reactions of allylic alcohols
In the last chapter we introduced the Heck reaction as a way to add nucleophiles to electrophilic
alkenes. The details of the mechanism are discussed there. The reaction also occurs with allylic
alcohols 218 and is a good way to make carbonyl compounds, particularly aldehydes, 219 as
the alternative conjugate addition of an organometallic compound to an enal often shows poor
regioselectivity (chapter 9).
Formation of the aryl palladium (II) complex ArPdI by oxidative insertion is followed by
π-complex formation and transfer of the aryl group from palladium to the alkene 221. Then
β-elimination 222 gives the enol 223 of the product. The other ligands on palladium are omitted.
Pd(0) 218
ArI ArPdI
The regioselectivity is not as good with allylic alcohols as it is with unsaturated carbonyl
compounds as there is only a steric preference for transfer of the aryl group to the end of the
alkene. Examples 224 and 226 show how this can be improved with extra substitution. 40
Pd-allyl acetate complexes
?
ArI
OH
Ar
ArMet +
CHO
CHO
cat Pd(0)
218 219 220
Ar
I
Pd OH Ar
PdI
H
OH
Ar
OH
221 222 223
OH
PhI
cat Pd(0)
Ph
CHO
218 224; 71% yield
84:16 regioselectivity
225
Allylic alcohols 218 can be converted into their acetates 227 by standard methods, e.g.
Ac 2O/pyridine or DMAP, without any allylic rearrangement. Reaction with Pd(0) gives initially a
π-complex 228 but this loses acetate as the Pd atom donates a pair of electrons to form an η 3 allyl
cation complex 229 of Pd(II).
OH
218
allyl alcohol
19 Regio- and Stereocontrolled Reactions with Nucleophiles 359
Ac2O
pyridine
OAc
227
allyl acetate
Pd(0)
OH
OAc
Pd
228
π-complex
PhI
cat Pd(0)
220
Ph
CHO
226; 96% yield
95:5 regioselectivity
Pd
229; η3-allyl cation
Pd(II) complex

360 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
These allyl cation complexes 229 are electrophilic and react with a variety of nucleophiles,
most notably with the stabilised enolates of β-dicarbonyl compounds such as malonates. The
immediate product is again a π-complex of Pd(0) 230 but there is now no leaving group so the
Pd(0) drops off and is available for a second cycle of reactions. Though the reaction strictly
requires Pd(0), the more convenient Pd(II) compounds are often used with phosphine ligands.
Reduction to Pd(0) occurs either because the phosphine is a reducing agent or by oxypalladation
and β-elimination.
The allyl cation complex has the Pd(II) atom at right angles to the allyl plane and more
or less in the middle of the triangle. It has therefore lost regiochemistry as the same complex
would be formed by either regioisomer. Simple versions of the reaction are still useful - geranyl
acetate 232 reacts only at the alkene that is part of the allylic acetate and gives mostly the
product of attack at the less hindered end of the allyl cation. 41 When malonate is the nucleophile,
the regiochemistry is 9:1 in favour of attack at the terminal carbon. With the sulfone 233, the
reaction is totally regioselective.
232; geranyl acetate
CO2Me +
OAc SO2Ph 233
You will appreciate that CO 2R groups may be removed from these various products by
hydrolysis and decarboxylation. The sulfones can be removed by reduction, for example with
sodium amalgam in ethanol - this is ‘dissolving metal’ reduction and works by electron transfer in
the style of a Birch reduction.
Stereochemistry of Pd-allyl cation complexes
(Ph 3P) 4Pd
The most important aspect of this chemistry is its stereoselectivity. The stereochemical integrity
of the alkene in the starting material may be preserved. This is not surprising with the geranyl
acetate just described but is also the case with the Z-isomer neryl acetate 235. The regioselectivity
is less (90:10, attack at the terminus being favoured) but the major product contains only the
Z-alkene present in the starting material. There is no rotation at any stage in the reaction.
235; neryl acetate
OAc
CO 2Me
Pd
229; η
CO2Me Pd
CO2Me CO2Me 3-allyl cation
Pd(II) complex 230; π-complex of Pd(0) 231 + Pd(0)
+
CO 2Me
SO2Ph
233
NaH
(Ph3P)4Pd
CO 2Me
CO2Me
CO 2Me
SO2Ph
234; 84% yield (>97:3 regio)
NaH CO 2Me
SO2Ph 236; 74% yield (90:10 regio)

In three dimensions the reaction is stereospecifi c with retention by double inversion.
The palladium approaches the alkene from the opposite face to the leaving group and the nucleophile
approaches from the opposite face to the palladium. This is clearly shown by reaction of the two
diastereoisomers 237 and 240 with malonate. [Note: These compounds are of course racemic
and attack at either end of the achiral η 3 allyl cation complexes 238 or 241 would give racemic
material anyway.]
CO 2Me
CO 2Me
OAc
OAc
(Ph 3P) 4Pd
(Ph 3P) 4Pd
CO 2Me
CO 2Me
CO2Me
CO2Me
CO2Me
CO2Me
The combination of stereo- and regiochemistry can be very powerful. The lactone 243 reacts
with malonate esters to give one regio- and stereoisomer of the triester product 41 244.
The palladium forms a π-complex 245 from the top face of the alkene, opposite the carboxylate
leaving group. The nucleophile then adds from the opposite face to the palladium. The η 3 allyl cation
complex is unsymmetrical and the nucleophile adds at the less hindered end. The selectivity is very
marked in both steps because the starting material is a folded molecule and the palladium much
prefers to add to the exo face of the alkene. The nucleophile has to add from the same face as the
CH 2CO 2 side chain so it prefers addition to the end of the complex as far from this side chain as
possible 246.
243
+
When the reaction is intramolecular, the question of ring size may affect both the regiochemistry
and the stereochemistry of the alkene. In general, we might expect smaller or larger rings to be
preferred to medium rings (8-13 membered) and it is obviously impossible to have an E-alkene
in, say, a seven-membered ring. So it is not surprising that the 16-membered ‘large’ ring 248 is
formed from 247 by attack at the end of the allylic system and with complete E-selectivity. This is
a good way to make macrolides (large ring lactones). 42
NaH
NaH
CO 2Me
CO 2Me
237 238 Pd
239 CO2Me
+
CO 2Me
CO 2Me
240 241 Pd
242 CO2Me
(Ph 3P) 4Pd
19 Regio- and Stereocontrolled Reactions with Nucleophiles 361
Pd
O
243
245
O
O
1. (Ph3P) 4Pd
NaH, CH2(CO2Me)2
O
2. CH 2N 2
MeO2C
MeO 2C
MeO 2C
MeO2C
Pd
246
244; 84% yield
CO 2
CO 2Me
CO 2Me
CO 2Me
etc
244

362 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
However, the formation of the eight-membered ring 253 with a Z-alkene from the E-allylic
acetate 249 with only a trace (6%) of the six-membered ring 250 was described by Trost 42 as a
‘shocking preference for cyclisation to the eight-membered ring’. Clearly the geometry of the η 3
allyl cation complex can change during the reaction and this seems to be particularly the case for
intramolecular reactions. The initially formed η 3 allyl cation complex 251 can cyclise either to the
six-membered ring or to the very unstable E-isomer of the eight-membered ring. Rotation to the
other η 3 allyl cation complex 252 must be faster than this cyclisation and the new complex can
cyclise to either product.
PhO 2S
O
O
O
OAc
The regioselectivity of the addition is affected by functionality. In another synthesis of
chrysanthemic acid, Ficini 43 combined the monoacetate of the cis (Z)-alkene diol 254 with
malonate to give only the trans (E)-adduct 255 in 80% yield.
HO
254
PhO 2S CO 2Me
247
O OAc
249
O
O
PhO2S PhO2S O
O
OAc
Pd(PPh 3) 4
(Ph 3P) 4Pd
NaH
NaH, (Ph 3P) 4Pd
PhO 2S
CH 2(CO 2Me) 2 HO
CO2Me
CO2Me
255; 80% yield
Evidently cis/trans isomerisation of the η 3 allyl cation complex is faster than addition. The
regioselectivity is remarkable. Either the steric hindrance of Me 2COH next to the alkene is worse
than that of the tertiary centre that is actually attacked or the OH group electronically discourages
nucleophilic attack as it does in simpler S N2 reactions. We shall see a related regioselectivity in the
reactions of diene monoxides in the next section.
254
Pd(PPh3)4
HO
Pd
HO
Pd
CO2Me CO2Me 255
256 257
O
O
Ph 2P
PhO2S CO2Me 248; 69% yield
Pd
250 251 Pd 252 253
O
O
PPh 2
PhO2S
250 + 253
O
O

Conjugating and electron-withdrawing groups such as CN or CO 2R make the remote end of
the allyl cation complex more electrophilic. The CN substituted compounds 259 are easily made 44
by acetylating the cyanohydrins of enals 258. Superfi cially this might look rather like a Heck
reaction but the nucleophile is added in a different position. These complexes are reagents for the
a 4 synthon 262 having umpolung while the Heck reaction gives products from natural conjugate
addition (a 3 263). The product 261 is formed as an E/Z mixture: if an ester group (CO 2Me) is the
activating group, only the E-isomer is formed.
R
CHO
R
258 259
Pd CO 2Me
R CN
260
19 Regio- and Stereocontrolled Reactions with Nucleophiles 363
Pd and monoepoxides of dienes
O
OAc
CN
O
Pd(PPh 3) 4
5 mol%
CO 2Me
NaH R CN
261; 97% yield
R CN
R CN
262
a4 synthon for
this reaction
263
a3 synthon for
Heck reaction
A clever variation on the reactions of allylic acetates is the palladium-catalysed reaction
of monoepoxides of dienes with nucleophiles. These monoepoxides can be made in two chief
ways. If the diene is symmetrical 264, epoxidation of one of the alkenes occurs more rapidly than
the epoxidation of the monoepoxide because the HOMO (ψ 2) of the diene is higher in energy and
therefore more nucleophilic than the HOMO (π) of an alkene. It is simply necessary to buffer the
epoxidation reagent as these monoepoxides 265 are sensitive to acid (chapter 17).
mCPBA
mCPBA
buffer
O slow O O
264 265
266
If the diene is unsymmetrical, particularly if the monoepoxide of the less substituted and
therefore less nucleophilic alkene is wanted, alternative methods are required. The enone 269
provides both epoxides 270 and 267. The sulfur ylid route converts the enone directly to one
epoxide while base-catalysed epoxidation followed by a Wittig reaction provides the other.
O
Ph 3P CH 2
O
O
Reaction of these epoxides with Pd(0) follows the pattern of the allylic acetate reactions.
The epoxide oxygen atom is the leaving group but the alkoxide intermediate is basic enough to
deprotonate nucleophiles such as malonates without added base. With cyclopentadiene monoxide
265, one regio- and stereoisomer 275 is formed. 45 The palladium adds to the opposite side of the
H 2O 2
NaOH
O
Me 2S CH 2
267 268 269
270
O

364 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
ring to the epoxide and the nucleophile adds to the opposite side to the palladium and at the end
of the allyl cation away from the OH substituent 274, as you should by now expect.
In general, substitution occurs at the less hindered end of the allyl cation and, unlike the cations
formed from allylic acetate, these cations are never symmetrical - one end always has the nearby
OH group that was the oxygen atom of the epoxide. The two isomeric epoxides 267 and 270 also
give isomeric products though there is no stereochemistry here.
267
In the simplest cases of open chain epoxides with terminal alkenes, 46 reaction is predominantly
at the end of the chain and the product is overwhelmingly the E-isomer.
R O CH 2(CO 2Me) 2
280
(Ph 3P) 4Pd
The control of remote chirality
R
– O
281
Allylic carboxylates and epoxides give the opportunity to control stereogenic centres that are not
next to one another and may be as far apart as a 1,4-relationship across a trans alkene. There is an
example of a similar problem solved by a [2,3] sigmatropic rearrangement earlier in this chapter.
In particular vinyl lactones such as 283 have special uses. Trost 47 fi rst checked the regiochemistry
of the reaction with lactone 283. This forms the usual η 3 allyl cation complex 284 that reacts with
the enolate at the end further from the carboxylate group. The alkene moves along the structure
and emerges in the E confi guration 285 corresponding to the conformation of the lactone.
O
(Ph 3P) 4Pd
O
Pd O
Pd
265 271 272
Pd
CH2(CO2Me)2
MeO2C MeO2C OH
MeO2C MeO2C 273
Pd
274 275; 57% yield
(Ph3P) 4Pd Pd Nu (Ph3P)4Pd
Nu
270
Pd
OH
OH
276 277
R CO 2Me
OH CO2Me
282; 84% yield, 98:2 E:Z
O
(Ph3P)4Pd
NaH
CH2(CO2Me)2 Nu Pd
CO2 MeO2C
CO2Me CO2H 283 284
285; >95% yield, >98% regioselectivity
O
Nu OH
OH
OH
278 279
Nu

Now for the stereochemistry. If a single diastereoisomer of the methylated lactone 286 is reacted
under the same conditions with the same nucleophile, a single diastereoisomer of the product 288
is formed in excellent yield. Because the stereogenic centres are so far apart, it was diffi cult to tell
one diastereoisomer from the other and Trost explains carefully how this was done.
O
O
(Ph 3P) 4Pd
NaH
CH2(CO 2Me) 2 Pd
These reactions are also used industrially. The Japanese company Teijin Ltd. uses the reaction
of a stable carbanion with an allylic carbonate to make a stable analogue 290 of prostacyclin
(PGI 2) for use in the treatment of diseases of the circulatory system. Prostacyclin itself 289 is an
enol ether and is too labile for medicinal use. 48
The reaction starts with an allylic carbonate 291 that gives the usual η 3 allyl cation complex
294 with Pd(0) though the ligand is the less usual chelating diphos 292 (Ph 2PCH 2CH 2PPh 2). The
leaving group is a carbonate anion 293.
MeO
O
The carbonate anion loses CO 2 to give methoxide ion which, like the anion released from a
diene monoepoxide, is basic enough to deprotonate the nucleophile, a bis-sulfone 296. The anion
from this 295 adds to the less hindered end of the allyl cation complex 294. The product 297 has the
skeleton of the prostacyclin analogue and the sulfones simply need to be removed by reduction.
293
CO 2
MeO2C
CO2Me
CO 2H
286 287
288; 90% yield >98% regioselectivity
O
O
19 Regio- and Stereocontrolled Reactions with Nucleophiles 365
CO 2Me
HO OH
HO OH
289; PGI2 or prostacyclin 290; Teijin's isocarbocyclin
MeO
+
Ph2P
Ph2P Pd
PPh2 PPh2 O +
R
293
R
RO
291
OR 292
Pd(dppe)2
methyl
carbonate
anion
RO
294
OR
CO 2 + MeO
PhO 2S CO 2Me
SO2Ph
PhO 2S CO 2Me
H
295
294
O
CO2Me
PhO 2S SO2Ph
SO2Ph
RO OR
296 297
Pd
CO 2Me
R
290

366 19 Allyl Alcohols: Allyl Cation Equivalents (and More)
Recent developments
The palladium-catalysed coupling of allylic esters with carbanions has now been extended to include
other reactions. The allylic carbonate 299 couples with the nitro compound 300 to give the
expected product 301 in good yield.
But if the acetate 298 was used the additional base required (here Cs 2CO 3) catalysed a further
intramolecular conjugate addition of the nitro-stabilised anion to the unsaturated ester to give a
new six-membered ring 302 with good stereoselectivity. This compound was converted into the
Erythrina alkaloid 49 303.
Since vinyl stannanes (chapter 18) couple with electrophiles under catalysis by Pd(0), it makes
sense to create the electrophile by the palladium-catalysed reactions of allylic acetates in the same
pot. 50 The vinyl stannane 304 reacts cleanly with the more complex allylic acetate 305 with 0.2
equivalents of Pd(0) to give the triene 306 in good yield. 51
O
Summary
The chemistry of allylic alcohols and their derivatives is remarkably rich. They can be used to
add allyl groups to other molecules with good regio- and stereochemical control. The methods in
this chapter, particularly the palladium-catalysed reactions and the sigmatropic rearrangements,
should allow you to make many otherwise diffi cult target molecules.
References
SnMe3
CO 2Me
RO O
298
298; R = Ac
299; R = CO2i-Pr
(Ph 3P) 4Pd
Cs 2CO 3
+
301
+
O
AcO
Cs 2CO 3
300
304 305
NO 2
O
O
O PMP
O
(Ph 3P)4Pd
NO2 302; 80% yield
CO 2Me
Pd2(dba)3
General references are given on page 893
1. J. F. Lane, J. D. Roberts, and W. G. Young, J. Am. Chem. Soc., 1944, 66, 543, J. F. Lane, J. Fentress and
L. T. Sherwood, J. Am. Chem. Soc., 1944, 66, 545.
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LiCl
O
O
O
NO 2
301; 83% yield
O
O
MeO
306; 87% yield
O PMP
O
CO2Me
N
H
303; Erythrina alkaloid
O

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Section D:
Stereochemistry
20. Control of Stereochemistry – Introduction ...................................................................... 371
21. Controlling Relative Stereochemistry .............................................................................. 399
22. Resolution ........................................................................................................................... 435
23. The Chiral Pool — Asymmetric Synthesis with
Natural Products as Starting Materials — ....................................................................... 465
24. Asymmetric Induction I Reagent-Based Strategy .......................................................... 505
25. Asymmetric Induction II Asymmetric Catalysis:
Formation of C–O and C–N Bonds ................................................................................... 527
26. Asymmetric Induction III Asymmetric Catalysis:
Formation of C–H and C–C Bonds ................................................................................... 567
27. Asymmetric Induction IV Substrate-Based Strategy ..................................................... 599
28. Kinetic Resolution ............................................................................................................... 627
29. Enzymes: Biological Methods in Asymmetric Synthesis ................................................ 651
30. New Chiral Centres from Old — Enantiomerically
Pure Compounds & Sophisticated Syntheses — .............................................................. 681
31. Strategy of Asymmetric Synthesis ......................................................................................717

20
Control of Stereochemistry – Introduction
Introduction
Stereochemistry denial
The Words We Use
Four ketones
Diastereomeric and diastereotopic
Enantiomers and enantiotopic
Homotopic
How to decide if two groups are homotopic, enantiotopic or diastereotopic
Stereoselectivity and stereospecifi city
The Structures We Draw
Racemates with one chiral centre
Racemates with two chiral centres
Optically pure compounds with one chiral centre
Optically pure compounds with two chiral centres
Sophisticated diagrams
Wiggly lines and two chiral centres
Racemates with one chiral centre which react to give a racemate with two
Achiral diastereomers
The Fundamentals of Stereochemical Drawings
Drawing tetrahedra
Drawings to avoid
Mental manipulation of tetrahedra
Stereochemical Descriptors
Including: d, l; d, l; R*, S*; r, s; Re, Si; (), (); and lk, ul
The Next Ten Chapters
Stereochemical Analysis
Introduction, steps 1 to 9, summary
Some Principles
Chiral auxiliaries
The Horeau principle
Popular Misconceptions
Misuse of words
‘Chiral’, ‘Chiral synthesis’, ‘Racemic synthesis’, ‘Homochiral’
Chiral centres and stereogenic centres
Pseudo-asymmetric centres
Unhelpful drawings
Bond rotation
Stereospecifi city revisited
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

372 20 Control of Stereochemistry – Introduction
Introduction
Stereochemistry denial
This chapter is – and the next ten chapters are – about stereochemistry. Nobody these days would
question the importance of stereochemistry. But inexperienced undergraduates – and, it has to be
said, some practising organic chemists – who are faced with a synthesis which involves a little
stereochemistry often ignore the stereochemical aspect, and focus entirely on the bond-forming
side of things. It is not hard to see why somebody might suffer from this ‘Stereochemistry Denial’.
Stereochemistry isn’t easy; it complicates matters and is probably the most diffi cult aspect of
organic chemistry for most chemists. One need only look in the literature from the early part of
the 20th Century to see syntheses where compounds were produced as diastereomeric mixtures,
where the fact that they were mixtures was of no concern to the authors, and where the fi nal
relative stereochemistry of the product was not known, and, at the time, could not have been. That
was then. Not any more.
In this chapter we introduce the language of stereochemistry and some of the concepts that are
used in later chapters within this section and also in the rest of the book. If you are unfamiliar
with some of the fi ner stereochemical points, then this chapter could well be a ‘baptism by fi re’.
Don’t be put off – come back to any diffi cult parts of this chapter after some of the others in this
Section (chapters 21–31).
Before coming to the fi rst section, it is worth pointing out that we assume you know: what an
enantiomer is, what a racemate is, what is meant by relative stereochemistry and what is meant by
absolute stereochemistry. 1 We also assume you know the term enantiomeric excess. 2
The Words We Use
Four ketones
O
O
Consider the four ketones 1 – 4. The fi rst three are achiral but the last is chiral and racemic.
O
O

1
achiral
If we just imagine the six membered rings to be fl at for a moment (they are not of course but
it doesn’t matter for our purposes) then the fi rst molecule has two mirror planes running through
it – one is in the plane of the paper and the other is a right angles to the paper 1a. The next two
molecules, 2 and 3, each have one mirror plane. The last ketone 4 has no mirror planes and has a
single stereogenic centre.
Now let us consider a reaction of each of these ketones with a nucleophile, Nu . In every case,
an sp 2 centre is replaced by an sp 3 centre to give alcohols 5 to 10.
1
achiral
5
achiral
O O O O
R R
2
achiral
1a
Two mirror planes
Diastereomeric and diastereotopic
3
achiral
R R
4
chiral
O O O O
R R
HO Nu HO Nu
HO Nu
HO Nu
R R
2
achiral
6 & 7
achiral
20 The Words We Use 373
We will come back to ketone 1. With ketone 2, there are two possible products 6 and 7. The
nucleophile could attack the ketone from one face or from the other 2a. Only the top face is on the
same side as the R group. The two possible products from the reaction are diastereomers and so
the two faces of the ketone are diastereotopic.
R
R
3
achiral
R R
(±)-8
chiral
R R
O
4
chiral
(±)-9 &
(±)-10
chiral
R
R
R

374 20 Control of Stereochemistry – Introduction
2
achiral
6 & 7
achiral
A similar situation arises with ketone 4. Attacking the carbonyl on one face leads to one
diastereomer while attack on the other face leads to another. Hence the faces are diastereotopic.
The ketone 4 is chiral and racemic so the two diastereomers 9 and 10 will also be
racemic.
Enantiomers and enantiotopic
Like ketone 2, ketone 3 can give two possible products and the nucleophile could attack the ketone
from one face or from the other. However, this time, the two lines of attack lie on either side of the
mirror plane that runs through ketone 3a. The two products are enantiomers and the two faces of
the molecule are thus enantiotopic. This reaction was the only reaction that started with an achiral
material but gave a chiral product. Because a reaction of ketone 3 leads to chiral products we can
also describe ketone 3 as prochiral.
3
achiral
(±)-8
chiral
Homotopic
O
R
HO Nu
R
O
R
R
Nu
HO Nu
R
HO Nu
R
(R)-8
R
OH
Nu
With ketone 1, it doesn’t matter at all which side of the molecule is attacked. The exact same
compound 5 results and there is no possibility of different enantiomers or diastereomers. The
compounds are superimposable. The two faces of the molecule are homotopic.
R
O
6 7
R
O
2a
Nu
HO Nu
R
(S)-8
DIASTEREOTOPIC FACES
OH
DIASTEREOMERS
3a ENANTIOTOPIC FACES
ENANTIOMERS

1
achiral
5
achiral
How to decide if two groups are homotopic, enantiotopic or diastereotopic
There is a test you can do to decide. It always works. First, substitute one of the groups you are interested
in with something else – which we will call X – to give a new molecule A. Now, instead, substitute
the other group you are interested in with X to give you a second molecule B. Now decide upon the relationship
between your two new molecules A and B. If they are enantiomers of one another then the two
groups must have been enantiotopic. If they are diastereomers of one another then the two groups must
have been diastereotopic. And if the two molecules you end up with are exactly the same – by which we
mean that one can be superimposed upon the other – then the two groups must have been homotopic.
O
R
HO Nu
R
O
O
R
R
The Stereochemical Test
NH
X H
replace HA with X
In the example above, the two protons H A and H B in oxazolidinone 11 are replaced in turn to
give two new molecules 12A and 12B. This replacement gives us diastereomeric products — the
protons themselves in the oxazalidinone (H A and H B) are therefore diastereotopic. In an NMR
spectrum we would expect protons H A and H B to have different chemical shifts. We could have
looked at other aspects of oxazolidinone 11 – the stereochemical relationship between the two
methyl groups for example.
Stereoselectivity and stereospecifi city
20 The Words We Use 375
Nu
OH
O
Stereospecifi city. Let us state at the outset that stereospecifi city is not just perfect stereoselectivity.
This is a very common misconception. There is a difference between 100% stereoselectivity
and stereospecifi city. The reaction from 13 to 14 proceeds by an S N2 mechanism. The nucleophile,
PhS , attacks from behind the leaving group and so, of course, the reaction proceeds with inversion.
This happens whether the molecule likes it or not. It is forced by the mechanism to give a
specifi c product from a specifi c starting material. A stereospecifi c reaction conveys the idea that
the other diastereomer will yield the opposite result: 15 must give 16.
O
11
NH
HB HA
replace H B with X
12A A and B are DIASTEREOMERS
12B
O
Nu
5 5
HOMOTOPIC FACES
OH
IDENTICAL COMPOUNDS
– SUPERIMPOSABLE –
O
O
NH
H X

376 20 Control of Stereochemistry – Introduction
R Br
SPh
S N2
13 14
Stereoselectivity. To continue with similar examples – in a stereoselective reaction the molecule
selects a particular reaction pathway for some reason. That reason might include steric hindrance,
kinetics or thermodynamics but the molecule isn’t forced by mechanism to react one way only.
In the reaction of 17, which proceeds by S N1 rather than S N2, the intermediate cation 18 may be
attacked from either side by a nucleophile (there is no longer the necessary inversion we see with
S N2). Attack occurs selectively from the less hindered face of the cation 18.
With stereoselectivity, there is the distinct possibility that different isomers will give the same
product. The intermediate cation 18 is the same whether that starting material is syn 17 or anti 17
and must give the same product 19.
These reactions contain stereoselective and stereospecifi c components. The starting materials
20 and 22 are chiral and racemic and the faces of the double bonds (in both cases) are diastereotopic.
Epoxidation is stereospecifi c since there is only one extra atom in the epoxide it must react with
the two carbon atoms on the same side if the reaction is concerted. But, with allylic alcohols the
reactions are also stereoselective since the OH will form a hydrogen bond with the peracid and
hence deliver the oxygen syn to the alcohol. It could in principal react to give the anti product but
it is not possible to make (as the major product anyway) the anti isomers 24 and 25 by this method.
Another example of a reaction that has both stereoselective and stereospecifi c components appears
in the pumiliotoxin synthesis in Chapter 21.
The Structures We Draw
Racemates with one chiral centre
R SPh
SPh SN2 R Br R SPh
15 16
SN1
R
Br
R
R
OH
17, anti 18 19, anti
SN1 R
Br
R
17, syn 19, anti
18
There are plenty of reactions that contain both stereoselective and stereospecifi c components.
One reaction might also be regioselective and even chemoselective and it is important to be able
to dissect a reaction into these different selectivity components. An example concerns the two
epoxidation reactions of 20 and 22.
OH
ArCO3H OH
O
OH ArCO3H OH
O
OH
O
OH
O
R
R
R
R
R
R
20 21 22
23 24; anti 25; anti
If the compound 26 is a racemate with only the one chiral centre then the bonds are best drawn
as ordinary straight lines. This implies a racemate – that there are equal amounts of the two
enantiomers (S)-26 and (R)-26. There is no need to draw a wiggly line, for instance.
OH 2
OH 2
R
OH

What we draw What it means
OH OH OH OH
(±)-26 (S)-26 50:50 (R)-26 (±)-26
Racemates with two chiral centres
Now things are more complicated. This is because, whether we have racemates or not, we need
to specify relative stereochemistry. The syn diol 27 contains two chiral centres. We have to draw
in stereochemistry because we need to defi ne which diastereomer we are concerned with. It is,
however, racemic. Similarly, what we draw with the anti diol is anti-27.
OH OH
27a
Interestingly, this is the point at which many chemists bail out of stereochemistry. Somehow,
even the thought of relative stereochemistry becomes all too much (a bit like the character in the
cartoon). Such a person would draw this diol as 27a which might mean anything. It really is worth
taking the time to think about what the stereochemistry is and drawing it in.
Optically pure compounds with one chiral centre
We can now draw the compound 26 as we mean it. There is no ambiguity.
Optically pure compounds with two chiral centres
20 The Structures We Draw 377
Correct but unnecessary
What we draw What it means
unnecessary
wiggly line
OH OH OH OH OH OH
syn-27
50 : 50
What we draw What it means
OH OH OH OH OH OH
anti-27
OH OH
(S)-26; We draw this.
We mean this enantiomer
and only this enantiomer
50 : 50
(R)-26; We draw this.
We mean this enantiomer
and only this enantiomer
Now if we draw syn-27, we would like it to mean only that enantiomer. But now comes the diffi culty.
How do we distinguish this diagram from the one we used for the racemic compound? They both
look the same. Sadly there is no easy answer to this and with two chiral centres it is ambiguous but
for a start we can label the drawing (±)-syn-27 if racemic. Sound advice is to spell it out on your

378 20 Control of Stereochemistry – Introduction
diagrams. Write (±) under the racemic compound and ‘optically pure’ under the optically pure
one, or else label it (S,S)-27 or () or whatever is right.
Sophisticated diagrams
OH OH OH OH OH OH
syn-27 (±)-syn-27
An attempt has been made to fi x this ambiguity and to use ‘blocks’ for relative stereochemistry
(±)-syn-27 and ‘wedges’ for absolute (S,S)-syn-27. And this would be quite a good system if every
body did it, but they don’t. Sadly, for the moment at least, this extra level of complexity is not
widely accepted and cannot be relied upon.
Wiggly lines and two chiral centres
A wiggly line can mean several things. It can simply mean that both confi gurations are present,
though as we saw above, it is not necessary with a racemic mixture. Suppose that we have only the
S confi guration of the amine 28 at the benzylic site.
NMe 2
This diagram 28 could mean several things —
OH OH OH OH
(±)-syn-27
NMe 2
optically pure syn-27
i) Both diastereomers (S,R)-28 and (S,S)-28 are present (though not necessarily in equal
amounts).
ii) There is only one diastereomer but we don’t know which one it is.
and it might even mean —
iii) We don’t care. (Because, say, of reactions to follow that make it unimportant).
Racemates with one chiral centre which react to give a racemate with two
optically pure syn-27
NMe 2
S S R S S
O
O
28 (S,R)-28 (S,S)-28
Consider a racemate with one chiral centre such as 29. We do not defi ne the stereochemistry since
there is only one centre. Note that the bond is not bold or hashed or even wiggly. If we reduce this
in a stereoselective reaction so that anti-27 results then we draw in the relative stereochemistry.
Even though the product is a racemate, and we’ve added the ‘±’ symbol to avoid any confusion,
we must defi ne the relative stereochemistry. Of course, we could equally have drawn the other
enantiomer 27a.
O

Achiral diastereomers
You do not need chirality to make defi nition of the stereochemistry essential. If there are two
possible diastereomers stereochemistry needs to be defi ned. This is the case where the achiral
ketone 30 is reduced to the achiral alcohol 31. Even though both starting material and product are
achiral – there is stereochemistry to be addressed, say anti-31 is formed and not syn-31.
t-Bu
We’ve gone on about how important it is to always draw in the stereochemistry but we will end
this section with one last point—beware of adding too much stereochemical information. Later in
this chapter is a subsection on Unhelpful Drawings under Popular Misconceptions. Triol 32 is an
example of a compound drawn with too much stereochemical information.
The Fundamentals of Stereochemical Drawings
Drawing tetrahedra
OH O
(±)-29
O
20 The Fundamentals of Stereochemical Drawings 379
reduce
reduce
t-Bu
OH OH OH OH
(±)-anti-27 (±)-anti-27a
We’ve all got into trouble from time to time when drawing stereochemistry. Most often it happens
when we are standing in front of a group of people. A few simple, and probably entirely obvious,
guidelines might help. As far as possible, try to keep two bonds in the plane of the paper. You
cannot get more than two tetrahedral bonds in the plane at a time but it is certainly possible to
draw structures with fewer and such drawings rapidly become very messy. If you need to draw
only three bonds then keep them at 120 to one another.
If you need to draw all four bonds then draw the third and fourth bond with a shallow angle
between them. If you need to indicate stereochemistry, keep the shallow angle between the thick
and hashed bonds. The other two are in the plane of the paper.
OH
t-Bu
30 anti-31 and not syn-31 32
Good: 120˚ angles, two bonds in plane of
paper
shallow angle
Approx. 120˚
OH
Bad: poor angles
OH
OH
Keep the shallow angle between stereochemical bonds
shallow angle
shallow angle
OH

380 20 Control of Stereochemistry – Introduction
Drawings to avoid
There are many. One of the most confusing is to use a stereochemical bond (ie a hashed or a bold
bond) between two stereocentres. For example, amine 33 and alcohol 34 can be drawn without
confusion in several ways two of which are shown below.
NH 2
redraw
The potential confusion arises when we have two stereogenic centres next to one another. The
fi rst depiction of aminoalcohol 35 makes perfect sense but the redrawn form is starting to get
confusing. Which centre does the bold bond refer to?
In fact, we can work out the stereochemistry in the second drawing of 35. If we look at each
centre in isolation and consider the bold bond to both then it works. But this is rare and works
here because we happen to have syn-35. How we would redraw anti-35 in a similar way? Would
we use a bold or a hashed bond to do it? There is no good answer. The best thing to do is follow
these two guidelines—
i) Keep the main chain of the molecule in the plane of the paper. This means that stereochemical
bonds will not appear in the main chain of the molecule.
ii) Do not use stereochemical bonds between two stereocentres. This will ensure the same.
Mental manipulation of tetrahedra
NH 2
Over the next few chapters it will often be necessary to redraw tetrahedra in different ways.
You need to become profi cient at this. We introduce two manipulations that will take you a long
way. We will start by looking back at the trivial manipulation we just did with amine 33. There
is nothing new here but we’ve invented the terms CBP and GSR to help you. Imagine a single
enantiomer of the amine 33. We would not normally draw in the hydrogen but we’ve done it in
the box just to remind you where it is. We know with tetrahedra that only two bonds can be in the
plane of the paper at any one time. The fi rst manipulation we encounter simply changes which
bonds are in the plane. This is something you very often have to do in reaction schemes. We shall
simply call this manipulation a “Change of Bonds in the Plane” or a CBP.
Notice that if we start with one of the bonds coming out of the paper then one of the bonds is
always coming out of the paper (but remember, you are not allowed to swap groups). If you are
OH
redraw
33 33a
34
34a
NH 2
redraw
NH 2
OH OH
syn-35
syn-35a
HNH 2
syn-35a
confusing
stereochemistry
NH2
NH 2
CBP NH2 CBP
redraw
OH
NH 2
OH OH ?
anti-35
anti-35a
33 33
33a
33b
NH2

not convinced by this, make a tetrahedral model and leave the fi nal hydrogen off the back. The
result leans like a (static) spinning top on its side and if you hold two bonds in the plane then the
other one pops up. The reverse is true too of course—if one of the groups is pointing away from
us then one must always be pointing away. See what happens when we do a CBP as with alcohol
36 below.
OH
No groups swap location when we perform a CBP. Now we meet the second type of manipulation
we shall call a “Group Swap by Rotation” or a GSR. If we do swap the location of two groups then
we must do so by rotating about one of the bonds 33c and, as a consequence, we move from one
thick bond to one hashed bond 33d (or from one hashed bond to one thick bond).
rotate about
this bond
You shouldn’t use these devices without understanding how they work. If necessary use models
to satisfy yourself that you understand how it works. Amaze yourself at how easy it is. If up until
now you have been a stereochemical denialist and work among other denialists then learning these
basic skills will earn you instant awe and respect at the fl ipchart!
Imagine the ring opening of cis-stilbene oxide 37 by an amine in an S N2 reaction. The product
is the amino alcohol 38. Redrawing this 38a so that we have the longest chain in a zig-zag is easy
by application of a GSR to the right hand portion of the molecule. Note that we have not drawn
any structure with a hashed or thick line between two chiral centres. In this sequence the question
of absolute stereochemistry does not arise as cis-stilbene oxide 37 has a plane of symmetry and
is therefore achiral.
Ph
37
Ph
Stereochemical Descriptors
O
20 Stereochemical Descriptors 381
OH
CBP CBP
Ph
Ph
Ph
36 36a 36b
This is a short section to describe what the various stereochemical descriptors mean. There are
several in common usage and we assume you know what R and S mean. The more antiquated
terms include d and l and D and L. Antiquated they may be but their use is still common and you
need to, or at least ought to, know what they mean.
d, l
These were once used to indicate the sign of optical rotation. So, d for dextrorotatory and l for
levorotatory. These have been replaced by () and () respectively.
OH
NH2 one thick
one hashed
Me
bond
bond
Me
33c
GSR
NH2 33d
RNH2
Ph
rotate about this bond
amino and methyl
groups swap
positions
OH
OH
NHR
GSR
Ph
Ph
Ph
NHR
38 38a

382 20 Control of Stereochemistry – Introduction
d, l
These are used mostly for carbohydrates and amino acids. The terms are obsolete and come from
a time when the confi gurations of lots of chiral compounds relative to each other were known
but the absolute confi guration was not. D-()-Glyceraldehyde is taken as the standard. Enantiomerically
pure compounds that could be related to D-()-glyceraldehyde by a series of reactions
or degradations were labeled D [or L if they related to L-()-glyceraldehyde]. Without going into
details, an amino acid is L if the amino group is on the left in a Fischer projection which has the
carboxylate at the top. They are smaller than normal capitals.
R*, S*
These are a sensible way to describe relative stereochemistry of racemic compounds. Suppose we
have a compound 39 with three asymmetric centres. We know that we have only one diastereomer.
The enantiomer drawn could be called (1R, 2S, 3S)-1,3-dihydroxy-2-aminobutylbenzene. But the
enantiomer, (1S, 2R, 3R)-1,3-dihydroxy-2-aminobutylbenzene will also be present. To indicate that
both are there we could either call it (1RS, 2SR, 3SR)-1,3-dihydroxy-2-aminobutylbenzene or (1R*,
2S*, 3S*)-1,3-dihydroxy-2-aminobutylbenzene.
OH OH
Br
1 2 3
MeS
NH2 (S)-40
39
r, s
These are a bit more complicated but important terms and are discussed in ‘Pseudoasymmetric
Centres’ below.
Re, Si
These two terms are in common usage and refer to which face of a fl at functional group such as
a carbonyl. The faces will either be enantiotopic or diastereotopic. They are very commonly used
terms and easy to understand if you already understand R and S. If the decending priority of the
groups defi ne a clockwise motion then the face being viewed is the Re face. Similarly, an anticlockwise
motion indicates that the Si face is being viewed. One thing to remember here is that
whether a face is Re or Si has nothing to do with whether the resulting compound is R or S. If it
were, then Re and Si would have to also depend upon the priority of the incoming group.
re, si
These are often, mistakenly, used for Re and Si but, in a way, they are to Re and Si as r and s are to
R and S. In other words they concern the formation of pseudoasymmetric centres from sp2 centres.
And we shall just leave it at that as they are not encountered very frequently. If you want to know
more, have a look in Eliel’s book on Stereochemistry.
(), ()
These simply refer to the direction of rotation of polarised light. Unlike R and S which are
determined by confi guration, their determination is entirely empirical. In other words, although
we know that hypothetical compound 40 has the S confi guation, we have no idea whether it is ()
or () and will not know until we put it into a polarimeter.
lk, ul
These might be called ‘derivatives’ since they are further removed from the stereochemical
information than R or S. As such they are less useful since they need more ‘decoding’ to get back
to the actual structure. They are used for compounds with adjacent chiral centres. They are easy
enough to understand – a compound with two R chiral centres (or one with two S chiral centres)
is a lk (lk for ‘like’) compound whereas a compound with one R and one S centre would be ul (ul
for ‘unlike’). Although this has the advantage of being unambigous, it does not convey a pictorial

image at all. Since organic chemists think with structures, ul and lk is considered by many not to
be helpful. For a more transparent device, see syn and anti below.
l, u
These are related to lk and ul but, instead of describing the relationship between two chiral centres,
they describe the relationship between a prochiral centre and the resulting chiral centre. A situation
where a Re face gives after reaction, an R centre is l (and Si face giving S centre) but Re face giving
S centre is u (and Si giving R). 3 They are not used very commonly.
syn, anti
We use these routinely in this book. Once a molecule has been drawn in the standard way with
its most extended chain 41 then if the two groups concerned are on the same side of the molecule
it is syn and if they are on the opposite side then they are anti. This is illustrated with the aldol
products syn- and anti-42.
longest chain fully extended
41
longest chain
extended but
not in plane
The advantage (or disadvantage depending on your point of view!) with syn and anti is that they
always need a picture to go with them. Compound 41 shows the skeleton of 42 with the longest
chain in its most extended form (zig-zag). Aldol syn-42a shows syn-42 redrawn but with the zigzag
chain not being kept in the plane and syn-42b with the longest chain not extended. Neither of
these is as good as syn-42 but it might well be necessary to draw some compounds like this (if there
is a macrocyclic ring for example we might have no choice). Something drawn in the way of 42b
would then look like anti rather than syn. There are no rules according to atoms priorites etc – the
picture is king. It is also fast to go from name to picture and no ‘decoding’ is needed.
If you take one thing away from this section it should be that any name or stereochemical
description should be tied fi rmly to a clear stereochemical diagram drawn on the lines we
have suggested. Everybody will then know what you are talking about.
The Next Ten Chapters
20 The Next Ten Chapters 383
O OH
O OH O OH
redraw
syn-42
syn-42a syn-42b
The next ten chapters are all to do with stereochemistry. The next chapter and Chapter 30 concern
relative stereochemistry and its control. All the other chapters are concerned with asymmetric
synthesis and the different strategies that can be employed. The different strategies can be broadly
divided into three groups. These are resolution, chiral pool and asymmetric induction.
Resolution Chiral Pool Asymmetric Induction
These main groups can be subdivided as shown below. This diagram shows not only the structure
of the fi eld asymmetric synthesis but how they are arranged in this book. Resolution, for instance
divides into ‘Classical’, ‘Kinetic’ and what we call ‘Fancy Kinetic’ which means dynamic kinetic
OH
O
anti-42
longest chain
not extended

384 20 Control of Stereochemistry – Introduction
resolutions and all the complicated stuff. All the resolution subdivisions involve the separation of
enantiomers. Classical resolution includes methods like the formation of diastereomeric salts whereas
in a kinetic resolution enantiomers may be separated because one reacts faster than the other.
Some of the subgroups can be divided further so reagent-based asymmetric induction divides
into catalytic and stoichiometric methods and even these may subdivide. Some of the subdivisions
are so important that they have entire chapters dedicated to them and others even have several
chapters devoted to them. For instance, we devote two chapters to catalytic asymmetric induction
(or three if you count enzymes) – one for C–O and C–N bond forming reactions and one for C–H
and C–C bond forming reactions. Although it looks as if there are clear divisions between the topics
it is, of course, not that simple and one chapter will refer to another. Finally, Section D rounds up
with a chapter on Strategy of Asymmetric Synthesis. The other chapters are self explanatory.
Classical
Resolution Chiral Pool Asymmetric Induction
Kinetic
Fancy
Kinetic
CHAPTER 31
'Strategy'
CHAPTERS 26 & 27
Reagent Based
Catalytic Stoichiometric
Substrate
Based
Many enantiomerically pure compounds can be made by a variety of strategies. Several conceivable
strategies for the synthesis of the quinolone antibiotic ofl oxacin 45 are shown below. The molecule
contains only one chiral centre and this may be introduced as a fragment from the chiral pool 47 or
by the resolution of a key intermediate 44 or indeed the fi nal product. 4 A synthesis developed 5 for the
preparation of racemic ofl oxacin which incorporates racemic aminoalcohol (±)-47, could in principle
F
F
F
F
CHAPTER 22
O
F
CHAPTER 28
CHAPTER 28
CHAPTER 23
Chemical
Enzymatic
Division of Topic and Chapters in Section D.
N
N
O
N
CHAPTER 24
CHAPTER 29
43 F CO2H 44
46
N
O
F
Chiral Reagent
Catalytic or
Stoichiometric
OH
O
N
X*
Me
Substrate Based
X* = chiral auxiliary
45; ofloxacin
O
Resolution
Chiral Pool
F
F
HO
O
47
CHAPTER 27
NH 2
NH
OAc

e turned into an asymmetric synthesis. 6 Alternatively an achiral intermediate 43 could be asymmetrically
reduced or a chiral auxiliary could be attached 46 to direct an asymmetric reduction. 7 The
application of different strategies means that several compounds show up in more than one chapter.
Stereochemical Analysis
Stereochemical analysis is a formal descripton of the stereochemical aspects of molecules and
their reaction. In many ways it is simply a formalisation of what chemists do anyway and is not
dissimilar to retrosynthetic analysis. But clarity is vital and clarity can be achieved only by using
the stereochemical words we have just met.
Stereochemical analysis uses stereochemical words to describe the properties of molecules and
of reactions. It uses words of symmetry and it avoids ambiguous words. The word ‘same’ means
different things to different people and depends upon the context. One chemist might describe
two enantiomers as being the ‘same’ because they have the same structure whereas another chemist
concerned with asymmetric synthesis might well describe them as ‘different’. ‘Different’ is
not much better but by using the word ‘enantiomer’ we know where we are. We have divided the
analysis into nine steps but, as we shall see, you will often feel you don’t need all of them.
Stereochemical
words
20 Stereochemical Analysis 385
Properties of molecules Properties of reactions
• Diastereotopic
• Enantiotopic
• Homotopic
• Chiral
• Racemic
Diastereomer
Enantiomer
Homomer
Achiral
• Stereoselective
• Enantioselective
• Stereospecific
Step No. 1
Look for symmetry in the starting material. Identify axes, planes or (less commonly) centres of
symmetry. For example, diol 48 has a axis of symmetry whereas diol 49 has a plane. Diol 48 is C 2
symmetric and chiral; 49 is achiral.
Ph
OH
OH
HO OH
HO OH
Ph
Ph
Ph
Ph Ph Ph Ph
OH
OH
48 48a; axis of symmetry
coming towards us
49 49a; plane of
symmetry
A word of warning straight away – be careful about how the molecule has been drawn (especially
if you have previously suffered from stereochemistry denial!). Redrawing the apparent syn diol
49 reveals the anti relationship between the hydroxyl groups 49b. The plane of symmetry is no
longer evident. In fact, the molecule has a centre of symmetry in this conformation. Diol 49 is
achiral however we draw it. Normally, our priority should be for planes and axes before we start
thinking about centres.
HO OH
redraw
Ph
OH
Ph
Ph Ph
OH
'syn' diol 49 anti-diol 49b
centre of
symmetry
C 2 axis of
symmetry
Step No. 2
Identify relationships within the molecule. For example, once you have identifi ed a plane of
symmetry in a molecule, you might decide that two ester groups are enantiotopic. ‘Enantiotopic’ is
Ph
OH
Ph
OH
syn-diol 48

386 20 Control of Stereochemistry – Introduction
the relationship. Make sure, by looking back at Enantiomers and Enantiotopic if necessary, why the
ester groups in 50 are enantiotopic while those in 51 are homotopic. Imagine being at a party where
no relationships were revealed – you would not know who is whose brother, sister, husband or wife. It
would be unfortunate to be without information of that kind (especially) if you were a bit of a gossip.
Relationships count and, just because a girl has a sister, it doesn’t stop her from having a brother too.
So don’t stop your analysis once you have identifi ed one relationship—be exhaustive. We have identifi
ed that the ester groups in 50 are enantiotopic, but we might also notice that the two protons at the
α-position are diastereotopic 50a. One is on the same side as the phenyl group and one is not.
O Ph O
O O
O Ph O
EtO OEt
EtO OEt
EtO OEt
H H
50 51 50a: diastereotopic protons
We shall now examine the epoxidation of the doubly allylic alcohol 52 to show how steps 1
and 2 give insight into the possible stereochemical outcome of this reaction. We shall assume that
mono epoxidation is possible. The fi ve-membered ring is fl at and the two bonds to the epoxide
oxygen must of course be on the same side of the ring. Step 1, looking for symmetry in the starting
material, reveals one symmetry element - a mirror plane through the OH group at right angles to
the ring 52a. The molecule is achiral.
RCO3H OH OH
O
52 53 52a
Step 2, identifying relationships within the starting material, is more revealing. The two alkenes
are refl ected in the mirror plane so they are enantiotopic. But the top and bottom faces of the ring are
diastereotopic - one is on the side of the OH group and one is not. So it is possible for any epoxidising
agent to choose either the top or bottom faces by steric hindrance or by bonding to the OH group.
Step No. 1
But the choice between the two enantiotopic top faces or the two enantiotopic bottom faces
would produce a single enantiomer, and that would require the introduction of asymmetry,
probably from the reagent.
OH
OH
diastereotopic
faces
OH OH
mirror plane
OH
Step No. 2
mirror
plane
OH
mirror
plane
OH
mirror
plane
Step No. 2
diastereotopic
faces
Step No. 1 Step No. 2
enantiotopic faces
mirror plane
Step No. 2
mirror plane mirror plane
enantiotopic faces

Step No. 3
Decide whether or not the molecule is chiral (not to be confused with step number 4). The amino
acid 54 is clearly chiral (whether or not it is racemic of course). A cursory glance at compound 55
may fail to expose that it is not chiral. Compound 55 in fact contains a centre of symmetry (rather
more diffi cult to spot) but redrawing 55 as 55a exposes a mirror plane within the molecule. Either
way, it cannot be chiral.
O
mirror
OH
Ph
Ph
redraw
plane
NH2 Ph
54 55 55a
Step No. 4
If the molecule is chiral, decide whether or not it is enantiomerically pure. You will often have to
know more about the reaction than is evident in the scheme. For instance, trans-stilbene oxide 56
is always chiral but may or not be racemic. It is not evident in the scheme below and it could easily
be either. It all depends how it was made. If only achiral starting materials and reagents were
used, the epoxide 56 must be racemic. If asymmetry was present somewhere, it may be a single
enantiomer. But had we put optically pure stilbene oxide 56 into the reaction then we could expect
to get an optically pure product 57 at the end. Amino acid 54 is likely to be enantiomerically pure
anyway (as are other compounds from the chiral pool) and if we were in any doubt it has been
drawn as a single enantiomer. In other situations we need to know the context to be sure.
asymmetric
starting material
or reagent?
20 Stereochemical Analysis 387
Ph
O N3 Ph
These fi rst four steps are the most important. They are not the whole story and it may be necessary
to go through the next fi ve steps as well. Experience will show you if they are needed and enough
experience may allow you dispense with this formal analysis.
Step No. 5
Identify the source of chirality and indicate the chiral centres or axes. You may feel this is unnecessary
but it doesn’t hurt to draw a ring around a chiral centre or draw in the symmetry plane
with a coloured pen.
Step No. 6
Look for more subtle symmetry relationships. These might be where molecules are only just short
of symmetry or where a small change in the molecule could increase its symmetry. For example,
we could raise the level of symmetry of the ester 58 by either hydrolysing it to give the diol 59 or
by esterifi cation of the remaining hydroxyl group to give the diester 60. It can often be instructive
to notice this sort of thing if only as a warning.
HO O
O
mirror plane
Ph
OH
N3
56 57
HO OH O O
O
mirror plane
58 59
60
Ph
O
Ph

388 20 Control of Stereochemistry – Introduction
A completely different issue, but another where we are just short of some symmetry, is that
of the pseudo-C 2 axis. The diol 62 has a pseudo-C 2 axis (Ψ-C 2) – removal of the phenyl group
would give us the genuine article 61 and 61a. Note that this term is applied to compounds where
the disruptive element is on the axis itself (or rather where this axis could be) because it is only
here that the substituent will be non-stereogenic. Hence we describe 62 as pseudo-C 2 but not 63 or
64. The pseudo-C 2 phenomenon is very real but there are those who do not like the name. There
is a movement to rename it pro-C 2. We hope this movement gathers momentum. It is a better
description (akin to prochiral) and is without the negative connotation of ‘pseudo’.
OH OH
C2 axis
OH OH
OH Ph OH
Ψ-C 2 axis
OH Ph OH
HO O
Step No. 7
Decide how the reaction infl uences symmetry. Is symmetry created, destroyed or even left unchanged?
If a molecule contains a mirror plane, for instance, and the new bonds are made within
the mirror plane we can expect the symmetry element to be retained. However, attack at one
side or other of the mirror plane will naturally destroy it. Ketone 65 has mirror plane that slices
through the ring 65a. The mirror plane contains the carbonyl and the central carbon of the tertbutyl
group. If we attack the carbonyl with a nucleophile, the nucleophile will have a line of attack
that is within the mirror plane and the resulting alcohol 67 will retain the mirror plane. This is not
the case if we make an enolate 66. The proton must be removed from one side or the other and this
will destroy the mirror plane. Notice that when this happens a chiral centre is formed where the
tert-butyl group connects to the ring.
O
t-Bu
61 62 63
61a
Chiral
centre
O
mirror
destroyed
Step No. 8
Is there an asymmetric aspect to the reaction? Are we, for instance, attacking one of two enantiotopic
groups selectively?
Step No. 9
How does the product differ to the starting material? If necessary, apply step numbers 1 to 6 to
the product too. It might be worth explicitly stating the ‘obvious’ that, in the very simple conjugate
O
OH OH
Ph
62a 64
Base
mirror plane
mirror
O Nu intact
OH
65 66 65a
67
Nu –

addition of a nucleophile to ethyl cinnamate 68, we started with an achiral planar material but the
product 69 is chiral and racemic.
Summary
So then, to summarise, here are the nine steps of stereochemical analysis —
1. Look for symmetry in the starting material
2. Identify relationships within the molecule
3. Decide whether or not the molecule is chiral
4. Decide whether or not it is enantiomerically pure
5. Identify the source of chirality and indicate the chiral centres or axes
6. Look for more subtle symmetry relationships
7. Decide how the reaction infl uences symmetry
8. Identify any asymmetric aspect to the reaction
9. Consider how the product differs to the starting material. Reapply steps 1 to 6.
Applying these nine steps to the simple nucleophilic conjugate addition to a cinnamate ester 68,
we can summarise our fi ndings.
2
enantiotopic
faces
3
1
Some Principles
In this section we look at the infl uence of some numbers on the outcomes of reactions.
Chiral auxiliaries
mirror plane
achiral molecule
20 Some Principles 389
O
OEt
Nu
In Chapter 27 (Substrate Based Strategy) we shall meet the use of chiral auxiliaries. If you ask someone
what properties a good chiral auxiliary should have you will get all the usual suspects – cheap,
both enantiomers available, easy to put on, easy to take off, effective at induction etc. However,
there is one property that gets very little attention. After the reaction the diastereomers should be
separable. Suppose we have a chiral auxiliary 70 with an enantiomeric excess of 96% which reacts
Nu
68 69
O
OEt
68a
4-6 Do not apply
7
8
O
Mirror plane is destroyed
OEt
Reaction not enantioselective
9 Product has a chiral centre
racemic
product
69

390 20 Control of Stereochemistry – Introduction
to produce the product 71 in 74% diastereomeric excess. What is the ee of the product 71? If the
product were hydrolysed without separating the two diastereomers of 71 what would be the enantiomeric
excess of the liberated acid 72? If the two diastereomers were separated before hydrolysis
what would be the ee of the liberated acid 72? Try to work the answers out for yourself before you
look at the answers.
O
N
O
70; 96% ee
O
Ph
O
The answer to the fi rst question is easy. The ee of 71 is 96%. The ee of the ‘wrong’ diasteromer
(which we’ll call 73) is also 96%. The answer to the second question is a bit surprising. It is 71%
ee. The best way to explain this is to draw out all four possibilities. A 96% ee means we will have
98% of one enantiomer 71a and 2% of the other 71b. And a 74% de means that we will have 87%
of one diastereomer 71 and 13% of the other 73. The ratio of 71a to 71b will be 98 to 2 as will
the ratio of 73a to 73b (keep your attention on the stereochemistry in the ring here – this will not
change regardless of the reactions going on nearby).
98
enantiomers
2
reaction
Ph
Ph
71a
71b
O
O
N
N
O
O
The ratio of 71a to 73a is 87 to 13 but the same is true with the other enantiomer in the reaction
so the ratio of 71b to 73b is also 87 to 13. The relative amount of each of the four structures can
then be determined. For example, the proportion of 71a is 0.98 0.87 0.853. If the compounds
are not separated before hydrolysis then everything will be included. One enantiomer of the acid
72 will result from 71a and 73b (0.853 0.003 0.856) and the other from 73a and 71b (0.127
0.017 0.144). The ee is 0.856 – 0.144/0.856 0.144 71.2%. This might surprise you as it
is lower than either the de or the ee of the reaction!
It is a different story if the diastereomers are separated fi rst. In this case both 73a and 73b
will have been thrown away. The ee is therefore 0.853 – 0.017/0.853 0.017 96%. This is an
important lesson. It shows how important separating the diastereomers is. As long as you can do
N
O
O
reaction
Ph
71; 74% de 72
O
O
O
N
O
O
O
OH
Ph
0.853 73a 0.127
Ph
0.017 73b 0.003
87 diastereomers
13
O
N
O
O

this, your de could be 0% (which would mean your auxiliary was a resolving agent) and you could
still get an ee of 96% or whatever the ee of the auxiliary was. This brings us to the next point, your
ee will only be as good as the ee of the auxiliary, so get 100% if you can.
The Horeau principle
We saw above how two numbers conspired to lower the quality of the product. In this next
example the reverse happens. We want to improve the ee of 36. Suppose we have alcohol 36a
and its enantiomer 36b in an 85:15 ratio, an ee of 70%. We’ll represent this by the area in the
box.
36a OH 36b
Ph
20 Some Principles 391
Ph
OH
70% ee
85:15 ratio of enantiomers
If the alcohol is reacted with oxalyl chloride then two molecules of alcohol react with each molecule
of oxalyl chloride. Two diastereomers result. One has enantiomers 75a and 75b and the other
is achiral 74. Assuming the molecules react statistically (and there is no chiral recognition) then
the proportion of 75a should be 0.85 0.85 72.25%. Here’s where the method works – most
of the unwanted enantiomer gets incorporated into the other diastereomer 74 (2 0.85 0.15
25.5%). Only a small amount of the enantiomer of 75b is produced (0.15 0.15 2.25%).
36a
Ph
36b
Ph
OH
OH
Ph
36a OH 36b
O
Ph
O
O
75a
74
O
Ph
Ph
The diastereomer 74 is removed to leave 75a and the small amount of 75b in a ratio of 97:3.
If these esters are cleaved then we have the alcohol 36 with an ee of 94% which is quite an
OH
74
75b
70% ee
85:15 ratio of enantiomers
Ph
Ph
O
O
O
O
O
O
O
O
Ph
Ph
74
75b

392 20 Control of Stereochemistry – Introduction
improvement. This is done at the expense of yield of course as some of the alcohol we wanted was
thrown away in diastereomer 74.
OH
Ph O
wrong diastereomer
(74) separated and
O
O Ph
thrown away
This method was successfully used 8 to improve the enantiomeric excess of alcohol 76 from
92% ee to 99.6% ee. The combination of substrates that are already of quite good enantiomeric
excess to give a product of even better ee is not uncommon and is sometimes referred to as the
Horeau Principle. 9
On the way to the antibiotic FR-900848, an intermediate with four contiguous cyclopropane
rings 80 was required. 10 Cyclopropane 77 was made in 88–90% ee. Dimerisation of 77 yields
a product of 98% ee for the same reasons as outlined above – if the correct enantiomer of one
compound combines with the wrong one of the other then a different diastereomer is produced
and removed, thus removing the wrong enantiomers. Only on the rare occasions that two wrong
enantiomers combine do they form the enantiomer of 78 and slip through the net to the next round.
Dimerisation of 79 improves the ee again, this time to 99.9%.
TBDPSO
76
Successful Application
92% ee → 99.6% ee
78% yield
TBDPSO
TBDPSO
77
=
SnBu +
3
i) sec-BuLi
ii) [ICuPBu 3] 4
iii) O 2
TBDPSO
SnBu 3
SnBu 3
O
75a
97 : 3 ratio of enantiomers
remains. 94% ee
Bu3Sn OTBDPS
78
TBDPSO
OTBDPS
The authors of the above work specifi cally mention the Horeau principle but its operation is
often less explicit. Take for example the production of acid 84 which can be produced in 90–92%
ee by the reaction of optically pure diester 83 of hydrobenzoin 81 in a Diels-Alder reaction. 11
79
75b
i) tert-BuLi
ii) [ICuPBu 3] 4
iii) O2
TBDPSO
88-90% ee
Br
Ph
O
O
O
75b
98% ee
80
O
Ph
> 99.9% ee
OTBDPS

Since two asymmetric reactions are going on the ee of the product will be enhanced (so long as
the diastereomer of 83 is separable and removed the auxiliary is forgiven if it only gets it wrong
once – it has to get it wrong twice for the wrong enantiomer to fi nd its way through). The acid is
cleaved from the hydrobenzoin which is recycled. Acid 84 was needed in part of a synthesis of
FK-506. In fact the authors say that the 90–92% ee material is formed from the reduction of the
crude cycloadduct 83. In which case the Horeau principle cannot be operating as we intimate above
unless the authors somehow inadvertently purifi ed their cycloadduct without realising during, for
example, the fi ltration through silica.
Ph
OH
OH
81
Ph
You might like to work out what the selectivity is in each cycloaddition reaction. To give you
a clue, look back at the graphical diagrams used for diester 84/85 and think about using square
roots. We shall see this sort of double reaction to enhance selectivity again in Chapter 28. One
reaction is a kinetic resolution and the reagent reacts twice. On the second pass it removes the
small amount of the wrong compound that was formed the fi rst time round.
Popular Misconceptions
Misuse of words
O
Cl
Et 3N
20 Popular Misconceptions 393
O
Ph
O
Ph
O
82;
O
>98% yield
TiCl 4
‘Chiral’. For the purist, this is an especially irritating misuse. A worker who has been using racemic
stilbene oxide is about to move onto using enantiomerically pure stilbene oxide. He describes the
enantiomerically pure stilbene oxide as ‘chiral stilbene oxide’ or more probably, in the abreviated
colloquial language of the lab as ‘my chiral compound’. Racemic stilbene oxide is no less chiral
than optically pure stilbene oxide and so ‘chiral stilbene oxide’ says no more than ‘stilbene oxide’.
‘Chiral’ is sometimes used in this way even by experienced and distinguished chemists!
‘Chiral Synthesis’. For the same reason as above, a reaction that features racemic materials is
no less chiral than one with optically pure materials. It should not, therefore, be refered to as a
‘chiral synthesis’: ‘asymmetric synthesis’ is a better term.
‘Racemic Synthesis’. We’ve heard many people object to this term but we really don’t know
why. If you can have an asymmetric synthesis, then why can’t you have a racemic synthesis? The
objection runs along these lines - ‘it is the compounds that are racemic and not the synthesis
and so it should not be refered to as a racemic synthesis’. We suppose so, but the same is true for
asymmetric synthesis isn’t it? Presumably we should not have a ‘comfortable armchair’ since it is
the person who sits in the armchair who is comfortable and not the armchair itself but we would be
allowed to have a ‘warm house’ since the house is indeed warm. Objections to ‘racemic synthesis’
are dogmatic in that they deny the transferred epithet (as in comfortable armchair) which is a
common feature of English.
‘Homochiral’. Is sometimes used to mean ‘optically pure’ and both the authors have used
it this way. But this use to mean optically pure should probably be avoided since ‘homochiral’
has another meaning; if two molecules have the same absolute stereochemistry they can be said
H
O
Ph
O
Ph
O
83
O
H
LiOH
MeOH
H2O
H
O
OH
84; 90-92% ee

394 20 Control of Stereochemistry – Introduction
to be homochiral. Hence if we say ‘those two aminoacids are homochiral’ then we have two
different meanings depending on how we are using ‘homochiral’. ‘Enantiomerically pure’ is
unambiguous.
Chiral centres and stereogenic centres
There has been a move away from describing something as a ‘chiral centre’. The argument is that
a centre, a point, cannot be chiral. Instead it is refered to as a stereogenic centre. If you replace
your ‘chiral centres’ with ‘stereogenic centres’ you will be on safe ground but you should be aware
that they are not necessarily the same thing. In the way that all elephants are mammals but not all
mammals are elephants so all chiral centres are stereogenic centres but not all stereogenic centres
are chiral ones. The dimethylcyclohexanes 85 and 86 illustrate a simple case. Neither compound
is chiral as they both contain a mirror plane. There are no chiral centres. However, changing the
confi guration of the carbon atom where the methyl joins the ring in 85, gives a different (achiral)
diastereomer 86. The centres are thus stereogenic (as they give rise to other stereoisomers) even
though they are not chiral centres.
85
Pseudo-asymmetric centres
We can continue with the above theme but things start to get a bit more complicated. Consider the
triol 87. It is not chiral and might be described by many as a meso compound. We’ll come back to
this compound but for now look at the central carbon atom. This is not a chiral centre and not an
asymmetric centre. You can see this if you try to decide whether it has an R or S confi guration. You
immediately run into trouble because two of the groups on either side are the same (enantiotopic).
This means we cannot give one a greater priority than the other as we usually would.
OH OH OH OH OH OH
R S R r S R S
2 3
OH
1
OH
It is, in fact, r (note lower case). In this situation the group with the R confi guration is given
greater priority than the one with S. Those priorites in 87a would mean an R confi guration if it
were a real chiral centre but since it isn’t we call it r. If we change its confi guration (to s) we get
a different meso diastereomer 88. In other words we get another achiral compound. Whatever we
do with that centre we get achiral diastereomers so it can scarcely be asymmetric—it is not an
asymmetric centre. However, when we change the confi guration we do get different diastereomers
so it is certainly stereogenic (gives rise to stereochemistry). So we see, something can be
a stereogenic centre without being a asymmetric, or chiral, centre. Such centres are sometimes
referred to as pseudoasymmetric centres. In a detailed and highly cited paper, Mislow points out
86
OH
87 87a; (R, r, S)
88; (R, s, S)

that chirotopicity (something that is chirotopic is in a chiral environment) and stereogenicity are
conceptually distinct. The centres above could be referred to as achirotopic (because the molecule
is not chiral they are not in a chiral environment) and stereogenic centres. 12
Unhelpful drawings
Let’s look at a diastereomer 89 of the triol 87 that we have just met. Again we focus on the central
carbon. Imagine trying to make the diastereomer of 89 by changing the confi guration at the central
atom (89 changes to 89a). We now rotate 89a by 180 and fi nd that 89b is identical to 89. Whatever
we do with the central OH (whether we have it coming forwards or going backwards) makes no
difference at all. In other words there is no stereochemical information at all. Triol 89 should be
drawn 89c with an ordinary bond to the central OH.
OH
OH
89
This lack of stereochemistry is typical of substituents that lie on a pseudo-C 2 axis and compound
60 was drawn correctly without stereochemistry to the central phenyl group. However, the central
substuent does disrupt the C 2 axis that would otherwise be there. Consider the two hydroxyl groups
on the left and right of the molecule. One of them will be on the same side of the molecule as the
central hydroxyl and one will not. The hydroxyl groups on the left and right of the molecule are
diastereotopic whereas they would be enantiotopic if the central hydroxyl were not there (because
they would be related by the C 2 axis)
Bond rotation
OH
change
configuration
OH
20 Popular Misconceptions 395
rotate 180˚
OH OH
correct drawing
OH OH
OH
OH
OH
89a 89b 89c
The misconception is that if a bond rotates fast enough, protons interchanging position by that
rotation will be the same. For example, we have already discussed diastereotopic protons in
molecules like 90. The diastereotopic nature of the protons H A and H B is quite obvious here
because it is clear that one will be on the same side of the fi ve-membered ring as the phenyl group
and the other will not be.
90 HN O
91
Ph
O
HB HA The protons in 91 are diastereotopic too. We can see this easily with the diastereotopicity test
we have discussed earlier. Nevertheless, there is sometimes a misconception that, because we now
have bond rotation, they are equivalent. After all, with 91 (unlike 90) we can swing proton H B
into the position occupied by H A and vice versa. But the rotation itself, changes the environment
too – putting H B where H A was also puts the OH in a different place, so H B does not experience
H 2N
Ph
OH
HB HA OH

396 20 Control of Stereochemistry – Introduction
the environment that H A did. Rotating the bond faster will not help as the environment will be
changed at exactly the same rate! As a dog cannot catch its own tail so we cannot get away from
the diastereotopicity.
Stereospecifi city revisited
If you fi nd yourself in a group of organic chemists and the conversation seems to be fl agging a
bit, try throwing in the word ‘stereospecifi c’ and before you know where you are you will fi nd
yourself in the middle of a lively debate about what the word means. We have already established
in the earlier section that stereospecifi city is not merely 100% stereoselectivity and we won’t look
at that again here, but there are other issues for chemists to argue about. The situation is nicely
illustrated by the reactions of the Schwartz reagent [Cp 2Zr(H)Cl] 93. This reacts across alkenes
by hydrozirconation to give a species 94 with a carbon–zirconium bond. This bond can be cleaved
by adding water (which adds a proton to the carbon as we would expect with an organometallic)
or electrophiles such as halides. It can be a very useful reaction.
H Cl hydro-
ZrCp2
Zr
zirconation
In one example alkyne 96 is activated by hydrozirconation. The zirconium is in the terminal
position 99. The two Cp rings are quite big and so it is usual for the zirconium to add preferentially
to the less hindered end of the triple (or double) bond. This is the regioselective aspect of the
reaction and not what concerns us here. Transmetallation to the organolithium and again with
Cu(I) gives the cuprate and this cuprate does a conjugate addition to the double bond of an enone
that looks suspiciously Robinson annelation-derived. 13 Before we move on, notice that the double
bond has a trans geometry – we shall come back to this.
O
+
92 93
94 95
96
O
Me
97
OSiR 3
1. Cp 2ZrHCl
2. 3eq MeLi
3. CuCN•LiCl
4. 97
O
Now then, the hydrogen and zirconium are added from the same side of the molecule at the
same time. If we have a molecule of styrene that is deuterated we can detect this. If we start with
the trans-dideuterated styrene 100 we get one diastereomer 101. But if we start with the cisdideuterated
styrene 102 we get the other diastereomer of product 103. It is a similar story with a
substrate with a triple bond. With phenylacetylene 104, addition of hydrogen and zirconium occur
from the same side. Thus after reaction of the organozirconium species we have a trans double
bond as we observed with 98 and 99.
H
Cl
Br 2
O
Me ZrClCp2 98
OSiR3
H
99
Br
OSiR 3

D
D
Cp 2Zr(H)Cl
93
D
Ph
20 Popular Misconception 397
H
DH
Cl
ZrCp2 Cp2Zr(H)Cl
H Cl
104 Ph
93
Ph
ZrCp2
105
Some chemists would argue that the reactions of the double bonds are stereospecifi c, but the
reaction of the triple bond is not. Their argument is that, for a reaction to be stereospecfi c, a specfi c
diastereomer of starting material must lead to a specfi c diastereomer of product and this implies
that there is an alternative diastereomer of starting material which would give the alternative diastereomer
of product. BUT, since the actylene has no diastereomer, this cannot be stereospecifi c.
Other chemists would argue that this is a load of rubbish and that both are examples of stereospecifi
city. We should be concerned with the mechanistic element of the reaction. We want to
know how the zirconium complex reacts, and this is what the stereospecifi city refers to; delivery
of hydrogen and zirconium to the same side of a multiple bond. The fi rst group of chemists would
probably come back with the argument that in order to probe the mechanism in the fi rst place you
need two diastereomers of starting material and how can we be sure that the reaction with the
triple bond goes by the same mechanism – and so on. Perhaps we should mention that Schwartz
himself describes the addition across a triple bond as stereospecifi c. 14
The defi nition used by Eliel 15 says that something is stereospecifi c when ‘starting materials
differing only in their confi guration are converted to stereoisomerically distinct products’. He
goes on to talk about changing the catalyst instead of the substrate and to discourage the meaning
‘highly stereoselective.’ This defi nition embraces the meaning of stereospecifi city in the double
bond scenario but not its extension to the triple bond. This denies the mechanistic spirit of the
word stereospecifi c. To return to an ordinary S N2 reaction of, say, an alkyl halide with an unspecifi
ed nucleophile. We know S N2 reactions always go with inversion and that an S N2 reaction
is stereospecifi c. The reaction goes with inversion because the antibonding orbital is populated as
the reaction proceeds and there is no other option. Is this stereospecifi c because it is defi ned by the
population of the antibonding orbital AND because there is another enantiomer of alkyl halide for
us to consider or is it just because the antibonding orbital defi nes the process exactly?
This is turning into a bit of a soap box but we would suggest that it is more instructive to use
the latter defi nition. Thus the different stereospecifi c outcomes from different starting material
isomers is a consequence of stereospecifi city of the reaction and not the other way round.
Perhaps the madness of needing to have another diastereomer of a starting material in order
for a reaction to be stereospecifi c is more obvious in the next example. Heptene 106 may be
dihydroxylated stereospecifi cally to give 107. But the reaction of cycloheptene 108 would not be
a stereospecifi c reaction because there is no such thing as a trans cycloheptene. Clearly this is
crazy – both reactions are stereospecifi c. But see what your friends think.
D
D
Cp2Zr(H)Cl
100 101
102 103
HO OH
OsO 4 OsO 4
stereospecific stereospecific?
93
D
Ph
H
HD
HO OH
106 107 108 109
Cl
ZrCp2

398 20 Control of Stereochemistry – Introduction
References
General references are given on page 893
1. Clayden, Chapter 16.
2. Clayden, page 1230.
3. Eliel, page 119.
4. S. Atarashi, S. Yokohama, K. I. Yamazaki, K. I. Sakano, M. Imamura and I. Hayakawa, Chem. Pharm.
Bull., 1987, 35, 1896.
5. H. Egawa, T. Miyamoto and J. Matsumoto, Chem. Pharm. Bull., 1986, 34, 4098.
6. L. A. Mitscher, P. N. Sharma, D. T. W. Chu, L. L. Shen and A. G. Pernet, J. Med. Chem., 1987, 30,
2283.
7. S. Atarashi, H. Tsurumi, T. Fujiwara and I. Hayakawa, J. Heterocycl. Chem., 1991, 28, 329.
8. I. Fleming and S. K. Ghosh, Chem. Commun., 1994, 99.
9. J. P. Vigneron, M. Dhaenens and A. Horeau, Tetrahedron, 1973, 29, 1055.
10. J. R. Falck, B. Mekonnen, J. R. Yu and J. Y. Lai, J. Am. Chem. Soc., 1996, 118, 6096.
11. J. A. Marshall and S. Xie, J. Org. Chem., 1995, 60, 7230.
12. Eliel p. 53 and 123; K. Mislow and J. Siegel, J. Am. Chem. Soc., 1984, 106, 3319.
13. B. H. Lipshutz and E. L. Ellsworth, J. Am. Chem. Soc., 1990, 112, 7440.
14. D. W. Hart, T. F. Blackburn and J. Schwartz, J. Am. Chem. Soc., 1975, 97, 679.
15. Eliel, page 1008.

21
Controlling Relative
Stereochemistry
Note Before We Start
Introduction
PART I – NO CHIRALITY IN PLACE AT THE START
Formation of Cyclic Compounds via Cyclic Transition States
Cycloadditions
Formation of Acyclic Compounds via Cyclic Transition States
Stereoselective aldol reactions
Nomenclature
Early work
The transition state model
Getting control – ketones
Getting control – esters
Reactions of Cyclic Compounds
Conformational Control with Six-Membered Rings
Addition of nucleophiles to cyclic ketones
Reactions of exocyclic enolates
PART II – CHIRALITY IN PLACE FROM THE START
Using one chiral centre to control another
Reactions of Cyclic Compounds: Conformational Control
The half-chair
Reactions of endocyclic enolates
Opening epoxides
Atoms move towards each other when a bond is made
Microscopic reversibility
Formation of a Cyclic Intermediate
Iodolactonisation
Predicting stereochemistry
Application of an iodolactonisation reaction
Variations on this theme
Formation of an Acyclic Compound via a Cyclic Transition State
Claisen rearrangement
The Ireland-Claisen rearrangement
Stereoselective Reduction of β-Hydroxy Ketones
Syn selective reductions
Anti selective reductions
The Evans-Tishchenko reduction
Kinetic diastereoselection of 1,3-diols
Aldol revisited
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

400 21 Controlling Relative Stereochemistry
Open Chain Chemistry - with Chelation Control
Grignards
Zinc borohydride
Open Chain Chemistry - in its Most Genuine Form
Felkin control over reactions of nucleophiles with carbonyl compounds
Role of electronegative substituents
The Houk conformation for reactions of alkenes with electrophiles
Allyl silanes
Note Before We Start: We assume you already know about conformational control in making
new chiral centres and about folded molecules preferring to react on the convex or exo face. You
are referred to Clayden chapters 33 and 34 for a basic treatment of this material.
Introduction
Most of the compounds we shall be looking at in this chapter will be in racemic form. We are concerned
only with the control of relative stereochemistry and not with the control of absolute stereochemistry.
However, many of the reactions have been developed into asymmetric versions. It is certainly true that
many of the reactions have been employed within asymmetric synthesis – that is, where the asymmetric
part has come from elsewhere and this idea will be revisited in Chapter 30. If we are to concern
ourselves simply with relative stereochemistry then, for there to be any stereochemical relationship,
we must have at least two chiral centres. If there is no chirality in the starting materials this means that
two chiral centres must form in one reaction and if there is only one new chiral centre that forms in the
reaction then there must have been a chiral centre already in one of the starting materials.
Some sort of ‘cyclic aspect’ is usually a feature of good stereocontrol. This aspect might be in
the form of a cyclic transition state or perhaps in the generation of a genuinely cyclic compound
but in any case a cyclic aspect is associated with fewer degrees of freedom – or less fl oppiness – in
whatever system we are considering which usually means better control. Without trying to be
exact, the cyclic aspect of reactions broadly decreases down the series –
Formation of cyclic compounds via cyclic transition states
Reactions of cyclic compounds
Cyclic intermediates
Formation of acyclic compounds via cyclic transition states
Open chain stereochemistry
Each of the above topics can be looked at either with no pre-existing chirality, or with a chiral
element already in one of the molecules.
PART I – NO CHIRALITY IN PLACE AT THE START
Formation of Cyclic Compounds via Cyclic Transition States
Cycloadditions
Cycloadditions are supremely powerful when it comes to the controlled formation of many stereogenic
centres. The stereochemistry of the products can be the result of many different stereochemical
aspects. Though strictly this example does not have a place in this chapter (because relative
stereochemistry is not generated), it is instructive.

21 Formation of Cyclic Compounds via Cyclic Transition States 401
1
+
CO 2H CO2H
2
This is a straightforward Diels-Alder reaction. The product is the racemic acid 3. The faces of
the dienophile 2 are enantiotopic – if the diene attacks from one face 4a we get one enantiomer
(R)-3 and the other (S)-3 if it attacks from the other 4b. However, it doesn’t matter at all which
face of the diene 1 reacts. Its faces are homotopic.
CO 2H
CO 2H
4a (R)-3
4b
CO2H
The Diels-Alder reaction is, of course, an excellent way of introducing several new chiral
centres at once. The E,E-diene 5 and unsaturated acid 6 can be expected to give the adduct 7. Note
that we move from no chiral centres in the starting material to four chiral centres. The product is
racemic (±)-7 since we have made no effort to make a single enantiomer.
No
Chiral
Centres
HO2C 5 6
R
The selectivity in the above reaction comes from two sources. Firstly there is the stereospecifi c
aspect. This demands that stereochemistry in the starting materials shows up in the products. That
is, the trans relationship between R and CO 2H in the unsaturated acid 6 shows up in the product
7 as a trans relationship. The same stereospecifi c dictat ensures that the two methyl groups of the
diene 5 end up on the same side in the product. This is less easy to see with a diene, but we would
expect the methyl groups to be trans to one another in the product only if we instead started with
the E,Z-diene. Secondly, there is the stereoselective aspect to the reaction - often referred to in
this context as endo selectivity. We will not go into why this happens here 1 but with normal endo
selectivity, the electron-withdrawing group of the dienophile will prefer to be close to the electronrich
diene. When 5 reacts with 8, we know that the two methyl groups must be on the same side of
the molecule and that the two CO 2Me groups must be on the same side of the molecule. But two
structures 9 and 10 answer this specifi cation. Which is formed?
+
5 8
+
CO2Me
?
CO 2Me CO 2Me
9
CO 2Me
or
3
R
CO2H
(±)-7
10
(S)-3
CO 2H
Four
Chiral
Centres
CO 2Me
CO 2Me

402 21 Controlling Relative Stereochemistry
Predicting the stereochemical outcome of a Diels-Alder reaction is easy once you know the
likely transition state. The trick is to identify all the groups that are on the same side of the sixmembered
ring. The fi gure below shows one way to do this with the bonds on the right hand side
exaggerated and placed in a box. Once the new six-membered ring has been made then these groups
stay on the same side. In this case all the hydrogen atoms are on the same side: the product is 10.
endo
selectivity
operating
here
MeO 2C
MeO 2C
H
H
H
H
groups on the same
side of the forming
six-membered ring
Many Diels-Alder reactions have both stereospecifi c and stereoselective aspects. It is as important
as ever at this point not to confuse perfect stereoselectivity with stereospecifi city. So,
let’s look at a real example. Pumiliotoxin C 11 (a toxin from a tropical frog) contains four chiral
centres and in the following synthesis, three of them were controlled by a Diels-Alder reaction. 2
The retrosynthetic analysis is quite instructive.
The fi rst disconnection 11b (reductive amination) takes no consideration of the chirality at
all – we will worry about this later. We already have a six membered ring and it now contains
all the chirality. The introduction of double bonds by FGA is used to considerable effect in this
retro-synthesis. The fi rst new alkene allows us to do an aldol disconnection 13 that not only
removes a carbon chain but also reveals an electron-withdrawing group on the six-membered ring
14. This is, of course, one vital component of the Diels-Alder reaction. The next FGA puts in the
double bond that allows us to do the retrosynthetic Diels-Alder step 15.
H
The trans relationship between the methyl group and the aldehyde 15 must be preserved in the
unsaturated dienophile 17. The other component (the primary enamine 16) will clearly not be a
stable compound and something will have to be done about that in the forwards route. The reagent
used for enamine 16 is carbamate 22 which is made 3 from unsaturated acid 18.
H
H
H
H
groups on the same side
of the newly-formed
six-membered ring
H
H
H H
H
H
Me
H
reductive
Me
H
N
H
H
N
H H
amination
O
NH2 11a; pumiliotoxin C 11b; pumiliotoxin C
12
Me H
H
NH 2
13
O
Bu
aldol
Me H
CHO
H NH2
14
FGA
Me H
CHO
H NH2 15
Diels-
Alder
16
10
CO 2Me
CO2Me
Bu
NH2
FGA
CHO
17

18
Curtius
CO 2H
rearrangement
1. ClCO 2Et
2. NaN 3
N
21; isocyanate
C O
O
19; acid azide
Ph OH
N N N
O
20; acyl nitrene
We are now ready for the key step in the sequence which is the reaction of the carbamate 22
with the unsaturated aldehyde 17 to give the Diels-Alder adduct 23.
O
This adduct 23 contains three of the four stereocentres and we should look a little more carefully
at the reaction that has just occurred. The two molecules 22 and 17 could have approached each
other in two ways which correspond to endo and exo selectivity. In the endo case, on the left,
giving 23, the anti relationship between the methyl group and the formyl group stems from the
trans geometry of crotonaldehyde and is stereospecifi c. The syn relationship between the formyl
group and the carbamate comes from the endo selectivity in the transition state and is stereoselective.
Had the two components of the cycloaddition chosen to come together in the alternative
exo way (on the right) then there would have been an anti relationship here and 24 would have
been formed.
endo
syn
H
21 Formation of Cyclic Compounds via Cyclic Transition States 403
H
H
CHO
NH
anti
H
CHO
CHO
110 ˚C
H
CHO
N
H
22
N
H
O Ph 17
NHCO2CH2Ph H
22 23, 67% yield
CO2CH 2Ph
syn
syn
NHCO2CH2Ph H
endo-adduct 23
H
stereospecific aspect
stereoselective aspect
exo
exoadduct
24 (not
formed)
H
H
O
H CHO
anti
O Ph
NH
CO 2CH 2Ph
H
CHO
H
anti
N
NHCO2CH2Ph H

404 21 Controlling Relative Stereochemistry
We have now discussed the main point of interest but we may as well fi nish off the synthesis.
Reaction of the aldehyde 23 with a phosphonate salt gives the unsaturated compound 25. This is
the Horner-Wadsworth-Emmons reaction described in chapter 15. Notice that the compound has
two double bonds that we do not actually want – they were there to aid the synthesis and have now
done their job.
H
H
CHO
NHCO2CH2Ph H
The fi nal step is hydrogenation which removes both of these unwanted double bonds. But the
hydrogenation does much more than this! For a start the nitrogen is deprotected 27 and exercises
its nucleophilic muscles once the α,β-unsaturation has been removed (it cannot reach the ketone
until this happens). The result is the imine 28 which can also be hydrogenated. Now the fi nal
stereocentre is introduced. The imine 28 is hydrogenated from its less hindered face. This is
an example of a folded molecule reacting on its convex face. There are several examples of
diastereoselective reactions on folded molecules in chapter 17.
H
Me H
23
NHCO2CH2Ph H
25
Formation of Acyclic Compounds via Cyclic Transition States
Stereoselective aldol reactions
O
O
H NH2
27
(MeO)2P
O O
NaH
H 2, Pd/C
HCl, EtOH
imine
formation
NHCO2CH2Ph H
25, 80% yield
From a stereochemical point of view, aldol reactions can provide us with another one of those fi a t
lux moments – stereochemistry appears to spring from nothing. As in the Diels-Alder reaction, the
stereochemistry comes from two places. Firstly, there is the geometry of the starting materials and
secondly, there are choices that are made in the transition state (remarkably like the Diels-Alder
reaction in fact). Let us focus on the geometry of the starting materials—whether enolates have a
cis or a trans geometry.
H
Me H
H
28
O
N
H H H
26; 95% yield
H
N
Hydrogenate
from this face
Bu

Nomenclature
Just before we go any further we need a quick note on nomenclature. We see below a lithium
enolate 29 and a titanium enolate 30 of an ester. By defi nition, the lithium enolate 29 contains
a Z double bond (lithium is lighter than carbon) whereas the titanium enolate 30 contains an E
double bond (titanium is heavier than carbon). But to call one E and the other Z is plainly crazy.
The important thing, as far as we are concerned, is that the substituent R is trans to the reactive
oxygen. In order to avoid confusion we shall refer to both of these as trans enolates regardless of
the metal 31. This is not universally done (some chemists will be outraged by such simplicity) but
is what we shall be doing in this book.
Early work
29
Z
'trans'
21 Formation of Acyclic Compounds via Cyclic Transition States 405
The pioneering work of Dubois 4 showed that trans enolates 32 of cyclopentanone react to give
selectively anti aldol products 33. The enolates have to be trans because the substituent is locked
into a ring. Heathcock showed that ketone 34 (note in particular the tert-butyl group on the left)
gave the cis enolate 35 and mostly syn products 5 36.
The transition state model
R
O Li
OMe
30
E
'trans'
O OLi O OH
H
trans-32 >95% anti-33
O OLi O
PhCHO
34 cis-enolate 35
R
O TiCl 3
i-PrCHO
So, trans enolates give anti aldol products whereas cis enolates give syn aldol products. Why? The
enolate and the electrophile fi t together in the transition state into a six-membered ring. Chemists
often refer to the model as the ‘Zimmerman-Traxler’ transition state. 6 The six-membered ring is in
a chair conformation. Consider the reaction of some aldehyde RCHO with a trans lithium enolate.
The lithium, the oxygen atom, adjacent carbon atom and nucleophilic carbon atom of the enolate
react via the six-membered ring transition state 37. The methyl group must go into an equatorial
position as it is trans to the oxygen atom of the enolate and is forced into this position. Finally,
there is one sp 2 centre (ArOC) that stays as an sp 2 centre from start to fi nish.
OMe
31
E or Z
'trans'
R
O Metal
OH
OMe
Ph
>98:2 syn : anti 36

406 21 Controlling Relative Stereochemistry
ArO
O
Li
Me
trans-enolate
O
R ArO
O
Li
O
sp H
O Li
O
R
R ArO Me
H
Me
2
centre
equatorial
position
– choice –
equatorial position
37 – no choice – 37; conformation
The R group of the aldehyde, however, can choose to take up an equatorial position 37 or it
could fold round the other way and go into the axial position 40. The favoured conformation 37
gives the anti-aldol 39 while the disfavoured conformation 40 would give the syn-aldol 42.
H
O
Li
O
R
ArO Me
H
equatorial position
– no choice –
O
H
Li
O
H
equatorial
position
– choice –
37; conformation
ArO Me
R
axial
position
equatorial position
– choice –
– no choice – 40
FAVOURED
BUT...
NOT FAVOURED
Li
O O
ArO R
Li
O O
ArO R
aqueous
work-up
O OH
ArO R
O OH
ArO R
What about cis enolates? Consider this time the reaction of a boron enolate. As the lithium was
in the six-membered ring last time so the boron atom is this time. Now the methyl group of the
enolate is forced to adopt the axial position 43 but the aldehyde still chooses to have its R group in
the equatorial position. The result is a syn aldol product 44.
PhS
O
BR 2 O
Me
cis boron enolate
R
Axial position
- no choice -
Me
O
B
O
R
PhS H
43
H
If it is not obvious to you how the six-membered transition states gives rise to the stereochemistry
in the aldol products then read on. The trick is to identify the carbon zig-zag in the six-membered
transition state that corresponds to the zig-zag in the open chain compound. The way we drew the
chairs allows for easy mental transfer of the stereochemistry. Firstly the conformation 37 giving rise
to compound 38 is redrawn 37a but with the hydrogen atoms on the stereocentres emphasised. Now
notice the front part of the six-membered ring – the zig-zag is highlighted in bold. The hydrogen
atoms are quite clearly anti to one another and will be anti to one another on the zig-zag in the fi nal
molecule 39a. In this molecule forward bonds are shown by wedges. The absolute stereochemistry
indicated in the transition state is the same as that in the fi nal product (satisfy yourself that this is
the case) but note that the zig-zags kink in opposite directions – we still have a little bit of work to
do in making the mental transfer.
H
O
Li
O
R
ArO Me
H
37 conformation
Li
O O
ArO R
H
38a
H
38
41
equatorial
position
– choice –
H
O
Li
O
R
ArO Me
H
37a showing anti H atoms
would
give
anti-aldol 39
syn-aldol 42
O OH
PhS R
syn-aldol 44
Li
O O
ArO R
H
H
39a showing anti H atoms

Getting control – ketones
It is all very well knowing what enolates give rise to what aldol products, but this is not much use
unless we can choose to have cis or trans enolates. Clearly with cyclopentanone there is no option
but to form a trans enolate. But with an acyclic ketone we will need a little more care. Boron enol
ethers provide an answer. Two common boron reagents used are 9-BBN chloride 46 (derived from
9-BBN 45) and another is dicyclohexylboron chloride 47. Other reagents include the corresponding
trifl ates. There are also the chiral boron reagents that we shall meet later chapters.
Amazingly, different combinations of base, alkyl groups, and leaving groups on the boron give
different enolate geometries. Broadly speaking, cis-enolates 49 are obtained by having a small
alkyl groups on boron (like butyl), a good leaving group (trifl ate) and a more bulky neutral base
(like i-Pr 2NEt). In contrast, trans-enolates 48 are obtained with sterically demanding alkyl groups
on boron (like cyclohexyl), a less good leaving group (chloride) used in combination with a small
neutral base (Et 3N). 7 The methodology to obtain trans-enolates selectively 8 was later in coming.
We will avoid explanations about why these combinations work but suggestions are available. 9,10
O
B(RBig) 2
O
O
B(RSmall) 2
(RBig) 2BCl (RSmall) 2BOTf
Et 3N i-Pr 2NEt
trans 48 pentan-2-one cis 49
Interestingly, although the 9-BBN group looks like a large group, it (like dibutyl) is often complementary
to a dicyclohexyl boronyl system. Since the groups on the boron are ‘tied back’ it probably
has fewer steric demands than one might initially imagine but also 9-BBN enolates readily
undergo equilibration. 11 Although the leaving group is important, 12 even keeping boron’s leaving
group the same and varying the nature of the alkyl groups can have dramatic effects. 8 The reaction
of propiophenone can thus be varied to give either anti 54 or syn 52 aldol products.
Ph
21 Formation of Acyclic Compounds via Cyclic Transition States 407
O
H
B
45; 9-BBN
Me
50; propio
-phenone
9-BBN-Cl
i-Pr 2NEt
c-Hex 2BCl
Et3N
Cl
B
46; 9-BBN-Cl
O
Me
Ph
B
cis enolate 51
Ph
O
c-Hex
B
B
B
Cl
Cl
46; 9-BBN-Cl 47; c-Hex2B-Cl c-Hex
Me
trans enolate 53
1. PhCHO
2. H 2O 2
1. PhCHO
2. H 2O 2
Ph
O
OH
Me
52; 98% syn
Ph
O
OH
Ph
Me
54; 95% anti
Ph

408 21 Controlling Relative Stereochemistry
But is isn’t as simple as this. The stereochemistry of the enolisation depends also on the group
on the other side of the carbonyl (phenyl in the above case). So, for example, while pentan-2-one
gives mostly cis boron enolate 55, branched ketone 56 give mostly trans. 13 The aldol reaction is
immensely complicated as there are so many variables. However, all the fundamentals from cis
and trans enolates to double stereodifferentiation can be found in a review by Heathcock. 14
O
pentan-2-one
O
56
(c-C5H9)2BOTf
(c-C 5H 9) 2BOTf
O B(c-C 5H 9) 2
cis-55
O B(c-C 5H 9) 2
cis-57
82 : 18
19 : 81
O B(c-C 5H 9) 2
trans-55
O B(c-C 5H 9) 2
trans-57
Ester 58 is a key intermediate in a synthesis concerned with swinholide A. 15 We can see that
two of the stereocentres could be controlled through the use of a syn-selective aldol.
MeO
O TBSO O
58
HO
O
syn selective
aldol
Indeed, the forwards reaction uses a boron trifl ate and a bulky base of the type we have seen
in order to make the cis boron enolate and achieve exactly this control. There are, of course, two
syn-aldol products possible here, 58 and 60, by virtue of the chiral centres present in the aldehyde
fragment, and both do indeed form (in a 16:84 ratio). Trying to achieve selective formation of
one of these syn diastereomers rather than the other syn diastereomer is beyond the scope of this
chapter, even though that too is relative stereocontrol. It is complicated because it involves enantiomerically
pure reagents in combination with the enantiomerically pure aldehyde and a match/mismatch
issue. These issues are explored more fully in Chapter 30. Examples include combinations
of chiral or achiral aldehydes with both achiral and chiral boron reagents.
Bu2BOTf
i-Pr2NEt
O O
BBu2
pentan-2-one
cis boron enolate
59
R
MeO
TBSO O
HO
O TBSO O
+
59
R
O
O
TBSO O
HO
O
O
syn-58 16 : 84 syn-60

Getting control – esters
With esters there is yet another variable that may be used – the nature of the esterifying alcohol.
In fact, we saw the enolates resulting from esters 61 and 64 earlier in the chapter when we were
discussing the transition states. The ester may have a hindered aromatic component 16 61 or be a
thioester 64 instead of an ester.
61
S
O
Ph
O
64
O
LDA
i-Pr 2NEt
R 2BOTf
R 2B
S
Ph
O
Corey used an ester and a thioester in combination with an optically pure boron reagent in order
to control both relative and absolute aldol stereochemistry. 10 The optically pure boron reagent was
busy with the absolute control (the details belong in chapter 27 but 69 was 94% ee and 71 97% ee
by virtue of the chiral boron reagent).
t-BuO
PhS
O
67
O
64
21 Formation of Acyclic Compounds via Cyclic Transition States 409
i-Pr 2NEt
The advantage with esters is that once the stereocontrol has been achieved, the alcohol or thiol
component of the ester may be replaced with something else entirely. That something else may not
contain a heteroatom at all as we shall see in the next illustration. Serricornine 72 is a sex pheromone
for the cigarette beetle and synthetic serricornine is used in the control of the beetle.
We are interested in this instance in the stereochemistry between the γ- and δ-positions. To use
aldol chemistry here would require a carbonyl at the β-position and it is conspicuous by its absence.
We shall have to put it in. Disconnection 72 of serriconin and FGI leads to an acid 74 which
is looking a little more like the kind of substrate we need for an aldol reaction.
O
O Li
trans enolate 62
cis enolate 65
RCHO
RCHO
O OH
ArO R
anti product 63
O OH
PhS R
syn product 66
OBR* 2
O OH
R* 2BBr PhCHO
93% yield
Et3N t-BuO
t-BuO
Ph 98:2 anti:syn
R*2BBr
trans enolate 68
PhS
OBR* 2
cis enolate 70
PhCHO
PhS
anti aldol 69
O
OH
syn aldol 71
Ph
93% yield
1:99 anti:syn
O OAc enolate
O I OAc
O OH
β alkylation
γ
FGI
δ
+
HO
72; serricornin
pentan-2-one 73
74; syn aldol required

410 21 Controlling Relative Stereochemistry
The synthesis starts with the thioester 64 to get the cis boron enolate 75 we need for the syn
product. Once the adduct 76 has been made, the sulfur has done its work and can be removed.
Transesterifi cation with MeOH and HgCl 2 and straightforward steps lead to iodide 78. Once
this iodide has reacted with the enolate of pentanone, there will be no trace of the carbonyl that
originally allowed the aldol chemistry to be performed.
PhS
O
i-Pr 2NEt
9-BBN-OTf
64 cis enolate 75
MeO
One noteworthy step is the control of the fi nal chiral centre. You will have noticed that we did
not worry about the stereochemistry at the α-position at all. Natural serricornine readily epimerises
at that position and so the workers knew they could leave nature to sort that out later. After deprotection
of 79 the mixture epimerised to serricornine 72. This synthesis by Baker and Devlin was
used as the basis for their enantioselective synthesis of serricornine. To intrigue you, something
other than PhS was used and this something could also be removed and was a chiral auxiliary. 17
Reactions of Cyclic Compounds
R 2B
PhS
Conformational Control with Six-Membered Rings
Addition of nucleophiles to cyclic ketones
O
76; syn only
Cyclic compounds have fewer degrees of freedom than their acyclic counterparts and this means
that not only can we expect a higher level of control, but the resulting stereochemistry is easier to
visualise. So reduction of the achiral ketone 80 could lead to the syn alcohol 81 or the anti alcohol
82. The question is which do we get and why?
In fact, either can be achieved by using different reducing agents 18 but let us fi rst look at
the issues concerned in conformational terms. Attack on the carbonyl group 80a will either be
PhS
O OH
O O Si I O Si
1. HgCl2 / MeOH 1. DIBAL
2. TBDMSCl
Im / DMF
77
EtCHO
etc
2. TsCl, Et 3N
3. NaI
O O O Si
O OH
1. LDA
Bu4NF 2. 78
79 72; mixture of epimers
78
stand in
CHCl 3
O OH OH
"H "
or ?
80 81; syn 82; anti
72
serricornine

axial or equatorial leading to the two alcohols 81 and 82 Note that both 81 and 82 are achiral
molecules—achiral molecules with stereochemistry.
axial attack
80a
O
equatorial
attack
"H "
Reducing Agent
NaBH4 7 : 93
L-Selectride 96.5
:
3.5
The product with the equatorial hydroxyl group 82 will certainly be the thermodynamic product
because both of its substituents are in the equatorial position. Let’s look at what reagents yield
what products. The combination of Li in NH 3 will generate solvated electrons. The reducing agent
is an electron. We will come back to this in a minute but for now notice that it is highly selective at
producing the diequatorial compound. Conversely L-Selectride®, LiBH(s-Bu) 3, is highly selective
at producing the other diastereomer. 19 At lower temperatures or with an even bulkier reducing
agent 99.5% 81 is formed.
There is stereochemical control in this reaction but we must be clear about one thing – the
tertiary butyl group is NOT responsible simply by steric hindrance. It is too far away to be of any
direct consequence. Its function is to lock the conformation of the ring. It is the ring itself that
provides the steric hindrance. Structure 80b shows that the there will be steric hindrance from the
axial protons on the ring. Another way to look at this is to consider the plane of the ketone 80c/d.
Some of you will fi nd the ‘right and left’ distinction of 80c easier to grasp and some the ‘top and
bottom’ distinction of 80d. Either way you should see that on one side is the rest of the ring while
on the other side there are merely two protons.
more hindered
axial approach
H
H
O
21 Reactions of Cyclic Compounds 411
We can explain the result with the L-Selectride quite easily. It is a very large reagent and will
thus approach from the less hindered side to give the compound with the axial OH. The result
with the Li in NH 3 takes a little more explaining. Small things are less affected by steric issues
than large things. Some of us know from experience that while closing doors and windows is a
very effective way of keeping cats out of your house, mice will get in through the tiniest of holes.
Trying to block the holes up is simply a waste of time – they will fi nd a way in! Similarly, while
large reducing agents can be expected to respond to steric hindrance, small ones, if they are
infl uenced at all, will be infl uenced by other things.
With this in mind we should look back to the result with the electron (Li in NH 3). This is the
smallest reagent that can be! It will take no notice of steric constraints whatsoever but may well
OH
axial alcohol 81;
from equatorial attack
Li, NH3, ROH 1 :
H H
more hindered
approach
less hindered t-Bu
80b equatorial approach
80c
O
H
less hindered
approach
H
thermodynamic product
H
H OH
equatorial alcohol 82;
from axial attack
99
more hindered
approach
H
H
t-Bu
H
O
H less hindered
approach
80d

412 21 Controlling Relative Stereochemistry
be infl uenced by other things. If the extra stability of the thermodynamic product shows up in the
transition state of the reaction then we would expect this reaction to go faster. This is clearly what
is happening with the electron. Although that appears to wrap it up, it may be that this argument
is simplest, largely because the transition state is probably more like the starting material than the
product and there are other factors at work. 20
Summary (whatever the explanation): large reagents add equatorially and small ones add
axially providing that the thing being added is smaller than the thing already there.
Reactions of exocyclic enolate
The above concerns an electrophilic centre in a six membered ring. The reverse would involve a
nucleophilic centre in a six membered ring. If anything the chemistry is now more straightforward
and is not so infl uenced by the size of the electrophile. With the exocyclic enolate 83, equatorial
attack is preferred. 21 But if the enolate is too reactive then there is little selectivity.
In this section we are not concerned with chirality being in place before the reaction but there
is an additional warning here. Even if a molecule does have a chiral centre in it, it may be that this
centre has nothing whatever to do with the stereocontrol observed. Consider the two unsaturated
ketones below. One of them 85 is chiral, one of them 86 is not.
In both cases, a nucleophile will come in across the unsaturated side of the molecule. The two
chiral centres at the bridgeheads of the chiral molecule 85 have nothing to do with this. The only
consequence of the chiral centres will be that the product will be a chiral diastereomer whereas
(with the achiral ketone 86) the product will be an achiral diastereomer.
PART II – CHIRALITY IN PLACE FROM THE START
Using one chiral centre to control another
Reactions of Cyclic Compounds: Conformational Control
The half-chair
axial attack
R
OLi
equatorial
attack preferred
83 84
85
chiral
O
E
O R
The fi rst concept that needs to be introduced here is the half-chair. Assuming you know how to
draw the chair form of a cyclohexane, then the half-chair is a way to describe cyclohexene. One
half of the normal chair has been fl attened – hence the term ‘half-chair’.
O
Nu Nu
E
86
achiral
product from
equatorial attack

21 Reactions of Cyclic Compounds: Conformational Control 413
cyclohexane
chair
cyclohexane
cyclohexene
The usual way to draw a half-chair is with the double bond at the front of the six-membered
ring 87. The two carbons that are furthest away from the double bond are less perturbed from their
chair-like arrangement and the substituents are axial and equatorial. Those next to the double bond
are not genuine axial or equatorial substituents and occupy what are called the ‘pseudo-axial’
and ‘pseudo-equatorial’ positions. Pseudo is indicated by a ‘Ψ’ symbol. We shall see in the next
section how a half-chair can develop into a chair.
Reactions of endocyclic enolates
The ketone 88 reacts with Me 3SiCl and base to give the more substituted silyl enol ether 89. This
has only one chiral centre and that is at the point where the tert-butyl group joins the ring. The silyl
enol ether 89 is turned into a reactive lithium enolate by the application of MeLi. This enolate then
reacts with the methyl acrylate to give 90 with the stereochemistry as shown. 22 If the tertiary butyl
group is in the equatorial position, which is to be expected, then the new group has been installed
in an axial position 90a. It is this that needs to be explained.
Me 3SiCl
87
substituents
in a half-chair
cyclohexene
axial
Ψ-axial
Ψ-equatorial
equatorial
1. MeLi
half-chair
cyclohexene
Et3N
2.
O OSiMe3 CO2Me O
88 89
90
O
90a
CO2Me
CO2Me
We need to consider how the conformation of the half-chair changes as it reacts. Enolate 91
is drawn as a half-chair with the tertiary butyl group at the back of the molecule in an equatorial
position. If the electrophile attacks from the top face then, as a bond forms to the electrophile
and the sp 2 hybridisation changes to sp 3 , a chair 92 starts to take shape (for clarity, we’ve omitted
the carbonyl double bond in the conformational diagram). We see that the electrophile occupies
an axial position. However, if the electrophile attacks from below, then a twist boat 93 starts
to develop instead. If this boat were fl ipped into a chair, the new electrophile would be in the
equatorial position. 22

414 21 Controlling Relative Stereochemistry
88
So attack on one side leads to an axial substituent whereas attack on the other leads to an
equatorial substituent (but only after the ring fl ips). Boats are, of course, much less favourable
than chairs and so axial addition is the usual outcome as the chair is formed during the reaction
and not afterwards. We shall refer back to this as the normal development of a half-chair.
Summary: If the starting material is not a chair (it might be a half chair), the most important
thing is to get a chair. The question of whether groups go equatorial or axial is less important. On
the other hand, if the starting material is already a chair (it might be ketone 80), the most important
question is whether groups or reagents are in equatorial or axial positions.
Opening epoxides
E
t-Bu
O
92 as chair
t-Bu
O
91
E
t-Bu
O
E
We can look at how epoxides are opened in a similar way. The fl attening of the six membered ring
by the strain of the three membered ring 95a is not dissimilar to the fl attening caused by a double
bond 94. We can attack the end of the epoxide 95 (with generic nucleophile, Nu ) that leads to a
chair 98 rather than the end that leads to a twist-boat 97. Compound 96 is the trans-di-axial product
as both Nu and OH occupy axial positions.
t-Bu
t-Bu
94
Nu
Atoms move towards each other when a bond is made
Nu
mCPBA
t-Bu
boat
t-Bu
When you think about the development of a half-chair into a chair it is important to remember that
atoms move towards each other as they form a bond. This sounds like rather an obvious statement
but there is subtle psychology at work – although chemists rarely make the mistake when the half
chair is the nucleophilic component, it seems all too easy to think absent-mindedly of an attacked
electrophilic carbon atom in a half-chair retreating away from the incoming nucleophile – and this
is not the case. The atoms move towards each other.
E
93 as twist-boat
O
95
chair
=
flip to
chair
t-Bu
O
O
O
97 95a
98
Nu
Nu
t-Bu
O
t-Bu
HO Nu
96
t-Bu
92
E
O E
93 as chair
Nu

Nu
atoms move towards
each other
Nu
H H
H
H
Cl
Microscopic reversibility
E
atoms move towards
each other
E
Another way to look at the opening of epoxides uses the principal of microscopic reversibility.
Microscopic reversibility is all about considering a reaction in reverse like watching a piece of fi lm
run backwards. You would expect the fi lm running backwards to be the exact reverse of the fi lm
running forwards. A clown receiving a custard pie from the left of his face, will have it removed to
the left of his face. We would never expect that, in reverse, it would disappear off to the right! The
same is true of reactions – as then run forwards, so shall they run backwards. At every step of the
way (frame by frame) they will be identical.
The justifi cation for this is that a reaction running forwards will run along the lowest energy
pathway. Hence it will run back that way too. If there were a lower energy pathway on the way
back then the forwards reaction would have found it and used it too! The lowest pass between
two valleys is the same whichever way one is travelling. Why should we bother with this? For the
simple reason that it is sometimes easier to consider a reaction in the reverse sense – easier to see
the orbitals concerned, the stereochemistry involved, the conformation necessary or whatever.
We will stick with the epoxide 95 we used in the half-chair analysis above and react it with RLi.
Since the nucleophile is organometallic the reaction is not reversible. We should be clear about this
point — the reaction does not have to be reversible to use a microscopic reversibility argument.
The two conceivable products 101 and 102 are drawn (assuming S N2 reaction).
t-Bu
O
RLi
We now draw the conformational diagrams 99a and 100a of the intermediates and consider the
reverse reaction that would lead back to the same epoxide 95. In the reverse reaction, the alkoxide
would have to come in behind the R group and displace it.
t-Bu
21 Reactions of Cyclic Compounds: Conformational Control 415
95
R
R
R
t-Bu
99
or
O
t-Bu
100
O
R
t-Bu
aqueous
work-up
Nu
atoms move towards
each other
Nu
O
t-Bu
95b O 98
R
t-Bu
101
or
OH
t-Bu
R
R
R
O
O
O line
of
t-Bu
t-Bu
t-Bu
R O
attack
line of attack
X
impossible
99a 99b
100a 100b
102
OH
R

416 21 Controlling Relative Stereochemistry
In one case this is clearly possible 99 and in the other it is not 100. And if R cannot be displaced
by O then the forwards reaction cannot happen either. So, once again, the diaxial product
is the product we would expect. It is not really necessary to get too involved with orbitals here as
the alignment (or lack of it) is very evident. But if we wanted to we could think of this from an
orbital point of view. The σ* of the C–O bond is populated when the epoxide is opened and goes
into forming the lone pair on oxygen and the C–R σ-bond. They would have to realign to turn back
into their former selves in the reverse reaction too.
Summary: Opening cyclohexene oxides with nucleophiles gives the trans-di-axial product.
Formation of a Cyclic Intermediate
Iodolactonisation
A stable cyclic intermediate can be a good way to control stereochemistry. The idea is often to
create stereochemistry in forming the ring and cleave the ring later with the stereochemistry
already in place. Treatment of acid 103 with iodine yields the iodolactone 104. This must take
place by an intramolecular version 105 of the reactions we have just been discussing. 23 This
reaction was also discussed in chapter 17.
CO 2H
I 2, NaHCO 3
KI
I
103 104
O
O
This reaction is worth looking at in a little more detail. It depends upon formation of an intermediate
species, the iodonium ion 105. There is nothing to stop the diastereomeric iodonium ion
106 from forming but cyclisation with the carboxylate ion cannot occur and, since the reaction is
reversible, the reaction will run back to the unsaturated acid 103 and try again. The two alternative
iodonium ion conformations with equatorial CO 2 groups cannot cyclise until the chain fl exes to
put the CO 2 axial.
attack
here
leads
to chair
O O
I
105a
attack
here
leads
to boat
O O
I
carboxylate cannot
attack here
106
The iodonium ion that does react cyclises 105 to give a chair 104a and not a boat. The 1,3- lactone
bridge must be diaxial - another reason why the CO 2 group must be axial for cyclisation to occur.
We can also see that the product 104 has the trans-diaxial relationship between the iodine and the
CO 2 group we are familiar with from the opening of epoxides.
The iodolactone 104 can be elaborated. Once again we should look at the compound from a
conformational point of view 104a. There is only one proton in an antiperiplanar relationship to
the axial iodine atom and so elimination will occur with this proton 107. When it comes to reaction
of the new double bond in 108, stereoselectivity will be dominated by the lactone bridge which
103
equatorial
proton
I
H
O
H
H
I
105
O
O
O
equatorial proton
104a
104
axial proton

will provide a barrier to incoming reagents. So, epoxidation leads to the oxygen being introduced
on the underside of the ring to give epoxide 109. On the other hand, if the lactone bridge is fi rst
opened a different epoxide 110 is formed.
B
H
O
H
O
DBU
O
H
I
O
107 108
109
Just before we continue let’s have a look at the reagents used in the iodolactone formation. The
iodine is obviously needed but notice the weak base, NaHCO 3. This will deprotonate the acid
(making it more nucleophilic) and make the reaction faster. Only one product is possible from 103
but in some cases the presence or absence of base leads to different products. The example 103 is
probably the most straightforward – we start with a ring to aid the control of another one. Things
become more complicated when we form iodolactones from open chain compounds The hexenoic
acid 112 can give two different iodolactones 24 111 and 113.
Ph
O
In one reaction base is used and in the other it is not. When base is not used the product is the
thermodynamic trans lactone 113 whereas with base then the kinetic cis lactone 111 is formed.
The decision about stereochemistry is made when the iodine fi rst attacks the double bond. But this
is not the end of the story. Once again we might expect addition of I 2 to be reversible (which means
that the decision is not yet irrevocable) and so the selectivity will be down to which of the iodonium
ions 114 or 115 cyclises. The infl uence of the base might be to change the rate determining
step of the reaction. With a more reactive nucleophile to hand (carboxylate instead of carboxylic
acid) we could imagine that the iodonium ion 114 would not have any time to equilibrate before
nucleophilic attack occurs.
Predicting stereochemistry
21 Formation of a Cyclic Intermediate 417
I
O
I 2
NaHCO 3
CHCl3
ArCO3H
Ph
O
CO 2H
It tends to be easier to predict the stereochemistry of thermodynamic products and in general,
thermo-dynamic control give good diastereoselection. With six-membered rings the bulkier substituents
will end up trans if they are substituted in a 1,2 pattern and cis if they are 1,3-related
(this is presuming there is some element of choice of course). With fi ve membered rings then the
substituents need to be 1,2-related if there is to be diastereoselection and then they will end up
trans. 25
O
104
base
MeOH
O
111 112
113
I 2
I 2
MeCN
111
Ph
I
NaHCO3 Ph
I2
Ph
I
113
CHCl3
MeCN
Ph
CO2
CO2H CO2H 114 112
115
O
I
O
O
110
CO2Me

418 21 Controlling Relative Stereochemistry
Application of an iodolactonisation reaction
(±)-Methyl shikimate 116 has been made using a strategy with iodolactonisation at its heart. 26
Note that shikimate has three chiral centres. Interestingly, these three centres are controlled in
the synthesis by a centre that is fi nally destroyed. The fi rst steps are iodolactonisation of 103 and
subsequent elimination and epoxidation to give 109 as described above.
103
CO 2H
Epoxide 109 is opened with Me 3SiBr (Ph 3P-catalysed) and another elimination with DBU gives
the allylic alcohol 117. The epoxidation that follows is controlled in a couple of ways. Firstly, the
axial alcohol can direct the reagent (the same peroxyacid used to make 109) to the bottom face of
the six-membered ring which is also the less hindered side of the molecule (opposite the lactone
bridge) 118. The synthesis is completed with basic methanolysis of the lactone 118 to give racemic
methyl shikimate 116.
109
1. Me 3SiBr
Ph 3P
2. DBU
HO
The last step in this reaction (the methanolysis) warrants a little more discussion as there is
quite a lot going on—the epoxide has gone and a new double bond has appeared. The fi rst step is
merely the methanolysis to give ester 119 but, under the basic reaction conditions, the ester can
be deprotonated to form enolate 120 which spontaneously opens the epoxide to give our target
material. Note that the stereochemical information at the α-position – the only chiral centre in the
starting material 103 – is lost with the deprotonation and never comes back.
Variations on this theme
1. NaHCO 3, I 2, KI
2. DBU, THF
O
O
ArCO 3H
O
There are several reactions that have a similar fl avour to iodolactonisation. 27 That is, where an intramolecular
nucleophile attacks an electrophilic site that is derived from a double bond. The most
O
108; 84% yield
O
ArCO 3H
Ar = 3,5-dinitrophenyl
HO
O
O
O
109; 81% yield
(+6% endo)
HO
O
MeOH HO
OH
117 118; 85% yield
116; 98% yield
O
K 2CO 3
O
118
K2CO3 HO CO2Me K2CO3 HO
OMe
116
MeOH
HO
O
HO
O
119 120
O
OMe

obvious cousin must be the bromolactonisation. Acid 121 was subjected to bromolactonisation in
the fi rst stage in the synthesis of a pheromone component. 28 But for a more complicated substrate,
bromolactonisation was used in Corey’s synthesis 29 of erythronolide B. Dienone 122 was reacted
with bromine and KBr to give bromolactone 123 in 96% yield. In fact, a few steps later, another
bromolactonisation was done which featured the other double bond.
121
Other varieties of this sort of reaction include bromoetherifi cation (where the nucleophilic
component is an alcohol rather than a carboxylic acid). Kishi 30 used this reaction to form one
of the tetrahydrofuran rings 124 to 125 in his synthesis of Monensin but he used NBS instead of
bromine as the source of electrophilic bromine. 31
Ar
H
O Et
Me
Formation of an Acyclic Compound via a Cyclic Transition State
Claisen rearrangement
21 Formation of an Acyclic Compound via a Cyclic Transition State 419
CO2H
Me
O
Me Me
Me
122
CO2H
Br 2 / KBr
O
Me
O
123; 96% yield
The Claisen rearrangement 32 converts an allyl vinyl ether 126 into a γ,δ-unsaturated carbonyl
compound 128. This is already useful simply because it is a good way to make γ,δ-unsaturated
carbonyl compounds but we are interested in the additional stereoselective aspects of the reaction.
This is a [3,3]-sigmatropic reaction 127.
R'
126
O
R
At fi rst sight it may appear that this reaction is not going to be terribly useful stereo-chemically.
For instance, in the above scheme we start with one chiral centre and end with none at all. However,
it should be noted, before we start to make the chemistry any more complicated, that the trans
geometry of the double bond is controlled by what R’ chooses to do in the transition state 129.
Me
Ar
OH Me
H
O
Et H
O
H
124 125
R'
127
O
R
heat
[3,3]
O
R' R
γ
R' R'
R'
O O
O
δ
O
Me Me
Me
Br
Br Me
trans geometry of 128
controlled by what
R' chooses to do
R'
O
R
R
R
R
126a 129 128a 129a
128

420 21 Controlling Relative Stereochemistry
The choice is reminiscent of what we have seen with the aldol reaction – where the electrophilic
aldehyde chooses to place its R group equatorial. Here too, R’ chooses the equatorial position.
The equatorial positions in cyclohexane are always parallel to one of the existing bonds within
the cyclohexane ring 129a. The relationship between that bond and the substituent R’ is already
trans before 126a and during the reaction 129. So, a trans double bond results. This reaction is
discussed in chapter 15.
We can make the situation much more complicated because substituents can be introduced to
both of the double bonds 130. Of all the substituents R’ and a-d, R’ is the only one that has any
choice—the others just have to do what they are told.
Allylic alcohol 131 reacts with enol ether 132 to give an allyl vinyl ether 133 which is ripe for
rearrangement. As it happens, 133 is optically pure and contains a trans double bond.
a
R'
OH
EtO
c
b
d
O
i-Pr
R
131
Me
130
132
/ H +
The two options for rearrangement are that the isopropyl group can choose whether it
adopts an axial 135b or an equatorial 135a position in the transition state. 33 The methyl group
has no choice at all – it has to be in an equatorial position because it is attached to the trans
double bond involved in the reaction. The product from 135a contains a trans double bond
and an S confi gured carbon atom while the product from 135b has a cis double bond and the
R confi guration.
equatorial
NO
choice
here
i-Pr
H
Me
O
135a
i-Pr
H
Me
The product E-134 resulting from the equatorial isopropyl group is the one that is favoured.
Note that the chiral centre we started with has been destroyed and a new chiral centre has been
introduced. This process is sometimes known as ‘chirality transfer’. Interestingly, if we start with
the other absolute stereochemistry and the other bond geometry 136, the outcome is the same. 34
So, cis compound 137 also gives aldehyde 134.
i-Pr
OH
136
To the shrewd operator, this can be quite a handy trick since it provides a way of using both
enantiomers, from a resolution say, to give the same enantiomer of product.
O
[ 3,3 ]
Me
i-Pr Me i-Pr H
133 134
O
=
i-Pr
H
H
O
O i-Pr O
i-Pr
O
Me
Me
R
=
=
H
i-Pr axial i-Pr
135b Z-(R)-134; Not favoured
i-Pr
O
137
O
equatorial
O i-Pr
H
138
O
O
=
S
i-Pr H
E-(S)-134; Favoured
O
H
H
E-134
i-Pr =
Favoured

i-Pr
OH i-Pr
(±)-139
Me
resolution
i-Pr
The Ireland-Claisen rearrangement
OH
(R)-140
OH
(S)-140
Me
There are many variations on this Claisen theme. Take, for instance the Ireland-Claisen
reaction 35 where an enol ether of an ester (a silyl ketene acetal) 143 is used instead of the simple
vinyl group in the standard Claisen reaction. The double bond geometry can be controlled by
the enolisation process. In this example 143 we have one chiral centre and two double bonds
before the reaction. Once again, the R group has choice but the substituents on the double bonds
do not.
OH
R
O
141 142
O
R
Following the reaction we have two chiral centres and one stereochemically controlled double
bond 145. Note that the chiral centre that was in place at the start has been destroyed but its chiral
essence has not — it is reborn in the two new chiral centres in 145.
H
OSiMe3
Me
R
H
O
Me
144
21 Formation of an Acyclic Compound via a Cyclic Transition State 421
[ 3,3 ]
An Ireland-Claisen reaction was employed by Hulme and Paterson in their synthesis of
the ebelactones. 36 Interestingly, the synthesis featured an unprotected ketone 146. This nice
piece of chemoselectivity probably relied upon the conditions of the enolisation process as
well as the steric congestion around the ketone. The enolisation reaction used an in situ
trapping by having a mixture of Me 3SiCl and Et 3N together with the ester before the LDA
was added. The cis silyl enol ether (or ‘E silyl ketene acetal’ if you prefer) 147 resulted and
following rearrangement and hydrolysis the E-ester 149 was isolated in 83% yield and 96:4
diastereomeric ratio.
Me
1. LDA
2. Me 3SiCl
H
OSiMe3
Me
R
H
O
Me
145
=
H
Me
H
Me
i-Pr
i-Pr
OSiMe3
143
O
145
OH
OH
136
131
O
R
OSiMe 3
R
134
134
1 × chiral centre
2 × double bonds
2 × chiral centres
1 × double bond

422 21 Controlling Relative Stereochemistry
MeO
O
O O OTBDMS
With all this talk of chair transition states it is easy to think that the outcomes of Claisen reactions
and their friends are easy to predict. Beware however, because they can occasionally proceed
through a boat transition state if the substituents make the chair too unfavourable.
A related reaction is the [2,3] Wittig rearrangement. 33, 37 This goes via a fi ve-membered
transition state – we shall not go into any more detail about that – but it too is a useful reaction
both for making homoallylic alcohols and because of the stereocontrol that can be achieved in
the process. Allylic ether 150 gives 38 only the diastereoisomer shown of alcohol 152. The [2,3]sigmatropic
rearrangement 151 creates an E-alkene at the expense of a Z-alkene and two new
chiral centres at the expense of one. The immediate product of the [2,3]-shift is an oxyanion
instead of a carbanion.
Stereoselective Reduction of β-Hydroxy Ketones
We shall look in this section at two methods to reduce β-hydroxy ketones 154. One method gives
the anti product 153 whereas the other gives the syn 155. In both cases, the existing chirality at
the carbinol carbon is dictating the reagent’s performance.
Syn selective reductions
O
BuLi
THF
–78 ˚C
O
HO
Ph
Ph
150 151 152
OH OH
R
153 (anti)
1 R2 OH-directed
reduction
OH O
R 1 R 2
OH-directed
reduction
OH OH
The overall process involves a stoichiometric reducing agent which is plain old NaBH 4 and another
boron species Et 2BOMe. We shall see in a minute that it is the job of this second boron species to
hold the β-hydroxy ketone 156 in a ring as the reduction proceeds. 39
OH O
146
O
O OTBDMS
149; 83% yield; 96:4 diastereomers
Bu Bu
156
Et 2BOMe, NaBH 4
MeOH / THF –70 ˚C
–78 ˚C
TMSCl / Et 3N
LDA
H
Ph
R 1 R 2
154 155 (syn)
OH OH
Me
Bu Bu
157; 99% yield
OSiMe3
O
H
OSiMe3 O O OTBDMS
Me
148
O
warm
[3,3]
diastereoisomer ratio:
99:1 syn:anti
147
OTBDMS

But fi rst consider the yield of the reaction. It is 99%. What is more, the diastereoselectivity
is 99:1. If you work in a lab yourself, you might refl ect on how many of your reactions go in
99% yield with such high selectivity. It really is a very good reaction indeed and this is how it
works. Under the reaction conditions the cyclic intermediate 158 is formed. Methoxide has been
displaced from Et 2BOMe and one of the carbonyl lone pairs also gets in on the act and binds the
boron in place. Reduction of 158 gives another boron chelate 159.
OH O
Bu Bu
156
We have two sp 2 centres in the ring (the carbonyl) and so have a half-chair 158a. We already
know from this chapter that half-chairs, by axial attack, develop into chairs. Axial delivery of
hydride from NaBH 4 gives 159a. Note the two hydrogen atoms in the resulting chair 159a. In your
mind, highlight the zig-zag of the carbon chain from one butyl group to the other to reveal that the
two hydrogen atoms are on one side of the chain and the two oxygen atoms on the other side. The
stereochemistry is in place. All that remains is to remove the boron to liberate the diol syn-157.
This hydrolysis is done with acetic acid.
Anti selective reductions
21 Stereoselective Reduction of β-Hydroxy Ketones 423
Et2BOMe
Et Et
Et Et
O
B
O NaBH4 MeOH
O
B
O
Bu Bu
Bu Bu
158 159
axial attack
syn protons
Bu
Bu
O
O
Et
B
Et
NaBH4 Bu
H Et
H
O
B
O
Et
AcOH
Bu
OH OH
Bu
Bu
158a
159a syn diol 157
Boron reagents are used once again in the anti selective reduction but this time one reagent does
all the work. Again, a look at the overall reaction reveals a reaction of the same calibre. 40
OH O
Bu Bu
156
Me 4N + (AcO) 3BH –
AcOH / MeOH, –40 ˚C
OH OH
Bu Bu
160; >90% yield
diastereoisomer ratio:
95:5 anti:syn
Once again it’s the hydroxy group that starts things off by binding to the boron 161. But this
time the hydride is delivered internally to the carbonyl group through a chair transition state 162.
The hydrogen atom forms part of the ring with the carbonyl oxygen axial and the butyl group
equatorial. Again, highlight the carbon chain in your mind and notice the substituents on it 163.
This time the two hydrogen atoms (and the two oxygen atoms) are on opposite sides of the chain.
(AcO) 2B
O
Bu
H
161
O
Bu
anti protons
Bu
H OAc
O
B
O OAc
H
Bu
H OAc
OH
O
B
OAc
H
Bu
OH OH
Bu
Bu
Bu
162 163
anti-diol 160

424 21 Controlling Relative Stereochemistry
The Evans-Tishchenko reduction
Another way to produce 1,3-diols in an anti-selective reaction also starts with a β-hydroxy ketone.
The reaction is catalysed by samarium iodide but the stoichiometric reducing agent is acetaldehyde
which ends up as the acetate ester in the product 165.
OH O OAc OH
MeCHO
164
The overall reaction gives the ester 165 and not, as we might expect, a diol or an acetal. The
alcohol 164 reacts with acetaldehyde to form a hemiacetal 166. It is the hydrogen on this hemiacetal
that is delivered as a hydride to reduce the neighbouring carbonyl but only after a Sm chelate 167
is formed. Compare this transition state 167 with 162 where trisacetoxyborohydride donated the
hydride ion. They are very similar: both transfer a hydride via a six-membered cyclic transition
state. In 162 the boron holds the two oxygens in a ring while in 167 it is samarium. 41
164
MeCHO
HO
Me
The selectivity (99:1) is astounding but made all the more impressive when we see that substrates
with other chiral centres react very selectively too. So, both syn and anti β-hydroxyketones 168 and
170 give excellent anti diastereoselection. But this reaction can be as fi ckle as frustrated chemists
rather expect – compound 172 does not react at all under these conditions while compound 173
reacts as expected.
Kinetic diastereoselection of 1,3-diols
H
O O
Hex
15% SmI 2
SmI 2
becoming
equatorial
165; 96% yield > 99:1 anti : syn
Sm
O
O
O
H
Hex
166 167
OH O i-Pr O OH
i-PrCHO
168, syn
15% SmI 2
15% SmI 2
169; 95% yield, > 99:1 anti : syn
OH O OAc OH
170, anti
MeCHO
O
171; 86% yield, > 99:1 anti : syn
While we are on the subject of anti and syn-1,3-diols, there is a very useful reaction that allows
their separation by means of reaction rather than, say, chromatography. The reaction is a kinetic
diastereoselection. With a kinetic resolution, one enantiomer of substrate reacts faster than the
anti
anti
BnO
BnO
Me
OH O
172; no reaction
OH O
165
173; reacts as expected

other. With a kinetic diastereoselection, one diastereomer of substrate reacts faster than the other.
As with a kinetic resolution, the quality of the material that is left behind improves as the reaction
is taken to greater levels of completion. Acetals 174 were made from a mixture of the corresponding
anti and syn diols. The acetals are hydrolysed with dilute acid and then the reaction is stopped
prematurely by the addition of base. The anti diastereomer hydrolyses more quickly to produce the
anti diol 175 while the syn acetal 176 is left behind. 42
Aldol revisited
2M HCl (5 mol%)
O O 20 ˚C / CH2Cl2 / 1 hr O O
63% conversion
OH OH
174; syn : anti, 1.2:1 175; syn : anti, 30:1 176; syn : anti, 1:2
Finally we’ll have a quick look at how combinations of these methods have been applied. In the
aldol reactions we have looked at so far there has been no chirality at the start. Both the aldehyde
and the enolate have been achiral species that have reacted in a stereoselective way to give a particular
diastereomer. With the aldol reaction there is a lot of opportunity to introduce aspects of
chirality. The enolate could be chiral as could the aldehyde. In addition to this, the whole reaction
could be mediated by a chiral catalyst. Although chiral enolates are most commonly associated
with asymmetric methods (most famously the method of Evans in Chapter 27) it is important to
remember that the components could just as easily be chiral and racemic. The diastereoselectivity
that allows the Evans’s chemistry to work with optically pure materials will operate whether the
auxiliary is optically pure or not.
In the next example, the chiral ketone happens to be optically pure but it is still an example
of relative stereocontrol. We shall see more of relative stereocontrol with optically pure
materials in Chapter 30. We saw in the Diels-Alder reaction that different features of reactivity
are responsible for different aspects of resulting stereochemistry — geometry of starting
materials, stereospecifi city of reaction and endo selectivity all have their part to play. Ketone
177 is reacted with a boron chloride to give boron enolate 178. Signifi cantly, this is a trans
enolate which means we can expect an anti relationship from the aldol reaction which we do
indeed see 179.
RO
21 Stereoselective Reduction of -Hydroxy Ketones 425
O
O
RO
OBn
OBn
B(cHex)2
anti
O OH
(cHex) 2Cl
Et3N, –78 ˚C
RO
OBn
trans anti
177 178 179
However, another anti relationship also appears in the product. The trans enol was not responsible
for this but the existing chiral centre was. Assuming that the trans-boron enolate will give its
anti relationship come what may, the two possible diastereo-mers were the anti, anti 179 and the
syn, anti 180. One chair transition state leads to one and another chair to the other.
+
RO
180
syn
O OH
OBn
anti

426 21 Controlling Relative Stereochemistry
If you would like to know more about how the existing chiral centre makes its infl uence felt
then you are directed to the paper 43 and a suggestion for transition states. 44 For now we continue
with the manipulations. The new hydroxyl group that has been formed in the aldol reaction can be
used to direct a stereoselective reduction of the ketone in the way that we have already seen. So,
β-hydroxyketone 179 is reduced to diol 181.
We now have four chiral centres. Three of them are new and put in place relative to the
starting chiral centre. Since that was optically pure we have an optically pure product. Diol 181
is an intermediate on the way to a fragment of Spongistatin 1 – a chain extension, asymmetric
dihydroxylation and stereoselective intramolecular Michael addition all feature on the way
there. 43
Open Chain Chemistry - with Chelation Control
Grignards
RO
O OH
OH OH
Me4N•(AcO) 3BH
MeCN, –30 ˚C to –20 ˚C
RO
OBn
OBn
179 181
When students fi rst encounter stereochemistry, there is a tendency for them to justify
stereochemistry based upon the way the compounds happen to have been drawn. So, when asked
to explain why ketone 93 reacts with BuMgBr to give mostly diastereomer 94 the answer is easy.
Why yes, obviously the butyl group comes in on the less hindered side of the carbonyl 182a which
is the one opposite the R group.
Ph O
O
Me
BuMgBr Ph O
BuMgBr
Me
R
R
182 183
HO Bu
attack from behind
Ph O
R
182a
But of course, the exact same question could be asked with the structures merely drawn in an
alternative conformation 182b and 183a. Sticking with the same enantiomer we now fi nd that
attack still occurs from behind even though that is now from the same side as the R group.
Ph
R
O
Me
HO Bu
BuMgBr R
BuMgBr
Me
O
Ph O
182b 183a
Something, somewhere must be controlling the conformation to give control of stereochemistry
and just drawing the molecules in a convenient way is going to give the right answer
only by chance. Chelation is the answer. In the example we’ve just seen, it is the magnesium of the
Grignard that is doing the work. Both the oxygen atoms bind to it to lock the conformation of the
Ph
R
O
182c
O
Me
O
Me
attack from
behind?

molecule 184. The butyl group does indeed attack the ketone from the less hindered side (opposite
the R group) and now we have a reason why.
182
MgX 2
Zinc borohydride
21 Open Chain Chemistry - with Chelation Control 427
Mg
Ph O
R
184
O
Me
attack from
behind
Ph O
Chelation control of this kind is commonly exploited in reduction and a favourite reagent is
zinc borohydride 45 [Zn(BH 4) 2]. As with the Grignard, we need a second oxygen atom to do the
binding. It works well with α-hydroxyketones 186. Generally speaking, the anti diastereomer will
be favoured. We can draw a conformation where the oxygen atoms are on the same side of the
molecule both bound to the zinc 187. The hydride will then be delivered from the less hindered
side of the molecule. If R 1 =Ph and R 2 =Me, the ratio anti:syn-188 is 98:2.
R1 R2 O
OH
R2 O
O
R1 Zn
hydride comes
in opposite R2 Zn(BH4) 2
H3B H
186 187
A similar sort of thing can be achieved with β-ketoesters where the major product is the syn
diastereomer as we shall see in the example given below. Interestingly, Zn(BH 4) 2 does not generally
work very well with β-hydroxyketones. But there are other very powerful methods available for
that sort of transformation which we have see already. Both the reduction of a β-keto ester and an
α-hydroxy ketone are put to use in the synthesis of racemic blastmycinone 46 190 – a key fragment
of blastmycin 189.
HN
CHO
OH
O
H
N
O
O
O
O
189; (±)-blastmycin
O
O
The synthesis of blastmycinone begins with a Reformatsky reaction. Although the resulting
allylic alcohol 192 is a required intermediate, it is formed in this reaction without any stereocontrol.
The alcohol 192 is oxidised in a Swern reaction to the enone 193 only to be resurrected in the next
reaction but this time with stereocontrol.
R 1
Mg
R
185
OH
O
OH
R 2
Bu
Me
+
R 1
OH
OH
183
R 2
anti-188 : syn-188
anti:syn = 98:2, R1 =Ph and R2 =Me
2 x C–O
ester
O
O
O
O
190; (±)-blastmycinone

428 21 Controlling Relative Stereochemistry
Ph
O
O
1. Zn
OH
Bu
(COCl)2
Me2SO
O
2.
Swern
Br
CHO
O OBn
O O Ph
191 192
193
The ketone 193 is reduced with Zn(BH 4) 2 via the chelate 194. In the enantiomer drawn,
the hydride attacks the molecule on the opposite side from the butyl group. After hydrolysis of
the zinc chelate of the product 195 the molecule is drawn as we have drawn it before 196 but in the
reacting conformation 194 both the oxygen atoms are on the same side of the molecule because
they are chelating the zinc atom.
193
The fi rst new stereocentre is thus taken care of. Next another carbonyl is revealed 197 by
ozonolysis of the double bond. We are now in a position to introduce with control the second
stereo-centre using the one we have just made!
This time chelation is with the ketone and the hydroxyl group 199. The chelate 199 is drawn
without the ester group for clarity and note (once again) that the oxygen atoms are on the same side
because they chelate the zinc atom and that attack occurs opposite the side chain.
O
OH
CO 2Bn
197a
= R
Zn(BH 4) 2
attack from
the front
The benzyl group is removed by hydrogenation which leads, by spontaneous ring closure, to the
lactone 200. The synthesis is completed by esterifying the remaining hydroxyl group.
OH
Zn(BH 4) 2
OH
O O Ph
196
Zn
O O
Zn
O
H
O
OBn
OBn
attack from the front
194
1. O 3
2. Me 2S
H 2 / Pd / C
O
OH
OH
O O Ph
Zn
O
199
O
R
HO
198a
pyridine
HO
O O Ph
O
O
O
O
198 200
190
Cl
Zn(BH4) 2
O
HO
OH
195 196
OH
197 198
O O Ph
O O Ph
OH
O
R
O
= 198

21 Open Chain Chemistry - in its Most Genuine Form 429
Open Chain Chemistry - in its Most Genuine Form
The most genuine form of open chain chemistry has no chelation to hold things in rings. But
there must be something controlling the conformation or there would be no control. We look at
two examples – the addition of nucleophiles to acyclic ketones and the addition of electrophiles
to alkenes.
Felkin control over reactions of nucleophiles with carbonyl compounds
We need to consider fi rstly the line of attack nucleophiles use in approaching carbonyl groups. The
nucleophiles come in to the C=O bond at an angle close to the tetrahedral angle of 109 and not
just at 90. We shall see that this is signifi cant. This is often referred to as the Bürgi-Dunitz trajectory
from the work by Bürgi and Dunitz who found an angle of 107 from crystal structures where
a nitrogen atom approached a carbonyl group. 47 Theoretical values are not wildly different. 48 Imagine
nucleophilic attack 201 on a carbonyl compound with a stereogenic centre next door. We
will call the groups L (for large) and M (for medium). The hydrogen can be S (for small). What
infl uence will the old chiral centre have on the newly forming chiral centre?
Nu
107˚
O
Nu
O
O Nu
L
H
M
R
Nu L
H
M
R
201 202
We view the molecule from the carbonyl carbon down towards the chiral centre which gives
us a useful (Newman) projection of the molecule. The most comfortable conformation for the
molecule is with the larger group being at 90 to the carbonyl functional group. The two rotamers
with this conformation are 203 and 204.
Step 1:
Place the large group L
orthogonal
to the carbonyl group
M
O
The nucleophile will come in opposite the large group and it would rather come in alongside the
small group 203a (which is often a hydrogen atom) than alongside the medium group 204a. We
see now why 107 is signifi cant. The model indicates that, as far as the nucleophile is concerned,
there would be no difference between the rotamers if the nucleophile came in at 90 as it would
come in between (rather than alongside) the M and S group.
Step 2:
Choose the more
reactive of the
two conformations
√
Consider then, the reduction of ketone 205 with LiAlH 4. Unlike some of the reductions we have
seen so far in this chapter, there are no coordinating sites in the rest of the molecule for chelation
control of any kind. The result of the reduction is alcohol 206 complete with stereocontrol.
L
S R
R M
203 204
M
O
L
S R
R M
Nu Nu
203a 204a
L
L
O
O
S
S
?
×

430 21 Controlling Relative Stereochemistry
Me
Ph
Me
And now the explanation. The phenyl group is the largest group and sits at 90 to the carbonyl.
Attack is alongside H 207. When working through the stereochemistry it is helpful to draw the
result with a Newman projection before drawing the molecule in the standard way. In redrawing
we have then performed a GSR (Chapter 20) to reveal that we have anti 206.
H3Al H
Me
207
O
H Me
Ph
The selectivity improves if the group adjacent to the carbonyl is increased in size. 49
Diastereoselectivity can be further improved by lowering the temperature. The 98% (i.e. 49:1)
selectivity that is observed when R=tert-Bu is increased to 99.8% when the temperature is
lowered from 35 C to 78 C.
Me
O
Ph
209
R
LiAlH 4
LiAlH 4
Role of electronegative substituents
O
LiAlH 4
Another thing to consider is the role of electronegative substituents. These can interact with the
carbonyl in an electronic way (as opposed to steric). They too have a tendency to sit at 90 to the
carbonyl. So the α-chloroketone 211 reacts with nucleophiles 212 to give the adduct 213 and
hence the alcohol 214 with the nucleophile anti to the OH group.
The explanation for this depends upon the interaction of orbitals and there are a couple of ways of
looking at this. One way is to think of the π* CO orbital interacting with the σ* CX orbital to give an even
lower antibonding orbital 50 216. This overlap can occur only if the orbitals are correctly aligned 215
and this will occur when the substituent is at 90 211a. There are no electrons in this orbital of course,
so the benefi t from the overlap will only occur once the nucleophile starts to feed in electrons.
Ph
Me
205 206
Me O
Redraw in
H Ph
Me
usual way
H Me
208; product in
Newman Projection
Ph
Me
OH
anti-210
R
Ph
206a
OH
OH
Me
Me
GSR
Ph
Me
OH
anti-206
R Me Et i-Pr t-Bu
anti : syn ratio 2.8:1 3.2:1 5:1 49:1
O
90˚ to carbonyl
Me O
Me O
HO Nu
Cl
Nu
Nu Cl
Cl
Nu H
H Me
Cl
211 212 213 214
Me

Cl
211a
21 Open Chain Chemistry - in its Most Genuine Form 431
The other argument (or the other part of the same argument) applies when the nucleophile
has already started to attack 212a. The σ-bond between the nucleophile and the carbonyl
carbon is partly formed (σ C–Nu). Once again, this can overlap with the σ* CX orbital 217 to lower
the energy a bit further. 51 The angles of the orbitals are slightly different because the attack
has started.
Cl
O
Nu
=
O
σ* CX
These explanations talk about the position of the electronegative atom just before the reaction
happens or as the reaction is happening (and are thus concerned with the ground state or the transition
state of the reaction). The electronegative atom may or may not be at 90 in the ground state
but who cares – it is where it is when the reaction is happening that counts!
The Houk conformation for reactions of alkenes with electrophiles
X
π* CO
215
O
The Houk conformation depends upon allylic 1,3 strain so we will look at this fi rst. 52 The strain
we are concerned with is between substituents on the double bond with substituents at the allylic
position. They will be in the same plane for the strain to be present 218. When the substituent on
the double bond is merely a proton, the allylic 1,3 strain is not too bad between the proton and a
larger group. About 25% of the conformations will have the proton and the substituent in the same
plane 218b but the rest will have two hydrogens in the plane 218a.
X Y
allylic 1,3-strain
218
R
R
σ* CX
212a 217
H H
This changes signifi cantly when the substituent on the double bond is something larger. Even
with a methyl group then the only signifi cant conformation 219b will have the proton eclipsing
the methyl group. And, just in case you are wondering, the methyl group will not prefer to stagger
itself between the two larger groups 219a. This is because it would result in allylic-1,2 strain on
the other side of the molecule. Allylic-1,2 strain is very bad news, worse than allylic 1,3-strain,
even between two protons. Conformations 219b and 219c have no 1,2-strain but 219c has worse
allylic 1,3-strain than 219b. Since we have only one signifi cant conformation, this is the only one
we need to consider for reactions. It is known as the Houk conformation.
X
R
R
O
σ* CX
216
σ C–Nu {from π* CO and n Nu}
allylic 1,3-strain -
not too bad with
H on double bond
π* CO
new LUMO
H R
R
H
218a; 75% 218b: 25%

432 21 Controlling Relative Stereochemistry
If R is larger than X in 220 we can expect electrophilic attack on the double bond to occur
opposite R 221. If the electrophile were a peroxyacid, the product would be the epoxide 222.
Epoxidation of the cis allyl sulfone Z-224 gives the stereochemical outcome we would
expect from a Houk conformation. 53 The selectivity with the trans compound E-224 is less
good – also as we would expect. Things are rarely quite so simple as this of course and
dihydroxylation of the same substrates gives rise not only to reduced selectivity but a reversal
in stereoselectivity 226.
80 : 20
78 : 22
H
Me RR
219a
Allyl silanes
X
R
Me H
Me H
X
Me H
E
220 221 (R > X)
222
HO
allylic
1,2 strain
H
OH
SO2Ph
SO2Ph 223 Z-224
OH
OH SO2Ph 226
OsO 4
pyridine
OsO4
pyridine
least strain worse allylic 1,3-strain
R
R
R
H
Me H
The steric interactions that go into controlling the Houk conformation can be reinforced by
electronics in the case of allyl silanes (or other σ-donors instead of silicon). 54 The silicon substituent
is large and also electron donating. We have already learned about β-cations being stabilised by
silyl groups. From a Houk point of view we can expect electrophiles to react as shown in 228. The
small group (S) is in the plane of the double bond and the large group (L) is usually the silyl group.
Hence reaction of 229 leads to 231 by attack of the electrophile (t-Bu ) on the opposite side to the
Me 3Si group in the Houk conformation 230 (an example of chirality transfer) and the usual loss
of silicon from the β-cation.
R
SO2Ph
E-224
m-CPBA
m-CPBA
O
Me R
219b 219c
O
SO2Ph 225
O
SO2Ph
227
X
R
95 : 5
75 : 25
R3Si
M
S
E
Me3Si
Ph
H Me
t-BuCl
TiCl4 Me3Si
Ph
H
t-Bu
Me
Ph
H
t-Bu
H
Me
228 229 230 231

Reaction with electrophiles can be by S E2’ reaction 232 as in the last example but the other
end of the double bond can react if it is part of, for example, an enolate 233. Reaction of 234 is an
example of the latter and highly stereoselective.
Nu
R 3Si
R
If the group on the double bond is merely a proton 236 then it is possible for the medium group
to move into the plane 237 so long as the medium group is itself quite small (typically a methyl
group). Although this 237 would not be the major conformation, it allows the electrophile to react
alongside the small group.
For large electrophiles, which clearly have diffi culty coming in alongside the medium group,
this selectivity is observed and illustrated by the reaction of 238 with OsO4 (large) to give mostly
240. However, once the medium group is made a bit larger (Ph instead of Me) there is a return53 E
L
S
236
H
237
S
H
M
M
E
L
to
the selectivity expected by 236. The reactivity depicted in 237 is not expected if the double bond
has anything larger than a proton cis to the chiral centre – the allylic strain would be too great.
References
E
PhMe 2Si O
Li
Ph OMe
E
21 References 433
PhMe 2Si O
Ph OMe
PhMe 2Si O
Ph OMe
232; SE2' reaction 233 234 97:3 235
PhMe 2Si
Me
PhMe 2Si
Ph
238
241
OsO 4
OsO 4
MeI
PhMe 2Si OH
Me
PhMe 2Si OH
Ph
OH
OH
239 34:66 240
OH
OH
242 92:8 243
General references are given on page 893
1. See Clayden, Organic Chemistry chapter 35 or Fleming, Orbitals for an explanation.
2. L. E. Overman and P. J. Jessup, Tetrahedron Lett, 1977, 1253.
3. L. E. Overman, G. F. Taylor, C. B. Petty and P. J. Jessup, J. Org. Chem, 1978, 43, 2164.
4. J. E. Dubois and M. Dubois, Chem. Commun., 1968, 1567.
5. C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn and J. Lampe, J. Org. Chem,
1980, 45, 1066.
6. H. E. Zimmerman and M. D. Traxler, J. Am. Chem. Soc., 1957, 79, 1920.
7. C. J. Cowden and I. Paterson, Org. React., 1997, 51, 1.
8. H. C. Brown, R. K. Dhar, R. K. Bakshi, P. K. Pandiarajan and B. Singaram, J. Am. Chem. Soc., 1989, 111, 3441.
9. J. M. Goodman and I. Paterson, Tetrahedron Lett., 1992, 33, 7223.
+
+
+
PhMe 2Si OH
Me
PhMe 2Si OH
Ph

434 21 Controlling Relative Stereochemistry
10. E. J. Corey and S. S. Kim, J. Am. Chem. Soc., 1990, 112, 4976.
11. T. Inoue and T. Mukaiyama, Bull. Chem. Soc. Jpn., 1980, 53, 174; This reference details equilibration
leading to regioisomers rather than stereoisomers.
12. H. C. Brown, K. Ganesan and R. K. Dhar, J. Org. Chem., 1993, 58, 147.
13. D. A. Evans, J. V. Nelson, E. Vogel and T. R. Taber, J. Am. Chem. Soc., 1981, 103, 3099.
14. C. H. Heathcock, in Asymmetric Synthesis, vol. 3, pp. 111–212.
15. I. Paterson, J. G. Cumming, J. D. Smith and R. A. Ward, Tetrahedron Lett., 1994, 35, 441.
16. C. H. Heathcock, M. C. Pirrung, S. H. Montgomery and J. Lampe, Tetrahedron, 1981, 37, 4087.
17. R. Baker and J. A. Devlin, J. Chem. Soc., Chem. Commun., 1983, 147.
18. N. Greeves in Comp. Org. Synth., vol. 8, page 14.
19. H. C. Brown and S. Krishnamurthy, J. Am. Chem. Soc., 1972, 94, 7159.
20. Eliel, pages 736 and 881.
21. D. A. Evans in Morrison, vol3, p 29–37; L. Mander in Eliel, pages 901–2; R. E. Ireland and L. N. Mander,
J. Org. Chem., 1967, 32, 689 (the year and volume number of this reference are wrong in Eliel); H. O.
House and T. M. Bare, J. Org. Chem., 1968, 33, 943.
22. Clayden, Organic Chemistry, pages 858–859.
23. M. D. Dowle and D. I. Davies, Chem. Soc. Rev., 1979, 8, 171; B. N. French, S. Bissmire and T. Wirth,
Chem. Soc. Rev., 2004, 33, 354.
24. F. B. Gonzalez and P. A. Bartlett, Org. Syn. Coll., 1990, VII, 164.
25. Eliel p. 909.
26. P. A. Bartlett and L. A. McQuaid, J. Am. Chem. Soc., 1984, 106, 7854.
27. P. A. Bartlett, in Asymmetric Synthesis, vol. 3, pp. 411.
28. S. Kuwahara, D. Itoh, W. S. Leal and O. Kodama, Tetrahedron Lett., 1998, 39, 1183.
29. For a full discussion of Corey’s synthesis of Erythronolide B, see Nicolaou and Sorenson p. 167.
30. T. Fukuyama, C.-L. J. Wang and Y. Kishi, J. Am. Chem. Soc., 1979, 101, 260.
31. For a full discussion of Kishi’s synthesis of Monensin see Nicolaou and Sorenson p. 185.
32. P. Wipf in Comp. Org. Synth., vol 5, chapter 7.2, pages 827–873; A. M. M. Castro, Chem. Rev., 2004,
104, 2939.
33. R. K. Hill in Morrison, vol 3, pages 503–572.
34. K.-K. Chan, N. Cohen, J. P. De Noble, A. C. Specian and G. Saucy, J. Org. Chem., 1976, 41, 3497.
35. R. E. Ireland and D. W. Norbeck, J. Am. Chem. Soc., 1985, 107, 3279; R. E. Ireland, D. W. Norbeck,
G. S. Mandel and N. S. Mandel, J. Am. Chem. Soc., 1985, 107, 3285.
36. I. Paterson and A. N. Hulme, J. Org. Chem., 1995, 60, 3288.
37. T. Nakai and K. Mikami, Org. React., 1994, 46, 105.
38. N. Sayo, E. Kitahara and T. Nakai, Chem. Lett., 1984, 259; D. J.-S. Tsai and M. M. Midland, J. Org.
Chem., 1984, 49, 1842.
39. K.-M. Chen, G. E. Hardtmann, K. Prasad, O. Repic and M. J. Shapiro, Tetrahedron Lett., 1987, 28, 155.
40. D. A. Evans, K. T. Chapman and E. M. Carreira, J. Am. Chem. Soc., 1988, 110, 3560.
41. D. A. Evans and A. H. Hoveyda, J. Am. Chem. Soc., 1990, 112, 6447.
42. S. E. Bode, M. Müller and M. Wolberg, Org. Lett., 2002, 4, 619.
43. I. Paterson and L. E. Keown, Tetrahedron Lett., 1997, 38, 5727.
44. I. Paterson and R. D. Tillyer, J. Org. Chem., 1993, 58, 4182.
45. L. A. Paquette, Ed., Encyclopedia of Reagents for Organic Synthesis, vol. 8 (John Wiley & Sons,
Chichester, 1995).
46. T. Nakata, M. Fukui and T. Oishi, Tetrahedron Lett., 1983, 24, 2657.
47. H. B. Bürgi, J. D. Dunitz and E. Shefter, J. Am. Chem. Soc., 1973, 95, 5065.
48. H. B. Bürgi, J. M. Lehn and G. Wipff, J. Am. Chem. Soc., 1974, 96, 1956.
49. M. Chérest, H. Felkin and N. Prudent, Tetrahedron Lett., 1968, 2199.
50. Eliel p. 877.
51. A. J. Kirby, Stereoelectronic Effects (Oxford University Press, Oxford, 1996) p. 51.
52. I. Fleming and J. J. Lewis, J. Chem. Soc., Perkin Trans. 1, 1992, 3257; L. Mander in Eliel, p 894–897;
K. N. Houk, N. G. Rondan, Y.-D. Wu, J. T. Metz and M. N. Paddon-Row, Tetrahedron, 1984, 40, 2257.
53. E. Vedejs and C. K. McClure, J. Am. Chem. Soc., 1986, 108, 1094.
54. I. Fleming, J. Chem. Soc., Perkin Trans. 1, 1992, 3363.

22
Resolution
Resolution
Introduction and an example (1-phenylethylamine)
Choice and Preparation of a Resolving Agent
Resolving a hydroxy-acid on a large scale
Resolving a hydroxy-amine on a large scale
Resolving an amino-acid on a large scale
Resolution via covalent compounds
Advantages and Disadvantages of the Resolution Strategy
When to Resolve
General rule: resolve as early as possible
Resolution of Diastereoisomers
Resolution of compounds made as diastereoisomeric mixtures
The synthesis of Jacobsen’s Mn(III) epoxidation catalyst by resolution
Resolution with half an equivalent of resolving agent
Physical Separation of Enantiomers
Chromatography on chiral columns
Resolution of triazole fungicides by HPLC
A commercial drug separation by chiral HPLC
Differential Crystallisation or Entrainment of Racemates
Conglomerates and racemic compounds
Typical procedure for differential crystallisation (entrainment)
Conventional resolution of L-methyl DOPA
Resolution of L-methyl DOPA by differential crystallisation
Finding a differential crystallisation approach to fenfl uramine
Resolution with Racemisation
Resolution of amino acids by differential crystallisation with racemisation
Differential crystallisation and racemisation when enolisation is impossible
Kinetic resolution with racemisation
Other methods of racemisation during resolution: the Mannich reaction
Resolution with racemisation in the manufacture of a drug
Resolution with Enzymes
Enzymes as resolving agents
Resolution by ester hydrolysis with enzymes
Resolutions of secondary alcohols by lipases
Kinetic resolution with proteolytic enzymes
Kinetic resolution with racemisation using proteolytic enzymes
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

436 22 Resolution
Kinetic resolution on diastereoisomeric mixtures
Comparison between enzymatic and classical resolution
Asymmetric Synthesis of a Prostaglandin with many Chiral Centres
Resolution
Introduction and an example (1-phenylethylamine)
Resolution is the separation of a racemic compound into its right and left handed forms. In the
world at large it is an operation we carry out whenever we sort chiral objects such as gloves or
shoes. Simply inserting your right foot into any shoe tells you at once whether it is a left or right
shoe: the combination of right foot and right shoe has different physical properties (it fi ts) to the
combination of right foot and left shoe (it hurts). Resolution also needs a “right foot”, a single
enantiomer of a resolving agent which we combine with the racemic compound to form a 1:1 mixture
of diastereoisomers. These will probably have different physical properties so that any normal
method of separation (usually crystallisation or chromatography) separates them; removal of the
resolving agent then leaves the optically active target molecule. We shall begin with a classical
resolution - almost the classical resolution. 1
A chemical
reaction
HO OH
O 2C CO 2H
Ph
O
Ph
1; prochiral
NH 3
4a; in mother liquor
NaOH, H 2O
extract with ether
distil
NH 2
Ph
(+)-(R)-amine 2
[α] D +24.5
recrystallise
sulfate
4.4 g (+)-(R)-amine 2
[α] D +38.3
NH4OAc
NaB(CN)H3
HO OH
HO2C CO2H
3; (+)-(R,R)-tartaric acid
cool slowly in MeOH
Ph
2; 25 g
HO OH
O 2C CO 2H
Ph
NH2
NH 3
4b; crystallises out
NaOH, H 2O
evaporate
to dryness
NH 2
Ph
6.9 g (–)-(S)-amine 2
[α]D –38.2
2; chiral but racemic
one compound
one NMR spectrum
one peak by HPLC
3; chiral
enantiomerically pure
one diastereoisomer
one enantiomer
[α] D +12.4
one peak by chiral HPLC
4a and 4b; two salts
diasterosiomers
different properties
different NMR spectra
two peaks by HPLC
(R)-2 and (S)-2; two
separate enantiomers
same NMR spectrum
different by chiral HPLC
equal and
opposite rotations

The amine 2 is made by a chemical reaction - the reductive amination of ketone 1. The starting
material 1 and the reagents are all achiral so the product 2, though chiral, must be racemic.
Reaction with one enantiomer of tartaric acid 3 forms the amine salt 4, or rather the amine salts
4a and 4b. Examine these structures carefully. The stereochemistry of tartaric acid 3 is the same
for both salts but the stereochemistry of the amine 2 is different so these salts 4a and 4b are
diastereoisomers. They have different physical properties: the useful distinction, discovered by
trial and error, is that 4b crystallises preferentially from a solution in methanol leaving 4a behind
in solution. Neutralisation of 4b with NaOH gives the free amine (S)-2, insoluble in water and
essentially optically pure.
Crystallisation doesn’t remove all of 4b from solution so the mother liquor contains mostly 4a
with some 4b. This is clear when the solution is neutralised and the free amine 2 isolated from it by
distillation. The rotation has the opposite sign to that of (S)-2, but is smaller. Recrystallisation of
the sulfate salt brings the rotation to the same value as that of (S)-2, but with the opposite sign and
we have a sample of pure (R)-2. You may feel that we have laboured this very simple resolution
but it is important that you understand this process before continuing not only this chapter but all
this section - chapters 22–31. The amine 2 is itself an important compound as you will see in the
next section.
Choice and Preparation of a Resolving Agent
Resolving a hydroxy-acid on a large scale
Chemists at Parke-Davis have been making hydroxy acids of the general structure 5 in their development
of an HIV protease inhibitor and they sought a method of resolution that would give
them both enantiomers. 2 The obvious resolving agent would be a single enantiomer of some kind
of amine so that a salt would be formed between the resolving agent and the carboxylic acid 5.
This would be the reverse of the resolution we have just seen. They tried many amines including 2,
but the best by far was 6. The salts between 5 and 6 were easily crystallised, the separation of the
diastereoisomers was straightforward, and the yield and % ee of the recovered 5 was excellent.
R1 R OH
CO2H 2
R1 R OH
CO2H 2
R1 R OH
CO2H 2 resolution?
and
Ph N
H
5 5a
5b
(R)-6
Now a diffi culty emerged. They wanted to carry out the resolution on a large scale but enantiomerically
pure 6 is expensive. The solution was to make it themselves from previously resolved
cheap 2. The obvious route is reductive amination using benzaldehyde and the only danger is
racemisation of the intermediate imine 7. They found that the imine 7 did not racemise as it was
prepared in toluene but that some racemisation took place when NaB(CN)H 3 was used for the
reduction. The solution was to use catalytic hydrogenation and they prepared 53 kg batches of
optically pure 7 in 98% yield by this method and used that to resolve the hydroxy acid 5.
Ph NH 2
(R)-(+)-2
22 Choice and Preparation of a Resolving Agen 437
PhCHO
toluene
reflux
H 2/Pd/C
Ph N Ph toluene Ph N
water
H
imine 7
(R)-6
Ph
Ph

438 22 Resolution
The preparation of 6 is not a resolution but the starting material 2 was prepared by a resolution
and enantiomerically pure 6 was used in a resolution. This sequence of identifying the best
resolving agent and then preparing it from a resolved starting material is standard practice. You
will meet the lithium derivative of compound 6 in chapter 26 as a chiral reagent. In the past many
racemic acids were resolved using toxic alkaloids such as strychnine. Nowadays simple amines
such as 2 or 6 are preferred. Top Tip: If you need to resolve an acid, try fi rst amine 2 or some
derivative of it such as 6.
Resolving a hydroxy-amine on a large scale
The Bristol-Meyers Squibb company wanted the simple heterocycle 8 for the preparation of a
tryptase inhibitor. As 8 is an amine, tartaric acid was the fi rst choice for a resolving agent. It again
turned out that a modifi ed version of the fi rst choice was the best. Tartaric acid is so good at resolutions
that simple variations, such as the dibenzoate ester 9, often work well.
N
H
OH
+
HO2C CO2H
1. crystallise from
EtOH at 74 ˚C
OH
O O
2. NaOH, pH 10.5 N
O
O
3. Boc2O, MeOBu-t
O Ot-Bu
(±)-8 9; (–)-di-benzoyl tartaric acid
(S)-(+)-10
In this instance, the exact proportions of the resolving agent and 8 and the purity of the
crystallisation solvent were important in getting good results. 3 After one crystallisation, the ee of
the salt was about 50% but this improved by 10-15% with each recrystallisation and reached 99%
after fi ve recrystallisations. By then the yield had dropped to 30% from a theoretical maximum of
50%. For the next stage in their synthesis, they really needed the Boc derivative (S)-()-10 so the
salt was directly converted to 10 in 99% ee on a 50 g scale. You will see later in this chapter that
an enzyme can be used to do the same resolution.
These two examples, 5 and 8, show that with two functional groups in a molecule it is better to
choose the one that can form a salt (here CO 2H and R 2NH) rather than the OH group as it would
be necessary to make a covalent compound to use that group.
Resolving an amino-acid on a large scale
Other companies (Cilag AG and R. W. Johnson) required the pyridine-containing β-amino acid
11 or, to be more accurate, the ester dihydrochloride 4 12. This combination of acidic and basic
functional groups offers a wide choice of resolving agents.
N
NH 2
CO 2H
The synthesis of the racemic compound is interesting and relevant. The simple aldehyde 13
could be combined with ammonia and malonic acid all in the same operation to give racemic 11.
NH 3
11
N
H 12
CO2Me
.2Cl

One of the functional groups now should be protected so that the other can be used for the resolution
and the amine was blocked with a Boc group to give 14.
N
13
CHO
CH 2(CO 2H) 2
NH 4OAc, EtOH
The best resolving agent was also a bifunctional compound, the natural amino alcohol ephedrine
15. Mixing 14 with ephedrine in warm ethyl acetate gave an immediate precipitation of the salt 16.
The crude salt already had an ee of around 90% but one recrystallisation again from ethyl acetate
gave pure salt 16 in 42% yield and 98% ee. Conversion to 12 required merely neutralisation
(NaOH) and reaction with HCl in MeOH to remove the Boc group and make the methyl ester.
The product 12 was isolated on a large scale in 82% yield with 98% ee. This is a spectacularly
successful resolution.
MeHN
Ph
OH
Resolution via covalent compounds
N
14
EtOAc
NH 2
(±)-11
CO2H
The calcium channel blocking dihydropyridine drugs 17, used in the important fi eld of heart disease
and easily prepared by the Hantszch pyridine synthesis, are chiral but ‘only just.’ The molecule
does not quite have a plane of symmetry, because there is a methyl ester on one side and an
ethyl on the other and because R may not be Me. An important example is amlodipine 18, a best
seller from Pfi zer, and this is more asymmetrical than some. Nevertheless resolving these compounds
is diffi cult.
X
MeO 2C
N
H
15; (1R,2S)-(–)-ephedrine
CO 2Et
22 Choice and Preparation of a Resolving Agen 439
Hantszch
pyridine
synthesis
X
MeO 2C
The method published by Pfi zer 5 relies on the formation of an ester 21 of an intermediate
carboxylic acid 19 with the alcohol 20 derived from available mandelic acid and the separation
of the diastereoisomers by chromatography rather than crystallisation. We can assume that the
classical crystallisation of diastereoisomeric salts was not successful. Removal of the ester was
simplifi ed as a transesterifi cation. CDI is carbonyl-di-imidazole.
Boc 2O
NaOH
H 2O/THF
N
NHBoc
14
NHBoc
CO2 MeH2N OH
N
Ph
16; salt of 14 and (1R,2S)-(–)-ephedrine
CHO CO 2Et
MeO 2C
R NH2ORN
H
CO 2Et
17 18; Amlodipine
Cl
CO2H
O
NH 2

440 22 Resolution
Cl
MeO2C
N
H
O
Ph
OMe
OH
HO
20
MeO2C
O
CDI
N3
N
H
19 21
Cl
Ph
O
The second example of resolution via a covalent compound also involves a decision about when
to resolve. Ketone 22 is the pheromone of the southern corn rootworm. It has the one functional
group and one stereogenic centre in a 1,9 relationship. Disconnection was guided by the long
distance between the ketone and the stereogenic centre and by the availability of undecenoic acid 6
25. The ketone is changed to an alkene and the 10-methyl group to CO 2H to allow disconnection
to a readily available starting material 25.
We need to add a propyl group to the di-lithium derivative 26 (chapter 2), reduce the CO 2H
group to CH 3, and convert the alkene into a ketone by the mercuration-reduction sequence
described in chapter 17.
The CO 2H group also helps resolution. Amide formation with the amine (S)-()-2 gave the
amide 30 - a likely crystalline derivative. It is of course impossible to predict with certainty
which compounds will crystallise, and particularly which diastereoisomer will crystallise. It
turns out that (R,S)-30 crystallises out, leaving (S,S)-30 in solution. Recrystallisation purifi es this
diastereoisomer until it is free from the other.
O
O
OMe
O H H
FGI
2 10
1
22
R
H
25
CO2H
(±)-27
24
2 x LDA
R
SOCl 2
H CO 2H
LiO OLi
enolate
alkylation
R
23
25
CO2H
H LiAlH4 R H
26 (±)-27 (±)-28
R
H
Pr–I
1. Ph 3PBr 2
2. LiEt 3BH
COCl
(±)-29
1. Hg(OAc)2
23 22
2. NaBH4 3. Cr(VI)
H
H2N Ph
(S)-(–)-2)
R
H
N3
Ph
O NH S
H R
1. separate
(chromatography)
2. EtOH
3. H 2, Pd/CaCO 3
OH
CO 2H
+
FGA
X
18
(R,S)-30
this diastereoisomer
crystallises out

The resolving agent must now be removed by hydrolysis of the amide. This is a risky business
as enolisation would destroy the newly formed stereogenic centre, and a cunning method was
devised to rearrange the amide 30 into a more easily hydrolysed ester by acyl transfer from N to
O. The rest of the synthesis is as before. By this means the alcohol 28 was obtained almost optically
pure, 0.4% of the other enantiomer being present. No further reactions occur at the newly
formed stereogenic centre, so the absolute chirality of 22 is as shown.
(R,S)-30
1. LDA
2.
O
Advantages and Disadvantages of the Resolution Strategy
These examples expose the main weakness of the resolution strategy: the maximum yield is 50%
as half the chiral molecule 2, 6, 8, 11, 19, or 24 must be the wrong enantiomer. In addition, extra
steps are needed to add and remove the resolving agent and, in the removal of the resolving agent,
racemisation is a danger. There are advantages too: in principle you get both enantiomers of the
target molecule so if you are making a chiral auxiliary, or don’t know the structure of a natural
product, or want to investigate the relationship between biological activity and stereochemistry,
all situations where having both enantiomers is a distinct advantage, resolution may be the best
strategy. You can minimise the disadvantages by resolving as early as possible: that way there is
least waste of time and materials. In favourable cases you can neutralise either or both disadvantages,
as we shall see soon. The maximum yield may be made 100% if the wrong enantiomer can
be recycled. Some extra steps may be avoided if no covalent compound is formed at all.
However, the fact remains that, even in the 21st century, most drugs that are sold as single
enantiomers are manufactured by resolution. When you see a paper about the preparation of a
single enantiomer that has in its title words like ‘practical’ ‘expedient’ or ‘effi cient’ you may guess
that resolution is going to be used. This situation will change. Asymmetric methods, the subjects
of chapters 26–28, particularly the catalytic methods, gain in effi ciency and ease of operation
every year and are likely to become steadily more important.
When to Resolve
General rule: resolve as early as possible
R
O
H
H
N
Ph
OH
O OH
H
H2O R
H + HO
Verapamil 33 is used in the treatment of cardiovascular disease. An asymmetric synthesis by the
resolution strategy would normally be planned around a synthesis of the racemic compound and
the important decision would be: when do you resolve?
MeO
MeO
22 When to Resolve 441
31
CN
Me
N
(R)-(–)-27
OMe
OMe
33
verapamil
N
H
32
H
Ph

442 22 Resolution
The most satisfactory answer is ‘as early as possible’. If the starting material can be resolved
then nothing is wasted. If the fi nal product is resolved then half of the starting material, the
reagents, energy, time and so on is wasted. And probably more than half; for few resolutions
produce even close to 50% yield of the wanted enantiomer. Here is the outline racemic synthesis
of verapamil without distracting details - where would you resolve?
1.
2.
3.
4.
MeO
MeO
CN
H
CN MeO
MeO
MeO
34 35 36
MeHN OMe
MeO
35
OMe
MeO
These are the questions you should ask, and the answers in this case:
CN
hydrolysis MeO
CN
What is the fi rst chiral intermediate?
Answer: the starting material 34.
Is it a suitable compound for resolution?
Answer: No doubt it could be resolved, though a nitrile is not particularly convenient, but the
chiral centre is immediately destroyed in the next reaction. No.
Which is the fi rst intermediate that can be conveniently and safely resolved?
Answer: The carboxylic acid 36. It has a very helpful functional group and the chiral centre,
being quaternary, is secure from racemisation.
Do any reactions occur later in the synthesis that might racemise the molecule?
Answer: No. The one chiral centre is unchanged in the rest of the synthesis.
We already have a good idea how to resolve a carboxylic acid by making a salt with an
enantiomerically pure amine. In this case the fi rst amine you think of, phenylethylamine 2, works
very well. Here is the asymmetric synthesis, carried out on a 50–100 g scale at Celltech. 7 The
hydrolysis of the dinitrile 35 is chemoselective because the intermediate 39 is formed. The salt
with 2 crystallises in good yield (39% out of a possible 50%) and in excellent ee.
34
36
CN
0.5 mol%
t-BuOK
t-BuOH
H2N Ph
2
37
EtOAc
seed with product
35; not
isolated
MeO
MeO
remove t-BuOH
NaOH, H 2O, EtOH
reflux, 18 hours
CN
36
CN
91% yield
O
38
Me
N
MeO
MeO
CO 2 H3N Ph
40: salt of 39 and 2, 39% yield, >95% ee
H
HN
i-Pr
OMe
OMe
CN
H
N O
Me 2S.BF 3
39
38 THF, 20 ˚C
reduce
amide
CO2H
(±)-33
Verapamil

Resolution of Diastereoisomers
When the compound itself contains more than one chiral centre the question of diastereoisomers
takes precedence over that of enantiomers. Resolution is normally performed on the wanted
diastereoisomer rather than on the mixture. In the case of sertraline 45, an anti-depressant that
affects serotonin levels in the brain, the active isomer was not known when both diastereoisomers
were prepared by a unselective route. 8 The starting material 41 was made by a Friedel-Crafts
reaction between 1,2-dichlorobenzene and succinic anhydride.
Cl
Cl
Cl
Cl
O
O
CO 2H
O
NaBH 4
Separation of the syn and anti diastereoisomers by crystallisation of the HCl salt revealed that it
was the syn diastereoisomer that was active and the reductive amination of 44 could be controlled
to give 70% syn-45. The diastereoisomers of 45 were separated before the resolution. There is no
point in resolving any earlier compound in the synthesis as even more material would be wasted in
the reductive amination step. Natural ()-(R)-mandelic acid 46 was a good resolving agent for 45
and 50% of the material derived from 44 could be isolated as the active ()-syn-(1S,4S)-45.
Resolution of compounds made as diastereoisomeric mixtures
Cl
Cl
It may be possible to prepare the correct diastereoisomer, assuming that this is known, by
stereoselective synthesis and avoid the problem. The anti isomer of the amino alcohol 48 can be
prepared from cyclohexene oxide 47 in high yield and with minimal contamination (3%) of the
syn- diastereoisomer. 9
47
Cl
Cl
O
41
43
MeNH2
EtOH
reflux
22 Resolution of Diastereoisomers 443
45
NaOH
H 2O, 80 ˚C
benzene
conc. H2SO 4
NHMe
OH
NHMe
Cl
Cl
(±)-anti-48
90% yield, >95% anti
Cl
Cl
44
42
OH
(+)-syn-45; sertraline
O
NHMe
O
CO 2
1. MeNH 2
TiCl 4
2. H2, Pd/C
O
acidic
work-up
OH
Ph CO 2H
46; (+)-(R)
mandelic acid
Me HO2C CO2H
Me
O
O
49; (+)-di-toluoyl tartaric acid

444 22 Resolution
Resolution with tartaric acid 3 required up to seven recrystallisations to get pure material
and by that time the yield was only 8%. Di-p-toluoyl tartaric acid 49 (cf 9 used earlier) was
spectacularly better when used in the right proportions (4:1 48:49). The solubility of the required
diastereoisomer as the salt of one molecule of ()-49 with two molecules of ()-48 was very much
less than that of ()-49 with two molecules of ()-48 so that merely mixing 48 and ()-49 in
the right proportions in ethanol at 60 C for twenty minutes, cooling, and fi ltering off the crystals
gave a 45% yield in 99% ee. Neutralisation with NaOH and extraction with t-BuOMe gave pure
()-48.
(±)-anti-48
49
EtOH, 60 ˚C
OH
NHMe
(–)-anti-48
in solution
The synthesis of Jacobsen’s Mn(III) epoxidation catalyst by resolution
Possibly the easiest resolution known is of the related trans diaminocyclohexane 50, used to
make the catalyst for Jacobsen’s asymmetric epoxidation (chapter 25). It is not even necessary to
separate the diastereoisomers fi rst and this is a big advantage as the commercial mixture of about
40:60 cis and trans-50 costs about one tenth of the pure racemic trans and about one hundredth
of the resolved trans isomer. You can usually tell if a commercial product is made by resolution as
the two enantiomers cost about the same.
The resolving agent is tartaric acid: 150 g are dissolved in water in a litre beaker. Then 240
ml of the mixture of isomers of 50 is added at 70 C followed by 100 mls acetic acid at 90 C and
the solution cooled to 5 C. The pure salt 51 separates out in 99% yield - that is 99% of all that
enantiomer originally present - and with 99% ee. This is almost incredibly good. Though the free
trans-diamine 50 can be isolated from this salt, it is air-sensitive and it is better to make the chiral
catalyst 52 directly from the salt as shown. The yield is better than 95% and the catalyst 52 can be
made in multi-kilogram quantities by this resolution. 10
OH
NH2Me.(+)-49 salt of (+)-anti-48 and (+)-49
crystallises out in 45% yield
NaOH
t-BuOMe
H 2N NH 2 H 2N NH 2 H 2N NH 2
enantiomers of trans-50 achiral cis-50
OH
NHMe
(+)-anti-48
98% yield, >99% ee
HO2C CO2H 1. add mixture of
cis and trans 50 at 70 ˚C
HO OH 2. 100ml HOAc at 90 ˚C
3. cool to 5 ˚C, filter
(+)-tartaric acid
150 g in 400ml water
H3N NH3 O2C CO2 HO OH
51; 160 g
1. ArCHO
K2CO3 2. Mn(OAc)2
air t-Bu
3. NaCl
N
O
t-Bu
Mn
Cl
N
O
t-Bu
99% yield, >99% ee 52
t-Bu

Resolution with half an equivalent of resolving agent
Since only half the compound (the maximum amount of either enantiomer) crystallises out, it may
seem extravagant to use a whole equivalent of resolving agent and in some cases the resolution is
much better with only just enough to crystallise one enantiomer, as with 48. A case in point is methylphenidate
11 53. The HCl salt of racemic syn 53 is marketed as ‘Ritalin’ for treatment of children with
ADHD (attention defi cit hyperactivity disorder). The resolving agent is unlike anything we have seen
so far: an axially chiral BINOL-derived cyclic phosphate 55. If the right amount is added to a solution
of 54 to crystallise just one enantiomer a very good yield (38% out of 50%) of the salt can be isolated
on a 50 g scale. Separation is now easier as one enantiomer is a salt and the other a neutral compound:
simple solvent/solvent extraction is used. The active enantiomer, (R,R)-53, can be isolated in an
overall yield of 32%.
53; racemic syn ('threo-') diastereoisomer
H 2
N
H
N
Ph
Ph
CO2Me
H2
N
Ph
CO2Me
It is not possible to give a comprehensive guide to the essentially practical skill of classical resolution
in this book. You are referred to the papers we quote and also to Eliel and Wilen, chapter 7,
pages 297 to 441 for a fuller account. We must move on to other styles of resolutions particularly
those that do not involve the separation of specially prepared diastereoisomers.
H2
N
Ph
CO2Me
Cl Cl Cl
1. i-PrOAc
2. NaOH,
NaCl, H2O
CO 2Me
0.5 equivs
resolving agent 55
i-PrOAc, MeOH
60-65 ˚C
seed with salt
of product
then cool
to 0-5 ˚C
O
O
22 Resolution of Diastereoisomers 445
P O
O
3. separate
organic layer
H
N
Ph
CO 2Me
54; racemic syn ('threo-') diastereoisomer
H 2
N
O
O
P
Ph
O
OH
Resolving Agent: binaphthyl
hydrogen phosphate 55
CO 2Me
salt of 55 and (R,R)-54; 36% yield on 50 g scale
resolution
NaOH
H 2O
53; active enantiomer
32% yield, >99.8% ee
H
N
1. conc. HCl
2. crystallise
Ph
CO 2Me
(R,R)-54 in organic layer
organic layer
i-PrOAc
aqueous layer

446 22 Resolution
Physical Separation of Enantiomers
Chromatography on chiral columns
One good way to separate enantiomers physically is separation on a chiral chromatography column.
There are now many of these available 12 usually consisting of silica functionalised with a linker
such as a 3-sulfanyl- or 3-amino-propylsilyl group 56 to which are attached enantiomerically pure
groups such as the covalently bound anthryl alcohol 57. Separation occurs when suitable racemic
compounds are passed down the column, usually in hexane containing about 10% i-PrOH. This
method is one of the best ways to assess the enantiomeric purity of a compound and ees are
routinely measured using chiral columns.
silica
surface
A column loaded with the amide 58 that is held in place merely by hydrogen bonds and electrostatic
forces is used preparatively to resolve the important axially chiral binaphthol 13 59. You will
meet compounds of this type as reagents and ligands in chiral catalysts in chapters 24–26.
H
Ph
HO 2C N
H
OH (EtO)3Si NH 2
OH
O
58
NO 2
NO 2
The anti-malarial compound chloroquine 60 is a salutary case. For many years it was thought
that both enantiomers were equally active against the parasites that transmit malaria. This was
because the only optically active samples available (rotations 12.3 and 13.2) were obtained by
conventional resolution with bromocamphor sulfonic acid 61 and were of low purity.
H H
NEt2 HN
HN
Cl N
Cl
N
(+)-(S)-chloroquine 60
[α] D +12.6
O OEt
Si
O
56
When the racemic compound was resolved on a poly-N-alanylacrylamide column, samples of
rotation 86.9 and 86.9 showed not only that the () isomer of 60 was more active against
NH 2
OH
OH
HN
Cl
N
59; binaphthol 60; chloroquine
(–)-(R)-chloroquine 60
[α] D –13.2
O OMe
Si
O
NEt2
57
S
Br
O
SO2OH
OH H
NEt2
61; bromo-camphor
sulfonic acid
CF 3

malaria, but that it also had fewer toxic side-effects. The active enantiomer is now made from
the dichloroquinoline 63 and the enantiomerically pure diamine 62 prepared by conventional
resolution.
Ph
H
HN
CO 2Et
O
Resolution of triazole fungicides by HPLC
n
poly-N-alanyl acrylamide
chromatography
of racemic 60
(+)-(S)-60
chloroquine
[α] D +86.9
nucleophilic
aromatic
substitution
H
NEt2 H2N 62; prepared by
conventional resolution
The triazole fungicides of general structure 64 such as hexaconazole 65 and fl utriafol 66 are a
rare case of human and plant medicine using similar compounds. They were initially used as
racemates but it was soon essential to discover the active enantiomers. Conventional resolution by
crystallisation of diastereomeric derivatives proved diffi cult.
HO R
X
N
N
N
64; a triazole fungicide
Cl
Cl HO
N
N
N
65; hexaconazole
F HO
The solution was to make the usual sort of diastereoisomers by acylation with camphanic acid
chloride and to separate them by standard (not chiral) HPLC on Dupont ‘Zorbax’ columns. Only 60
mg was separated at a time but that was enough to accumulate grams of material. The craft needed
in such separations is best illustrated by the solvent composition needed for good separation of 65.
You must use 918:80:2 of F 3C-CCl 3, MeCN, and Et 3N. The () isomer was biologically active. 14
64
hexaconazole
1.
NaH
DMF
22 Physical Separation of Enantiomers 447
2.
(–)-camphanic
acid chloride
COCl
O
O
If you need any more convincing, applying the same method to fl utriafol 66 gave the camphanic
esters as before but now no separation could be achieved even with HPLC. Esters 69 of a different
acid 68 could be separated on the same column but using 1:1 CH 2Cl 2/EtOAc as eluent. You will
not be surprised to know that fl uconazole 70 is now a leading fungicide in this area. It is not
chiral.
O
O
O
Ar
O
67
N
N
N
Cl
N
N
N
66; flutriafol
1. HPLC
2. NaOMe
THF
63
F
Cl
N
separated
(+)- and (–)-64
hexaconazole

448 22 Resolution
66
flutriafol
1. NaH, DMF
2. OPh
F
O
OPh 1. HPLC
2. NaOMe
THF
ClOC
(+)-68
N
O
N
N
69
A commercial drug separation by chiral HPLC
Cetirizine 71·2HCl is an antihistamine marketed as Zyrtec. It has a ‘low grade’ chiral centre
(arrowed) - the molecule is chiral only because one of the benzene rings has a para-chloro substituent.
It is very diffi cult to resolve cetirizine or to synthesise it asymmetrically. One company,
Sepracor Inc., whose business is making single enantiomers, found that the related amide 72 could
be separated by chiral HPLC on Chiral Technologies ‘Chiralpak AD’ columns: the two enantiomers
having very different retention times (4.8 and 8.8 minutes). They could separate nearly 40 g
of racemic material with one injection and, by repeated injections, could easily separate 1.6 kg of
()-(R)-72 with 99.8% ee. The separate enantiomers were converted to cetirizine in two steps and
the ()-(R)-enantiomer 73 found to be biologically active. 15
Cl
N
N
Chiral HPLC is the method of choice for analysing enantiomers and determining % ee. It can
be used preparatively. In either application it is best to consult an expert when choosing columns
and solvents.
Differential Crystallisation or Entrainment of Racemates
Conglomerates and racemic compounds
F
O CO2H
N
N
separated
(+)- and (–)-66
flutriafol
O CONH2
F HO
Most chiral compounds crystallise as racemic crystals, each crystal containing equal numbers
of right and left handed molecules, and cannot be separated by crystallisation. Some racemates,
unfortunately only about 15% of those known, crystallise as “conglomerates” or “racemic
compounds”; that is each crystal consists only of one enantiomer though the crystalline mass
contains equal numbers of right and left handed crystals. 16 You may recall that Pasteur 17 did the
very fi rst resolution by picking out right and left handed tartrate crystals by eye. If a saturated
solution of such a compound is seeded with crystals of one enantiomer (usually quite a lot is
needed: 5–25% by weight), that enantiomer may crystallise out fi rst in the process known as
differential crystallisation (or sometimes as entrainment).
F
N
N
N
N
N
70; fluconazole
1. HCl, MeOH
2. HCl, H2O N
.2HCl
Cl
Cl
71; cetirizine (as .2HCl) (–)-(R)-amide 72
(+)-(R)-cetrizine 73
N
N
O CO2H

Racemic Compounds
Each crystal
contains a
1:1 mixture of
enantiomers
85-90% of compounds
Racemates (Racemic Mixtures)
1:1 mixtures of enantiomers of any kind
Conglomerates can be recognised by a number of features:
1. The m.p. of the racemate is the same as that of the single enantiomer
2. The IR spectrum of the solid racemate is the same as that of the single enantiomer
3. The racemate is more soluble than either enantiomer in a chosen solvent.
There is no guarantee that a given group of molecules nor any derivatives of them will provide
conglomerates but there are some well known cases, thus with α-amino acids, certain known
derivatives, such as the N-acetyl amides, generally crystallise as conglomerates. We shall give
some examples to show how the method works.
Typical procedure for differential crystallisation (entrainment)
Conglomerates
Each crystal contains a
single enantiomer
10-15% of compounds
*crystallisation of racemic
compounds of >85% ee
usually enhances optical purity
cis-Stilbene diols form conglomerates. A solution of 11 g racemic cis stilbene diol 74 and a small
amount (usually about 5–10%, here 0.37 g) of ()-74 in hot ethanol is cooled and seeded with
10 mg ()-74. After 20 minutes 0.87 g pure ()-74 has crystallised out. The excess of the one
enantiomer is less soluble than the racemate but the yield is only about twice as much as the
amount of pure enantiomer added in the fi rst place.
Ph
OH
OH
22 Differential Crystallisation or Entrainment of Racemates 449
Ph
+
Ph
OH
11 g syn racemic 74
OH
Ph
+
Ph
OH
OH
2. Cool to 15 ˚C
OH
seed with 10 mg (–) 74
stir 20 min 0.87 g (S,S)-(–) 74
optically pure
The solution is now enriched in the other enantiomer so we replace the lost racemate by adding
another 0.87 g heating and cooling as before but seeding with the other enantiomer ()-74. We
get about 0.87 g of ()-74 crystallising out. And so on. After fi fteen cycles 6.5 g ()-74 and
5.7 g ()-74, each 97% ee, had been separated. This compound is more effi ciently prepared by
asymmetric dihydroxylation (chapter 25).
Ph
0.37 g (S,S)-(–) 74
mother
1. add 0.87 g racemate
heat to dissolve
liquor
2. Cool to –15 ˚C
seed with 10 mg (+) 74
stir 20 min
Ph
OH
OH
Ph
1. dissolve in
85 g 95% EtOH
by heating
0.87 g (R,R)-(+) 74
optically pure
Ph
OH
Ph

450 22 Resolution
Conventional resolution of L-methyl DOPA
The aromatic amino acid L-methyl DOPA (Di Hydroxy PhenylAlanine) 80 is used to make an antihypertensive
compound. Synthesis by the Strecker method clearly requires the aromatic ketone
77, and the synthesis follows the pattern below. 18 The intermediates and fi nal product have been
resolved in various ways.
O
O
O
O
75
CN
Me
HN
78; 88% yield
EtOAc
NaOAc
EtOH
O
O
NH
O
O
Ba(OH)2
H 2O
CN
H2SO4 O
O
H2O O
O
76; 98% yield 77; 57% yield
The synthesis of L-methyl DOPA 80 by the Strecker reaction was straightforward and of
course produced racemic material. A conventional resolution by crystallising the menthyl ester 83
from hexane and hydrolysis of acetal, ester and amide in 48% HBr (note that no racemisation by
enolisation can occur) gives good yields. 19
Resolution of L-methyl DOPA by differential crystallisation
O
O
CO 2H
Careful study of m.p./composition diagrams and infra red spectra revealed that aryl sulfonate salts
of aromatic amino-acids may form conglomerates, and 79 has indeed been purifi ed by differential
crystallisation. Batches of racemic salt are seeded with about 20% by weight of pure L-79. This
gives a yield of about 40% of pure L-79. This is again about twice the original excess of the single
enantiomer. The mother liquor is rich in D-79, so seeding with that enantiomer gives a similar yield
of pure D-79, and the process can be repeated. 20
O
O
(±)-79
menthol
base
NH2
CO2H
NH2
(±)-79, 100% yield
O
CO2H Ac2O O
HN
Ac2O
heat
81 O
O
O
O
NHAc
83
O
O
O
48% HBr
NH3
CO2H
(±)-79 sulfonate salt of 79
O
O
1. crystallise
from hexane
2. 48% HBr
HO
(NH4)2CO3, KCN
EtOH, H2O
NH2
HO
(±)-80, 84% yield
82
(S)-80
L-methyl
DOPA
O3S
N
O
O
OH
CO2H

Finding a differential crystallisation approach to fenfl uramine
The anorectic drug fenfl uramine 85 is made by the alkylation of the simpler amine 84. Either
compound could be resolved and, though a classical resolution of the camphoric acid salt of
fenfl uramine was known, chemists at Rouen were determined to achieve better results by
differential crystallisation. 21
Just how determined you will see. They looked at salts of both amines with ‘about fi fty’ achiral
acids of which eight proved to be conglomerates, three for 84 and fi ve for 85 (this is about what
would be expected - about 10%). Of these eight, two could not be separated by crystallisation
because one salt 86 had crystal facets that acted as seeds for the other enantiomer while the conglomerate
of another 87 was unstable and easily reverted to a racemic compound.
CF 3
CF 3
NH 3
That left six candidates, two for 84 and four for 85. All six salts could be separated by
crystallisation as we have described giving alternately one enantiomer and then the other but the
best were the salts of 85 with the two arylacetic acids. You may feel that this heroic effort, though
successful, is rather discouraging.
Resolution with Racemisation
NH 2
Resolution of amino acids by differential crystallisation with racemisation
The separation of the enantiomers of most amino acids can be achieved by differential crystallisation
of their N-acetyl derivatives, such as that of leucine. Racemic N-acetyl leucine 88 is dissolved
in the right solvent mix cooled and seeded with 4% by weight of natural (S)-88. Pure (S)-88
crystallises out in good yield. 22
CF3
HN
84 85; Fenfluramine
CHCl2CO 2
CF 3
H 2N
PhO CO 2
86; salt of 84 with chloracetic acid 87; salt of 85 with phenoxyacetic acid
CF 3
NH 3
salts of 84 with acids: salts of 85 with acids:
Ph
CO 2
22 Resolution with Racemisation 451
Me SO2O
Cl
Ph
CF 3
CO2
CO 2
O 2N
H 2N
Ph 3C CO 2
CO 2

452 22 Resolution
solubility in 10:1
AcOH:Ac 2O is 88 g
HN
CO 2H
O
150 g racemic 88
1. cat Ac2O (10 ml)
90 ml AcOH, reflux
2. cool to 100 ˚C and
seed with 6 g enantiomer
3. cool at 10 ˚C/hour with stirring
4. at 75 ˚C, add 10 ml Ac 2O
5. stop at 40 ˚C and isolate
CO2H
In fact your suspicions may have been aroused by the quantity of material put in. We started
with 150 g racemic 88, that is 75 g of each enantiomer and we seeded with 6 g of (S)-88 making
81 g of (S)-88 altogether. But the yield of pure crystalline (S)-88 was 112.6 g - too much! Clearly
the other enantiomer is somehow being converted into the enantiomer that crystallises. The clue
is the addition of that extra Ac 2O at step 4. This forms a mixed anhydride 89 that racemises by
enolisation 90 and crystallisation can continue.
HN
CO 2H
Sometimes these differential crystallisations with racemisations are very easy to do. Racemic
N-butyroyl proline 91 gives a good yield of one enantiomer in moderate ee just by melting the
racemic compound with catalytic acetic anhydride and seeding with one enantiomer. Further
crystallisations improve the ee. The yield is 6.3 from 10.5 g or 60% of the total material. This
process is clearly a great improvement on simple differential crystallisation both in simplicity of
operation and because it is no longer necessary to alternate the isolation of enantiomers.
Differential crystallisation and racemisation when enolisation is impossible
HN
O O
We return to the asymmetric synthesis of L-DOPA noting that it is an amino acid that cannot
racemise by enolisation as it has no proton between the NH 2 and CO 2H groups. We again use the
Strecker reaction - the only change is a minor alteration of phenolic protecting groups. The Strecker
synthesis gave a good yield of the amino-nitrile 93 that could be converted into L-DOPA 80 with
conc. HCl. Unfortunately no derivatives of 93 could be separated by differential crystallisation.
MeO
HO
92
Ac 2O
HN
O
112.6 g (S)-88, 98.8% ee
O
O
O
88 89 90
N
CO 2H
O
10 g racemic 91
O
NH3, HCN
i-PrOH
MeO
HO
O
100 ˚C (melt), cat Ac 2O
seed at 100 ˚C
with 0.5 g enantiomer
then add toluene
CN
NH 2
93; 93.5% yield on 400 g scale
N
HN
CO 2H
O
6.3 g (S)-91, 62% ee
Ac2O
97% yield
MeO
HO
OH O
O
94; 25 g racemic
CN
NHAc

When the N-acetyl derivative of the intermediate 94 was crystallised from isopropanol with
seeding a good yield of enantiomerically pure L-DOPA could be crystallised out. Treatment of
the residue from the mother liquor with NaCN in DMSO led to complete racemisation and the
differential crystallisation could be repeated. 23
(±)-94
crystallise
from i-PrOH
seed with 5%
enantiomer
MeO
HO
(S)-94
This racemisation is a separate chemical reaction from the crystallisation but one cycle gave
63% yield of L-DOPA of 100% ee. Evidently the cyanide is lost from 94 by elimination and
readdition 95 gives racemic 94.
MeO
HO
O
(R)-94
CN
Kinetic resolution with racemisation
N
H CN
Amine (S)-()-97 is needed for the synthesis of a gastrointestinal hormone antagonist, Merck’s
cholecystokinin antagonist 96, by acylation with indole-2-carboxylic acid.
Me
Ph
N
CN
NHAc
MeO
HO
conc. HCl
CO 2H
The racemic compound is available by methods used (Disconnection Textbook, page 250) for
the closely related benzodiazepines like diazepam, used in the treatment of depression. The one
stereogenic centre is next to a primary amine, and the compound forms a crystalline salt with camphor
sulfonic acid 98 (cf. 61). The maximum yield is 50%, but the amine (S)-97 can be released from the
salt simply by neutralisation. 24 This is a classical resolution by crystallisation of diastereoisomers.
A remarkable improvement happens if the salt is crystallised in the presence of
3,5-dichlorobenzaldehyde 99: 90% optically active salt crystallises out. Clearly the non-crystalline
enantiomer is racemising via the still chiral imine 100 by imine exchange with achiral imine 101.
heat
95
O
HO
HO
O
Me
O
H
C–N
N
N
NH2 N H O
N
H
amide
N H
Me
96; L-364,718
N
N
O
Ph
racemic 97
NH 2
22 Resolution with Racemisation 453
+
O
SO2OH 98; (+)-camphor
sulfonic acid
Ph
97
Me
N
N
NH2
(S)-80; 100% yield
O
+
NH 3
CN
HO 2C
N
H
Ph
N H
SO2O O
(+)-97 salt crystallises in 40-42% yield
(±)-94

454 22 Resolution
OHC
Me
Ph
Cl
N
N
Cl
O
N
Cl
Cl
Other methods of racemisation during resolution: the Mannich reaction
Even more complicated reactions can be used to racemise during a resolution. The amino ketone
102 is needed for the synthesis of the analgesic and useful asymmetric reagent (see chapter 24)
DARVON. Classical resolution with dibenzoyl tartaric acid 9 succeeds in crystallising the ()
enantiomer and racemising the mother liquors by reverse Mannich reaction. 25
Ph
O
6 kg racemic 97
Ph NMe 2
H
racemic ketone (±)-102
OH
99
3,5-dichloro
benzaldehyde
The enantiomerically pure ketone ()-(R)-102 can be converted to DARVON 104 by a
chelation controlled diastereoselective addition of benzyl Grignard and acylation. Using the other
enantiomer of 9 gives the other enantiomer ()-(S)-104 which is called NOVRAD.
O
reversible
Mannich
CH 2 NMe2
(+)-camphor sulfonic acid
3 mol % ArCHO, 20-15 °C
seed with 10 g (S)-(+)-97
crystallise from MeCN/i-PrOAc
then neutralise
A case where two stereogenic centres are equilibrated in one step, and a third in another
occurred in Oppolzer’s synthesis 26 of ()-vincamine 105, a natural alkaloid used for the treatment
of cerebral insuffi ciency in man. It has three stereogenic centres, but one of them epimerises at
Me
Ph
100 101
+
Ph MgCl
PhCOO OCOPh
HO2C CO2H 9; (–)-dibenzoyl
tartaric acid
Ph
O
crystallise
Ph NMe2
H
(–)-(S)-102; this
enantiomer racemises
by reverse Mannich
OH
N
N
Me
O
N
N
N
O
H
NH 2
Ph
90% yield (S)-(+)-97
EtCOCl
O
Cl
O 2C CO 2H
Cl
PhCOO OCOPh
Ph NMe2 H
H
salt of (+)-(R)-102 and 9
crystallises out
Ph
H
NMe2 Ph
H
NMe2 Ph
H
NMe2 (+)-(R)-102 103
104
Ph
O
O

oom temperature by equilibration with the ketone 106 so need not be controlled - it equilibrates
in nature too, so it will automatically be correct.
105;
(+)-vincamine
Earlier in the synthesis the heterocycle 107 was combined with 108 to give an advanced intermediate
109 as a mixture of diastereoisomers. As both starting materials are achiral 109 is also racemic.
N
H
107
HO
N
CO 2Me
Heating the mixture of isomers of 109 with TsOH equilibrates the diastereoisomers so that the
required more stable syn (H and Et syn) diastereoisomer of 109 crystallises out. Treating this with
() malic acid leads to crystals of the natural enantiomer ()-syn-109. Both the unwanted antidiastereoisomer
and the unwanted enantiomer can be equilibrated again with TsOH. This cannot
be enolisation as there are no α-hydrogens and is presumably equilibration by reversible Mannich
reaction as 110 lacks either stereogenic centre and so epimerises both!
racemic
(±)-109 as
mixture of
diastereoisomers
HO
CO 2H
CO2H
N
(R)-(+)-malic acid
22 Resolution with Racemisation 455
+
Resolution with racemisation in the manufacture of a drug
Br
H
N
108
OSiMe 3
TsOH TsOH
N
N
H
HO
TsOH
N
H
110
OHC
H
(–)-syn-109 in mother liquor
crystallise (+)-malate
Resolution with racemisation is used in the manufacture of the cardioprotective drug CP-060S 111
by the Chugai Pharmaceutical company. 27 The drug itself can be resolved with some diffi culty but
as it is made from the simpler carboxylic acid 112 this looks a better bet.
N
N
H
MeO2C
N
H
H
O
OHC
N
H
N
106
racemic (±)-109
mixture of diastereoisomers
N
H
OHC
H
N
racemic syn-109
N
H
OHC
H
N
crystals of (+)-syn-109

456 22 Resolution
t-Bu
HO
t-Bu
The resolving agent for the acid 112 is the simple amine 6 that we discussed at the start of
this chapter. A 27% yield of the salt of (S)-()-6 with the required (S)-112 with ee 99% was
crystallised from i-PrOH/i-Pr 2O. This is not a good recovery but they preferred to sacrifi ce yield
to near perfect ee as the mother liquor was racemised by treatment with NaOH in water at room
temperature. The resulting solution had 1% ee – the one time when low ee is a good thing – and
was used in the next resolution.
You are fortunate if you can fi nd a way to resolve and racemise in the same solution but, in
theory, any reversible reaction such as the important Diels-Alder or aldol reactions could do the
job so this method has wider application than might appear at fi rst sight.
Kinetic Resolution with Enzymes
Enzymes as resolving agents
S
N
O
N
Me
HO2C
O
CO 2H
There is a chapter soon (29) about enzymes as reagents in organic synthesis, but they are also
widely used in industry as resolving agents. The basis of this application is the enantioselectivity
of enzymes. They react with only one enantiomer of a racemic mixture and can be used to create
the wanted enantiomer or destroy the unwanted. A process in which one enantiomer reacts and
the other does not is called a kinetic resolution (chapter 28) since the resolution depends on the
rates of two competing reactions. The result is that instead of separating enantiomers or even diastereoisomers,
one is separating two compounds of different structure that also happen to belong
to the two opposite stereochemical series.
Zeneca market a herbicide for broad leaved crops, Fusilade 28 (fl uazifop butyl) 113. This is a
carboxylic ester with two ether linkages, one between two aromatic rings.
Disconnection of the ethers 113a is guided by our mechanistic knowledge that nucleophilic substitution
is possible on alkyl halides, and on 2-halo-pyridines such as 114, but not easy on halobenzenes.
O
O
t-Bu
HO
t-Bu
(S)-111; CP-060S as hydrogen fumarate 112
Me
(±)-112 +
Ph N
H
(S)-(–)-6
Ph
CF3
N O
S
O Me
t-Bu
N
dil HCl
Ph N Ph
CO2
H2
HO
t-Bu
salt of (S)-112 and (S)-(–)-6; 27% yield, >99% ee
O
O
H
O
S
(R)-113
Fluazifop Butyl
"Fusilade"
N
O
CO 2H
(S)-112
23% overall yield
99.8% ee

The only chiral intermediate is the chloroacid 116 which Zeneca manufacture as a racemic
compound. They use the enzyme chloropropionic acid dehalogenase to destroy the unwanted
isomer by conversion to lactic acid. It is easy to separate these two compounds as they are not
even isomers.
Cl
CF 3
O
H
OH
N O
chloropropionic acid
dehalogenase
racemic (±)-116 (S)-116
It is important to follow the fate of stereogenic centres made early in a synthesis and they have
established that the nucleophilic substitution of 115 with 116 to give 117 goes with inversion and
not, as happened to amino acid derivatives in chapter 23, with unexpected retention. The active
product is therefore the (R)-113 enantiomer shown.
115
NaOH
HO
(S)-116
CF3
117
22 Kinetic Resolution with Enzymes 457
N
113a
Kinetic resolution by ester hydrolysis with enzymes
O
Cl
H OBu
By far the commonest reaction used in kinetic resolution by enzymes is ester formation or
hydrolysis. Normally one enantiomer of the ester is formed or hydrolysed leaving the other
untouched so one has the easy job of separating an ester from either an acid or an alcohol.
There are broadly two kinds of enzymes that do this job. Lipases hydrolyse esters of chiral
alcohols with achiral acids such as 119 while esterases hydrolyse esters of chiral acids and
achiral alcohols such as 122. Be warned: this defi nition is by no mans hard and fast! If the
unreacted component (120 or 123) is wanted, the reaction is run to just over 50% completion,
to ensure complete destruction of the unwanted enantiomer, while if the reacted component
(121 or 124) is wanted it is best to stop short of 50% completion so that little of the unwanted
enantiomer reacts.
O
OH O
+
Cl HO
+ Cl
H
+ BuOH
OH
114 115
O
CO2H H
114
2 x NaOH
CF 3
O
H
OH
N O
3 x C–O
one ester
two ethers
(S)-116
+
118
HO
O
H
OH
(+)-(R)-lactic acid
(natural)
O CO2H H
BuOH
H
(R)-113

458 22 Resolution
There is an inherent problem with either type of enzyme as the reactions are reversible. One
way to make the reaction run in the direction of ester formation is to use a non-aqueous solvent
(you may be surprised that enzymes function in, say, heptane, in which they are insoluble, but
lipases do). One way to make the reaction run in the other direction is to make the alcohol component
an enol so that, on hydrolysis, it gives the aldehyde or ketone and does not reverse.
Resolutions of secondary alcohols by lipases
Simple secondary alcohols 121 (R alkyl or aryl) are enantioselectively esterifi ed by the reactive
trichloroethyl ester 125 using porcine pancreatic lipase in anhydrous ether. The products, one
enantiomer of 121 and the other enantiomer of the ester 126, are both formed in 90% ee, and are
easily separated from each other and from the insoluble enzyme. 29
Me
O
Me
+ porcine pancreatic lipase
+
R OH
(±)-121
O
125
CCl3 anhydrous ether R OH
(S)-121
Me O
R O
(R)-126
The reaction occurs in the reverse direction in aqueous buffer (pH 7, 20 C) using a lipase
from Pseudomonas spp. The reactive chloroacetates, e.g. 127, give the best results with nearly
quantitative yields of (R) alcohol 128 and (S) ester 127 separated by fl ash chromatography
on a 250 g scale. The ester (S)-127 was easily hydrolysed to the (S) alcohol 128 without
racemisation. 30
Me
O
Ph O
(±)-127
Me
R O
Cl
O
lipase
Me
R O
(±)-119 (S)-120 (R)-121
O
O
O
MeO
R
esterase
MeO
R
+ HO
R
+ MeOH
Me
Me
Me
(±)-122 (S)-123 (R)-124
Pseudomonas lipase Me
Me O
+
water, pH 7, 20 °C Ph OH Ph O
(R)-(+)-128 (S)-(–)-127
48% yield, 99% ee 47% yield
The same enzyme catalyses the esterifi cation of racemic 129 in non-aqueous solution with
vinyl acetate. The released alcohol is CH 2CHOH, the enol of acetaldehyde: it immediately forms
acetaldehyde which self condenses and is removed from the equilibrium. The enzyme is fi ltered off,
the enantiomerically pure alcohol (S)-129 and acetate (R)-130 separated by fl ash chromatography,
and the ester hydrolysed to the alcohol without racemisation. Either method (esterifi cation or hydrolysis)
gives both enantiomers of a range of secondary alcohols. 31
O
Me
+ + AcOH
R OH
Cl
K 2CO 3
MeOH
Me
Ph OH
(S)-(–)-128
97% yield, 99.5% ee

(±)-129
OH
OAc
Pseudomonas lipase
t-BuOMe, 20 ˚C
OH
(+)-(S)-129
48%yield, 95% ee
Kinetic resolution with proteolytic enzymes
The simple furan alcohol 131 is successfully resolved 32 with a lipase from Candida cyclindracea
and you should note that the same enzyme is used to form the octanoate 132 and, under different
conditions, to hydrolyse it to the pure alcohol ()-(R)-131.
O
OH
(±)-131
C7H15CO2H Candida lipase
hexane
room temperature
O
OH
(–)-(S)-131
+
However, the closely related amino acid 133 was not a substrate for either lipase (from pigs or
Candida) but could be resolved with the proteolytic enzyme papain. This acted as an esterase,
hydrolysing the methyl ester rather than the amide. Note that this kinetic resolution produces a
single enantiomer of the carboxylic acid rather than the alcohol and that separation of 134 from
133 is very easy as the free acid can be extracted from organic solvents by aqueous base in which
it is soluble as the anion.
O
CO 2Me
NHCO2Et
(±)-133
papain
DMF/H 2O
pH 7
22 Kinetic Resolution with Enzymes 459
CO2Me O
+
NHCO2Et
(+)-(S)-133
Perhaps the ideal enzymatic resolution is that of phenylalanine 137 by the proteolytic enzyme
subilopeptidase, marketed as Alcalase® acting as a lipase on the ester amides 135. The reaction
stops after one enantiomer is consumed: the yields and ees of the two products are close to 100%.
The amide (S)-136 can be hydrolysed directly to natural phenylalanine (S)-137. The unnatural
(R)-135 can of course be hydrolysed to the arguably more valuable (R)-137 but it can also be
racemised by NaOMe in MeOH for the next cycle of reactions. 33
+
NH2
OAc
(+)-(R)-130
46%yield, >99% ee
K 2CO 3
MeOH
OH
(–)-(R)-129
48%yield, 95% ee
O
Candida lipase
O
OCOR
(+)-(R)-132
water, pH 7.5
room temperature
OH
(+)-(R)-131
O
CO 2
NHCO2Et (–)-(R)-134
CO2H
CH 2N 2
CO2Me Alcalase CO2Me CO2H NHAc
NHAc
NHAc
®
+
water, pH 7.5
45 minutes
(±)-135
room temperature
(–)-(R)-135, 98% yield (+)-(S)-136
96% yield, 98% ee
(+)-(S)-137
78% yield, 98% ee
pH 3
CO2Me O
NHCO2Et
(–)-(R)-133
42% yield, 97% ee
5M HCl
reflux

460 22 Resolution
More recently acids have been resolved with enzymes cloned and over-expressed in their own
organisms, such as an esterase from Bacillus subtilis that resolves ibuprofen methyl ester 138 to
give ibuprofen 139 of 99% ee. A range of anti-infl ammatory arylpropionic esters, including 138,
could also be resolved with a cell-free extract from Pseudomonas fl uorescens showing that purifi
ed enzymes are not essential. 34
Kinetic resolution with racemisation using proteolytic enzymes
In all these enzymatic resolutions so far the maximum yield of one enantiomer is of course 50%
and only in the last example have we seen the recycling of the other enantiomer. However in the
resolution of esters 140 of the anti-infl ammatory drug ketorolac 141, the easily enolised ester 140
racemises in moderately basic conditions and, after a survey of four lipases and four proteases,
one was found 35 that hydrolyses the ester 140 enantioselectively at pH 9.7. The product of the
reaction is ()-(S)-ketorolac 141 in 92% yield but only 85% ee. One recrystallisation improves
this to 94% ee.
O
N
(±)-140
CO 2Me
Streptomyces
griseus protease
water, pH 9.7
Kinetic resolution on diastereoisomeric mixtures
(+)-(R)-140
Derivatives of chrysanthemic acid such as (1R,3R)-permethrinic acid 143 are in demand for the
manufacture of highly specifi c insecticides that do not persist in the environment. Mixtures of the
esters 142 are easy to make and contain various proportions of the cis and trans diastereoisomers.
Pig liver esterase accepts only the trans esters as substrates so complete hydrolysis gives the
unchanged cis esters and hydrolysed but poorly resolved trans acids. At 50% conversion, kinetic
resolution of the trans esters occurs. 36
Cl
Cl
CO 2Me
(±)-cis/trans-142
(±)-138
porcine liver
esterase
CO2Me esterases
CO2H Cl
Cl
Cl
+
N
CO 2H
O
(–) (S)-141; 92% yield, 85% ee
CO Cl
2Me
CO2Me (1R,3S)-cis 142 (1S,3R)-cis 142
Cl
(S)-139; Ibuprofen
CO 2Me
Cl
Cl
Cl
CO2H
(–)-(1S,3S)-trans 142 (+)-(1R,3R)-trans 143

At 50% conversion, the product contains three esters, the two cis-142s and the (1S,3S)-trans
ester together with a little (1S,3S) -trans acid and all of the (1R,3R)-permethrinic acid 143. The
ratio of these last two is 10:90 but one recrystallisation from petrol gives (1R,3R)-permethrinic
acid 143 in 98% ee. This approach works for several different cyclopropane-based carboxylic
acids in much the same way.
Comparison between enzymatic and classical resolution
Earlier in this chapter we described the resolution of the piperidine 8 by classical resolution.
The Bristol-Meyers Squibb company also investigated an enzymatic resolution. 3 Various
esterases and lipases had been used before on various derivatives of 8 but none was efficient. Two
methods were successful. Accurel PP, a lipase immobilised on polypropylene, resolved
the N-Cbz derivative 10 to give 46% yield of (R)-()-10 with 99.4% ee. Unfortunately
this is not the wanted enantiomer and the ester (S)-()-144 could be isolated only by
chromatography.
N
H
(±)-8
OH
O
N
Ot-Bu
10
OH
The separation problem was solved by esterifying racemic 10 with succinic anhydride. The
(R)-ester 145 now has a free carboxylic acid group and can be separated simply by extraction
with weak base (NaHCO 3) without any chromatography. The ester is easily hydrolysed to (S)-
()-10 which was obtained in 32% overall yield (maximum 50%) and 98.9% ee. They do not
say whether they prefer this resolution to the classical version with dibenzoyl tartaric acid but
both are good.
10 +
O
22 Asymmetric Synthesis of Prostaglandins with many Chiral Centres 461
O
succinic
anhydride
O
Accurel PP
Asymmetric Synthesis of Prostaglandins with many Chiral Centres
OAc
Accurel PP
O
N
Ot-Bu
(R)-(–)-10
We end with a stereochemically involved synthesis of a prostaglandin 155. The racemic synthesis
is summarised below - each compound is a single diastereoisomer and all from 146 to 155 are
chiral but all are racemic as the synthesis starts with achiral materials. There are 14 steps in the
synthesis and the fi nal product 155 contains four chiral centres. 37 If we want a single enantiomer,
where should we resolve?
N
O Ot-Bu
(R)-(–)-10
OH
+
O
OH
N
+
Ot-Bu
O
O
N
Ot-Bu
(S)-(+)-144
O
(S)-(+)-145
OAc
CO 2H

462 22 Resolution
O
Cl O O
COCl
Cl
Cl
Cl
Zn
O
O
O
The obvious answer is as early as possible. The fi rst chiral intermediate is 146 and that
already has two chiral centres. The fi rst intermediate with a useful functional group is 149
with its two alcohols. The chemists at what was then Glaxo (now GlaxoSmithKline) chose an
ingenious resolution of the stable ketone 147. Because this is a strained ketone it forms a stable
adduct with bisulfi te and that could be resolved as a salt with our old friend 1-phenylethylamine
2. The bisulfi te compound reverts to the ketone 147 on treatment with base and the resolution
was complete.
More recently enzymes have been used to resolve related intermediates also used in prostaglandin
synthesis. 38 Acylation with vinyl acetate catalysed by twelve lipases was tried and
the best was ‘Amano PS’ from Pseudomonas cepacia. At 55% conversion the alcohol ()-
156 was obtained in 40% yield and 91% ee and the acetate ()-157 in 78% ee. This low
enantiomeric purity could be enhanced to 95% by hydrolysis to ()-156 and reacetylation
with the enzyme. Note that the alcohol and acetate of the same series have opposite signs of
rotations.
O
O
O
O
O
O
HO OH
149
oxidise
O
O
C5H11 O
O OSiPh2t-Bu O CHO
O
O
O
150 151 152 153
Wittig
O
Et 3N
O
OH
O
racemic 147
protect
deprotect
cis-146 cis-147 cis-148
OH
C5H 11
Wittig reduce
CO 2H
deprotect
O
OH
Prins
OH
154 155
SO 2, H 2O, CH 2Cl 2
H2N 2
Ph
O O
HO S O
H 2N
RCO3H
Ph
salt of bisulfite adduct and 2
1. crystallise
2. Na2CO3, H2O
O
C 5H 11
OH
O
OH
CO 2H
enantiomerically
pure 147
protect
oxidise
C 5H 11

H
O
It should not be assumed that all these adventures are successful. The same workers attempted
to resolve the fi rst chiral intermediate 159 in the synthesis of 156 by acylation of the related
alcohol 160 with the same range of lipases but with only very limited success. 39 The ee of 160 was
34–66% with the various enzymes. Neither could 160 be resolved with chiral HPLC. You may see
that it is asymmetric in the ring remote from the alcohol.
Returning to the resolution of amines, an enzymatic acylation of racemic amines in aqueous
solution by a penicillin acylase (enzymes used in industry in the synthesis of penicillins) from
Alicaligenes faecalis has recently been reported. 40 The best acylating agent is the amide 161 of
phenylacetic acid. There is a big advantage here. Unlike the ester formations and hydrolysis we
discussed earlier, no amide exchange occurs with simple amides like 161. The amide (R)-162 was
formed in 45% yield and 98.5% ee. Once it has been separated from free (S)-2, it can be hydrolysed
to free (R)-2 with the same enzyme! This automatically perfects the ee.
References
H
O
OH
OAc
Amano PS
H
O
H
O
OH
(±)-156 (+)-156
(+)-157
H
O O
H
158
Baeyer-
Villiger
O
22 References 463
H
+
O
General references are given on page 893
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H
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K 2CO 3
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MeOH
HO
H
O
H
(–)-156
H
H
159 160
NH2
+ H2N penicillin
acylase
H
N
+ H2N O
water, pH 10
Me
O Me
Me
161 (±)-2 (R)-162; amide of (R)-2
(S)-2
H
O
OH
O
O

464 22 Resolution
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34. I. Kumar, K. Manju and R. S. Jolly, Tetrahedron: Asymmetry, 2001, 12, 1431.
35. G. Fülling and C. J. Sih, J. Am. Chem. Soc., 1987, 109, 2845.
36. M. Schneider, N. Engel and H. Boensmann, Angew. Chem., Int. Ed., 1984, 23, 64.
37. E. W. Collington, C. J. Wallis, and I. Waterhouse, Tetrahedron Lett., 1983, 24, 3125.
38. G. Zanoni, F. Agnelli, A. Meriggi and G. Vidari, Tetrahedron: Asymmetry, 2001, 12, 1779.
39. G. Zanoni and G. Vidari, J. Org. Chem., 1995, 60, 5319.
40. D. T. Guranda, L. M. van Langen, F. van Rantwijk, R. A. Sheldon and V. K. Svedas, Tetrahedron: Asymmetry,
2001, 12, 1645.

23
The Chiral Pool
— Asymmetric Synthesis with Natural
Products as Starting Materials —
Introduction: The Chiral Pool
PART I – A SURVEY OF THE CHIRAL POOL
The Amino Acids
Important reactions of amino acids
Reduction of amino acids
Hydroxy Acids
Amino Alcohols
Terpenes
Carbohydrates - the Sugars
The Alkaloids
PART II – ASYMMETRIC SYNTHESES FROM THE CHIRAL POOL
Amino Acids
The synthesis of captopril
The synthesis of ramipril
HIV-Protease inhibitors
Hydroxy-Acids
The synthesis of bestatin
The synthesis of ()-laurencin
Streptazolin from tartaric acid
Amino Alcohols
Synthesis of quinolone antibiotics
The oxazolidinone antibiotics
The synthesis of anti-viral nucleoside analogues
The New Chiral Pool
Glycidol as a chiral pool member
Phenylglycine as a chiral pool member
C2 symmetric diamines as chiral pool members
Amino-indanols
The synthesis of crixivan (Indinavir)
Conclusion: Syntheses from the Chiral Pool
The synthesis of agelastatin
The synthesis of LAF389, a Novartis anti-cancer agent
PART III – THE CHIRAL POOL
A listing of potential starting materials from the old and new chiral pool
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

466 23 The Chiral Pool
Introduction: The Chiral Pool
The chiral pool is that collection of available natural products considered cheap enough to use
as starting materials for organic synthesis. The chiral pool strategy is the incorporation of part
or all of one of these compounds into the target molecule. 1 Chiral pool compounds were used
as resolving agents (chapter 22) and derivatives of them will be used as reagents (24), catalysts
(25 and 26) and chiral auxiliaries (27) and in this chapter we give the synthesis of many such
compounds. There is of course no hard and fast defi nition of which natural products qualify
for the chiral pool but our list appears at the end of the chapter. Most amino acids are cheap
enough for anyone, and sucrose is one of the cheapest pure organic compounds anywhere,
but if you plan the synthesis of a very active compound, say a prostaglandin, when only a few
hundred grams per annum is needed, then a quite expensive compound becomes a suitable
starting material. The Syntex headquarters is in Mexico City because R. E. Marker found that
the Mexican yam Dioscorea could replace animals as a source of steroids since the vegetable
“steroid” diosgenin 1 could be converted into optically active birth control ingredients 2 like
pregnenolone acetate 2.
HO
We shall introduce the chiral pool in the fi rst half of this chapter, taking each type of natural
product, such as the amino acids, in turn and give the key reactions that allow their use
in synthesis. We shall illustrate this section with the synthesis of important resolving agents,
reagents and catalysts for asymmetric synthesis, and chiral auxiliaries. We shall reveal that
there is now what we shall call the ‘new chiral pool’ - compounds so easily made from natural
compounds that they are readily (and often commercially) available. Then we shall look at
syntheses of more complex targets, showing how the decision was made to use the chiral pool
strategy.
PART I – A SURVEY OF THE CHIRAL POOL
The Amino Acids
H
H
H
H
H
O
H
O
AcO
1; diosgenin 2; pregnenolone acetate
The α-amino acids found in proteins are widely available and reasonably priced - many indeed are
cheap. 3 They have the general structure 3, where R can be alkyl 4, 5, cycloalkyl 6 and functionalised
alkyl 7 or aryl. They are all L, most are also (S) (all except cysteine and cystine), and some
are () and some () as you would expect. Some are also available as the D enantiomer, usually
more expensive, but the synthesis 4 of D amino acids (e.g. by enzymatic resolution, chapter 29) is
making them cheaper. These examples 4–7 are very important.
H
H
H
O

R
O
OH
Ph
If you are manufacturing aspartame 8, it is pretty obvious that you will use the natural amino
acids Asp 9 and Phe 4, modifi ed only by turning Phe into its methyl ester 10. Standard peptide
coupling gives the artifi cial sweetener. However, to make more interesting compounds, the natural
amino acids must be transformed by stereospecifi c reactions before they are incorporated.
Important reactions of amino acids
O
OH
NH2
NH2 3; (L)-amino acids 4; (S)-(–)-Phe
phenylalanine
O
Ph
HO2C NH2 N
H
CO2Me 8; Aspartame (Nutrasweet)
C–N
amide
O
NH2
5; (S)-(+)-Val
valine
HO 2C
Diazotisation of amino acids gives diazonium salts such as 11 derived from valine 5. This reaction
obviously goes with retention as the chiral centre is not affected. The internal CO 2H group is
the best nucleophile and displaces N 2 with inversion. Any nucleophile now opens the α-lactone
12 by S N2 displacement at the alkyl centre, again with inversion to give 13 with overall retention
from the original amino acid. 5 Most lactones react with nucleophiles at the carbonyl group but
α-lactones react at saturated carbon as that relieves the strain of the 3-membered ring.
O
The same reaction works well with chloride as nucleophile to give 14 and, after reduction of the
acid group and cyclisation of the alcohol 15, the epoxide 16. Such epoxides, made from many of the
amino acids, now count as members of the new chiral pool. The diazonium salt 11 and the chloroacid
14 are susceptible to racemisation by enolisation and it is only after two distillations that the epoxide
16 has 97% ee. There are very detailed Organic Syntheses procedures for both these steps. 6
O
OH
NH2 5; (S)-(+)-Val
1. AcOH
2. NaNO2
OH
NaNO2
OH
NH2 HCl
Cl
5; (S)-(+)-Val 14; 58-65% yield
23 The Amino Acids 467
O
OH
N
H
CO2H
6; (S)-(–)-Pro
proline
NH2 9; Asp
(S)-(+)-aspartic acid
LiAlH4
HO2C
O Ph
OH
O
OH
SN2 intra-
AcO O
N2
molecular
O
11 12; α-lactone
+
OH
Cl
15; 70% yield
O
NH2
7; (S)-(+)-Glu
glutamic acid
H2N CO 2Me
10; (S)-(+)-Phe-OMe
phenylalanine methyl ester
S N2
AcO
KOH
O
O
16; 87% yield
97% ee
OH
OH
OAc
13; 98% yield

468 23 The Chiral Pool
Glutamic acid 7 has its own internal nucleophile: the diazonium salt initially cyclises to the
α-lactone 17 which is then opened by the other CO 2H group to give the γ-lactone 18. Selective
reduction of either the lactone or the acid gives two useful intermediates 7 19 and 21.
HO 2C
O
CO 2H
NH2
7; (S)-L-(+)-Glu
This type of reaction can be used to invert the natural series to give a rare and expensive
(R)-amino acid. Phenylalanine 4 is converted into the hydroxyacid 22 with retention. Displacement
of trifl ate from 24 with inversion and removal of the benzyl ester gives Boc-protected (R)-Phe 26.
In fact this method was used to make 15 N-(R)-Phe so the nitrogen nucleophile was labelled but it
is the inversion that matters to us. 8
Ph
Ph
Reduction of amino acids
HONO
HO
O
17
O
O
H
CO2H (S)-(+)-18
H HO
CO2H H
HO
O
H
CO2H
DIBAL
(S)-(+)-18
B2H6 O
O
H
19 20 21
NH 2
O
4; (S)-(–)-Phe
O
OH
OBn
2. NaNO 2
Boc
H
N Boc
Ph
Ph
OH
O
22; 70% yield
Reduction of the carboxyl group of the amino acids gives a range of amino alcohols, usually
named after the parent acid such as valinol 27 and prolinol 28. It is important that the reduction
does not threaten racemisation. Various methods have been used such as NaBH 4 in acid solution 9
(no doubt producing borane in situ) and LiBH 4 with Me 3SiCl. 10
OH
OTf
BuLi
NBoc2 24; 98% yield –78 ˚C 25; 98% yield
O
OH
NH2 5; (S)-(+)-Val
1. H 2SO 4
O
O
O
OBn
BnBr
C2CO 3
DMF
1. TFA
2. Pd/H 2
Ph
Ph
OH
O
23; 98% yield
OBn
O
OH
NHBoc
(R)-26; 88% yield
Tf 2O
lutidine
[H]
NH2 OH
N
H
CO2H [H]
N
H
OH
27; (S)-valinol 6; (S)-(–)-Pro
28; (S)-prolinol
OH

Valinol 27 and phenylalaninol 29 are used to make the Evans chiral auxiliaries used in
asymmetric aldol reactions (chapter 27) and Evans prefers reduction with borane itself as its
complex with Me 2S. The phenylalanine based auxiliary 30 is generally preferred as the compounds
are more likely to be crystalline and can easily be made 11 on a 150 g scale.
Ph
H 2N
Prolinol methyl ether 31 is used in Enders’s SAMP and RAMP chiral auxiliaries (chapter 27) and
(S)-()-SAMP 32 can be made in 50–58% overall yield from (S)-L-()-proline on a 75 g scale. 12
Hydroxy Acids
CO2H
4; (S)-(–)-Phe
1. BF3.Et2O 2. BH3.Me2S 3. NaOH, H 2O
Ph
H2N
A few hydroxy acids are very cheap. (S)-()-Lactic acid 33 occurs in milk, (R)-()-malic acid in
apples, and both enantiomers of the very important tartaric acid 35 and 36 are reasonably cheap.
()-Tartaric acid 35 is usually called “natural” as it occurs in grapes, but ()-tartaric acid 36 is
natural too as it occurs in the West African tree Bankinia reticulata. The other enantiomers of
malic and mandelic acids are commercially available and are not that much more expensive.
H
One of the most important specifi c applications of tartaric acid is the preparation of Seebach’s
TADDOLs, e.g. 40. The dimethyl ester 38 is protected as the acetal 39 and reacted with four
molecules of an aryl Grignard to give the TADDOL 13 40. All these compounds are C 2 symmetric
and various TADDOLs have found applications as resolving agents, NMR additives, asymmetric
catalysts and so on. 14 Some of these will feature later in the book.
OH
29; 73-75% yield
(EtO) 2CO
K2CO 3
HN
O
O
Ph
30; 78-79% yield
OMe
OMe
N CO2H N
N
H
H
NH2 6; (S)-(–)-Pro 31 32; (S)-(–)-SAMP
OH
CO 2H
33; (+)-(S)
-lactic acid
HO H
CO 2H
CO2H 34; (–)-(R)
-malic acid
23 Hydroxy Acids 469
HO OH
HO 2C CO 2H
(R,R)-(+)-35
tartaric acid
"natural"
HO 2C
CO 2H
(S,S)-(–)-36
tartaric acid
"unnatural"
37; (R)-(–)mandelic
acid
O
MeO
O OH
OH O
OMe
BF3 OEt2
O
MeO2C O
CO2Me PhMgBr
Ph
Ph
O
OH
O
HO
38; dimethyl tartrate 39; 77% yield
40; TADDOL
HO
OH
OH
Ph CO2H
Ph
Ph

470 23 The Chiral Pool
Both enantiomers of a member of the new chiral pool, propylene oxide 44, can be made from
lactic acid 33. The idea is to reduce the acid and cyclise in two different ways. One is simple
enough. Ethyl lactate 41 is mesylated, to turn the secondary alcohol into a leaving group 42,
and then the ester is reduced. Cyclisation uses the primary alcohol of 43 as the nucleophile in an
internal S N2 reaction so that inversion gives (R)-propylene oxide 15 44.
The second sequence starts with reduction of the ester to give the diol 45 with no change in
stereochemistry. Reaction with HBr and HOAc gives an 89% yield of a mixture (94:6) of 46 and
47 which sounds like disaster. Not so as 46 and 47 react in different ways.
41
H
OH
LiAlH 4
THF
H
The HBr/HOAc reaction goes via the cation 48 that reacts either with or without inversion to
give 46 or 47. Treatment of the mixture with RO cleaves the ester to release the oxyanions 48 and
49 which cyclise to 44 without inversion 48 or with inversion 49. The molecule either undergoes
no inversion (via 46) or two inversions (via 47) and the result is retention. 16
O
47 Br
inversion
O Br 46
no inversion
Malic acid 34 is useful for the simple functionalised skeleton it contains and so it is more likely
to be incorporated into the target molecule than form part of a reagent. It will feature more in the
second half of the chapter.
Amino Alcohols
OH
(+)-(S)-45
81% yield
48
OH
Me
H
OAc
(S)-46
94 parts
H
O
Br
Br
O
49 50
no inversion inversion
The amino alcohols 51 derived from amino acids have been mentioned already. Amino alcohols
available directly from nature are the ephedrine family: ephedrine 52, its anti-diastereoisomer
pseudoephedrine 53 and norephedrine 54 lacking the N-methyl group. The enantiomers of these
compounds are also available: ()-52 is about twice as expensive, ()-53 slightly (about 25%)
more expensive, and ()-54 about the same price.
R
CO 2Et
41; (+)-(S)ethyl
lactate
S
NH2
MsCl
Et3N
PhMe
OH
51; amino-alcohols
from amino-acids
H
HBr
HOAc
Ph
OMs
S
CO2Et
(–)-(S)-42
98% yield
OH
R
NHMe
52; (1 S, 2R)-
(+)-ephedrine
AlH 3, THF
[LiAlH 4
+ H 2SO 4]
Br
+
S
Ph
H
H
OH
OMs
(S)-43
not isolated
Br
(R)-47
6 parts
S
NHMe
OH
OAc
KOH
H2O (+)-(R)-44
72% from 42ß
RO K
ROH
S
Ph
H
O
(–)-(S)-44
54% from 41
OH
R
NH 2
53; (1 S, 2S)-(+)- 54; (1 S, 2R)-(+)pseudoephedrine
norephedrine
H
O

Derivatives of these aminoalcohols are used as bases for asymmetric deprotonation. There is
more about this in the next chapter (asymmetric reagents) but we should note here that amino
alcohols such as 55 and 58 or diamines such as 56 and 57 have been used successfully. Some, such
as 55, are derived from amino acids, others, such as 58, are derived from the ephedrine family. 17
N
H
H
Ph
H
N R
N
Ph
OLi
Ph
MeN LiN
Ph
OLi
55
R N
H
56 57
NR2 58
One useful reaction is the desymmetrisation of 4-substituted cyclohexanones 59 to give the
silyl enol ethers 60 using the chiral base 57. The chirality can be made more permanent by oxidative
cleavage of the alkene to give the dicarboxylic acid 61, or by Pd(II) oxidation (chapter
33) to the enone 62.
R
1. 57
2, Me 3SiCl
R
MoO 2
(acac) 2
t-BuOOH
HO 2C
CO2H
O
OSiMe3 O
59 60 61 62
A dramatic application was the asymmetric synthesis of epibatidine 70 by Simpkins. 18 Diels-
Alder reaction of the deactivated pyrrole 63 with the alkynyl sulfone 64 gave the bicyclic core 65
of epibatidine. Selective reduction gave the compound 66 needed for epibatidine, but in racemic
form. A directed lithiation (chapter 7) and sulfonation led to achiral bis sulfone 67.
NBoc +
H
Boc
Boc
N
N
85–90 ˚C H2, Pd/C 1. BuLi
MeCN
SO2Ar
SO2Ar SO2Ar
SO2Ar
63 64 65 (±)-66 67
Catalytic reduction from the exo-face gave achiral 68 ready for desymmetrisation. Elimination
with the chiral base (simply the sodium salt 69 of pseudoephedrine 53) gave a single enantiomer
of 66 ready for conjugate addition of the pyridine and conversion into epibatidine 70.
67
H2
Pd(OH) 2/C
800psi
CH2Cl 2
EtOAc
23 Amino Alcohols 471
The same type of amino alcohol is used as ligand for various organo-lithium additions.
N-Dialkylated norephedrines 58, made by dialkylation of ephedrines, 19 are effective in catalysing the
addition of lithium acetylides to carbonyl compounds. 20 This was particularly useful in Merck’s
R
2. ArSO2F
R
Boc
N
SO2Ar
Boc
N
Ph Me
Boc
N
H
N
Cl
H NaO NHMe
N
H
SO2Ar
69
SO2Ar 68
SO2Ar
66 70; epibatidine

472 23 The Chiral Pool
preparation of the anti-HIV drug efavirenz. 21 The ketone 71 was combined with the lithium derivative
74 and the lithium acetylide 72 (both made with BuLi) to give the adduct 73 in 96–98% ee
improved to 99.5% by crystallisation.
Cl
Terpenes
The molecules we have seen so far have usually been incorporated into the target molecule complete.
There are two further and most important groups of larger molecules, the sugars and the
terpenes, from which pieces are usually snipped out for incorporation. The simple monoterpenes
(C 10 compounds) citronellol 75, citronellal 76, and citronellic acid 77 are good examples. They are
not cheap but both enantiomers are available, not always in excellent ee.
OH
CHO
CO2H 75; (R)-(+)-citronellol 76; (R)-(+)-citronellal 77; (R)-(+)-citronellic acid
These compounds are often used by oxidative cleavage of the alkene to give a C 7 unit with
functionality at both ends, e.g. 78 from citronellic acid. Notice how the functional groups are
carefully made different so that one end can be reacted selectively. This compound 78 was used
by Mori in natural product synthesis. 22
H
CO2H
77; (R)-(+)-citronellic acid
1. O3, MeOH
2. Me 2S
3. TsOH, MeOH
H
MeO CO2H
The cyclic monoterpenes are also very useful. Menthol 79 is very cheap and the ketones
pulegone 81 and carvone 82 are moderately cheap. All are available as the other enantiomer, e.g.
80. An important application is as a chiral auxiliary, the favourite being 8-phenylmenthol 83 made
from pulegone, 23 see chapter 30.
2 1
5
79; (1R, 2S, 5R)
-(–)-menthol
CF 3
N
H
O
Ar
71; Ar = p-methoxy-C6H 4
OH OH
80; (1S, 2R, 5S)
-(+)-menthol
74
72
Li
Cl
N Ar
H
73: 80% yield, 96-98% e.e.
81; (R)-(+)pulegone
Pulegone has also been used to make the chiral auxiliary 86 that acts as an asymmetric
d 1 reagent. Conjugate addition of the thiol PhCH 2SH gives a diastereomeric mixture of ketones 84
from which the single compound 85, having all substituents equatorial, can be made by reduction.
O
CF 3
OH
OMe
H
O
78
82; (R)-(–)carvone
74
OLi
N
Ph
OH
83; (–)-8phenylmenthol

Formaldehyde introduces one carbon that is the d 1 centre in bicyclic 86. A carbonyl group 87 is
added by lithiation and reaction with an aldehyde followed by Swern oxidation. Nucleophiles add
to this ketone from the front, i.e. opposite the sulfur rather than the oxygen atom, to give, after
removal of the auxiliary, single enantiomers of the alcohols 24 88.
O
81; (R)-(+)-pulegone
(CH2O)n
cat. TsOH
benzene
reflux
Ph SH
NaOH
THF
reflux
S
O
86; 86-89% yield
There are bicyclic monoterpenes too - α-pinene 89 and β-pinene 91 share a common skeleton
with four- and six-membered rings but have the alkene in different places. There is a discussion
in chapter 24 on the variable ee of α-pinene and it is better to make the ()-enantiomer from the
more reliable β-pinene 91 (99% ee) that can be isomerised with strong base (‘KAPA’) 92 in 93%
yield to ()-90 without loss of ee. Many asymmetric reagents for reduction (chapter 24) and chiral
auxiliaries for asymmetric aldol reactions (chapters 27 and 30) are based on α-pinene. 25
89; (1R)-(+)-α-pinene
Camphor 93, a bridged monoterpene with one six- and two fi ve-membered rings is available in
both enantiomeric forms and was used by Woodward in the synthesis of vitamin B 12. Sulfonation
on camphor occurs on the bridgehead methyl group by a series of rearrangements described in the
workbook. You will see in chapter 27 how Oppolzer’s sultam 95 is used as a chiral auxiliary and
in chapter 33 how oxaziridines such as 96 are used in asymmetric oxidation. Both are made from
camphor-10-sulfonic acid 94.
R
R
Carbohydrates - the Sugars
O
93; (+)-camphor
H 2SO 4
23 Carbohydrates - the Sugars 473
1. BuLi
2. R1CHO 3. DMSO
(CF3CO) 2O
HO 3S
The sugars are generally both cheap and optically pure, and more compounds have been made
from glucose 97 than any other member of the chiral pool. It is rare that a target molecule looks
S
Ph
O
84; 90% yield, mixture
S
(–)-90
R
O
94; (+)-camphor-
10-sulfonic acid
S
O
87
KAPA
93% yield
O
Na, NH3(l)
MeOH
–78 ˚C
R 1
1. R 2 MgBr
2. NCS
AgNO3
91; (–)-β-pinene
NH
S
O O
95; Oppolzer's
chiral sultam
SH
OH
85; >80% one isomer
H
O
HO R 2
88
NH2
R 1
NH K
92; KAPA
N
S O
O O
96; Davis's
asymmetric oxidant

474 23 The Chiral Pool
much like glucose, but by keeping in mind that glucose can exist in three forms, the normal pyranose
97, the open chain 99, and the furanose 101, resemblances are easier to fi nd. Each form may be
trapped by suitable acetal formation: benzaldehyde prefers the pyranose form with all substituents
(including the Ph group) equatorial except the anomeric OMe group, which prefers to be axial 98.
A thiol traps the free aldehyde 99 as the bis-alkylthioacetal 100. Acetone prefers fi ve-membered
acetals from cis substituents, and so traps the furanose form 102.
97; α-D-glucose
pyranose form
99; α-D-glucose
open chain form
101; α-D-glucose
furanose form
Mannose 103 resembles glucose closely except for the axial OH at C-2. This is a signifi cant
difference as the open chain form 104 makes clear: it is nearly C 2 symmetric and, on reduction,
becomes so in the form of mannitol 105.
HO
HO
OH
O
OH OH
HO
2
HO
CHO
OH
OH OH
103; mannose 104; open-chain mannose
OH OH
105; mannitol
If mannitol is protected as the bis-acetal 106 (acetone prefers to form two acetals without
stereochemistry rather than a single acetal in the middle - acetal formation is under thermodynamic
control) and cleaved oxidatively, both halves give the same product - a protected form of the
unstable D-glyceraldehyde 26 107.
105
mannitol
HO
HO
HO
ZnCl2
acetone
20 ˚C
O
O
OH OH
HO CHO
HO
HO
H
OH
HO
OH
O
OH
O
OH
OH
OH
OH
OH
1. MeOH, H
2. PhCHO, H
An alternative sequence that gives 100% yield uses silyl and benzyl protecting groups 109. This
form of protected glyceraldehyde reacts with allyl silane to give 110 with good stereoselectivity
that is dependent on the Lewis acid used as catalyst. 27 The products have been used in the synthesis
of the immunosuppressant FK506 useful in transplant surgery. 28
O
RSH, H
acetone, H
O
106; bis-acetal of mannitol
HO
NaBH 4
Ph
O
Pb(OAc) 4
or NaIO 4
HO
OH
O
OH
OH OH SR
H
O
O O
H
HO
O
HO
H
O
O
O
OH
O
O
HO OMe
SR
OH
H
107; acetal of
glyceraldehyde
98
100
102
OH

OH OBn
OTBDMS
TBDMSO
OBn OH
108; protected mannitol
TBDMSO
OH
110; syn:anti >92:2 >98% yeild
Glyceraldehyde, of which 107 and 109 are protected forms, is the only three-carbon sugar.
There are two four-carbon sugars: erythrose 111 and threose 113. Both exist in hemiacetal
(furanose) and open chain forms and both are chiral but their symmetry properties differ. The
tetrols formed by reduction of the aldehydes are meso erythritol 112 and C 2 symmetric threitol
114 having the same stereochemistry as tartaric acid 35. Threose or threitol can be oxidised to
tartaric acid. These sugars are the origin of the terms ‘erythro’ and ‘threo’ sometimes used to
describe such diastereomeric relationships.
Threitol 114 has been used in many asymmetric syntheses, for example, the preparation of
the C 2 symmetric bis-epoxide 117 by protection of the secondary and activation of the primary
alcohols. Cyclisation of 116 could in principle give two fused four-membered rings, but threemembered
rings are greatly preferred kinetically. The bis-epoxide 117 reacts with nucleophiles
at the terminal carbons. 29
The Alkaloids
OBn
TiCl 4
SiMe3
Pb(OAc) 4
109
These nitrogen-containing natural products, often with powerful biological properties, are not
usually incorporated into target molecules. However, they are important in asymmetric syntheses
as the foundations of many reagents and catalysts. Quinine 119 is familiar as an anti-malarial and
an ingredient in tonic water. Quinine and its twin cinchona alkaloid quinidine 118 are referred to
as pseudo enantiomers. Each occurs naturally as one enantiomer only but the two structures are
nearly enantiomeric: only the vinyl side-chains disturb the symmetry and they act as enantiomers.
The vinyl side-chains are reduced and two molecules of, say, dihydroquinine (DHQ) are joined
O
TBDMSO
H
OBn
109; 100% yield
BF 3 Et 2O
SiMe3
TBDMSO
OBn
OH
110; syn:anti 19:81 90% yield
O
OH
OH
OH
HO
H NaBH4 HO
OH
HO OH
OH O
OH
111; erythrose
111; erythrose
112; erythritol
O
OH
OH
OH
HO
H NaBH4 HO
OH
HO OH
OH O
OH
113; threose 113; threose
114; threitol
114
threitol
HO
23 The Alkaloids 475
O O
1. MsCl
pyridine
MsO
OH
OMs KOH
H
OH
2. MsOH
EtOH, H2O OH
EtOH
H2O O
H
115 116 117
O

476 23 The Chiral Pool
by a spacer such as phthalazine (PHAL) to form the catalyst (DHQ) 2-PHAL 120 that accelerates
dihydroxylation of alkenes by OsO 4.
MeO
Other alkaloids such as brucine were used as resolving agents but their expense and extreme
toxicity has made them unpopular and the availability of a range of amines (chapter 22), often
made from the chiral pool, has made them unnecessary.
PART II – ASYMMETRIC SYNTHESES FROM THE CHIRAL POOL
Here we discuss syntheses of target molecules based on the chiral pool strategy using the same
sequence of natural products as part 1. This time we discuss why the chiral pool strategy was
chosen and try to demonstrate the particular value of each type of compound.
Amino Acids
With some targets the structure of an amino acid is immediately obvious. The thyroid hormone
thyroxine 121 present in the thyroid gland contains the skeleton of the proteinaceous amino acid
tyrosine 122 and can indeed be made from it.
HO
I
I
I
CO2H
CO 2H
HN
O
I
NH2
HO
NH2 CO2H
121; thyroxine 122; tyrosine
6; proline
We have already met proline 6 and its structure is clearly contained in the Bristol-Meyers
Squibb ACE inhibitor captopril 123. In other cases the relationship is not so obvious. Other ACE
inhibitors, also used to treat high blood pressure, such as ramipril 124 and fosinopril 125, also
contain the elements of proline but it is not obvious how we should use that observation.
SH
O
N
N
123; captopril
OH
CO 2H
HO
Ph
N
N
N
N
N
118; quinidine 119; quinine
120; (DHQ)2-PHAL
RO2C H H
N
H
OMe MeO
O
N
CO2H
N
Ph
OR
P
O O
124; ramipril 125; fosinopril
O
N N
O
N
N
CO 2H
OMe

The synthesis of captopril
The fi rst disconnection is easy 123a: it is in the middle of the molecule, at the amide bond and
reveals the molecule of proline 6. The thiol acid 126 has a 1,3-relationship between SH and CO
and can be made by conjugate addition.
HS
N
C–N
amide
HN
+
HS
3
2
OEt
1
C–S
1,3-diX
HS +
O CO2H CO2H
O
123a; captopril 6; proline 126
Thiolacetic acid 126 is used as a reagent for nucleophilic SH (it is a carbonyl compound and the
S atom is the nucleophile) and does the conjugate addition well. The racemic product 127 is coupled
to protected proline 128 and the t-butyl ester hydrolysed to give a mixture of diastereoisomers of
129. The salts of these can be separated and, after cleavage of the thiolester, the right isomer gives
captopril. Proline acts as a resolving agent as well as providing half of the target molecule.
Three reagents deserve some comment. Quinol 132 is easily oxidised to quinone and protects
the thiolacid 128 against disulfi de formation. DCC 133 is a standard peptide coupling agent
uniting free NH 2 and CO 2H groups by removing water to give dicyclohexylurea. The simple
amine 134 is suffi cient for separation by crystallisation during the resolution as the resolving agent
( proline) is already present in the molecule and a crystalline salt is all that is needed. Making
both diastereoisomers separately (each as a single enantiomer of course) established that 123 was
several orders of magnitude more active than the other isomer. 30
HO N C N N
O
H
132
quinone 133: DiCyclohexylCarbodiimide
134
The synthesis of ramipril
Ramipril 124, the Hoechst ACE inhibitor, is obviously more complicated. The fi rst amide
disconnection is the same and we can see the structure of alanine in the acid 135. The amine
136 looks like proline but no reactions spring to mind to make the bonds corresponding to
the disconnections.
Ph
O
128
SH
RO2C H H
N
H
OH
O
N
124a; ramipril
CO 2H
23 Amino Acids 477
O
alanine
RO2C
H H
C–N
N
OH
+
HN
?
amide
Ph
H
O
CO2H 135
136
HN
O
127
1. 133
127 AcS
HN
(DCC) AcS
N
1. 134
CO2H +
132
2. TFA
2. separate
t-BuO2C
O CO2H 3. NH3
129 130
131
MeOH
OH
proline
123
CO2H 6

478 23 The Chiral Pool
In practice 136 was not made from proline. Breaking open the other, more functionalised,
ring 136a is possible with the idea of a radical cyclisation onto an alkene 137. FGI of hydroxyl for
iodine reveals the elements of another amino acid, serine 140 and an allylic bromide 139.
H
HN
The key step in the synthesis was the radical cyclisation of 141 that gave an excellent yield of
two diastereoisomers: both had cis ring junctions and the compounds could be separated after conversion
to the bis benzyl esters 143 and 144. Hydrogenation of 143 released 136. Once again the
chiral pool material (serine) acts both as starting material and resolving agent though here there
was some selectivity (1.25:1) in favour of the right diastereoisomer 31 143.
Z
H
An ester of 136 is now used as resolving agent in coupling to the rest of the ramipril molecule.
Conjugate addition of alanine to the ketoester 145 gives a 2:1 mixture of 146 and its diastereoisomer.
Coupling with 136 allows separation of the right compound and hence completes the synthesis of
ramipril.
Ph
EtO
O
145
O
1. EtOH, Et 3N
H 2N
CO 2Bn
2. Pd/C, H 2, AcOH
Ph
EtO2C
The losses in yield when these semi-resolutions occur are not ideal and some ACE inhibitors
are made with much better selectivity. Enalapril 147, Merck’s Vasotec, is easily disconnected to
three simple pieces, proline 6, alanine 149, also part of ramipril, see 135, and the keto-acid 148,
assuming we can make the amine by reductive amination.
Ph
CO2H 136a
N
H
CO2Me
CO2Me
141; Z = CO2Bn 142; 88% yield
EtO 2C
radical
cyclisation
I
H
HN
N
N
H
O
147; enalapril
CO 2H
Bu3SnH H
H
PhCH2OH AIBN
Z
N
(i-PrO) 4Ti
78% yield
CO2H
I
FGI
2 x C–N
amide
amine
H
N
H
O
OH
146; 2:1 diastereomers
Ph
HN
137 138
EtO 2C
Z
H
N
C–N
OH allylation
CO2H CO2Bn
143
H
Br H2N OH
139
CO2H 140; serine
1. 136 benzyl ester
K 2CO 3, (EtMePO) 2
2. H 2, Pd/C, MeOH
124
O
+
H2N
OH + HN
O
CO2H 148 149; alanine 6; proline
+
Z
1.25:1
H
N
CO2Bn
144
H

Normal peptide coupling (N-Boc-Ala with proline benzyl ester coupled with DCC and removal
of the protecting groups) gives the dipeptide 150. Formation of the imine 151 and reductive
amination gives a 62:38 selectivity in favour of 147 providing that the reducing agent is hydrogen
with Pd/C. Sodium cyanoborohydride gives almost 50:50. The maleate salt of 147 was separated
by crystallisation. 32
HIV-protease inhibitors
The HIV-protease inhibitors, probably the most successful drugs used to prevent HIV turning into
AIDS, are all protein mimics with an unreactive CC bond replacing an amide link. That bond
is marked with a broad arrow in norvir 152, Bristol-Myers Squibb’s entry in this class. Amide
disconnection reveals that the key central part of the molecule 154 looks like a phenylalanine
dipeptide except that it has the CC bond. So can we make 154 from phenylalanine 4?
N
N
H2N O
CO2H 150; L-ala-L-pro
S
N
S
153
O
O
O
X
H
N
O
Ph
HO Ph
H 2N
Ph
2 x C–N
N
H
O
amides
Me
H
N N
Phenylalanine 4 is protected with benzyl groups 156 and combined with the anion of acetonitrile
to give 157. Benzyl Grignard attacks the nitrile to give the enaminone 158 which is immediately
reduced to the boron complex 159 that shows remarkably high 1,4-stereoselectivity (95:5). Still
without isolation, reductive cleavage of 159 gives 160, a protected version of 154, again with
excellent stereoselectivity. 33 The deprotected intermediate 154 is isolated in 60% yield from the
enaminone 158 after debenzylation by Pd-catalysed transfer hydrogenation with
ammonium formate.
NH 2
O
Ph
OH O
X
N
S
Me
H
N N
O
154 155
152
norvir
HIV-protease
inhibitor
O
O
O
H2N OH
BnCl Bn2N
OBn
MeCN Bn2N
CN
Ph MgCl
K2CO3
NaNH2
THF
Ph
4; phenylalanine
Ph
156; 94% yield
Ph
157; 78% yield
Bn 2N
O NH 2
23 Amino Acids 479
EtO 2C
155
H2, Pd/C
N
147
Ph
N
enalapril
EtOH EtOH
O
CO2H 62:38
151; E/Z-mixture of imines
diastereomers
OR
B
O NH
Ph
Ph
2.5 NaBH4 MsOH
THF, i-PrOH
Bn2N 1
Ph
4
Ph
NaBH3(OR)
R = CF3CO Bn2N Ph
Ph
158 159: 95:5 diastereoselectivity
160; 93% of mixture
N
S
OH NH2

480 23 The Chiral Pool
Hydroxy-Acids
The synthesis of bestatin
The potent enzyme (aminopeptidase) inhibitor bestatin 161 provides another perfect bridge
between the amino- and the hydroxy-acids. At fi rst sight bestatin appears to be a dipeptide but only
one of the components, leucine 163 is a normal α-amino acid. The other half 162 is a β-amino
acid and also an α-hydroxyacid and that might give us the idea that malic acid 34, with the same
absolute confi guration at the secondary alcohol, could provide a chiral pool starting material.
Ph
First the benzyl group must be added. The di-lithium derivative of diethyl malate 164 is
alkylated on the opposite side to the OLi group (chapter 30). Now the two ester groups must be
distinguished. Reaction of the free diacid with trifl uoroacetic anhydride and then with ethanol
gives 166. Presumably the two acids form a cyclic anhydride and the free OH forms an ester.
Reaction with ethanol occurs at the more reactive (next to OCOCF 3) and less hindered (not next to
benzyl) carbonyl group of the anhydride and the trifl uoroacetyl groups fall off during work-up.
EtO
O
The free acid group is converted into an amine with diphenylphosphoryl azide 167. A Curtius
rearrangement with retention at the migrating group gives the isocyanate 168 which is captured
by the OH group to give the cyclic carbamate 169. Peptide coupling with leucine methyl ester
using a water soluble carbodiimide (EDC), N-methyl morpholine (NMM) as base, and hydroxybenzotriazole
(HOBt) as catalyst gives a slightly disguised form of bestatin 161 with all the
stereochemistry correct. 34
O
166
(PhO)2P N3
167
diphenyl
phosphoryl
azide
O
H2N N
OH
H
OH
O
164; diethyl malate
Ph
OEt
N
C
O
CO 2H
1. 2 x LiHMDS
2. PhCH 2Br
OH
168
CO2Et
Ph
H2N OH
EtO
Ph
O
Ph
HN
OH
161; bestatin 162
O
O
OH
165
O
+
H 2N CO 2H
OEt
163; leucine
1. NaOH
2. (CF3CO) 2O
3. EtOH
HO
HO
Ph
166
OH
Ph
O
O
CO2Et 1. LiOH
2. 170-OMe
EDC, NMM
HOBt
HN
O
N
H
169
O
170
O
O
OH
34; malic acid
O
O
OEt
OH
CO2Me

The synthesis of ()-laurencin
Some molecules that can be made from the chiral pool give little hint of that when you fi rst inspect
their structures. It is only after the disconnection process had started that smaller fragments reveal a
possible natural starting material. Laurencin 171 reveals its marine origin by the bromine atom and
the eight-membered ring that is the heart of the molecule. Trimming off the side chains and writing
a lactone 172 having the right sort of functional groups in the right places makes the problem much
simpler and opening the lactone reveals a relatively simple open chain intermediate 173.
FGI
Br
O
H
?
HO
O
H C–O
lactone
HO
HO2C HO
H
OAc
O OH
OH
171; (+)-laurencin 172 173
Since there is a cis alkene in the middle of 173 a Wittig disconnection 173a makes sense and
the starting materials 174 and 175 turn out to be four-carbon units with functionality, mostly in
the form of oxygen atoms, at C-1, C-2 and C-4. This is job description for malic acid and both
compounds can indeed be made from (R)-()-malic acid 35 34.
HO2C
OH
Wittig
OH OH
Wittig PPh3 OH
CHO
HO2C OH
174 173a
175
A protected version of the aldehyde 174 comes from acetal formation and reduction of the
remaining CO 2H group. Acid catalysed hydrolysis of the acetal gives the lactone 177 that is protected
as 178. Hydrolysis and oxidation give 179 ready for the Wittig reaction.
HO 2C
OH
3. Ph O Cl
i-Pr 2NEt
CO 2H
34; (R)-(+)-malic acid
MeO
TsOH
OMe
O
CO 2H
O OBn
O
O
1. EtOH, K2CO3 2. Swern
EtO2C
O OBn
CHO
178; 75% yield 179; 58% yield
The phosphonium salt 175 requires similar operations but malic acid 34 is reduced to the triol
180 before selective protection 181 leaves just one alcohol for conversion to tosylate, bromide and
fi nally protected phosphonium salt 182.
34
BH3.SMe2
(MeO)3B
23 Hydroxy-Acids 481
O
O
176; 75-85% yield
1. BH 3
2. H +
HO
OH OH
Me2C=O
TsOH
O
O OH
1. TsCl, pyr
2. NaBr
3. Ph3P, LiI, melt
180; 98% yield 181; 82% yield
O
O
177
OH
OH
O
O
PPh3
182; 100% yield

482 23 The Chiral Pool
The Wittig reaction between the ylid formed from 182 with BuLi and the protected aldehyde
179 does indeed give the Z-alkene 183, a protected version of 175, ready for cyclisation and completion
of the synthesis of laurencin. Notice how far apart (1,6-related) are the chiral centres in
183. Making both independently from malic acid ensures that the right diastereoisomer, as well as
the right enantiomer, results.
Streptazolin from tartaric acid
Streptazolin 184, an antibiotic from a Streptomyces species, has a cluster of three rings, an
awkward exocyclic alkene with geometry and three neighbouring chiral centres. There is no
obvious chiral pool starting material. Disconnecting the lactone is obvious and we might be able to
control the alkene geometry by the kind of Pd-catalysed coupling we met in chapter 18. This gives
185 from which we can remove the carbamate. The aldehyde can be reconnected to the nitrogen
atom to give 186 - atoms 1 and 5 have been joined as an amide. Now the possibility emerges of
making streptazolin from tartaric acid 36 35.
N
O
H
O
H
184
To get back to tartaric acid from 186 we must disconnect as in 186a and the obvious synthon
is 187 with the proviso that the nucleophilic end must control the geometry of the alkene. A vinyl
silane is a good answer (chapter 18) with some leaving group at the other end 188 together with
the imide 189 obviously derived from tartaric acid 35.
N
H
Me
OH
O
OBn
186a
Ph 3P
OBn
Pd-diene
synthesis
C–O
lactone
add
protection
O
O
1. BuLi, THF O OBn O
182
2. 185
HO2C Z-183; 73% yield
OBn reconnect
1-5
H
1
2
1
N 2 OBn
N
4 CHO FGI
3
H
5 reduce
3
EtO2C OBn
O 5 4
OBn
185 186
Me3Si
The imide 189 is easily made from protected tartaric acid 190 and the vinyl silane 188 coupled
in a Mitsunobu reaction. Reduction of one of the carbonyl groups of the imide 191 may seem
tricky but the molecule is C 2 symmetric so the two carbonyl groups are the same and once one is
reduced the molecule is a much less reactive amide. The stereochemistry of the acetate in 192 does
not matter as it disappears in the cyclisation to 186. Notice that the alkene geometry is retained.
HN
X
HO
O
OBn
synthon 187 reagent 188 189
+
O
OBn
O
?
HO2C
HO 2C
2
HO2C HO 2C
3
4
OH
OH
(R,R)-(+)-35
tartaric acid
OH
OH
5
(R,R)-(+)-35
tartaric acid

The next few steps including the vital palladium-catalysed cyclisation revealed a problem in
this synthesis and it is continued in the workbook. An improved synthesis by Trost uses two
alkynes in the cyclisation and the problems disappear. This starts from protected mannitol
106 and the oxidative cleavage is followed at once by imine formation 193. Addition of the lithium
derivative 194 goes with good selectivity (13:1 in favour of 195). Adjustment of protecting groups
and hydrolysis of the acetal leads to the key intermediate 37 197.
The second alkyne is introduced after oxidation to an aldehyde again with good selectivity
(6:1 in favour of 198). Protecting groups are added or adjusted before the Pd(0)-catalysed cyclisation
gives both alkenes in 199 in the right place with the right geometry. The mechanism of the
cyclisation was already established by Trost 38 and is discussed in the workbook. Cyclisation and
deprotection gave streptazolin 184 in only 11 steps from the chiral pool.
197
1. DMSO
(COCl) 2
Et3N CH2Cl2 2. ZnCl2 RMgBr
R = propynyl
PMBO
HN
O
O
198; 50% yield
Me3Si
OH
1. TBDMSCl
imidazole
75% yield
2. DDQ
93% yield
3. TsCl, pyr
75% yield
4. Pd2(dba) 3
HCO2H, Et3SiH 64% yield
TsO
Me 3Si
EtO2C EtO2C OBn
OBn
NH3 189
188
DEAD
Ph3P
N
O
1. NaBH4
2. Ac2O
OBn DMAP N
OAc
BF3 Et2O 186
99% yield
OBn
190
O
OBn
O
OBn
191; 77% yield
192; 93% yield
O
O
OH
OH
O
O
106; bis-acetal of mannitol
PMBO
HN
O
195; 69% yield
O
1. NaIO 4, H 2O, 0 ˚C
2.
1. Pd(dba) 2
dppb, 2-thiosalicylic
acid
2. PhOCOCl
NaHCO 3, H 2O
23 Hydroxy-Acids 483
NH2
PMBO
PhO
O
N
H
N
O
O
193; 95% yield
196; 99% yield
O
HN
O
O
1. TsOH
MeOH
2. K 2CO 3
H
O
199
PMBO
+
PMBO
H
Me
HN
O
O
197; 88% yield
OR
Li
194; PMB =
p-MeO-benzyl
from alkyne
and BuLi
Me 3Al
1. NaH, THF
84% yield
2. TBAF
THF
99% yield
OH
184

484 23 The Chiral Pool
Amino Alcohols
Synthesis of quinolone antibiotics
Quinolone antibiotics such as ofl oxacin 200 are totally different from β-lactams, tetracyclines and
so on and work in a different way. They offer some hope that resistance may be slow to appear.
They all contain the ‘quinolone’ core: a benzene ring fused to a γ-pyridone. Most have various
amine substituents and ofl oxacin has a fl uorine atom. Disconnection of the enamine reveals a
benzene ring with a series of heteroatom substituents (N, N, O, F) and the one fl uorine suggests
that a series of nucleophilic substitutions might provide a synthesis.
MeN
The acid chloride of tetra-fl uoro benzoic acid 203 acylated the magnesium enolate 204 of
diethyl malonate to give 205. The chelated magnesium enolate avoids O-acylation. Condensation
with ethyl orthoformate puts in the masked aldehyde group and 206 is ready for a succession of
aromatic nucleophilic substitutions. 39
Reaction with the amino alcohol alaninol 207 from the chiral pool forms the enamine 208 and
introduces the only chirality. The fi rst two substitutions are controlled by the tether. The amine
can reach only the ortho position to give the quinolone 209 and now the hydroxyl group can reach
only the meta position to give 210. The geometry of the enamine 208 means nothing as it is a conjugated
enaminone and such double bonds rotate easily. The displacement of F by N to give 209 is
activated by the carbonyl group but that of F by O to give 210 is not. The three fl uorine atoms in
the ring help and it is an intramolecular reaction.
206
HO
F
N
Mg
O O
207
NH 2
O
EtO OEt
204
F
F
O
N
200; ofloxacin
F
F
F
F
CO2H
O
F
HO
NH CHO
C–N
enamine
N
SNAr 2 x C–N
MeN
O
C–O
203
O
F
Cl
CO2Et KF
NH
1. 204
DMF
F
2. hydrolyse
3. heat (–CO 2)
F
F
F
F
F
O
N
CO2Et
KF
DMF
F
208 209 OH
210
O
CO2H
201 202
F
O
F
F
F
F
CO2Et F
CH(OEt)3
O
O
O
F CHO
F
Ac2O F
F
205
F
206
N
CO 2H
O
CO 2Et
CO 2Et
OEt

That leaves just one nucleophile to introduce, the piperazine ring. After hydrolysis of the ester,
N-methylpiperazine 212 displaces the fl uorine para to the ketone and ofl oxacin is formed. Amino
alcohols are closely related to amino acids so this one example will be enough. The next group of
antibiotics also look as though they might come from amino alcohols, but wait…
210
NaOH
H2O
The oxazolidinone antibiotics
F
F
O
O
N
211
CO 2H
MeN
The oxazolidinones, general structure 213, such as the Upjohn compound U100766, 213; R
morpholine, are antibiotics that act by a different mechanism to all others. Amide disconnection
takes us back through amine 214 and azide 215 to alcohol 216.
R
F
23 Amino Alcohols 485
Opening the oxazolidinone ring reveals a three carbon chain with one functional group on each
carbon atom 217. Glycidol, available as either enantiomer, is an ideal starting material.
One of these antibiotics 224 was made by Upjohn from the Cbz-protected aromatic amine 219
and the ester 222 in place of glycidol. The lithium derivative of 219 attacks the epoxide releasing
an oxyanion that attacks the Cbz group 220 releasing PhCH 2O that in turn cleaves the butyrate
ester and gives 221 in one pot and 85% yield. 40
212
NH
Me
N
F
N
O
200
O
O
O
C–N
FGI FGI
N O
H amide
ArN O
ArN O
N
NH2 N3 H
213 O
H
214
H
215
O
N
CO2H
O
ArN O
O
ArN O
C–O EtO2C ArN
OH 1,2-diO
O
=
O H O
O Pr
216a
H
OH
ester
H
OH
217
C–N
H
OH
218
OH
(R)-(+)-glycidol
O
222
(R)-Glycidyl butyrate
O
N
F
1. BuLi
–78 ˚C
2. 222 O
NHCbz
Pr O
219 220
O
Ar N OBn
O
O
N
O
221; 85% yield
H
216
F N O
OH
OH

486 23 The Chiral Pool
The synthesis is completed with mesylation and azide displacement to give 223 then reduction
of N 3 to NH 2 and acetylation. This 224 is U100766, an antibiotic with a potency similar to that of
vancomycin that might not stimulate resistance as quickly as β-lactams. 41
221
1. MsCl
Et 3N
2. NaN3
DMF
O
N
The synthesis of anti-viral nucleoside analogues
O
Many anti-viral compounds are analogues of the natural nucleic acid nucleosides such as adenosine
225. This example 226, known as (S,S)-iso-ddA (dda stands for di-deoxy-adenosine), has a
severely modifi ed sugar 227 but the purine, adenine 228, is unaltered. The purine is attached to
C-2´ instead of C-1´ making the molecule more stable and two of the OH groups have been removed.
Coupling adenine to the modifi ed sugar 227 needs a Mitsunobu process. 42
Since 227 has a 1,2-diX relationship, one way to make it would be to change the terminal OR
into I 229 and use an iodine cyclisation of the alkene 230. That allows us to recognise a glycidol
unit 231 by disconnection of the vinyl group.
227
HO
FGI
O
I
N
N
H2N
OH OH
225; adenosine
N
229
O
It turns out that we need to protect only one of the hydroxyl groups: the primary OH of
glycidol as a t-butyl diphenylsilyl ether 232. The epoxide is opened by a vinyl cuprate and the
iodo etherifi cation occurs regio- and stereoselectively (no four-membered rings are formed and the
trans stereochemistry of 230 is preferred). Iodide is displaced by the p-nitrobenzyloxide 233 and
fi nally the Mitsunobu reaction with adenine goes on the right nitrogen atom to give 234.
1. H 2
Pd/C
F N O
2. Ac2O F N O
N3 pyridine
NHAc
223 224; 85% yield from 226
N
OH
O
Iodoetherification
N
RO N
N
2'
226; adenosine
analogue
NH 2
Protect?
N
OH
230
O
Mitsunobu
OH
C–C
N
OR
O
+
OH
227
sugar analogue
O
N
N
H
NH2
N
228; adenine
a purine
N
OH
=
O H
OH
O
Protect? 231
(R)-(+)-glycidol

231
O 2N
The New Chiral Pool
Glycidol as a chiral pool member
You may have felt that all this was out of place as glycidol is not available from natural sources. But
both enantiomers are available quite cheaply by several processes such as Sharpless asymmetric
epoxidation (chapter 25) and enzymatic hydrolysis of glycidol esters (chapter 29). We propose to
elect glycidol and a number of other small molecules to the ‘New Chiral Pool’ as they now fi ll the
same role as, say, the amino acids – cheap sources of enantiomerically pure small fragments of
molecules that can easily be added to other fragments with predictable stereochemistry.
Whenever you require an electrophilic three-carbon fragment with functionality at all three
carbons, glycidol 231 or 235 is a natural choice. But there’s another, arguably even more useful
reagent that does much the same thing – epichlorhydrin 236 and 237.
O
H
O
K
233
OH
O
231
(R)-(+)-glycidol
OTBDPS
232
O
1. MgCl2 CuCN
234 RO
DMSO
18-crown-6
23 The New Chiral Pool 487
2. TBAF
H
OH
235
(S)-(–)-glycidol
O
OH
There is a complication: it is obvious that the terminal epoxide atom of glycidol is attacked by
nucleophiles, but epichlorhydrin could be attacked at the terminal epoxide atom or at the CH 2Cl
group. This matters a great deal: direct displacement of chloride 240b gives one enantiomer of 241
but attack at the epoxide 240a followed by cyclisation 239 gives the other 238.
This sequence is particularly important in the synthesis of β-blockers such as propranolol 242.
Disconnecting α-naphthol 243 and i-PrNH 2 reveals a C 3-synthon 244, electrophilic at both ends,
that must be chiral. Epichlorhydrin is ideal.
OH
OH
230; 98% yield
227; 73%
adenine
PPh3 DEAD
DMF
O
I 2, NaHCO 3
CH 3CN
O 2N
H
Cl
236
(R)-(–)-epichlorhydrin
I
O
OH
229; 71% yield
O N
O
O
234; 62% yield
N
H
Cl
NH2
N
237
(S)-(+)-epichlorhydrin
O
(R)-(–)-epichlorhydrin
Nu
O
Nu
O
O
Nu
Cl
Nu
Cl
Nu
238 239 240a 240b
241
N

488 23 The Chiral Pool
If we react epichlorhydrin with α-naphthol 243 and an amine, the amine (pK aH about 11) will
remove the proton from the phenol and that will attack epichlorhydrin 245 to give the alkoxide 246
that will remove a proton from the amine salt to give the intermediate 247.
ArOH
pKa ~10
OH
OH
H
2 x 1,2-diX
O N
OH H2N 242; propranolol
O
O
ArO
R2NH R2NH2
pK aH ~11
ArO
245
If we want to do the reaction in one step we must use a stronger base, such as NaOH, so that the
intermediate 246 has a long enough lifetime to cyclise to the new epoxide 248 that will react with
i-PrNH 2 to give propranolol. 43
O Cl
NaOH
243
O
236; R-(–)epichlorhydrin
To make enantiomerically pure propranolol, it doesn’t matter which way round the reaction
goes as long as you know which and as long as it goes one way or the other. Glycidol 235, easily
made from mannitol, was made by Sharpless using asymmetric epoxidation (chapter 25) and converted
into the tosylate 249. This reacts with the anion of α-naphthol 243 at the CH 2OTs end and
not at the epoxide end to give 250 and hence propranolol. 44 But we must use the other enantiomer,
(S)-glycidol 235, whereas we used (R)-epichlorhydrin 236.
O
H
OH
235
(S)-(–)-glycidol
248
Phenylglycine as a chiral pool member
C–O, C–N
Cl
TsCl O H
OTs
243
Et3N NaH
249
DMF
O
O
243; α-naphthol
i-PrNH 2
Phenylglycine doesn’t occur in proteins but is available as either enantiomer. When Schering-
Plough made the racemic drug 251 as an NK1 antagonist, the task was easy. Because a trusty
hydantoin synthesis already existed, they mixed the ketone 253 with potassium cyanide and
ammonium carbonate to get 252 and reduced out the spare amide carbonyl with LiAlH 4.
H
250
246
OAr
Cl
i-PrNH2
pK a ~11
synthon
244
O
ArO
i-PrNH 2
OH
Cl
247; pKa ~15
OH
242; propranolol
i-PrNH
H
N
OAr
242; propranolol

O
HN
Ph
NH
O
When they wanted a single enantiomer, this synthesis was useless. Where could chirality be
introduced? Instead they disconnected the other two CN bonds in the ring 252a and worked
their way back to the enolate of phenylglycine 255 and some alkylating agent 256.
O
HN
Ph
They did not know, of course, which enantiomer would be more active but it turned out that the
methyl ester 257 was the right choice. Conversion to the amide 258 and aminal formation with
pivalaldehyde 259 allowed control of enolate alkylation by Seebach’s relay method (chapter 30).
Hydrolysis of 260 and reaction with ClSO 2NCO gave one enantiomer 45 of 251.
H3N CO2Me MeNH2 H2N CONHMe t-BuCHO
Ph H
H2O Ph H
257; >99%ee
CF3 O
+ KCN, (NH4) 2CO3 FGA
HN
NH
O
hydantoin
synthesis O
CF3 Ph
O Ar 2 x C–N
Ph
O Ar
251 252 253
NH
2 x C–N
O
O
252a
Ar amides
H2N CO 2H
258; >97%ee
C 2 symmetric diamines as chiral pool members
Ph
254
O Ar
H 2N CO 2H
Ph
255; enolate
O Ar
t-Bu
t-Bu
NMe 1. LDA NMe
HN
Ph H
O 2. 256
(X = Br)
HN
Ph
O
O Ar
259; 49% yield 260; 70-75% yield
One mono-amine 261 and one diamine 262 were resolved in chapter 22 by the simplest of
processes. They are joined in the new chiral pool by two closely related C 2 symmetric diamines,
263 and 264, made by rather different procedures. Though we show only one enantiomer of these
amines, both are available at about the same price as they are all made by resolution.
NH2
23 The New Chiral Pool 489
NH 2
Diamine 264 is made from the α-diketone benzil by a simple but multiple cyclisation to give
the heterocycle 265. Stereoselective dissolving metal reduction gives anti-266 and hence racemic
264 on aminal hydrolysis. Resolution with tartaric acid brings down crystals of the tartrate of one
enantiomer. With L-()-tartaric acid, the salt with (S,S)-264 is less soluble while (R,R)-264 requires
treatment with D-()-tartaric acid. One important application is the asymmetric Lewis acid 46 267.
C–C
alkylation
NHMe
NH2
NHMe
NH2 261 262 263 264
+
X
NH 2
256

490 23 The Chiral Pool
Ph
O
O
benzil
Diamine 263 is made by the radical (pinacol style) dimerisation of the benzaldehyde imine
268. This gives a diastereomeric mixture equilibrated in favour of the syn isomer with lithium in
isoprene and separated (51% yield) from the meso isomer by crystallisation with racemic tartaric
acid. 47 Finally, (±)-263 is resolved with a single enantiomer of tartaric acid giving 90% yield of
either (S,S)-263 or (R,R)-263, depending on which enantiomer of tartaric acid is used, in 99% ee.
The isomer remaining in solution can be isolated with only slightly worse ee: 96%.
This diamine has had many uses. The bis m-trifl uoromethyl compound 270 made in the
same way from m-trifl uoromethylbenzaldehyde, is a chiral NMR shift reagent that gives better
spectra than the more traditional Eu-based shift reagents and allows the reliable determination
of ee. Terpenes are notorious for low ees and the ee of myrtenal 271 was determined as 96% by
formation of the aminal 272 and the measurement of its 19 F NMR spectrum. 48 The signals for the
two diastereoisomers were easily distinguished and integrated even though the compounds were
diffi cult to separate by chiral HPLC.
F 3C
Ph
RESOLUTION
1. L-(+)-tartaric acid
2. filter
3. recrystallise
4. NaOH
Ph
O
H
O
NH 4OAc, AcOH
MeNH 2
H 2O
Ph
NHMe
NH 2
NHMe
N
Ph
NH2 (S, S)-264
57-66% yield, >98%ee
CF3
Compound 263 itself forms C 2-symmetric aminals and the one from glyoxal 273 is valuable in
controlling nucleophilic attack on the remaining aldehyde group 274 or on electrophilic alkenes
such as 275 formed in a Wadsworth-Horner-Emmons reaction (chapter 15). The aminal can be
hydrolysed with acid in conditions that do not cause any racemisation even next to an aldehyde. 49
CHO
270; chiral NMR shift reagent 271; myrtenal
N
Ph Ph
265; ~ 95% yield
+
Ph
+
1. Li, THF
2. EtOH
NH 2
Ph
NH2 (R, R)-264
in solution
HN
NH
Ph Ph
anti-266
3. HCl
4. NaOH
Ph
Ph
N
Al
N
Me
SO 2CF 3
N
272
Ph
Me
SO2CF3 267
NH2
Ar
N
Me
Ar
Ph
NH2 (±)-264; ~ 90% yield
syn but racemic
N
Me
1. Zn, Me3SiCl MeCN
Ph
NHMe
Ph
1. Li,
Ph
NHMe
Ph
Ph H 2. Hydrolysis NHMe
2. racemic
tartaric acid
NHMe
268; 95% yield 269; syn + anti 3. NaOH, H2O (±)-263
use crude
syn but racemic

Ph
O
H
H
O
Me
H
O
N
N
Me
Ph (EtO) Ph
273; glyoxal
263
274
Ph
O
2P CO2Et NaOEt
Me
N
Ph
EtO2C
N
Me
E-275; 77% from 267
Me
Bu2CuLi EtO2C
N
N
Me
Ph
H
H2O
EtO2C CHO
276; >99:1 diastereoselectivity (S)-277; >99% ee
The aminal 279 with pyridine-3-aldehyde 278 adds cuprates in the 4-position with excellent
stereoselectivity to give partly reduced pyridines 280 that are immediately acylated 281. This example
can be reduced and cyclised to the alkaloid 282 with two chiral centres under control. 50
N
MeO
MeO
278
Amino-indanols
These may seem strange molecules to have a place in the new chiral pool but they were made on
a vast scale by Merck in the synthesis of their HIV protease inhibitor crixivan (Indinavir). They
both come from Jacobsen epoxidation of indene 283 (chapter 25): the anti-compound 285 by
opening the epoxide 284 at the benzylic centre with azide ion. 51
283; indene
CHO
263
N
Jacobsen
epoxidation
chapter 25
O
MeN
N
23 The New Chiral Pool 491
MeN
Me
N
Me
N
Ph
O
Ph
MeLi
2CuBr.SMe2
281 Ph
282
The syn compound 286 is more interesting. It was absolutely necessary for the synthesis of
crixivan and is clearly visible at the right hand end of 287. It is not a natural product.
4 LiBr
NH2
OH
284 285
286
H
N
MeN
Me
N
279 Ph
280 Ph
1. LiAlH4 2. CF3CO2H 3. (CF3CO) 2O
4. MeOH, NaOMe
MeO
MeO
H
N
Ph
ArCH 2COCl
CHO
NH 2
OH

492 23 The Chiral Pool
Merck devised a synthesis that was so effi cient that 286 is now available commercially (it was
only a rumour that Merck would give it away free as they had so much) and has been used in asymmetric
synthesis in many ways. The synthesis is described 52 in full by the Merck team in Organic
Syntheses. The epoxide 284 is protonated by acid to give the cation 288 that captures acetonitrile
in a Ritter reaction giving the heterocycle 290 that is easily hydrolysed to 286.
MeCN
O H
OH MeCN 284
H2SO4 (fuming)
N
O
H2O 286
The stereochemistry of this reaction looks all wrong. In fact the cation 289 prefers to capture
acetonitrile 292 from the top side, opposite the OH group, to give anti-291. But this intermediate
cannot cyclise and is in equilibrium with 292. Only when syn-291 is formed can cyclisation occur
and the cations are removed from the equilibrium. Even the cyclisation that does occur looks bad
enough but 5-endo-dig reactions are all right.
N
Me
OH
Me N
OH OH
anti-291 292
syn-291
The amino-indanol 286 is the basis for many important asymmetric reagents such as the
enolates derived from 293 and the metal complexes such as 295 derived from the dimer 294. These
are effective as catalysts for Diels-Alder reactions. 53
Ph
287
Merck's HIV-protease
inhibitor
crixivan (Indinavir)
O
N
O
N
N
288 289 290
O
N N
t-BuNH
O
N
O
OH
Cu(OTf)2
Ph
O
N
H
N
Me
O
OH
N
Cu
N
TfO OTf
293 294 295
O
290

The synthesis of crixivan (Indinavir)
Further steps in this synthesis are interesting as the alkylation of the enolate of 293 with glycidol
tosylate 249 puts in the next two chiral centres. Attack occurs at the epoxide end of the electrophile
296 and the stereochemistry at C-2 is controlled by the amino-indanol. The stereochemistry at
C-4 is controlled by the electrophile and is again unchanged when the epoxide 297 is attacked by
the piperazine nucleophile. 54 The remaining centre in crixivan is in the piperazine ring and this
is secured by asymmetric hydrogenation (chapter 26). We have now explored both new and old
chiral pool enough to look at a few syntheses without prejudging the starting materials.
293
Conclusion: Syntheses from the Chiral Pool
The synthesis of agelastatin
Agelastatin 299 is an interesting molecule partly because it is an anti-neoplastic and partly because
of the massing of functionality around such a small frame. It contains a cluster of heteroatoms
all having 1,1-diX relationships and removal of these reveals the basic carbon skeleton having a
carbonyl group in a 1,3-relationship to the pyrrole nitrogen. Disconnection 300 with conjugate addition
in mind reveals a much simpler compound 301 with just two neighbouring chiral centres.
Br
(Me 3Si) 2NLi
TsO
N
HO
NH
Me
N
NH
O
299; agelastatin
O
1,1-diX
3 x C–N
Br
N
Disconnecting the amide 301a isolates the fi ve-membered ring containing both chiral centres
303. It is not obvious whether this compound could be made from the chiral pool but literature
search revealed a glucosamine derivative 304 that looked promising. Neither of your authors has
detailed knowledge of the sugar literature, and neither author would have seen this possibility.
Br
249
NH
O
Ph
NH
O
301a
O
23 Conclusion: Syntheses from the Chiral Pool 493
O
TsO
NH 2
O Li
N
O
Ph
O
NH
O
OTs
O
296 297 298; 72% yield
Br
2
NH 2
N
1,3-diX
C–N
Br
NH
O
O
300 301
amide ?
NH +
NH C–N
2
CO 2H
NH 2
O
302 303
O
Ph
Ph
O
O
O
4
304
NH
N
H
O
O
O
N
NH 2
OMe
O

494 23 The Chiral Pool
Glucosamine can be N-benzoylated 305 and protected as a methyl glucoside and a benzylidene
acetal leaving just one OH free 306. Tosylation of this free OH and treatment with base gives the
three-membered ring 55 304.
HO
HO
HO
1. MeOH, H Ph O
TsCl Ph O
O
Na
O
O
O
O
OH
HO
TsO
i-PrOH
NHBz
BzNH BzNH
OMe
OMe
+
2. PhCHO
pyridine
ZnCl2 305 306 307
The synthesis of agelastatin from 304 is too long to describe in detail so we shall just pick out the
most important stages. The trans relationship between the two nitrogen atoms in 303 was established
by opening the N-acylated aziridine 308 with azide ion. The trans-diaxial product 309 is formed
(chapter 21). Further functional group and protecting group manipulations (fi ve steps) give 310. The
protecting group SES is Me 3SiCH 2CH 2SO 2 , designed to be removed by fl uoride ion.
Now two critical steps. The iodide 310 is fragmented by zinc in aqueous THF 311 to give the
unsaturated aldehyde 312 in astonishing yield. The mechanism 311 has the NHR group omitted for
clarity: the loss of the MeO group may not be concerted with the rest. Though Wittig and Peterson
failed, a Kocienski-Julia reaction (chapter 15) gave the diene 313 used immediately in the next step.
Zn
ClCO 2Me
304 pyridine
I
Et3SiO
Ph
O
O
O
O
N OMe
CO2Me
NH4Cl DMF MeO2CNH OMe MeO2CNH OMe
308; 86% yield 309; 88% yield 310; R = SES
Et 3SiO
NaN 3
Ph
CHO
N N
N
N
Ph
Et3SiO
MeO2CNH OMe MeO2CNH NHSES (Me3Si) 2NK MeO2CNH NHSES
311 312; 97% yield 313
We hope you guessed that metathesis was used to close the fi ve-membered ring. The modifi ed
Hoveyda-Grubbs catalyst 314 gave the best results and the product 315 cyclised to 316 after
removal of the Et 3Si and CO 2Me protecting groups. This compound contains all the functionality
and stereochemistry of 303. So was it all worth it, just to use glucosamine from the chiral pool?
Well, this was the fi rst asymmetric synthesis. 56
R
N N
Cl
Cl
i-Pr
Ru
O
314
R
313
314
Et 3SiO
The fi nal stages 57 are better seen if we turn 316 round to make it look more like 303. Protection
of the ring nitrogen 317 allowed acylation of the other nitrogen by the pyrrole 318 having Me 3Si
in place of Br.
O
O
MeO2CNH NHSES
315
N3 O
K 2CO 3
MeOH
SO 2Me
O
I
Et3SiO
O
N
H
NHR
O
NHSES
316; 36% yield from 312
304

O
While 319 could be converted into the required enone 320, no amount of trying allowed further
progress with the synthesis. Conjugate addition occurred but other reactions followed. The answer
was bromination. This gave a mixture of mono-, di-, and tri-brominated pyrroles but they all
cyclised with Hünig’s base to a mixture of protected 300 brominated in various places from which
agelastatin was fi nally made.
Me 3Si
NHSES
316
O
NH
H
N
1. BuLi
2. Me
ClOC N Bn
O
O
O
319 320
The synthesis of LAF389, a Novartis anti-cancer agent
O
N
Me
NSES
O
O
Me
NHSES
317; 88-94% yield
N Bn
O
N
O
N Bn
Me 3Si
Me3Si
The natural product bengamide B shows promising anti-cancer activity and Novartis have initiated
a programme to synthesise the analogue LAF389 321 on a large scale. 58 It contains a side chain
with four contiguous chiral centres joined by an amide to a seven-membered ring heterocycle with
two chiral centres.
t-Bu
There is a 1,4-relationship both between the chiral centres on the ring and between those on the
side chain and the nearer on the ring. This makes the ester and amide disconnections shown on
321 attractive giving three starting materials.
C–O and C–N
321
ester and amide
23 Conclusion: Syntheses from the Chiral Pool 495
OH
t-Bu
OH
OH
OMe
1
O
H
N
OH
4
O
OMe
The side chain fragment 322 has the look of a sugar and, if the alkene is removed with a Julia
reaction in mind (as it is an E-alkene, chapter 15), it has six carbon atoms with oxygen on each
one 325. Unfortunately two of the centres are not those in glucose 99. However a C 7 sugar, the
NH
1
+
O
O
NH
318
H
N
O
O
Cl
Et3N, DMAP
THF, RT
four hours
H
Me
N N
Bn
O
NH
321
Novartis's
LAF389
H2N NH
OH + +
OH OH O
OH
322 323 324
O
319
89%
yield
CO 2H

496 23 The Chiral Pool
gulo-heptonic acid 326 is available. It has all the right stereochemistry at C-2 to C-5, only C-6 is
unwanted but as it also has one too many carbon, that centre can be removed in making the aldehyde
325. Again, a search of the sugar literature would be helpful.
322 Julia
OHC
OH
OH
OH
CO 2H
HO CHO
OH
OH OH
OH OH
325 99; glucose
326; gulo-heptonic acid
The acid 326 exists as the lactone 327 and can be selectively protected as 328 for oxidative
cleavage by periodate to give 329. The development synthesis was similar to the laboratory
synthesis but in this step as in many others careful improvements were needed for it to be safe and
effective on a large scale.
HO
O
OH
OH
O O
O O
327; gulo-heptonic acid
γ-lactone 328 329
The other chiral component, the lactam 323, is clearly a cyclised version of 5-hydroxy-lysine
330. This and hydroxyproline 331 occur in the connective protein collagen. The hydroxy groups
are added after the collagen is assembled but as they can be obtained by hydrolysis of collagen,
they are members of the chiral pool.
Hydroxyproline is abundant but hydroxylysine is not. Fortunately it can be made 59 from an
abundant member of the chiral pool - malic acid 34. Borane reduction gives the triol 332 and
anisaldehyde gives the diequatorial acetal 333 under thermodynamic control.
HO2C
OH
H 2N
OH
O
O
323a
CO 2H
NH
OH
OH
Me2S.BH3 B(OMe) 3
C–N
amide
HO
HO
H 2N
OH
OH
The free OH group can be converted into the azide 334 by the usual sequence. Now comes
a critical step. The acetal is opened by reduction with remarkable (in their words ‘unexpected’)
selectivity to give 335. The key is to have a Lewis acid (a silyl chloride) present. If a proton is used,
the opposite selectivity is achieved.
OH
O
OH
O
NH 2
HO
OH
OMe NaIO4 OHC
CO2H
330; (2S,5R)-5-hydroxy-lysine
OH
34; (R)-malic acid 332
OH
ArCHO
pyr.HOTs
HO
HO
6
5
OH
OH
3 1
4 2 CO2H
O
CO
N
2H
H
331; (2S,4R)hydroxy-proline
O
O
O
333; 89% yield from 34
OMe
OMe

Now the terminal OH group can be deprotected, turned into a leaving group 336, and used to
alkylate an asymmetric glycine anion equivalent, the heterocycle 337. The azide is then reduced
and protected to give 338, a protected version of 330. The yield in the alkylation was 94% and only
one diastereoisomer was detected.
The synthesis of 323 needed activation as the methyl ester for cyclisation to occur spontaneously.
Protection of the primary amine was needed to get selective acylation of the alcohol to give 340.
330
333
2. NaN3, DMF, 55 ˚C (88%) N3
O
O
334
Ar
1. TsCl, Et 3N, DMAP (98%) NaB(CN)H3 t-BuMe2SiCl N 3
TBDMSO
Me 3SiCl
MeOH
methyl
ester
of 330
1. Et3N 2. (Boc) 2O
BocNH
The fi nal stages of the synthesis of LAF389 require only the combination of 340 with the Julia
reagent 341 and deprotection and the synthesis of the drug molecule 321 from two different members
of the chiral pool is complete.
t-Bu
336
O O
S
PART III – THE CHIRAL POOL
S
341
23 Conclusion: Syntheses from the Chiral Pool 497
I
Cbz
N
N
Ph
O
337
O
Ph
1. BuLi
2. Me3SiCl 3. 329
1. (Me3Si) 2NNa
15-crown-5
2. 336
3. Ph3P, H 2O
4. (Boc)2O
O
BocNH
TBDMSO
N3 TBDMSO
335; 89% yield
NH 1. RCOCl
NH2 NH
O
2. 2M HCl
EtOAc
339
OH
O
340
In the following tables the main members of the traditional chiral pool with our selection from
the ‘new chiral pool’ are listed with the compound numbers given them in this chapter. The most
accessible full listing is in Morrison 60 and the most comprehensive in Houben-Weyl 61 (this volume
is in English). Valuable (and free) source books are the catalogues of chemical suppliers. These
are the only way to fi nd out prices as these change year-by-year.
O
O
Cbz
338
O
N
O
OCH 2Ar
Ph
O
t-Bu OMe 1. 340, base
342
O
2. 1M HCl
3. H2O
EtOH
O
Ph
321

498 23 The Chiral Pool
The amino acids
The proteinaceous α-amino acids are all available. They have the general structure 3 where
R can be an alkyl group or a variety of substituted groups. 3,4 There are full listings in many
textbooks. 62 Important members of this class described in the chapter include phenylalanine 4, valine
5, proline 6, glutamic acid 7, aspartic acid 9, alanine 149 and leucine 163. To these we add two
functionalised amino acids, the thiol cysteine 343 and the amine lysine 344 with two heterocyclic
amino acids, the imidazole histidine 345 and the indole tryptophan 346.
Ph
O
OH
NH2 4; (S)-(–)-Phe
phenylalanine
HS
O
Hydroxyamino acids are useful because the OH group can be converted into a leaving group. We
saw serine 138 earlier in the chapter. The other three have a secondary alcohol at a potentially useful
chiral centre. Threonine 347 is found in normal proteins. The other two are present in collagen
and the extra hydroxyl groups are added by oxidation after the protein is formed (‘post-translational
modifi cation’). Hydroxyproline 331 is abundant, hydroxylysine 330 less so. We might also add
synthetic phenylglycine as a new member.
Hydroxy-acids
OH
O
NH2 5; (S)-(+)-Val
valine
R
OH
O
NH 2
O
N
H
OH
CO2H
6; (S)-(–)-Pro
proline
OH
3; (L)-amino acids
H
N
HO2C
NH2 7; (S)-(+)-Glu
glutamic acid
A few hydroxyacids are available: lactic 33, malic 34, tartaric in both forms 35 and 36, and
mandelic 37.
O
OH
O
HO2C OH
NH2 9; Asp
(S)-(+)-aspartic acid
NH2 NH2 NH2
NH2
NH2
N
N
343; (R)-(+)-Cys
H
cysteine 344; (S)-(+)-Lys; lysine 345; (S)-(–)-His; histidine 346; (S)-(–)-Trp; tryptophan
HO
H
NH2
138; (S)-(+)-Ser
serine
OH
CO 2H
33; (+)-(S)
-lactic acid
O
OH
HO
NH2 347; (2S,3R)-(–)-Thr
threonine
HO H
CO 2H
CO2H
34; (–)-(R)
-malic acid
O
OH
H 2N
OH
O
OH
NH 2
CO 2H
330; (2S,5R)-5-hydroxy-lysine
HO OH
HO 2C CO2H
(R,R)-(+)-35
tartaric acid
"natural"
HO
HO2C
OH
CO2H
(S,S)-(–)-36
tartaric acid
"unnatural"
HO
O
CO
N
2H
H
331; (2S,4R)hydroxy-proline
OH
Ph CO2H
37; (R)-(–)mandelic
acid
OH

Derived from them and from other chiral pool members is a small collection of epoxides that
are members of the new chiral pool: both enantiomers of propylene oxide 44, of glycidol 231 and
235, and of epichlorhydrin 236 and 237, and the bis-epoxide 117.
H
O
H
O O H
OH
O H
OH
O H
Cl
O H
Cl O
H
O
231
235
(+)-(R)-44 (–)-(S)-44 (R)-(+)-glycidol (S)-(–)-glycidol
236
(R)-(–)-epi
chlorhydrin
237
(S)-(+)-epi
chlorhydrin
H
117
Amino alcohols
Reduction of amino acids (usually with borane) gives amino alcohols such as valinol 27, prolinol
28 or phenylalaninol 30: they have the general structure 51.
Other amino alcohols occur naturally, including the ephedrine family 52 – 54. We can add the
famous amino-indanol 286 to this collection.
Diamines
These important compounds are all members of the new chiral pool and are all C 2 symmetric.
Terpenes
OH
N
OH
NH2 H
27; (S)-valinol 28; (S)-prolinol
OH
S
R
Ph
NHMe
52; (1S, 2R)-
(+)-ephedrine
23 Conclusion: Syntheses from the Chiral Pool 499
NH 2
OH
S
S
Ph
NHMe
53; (1S, 2S)-(+)pseudoephedrine
NHMe
Ph OH
The variety of terpenes is great but they may not be available in high ee. Here is a selection: these
are all monoterpenes (C 10) and may be linear, cyclic or bicyclic. We have included the new chiral
pool members 8-phenyl-menthol 83 and camphorsulfonic acid 94.
R
OH
NH2
NH2 51; amino-alcohols
30; (S)-phenylalaninol from amino-acids
OH
S
R
Ph
NH 2
54; (1S, 2R)-(+)norephedrine
S
NH 2
OH
286
the aminoindanol
NH 2
NH2 NHMe
NH2 262 263 264

500 23 The Chiral Pool
Sugars
5
2 1
OH OH
79; (1R, 2S, 5R)
-(–)-menthol
80; (1S, 2R, 5S)
-(+)-menthol
81; (R)-(+)pulegone
82; (R)-(–)carvone
There is again a great abundance of sugars with every stereochemistry at every centre available at
a price and their use in asymmetric synthesis is described in recent books. 63 The most important
C 6 compounds are glucose 99 and mannose 104 and its reduction product mannitol 105. The
sugars are shown in their open chain forms so that the stereochemistry is clear. You are referred
to the earlier parts of the chapter for the pyranose and furanose forms.
The C 5 sugars were not featured in the chapter but include arabinose, ribose and xylose. They
each have corresponding alcohols among which beware that achiral xylitol is not much use in
asymmetric synthesis.
The two C 4 sugars and their alcohols belong to the erythro or threo series. One alcohol 114 is
C 2 symmetric (the bis epoxide 117 is made from it) but the other 112 is achiral with a plane (or a
centre) of symmetry.
O
OH
CHO
CO2H 75; (R)-(+)-citronellol 76; (R)-(+)-citronellal 77; (R)-(+)-citronellic acid
89; (1R)-(+)
-α-pinene
OH
91; (–)-β-pinene
OH
HO CHO
OH OH
99; open chain α-D-glucose
HO
OH
OH
HO
CHO
HO
CHO
OH OH
OH OH
D-(–)-arabinose
D-(–)-ribose
open chain form open chain form
R
R
HO
O
OH
93; (+)camphor
OH
OH
CHO
OH OH
104; open-chain mannose
OH
H
HO 3S
OH
D-(+)-xylose
open chain form
O
HO
CHO
S
R
Ph
OH
83; (–)-8phenylmenthol
O
94; (+)camphor-
10-sulfonic
acid
OH
OH
OH OH
105; mannitol
OH
OH
HO
OH
OH OH
xylitol
WARNING! achiral

HO
The only C 3 sugar is the rather unstable glyceraldehyde best used in a protected form such as
107 or 109 available from the oxidative cleavage of mannitol derivatives such as 106.
Alkaloids
Not much used as building blocks for target molecules but invaluable for designing reagents and
catalysts. See structures 118 and 119.
References
OH
H
HO
OH
OH
OH O
OH
OH O
OH
111; erythrose 112; erythritol
113; threose 114; threitol
O
O
OH
OH
O
O
106; bis-acetal of mannitol
23 References 501
Pb(OAc) 4
or NaIO 4
O
General references are given on page 893
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Acids, Wiley, New York, 1987.
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M. Wang, Tetrahedron, 1994, 50, 4643; D. Seebach, R. Dahinden, R. E. Marti, A. K. Beck, D. A. Plattner
and F. N. M. Kühnle, J. Org. Chem., 1995, 60, 1788.
HO
O
O
H
107; acetal of
glyceraldehyde
OH
H
HO
TBDMSO
OH
O
OBn
109; alternative
protected form of
glyceraldehyde
H
OH

502 23 The Chiral Pool
15. B. T. Golding, D. R. Hall and S. Sakrikar J. Chem. Soc., Perkin Trans. 1, 1973, 1214.
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27. M. T. Reetz and K. Kesseler, J. Org. Chem., 1985, 50, 5434.
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42. Y. Díaz, F. Bravo and S. Castillón, J. Org. Chem., 1999, 64, 6508.
43. A. F. Crowther and L. H. Smith, J. Med. Chem., 1968, 11,1009.
44. J. M. Klunder, S. Y. Ko and K. B. Sharpless, J. Org. Chem., 1986, 57, 3710.
45. G. A. Reichard, C. Stengone, S. Paliwal, I. Mergelsberg, S. Majmundar, C. Wang, R. Tiberi, A. T.
McPhail, J. J. Piwinski and N.-Y. Shih, Org. Lett., 2003, 5, 4249.
46. S. Pikul and E. J. Corey, Org. Synth., 1993, 71, 22, 30.
47. A. Alexakis, I. Aujard, T. Kanger and P. Manganey, Organic Syntheses, 1999, 76, 23.
48. D. Cuvinot, P. Mangeney, A. Alexakis, J. F. Normant and J. P. Lellouche, J. Org. Chem., 1989, 54,
2420.
49. A. Alexakis, J.-P. Tranchier, N. Lensen and P. Mangeney, J. Am. Chem. Soc., 1995, 117, 10767.
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51. M. Takahashi and K. Ogasawara, Synthesis, 1996, 954.
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Org. Synth., 1999, 76, 46.
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23 References 503
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Reamer, R. P. Volante and P. J. Reider, Tetrahedron Lett., 1996, 37, 6843; P. E. Maligres, V. Upadhyay, K.
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Tetrahedron, 1996, 52, 3327; W. J. Thompson, P. M. D. Fitzgerald, M. K. Holloway, E. A. Emini, P. L.
Darke, B. M. McKeever, W. A. Schleif, J. C. Quintero, J. A. Zugay, T. J. Tucker, J. E. Schwering, C. F.
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S. Hanessian, Total Synthesis of Natural Products: The ‘Chiron’ Approach, Wiley, 2004.

24
Asymmetric Induction I
Reagent-Based Strategy
Introduction to Reagent-Based Strategy
New stereogenic centres from prochiral units in planar molecules
Enantiotopic and diastereotopic groups
Asymmetric Reduction of Unsymmetrical Ketones
Asymmetric boron or aluminium hydrides
Asymmetric reduction by boranes
Reduction of ketones with Ipc 2BCl (DIP-Chloride)
Asymmetric Electrophiles
Asymmetric hydroboration of alkenes
Asymmetric Nucleophilic Attack
Transfer of Allylic Groups from Boron to Carbon
Reactions of chiral allylic boranes with carbonyl compounds
Reactions of chiral allyl boranes with imines
Asymmetric Addition of Carbon Nucleophiles to Ketones
Addition of alkyl lithiums to ketones
Asymmetric epoxidation with chiral sulfur ylids
Asymmetric Nucleophilic Attack by Chiral Alcohols
Deracemisation of arylpropionic acids
Deracemisation of α–halo acids
Asymmetric Conjugate Addition of Nitrogen Nucleophiles
An asymmetric synthesis of thienamycin
Asymmetric Protonation
Enantioselective lactonisation of achiral hydroxy diacids
Asymmetric Deprotonation with Chiral Bases
Asymmetric deprotonation with sparteine
Asymmetric Oxidation
Introduction to Reagent-Based Strategy
So far we have used racemic compounds and resolved them (chapter 22) or started with enantiomerically
pure materials (chapter 23). In the next four chapters we deal with the more demanding
but ultimately more versatile and important creation of new stereogenic centres. Naturally the
stereogenic centres are not really created: the chirality already exists and is transferred to the
growing molecule from what may be called a chiral auxiliary: this process is called asymmetric
(sometimes chiral) induction. In this chapter (reagent-based strategy) the chiral auxiliary is either
part of the reagent or a chiral ligand on a metal. In the next two chapters it will be part of a chiral
catalyst. In the fourth chapter, the chiral auxiliary is covalently bound to the growing molecule
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

506 24 Asymmetric Induction I Reagent-Based Strategy
(substrate-based strategy) and so remains attached at the end of the reaction. Later in chapter 29
we shall discuss another kind of reagent - the enzyme.
A new stereogenic centre normally appears when a trigonal carbon atom becomes tetrahedral
during a reaction (chapter 21). The unsymmetrical ketone 1 could be reduced to the chiral alcohol
2 or enolised and combined with an electrophile to give 3. The starting material 1 is prochiral, and
both the CH 2 and the CO groups are prochiral centres. If one hydrogen atom, say H A rather than
H B , is replaced by the electrophile E, a single enantiomer of 3 is formed. Similarly, if one face of
the CO group, say the one on our side of the paper, is attacked by the reducing agent, a single
enantiomer of the alcohol 2 is formed. The two hydrogen atoms and the two faces of the carbonyl
group are enantiotopic: you need to know your right from your left to tell them apart. An NMR
machine, or an achiral reagent such as NaBH 4, cannot tell its right from its left, so H A and H B have
the same chemical shift, and NaBH 4 gives an exactly 50:50 mixture of the enantiomers of 2.
prochiral
starting
materials
Ph
Ph
O
HA HB 1
OH
1a; enol form
reducing agent
E electrophile
If we want to produce high yields of one enantiomer of 2 or 3, we must use a reagent which can
tell its right from its left, that is an enzyme or an asymmetric reagent with some built in mechanism
for distinguishing two enantiotopic features. This is the subject of this chapter. Chapter 27
deals with the alternative strategy, making the Hs or faces of the CO group diastereotopic so that
achiral reagents can tell them apart.
Other trigonal carbons which can give rise to new stereogenic centres are simple alkenes undergoing
electrophilic attack, e.g. epoxidation of 4, and unsaturated carbonyl compounds 6 undergoing
Diels-Alder reactions. These reactions may produce several stereogenic centres at once
whose relative stereochemistry is controlled by the stereochemistry (E or Z) of the double bond,
and by the endo selectivity of the Diels-Alder reaction.
R
Ph
6
O
We are concerned with the absolute stereochemistry of the product: does epoxidation give 5a or
5b? Does the Diels-Alder reaction give 7a or 7b? There is also a small group of prochiral tetrahedral
carbon atoms with enantiotopic functional groups such as the diester 8 or the diene 9. We shall meet
examples of all these (and more!) in this chapter.
Ph
Ph
OH
HA HB 2
O
?
E
3
epoxidation
Ph
O
and/or
Ph
O
4 5a 5b
Diels-Alder
R
reaction
+ and/or
?
new
stereogenic
centre
new
stereogenic
centre
O
O
7a 7b
R

This chapter and the next two deal with two approaches. Asymmetric reagents are enantiomerically
pure compounds used in stoichiometric amounts to make single enantiomers of the
products. Asymmetric catalysts are enantiomerically pure compounds used in sub-stoichiometric
amounts to catalyse the reaction of stoichiometric but achiral reagents to achieve the same result.
You might think it would be easy to distinguish these approaches and often it is. However it can be
diffi cult and broadly we shall describe stoichiometric compounds that transfer the odd atom to the
fi nal product as ‘reagents’ and compounds that are used in substoichiometric amounts and usually
transfer no atoms to the product as ‘catalysts’. In outline this chapter will deal with asymmetric
reduction, asymmetric acids and bases, and asymmetric nucleophiles and electrophiles. Asymmetric
oxidation will mostly be dealt with in chapter 25
Asymmetric Reduction of Unsymmetrical Ketones
The reduction of unsymmetrical ketones such as 1 with achiral reagents NaBH 4 or LiAlH 4 gives
racemic alcohols. The obvious way to make such a reduction asymmetric is to replace some of the
H atoms around B or Al with ligands that form good bonds to boron or aluminium. This is usually
done by reacting the achiral reagents with chiral diols or amino-alcohols.
Asymmetric boron or aluminium hydrides
One of the earliest was the darvon complex of LiAlH 4. We saw in chapter 22 that both enantiomers
of the amino-alcohol 11 (DARVON and NOVRAD) are available by resolution of the precursor
10. DARVON 11 is also available as Chirald®. Reaction of DARVON 11 with LiAlH 4 replaces
two hydrides with the OH and NMe 2 groups to give the reagent DARVON-H that presumably has
the structure 12.
O
Ph NMe2 H
Ph MgCl
Ph
OH
Ph NMe2 H
This complex chiral hydride 12 reduces acetylenic ketones such as 13 with reasonable selectivity.
1 The other enantiomer of 14 comes from reduction of 13 with the enantiomeric reagent derived
from NOVRAD. Note that the absolute sense of the induction in the reduction of 13 is the same
with 12 and with the Alpine borane from ()-α-pinene, below.
LiAlH 4
(+)-(R)-10 (2S,3R)-(+)-11; DARVON 12
R 1
24 Asymmetric Reduction of Unsymmetrical Ketones 507
R
8 9
OH
H LiAlH4
14a
72-82% ee
R 2
MeO 2C CO 2Me
NOVRAD
R 1
O
13
R 2
LiAlH 4
DARVON
R 1
Ph
OH
H
Ph
14b
72-82% ee
H H
Al
O NMe2 R 2
H

508 24 Asymmetric Induction I Reagent-Based Strategy
It is necessary for the two groups on the ketone to be sterically different and one of the best
results is achieved with a linear acetylenic group on one side and a branched alkyl chain on the
other. Even so the ee of this example is only 82% and newer reagents can improve on this.
A more successful development 2 was the reagent derived from LiAlH 4 and BINOL. Enantiomerically
pure BINOL 15, available as either enantiomer, is combined with LiAlH 4 to give 16 and
then with a simple achiral alcohol such as ethanol. The reagent, known as BINAL-H, probably
has structure 17.
This is a better reagent in two ways. Acetylenic alcohols give higher yields and higher ees. The
scope is also wider: though some contrast between the two sides of the ketone is still needed, simple
ketones and, most usefully, α,β-unsaturated ketones work well. The reductions of α- tetralone 18
and ionone 20 illustrate the typical high yields and high ees.
18
O
Asymmetric reduction by boranes
O
13; R 1 = i-Bu, R 2 = Me
OH
OH
LiAlH 4
THF
15 16
BINAL-H
–100 ˚C to –78 ˚C
LiAlH 4
darvon
O
AlH2
O
A different style of reduction comes with the use of trialkyl boranes derived from α-pinene.
Hydro boration of α-pinene 22 occurs from the less hindered face away from the gem-dimethyl
groups to give the tertiary borane 23 with the usual regioselectivity (chapter 17). The marked
hydrogen atom is transferred from boron to carbon. 3
a-pinene
OH
OH
H
14; R 1 = i-Bu, R 2 = Me
EtOH
O
O
O
probable structure
of 17; BINAL-H
BINAL-H
–100 ˚C to –78 ˚C
Al OEt
H
19; 91% yield; 87% ee 21; 87% yield; 100% ee
20
= =
a-pinene
H BR2 BR 2
H
22 23
OH

On reaction with ketones, a bond is fi rst formed between oxygen and boron 24 and then the
same marked hydrogen atom is transferred 25 to the ketone through a tight six-membered cyclic
transition state 26. These reducing agents deliver a hydrogen atom from carbon rather than from
boron. The larger group (R L) on the ketone prefers to occupy an ‘outside’ position in the transition
state 26 away from the pinene-derived cage leading to one enantiomer 27 of the alcohol.
R R
B
O
H
RS RL H
R R
B
R S
An early success 4 was Midland’s Alpine-Borane ® , derived from 9-BBN 28 and α-pinene 22.
Hydroboration takes place from the less hindered side of the double bond, away from the gem
dimethyl groups, to give alpine borane 29. The reagent works well for acetylenic alcohols and the
transition state 30 puts the acetylene in the ‘outside’ position.
H
B
28; 9-BBN
0.5 molar THF solution
The general scope of the ketones 31 is large and the results, especially for ee in the alcohol
products 32, are good. An example is the simple alcohol 34. This enantiomer is the same as the
one obtained from DARVON-H above.
R 1
O
31
One advantage of this reagent is that both enantiomers of α-pinene 22, the chiral auxiliary,
are available from nature. Both enantiomers of Alpine-Borane® are available as THF solutions.
However, the quality of natural α-pinene is erratic, and the table shows that you get what you pay
for here as elsewhere. The prices are approximate relative prices to that of benzoic acid.
O
R L
R R
B
H O
RL RS 24 25 26 27
R 2
24 Asymmetric Reduction of Unsymmetrical Ketones 509
+
22; (+)-α-pinene
11 mmol
(+)-Alpine-Borane®
two days
room temperature
5 mmol
reflux
THF
25 hours
R 1
OH
H
R2 32; 59-98% yield
77-100% ee
(1R)-(+)-α-pinene 22
rotation about +51.7
from North American conifer oils
[a] 21D ee price/100 g
+50.7 97% 240
91% 22
0% 10
H
B
29; (+)-Alpine-Borane®
0.5 molar THF solution
R 1
H
O
B
30
R S
O (+)-Alpine- OH
Borane®
H
33
Table: Commercially Available α-pinene
OH
R 2
34; 78% yield
99% ee
(1S)-(−)-α-pinene
rotation about −51.7
from European conifer oils
[a] 21D ee price/100 g
−50.7 97% 235
87% 36
81% 8.4
R L

510 24 Asymmetric Induction I Reagent-Based Strategy
Reduction of ketones with Ipc 2BCl (DIP-Chloride)
There are many other reducing agents derived from α-pinene and various boranes. It is worth
referring to Brown’s articles for details. 3 We shall describe just one of these 5 as it is rather different
both sterically and electronically and seems to be the reagent of choice at the moment. Hydro boration
of α-pinene with ClBH 2 occurs twice to give Ipc 2BCl 35 (strictly B-chloroisopinocampheylborane
and available as DIP-Chloride).
a-pinene
=
a-pinene
=
Cl BH2 BCl
H
22 35
This borane has been used in the preparation of enantiomerically pure prozac, 6 (S)-
Fluoxetine 38. The simple ketone 36 is reduced to give the alcohol 37, easily transformed
into prozac 38.
O
Cl
Ipc 2BCl
OH
36 37
It is a mistake to dismiss these reagents as expensive academic toys not fi t for serious chemistry
as Ipc 2BCl has been used by Alcon Laboratories 7 in the large scale production of their glaucoma
treatment Azopt 39. Disconnection of most of the structural C–X bonds reveals the simple heterocycle
40 (note that inversion will occur when the EtNH group in 39 replaces the OH group in
40). The saturated ring could come from cyclisation of 41 and either 40 or 41 could be made by
enantioselective reduction of the corresponding ketones.
O
S
H2N
O
S
HN Et
S N
O O
39; AL-4862 (Azopt)
OMe
2 x C–N
1 x C–S
note
inversion
In fact they chose to make 41 by asymmetric reduction of the ketone 45 easily made from a
thiophene available from Lancaster Synthesis.
Cl
Cl
S
OH
F3C
O
2
NHMe
38; (S)-Fluoxetine (Prozac)
C–N
HO
Br
S NH
Cl
S S
NH2
O O
O O
40 41

O
Cl
S
Lancaster
Synthesis
Cl
2. air bubbled in
3. NH3 bubbled in
4. H2O 2,
Na 2WO 4.2H 2O
NaSBn
EtOH
Cl
Cl
O
S
O
42; 97% yield
S S
NH2
O O
44; 71% yield
The alcohol 41 was unstable and was cyclised immediately to 40. The yield of enantiomerically
pure 40 (98% ee) from 45 was 77% on a 500 g scale. The only change to the newly introduced
chiral centre is the inversion during the formation of the fi nal product.
45
Ipc 2BCl
MeOBu-t
41
OH
The functional groups in 45 clearly do not interfere with the reaction but some functional
groups have a large effect. Reduction of β-keto-esters 48 gives poor yields and ees. By contrast the
free acids 49 give alcohols 50 with high yields (87–92%) and very high ees (91 – 98%). Clearly
the CO 2H group binds to the boron atom and cooperates with the Ipc group in delivering the H
atom to one face of the ketone. 8 We shall return to these reagents under ‘asymmetric electrophiles’
when we discuss hydroboration of alkenes.
SBn
1. Cl2
pyrHBr.Br 2
toluene
98% ee
Cl
O
Br
H2SO4
EtOAc
Cl
S S
NH2
O O
45; 72% yield
S
S
OH
O
43
S N
O O
46
S
47; 69% yield on 1 kg scale
N
OH
O
1. MeC(OMe) 3
1. BuLi
2. SO2 O
H2N S
S
OMe
2. TsCl, Et 3N
3. EtNH2 39; AL-4862 (Azopt)
61% yield, >99% ee
500 g scale
3. NH2OSO2OH O O
4. 12M HCl
R 1
24 Asymmetric Reduction of Unsymmetrical Ketones 511
CO2R2 O
R1 O
CO2H R1 Et3N, (–)-Ipc2BCl OH
CH2Cl2, 0 ˚C, 2 hours
CO2H 48 49 50
S
Cl
OMe

512 24 Asymmetric Induction I Reagent-Based Strategy
Asymmetric Electrophiles
Asymmetric hydroboration of alkenes
A hydroborating agent must have a free B–H bond and the obvious choice for asymmetric hydroboration
is something derived from borane (BH 3 or B 2H 6) and α-pinene. The Me 2S-BH 3 complex
reacts rapidly once with α-pinene, nearly as rapidly a second time to give good yields of Ipc 2BH
51, but fails to react a third time. This is good news in a way as the reagent 51 is easy to prepare
but is also a warning that it is unlikely to react with any hindered alkenes. 9
α-pinene
= =
α-pinene
22
Me 2S BH 3
In fact, Ipc 2BH 51 reacts well with cis-disubstituted alkenes. Using crystalline Ipc 2BH 51 of
99.1% ee, cis butene gave (R)-()-2-butanol 53 of 98.1% ee in 73% yield and norbornene 54 gave
exo-alcohol 55 of 83% ee in 63% yield. In this second case there is diastereoselectivity too. There
are other examples in Brown’s reviews. 3
For more hindered alkenes the mono-substituted borane IpcBH 2 is better. 10 Direct hydro boration
of α-pinene cannot be stopped after one hydroboration and gives Ipc 2BH 51 in good yield but the
hydroboration is reversible. Adding TMEDA to a solution of Ipc 2BH 51 in ether precipitates the
crystalline complex 56 of two molecules of IpcBH 2 and one of TMEDA. The yield is only 80%
but if α-pinene of 94% ee is used, 56 crystallises with 100% ee.
The reagent itself, IpcBH 2 57 is released from the crystalline complex 56 by treatment with BF 3
in THF. TMEDA prefers to form a complex with the more electron-defi cient BF 3: this crystallises
leaving pure IpcBH 2 57 in solution ready for hydroboration of alkenes. Reactions with simple
trans-disubstituted alkenes 58 are reasonable: trans butene gives ()-(R)-2-butanol of 73% ee in
73% yield. 11
H
51; Ipc2BH
Ipc2BH –25 °C
BIpc2 H2O2 OH
1. Ipc2BH –25 °C, THF
OH
THF
NaOH
2. H2O2, NaOH
52 (R)-(–)-53 54; norbornene (–)-55
Me 2S BH 3
Et 2O
22 51; Ipc2BH
H
BH
2
Me 2N NMe 2
TMEDA
H
B
2
H
Me 2N NMe 2
BH2 H2B
56; (IpcBH 2) 2.TMEDA, m.p. 140-141 ˚C

56
Et 2O BF 3
THF
24 Transfer of Allylic Groups from Boron to Carbon 513
Trisubstituted alkenes - the type that do not react at all with Ipc 2BH - perform particularly
well. Regioselectivity is usually excellent and the ees are generally better than those with simple
trans-disubstituted alkenes. 2-Methylpent-2-ene 60 gives only 58% ee but the champion is
1-phenylcyclopentene 62 that gives 92% yield of the anti alcohol 63 in 100% ee. Brown 12 has
improved on most of these ees by using modifi ed ‘pinenes’ with larger bridgehead substituents
but these ‘pinenes’ have to be prepared and the Ipc reagents retain their popularity.
More recently, the effects of functional groups on the alkene have been explored. Enol ethers
are more nucleophilic than ordinary alkenes and the two enol ethers E- and Z-64, give good yields
of different diastereoisomers of the half-protected diol 65. Though 64 is a trisubstituted alkene, it
reacts rapidly with Ipc 2BH with good enantioselectivity. 13
Asymmetric Nucleophilic Attack
BH 2
This commoner type of reaction involves the attack of carbon or heteroatom nucleophiles onto
carbonyl compounds, by direct or conjugate addition, and onto imines. Because we have just dealt
with boranes we shall start with the reaction of allylic boron compounds with such electrophiles.
You might strictly not call this nucleophilic attack.
Transfer of Allylic Groups from Boron to Carbon
Reactions of chiral allylic boranes with carbonyl compounds
H
57; IpcBH2
1. 57, THF, –25 °C
2. H2O2, NaOH
60
OH
2-methylpent-2-ene (S)-(–)-61
1. Ipc 2BH
–25 ˚C, THF
OH
OMe
2. H2O2, NaOH
OMe
E-64
(2R,3R)-(–)-65
72% yield, >97% ee
Simple alkyl boranes do not react with aldehydes and ketones but allyl boranes react rapidly
because they can use a six-membered cyclic transition state 68 not unlike that of the Claisen
rearrangement. The evidence for this is that the allyl group is rearranged in the product. In this
example a crotyl borane 66 adds to an aldehyde to give anti-70 since both R and Me prefer to be
equatorial in the transition state 68.
R
R
1. 57, THF, –25 °C
2. H2O 2, NaOH
R
OH
trans (E-)-58 (R)-59
Ph Ph
1. 57, THF, –25 °C
HO
2. H2O2, NaOH
62
1. Ipc 2BH
–25 ˚C, THF
R
(1S,2R)-(+)-63
OH
2. H2O2, NaOH
MeO OMe
Z-64
(2R,3S)-(+)-65
77% yield, 90% e

514 24 Asymmetric Induction I Reagent-Based Strategy
BR2 RCHO
R
O B
R R
R
O
Me
R
B
R
O BR 66
R
2
R
OH
a crotyl borane 67 68 69 70
Allyl dialkyl boranes do this reaction, transferring only the allyl group as the mechanism 67
requires, so asymmetry can be introduced by replacing BR 2 with Ipc 2B to give 71. In this specifi c
instance, the reaction with acetaldehyde gives predominantly just one enantiomer (2R,3S) of the
anti-diastereoisomer of 72 accompanied by some of the other anti enantiomer and traces of the
syn-diastereoisomer. 3 The diastereoselectivity is therefore 99:1 and the ee 90%.
BIpc 2
MeCHO
The allylic boranes can be made from allylic Grignard or lithium reagents with Ipc 2BCl 35
(used above in reductions). An interesting example is Barrett’s synthesis 14 of the C 2-symmetric
compounds 76. The dilithium derivative 74 reacts with two molecules of Ipc 2BCl 35 to give the
C 2-symmetric allylic double borane 75, both Ipc groups having the same chirality. Reaction with
an aldehyde gives the C 2-symmetric diols 76.
Various aliphatic and aromatic aldehydes can be used and either enantiomer of the
metric diastereoisomer 76 can be made depending on the enantiomer of Ipc 2BCl used. Two allylic
transfers occur, each with same sense of asymmetric induction and this is easier to see if 75 is
redrawn and the intermediate 77 also redrawn before reaction. The ratio of the C 2 to the meso
diastereoisomers is usually greater than 90:10 and the ees uniformly 95%.
Reactions of chiral allyl boranes with imines
OH OH OH OH
71
Ipc 2 crotyl borane (2R,3S)-72; 94.5% (2S,3R)-72; 4.5% (2R,3R)-72; 1% (2S,3S)-72; trace
BuLi
TMEDA
hexane
Ipc 2BCl
Li Li Et2O Ipc 2B
BIpc 2
Boranes other than those based on α-pinene are particularly useful in allylic transfer to imines
to make single enantiomers of unsaturated amines. One good combination is an allylboron compound
80 complexed with an N-sulfonyl amino alcohol such as 78, derived from nor-ephedrine
(see chapter 23) with an N-silyl imine such as 81. The unsaturated amines 82 are formed in good
RCHO
73 74 75 76
IpC 2B
75
BIpc 2
RCHO Ipc2B
OH Ipc2B
R
=
77 77
R
R
OH
OH RCHO
76
OH
R

yields 15 with ees around 90%. Brown has shown 16 that the water content of such reactions is
critical - no reaction occurs in the complete absence of water!
Ph
Me
OH
B Et3N Ph O
B
N
NHTs
Me N
Ts
R H
SiMe +
+
3
NH2 3 THF
HCl
workup R
78 79 80 81
82
Asymmetric Addition of Carbon Nucleophiles to Ketones
The chapters on asymmetric catalysis will describe catalytic versions of the reactions we are about
to describe. Catalysis is a fundamentally more effi cient way of asymmetric induction and we shall
restrict our discussion here to cases where catalysis proved ineffective.
Addition of alkyl lithiums to ketones
Merck’s HIV-1 reverse transcriptase inhibitor Efavirenz 83 is one of the simplest anti-HIV drugs
yet produced. The most straightforward synthesis 17 is based on closure of the amino alcohol 84
with some phosgene equivalent and the preparation of 84 by asymmetric addition of cyclopropylethynyl-lithium
86 to the ketone 85.
Cl
F 3C
O
F3C C–N
C–O Cl
C–C
OH
N
H
O
NH2
NH2 Li
83 84 85 86
It was already known that amino alcohols of the kind we have just used 78 were good at this
kind of asymmetric addition but this particular combination of an acetylenic nucleophile and an
aryl trifl uoromethyl ketone was uncharted territory. After some exploration, stoichiometric pyrrolidine
alcohol 88 prepared by alkylation of norephedrine 87 from the chiral pool (chapter 23)
proved the best and the ketone 85 had to be used as its N-4-methoxybenzyl derivative 18 89.
HO
Ph
24 Asymmetric Addition of Carbon Nucleophiles to Ketones 515
NH 2
Me
87
(1R,2S)-norephedrine
Br Br
NaHCO3, toluene
HO
Ph
The conversion of ligand 88 into the reagent 91 required the specifi c conditions set out in the
chart. Titration of BuLi against Ph 3CH produced the lithium alkoxide 90 with enough BuLi left
over to make the lithium derivative 86 and the reagent 91 turned out to be a tetramer. 18
N
Me
Cl
Cl
CF 3
O
CF 3
N
H
88; 97% yield 89; Ar = 4-MeOC 6H 4
O
Ar

516 24 Asymmetric Induction I Reagent-Based Strategy
88
3.31 kg
LiO
Addition of the reagent 91 to the modifi ed ketone 89 also required exact conditions but all
this care was rewarded with an excellent yield and an essentially perfect ee. The rest of the
synthesis involves the oxidative removal of the protecting group via 93 and the closure of the
cyclic carbamate to give 83.
91
1. 1.6M BuLi in hexane
added until Ph 3CH went red
2. 1.6M BuLi in hexane
add same amount again
1.05 kg ketone 89
added slowly
at –50 ˚C
work-up with
citric acid
crystallise from
toluene/hexane
2. NaOH
MeOH
NaBH 4
Cl
Cl
This one example reveals that it is usually necessary to fi nd the right ligand for any direct
addition of RLi or RMgX to a carbonyl group. If you are lucky you may fi nd a catalytic method.
If not, an amino-alcohol based stoichiometric method should be possible.
Asymmetric epoxidation with chiral sulfur ylids
Ph
F 3C
F 3C
N
N Ar
H
92; 91% yield, >99.5% ee
+ BuLi

The alkylation of the sulfi de 96, the formation of the ylid 99, and the reaction with the aldehyde
are all carried out in one operation. The sulfi de is a good nucleophile for alkyl halides and forms
the sulfonium salt 98. This gives the ylid 99 with NaOH as a convenient base in aqueous tertbutanol.
The ylid selectively attacks the aldehyde to give the betaine 100 that closes to the epoxide
and releases the sulfi de 96 for the next round.
96
Br Ph
Me Me NaOH
S
Ph
98
sulfonium salt
Ph O
Enolisable aldehydes such as 101 or 103 do not give quite such good yields but the ees are still
good and the diastereoselectivity in favour of the trans epoxides 102 and 104 is excellent. The
secret of this method is the simple preparation of the reagent 96. In the next chapters you will see
that superior catalytic methods are available for asymmetric epoxidation of allylic alcohols and of
cis-alkenes but they are less good for the trans disubstituted alkenes that would give 97, 102, or
104. You will also see catalytic versions of sulfur ylid epoxidation.
Asymmetric Nucleophilic Attack by Chiral Alcohols
Deracemisation of arylpropionic acids
Me Me
S
99
ylid
CHO
O
Ph
101
102; 75% trans epoxide
94% ee
103
Arylpropionic acids such as ibuprofen 105 are important NSAIs (non-steroidal anti-infl ammatories).
Only one enantiomer is active and some are administered as enantiomerically pure compounds
through there is a problem with racemisation in the body by enolisation. This can be turned to
advantage in ‘deracemisation’. Weak bases are enough to convert the acid chloride 106 into an
enolate that eliminates 107 to form the achiral ketene 108. Addition of, say, ethanol then gives
racemic esters 109; R Et of ibuprofen.
H
CO 2H
105; racemic Ibuprofen
24 Asymmetric Nucleophilic Attack by Chiral Alcohols 517
Cl
O
SOCl 2
DMF
Ph
C O
CHO
H
Me Me
S
Ph
COCl
ROH
O
100
Ph
O
96 + 97
Ph
104; 70% trans epoxide
93% ee
EtNMe 2
heptane heptane
H
CO 2R
107; achiral enolate 108; achiral ketene 109; racemic ester of ibuprofen
106

518 24 Asymmetric Induction I Reagent-Based Strategy
Asymmetric induction would in theory be possible if a chiral alcohol were used in the last
step 20 and, amazingly, providing α-hydroxy-esters or lactones are used, can actually be realised. 21
The elimination is followed by infra red until the ketene is completely formed (2,100 cm 1 ) and
then the asymmetric oxygen nucleophile is added in heptane at 78 C. The best reagents are (S)-
()-ethyl lactate and (R)-()-pantolactone 112 from the chiral pool - they give opposite enantiomers
with excellent ees. In this case R/S does give a good indication of chirality as the functional
groups are virtually the same. The induction takes place on the protonation of the enolate rather
than the addition of the alcohol. Ethyl lactate gives the ester 111 in a 97:3 ratio of diastereoisomers
that becomes 89% ee on hydrolysis to 105. Even under the very mild hydrolysis conditions shown,
some racemisation occurs during hydrolysis.
106
EtNMe 2
The other enantiomer (S)-105 comes from reaction with (R)-()-pantolactone 112 in rather
better ee - evidently the hydrolysis of the ester 113 is faster and occurs without racemisation. In
both cases, rather precise conditions are necessary. This should be seen as both a warning and an
encouragement.
Conditions for asymmetric induction by attack of homochiral alcohols on ketenes
Same solvent and catalyst used for synthesis and reaction of ketene:
Solvent: Heptane best, toluene all right, polar solvents no good.
Catalyst: Me 3N and N-Me-pyrollidine best, Et 3N and i-Pr 2NEt all right.
Temperature unimportant: only 7% decrease in ee at room temperature cf. 78 C.
Dilution critical: 90% ee. at 1M; 97.2 ee at 0.02M.
Work-up: treat with aqueous AcOH to cleave any anhydride formed.
EtNMe 2
106 heptane
heptane
108
detected
by IR
Deracemisation of α–halo acids
H
OH
CO 2Et
heptane
–78 ˚C
O CO 2Et
HOAc, 2M HCl
H 2O, 85 ˚C
The same reagent (R)-()-pantolactone 112 gives good results with α-halo acids that are good
precursors for many other compounds such as α-amino acids by nucleophilic displacement. The
α-halo acid chlorides 115 are prepared directly from the simple acids 114 and treated with the
same tertiary amine EtNMe 2 used above to give the unstable ketenes 116 and hence the esters 117
by reaction with (R)-()-pantolactone 22 112.
O
H
O CO 2Et
proton
transfer
O
or LiOH, H2O MeCN, 5 ˚C
O
111; 92% yield; 97:3 diastereoisomers (R)-105; 89% yield; 89% ee
108
detected
by IR
+
OH
O
O
112; pantolactone
heptane
–78 ˚C
110
113
H
O
O
O
O
H
OH
(S)-105
89% yield
99% ee

R CO 2H
PCl 5
X2
X EtNMe 2
R COCl
It is best not to isolate the ketene but to add a solution of the acid chloride 115 in THF to a mixture
of (R)-()-pantolactone 112 and EtNMe 2 also in THF at 78 C. R is always alkyl and X can be Br
or I. The esters 117 are isolated as mixtures (7:1 to 19:1) of diastereoisomers: two examples follow.
It is essential that the ketene is formed: reaction of the acid chlorides 115 with (R)-()pantolactone
112 also gives the esters 117 but as a 1:1 mixture of diastereoisomers. A useful application
is the preparation of unusual amino acids such as 120 by S N2 displacement of halide with azide
and reduction of the azido group. It is best to hydrolyse the ester at the azide stage 118 to reduce
racemisation but even so some does occur both in the azide displacement and in the hydrolysis.
Asymmetric Conjugate Addition of Nitrogen Nucleophiles
The work of Steven Davies 23 at Oxford has made conjugate addition of nitrogen nucleophiles a
reliable and useful reaction. The essential reagent is the amine 121, prepared on a large scale by
resolution (chapter 22). This amine does not react with unsaturated esters like 123 but the lithium
derivative 122 adds in a conjugate fashion to give the ester 125 via the enolate 124.
Ph N
H
114 115
Br
OH
O
112
COCl
O
LiOH
112
EtNMe 2
X
THF, –78 ˚C
THF/H 2O
R COCl
EtNMe2
THF, –78 °C
N 3
Br
O
I
O
X
R
O
C
117a; 19:1, 73% yield
O
O
OH
O
O
O
112
R
X
O
O
116 117
NaN 3
DMF
60 ˚C
O
O
NH 2
O
Br
O
O
O
117b; 8:1, 78% yield
115c 117c; 14:1, 79% yield
118; 7:1, 70% yield
Ph
BuLi
THF
–78 ˚C
Ph N
121 122
24 Asymmetric Conjugate Addition of Nitrogen Nucleophiles 519
119; 70% yield, 72% ee 120
Li
Ph
Ph
123
CO2t-Bu
Ph
N
Ph
OLi
N 3
O
OH
Ph Ot-Bu
124
O
O
O
O
O
O
Ph
H
H2O Ph N
Ph
CO2t-Bu 125; 92% yield; 95% de

520 24 Asymmetric Induction I Reagent-Based Strategy
Here at last some explanation can be offered. The lithium derivative 122 forms a Li–O bond
to the carbonyl group of the ester 123 in its best ‘s-Z’ conformation and the nitrogen atom adds to
the conjugate position ‘like a butterfl y settling on a leaf’ 126 to give the lithium enolate 124 in the
same conformation 124a.
122 + 123
The two benzyl groups on the nitrogen atom can be removed by hydrogenation – remarkably the
third benzylic bond to nitrogen is not cleaved - and the t-butyl ester hydrolysed in acid solution to give
‘β-phenylalanine’ 128 in good yield and ee. The reagent 122 has supplied just one nitrogen atom to
this fi nal product 128 and no recycling of 121 is possible. Fortunately 121 is very easy to make.
125
H2, Pd/C
An asymmetric synthesis of thienamycin
Ph
Ph
Ph
Ph
O
Li H H
N H
Me
O
N
Me
H
O
H
Ph
LiO
H Ph
126 124a
O
NH2 CF 3CO 2H
HOAc Ph O
Ph OH
127; 84% yield
In this sequence valuable chemical information is discarded. Not only is 124 a specifi c enolate,
it has a specifi c geometry (‘Z’ lithium enolate). This information can be used in a tandem style
of reaction described in chapter 36. We shall continue with an alternative. Replacing the benzyl
group in 121 with an allyl group 129 and adding to a dienoate ester (t-butyl sorbate) gives the
product 131 from regioselective addition 24 at C-3.
H N Ph
1. BuLi
This ester 131 forms the usual ‘E’-enolate with LDA that can be trapped as the boron enolate
132. Reaction with acetaldehyde gives, as expected, an anti aldol (chapter 4). The major product
is 133 in a 91:9 ratio with the other anti aldol. This diastereoisomer can be isolated in 75% yield.
The absolute stereochemistry is decided by the chiral centre already in place in 132 - it remains
as C-4 in 133. The next centre along (C-3) is controlled by C-4 and the relative stereochemistry of
C-3 and C-4 is controlled by the geometry of the enolate.
NH2
O
128; 100% yield; 95% ee
1.
CO2t-Bu Li
N Ph N Me
2. NH4Cl, H2O t-BuO O
129 130
131; 87% yield, 99:1 diasts
1. LDA
Me CHO
3
131 N Me
Me 2 4
2. B(OMe) 3
t-BuO2C H
(MeO) 2B OR
Ph
132; 'E' boron enolate
OH
133; 75% yield
Ph
Ph
N Me
124

This compound was used in an asymmetric synthesis 25 of the antibiotic thienamycin
138. The N-allyl group was removed with Pd(0) catalysis to give 134 and the t-butyl ester
hydrolysed to give the redrawn acid 135. Cyclisation by the pyridyldisulfi de reagent gave the βlactam
core 137 of the antibiotic 138.
133
(Ph 3P) 4Pd
136
PyrS-SPyr
Ph3P
OH
Me
t-BuO2C Asymmetric Protonation
H
134
Enantioselective lactonisation of achiral hydroxy diacids
Reduction of the achiral ketodiester 139 gives the racemic lactone 140. Hydrolysis of both ester
groups then gives the again achiral hydroxydicarboxylate 141. This compound is prochiral and the
−
two CO2 groups are enantiotopic. If one could be protonated selectively by an enantiomerically pure
acid, one enantiomer of the monoacid would be formed. This sounds like an improbable event.
As you may guess, it does work. Camphor sulfonic acid 142 (used in chapter 22 as a resolving
agent) protonates just one of the carboxylate anions and cyclisation then gives the lactone 26 144
in remarkably high ee (94%). The two carbonyl groups are now different enough to be developed
separately.
Asymmetric Deprotonation with Chiral Bases
N
H
Ph
Me
OH
H H
Me
N Ph
O
Me
137; 98% yield
O NaBH 4
CF 3CO 2H
OH
H
Ph
Me
N
H
CO2H Me
135; 98% yield
A more widely used method is deprotonation to make, say, an enolate, with one enantiomer of a
base. The base must form a close association with the substrate and that usually means a lithium
Me
OH H H
O
N
CO 2H
S
138; (+)-thienamycin
O
N N
Me Me
O
EtO2C CO2Et CO2Et O2C CO2 139 (±)-140 141
O
SO2OH 142; (+)-camphor
sulfonic acid
24 Asymmetric Deprotonation with Chiral Bases 521
141
O
O
OH
Na
HO2C CO 2
NaOH
HCl
EtOH
NH 2
OH
143 144; 94% ee
O
O
136
CO 2H
2Na
O

522 24 Asymmetric Induction I Reagent-Based Strategy
amide. You may object that a planar enolate is not intrinsically chiral, but desymmetrisation of a
symmetrical ketone is ideal. Simpkins’ synthesis of anatoxin 145 is a good example. 27 This highly
toxic compound (known as ‘sudden death factor’) is the model for potentially useful pain killers.
Simpkins wanted to make it from readily available tropinone derivatives 147.
HN
O
145
(+)-anatoxin-a
HN
A lot of work has to be done. A carbon atom needs to be added and the ketone moved round to
allow addition of a d 1 reagent. But this is an attractive strategy because tropinone is achiral and
enolate formation desymmetrises the molecule. It was not easy to fi nd the right base. In the end
the C 2-symmetric double base 148 gave the silyl enol ether 149 in good yield, and, as we shall see
later, good ee.
Clearly the lithium enolate 150 must be formed asymmetrically and is trapped by Me 3SiCl to
give the silyl enol ether 149. Simmons-Smith-style cyclopropanation adds the extra carbon and the
product 151 is cleaved with Fe(III) to give the enone 153. This is not the same as 146 but has an
electrophilic carbon in the right place. The enone 153 is crystalline and can be obtained optically
pure for conversion to a single enantiomer of anatoxin 145. Further details are in the workbook.
147
Asymmetric deprotonation with sparteine
O
O
? HN
?
145a 146
MeO2C N
O
+
Ph
Ph Ph
N N
Li Li Ph
Me3SiCl MeO2C N
OSiMe3 147; R = CO2Me 148 149; 90% yield
148
FeCl 3
DMF
MeOH
MeO 2C
MeO 2C
N
N
150
152
Cl
O
OLi
Me 3SiCl
NaOAc
DMF
MeOH
149
90% yield
MeO 2C
Et2Zn
ClCH 2I
By far the most popular asymmetric deprotonation uses sparteine as a ligand for lithium. 28
Sparteine 154 is a bicyclic alkaloid from lupins and gorse and has two nitrogen atoms that can, in
one favourable conformation 154a, chelate a lithium atom. In spite of appearances, it is not (quite)
C 2-symmetric and only one enantiomer is available.
N
ClCH 2CH 2Cl
MeO 2C
O
153; 71% yield
99% e.e. after recrystallisation
R
N
N
147
O
OSiMe3 151; 99% yield
HN
O
145

H
H
N
H
H
154; (–)-sparteine 154a; chelating 154b; non-chelating
A simple application is the asymmetric alkylation of carbamates 155 of cyclic amines. Removal
of one of the diastereotopic protons from 155 gives a more stable sparteine chelate 156. This is
not an enolate but has a C–Li bond stabilised by coordination to the carbonyl group. Alkylation
occurs with retention of confi guration to give, after hydrolysis, one enantiomer of the secondary
alcohol 28 158.
Hoppe has extended this work to d 3 reagents 159 (homoenolates - see chapter 13 for achiral
versions) by the addition of a double bond. 29 Lithiation occurs at C-1 by removal of one of the
enantiotopic protons at C-3. Aldol reaction with acetone occurs at C-3 of the complex 160 as
expected for a homoenolate (chapter 13) giving a single enantiomer of the homoaldol product 161.
All these reactions use an excess of sparteine.
i-Pr 2N
Cby
N
O
O
O
O
CbyO
Asymmetric Oxidation
H
N
H
Me
H
Bu
157; 87% yield
sec–BuLi
N N
N
sparteine
155 156
H
1 3
159; Z:E 92:8
H
24 Asymmetric Oxidation 523
n-BuLi
(–)-sparteine
i-Pr 2N
O
hydrolysis
The most important example of stoichiometric asymmetric oxidation is probably the titaniumcatalysed
conversion of sulfi des into sulfoxides by cumene hydroperoxide in the presence of stoichiometric
diethyl tartrate. A simple example is the effi cient asymmetric synthesis of methyl p-tolyl
sulfoxide 162, an important starting material for much sulfoxide-controlled asymmetric synthesis. 30
O
Li
N
Sp
N
N
O
N
O
Me
HO
Li
N
H
H
Bu
N
158: 93% yield, 98% ee
Me2CO
i-Pr 2N
O
O
MeI
OH
H
160: Sp = sparteine 161; 69% yield, 97% ee

524 24 Asymmetric Induction I Reagent-Based Strategy
The very important anti-ulcer drug omeprazole is a sulfoxide and is invariably made by
oxidation 31 of the sulfi de 163. AstraZeneca workers have reported 32 that the same mixture gives
the enantiomerically pure drug 164, to be marketed as esomeprazole, in good ee. An important
difference is that the asymmetry comes from only 60 mol% of tartrate and they were able to get
91% ee with only 4% tartrate. We are entering the more effi cient realms of catalysis - the subject
of the next two chapters.
OMe
N
References
S Me
EtO 2C
OH
OH
(S,S)-(–)-DET
Ti(OiPr) 4, CH 2Cl 2, H 2O
CO 2Et
S Me
General references are given on page 893
1. R. S. Brinkmayer and V. M. Kapoor, J. Am. Chem. Soc., 1977, 99, 8339.
2. R. Noyori, I. Tomino, M. Yamad and M. Nishizawa, J. Am. Chem. Soc., 1994, 106, 6709; 6717.
3. H. C. Brown and P. V. Ramachandran, Pure Appl. Chem., 1991, 63, 307; Acc. Chem. Res., 1992, 25, 16.
4. M. M. Midland, D. C. McDowell, R. L. Hatch and A. Tramontano, J. Am. Chem. Soc., 1980, 102, 867;
M. M. Midland, Chem. Revs., 1989, 89, 1553.
5. H. C. Brown, J. Chandrasekharan and P. V. Ramachandran, J. Am. Chem. Soc., 1988, 110, 1539; P. V.
Ramachandran, A. V. Teodorovic, M. V. Rangaishenvi and H. C. Brown, J. Org. Chem., 1992, 57, 2379.
6. D. W. Robertson, J. H. Krushinski, R. W. Fuller and J. D. Leander, J. Med. Chem., 1988, 31, 1241.
7. R. E. Conrow, W. D. Dean, P. W. Zinke, M. E. Deason, S. J. Sproull, A. P. Dantanarayana and M. T.
DuPriest, Org. Process Res. Dev., 1999, 3, 114.
8. Z. Wang, C. Zhao, M. E. Pierce and J. M. Fortunak, Tetrahedron: Asymmetry, 1999, 10, 225.
9. H. C. Brown, M. C. Desai and P. K. Jadhav, J. Org. Chem., 1982, 47, 5065.
10. H. C. Brown, A. K. Mandal, N. M. Yoon, B. Singaram, J. R. Schwier and P. K. Jadhav, J. Org. Chem.,
1982, 47, 5069; H. C. Brown and B. Singaram, J. Am. Chem. Soc., 1984, 106, 1797.
11. H. C. Brown, P. K. Jadhav and A. K. Mandal, J. Org. Chem., 1982, 47, 5074.
12. H. C. Brown and U. P. Dhokte, J. Org. Chem., 1994, 59, 2365.
13. D. Murali, B. Singaram and H. C. Brown, Tetrahedron: Asymmetry, 2000, 11, 4831.
14. A. G. M. Barrett, D. C. Braddock and P. D. de Koning, Chem. Commun., 1999, 459.
15. S. Itsuno, K. Watanabe, T. Matsumoto, S. Kuroda, A. Yokoi and A. El-Shehawy, J. Chem. Soc., Perkin
Trans. 1, 1999, 2011.
16. G. Chen, P. Ramachandran and H. C. Brown, Angew. Chem., Int. Ed., 1999, 38, 825.
17. M. E. Pierce, R. L. Parsons, L. A. Radesca, Y. S. Lo, S. Silverman, J. R. Moore, Q. Islam, A. Choudhury,
J. M. D. Fortunak, D. Nguyen, C. Luo, S. J. Morgan, W. P. Davis, P. N. Confalone, C. Chen, R. D. Tillyer,
O OH
cumene hydroperoxide
O
162; 68% yield
99.5% ee
OMe
cumene
hydroperoxide
60 mol%
O
S
HN
N
OMe
(S,S)-(–)-DET
Ti(OiPr)4, H2O i-Pr2NEt toluene
N
S
HN
N
OMe
163 164; esomeprazole, >99.5% ee

24 References 525
L. Frey, L. Tan, F. Xu, D. Zhao, A. S. Thompson, E. G. Corley, E. J. J. Grabowski, R. Reamer and P. J.
Reider, J. Org. Chem., 1998, 63, 8536.
18. A. Thompson, E. G. Corley, M. F. Huntington, E. J. J. Grabowski, J. F. Remenar and D. B. Collum,
J. Am. Chem. Soc., 1998, 120, 2028.
19. K. Julienne, P. Metzner, V. Henryon and A. Greiner, J. Org. Chem., 1998, 63, 4532; K. Julienne, P.
Metzner and V. Henryon, J. Chem. Soc., Perkin Trans. 1, 1999, 731. See also C. L. Winn, B. R. Bellenie
and J. M. Goodman, Tetrahedron Lett., 2002, 43, 5427.
20. C. Fehr, Angew. Chem., Int. Ed., 1996, 35, 2566.
21. R. D. Larsen, E. G. Corley, P. Davis, P. J. Reider, and E. J. J. Grabowski, J. Am. Chem. Soc., 1989, 111,
7650.
22. T. Durst and K. Koh, Tetrahedron Lett., 1992, 33, 6799.
23. S. G. Davies, N. M. Garrido, O. Ichihara and I. A. S. Walters, J. Chem. Soc., Chem. Commun., 1993,
1153; S. G. Davies and D. R. Fenwick, J. Chem. Soc., Chem. Commun., 1995, 1109.
24. N. Asao, N. Tsukada and Y. Yamamoto, J. Chem. Soc., Chem. Commun., 1993, 1660; N. Asao, T.
Uyechara and Y. Yamamoto, Tetrahedron, 1990, 46, 4563.
25. S. G. Davies, C. J. R. Hedgecock and J. M. McKenna, Tetrahedron: Asymmetry, 1995, 6, 827; 2507;
S. G. Davies and D. R. Fenwick, Chem. Commun., 1997, 565.
26. K. Fuji, M. Node, S. Terada, M. Murata, H. Nagasawa, T. Taga and K. Machida, J. Am. Chem. Soc.,
1985, 107, 6404.
27. N. J. Newcombe and N. S. Simpkins, J. Chem. Soc., Chem. Commun., 1995, 831.
28. D. Hoppe, F. Hintze, P. Tebber, M. Paetow, H. Ahrens, J. Schwerdtfeger, P. Sommerfeld, J. Haller, W.
Guarneri, S. Kolczewski, T. Hense and I. Hoppe, Pure Appl. Chem., 1994, 66, 1479; Clayden, Lithium,
pages 226–235 and 258–269.
29. M. Seppi, R. Kalkofen, J. Reupohl, R. Fröhlich and D. Hoppe, Angew. Chem., Int. Ed., 2004, 43, 1423.
30. S. H. Zhao, O. Samuel and H. B Kagan, Org. Synth., 1989, 68, 49.
31. Saunders, Top Drugs, chapter 5, page 37.
32. H. Cotton, T. Elebring, M. Larsson, L. Li, H. Sörensen and S. von Unge, Tetrahedron: Asymmetry, 2000,
11, 3819.

25
Asymmetric Induction II
Asymmetric Catalysis: Formation
of C–O and C–N Bonds
Introduction: Catalytic methods of asymmetric induction
PART I – SHARPLESS ASYMMETRIC EPOXIDATION
The AE Method
The ligands
The catalyst
Catalyst structure
The mnemonic device
The synthesis of propranolol
Modifi cation after Sharpless Epoxidation
Oxidation after Sharpless epoxidation
The Payne rearrangement
Asymmetric Induction at the Allylic Alcohol Centre: AE is anti-Selective
No Asymmetric Induction from Remote Allylic Alcohol Centre: Reagent Control
Asymmetric Synthesis of Diltiazem
Summary of Sharpless Epoxidation
PART II – SHARPLESS ASYMMETRIC DIHYDROXYLATION
The AD Method
The ligand
Solvent dependence
The catalytic cycle
Methanesulfonamide
Substrate Dependence and the Mnemonic Device
Recommended ligands for different classes of alkenes
Applications of the Sharpless AD Reaction
The synthesis of indicine
The synthesis of a C2-symmetric piperidine
The synthesis of the alkaloid reticuline
Dihydroxylating Compounds with More than One Double Bond I—Regioselectivity
Dienes
Guidelines
When guidelines combine or compete
A synthesis of aspicillin
Designer ligands to improve selectivity
Dihydroxylating Compounds with More than One Double Bond II—Diastereoselectivity
Advanced dihydroxylation strategy
Scaling Up the Asymmetric Dihydroxylation
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

528 25 Asymmetric Induction II Asymmetric Catalysis
PART III – AMINOHYDROXYLATION
PART IV – CONVERTING 1,2-DIOLS INTO EPOXIDES
Applications of the AD to epoxide transformation: propranolol and diltiazem
PART V – JACOBSEN EPOXIDATION
PART VI – DESYMMETRISATION REACTIONS
Opening anhydrides
Opening epoxides
Comparison of desymmetrisation and kinetic resolutions
Mono esterifi cation of diols
PART VII – HETERO DIELS-ALDER REACTIONS
Introduction: Catalytic methods of asymmetric induction
In the previous chapter we discussed various reagent-based strategies for the enantioselective formation
of chiral centres. The next two chapters are also concerned with reagent-directed strategy
but with an important difference. The source of asymmetry is used in a much lower concentration:
it is a catalyst. We may put in a few milligrams of an optically active compound and get out grams
or even kilograms of enantiomerically pure product. This chapter concerns the formation of C–O
and C–N bonds, the next the formation of C–H and C–C bonds.
We dedicate a large part of this chapter to two very important, and extraordinarily useful,
enantioselective methods – catalytic asymmetric epoxidation (AE) and catalytic asymmetric
di hydroxylation (AD). Impressively, both these methods were developed by Professor Barry
Sharpless’s research group and are therefore often referred to as the Sharpless epoxidation and the
Sharpless dihydroxylation. Both are examples of ligand-accelerated catalysis.
PART I – SHARPLESS ASYMMETRIC EPOXIDATION
There are many asymmetric epoxidation reactions but none is as reliable or has been as widely
used as the Sharpless Asymmetric Epoxidation 1 (AE), the subject of this section, and the Jacobsen
epoxidation, the subject of a later section in this chapter. 2
The AE method
The Sharpless epoxidation converts a prochiral allylic alcohol 1 into a chiral epoxy alcohol 2 and
gives that epoxy alcohol with a very high enantiomeric excess.
R OH
1
R OH
2
There is a great deal of fl exibility allowed within the framework of this reaction – the substituents
on the starting material can vary a great deal and the double bond can be E or Z. However,
there is one restriction and that is that the substrate must be an allylic alcohol. If it isn’t the reaction
will not work because, as we shall see, the hydroxyl group plays a crucial role in the reaction.
The reagents used are an oxidising agent (usually, tert-butyl hydroperoxide t-BuOOH, but other
O

hydroperoxides can be used), a catalyst, and – for the asymmetric induction – a chiral and enantiomerically
pure ligand. There is an Organic Synthesis procedure for a typical case. 3
The ligands
The ligands used are the dialkyl tartrates. Most commonly, the diethyl or diisopropyl tartrates
are used. Diethyl tartrate is often abbreviated to DET, diisopropyl tartrate to DIPT and dimethyl
tartrate to DMT.
HO
O
Importantly, both enantiomers of tartaric acid are available. However (and also importantly)
one is very much more expensive than the other. The cheap one is L-tartaric acid 3 and is often
referred to as ‘natural’ tartaric acid. It is about 35 times cheaper than the ‘unnatural’ D-tartaric
acid though, in fact, there is nothing unnatural about this acid at all – it too comes from natural
sources. The ethyl 4, 5 and iso-propyl esters of both enantiomers are also available. These are the
enantiomers of C 2 symmetric DET, the other diastereoisomer, meso-DET 6 is achiral. The ligand
can be used catalytically providing that molecular sieves are added. 4
The catalyst
The metal at the heart of the active catalyst is titanium. This holds everything together—the tartrate
ligand, the substrate (the allylic alcohol) and the oxidant tert-butyl hydroperoxide t-BuOOH. The
structure of the catalyst before substrate or ligand binding is thought to be as shown in the fi gure
below. There are two titanium atoms and two unsymmetrically bound tartrate units.
Catalyst structure
The most likely structure of the catalyst is based on X-ray structures of related compounds and
reinforced by calculations. 5 It is dimeric with two Ti atoms, two tartrates and four alkoxides. We
show one of two degenerate structures. When the catalyst combines with the allylic alcohol and
the hydroperoxide, the same titanium atom takes both and only one diastereotopic face of the
alkene is presented to the active oxygen atom.
RO
O
RO
OH
OH
OR
Ti
O
O
RO 2C
E
OH
3; (R,R) L-(+)-tartaric acid
O
O
EtO
OR
Ti
O
Likely catalyst structure
E = CO2R
O
25 The AE method 529
O
OR
OR
OH
OH
O
OEt
R OH
t-BuOOH
EtO
O
RO
O
RO
OH
OH
OR E
O
Ti
O
O
O
OEt
RO 2C
t-Bu
EtO
4; (R,R) L-(+)-DET 5; (S,S) D-(–)-DET 6; meso-DET
O
OH
O
Ti
O O
E
OH
Proposed 'loaded' catalyst structure
E = CO 2R
O
R
O
OEt

530 25 Asymmetric Induction II Asymmetric Catalysis
The mnemonic device
The absolute confi guration of the epoxide product depends upon the enantiomer of the tartrate
ligand that is used. The empirical observation is very reliable—when the allylic alcohol is drawn
with the carbinol carbon in the SE quadrant as in the fi gure below, the L-tartrate directs attack of
the oxygen atom from the oxidising agent t-BuOOH to the bottom face of the olefi n while the Dtartrate
directs it to the top.
SW
R 1
NW
The synthesis of propranolol
D-(–)-dialkyl tartrate
R 2
OH
L-(+)-dialkyl tartrate
R 3
SE
Propranolol 7 is a β-blocker. Let’s consider how it could be disconnected. The fi rst thing to notice
is that there are two 1,2-related functional groups. We have an ether and an alcohol on the lefthand
side of the molecule and, on the right, a 1,2-aminoalcohol.
Because we have an alcohol in the middle of the molecule, we can imagine disconnections 7a
or 7b that rely upon the attack of a nucleophile on the terminal position of an epoxide. Notice that
there is only one chiral centre in this molecule.
8
OH
O
7; (–)-propranolol
Either disconnection a or b would be fi ne. However, the way it was done 6 involved disconnection
b. The next disconnection is akin to a in that it uses α-naphthol 8 as the nucleophile.
a
NE
1
O N
OH
H
2 2
R
R
O
2
O
ent-2
N
a
O N b
H
H
H2N OH O
9 O 11
b
7a; disconnection of
(–)-propranolol
10
OH
OH

O
10a
Mesylate was chosen as the leaving group and the epoxy mesylate 9 could be made from the
corresponding alcohol 12 and that, in turn, from allyl alcohol 13 by Sharpless epoxidation.
In fact, allyl alcohol 13 was not used at the start of this synthesis because low ees result if there is
no substituent on the alkene trans to the alcohol (R 2 in the mnemonic should be something other than
H). It is much better here to add a removable group and so the silyl alkene 14 was used instead of 13.
The silyl group allowed the isolation of the epoxy alcohol 15 in a much higher yield than was possible
using allyl alcohol itself and the ee of 15 was 95%. The alcohol was converted to a mesylate 16.
HO
The mesylate was then displaced using sodium naphthoxide made from 8 with base. The
silyl group is not wanted in the fi nal product and was removed with TBAF (tetrabutylammonium
fl uoride, Bu 4N F ). Finally the epoxide 10 was opened with isopropylamine 11. This synthesis
depends on regioselective opening of an epoxide at the less substituted end.
Modifi cation after Sharpless Epoxidation
Oxidation after Sharpless epoxidation
O
C–O
ether
Disparlure 18 is the sex attractant of the gypsy moth. The only functional group in disparlure is
the epoxide and we need an alcohol somewhere if the stereoselective introduction of this group is
to be done by AE. Our disconnection strategy7 is dominated by that thought – an alcohol must be
introduced somehow at one of the allylic carbons in 19.
OH?
8
OH
+
OMs
O O
Me
S
O
9a
O
C–O
ester
HO
12
O
AE
HO
13
9
O
Ms = MeSO2
SiMe3 (–)-DET
t-BuOOH
HO
O
SiMe3 MsCl
Et3N
MsO
O
SiMe3 14 15; 60% yield, >95% ee
16
8
Bu4N F
11
16 O
SiMe3 O
7
base
O
O
O
25 Modifi cation after Sharpless Epoxidation 531
17
18; (+)-disparlure
AE?
OH?
19
10

532 25 Asymmetric Induction II Asymmetric Catalysis
It is best to add the OH group in a reaction that allows a helpful disconnection so an alkene
was introduced (Functional Group Addition) to give the vinyl epoxide 20. The double bond can be
disconnected by a Wittig reaction. Although we might expect a mixture of double bond geometries
using the Wittig reaction it doesn’t matter here—this double bond is going to be removed anyway.
Aldehyde 21 could come from alcohol 22 which is the product from an AE reaction on the
Z-allylic alcohol 23. The geometry of this alkene must be controlled and fortunately Z-allylic
alcohols are easily made by partial reduction of alkynes (chapter 15).
18
FGA
O
R
20; R = n-C10H19 The (Z)-allylic alcohol 23 was epoxidised at 40 C to give 22 in 91% ee and 80% yield. Sharpless 7
says ‘The crystallinity of the epoxy-alcohol 22 greatly simplifi es its isolation (no chromatography
needed.)’. Oxidation, Wittig reaction and hydrogenation of the alkene complete the synthesis of
()-disparlure 18 that did indeed attract the moths.
OH
R
23
The Payne rearrangement
Wittig
O
The products of a Sharpless epoxidation, such as epoxides 12, 16, or 22, are potentially unstable
in base as the anion of the alcohol can attack the epoxide 24 in the Payne rearrangement. This is
easily seen with the simplest compound 12. It doesn’t and we have rather given the game away by
the compound numbers. The OH groups in the right hand and in the left hand compounds 12 are
homotopic. Sharpless made the defi nitive statement of this in his propranolol synthesis. 6
HO
OH
(–)-DET
(i-PrO) 4Ti
CrO3. 2pyr
t-BuOOH
–40 ˚C
O
R
CH2Cl2
22; 80% yield, 91% ee
12
O
base
O
24
O
If the carbon skeleton is unsymmetrical 2 the danger is different: the Payne rearrangement
gives a mixture of two products 2 and 25. There are now three places where a nucleophile might
attack: C-3 in 2, C-1 in 25, and C-2 in both but with different stereochemical outcomes. We much
prefer to make 1 rather than 26 by AE as 26 is already chiral and the AE reaction would be a
kinetic resolution.
Of the two compounds 2 and 25, the more substituted epoxide 2 is the more stable and therefore
the more abundant. But the mixture reacts with nucleophiles preferentially at the least substituted
CHO
HO R
AE
HO
1
2
3
O
R
Payne
base
1
O 2
OH
3 R
1
2 25
O
OH
FGI AE
O
OH
R
R
R
21 22 23
CHO
R
21; 88% yield
O
24
1.
Ph 3P
O
2. RhCl, H 2
O
AE?
18; (+)disparlure
47% yield
12
OH
26
OH
R

carbon, that is C-1 in 25. The minor component of the mixture 25 gives the major product 27. So
AE on 1 can be used to make products from 2 or 25 according to the reaction conditions.
AE
1 3
Payne
1
OH
HO R HO
2 O
R
base
O 2
3 R
1
2 25
Our illustration comes from Sharpless’s sugar syntheses. 8 The mono benzyl ether 28 responds
well to AE and reaction of the epoxide 29 with PhSH in basic solution gives mostly (4.5:1) the
product 30 of the Payne rearrangement.
BnO
28
OH
(+)-DET
(i-PrO) 4Ti
t-BuOOH
Asymmetric Induction at the Allylic Alcohol Centre: AE is anti-Selective
It is possible to make the CH(OH) centre of the allylic alcohol asymmetric by an AE reaction. This
is a kind of symmetry breaking, It is well illustrated by Fürstner’s synthesis of the only interesting
piece 32 of the natural product ()-balanol 31: a potential lead for development of protein kinase
inhibitors. 9 The two disconnections are trivial.
It does not look initially as if the cyclic amine 32 can easily be made by AE. However, the two
substituents on the seven-membered ring are anti and could come from an epoxide opening. The
key idea is to make the seven-membered ring by olefi n metathesis (chapter 15). An alkene must
again be added and Fürstner placed it so as to make the alcohol allylic 33. Reversing the metathesis
gives a non-cyclic starting material 34. Now he removed one of the amines and replaced it
by a second OH group to give 35.
32
25 Asymmetric Induction at the Allylic Alcohol Centre: AE is anti-Selective 533
HO 2C
FGA
H
O
H
O
O OH
OH
N
O
O
Nu
Nu
OH
27
OH
O
BnO
OH PhSH
BnO
SPh
NaOH
OH
29; 85% yield, 99:1 30; 88% yield, 4.5:1
N
H
31; (–)-balanol
NH2
C=C
metathesis
H
N
O
OH
C–O
ester
C–N
amide
OH
N
H
32
NH2
H
H
H
33 34 35
OH
N
NH2
FGI
OH
N
OH
OH
R

534 25 Asymmetric Induction II Asymmetric Catalysis
Disconnection of a 1,2-diX relationship gives allyl amine 36 and an epoxide 37 that might be
made by AE. The starting material is indeed an achiral allylic alcohol 38 but it has two alkenes.
They are in fact enantiotopic and AE will probably be able to discriminate between them. A more
diffi cult question is what will be the stereochemistry of the alcohol in 37 as it becomes a stereogenic
centre during the AE reaction. It turns out (by experiment) that AE has anti-selectivity:
the catalyst delivers the epoxide oxygen to the opposite face to the OH group. This is surprising
because both oxygen atoms are Ti-bound. But inspection of the loaded catalyst structure above
shows that a substituent (here vinyl) on the allylic alcohol would prefer to be on the opposite face
of the alkene to that attacked by t-BuOOH when both are bound to Ti. The symmetry aspects of
this reaction are discussed in more detail in chapter 28.
OH
35
NH
OH
1,2-diX
C–N
‘Unnatural’ D-DET was needed to get the right absolute stereochemistry and 37 was not isolated
but protected as a benzyl ether 39 before reaction with allylamine gave the carbon chain of 35.
Conversion of OH into NH 2 now required inversion.
OH
38
After N-Boc protection, metathesis worked very well to give doubly protected 42 and inversion
with diphenylphosphoryl azide under Mitsunobu conditions gave the azide 43. This order of
events allowed a triple reduction - of the alkene, the azide and the benzyl group - in one step and
Boc-protected 44 could then be used in the synthesis of balanol itself.
OBn
41
N
Boc
OH
No Asymmetric Induction from Remote Allylic Alcohol Centre:
Reagent Control
OH
NH 2
If there is already a chiral centre in the molecule that has already been controlled by asymmetric
synthesis, the AE reaction will ignore it if it is far enough away. Yamada’s synthesis 10 of the
biologically active diterpenoid 45 illustrates this and demonstrates control when nucleophiles attack
an unsymmetrical epoxide. Preliminary disconnections with a Diels-Alder in mind took the
chemists back to the diol 48.
O
OH
36 37
=
(D)-(–)-DET
37
NaH
OBn
36
OBn
t-BuOOH
(i-PrO) 4Ti
BnBr
O
OH
N
H
39; 95% yield 40; 94% yield
metathesis
Mo-carbene
catalyst
OBn
N
OH
(PhO) 2PO.N 3
Ph 3P, DEAD
OBn
O
AE?
OH
Boc
Boc
Boc
42; 94% yield 43; 91% yield 44
N
N3 H2, Pd/C
acid
38
OH
N
NH 2

H
H
H
NHCHO
O
Cl
45; kalihinene X
H
H
O
H
O
Cl
Cl
Cl
46 47 48
The tetrahydropyran ring 48 has a tertiary carbon joined to oxygen 48a and this C–O bond
can be made by addition of an alcohol to an alkene. Addition of an anion-stabilising sulfone 50
allows a C–C disconnection back to the epoxide 51 that does look like an AE product except for
the allylic chloride.
OH
OH
H
O
C–O
OH
OH
H
OH
The substrate chosen for the AE reaction was the bis allylic alcohol 53 having the same carbon
skeleton as 51 but with an inverted alcohol replacing the chloride. This was a strange choice
as one of the allylic alcohols must be protected and there remains the question of the infl uence
of the stereogenic centre on the AE reaction. Protection was easy: silylation with t-BuMe 2SiCl
(TBDMSCl) occurred only on the primary alcohol, silylation with t-BuPh 2SiCl (TBDPSCl)
could be forced onto the one remaining OH and selective methanolysis of the less hindered silyl
group gave 54. The AE reaction was, as expected, regioselective for the allylic alcohol but most
signifi cantly was highly reagent controlled (10:1 in favour of 55 over the other diastereomer).
Reaction with the lithium derivative of the sulfone 52 gave 56 which could be converted into 51 by
acetylation of the two OH groups, desilylation and Mitsunobu-style inversion of the alcohol with
Ph 3P and CCl 4. These reactions are discussed in the Workbook.
HO
25 No Asymmetric Induction from Remote Allylic Alcohol Centre: Reagent Control 535
t-BuOOH
(–)-DIPT
(i-PrO) 4Ti
Diels-
Alder
Cl
Cl
Cl
Cl
48a 49 50 51
HO
t-ether
FGA
OH
OH
H
OH
SO 2Ph
C–C
sulfone +
epoxide
1. TBDMS-Cl, DMAP, Et 3N
2. TBDPS-Cl, imidazole HO
OH
3. MeOH, PyrH OTBDPS
+ TsO –
53 54; 83% yield
O
55; 95% yield
OTBDPS
1. 52-OBn, BuLi
2. Na/Hg, Na 2HPO4
BnO
O
H
OH
O
HO
O
C–C
OH
+
HO
56; 89% yield
OH
OH
H
O
SO2Ph
52
OTBDPS

536 25 Asymmetric Induction II Asymmetric Catalysis
Should the starting material 53 be enantiomerically pure? Yes, as there is virtually no kinetic
resolution. The asymmetric centre in 53 is evidently too far from the alkene that reacts by AE
to have more than a minor effect on the stereoselectivity. Enantiomerically pure alcohol 53 was
already available from asymmetric reduction (using CBS, see chapter 26) of the corresponding
enone. Sharpless epoxidation does have limitations but it is supremely practical.
Asymmetric Synthesis of Diltiazem
Diltiazem is a calcium channel blocker used in the treatment of angina and hypertension. The
active compound is the () enantiomer of the cis-diastereoisomer 57. The side chain (R
Me 2NCH 2CH 2- in 57) can be added by alkylation of 58. The amide is an obvious disconnection.
OMe
S
C–N
S
O
N
OMe
alkylation
in base
N
R
O
H
O
57; (+)-cis diltiazem 58
The intermediate 59 has two 1,2-diX relationships but only one can reasonably be derived from
an epoxide and redrawing 59a to show the anti- stereochemistry between S and O that would
result from opening an epoxide unfortunately reveals an epoxide 60 from a cis unsaturated ester.
NH2
S
2
Ar
2
RO2C 1
O
59
OMe
redraw
NH2
We need an allylic alcohol if we are to use AE and we much prefer a trans allylic alcohol. So
two inversions will be needed. The epoxide 63 was made in excellent yield and ee provided cumyl
hydroperoxide 61 was used as the oxidant. Oxidation gave the required ester 64.
Now for the fi rst inversion. It turns out that nucleophilic attack by chloride ion occurs next
to the electron-rich aromatic ring rather than next to the ester. The thiol 66 was used so that the
thiolate anion could be made with a weak base, and the required regio- and stereochemistry is
in place 67. The rest of the synthesis 11 is in the Workbook. We shall be seeing other syntheses of
diltiazem later in this chapter that use other asymmetric methods.
Ar
S
O
59a
CO 2R
OMe
O
C–S
1,2-diX
OMe
OMe
Ar
O
C–N
amide
60
CO2R
(i-PrO) 4Ti
O
1. RuO2, NaIO4 O
CO2Me Ph OOH Ar OH (+)-DET, 61 Ar OH 2. Me2SO Ar
4
61 62 63 64

64
py HCl
HCl
Ar
OH
CO2Me
Summary of Sharpless Epoxidation
Cl
This exceptionally accommodating reaction can be made to work for most kinds of allylic alcohol
but there are some general guidelines that we shall summarise here:
1. The substrate must be an allylic alcohol such as 1. The next best is a homoallylic alcohol 68
but then the reaction is slow and the ees generally poor.
2. The best results come with terminal allylic alcohols that have E-alkenes with some substitution
such as 1, 69, and 70.
3. Allylic alcohols with Z-alkenes (that is an alkyl group cis to the OH group 71 – 73) generally
give poor results. The mnemonic device above shows that the fi t is poor.
4. Terminal alkenes other than allyl alcohol itself are not much use. The epoxide from one
achiral type 75 is very susceptible to nucleophilic attack and the Payne rearrangement, while
the other achiral type 76 gives poor ees. The chiral compounds 77 and 78 belong to the realm of
kinetic resolution (chapter 28).
OH
PART II – SHARPLESS ASYMMETRIC DIHYDROXYLATION
+
65 66
R OH
1
The Sharpless dihydroxylation reaction (AD) is arguably the most important discovery in organic
chemistry of the 20th century. There is no question that asymmetric synthesis is at the forefront
of modern synthetic organic chemistry. And the most impressive asymmetric methods are those
which are catalytic. The Sharpless epoxidation achieved this and more. But those methods that
NO 2
SH
R
Et 3N
68
OH
NO2
R OH
R OH
R1 R2 1 69 70
R
25 Summary of Sharpless Epoxidation 537
R 2
OH
OH
R1 R2 OH
71 72
73
OH
R R
R OH
74 75 76 77 78
R
R 3
OH
S
R 2
Ar
67
OH
OH
CO 2Me
R 1
OH

538 25 Asymmetric Induction II Asymmetric Catalysis
combine high enantiomeric excesses and high catalyst turnover with activity over a broad range
of substrates become supremely useful when they are simple to perform and require no fancy
solvents, temperatures or other rigorously controlled conditions. The Sharpless Asymmetric Dihydroxylation
(AD), an asymmetric version of the familiar dihydroxylation of alkenes with osmium
tetroxide, is such a method. 12 As testimony to their ease of use, both the Sharpless epoxidation and
the Sharpless dihydroxylation have now found their way into undergraduate laboratory practicals.
The AD Method
Professor Barry Sharpless 13 wrote, ‘It reacts only with olefi ns and it reacts with all olefi ns (slight
poetic licence here)’ The “It” is, of course, osmium tetroxide which reacts with those olefi ns to
give 1,2-diols. 14 It does so stereospecifi cally, introducing the two hydroxyl groups on the same side
of the fl at double bond 79 to give the syn diastereoisomer 80. In addition to this stereospecifi city, in
the presence of an appropriate ligand, osmium tetroxide may react with olefi ns enantio selectively,
attacking one or other of the two enantiotopic faces to give 80 or ent-80.
R 1
R2 OsO4
R 1
The reaction has been developed by Sharpless 15–18 and others 19 from one which required a
stoichiometric amount of prohibitively expensive osmium tetroxide to one where as little as
0.002 mol% of osmium may be used. 13 What is more, the former method performs a racemic
transformation whereas the latter yields essentially optically pure diols.
Look at that quote again. The variety of substrates that can be used is enormous and even for an
asymmetric reaction, no other functionality is required. Of the fi ve compounds illustrated below,
only the allylic alcohol 83 forms a suitable substrate for the Sharpless epoxidation but all are
suitable for the asymmetric dihydroxylation (AD) reaction.
It is certainly appropriate for us to describe here some of the important aspects of Sharpless dihydroxylation
methodology. This background is essential to chemists who do, or are thinking about
doing, the reactions. However, a detailed discussion of, for instance, the mechanism of the reaction,
or the explanations behind the origin of the enantioselectivity, are beyond the scope of this book
and so, where this sort of thing is described at all, it is done mostly from an empirical standpoint.
Some history. The development of the current state of the art makes an interesting story. The
reaction of osmium tetroxide with olefi ns was discovered 14 in the 1930s. The reaction fi rst gives an
osmate ester 86. This ester is a stable species but can be hydrolysed to yield the diol 80.
OH
OH
OH
79 80 ent-80
Ph Ph OBn Ph OH Ph OAc Ph
CO2Me
81 82 83 84 85
stoichiometric
dihydroxylation
R 1
R 2
+
R2 OsO4 Os
O O
R1 R2 O O
R1 R2 hydrolysis
OH
OH
79 86; osmate ester
(±)-80
R 1
OH
R 2

Osmium tetroxide is very expensive and very toxic which made using it quite unattractive. For a
long time, many people who used osmium tetroxide to convert olefi ns to diols—and this was long
before enantioselective dihydroxylations came on the scene —used the Upjohn procedure. 20 This
process used catalytic amounts of osmium tetroxide, NMO (N-methylmorpholine N-oxide) 87 as
the stoichiometric oxidant, and one solvent phase. The solvent was water, acetone and tert-butyl
alcohol. The osmate ester 86 was hydrolysed under these conditions and the osmium (VI) species
was reoxidised to OsO 4 by NMO.
catalytic
dihydroxylation
O
N
Me O
The ligand
The simplest asymmetric ligands that were used, and from which all of the state-of-the-art ligands
are derived, were esters of either dihydroquinidine 88 or dihydroquinine 90. Sharpless fi rst
developed a stoichiometric process using these ligands but many years passed before the catalytic
asymmetric dihydroxylation was achieved when the ligands were added to the standard Upjohn
process. 15 The two cinchona alkaloids (and their ester ligands 89 and 91) are not, in fact, enantiomers,
but diastereomers. The absolute confi gurations of the centres in one complement those in the
other at all but one centre – where the ethyl group joins the quinuclidine unit – and so they function
as enantiomers. Cinchona is pronounced sinkowner: “Named by Linnæus after the countess
of Chinchon, who, when vice-queen of Peru, was cured of a fever by Peruvian bark, and afterwards
brought a supply of it into Spain” according to the Shorter Oxford English Dictionary.
R
O
Et
N
N
H
OMe
88; dihydroquinidine (R = H) (DHQD)
89; (R = p-chlorobenzoyl)
Et
MeO
These ligands were superseded with the development of the phthalazine (PHAL) ligands in
which two cinchona alkaloid units are connected together. The two most widely used ligands are
the phthalazine ligands (DHQD) 2-PHAL 93 and (DHQ) 2-PHAL and these are used in the two
commercially available asymmetric dihydroxylation mixes – AD-mix-α and AD-mix-β.
MeO
87; NMO
N-methyl
morpholine
N-oxide
H
N
N
Et
O
R 1
N
79
N
Et
O
93; (DHQD)2-PHAL
25 The AD Method 539
R 2
“Upjohn procedure”
OsO 4
NMM
N
H
N
N
O R
90; dihydroquinine (R=H) (DHQ)
91; (R = p-chlorobenzoyl)
N
H
Os (VI)
NMO
OMe
O O
Os
O O
R1 R2 86
Alk*O
hydrolysis
H 2O
acetone
t-BuOH
N
N
92; quinuclidine
(achiral)
N
R 1
OH
OH
(±)-80
OAlk*
94; phthalazine ligands
(DHQ)2-PHAL or (DHQD) 2-PHAL
simpler representation
R 2

540 25 Asymmetric Induction II Asymmetric Catalysis
The diphenylpyrimidine (PYR) 95 and the indoline (IND) substituted ligands 96 are other
types. The indoline ligands contain just the one alkaloid unit. The three different ligand types
(PHAL, PYR and IND) are suitable for different types of olefi n.
More recently discovered ligands 21 include the diphenylpyrazinopyridazine (DPP) 98 and
anthraquinone (AQN) 99 ligands as well as the diphenyl analogue of the phthalazine ligands
(DP-PHAL) 97.
Ph
Ph
Alk*
Solvent dependence
There are two solvent systems commonly used for dihydroxylations. The fi rst involves just one
phase and consists of either water and acetone 22 or water, acetone and tert-butyl alcohol. 14 The
second, and more modern, solvent system is a two phase mixture and consists of water and
tert-butyl alcohol. The impact that the two phase system has on enantioselectivity is profound.
This is because it prevents the deleterious ‘second cycle’ which can otherwise occur. In fact, the
single phase method is still used for certain applications including multiple dihydroxylations.
The catalytic cycle
O
Ph
N N
Ph
O Alk*
95; diphenylpyrimidine ligands
(DHQ)2-PYR or (DHQD) 2-PYR
simple representation
OAlk*
N
N
OAlk*
97; diphenylphthalazine
(DP-PHAL) ligands
Ph
Ph
Et
MeO
N
N
One of the problems encountered in the development of the AD reaction was a second cycle. 23 The
fi rst cycle is the same as the cycle we saw in the Upjohn procedure with one modifi cation. It is
possible for the osmium in the osmate (VI) ester to become oxidised before hydrolysis to form an
osmate (VIII) ester. If this species simply hydrolyses to diol and OsO 4 then there is no problem but
otherwise this is where the trouble starts. In the second cycle the osmate (VIII) ester reacts with
another olefi n instead of being hydrolysed. It does so with low enantioselectivity (and sometimes
in the opposite sense to the fi rst cycle) which results in the poorer enantiopurity of the product
(step D rather than step C below). One way round this is to keep the olefi n concentration as low as
possible which can be done by adding the olefi n slowly. 22,23 Although slow olefi n addition resulted
in a profound improvement in enantiomeric excess, it was inconvenient and no way near as effective
as the alternative which was to alter the conditions. The use of two phases makes it impossible
for the second cycle to occur. 19,24
H
OAlk*
N
N
OAlk*
N
N
O
O
96; (DHQIND)
98; diphenylpyrazinopyridazine
(DPP) ligands
N
O
O
OAlk*
OAlk*
99; anthraquinone
(AQN) ligands

R
R
step A
R
O
O
OH
O
R
O
O
Os O
O
L
OH
Os O
L
R
R
O
O
O
Os
O
O
Before the osmate (VI) ester, resulting from the addition of olefi n and osmium tetroxide, can react
with a second olefi n it has to be reoxidised (step B). With two phases, the osmate ester and olefi n are
in the organic layer and the oxidant [Fe(CN) 6 3 ] is in the aqueous layer. Hence the osmium cannot
be oxidised while it is in the form of the osmate (VI) ester to an osmate (VIII) ester. Only after the
osmate ester has hydrolysed may the osmium enter the aqueous phase and be reoxidised for another
cycle (step Y). 12 It is critical that the reaction mixture is biphasic. Just using a water/tert-butyl alcohol
solvent system is not enough because these two solvents can be miscible. It was demonstrated 24
that stoichiometric osmylation of styrene in 1:1 tert-butyl alcohol/water, a homogeneous reaction,
gave a product with 58% ee. That same stoichiometric reaction performed in the presence of either
K 3Fe(CN) 6 or potassium carbonate led to a 74% ee. These salts stop the water and tert-butyl alcohol
mixing. The addition of K 2CO 3 is essential. Although it may be partially replaced with NaHCO 3 for
base-sensitive materials the AD reaction fails to turn over with its complete omission. 12,24
Osmate (VI)
ester
First Cycle
high enantioselectivity
Osmate (VI)
ester
O
O
Organic
Aqueous
R
O
Os O
L
2 OH – , 2 H 2O
R
25 The AD Method 541
H 2O
step C
step B
[O]
step X
L +
HO
HO
R
R
L
Osmate (VIII)
ester
R
O
Os
O
OH
OH
OH
OH
OH
OH
R
R
step D
R
2–
R
R
step F
step Y
L
R
R
R
O
O
R
O
O
O
Os
O
Os
O
O
O
O
O
Second Cycle
low enantioselectivity
H 2O, L
HO
HO
step W
O O
O Os O
O
Os
O
O
O
R
step Z
2–
R
R
+ L
2 OH –, 2 Fe(CN) 6 3– 2 H 2O, 2 Fe(CN) 4 3–
R
R
R
step E
[O]
2 OH –

542 25 Asymmetric Induction II Asymmetric Catalysis
Methanesulfonamide
Another key development was the discovery that methane-sulfonamide MeSO 2NH 2 accelerated
the rate of hydrolysis of the intermediate osmate ester (not to be confused with the rate of the
addition of osmium tetroxide to the olefi n). Reaction times can be reduced by as much as 50 fold.
After 3 days at 0 C in the absence of methanesulfonamide, trans-5-decene had been only 70%
converted to the corresponding diol but the diol was isolated in a 97% yield after just 10 h at 0 C
in the presence of methanesulfonamide. This improvement means that reactions can be run at 0 C
instead of room temperature. However methanesulfonamide slows down the reaction of terminal
olefi ns. It is thus omitted from such reactions. 16
Substrate Dependence and the Mnemonic Device
In order to predict facial selectivity, Sharpless and co-workers invoke a mnemonic device. 25
To an approaching olefi n, the greatest steric constraints are presented by the NW, and to
an even greater extent, the SE quadrants. The SW and NE quadrants are more open and, in
addition, the SW quadrant contains what is described as an “attractive area”. The attractive
area is particularly well suited to accommodate fl at aromatic groups. The olefi n positions itself
according to the constraints imposed by the ligand and is dihydroxylated from above (β-face),
in the case of dihydroquinidine derivative, or from below (α-face) in the case of dihydroquinine
derivatives. The commercially available AD-mix-α and AD-mix-β are chosen according to this
mnemonic.
The Mnemonic Device
SW
attractive
area
NW
R L
R S
dihydroquinidine
derivatives
β-face
Inspection of this mnemonic illustrates why stilbene is such a good substrate for these ligands:
its two aromatic portions can align nicely with two-fold degeneracy into the ligand pocket with
only hydrogen atoms in the sterically demanding areas. In contrast, we can see why cis alkenes
make such poor candidates – one of the substituents will have to be in a sterically demanding area.
Of all the alkene classes, 25 the cis-di-substituted alkenes are the least good. They need a unique
ligand - the indoline substituted alkaloid 18 96 and even then enantiomeric excesses rarely exceed
80%. The fi gure below outlines the ligands that Sharpless recommends for each of the six olefi n
classes. Five of the six work very well with either PHAL or PYR. The AQN ligands are particularly
suited to allylically substituted terminal olefi ns 21 and the PYR ligands are good for sterically
congested olefi ns.
H
α-face
dihydroquinine
derivatives
RM
SE
NE

Recommended ligands for different classes of alkenes
mono-
PHAL
PYR
AQN
cis-di-
IND
PHAL
30-97%
ee
20-80%
ee
Applications of the Sharpless AD Reaction
That was the background. And now we look at the application of the AD reaction. First of all we
look at a few retrosyntheses before moving on in the section dihydroxylating with more than one
double bond to consider the more complicated issues. It is often easy to spot when a Sharpless
AD strategy might be used if there are two hydroxyl groups in the target molecule which are 1,2related.
The synthesis of indicine
Cl
Ph
95% ee (R, R)
(DHQD) 2PHAL
gem-di-
PHAL
trans-di
PHAL
tri- tetra-
90-99%
ee
25 Applications of the Sharpless AD Reaction 543
97% ee (R)
(DHQD) 2PHAL
90% ee (S)
(DHQD) 2AQN
72% ee (1R, 2S)
DHQD-IND
56% ee (1R, 2S)
DHQD-IND
98%ee (R)
(DHQD) 2PHAL
PHAL
PYR
70-97%
ee
90-99.8%
ee
20-97%
ee
94% ee (R)
(DHQD)2PHAL
30% ee (R)
(DHQD) 2PHAL
Ph
Ph
99.8% ee (R, R)
(DHQD)2PHAL
95%ee (R, R)
(DHQD) 2PHAL
Indicine 100 is an alkaloid which has antitumour activity but hepatic toxicity. 26 The molecule
clearly consists of two enantiomerically pure chunks which we would like to separate in our
retrosynthesis. What is more, those two portions are conveniently connected by an ester linkage
making the fi rst disconnection very easy.
Ph
47% ee (R)
(DHQD) 2PYR
MeO
64% ee (S)
(DHQD) 2PHAL

544 25 Asymmetric Induction II Asymmetric Catalysis
We shall not concern ourselves with the whole synthesis of ()-retronecine 101 at this stage but
just with the diol 102. Diol 102 comes from the corresponding alkene by Sharpless AD.
HO
OH
O OH
102
The substrate for the Sharpless AD was, in fact the ethyl ester 104 of the α,β-unsaturated
acid 102. This was dihydroxylated using AD-mix-α and then the ester 105 was hydrolysed using
barium hydroxide. Before the resulting acid was coupled with alcohol 101, the diol functionality
was protected as an acetal 106. The coupling was performed using DCC and DMAP and the
protecting group was removed under acidic conditions to give indicine 100.
EtO
HO H
O
MeO OMe
cat. HCl
N
HO 2C
O
Sharpless AD
When fi tting olefi n 104 into the pocket provided by the mnemonic device we notice that the
isopropyl group and the ester function in olefi n are of similar size. As a result, we might expect
the ee to be low and yet 90% is achieved.
The synthesis of a C 2-symmetric piperidine
O
O
100; indicine
AD-mix-α
OH
O
OH
EtO
Sharpless AD
O
OH
HO H
When we think about retrosynthesis, two 1,2-related oxygen atoms, each on stereogenic carbon
atoms, as in 100, may scream to be ‘retro-dihydroxylated’ but it is harder to spot where the strategy
may be useful if there is only one oxygen atom or where heteroatoms are not even 1,2-related.
Consider, for instance, the C 2-symmetric 2,6-disubstituted piperidine 27 108. We notice for a start
that the two oxygen atoms are most certainly not 1,2-related. At best they are 1,5. Both the oxygen
atoms are 1,2-related to the nitrogen atom however. Two carbon – nitrogen bonds can be disconnected
at once to give the tosylated tetraol 109. We are going to have to think about protection
OH
104 105; 81% yield, 90%ee
(+)-106; 76% yield
C–O
ester
1. DCC, DMAP
cat. H +
2. (+)-100
OH
HO H OH
+ HO
N
101
N
HO
O
O
103
Ba(OH) 2·8H 2O
107
O
O
HO
O
O
O
102
H +
OH
OH
OH
(–)-102; 96% yield
100
84% yield

ecause the secondary alcohols are the ones that need to be tosylated – we will worry about that in
the forwards synthesis. As the tetraol 110 is C 2 symmetric it could be made by bis dihydroxylation
of diene 111 using the same asymmetric ligand.
HO
N
Bn
108
OH
OH OH
HO OH
Diene 111 was dihydroxylated using AD-mix-β to give the C 2 symmetric tetraol 110 and its
meso diastereomer 114 in a combined yield of 87%. The primary hydroxyl groups are selectively
protected using TBDMS chloride and imidazole – otherwise they would react with tosyl chloride.
The secondary alcohols are then activated with tosyl chloride to yield 113 and meso isomer in 47%
yield from the tetraol. Reaction with benzylamine yields the target material 108 in 47% and the
unwanted meso amine 115 in 30% yield.
111
TsCl
Et 3N
AD mix β
Take particular note that two hydroxylations are done on the same substrate 111 at the same time.
We will not dwell too much on this here, but from the point of view of enantiomeric excess this is an
aspect of asymmetric methodology that can be very useful. See Double Methods in chapter 28.
The synthesis of the alkaloid reticuline
2 x C–N OTs OTs
FGI
OTs OTs
TBDMSO OTBDMS
113; 47% yield
HO OH
Sharpless AD
If it is diffi cult to spot where a product results from a dihydroxylation because there is only one
oxygen in the product then it must be even more diffi cult to spot when there are none. Reticuline
117 is a natural product which can be used in the synthesis of morphine 116.
HO
O
HO
25 Applications of the Sharpless AD Reaction 545
110, 87% yield
109
110 111
TBDMSCl
imidazole
OH OH
TBDMSO OTBDMS
1. Ph NH2 2. deprotect
112
OH OH
HO OH
HO
N
OH
114 Bn 115
NMe
116; morphine
MeO
OH
NMe
OH
TM 108
47% yield
OMe
117; (R)-reticuline

546 25 Asymmetric Induction II Asymmetric Catalysis
We will come onto the stereochemistry in just a moment but fi rst we can simplify the structure
by disconnecting the six-membered amine ring. We should be able to make this C–C bond 117a
using a Friedel-Crafts reaction. Right, we notice that there is no oxygen functionality involved in
reticuline’s one chiral centre. If we are to use a Sharpless AD reaction then the fi rst thing to do is
to put in some oxygen functionality.
The C–N bond of the amine can now be disconnected 118. If we imagine that it was introduced
by an S N2 displacement, then we invert that stereocentre and introduce an oxygen-based leaving
group to give the diol 119. Now we have the sort of compound that we are looking for! We can
instantly see that this comes from the corresponding stilbene 120. Notice that the hydroxyl groups
in 120 are homotopic and that the diol 119 is C 2 symmetric.
MeO
OH
OH
OH
OMe
Sharpless AD
OH
MeO
119 OH 120
The stilbene 121 (which is dibenzylated 119) is dihydroxylated to yield diol 122 in 82% ee and
88% yield. This diol needs to be activated. It is reacted with SOCl 2 to yield a cyclic sulphite which is
oxidised to cyclic sulphate 123. This is redrawn as 123a. Both cyclic sulphites and cyclic sulphates
are very useful synthetic building blocks with, of course, two electrophilic carbon atoms. 28 The two
benzylic oxygen atoms here are homotopic so attacking either benzylic position will yield the same
enantiomer of product. In fact a protected aminoaldehyde was used as nucleophile as this makes
the cyclisation easier. 29 This and the deprotection steps are given in detail in the Workbook.
MeO
MeO
123
OBn
MeO
OH
MeO
121
NMe
117a
NHMe
OH
OBn
OMe
AD
(MeO)2CH
MeO
OMe
1. C–C
Friedel
-Crafts?
2. FGA
Ar
NMe
OH
OH
MeO
OH
Ar
122; 82% ee
X
OBn
OBn
124; 65% yield from diol
OH
1. SOCl 2
Et 3N
2. RuCl 3
NaOCl
OMe
NMe
118
Ar
OH
OH
O SO2
Ar
OH
OMe
=
C–N
S N2
OMe
O O
S
O O
O Ar Ar
123 123a
117
(R)-reticuline

Note that to keep a straight carbon chain in our drawing of the cyclic sulfate 123a we need
to draw the two S–O bonds in a very curvaceous way 123. This technique is often used to keep
emphasis on the syn nature the two hydroxyl groups of diols when the diols are converted to cyclic
sulfates or acetals.
The disconnection we used to plan the synthesis of reticuline is rather unusual. Reticuline is often
drawn in a way 117b that is rotated clockwise by 60 from the way drawn above 117a. The disconnections
are more often a C–C disconnection between the aromatic ring and an imine resembling
the Mannich reaction as the imine is formed by the attack of an amine 125 on an aldehyde 126. This
is an easy reaction to carry out but it forms two bonds and a chiral centre all in one step and is diffi
cult to make asymmetric. Because we wanted to use AD, we needed a different disconnection.
Dihydroxylating Compounds with More than One Double
Bond I—Regioselectivity
Here we think about which double bond will be dihydroxylated if a molecule contains more than
one. We postpone the question of how one already dihydroxylated double bond infl uences the diastereoselectivity
in the dihydroxylation of a second double bond until the next section.
If there is more than one double bond in a molecule then, unless we have something like a
symmetrical diene, there will be a question of regioselectivity. Predicting that regioselectivity can
be a bit of a minefi eld and you need to know what you’re doing. 12 In this section we will deal with
some of the simpler guidelines. The Workbook deals with some of the more subtle rules and fi ner
methods. We start with dienes.
Dienes
25 Dihydroxylating Compounds with More than One Double Bond I—Regioselectivity 547
MeO
HO
H
117b
NMe
OH
OMe
C–N
C–C
MeO
NHMe
With two double bonds only, we need to worry about two main things – whether or not they are
conjugated to each other, and whether or not they are equivalent from a symmetry point of view
127 – 130. A substrate may contain two double bonds which are – because they are related by
a symmetry element that makes them so – equivalent. Then they may be conjugated or not. The
double bonds may, of course, be different electronically and/or sterically. For the sake of strategy
we must have some idea how one double bond reacts in the presence of another. For the moment
we will concern ourselves only with monodihydroxylation of dienes and outline a few guidelines.
Guidelines are not rules. For a given substrate, the Guidelines may support each other or they may
confl ict with one another. In the latter case, predicting what will happen can be a bit tricky!
127
conjugated
and equivalent
Mannich
style
128
non-conjugated
and equivalent
HO
+
CHO
125 126
129
conjugated
and non-equivalent
OH
OMe
130
non-conjugated
and non-equivalent

548 25 Asymmetric Induction II Asymmetric Catalysis
Guideline One. – Double bonds which are trans-di- 131 or tri- 132 substituted react faster than
those which are either cis-di- 133 or mono- 134 substituted. The simple diene 135 reacts regioselectively
at its trans double bond when it is dihydroxylated using (DHQD) 2PHAL as the ligand.
Guideline Two. – Electron-rich double bonds react in preference to more electron-defi cient double
bonds. You can see that this is partly responsible for Guideline One but the principle extends
beyond this. The benzoate ester 138 contains two trans double bonds but one is evidently much
more reactive than the other. The double bond on the left is part of an allylic ester and is deactivated
by the electron-withdrawing benzoate group.
Ph
O
131
132
allylic portion
O
>
>
138
133
134
AD
(DHQD) 2
-PHAL
BzO
Guideline Three. – In a conjugated system, the double bond that reacts will be the one that
leaves the most conjugated system behind. This means that the double bonds at the end of a conjugated
system are the more reactive. Conjugated diene 141 has one ‘end’ only because the benzene
ring is included in the conjugated system but is not reactive. It is perhaps worth noting that in a
simple conjugated system – like, for instance, octatetraene – the highest HOMO coeffi cient and
the highest LUMO coeffi cient will both be on the terminal carbon.
This guideline predicts that dihydroxylation of the diene 141 would give the diol 142 as the
main product. 30 This is indeed the case but, as we shall see, this selection is easy to overturn. In
this case, if the bulk of the aromatic ring is increased then the selectivity is reversed.
Guideline Four. – Other Guidelines being equal, the least hindered double bond will react
preferentially. 30 Thus 130 gives mainly 144.
OH
OH
BzO
+
OH
OH
OH
139 14:1 140
AD
+
(DHQD)2
-PHAL
OH
141 142 4:1
143
AD
(DHQD) 2–PHAL
135
130 144 20:1 145
AD
OH
OH 3 : 1
136; 90% ee 137; 72% ee
OH
OH
+
+
HO
OH
OH
OH
OH
OH

25 Dihydroxylating Compounds with More than One Double Bond I—Regioselectivity 549
When guidelines combine or compete
Combinations of these simple systems can be seen. Triene 146 has three different sorts of double
bond—a cis, a trans and a terminal double bond. Which of these will react preferentially? Two
of the guidelines come into play here. We have a conjugated system and so we would expect one
of the double bonds at the end of that system to react by Guideline Three. However, Guideline
One tells us that double bonds which are trans-di- substituted are more reactive than those
which are either cis-di or mono- substituted. So maybe the triene reacts in the middle! The
answer is, in fact, that it reacts at the right hand end. Conjugation is more important than alkyl
groups. 30
A synthesis of aspicillin
C5H11 AD with (DHQD)2-PHAL C5H11 OH
0 ˚C
146 147
In the synthesis of ()-aspicilin 148, a lichen macrolide, by Sinha and Keinan 31 all the chiral
centres were introduced using the AD reaction. An intermediate in the synthesis of this compound
was compound 149.
If we draw the carbon backbone of 149 in a slightly straighter fashion 149a it’s easier to see the
retrosynthetic step that follows. This means that we are forced to draw the acetal 150 in the same
distorted way that we used with cyclic sulfates. We can install the diol at the end of the molecule
using AD-mix-α.
O
O
O
O
O
O
OH
OH
OH
OH
OH
148; (+)–aspicilin 149
AD-mix-α
149a 150
We can then remove both of the acetal protecting groups to reveal the tetraol 151. The stereochemistry
of both the diols in 151 demands the use of AD-mix-β on 152.
O
O
O
O
O
OH
OH
O
O
OH
O

550 25 Asymmetric Induction II Asymmetric Catalysis
150
1,1-diX
acetals
It is when we look at the synthesis in the forward direction that we see just how clever it is.
We react triene 152 with AD-mix-β and there are three double bonds which could react. There
are two terminal double bonds and one trans double bond. Guideline One would suggest that the
fi rst double bond to react would be the trans one to give product 153. Sinha and Keinan 31 who
thoroughly investigated the dihydroxylations of this triene, found that this was indeed the case.
The diol forms with a 96% enantiomeric excess. We are then left with two terminal double bonds.
Which of these will react? In a conjugated diene, the dihydroxylation of one double bond reduces
the reactivity of the second one considerably. Hence the second dihydroxylation yields mostly 151
which is formed with an 86% diastereomeric excess. The tetraol is protected before we react the
fi nal double bond with, this time, AD-mix-α.
152 AD-mix-β
OH
OH
153; 96% ee
This synthesis uses both enantiomeric asymmetric dihydroxylation reactions. They are used
successively to exploit the regioselectivity dictated by the inherent relative double reactivities. For
certain substrates this makes the asymmetric dihydroxylation a tremendously powerful reaction.
Designer ligands to improve selectivity
It is also possible to select our regioselectivity by the synthesis of ‘designer’ ligands. Corey 32 has
synthesised a ligand which provides superior selectivity for some substrates. One difference is
that, rather than having the methyl ether of the quinoline ring we fi nd in quinine, it has a 4-heptyl
ether. The idea is that this further sterically encumbers the ligand.
One might imagine that regioselectivity in the case of either geranyl geranyl acetate 154 (with
four double bonds) or squalene 155 (with six double bonds - notice the symmetry here) would be
a tricky business.
I II
III
OH
OH
OH
OH
AD-mix-β
151 152
AD-mix-β
151
86% de
It is. If squalene 155 is mono-dihydroxylated with OsO 4 using (DHQD) 2PHAL as the ligand,
the three double bonds I, II and III react in a ratio of 2.4:1.8:1.0. If no ligand is present at all
they react in a ratio of 1:1:1 but with Corey’s ligand, reaction of double bond I and the sum of the
reactions of II and III give a product ratio of 8:1.
OAc
acetal
150
AD-mix-α
154; geranylgeranyl
acetate
155
squalene
149

25 Dihydroxylating Compounds with More than One Double Bond II—Diastereoselectivity 551
Dihydroxylating Compounds with More than One Double
Bond II—Diastereoselectivity
There are two main issues here. Firstly, if one of two double bonds has reacted, does the remaining
one become more or less reactive than it was in the fi rst place? Secondly, how does the stereochemistry
of the fi rst dihydroxylated double bond infl uence the stereochemistry of subsequent reactions?
The factor that has the biggest infl uence - at least on the fi rst of these questions - is the solvent
system that is used. Up until now we have been looking at the regioselective monodihydroxylation
of substrates containing more than one double bond. The solvent system that we have used has
been the biphasic tert-butanol and water system.
Advanced dihydroxylation strategy
Just have a look at cyclododecatriene 156. It has twelve carbon atoms, two trans double bonds and
one cis double bond. This compound, with its three double bonds, presents us with all sorts of
opportunities. 33 The fi rst thing to realise is that the trans double bonds will react with OsO 4 more
quickly than the cis double bond. In fact, both the trans double bonds will react before the cis
double bond. We can dihydroxylate 156 to give us the diol 157. A better ee is obtained (94%) when
this reaction is allowed to go to completion because the minor enantiomer is removed by kinetic
resolution. The phenomenon of enantiomeric enhancement by kinetic resolution and the idea of
match/mismatch in the context of a diol substrate with AD reagents are explored in Chapter 28.
OsO 4
(DHQD) 2PYR
There is clearly an option for further dihydroxylation. The diol can be protected and how we
protect it depends on the dihydroxylation we want to do next. It turns out that the disilyl ether 158
is matched with (DHQ) 2PYR whereas dioxolane 159 is matched with (DHQD) 2PYR. Hence we
may, by judicious protection, maximise subsequent stereoselectivity. Obviously, the disilyl ether
of the enantiomer of 157 would be matched with (DHQD) 2PYR and the enantiomer of dioxolane
159 with (DHQ) 2PYR.
Matched with
(DHQ)2PYR
RO
OR
The major product from the dihydroxylation of 159 is the partially protected tetraol 160. If
this were deprotected it would form the C 2 symmetric tetraol 162. Note that 162 results from two
HO
OH
156 157; 84% yield, 94% ee
Matched with
(DHQD)2PYR
O
158; R = TBDMS 159
O
OsO 4
(DHQD)2PYR
HO
HO
O
O
+
HO
HO O
160 99:1 161
O

552 25 Asymmetric Induction II Asymmetric Catalysis
successive treatments of dodecatriene 156 with OsO 4 in the presence of (DHQD) 2PYR. If we
wanted to make tetraol 163 – which is achiral – we would be advised to use diether 158 and treat it
with OsO 4 and (DHQ) 2PYR before deprotection. This chemistry is explored in the Workbook.
Scaling Up the Asymmetric Dihydroxylation
This important reaction has been applied on a large scale by the pharmaceutical industry. The
amplifi cation of chirality from small amounts of catalyst and the minute amounts of osmium make
it very attractive but the expense of K 3Fe(CN) 6 and the diffi culty of removing it from the reaction
mixture on a large scale suggest using NMO instead. The by-product is then the simple amine
N-methylmorpholine that can simply be extracted in the workup as can the ligand. The fi rst of
these examples was a 2.5 kg reaction 34 while the second gave 42 kg of crystalline diol 166 in
98% ee from methyl trans cinnamate. 35
MeO
O
K 2OsO 2(OH) 4
MeO
PART III – AMINOHYDROXYLATION
Not content with revolutionising the world of asymmetric synthesis with the catalytic
asymmetric epoxidation reaction and the asymmetric dihydroxylation, Sharpless went
on to develop the asymmetric aminohydroxylation 36 (AA). This is very similar to the dihydroxylation
except one of the oxygen atoms is replaced with a nitrogen atom in the product
169. This complicates matters because we may have the additional question of regioselection.
You will now be familiar with all of the ingredients in the reaction – K 2OsO 2(OH) 4 is
the source of OsO 4 although the reactive species in this reaction is not OsO 4 since one of
those oxygen atoms has to go. The ligand is the familiar double cinchona ligand (DHQD) 2-
PHAL 93 as is the mixture of alcohol and water (though isopropanol is used in this case)
for the solvent. The one new component is the source of nitrogen. This is chloramine-T
167 (the sodium salt of N-chloro-p-toluenesulfonamide). 37 Here is a typical asymmetric
aminohydroxylation reaction.
R
82 g (DHQD) 2PHAL
NMO 87
t-BuOH, H2O 164 165
R
+
HO OH
HO OH
HO OH HO
OH
O O
S N
Cl
Na
167; chloramine-T
162 163
OH
O
cat. K 2OsO 2(OH) 4
ligand
i-PrOH, H 2O
OH
Ts
R
NH
OH
CO2Me
OH
166; 42 kg, 70% yield
>98% ee (crystals)
OH
R
R
NH 2
168 169
OH
R

The reaction in the box below shows a typical AA with methyl cinnamate as the substrate.
Methyl cinnamate 170 reacts in moderate yield and good, though not spectacular ee. Well never
mind, this is a powerful transformation and not to be sneezed at. And from a practical point of
view, it is often the case that the resulting amino alcohols can be recrystallised to very high ee.
Note the regioselection in the reaction. With a cinnamate (or other α,β-unsaturated carbonyl
compound) we have a nicely differentiated double bond which, in the absence of symmetry, is
much better than two ends of a double bond that are only slightly different. We fi nd the nitrogen
atom bound to what was the more electrophilic end of the double bond 171. This is a handy
mnemonic for the selectivity with a standard ligand – the more nucleophilic nitrogen atom binds
to the more electrophilic end of the double bond (though, of course, it is only a mnemonic and not
any sort of explanation). Three alternative nitrogen sources are 172 – 174 (but there are plenty
more). While chloramine-T 167 and N-chloromethylsulfonylamide 172 are added to the reaction
as salts, the carbamate salts (BocNClNa 173 and CbzNClNa 174) are prepared in situ from the
carbamates.
Ph
O
Ts
NH O
OMe Ph
OMe
OH
Boc N Cbz
Cl
N Ms
Cl
N 168; chloramine-T
4 mol% K2OsO2(OH) 4
Cl
172
170
5 mol% ligand 92
room temperature
i-PrOH, H2O 171; 60% yield, 82% ee
173
174
Incredibly, changing the ligand to (DHQD) 2-AQN 94 gives us the opposite regioselection
(regioisomer 175) and yet the ee is similar to that obtained with (DHQD) 2-PHAL and the same
enantiotopic side of the double bond attacked.
Ph
25 Scaling Up the Asymmetric Dihydroxylation 553
170
O
OMe
168; chloramine-T
4 mol% K2OsO2(OH) 4
5 mol% ligand 93: (DHQD) 2-AQN
room temperature
i-PrOH, H 2O
The reaction also scales up nicely 38 – using N-bromoacetamide this time – and in a reaction that
was 630 times larger than Sharpless’ standard mmol scale reaction, 120g of isopropyl cinnamate
was reacted to give acetamide 177. The yield is good and the ee excellent. Hydrolysis of both the
ester and the amide give (2R, 3S)-3-phenylisoserine 178 which is a precursor to one of the side
chains of Taxol. ® The β-amino alcohol function is found in many biologically active compounds
and this catalytic reaction will be attractive to process research groups.
Medium Scale
O
AcNHBr, LiOH
NHAc O
1.5 mol% K2OsO2(OH) 4
Ph Oi-Pr 1 mol% (DHQ) 2PHAL, 92
t-BuOH, H2O, 4 ˚C
Ph
OH
Oi-Pr
176; 120 g 177; 71% yield, 99% ee
Many of the application of AA have used conjugated alkenes but simple, even mono-substituted
alkenes such as 179 can be used providing there is some defi nite difference between the
ends - here with this naphthalene compound 180 between no substituent and an aromatic ring. The
synthesis of lactacystin using AA is described in chapter 31.
Ph
OH
O
NHTs
175
OMe
NH 2
O
Ph OH
OH
178

554 25 Asymmetric Induction II Asymmetric Catalysis
Aminohydroxylation is the least well developed of the methods in this chapter but in many
ways the most promising. Research continues. We shall now return to epoxidation as this is an
alternative route to unsymmetrically substituted derivatives.
PART IV – CONVERTING 1,2-DIOLS INTO EPOXIDES
We have already seen how cyclic sulfates such as 123 can be converted into amino alcohols that might
have been made by amino hydroxylation. The conversion of 1,2-diols, made by the AD reaction, into
epoxides has been very widely used. A combination of acetyl bromide and an orthoester gives a bromoacetate
via an oxonium ion 182. The ion is formed with retention, bromide opens it with inversion at
the benzylic centre, and epoxidation in base inverts it again. The net result is retention. 39
Ar
OH
OH
AcBr
MeC(OMe) 3 Ar
O
OMe
Applications of the AD to epoxide transformation: propranolol and diltiazem
O
We return to two compounds we made earlier by the AE reaction: propranolol 7 and diltiazem 67.
In both cases the synthesis is easier as we do not have to start with an allylic alcohol. The synthesis
of propranolol 41 uses the allyl ether 188 that gives the diol 189 with good ee in the AD reaction for
a monosubstituted alkene. Transformation to the epoxide 190 shows no loss of ee. Reaction with
i-PrNH 2 was already known to give propranolol 7. This is a very short synthesis from easily made
starting materials.
Br
Ar
Br
OAc
K 2CO 3
MeOH Ar
181 182 183 184
It seems at fi rst that regioselectivity is going to be a problem with diols such as 79 but this is not
the case. A mixture of bromoesters 185 and 186 is indeed formed but both give the same epoxide
187 in base as each centre undergoes either no change or a double inversion. The result is again
retention at both atoms and we have made the epoxide 187 from the alkene 79 asymmetrically. 40
R1 R2 AD
R1 R2 OH
AcBr
MeC(OMe) 3 R
OH
1
R2 Br
R
OAc
1
R2 OAc
K2CO3 MeOH
Br
R1
R2 +
O
79 ent-80 185 186 187
O O
188
179
AD-mix-β
Boc N Cl 174
4 mol% K2OsO2(OH) 4
1 mol% (DHQ) 2PHAL, 92
MeCN, H 2O, 4 ˚C
OH
189; 90% yield, 91% ee
OH 1. AcBr
MeC(OMe) 3
O
2. MeOH
K 2CO 3
BocNH
180; 70% yield, 98% ee
OH
O
O
190; 92% yield, 91% ee

The synthesis of diltiazem 42 starts with the cinnamate that was actually used to make the allylic
alcohol 62, the substrate for the AE route described above. No special extra inversion is required
here if the intermediate 193 is used as the electrophile rather than the epoxide derived from it.
Again, this is shorter and simpler than the previous synthesis.
MeO
NH 2
S
CO2Me
MeO
However, it would be better if we had an asymmetric epoxidation that, unlike AE, did not
require any particular functionality. We do: it is the Jacobsen epoxidation, the third of the great
triumvirate of catalytic reactions in this chapter.
PART V – JACOBSEN EPOXIDATION
NH2
S
OAc
CO 2Me
CO 2Me
AD
OH
MeO
MeO
191 192; 80% yield, >97% ee 193
194
The catalyst in this type of epoxidation is a salen, that is a compound derived from a salicylaldehyde
and a diamine. 43 One of the best is 198, made from the substituted salicylaldehde 197
and the tartrate salt of the C 2 symmetric diamine 196 that results from a very simple resolution
(chapter 22). There are others: they are all C 2 symmetric salens made from C 2 symmetric diamines
and have large groups on the two benzene rings.
H 3N NH 3
193
t-Bu
CHO
t-Bu
The active catalyst is a Mn(III) complex 199 of the salen used at 1 mol% or less. The
stoichiometric oxidant is bleach (NaOCl) and again a two-phase system (CH 2Cl 2 and water) is
best. Various additives such as pyridine-N-oxides improve performance.
OH
MeO
195 62; diltiazem
OH
HO OH
EtOH, H2O, K2CO3, 80 ˚C
t-Bu OH HO
t-Bu
O 2C
196
25 Scaling Up the Asymmetric Dihydroxylation 555
CO 2
197
H H
N
t-Bu
N
t-Bu
198; 95-99% yield
S
O
Cl
OAc
N
O
R
OMe
CO2Me

556 25 Asymmetric Induction II Asymmetric Catalysis
The Jacobsen method gives very good results with cis-alkenes, including cyclic alkenes, and
trisubstituted alkenes. But is not so good with trans alkenes. Typical ees for these three classes of
alkenes are shown for 200 to 202.
Two phase system: water and CH 2Cl 2
Stoichiometric oxidant: NaOCl
Catalytic salen complex (

MeCN
H 2SO 4
SO 3
3 mol% 203
N
O
Me
Another important application is the asymmetric epoxidation of cis cinnamate esters 210. They
are poor substrates for AD and the allylic alcohols derived from them by reduction are poor
substrates for AE. Jacobsen epoxidation gives epoxides in good yield (90%) but not all is the
cis-epoxide 211. There is some leakage to the trans epoxide 212 a typical ratio of 211:212 being
5:1. The cis epoxide is formed in excellent ee but the trans epoxide in only moderate ee.
Ph CO2Et
206; indene
208
NaOCl, CH2Cl2, 0 ˚C
0.6 mol% salen catalyst
NaOCl (13 mol%), 203 (1 equivalent)
(R,R)-199 (5 mol%), ClCH 2CH 2Cl, 4 ˚C
Electron-donating groups on the benzene ring improve the cis:trans ratio and iso-propyl esters
improve the ee. This make for a simple synthesis of diltiazem 62: a compound we have already
made by AE and AD. Epoxidation of 213 gives a reasonable yield of nearly enantiomerically pure
cis-epoxide 214 (only 10% of the trans epoxide is formed).
The epoxide is opened regioselectively with the anion of the nitrobenzene thiol 66 and the rest
of the synthesis is essentially as described earlier (reduction, cyclisation, addition of substituents
to O and N).
H2O
N O
tartaric acid
NH2
O
207; 71% yield
84-86% ee
OH
209; 50% overall yield,
>99% ee on 600 Kg scale
Ph CO2Et
O
Ph
O
CO2Et
210 211; 93% ee 212; 50-60% ee
MeO
NO 2
SH
25 Scaling Up the Asymmetric Dihydroxylation 557
213
214
NaHCO 3
CO 2i-Pr
MeO
66 215
NaOCl
(R,R)-199 (5.5 mol%)
3 mol% Me N O
NO2
S
OH
CO2i-Pr
MeO
+
CO 2i-Pr
O
214; 62% yield, 96% ee
S
O
N
O
R
62; diltiazem
OMe
OMe

558 25 Asymmetric Induction II Asymmetric Catalysis
Other improvements include the development of more sterically hindered ligands 46 and changes
in oxidant to mCPBA and NMO to give effi cient asymmetric synthesis of monosubstituted epoxides.
47 The asymmetric epoxidation of dimethylchromenes such as 216, a previously problematic
task, is easy with Jacobsen epoxidation and these epoxides such as 217 have been used to make
calcium channel antagonists 218.
NC
216
PART VI – DESYMMETRISATION REACTIONS
So far we have looked largely at substrates which are fl at achiral objects that have chiral centres
introduced by means of a reagent. Desymmetrisations are slightly different. Molecules which are
desymmetrised tend to be of a meso type. That is, they are achiral because they have a mirror
plane and the sides of the molecule contain left and right handed portions 219. This is in contrast
to the C 2 axis present in many catalysts such as the TADDOLate 218. Desymmetrisations are
powerful because there may be several chiral centres embedded in an achiral molecule which
suddenly become much more useful in the newly formed chiral molecule. There are a large variety
of symmetrical substrates that have been enantioselectively desymmetrised 48 and we look at a few
of the more important classes.
C 2symmetric
TADDOLate
218
O
Opening anhydrides
O
O
Jacobsen
epoxidation
(S,S)-199
(3.7 mol%)
Ar Ar
H
O
Oi-Pr
Ti C2 axis plane
O Oi-Pr
H
Ar Ar
For example, acid anhydride 219 is achiral and the molecule can be drawn above to highlight the
mirror plane running through it. It has an R and an S chiral centre, one on either side of the mirror.
The anhydride can be cleaved with Al(Oi-Pr) 3 in a reaction catalysed by a titanium TADDOLate
218. The resulting ester 49 220 is formed in 88% yield and 88% ee.
O
219
O
O
NC
O
90 mol% (i-PrO) 3Al
THF, –20 ˚C
O
217; 96% yield, 97% ee
10 mol% TADDOLate 218
ArOH
NC OH
O
O
O
(R)
H
H
(S)
CO2H
CO2i-Pr
220; 88% yield
88%ee
O N N Me
O
218; 85% yield, 97% ee
O
mesoanhydride
219

We have seen much of quinine and quinidine in this chapter alone. They are among those
‘privileged structures’ which seem to turn up time and again as being useful for asymmetric
reactions. Oda 50 had found that 10% of guinidine would catalyse the opening of anhydride
221. The trouble was that the ee of the ester 222 was modest (67%) and the reaction took
4 days.
221
Bolm 51 was able to improve matters by piling in the quinine (so that over an equivalent was
used – 110%) which enabled the reaction of anhydride 223 to be done at a lower temperature (giving
a better ee) in a mere 1.5 days. The pseudo-enantiomer quinidine could also be used to give ester
224. A range of rings 225 to 229 works.
CO2Me
223; 85% yield, 98%ee
Ph
CO2H
O O O O O O O
O
O
O
225 226 227 228 229
But matters were really signifi cantly improved by Chen et al. 52 If one cinchona alkaloid works,
what about the double cinchona alkaloid ligands that are used in the asymmetric dihydroxylation
reactions? Amazingly, these ligands work really well for desymmetrisations of anhydrides such as
230. Only 5% of catalyst is needed and they can be done at room temperature or 20 C for better
enantiomeric excess. Once again a range of anhydrides can be used 232–234.
230
Opening epoxides
O O O
O
O
25 Scaling Up the Asymmetric Dihydroxylation 559
O
H
MeOH in
toluene/CCl 4 –50 ˚C
219
110% quinine 110% quinidine 1.5 days
OH
MeOH in
toluene/CCl 4 –50 ˚C
232 O 233 O 234
H
O
O
MeOH in
Toluene room temperature 222
10% Quinidine / 4 days
HO2C CO2Me 100% yield
67% ee
5 mol%
(DHQD) 2AQN
O
O
Another privileged structure is the salen complex we have already seen as the catalyst 199 for
Jacobsen epoxidations. Here the equivalent cobalt complex 235 is used to catalyse the opening of
an achiral epoxide. 53
O
O
O
O
CO2Me
CO2H 224; 83% yield, 98%ee
MeOH / toluene
231; 85% ee
room temperature
2 hours
or
CO2H 100% yield (based
on SM consumed)
or
MeOH / Et2O –20 ˚C
CO2Me
231
93%yield,
98% ee
O
O
O
O
O
O

560 25 Asymmetric Induction II Asymmetric Catalysis
Cyclohexene oxide 236 is opened with benzoic acid catalysed by 2.5% of the cobalt salen complex
235 to give the asymmetric half ester 237. Although the ee is only 75% this is improved by
recrystallisation to 98% ee. Epoxides on other ring sizes can also be opened enantioselectively.
OH
OH
238; 98% yield
94% ee
oligomeric Co
salen
O
PhCO2H 2.5% Co catalyst 235
i-Pr2NEt 0– 4 ˚C
OH
O
O
recrystallise
Ph
237
75% yield
98%ee
236 237; 98% yield, 77%ee
The (very useful) hydrolysis of cyclohexene oxide 236 to give the C 2 symmetrical diol 238
is diffi cult with the standard Co salen 235. However, this reaction can be achieved in high yield
and enantiomeric excess with a special oligomeric form of the salen. 54 The oligomeric form simply
contains several salen complexes connected together in each molecule. This has enhanced
reactivity for certain reactions. Reactions which proceed exceptionally well with a dimeric form of
the catalyst are believed to make use of two active sites and thus benefi t from the entropic advantage
of having them both in the same species. 55
Comparison of desymmetrisation and kinetic resolutions
As we shall see further in Chapter 28, a kinetic resolution is the more rapid reaction of one enantiomer
of starting material over the other. In the absence of anything fancy (like a dynamic kinetic
resolution) they are limited to 50% yield of product (or starting material). But because a desymmetrisation
starts with one achiral molecule (instead of a pair of enantiomers) this limitation is
removed as are other complications we face in kinetic resolutions such as the build up of the wrong
enantiomer which makes selectivity more diffi cult. However, it is worth noting that desymmetrisation
and kinetic resolutions are brothers in the stereochemical world.
OH
t-Bu
OH OH
H H
N N
OH OH
kinetic resolution
+ +
Co
O O
t-Bu t-Bu
(S, S)-235
R-239 S-239 R-239
S-240
desymmetrisation
t-Bu
OH OAc
241 242
OAc

Consider, for example, a hypothetical kinetic resolution of enantiomers (R) and (S)-239 by
esterifi cation of one of them. Compare this to the esterifi cation and desymmetrisation of diol 241.
In many ways, a desymmetrisation is a kinetic resolution but with the two enantiomers joined
together in the same molecule. The features that make a reagent work well in a desymmetrisation,
may well make it work in a kinetic resolution. Indeed, in Double Methods in Chapter 28 we see
that this is the case.
Mono esterifi cation of diols
Diol 241 is very enantioselectively acylated with 1% of Fu’s chiral 56 version 243 of DMAP 244.
The enantiomeric excess is a staggering 99.7% ee. Other, rather less fancy, chiral nucleophilic
catalysts 57 have been used very effectively including pyrrolidine derivative 247 for the asymmetric
benzoylation of 245.
241
1 mol% 243
Ac 2O, 0 ˚C
NEt 3, t-AmylOH
OH
OH OAc
OH
PhCOCl, Et3N OBz
245 246; 83% yield
96% ee
PART VII – HETERO DIELS-ALDER REACTIONS
Hetero-Diels-Alder reactions are not as straightforward as ordinary Diels-Alder reactions. In an
ordinary (normal electron demand) Diels-Alder reaction we are accustomed to having an electronrich
diene and an electron-defi cient dienophile. In asymmetric catalysis, early successes with a
hetero-Diels-Alder reaction 58 typically needed a very electron rich diene, such as Danishefsky’s
diene 248, or very electron defi cient dienophiles like a glyoxylate 249.
very
electron-rich
dienes
e.g. 248
25 Scaling Up the Asymmetric Dihydroxylation 561
0.5 mol% 247
Me 3SiO
242; 91% yield
99.7% ee
In the example below with a modifi ed Danishefsky’s diene 59 250, the asymmetry comes from
a menthyl auxiliary while the reaction is catalysed by a europium complex. The ee (determined
on a subsequent fragment) is a modest 27% but can be dramatically improved by using an
OH
N
N RFe
R
243 R
usual hetero-Diels-Alder reactions
OMe
and/or
R
O
OEt
O
247
R
N
Me
R
Me Me
N
Me
N
N
244; DMAP
Bn
very
electron-deficient
dienophiles
e.g. 249

562 25 Asymmetric Induction II Asymmetric Catalysis
optically pure catalyst, Eu(hfc) 3, in the reaction together with the auxiliary. Excellent yield
and enantiomeric excess have been achieved using a copper catalyst featuring a bisoxazoline
ligand 60 but again we see a very electron-rich diene 248 coupled with a very electron-defi cient
dienophile 252.
Me 3SiO
A further complication is whether the HDA reactions really proceed by a pericyclic mechanism
or whether they are stepwise reactions (aldol then cyclisation). Both are conceivable and
possible. 61 The salen complexes like those of Co 235 or Mn 199, but this time with chromium at
their heart, catalyse the reaction of Danishefsky’s diene and benzaldehyde. 62 The yield and ee are
excellent and the reaction works with a variety of aldehyde dieneophiles and, although the ee’s
are not always spectacular, the products can sometimes be recrystallised to high ee. The question
of [42] versus aldol-then-cyclisation is also addressed. The intermediate compound that would
be expected from the aldol reaction was found not to cyclise under the reaction conditions which
indicates that the [42] mechanism is active.
Me 3SiO
248
+
OMen
250; Men = menthyl
O
OMe
O
OMe
Ph
Ph
O
Me3SiO
O
248 252
Eu(fod) 3
OMe
2. 2% Cr Salen
–30 ˚C
2. H +
Me 3SiO Ph
O
This is all very well but what about using dienes which are more typically electron rich (with
one oxygen substituent instead of two) 255 in combination with normal aliphatic aldehydes 256?
A catalyst that could achieve this would be very useful. One solution is a modifi cation of the
chromium salen complex which replaces half the salen with an adamantyl group and the other
half with cis-aminoindanol 209. The synthesis of this complex 258 is straightforward since
commercially available compounds 257 and 209 are combined in high-yielding reactions and
the complex itself is impressively enantioselective. 58 The hexafl uoroantimonate catalyst 260 was
more enantioselective than the corresponding chloride 259.
O
O
OMen
251; 27% ee
1. 10% Cu bis-oxazoline
–78 ˚C to –40 ˚C
2. H +
Ph
254; 85% yield
87% ee
MeO
t-Bu
O
O O
Me
O
F F
F F
COMe
Me
H
+ Bu ?
O
Me
255 256
CF3
fod = 6,6,7,7,8,8,8-heptafluoro
-2,2-dimethyl-3,5-octanedionate
253; 96% yield
99% ee

Me
OH
257
2.
1. SnCl 4, (CH 2O) n
2,6-lutidine
Me
N O
Cr
O Cl
209
259; 99% yield
NH 2
OH
AgSbF6
N OH
OH
258; 88% yield from 257
The application of this catalyst is nicely illustrated in a synthesis of ambruticin. 63 Ambruticin
261 is an antifungal compound. The tetrahydropyran on the left hand side of the molecule and
the dihydropyran on the right both contain two stereogenic centres which could be controlled in a
hetero Diels-Alder reaction via 262 and 263.
OH
OH
The fi rst HDA reaction is between aldehyde 264 and diene 265 at room temperature. The
diene is reasonably electron rich and the aldehyde an ordinary aliphatic. Note that there are
no stereocentres that arise merely from stereospecifi c reactions of the substrates. The pyran
is formed in 97% ee and the subsequent hydroboration is regio- and diastereoselective to give
alcohol 267 as a single diastereomer. The other pyran ring (for the right hand side of ambruticin)
OTBDMS
RO
O
OBn
264; R=TBDPSi 265
25 Scaling Up the Asymmetric Dihydroxylation 563
OH
OH
room
temperature
10% ent-259
261; ambruticin
OR
OTBDMS
O
OBn
266; 64% yield, 97% ee
Me
1. BH 3 THF
2. H 2O 2
NaOH
Me
N O
Cr
O
260
OR
SbF 6
1. CrCl 2
2. air
3. 2,6-lutidine
H
O
O
O
O
CO2H O CO2H Me Me Me OH
262 Me
263
Me
Me
Me
OTBDMS
OH
O
OBn
267; 94% yield

564 25 Asymmetric Induction II Asymmetric Catalysis
is made in a very similar manner but using the other enantiomer of catalyst 259. This time the
yield was 87% and the ee 99%!
Several other interesting reactions are employed in the synthesis including an asymmetric
cyclopropanation and an asymmetric hydroformylation but we’ll end by highlighting the Kociénski-
Julia olefi nation. Rather than employing the ordinary sulfone of the Julia reaction 64 or the one-pot
(Sylvestre) Julia method 65 which employs benzothiazolyl sulfones, the Kociénski variant 66 uses a
tetrazole substituted sulfone 269 (chapter 15). The key advantage over the benzothiazolyl sulfone
being that the aldehyde and sulfone do not need to be premixed before the addition of base. The
E/Z selectivity by using LiHMDS in DMF/HMPA is very good at 30:1 but with NaHMDS
in THF the E/Z selectivity is reversed to 1:8. A lithiated tetrazolesulfone sporting a tert-butyl
267
1. TBSOTf
base, –30 ˚C
2. Pd/C, H2 3. NMO
cat. TPAP
OR
(as opposed to the phenyl group seen here) is even more stable. 67 Returning to the synthesis of
ambruticin – deprotection and oxidation of 270 gave the fi nal product 261.
Catalytic reactions look like the best bet for the future of asymmetric synthesis. In the next
chapter you will see how C– H and C–C bonds can also be made by catalytic asymmetric
reactions. The only limitation at the moment is the relatively small number of reactions that have
been developed. Some of those you have met in this chapter – Sharpless AE and AD and Jacobsen
epoxidation – are among the best.
References
OR
OTBDMS
OTBDMS
+
N
N
N
N
S
O CHO
Ph O O
268; R=TBDPSi
OTBDMS
OTBDMS
LiHMDS
DMF/HMPA
–35 ˚C
O
Me
Me
270; >30:1 E / Z
General references are given on page 893
1. R. A. Johnson and K. B. Sharpless, Ojima, Asymmetric, pages 231–285.
2. T. Katsuki, Ojima, Asymmetric, pages 287–325.
3. J. G. Hill and K. B. Sharpless, Org. Synth., 1985, 63, 66.
4. R. M. Hanson and K. B. Sharpless, J. Org. Chem., 1986, 51, 1922.
5. M. G. Finn and K. B. Sharpless, J. Am. Chem. Soc., 1992, 113, 113 and in Morrison, Vol. 5, pp. 247–308;
R. A. Johnson and K. B. Sharpless in Ojima, Asymmetric, pp. 271–2.
6. J. M. Klunder, S. Y. Koo and K. B. Sharpless, J. Org. Chem., 1986, 51, 3710.
7. B. E. Rossiter, T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 1981, 103, 464.
8. T. Katsuki, A. W. M. Lee, P. Ma, V. S. Martin, S. Masamune, K. B. Sharpless, D. Tuddenham and
F. J. Walker, J. Org. Chem., 1982, 47, 1378.
9. A. Fürstner and O. R. Thiel, J. Org. Chem., 2000, 65, 1738.
Me
O
Me
Me
Me
269
Me
2. TBAF
2. Pt, O 2
H 2O, acetone
Me
O
TM261
ambruticin
Me
Me

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566 25 Asymmetric Induction II Asymmetric Catalysis
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26
Asymmetric Induction III
Asymmetric Catalysis: Formation
of C–H and C–C Bonds
Introduction: Formation of C–H and C–C Bonds
PART I – ASYMMETRIC FORMATION OF C–H BONDS
Introduction: Catalytic hydrogenation with soluble catalysts
Hydrogenation with C 2-Symmetrical bis-Phosphine Rhodium Complexes
C 2 symmetric ligands (DIPAMP, DIOP, PNNP)
Reduction of 2-acylamino acrylates to give aminoacids
Hydrogenation with C 2-Symmetrical BINAP Rh and Ru Complexes
Asymmetric Hydrogenation of Carbonyl Groups
Regioselective asymmetric hydrogenation of enones
Asymmetric reduction of ketones with kinetic resolution
A Commercial Synthesis of Menthol
Noyori’s synthesis of menthol by Rh -catalysed [1,3]H shifts
Corey’s CBS Reduction of Ketones
A synthesis of the H 1 blocker cetirizine
PART II – ASYMMETRIC FORMATION OF C–C BONDS
Organic Catalysis
The Robinson annelation
The proline-catalysed aldol reaction
Reactions with hydroxy-acetone
Conjugate addition
Catalysed asymmetric Baylis-Hillman reactions
Catalysed Asymmetric Diels-Alder Reactions
Organic catalysis
Diels-Alder reactions catalysed by metal complexes
C 2-Symmetric Lewis acid catalysis
Origins of enantioselectivity in catalysed Diels-Alder reactions
Box and pybox catalysts in asymmetric Diels-Alder reactions
Cyclopropanation
Application to the synthesis of medicinal compounds
Asymmetric Alkene Metathesis
Asymmetric Pericyclic Additions to Carbonyl Groups
2 2 Ketene cycloadditions
Synthesis of enalapril
Carbonyl ene reactions
Alder ene reactions
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

568 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
Nucleophilic Additions to Carbonyl Groups
Allyl metals
Alkynyl metals
Addition of alkyl organo-zinc reagents
Palladium Allyl Cation Complexes with Chiral Ligands
Summary
Introduction: Formation of C–H and C–C Bonds
The last chapter was mostly about the asymmetric introduction of functionality using catalytic
reagents. The fi rst part of this chapter concerns the modifi cation of the carbon skeleton, or of
existing functional groups, by asymmetric catalytic reduction, usually by hydrogenation with Rh
or Ru catalysts. The second part is more varied: metals are again used for some reactions but
there are also examples of an exciting modern approach: organic catalysis. New C–C bonds are
formed by a variety of reactions ranging from cyclopropanation through Robinson annelation to
alkene metathesis. All are asymmetric. A valuable general reference for this chapter and the last
is Ojima’s book 1 Catalytic Asymmetric Synthesis. It contains a useful list of ligands and their
acronyms on pages 801-856 just before the index.
PART I – ASYMMETRIC FORMATION OF C–H BONDS
Introduction: Catalytic hydrogenation with soluble catalysts
Catalytic hydrogenation using hydrogen gas and insoluble palladium catalysts such as Pd/C will
be well known to you already. This story starts with the invention of Wilkinson’s catalyst, the
Rh(I) phosphine complex (Ph 3P) 3RhCl that can be used for catalytic hydrogenation in organic
solvents such as benzene. It catalyses the reduction of simple alkenes such as 1 or conjugated
alkenes such as 3 to give (racemic) products 2 and 4 having new chiral centres. 2
Ph
(Ph3P) 3RhCl
H
(Ph3P) 3RhCl
H
H2 Ph
Ph CO2H H2 Ph CO2H 1 2 3 4
Hydrogenation using Wilkinson’s catalyst is still used for diastereoselective reduction as in
the transformation of the functionalised enone 5 into the ketone 6 with high diastereoselectivity. 3
Other (homogeneous or heterogeneous) catalysts were less effective.
RO
Me 3Si
H
O
(Ph3P)3RhCl
H2 benzene, 65 °C
Me 3Si
RO
5 6 7
H
O
Me
P

Horner 4 at Mainz in Germany and Knowles 5 at the Monsanto works in the USA realised at more
or less the same time (1968) that if Ph 3P were replaced by an enantiomerically pure phosphine
such as 7, asymmetric induction might accompany the reduction. Unsymmetrical phosphines are
enantiomerically stable, unlike the corresponding amines, as pyramidal inversion is much slower
with P than with N. The phosphine was not available in high enantiomeric purity but Horner made
compound 2 in 8% ee while Knowles made compound 4 in 15% ee. Such results would be scorned
today but they were the fi rst.
P
Rh Cl
Me
Pr
Catalyst 8: 69% 'optical purity'
Hydrogenation with C 2-Symmetrical bis-Phosphine Rhodium Complexes
C 2 symmetric ligands (DIPAMP, DIOP, PNNP)
The real breakthrough came when Kagan 6 realised that only one of the three phosphines in
Wilkinson’s catalyst was displaced by the alkene substrate - alkenes, like phosphines, are
two electron donor ligands. If the remaining two phosphines were linked together to form
a more rigid chiral ligand, results should be much better. There is now a large selection of
such catalysts, usually having C 2 symmetry, some chiral at both phosphorus atoms such as
DIPAMP 9, some chiral in the backbone such as DIOP 10, derived from tartrate and Kagan’s
first successful catalyst, or PNNP 11, derived from α-methylbenzylamine and chiral in the
side chain. 7
Reduction of 2-acylamino acrylates to give aminoacids
H 2, catalyst 8
MeOH, 25-80 °C
300-400 lb/in 2
One of the most famous examples is a general synthesis of aromatic amino acids 14, both natural
like phenylalanine 14; Ar Ph, and unnatural. The easily prepared N-acyl enamines 12 are
hydrogenated in methanol catalysed by the rhodium-DIPAMP complex, to give the saturated
amides 13 in almost perfect ee. Hydrolysis releases the amino acid 14. This process was discovered
by Knowles at Monsanto.
O Ar
26 Hydrogenation with C 2-Symmetrical bis-Phosphine Rhodium Complexes 569
H
N CO 2H
12
Ph Ph
P P
OMe MeO
9; (S,S)-(+)-DIPAMP
(COD) 2Rh (DIPAMP)
ca 0.01 g per g substrate
H 2, MeOH, 3 atmospheres
50 ˚C, ca 1 hour
3
H
O
PPh2 PPh2 O
H
10; DIOP
H H
N CO2H
O
Ar
13; 96-100% ee
amide
hydrolysis
(S)-(+)-
15% ee
Ph N N Ph
Ph2P PPh2 11; PNNP
H
H2N CO2H Ar
14; 96-100% ee

570 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
Though it is often diffi cult to say exactly how asymmetric induction occurs, the complex
probably adopts a C 2 symmetric conformation 15 allowing the enamine to bind to the rhodium
both at the alkene and at the amide group 16. Transfer of hydrogen from Rh to the bound alkene
gives 13. The enantiotopic alkene faces in 12 become diastereotopic by complexation with the
chiral catalyst.
Ph
Phenylalanine is manufactured for incorporation into the sweetener Aspartame (nutrasweet)
18 by a process using PNNP 11. This has the advantage that even lower catalyst loadings are
possible and a high pressure is not needed.
AcNH CO 2H
MeO
P Rh P
OMe
Ph
15; (DIPAMP)Rh
1. H 2, (PNNP)Rh
(15,000:1), EtOH
H 2N CO 2Me
HO 2C
Ph
2. MeOH, H
Ph
O
Ph
12; Ar = Ph 17; Ph-OMe; 83% ee
crystallise to 97% ee
18; aspartame
Hydrogenation with C 2-Symmetrical BINAP Rh and Ru Complexes
H
N CO 2Me
The fi rst place in catalytic hydrogenation nowadays is taken by Rh or Ru complexes of BINAP.
This ligand has axial chirality as the naphthalene rings cannot rotate past each other. These
compounds were developed by Noyori, who with Knowles and Sharpless received the 2001 Nobel
prize for their contributions to asymmetric synthesis. BINAP 20 is usually made from BINOL
19 and either 19 or 20 can be resolved. Rhodium complexes similar to those we have met include
a molecule of cyclooctadiene and, as these are Rh(I) compounds, a counterion, often trifl ate 21.
Both enantiomers of BINAP are available commercially. 8
OH
OH
19; (R)-(+)-BINOL
12
Though BINAP is almost always represented as 20, it is important to realise that 20a is an
equally good representation. The two naphthalene rings are not co-planar and can rotate by less
than 90 around the bond joining them. The true structure is more like 20b (seen looking along
the bond joining the two naphthalenes).
Me
PPh 2
PPh 2
20; (R)-(+)-BINAP
H
N
O
Ar
A
Rh
Ph
16
P
P
OMe
Ph
P
NH 2
Ph Ph
Rh
P
Ph Ph
OMe
21; [(R)-(+)-BINAP(COD)Rh]OTf

26 Hydrogenation with C 2-Symmetrical BINAP Rh and Ru Complexes 571
PPh 2
PPh 2
Ph 2P
Rhodium complexes of BINAP can be used in much the same way as those we have just seen.
In the synthesis of the Merck HIV protease inhibitor crixivan an enantiomerically pure piperazine
23 essential for activity was prepared by reduction of an N-acyl enamine 22 with 2% of catalyst
21. Though the catalyst loading is relatively high, the essentially perfect yield and enantiomeric
purity of the product make this worthwhile. 9
The achievements of the Noyori group using ruthenium BINAP catalysts are extensive and
remarkable. Simple alkenes are reduced whether conjugated or not: the very effi cient synthesis of
the analgesic and anti-infl ammatory naproxen 25 from an unsaturated acid 24 resembling 1 is a
good example.
The presence of functionality does not disturb these excellent results. The cyclic enol ester 26
is cleanly reduced without reduction of the lactone.
Reduction of geraniol 28 shows remarkable chemoselectivity: only the allylic alcohol is reduced
to give citronellol 29 of higher enantiomeric excess than that found naturally. The catalyst is used
at 7 mol%: that means 3 mg/g of geraniol. The catalyst must have acetate as the counterion or it is
not so chemoselective. 10 You will see an alternative synthesis of the other enantiomer of citronellal
shortly.
PPh 2
20; (R)-(+)-BINAP 20a; (R)-(+)-BINAP
t-BuO
MeO
O
N
N
t-BuNH O
22
26
24
O
O
OBn
O
CO 2H
H 2, 2% catalyst 21
70 bar, MeOH
H2
H 2
Ru(BINAP) 2
(S)-BINAP-Ru
O
MeO
O
Ph 2P
t-BuO
O
N
PPh 2
N
t-BuNH O
O
23; 96% yield; 99% ee
27; 94% ee
20b;
(R)-(+)-
BINAP
CO 2H
25; Naproxen: 97% ee
OBn

572 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
Ru(OAc)2[(R)-BINAP]
OH
OH
MeOH, H2O 28; geraniol 90 atmospheres
29; (S)-(–)-citronellol
20 ˚C, 8-16 hours
93-97% yield, 98% ee
Asymmetric Hydrogenation of Carbonyl Groups
It is more diffi cult to hydrogenate carbonyl groups than alkenes as the CO group is considerably
more stable thermodynamically than the CC bond. Asymmetric hydrogenation of ketones with
Ru-BINAP catalysts is possible, though increased pressure and higher temperatures are usually
needed. Hydrogenation of β-ketoesters 30 is a general reaction giving good yields and excellent
chemo- and enantio-selectivity. 11
O O
R OMe
RuCl 2[(R)-BINAP]
Both carbonyl groups of β-diketones 32 are reduced and the two reductions are independently
enantioselective in the same sense so that the chiral (C 2 symmetric) product 33 predominates by
99:1 over the meso compound 34. This makes symmetrical 1,3-diols such as 33 readily available. 12
Elsewhere you will meet methods that use one centre to induce another in a 1,3-relationship,
maybe by diastereoselective reduction - this is a quite different strategy.
O O
32
30
H 2, 50 kgw/cm 2
RuCl2[(R)-BINAP] MeOH
50 ˚C, 20 hours
Regioselective asymmetric hydrogenation of enones
H 2
MeOH
4 atmospheres
100 ˚C, 6 hours
H2
OH O
R OMe
31; >90% yield
95-100% ee
R = alkyl, aryl,
alkyl with O- or
N-substituents
OH OH OH OH
33; 98% yield, >99% ee
99:1
anti:syn
33:34
The situation is different when both CC and CO groups are present in the same molecule. We
have seen the rather special case of the enol ester 26 and the usual result with conjugated enones
is also that reduction of the alkene is preferred. High pressures are needed but good enantiomeric
excess can be achieved with unsaturated lactones 35 and ketones 37. The lactone needs the RuCl 2
catalyst but the ketone gives better results with the corresponding acetate. 13 Notice that use of each
enantiomer of BINAP gives a different enantiomer of the product 36 or 38.
O
O
100 atmospheres H 2
RuCl 2[(S)-BINAP]
CH 2Cl 2
O
O O
35 50 ˚C, 60 hours 36; 100% yield
95% ee
37
+
34
100 atmospheres H2 Bu Ru(OAc) 2[(R)-BINAP]
CH2Cl 2
O
Bu
50 ˚C, 60 hours 38; 100% yield
98% ee

When asymmetric reduction of the ketone of an enone such as 39 is wanted, the catalyst
must be further modifi ed 14 by using the very crowded BINAP derivative XYLBINAP 41 and
the diamine additive DAIPEN 42. The results are then excellent but this example makes the
point that it is essential to follow closely related examples when attempting the asymmetric
reduction of any but the simplest alkene.
O
Asymmetric reduction of ketones with kinetic resolution
Since β-keto-esters enolise rapidly and extensively, dynamic kinetic resolution is possible
in which one enantiomer is reduced more rapidly than the other. 11 By this means two chiral
centres may be developed simultaneously especially when there is an N-acetyl substituent
on the middle atom as in 43. The synthesis of unusual functionalised amino acids related to
threonine becomes straightforward. A fuller discussion of dynamic kinetic resolution appears
in chapter 28.
O
O
39
A Commercial Synthesis of Menthol
P
P
10 atmospheres H 2
RuCl 2[(S)-XYLBINAP].[(S)-DIAPEN]
10,000:1 substrate:catalyst
i-PrOH, K 2CO 3, 30 ˚C, 43 hours
2
2
RuCl2
One of Noyori’s most remarkable achievements is a commercial synthesis of ()-menthol 51 used
since 1983 by the Takasago International Corporation on a scale of thousands of tonnes a year.
This and related processes are discussed in detail by S. Akutagawa and K. Tani in chapter 3 of
Ojima’s Catalytic Asymmetric Synthesis. The process is summarised here:
OH
40; 99% yield, 100% ee
H 2N
H2N
OMe
41; (S)-XYLBINAP 42; (S)-DAIPEN
43
26 A Commercial Synthesis of Menthol 573
O
NHAc
CO 2Me
H 2
RuCl 2[(R)-BINAP]
O
OH
OMe
CO 2Me
CH2Cl2 100 atmospheres O
NHAc
20 ˚C, 6 hours 44; 99:1 syn:anti, 94% ee

574 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
Noyori’s synthesis of menthol by Rh -catalysed [1,3]H shifts
Various natural terpenes, including β-pinene 45, can be used to make myrcene 46. Addition of
lithium diethylamide to the diene portion of 46 gives the achiral allylic amine 47. Now comes the
asymmetric catalytic process: a [1,3]H shift rather than a hydrogenation giving the enamine 48
easily hydrolysed to citronellal of higher enantiomeric purity than can be found naturally. The
[1,3]H shift probably involves complexation of Rh to the nitrogen atom 52, removal of hydrogen
to create an imine complex 53, transformation to an allyl cation Rh complex 54, rather like the Pd
complexes we met in chapter 19, and replacement of the original H atom to give the enamine 55,
more stable because of conjugation than the original allylic amine 47. The decisive moment is the
selection of one of the enantiotopic H atoms (marked in 52) so that the Rh atom occupies the lower
face of 53–55 and returns the H atom to that same face.
47
45; β-pinene
H
Rh
R
R
Rh
H N
Et2
52 53
H
Rh
NEt2
The rest of the synthesis involves a Zn(II)-catalysed oxo-ene reaction 56 going through a chair
transition state 57 to put all the substituents equatorial in the product 50 and thus create the relatively
remote two remaining chiral centres. A classical hydrogenation gives the iso-propyl group.
Menthol itself is in great demand but Takasago also fi nd a market for the other terpene intermediates
such as citronellal.
49
known
reaction
NEt 2
H
H 2O
46; myrcene
O
H
ZnCl2
1. Et2N Li NEt2 CHO
48; 100% yield, 98% ee 49; citronellal
H
ZnCl 2
R
H
Rh
R
H
Rh
NEt2 NEt2 54 55
56 57
50
O
H
H 2
Rh [(S)-BINAP] 2
10,000:1
2. H 2O 100 ˚C, 15 hours
7 tonne batches
50
47
OH OH
catalyst
51; (–)-menthol
OH
48

Corey’s CBS Reduction of Ketones
Among the very few worthwhile methods for catalytic reduction that do not depend on hydrogenation
is Corey’s CBS 15 reagent 60, derived from proline 58 by protection and addition of phenyl Grignard,
giving the bulky amino-alcohol 59. This is converted into the stable crystalline boron compound 60.
H
NH
CO2H
58
(S)-L-(–)-proline
Ph
Ph
H
OH
NH
59
MeB(OH) 2
toluene
Dean Stark
Ph
H
Ph
O
N
B
Even this method is only semi-catalytic as usually about 10-15% of the reagent 60 is used with
stoichiometric borane, to give 61 which reduces simple ketones with high enantioselectivity to
give 62. The advantage of this method is that reduction of carbonyl groups is the favoured reaction
and takes place under mild conditions - not the situation with hydrogenation.
Ph
H Ph
O
N
B
Me
60; 10 mol %
BH 3.THF
THF
Ph
H Ph
O
N
B
BH3 Me
61
This 61 is a genuine chiral borohydride, but presumably relies on complexation of the ketone
oxygen by the other boron atom 63. In general, high enantioselectivity on acyclic substrates requires
a rigid complex such as 63 to stop the substrate rotating. It is obviously no use ensuring
delivery of H from, say, the top face of the molecule if the molecule is rotating and the “top” face
is continually changing. Intramolecular transfer of hydride gives the boron ester 65 of the product
62 and returns the catalyst 60 ready for reaction with another molecule of borane.
61
N
B
O
B
O Me
H
H H
RL Rs
The general rule is expressed in 65 using R L and R S to show the large and small substituents on
the ketone. Proline is naturally and cheaply available only as one enantiomer so it is interesting
to note that this most general of asymmetric ketone reductions generally gives the opposite
enantio mer to the most general of enzymatic reductions, that with baker’s yeast. (see chapter 29)
R S
Ph
H
OH
Ph
R L
26 Corey’s CBS Reduction of Ketones 575
baker's
yeast
sucrose
Ph Ph
H
O
N B
R S
O
R L
O
Ph
H
CBS
Ph
O
N
B
catalyst
from (S)-pro
Ph
60
OH
Ph
Me
62; 99% yield
96.5% ee
H
H
B
H
O
Me
Me
+ H2B H O
RL Rs RL Rs 63 64 60 65
R S
OH
R L
62;
RL = Ph
Rs = H

576 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
A synthesis of the H 1 blocker cetirizine
The synthesis of the H 1 blocker cetirizine 66 is an interesting application of this reagent. Cetirizine
can obviously be made by substitution on some derivative of one enantiomer of the alcohol 68 by
the piperazine 67. Asymmetric reduction of the ketone 69 might provide 68 but the difference in
size between the two substituents is altogether insuffi cient for asymmetric induction.
N
N
O
CO 2H
N
N
H
O CO2H
Cl
Cl
66; Cetirizine 68 69
Corey’s solution 15 was to make one of the aromatic rings much larger than the other by complexation
with Cr(CO) 3 70. This is a very large substituent as the three CO molecules stretch out
linearly from the Cr atom. To get full value from this substituent, he used it to direct lithiation
and acylation to give the ketone 71 with one ring defi nitely much larger than the other and reduction
with the CBS reagent 60 using catechol borane as the stoichiometric reducing agent gave the
alcohol 72 in excellent yield and ee.
You may have noticed that this appears to be the wrong enantiomer for cetirizine. Not so as the
Cr(CO) 3 has a fi nal job to do. It stabilises cations and this substitution is likely to occur by the S N1
mechanism as the doubly benzylic cation is so stable. Treatment of 72 with HBF 4, a strong acid
with a non-nucleophilic counterion, creates the cation. The Cr(CO) 3 sits on one side of this planar
system and preserves its chirality. The nucleophile attacks on the face not occupied by Cr(CO) 3
and the substitution occurs with retention.
72
Cr(CO) 3
70
1. HBF 4
CH2Cl2
2. 67 as
t-Bu ester
1. n-BuLi
TMEDA, THF
2. CuBr•Me2S 3. ArCOCl
C–N
Cr(CO) 3
N
N
Cr(CO) 3
O
67 +
71; 78% yield
O CO 2t-Bu
Cl
73; 86% yield; 98% ee
pyridine
Cl
OH
15 mol% 60
O
B
O
N
N
H
O
OH
Cl
Cl
Cr(CO) 3
72; 99% yield; 98% ee
O CO 2t-Bu
Cl
74; 92% yield; 98% ee
HCl
66
86% yield

Nowadays much less catalyst is needed. This is particularly important in large scale syntheses
as of the intermediate needed by Merck 16 for the drug intermediate 79. The starting material is
ketone 75 easily made by a Friedel-Crafts reaction. Reduction using only 0.5% CBS catalyst 60
gave alcohol 76 of 98.9% ee. Even with only 0.1% 60, the ee of the product 76 was still 94.2%.
F
The synthesis continued with displacement of Cl by an amine, actually via an epoxide, to give
77, conjugate addition of acrylonitrile 78 and ring closure with inversion and high stereoselectivity
at the nitrile centre.
PART II – ASYMMETRIC FORMATION OF C–C BONDS
Metal complexes remain with us in the formation of C–C bonds, indeed a wider variety of metals
as Al, Co, Cu, Mo, Ru, Ti and Zn all have parts to play in a wide variety of reactions. But we must
also introduce a new type of catalyst – the simple organic compound – and we must start with
organic catalysis as it is involved in some of the same reactions as the metal complexes.
Organic Catalysis
O
F
F
F
Cl
Cl
75 76 77
The Robinson annelation
Et 3N-BH 3
F
Pride of place here must go to the asymmetric Robinson annelation, discovered as long ago as
1974, but not appreciated at the time for the landmark that it undoubtedly was. 17 The normal Robinson
annelation (text chapter 36) is fi rst a Michael addition to produce an achiral triketone 82
which cyclises when the enol of the methyl ketone adds, aldol fashion, to the syn face of either of
the other ketones to give 83, and hence the enone 84, the north east corner of a steroid.
O
80
achiral
+
O
77
H O
81
achiral
CN
H2O
20 °C
5 days
F
O
(S)-60
26 Organic Catalysis 577
F
OH
N
R
78; R = t-Bu
O
82; achiral
88% yield
O
OH
t-BuNH 2
MeOH
CN
O
(EtO)2P Cl
N
H
HOAc, pH 7
3 days
LiHMDS
F
F
F
N
R
79; R = t-Bu
O
TsOH
O
OH
83; 100% yield
all syn but racemic
O
OH
NHt-Bu
CN
84
O

578 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
The top and bottom faces of the fi ve-membered ring in 82 are diastereotopic and the intramolecular
reaction selects the syn face. But the two ketone groups in 82 are enantiotopic. If the
enol attacks the right hand ketone one enantiomer of 83 is formed while if it attacks the left hand
ketone, the other enantiomer is formed.
O
OH
O
O
Me
O
OH
The reaction is normally catalysed by weak acids and weak bases, such as piperidine and acetic
acid. Replacing these with a catalytic (50:1) amount of proline 58 led to optically active 83 in an
astonishing 93.4% ee and 100% yield. Dehydration gave the enone 84 with some loss of ee (by
reverse aldol?), but recrystallisation from ether gave 100% ee.
The chiral auxiliary must obviously be involved intimately with the cyclisation, perhaps by
forming an imine 85 or an enamine 86, so that only the enantiomer 83 of the cyclisation mechanism
applies. In both these proposals, the free CO 2H group of proline interacts by hydrogen bonding
with a ketone or OH group. Explanations involving two molecules of proline have now been
discredited and the most recent explanation 18 is that the enamine mechanism 86 is correct with
that step as the rate determining step, closely followed by addition of water to the iminium ion 87.
The transition state has a chair-like central portion 88.
O
O
O
82; 2 g scale
Me
85
Proline is now recognised as a fi rst class chiral auxiliary, having a rigid structure and a high
grade stereogenic centre carrying contrasting sterically and electronically demanding substituents.
HO
Me
O O
one enantiomer the other enantiomer
N
HO
O
O
O
H
O
35 mg 58
(S)-(+)-proline
N
H
CO2H
H
Me
O
86
O
O
OH
(+)-aldol 83
100% yield, 93.4% ee
O
HO
N
O
H
88
O
O
(–)
O O
N
(+)
TsOH
O
O
OH
O
O
(+)-enone 84
99.4% yield, 88% ee
OH
87
O
N
O
83

This was an extraordinary result when it was published in 1974 as it was well ahead of its time. It is
still one of the best asymmetric reactions with catalytic amounts of a chiral reagent. An example
of an asymmetric Robinson annelation using stoichiometric ‘catalyst’ is in the workbook.
The proline-catalysed aldol reaction
The asymmetric Robinson annelation relies on an intramolecular aldol reaction to create the new chiral
centre. More recently List 19 and MacMillan 20 have used proline 58 to catalyse intermolecular aldol
reactions with nearly as good results. Acetone and isobutyraldehyde 89 can be condensed to give a
single enantiomer of the aldol 90 in excellent yield and ee providing 30% proline is used as catalyst.
O
O
30 mol % proline
O OH
+
H
4:1 DMSO/acetone
room temperature
89 90; 97% yield, 96% ee
Acetone, the component that must enolise, is present in large excess but the achievement is considerable.
The reaction involves formation of the proline enamine of acetone 91 which then attacks
the aldehyde through a chair-like transition state 92 held together by the acidic proton of proline’s
carboxylic acid. This gives the imine salt 93 hydrolysed to the product with regeneration of proline.
The intermediates are like those in the Robinson annelation: enamines and imines. Organic
catalysis with amines relies on equilibria between these intermediates and carbonyl compounds.
acetone
+
proline
At the moment the limit is reached when both components in a crossed aldol reaction are enolisable
aldehydes. One is indeed propionaldehyde 94 - a compound notorious for self-condensation - that
reacts cleanly with isobutyraldehyde 89. However, it is necessary to add the propionaldehyde slowly
by syringe pump. The aldol 95 is produced in very high yield considering the similarity of the two
aldehydes but the most amazing aspect is the very high diastereo- and enantioselectivity. 20
Reactions with hydroxy-acetone
It turns out that one of the best ketones for these asymmetric crossed aldol reactions is hydroxyacetone
96. Combination with isobutyraldehyde 89 gives an aldol that is also an anti-diol 97 with
almost perfect selectivity. 21 The proline enamine of hydroxyacetone is evidently formed preferentially
on the hydroxy side. You will recall from chapter 25 that asymmetric synthesis of anti-diols
is not as easy as that of syn diols.
N
H
CO2H
H
58; (S)-(–)-proline
CO
N
2H RCHO
91; proline-acetone
R
H
O
N
H
O
O
N
CO2 OH
H2O 84
+
proline
enamine 92
93
H
O
+
26 Organic Catalysis 579
H
O O OH
10 mol % proline
DMF, 4 ˚C
94 89 95; 82% yield, >99% ee
24:1 anti:syn

580 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
Hydroxyacetone 96 is a reagent in an even more remarkable reaction: the asymmetric direct
three-component Mannich reaction. It is combined with an aromatic amine 98 and the inevitable
isobutyraldehyde 89 with proline catalysis to give a very high yield of a compound 99 that might
have been made by an asymmetric amino-hydroxylation. The proline enamine of hydroxyacetone,
must react with the imine salt formed from the amine and isobutyraldehyde. This is a formidable
organisation in the asymmetric step.
O
OH
There is something different here. The absolute stereochemistry at the OH group (the one that
comes from hydroxyacetone) is the same in 99 as it was in 97 but the relative stereochemistry is
different: anti in 99 but syn in 97. The electrophile (ketone in 97 or imine in 99) must approach the
proline enamine in different ways. List’s suggestion is that the large N-aryl group prefers to keep
away from the rest of the molecule in the transition state 100 leading to 99 but that the side chain
on the aldehyde is more important in the transition state 101 leading to 97. The dotted arrows in
100 and 101 show where that clash would come and the black dots mark the atoms that join to form
the new bond. There is a review of the catalytic asymmetric aldol reaction that includes material
from other chapters. 22
Conjugate addition
OMe
+ +
H2N
96 98
O
O
OH
96
NHAr
+
R
H
O
89
Ar
20-30 mol % proline
DMSO
room temperature
OHC
N
N O
H
89
O
20 mol%
(S)-proline
DMSO
room
temperature
α,β-Unsaturated carbonyl compounds also reversibly form iminium salts with secondary amines and
that offers opportunities for asymmetric conjugate addition and, as we shall soon see, asymmetric
Diels-Alder reactions. The pioneer in the development of modern organic catalysis has been Dave
MacMillan 23 at Berkeley and he reported the asymmetric conjugate addition of heterocycles such
as pyrroles to enals catalysed by the amine 102 prepared from phenylalanine. The amine forms an
iminium salt 103 reversibly and this salt is more electrophilic than the enal.
O
OH
HN
OMe
99; 92% yield, >99% ee
>97:3 syn:anti
H
H
HO
HO
OH
OH
R
R
99 100 101
97
O
O
N
OH
H
OH
O
O
97
82% yield,
>99% ee
>20:1 anti:syn
O
OH
R

CO2H O Me
N
Ph
CHO
Bn
Bn NH2
phenyl-
Bn
N
H
Me
Me
Ph
Me
N
N
Me
alanine 102 103
When N-methyl-pyrrole 104 is the nucleophile, clean conjugate addition occurs at its α-position
with good ee in the product. Conjugate addition is normally a problem with aldehydes (chapter 9)
so both regio- and enantioselectivity are impressive. The catalyst loading is quite high but clearly
the catalyst can detach itself quickly enough from the fi rst formed adduct to maintain a concentration
of 103 large enough to swamp the slower reaction of 104 with the enal.
N
Me
Ph
CHO
A new catalyst 106, also derived from phenylalanine but with extra chirality, is needed for
conjugate additions to crotonaldehyde. Nucleophilic benzene rings such as 107 react with good
regio- and stereoselectivity 24 in the same sense as 105.
Bn
This method has been applied to the synthesis of a COX-2 inhibitor 110, one of a new generation
of analgesics under development by the Merck company. This requires conjugate addition to
the 3-position of an indole 109 and the same catalyst is used. 25
MeO
104
O Me
N
H
N
+
H
t-Bu Me2N
106 107
N
109
OMe
20 mol% catalyst 102
CF 3CO 2H, –30 ˚C
Catalysed asymmetric Baylis-Hillman reactions
26 Organic Catalysis 581
Br
1.
Other reactions are possible with iminium salts derived from α,β-unsaturated carbonyl compounds.
The Baylis-Hillman reaction (chapter 18) also uses conjugate addition as a fi rst step and we shall deal
with that immediately. Much more work has been done on the Diels-Alder reaction: that will follow.
The Baylis-Hillman reaction between an electrophilic α,β-unsaturated carbonyl compound and an
CHO
10 mol% catalyst
CH2Cl2, –40 ˚C
CHO
20 mol% catalyst 106
CH2Cl2, i-PrOH
–40 ˚C
2. [O]
MeO
N
Me
Ph
CHO
105; 87% yield; 93% ee
OMe
Me
Me2N 108; 86% yield, 89% ee
N
O
Me
CHO
CO 2H
Br
110; 82% yield, 87% ee

582 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
electrophilic aldehyde is catalysed by tertiary amines and lowish yields are generally acceptable as so
much is achieved in a one-pot reaction. The obvious source of asymmetry is a chiral amine catalyst but
only recently has the right amine and the right α,β-unsaturated carbonyl compound been identifi ed. 26
R
The unusual catalyst 113 must add to the unusual ester 111 in a reversible conjugate addition 114
to give the enolate that adds to the aldehyde in the asymmetric step 116. The bicyclic amine must be
placed close to the carbonyl group of the aldehyde: Hatakeyama suggests an H-bonding interaction
with the OH group on the quinoline ring of the catalyst. Finally, elimination of the catalyst launches
a second cycle. The next few years are likely to see considerable development here.
R* 3N
O
+
O
O
114
Catalysed Asymmetric Diels-Alder Reactions
Organic catalysis
O CF 3
111
CF 3
CF 3
O CF3
R
O
R*3N
O
O CF3
This is an important area with many available methods. We shall look fi rst at organic catalysis and
then change to catalysis by metal complexes. The same type of intermediate 117 used for conjugate
addition is clearly also suitable for Diels-Alder reactions with the same proviso: it must be more
reactive then the α,β-unsaturated carbonyl compound as that too can do Diels-Alder reactions.
And of course the fi rst formed product 118 must hydrolyse rapidly to release the catalyst 102.
R
R
10 mol%
QD4 (113)
DMF
–55 °C
CHO
Me
N
118
102
Bn
OH
R
N
Me
Me
An early example was the reaction between cyclohexadiene and cinnamaldehyde catalysed by the
phenylalanine-derived amine 102 to give the endo adduct 119 with good selectivity of all kinds. 23
CF 3
O
O
CF 3
R O CF3
R*3N
115 116
O
O
CF 3
R O CF3
112; ~50% yield, 91-99% ee
Bn
O
N
N
Me
Me
Me
117
R
OH
N
CHO
+ 102
O
N
113; catalyst 'QD4'
112

Ph
CHO
More recent developments include the refi ned catalyst 123 with extra bulk and an extra chiral
centre. This catalyses reactions between functionalised dienes such as 120 and acyclic enones
such as 121. The very high yields, ees, and endo:exo selectivity of the product 122 compensate for
the 20% catalyst loading. It is very diffi cult to get high ees in Diels-Alder reactions with acyclic
ketones and you will see in the next section why this catalyst is successful. 27
+
NHCbz
Diels-Alder reactions catalysed by metal complexes
C 2-Symmetric Lewis acid catalysis
+
120 121
O
20 mol%
catalyst 123
20 mol% HClO4 EtOH, –30 ˚C
5 mol% catalyst 102
MeOH, H2O, 21 hours
room temperature
CbzNH O
122
The best results before organic catalysis were with amides 125 and Lewis acid catalysts based
on Al, Ti, and Cu(II) with C 2-symmetric ligands. Corey’s aluminium complex 127 derived from
the diamine whose resolution was described in chapter 22 works well with substituted cyclopentadienes
124 and the product 126 was used in prostaglandin synthesis. 28 There are three
aspects of stereoselectivity in this reaction: which diastereotopic face of 124 is attacked? (that
anti to the CH 2OBn group), is the product exo or endo? (endo) and which endo product is formed,
126 or its enantiomer? Only for the last question is asymmetric catalysis necessary, though Lewis
acid catalysis of any kind enhances endo/exo selectivity.
OBn
+
O
124 125
26 Catalysed Asymmetric Diels-Alder Reactions 583
O
N O
10 mol%
catalyst 127
BnO
Seebach’s TADDOL auxiliaries, derived from tartrate (chapter 23), combine well with Ti(IV)
to make an effective Lewis acid catalyst 130 for Diels-Alder reactions. The reaction of isoprene
with the doubly activated amide dienophile 128 gives one adduct 129 in good yield. 29 Polymer
supported versions of this catalyst are available.
+
isoprene
+
amide 128
O
O
Ph
CHO
122
91% yield
98%ee,
>100:1
endo:exo
Bn
126
94% yield
O 95% ee
endo only
O N O
119
82% yield
94% ee
1:14 exo:endo
O Me
N
N
H
Me O
catalyst 123
Ph Ph
TfN
Al
NTf
Me
catalyst 127
CO2Me CO2Me Ph
N
O
N
O
O
O
O
O
Ti
O
O
Ph
10 mol%
TADDOL
Ti catalyst
130
Ph
Me
Ph
Ph
Cl
Cl
129; 94% ee TADDOL-Ti catalyst 130

584 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
Origins of enantioselectivity in catalysed Diels-Alder reactions
You may be wondering why these dienophiles 125 and 128 have a heterocyclic ring attached to
the carbonyl group. Later in chapter 27 you will see that chiral versions of this oxazolidinone
are essential for other Diels-Alder reactions. But this ring is not chiral and its role is to chelate
the metal 131. By this means the two lone pairs on the ketone oxygen atom are distinguished
and the asymmetry of the catalyst activates one face of the alkene rather than the other. Such
a distinction is not possible for a ketone such as 121 and that is why organic catalysts such
as 123 are much more effective. The iminium salt 132 shows the same kind of shape as the
complex 131. In both these diagrams 131 and 132 the orientation of the alkene cannot be stated
for certain.
lone pair
discrimination
Box and pybox catalysts in asymmetric Diels-Alder reactions
O Me
N
Another important group of ligands for metal-catalysed reactions are based on oxazolines derived
from amino acids. Evans 30 has used the bis-oxazoline or ‘box’ ligands in Cu(II)-catalysed Diels-
Alder reactions. Ligand 133 is derived from the unnatural amino-acid tert-leucine and, complexed
with Cu(OTf) 2, catalyses Diels-Alder reactions of the same dienophile 125 with various dienes.
The best counterions are trifl ate (OTf) and SbF 6.
O
N N
O
t-Bu t-Bu
O
L L
131
M
O
N O
O
121
bis-oxazoline ligand 133 125
catalyst
123
The more highly chelating pybox ligands such as 135, also prepared from tert- leucine, catalyse
Diels-Alder reactions even with aldehydes such as 136. Now the counterion really must be the
very non-nucleophilic SbF 6. In these examples diastereo- (endo/exo) and enantioselectivity are
excellent. 31
t-Bu
O
N
N
N
O
t-Bu
pybox ligand 135
+
+
O
O
N O
136
O
H
Bn
Cu(II)
10 mol%
box 127
–50 ˚C
N
Cu(SbF 6) 2
5 mol%
pybox 135
–40 ˚C
132
Me O
O
O N O
134; 97% ee
98:2 endo:exo
O H
137; 92% ee
97:3 endo:exo

Cyclopropanation
Historically one of the fi rst asymmetric methods to be explored, cyclopropanation came of age 32
with box and salen ligands on Cu(I). Diazo compounds, particularly diazoesters 138, react with
Cu(I) to give carbene complexes 140 that add to alkenes, particularly electron-rich alkenes to
give cyclopropanes 141. The reaction is stereospecifi c with respect to the alkene - trans alkenes
giving trans cyclopropanes - and reasonably stereoselective as far as the third centre is concerned.
Any enantioselectivity comes from the chiral ligand L*. You have already seen the Ru carbene
complexes are intermediates in olefi n metathesis (chapter 15).
N
N CO 2Et
H
H
N CO2Et A good test case is styrene. With the box ligand 133 the best diazoester is the acetate of ‘BHT’,
2,6-di-t-butyl-4-methylphenol. This gives excellent diastereoselectivity and near perfect ee in the
trans-cyclopropane 30 142.
The early salen-type catalysts 143 of Aratani gave moderate results when menthyl diazoacetate
was used, 32 but more modern versions, such as the salen-Co catalyst 145 of Katsuki 33 are much
more impressive. You saw such catalysts in the last chapter under Jacobsen epoxidation.
MeO
L*Cu(I)
Application to the synthesis of medicinal compounds
N
L*Cu
–N 2
H CO 2Et
Cilastatin 147 is used to increase the potency of β-lactam antibiotics. It is manufactured commercially
by asymmetric cyclopropanation of isobutylene with ethyl diazoacetate catalysed by the Aretani Cu(I)
complex 143 that is more effective with this trisubstituted alkene than with styrene. 34
L*Cu
R
L*Cu(I)
138 139 140
141
R =
('BHT')
t-Bu Me
O
t-Bu
N
O Cu
O
R
R
Aratani catalysts 143
Ph Ph
N N
O
Co
Br
O
Katsuki salen catalyst 145
26 Cyclopropanation 585
Ph
styrene
OMe
Ph
Ph
N 2 CO2R
CuOTf
bis-oxazoline 133
N 2 CO2M*
143
M* = menthyl
N 2 CO2t-Bu
Co-salen 145
R
R
CO 2R
Ph
142; trans:cis 94:6
trans: 99% ee
Ph
Ph
CO 2Et
R
CO 2M*
144; trans:cis 86:14
trans; 70-80% ee
CO2t-Bu
146; trans:cis 96:4
trans; 93% ee

586 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
The antidepressant tranylcypromine 151 was made using the Evans box ligand 133. A different
bulky ester 149 gave good ee but only moderate diastereoselectivity. 35 The trans diastereoisomer
hydrolyses faster than the cis so the free acid was essentially pure trans. Further reactions including
a Curtius rearrangement with retention gave tranylcypromine 151.
Ph
H
N
O CO 2
N 2 CO2CHR 2
CuOTf
bis-oxazoline 133
R = cyclohexyl
Ph
Asymmetric Alkene Metathesis
CO2CHR 2
149; trans:cis 88:12
trans: 97% ee
25% NaOH
EtOH
10 hours
CO2H
Ph
150; 79% yield
trans:cis 130:1
Metal carbene complexes are also involved in metathesis (described in chapter 15). Exchange
of carbene complexes with alkenes via a metallacyclobutane releases volatile alkenes such as
ethylene with the formation of new alkenes. Ring closing metathesis is particularly favoured but
normally leads to no new chiral centres. The simple Mo and Ru carbene catalysts described in
chapter 15 cannot of course be used to induce asymmetry but a new generation of asymmetric
Schrock 152 and Grubbs 153 catalysts can create asymmetry if a choice between two enantiotopic
alkenes is offered. 36
i-Pr
Mes
O
O
Mes
147
N
Mo
S
i-Pr
Ph
NH 3
As we largely discussed Grubbs Ru catalysts in chapter 15 we shall redress the balance
by using examples of the Mo catalyst 152. The necessary parts of the substrate are (a) a
monosubstituted alkene so that metathesis starts there and (b) a choice between two at least
disubstituted enantiotopic alkenes for the second stage in the metathesis. So the amine 154
forms first the metallacyclobutane 155 and hence the new carbene complex 156 that can
choose between the remaining two alkenes. In this case it does so very well indeed to give
a high yield of the eight-membered cyclic amine 158 as a single enantiomer. The conditions
are mild: 2 mol% of 152 in benzene at 22 C for 25 minutes. Other than the solvent,
all is fine.
CO 2
N2CHCO 2Et
152; Asymmetric Schrock 153; Asymmetric Grubbs
143
Cl
N
O
Ru
RO
Ph
NH 3Cl
151
tranylcypromine
N
CO 2Et
148; 92% ee
Mes

N
Ph
Ph
*Mo R
154 155 156
Mo*
Examples of oxygen heterocycles include the fi ve-membered ring 160 and the six-membered
ring 161. It may seem at fi rst sight that the obligatory extra alkene in all the products is a disadvantage
but this is a useful functional group that can be used to develop functionality or can simply be
oxidised to a carbonyl group. It is generally more reactive than the alkene embedded in the ring.
The silicon compound 162 can also be cleaved at both Si – O and, if necessary, Si – C bonds to
give an open chain compound.
O
159
Asymmetric Pericyclic Additions to Carbonyl Groups
2 2 Ketene cycloadditions
H
N
catalyst
152
N
Ph
H
Ph
In chapter 25 you met the ‘pseudoenantiomers’ quinine and quinidine when their dihydroderivatives
were used in Sharpless asymmetric dihydroxylation. The cinchona alkaloids themselves are
used to catalyse a 2 2 cycloaddition of ketene to chloral in an important industrial process. 37
Chloral reacts with ketene 163 from a generator in the presence of quinine or quinidine to give the
β-lactone 164. Catalysis by quinine gives the other enantiomer. Hydrolysis opens the lactone ring
and hydrolyses the CCl 3 group to CO 2H to give either enantiomer of malic acid 165.
Cl 3C
26 Asymmetric Pericyclic Additions to Carbonyl Groups 587
O
157
2 mol%
146
benzene
22 ˚C
25 minutes
+
H
O
chloral 163
ketene
N
*Mo
R
158; 93% yield, >98% ee
O
160; 99% yield
up to 95% ee
–50 ˚C
toluene
0.5-2 mol%
quinidine
O
O
Cl3C
164; 95% yield
>96% ee
+
Me
O Si
Me
161
NaOH
H2O *Mo H
catalyst
for next
cycle
HO2C
N
Ph
*Mo
CH 2
+
R
CH 2
2 mol%
152
benzene
22 ˚C
O
Si
25 minutes Me Me
162; >99% yield
>95% ee
OH
CO2H
165; 95% yield
>96% ee
(S)-(–)-malic acid

588 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
This is probably not strictly a 2 2 cycloaddition but an addition of the chiral amine 169 to
the ketene 166 to give a chiral enolate that adds to chloral in the step that induces asymmetry 167.
Ring closure 168 gives the lactone 164 and regenerates the quinidine for the next cycle. 38
O
•
The mechanism of the hydrolysis both of the lactone and of the CCl 3 group by hydroxide must
be understood to interpret the stereochemistry. 39 Whereas simple β-lactones tend to react at sp 3
carbon by an S N2 reaction (B Alk2) as that releases ring strain in the slow step, the CCl 3 group slows
down the S N2 reaction and lactone 164, like most lactones, is attacked at the carbonyl group by
hydroxide ion 170. The confi guration at the chiral centre is retained in this step. The hydrolysis of
the CCl 3 group in 171 to CO 2H however occurs with inversion at the chiral centre - the details of
this reaction are in the workbook. The other enantiomer (R)-()- of malic acid thus joins the new
chiral pool (chapter 23).
164
NaOH
H2O
O
O
CCl3
170
OH
B AC2
HO
O
CCl3 (R)-171
O
=
Cl3C
OH
CO2 NaOH, H2O
INVERSION
(S)-165
Reaction with trichloroacetone is similarly high-yielding and enantioselective giving the βlactone
172 and after hydrolysis with inversion, (S)-citramalic acid 173. Again, quinine gives the
other enantiomer.
O
Me CCl 3
trichloroacetone
+
O
•
–50 ˚C, toluene
0.5 — 2 mol%
quinidine 169
Hydrolysis of both lactones 163 and 172 by hydroxide ion occurs with inversion during the
conversion of the CCl 3 group to CO 2H. Weaker nucleophiles clearly attack the carbonyl group 176
to make available a series of derivatives such as the amides 174 and 175.
HO
R 2N
HO2C
NR*3
Me
O
R* 3N
O
163
ketene
HO
R 2N
Cl3C
O
Cl3C H
Cl3C H
Cl3C
166 167 168 164
Me
O
O
O
Cl3C
Me
172; 95% yield
>96% ee
RETENTION
HNR 2
NaOH
INVERSION
O
Cl 3C Me
174 175 176
O
R* 3N
O O
O
O
HO2C
OMe
N
OH
CO2H
173; >96% ee
(S)-citramalic acid
NaOH
INVERSION
OH
173
N
169; (+)-quinidine

Synthesis of enalapril
The ACE (Angiotensin Converting Enzyme) inhibitors are a group of important drugs that reduce
high blood pressure and help to prevent strokes and heart attacks. One is enalapril 182 that can be
made from the β-lactone 164. A Friedel-Crafts acylation (note that attack at the carbonyl group is
preferred) gives the ketone 177 reduced to the diol 178 and hence to the lactone 179 both as single
enantiomers of mixtures of diastereoisomers. 40
164
>96% ee
benzene
3 x AlCl 3
5 ˚C
O OH
Ph CCl 3
177; 90% yield
>99% ee
LiAlH 4
OH OH
Catalytic hydrogenation of the benzylic C–O bond in 179 removes the second chiral centre and
the hydroxy-ester 180 is prepared for coupling to an enantiomerically pure amine by conversion to
the trifl ate 181. The coupling goes with inversion to give enalapril 41 182.
1. H2, Pd/C
OH
OTf
AcOH
Tf2O 179
Ph
2. EtOH Ph CO2Et Ph CO2Et 180; 67% yield
Recent developments extend the asymmetric β-lactone formation to dichloroaldehydes 183
with formation of the ketene 163 by elimination on acetyl chloride rather than from a ketene
generator. A mixture of the aldehyde 183, Hünig’s base and 2 mol % quinidine 169 is treated with
acetyl chloride to give the β-lactones 184 in good yield (40–85%) and excellent ee. Reduction with
DIBAL gives the diol 185 with the two chlorine atoms intact. 42
O i-Pr 2NEt
Cl
26 Asymmetric Pericyclic Additions to Carbonyl Groups 589
Among various further developments, the formation of the azido ketone 188 is especially
promising. It also illuminates aspects of the mechanism of the hydrolysis of 157 and 165. The
closure of the epoxide 187 and its opening by azide ion with inversion and the exposure of the
carbonyl group 188 by loss of chloride all also occur in the hydrolysis of the CCl 3 group in 157
and 165 (see workbook).
NaOH
OH
THF Ph CCl3 H2O
Ph
O
O
178; 100% yield 179; 75% yield
181
EtO 2C
N
H
O
182; enalapril
N
CO2H
O
•
R
O
H
R
O
O
Cl Cl
Cl Cl
+
2 mol%
quinidine
toluene
DIBAL
25 ˚C
R
OH
OH
163
–25 ˚C
CH2Cl2 Cl Cl
ketene 183 (R)-184; 93-98%ee (R)-185; 95% yield
OTIPS
NaN 3
(R)-185;
i-Pr3SiCl R
OH OTIPS
NaH O
R = C6H13 imidazole
THF R
DMF Cl Cl
Cl
(R)-186; 97% yield (R)-187; 92% yield
DME
H 2O
R
N 3
OTIPS
O
(S)-188; 83% yield

590 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
Carbonyl ene reactions
The carbonyl ene reaction is between a similarly reactive aldehyde and an alkene rather than a ketene.
Glyoxalate esters and chloral are typical of the carbonyl compounds involved. Asymmetric versions
rely on Lewis acid catalysts similar to those used in Diels-Alder reactions based on Ti and Al among
other metals. 43 A simple example is the formation of 190 from methyl glyoxalate and an alkene 189
catalysed by 0.5 mol% of a BINOL-Ti complex 191. Other alkenes that react well are 192 - 195.
Ph
Alder ene reactions
The original ene reaction, invented by Alder, was between an alkene such as 192 and a
dienophile - that is a conjugated unsaturated carbonyl compound. If the reaction is intramolecular,
the alkenes need not be specifi cally activated by conjugation but they must be clearly distinct in
reactivity. Xumu Zhang and group 44 have recently reported asymmetric tetrahydrofuran syntheses
using the BINAP Rh(I) catalyst 21 so successful in hydrogenations. A Z-allyl propargyl ether 196
reacts with this Rh catalyst in an ene reaction that corresponds to the tortured mechanism 197.
The substituents R 1 and R 2 can be a range of alkyl, aryl, and functionalised groups. No absolute
stereochemistry is given but each enantiomer of BINAP produces a different enantiomer of 198.
R 1
O
Nucleophilic Additions to Carbonyl Groups
Allyl metals
H
O
Ti*
0.5 mol%
catalyst
OH
CO2Me Ph CO2Me 189 190; 84% yield, 95-95% ee
192 193
R 2
10 mol%
Rh(COD)Cl 2
194 195
R 1
12 mol%
BINAP
AgSbF6 O
196 197
Closely related to the previous section is the asymmetric addition of allyl stannanes to aldehydes.
The catalyst is the same and the main difference is that an R 3Sn group is lost instead of a proton.
This has the advantage that there is no ambiguity about the position of the alkene in the product.
An example is the addition of an allyl group to the functionalised aldehyde 199. Complexation of
either or both oxygen atoms to the Ti is indicated. 45
BnO
O
H
+
SnBu3
(S)-BINAP-Ti
catalyst 178
–20 ˚C, CH 2Cl2
BnO
OH
199 200 201
H
R 2
R 1
O
O
OR
Ti
OR
O
191; (R)-(+)-BINOL-Ti catalyst
198; 82-96% yields
99.0 to >99.9% ee
R 2

Recent improvements include the replacement of the toxic tin reagent 200 with the allyl silane 46
203. Addition to the alkoxyaldehyde 202 gives 204 that can be transformed into the half-protected
dialdehyde 205.
OR
O
+
H
202 203
Alkynyl metals
SiMe 3
(S)-BINAP-TiF 4
catalyst
0 ˚C, CH 2Cl 2
OR OH
O OH O
204; 97% yield, 91% ee
(97% after recrystallisation)
Ideally it should be possible to add organo-Li and Grignard reagents to prochiral aldehydes and
ketones with a chiral catalyst to give alcohols in good enantiomeric excess. This is diffi cult since
the uncatalysed rate of addition is so high. It is possible to add the less reactive lithium acetylides
such as 207 to ketones in the presence of stoichiometric lithium derivatives of amino alcohols such
as 209, analogues of ephedrine. The product 208 is used in the asymmetric synthesis of the Merck
anti-HIV compound Efavirenz. 47
Cl
CF 3
N
H
O
Ar
206; Ar = 4-MeOC 6H 5
207
Li
Cl
N Ar
H
208; 80% yield, 96-98% e.e.
Among the best catalytic versions of such reactions are Carreira’s additions of alkynyl zinc
reagents to carbonyl compounds. 48 Organo-zinc reagents are very much less nucleophilic than
organo-Li or Mg compounds so the rate of the uncatalysed reaction is small. The catalysts are
again amino alcohols related to ephedrine (such as N-methylephedrine 212) and a big advantage
is that no separate step is needed to create the alkynyl zinc reagent as the acetylene, Zn(OTf) 2
and the amine do the trick. With stoichiometric catalyst 212 the reaction is general for propargyl
alcohols 210 such as 211 and the toluene used as solvent need not be completely dry.
O
R 1 H
H R 2
R 1
OH
The catalytic reaction, using admittedly 20 mol% Zn(OTf) 2, 22 mol% catalyst 212, and 50 mol%
Et 3N, is successful with a variety of functionalised aldehydes and acetylenes such as 213 and 214.
Though toluene is used as solvent, in fact no solvent is necessary. 49
TIPSO
Zn(OTf) 2, 212
toluene, 23 ˚C
26 Nucleophilic Additions to Carbonyl Groups 591
OH
CF3
OH
R2 Ph
210 211; 88% yield, 99% ee
H
205
209
OLi
Ph Me
N
O
HO NMe2
212; N-methylephedrine
O
H +
H
NBn2 20 mol%Zn(OTf)2
22 mol% 212
50 mol% Et3N toluene, 100 ˚C
TIPSO
OH
NBn2 213 214 215; 80% yield, 95% ee

592 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
Addition of alkyl organo-zinc reagents
Though not so general as the reactions we have just seen, the catalysed addition of dialkyl zincs to
certain aldehydes sets a new standard for catalysis that needs some explaining. Dialkyl zincs add
to the pyrimidine aldehyde 216 under catalysis from amino alcohols, amino acids such as leucine
219, hydroxy acids, and simple secondary alcohols or amines such as 218 to give enantiomerically
enriched alcohols 217. Plain sailing so far, except for the extraordinary range of catalysts.
Me
N
The strange thing is that catalysts of low enantiomeric excess, even as low as 0.1% ee, induce asymmetry
of a much higher order (here 95%). This ‘asymmetric amplifi cation’ is particularly intriguing
since ees of about 0.1% can be produced by irradiating racemic leucine with circularly polarised light.
The true catalyst in these reactions is the zinc alkoxide 220 of the product. The ‘initiators’ as they are
better known, such as leucine, merely create a small amount of this true catalyst. 50
Me
N
N
216
O
H
i-Pr 2Zn
catalyst
220
Me
N
N
220
OZni-Pr
1. HCl, H2O
2. NaHCO3, H2O
217
88% yield
85% ee
This is easily demonstrated in what Soai calls ‘practically perfect asymmetric autocatalysis’
with the special aldehyde 221 using 20 mol% of the previously prepared product 222 as catalyst
and enough i-Pr 2Zn to allow for the conversion of the catalyst to the zinc alkoxide. There is considerable
amplifi cation: if the catalyst 222 has 5.5% ee, the product (also 222) is 70% ee. But if
enantiomerically pure catalyst is used, the yield and the ee of the product are practically perfect.
Each molecule of catalyst produces fi ve molecules of itself as product. The amplifi cation factor is
six and if the whole of the product is used in a second reaction with fi ve times as much aldehyde a
second batch of 222, 36 times as much, is the product. 51
t-Bu
O
OH
NHMe
NH2
H
i-Pr2Zn N
'initiator'
Ph
CO2H N
~0.1% ee Me N
216 217; 88% yield; 85% ee 218 219; (S)-leucine
N
221
N
O
H
1.7 equivalents i-Pr2Zn
20 mol% catalyst 222
cumene, 0 ˚C, 3 hours
So how are we to explain such remarkable results? The key point is that all the aldehydes must
have a pyrimidine 216, 221, pyridine 223, or quinoline 225 ring joined to the carbonyl group and
the heterocyclic nitrogen must be meta to the aldehyde.
N
N
OH
5.5% ee catalyst
t-Bu
222; >99% yield; 70% ee
>99.5% ee catalyst 222; >99% yield; >99.5% ee

O
NR 2
N
CHO
i-Pr 2Zn
O
NR 2
Non-linear relationships between ee of catalyst and ee of product require some dimeric
species. Suppose the true catalyst, the zinc derivative of the product, forms dimers. There are two
diastereoisomers of these, a meso dimer 229 and a homochiral dimer 230. If the meso dimer is
more stable than 230 it will absorb all the minor enantiomer 227 leaving only the major enantiomer
228 to catalyse the reaction. Of course, it could be the homochiral dimer 230 that is the active
catalyst as the dimers have spare coordination sites on zinc. This phenomenon is described in
more detail in an excellent paper. 52
Palladium Allyl Cation Complexes with Chiral Ligands
N
OH
i-Pr
In chapter 19 we discussed the uses of palladium allyl cation complexes as electrophiles. We
established that Pd(0) adds to the opposite face of the allylic system to the leaving group 232 to form
an η 3 cation complex 233 and that the nucleophile attacks from the opposite face to the Pd so that
the two inversions lead to retention. We established that regioselectivity and diastereoselectivity
can be well controlled. If this seems unfamiliar we suggest you read the relevant section of chapter
19 before proceeding.
What is new here is that attack of the nucleophile on the complex 233 can lead to asymmetric
induction in a number of ways. For example either enantiomer 234 or 235 could be formed from
the symmetrical complex 233. This involves attack at one enantiotopic end of the allylic system
rather than one enantiotopic face and in this sense rather resembles the ring closing step (82 →
83) in the asymmetric Robinson annelation. Though essential early work 53 was done on the symmetrical
complex 233; R Ph, we shall concentrate on more recent results.
Trost established 54 that the ligand 236 was the best for many of these reactions. Thus racemic
allylic acetate 237 gives a symmetrical allylic cation complex like 233 and the ligand directs the
N
CHO
i-Pr 2Zn
223 225
224; 56 → 85% ee 226; 9 → 59% ee
i-Pr2Zn
216 +
N
H
Me
26 Palladium Allyl Cation Complexes with Chiral Ligands 593
OZnL n
N
227
(R)-monomer
N
H
Me
OZnL n
N
228
(S)-monomer
N
H
R
O
N
Zn
Zn
i-Pr
i-Pr
N N
O
R
H
229; racemic (R,S)-dimer
N
H
R
O
N
Zn
N
i-Pr
Zn
i-Pr
OH
N N
O
R
H
230; (S,S)-dimer
OAc
OAc
Nu
Pd(0)
R R
Nu
R
231
R R
Pd
232
R Pd
233
R
234
R R
235
Nu
i-Pr
R

594 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
malonate nucleophile to one end only to give 238. High ees are achieved only if the counterion is
large - (Hexyl) 4N being the best.
Desymmetrisation of bis allylic esters such as 239 adds another dimension. Asymmetry is
already introduced in the η 3 cation complex 240 by selection of one of the enantiotopic benzoates
as leaving group. Attack of the nucleophile occurs on the same side as the other benzoate, as that
is the side opposite the Pd atom and so there is strong regioselectivity for the site away from the
second benzoate. Since the fi rst formed product 241 is still an allylic benzoate, further reaction
is possible.
O
Cyclisation of the intermediate 241 in the same pot closes the fi ve-membered ring 243 leading
to 244, an intermediate in the synthesis of the anti-viral drug carbovir. Both stereo- and regioselectivity
are controlled by the short tether. 55
241
Pd(0). 236
base
PhO2S
O
N
O
242
Pd
PhO 2S
Catalyst 236 is by no means the only one to achieve such results. Helmchen 56 uses the manganesecontaining
monophosphine 245 for alkylation of malonates with racemic allylic chloride 246 to
give the adduct 247 that is used in the synthesis of the lactone 248.
O
N
O
Ph
O O
Ph Ph
239
P
245
NH
O
HN
PPh 2 Ph 2P
ligand 236
O
NO 2
SO 2Ph
Pd(0). 236
Mn(CO) 3 PdCl
246
Cl
Pd
AcO
OAc
Ph O
PhO2S O
O
N
O
240 241
H
MeO 2C
O N
O
HO
H
243; 97% yield, 96% ee 244
2
CO 2Me
CO2Me
CO2Me
CO2Me
Pd(0). 236
OAc
H CO2Me
CO2Me
H
247; 96% yield
99.5% ee
CO2Me
CO 2Me
237 238; 98% yield, 98% ee
H
Ph O
O
O
H
248
OH
O

Enantioselectivity with open chain compounds is more diffi cult but Trost uses ligand 236 for
the simplest of these: the symmetrical allylic carbonate 249 (note the different leaving group: CO 2
is lost, see chapter 19) with malonate anions formed with CsCO 3. However, this is the best result
from a variety of different open chain allylic carbonates. 57
Intramolecular reactions generally give excellent results. Allylation of the nitroalkane
portion of the indole 251 closes the six-membered ring of the ergoline alkaloids such as
chanoclavine 253. Genet’s study of various ligands revealed that BINAP provided the best
results. 58
AcO
O OEt
249
NO 2
O
NH
+
Pd(OAc) 2
(S)-BINAP
K2CO 3
THF
CO 2Et
CO2Et
Cs2CO3
NO 2
More recently, Trost has developed 59 a clean way to form the diffi cult bicyclic core of the
cinchona alkaloids with good diastereo- and enantioselectivity using his favourite ligand 236.
Chirality is developed at both ends of the new bond: at the allylic carbon (marked with an empty
circle) and at the former enol carbon (marked with a black blob). The two diastereoisomers of
the product 255 and 256 form the core of the quinine alkaloids. They have the same absolute
stereochemistry in the bicyclic core but the stereochemistry of the vinyl group is different.
There is a strong match/mismatch effect: (R,R)-236 gives 4.6:1 diastereoselectivity in favour
of 255 and excellent ee while (S,S)-236 gives 8:1 diastereoselectivity in favour of 256 and
poor ee.
EtO 2C
HO
26 Palladium Allyl Cation Complexes with Chiral Ligands 595
Controlling enantioselectivity at the enol centre alone can be achieved with special reagents
and a very complex catalyst. An allylic carbonate with a fl uorinated esterifying group allylates
a prochiral enolate derived from i-propyl cyanopropionate catalysed by Pd, Rh, and the chiral
Fe ‘TRAP’ ligand 257, gives excellent results. The explanations for these last two examples are
complicated and you are referred to the papers if you want to know more. 60
236
NH
Ph
EtO2C
CO2Et H
250; 98% yield, 92% ee
NHMe
251 252; 60% yield, 95% ee 253; (–)-chanoclavine
N
H
H
3 mol% 236
Pd2dba3.CHCl3 CO2Et
CO2Et
O
O
OCO2Me
CH2Cl2 N
N
254 255 256
(R,R)-236 84% yield, >99% ee
(R,R)-236 + Eu(fod) 3
85% yield, 68% ee
NH

596 26 Asymmetric Induction III Asymmetric Catalysis: Formation of C–H and C–C Bonds
Fe
Summary
This is a very big and growing subject. There are many catalytic reactions, such as the phase-transfer
catalysed alkylation of enolates, that we have no space to discuss here. That particular one is treated
in the workbook.
References
Ar 2P
PAr2
Fe
257; Ar = p-MeOC6H 4
NC
O CF 3
O O CF 3
Me
O
O
Rh(acac)(CO)2
Pd(cp)(π-C 3H 5)
ligand 256
THF, –40 ˚C
6 hours
General references are given on page 893
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21. W. Notz and B. List, J. Am. Chem. Soc., 2000, 122, 7386.
O
Me CN
O
258; 93% yield, 99% ee

26 References 597
22. T. D. Machajewski and C.-H. Wong, Angew. Chem., Int. Ed., 2000, 39, 1352.
23. K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am. Chem. Soc., 2000, 122, 4243; N. A. Paras
and D. W. C. MacMillan, J. Am. Chem. Soc., 2001, 123, 4370.
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25. J. F. Austin and D. W. C. MacMillan, J. Am. Chem. Soc., 2001, 123, 1172.
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E. J. Corey, Org. Synth., 1993, 71, 30.
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39. H. Wynberg and E. G. J. Staring, J. Chem. Soc., Chem. Commun., 1984, 1181.
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27
Asymmetric Induction IV
Substrate-Based Strategy
Introduction to Substrate-Based Strategy
Chiral Carbonyl Groups
The asymmetric Strecker reaction
Chiral Enolates from Imines of Aldehydes: SAMP and RAMP
Chiral Enolates from Amino Acids
Schöllkopf’s bislactim ethers
Other chiral glycine enolates: Williams’s method
Seebach’s relay chiral units
Chiral Enolates from Hydroxy Acids
Seebach’s relay chiral units
Chiral Enolates from Evans Oxazolidinones
Application of asymmetric alkylation with Evans auxiliaries
Aldol Reactions with Evans Oxazolidinones
The syn aldol reaction with boron enolates
Anti-aldols by Lewis acid-catalysed reactions with Evans oxazolidinones
Chiral Auxiliaries
Asymmetric aldol, conjugate addition, and Diels-Alder reactions compared
The Asymmetric Diels-Alder Reaction
Introduction
Diels-Alder reactions with Oppolzer’s chiral sultam
Diels-Alder reactions with pantolactone as chiral auxiliary
Chiral auxiliaries attached to the diene
Improved Oxazolidinones: SuperQuats
Asymmetric Michael (Conjugate) Additions
Michael additions with 8-phenylmenthyl esters of unsaturated acids
Chiral auxiliaries attached elsewhere in asymmetric Michael additions
Other Chiral Auxiliaries in Conjugate Addition
The Evans oxazolidinones
Chiral sulfoxides
Asymmetric Birch Reduction
Birch reduction of benzene
Asymmetric Birch reduction of heterocycles
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

600 27 Asymmetric Induction IV Substrate-Based Strategy
Introduction to Substrate-Based Strategy
In the last few chapters we have started with a prochiral molecule having enantiotopic features:
the faces of an alkene for instance - and differentiated these faces with enantiomerically pure
reagents or catalysts. In this chapter we explore the alternative approach. The enantiotopic faces
are transformed into diastereotopic faces by the covalent attachment of a chiral auxiliary. It seems
inevitable that this auxiliary must be stoichiometric but you will even see that ‘catalytic’ substrate
methodology is starting to emerge. It also seems inevitable that two extra reactions will be needed:
the attachment and the removal of the chiral auxiliary. In spite of this, one of the most important
methods of asymmetric synthesis, centred around Evans’s amino acid-based chiral auxiliaries,
uses this approach.
R O R N Ph
1 2 3
Ph
4
Thus the faces of the carbonyl group in the aldehyde 1 are enantiotopic but after attachment
of a chiral amine they become diastereotopic in the imine 2. The faces of the enolate of the
ester 3 are enantiotopic but those of the enolate of the amide 4, after attachment of the Evans
phenylalanine-derived oxazolidinone, are diastereotopic.
You may notice something else that is different in this chapter. It is much easier to offer
reasonable explanations for substrate-style asymmetric induction because we have a better idea
of the conformation the compound adopts during the reaction as the confi guration of the product
is a guide.
Chiral Carbonyl Groups
The asymmetric Strecker reaction
The Strecker reaction is a way to make α-amino acids 7 from aldehydes 1 with cyanide and ammonia.
Cyanide adds to the unstable imine 5 to give the stable amino nitrile 6 that can easily be hydrolysed
to the inevitably racemic α-amino acid 7.
NH3 H2O R
1
O
HCN
R
5
NH
HCN
R NH2 6
R NH2 7
One asymmetric Strecker reaction 1 uses the enantiomerically pure amine 8, available as both
enantiomers since it is easily prepared by resolution (chapter 24), as a way to make the imine 2
have diastereotopic faces. Cyanide addition is reasonably diastereoselective giving mainly the
amino nitrile 9.
O
CN
OR
CO 2H
R O
+
H2N Ph R N Ph HCN R N
H
1 8 2 9
CN
O
N
Ph
O
O

The most likely explanation is that the imine prefers a Houk-style conformation 2a with the
two marked H atoms in the plane and the cyanide adds 10 to the face of the C=N bond opposite
the larger phenyl group.
R
H
N Ph
=
R
H
H
N Ph
Me
N C
2 2a 10
An advantage of the substrate-based strategy is that the chiral auxiliary is still attached to the
molecule after the induction reaction and so the product, 9 in this instance, can be purifi ed as one
diastereoisomer before the chiral auxiliary is removed. An example of the asymmetric Strecker
reaction in practice is the synthesis of the ‘fat’ amino acid 16 having an adamantyl group to
increase solubility in fats and hence permeability to cell membranes. 2 After purifi cation of the
amino nitrile 13 hydrolysis gives the amide 14, hydrogenation removes (and sadly destroys) the
chiral auxiliary, and a fi nal hydrolysis gives the ‘fat’ amino acid 16.
O NH2
N
H
Ph
Chiral Enolates from Imines of Aldehydes: SAMP and RAMP
R
Aza-enolates derived from imines were introduced in chapter 10. It is easy to see that imines from
chiral amines might well be used to make aza-enolates that would react asymmetrically with
electrophiles. Among the most famous examples are the hydrazones SAMP and RAMP derived
by Enders from proline. 3 The starting material derived from natural (S)-()-proline 17 is called
SAMP 18 and the one derived from unnatural (R)-()-proline is RAMP. The reactions of the two
are identical except that they lead to products of opposite chirality.
Imines 20 formed from SAMP and enolisable aldehydes prefer an E-confi guration across the C=N
bond. Lithiation gives the aza-enolate 21 also with the E-confi guration derived from the preferred
conformation of 20. Reaction with an electrophile gives mostly the diastereoisomer 22.
H
N
O NH2
Me
H
CHO 8
HCN
N Ph
N
11 12; 100%
H
13; 75% yield
14; 81% yield as .HCl
17
(S)-L-(–)-proline
27 Chiral Enolates from Imines of Aldehydes: SAMP and RAMP 601
N
H
H 2,Pd/C
HCl, EtOH
CO 2H
Ph
HCN
37% HCl
R
CN
CN
N
H
9
Ph
Ph
HCl
H2O
O OH
NH2 90 ˚C
4 hours
NH2 15; 86% yield 16; 79% yield
N
NH2 OMe
18; (S)-(–)-SAMP
50-58% overall yield
from (S)-L-(–)-proline
on 75 g scale

602 27 Asymmetric Induction IV Substrate-Based Strategy
R
CHO
19
18
SAMP N
N
R
OMe
1. LDA
The side chain OMe group is essential for the asymmetric induction as it complexes the lithium
atom of LDA so that only one of the diastereotopic protons is removed 23 and holds the aza-enolate
in one confi guration 24 with Li bonded both to N and to O. Electrophilic attack then occurs anti
to the lithium atom on the unhindered face of the aza-enolate 24 to give the product in the same
conformation 22a.
20 LDA
i-Pr
H
R H
i-Pr
N
This is an excellent and popular method but removal of the chiral auxiliary is rather diffi cult
and must be carried out oxidatively to produce the aldehyde product 25A. The chiral auxiliary
emerges as the N-nitroso compound 23 and this can be recycled. An alternative is alkylation
(MeI) and acidic hydrolysis. Reductive removal gives the amine 25B and an intermediate 26 in
the synthesis of SAMP.
N
NO
The electrophile E can be an alkyl halide or sulfate, an aldehyde to give aldol products, or
an α,β-unsaturated ester when conjugate addition is preferred. Examples from simple alkylation
show that the alkyl halide can be primary alkyl, allylic 33, and even an α-bromoester
or γ-bromo-α,β-unsaturated ester 31. The original carbonyl compound that forms the chiral
imine with SAMP or RAMP can be an aldehyde 27 or 29, a ketone (symmetrical 32 or blocked
on one side 35), or an enone. Only the reagents and products are shown with oxidative [O] or
hydrolytic [H 2O] workup. Notice that SAMP is used for the formation of either enantiomer of
28 by using different starting materials but that RAMP is used to enter the other enantiomeric
series from 32.
N
N
OMe
R
R E
20 21; SAMP-azaenolate 22
Me
Me
Me
Li
N
O
N
R
Li
N
O
N
R
E
N
O
N
H
E
23 24 22a
23 oxidative cleavage: reductive cleavage:
26
E
OMe
R CHO
25A
ozone,
CH2Cl 2,
–78 ˚C
or hydrolysis:
1. excess MeI,
2. 5M HCl,
pentane
N
N
OMe
Li
2. E
R E R
22
1. catechol
borane
2. Raney
nickel
E
25B
N
N
N
H
NH2
OMe
OMe

O
27
CHO
Etl
[H 2O]
CO 2Et
RAMP
[H 2O]
Br
Reactions with aldehydes give syn-aldol products 36 in moderate ee but the hydrazones are
crystalline so, at the expense of yield, ee can be raised to 100%. Conjugate addition gives good ees but
moderate yields and the fi rst formed products, e.g. 37, can be converted into useful lactones, e.g. 38.
Chiral Enolates from Amino Acids
Schöllkopf’s bislactim ethers
CHO
(S)-28; 95% ee
71% yield
CO 2Et
OEt
OEt
(S)-30; >95% ee, 80% yield 31 32 33
35
MeCHO
O
3. MeO2C +
O
+
A simpler way to restrict the conformation of an enolate is to confi ne it in a heterocycle and an important
group of chiral enolates come from various derivatives of amino acids. The fi rst successful such
compounds were Schöllkopf’s ‘bislactim ethers’ 41 derived from the diketopiperazines 40 formed
when an amino acid such as alanine 39 condenses with itself. 4 Treatment of 41 with butyl lithium
creates a lithium enolate on one position in the ring: the methyl group in the other position keeps
the chirality intact. Alkylation occurs selectively on the opposite side to the remaining methyl group
42 and hydrolysis releases a new tertiary amino acid 43 and one of the original alanines.
O
1. SAMP
2. LDA
3. PhCHO
1. SAMP, 2. LDA
NH 2
OH
39
(S)-(+)-alanine
1. BuLi
27 Chiral Enolates from Amino Acids 603
(S,S)-adduct
86% yield
72%ee
MeO 2C
CHO
(R)-28; 95% ee
65% yield
Br
1. crystallise
hydrazones
2. Hydrolyse
CHO
37; 46% yield [H 2O]
H
N O
O N
H
40; ‘diketo
-piperazine’
N OMe
Et 3O
BF 4
2. RBr MeO N
R 3. H3O
MeO
NaBH 4
Mel
[O]
SAMP
[H 2O]
O OH
O
O
29
(S,S)-36, 35% yield, 100%ee
H2N
42 43
N
CO 2H
R
CHO
(S)-34; >97% ee, 61% yield
O
N OMe
41; ‘bislactim
ether ’
(R)-38
35% yield
from MeCHO
>95%ee

604 27 Asymmetric Induction IV Substrate-Based Strategy
A better version 47 has a larger isopropyl group, derived from valine 44, to differentiate the
faces on the enolate, and no substituent at the enolate site. The starting material 46, prepared from
valine 44 and glycine, is commercially available, as is its R-isomer and the derived bislactim ether
47.
HO
NH 2
O
COCl 2
Cl
Treatment with BuLi generates chemoselectively the lithium enolate of the less substituted
lactim and electrophiles attack the face opposite the branched isopropyl group. Selectivity is
good: the purifi ed diastereoisomers can be isolated in over 80% yield and hydrolysis requires only
dilute aqueous acid as these are easily protonated imines. These examples show a benzylic and
an allylic halide. The fi rst 50a is unnatural (R)-phenylalanine and the second 50b is an unnatural
amino acid.
47
THF
40 ˚C
44; (S)-(+)-valine 45
1. BuLi
H
N O
Et 3O
BF4
Conjugate addition is also possible with α,β-unsaturated esters and the interesting pyridine
derivative (E)-51 gives a 90% yield of the conjugate addition product 52 that is 95% one diastereoisomer.
Purifi cation and hydrolysis gives the substituted proline derivative 54 via the amino acid
53. Many variations of this theme have been played with different electrophiles.
H
N
O
Cl
O
1. Et3N
H 2N
N OMe
O N
H
MeO N
46; 91% from Val 47; 82% yield
MeO
0.25M
HCl
H 2O
Li
N OMe
N
48
H 2N
CO2H
Ph
2. RBr
50a; (R)-Phe
73% yield, 92% ee
H 2N
CO2H
CO 2Et
2. reflux, toluene
N OMe
MeO N R
49a; R = Bn, 81% yield
49b; R = cinnamyl, 90% yield
Ph
(R)-50b
89% yield, >95% ee

47
2.
N
HCl
H 2O
H 2N
1. BuLi
CO2Me
(E)-51 52
CO2Me H
CO2Me
N
O
N
H
53 54
Other chiral glycine enolates: Williams’s method
N OMe
MeO N
CO2Me
Continuing the theme of pyridine in amino acids we take (S)-azatyrosine 56 as an example
of Williams’s chiral glycine enolate equivalent. 5 The only difference between tyrosine 55 and
aza-tyrosine 56 is the nitrogen atom in the benzene ring yet the one is an amino acid found in
protein and the other an antibiotic. The most appealing approach to aza-tyrosine is the alkylation
of some asymmetric equivalent of glycine enolate 57 and, probably, a protected version of 58.
HO 2C
NH2
55; (S)-L-tyrosine
in proteins
OH
HO2C
NH2
N
The unusual amino acid 56 has been synthesised 6 by alkylation with the silylated bromide 61
prepared from commercially available 59. You might notice the radical bromination step giving
only moderate yields.
N
59; commercially
available
OH t-BuPh2SiCl
27 Chiral Enolates from Amino Acids 605
imidazole
DMF
56; (S)-L-Azatyrosine
antibiotic
The chiral glycine equivalent 62 is available from Glytech Inc., Fort Collins, Colorado. Its
sodium enolate reacts with 61 to give a reasonable yield of one pure diastereoisomer of 63 from
which the silyl group is easily removed to give 64.
OH
OSiPh 2t-Bu NBS
H
N
HO2C
N
NH2
CO2Me
+
X
57 58
N
AIBN
CCl4 Br
N
60; 100% yield 61; 51% yield
N
OSiPh 2t-Bu
OH

606 27 Asymmetric Induction IV Substrate-Based Strategy
Ph
Ph
O
Removing the chiral auxiliary is more tricky. One hydrogenation cleaves both benzylic C–O
bonds and releases 65. This is not isolated but hydrogenated under stronger catalysis in acidic
solution to cleave the benzylic C–N bond and release aza-tyrosine 56 as its dihydrochloride. The
chiral auxiliary is destroyed in this process.
64
Seebach’s relay chiral units
N
O
CO2Bn 62
Ph
Ph
O
N
Ph
Ph
CO 2Bn
O
Probably the most important and useful of all these amino acid-based chiral enolates are those
of Seebach. 7 The simplest is made from proline 17 simply by forming the N,O-acetal 66 with
pivaldehyde (t-BuCHO). The lithium enolate 67 is alkylated diastereoselectively with various
electrophiles E to give one diastereoisomer of 68.
N
H
1. H 2 (50 psi)
Pd(OH) 2/C, THF
CO2H
17; (S)-L-Proline
TBAF
THF
Ph
Ph
t-BuCHO
pentane
cat. CF 3CO2H
HO
1. NaHMDS
N
H
2. 61
There is a lot to explain here. It looks very odd that syn-66 is preferred and even more so that
alkylation of the enolate 67 occurs on the same face as the undoubtedly large t-butyl group. Both
these issues matter as the original chiral centre in proline is destroyed in 67 and only the newly
introduced chiral centre in 66 retains the stereochemical information from proline. This centre acts
as a relay for the stereochemical information. Others call this a ‘memory’ effect. The acid-catalysed
formation of the N,O-acetal 66 is under thermodynamic control (acetal formation is reversible) and
the conformation 66a shows that the molecule folds about the necessarily cis ring junction and the
t-butyl group prefers to be on the outside (or exo- face). 8 The enolate 67 has a fl attened conformation
67a (probably more fl attened than this!) and its alkylation is under kinetic control. Attack is
preferred on the outside, exo-face. Note that this happens to restore the original confi guration at the
ex-proline chiral centre.
O
N
N
O
CO2Bn
63; 60% yield, one diastereoisomer
OH
64; 79% yield, one diastereoisomer
N
O
65
H
O
O
N
t-Bu
66; 92% yield
1. LDA
–78 ˚C
THF
OH
2. H2 (50 psi)
Pd/C, HCl/H 2O
t-Bu
N
O
67
N
OSiPh 2t-Bu
CO2H
OH
H2N
N
56; 64% yield (.2HCl)
OLi
2. E
t-Bu
N
E
O
68
O

t-Bu
N
H
O
O
=
N
O
H
66
H
66a
The examples below show that alkylation with a variety of groups gives good yields of the
purifi ed diastereoisomers shown (69–71). The last example 71 shows that hydrolysis gives the
alkylated proline 72. As these are tertiary amino acids, there is little chance of racemisation.
MeI
Alkylated prolines can be incorporated into synthetic peptides as mimics for the β-turn found in
the conformation of folded proteins. One such compound 9 combines a spirocyclic proline derivative
77 with tyrosine. The allyl group in 74 is oxidatively cleaved to give 75 and eventually coupled to
the nitrogen atom of the amide in 76 by a Mitsunobu reaction.
70
67
67
RNH 2
Chiral Enolates from Hydroxy Acids
Seebach’s relay chiral units
27 Chiral Enolates from Hydroxy Acids 607
O
Ph Br
N
Me
O
O
Even more famous is Seebach’s related chemistry on hydroxy acids 10 such as lactic and mandelic
acids from the chiral pool (chapter 23). Mandelic acid 78 gives the cis pivaldehyde acetal 79
in 74% yield after a recrystallisation to remove a small amount of the anti isomer. The lithium
N
H
OLi
O
E
O
O
E
N
H
67a 68a
t-Bu
t-Bu
69; 93% yield 70; 87% yield
N
H
NaBH4
deprotect
N
O
67
Ph
O
t-Bu
71; 91% yield
O
N
48% HBr
Br
N
H
N
O
Ph
CO 2H
72; 71% yield
NHR Cbz NHR
Cbz NHR
73 74 75
OH
O
OsO 4
NaIO 4
N
Cbz
O
NHR
Ph3P DEAD
N
H
O
76 77
N
NR
O
CHO
O

608 27 Asymmetric Induction IV Substrate-Based Strategy
enolate 80 reacts on the side opposite the t-butyl group to give 81. As with the amino acids, the
original chirality is restored. Hydrolysis gives the new hydroxy acid 82.
Lactic acid 83 does much the same thing though the stereoselectivity in forming the initial
acetal 84 is not so good - as might be expected with the smaller methyl group.
HO
Me
CO2H
83; (S)-(+)lactic
acid
Ph
HO CO2H
78; (S)-(+)mandelic
acid
t-BuCHO
PrI
pentane
cat. TsOH or
CF 3CO 2H
pentane
cat. TsOH or
O
CF3CO2H t-Bu
t-Bu
O
O
t-Bu
Ph
Me
O
O
O
Ph
O
O
84; 4:1 diasts; 87% yield
recrystallise twice
to 96% de
1. LDA
–78 ˚C
THF
The scope and diastereoselectivity of reactions with various electrophiles are shown below.
The only weak point is the poor diastereoselectivity in aldol reactions with aldehydes. These
methods have been widely used as they are robust and reliable. Nevertheless the methods we have
so far described for chiral enolates are less signifi cant than the Evans chiral oxazolidinones in
the next section.
EtI, allyl and
benzyl bromides
t-BuCHO
81
O
79; 24:1 diasts
recrystallise
74% yield
1. LDA
KOH
MeOH, H2O
10 minutes
60 ˚C
R Me
HO
R
R
Me
O
O
O
O
O
O
t-Bu
t-Bu
77-82% yield
95-98% de
–78 ˚C
THF
ketones: acetone
cyclopent- and hexanone
83-87% yield
>95% de
t-Bu
HO
O
O
t-Bu
82
Me
O
Ph
Ph
O
80
CO2H
OLi
OLi
2. E
t-Bu
R
O
85 86
aldehydes
MeCHO, PhCHO
HO H
R Me
O
t-Bu
O
O
84-85% yield
82-84% de
two aldol diastereoisomers
Me
O
O

Chiral Enolates from Evans Oxazolidinones
The main Evans oxazolidinones are 87/88, derived from phenylalanine, and 89/90, derived from
valine. All are available at a price - higher naturally for the unnatural R-isomers. Generally 87/88
are preferred as most of their derivatives are crystalline so that purifi cation of diastereoisomers
is easier. 11
The preparation of each is easy and this is the route to 87/88 as described by Evans 11 in Organic
Syntheses. Reduction of the free acid 91 with the borane-dimethylsulfi de complex is easy if smelly
and the rest is straightforward. The same auxiliary 87 can be used with any acid: acylation with
the acid chloride gives the chiral derivative 93 ready for enolate formation.
Ph
H 2N
HN
CO2H
O
O
Ph
87; oxazolidonone
78-79% after
recrystallisation
R
O
Cl
The benzyl group has three jobs to do: (i) force conformation 93a with R 1 anti to N, (ii) Make
the ‘cis’ or ‘Z’ enolate 94 selectively from this conformation, and (iii) direct the electrophile to
the top face of the enolate to give 95. Chapter 4 reveals the reason why this enolate is called Z.
Cleavage of the product 95 to give the free acid 96 is best done with LiOOH made from H 2O 2 and
LiOH. This is the best nucleophile for attacking the ‘exo’ carbonyl without epimerisation through
enolisation.
R 1
Ph
HN
Ph
O
O
N
O
87 (S)-(–)-4-benzyl-
2-oxazolidinone
O
O
27 Chiral Enolates from Evans Oxazolidinones 609
91; (S)-(+)-Phe
165 g scale
LDA
Ph
R 1
HN
O
Ph
O
88 (R)-(+)-4-benzyl-
2-oxazolidinone
1. BF3.Et2O 2. BH3.Me2S 3. NaOH, H2O
2.
O Li
1. BuLi
N
O
O
H 2N
R
OH
Ph
K2CO3 92; phenylalaninol
73-75% after
recrystallisation
R 2 Br
R 1
O
N
(EtO) 2CO
O
O
Ph
93; chiral acid
derivative
R = Me; 91-96%
R 2
Ph
O
N
O
O
H 2O 2
LiOH
93a 94; 'Z'-enolate 95 96
HN
O
O
89 (S)-(–)-4-isopropyl-
2-oxazolidinone
HN
R 1
O
R 2
O
90 (R)-(+)-4-isopropyl-
2-oxazolidinone
O
OH

610 27 Asymmetric Induction IV Substrate-Based Strategy
If the other enantiomer is wanted, two strategies are available. Either the alkyl groups can be
added in the reverse order, if this is mechanistically reasonable, or the oxazolidine 93c can be
constructed from nor-ephedrine from the chiral pool (chapter 23). Hence both enantiomers of 96
can be made in good yield and high ee.
R 2
Ph
O
N
O
Application of asymmetric alkylation with Evans auxiliaries
O
Modern treatments for arthritis includes inhibition of the collegenase enzymes that attack connective
tissue in the affected joints. One such is the peptide analogue 97 clearly made from a tyrosine
derivative and the unusual carboxylic acid 98 also containing a hydroxamic acid. This unusual
functional group can be made from a carboxylic acid so the target is a diacid derivative of 98 with
the two acids distinguished in some way.
H
O
R 1
N
H
O
HN OH
93b
O
N
O
Me Ph
93c
O
O
97; collegenase inhibitor
1. LDA
2. R 1 Br
1. LDA
2. R 1 Br
R 2
R 1
The Evans alkylation method is ideal for this compound. 12 The phenylalanine-derived auxiliary
87 is acylated to make the starting material 99. The sodium enolate is alkylated with t-Bu
bromoacetate to give 100 with the expected stereoselectivity. Exo-cleavage gives 101 that has one
free CO 2H group and one protected as a t-Bu ester. This was used to make 98.
Ph
O
99
N
O
O
OMe
1. NaHMDS
THF, –78 ˚C
2.
Br CO2t-Bu C–N
amide
t-BuO2C
R 1
Ph
R 2
98
O
95b
O
N
N
O
O
O
O
Me Ph
95c
H
O
O
OH
O
HN OH
N
O
O
Ph
100; 74% yield, >95% de
+
H 2O 2
LiOH
H 2O 2
LiOH
H 2N
ent-96
O
OMe
(S)-tyrosine derivative
H
O
LiOH
H 2O 2 OH
CO2t-Bu
101; 91% yield
'enantiomerically pure'

Aldol Reactions with Evans Oxazolidinones
The syn aldol reaction with boron enolates
The boron enolate of the starting material 102 reacts with an aldehyde such as PhCHO to give 103
with excellent selectivity: the induction from the oxazolidinone to the methyl group is near perfect
and the relative stereochemistry of the aldol 11 is 500:1. Hydrolysis gives the hydroxy-acid 104 in
nearly 100% ee and recovered auxiliary 87.
Ph
O
N
102
O
O
1. Bu2B OTf
Ph
OH
The stereochemistry is more tricky to understand than that of the alkylations. Aldol reactions of the
lithium enolates such as 94 are nowhere near so stereoselective as either alkylation or boron-mediated
aldols. The key point is that lithium can coordinate to four different atoms at a time whereas a Bu 2B
group has only two spare coordination sites. The Z-boron enolate 105 is formed but coordination of
the incoming aldehyde to the boron atom displaces the oxazolidinone C=O group and the left hand
half of the molecule rotates about the C–N bond by 180 to give 106. Why it should do this is open to
question. Evans suggests that there is better (longer) conjugation as a result. Aldol reaction through a
six-membered cyclic mechanism 106 gives 107, more usually drawn as 107a.
1. Bu2BOTf 93a
2. Et 3N
27 Aldol Reactions with Evans Oxazolidinones 611
2. Et3N 3. PhCHO
HO
R 1
R 2
O
Ph
N
The stereochemistry of the aldol step 106 results from the chair-like conformation of the transition
state 109a with R 1 forced to be axial because it comes from the Z-enolate 108 and R 2
choosing to be equatorial (see explanation of simple syn/anti aldols in chapter 21). The absolute
stereochemistry comes from the blocking of the lower face of the enolate by the benzyl group of
the chiral auxiliary 109b.
O
N
O
O
Ph
103; 84-93% yield
500:1 syn aldol selectivity
>97% one diastereoisomer
O O
B
Bu Bu
105
N
R
O
1
O
O
R2 =
R 2 CHO
OH
R 1
Ph
O
Bu
Ph
107 107a
Bu
N
O
B
O
LiOH, H 2O 2
THF, H 2O
R 2
O
O
R 1
Ph
106
N
Ph
OH
O
OH
104; 80-90% yield
>99% ee
+ 89% recovered
auxiliary 87
O
O

612 27 Asymmetric Induction IV Substrate-Based Strategy
105
Bu 2B
R 1
O NR 2
Z-enolate 108
R 2 CHO
B
O O
R1 H
H
R2 Bu
Bu
Anti aldols by Lewis acid-catalysed reactions with Evans oxazolidinones
Though either enantiomer of a syn-aldol can be made by using the right auxiliary in an Evans aldol
reaction the anti aldols cannot be made this way. The addition of a Lewis acid catalyst transforms
the situation. 13 Using the valine-derived chiral auxiliary 89, the same Z-boron enolate 111 is used
but the aldehyde is added in the presence of a threefold excess of the Lewis acid Et 2AlCl. The
product is predominantly one enantiomer of an anti-aldol 112.
R 1
O
N
O
O
1. Bu2B OTf
2. Et 3N
R 1
Instead of complexing to the boron atom, the aldehyde prefers the Lewis acid and the ‘open’
or ‘extended’ transition state 113 leading to the stereochemistry shown in a Newman projection
as 114. In fact, as well as the anti-aldol 112, both enantiomers of syn-aldols are formed in small
amounts - around 5% of 116 and traces of 117.
With a ‘smaller’ Lewis acid (TiCl 4) a slightly different ‘open’ or ‘extended’ transition state 115
is preferred leading predominantly to one syn-enantiomer 116. These variations on aldol reactions
with the Evans auxiliaries allow the synthesis of almost any enantiomer in good yield.
NR2
O
B
O O
R1 H
H
R2 Bu
Bu
109a 109b
O O
B
Bu Bu
N
O
R 2 CHO
3 equivalents
Et 2AlCl
63-86% yield
110 111; Z-boron enolate 112; anti-aldol
R 2 CHO
111 3 equivalents
Et 2AlCl
1. Bu2BOTf
2. Et3N 110
3. R2CHO 2 equivalents
TiCl4 Et
R 1
Cl4Ti
R 2
O
Al
Cl Et
H
Bu Bu
O B
H
N
O
O
R 1
R 2
O
HO H
H
N
O
O
R 2
R
HO
2
OH
H
R 1
O
N
O
R1 H
113 114 112
H
O R1 R2 O O
N O
H
B
Bu Bu
R 2
OH
R 1
115 116; 87-94 parts of
50-72% yield
O
N
O
O
R 2
OH
R 1
H
Ph
O
N
117
N
N
O
O
O
O
O
O
O

Chiral Auxiliaries
Asymmetric aldol, conjugate addition, and Diels-Alder reactions compared
Since conjugate (Michael) addition and Diels-Alder reactions use α,β-unsaturated carbonyl
compounds, asymmetric versions of these reactions could use the auxiliaries that we have seen
in aldol reactions in the form of 118 and 119. Diels-Alder reactions work very well with these
unsaturated amides and also with amides 121 derived from Oppolzer’s chiral sultam 14 120,
prepared simply from camphorsulfonyl chloride.
O
O
R N O
O
O
R N O
S
Ph
O O
S
O O O
118 119
120 121
There are other considerations than mere analogy. If R* represents some chiral auxiliary, a
Diels-Alder reaction on 124 gives a product 125 with two new chiral centres, one, at C-2 in exactly
the same place as in the aldol products such as 107. Michael (conjugate) addition to 124 on
the other hand gives a compound 122 with only one new chiral centre (C-3) one atom further
away from the chiral auxiliary. Another substitution pattern 128 still creates a new chiral centre
at C-2 in the Diels-Alder adduct 129 but this time Michael addition does the same. However,
the new centre is not created in the conjugate addition step, as that gives the enolate 127, but in
the protonation of 127, an inherently less well controlled and probably reversible step. We shall
therefore consider Diels-Alder reactions fi rst and tackle the more troublesome Michael additions
in the next section.
R
X
X
O
R*
R
X
OH
R*
A study of the substituents on the oxazolidinone ring revealed that the highest diastereoselectivity
in methylation of the lithium enolate of 122 was achieved when R t-Bu. The normally
used auxiliaries, with R i-Pr and Bn respectively, performed less well, but the compound with
R Bn was the best compromise between availability and selectivity. 15
O
N
R
O
3
3
R
122
O
123
OH
124
O
125
O
R
2
R*
H
X
2
R*
X 3
2
1 R*
3
2
R
R
R
126 127 128 129
O
1. LDA,
–30 ˚C,
THF
2. MeI
H
130 131a 131b
27 Chiral Auxiliaries 613
O
N
R
O
O
X
+
3
2
O
1
O
NH
R*
N
R
O
O
N
R
3
2
O
R*
R*
R
R 131a:131b
Ph 2:1
i-Pr 6:1
benzy1 20:1
t-Bu >100:1

614 27 Asymmetric Induction IV Substrate-Based Strategy
The Diels-Alder reaction with the analogous compound 132 needs Lewis acid catalysis and
shows the expected regioselectivity 135. The predicted stereoselectivity is endo addition to the
face of the diene opposite group R 133 to give the diastereoisomer 135a.
Et Et
Et Et
O O
Al
O O
H
Al
O O
O O
N O
Et2AlCl –30 ˚C
N O
N O
N
R
CH2Cl2 toluene
R
H
R
R
132 133
134 135a
The isomer 135a is indeed favoured and the actual results for the four compounds are remarkably
like those for the alkylation. The minor product 135b has the anti stereochemistry across the
new six-membered ring but these two centres have the opposite stereochemistry relative to that of
the chiral auxiliary. The message is that, in most cases, R benzyl is the sensible choice but that
if it performs poorly there ought to be a big improvement with R t-Bu.
O
N
The Asymmetric Diels-Alder Reaction
Introduction
O
O
Et2AlCl
–30 ˚C
R
R
R
CH2Cl2, toluene
132 135a
135b
Most asymmetric Diels-Alder reactions have the chiral auxiliary attached to the dienophile as
in the example we have just seen. 14 One of the earliest was the blocked α-hydroxyenone 16 136
that cyclises with electron-rich dienes to give adducts such as 139 and was used in a synthesis of
pumilio toxin 143 based on that of Overman. 17 The weakness here is the cleavage of the auxiliary
requires reduction to a diol and periodate cleavage with the inevitable destruction of the auxiliary.
O
O
CHO
NHCO2Bn
1. LiBH4
OH
OH
ZnCl2, –78 ˚C
toluene
NH
CO2Bn
2. NaIO4 MeOH, H2O (diol cleavage)
NH
CO2Bn 136 137 138
N
O
O
O
+
O
N
O
O
O
R 135a:135b
Ph 4:1
i-Pr 10:1
benzy1 17:1
t-Bu 68:1

This time the Lewis acid is ZnCl 2 and this holds the chiral dienophile in a fi xed conformation
139. Reaction through the endo arrangement 140 gives one enantiomer of the product 137 in 67%
yield and 99% ee.
136
ZnCl 2, –78 ˚C
toluene
The rest of the synthesis of pumiliotoxin is straightforward involving a Horner-Wadsworth-
Emmons olefi nation (chapter 15) and a hydrogenation that accomplishes reductive amination and
the control of another chiral centre. This synthesis is also discussed in chapter 21.
138
H
cis
H
H
N
CO2Bn H
t-Bu
H
O
OH
O
Zn O
O
Zn
H
O
H
NH
CO2Bn
139 140 137
(MeO 2P
Diels-Alder reactions with Oppolzer’s chiral sultam
O
H H
NaH
O
NH
H 2 O
Bu
Bu
H H
NHCO 2Bn
Oppolzer’s chiral sultam 120 is easily converted to the amide 144 with α,β-unsaturated acid
chlorides and reacts with dienes with the Lewis acid EtAlCl 2 as catalyst. The adduct 145 is
essentially a single compound and LiOH hydrolysis gives the simplest of all Diels-Alder adducts
146 as a single enantiomer in good yield. 18
NH
S
O
O
120; Oppolzer's
chiral sultam
27 The Asymmetric Diels-Alder Reaction 615
S
O
N
O O
144
H
141
H H
O
Bu
N
H H H
H 2, Pd/C
HCl, EtOH
142 143; (+)-pumiliotoxin C
EtAlCl 2
–78 ˚C
CH2Cl 2
N
S
O
O O
145; 81% yield, 99% de
after recrystallisation
LiOH
CO 2H
146; 100% ee
82-84% yield
after recrystallisation

616 27 Asymmetric Induction IV Substrate-Based Strategy
The Lewis acid holds the acylated sultam in conformation 147 and the diene approaches from
the less hindered lower face away from the camphor cage. As both enantiomers of camphor are
available, either enantiomer of Diels-Alder adducts can be prepared in this way. This one 146
was used in an asymmetric synthesis of shikimic acid 148, the biological precursor of aromatic
rings. 19
144
EtAlCl 2
–78 ˚C
CH2Cl 2
S
O O
N
O
Al
Et
147
1
CO2H Only relative stereochemistry (chapter 21) now needs to be controlled and an iodolactonisation
followed by elimination gives 149, epoxidation and elimination 151, a second epoxidation
and then simple treatment of 152 with basic methanol gives the methyl ester 153 of the target
molecule.
O
O
ArCO 3H
O
O
O
HO
O
152; 89% yield
MeOH
Na2CO 3
The mechanism of the last step is interesting. The lactone 152 cannot form an enolate as it
would be at a bridgehead but after methanol has opened the lactone to give 154, the enolate 155
can form and immediately fragments. Notice that the original chiral centre, introduced in the
asymmetric Diels-Alder reaction, is destroyed in this step after it was used to control the formation
of the three OH groups. This synthesis is also discussed in chapter 21.
HO
O
146
1. I2,
NaHCO 3
2. DBU
O
MeOH
O
146
1. DBU,
Ph 3P
Me3SiBr
?
HO
HO
O
2. 1M HCl HO
149; 84% yield 150; 81% yield 151; 85% yield
HO
O
Na2CO3 HO
O
HO
152 154 155
O
OMe
HO
153;
methyl
shikimate
96%
yield
O
O
O
OMe
6
5
4
OH
2
3
148; shikimic acid
HO
HO
O
ArCO3H
OH
153
CO 2Me

Diels-Alder reactions with pantolactone as chiral auxiliary
We saw pantolactone 156 acting as a reagent in chapter 26. Here it esterifi es an unsaturated acid to
control a Diels-Alder reaction. It has two main advantages. It is easy to use on a large scale and it is
easily removed from the product. The simple acrylate derivative 157 reacts with cyclopentadiene
to give essentially pure (by HPLC) adduct 158 in 81% yield after two recrystallisations. 20
OH
O
O
Cl
O O
10 mol% TiCl 4
O
O
Et3N
7:1 CH2Cl2, petrol
156; (R)-(–)-D
CH2Cl2, –24 ˚C
O
1 hour –10 ˚C
pantolactone 157; 88% yield
100 g scale distilled
Hydrolysis is simpler than those we have seen before and the separation of the crystalline Diels-
Alder adduct 159 from the soluble pantoic acid 160 simplicity itself. Acidifi cation then recreates
the chiral auxiliary 156 for the next reaction.
158
275 g scale
+
O OH
159; crystallises
135 g; 89% yield
100% ee
Chiral auxiliaries attached to the diene
CO 2H
OH
160
pantoic acid
in solution
Most asymmetric Diels-Alder reactions have the chiral auxiliary attached to the dienophile as an
ester or an amide. There is no such obvious place to attach an auxiliary to a diene but the chiral
analogue 161 of Danishefsky’s diene has a C 2 symmetric amine 164 attached as an enamine.
Cycloaddition without a Lewis acid gives good selectivity in the formation of adduct 21 162.
Reduction and hydrolysis releases the enone 163 in reasonable ee.
RO
Ph
1. 5M NaOH
1.1 L THF
550 mL MeOH
1.1 L H2O N
161
2. 4M HCl
Ph
27 The Asymmetric Diels-Alder Reaction 617
CHO
–10 ˚C
toluene
RO
Ph
N
OH
CHO
Ph
162; 71% yield
R = t-BuMe 2Si
1. LiAlH 4
2. 10% HF
MeCN
O
O
O
O
158; 81% yield
after two recrystallisations
90-95 ˚C
2-3 hours
extract
EtOAc
O
Ph
OH
O
O
156; D-pantolactone
122 g; 85% yield
100% ee
163; 79% yield
88% ee
H
N
164
OH
Ph

618 27 Asymmetric Induction IV Substrate-Based Strategy
Danishefsky’s diene 165 reacts with the same dienophile to give racemic 163. The hydrolysis of
the adduct is much the same in both cases but protonation of the nitrogen atom 166 is easier.
RO
165
OMe
RO
Ph
Improved Oxazolidinones: SuperQuats
H
N
166
Ph
In spite of the excellence of all these auxiliaries in their various fi elds, the oxazolidinones remain
the most widely useful. And they, like many of the others, still cause problems in the vital step of
hydrolysis to remove the chiral auxiliary. Here are three examples 22 where hydrolysis is carried
out with the standard reagents: 4–8 equivalents of 30% H 2O 2, then 2 equivalents LiOH in 3:1
THF:H 2O. The fi rst two examples give signifi cant amounts of unwanted endo hydrolysis while the
last is partially epimerised at C-2.
One solution is to make the oxazolidinone ring more resistant to hydrolysis by packing it
with substituents. Among the best examples are the ‘SuperQuats’ developed by Steve Davies at
Oxford. 23 Valine (the unnatural isomer in this case) is used to construct an oxazolidinone with
two geminal methyl groups 171. We show a simple alkylation of the lithium enolate: note the high
yield of both the fi nal product after hydrolysis 174 and the chiral auxiliary 171 ready for recycling.
There is no endo hydrolysis nor epimerisation.
OH
RO
+ 164
O O
H
O O
OH O O
N3
N O
N O
N O
N O
Ph
Ph
R
Ph
2
O O
R1 hydrolysis
exo endo 2
167; 91% yield >99% ee
6% endo hydrolysis
168; 76% yield >99% ee
16% endo hydrolysis
169; epimerisation
at C-2 during hydrolysis
BocHN
CO 2Me
170; (R)-D-Boc-valine
1. LiHMDS
THF, –78 ˚C
2. BnBr
Ph
O
1. 4 x MeMgBr
2. t-BuOK, THF
N
O
O
173; 71% yield >95% de
LiOH
HN
O
O
171; 63% yield
THF/H 2O
Ph
1. BuLi
2. EtCOCl
O
OH
174; 98% yield
>95% ee
+
OH
O
N
HN
O
O
O
172; 73% yield
O
171; 98% yield
163

Asymmetric Michael (Conjugate) Additions
Michael additions with 8-phenylmenthyl esters of unsaturated acids
Though some of the auxiliaries we have been discussing will initiate asymmetric Michael
additions, there are two that are particularly effective and we shall discuss mainly those. The
fi rst is based on a cyclohexane ring with an equatorial OH and an aromatic blocking group.
The most famous is 8-phenylmenthol 175, made from the natural terpene pulegone 24 (chapter
23) though later discoveries have shown that much simpler auxiliaries, even the bare bones 177
can work quite well. 25
Ph
OH
175; 8-phenylmenthol
Ph
O
O
R
OH O R
176 177
178
Conjugate additions of organocuprates as their BF 3 complexes (RCu BF 3) add with good
stereo-selectively to 176; R Me even though the nearest stereogenic centre in 176 to the one
being created has a 1,5 relationship, evident in the product 179. Two examples, 180 with an
aryl and 181 with an alkyl nucleophile, show high selectivity 99% ee in both cases. 26 Other
nucleophiles such as amines and thiols also give good results. 27
176; R = Me
RCu•BF 3
Ph
O
O R
Me
H
Me
O Ph H
HO
Me
O Bu H
HO
This and many other results, including the much lower diastereoselectivity when the cis alkene
is used, suggest that π-stacking between the alkene and the benzene ring means that the conformation
of 176 in reaction is 176a rather than 176b. The same conformation with the cis-alkene 182b
would be destabilised.
O
176a
O
27 Asymmetric Michael (Conjugate) Additions 619
R
179
176b
ester
hydrolysis
The same auxiliary gives high enantioselectivity in Diels-Alder reactions 28 with cyclopentadiene
and butadiene - it gives good yields of 146 used in a synthesis of sarkomycin. 29 In a later
section of this chapter you will see it used in asymmetric Birch reduction.
O
O R
182b
O
(S)-(–)-180
75% yield
>99% ee
(R)-(–)-181
76% yield
>99% ee
O
O
R

620 27 Asymmetric Induction IV Substrate-Based Strategy
Chiral auxiliaries attached elsewhere in asymmetric Michael additions
Cyclic α,β-unsaturated carbonyl compounds cannot have a chiral auxiliary attached in the same
way. We shall illustrate the many ingenious solutions to this problem with two heterocyclic
examples. Both also show the effects of modifi cations of 8-phenylmenthol. The fi rst is a pyridinium
salt 184 and the chiral auxiliary is attached through an ester group to the nitrogen atom of the parent
pyridine 183; R 3Si TIPS, i-Pr 3Si. Addition of a Grignard reagent to the less hindered carbon
atom next to N gives the enol ether 185 and hence the enone 186 on workup. 30 Though many variations
in the group R* were tried, the best results were with 8-phenylmenthyl itself (R*OH 175).
OMe
N
SiR3
OMe
N
CO2R* SiR3
RMgX
N
CO2R* The second is a dihydropyridone with the chiral auxiliary also attached to nitrogen 31 through
an ester group 187. The nucleophile is an allyl silane, requiring Lewis-acid catalysis for reaction
(chapter 12). The chiral auxiliary is attached to the opposite end of the electrophilic enone system
this time but at about the same distance from the prochiral electrophilic carbon. Though 187;
R Ph gave quite good results (92:8 in favour of 188), much better results were achieved with 187;
R 2-naphthyl (97:3) suggesting that some conformation such as 189, with good π-stacking
making for a very hindered face of the enone, is responsible.
R
R*OCOCl
The simpler auxiliaries we mentioned at the start of this section are effective in the addition
of amines under pressure to crotonates. Of many auxiliaries tried, the simple trans cyclohexanol
carrying a β-naphthyl substituent on a tertiary carbon, was the most effective. 25
The preferred conformation for the reaction is 193 with excellent π-stacking: the nucleophile
adds from the front as drawn. These chiral auxiliaries are easily made as either enantiomer so
R
OMe
SiR3
H
H 2O
R
O
N
CO2R* 183 184 185
186
O
O
N
O
Me 3Si
TiCl4
R
O
187 188 189
OH O
190
O
191
O
N
O
Ph2CHNH2
MeOH
20 ˚C, pressure
O
O
O
TiCl4
N
O
SiR3
O NHCHPh2
192
TiCl 4

oth series can be entered. The chiral auxiliary and protecting group can be removed reductively
to give the simple amino alcohol (S)-()-195 and this sequence is complementary to the Davies
chiral amine addition to unsaturated esters discussed in chapter 26.
O
Other Chiral Auxiliaries in Conjugate Addition
The Evans oxazolidinones
The original Evans auxiliaries have been used in a synthesis of the heart drug ()-diltiazem 200
based on asymmetric conjugate addition of a sulfur nucleophile. The enone 197 was prepared by
an aldol condensation with valine-derived 196 and anisaldehyde. This gave a 4:1 mixture of Z and
E-197 but fortunately both isomers reacted with an excess of ortho-aminobenzene thiol and base to
give about the same ratio of diastereoisomers of the adduct 198. Cyclisation with Me 3Al removed
the chiral auxiliary and diltiazem 200 then needs only the removal of the protecting group. 32 This
is a rare example of successful asymmetric Michael addition to a trisubstituted alkene.
MeO
OR
193
O
N
Chiral sulfoxides
O
O
S
O
RO
O
1. LDA
2. ArCHO
192
3. MsCl, Et3N 4. DBU
N
O
O
LiAlH4
MeO
HO
H 2, Pd(OH) 2/C
NHCHPh2 MeOH
(S)-(+)-194
Cyclic enones or unsaturated lactones inevitably have a fixed conformation (s-trans), but the
chiral auxiliary cannot be attached to the carbonyl group. Chiral sulfoxides can be attached
directly to the double bond (cf. enone synthesis strategy of chapter 5) and have been used
chiefly by Posner 33 based on work by Solladié 34 in asymmetric Michael additions. Any
sulfur-based functional group can be removed reductively with Raney nickel. Posner 35 has
used this strategy in the synthesis of the anti-tumour lignan ()-podorhizon 201. Acylation
of the lactone 203 with 202 would give podorhizon and 203 could be made by asymmetric
Michael addition of 204 to the achiral butenolide 202. But where can the chiral auxiliary be
attached?
RO
196 197; 61% yield, 4:1 Z:E
NH2
H
N
O
198; 97% yield, 82:18
diastereisomeric ratio
27 Other Chiral Auxiliaries in Conjugate Addition 621
Me 3Al
CH 2Cl 2
S
O
N
OR
O
O
TiCl 4
NH2
SLi
NH2
HO
NH2
(S)-(+)-195
OMe
OMe
199, 78% yield 200, 83% yield
SH
H
N
S
O
OH

622 27 Asymmetric Induction IV Substrate-Based Strategy
MeO
MeO
MeO
O
O
O
201
The answer is at carbon as a sulfoxide 206 to make the butenolide chiral and to enhance the
electron defi ciency of the alkene, so that a Grignard reagent will do instead of a cuprate. After
the sulfoxide is removed and the acylation complete, podorhizon is formed in good yield and
95% ee.
p-Tol
O
S
(–)-206
A Lewis acid is needed to hold the sulfoxide in a fi xed conformation 208: addition then occurs
to the face of the alkene occupied by the lone pair and opposite to the aryl group.
Asymmetric Birch Reduction
O
Birch reduction of benzene
O
O
O
1,3-diCO
MeO
MeO
MeO
202
O
O
O 1. H
ZnBr2
S
p-Tol
2. MgBr O
O
(–)-206
O
O
208
207
The normal Birch reduction is most interesting when applied to aromatic ethers 209 or acids 213.
The addition of two electrons may make a dianion in which the charges keep away from the ether
210 but conjugate with the acid 214. Protonation of 210 gives the enol ether 211 and hence the
non-conjugated enone 212. The dianion 214 has a proton which transfers to the less stable anion
leaving the enolate 215 that can be alkylated to give 216. None of these compounds is chiral and
there appears to be little scope for asymmetric induction.
O
+
O
X
Raney
Nickel
O
O
asymmetric
cuprate
addition
Cu
O
O
O
203 204
203
70% yield
202;
X = OCO 2Et
Koga's
proceedure
O
Zn
O
O
1. ZnBr2 p-Tol
S
O
2. RMgBr
p-Tol
S
H
R
207
O
205
O
201
(–)-podorhizon
95% ee
O
O

OMe
CO2H
Na, NH 3(l)
t-BuOH OMe
Na, NH 3(l)
CO2H
t-BuOH
209 210 211
Schultz’s remarkable work combines ether and acid in the same molecule and adds a chiral
auxiliary (the same proline derivative 26 used in SAMP) to the acid. 36 Both enantiomers of the
starting material 217 are available from Aldrich at about the same price. Birch reduction with
potassium in ammonia gives the chelated intermediate 218 that is alkylated on the face opposite
the CH 2OMe side chain to give 219 and hence 220 by hydrolysis of the enol ether.
An interesting version of iodolactonisation is used to remove the chiral auxiliary from 220.
Iodine attacks the alkene with participation of the amide oxygen atom 221 to give a salt 222 that
hydrolyses to the iodolactone 223 with recovery of the auxiliary 26 if required.
220
O
O
OMe
213 214 215 216
I2, H2O
THF
N
O
OMe
27 Asymmetric Birch Reduction 623
217
R
N
OMe
OMe
O
K, NH 3
THF, –78 ˚C
6M HCl
R
N
O
O
RBr
1 x t-BuOH K –78 ˚C
O
OMe
N
O
Me
218
219 220
OMe
RBr
H3O
OMe
R
212
O
CO 2H
O N
O
N
O
O
R
OMe
R
OMe
H2O
R
I O
I O
I O
221 222 223

624 27 Asymmetric Induction IV Substrate-Based Strategy
The iodolactone 223 can be fragmented in two different ways by different reagents to give the
lactones 224 or 225 that bear little resemblance to the original benzene ring.
O
O
Asymmetric Birch reduction of heterocycles
8-Phenylmenthol is the auxiliary in an asymmetric Birch reduction of pyrroles by Donohoe 37
Lithium in ammonia does the reduction and the enolate is trapped with various alkyl halides.
Hydrolysis of the esters 227 releases the enantiomerically enriched (78–90% ee) dihydropyrroles
228 in good yield. Furans give similar products with a C 2 symmetric amine as auxiliary. This
should become a general route to a variety of heterocycles.
References
224
N
Boc
R
CO 2R 1
Ph
O
O
LiOR 1
THF
O
I
O
H2O, THF O
O
223 225
General references are given on page 893
1. R. M. Williams, Synthesis of Optically Active Amino Acids, Pergamon, Oxford, 1989.
2. K. Q. Do, P. Thanei, M. Caviezel and R. Schwyzer, Helv. Chim. Acta, 1979, 62, 956.
3. D. Enders, P. Fey and H. Kipphardt, Org. Synth., 1987, 65, 173, 183.
4. U. Groth and U. Schöllkopf, Synthesis, 1983, 37; D. Pettig and U. Schöllkopf, Synthesis, 1988, 173.
5. R. M. Williams and M. Im, J. Am. Chem. Soc., 1991, 113, 9276.
6. S. R. Schow, S. Q. DeJoy, M. M. Wick and S. S. Kerwar, J. Org. Chem., 1994, 59, 6850.
7. D. Seebach, M. Boes, R. Naef and W. B. Schweizer, J. Am. Chem. Soc., 1983, 105, 5390.
8. Clayden, Organic Chemistry, chapter 33.
9. M. G. Hinds, J. H. Welsh, D. M. Brennand, J. Fisher, M. J. Glennie, N. G. J. Richards, D. L. Turner and
J. A. Robinson, J. Med. Chem., 1991, 34, 1777.
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Tetrahedron Lett., 1981, 22, 4221.
11. J. R. Gage and D. A. Evans, Org. Synth., 1990, 68, 77, 83.
12. R. P. Beckett, M. J. Crimmin, M. H. Davis, and Z. Spavold, Synlett, 1993, 137.
13. M. A. Walker and C. H. Heathcock, J. Org. Chem., 1991, 56, 5747.
14. W. Oppolzer, Angew. Chem., Int. Ed., 1984, 23, 876.
15. D. A. Evans, K. T. Chapman, and J. Bisaha, J. Am. Chem. Soc., 1988, 110, 1238.
16. S. Masamune, L. A. Reed, J. T. Davis, and W. Choy, J. Org. Chem., 1983, 48, 4441.
O
R
Li, NH 3, –78 ˚C
(MeOCH 2CH 2) 2NH
RX
R
LiOH
N CO2H Boc
228
N
Boc
R
Ph
226 227
1. CF3CO2H 2. NaOH, H2O 3. (Boc)2O
O
O
R
CO 2H

27 References 625
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22. D. A. Evans, T. C. Britton, and J. A. Ellman, Tetrahedron Lett., 1987, 28, 6141.
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24. O. Ort, Org. Synth, 1987, 65, 203.
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27. J. d’Angelo and J. Maddaluno, J. Am. Chem. Soc., 1986, 108, 8112.
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30. D. L. Comins and L. Guerra-Weltzien, Tetrahedron Lett., 1996, 37, 3807.
31. M. Sato, S. Aoyagi, S. Yago and C. Kibayashi, Tetrahedron Lett., 1996, 37, 9063.
32. O. Miyata, T. Shinada, I. Ninomiya and T. Naitu, Tetrahedron Lett., 1991, 32, 3519.
33. G. H. Posner, Morrison, 2, 225.
34. M. Hulce, J. P. Mallamo, L. L. Frye, T. P. Kogan and G. H. Posner, Org. Synth., 1986, 64, 196.
35. G. H. Posner, T. P. Kogan, S. R. Haines and L. L. Frye, Tetrahedron Lett., 1984, 25, 2627.
36. A. G. Schultz, Chem. Commun., 1999, 1263.
37. T. J. Donohoe, P. M. Guyo and M. Helliwell, Tetrahedron Lett., 1999, 40, 435.

28
Kinetic Resolution
Types of Reactivity
The Water Wheel
An unselective wheel
A selective wheel
S Values, Equations & Yields
Standard Kinetic Resolution Reactions
Chiral DMAP
Epoxidation reactions
Unwanted kinetic resolutions
Enzymes
Dynamic Kinetic Resolution
Reaction of epichlorhydrin
α-Acetoxysulfi de
Enzymes and metals together
Hydrogenation
Parallel Kinetic Resolutions
Regiodivergent resolutions
Double Methods
Desymmetrisation then kinetic resolution
Resolution is the separation of enantiomers. We have seen resolution before in Chapter 22. A
kinetic resolution is a resolution which works simply because, under the right conditions, one
enantiomer of a racemic mixture reacts faster than the other. 1
Types of Reactivity
With a kinetic resolution, the substrate will already have a chiral centre. The question comes down
to how much notice the reaction conditions take of this chirality. So for instance, allylic alcohol
1 could be acylated. Both enantiomers react at the same rate and the reaction pays no attention at
all to the chiral centre. For a kinetic resolution to operate, that chiral centre would have to demand
attention so that one enantiomer reacted and the other did not.
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

628 28 Kinetic Resolution
OH
The reactions above illustrate another point. This simple acylation of a racemic alcohol can be
turned, in principle, into a kinetic resolution. We shall see several reactions we have encountered
in this book that also can be involved in kinetic resolutions. The above reaction did not create
any extra chiral centres but that too is possible – even quite common – and naturally adds to the
complexity of the reactions.
The Water Wheel
A good visual depiction of kinetic resolution is a water wheel image. Imagine a tray containing black
and white balls which have to run through the water wheel in order to get to the tray underneath
The black and white balls represent R and S enantiomers and moving through the wheel is a transformation
that yields the products in the tray underneath. This visualisation will also allow us to
explain one of the more subtle and crucially important aspects of kinetic resolution—the degree
of completion.
An unselective wheel
1
OH
Kinetic
Resolution
O
O
1 (S)-2 (R)-1
Starting Materials
Products
No
Resolution
With an unselective wheel, the balls just fl ow randomly through the wheel and we get a 50/50 mix
black and white products and, similarly, the starting materials are consumed in an unselective way.
Starting Materials
Products
2
R S
O
O
Unselective Catalyst
R S
OH

Starting Materials
A selective wheel
Products
Imagine now a wheel which is selective for the black balls and prefers to let them through. The
result is a product that is rich in black balls and a starting material that becomes increasingly rich
in white balls. The wheel is not perfect, however, and occasionally lets a white ball through.
Starting Materials
Unselective Catalyst
R S
It is instructive to look at how rich the products and starting materials are in black and white
balls as the reaction proceeds. When the reaction is 50% complete we have 80% ee of product and
80% ee of starting materials. One of the white balls has made it through to the product.
Starting Materials
Products
Products
28 The Water Wheel 629
Enantioselective Catalyst
R S
Enantioselective Catalyst
R S
Reaction at 50%
completion
80% ee
80% ee
It is a crucial feature of kinetic resolutions that if we want a very good enantiomeric excess in our
starting materials then we will have to run the reaction past 50%. It is typical with kinetic resolutions

630 28 Kinetic Resolution
to fi nd that the best quality material is what is left behind. If we continue to 75% completion then
we can see that all of the black balls have been consumed and the remaining starting material has
100% ee. This is at the cost of the ee of the product of course which has fallen to 33% ee.
Starting Materials
Products
Keep this in mind. When you see a starting material with 98% ee in a paper, look to see how
much conversion was needed to leave this sort of quality behind. If only 51% conversion was
needed it is excellent, but if the workers needed to run the reaction to 90% conversion, then there
can only be at most, 10% of this quality starting material – not so good! We look at this in more
detail in the next section.
S Values, Equations & Yields
Enantioselective Catalyst
R S
Reaction at 75%
completion
100% ee
33% ee
With the water wheel it is not merely a question of one enantiomer reacting and the other one not.
It is, rather, a question of one reacting quickly (k fast) and the other reacting slowly (k slow). We will
see much more of something called the ‘s value’ later. This is the selectivity factor and is quite
simple: s = k fast / k slow or, in other words, the relative rate. Consider two enantiomers of an alcohol
being enantioselectively acetylated by some means. One reacts fast and one more slowly.
OH OAc OH OAc
k fast
(S)-3 (S)-4 (R)-3
(R)-4
The graph shows several plots which show the % ee of the remaining alcohol 3 against the
% level of conversion. 2 This graph would be valid for any standard kinetic resolution. The perfect
kinetic resolution where k fast / k slow = ∞ obviously gives 100% ee of the remaining alcohol at 50%
conversion but it is instructive, and quite amazing, to note that the curve for k fast / k slow = 25 is
nearly as good. It is possible to get nearly 100% ee of starting material even when k fast / k slow is as
low as two, but the yield would be approaching 0% because the reaction has to be run until there
is hardly any starting material left. 3
k slow

Other symbols used in the realm of kinetic resolution include C, the level of conversion where
0 C 1. In a classical kinetic resolution where one enantiomer reacts faster than the other and
the other is left behind then the following equation is true. 4 This equation is important as relates
three crucial factors—conversion, ee and selectivity. 5
The second equation tells us what we already know about kinetic resolutions from the graphical
‘water wheel’ description—in other words, you can’t have it all! A good ee means that
you will have to compromise on yield and vice versa. But the better your s value, the less severe
those compromises need to be. Ee’ is the enantiomeric excess of the product and ee is the
enantio meric excess of the remaining starting material. Remember that although the ee of starting
material will increase as a reaction proceeds, the ee of the product must go down once conversion
exceeds 50%.
Standard Kinetic Resolution Reactions
Chiral DMAP
100
% ee of
remaining
alcohol
50
0
0
28 Standard Kinetic Resolution Reactions 631
s = 25 is almost
as good as s = ∞
s = ∞
In[(
1−C)( 1−ee)]
S =
In[(
1− C)( 1+
ee)]
Let us return to the reaction we mentioned at the very start of the chapter – the reaction of a
chiral alcohol to form an ester. DMAP is used to catalyse the acylation of alcohols reactions by
nucleophilic catalysis.
25
8
4
s = 2
with s = 2 we approach 100%
ee of starting material as we
approach 0% yield
50 100
% conversion
ee C
ee′
C
= 1−

632 28 Kinetic Resolution
O O
O
5
Me 2N
DMAP
achiral
N
DMAP itself is achiral but a chiral version would make the achiral reactive intermediate 6 chiral.
Since the alcohol 7 reacts with this species, there is the possibility that one of the alcohol enantiomers
will react more quickly than the other and there will be a kinetic resolution. All that needs
is for a chiral version of DMAP to be developed. Because DMAP has two planes of symmetry, this
takes some doing. One way that was developed by Spivey et al. was to use an axis of chirality. 6 One
plane of symmetry is removed because a naphthyl ring is attached on one side and not the other while
the chiral axis differentiates the back and front faces of the pyridine ring 8. For the esterifi cation of 9
the s factor was 27 which means good levels of ee in both the starting material and the product should
be possible. Indeed 97% ee of the starting material can be achieved at around 56% conversion.
9
OH
An important consideration with any catalysed asymmetric reaction is the rate of the background
reaction. In other words, the reaction of the isobutyryl anhydride 5 with the alcohol without the
catalyst. This reaction will generate racemic material and so clearly it has to be slow (relative to
the asymmetric reaction) if asymmetric catalysis is to be effective.
The same alcohol 9 was kinetically resolved by Heathcock using porcine pancreatic lipase. 7 There
OH
O
OH
Cl3C
O O
O
5
(+)-catalyst 1 mol%
–78 ˚C
toluene
O
O
porcine pancreatic
lipase, heptane
9 10
is a striking contrast between the conditions used in the two reactions. The enzymatic reaction is
conducted at 60 C and takes several days! The reactive enantiomer is esterifi ed. Heathcock reveals
that the S alcohol that remains at the end of the reaction contains 2–5% of the R enantiomer. This
is upgraded by two recrystallisations to 99.5% ee.
Another chiral DMAP 11 has been developed by Fu. 8 This contains neither a chiral centre nor
an axis of chirality and is probably best described as having planar chirality. The s factor was
improved from 14 to a very useful 43 simply by changing the solvent and reaction temperature
The references contain useful sample experimental procedures. 8, 9 Several alcohols including
12–15 have been resolved with this but in looking at the ees, remember to note the conversion
necessary to achieve them. Clearly the acetylene 15 was more diffi cult to resolve. 9
6
N
N
(R)-9; 43% yield
97% ee
O
O
R
OH
OH O
+
s = 27
+
7
NEt 2
Ph
N
8
Chiral version
of DMAP
O
56% yield
73.7% ee
(S)-9; 90-96% ee

11
N
R
R
OH
12
99% ee at
55% conversion
N RFe
R
R
While we are on the subject of chiral DMAP it is worth noting that even phosphines 10 can be used
to catalyse acylation reactions and some of the s values that can be achieved are quite spectacular.
The phosphines are bicyclic compounds 16 and 18. The nature of the phosphine is very important
and the focus of the work was not on enantiomeric excess but rather the all-important s value.
The synthesis of 16 starts using a lactate derivative and makes cunning use of a lithium-binding
chain to achieve the selectivity required in producing intermediate 17. 11 The even better catalyst 18
was prepared from the same key intermediate 17.
H
Me
OH
Cl
13
98% ee at
56% conversion
The reaction catalysed by 16 was an esterifi cation with benzoic anhydride and the best kinetic
resolution obtained (s = 67) with benzylic alcohol 19 was at – 40 C. A value of 67 is very good for
a kinetic resolution. However, exceptional results were obtained using phosphine 18. This catalyst
is effective with a variety of alcohols and conditions. The best result was obtained with 20, Ac 2O
and, crucially, catalyst which had been recrystallised to 99.9% ee. In this instance s = 390!
OH
16
Ph Bu t
19
Me
Me
P
H
28 Standard Kinetic Resolution Reactions 633
Ph
H
Me
Me
Vedejs points out that with these high s values, the importance of the enantiomeric excess of the
catalyst becomes very important. 12 For example, an s value of 145 obtained with catalyst with an
ee of 99.6% is expected to improve to s = 204 with catalyst of 100% ee. With s values lower than
40 the effect is much less signifi cant.
The Fu and Vedejs catalysts are excellent and work with a range of substrates but good kinetic resolutions
can be achieved even with some very simple chiral diamines. A catalyst derived from proline
21 was used at low temperature and low loading to resolve the secondary alcohol 22 very effectively. 13
The use of the proline-derived catalysts has been extended to some primary alcohols. 14
OH
Me
Me
H
O
Ph
SO2 O
17
OH
Me Me
20
Me
With Ac2O and Et 3N
2% catalyst
room temp.
Et 2O
s = 14
OH
14
96% ee at
58% conversion
H
Me
N
Me
Me
Me
P
H
18
N
21
1% catalyst
0 ˚C
t-amylOH
Ph
s = 43
OH
15
95% ee at
86% conversion
Bu t
Bu t

634 28 Kinetic Resolution
(±)-22
OH
Ph
Epoxidation reactions
+
BzCl
0.3 mol% 21
Et 3N
molecular sieves
– 78 ˚C
Perhaps the most famous and widely used kinetic resolution is the Sharpless epoxidation of allylic
alcohols 5, 15 – a reaction we encountered 16 in Chapter 25. This is where matters become marginally
more complicated than the simplest kind of kinetic resolution because we are introducing more
chiral centres to the molecules in addition to exploiting the ones that are already there.
The tartrate complex is the same as the one we have previously encountered in chapter 25. Two
enantiomers of allylic alcohol can form two diastereomeric reactive complexes with the single
enantiomer of titanium complex. This is illustrated below with, in this instance, the chiral centre
at the carbinol carbon of the allylic alcohol. The general allylic alcohol 23 is arranged with the
double bond reaching round to the hydroperoxide ready for reaction. In one of the diastereomeric
complexes the R group clashes sterically with the titanium complex. In the other complex the R
group is able to occupy uncongested space. Not surprisingly, the enantiomer of allylic alcohol 23
that must react via the congested complex is the slow-reacting enantiomer.
i-PrO
RR
i-PrO
Ti
O
CO2Et
Ti
EtO2C
O
O O
O
O
EtO2C
EtO
t-Bu
R2 the active Ti complex for asymmetric epoxidation
O
O
A compound which is nicely illustrative of this reaction (and often cited) is allylic alcohol 17
24. With L-()-diisopropyl tartrate this alcohol has a fast-reacting (S) and a slow-reacting (R)
enantiomer but what is not addressed in the above diagram is that, in principle, both enantiomers
could give two different diastereomers 25 and 26.
(S)-24
(R)-24
R 3
S
R
OBz
+
OH
Ph
Ph
49%, 96% ee
s = 160
48%, 95% ee
R 1
O
OH OH
OH
k fast
k slow
O
OH
R 2
HO
R3 R 3
HO
R
R3 R 1
R
O
O
R 2
R 2
OH
R 1
R 1
R
(±)-23
Fast-reacting
enantiomer
(S)-23
Slow-reacting
enantiomer
(R)-23
OH
(S)-25 98:2
(S)-26
(R)-25
38:62
OH
(R)-26

With the fast-reacting enantiomer there is good diastereoselection
in this reaction too and the main product is 25 in
a 98:2 ratio. The slow-reacting enantiomer is less selective
giving a 38:62 ratio. It is not uncommon for allylic alcohols
in this context to be drawn in a different orientation –
25a is merely an alternative drawing of 25b. How much
faster the fast reaction is depends on the nature of the
catalyst. The selectivity increases from dimethyl- to diethyl-
to diisopropyl tartrate from 19 to 36 to 104. 18
Before the dihydroxylation reaction burst onto the asymmetric scene, asymmetric epoxidation
and associated kinetic resolutions were possibly the most popular methods of producing single
enantiomers simply because they worked so well. The epoxidation could, for example, be used
reliably in undergraduate laboratories.
We will see Sharpless epoxidation reactions in the Double Methods section towards the end of the
chapter. Interestingly, Sharpless’ other famous asymmetric method – dihydroxylation – has not found
widespread use in kinetic resolution. This is probably because the AD is just too powerful or, to be anthropomorphic,
too wilful. In other words, it is not sensitive to the chirality of the substrate and charges
ahead and reacts with both enantiomers. That is not to say there are not examples of kinetic resolution
with dihydroxylation, 19 but they are more rare. However, the dihydroxylation is even more useful and
much more general than the kinetic resolution of allylic alcohols by asymmetric epoxidation and was
discussed in Chapter 25. A slightly complicated case of kinetic resolution of alcohols by asymmetric
dihydroxylation is in the Double Methods section.
Epoxides are a familiar sight in the world of kinetic resolutions. As well as being made by kinetic
resolution, racemic epoxides can themselves be the substrates in a kinetic resolution. For example,
the use of cobalt-salen complexes – something we shall see again in the dynamic kinetic resolution
section – can be used to mediate the formation of enantiomerically pure oxazolidinones. 20 Enzymes
can be used to react with one enantiomer of epoxide. 21 And enzymes are a good way to kinetically
resolve compounds and can work under surprising conditions – supercritical CO2 for example. 22
O
OH
O
OH
25a
25b
Unwanted kinetic resolutions
28 Standard Kinetic Resolution Reactions 635
Something to watch out for is unwanted kinetic resolutions. An example is found in the determination
of enantiomeric excess by making derivatives like Mosher’s esters using an optically pure reagent.
Consider the following. An alcohol 27 has been made in 60% ee – four parts S alcohol to one
part R alcohol – but the ee has not yet been determined. Suppose that a reaction to make Mosher’s
esters is done to 80% completion and that the R alcohol reacts very much faster than the S.
S
R
Ar
Ar
OH
OH
27
4 parts
Reality = 60% ee
1 part
O
CF3 Cl Ar
Ph
OMe
Mosher's esters
Ar
O
O
O
Ph
O
Ph
implied ee
CF 3
OMe
CF3
OMe
80% completion 100%
If R
reacts much
faster
1
If S
reacts much
faster
0
3 4
50% ee
100% ee
completion
R or S
reacts
faster
1
4
60% ee

636 28 Kinetic Resolution
The result would be three parts S alcohol (now incorporated into the ester) to one part R. The
implied ee is 50%. Perhaps worse is the case if the S enantiomer reacts very much faster. We would
have four parts S alcohol to no parts R and the implied ee would be 100%!
It is crucial that the reaction is taken to 100% completion so that every last bit of the starting alcohols
show up in their derivatives. That way the 4:1 ratio is maintained and the real ee uncovered.
Enzymes
The whole of the next chapter (Chapter 29) looks at enzymes and their application. Nevertheless, it is
worth examining a simple case here in the context of kinetic resolution. The selectivity of enzymes
is often so good that the reaction can be run to 50% completion so that the enantiomeric excess
of both the product and the unreacted starting material is excellent. Lipase from Pseudomonas
fl u ores ce n s will hydrolyse one of the enantiomers of the acetate 4 very effectively in water at
(±)-4
OAc OH OAc
Pseudomonas fluorescens
lipase
H 2O, pH 7
(R)-3; 48% yield
>99% ee
(S)-4; 48% yield
>99% ee
neutral pH. Hence the (R)-enantiomer of alcohol 3 is produced in 48% yield and 99% ee while
the unreacted enantiomer is left behind in 48% yield and 99% ee too!
It is the (R)-enantiomer that reacts. So if we started with racemic alcohol (instead of racemic
(±)-3
OH
Pseudomonas fluorescens
lipase
OAc
t-BuOMe
(R)-4; 45% yield
>99% ee
acetate) and ran the reverse reaction using the same enzyme, then the molecule that would be left
behind would be the (S)-enantiomer of alcohol 3. This does indeed work. 23
Interestingly, we can thus make either enantiomer of alcohol using the same enzyme. However,
the yields and ees show us that the reverse reaction is not quite so good. The use of vinyl acetate as
the acetylating agent is a common trick and cunning because the displaced vinyl alcohol 29 does
not hang about but tautomerises into acetaldehyde 30 – thus removing it from the equilibrium and
helping to drive the reaction forwards. The one drawback is that the increasing concentration of
acetaldehyde is detrimental to the reaction (presumably by reducing the activity of the enzyme).
Pseudomonas is found in the section below on Dynamic Kinetic Resolutions. We will meet
Pseudomonas fl uorescens again in the next chapter where we also see enzymes in kinetic
resolutions with racemisation of starting material (dynamic kinetic resolution).
O
28
O
28
+
OAc OH
+
(S)-3; 41% yield
>93% ee
29
O
+ +
R OH OH R O
30
H
O

Dynamic Kinetic Resolutions
The biggest problem with a kinetic resolution is that, even with the best selectivity and thus product with
100% ee, your yield is limited to 50%. The unwanted enantiomer goes to waste. A dynamic kinetic
resolution (DKR) gives us the opportunity to raise this theoretical maximum to 100%. In the simplest
DKR, the starting material is racemised under the reaction conditions but only one of the enantiomers
then goes on to react. The continual racemisation of starting material ensures that the unwanted
enantiomer never builds up. This racemisation has an added bonus when it comes to selectivity. With
a standard kinetic resolution, in becomes increasingly tricky for the reagent or catalyst to be selective
for the desired enantiomer as we approach 50% completion because there is so much of the unreacted,
undesired material competing for its attention. With a DKR, since there is no such build up, it is less
diffi cult for a reagent to be selective at the end of the reaction.
In Chapter 22 we saw resolution with racemisation applied to the synthesis of L-364,718. That
could have been described as a dynamic resolution or possibly even a dynamic thermodynamic
resolution but not a dynamic kinetic resolution as it did not depend on one enantiomer reacting
faster than the other. Rather it depended on the thermodynamic stability of one crystalline form
over the other.
Reaction of epichlorhydrin
28 Dynamic Kinetic Resolutions 637
Racemic epichlorhydrin 32 can be dynamically kinetically resolved using a salen chromium
complex 31. The enantiomeric excess of the product 33 is excellent at 97% and the yield 76%. 24
t-Bu
H H
N N
Cr
O N O
3
Bu-t t-Bu
Bu-t
On fi rst inspection of the reaction scheme it looks as though the epoxide is opened with azide
and the process mediated by the chromium complex. But this would be a standard KR and give us
a maximum yield of 50% – something else must be going on to interchange the two enantiomers
of epichlorhydrin. Imagine epichlorhydrin opened by a chloride ion. We would have a species
with a plane of symmetry 34 and formation of the epoxide on the other side of the molecule would
transform one enantiomer into another.
Cl
(S)-32
O
31
(S, S)
OH
Something akin to this happens in the reaction above. In the normal course of events the azide
complex 31 reacts with epichlorhydrin to give an intermediate which reacts with TMSN 3 to regenerate
the reagent and silylate the oxygen. But there is a side reaction which generates the chloride
salen complex 35.
Cl
Cl Cl
34
plane of symmetry
32
O
1. 2 mol% 31
0.5 eq TMSN 3
2. 0.5 eq TMSN 3
slow addition
OSiMe 3
Cl N 3
33; 76% yield, 97% ee
O
(R)-32
Cl

638 28 Kinetic Resolution
Cl
Cr
O
Cl
O
N3
Me3SiN3 Cl
OSiMe3 N3 +
Cr
N3 (S)-32 33 31
It is this complex which can add to epichlorhydrin and, in a reverse reaction that may happen from
either side, racemise it 36. Note that under the reaction conditions the azide half of TMSN 3 adds quickly
but the Me 3Si half slowly – the reactive enantiomer of epichlorhydrin is there to be had at the start but
must be made by continuous racemisation in the second part of the reaction. A potential by-product
from these reactions is the double azide 37 which the authors think looks suspiciously explosive.
Cl
O
The azide 33 is readily transformed into the convenient reagent 38 which has been incorporated
into a fi nal intermediate 38 in the synthesis of the oxazolidinone antibiotic 39. 24
Cl N 3
CbzN
OSiMe 3
33
N
F
α-Acetoxysulfi de
Cr
Cl
35
N
H
side reaction
35
Cr
Cl
Cr
O
Cl Cl
1. MeOH, cat. TFA
2. H2, PtO2
3. Ac2O, Et 3N
O
O Ph
36 37
Cl NHAc
A synthesis of lamivudine in optically pure form requires the use of α-acetoxysulfi de (R)-40. 25 This
can be produced in optically pure form by a kinetic resolution using the lipase from Pseudomonas
fl u ores ce n s. This enzyme hydrolyses the enantiomer that we do not want and leaves behind the one
that we do. The authors investigated a range of sulfi de side chains and the acetal 40 that is used in
the synthesis of lamivudine worked perfectly. 26 The solvent is important. The use of chloroform
instead of t-BuOMe gives low ees in the opposite sense.
HO
OAc
1. BuLi, –78 ˚C
2. 2 equivs. 38
0 to 60 ˚C
S
lamivudine
O
K 2CO 3
MeOH
N3
OSiMe 3
CAUTION!
98% yield 38
O
N N
CbzN
NH2
N
F
39
O
O
N O
N 3
NHAc
NHAc

MeO 2C S
OAc
(±)-40
OEt
OEt
28 Dynamic Kinetic Resolutions 639
100 mg substrate
2 mg lipase
2 ml buffer
0.5 ml t-BuOMe
30 ˚C, 2 hr
MeO2C S
OEt
OEt
+
MeO2C S
OAc
OH
(R)-40; 45% yield, >95% ee (S)-41
This is the result of kinetic resolutions that we have come to expect and although the selectivities
are excellent (ee 95%) the yield can never be more than 50%. In order to get more than 50% we
would need to recycle the unreactive enantiomer.
R H
O
42
R'SH
43
R SR'
OH OAc
R SR'
+
OAc
R SR'
Racemic α-acetoxysulfi des 45 can be made by the addition of a thiol 43 to an aldehyde
42 followed by acetylation of the resulting hydroxyl group with Ac 2O. 27 The idea that the lipase
from Pseudomonas fl u ores ce n s might be used to mediate the acetylation instead, using vinyl
acetate as the stoichiometric reagent, to give (S)-45 works. But we have still not achieved a dynamic
kinetic resolution. We would need to return the unacetylated material (R)-44 to starting materials
for this to happen. However, it was found that hemithioacetals decomposed during column
chromatography on silica to give the starting thiol 43 and aldehyde 42. This led the workers to the
idea of adding silica to the reaction mixture to promote reformation of the starting aldehyde and
thiol. It worked. 27 In the presence of silica gel the yield is substantially greater than 50% because
the wrong enantiomer of the intermediate hemithioacetal can return to starting materials.
O
methyl glyoxalate
lipase
Several thiols were looked at with 46 being one of several that gave high ee of product.
Overall the enantioselectivities for the acetylation reactions are slightly higher than those for the
hydrolysis reactions which the authors suggest is due to greater conformational rigidity of the
enzyme in organic rather than in aqueous solvents. You may have noticed that since this reaction
is concerned with the esterifi cation of the (S)-enantiomer rather than the hydrolysis of the
(S)-enantiomer we generate the (S)-acetate 47 and sadly not the one that is actually needed for the
synthesis of lamivudine! The authors went on to use Pseudomonas fl u ores ce n s for the hydrolysis
of diacetate 48 (a standard kinetic resolution reaction) to give a key intermediate of the correct
enantiomer (R)-48. In this case a primary acetate is hydrolysed. 28
AcO
MeO
O
S
OAc
OH
(±)-44 (S)-45 (R)-44
H HS
46
OSiEt 3
OSiEt 3
AcO
OAc
50 mg methyl glyoxalate
t-BuOMe
50 mg lipase
10 mg silica gel
S
OAc
(±)-48 (R)-48
MeO
OSiEt3 +
HO
(±)-44
O
Ac 2O
DMAP
S
py
OEt
OEt
R SR'
OAc
(±)-45
OSiEt 3
OAc
(S)-47; 83% yield, 90% ee
S
OAc
OSiEt3

640 28 Kinetic Resolution
Enzymes and metals together
OH
(S)-3
racemise?
OH
(±)-3
In the above example, an enzyme for the kinetic resolution was combined with
silica to provide the dynamic part of a dynamic kinetic resolution. The role of the
silica is to racemise the hemithioacetal that does not get acetylated. The racemisation
of most alcohols is unlikely to be so straightforward. Consider sec-phenethylalcohol
3; how would we racemise this? Silica is unlikely to do the job.
Williams was in the unusual position for a worker in asymmetric synthesis
of trying to fi nd a catalyst that was good at racemisation. 29 An ingenious solution
is to use the transfer hydrogenation of acetophenone. If (S)-alcohol can be
the hydrogen source for the reduction of acetophenone then, so long as there is
no enantioselection of any kind, the products will be regenerated acetophenone
(from the optically pure alcohol) and racemic alcohol from the achiral acetophenone.
Numerous catalysts were investigated including those based on iridium and
ruthenium. Two results with aluminium and rhodium are shown below.
OH
(S)-(–)-3
Ph
O
catalyst
(±)-3
OH
catalyst yield, ee
20 mol% Al(OPr-i) 3
3 mol% Rh 2(OAc) 4 +
KOH + phenanthroline
80% 0%ee
73% 0%ee
The racemisation process was then combined with enzymatic kinetic resolution. The overall
picture can be seen below. 29 Racemisation is going on in the box and the lipase from Pseudomonas
converts the (R)-enantiomer of alcohol into its acetate. At 60% conversion the product has 98%
ee. The 60% may not seem all that impressive but in a standard kinetic resolution, the maximum
ee that is possible at 60% conversion (product therefore contains 50% of one enantiomer and 10%
of the other) is 67%. Another result gave 76% ee at 80% conversion. The maximum ee of product
at this conversion with a kinetic resolution is a mere 32%!
Ph
Ph
Ph
OH
O
OH
Ph
O
OAc
Lipases have also been combined with palladium catalysts to provide the dynamic aspect of
the kinetic resolution. 30 In the example below the unreacted allyl acetate (S)-49 is racemised. The
formation and reactions of Pd-allyl cations are discussed in chapter 18.
OAc
Pseudomonas fluorescens
lipase
2 mol% Rh 2(OAc) 4
phenanthroline
Pseudomonas
cepacia
lipase
i-PrOH
Ph
OAc
60% conversion
98% ee
(theoretical maximum ee
at 60% conversion is 67%)
N
N
phenanthroline
OH OAc
(±)-49 72% yield, 98% ee
(S)-49
Pd(0); Pd(PPh3) 4 + Pd(dppf) 2
+

OH O
51
Hydrogenation
Something that we have not addressed is the rate at which racemisation occurs relative to the rate
of the kinetic resolution. Clearly if the rate of racemisation is too slow, there will be a build up of
the less reactive enantiomer. For the best selectivity the starting materials should remain racemic
which means that the rate of racemisation must be faster than the fast kinetic resolution reaction.
This is the case in the hydrogenation of β-ketoester 50. 31 Racemisation is fast and occurs via the
enol 51. The product has 99% ee. Most of the impurity is the wrong diastereomer but nevertheless
the syn:anti is a healthy 96.4:3.6. The ligand on the ruthenium is a slightly modifi ed version of
BINAP. The phenyl rings of ordinary BINAP are replaced with xylyl rings.
OMe
NHCOPh
O O
OMe
NHCOPh
(S)-50
O O
k inv
OMe
NHCOPh
(R)-50
Parallel Kinetic Resolutions
28 Parallel Kinetic Resolutions 641
H 2
(R)-xylBINAP-Ru
kS
k inv > k S
xylBINAP-Ru
k R
OH O
Kinetic resolutions are a bit like a big tin of assorted sweets at Christmas with an aunt who likes
to eat the blue triangles. Initially, she has an easy time fi nding the blue triangles and eating them
up—delicious. But as time goes on, those blue triangles become more scarce and thus harder to
fi nd amongst the red squares etc. Similarly, a reagent selecting an enantiomer from a racemic
mixture fi nds it hard and harder to fi nd the enantiomer it wants. Really what we need is an uncle
who eats those red squares.
Alternatively, think back to the image at the start of the chapter with the black and white balls
for another analogy. Remember that the wheel is selective for white balls. Towards the end of the
reaction, there are hardly any white balls left and the wheel, which doesn’t have perfect selectivity
anyway, will fi nd it increasingly hard to pick them out. And if all the white balls have gone, then
the wheel, if it continues reacting, will be forced to react with the black balls. This is all bad news
for selectivity. If there were another water wheel which was selective for black balls (but delivered
them to a separate container) then the concentration of black balls would not increase.
With a parallel kinetic resolution, one enantiomer reacts to give one product while the other
reacts to give something else. The main advantage is that the increasingly steep uphill struggle is
removed since the concentration of the desired enantiomer does not decrease relative to the one
that is not wanted. The one that is not wanted is being reacted too – but to give something else.
Ideally they should both react at a similar rate.
One way to make sure that two enantiomers of starting material react at an equal rate is
to use a racemic reagent. But, of course, this is totally useless as we shall just get a racemic
OMe
NHCOPh
99% ee
96.4:3.6 syn:anti
OH O
OMe
NHCOPh
OH O
OH O
OMe
NHCOPh
OMe
NHCOPh
PAr 2
PAr 2
Ar = 3,5-Me 2C 6H 3
(R)-3,5-xylylBINAP

642 28 Kinetic Resolution
product at the end! However, with a reagent that is nearly racemic, as it were, we can achieve
parallel kinetic resolution. What we mean by ‘nearly racemic’ should become clear and such a
method was illustrated by Vedejs. 32 The reagent is a chiral form of DMAP which has already
been acylated. Note that the reagent is, in fact two optically pure reagents that are almost enantiomers
of one another. The idea is that one reagent will react with one enantiomer of material and
the other with the other and that the products will be separable. Each pseudo-enantiomer of reagent
(53 and 56) delivers a different acyl group so that the ‘enantiomers’ are different compounds
and can be distinguished. Additionally, the trichlorobutyl protecting group can be removed with
zinc and acetic acid to give the alcohol (S)-9 and leave the fenchyl carbonate 57 intact.
NMe2
N
NMe2
N
NMe 2
OMe Cl3C O O
52 53
55
OBn
Bu-t
Bu-t
N
NMe2
N
O O
56
OMe
OBn
Bu-t
Bu-t
MgBr 2 / Et 3N
The main advantage of parallel kinetic resolution is that the selectivity value, s, need not be
nearly so high to get good results. With a standard kinetic resolution, we would need s = 200
in order to obtain both 50% of starting material and product with 96% ee. A parallel kinetic
resolution needs s = 49 to obtain the same results (there are two s values in a parallel kinetic
resolution—one for each reaction, we assume here that they are equal). However, we can see that
it is quite a business designing a parallel kinetic resolution and for many applications it simply
would not be worth the bother if the s value is good.
With a parallel kinetic resolution, the two reactions should not interfere with one another. In
the example above, both reactions were acylations but the use of stoichiometric reagents meant
that the right acylating group was attached to the right enantiomer. Even here, Vedejs does not rule
out a small amount of leakage between the paths (once the chiral DMAP is liberated it can get in
on the act with the other pathway). A PKR becomes more diffi cult if, in addition to the reactions
being related, they are also catalytic.
In the example below, one enantiomer of compound is acylated by a lipase and the other by
a phosphine-catalysed process. 10, 33 We want the lipase to catalyse the reaction between vinyl
pivalate 58 and the R-alcohol, and the phosphine to catalyse the acylation of the S-alcohol using
the polymer-bound anhydride 60. But, the lipase must not use the polymer-bound anhydride or the
wrong enantiomer of alcohol will end up polymer-bound. Similarly, the phosphine must not react
with the vinyl pivalate. Fortunately, the phosphine does not react with the vinyl pivalate and the
lipase, which is insoluble, cannot interact with the polymer bound material. Also, the lipase will
be kept away from the potentially damaging P-acylphosphonium intermediates. The conditions
are described as a ‘Three-Phase System’. The three phases are the solution phase and the two
separate insoluble phases of the polymer bound anhydride and the cross-linked lipase.
OH
9
O O
O
O
54; 49% yield, 86% ee
O O
57; 43% yield, 93% ee
CCl3

9
OH Lipase
28 Parallel Kinetic Resolutions 643
Phosphine
O O
O
O
O
58
O
Bu-t
polymer
O Bu-t
The s-values for the lipase route and the phosphine route were not the same, but this is less
important than the rates of enantiomer consumption being equal. Hence the relative amounts of
lipase and phosphine were adjusted so that the rates of enantiomer consumption were equal. At the
end of the reaction, one enantiomer of alcohol is bound to the polymer and the other has formed an
ester in solution. They may be separated by fi ltration. Both reactions have products of higher ee’s
than predicted for the simple kinetic resolution reactions at 50% conversion. Note that really quite
different reagents were used to react with the two enantiomers.
If you have got the idea by now that parallel kinetic resolutions are a complicated business then
the next example will show just how simply they can be achieved. Eames set about using different
(pseudo-enantiomeric) Evans’ auxiliaries to resolve an ester. 34 However, the ‘auxiliaries’ are nothing
of the sort in this reaction. On each side of the reaction, an enantiomerically pure oxazolidinone
is reacted with a racemic ester 63 which is to be resolved. A crucial foundation to the work was to
establish which chiral oxazolidinones show good selectivity. This was done with racemic oxazolidinones
and racemic substrate. Using racemic oxazolidinone exposes the diastereoselectivity of
the reaction without the complication of the concentration of the substrate enantiomers varying as
the reaction proceeds. It also mimics the environment of the parallel kinetic resolution itself.
Hence it was found that while valine-derived oxazolidinone 62 and phenylglycine-derived 67
gave good selectivity (for the syn diastereomer) norephedine-derived 66 did not.
HN
O
O
Ph
1. BuLi
Me
O
OC 6F 5
60
Ph
Me
s = 34
For the parallel kinetic resolution itself, (S)-62 and (R)-67 were used together with racemic ester
63 in an effi cient and readily achieved kinetic resolution. Despite the similar appearance of 64 and
68 they could be separated. It is worth pointing out that the major syn products are complimentary
to the anti products to be expected from a standard alkylation of an oxazolidinone like 69.
O
N
O
O
+
Ph
O
O
Me
O
O
59
96% ee
61
92% ee
(±)-62 63
(±)-64 - anti 5 : 95 (±)-65 - syn
HN
2.
O
O
HN
O
Me Ph Ph
(±)-66 (±)-67
O
Ph
O
Ph
69
N
O
O
N
polymer
O
O

644 28 Kinetic Resolution
HN
O
Regiodivergent resolutions
O
2.
Ph
1. BuLi
Me
O
OC 6F 5
Ph
Me
(±)-62 63
(±)-64 - anti 5 : 95 (±)-65 - syn
Initially this sort of thing looks like one of those academic fancies that will not actually be of
any use to a medicinal chemist working at the coal face of pharmaceutical production. But don’t
give up just yet, later we come onto applications to regioselectivity in steroid chemistry. In this
next example, one enantiomer of substrate reacts with the optically pure base in one way and the
other enantiomer in another – hence the ‘divergence’. Before we get started with the reaction, the
substrate needs careful stereochemical analysis.
t-Bu
O
O
t-Bu
Ph N Ph
Me3SiCl 70
H
H
70a
Li
71
t-Bu
72
With achiral ketone 70, an optically pure base 71 chooses between one enantiotopic proton and
another to make the enolate enantioselectively. The choosing goes on within the compound – there is
no enantiomer of the starting material. However, things are a little more complicated when we move
to a racemic substrate. The protons on either side of the carbonyl of ketone 73 are not enantiotopic
but diastereotopic. The enantiomeric proton can be found in the other enantiomer of compound. We
might imagine, therefore, in a straightforward situation, that a chiral base would deprotonate one
enantiomer of starting material and ignore the other completely. Thus we would have enantioselection
and all would be well. With ketone 73 it is not quite so simple.
H
O
BocN
H H
=
Locally
superimposable
BocN
(R,R)-73
parts of the (R,R)-73
H O
two enantiomers
in the frames.
=
BocN
H H
BocN
(S,S)-73 (S,S)-73
We know that enantiomers cannot be superimposed. However, if we compare (R,R)-73 and
its enantiomer, we can see that a crucial part of each molecule can be superimposed. This local
congruence in the molecules can be exploited. It is this region that is attractive to the chiral base
and it corresponds to different parts in each enantiomer. Thus we can expect the regioselection of
one enantiomer to be different from that in the other.
O
N
O
O
+
Ph
H
H
H
H
H
Me
O
O
H
O
N
O
O
OSiMe 3

N
N
Li
Ph
Me (R)-76
base 77 : 78
LDA 64 : 36
(R)-76 95 : 5
(S)-76 24 : 76
28 Regiodivergent resolutions 645
When a single enantiomer of (R,R)-73 was reacted with base 71, a 94:6 ratio of the regio isomeric enol
ethers 74 was generated. When the other enantiomer (S,S)-73 was reacted with the same base 71 then the
preference for the regioisomers was the other way round at 21:79. These numbers are not 6:94 as well because
the molecule also has an inherent preference for which position it would like to be deprotonated. For
the sake of simplicity we shall ignore this modest match/mismatch issue and move on. So, the question then
is what would we expect to see if we had started with racemic 73. Regioisomer 74 would be generated in
94 parts from one enantiomer and in 21 parts from the other. We would therefore expect the ee to be 63%.
Meanwhile, the other regioisomer 75 is generated in 79 parts from one enantiomer 75b and only 6 parts
from the other 75a so we can expect an ee of 86%. The ees determined experimentally when racemic 73
was used were 60% and 83%. The relative amounts of 74 and 75 we can expect would be (9421): (6 79) =
58:42. Experimentally 35 it was 55:45.
BocN
BocN
BocN
H
H
H
H H
(R,R)-73
Me3SiCl
–90 ˚C
Ph N Li
H 74a
H
H
75a
O
OSiMe 3
OSiMe3
6%
O
Me 3SiO
Me3SiO
79%
NBoc
Broadly, what has been achieved here is one enantiomer reacting to give one product and the other
enantiomer reacting to give the regioisomeric product. Hence the term - regiodivergent resolution. This
is really another example of a parallel kinetic resolution. The implications are of more general use, of
course, than the rather specialist example given here. Consider for instance the reaction of the optically
pure steroidal ketone. Deprotonation with LDA and quenching with TMSCl gives a mixture of the two
enol ethers 77 and 78 with moderate selectivity. Before we move on to using a chiral base in this situation,
it is worth noting that the use of an achiral base, LDA, has uncovered an inherent preference (in a
kinetically controlled reaction) of the molecule itself – this was something we ignored with ketone 73
but which was clearly present too. 36 Anyway, by making use of an optically pure base, we can either
improve the selectivity or overturn the molecules’ preferences. Both of these options are useful.
N t-Bu
O
H
H
H
Me
H
H
steroidal ketone
H
H
H H
(S,S)-73
Ph
Me3SiCl
–90 ˚C Ph N
Li
94%
OBu-t
base
Me3SiCl
Me3SiO
74b
75b
H
H
H
H
H
H
NBoc
NBoc
H
Me
H
Ph
21%
OBu-t
Predicted Results
for racemate
Me3SiCl
–90 ˚C
ee =
ee =
Ph N Li
Ph
94 – 21
× 100 = 63%
94 + 21
79 – 6
79 + 6
H
Me3SiO
H
77 78
+
H
H
× 100 = 86%
H
Me
H
OBu-t

646 28 Kinetic Resolution
Double Methods
If a selective process can be applied twice then we might expect the quality of the resulting material
to be very high. In the next example, the selective process is applied fi rst to produce mostly a single
enantiomer. When applied the second time, it removes the small amount of the wrong enantiomer
that was produced the fi rst time round! In Chapter 25 we mentioned that desymmetrisations and
kinetic resolutions were brothers. Both are used in each of the examples below.
Desymmetrisation then kinetic resolution
The doubly allylic alcohol 79 is reacted under Sharpless epoxidation conditions. 37 Selectivity
is good because k fast/k slow is high at 104. This fi rst reaction is not a kinetic resolution because
we are not resolving anything and, indeed, the starting material is achiral (and prochiral). This
fi rst reaction produces mostly enantiomer 80a with a little of enantiomer 80b. With such good
selectivity we would expect good ees even after the fi rst round and so we do. At 50% conversion
we have a 48% yield of 80a and already excellent ee of 99.4%.
The second reaction converts each enantiomer 80a and 80b into the same double epoxide
81. Here is the key to the enhancement process – the double bond that the reagent found more
attractive in the starting material 79 (and hence reacted with fast) is the one that remains unreacted
in product 80b. Hence we might expect this undesired product 80b to react faster than 80a to give
the double epoxide. At 99% conversion, the yield of 80a is 93% and the ee 99.96%. The reference
contains plenty of the maths behind this rather complicated process. 37
79; achiral
OH
fast
slow
k fast / k slow = 104
O
80a
80b
If the enhancement of enantiomeric excess did not impress you much (though it should,
99.96% is very diffi cult to achieve in one go!) perhaps an example where the ee is a bit lower
after the fi rst round will make the point more effectively. The bistrifl ate 82 contains a biaryl bond
with restricted rotation so that replacing one of the trifl ates with something else will give us a
chiral molecule (83a and 83b are enantiomers). As above, the fi rst reaction is a desymmetrisation
and the second reaction a kinetic resolution upon the products from the fi rst. Both reactions are
palladium mediated cross-couplings of an aryl trifl ate and phenyl Grignard.
An optically pure palladium complex 85 catalyses the formation of a biaryl bond and selects
between the two enantiotopic trifl ates. The selectivity is less good than the example above with the
fast reaction only 12 times faster than the slow reaction for the fi rst stage. We would expect that
the best enantiomeric excess in a product that could be obtained with a rate ratio of 12:1 would be
85% ee [(121)/(121) 100]. With a slight excess of PhMgBr we observe 39% of product 83
and an ee of 85%.
O
OH
OH
slow
fast
O
O
81; achiral
OH

TfO OTf
82
N
Ph Cl
Pd
Cl
N
85
28 Double Methods 647
85
PhMgBr TfO Ph
SLOW
FAST
85
PhMgBr
Ph OTf
It is worth reiterating something here before we move on to the second reaction. With a kinetic
resolution, the ee of a product is limited by the relative rates of the reactions. But the ee of the
starting material left behind is not limited in this way. The ee can be increased by letting the
reaction run a bit further to completion. There is a price to be paid in yield, of course, and you
might fi nd that to get your 98% ee you end up with only 2% yield but it can be done. In the second
reaction (the reaction of 83a and 83b), the compound we want 83b is one of the starting materials.
The relative rates of reaction are quite poor at 5:1 but we already have a head start in ee anyway.
The wrong enantiomer 83a is eaten up in the second reaction With 2.1 eq we end up with an 87%
yield of product in 93% ee with 13% of the doubly arylated product 84. 38 If we wanted to increase
this 93% further, we could run the reaction a bit further still.
These double methods look quite esoteric but they are more widespread than one might imagine.
They need looking out for because they are sometimes not even noted by the authors of the work.
In Fürstner’s synthesis of ()-balanol, 39 which we looked at in chapter 25, the chiral centres in
the seven membered ring originate in a Sharpless asymmetric epoxidation (see chapter 25). We
can see that the starting material 86 is a double allylic alcohol of the kind we saw earlier 79. The
enhancement of enantiomeric excess is certainly operating to give a product 87 of excellent ee.
After a few manipulations, the opening of the epoxide with allyl amine and a ring closing metathesis,
the key ring 88 has all the stereochemistry that it needs.
OH
86
OBn
NH
OH
In the above examples enantiotopic reactive sites on either side of the compound were reacted
before we moved onto more complicated matters. The next example is a variation on that theme
FAST
83a
rate 12 : 1 rate 5 : 1
83b
(–)-DET
OH
t-BuOOH NaH
Ti(OPr-i) 4 –20 ˚C
Boc2O
Et3N
OBn
N
OH
O
SLOW
Boc
Boc
94% from 87 100%
88%
87
Cl
Cl
PCy3 Ph
Ru
PCy3 8 mol%
BnBr
Ph Ph
bisphenyl 84
83
84
1.1 eq PhMgBr 39% 85% ee 0%
2.1 eq PhMgBr 87% 93% ee 13%
OBn
N
OBn
OH
O
(PhO) 2PON 3
Ph 3P,
DEAD
NH 2
OBn
N 3
N
Boc
88, 91%

648 28 Kinetic Resolution
but this time we start with enantiotopic faces of a double bond. When triene 89 is reacted with
OsO 4 and (DHQD) 2PYR and allowed to go to a high level of completion then the product can be
obtained enantiomerically pure. However, if the same reaction is stopped at low conversion then
the enantiomeric excess of the product is only 95%.
89
OsO 4
(DHQD) 2-PYR
The explanation 40 is that there is a kinetic resolution going on—the minor enantiomer is being
removed as the reaction proceeds. It reacts more quickly under the reaction conditions. We could
leave the explanation at that but we shall not gloss over this point because it is worth consideration
in a little more depth. In order to understand the nature of this process we need to know about the
reactivity of diol 90.
Both the chiral centres in diol 90 have the R confi guration. We see perhaps the most revealing result
when enantiomerically pure diol 90 is dihydroxylated with OsO 4 using an achiral ligand – quinuclidine.
This is important because it tells us how the substrate likes to react with osmium tetroxide. There is a
3:97 product ratio in favour of the meso compound 92 rather than the C 2 symmetric compound 91. In
other words, the molecule with two R chiral centres prefers the reaction that leads to the formation of
two new chiral centres of opposite confi guration – S.
HO
R
R
OH
OsO 4
quinuclidine, etc.
N
HO
R
R
OH OH
HO
R
R
So we see how the substrate likes to react but the reagents, of course, may have other ideas. The
chiral ligand (DHQ) 2PYR prefers to form two S chiral centres from a trans double bond of the
kind we have in 90. The diene 90 wants that too so we have the matched case and a high selectivity
of 0.3:99.7.
However, (DHQD) 2PYR, the pseudo-enantiomer of (DHQ) 2PYR (see chapter 25), would prefer
to form two R chiral centres. The substrate and reagent are in competition here—the mismatched
case. The selectivity is turned over to 75:25 in favour of the C 2 symmetric product 91 this time.
So the reagent wins but not outright; there is still much of the meso diastereomer formed. Now we
can return to the original question which concerns the reaction of triene 89.
HO
90
OH
HO
S
S
OH OH
HO
R
R
90 91 (C2 isomer) 3 : 97 92 (meso isomer)
90
OsO4
(DHQ) 2PYR
C2 91 0.3 : 99.7 92
90
OsO 4
(DHQD)2PYR
C 2
+
91 75 : 25 92
meso
meso

89
Triene 89 reacts to form the diol 90. A small amount of the enantiomeric diol, ent-90, is also
formed. The crucial point is that this minor product is matched with the reagent and is reacted
away, and quickly, to the tetraol 92a (92a = 92 but is drawn in a different way). The major product
91 is mismatched with the reagent and reacts more slowly. The fi rst dihydroxylation (of 89) is the
fastest of all three.
References
Major
enantiomer
OsO 4
(DHQD) 2-PYR
Minor
enantiomer
28 References 649
HO
HO
R
OH
R
General references are given on page 893
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2. This graph was produced with the kind assistance of Prof. Guy Lloyd-Jones
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16. T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 1980, 102, 5974.
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Tartrate Catalysts, vol. 5 (Academic Press, Orlando, 1985).
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Press, Orlando, 1985).
19. M. S. VanNieuwenhze and K. B. Sharpless, J. Am. Chem. Soc., 1993, 115, 7864.
20. G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, P. Melchiorre and L. Sambri, Org. Lett., 2005, 7, 1983.
21. I. V. J. Archer, Tetrahedron, 1997, 53, 15617.
22. T. Matsuda, T. Harada, K. Nakamura and T. Ikariya, Tetrahedron: Asymmetry, 2005, 16, 909.
23. S. M. Roberts, Ed., Biocatalysts for Fine Chemicals Synthesis (John Wiley & Sons, Chichester, 1999).
90
S OH
S
ent–90
reacts quickly
HO
R
R
OH
HO
S OH
S
92a

650 28 Kinetic Resolution
24. S. E. Schaus and E. N. Jacobsen, Tetrahedron Lett., 1996, 37, 7937.
25. M. F. Jones and C. M. Rayner, Tetrahedron Lett., 1995, 36, 6961.
26. J. Milton, S. Brand, M. F. Jones and C. M. Rayner, Tetrahedron: Asymmetry, 1995, 6, 1903.
27. S. Brand, M. F. Jones and C. M. Rayner, Tetrahedron Lett., 1995, 36, 8493.
28. S. Brand, M. F. Jones and C. M. Rayner, Tetrahedron Lett., 1997, 38, 3595.
29. P. M. Dinh, J. A. Howard, A. R. Hudnott and J. M. J. Williams, Tetrahedron Lett., 1996, 37, 7623.
30. Y. K. Choi, J. H. Suh, D. Lee, I. T. Lim, J. Y. Jung and M.-J. Kim, J. Org. Chem., 1999, 64, 8423–8.
31. M. Kitamura, M. Tokunaga and R. Noyori, J. Am. Chem. Soc., 1993, 115, 144.
32. E. Vedejs and X. Chen, J. Am. Chem. Soc., 1997, 119, 2584.
33. E. Vedejs and E. Rozners, J. Am. Chem. Soc., 2001, 123, 2428.
34. G. S. Coumbarides, M. Dingjan, J. Eames, A. Flinn, J. Northen and Y. Yohannes, Tetrahedron Lett.,
2005, 46, 2897.
35. K. Bambridge, B. P. Clark and N. S. Simpkins, J. Chem. Soc., Perkin Trans. 1, 1995, 2535.
36. M. Sobukawa, M. Nakajima and K. Koga, Tetrahedron: Asymmetry, 1990, 1, 295.
37. S. L. Schreiber, T. S. Schreiber and D. B. Smith, J. Am. Chem. Soc, 1987, 109, 1525.
38. T. Hayashi, S. Niizuma, T. Kamikawa, N. Suzuki and Y. Uozumi, J. Am. Chem. Soc., 1995, 117, 9101.
39. A. Fürstner and O. R. Thiel, J. Org. Chem., 2000, 65, 1738.
40. H. Becker, M. A. Soler and K. B. Sharpless, Tetrahedron, 1995, 51, 1345.

29
Enzymes: Biological Methods
in Asymmetric Synthesis
Preliminary note on biological methods
Introduction: Enzymes and Organisms
Good and bad features of enzymes as catalysts
Organisms: Reduction of Ketones by Baker’s Yeast
Ester Formation and Hydrolysis by Lipases and Esterases
Kinetic resolution with racemisation
Enzymes versus whole organisms
Desymmetrisation with lipases
Immobilised enzymes in desymmetrisation
Polymer-supported reagents and enzymes
Effects of amines on lipases and esterases
Other acylating enzymes
Enzymatic Oxidation
Asymmetric dihydroxylation of benzenes
Epoxidation
The Baeyer-Villiger reaction
Baeyer-Villiger reactions with engineered baker’s yeast
Nucleophilic Addition to Carbonyl Groups
Asymmetric addition of cyanide to aldehydes
Products derived from cyanohydrins
Enzymatically catalysed aldol reactions
Synthesis of syringolide using an enzyme-catalysed aldol reaction
Engineered aldolase
Practical Asymmetric Synthesis with Enzymes
A calcium channel blocker: diltiazem
Insecticides based on chrysanthemic acid esters
Anti-fungal triazole-containing tetrahydrofurans
Bristol-Meyers Squibb anti-psychotic agent BMS 181100
An Eli Lilly protein kinase inhibitor
Lotrafi ban: A GlaxoSmithKline drug to prevent blood clots
Two desymmetrisations
Preliminary note on biological methods
This chapter concerns methods totally different from anything else in this section. It is mainly
about enzymes as catalysts but also deals briefl y with whole organisms. These methods are outside
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

652 29 Enzymes
the experience of most organic chemists and we urge you to study the literature thoroughly before
attempting any of them. Fortunately there are books dealing both with laboratory and commercial
practice, including three particularly good ones. 1
Introduction: Enzymes and Organisms
Good and bad features of enzymes as catalysts
Whether you use isolated enzymes or whole organisms, you are really employing one or
more enzymes as catalysts in chemical reactions. Enzymes are the most refi ned catalysts in
existence. They are usually highly specifi c: catalysing the reaction of only one compound at
a specifi c reaction site with defi ned stereochemistry including enantioselectivity. They bring
about almost incredibly large rate accelerations - 10 9 to 10 12 is commonplace. They do so
in reactions in dilute aqueous solutions at 37 C and at low concentrations. They do all this
with inherently ineffi cient catalytic mechanisms - general rather than specifi c acid and base
catalysis - that are successful because the protein binds the substrate so that the reagents (such
as coenzymes, if any, or water) and the catalytic groups are in exactly the right positions to
exert maximum synergistic effects. No wonder that organic chemists use them as catalysts in
organic reactions.
So why are chemical reagents rather than enzymes used for most reactions? Each enzyme
virtue may be a vice in organic synthesis. High specifi city is disastrous: who would want a reagent
that would reduce just one ketone enantioselectively, however effi cient it might be? Alongside
large rate accelerations go small turnovers and long reaction times. Living things want to produce
small amounts of many different compounds at a trickle over days or even years. Chemists want
tonnes of compounds in a few hours. We don’t want to use low concentrations in water. We are
not restricted to general acid or base catalysis: NaOH at 100 C hydrolyses esters by specifi c base
catalysis much faster than the fastest enzymes. And the binding is a problem too: enzymes have
molecular weights of tens or hundreds of thousands so that even 1 mole % catalyst might weigh
more than the substrate!
Now the boot is on the other foot - why should chemists use enzymes? This chapter will show
that many enzymes are not very substrate specifi c and will for example reduce a large variety of
ketones with essentially perfect enantioselectivity. Some of these enzymes catalyse reactions that
are essentially impossible with chemical reagents. Some can be used in organic solvents at high
temperatures. Practically they may be easy to use once someone else has worked out the details
and, if they are immobilised on polymers, for example, they can be used again and again with a
trivial workup since the starting material gives the product and nothing else. Genetic engineering
allows simple organisms such as E. coli to promote, say, enantioselective Baeyer-Villiger oxidations
of ketones. As with all synthetic methods, enzymes are used in some reactions with great
success and are to be avoided in others. Their use will grow both in the laboratory and in the
manufacturing plant.
Organisms: Reduction of Ketones by Baker’s Yeast
The ordinary yeast used by bakers in their bread making is a valuable organism for the enantioselective
reduction of unsymmetrical ketones. 2 It is particularly effi cient at the reduction of
β-keto-esters such as ethyl acetoacetate 1. An Organic Synthesis procedure 3 reveals that the true
reagent is sucrose, which provides just one H atom, that plenty of yeast is required, and that 3–4
days are needed to make 20–30 g product 2 in only 85% ee.

O
1; 40 g
CO 2Et
200 g baker's yeast, 500 g sucrose
1.6 L water, 20–30 ˚C, 75–85 hours
The mnemonic for these reductions is based on the size of the two groups on the ketone. In this
case 1 the ‘large’ group is CH 2CO 2Et and the ‘small’ group Me. With the keto-ester 3, though the
‘small’ group still appears to be Et rather than CH 2CO 2Et, in fact the other enantiomer (R)-4 is
produced in low ee. The solution in such cases is the make the ester group very large, octyl being
a popular choice 5. Now we get (S)-6 in good ee.
On a large scale, slow addition of the ketone and good aeration are essential to cut the reaction
time and then kilos of 1 can be reduced in excellent ee in only 3-4 days. 4 Under these conditions,
each kg of product requires 1.8 kg ethyl acetoacetate 1, 3.9 kg yeast, and 3.5 kg sucrose.
On a large scale, smaller quantities of materials can be used if the sucrose is replaced with
ethanol. Since the yeast is an organism there are other enzymes present and EtOH is converted
enzymatically into the coenzyme NADPH, the true reducing agent, produced from sucrose in the
reductions above. Aeration is again crucial and a bubble column reactor is used. Ethyl acetoacetate
1 is again effi ciently reduced and so is hydroxyacetone 7 to give the useful diol 5 8.
1
60 g
O
RS RS RL RL sucrose
O
29 Ester Formation and Hydrolysis by Lipases and Esterases 653
O
O
3
5
CO 2Et
CO 2Oct
CO 2Et
1; 2.25 kg
112 g baker's yeast
104 g EtOH
1 L water, pH 3-4
25 L air per minute
30 ˚C, 62 hours
baker's yeast
baker's yeast
sucrose
baker's yeast
sucrose
Ester Formation and Hydrolysis by Lipases and Esterases
CO 2Et
Lipases and esterases are enzymes that hydrolyse esters in one direction or make them in
the reverse direction. A wide variety of such enzymes is commercially available and you
are advised to seek a close analogy before choosing one or another. 6 If the alcohol 9 is the
interesting part, these enzymes can be used to provide enantiomerically enriched alcohol or
ester by either reaction.
OH
OH
OH
CO 2Et
CO 2Oct
(S)-6; 99% ee
5 kg baker's yeast, 1 kg sucrose
slow addition of ketone to fermenter
40 L water, pH 3-4, 10 L air per minute
20-30 ˚C, 100 hours
2; 40.5 g
56% yield
99.3% ee
O
7; 40 g
OH
OH
2; 24-31 g; 85% ee
Mnemonic for
baker's yeast
reduction
OH
OH
CO2Et
(R)-4; 40% ee
OH
CO 2Et
CO 2Oct
(S)-2; 1.29 kg; 56% yield
95-97% ee
112 g baker's yeast
18 g EtOH
1 L water, pH 3-4
3 L air per minute
30 ˚C, 38 hours
OH
OH
8; 22 g; 56% yield
98.2% ee

654 29 Enzymes
enzymatic esterification
of racemic alcohols
enzymatic hydrolysis
of racemic esters
R 1
R1 OH
R1 O R2 O
R1 OH
O
R1 O R2 O
R1 racemic 9
R OH
2
+
(S)-10 (R)-9
O
+
racemic 10 (S)-9 (R)-10
On the other hand if the acid is the interesting part then the same two types of reaction can be
carried out to produce enantiomerically enriched esters or acids as required. Both these reactions
are equilibria. Both are also kinetic resolutions (chapter 28) and it is not usually possible to get
both products in high ee. The key statistic is the rate ratio (‘E’) of hydrolysis or esterifi cation of
the two enantiomers. Since the molecules we shall be using are not natural substrates of lipases,
the E value will vary considerably but, as you know from chapter 28, it does not need to be very
large for acceptable results. This ‘E’ is often called k S/k R in chemical kinetic resolution and called
the ‘s value’ in chapter 28.
asymmetric formation of
esters from racemic acids
asymmetric formation
of acids by hydrolysis
of racemic esters
R1 R
CO2H 1
CO2R2 R1 +
CO2H racemic 11 (S)-12 (R)-11
R1 CO2R2 R1 CO2H R1 CO2R2 +
racemic 12 (S)-11 (R)-12
Important examples of this last type are the 2-aryl propionic acids, widely used as
anti-infl ammatory drugs. The active enantiomer of ibuprofen 14 can be formed by hydrolysis
of esters 13 with the lipase from Candida cylindracea. The natural enzyme gives E = 10 but
if it is refolded by precipitation from solution in 1:1 EtOH/Et 2O with sodium cholate the E
value rises to >100. The unnatural substrate 13 fi ts the refolded enzyme better than it fi ts the
native enzyme. 7
13
CO2R Candida cylindracea lipase
CO2H 14; (S)-Ibuprofen
Typical kinetic resolutions of the arylpropionic acids are those of fl urbiprofen 16 and ketoprofen
18 with a cell-free extract of Pseudomonas fl uorescens. Note the special ester (trifl uoroethyl)
selected for maximum effi ciency and how successful that is: perfect ee in the hydrolysed products
at close to 50% conversion. 8 The unreacted esters 15 and 17 can of course be racemised by
enolisation and added to the next resolution.

In some cases two different enzymes may show opposite enantioselectivities. The lipase
from Candida cylindraceae (CCL) and the esterase from pig liver (PLE) do so with racemic
cyanohydrins 9 such as 20. Note that the acetate is hydrolysed rather than the ethyl ester. Each
enantiomer may be reduced in high yield to a single enantiomer of the amine 21. The literature
value for the rotation of this compound is [α] D 20.8 and the measured value for (S)-21 was 20.9
and for (R)-21 was 20.6. Though this is not usually a reliable method of assessing enantiomeric
purity, it is quite convincing here. Later in this chapter you will meet an alternative way to make
the same sorts of compounds using different enzymes.
OH
CO2Et NC
(S)-19; 48% yield
excess BH3.THF (S)-19
NiCl2.6H2O, i-PrOH
PLE
60% conversion
H2N
OH
Kinetic resolution with racemisation
NC
OAc
CO 2Et
CO 2Et
CO2Et
Clearly the effi ciency of these reactions is improved if the starting material is racemising under
the reaction conditions (see dynamic kinetic resolution in chapter 28). Ketorolac 23, another aryl
propionic acid, has an acidic proton and its esters racemise at slightly alkaline pH (9-10). Is it
possible to fi nd an enzyme system that will operate in this pH range? First a lipase had to be found
that would do the hydrolysis of the ester 22 in the right sense. A selection of lipases gave the wrong
enantiomer (R)-23 except for porcine pancreatic lipase but that gave low ees.
Ph
O
N
F
29 Ester Formation and Hydrolysis by Lipases and Esterases 655
15
17
CO 2CH 2CF 3
CO2Me
CO 2CH 2CF 3
20
H2N
OH
CCL
40% conversion
(S)-21; 93% yield (R)-21; 100% yield
pH 8
cell-free extract of
pseudomonas fluorescens
pH 7.5 (NaOH), 20 hours
47% conversion
48% (R)-15 recovered
Ph
cell-free extract of
pseudomonas fluorescens
pH 7.5 (NaOH), 20 hours
48% conversion
48% (R)-15 recovered
OH
CO2Et NC
(R)-19; 32% yield
excess BH 3.THF
NiCl2.6H 2O, i-PrOH
O
(±)-22
O
(R)-23 ketorolac
O
(S)-22
Lipase from Mucor meihei 94% ee 90% ee
Lipase from Pseudomonas spp. 90% ee 93% ee
Lipase from Candida cylindracea 74% ee 94% ee
Porcine Pancreatic Lipase (S) 32% ee (R) 4% ee
N
CO2H
+
Ph
O
F
N
CO2H
(S)-16; ,43% yield, >99% ee
CO 2H
(S)-18; 40% yield, >99% ee
(R)-19
CO 2Me

656 29 Enzymes
A selection of proteases did much better giving the right isomer of ketorolac (S)-23 in good
yield and ee and one, the protease from Streptomyces griseus, did exceptionally well. This was at
pH 8 - the normal pH for the enzyme.
Ph
O
Protease from Aspergillus saitoi 96% ee
80% ee
Protease from Bacillus subtilis 96% ee 62% ee
Protease from Aspergillus oryzae 70% ee >96% ee
Protease from Streptomyces griseus >96% ee >96% ee
With the protease from Streptomyces griseus at pH 9.7 racemisation occurred at a reasonable
rate and the enzyme still operated effi ciently, giving (S)-23 in good yield and only slightly reduced
ee. One crystallisation gave 94% ee, acceptable for an anti-infl ammatory. 10
Ph
O
CO2Me
CO2H
N
pH 8
Ph
N
+
Ph
N
(±)-22
O
(S)-23 ketorolac
O
(R)-22
Enzymes versus whole organisms
We have discussed examples of pure enzymes - the lipases - and whole organisms - baker’s
yeast and before we continue it is worthwhile to pause and consider the relative merits of the
two approaches. Many of these points will be elaborated in the rest of the chapter. There are
other methods, as you will see, that fi t neither of these descriptions exactly such as engineered
micro-organisms that have a particular enzyme over-expressed. There will be examples of these
later. Meanwhile here are the main points:
Cost: Pure enzymes are expensive while organisms such as yeasts are cheap. Individual cultures
of microorganisms may also be expensive.
Scale: Very little pure enzyme or bacteria may be needed in contrast to the large quantities of yeast.
Specifi city: A pure enzyme normally catalyses only one reaction while a living organism contains
many enzymes and may catalyse many reactions.
Reagents: Pure enzymes normally need no more than pH adjustment though some, say enzymes
that catalyse redox reactions, need expensive co-factors. These can normally be supplied by a
second enzyme the recycles the co-factor. Organisms need feeding - this is cheap but may require
a lot of material.
Work-up: Reactions with pure enzymes are clean to work-up though re-isolation of the enzyme
will normally be preferred. Immobilised enzymes avoid this problem. The work-up of a reaction
with a yeast is very messy indeed.
Waste products: None with an enzyme, lots with a yeast but at least they are environmentally friendly.
Desymmetrisation with lipases
N
(±)-22
CO 2Me
Streptomyces griseus protease
pH 9.7 (Na 2CO 3/NaHCO 3)
24 hours, 22 ˚C
acidify to pH 2 to precipitate acid
These are hydrolyses of meso diesters rather than kinetic resolutions and can give quantitative yields
of single compounds. The products are half acid, half ester and care must be taken to preserve this
Ph
N
CO 2H
O
(–)-(S)-ketorolac 23
92% yield, 85% ee
CO 2Me

difference. One useful group is the Diels-Alder products such as those formed from butadiene and
maleic esters 24. Hydrolysis with various lipases 11 gives one enantiomer of the half ester 25.
+
CO 2R
CO 2R
Diels-Alder
The results are sensitive to the esterifying alcohol ROH. If R = Me 26, results are excellent
(99% yield, 98% ee) but fall off as R gets larger. Even with R = Et things are signifi cantly worse
(67% yield, 27% ee) and with R = i-Pr they are hopeless (5% yield, 2% ee). It does not do to move
too far away from the natural substrates. Three and fi ve-membered rings also give good results:
in each case the ester that is hydrolysed is marked - this is not always what one would expect -
contrast 27 and 28.
CO 2Me
CO2Me 26
various
lipases
CO2Me
CO2H 27; 99% yield
100% ee
Another group of meso diesters are the acyclic compounds 30 and 31. Pig liver esterase is good
at forming the mono-ester 33 and this compound can be transformed by selective reduction into
either 32 or 34. These lactones are enantiomers so that either series may be entered from the same
meso starting material. 12 In addition the precarious chirality of 33 is more secure in the lactones.
R 2
R 1
CO2H
CO 2Me
30; usually
>85% ee
Immobilised enzymes in desymmetrisation
CO 2R
various
lipases
CO 2H
CO2R CO2R 24 25
The starting material for the next desymmetrisation comes from an interesting reaction fi rst
described in chapter 19. The Pd-catalysed attack of AcOH on the mono-epoxide (±)-35 gives the
racemic monoester 36. In order to convert this to a single enantiomer it is fi rst made into the meso
diester 13 37.
O
(±)-35
29 Ester Formation and Hydrolysis by Lipases and Esterases 657
Now the acetyl cholinesterase from the electric eel (EEAC) effi ciently desymmetrises the
diacetate to give the enantiomerically pure monoester 36. The enzyme can be used as a lyophilised
powder or is available (from Sigma) immobilised on agarose beads. This form is easy to use and
easy to isolate after the reaction. Other cyclic examples work well as does the most impressive
open chain example 38 with an E-alkene. 14
O
CO 2H
CO2Me
28; 90% yield
99% ee
O
CO 2H
CO 2Me
29; 85% yield
82% ee
R
R
H
O
O
LiBH4
EtOH
R
H
CO2H
CO2Me
BH3 H
R
2
R1 CO2H CO2Me 31; usually
>70% ee 32 33 34
0.2 mol% (Ph 3P) 4Pd
AcOH, THF
HO OAc Ac2O AcO
OAc
imidazole
36; 72-76% yield 37; 96-98% yield
O
O

658 29 Enzymes
18.6 mg EEAC, NaN3 AcO OAc NaH2PO3 buffer, pH 9 HO
OAc
The product 36 can be converted by simple chemistry into either enantiomer of the
enone 40 (R = TBDMS). Notice that another enzyme, this time a plant lipase, is used to hydrolyse
the acetate 41 effi ciently. There is no asymmetric induction in this step as 41 is already a
single enantiomer. 15
HO OAc t-BuMe2SiCl O
PCC
CH 2Cl 2
41; 83% yield
OAc
Et 3N, DMAP
CH 2Cl 2
wheat germ
lipase
phosphate
buffer
RO
Polymer-supported reagents and enzymes
O OH
Polymer-supported enzymes have been combined with polymer-supported reagents in the synthesis
of the bryostatins. The nitrone derived from the nitro compound 43 supported on a soluble aryl
poly-ether polymer undergoes an effi cient 1,3-dipolar cycloaddition with butenone to give the
isoxazoline 44 and hence by reduction the racemic syn compound 45 required for the synthesis. 16
The single enantiomer of 45 is produced by enantioselective acylation with vinyl acetate
catalysed by Novozym 435, an immobilised lipase from Candida antarctica containing about
1% w/w enzyme on a macroporous polypropylic resin. You will appreciate that as both substrate
and catalyst are on polymers, one at least must be soluble in the reaction mixture. The polymer is
stripped from the substrate 45 with HF.
(±)-syn-45
9-12 hours
37; 16 g room temperature 36; 11.3 g, 96% ee
86-87% yield
36
OAc
Novozym 435
anhydrous toluene
70 ˚C, 4 hours
40% conversion
O NO 2
43
L-Selectride
CH 2Cl 2
O
OAc
1. NaOMe
MeOH
t-BuMe 2SiCl
CH 2Cl 2
RO
2. MnO2
39; 77-80% yield CH2Cl2 (S)-40; 87-90% yield
42; 60% yield
PhNCO
O
O
O
N O
Et 3N, DMAP
OH
syn-45; 93% yield racemic
N O
OH
(+)-45; 96% yield; >99% ee
N O
44; 93% yield
HF, H 2O
MeCN
HO
OH
OAc
38; 92%ee, 77% yield
O
O OR
(R)-40; 87-90% yield
O
N O
(+)-46
OH

This is a kinetic resolution that works by enantioselective acylation of the unwanted enantiomer
of the alcohol. The reaction is therefore an ester exchange and vinyl acetate is an effi cient acetate
transfer agent since the other product is ‘vinyl alcohol’ better known as the enol of acetaldehyde
so the reaction is irreversible.
O
syn-45
N O
OH
Effects of amines on lipases and esterases
+
OAc
Novozym
435
OH +
MeCHO
We end this section with two examples of the effects amines may have on esterase activity. The
aggressive nitrogen nucleophile can obviously interfere with ester formation or hydrolysis. In
designing a synthesis based on these enzymes we must fi nd a symmetrical intermediate that might
be desymmetrised. In the synthesis of the simple β-lactam 48, simple disconnections led to the
symmetrical amino-diester 50, with the nitrogen atom protected.
O
Synthesis of a suitable substrate from citric acid 51 was straightforward 17 and Ohno 18 found
that the Cbz-protected dimethyl ester 53 could be desymmetrised effi ciently with pig liver esterase
(PLE) or with even higher enantioselectivity, with the microbial enzyme from Flavobacterium
lutescens (98% ee). The β-lactam 48 could be closed by the dipyridine-disulfi de/Ph 3P method.
The selectivity of hydrolysis of this type of diester 55 (see also 31) by PLE depends on the
substituents. The two enantiomers of 56 are formed as shown with various degrees of ee and you will
notice that there is no easily discerned system. Thus R = Pr and R = i-Pr give opposite enantiomers
as do amides such as 53 and the corresponding free amine. 19
55
O
N O
(–)-47
NH
CO2Me C–N
amide
HO2C
NH2
CO2Me protect NH2 esterify
MeO2C NHZ
CO2Me 48; β-lactam 49 50
HO CO2H
O
NHCbz
HO2C CO2Me 54; 93% yield
1. NH 4 AcO
Na(CN)BH3
H
NHCbz
HO2C CO2H 2. HCl
MeOH MeO2C CO2Me 2. Et3N ClCO2CH2Ph MeO2C CO2Me 51; citric acid 52; 700 g scale 53
400 units PLE
0.1M phosphate buffer
pH 8, 25 ˚C, 1.5 hours
R
MeO 2C CO 2Me
29 Ester Formation and Hydrolysis by Lipases and Esterases 659
1. H 2SO 4
fuming
PLE
1. H 2, Pd/C
2. PySSPy
Ph 3P, MeCN
R (S)-56; R = Bn,
Bz, i-Pr
Ph(CH2) 2
HO2C CO2Me and
RCONH
CO2Me
NH
O (S)-(+)-48
84% yield; >96% ee
OAc
R
(R)-56;
or
R = Me, Et,
n-Pr, AcO,
HO2C CO2Me and NH2

660 29 Enzymes
Other acylating enzymes
Amide formation and hydrolysis is of course also catalysed by enzymes and the recent report that
the penicillin acylase from Alcaligenes faecalis catalyses an effi cient kinetic resolution of racemic
primary amines is very promising. A typical case is our old friend α-methylbenzylamine 57 (see
chapter 22). One equivalent of an acyl donor 58 is needed and nearly 50% of the amide 59 can be
isolated in excellent ee. The E value is 350 for this amine. 20
H 2N Ph
(±)-57; α-methyl
benzylamine
A selection of four amines shows the possible range. Some have aromatic substituents, some
aliphatic and one 66 has an alcohol but no ester formation is observed. Though E varies from
about 100 to over 1000, these numbers are all large enough to ensure excellent ee (see chapter 28)
and the yields are all close to the maximum 50%. If the free amines are wanted, the same enzyme
can be used to hydrolyse the amides. This process ensures essentially 100% ee as there is a further
kinetic resolution in the hydrolysis.
H 2N
H 2N
60; E = >1000
Cl
Enzymatic Oxidation
Ph
NH2
O
58; acyl donor
Asymmetric dihydroxylation of benzenes
+
penicillin acylase, water,
pH 10 (KOH), 10–30 minutes
one equivalent 58
amide product precipitates
Ph
H
N Ph
O
59; 47.3% yield
98.5% ee
Bn
H
N
Cl
H2N Ph Bn
H
N
Ph
O
O
61; 49% yield; 99.3% ee 62; E = 120 63; 45% yield; 96% ee
H
H2N Ph Bn
H
N Ph
Bn N
O
OH
O
OH
64; E = 250 65; 46.8% yield; 98.1% ee 66; E = >100 67; 43% yield; 98% ee
When benzene falls on the soil it is processed (and so detoxifi ed) by micro-organisms such as Pseudomonas
putida by oxidation fi rst to a diol 21 then to catechol and fi nally to CO 2. The diol 68 cannot
be isolated as the dehydrogenase is too effi cient but in 1970 Gibson discovered mutant F39D of Pseudomonas
putida that lacks the dehydrogenase and produces the cis diol 68 in good yield. 21
OH
dioxygenase dehydrogenase
OH
OH
68; cis diol catechol
This mutant has been developed by Ley, Hudlicky and others into a practical method for the
asymmetric oxidation of substituted benzenes to give the unstable diols best preserved as acetals.
Even one substituent is enough to make the diol chiral and dihydroxylation normally occurs at
OH
CO 2

the 2,3-bond in the ring. Bromobenzene gives the diol 69 and hence the acetal 70 in 100% yield
without isolation of the diol. 22
Br
Pseudomonas
putida
Br
69
OH
OH
OMe
OMe
The practical details 23 are given in Organic Syntheses. One colony of Pseudomonas putida
F39D from an agar plate is incubated in 50 mls broth at 30 C for 24 hours with arginine to
induce the dioxygenase enzyme for the substrate provided. This is added to 500 mls broth with
10 mls PhCl and arginine. The broth contains phosphate, K(I), Mg(II), Ca(II), molybdate, Fe(II),
N(CH 2CO 2H) 3 as well as the trace metals Zn(II), Fe(II), Mn(II), Cu(II), Co(II), Na 2B 4O 7, and
EDTA. Incubation at 30 C for 48 hours gives the diol.
The acetonide 70 has been used to make both enantiomers of pinitol 73. The rigid acetonide
directs dihydroxylation or epoxidation to the bottom face of the ring to give 71 and 74. The epoxide
rings in 72 and 74 can be opened regioselectively with methanol to give the usual trans-diaxial
products such as 75. Carrying out the reactions in two different orders gives the two enantiomers 24
()-73 and ()-73.
70
OsO4 MNO
H2O mCPBA
CH2Cl2
Br
O
HO
Br
O
O
OH
71; 85% yield
2. mCPBA
HO
O
2. LiAlH4 MeO
O
O
OH
74; 80% yield 75; 85% yield
All monosubstituted benzenes react with the same regio- and enantio-selectivity whether the
substituent is halogen, alkyl, alkenyl, CO 2H, CN, COMe, OMe or CF 3. Thus toluene gives the diol
76 that can be produced at 3g/litre in the broth described above. It is also a commercial product.
Me
toluene
Pseudomonas
putida
1. MeOH
Al 2O 3
29 Enzymatic Oxidation 661
Me
1. LiAlH 4
OH
OH
76; 3 g per litre
The acetonide 77 has been used in the synthesis of prostaglandins such as PGF 2α 80. Once
the aromaticity of the benzene ring is broken, further oxidation is easy and the diene 77 can be
ozonised to the keto-aldehyde 79 that readily undergoes an intramolecular aldol to give the enone
79. It is more obvious that 79 can be a precursor to 80 when it is redrawn to show the possibility of
adding the side chains by conjugate addition and enolate trapping 22 (chapters 9 and 10).
+
O
O
O
O
OH
72; 86% yield
+
OMe
OMe
TsOH
1. MeOH
Al 2O 3
2. HCl
H2O
acetone
1. OsO4
MNO, H2O 2. HCl, H2O acetone
TsOH
Br
O
O
70; 100% yield
MeO
HO
HO
MeO
OH
OH
(+)-73; pinitol
OH
OH
(–)-73; pinitol
Me
O
O
77
OH
OH
OH
OH

662 29 Enzymes
O3
O Al2O3
O
77
–60 ˚C DME
EtOAc
Dihydroxylation of quinoline, to give 81, isoquinoline, to give 82, and dibenzothiophene to
give 83 are less predictable but in each case it is a benzene rather than a heterocyclic ring, and the
2,3-bond next to a carbon rather than a heteroatom that reacts. 25 The products are drawn to show
the identity of the enantioselectivity.
N
Me
OHC
Other organisms may give different results: benzoic acid gives the expected diol 85 with
Pseudomonas putida but reacts at the bond bearing the CO 2H group with Alcaligenes eutrophus
to give 26 84.
HO 2C
OH
OH
Alcaligenes
eutrophus
CO 2H
Pseudomonas
putida
CO 2H
84 85
Recent developments include the over-expression of the gene for the dihydroxylation and its
transfer 27 into the common and easily grown organism Escherischia coli to form recombinant
JM 109 (pDTG601A). This organism creates diols 87 from many monosubstituted benzenes
more conveniently. The closely related recombinant organism carries out the rearomatisation
to give 88.
R R
86
OH
O
OH
81 82
O
Pseudomonas putida
mutant 39D
E. coli recombinant
JM 109(pDTG601)
N
O
O
87
OH
This method was used by Hudlicky in a synthesis of the alkaloid narciclasine. The diol 90
was trapped as the usual acetal and reacted as a diene with the nitroso ester MeO 2C-NO in a
hetero-Diels-Alder reaction to give 91. Suzuki coupling of the vinylic bromide with the right
aryl boronic acid gave 92 and the N–O bond was reduced with Mo(CO) 6 to give the advanced
intermediate 93 on the way to narciclasine 28 94.
OH
OH
O
OH
O
O
O
E. coli recombinant
JM 109(pDTG602)
HO OH
78; 70% yield 79; ~100% yield 80; PGE2α
=
S
83
R
OH
OH
OH
88
OH
OH
OH
CO 2H

Br
O
O
Epoxidation
There are all sorts of problems with epoxidation by micro-organisms and in general laboratory
chemists prefer to use the Sharpless or Jacobsen epoxidations described in chapter 25. The
ω-hydroxylase from Pseudomonas oleovorans does epoxidise aryl ethers of allylic alcohols with
good selectivity and one product has been used in the synthesis of the β-blocker metropolol. 29
However the organism requires gaseous hydrocarbons as carbon sources and the epoxide products
poison it.
95
89
OAr
ω-hydroxylase
Pseudomonas
oleovorans
O H
The Nippon Mining Company uses the soil micro-organism Nocardia corralina B-276
to produce a series of epoxides that are available commercially as single enantiomers. This
micro-organism uses glucose as a carbon source and is not poisoned by the epoxides it produces. It
also is very versatile as the selection 98 - 104 shows. The two epoxides 103 and 104 are especially
notable as they are both made from hexa-1,5-diene. 30
O H
Br
OMe
92
E. coli
JM109
(pDTG601A)
Br
Br
O
O N
O
CO2Me The Baeyer-Villiger reaction
29 Enzymatic Oxidation 663
Br
O
OH
OH
Mo(CO)6
The Baeyer Villiger reaction is an oxidation of ketones by peroxyacids that inserts an oxygen
atom between the carbonyl group and the more substituted side of the ketone. The biological
MeO
i-PrNH 2
i-PrNH
HO
96; ~100% ee 97; metropolol; 98.4% ee
O
OR
H
O
Alkyl
Me
O
Alkyl
H
98; C6 to C18 99; C6 to C11 100; R = C5 to C12 Ar
1. TsOH
(MeO) 2CMe2
2. NaIO4 NH2CO2Me O H
H
O
O H
CF3
Ar
101 102
O H
103 104
O
Br
O
O
NHCO2Me
Br
O
O N
O
CO2Me
90; 4g/litre >99%ee 91; 70% yield
93
O
O
ArB(OH) 2
Pd(Ph 3P) 4
Na 2CO 3
EtOH
OH
NH
OH O
94; narciclasine
HO
O
OH
OH
MeO

664 29 Enzymes
version does the same thing and is particularly interesting to us when it creates asymmetry from
a symmetrical ketone. The enzymes are mono-oxidases that are coupled to the reducing enzyme
glucose dehydrogenase. 31
The Chemical
Baeyer-Villiger
Rearrangement
Examples include simple achiral ketones such as 105 and meso compounds with some
stereochemistry 32 such as 107 that initially gives the seven-membered lactone 108 but this
rearranges into the fi ve-membered lactone 109.
O
Nature has many surprises in the chemistry she does. One organism produces a scarcely credible
result in the Baeyer-Villiger reaction. Acinetobacter calcoaceticus catalyses a kinetic resolution of
the important bicyclic ketone 111. The chemical reaction gives the expected lactone 110 with
migration of the more highly substituted carbon atom. The biological reaction does indeed give
one enantiomer of the same lactone but the remaining material is not unreacted 111. Instead the
other regioisomer 112 in the other enantiomeric series is formed in good yield and ee. Nature can
accomplish reactions impossible to us, so far. 33 The latest news 34 on this reaction is that recombinant
whole cells of E. coli expressing cyclohexanone mono-oxygenase are even more effi cient.
Baeyer-Villiger reactions with engineered baker’s yeast
O
O
105 106; 80% yield
>98% ee
107 108
H
mCPBA
O
O
HO
H
(±)-110 (±)-111
O
The mono-oxygenase from Acinetobacter sp NCIB 9871 can be cloned and expressed in the same
baker’s yeast that we met at the start of this chapter. This yeast carries out Baeyer-Villiger reactions
and supplies its own NADPH from other enzymes in the yeast. A conventional kinetic resolution
of cyclopentanones 113 gives single enantiomers of lactone and starting material. 35
O
113
R
mCPBA
O
O
engineered
baker's yeast
O
O 2
monooxidase
H 2O
O
Acinetobacter
calcoaceticus
O
NCIB 9871
O
NADPH
NADP
coenzymes
HO
15C(pKR001)
R
R = Me 114; 36% yield; 32 ee
H
O
O
O
H
110; 44% yield
>95% ee
+
6-phosphogluconate
glucose
dehydrogenase
glucose-6phosphate
O
O
OH
H
109; 88% yield
>98% ee
H
O
O +
O
O
H
112; 42% yield
>95% ee
R = n-Hex 116; 32% yield; >98% ee 117; 42% yield; >98% ee
R
115; 34% yield; 44% ee
The Biological
Baeyer-Villiger
Rearrangement

Whole cells of engineered E. coli BL21(DE3)(pMM4) desymmetrise cyclohexanones with
substituents in the 4-position with variable results. 36 Simple mono-substitution 118 and 120
gives good results but the enzyme is very sensitive to hydroxyl groups giving a lower yield with
the tertiary alcohol 122 and poor ee with the secondary alcohol 124.
O
O
O
O
engineered
engineered
Et
E. coli
Et
O
Br
E. coli
Br
O
H
H
H
H
118 119; 91% yield
120
121; 63% yield
O engineered
97% ee
O
O engineered
97% ee
O
E. coli
E. coli
Et
Et
O HO
HO
O
HO
HO
H
H
122 123; 54% yield
124
125; 61% yield
94% ee
9% ee
Nucleophilic Addition to Carbonyl Groups
Asymmetric addition of cyanide to aldehydes
Oxynitrilase enzymes from various plants catalyse the addition of cyanide ion to aldehydes to
give the cyanohydrins present in many plants. Amygdalin, the cyanohydrin of a trisaccharide, is
perhaps the most notorious of these as it releases HCN from oil of bitter almonds and has been
responsible for the death of people drinking old samples of the liqueur noyeau. 37
The (R)-oxynitrilase from the almond Prunus amygdalis has unusually low substrate specifi city
and gives good yields of a variety of cyanohydrins 126 providing that the reaction medium has two
phases to inhibit the uncatalysed addition of HCN to the aldehyde. 38
O
R H
(R)-oxynitrilase, KCN, AcOH
two-phase reaction mixture:
i-Pr2O, H 2O or EtOAc/Avicel
OH
H
R CN
(R)-126
R = Ph; 95% yield, 99%ee
R = 3-thienyl; 95% yield, >99%ee
R = MeS(CH2) 2; 98% yield, 96%ee
R = Ph(CH 2) 3; 94% yield, 90%ee
The (S)-oxynitrilase from Sorghum bicolor produces the other enantiomer but only from aromatic
aldehydes. 39 The products can be directly converted into hydroxyacids 127 without loss of ee.
O
R H
29 Nucleophilic Addition to Carbonyl Groups 665
(S)-oxynitrilase, KCN, AcOH
two-phase reaction mixture:
i-Pr2O, H 2O
OH
H
R CN
(S)-126; 78-97% yield
52-97% ee
H 2O R CO 2H
These two methods involve the potential release of toxic HCN during the reaction and a cleaner
as well as a safer method is to use acetone cyanohydrin 128 as a cyanide transfer reagent. The
enzyme from the Brazilian rubber tree Hevea brasiliensis, called a hydroxynitrile lyase, catalyses
cyanohydrin formation from aliphatic as well as aromatic aldehydes. 40
OH +
O
hydroxynitrile lyase
OH
H
CN
128
R H
Na-citrate buffer, pH 4.0, 2 hours
room temperature
R CN
(S)-126
H
OH H
(S)-127; 63-76% yield
no loss of ee
R = Ph; 94% ee
R = n-Pr; 80% ee
R = i-Pr; 81% ee
R = n-Bu; 84% ee

666 29 Enzymes
The commercial process run by Solvay Duphar, based on the work of van der Gen, 41 uses an
aqueous extract of almond meal for (R)-126 and the sorghum enzyme for (S)-126. Again a twophase
system (H 2O/Et 2O) is used and the rather unstable cyanohydrins, that may racemise by reversible
loss of HCN, are stabilised by conversion to silyl ethers such as 129–131. The last example
shows that direct is preferred to conjugate addition.
RCHO
Products derived from cyanohydrins
The obvious hydrolysis of the nitrile must be carried out carefully to avoid racemisation. 39,42 Two
successful ways are direct conversion into esters 134 in acid solution or a two step process to the
acids 132 via the much less easily racemised amides 133.
OH
H
conc HCl OH
H
conc HCl OH
H
1. HCl, MeOH OH
H
R CO2H (R)-132
100 ˚C
R CONH2 (R)-133
20 ˚C
R CN
(R)-126
2. H2O
R CO2Me (R)-134
Conversion to other carbonyl compounds is more tricky because of the increased likelihood
of enolisation. The protected cyanohydrins 136 can be reduced to the aldehydes 135 with 1.5
equivalents of DIBAL and cautious acidifi cation. The more stable ketones 138 are best made in
two stages. 41 Additions of Grignard reagents gives the imine derivatives 137 that can be worked
up in acid to give the ketones 133.
OTBDMS
H
1. rapid addition of
DIBAL, THF, 20 ˚C
OTBDMS
H MeMgI
OTBDMS
H
R CHO 2. cautious
acidification
R CN
R
NMgI
135 136 137
Secondary amines can be formed from the same starting materials 136 by tandem Grignard
addition and borohydride reduction. 43 The reduction shows good Felkin-Anh selectivity (chapter 21)
and the silyl group can be cleaved from the products 140, as they are safe from racemisation, to
give a range of amino alcohols 141. Compounds like these can also be made by asymmetric
amino-hydroxylation (chapter 25).
OTBDMS
H
R 1 CN
128
(R)-oxynitrilase
two phases:
H2O/Et2O
OH
H
R CN
(R)-126
R1 OTBDMS
R H
R2 2MgI 1. NaBH4
2. HCl
O
O
OR
H
CN
O
OR
H
CN
H OR
CN
129; R = TBDMS 130; R = TBDMS 131; R = TBDMS
H 2SO 4
H2O, 0 ˚C
R
OTBDMS
H
O
138; R = Ph;
80% yield, 92% ee
NMgI
NH2.HCl NH2.HCl 136 139 140 141
R 1
OTBDMS
H R 2
1. HF
2. HCl
R 1
OH H R 2

Enzymatically catalysed aldol reactions
The aldol reaction is extensively used in Nature as in the laboratory to make C–C bonds
and some aldolases have been used in asymmetric synthesis. One of the most popular has
been the fructose-6-phosphate aldolase 44 from rabbit muscle, familiarly known as RAMA.
The enzymatic reaction combines the enol from dihydroxyacetone phosphate (DHAP) 142 with
glyceraldehyde-3-phosphate 143 in a diastereo- and enantioselective aldol reaction. PO in these
diagrams means phosphate.
PO
O
OH
142; DiHydroxyAcetone
Phosphate (DHAP)
H OP
The rabbit enzyme requires DHAP for the enol component but is more relaxed about the
aldehyde. The azido-aldehyde 145 reacts cleanly with the formation of two new chiral centres 146
and the phosphate is removed by treatment with a second enzyme, a phosphatase. 45 Then reduction
of the azide gives the trihydroxy pyrrolidine 147 with excellent control over a third chiral centre,
less than 10% of the epimer being formed. The ees of the compounds are not easily determined
from the published work.
H
+
The insect pheromone exo-brevicomin 151 has been made this way using the ketoaldehyde 148 as
the electrophile with DHAP as the usual enol component. 46 The reaction is entirely chemoselective:
the ketone in 148 acts neither as enol nor electrophile. The product is a diol that one might think
of making by an AD reaction (chapter 25). In acid solution it forms a cyclic acetal 150 having the
skeleton of brevicomin. The rotation but not the ee of the brevicomin made this way is quoted.
OHC
O
145
N3
O
148; 3 fold excess
29 Nucleophilic Addition to Carbonyl Groups 667
1. DHAP, RAMA
H 2O, pH 6.8
2. acid
phosphatase
1. DHAP
RAMA
H2O, pH 6.3
2. acid
phosphatase
Synthesis of syringolide using an enzyme-catalysed aldol reaction
O
OH
143; Glyceraldehyde
3-phosphate
HO
HO
O
FDP
aldolase
Syringolide 152 is a natural product that elicits an immune response from soyabeans. A series of
straightforward disconnections leads back to a tetraol 156 that looks like an aldol product from
OH
PO
O
OH
OH OH
144; Fructose
1,6-diphosphate
OH
N3
Pd(OH) 2/C
HO
N
H
146; 78% yield 147; 74% yield
O
O
OH
OH O
149; 48% yield
O
151; exobrevicomin
H 2
H
O
HO
O
150
O
OP
OH
OH

668 29 Enzymes
DHAP and a very simple aldehyde. Other than doubts about the geometry of the alkene in 155 and
chemoselectivity with all the OH groups, it is a simply designed synthesis. 47
152
(–)-syringolide
R = n-heptyl
R
HO
HO
O
The solution to the chemoselectivity problem is minimal protection: a p-methoxybenzyl group for
the hydroxyaldehyde and an acetal 158 for the diol unit in the product 157 of the enzyme-catalysed
aldol reaction. The solution to the alkene geometry problem is going to be intramolecular trapping
by the one remaining free OH group.
HO
O
OP
OR
O
1
R1 = p-MeOC6H4CH2 1. FDP
aldolase
2. acid
phosphatase
HO
O
The Meldrum’s acid derivative 159 was chosen to represent the keto-acid electrophile in
reaction with the carbonyl group of 158. One of the two carboxyl groups can be captured by the
free OH group in 158 so that the geometry of the alkene is automatically correct in 160. Removal
of the p-methoxybenzyl group by oxidation and the acetonide with acid allows conjugate addition
and hemiacetal formation to give ( – )-syringolide 152 in one step from 160.
R
O
O
R
H
HO
CO 2H
O
OH
OH
H
O
O
O
1,3-diCO
aldol
R
1,1-diX
hemiacetal
O
R
HO
HO
CO2H
HO
OH
HO
OH
155 156
Three new chiral centres are created in this step. Removal of the p-methoxybenzyl group
from 160 gives the free OH group that carries out conjugate addition 161. It approaches the
underside of the lactone as the fi ve-membered acetal is planar and the CH 2OH group is already
on the underside. Protonation of the enol product is under thermodynamic control and may
change in the next reaction. Removal of the acetal gives two more free OH groups only one
being able to add to the ketone 163 to give the hemiacetal in 152. The stereochemistry of
this centre is also under thermodynamic control and each addition ensures that each pair
of fi ve-membered rings have the more stable cis fusion in the fi nal product 152.
O
OH
Me 2CO
HO
OR1 TsOH
OR1 O
157; 65% yield 158; 67% yield
O
O
R
O
O
O
O
OR1 1. 158, THF
reflux
1. DDQ
H2O/CH2Cl2
(83% yield)
OH
H
R
O
O
O
2. SiO2
hexane
-EtOAc
O
O
2. TsOH
H2O/acetone (55% yield)
H
HO
O
159 160 (–)-152
H
O
O
O
O
HO
153 154
OH
1,3-diX
conjugate
addition
1,3-diCO
aldol
R
HO
O
O
HO
O
O
O
OH
O
O
OH
OH
C–O
ester
OH

160
[O]
Engineered aldolase
O
O
O
H
O
O
H
O
R
O
O
R
O
O
H
R
HO
O
O
161
OH
O
162
O
HO
O
163
A different aldolase has been over-expressed in E. coli and used by Chi-Huey Wong in his synthesis
of epothilones. It is 2-deoxyribose-5-phosphate aldolase (DERA) and the natural reaction is
the condensation of acetaldehyde as enol with glyceraldehyde-3-phosphate 164 as electrophilic
component to give an aldol product 165 that is trapped as a hemiacetal 166.
O
PO H
+
H
OH
164; glyceraldehyde
-3-phosphate
O OH
PO
This enzyme is much less fussy than RAMA and will accept other enol components or
electrophiles. In this case the β-hydroxyaldehyde 167 gives the six-membered cyclic hemiacetal
169 and the acetal 170 of unstable 2-hydroxypropanal gives one diastereoisomer of the aldol 171
by dynamic kinetic resolution and hence 172 in moderate yield. 48
Both these products were used in the synthesis of epothilone A 173. The disconnection of the
lactone is simple but the other is less obvious. The epoxide must come from a cis alkene and that
can be made by a Suzuki coupling of a borane derived from 174 and the Z-vinyl iodide 175. As you
will see, 174 was made from 169 and 175 from 172, unlikely as it seems.
HO
HO
MeO
OMe
H
OH
170
O
Me
167
O
OH
H
29 Nucleophilic Addition to Carbonyl Groups 669
MeCHO
DERA
1. Dowex (H + )
2. MeCHO
DERA pH 7.5
O
O
O
173; epothilone A
HO
S
N
Me
OH
OH
168
OH
171
RO
OH
165
CHO
CHO
O
CHO
I
Suzuki
OR
PO
O
152
OH
HO
166; 2-deoxy-D-ribose
-5-phosphate
CO2R
Me
O
OH
OH
169; 48% yield
O
174 175
OH
HO
172; 38% yield
S
N
OR
macrolactonisation

670 29 Enzymes
The hemiacetal 169 was fi rst oxidised to the lactone 176 and the lithium enolate allylated
with the expected stereoselectivity to give 177 and then, by a series of reactions described in the
workbook, into the aldehyde 178.
169
A stereoselective aldol reaction between the β-ketoester 179 at the less enolisable position and
178 creates the complete carbon skeleton of 174 with excellent stereoselectivity at the new OH
group 180. This OH group was used to control the stereochemistry of an Evans 1,3 reduction
(chapter 21/30) before it was oxidised to the required ketone 181: this is the same as 174 but has
the protecting groups specifi ed.
H
CO 2t-Bu
1. NaH,
2. BuLi
RO
O
3. 178
OH O
179 180; 70% yield
CO 2t-Bu
1. Me 4NBH(OAc) 3
–30 ˚C, 83% yield
2. TBMSOTf
2,6-lutidine
100% yield
3. Dess-Martin
90% yield
O OTBDMS
181; R = p-MeOC6H4CH2 The other half was made from 172 by formation of the protected keto-aldehyde 183 followed
by successive stereoselective Wittig-Horner and Wittig reactions to put in the two alkenes with
control over stereochemistry. The Wittig-Horner is under thermodynamic control giving the
trisubstituted E-alkene 185 while the Wittig is under kinetic control giving the Z-iodoalkene 175;
R = Ac (chapter 15).
172
O
Ph 2P
Br 2
BaCO 3
184
Me
S
N
O
O
OH
176; 62% yield
1. AcCl, pyridine, 95% yield
2. BF3.Et2O, 84% yield
3. HS(CH2) 3SH, TiCl 4, 97% yield
1. BuLi
–78 ˚C
2. 183
1. LDA
2. allyl
bromide
S
Me
S
S
S
The Suzuki coupling works very well - the moderate yield being offset by the degree of
convergence achieved. Removal of the acetate and t-butyl ester groups allows a very effi cient
Yamaguchi lactonisation (see workbook) and then removal of all the remaining protection groups
gives the cis alkene 188 that can be epoxidised stereoselectively by dimethyldioxirane though only
in 45% yield to give epothilone A 173. All the chiral centres in the fi nal product, as well as some
that were discarded en route, come from the original enzymatic aldol reaction.
O
OAc
OH
OAc
185; 88% yield
O O OR
OH
177; 85% yield 178; R = p-MeOC6H4CH2 N
Swern
DMSO
(COCl)2
RO
182 183; 95% yield
S
S
S
1. Hg(ClO 4) 2
2. Ph 3P=CHI
CO 2t-Bu
OAc
O
175; R = Ac
60% yield
(2 steps)

RO
181
1. 9-BBN
2. 175; R = Ac
[PdCl 2(dppf)2]
Ph3As, Cs 2CO 3
RO
OH
CO2H Practical Asymmetric Synthesis with Enzymes
If you have reached this point in the chapter with the feeling that enzymes are all very well for
the experts but that you are unlikely ever to use one, then this section is for you. Immobilized
enzymes are now freely available from several companies and pharmaceutical companies use
them on a large scale almost as a matter of routine. There are still problems of course and most
asymmetric synthesis is not done with enzymes. In this section we set out to convince you that
enzymes are practical reagents in organic solvents as well as in water and that practical minded
chemists use them. An excellent review may convince you more. 49 Recently a whole issue of the
journal Organic Process Research and Development (2002, 6, issue 4, 420 ff.) was devoted to
bioca talysis and the introductory article 50 makes the point too.
A calcium channel blocker: diltiazem
O
O OTBDMS
187; 78% yield (last two steps)
CO2But OAc
OTBDMS
186; 65% yield
S
N
1. Yamaguchi
lactonisation
85% yield
2. DDQ, CH 2Cl2
99% yield
3. HF, pyridine
95% yield
Calcium channel blockers, such as amlodipine introduced in chapter 22, are used to treat angina
and hypertension. Diltiazem 189 was introduced by the Tanabe company in 1984 and is a simple
derivative of the benzothiazepine 192 having two adjacent chiral centres on the heterocyclic
seven-membered ring.
Me 2N
29 Practical Asymmetric Synthesis with Enzymes 671
OMe
Disconnecting the ring amide reveals a 1,2-difunctionalised compound 193 that can be
made by the nucleophilic opening of the epoxide 195 with the anion of the thiol 194. To avoid
chemoselectivity problems the corresponding nitro thiol is used. The chirality is already present in
the epoxide which can be made by an asymmetric Darzens reaction or by Sharpless epoxidation.
You may notice that the opening of the epoxide is, strangely a cis opening (see the workbook for
details). Originally the resolution of an intermediate was used. 51
HO
OMe
S
N
O
OH
188
1. MeONa, MeOH
85% yield
2. TBDMSOTf
2,6-Lutidine
3. NaOH (cat.)
MeOH
S
C–O
S
C–O
S
OAc
C–N
O
C–N
N
O
N
O
O
N
H O
189; ditiazem Me2N 190
Me2N 191
Cl
192
O
O
R
OH
173
OMe

672 29 Enzymes
192
C–N
amide
Enzymatic methods use lipase catalysed reactions on epoxides 195 or the adducts such as 193.
Racemic trans methyl ester 195; R = Me can be hydrolysed by Candida cylindraceae lipase using
mixed solvents MeCN, CH 2Cl 2, or cyclohexane and water while no hydrolysis occurred in pure
water. Cyclohexane gave the best results: the ‘wrong’ ester was hydrolysed while the ‘right’ one remained
behind in the organic layer making separation simple. Ten grams could be turned over in 1.5
hours at room temperature. 52 Transesterifi cation with chymotrypsin or lipases was less effective.
Acylation of the adduct 196 of o-nitrophenylthiol and the epoxide (±)-195 with acetic
anhydride or vinyl acetate in THF at room temperature catalysed by the lipase from Pseudomonas
cepacia gave better results. Reactions with acetic anhydride are of course not possible in aqueous
solution. The reaction took 2 days with Ac 2O and 7 days with vinyl acetate but the yields and ee
were excellent. At 50% conversion, 100% yield of the acetate product 197 and the other enantiomer
of the unreacted alcohol 196 can be isolated. 53
NO 2
O
NH 2
S
OMe
MeO2C (±)-trans-195; R = Me
RO2C OH
(±)-196; R = Me
OMe
Pseudomonas
capacia lipase
Ac 2O or
Insecticides based on chrysanthemic acid esters
The most important insecticides today are based on chrysanthemic acid: they are incredibly potent
and can be used in small amounts only on the target pest. Chrysanthemic acid 198 is natural
but the natural pyrethrin insecticides are too light sensitive to fi nd much use. Chiral synthetic
compounds such as cypermethrin 200 and deltamethrin 199 are used as single enantiomers. 54
They are based on the cis acid while natural chrysanthemic acid is trans.
OH
O
198; trans- chrysanthemic acid
S
RO2C OH
193
Candida
cylidracea
lipase
pH 7.4, H 2O
cyclohexane
OMe
X
1,2-diX
C–S
OAc
O
NH2
OMe
MeO2C HO2C (2R,3S)-trans-195; R = Me
30-40% yield, 96-98% ee
(2S,3R)-trans-195; R = H
NO 2
SH
S
RO2C OAc
(2S,3S)-197; R = Me
100% yield, >95% ee
OMe
X
O
O
O CN
199; X = Br, (1 R,cis,αS)-deltamethrin
200; X = Cl, (1R,cis,αS)-cypermethrin
+
+
RO2C
O
O
194 195
OMe
OMe

The synthetic compounds are obviously esters of a cyclopropane carboxylic acid and
a cyanohydrin 202. Enantioselective transesterifi cation of butanol and the acetate 201 of
the cyanohydrin using immobilised lipases gives the required (S)-alcohol 202 and the unreacted
enantiomer of the acetate (R)-201 easily racemised with Et 3N. Reports using different lipases
appeared at the same time: CHIRAZYME® L-6, the lipase from Pseudomonas immobilised on
sephadex DEAE was used in i-Pr 2O and the racemisation carried out with Et 3N under refl ux in
the same solvent. 55
AcO
BuOH, lipase
OPh organic solvent
AcO
OPh
+ HO
CN
35 ˚C
CN
CN
(±)-201 (R)-201 (S)-202
Alternatively the Amano immobilised lipase P gave (S)-202 in 49% yield and 99% ee with
(R)-201. The mixture was separated by esterifi cation with the chrysanthemic acid derivative giving
the wanted ester and the easily separated unreacted acetate (R)-201 racemised with Et 3N at 80 C
in toluene. The acid was prepared in only 86% ee so the alcohol (S)-202 also acts as a resolving
agent. Cypermethrin 200 is isolated in good yield and excellent diastereo- and enantiomeric purity
after one recrystallisation. 56
Cl
Cl
O
203; 86% ee
Anti-fungal triazole-containing tetrahydrofurans
Cl
(R)-201 + (S)-202
pyridine, 0 ˚C
Cl
O
Cl
OPh
O CN
200; X = Cl, (1R,cis,αS)-cypermethrin
82% yield, 99% de after recrystallisation
A major breakthrough in modern medicine has been the discovery of effective anti-fungal
compounds. One family such as ketoconazole 204 or saperconazole 205 has a dioxolan core
carrying the active imidazole or triazole functionality. Schering-Plough have developed a new type
having an apparently simpler tetrahydrofuran (THF) core such as 206. This compound presents
special problems for asymmetric synthesis.
X
X
O
O
N
29 Practical Asymmetric Synthesis with Enzymes 673
Z
O
N
204; X = Cl, Z = CH, ketoconazole
205; X = F, Z = N, saperconazole
N
N R
Initial attempts used the Sharpless epoxidation of the allylic alcohol 207 followed by addition of
a carbon nucleophile and the triazole to give the ditosylate 208. The two tosylates are diastereotopic
but all attempts at cyclisation led to the anti THF 209 as the major product.
F
F
O
N
N
N
O
N
OPh
206; SCH51048, anti-fungal compound
N R

674 29 Enzymes
A more positive discrimination between the two primary OHs might be made if a
reagent-dominated reaction were used and an enzyme is ideal for this job. Various lipases could
be used either in the acylation of the triol 210 or in the hydrolysis of the diester 212. In either
case, the required monoester 211 could be formed in excellent ee. Novozyme (Novo Nordisk) SP
435 catalyses the monoacetylation of 210 in MeCN solution to give 211; R = Me in 95% yield and
96.6% ee after only 55 minutes.
A simpler approach gave even better results. The prochiral diol 213 was cleanly monoacetylated by
the same enzyme (98% yield, 98% ee) and iodo-etherifi cation gave the required diastereoselectivity
215 with suitable functionality for the introduction both of the triazole and of the other side chain. 57
F
F
F
213
OH
OH
SP435
Bristol-Meyers Squibb anti-psychotic agent BMS 181100
OAc
F
F
A related though simpler compound from Bristol-Meyers Squibb 216 is their anti-psychotic agent
BMS 181100. It has two p-fl uorophenyl groups joined through a C 4-piperazine linker containing
a chiral secondary alcohol. The compound is easily made 58 by alkylation of an amine with the
primary chloride 217. There are two opportunities from enzymatic resolution.
F
F
F
OTs
OTs
OTs
F
F
F
OH
OH
O
F
N
N
F
N
N
207
N
208; >98% ee
N
209; 60:40 anti:syn
OH
OH
OH
N
N
F
N
N
F
N
N
N
210; >98% ee 211
N
212
N
OH
OH
OH
N
N
(R)-(+)-216; BMS 181100
F
F
F
OCOR
OH
OAc
OH
F
214 215
217
OH
I 2
+
Cl
F
HN
F
N
OCOR
O
I
OCOR
OAc
F

Racemic 217 could readily be acetylated with isopropenyl acetate catalysed by the Amano
lipase PS 30. The resolution was successful only in organic solvents and heptane was the best. Any
water reduced both the rate of the reaction and the ee of the product. Acetylation occurred on the
wanted (R) enantiomer 218 but the product could be hydrolysed to (R)-217 with the same enzyme
with added water. The reactions were carried out on a 100 g scale using 200 g of immobilised
enzyme that could be fi ltered off and used again and again with little diminution in ee. This
sounds like a lot of enzyme but it is a polymer-supported enzyme so the bulk is polymer.
Alternatively, the acetate 219 of the fi nal product (±)-216 could be enantioselectively hydrolysed
with another Amano lipase GC-20, chosen after a survey of fourteen enzymes. At this stage
both enantiomers of the drug were needed for evaluation and the unreacted (S)-acetate could be
hydrolysed to (S)-215 without racemisation. Again organic solvent was necessary: E was 1 in pure
water and maximum (>100) in toluene or CH 2Cl 2.
F
(±)-217
OAc
An Eli Lilly protein kinase inhibitor
F
Protein kinase inhibitors are in the news as cancer drugs but Eli Lilley have a saturosporinone
analogue 220 to help diabetes patients overcome problems such as sight loss from retinopathy. The
bis-indole portion 221 does not concern us but the chiral fragment 222 does.
O
N
O
Amano PS-30
heptane
OAc
Me
N
N
29 Practical Asymmetric Synthesis with Enzymes 675
N
(±)-219
O
(S)-217
N
2 x
C–N
+
The near-symmetry of 222 suggests that writing OH or OR for the functionality 223 would
be helpful. This reveals a 1,6 relationship between the two OH groups that might be made by
oxidative cleavage of a cyclohexene 224. This in turn could be derived from a Diels-Alder reaction
OAc
Cl
(R)-218; 95-98% ee
F
Amano
lipase
GC-20
pH 7
toluene
water
NMe2 220: protein kinase inhibitor 221
O
N
H
H 2O
Amano PS-30
heptane
(R)-(+)-216
BMS 181100 + (S)-219
47.6% yield
97.9% ee
Me
N
N
H
O
X
(R)-217
100% ee
Na 2CO 3
H 2O
MeOH
O
X
(S)-216
[NMe 2]
222
X = leaving group
[NMe 2] protected

676 29 Enzymes
providing that the CH 2OR group is fi rst replaced by a carbonyl group 225. This ester might be
resolved enzymatically.
HO OH
1 6
2 5
3 O 4
OR
223
The commercial solution of ethyl glyoxylate 226; R = Et in toluene was heated in an autoclave
with butadiene to give the adduct 225; R = Et in 50-60% yield, easily purifi ed as the polymeric
by-products are soluble in toluene. A survey of various enzymes and formulations showed that
cheap aqueous B. lentus protease gave the best results. Only 90 mls of a 5% solution of the enzyme
was needed to hydrolyse 150 g of 225; R = Et in eight hours. Under these conditions E is 36.6 and
35–40% yield of (S)-225; R = Et having ee 99.5% could be extracted with toluene. The free acid
225; R = H remains in the aqueous layer. The trityl-protected bis-mesylate 227 was produced in
good yield on a multi-kilogram scale with 96.7% ee and used to make the drug 59 220.
O
Lotrafi ban: a GlaxoSmithKline drug to prevent blood clots
During the scale-up of an asymmetric synthesis of lotrafi ban 228, a drug for the prevention of
thrombotic ‘events’, racemisation proved to be a problem. The synthesis used the chiral pool
strategy (chapter 23), the fragment in the frame of the intermediate 229 being derived from
aspartic acid.
HO 2C
CO 2Et
225; R = Et
O
HN
1,6-diO
reconnect
B. lentus
protease
pH 7 buffer
NaOH, H 2O
N
Me
O
O
CO 2Et
225; R = Et
FGI
O
O
224
OR
CO2R 225
CO2R 226
1. LiAlH 4
2. TrCl
DMAP
pyridine
HO2C
N
NH2 O
228; SB 214857 Lotrafiban 229
CO 2Bu t
Since they already had a good synthesis of racemic ester, a late stage in the synthesis,
an enzymatic hydrolysis looked a good bet. In the event hydrolysis with Candida antarctica
lipase was superlative: hydrolysis gave only the required enantiomer and stopped cleanly at 50%
conversion. Various supported versions were tried and the best was the Boehringer L-2 preparation
in which the enzyme is covalently bound to a cross-linked resin making it stable in aqueous
solution. In the pilot plant 76 kgm of racemic methyl ester 230 react in 2.5 hours with 6 kg of
supported enzyme. Benzyl chloroformate in CH 2Cl 2 is added and the unreacted ester (R)-230,
O
224; R = Tr
hetero
Diels-Alder
OTr
O
HN
1. O 3
CH 2Cl 2
2. NaBH 4
3. MsCl
Et 3N
N
MsO
Me
O
227
OMs
OTr

now Cbz derivatised, remains in the CH 2Cl 2 layer (and is later recycled by racemisation) while
the product is in the aqueous layer. The enzyme could be reused at least 100 times without loss of
activity. 60
Two desymmetrisations
MeO2C
We end this chapter with two much simpler reactions - a couple of desymmetrisations - each special
in their own way. The fi rst is amazingly effi cient, using a lipase/esterase from a thermophilic
organism supplied as a recombinant protein by the Diversa corporation. The symmetrical
Diels-Alder adduct 231 is rapidly and perfectly desymmetrised to the monoacid 61 232 at 70 C.
231
The second is even more remarkable. The amlodipine type of dihydropyridine drugs are chiral
but only just so. In some cases the only distinction is a methyl ester on one side and an ethyl
ester on the other. The symmetrical compound 234 can be easily made by the Hantzsch pyridine
synthesis and desymmetrisation looks as good as anything in attempting an asymmetric synthesis.
Work from the Amano company using their own lipase AH established, almost incredibly, that
one enantiomer is formed in i-Pr 2O but the other in cyclohexane (both solvents are saturated with
water). 62 One problem with enzymes is generally that they can give only one enantiomer. With an
unnatural substrate in unnatural media this may not be the case!
HO 2C
Me
References
O
HN
N
NO 2
Me
CO 2Me
CO2Me
N
O
(±)-230
29 References 677
ESPESL (Diversa)
phosphate buffer
70 ˚C
CO2H
CO 2Me
232
98% yield
>99% ee
Amano
Amano
lipase AH
lipase AH
CO2i-Pr i-Pr2O i-PrO2C CO2i-Pr cyclohexane
i-PrO2C CO2H saturated
saturated
N Me
with water
Me N Me
with water
Me N Me
H
H
H
(S)-233 (±)-234 (R)-233
General references are given on page 893
1. Collins, Chirality in Industry, K. Faber, Biotransformations in Organic Synthesis, Springer, 4th edition,
2000; Drauz and Waldmann, Enzyme Catalysis in Organic Synthesis.
2. Review: C. J. Sih, Angew. Chem., Int. Ed., 1984, 23, 570.
3. D. Seebach, M. A. Sutter, R. H. Weber, and M. F. Züger, Org. Synth., 1985, 63, 1.
NH
NO 2
Candida
antarctica
lipase
Boehringer L-2
pH 6.2, 30 ˚C
water
1.5 M NH3 (R)-230 + (S)-228
42% yield
99% ee
NO 2

678 29 Enzymes
4. B. Wipf, E. Kupfer, R. Bertazzi and H. G. W. Leuenberger, Helv. Chim. Acta, 1983, 66, 485; see also
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29. S. W. May and R. D. Schwartz, J. Am. Chem. Soc., 1974, 96, 4031.
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31. Drauz and Waldmann, Vol II, 1992, p 755.
32. J. M. Schwab, W.-B. Li, and L. P. Thomas, J. Am. Chem. Soc., 1983, 105, 4800.
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7157.

30
New Chiral Centres from Old
— Enantiomerically Pure Compounds &
Sophisticated Syntheses —
The Purpose of this Chapter
New Chiral Centres from Old
Creating New Chiral Centres with Cyclic Compounds
Conformational control
Cyclisation: ring-closing reactions
Thermodynamic control in formation of cyclic compounds
Cyclic intermediates
Stereochemical control in folded molecules
Stereochemical Transmission by Cyclic Transition States Sigmatropic rearrangements
Mapp and Heathcock’s synthesis of myxalamide A
Control of Open Chain Stereochemistry
Felkin-Anh control
Houk control
Reactions of allyl silanes with electrophiles
New chiral centres by 1,3-control
Aldol reactions
1,3-Anti induction
Introduction to 1,4- 1,5- and Remote Induction
Remote control by substrate-controlled induction
1,4 -Syn induction in the aldol reaction
1,4-Control by sigmatropic shifts
1,5-Induction by the aldol reaction
The Asymmetric Synthesis of ()-Discodermolide
Making discodermolide on a large scale
The Purpose of this Chapter
We have already seen in earlier chapters how one chiral centre can lead to another. We have seen
this in the context of racemic compounds and in the context of optically pure ones. So for instance,
new chiral centres are made when unsaturated acid (±)-2 reacts to form the iodolactone 1. If the
acid 2 is racemic, both enantiomers of one diastereoisomer of the lactone 1 are formed but if 2 is
optically pure, only one is formed. The existing chiral centre in 2 controls the two new ones in 1.
The relative stereochemistry in the racemic product (±)-1 is exactly the same if we start with optically
pure material.
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

682 30 New Chiral Centres from Old
I
O
O
+
O
O
I2
CO 2H CO 2H I2
I
NaHCO3
NaHCO3
I
(±)-1 (±)-2 optically pure 2 optically pure 1
There is a clear overlap in concept between this chapter and chapter 21 but the purpose of this
chapter is to explore how new chiral centres are made from old ones in some more sophisticated
molecules, to look at some strategies we have not seen before, and to see how things are different
when the starting material is a single enantiomer. We shall revisit the principles of chapter
21 so return there if you are in doubt about any of them. We shall use the asymmetric methods
of chapters 22–29 and consider what advantage there is in having both substrate and reagent as
single enantiomers. But fi rst we shall look at an application of iodolactonisation in asymmetric
synthesis.
We pointed out in chapter 27 that Schultz’s asymmetric Birch reduction can be developed
with iodolactonisation to remove the chiral auxiliary and set up new chiral centres. Now we
shall see how he applied that method to alkaloid synthesis. 1 The fi rst reaction is the same as
in chapter 27 but the alkyl halide is now specifi ed: this gave diastereomerically pure acetate
in 96% yield and hydrolysis gave the alcohol 4. Mitsunobu conversion of OH to azide and
enol ether hydrolysis gave 5, the substrate for the iodolactonisation. Iodolactonisation not only
introduces two new chiral centres but cleaves the chiral auxiliary, as described in chapter 27.
Reduction of the azide 6 to the amine with Ph 3P leads to the imine 7 by spontaneous ring
closure.
O OMe
N
2.
Br
OAc
OMe
3. KOH, MeOH
OMe
3 4
N 3
O OMe
O
N
Acylation with 8 moves the imine to an enamine 9 and opening the lactone with the lithium
alkoxide of benzyl alcohol gives the epoxide 10 ready for the key cyclisation.
O
O
Br
Cl
1. K, NH3, t-BuOH
O
OH
O
5 6
7
Et3N
CH 2Cl2
O
O
I 2
THF
H 2O
Br
I
O OMe
O
N 3
N
Ph 3P
THF
reflux
N
O
O
1. DEAD, Ph 3P
(PhO) 2PO.N3 2. HCl, MeOH
O
O
O
8 9 10
N
O
I
O
BnOH
BuLi
THF
O
O
Br
7
I
N
O
O
O
CO 2Bn

This synthesis was designed around a radical cyclisation to close a six-membered ring and
create yet another two new chiral centres. The radical may be induced either by Bu 3SnH or photochemically
and cyclises in a 6-endo-trig manner from the top face of the enamine giving cis 5/6
and trans 6/6 ring junctions. The original six-membered ring that was the benzene ring in 3 now
has fi ve chiral centres. One was created in the original asymmetric Birch reduction but the other
four were introduced two by two using iodolactonisation and cyclisation as diastereoselective reactions.
Product 12 has the skeleton and most of the functionality of the lycorine alkaloids.
10
Bu3SnH
AIBN
New Chiral Centres from Old
O
O
CO2Bn H
O
H
N
O
N
O
O
11 12
The starting materials in this chapter will already be single enantiomers and will have been made
so by one of the methods we have discussed at length over the last eight chapters: Resolution
(chapter 22), Chiral Pool (23), Asymmetric Reagents (24) Asymmetric Catalysis (25 and 26),
Substrate-Based Strategy (27), Kinetic Resolution (28) or Enzymes (29). These strategies will be
identifi ed by chapter titles and you are invited to check back if such descriptions are obscure or to
check the references for more detail.
The starting materials will generally have one or two chiral centres and methods for transmitting
this information across the molecule to form new chiral centres will be based on the discussion
in chapter 21 and will involve:
Use of Rings: preformed rings, conformational control, ring formation, folded molecules.
Cyclic Transition States: chelation control, reagent delivery, rearrangements.
Open Chain Stereochemistry: 1,2-control by Felkin-Anh and Houk transition states.
More Distant Control: 1,3-, 1,4- and remote control.
It will not be possible to separate these methods totally as many syntheses involve several of them sequentially
or together but we shall usually introduce an area with a simple example to set the scene.
Creating New Chiral Centres with Cyclic Compounds
O
Rings have fewer conformations than open chains. This is as important in transmitting asymmetry
as it was in chapters 20–29 in creating asymmetry. A simple illustration is Bailey’s synthesis
of cis-5-hydroxypipecolic acid 15 by a chiral pool strategy from natural (S)-glutamic acid 13.
Bailey’s original idea was to cyclise the α-chloroketone 14 but this was not successful, even when
NH 2 and CO 2H were protected. 2
HO2C
30 Creating New Chiral Centres with Cyclic Compounds 683
H2N CO2H Cl H2N CO2H 13; (S)-glutamic acid
O
14
?
HO
O
N CO2H
H
15; cis-5-hydroxy
pipecolic acid
CO 2Bn

684 30 New Chiral Centres from Old
The corresponding protected alcohol 17 would cyclise but reduction of 16, though giving a
good yield, was totally non-stereoselective, giving cis- and trans-17 in a 1:1 ratio. This is not
surprising: drawn out as a straight chain compound 16 has a 1,4-relationship between the existing
chiral centre and the prochiral carbonyl group. This is usually too far for effective induction.
Cl
O
1
CO2Me 2 3 4
16
NHCbz
Cyclisation of the mixed (silylated) alcohols 17 and oxidation to the ketone 18 allowed a comparison
between reduction of the open chain 16 and cyclic 18 ketones. Reduction of 18 gave just
one diastereoisomer cis-19 and so, after deprotection, the target molecule. Later improvements
allowed a shorter route to 18 by rhodium-catalysed carbene cyclisation. 3
17
1:1 cistrans
1. R3SiCl, base
2. NaH, DMF
3. CrO3, acetone
4. HF, H 2O, MeCN
The high selectivity is due to the single conformation of 18 in contrast to the many conformations
available for 16. The CO 2Me group is axial to avoid eclipsing the planar Cbz group that
is conjugated with the planar nitrogen atom. Reduction with the small reducing agent NaBH 4
gives, as usual, the equatorial alcohol 19. Conformations of six-membered rings are particularly
well defi ned but all rings have better defi ned conformations than the corresponding open chain
compounds.
Conformational control
O
NaBH 4
MeOH
18
OH
Cl CO2Me + Cl CO2Me N
CO 2Me
Cbz
NHCbz
NHCbz
cis-17 96% yield; 1:1 trans-17
NaBH 4
In chapter 27 we recommended 8-phenylmenthol 21 as a chiral auxiliary. The three chiral centres
in 8-phenylmenthol are made by from the terpene pulegone 22 (chiral pool) having only one chiral
centre. The new chiral centres have 1,3- and 1,4-relationships to the centre already present in
pulegone and the key to their successful control is conformational analysis. 8-Phenylmenthol has
all three substituents equatorial.
Copper-catalysed conjugate addition of PhMgBr to pulegone gives the enolate 23 with no new
chiral centres but protonation gives a 55:45 mixture of the cis- and trans-ketones 24. This is
disappointing as we might have expected greater selectivity for the all-equatorial trans-24. In fact
equilibrium was not achieved in acid and a separate treatment with KOH in ethanol under refl ux
converts the 55:45 mixture into an 87:13 mixture. 4
MeOH
HO
N
OH
CO 2Me
Cbz
cis-19; 93% from 18
1. NaOH
H2O, MeOH
2. H 2, Pd/C
OH
OH
Ph
OH
Ph
O
20; (–)-menthol 21; (–)-8-phenylmenthol conformation of 21
22; (+)-pulegone
15

PhMgBr
CuBr
2M HCl
+
O
Et2O
–20 ˚C
Ph
O
Ph
O
Ph
O
22; (+)-pulegone
23 trans-24 cis-24
The mixture is reduced with sodium in i-PrOH to give the same proportions (87:13) of two
alcohols 21 and 25. This thermodynamically controlled reduction is totally stereospecifi c, giving
the equatorial alcohol in both cases. Presumably the equilibration of the ketone 24 is less successful
because the large PhCMe 2 group eclipses the carbonyl group when it is equatorial. The two
alcohols are easily separated as their chloroacetyl esters.
trans-24
cis-24
KOH
EtOH
reflux
Ph
trans-24 (87:13
mixture with cis-24)
Cyclisation: ring-closing reactions
O
Na
i-PrOH
Schultz’s lycorine 12 synthesis started with the creation of asymmetry (one centre) in one ring and
built two other rings onto that ring by cyclisation reactions. This is a good strategy and can be
applied to much simpler molecules such as Merck’s anti-schizophrenia drug MGS002836. The
fi rst centre was introduced by asymmetric allylic alkylation of the palladium allyl cation complex
28 from the racemic acetate 26 using the Trost ligand 29 to provide the asymmetry. 5
OAc
+
Cl
Pd Pd
Cl
L*Pd
26 27 28
The nucleophile is the enolate anion from ethyl 2-fl uoroacetate 30 formed with NaH in the
presence of n-Hex 4N Br . The complex 28 would be achiral except for the ligand which directs
the nucleophile to one end of the allyl cation on the opposite face to the palladium. With only
1 mol% of the catalyst up to 96% ee was achieved though only one centre in 31 is controlled.
OAc
26
30 Creating New Chiral Centres with Cyclic Compounds 685
+
O
F
30
CO2Et
NaH, n-Hex 4N Br
This is not important as deacylation destroys that centre anyway 32. Epoxidation followed: the
best route was bromohydrin formation with NBS in water followed by elimination with DBU and
gave an 8:1 selectivity for epoxidation on the opposite face to the substituent 33.
Ph
1 mol% Allyl-Pd-Cl
Trost ligand 29
OH
+
Ph
21 25
O O
NH HN
O
PPh 2Ph 2P
F
H
CO 2Et
OH
31
89% yield
94-96% ee
29; L*
Trost
ligand

686 30 New Chiral Centres from Old
O
F
31
H
CO 2Et
NaOEt
EtOH
Now comes the critical cyclisation: treatment with a stronger base (LiHDMS) creates the
prochiral enolate centre which cyclises onto the epoxide. The three centres on the ring are controlled:
two are not involved and the third is stereospecifi cally inverted by the intramolecular S N2.
The new fl uorinated centre on the three-membered ring 34 is controlled stereoselectively with the
larger CO 2Et group on the outside (convex or exo face of the folded molecule - see below). Further
reactions involve the oxidation of the alcohol 34, bromination of the ketone, again on the outside
of the folded molecule 35, and introduction of an amino acid to give Merck’s potential schizophrenia
drug 36. Each chiral centre was developed from the original asymmetric allylation.
O
F
H
CO2Et
H LiN(SiMe3) 2
33
Et 3Al, THF
–78 ˚C
H
Thermodynamic control in formation of cyclic compounds
F
F
H
CO2Et
H
1. NBS, H2O, acetone
2. DBU, CH 2Cl 2
The rather complex anti-fungal compound itraconazole (Sopranox) 37 has two triazole rings each
substituted with chiral units. They are very far apart and each must be made separately. 6
N
Chemists at Sepracor appreciated that the left hand unit 38, being an acetal, could be made only
by the usual acetal formation from a ketone 39 and a diol 40. Note that the diol is precariously
chiral as if R H, the compound has a plane of symmetry.
N
N
N
N
N
Cl
O
Cl
O
O
F
H
CO2Et H
32; 100% yield 33; 85% yield (8:1)
CO2Et
H
1. IBX (96%)
H
F
CO2Et
HO
2. Br2, CH2Cl2 (100%) O
O NH2 34; 90% yield
Br
35
36; MGS0028
Cl
O
37; Itraconazole (Sporanox)
Anti-fungal
O
Cl
1,1-diX
acetal
Cl
+
HO
O
trans-38
OTs
N
N
N
39
O HO
40
Cl
H
N N N
O
N
N
H
F
OR
CO2H
H
CO2H

Diol derivatives 40 can be made from protected glyceraldehyde (chiral pool strategy) and the
obvious choice for R is Ts so that the new C–O bond needed for itraconazole can be made by
alkylation of the phenol. Reaction of the diol 40; R Ts with the ketone 39 in acid solution gave
a mixture of trans- and cis-38 in an acceptable 3:1 ratio. The preferred diastereoisomer has the
benzene ring on the opposite side to the CH 2OH group. The triazole ring is further away and so
less hindering. Trans-38 can easily be separated from cis-38 by crystallisation and the overall
yield (51%) from 41 is excellent. Cis-38 can of course be recycled as acetal formation is reversible:
an advantage of thermodynamic control.
O
O
41
Cyclic intermediates
CHO 1. NaBH4 HO
2. TsCl, pyridine
3. HCl, acetone
HO
40; R = Ts
OTs
The conversion of prochiral centres in cyclic intermediates into fully blown chiral centres is a profi table
way to transmit stereochemical information. The ant trail pheromone monomorine 42 when re-drawn
so that we can see all three hydrogen atoms on the same surface of the molecule 42a, is an ideal candidate
for synthesis by reductive amination. One of the three centres must be made asymetrically and
then the other two set up by reduction of imines formed from that amine and two ketones as in 43.
H
H
The synthesis we are going to describe is particularly ingenious. A Stetter reaction (chapter 14)
with the Diels-Alder adduct 44 (it doesn’t matter that this is racemic and a mixture of exo/endo
isomers) and the enone 45 provides the 1,4-diketone in 85% yield and hence, by retro-Diels-Alder,
the achiral enedione 47 in 81% yield. 7
The amine 49, made from one enantiomer of propylene oxide by simple reactions, is the source
of the chirality. A cross-metathesis with 47, using the Grubbs catalyst 50 gave a surprisingly
excellent yield (89%) of the complete carbon skeleton 49 of monomorine.
H
39
trans-38
+ cis-38
3:1 ratio
crystallise
HOTs salt
trans-38
51% yield
from 41
reductive
amination
N
N
O
H
O Bu
H
Bu
H2N
42; monomorine 42a 43
+
O
Stetter
CHO
Bu
thiazolium
salt
O
44 45 46
O
propylene
oxide
30 Creating New Chiral Centres with Cyclic Compounds 687
48
NHCbz
47
Grubbs
catalyst
O
NHCbz
49
O
O
Bu
heat
O
MesN NMes
Cl
Cl
Ru
O
47
O
Grubbs
catalyst
50

688 30 New Chiral Centres from Old
Catalytic hydrogenation of 49 produces monomorine in one step and in 75% yield. First the
alkene must be reduced to give the molecule the fl exibility to cyclise. Hydrogenation removes the
Cbz group and the amine cyclises onto the nearer ketone to give the imine 51 which is reduced
from the less hindered face opposite the Me group to give 52. Now cyclisation to the second ketone
produces the imine salt 53 and a second reduction from the same side gives ()-monomorine. The
fi rst reduction of 51 is totally stereoselective but the second gives about 15% of the other epimer.
Since the origin of the stereochemistry is only a methyl group, this is remarkably good.
H2, Pd/C
MeOH
43
N
O Bu
NH O Bu
Other prochiral units that can be trapped in rings are enolates. One famous application is the
alkylation of β-hydroxy acid derivatives available from the chiral pool (chapter 23), by asymmetric
aldol reactions (chapter 27) and by asymmetric reduction of β-keto-esters either by catalytic
hydrogenation (chapter 26) or by enzymes (chapter 29). Fráter found that the alcohol 55, from
the baker’s yeast reduction of the ketoester 54, formed the enolate 56 held in shape by chelation.
Alkylation occurred on the top face. 8 This is not so much because the OH is down in 55 as that the
methyl group is down in 56.
O
CO 2Et
Seebach has done similar work with malic acid. A detailed account 9 of the allylation of the
enolate 59 formed preferentially on the unsubstituted carbon atom with allyl bromide giving a
92:8 ratio of diastereoisomers 60 is in Organic Syntheses.
H
51 52 53
Fráter quotes an interesting example 62 where NaBH 4 reduction gave the all equatorial trans-
61 (racemic of course) while baker’s yeast reduction gives one enantiomer of the cis compound 61
evidently by reagent controlled dynamic kinetic resolution (chapter 28). Allylation of the enolate
of cis-61 goes with the expected anti selectivity. 10
OH
54
EtO 2C
OH
baker's
yeast
CO2Et
H
H
N
Bu
(+)-42
75% yield
OH
CO2Et 2 x LDA
O
Li
O
Li
OEt
RBr
OH
R
CO2Et 55 56 57
EtO2C
Li Li
O O
OEt
Br
EtO 2C
58; diethyl malate 59
60; 70% yield
CO 2Et
NaBH 4
O
CO 2Et
baker's
yeast
OH
CO 2Et
1. LDA
2.
Br
OH
CO 2Et
OH CO2Et
(±)-trans-61 62
(+)-cis-61 63; 95% yield

If the β-hydroxy acid derivative is a lactone, the chain is turned the other way and no chelation
is possible. The lactone 65 can be prepared from malic acid 64 (either enantiomer) and the
dilithium derivative 66 cannot be chelated. Instead the solvated (THF is the solvent) LiO group
blocks the top face of the almost planar enolate. The selectivity is anti as before but when the chain
is opened out 68 by hydrolysis of the lactone it is clear that the other diastereoisomeric relationship
to that in 60 has been made. 11
OH
HO2C
CO2H HO
64; (S)-(–)-malic acid 65
O
O
LiO
We shall illustrate this with Prestwich’s synthesis 11 of the natural anti-cancer compound ()aplysistatin
69. This interesting compound with a seven-membered cyclic ether and a bromine
atom proclaiming its marine origin is probably made in nature by a polyolefi n cyclisation and that
strategy was used in the synthesis. The alkene must be removed 70 before the cyclisation can be
reversed. The stereochemistry of the extra centre in 70 is unimportant until the realisation that it
can be made by alkylation of a hydroxylactone 71 whose stereochemistry must be anti.
Br
2 x LDA
THF
–78 ˚C
H
O
Br
H
69; (–)-aplysistatin 70
The (R)-()-isomer of malic acid 72 must be used and the lactone 73 is the enantiomer of 65.
The alkylating agent is the terpene derivative homogeranyl iodide and the selectivity is anti as
expected. The yields in this synthesis are not wonderful but it is short and biomimetic.
The cyclisation uses the convenient brominating agent 74 and the preferred conformation for
cyclisation has an all chair arrangement of the side chain 75. By this means the two chiral centres
in 71 induce three more in 70. The remaining double bond is introduced by selenium chemistry
(chapter 33). In this process the chiral centre introduced by alkylation of 73 is destroyed but it has
played its part in controlling the conformation 75.
74
Br
H
O O
HO 2C
FGI
72; (R)-(+)-malic acid
O
Br Br
30 Creating New Chiral Centres with Cyclic Compounds 689
OH
Br
CO2H
"Br "
HO
OLi
O
RBr
R
HO
66 67
H
O O
73
O
O
OH H
O
75; preferred chair-like
transition state for cyclisation
H
2.
O
O
O
O
polyolefin
cyclisation
1. 2 x LDA, THF, –78 ˚C
Br
HO
H
I
R
68
71
CO 2H
OH
HO
71
H
H
H
O O
anti-70
H
O
O
O

690 30 New Chiral Centres from Old
Stereochemical control in folded molecules
When two small rings are fused together, the molecule is folded rather like a half-opened book. When
more rings are added, the molecule may adopt a bowl shape. 12 In both cases the molecule has a convex
or exo face on the outside that reagents fi nd easy to reach and a concave or endo face on the inside that
is much more diffi cult to reach. Astericanolide 76 has two fi ve- and one eight-membered rings and is
bowl-shaped as all four hydrogen atoms at the ring junctions are on the same side. Paquette 13 decided
to close the eight-membered ring by ring-closing metathesis (RCM, chapter 15) and so removed the
ketone, the remote chiral centre (C-7) and the lactone carbonyl 77 as a preliminary. Disconnection
gave 78 as the substrate for metathesis, the two arrowed carbons being destined for cyclisation.
The 5/5 fused system in 78 is folded but has the side chain on the inside: it may be possible to
force it inside by adding the hydrogen atom last. The synthesis starts with a vinyl-lithium reagent
derived from 79 (chapter 16): reaction with a single enantiomer of menthyl p-tolylsulfi nate gave
the sulfoxide 80. Michael addition of the propargyl alcohol 81 was not very effi cient but could be
persuaded to give one diastereoisomer of the adduct 82 in 38% yield. As we shall see in chapter 36,
this sacrifi ce in yield is worthwhile when a tandem reaction occurs. Here Michael addition of the
alcohol has been followed by Michael addition of the resulting anion to the acetylenic ester.
O
O
Br
1. BuLi
2. R*SO2Tol O
O
O
S
R* = menthyl
79 80; 77% yield
Tol
Hydrogenation with Raney nickel removes the chiral auxiliary and, as we had hoped, hydrogenates
the alkene from the less hindered exo-face, pushing the side chain inside the folded molecule
83. The ketone is converted into the only possible vinyl trifl ate for Stille coupling with a vinyl
stannane to give the diene 84.
82
H 2, Raney Ni
MeOH
O 7
H H
O
H
H
O
H
H
FGI
CO2Me
KHMDS
PhNTf2
THF, –78 ˚C
H H
H
O
O
H
O
H
O
76; (+)-astericanolide 77 78
TfO
The next few stages to produce the metathesis substrate 78 are straightforward and involve the
creation of no new chiral centres. The metathesis was very successful with the original Grubbs’
catalyst 85 and gave the cyclic diene 86. Now the two carbonyl groups and the last two chiral
+
HO
H
H
O
CO2Me
83; 88% yield 98% yield
H
RCM
K 2CO 3
THF
O
R*
H
O
81 82
H
CO2Me
H
Bu3Sn
Pd2(dba) 3
CHCl3
LiCl, THF
H
H
H
CO2Me
O
H
84; 98% yield
CO 2Me

30 Stereochemical Transmission by Cyclic Transition States: Sigmatropic Rearrangements 691
centres must be added. Porphyrin-sensitised (TPP tetraphenylporphine) photochemical
addition of singlet oxygen by an ene reaction 87 occurred also on the exo-face and gave, after
reduction of the hydroperoxide, the doubly allylic alcohol 88.
Cl
Cl
PCy3 Ru
PCy Ph
3
85; Grubbs
catalyst
78
This new centre does not appear in the natural product 76. It is oxidised to the ketone and both
alkenes reduced catalytically, both hydrogen molecules being added from the exo-face to set up
both chiral centres in one step. The THF is fi nally oxidised to the lactone with Ru(IV). After the
initial Michael addition, controlled by the sulfoxide, every chiral centre depends on the folded or
bowl-shaped molecule.
88
Dess-Martin
periodinane
O
Stereochemical Transmission by Cyclic Transition
States: Sigmatropic Rearrangements
H
O 2
TPP
H hν
CH2Cl2 H
H
H
O
H
O
H
O
86; 93% yield 87 88; 67% yield
H
O
H
89
H
Rearrangements are more commonly used to move chirality around a molecule without
actually creating new centres. That new centres can be made is illustrated clearly by Mulzer’s
Ireland-Claisen approach to indolizidine alkaloids 14 such as ()-petasinecine 98 from proline
(chiral pool). Proline is converted into the allylic alcohol 91 which is acylated to give the substrate
92 for an Ireland-Claisen rearrangement.
H
OH
Cl
O
H 2, Pd/C
EtOH
O Ph
Treatment with LiHMDS [LiN(SiMe 3) 2] gives the Z-enolate 93 because of chelation and
hence the silyl enol ether 94 that undergoes the [3,3] sigmatropic rearrangement to give one
diastereoisomer of 95 with two new chiral centres both controlled by the original one from
proline.
H
O
O
O
H
H
H
H
H
O
H
90; 67% from 88
LiAlH 4
RuCl 3
NaIO 4
CCl 4
MeCN
H2O
N
Boc
pyridine
N
Boc
91 92; 98% yield
H
O
O
HO
O
H
H
H
H
H
O
O
76; 63% yield
OBn

692 30 New Chiral Centres from Old
LiHMDS
Me3SiCl
Bn
Li
O
H
O
N Boc
O
BnO
N Boc
Removing the Me 3Si and Boc groups and redrawing the structure reveals the amino acid 96
that cyclises in acid solution to bicyclic 97 having the skeleton of the indolizidine alkaloids. Further
steps lead to ()-petasinecine 98. This sequence looks involved but in fact only three intermediates
are isolated: 92, 96, and one between 97 and 98.
95
CF 3CO 2H
BuOH
A more complicated example is the synthesis of ()-hastanecine by Hart and Yang. 15 (R)-()-
Malic acid 99 was used as a chiral pool starting material and converted into the anhydride 100 by
straightforward steps. Reaction with the amine 101 gave the pyrrolidine 102.
HO2C OH
HO 2C
99; (R)malic
acid
Reduction of the anhydride gave 103 with complete regioselectivity in favour of the carbonyl
next to the acetate but without stereoselectivity. This doesn’t matter as treatment with acid
initiated a rearrangement - cyclisation sequence giving a the alcohol 104 after hydrolysis of
its formate. This time there is complete stereoselectivity in the creation of three new chiral
centres.
102
NaBH4
MeOH
Loss of water from 103 gives the iminium salt that undergoes the [3,3]-sigmatropic rearrangement
105 to give 106 with two of the new chiral centres already fi xed. An ionic cyclisation 106
fi xes the third and the cation 107 picks up water to give 104 or formic acid to give its formate
ester.
H
OSiMe 3
O
[3,3]
BnO
H
H
N
Boc
93 94
95
H
OSiMe 3
H
NH
OBn
CO2H H
N
OBn
H
N
96
O
97; 82% from 92
O
98
O
O
OAc
1. amine 101
BnO
2. AcCl, CH 2Cl 2
NH 2
BnO
O
100 102; 81% yield
HO
OAc
1. HCO 2H, 25 ˚C
BnO
BnO N
2. NaOH, H2O, MeOH
HO
N
O
O
103; 83% yield
104; 73% yield
O
N
H
O
OH
O
OH
OAc
OAc

30 Stereochemical Transmission by Cyclic Transition States: Sigmatropic Rearrangements 693
103
–H2O
The stereochemistry of these steps is of course controlled by the original chiral centre derived
from malic acid. The acetate prefers to adopt a pseudo-equatorial position in the cation 105 and
the conformational drawings 105a–107a show that a chair conformation for the [3,3] step with
equatorial substituents gives the fi rst two new chiral centres and a pseudo-equatorial position for
the isopropyl substituent in the ionic cyclisation gives the third.
H
BnO
OBn
N
[3,3]
OAc
Mapp and Heathcock’s synthesis of myxalamide A
O
H
These [3,3]s and the related [2,3] sigmatropic rearrangements were used in the synthesis of the
far more complicated anti-fungal and anti-viral myxalamide A 108. At fi rst sight the worst problem
seems to be the chain of trans and cis alkenes dominating the structure. There is also some
three-dimensional stereochemistry. At the right hand end is an amide of alaninol that will cause
no problem but at the other end is a section with three chiral centres. This piece was disconnected
at the fi rst alkene and the necessary aldehyde functional group replaced by an alcohol 109 to avoid
racemisation by enolisation. It is now clear that, while two of the chiral centres are adjacent, the
third has a 1,4 relationship with the OH group and, worse, is separated by a trans double bond. At
fi rst sight it appears impossible to control this relationship. But look and wonder: a combination of
[2,3] and [3,3] shifts succeeds. 16
HO
108
myxalamide A
BnO
The synthesis started with an Evans’ aldol between the phenylalanine-derived oxazolidinone 110
and the aldehyde 111. Reductive cleavage of the syn-aldol 112 gave the diol 113 in excellent yield.
This type of aldol reaction is discussed in detail in chapter 27. You may be impressed by the near
perfect stereoselectivity but unimpressed that 113 is the wrong diastereoisomer. Look and wonder.
O
Bn
N
110
O
105
[3,3]
OBn
N
N
N
OAc
OAc
H
H
H
H
105a 106a 107a
1. Bu2BOTf, Et3N
2.
t-BuS
111
CHO
t-BuS
O
OH
112
H
N
OAc
BnO
O
106 107
NH
O
Bn
N
OH
O
aldol?
Wittig?
FGI
LiBH 4
Et 2O
H 2O
4
t-BuS
H
H
N
OAc
O
OBn
OAc
2
HO OH
109
1
OH
113; 90% from 110
OH

694 30 New Chiral Centres from Old
Protection of the primary and acylation of the secondary alcohol prepares the way for an
Ireland-Claisen rearrangement. The E-enolate is produced and the [3,3] sigmatropic rearrangement
transmits the chirality across the alkene to set up two new centres. The mechanism of the
Ireland-Claisen rearrangement is described above 94 and occurs suprafacially across the backbone
of the molecule through a chair-like transition state. We hope you agree both with the relative
stereochemistry of the new centres and the E stereochemistry of the new alkene.
113
1. t-BuMe2SiCl
Et 3N, imidazole
88% yield
2. EtCOCl
pyridine
92% yield
The ester group is transformed into an ethyl group in simple fashion 116 and the position and
stereochemistry of all the chiral centres corrected by an Evans-Mislow rearrangement. Oxidation
to the sulfoxide 118 allows a [2,3] sigmatropic shift across the top face of the molecule giving an
unstable sulfenate ester 119 from which sulfur is removed by a phosphite ‘thiophile’ to give the
alcohol 117 with the correct anti-stereochemistry. The alkene returns to its original position and
stereochemistry. The rest of the synthesis involves the construction of the polyene chain. 16
Control of Open Chain Stereochemistry
In chapter 21 we emphasise that the most reliable method of controlling one chiral centre by
another in open chain compounds is by Felkin-Anh orbital control of nucleophilic attack on a
carbonyl group next to a chiral centre. We shall start this discussion with that method and follow
with the next most reliable - Houk control of electrophilic attack on alkenes also next to a chiral
centre. These are of course both 1,2-control and we shall deal with that before discussing 1,3-,
1,4- and remote control.
Felkin-Anh control
t-BuS
O
O
114; R = TBDMS
OR
1. LDA, THF
2. t-BuMe2SiCl 3. room
temperature
4. K2CO3, H2O 5. CH2N2 MeO 2C
t-BuS
OR
1. mCPBA
2. (MeO)3P
t-BuS
MeOH
OH
116; R = TBDMS 117; R = TBDMS
t-Bu
mCPBA
S O
OR
[2,3]
suprafacial
t-BuS
115; R = TBDMS, 86% yield
MeOH
118; R = TBDMS 119; R = TBDMS
We start with simple but important example. The search for a manufacturing method for Janssen’s
anti-cancer drug 120 as one enantiomer of one diastereoisomer in high yield led to the racemic
amino-ketone 123 easily made from 121 via a Friedel-Crafts acylation and a substitution with
dimethyl amine. 17
O
OR
OR
P(OMe) 3
OR

N
N
N
S N
H
NMe2 120; Janssen's R116010
N
S N
H
O
Cl
Me 2NH
H 2O
i-PrOH
Dynamic kinetic resolution (chapter 28) of 123 with ()-di-p-toluoyltartaric acid equilibrated
the easily enolisable chiral centre and precipitated a 90% yield of the salt of the (S)-amine having
80% ee. Reduction with NaBH 4 in i-PrOH was very diastereoselective giving 99:1 syn:anti-124.
(±)-123
This is Felkin-Anh control: the NMe 2 group sits at right angles to the carbonyl group and nucleophilic
hydride approaches at the Bürgi-Dunitz angle alongside the H atom 125. The synthesis is completed
by displacement of OH with an excess of imidazole using CDI (carbonyl-di-imidazole) 126 to
activate the alcohol. Participation by the NMe 2 group is responsible for the retention of confi guration.
Even one methyl group can be enough to give reasonable Felkin selectivity. A vital step in
Chi-Huey Wong’s epothilone synthesis 18 is the addition of the double enolate 128 to a single enantiomer
of the syn,anti-aldehyde 129 to give good diastereoselectivity (8:1) at the new chiral centre
C-5. Though this is an aldol reaction of sorts, it is not a stereoselective aldol in the usual sense
(chapter 3) but Felkin control in attack on the α-chiral aldehyde 129.
N
S N
H
121
N
S N
H
(±)-122 (±)-123
N
S N
H
NMe2
(S)-123 as di-p-toluoyl-tartrate
Me2N
O
Ar
125
Me
H
N
O
O
N N
126
CO2t-Bu 1. NaH
2. BuLi
Ot-Bu
O OLi O
127
128
DERA
an aldolase
30 Control of Open Chain Stereochemistry 695
OR
129
CHO
NaBH 4
i-PrOH
NaOH
N
(S,S)-124
imidazole
EtOAc
N
Cl
O
O
Cl
AlCl3, CH2Cl2
NMe2
OH
S N
H
NMe2
(S,S)-124; 80% yield, 80% ee
OR
(S,S)-120
5
OH
O
CO2t-Bu
130; 70% yield, 8:1 diastereoisomers

696 30 New Chiral Centres from Old
Since Felkin control has been well established in chapter 21, we shall simply give a couple of
examples and two warnings before moving on to the less familiar Houk control. The fi rst warning
is that chelation control, particularly when metals such as magnesium are involved, may reverse
the normal sense of induction. The second is that Felkin (or chelation) control cannot be guaranteed
even when there is a large electron-withdrawing group next to the carbonyl group.
In the original synthesis 19 of the HIV protease inhibitor viracept by Aguron Pharmaceuticals
the key intermediate 133 was made from serine (chiral pool) 131 via the simple ketone 132. Reduction
of 132 with NaBH 4 gave mostly the stereochemistry required 133. The Felkin conformation
is 134 with the large (and electronegative) NHCbz group orthogonal to the carbonyl group
and nucleophilic hydride approaching alongside the small H atom. Yet the stereoselectivity is poor
and this was not the route chosen for the manufacture of the drug. 20
NH2
NHCbz
NaBH 4
NHCbz
OH
CO2H PhS O
Cl
THF
H2O PhS OH
Cl
H O
131; (S)-serine 132
133
134
The anti-tumour antibiotic ()-FR900482 135 is particularly interesting as it contains a
hemiacetal. Disconnecting this reveals an eight-membered ring with stereochemistry 136.
Martin 21 decided to make this ring by metathesis so that a protected version of 137 becomes an
intermediate.
OHC
OH
N
OCONH 2
OH
O NH
1,1-diX
hemiacetal
Now stereochemistry must be controlled in open chain chemistry. They were able to make
a single enantiomer of 138 by desymmetrisation with a lipase (chapter 29). Reaction with vinyl
Grignard gave one diastereoisomer of 139a whose silyl ether 139b underwent excellent metathesis
with a Schrock Mo catalyst to give 140 and hence FR900482. They say disarmingly that ‘the
stereochemical outcome…may be rationalised either…(by)…chelation control or by the Felkin-
Anh model’. Take your choice! It may appear that this new centre is unnecessary but it is in fact
vital to control the formation of the aziridine.
OH
OHC N
OCONH 2
O
NH
PhS
HO
HO
135; FR900482 136 137
OBn
N
OMPM
CHO
OBn Boc
138; MPM - p-MeOC6H4CH2 BrMg
OBn
N
OBn Boc
139a; R = H
139b; R = SiMe2But OH
Cl
OHC N
OMPM
OR OBn
Schrock Mo
metathesis
catalyst
OBn
Boc
140
NHCbz
OCONH2
O
N
OMPM
OR

Houk control
Houk control concerns electrophilic attack on alkenes, enolates and the like. The alkylation
of enolate 56 would be an example if it were not held in a ring by chelation. It can in fact
be diffi cult to tell whether chelation is involved or not with many enolates and the outcome
of the reaction may tell which. Chamberlin’s asymmetric preparation of both pyrrolidine 2,3dicarboxylic
acids 141 and 142 from natural aspartic acid illustrates this perfectly. The key to
the stereochemical control is the very large protecting group 9-phenylfl uorenyl- 143 introduced
by Rapoport. 22
CO 2H
CO 2H
CO 2H
and
H2N CO2H N
CO2H N
CO2H
(S)-aspartic acid
H
141
H
142
Ph
143: PhFl group
Aspartic acid is protected as the dimethyl ester 144 with the nitrogen atom carrying one benzyl
group and one PhFl- group. Potassium or lithium enolates, made with K/LiN(SiMe 3) 2, were
alkylated with allyl iodide. The lithium enolate gave a 23:1 mixture (96% yield) favouring syn-145
but the potassium enolate gave a 10:1 mixture (94% yield) favouring anti-146. These were converted
into 141 and 142 by ozonolysis, deprotection and reductive amination.
CO2H
H 2N CO 2H
(S)-aspartic acid
CO 2Me
Bn
N CO2Me PhFl
144
1. MN(SiMe 3) 2
2.
The lithium enolate is expected to have the E(enolate) confi guration 147. Chelation is impossible
and it adopts the Houk conformation 147a with the H atom on the inside eclipsing the
π-bond. The enormous protected amine forces the allyl bromide to the opposite face. The
potassium enolate prefers the chelated structure 148 and the same group directs the allyl iodide to
the bottom face.
OLi
OMe
Bn
N CO2Me PhFl
147; E-Li enolate
30 Control of Open Chain Stereochemistry 697
MeO2C
Bn
N
H
FlPh
In these examples the sheer size of one of the groups controlled the transmission of stereochemical
information. If the directing group is a silicon atom, electronic factors are important
too. 23 Alkylation of the enolate from 149 was used in a synthesis of tetrahydrolipstatin. 24
There is no question of chelation here as no chelating group is present. The Houk conformation
151 of the lithium enolate has H inside and the Me 3Si group directs the alkylation to the
bottom face.
I
O Li
OMe
147a; Li enolate in
Houk conformation
Bn
CO 2Me
N CO 2Me
+
Bn
N CO2Me
PhFl
PhFl
syn-145 anti-146
Bn
PhFl
N
H
MeO
MeO
O
K
O
148;
chelated
potassium
enolate
CO 2Me

698 30 New Chiral Centres from Old
CO2Bn R1 SiMe3 CO2Bn
R1 R
SiMe3 2
1. LDA
2. n-C6H11I 149; R 1 = n-C 11H 23
Reactions of allyl silanes with electrophiles
150; R 2 = n-C 6H 11
Me 3Si
O Li
OBn
We shall see in this section that allyl silanes can direct the transfer of chirality through Houk
conformations without the need to form an enolate. The typical reaction of an allyl silane with
an electrophile (chapter 12) is at the remote atom of the alkene with loss of the silyl group. This
transfers, but does not create, chirality. So the allyl silane 152 reacts with formaldehyde and a
Lewis acid to give the homoallylic alcohol 153 with no loss of ee. The silyl group has gone, the
alkene is transposed, and the sense of the S E2´ reaction is anti. All this is explained by the Houk
conformation 154 with the C–Si bond able to interact with the alkene to raise the energy of the
p-orbital and direct both the regio- and the stereoselectivity. 25
Ph
CH 2O
TiCl 4
Ph
Me 3Si
SiMe3
H
OH Ph
152; 85% ee 153; 86% ee 154
To create new chirality we need a prochiral electrophile. Single enantiomers of functionalised
allyl silanes 155 are made by kinetic resolution with a lipase. 26 Reaction of 155 with an aldehyde
and a Lewis acid gives the syn and anti homoallylic alcohols 156 and 157.
CO 2Me BnO CHO
BnO
SiMe3 Et2O-BF3 SiMe3 SiMe3 155 syn-156 anti-157
With BF 3, the syn product 156 predominates by 87:13 but with MgBr 2, the anti 157 is even
more dominant (92:8). Both products have the same stereochemistry at C-5, determined by the
Me 3Si group as in 154. The mechanism 158 forces the electrophile to approach the alkene from
the top face - opposite the Me 3Si group - but a detailed transition state such as 159 is needed to
explain the new chiral centre at C-6. Panek suggests that 159 is the anti-peri-planar transition state
and that MgBr 2 adopts a ‘synclinal’ transition state.
F 3B
O
R
SiMe 3
CO 2Me
The electrophile, the substitution pattern, and the silyl group can all be varied: acetals and
amines combine to form imines such as 162 under Lewis acid catalysis and these react in the same
R 1
H
151
OH CO2Me OH
5 + BnO
5
syn-156
F 3B
Me
158 159
O
H
H
R
H
Me
SiMe 3
R
CO 2Me

way with allyl silanes such as 160 to give good yields of carbamates 161 with excellent stereoselectivity.
27
OMe
NHCO2Me H
CO2Me SiMe2Ph Ph OMe
H2N CO2Me
Et2O.BF 3
Ph CO2Me Ph N
CO2Me 160 161; 94% yield >30:1 162
An impressive application is the total synthesis 28 of the anti-tumour antibiotic ()-macbecin I
163. The amide disconnection is obvious and the decision to make the amino quinone from an
aromatic nitro compound 164 sensible. Less obvious is the synthon 165 as the anion at C-14 could
be an allyl silane but the further disconnections of 165 all correspond to allyl silane chemistry.
MeO
15
MeO
O
O
N
H
OMe
O
163; (+)-macbecin I
7
O
O NH2
MeO
Three reactions of single enantiomers of allyl silanes were used to add each section of 165. First
the allyl silane 166 was coupled to the acetal 164 with Me 3SiOTf as the Lewis acid. The silyl group
at C-12 controls the stereochemistry of both new chiral centres and the new alkene. The product
is transformed into the aldehyde 168 for the next reaction.
14
1
Now coupling to the simpler allyl silane 169 with the same Lewis acid but also with MeOSiMe 3
gives the new alcohol as its methyl ether 170. Once again control is from silicon as the aldehyde
has no neighbouring chiral centre to exert Felkin control. New chiral centres at C-10 and C-11 are
created.
10
12
12
OBn
SiMe 2Ph
CO 2Me
164
Again the product 170 is converted into an aldehyde 171 for the third allyl silane 172 reaction.
This adds two more chiral centres by Houk control 173 and completes all seven chiral centres
in the fragment 165. The diene side chain is added but this involves no new chiral centres
15
OMe
164
OMe OBn
OMe
OMe
14
Ar 15
CO2Me 166 167
8
CO2Me SiMe2Ph 169
30 Control of Open Chain Stereochemistry 699
Me3SiOTf
168
Me3SiOTf
Me3SiOMe
Ar
OMe
OMe
12 10
OMe
170
NO 2
14
8
12
OMe
Ar
OMe
CO2Me
165
OMe
1
HO2C 168
OH
7
12
OMe
CHO
171
5

700 30 New Chiral Centres from Old
and the synthesis of ()-macbecin I 163 was completed by reduction, deprotection and amide
formation. 28
Ar
OMe
OMe
OMe
171
New chiral centres by 1,3-control
SiMe2Ph
OMe
Ar1 OMe OMe OAr1 MeO
8 CHO 172
Ar
8
7 5
Me3SiOTf
CH2OSiMe3 OMe
173
1,3-Control - the transmission of stereochemical information to the next-but-one carbon atom - is
inherently more diffi cult than 1,2-control and almost impossible unless the molecule is held in
some fi xed conformation, usually by a ring (we shall not deal with that aspect as we have already
discussed it at length), chelation, a cyclic intermediate, or a cyclic transition state. The next stage
in the synthesis of tetrahydrolipstatin, the hydroboration of the alkene in 150 appears to involve
1,3-control in an open chain compound. However, the attack of 9-BBN on the alkene, which does
indeed occur anti to the SiMe 3 group 174, really occurs through a cyclic mechanism 176 involving
1,2 as well as 1,3-control. The B and H atoms add stereospecifi cally cis but stereoselectively anti
to the SiMe 3 group. 24 The oxidation of the borane 174 to give the alcohol 175, occurs stereospecifi -
cally with retention (chapter 17).
150
R1 = n-C11H23 R2 9-BBN
= n-C6H11 R 2B
R 2
R 1 SiMe 3
CO 2Bn
H 2O 2
NaOH
R 1 SiMe 3
CO2Bn
SiMe 3
R H
1
E
R2 R2B H
176; E = CO2Bn The proline-catalysed aldol reaction (chapter 26) of the heterocyclic ketone 177 with benzaldehyde
gave the anti-aldol 178. Reduction by the Prasad method (chapter 21) gave the anti,antidiol
179 and so, by desulfurisation with Raney Ni, the anti,anti-diol 179. The reduction could be
controlled by the neighbouring chiral centre but the Prasad method uses 1,3-control by chelation
with BEt 2 and external axial delivery of nucleophilic hydride from NaBH 4 181. This is 1,3-control
via a cyclic intermediate. 29
O
PhCHO
proline
O
OH
The alternative method of reduction of such hydroxyketones is the anti-selective Evans’ intramolecular
delivery of nucleophilic hydride through a cyclic transition state. In Janda’s bryostatin synthesis,
the diol monoester 182, produced by kinetic resolution with an immobilised lipase (chapter
29) is reduced to the anti-diol 183 by acetoxy-borohydride. The hydride delivery is intramolecular
through a chair transition state 184. This is 1,3-control via a cyclic transition state (chapter 21). 30
HO
R 2
174 175; >95:5 anti:syn
Et2BOMe
NaBH 4
OH
OH
Raney Ni
EtOH, THF
DMF
Ph
Ph
pH 5.2
Ph
H3B H
S
S
S
177 178; 92% yield 179 180; 94% yield
OH
OH
Et Et
O
B
S
181
O
Ph

R
O OH
Apart from cases like these, we shall look for special methods to exercise 1,3-control. The
importance of 1,3-control is immediately obvious from the structure of important cholesterollowering
drugs like Lipitor (atorvastatin) 185. The syn-1,3-diol is a challenge but might be made
from the amine 186 or the nitrile 187.
One successful approach is to use the enzyme DERA (chapter 29) to combine two molecules of
MeCHO and one of ClCH 2CHO in a double aldol reaction. Each aldol creates a new chiral centre:
the fi rst is controlled entirely by the enzyme but the second, using the chiral aldehyde 189 as the
electrophile, could be affected by 1,3-control. 31 As might be expected for an enzyme-catalysed reaction,
the catalyst dominates and the same stereoselectivity is found 190. The product is isolated
in the form of the lactol 191.
Cl
Transformation into a protected form of 187 is straightforward: oxidation with household
bleach gives the lactone 192, displacement with cyanide ion, acetal formation and esterifi cation
with trimethylsilyl diazomethane gives 193. The synthesis of atorvastatin from 193 was already
known. The next section discusses 1,3-control in non-enzymatic aldol reactions.
Aldol reactions
Me 4N B H(OAc) 3
MeCN, AcOH
OAc
182 183
PhNHCO
CHO
188
191
Ph
30 Control of Open Chain Stereochemistry 701
N
F
R
OH OH
OH OH
CO2H
185
atorvastatin
(Lipitor)
MeCHO OH
MeCHO
DERA
CHO
DERA
H2O H2O O
AcO H
B
(–)
O (–)
We have already seen how relative stereocontrol may be achieved in aldol reactions at the positions
labelled 1 and 2 in 194 (chapters 4 and 27). One of these chiral centres is formed from the aldehyde
electrophile and the geometry of the double bond of the enolate determined whether we got anti or
syn geometry (chapters 4 and 21). The absolute stereochemistry at these centres could be controlled
by a variety of methods (chapters 23–29), including the use of a chiral auxiliary (chapter 27).
OAc
H2N
OH OH
OAc
R 1
OH OH
R
184
Evans' anti-
1,3-selective
reduction
CO2H 186
OH OH
NC
187
CO2H
CHO
Cl Cl
OH
189 190 191
NaOCl Cl
O O
1. NaCN, DMF, H 2O, 40 ˚C
HOAc
O O
H2O
OH
2. Me2C(OMe) 2, H
3. Me3SiCHN2
NC CO2Me 192; 45% from 188
>99.9% ee, >99.8% de
193; protected 187; 48% from 192
Cl
O
OH

702 30 New Chiral Centres from Old
O OH
1
Aldol reactions have become very much more sophisticated in the level of control that may be
achieved. The types of control we are about to discuss do not depend upon double bond geometry.
In each case from 1,3 195 to 1,5-related stereocentres 197 the newly forming alcohol is one of the
stereocentres and the other may be either in the incoming enolate fragment 196, 197 or already
present in the aldehyde 195. So the chiral centres are on either side of the ketone in 196 and 197
but both on the same side of the ketone in 195.
1,3-Anti induction
2
O OH OPMB
1 3
BnO
Good levels of 1,3-anti induction can be achieved with aldehyde 199 when it is attacked by silyl
enol ether 198. The aldehyde hydroxyl is the chiral centre and p-methoxybenzyl (PMB) is the
best protecting group. Chelating Lewis acids (Ti, Li) are less effective than the combination of a
silyl enol ether and BF 3 as the Lewis acid. The nature of the enol derivative is important and good
selectivity is not achieved when an enol borinate is used. 32 We shall see in a moment that this lack
of infl uence can be useful too.
Evans suggests that an extended transition state is best with a Felkin-like orthogonal orientation
of the chiral substituent to the carbonyl group. Conformation 201 shows an orientation in which
the dipoles of the CO and OPMB groups are as far apart as possible and with the nucleophile approaching
alongside an H atom at the Bürgi-Dunitz angle. There are other possible explanations. 33
We referred above to a synthesis of bryostatin that contained a reduction controlled by a 1,3relationship.
Evans’ synthesis 34 contains a 1,3-selective aldol as well as a 1,3-controlled reduction
The aldehyde 202, made by an asymmetric aldol reaction, was combined with the double silyl enol
ether of methyl acetoacetate to give, as expected, the anti-aldol 203. However, the only Lewis acid
that gave this good result was (i-PrO) 2TiCl 2 and not BF 3 thus emphasising the rather empirical
aspect of this type of control. Evans’s own 1,3-controlled reduction gave the anti,anti-triol 204
that was incorporated into bryostatin.
1
O OH
4
R
TBSO
194 195 196 197
OSiMe3 O OPMB
+
H
198 199; PMB = p-MeO-benzyl
Ph
Ph
PMBO
CHO
Me 4N B H(OAc) 3
Me 3SiO
Ph
O OH OPMB
BF 3 Et 2O O
(i-PrO) 2TiCl 2
Ph
OSiMe3
OMe
PMBO
200; 92:8 anti : syn
Ph
Ph
OH OH
PMBO
CO 2Me
Nu
OH O
1
F3B H
202; PMB = p-MeO-benzyl anti-203; 83% yield, 94:6 anti:syn
AcOH, MeCN
anti,anti-204; 92% yield
H
O OH
dipole
H
5
R
R
OPMB
H
dipole
201
CO2Me

These aldols have all had just one chiral centre in the starting material. Should there be more than
one, double diastereomeric induction produces matched and mismatched pairs of substrates and reagents,
perfectly illustrated by the Evans’ aldol method applied to the syn and anti aldol products 205
themselves derived from asymmetric aldol reactions. The extra chiral centre, though carrying just a
methyl group, has a big effect on the result. The absolute stereochemistry of the OPMB group is the
same in both anti-205 and syn-205 but the stereoselectivity achieved is very different. The matched
case favours Felkin selectivity as well as transition state 201 but, with the mismatched pair, the two
are at cross purposes. It is interesting than 1,2-control does not dominate in this case. 33
OHC
OHC
anti-205
syn-205
OPMB
OPMB
198
198
O OH OPMB
O OH OPMB
syn,anti-206
O OH OPMB
O OH OPMB
syn,syn-206
So far we have looked at the enolates of methyl ketones e.g. 198. This has been deliberate in
order to decouple these more remote selectivity issues from those of double bond geometry that
we would also encounter if we were making enolates from, say, ethyl ketones such as 207. In fact,
although we have seen good selectivity, it is easier to obtain selectivity with the added congestion
that arises with ethyl ketones. So, for instance the reaction of methyl ketone 198 leads to an anti
selective product in a ratio of 94:6. Contrast this with the reaction of ethyl ketone 207 where there
are four possible products rather than two and where the selectivity is 95:5 – the ‘95’ being the
major isomer 209 and the ‘5’ being the sum of all the others! Note that the selectivity is observed
without the use of chiral ligands. 35
BnO
The trans double bond in 208 is responsible for the anti relationship between the alcohol and
the adjacent methyl group. In fact, in a study with a variety of aldehydes, the most abundant of the
three minor isomers also has that anti relationship. If we were to have a cis double bond in the enol
borinate instead then we would expect to observe syn relationships here and that is exactly what
happens. That is 1,2-control.
Now, whether this local syn arrangement is anti or syn to the more remote chiral centre in the
enol borinate (1,3-control) can be controlled by the use of one enantiomer or other of a chiral
boron reagent. The cis enol borinate with achiral boron reagent does not have much will of its own
and leads to a 1:1.2 ratio of syn, syn: anti, syn.
BnO
O
Et2O.BF3
Et 2O.BF 3
BnO
OBR 2
+
98:2
+
56:44
BnO
O
anti,anti-206
anti,syn-206
207 E-208: an E-enolate
anti,anti-209; 72% yield
OBR 2
30 Control of Open Chain Stereochemistry 703
R 2BOTf
PrCHO
BnO
O
PrCHO
OH
Pr
BnO
Z-208: a Z-enolate syn,syn-209 1:1.2 anti,syn-209
+
OH
O
Pr
95 : 5
anti,anti:
the rest
OH
Pr

704 30 New Chiral Centres from Old
This is an advantage in that the enantiomers of Ipc (chapter 24) can exert their infl uence. Since
both enantiomers of Ipc are available, we can make the diastereomers of the aldols 209 too using
()- or ()-(Ipc) 2BOTf to make the boron enolates. 36 And of course if ()-(Ipc) 2BOTf gives
syn,syn-209, ()-(Ipc) 2BOTf gives anti,syn-209.
BnO
O OH
anti,syn-210
syn
93 : 7
anti, syn : syn, syn
(–)-Ipc
used
OB(Ipc)2
OHC BnO
OHC
Z-208; R = Ipc
Introduction to 1,4- 1,5- and Remote Induction
cis
syn,syn-210
7 : 93
anti, syn : syn, syn
Hepatitis C is the one that causes liver cancer and more effective treatments are urgently required.
One approach is to discover specifi c protease inhibitors that should prevent replication of
the virus. The Boehringer company 37 have found BILN 2061 211 which they have made by the
strategy outlined in 211.
MeO
N
S
N
NH
O
SN2 ether
C–N
amide H
C–N
amide H
O N
N
O
O
N CO2H O
C=C
metathesis
211; BILN 2061 protease inhibitor
212
MeO
The achiral aromatic part 212 can easily be removed. The rest of the molecule has fi ve chiral centres
in three groups and the best strategy is to assemble each group separately. The amino acid fragment
215 can be made by asymmetric catalytic reduction (chapter 26). Hydroxyproline 213 is from
the chiral pool and the cyclopropane 214 was made as a racemate and resolved. Linking these three
fragments by stereospecifi c reactions (note that two inversions will be needed during ether formation
with 212 to keep the trans arrangement across the ring) or by reactions that do not affect the
chiral centres ensures that the fi nal product has the correct absolute and relative stereochemistry.
Another popular strategy is to use a reagent-controlled reaction to add any further centres
independently of those already present, trusting in the remoteness of the relationship to prevent
any induction. A simple example is the anti-fungal agent ()-PF1163B 216, a compound from
a Streptomyces species. Again a metathesis was added to the obvious disconnections (ester
and amide) to give an amino acid fragment 218, an achiral fragment 219, and the interesting
unsaturated alcohol 217 having a 1,4 relationship between the two chiral centres. 38
H 2N
(+)-Ipc
used
N
CO2H
OH
HO
215
213
BnO
S
N
N
H
NH
CO 2H
O OH
syn
H2N CO 2H
214

O
C–O ester
R
O O
NMe
C–N amide
C=C
metathesis
Me
216; R = n-C5H11; (–)-PF1163B
(S)-Citronellene 220 was available from the chiral pool so an oxidative cleavage gave the aldehyde
221 and the n-pentyl group could be added as an organozinc reagent by the method of Kobayashi 39
using the powerful C 2 symmetric catalyst 222. The catalyst-dominated reaction ignores the chiral
centre already present and gives excellent ee (98%).
Me
220; (S)-citronellene
These strategies are often chosen when relationships are 1,4- or more remote. In 211 and 216
the relationships between the groups of chiral centres are 1,4 at best. However, it is possible to
control 1,4-relationships, and even a few that are more remote, by induction (that is stereoselective
reactions) from existing centres and that is the concern of this part of the chapter. We shall fi rst
look at some relatively simple methods and then return to the aldol reaction.
Remote control by substrate-controlled induction
O
OH
HO2C NMe
OH 218 HO2C
There are probably more different reagents for reducing carbonyl groups than for any other reaction
and some of these are very effective in controlling stereochemistry. 40 Many of these methods
use reagent control but we are concerned with those that induce stereochemistry from an existing
centre. The most famous example is the secondary alcohol in the prostaglandin side-chain. This
is particularly diffi cult as the prochiral ketone in it is separated from the existing chiral centre by
a trans alkene. 41 In the event, 42 the achiral reducing agent 224, a bulky version of DIBAL, gave a
92:8 ratio of diastereoisomers of 225.
O
O
30 Introduction to 1,4- 1,5- and Remote Induction 705
1. mCPBA
(90% yield)
2. H5IO 6
(63% yield)
R
Me
CHO
10 equivs
224
toluene
–78 ˚C
221
R
Me
217; R = n-C 5H 11
(C 5H 11) 2Zn
0.08 equiv
catalyst 222
(i-PrO) 4Ti
Et 2O
R
Me
OH
217; R = n-C5H 11
50% yield, 98% ee
HO
O
HO
OH
Me
223; R = n-C5H11 225; R = n-C5H11 224
O
O
R
t-Bu
O
219
OH
NHTf
NHTf
222
catalyst for
organo-Zn
addition
O Al(i-Bu) 2
t-Bu

706 30 New Chiral Centres from Old
The requirement for such a large excess of 224 suggests that a second molecule binds to the
OH group thus shielding one face of the ketone from reduction 226. Though asymmetric reduction
would now be preferred to this method it is remarkable that such a remote centre (and the OH is
fi ve atoms from the carbonyl group) exerts such a powerful effect.
A more typical early example is Kishi’s polyether antibiotic syntheses using a sequence of epoxides
made by controlled oxidation. The sequence starts with a somewhat similar reduction: LiAlH 4
with the diamine 229 reduces ketone 227 highly stereoselectively in a Felkin sense 230 to give almost
exclusively anti-228 which was resolved as a urethane (chapter 22) to give the enantiomer shown. 43
O
O
R2 Al
R
O
H
226
OAr
MeO
N
H
H
N
229
The hydroxyl group now directs the epoxidation of the nearer alkene using a vanadium directed
delivery of t-BuOOH that gives an 8:1 selectivity. This resembles the last example being 1,4-control
from OH though there is a nearer (1,3) chiral centre. The epoxide was not isolated but cyclised in
situ to the THF 231. This releases a new OH group that directs a second epoxidation and cyclisation
with the same reagents to the bis-THF 232. The stereochemistry of the THFs makes it clear that the
OH is a 1,4-syn directing group for the epoxidations.
228
O
1,4 -Syn induction in the aldol reaction
O
When we discussed how E-enolates of ethyl ketones such as 207 gave 1,3-control in the aldol reaction,
we noted that there was 1,4-control too. Paterson did the same reaction on the corresponding methyl
ketones and found that the lithium enolate (M Li in 234) was unselective. The boron enolate with
an achiral group 9 (M dicyclohexyl-B) was selective giving 88:12 syn:anti-235 in 84% yield but
with a chiral group [M ()-(Ipc) 2B] the stereoselectivity was signifi cantly better 35 (92:8).
BnO
1. t-BuOOH
VO(acac)2
NaOAc
2. HOAc
(+)-233
O
LiAlH 4
229
MeO
Me O
Me
R
H
OH
227 228; 97% yield, >10:1 anti:syn
OH
H Ar
H Ar H OH
230 228 228
1. t-BuOOH
Ar
O
Et OH
VO(acac)2
NaOAc
2. HOAc
Ar
O
Et H
O
Et
OH
231; 75% yield, 8:1 diasts 232; % yield, 5:1 diasts
BnO
234
OM
PrCHO
BnO
O
syn-235
OH
R
=
Pr + anti-235
Me
Ar
H
R

This must be entirely 1,4- control. As these adducts 235 are barely distinguished by 13 C NMR
and could not be separated even by HPLC, high diastereoselectivity is essential. One explanation
is a Houk-like arrangement of the enolate but with methyl ‘inside’ (as the large groups on boron
allow only H to be nearby) with the aldehyde arranged with Pr and BR 2 ‘trans’ 236.
1,4-Control by sigmatropic shifts
Some pages back we described part of a synthesis of macbecin 163 by allyl silane chemistry. An
alternative approach uses sigmatropic rearrangements to transfer and create new chiral centres. 44
The starting material gives a [2,3] Wittig rearrangement 238 after treatment with base. Centres 2
and 3 in the product 239 survive intact. Centre 6 is transposed from 4 by the rearrangement and
centre 7 is created. The new alkene is E and all this is controlled by the chair-like transition state.
This product 239 has two families of adjacent chiral centres 1,4-related across the new E-alkene.
O
N
O
MOMO
237
30 Introduction to 1,4– 1,5- and Remote Induction 707
O
Pr
N
O
H
Ipc
B Ipc
O
H
OBn
236
LDA
O
[2,3]
N
4
O
7
6
3
2
OBn MOMO OBn
OH MOMO
238 239
Further transformations involving the Felkin style creation of a new chiral centre at C-8 allow
a second [2,3]-rearrangement after the exchange of the Bu 3Sn group for Li. Another trans alkene
is formed and the centre at C-8 transposed to C-10.
Bu3Sn
O
239 7
3 1
8 6 2
OMe MOMO OBn
This strategy is generally more effi cient than the direct creation of new centres by, for example,
nucleophilic addition of organometallic compounds to carbonyl groups separated by an alkene
from even such a powerful directing group as an amine. The cis-alkene Z-242 reacts with a range
of organolithiums (R 2 alkyl or aryl) giving syn-243 with usually 90:10 selectivity. Direct coordination
of Li to the amino group in a Houk-like arrangement 244 explains this result. 45
R 1
NBn 2
Z-242
CHO
240
R 2 Li
–100 ˚C
MeLi
[2,3]
R 1 R 2
OH
10
7
6
1
OBn
OMe MOMO OBn
241
Bn2N Li R2
Bn2N HO R1 H O
H
Z-syn-243 244
3
2
1

708 30 New Chiral Centres from Old
The trans-alkene E-242 also gives reasonable stereoselectivity for the syn adduct E-syn-243 but
requires an organocuprate, HMPA in the solution, and the product must be trapped with Me 3SiCl to
get between 80:20 and 90:10 selectivity. One possible explanation is that the alkene-Cu π-complex
245 bridges the longer gap between the amino group and the aldehyde.
R 1 CHO
NBn2
E-242
(R 2 ) 2CuLi, –78 ˚C
HMPA, Et 3N, Me3SiCl
1,5-Induction by the aldol reaction
R 1
NBn2 R2 OSiMe3 R1 R
Bn
Cu
2N
H
H
O
SiMe3
2 R2 E-syn-243 245
Highly 1,5-diastereoselective reactions can be achieved when the β-hydroxy group is present in
the boron enolate of a methyl ketone such as 246 instead of the aldehyde. Notice that we already
have a regioselectivity issue here – the Bu 2BOTf/i-Pr 2NEt combination selectively reacts with
the methyl group and not the methylene group. Reaction with dihydrocinnamaldehyde gives
an aldol 247 with 95:5 anti:syn selectivity. In interesting contrast to the 1,3-diastereoselective
aldols 200 above, silyl enol ethers give no 1,5-diastereoselectivity at all. 32 Selectivity can also
be switched off by replacing the methoxybenzyl protecting group (PMB) with a silyl protecting
group (TBDMS).
PMBO
246
O
1. Bu 2BOTf, i-Pr 2NEt
2. OHC
Ph
PMBO O OH
247; 95:5 anti : syn
The non-selective reactions that result if boron enolates are used in the 1,3 case or if silyl enol
ether are used for a 1,5 case means we can choose to switch off selectivity that might otherwise
clash (mismatch). Boron enolate 248 combines with aldehyde (S)-249 and, in another reaction, its
enantiomer (R)-249. As we do not want the chirality of the aldehyde to be in control, boron enolates
are what we need. The 1,5 anti relationship is controlled in both cases but the 1,3 anti or syn
relationship develops by default and not by control.
OTr
O O
Ph
248
1,3 OFF
1,5 ON
OBBu 2
H
H
O
O
OTBS O
(S)-249
OTBS O
(R)-249
OR
OR
O O
Alternatively we can combine the chiral nucleophiles 252 and 253 and a chiral aldehyde 254,
keeping the chiral aspects of the molecules the same in each reaction, but changing the nature
of the enolate to suit us. Hence 1,5-induction operates when boron enolate 253 is used but 1,3induction
operates with the silyl enol ether 253.
OTr
OTr
Ph
O O
Ph
5
5
anti
O
O
syn
1 3
Ph
OH OTBS O
250; 91:9 85% yield
anti
anti
1 3
OH OTBS O
251; 91:9 85% yield
OR
OR

TrO
TrO
O O
Ph
252
O O
Ph
253
30 The Asymmetric Synthesis of (+)-Discodermolide 709
OBBu 2
OTES
Note the strategy in these two schemes: one enantiomerically pure fragment is being combined
with another enantiomerically pure fragment and, where they join, conditions are selected to
determine which of these fragments controls the new chiral centre. This is a substrate-based
strategy in all respects. One thing we have not done is to use an external chiral factor, such as a
chiral boron reagent, and we will see this strategy now.
We have already mentioned that the use of a silyl protecting group is not effective for 1,5-anti
induction. So, if the boron enolate from 258 reacts with methacrolein, the resulting selectivity
(71:29) is not too bad – though not as good as with a benzyl protecting group 257. An alternative
method of obtaining good stereocontrol, if we want to keep silyl protection, is to introduce reagent
control and replace the achiral boron chloride with ()-Ipc 2BCl. This improves selectivity markedly
with no drop in yield (which is 80% in both cases).
BnO
1,3 OFF
1,5 ON
1,3 ON
1,5 OFF
OTES OP
257; P = PMB
258; P = TBDMS
O
We have already collected some powerful tools for use in stereocontrolled aldol reactions,
but we have not fi nished. We shall see now in Paterson’s synthesis of ()-discodermolide, how
reagent control is used not to enhance the intrinsic substrate selectivity, but to overturn it. The
aldol reaction is undoubtedly one of the most powerful ways of making carbon-carbon bonds and
nature thinks so too. There are numerous natural products that are replete with 1,3 related oxygen
functionality. Many of these are acetate or propionate-derived in nature. The methods detailed
above developed from studies into the syntheses of these natural products. The manipulations of
chiral ethyl ketones of this kind are of particular interest when it comes to natural products that
are polypropionate-derived.
The Asymmetric Synthesis of ()-Discodermolide
H
O OPMB OBn
(S)-254
1. (c-Hex) 2BCl, Et 3N
2.
H
O
O O
As one might expect, there are very many aldol reactions to be found in Paterson’s synthesis 46 of discodermolide
261. The synthesis involves 23 steps (in the longest linear sequence) and the overall yield
is 10.3%. If we naïvely equate the yield with those 23 steps then we have an average yield in every
step of around 90%. Several other groups are interested in the synthesis of discodermolide. 47,48
TrO
TrO
BnO
Ph
O O
Ph
5
5
anti
O OH
O OH
syn
1 3
255; 96:4 81% yield
syn anti
1 3
256; 82:18 66% yield
OTES OP O OH
259; P = PMB 91:9 anti:syn
260; P = TBDMS 71:29 anti:syn
1. (–)-Ipc 2BCl, Et 3N 260; P = TBDMS 90:10 anti:syn
OPMBOBn
OPMBOBn

710 30 New Chiral Centres from Old
O
O
OH
HO
a
OH
OH O O
Although the molecule contains thirteen chiral centres, the synthesis starts with only three.
They are ethyl ketones 262, 263 and 264. Discodermolide is retrosynthetically divided 261 into
three sections and all of the chiral centres in each of these sections derive from one of the ketones.
Ketones 262 and 263 differ only in the nature of the protecting benzyl group.
BnO
O
(S)-262
We shall not go through every detail of the synthesis – you are directed to the paper for that –
but we will highlight three details. Firstly, there is the reaction of 262 which (in one pot!) is
transformed into the advanced intermediate 265 in 86% yield and 97% diastereomeric excess.
Secondly, there is the late-stage coupling of fragments (the C–C bond made is disconnection ‘b’ in
261) and fi nally there is the overturning of selectivity by reagent control that we alluded to earlier.
BnO
So, to kick off, ketone 262 is reacted to form trans boron enolate 266 that combines with acetaldehyde
to give the intermediate 267. The 1,2-anti stereocontrol comes from the enolate geometry
and the chiral centre of the original ketone imposes the 1,3-anti control in the way we have seen
already in this chapter. The intermediate 267 is reduced without working the reaction up and the
boron removed to give 268.
BnO
The newly formed chiral centre bearing the alcohol in 266 determines the new 1,3-anti relationship
that develops as the carbonyl is reduced by LiBH 4. Hydride attacks axially 269 (as in Chapter 21).
b
NH 2
261;
(+)-discodermolide
PMBO
OBz
O
O
(S)-263 (S)-264
aldol stereoselective
BnO
MeCHO
reduction
O
OH OH
(S)-262 265; 86% yield, >97% ds
MeCHO
BnO
1,3-anti
O
BR2
O
B
O
E-266; R = cyclohexyl
R2
267
1,2-anti
1. LiBH 4
–78 ˚C
2. H 2O2
NaOH
BnO
268
OH
OH

The alcohol that resulted from the aldol reaction is oxidised later (on the way to 270) and so one
chiral centre is destroyed after it has done its work.
Recently formed
chiral centre
Me Me
Hydride arriving
with axial attack
H R
H
O
B
R
O
R
269
268 MeO2C
TBDMSO O
With all this boron enolate chemistry it is easy to forget some of the older enolate methods
that are still available. The use of an ester containing a hindered phenolic group has been seen
before in Chapter 21 to control the formation of trans enolates so that anti aldol products may be
produced. It is used here to couple two fragments in just that way. Ester 271 reacts with the
hindered base LiTMP (in combination with LiBr) to give trans enolate 272 which was combined
with aldehyde 273 to give 49 the aldol adduct 274.
PMBO
H
OH
O OPMB
30 The Asymmetric Synthesis of ()-Discodermolide 711
271
O
O
272
PMBO
LiTMP
LiBr
PMBO
The syn selectivity is controlled by the double bond geometry of the trans enolate 272
whereas the more remote aspects of the stereocontrol are controlled by the molecules themselves.
Just a note at this point: we normally associate trans enolates with anti aldol products –
the product observed is called syn only because of the way it is drawn, there is nothing unusual
here 275. The chiral centres in the enolate 272 are too remote to be effective and it is those in the
aldehyde 273 that control the more remote aspects of stereochemistry. If we want to explain this
selectivity, we need to have a reason for why one diastereotopic face of the aldehyde is attacked
and not the other. As might be expected, the aldehyde reacts with Felkin-Anh selectivity as described
earlier in this chapter.
Our fi nal highlight in the discodermolide synthesis is the use of reagent control to get what we
want and not what the molecules want. The combination of enol borinate 276 and an aldehyde
277 featuring a cis double bond, led to the formation of aldols anti- and syn-278. A model study
had shown that the inherent selectivity with these enals could be improved by the use of ()-
Ipc groups on boron instead of cyclohexyl but it is not the selectivity that was wanted. ()-Ipc
groups were able to turn around the selectivity and improve the yield of the reaction while they
were at it. 50
ArO
syn
273 OH 274
OH
272; trans-enolate
O
syn
OH OPMB
270
OAr
RO
OLi
O OH
anti-275
RO
O
OH
'syn'-275
REDRAW

712 30 New Chiral Centres from Old
MeO 2C
The tricky thing with a mismatched situation is that you do not know whether you will win
(with reagent control) or whether the molecules will get their way (substrate control) but either way
the result will be the product of a confl ict. It is all the more impressive, therefore, when good levels
of reagent control can be achieved in a mismatched situation.
Making discodermolide on a large scale
Discodermolide is a promising anti-cancer drug and the Novartis company decided to blend the
best parts of the published academic syntheses with their own ideas and make 60 grams of the
compound for clinical trials. This was a decision necessitated by the very meagre supply from
natural sources but a bold decision too as a large scale synthesis of such a complex molecule was
without precedent. Discodermolide has three Z-alkenes and 13 chiral centres with, at fi rst sight,
no particular pattern. Smith noticed 47 that there were three repeating triads of centres marked with
circles in 261a and that each of these might be made from a ‘common precursor’ 279.
O
BR2
O
O
OH
HO
O
OTBDMS
anti-276
H R'
TBDMSO
277
OH
MeO 2C
R = c-Hex (67% yield)
R = (+)-Ipc (87% yield)
261a;
(+)-discodermolide
HO
O R'
TBDMSO
TBDMSO
anti-278 syn-278
OH O O
TBDMSO
The Novartis company decided to use 279 as starting material for three fragments 280, 281 and
282 and to use Paterson’s aldol methodology (described above) to link them together and complete
the synthesis. 51 In the event, they modifi ed the original plan in many ways to make the synthesis
practical. Key points were the production of 279 without chromatography, the conversion of 279 to
281 via all crystalline intermediates, a Suzuki coupling (chapter 18) and a Still-Gennari Z-alkene
synthesis (chapter 15) and many other reactions already treated in this book.
NH 2
88:12
16:84
MeO 2C
O R'
OMe
PMBO N Me
OH
TBDMSO
O
279;
Amos Smith's
'common precursor'
OMe
PMBO
I
N
Me
TBDMSO
O O OTBDMS
O OR O
280
Ar
281; R = p-MeOC6H4 282; R = TBDMS
+
HO

Though improvements continue to appear, such as a revised route to the lactone portion, 52 and
no doubt will continue to appear, this is a staggering achievement involving 43 chemists and you
are particularly directed to the fi fth paper in the series. 51 Commenting on the synthesis as a whole
they say: ‘The success of this project and its chemistry paves the way for other, perhaps even more
complex, natural products to be prepared for early-phase clinical evaluations and sends a positive
message to both the isolation and synthetic academic community and possibly other pharmaceutical
companies that; “your work need not just be of academic interest” and it may be worth taking
a few risks.’
Conclusion
Creating more chiral centres with enantiomerically pure rather than racemic starting materials is
different in some important ways.
1.
2.
3.
Remote diastereomeric relationships can be controlled by using enantiomerically pure components
when it is impossible to control them by diastereoselective reactions.
Double diastereodifferentiation (using enantiomerically pure reagents and substrates) can
enhance diastereoselectivity if we have a matched case, but can erode it if we have the mismatched
case.
It is important to check the ee of the fi rst product formed with extra chiral centres. There are
three considerations here:
(a) The starting material may racemise under the conditions of a reaction.
(b) Coupling a starting material that is racemic or of low ee to an enantiomerically pure
starting material may allow effective resolution of the product.
(c) Once two or more chiral centres are in place, the enantiomeric purity of the molecule can
be checked by ordinary NMR spectra as epimerisation leads to a diastereoisomer and
simultaneous epimerisation of two or more centres without forming another diastereoisomer
is unlikely (though not unknown).
References
30 References 713
General references are given on page 893
1. A. G. Schultz, M. A. Holoboski and M. S. Smyth, J. Am. Chem. Soc., 1996, 118, 6210.
2. P. D. Bailey and J. S. Bryans, Tetrahedron Lett., 1988, 29, 2231.
3. D. R. Adams, P. D. Bailey, I. D. Collier, J. D. Heffermann and S. Stokes, Chem. Commun., 1996, 349.
4. O. Ort, Org. Synth., 1983, 63, 203.
5. F. Zhang, Z. J. Song, D. Tschaen and R. P. Volante, Org. Lett., 2004, 6, 3775.
6. G. J. Tanoury, R. Hett, S. Wilkinson, S. A. Wald and C. H. Senanayake, Tetrahedron: Asymmetry, 2003,
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7. S. Randl and S. Blechert, J. Org. Chem., 2003, 68, 8879.
8. G. Fráter, Helv. Chim. Acta, 1979, 62, 2825, 2829.
9. D. Seebach, J. Aebi and D. Wasmuth, Org. Synth., 1983, 63, 109.
10. G. Fráter, Helv. Chim. Acta, 1980, 63, 109.
11. H.-M. Shieh and G. D. Prestwich, J. Org. Chem., 1981, 46, 4319; A. R. Chamberlin and M. Dezube,
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714 30 New Chiral Centres from Old
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30 References 715
51. S. J. Mickel, D. Niederer, R. Daeffl er, A. Osmani, E. Kuesters, E. Schmid, K. Schaer, R. Gamboni, W.
Chen, E. Loeser, F. R. Kinder, K. Konigsberger, K. Prasad, T. M. Ramsey, O. Repic, R.-M. Wang, G.
Florence, I. Lyothier and I. Paterson, Org. Process Res. Dev., 2004, 8, 122.
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2005, 70, 150; A. B. Smith, B. S. Freeze, M. J. LaMarche, T. Hirose, I. Brouard, P. V. Rucker, M. Xian,
K. F. Sundermann, S. J. Shaw, M. A. Burlingame, S. B. Horwitz and D. C. Myles, Org. Lett., 2005, 7, 311;
S. J. Mickel, R. Daeffl er and W. Prikoszovich, Org. Process Res. Dev., 2005, 9, 113.

31
Strategy of Asymmetric Synthesis
This chapter examines the asymmetric synthesis of compounds that have been made by several different
methods and assesses the factors that make one synthesis the most favourable. It also revises material
from the rest of this section (chapters 20–30)
Introduction: Strategy of Asymmetric Synthesis
PART I – (R) AND (S)-2-AMINO-1-PHENYLETHANOL
Methods rejected for development
Methods considered for development and tried experimentally but rejected
A successful large scale asymmetric synthesis by resolution
PART II – (2S,4R)-4-HYDROXYPIPECOLIC ACID
A simple heterocyclic acid needed for an anti-HIV drug
A chiral pool synthesis from aspartic acid
Choosing a new reaction to solve the stereochemistry problem
Making the new reaction asymmetric
PART III – GRANDISOL AND SOME BICYCLO[3.2.0]HEPTAN-2-OLS
A bicyclic insect attractant used in agriculture
Chiral Pool Syntheses from Other Terpenes
An attempt from linalool
An attempt from citronellol using carbene chemistry
Asymmetric Synthesis
Asymmetric addition of an organo-zinc to an aldehyde
Synthesis by asymmetric dihydroxylation of a non-conjugated diene
A Disappointment and a Resolution
PART IV – METALLOPROTEINASE INHIBITORS
A group of compounds that protect cartilage from enzymatic degradation
Asymmetric alkylation of Evans’s chiral enolates
Asymmetric synthesis from an enantiomerically enriched hydroxy-acid
PART V – CONFORMATIONAL CONTROL AND RESOLUTION: KINETIC OR NOT?
A tetrahydropyran that inhibits leukotriene biosynthesis
Asymmetric synthesis of 2-methyl-tetrahydropyran-4-one by kinetic resolution
PART VI – ASYMMETRIC DESYMMETRISATION OF A DIELS-ALDER ADDUCT
Ifetroban sodium: a thromboxane receptor antagonist
A laboratory synthesis starting with a Diels-Alder reaction
Desymmetrisation of a symmetrical anhydride with a chiral Grignard reagent
Laboratory and process routes compared
PART VII – ASYMMETRIC SYNTHESIS OF A BICYCLIC β-LACTONE
Lactacystin: a natural proteasome inhibitor
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

718 31 Strategy of Asymmetric Synthesis
Strategies used in the synthesis of lactacystin, the β-lactone, and analogues
PS-519: A lactacystin analogue
A chiral pool synthesis of lactacystin from glucose
Chiral pool syntheses of lactacystin from amino acids
The reagent strategy: asymmetric epoxidation and asymmetric allylboration
Enzymes as reagents in the synthesis of lactacystin analogues
Syntheses of 3-hydroxyleucine by other strategies
A large-scale synthesis of lactacystin analogues using AD and an asymmetric aldol reaction
Introduction: Strategy of Asymmetric Synthesis
In the last seven chapters we have introduced the main approaches to the synthesis of single enantiomers.
In this chapter we gather together those ideas and consider why anyone should choose one
of these approaches rather than another. We shall look at simple and not-so-simple compounds that
have been made by different routes. We shall examine why chemists rejected some of those routes
and preferred others. Some compounds will be needed for laboratory syntheses on a small scale:
others for commercial production on a large scale and different criteria will apply to these two
situations. These are strategic considerations and the main point will be, as it always is, to get high
yields in few steps with maximum selectivity. Here though the enantiomeric excess achieved by
the different methods will also be important. We start with a very simple compound. More complicated
molecules are considered in detail in Nicolaou and Sorensen, a book we highly recommend.
PART I – (R) AND (S)-2-AMINO-1-PHENYLETHANOL
This simple compound 2 was needed by Novartis Pharma Inc. (Basel) for the preparation of a
new class of anti-diabetic agents 1. Both enantiomers were needed on a large scale to explore the
relationship between stereochemistry and biological activity. 1
OH
H
N
Alk
Methods rejected for development
Ph
reductive
amination
OH
NH2 O
+
1; anti-diabetic drugs 2; 2-amino-1-phenylethanol
The fi rst step is to search the literature. Many methods had already been published but four of these
were immediately discarded as being unsuitable for scale-up. Asymmetric reduction (chapter 26)
of the amino-ketone 3 required ligands that were not available and would themselves have to be
the subject of asymmetric synthesis. Then pressures greater than 50 atmospheres were needed to
reduce the rather stable carbonyl group and even then ees were about 93% at best and usually much
lower. Finally the turnover was slow so a lot of catalyst would be needed to make an effi cient process.
An alternative to chemical reduction would be baker’s yeast (chapter 26). This gave only one
enantiomer and required high dilution to be effective. Even then there was a very low throughput.
O
O
OH
H2/cat baker's yeast
NH2
2
NH2 NH2 Ph
Ph
Ph
3
3 (R)-2
Alk
Ph

Ph
The racemic amino alcohol 2 was easy to prepare so one obvious choice is an enzyme-catalysed
acylation or deacylation process (chapter 26). These worked reasonably well. Deacylation of the
ester-amide 6 gave the amide 5 which was diffi cult to hydrolyse. Acylation gave the monoester 4
but this equilibrated rapidly with the same amide 5. Both gave the same enantiomer of the amino
alcohol and of course the maximum yield is only 50%.
Ph
OH
rac-2
NH2
enzyme
Ph
R
O O
NH 2
Finally they rejected the crystallisation of a conglomerate. It was known that the salt between
the amine 2 and m-aminobenzoic acid formed a conglomerate that could be crystallised with seeding
of either enantiomer (chapter 22) but only from the rather expensive solvent THF. In any case
the yield was only moderate and the ees too low to make this method worthwhile.
Methods considered for development and tried experimentally but rejected
Two methods were promising enough for serious consideration but were eventually rejected on
practical grounds. They both amount to chiral pool strategies (chapter 25) though the fi rst starting
material, styrene oxide 7, is not a natural product. Both enantiomers of 7 are commercially
available.
O
7; (R)-(+) styrene
oxide
Treatment of styrene oxide with ammonia in methanol gave mostly (R)-2 by nucleophilic attack
at the less hindered end of the epoxide. However, some of the regioisomer 8 was formed by attack
at the benzylic carbon and this proved diffi cult to remove. Crystallisation of the salt 2.HCl and
neutralisation gave the best samples (99% ee) of (R)-2 but only in 43% yield and still contaminated
with about 3.5% of the impurity 8. This is not good enough.
Mandelic acid 9, available as both enantiomers, was used to make the other enantiomer, (S)-2,
for a change. The cyclic acetal ester 10 reacted with ammonia to give a good yield of the amide
11 but with signifi cant racemisation. Worse, reaction with LiAlH 4 gave incomplete reduction
even with a large excess of reducing agent so that the product, (S)-2, was contaminated with
large amounts (about 30%) of unreacted amide 11. Complete reduction could be achieved with
a large excess of borane to give 90% (S)-2, without racemisation, but this is not practical for
scale-up.
Ph
O
OH
4 5
NH
R
enzyme
OH
OH
NH3
MeOH Ph
NH2 HCl
Ph
NH3 Cl
crystallise
EtOAc
NaOH, H2O
toluene
(R)-2; 70% yield
(R)-2.HCl
OH
Ph CO 2H
9; (S)-(+)mandelic
acid
O
H2SO4
31 Introduction: Strategy of Asymmetric Synthesis 719
Ph
O
O
NH 3
EtOH
Ph
OH
NH2
O
O
10; 80% yield 11; 87% yield
LiAlH4
THF
Ph
Ph
OCOR
rac-6
(R)-2
43% yield
99% ee
OH
NHCOR
Ph
NH2 +
(S)-2; 60% yield
93% ee
NH2
OH
8; main
impurity
11
30%
yield

720 31 Strategy of Asymmetric Synthesis
A successful large scale asymmetric synthesis by resolution
Initially resolution looked the least promising of all strategies. Resolution with tartaric acid was
known but the best that could be done was a 3.7% yield of material with 63% ee. Trials with ten
other acids gave better results, e.g.: (fi gures in brackets are ees after one recrystallisation) camphoric
acid (38%), pyroglutamic acid (67%), Boc-alanine (69%). However the best resolutions
were with acyl derivatives of tartaric acid and the very best was di-p-toluoyl tartaric acid (12;
DPTTA). The salt from technical grade racemic 2 with DPTTA was crystallised from aqueous
iso-propanol on 100 g scale giving eventually 80% yield of (R)-2 with 99.8% ee. This has now
been scaled up to 9 kg and is the method chosen for production.
PART II – (2S,4R)-4-HYDROXYPIPECOLIC ACID
A simple heterocyclic acid needed for an anti-HIV drug
The HIV protease inhibitor palinavir 13 (from Bio-Méga/Boehringer, Québec) is a complex molecule
that can be disconnected simply to fi ve components. Two of these (14 and 18) are simple
achiral aromatic compounds and two can be derived from the chiral pool (chapter 25): the amino
acid valine 15 and an epoxide 16 derived from phenylalanine. The fi fth 17 is the subject of this
section. This compound has two chiral centres so we must fi rst produce the right (syn-) diastereoisomer
and then the right enantiomer.
C-N
N
H
N
N
H
A chiral pool synthesis from aspartic acid
O
O
Though (2S,4R)-4-hydroxy pipecolic acid 17 is a natural product it cannot be obtained in
suffi cient quantity from nature. A chiral pool synthesis from aspartic acid 19 is known involving
Ph
OH
O
N
H
N
amide C-N amide C-C 1,2-diX C-O ether
H 2N CO2H
HO 2C
O
CO 2H
O O
12; di-p-toluoyl tartaric acid (DPTTA)
N CO2H H2N O
OH
14 15; valine
16
17 18
O
Ph
HN
O
CO 2H
13; palinavir
an HIV protease
inhibitor
X
N
N

a Pd-catalysed coupling of a vinyl stannane to an acid chloride. 2 This works well, but stoichiometric
toxic tin is not acceptable in production.
HO
O
H 2N CO 2H
19; (S)-Laspartic
acid
Et 2O.BF 3
F 3C
O
N
O
F3C CF3
O
CF3 22
O
An important point from this synthesis is the transmission of chiral information (chapter 30)
from the acid group in 23 to the OH group in 17 by reduction with the bulky reagent K-selectride.
This sterically demanding reagent prefers an equatorial approach (chapter 21) and we can therefore
deduce that the CO 2H group in 23 and both the CO 2H and OH groups in 17 are axial. The
CO 2H group adopts an axial conformation in 23a because the planar and conjugated (to N) Boc
group would eclipse an equatorial CO 2H group. This information is vital for other syntheses.
Boc
N
Choosing a new reaction to solve the stereochemistry problem
H 2O
HO
F 3C
O
HN
O
A simple reaction that creates both chiral centres in one step was already in the literature. 3 It is a
cross between a Mannich and a Prins reaction involving the condensation of an unsaturated amine
24 with glyoxylic acid (25; available as an aqueous solution - fortunately the reaction works in
water) to give a heterocyclic bridged lactone 26 with the right relative stereochemistry (but of
course racemic).
NH
R
24
31 Introduction: Strategy of Asymmetric Synthesis 721
CO2H
23a
O
O
CF3 20
O
2.
SnBu 3
i-PrOH [K(s-Bu)3BH]
N CO2H K-Selectride
[K(s-Bu) 3BH]
H
23
Boc
O
N
1. SOCl 2
BnPdCl(PPh3) 2
K-Selectride
OH
CO2H
17a
H
OH
F 3C
OH
O
HN
N CO 2H
H
(2S,4R)-17
H atom
added
equatorial
CHO
heat 6M HCl
+
O
CO2H H2O reflux
MeCN N
25
N CO2H glyoxylic
R
R
acid 26 27
O
CF3 21
O

722 31 Strategy of Asymmetric Synthesis
Presumably the aldehyde forms an iminium ion 28 with the amine and this is attacked by the alkene.
One way to draw this would be 28 → 29 but it looks better to have concerted attack by the CO 2H group
on the cation as it is formed 30. At all events, the lactone 26 must have a 1,3-diaxial bridge 26a.
N CO2H N CO2H R
N
R
N
R
R
28 29 30
26a
Making the new reaction asymmetric
The workers at Bio-Méga/Boehringer turned this promising reaction into an asymmetric synthesis.
4 They fi rst tried resolution of 26 with R benzyl as the group ‘R’ on nitrogen must be
removable. The amine 24; R Bn could be made in only 41% yield - dialkylation was a problem.
The new reaction with glyoxylic acid worked well and the lactone 26; R Bn could be resolved
with a 55% amount (see chapter 22) of a bromocamphor sulfonic acid 31 but the yield was only
30% making it 12% overall from but-3-en-1-ol (see below) and the ee was not perfect (95.4%).
However, they did fi nd that the lactone could be hydrolysed to 27; R Bn without loss of stereochemical
integrity.
HO 3S
31
O
H
Br
2. NH 4OH
Their method of choice was part asymmetric induction and part resolution. The benzyl group
was replaced by the chiral α-methylbenzyl group. This reduced dialkylation in the formation of
the allylic amine 32 and allowed modest asymmetric induction in the formation of the lactone:
33 was 60:40 ratio of diastereoisomers. Crystallisation of the salt of 33 with the same sulfonic acid
31 completed the separation of one diastereoisomer and this gave 17 in good yield and essentially
perfect ee. Note that the yield of pure 33 (41%) is actually quite good as the crude sample contained
only 60% of the right diastereoisomer. The α-methylbenzyl group is removed by hydrogenation
but its chirality is destroyed as it gives ethylbenzene. Recent work (discussed in the Workbook) at
Chirotech leads to both enantiomers of both diastereoisomers. 5
OH
26
R = Bn +
1. TsCl, Et 3N
2.
Ph
NH 2
NH
Ph
32
CHO
CO2H 26
1. crystallise salt from
MeOH/EtOH/EtOAc
(30.8% yield)
O
O
heat N
H2O MeCN
Ph
33; 67-72% yield
60:40 diasts
HO
1. crystallise
sulfonate salt
with 31
2. NH 4OH
N
O
O
O
Bn
26; R = Bn
30% yield, 95.4% ee
N
O
Ph
33; 41% yield
96.4% ee
6M HCl
reflux
O
27
1. H2/Pd(OH)2 O
2. 6M HCl
reflux
3. ion-exchange
resin
O
17;
88% yield
99.8% ee

PART III – GRANDISOL AND SOME BICYCLO[3.2.0] HEPTAN-2-OLS
A bicyclic insect attractant used in agriculture
A modern approach to dealing with insect pests that wreck crops is to use specifi c attractants
to lure the pest to its doom while offering no threat to benefi cial creatures. Compounds such as
grandisol 34 are not themselves toxic but they are irresistible to specifi c insect pests. Grandisol,
marketed as ‘grandlure’, an attractant for male cotton boll weevils, is one of a family of unusual
monoterpenes containing a four-membered ring. Others are lineatin 35, an attractant for ambrosia
beetles that bore into conifers, fi lifolone 36, and raikovenal 37 (a sesquiterpene).
HO
H
Chiral Pool Syntheses from Other Terpenes
An attempt from linalool
O
O
H
34; (+)-grandisol 35; (+)-lineatin 36; (–)-filifolone 37; raikovenal
This subject has recently been reviewed 6 and we shall concentrate on the different approaches to
grandisol outlined in that review. Many of these approaches can clearly be used for the other compounds.
An early approach was a chiral pool strategy from the simpler and commercially available
terpene (R)-()-linalool 38. Though this did not lead to a useful synthesis, it pointed the way to effective
methods, particularly the Cu(I)-catalysed photochemical closure of the four-membered ring.
OH
38; 3R-(–)-linalool
31 Chiral Pool Syntheses from Other Terpenes 723
The photochemical closure by a 2 2 cycloaddition of the two alkenes in 39 gave one diastereoisomer
of 40. The cis ring junction is inevitable and the rings fold so that the methyl group at the third
centre is exo to the fold though the Cu(I) catalyst may be important for this. The bicyclic ring system in
40 makes it a useful precursor for compounds 35–37. The next step is an unusual elimination catalysed
by HMPT [(Me 2N) 3P]. The main product is the cyclic alkene 44 that gives the required intermediate
42 after ozonolysis but signifi cant amounts of the exo-methylene compound 43 are also produced.
40
6 steps
1. HMPT
heat
OH
hν
CuOTf
HO
H
H
H
O
1. HMPT,
heat
2. O 3
3. Zn
4. Jones
H
H
O
H
H
CHO
HO 2C
OH
39 40 41 3:7 ratio 42
43
H H
+
3:7 ratio
44
2. O 3
3. Zn
4. Jones
42
+
O
H

724 31 Strategy of Asymmetric Synthesis
What really makes this synthesis useless is that it would give the wrong enantiomer of grandisol
(see the ring junction stereochemistry). While (R)-()-linalool is available in 100% ee, the
(S)-()-enantiomer is both more expensive and available in only 64% ee.
An attempt from citronellol using carbene chemistry
Citronellol 45 is a useful source of an isolated unfunctionalised chiral centre (chapter 23). It can be
transformed into the ester 46 and then into the diazosulfone 47 by standard chemistry. 7 Now comes
the interesting bit: an alternative to photochemistry for four-membered ring formation. Rhodium
carbene complexes can be made from diazocompounds and insert into CH bonds, particularly if a
fi ve-membered ring can be formed. This one inserts into the chiral centre of 47 and does so with
retention as expected. The centre might appear to be inverted because it is drawn differently in
the two compounds. The chain is kinked downwards at the chiral centre in 47 but upwards in 48.
Conversion of the MeO group into a leaving group and cyclisation give the [3.2.0] bicyclic system
with the right absolute stereochemistry but still having the sulfone attached. Compound 50 was
converted into grandisol but the synthesis is very long (11 steps from 46) and contains an elimination
step like that in the previous synthesis (from 40) but even less regioselective. Try again.
Asymmetric Synthesis
Asymmetric addition of an organo-zinc to an aldehyde
There are many examples of asymmetric addition of organo-metallic reagents to aldehydes (chapter
27) and the one that works here uses Seebach’s TADDOL 51 as a ligand for zinc. 8 The TAD-
DOL 51 is prepared from tartaric acid and used as its titanium (IV) complex to catalyse the addition
of the organozinc compound to acrolein. After photochemical cyclisation in the presence of
Cu(I), the bicyclic alcohol 53 was isolated in good yield and 98% ee.
O
O
Ar Ar
H
H
Ar Ar
OH
OH
51; a TADDOL
Ar = 2-naphthyl
OH CO 2Me
O HO
1. ZnCl2 MgBr
OMe 2. NaN3, HOAc
OMe
2. Ti(OPr i ) 4
TADDOL 51
3. –30 ˚C
acrolein
52; 51% yield
ee >98%
hν
CuOTf
O
N2
SO2Ph 45; (R)-(+)-citronellol 46; 81% yield
47
Rh2(OAc) 4
O
H
SO2Ph
48; 60% yield
OMe
O
1. PhSO 2CH 2Li
H O
SO
SO
2Ph
2Ph
49
I
HO
H
50
53; 95% yield

The remainder of the synthesis involved destruction of the original chiral centre from 52 and
regioselective elimination. Several more steps were needed to give optically pure grandisol. The
most interesting are the regioselective oxidation of the silyl enol ether 55 and the ingenious elimination
that avoids formation of the exo-methylene compound 43 by an unusual base-catalysed
elimination on a tertiary ether 57. This process is too long for further development.
53 Cr(VI)
O
H
54; 69% yield
Me 3SiO
Synthesis by asymmetric dihydroxylation of a non-conjugated diene
Since the alcohol 39 is already known as a precursor for the wrong enantiomer of grandisol, an
asymmetric synthesis of the right enantiomer would complete an effi cient synthesis. The diene 58 is
an ideal substrate for a Sharpless asymmetric epoxidation - reaction occurs only at the allylic alcohol
(chapter 25). Two stage conversion of the OH into an iodide and treatment with zinc leads to an
elimination 60 and the correct enantiomer of the tertiary alcohol 39 for conversion to grandisol. 9
58
1. LDA
2. Me3SiCl A Disappointment and a Resolution
H
55; 94% yield
All the methods so far described use either a photochemical cycloaddition or a transition metal
carbene complex. Neither is well adapted to large scale production. The workers at Bologna 7
sought a new method. They found it in a thermal cycloaddition of a ketene and an alkene. The
mixed anhydride 62 gave a single diastereoisomer of the bicyclic ketone 63 in 82% yield simply
on heating. No UV light, no metals.
OH
O
60
31 A Disappointment and a Resolution 725
CO 2H
OH
Ac2O
AcOK
ZnI
1. O 3
2. NaBH4
3. H +
They then tried the same reaction on a single enantiomer of the alcohol 61 but to their great
disappointment found only racemic product. It appears that this is indeed a 2 2 cycloaddition of
the ketene 64 and this is an achiral molecule. However, reduction of the ketone with LiAlH 4 gave
O
1. (+)-DIPT, t-BuOOH
Ti(Oi-Pr) 4 etc
2. (MeO) 3P, TsCl,
DMAP, Et 3N
OAc O
61 62
O
H
56; 73% yield
1. MeLi
(71%)
1. TsOH
(51%)
O
O
57
59; 94% yield, >95% ee
H
OTs
OH
(S)-(+)-39, 80% yield, >95% ee
OAc
reflux
4 hours
H
1. LDA
2. H +
Zn/Cu
O
63; 82% yield
NaI
43
64% yield

726 31 Strategy of Asymmetric Synthesis
only the endo alcohol 65 (the reagent approaches on the outside of the folded molecule) and this
could be resolved effi ciently with camphanic acid chloride 66.
64
C O H
H
O
racemic 63
THF
–65 ˚C to RT
The rest of the synthesis is straightforward but you should notice the catalytic Ru(III) oxidation
used both on 65 and 67, the periodate cleavage to replace ozonolysis in the formation of 68 and the
Peterson reaction (chapter 15) used to make the alkene 69. This method was used for the synthesis
of quantities of both enantiomers of grandisol 34.
PART IV – METALLOPROTEINASE INHIBITORS
A group of compounds that protect cartilage from enzymatic degradation
Arthritis attacks all of us who live long enough. The stiffness in the joints arises because the
collagen that lubricates them is eaten away by over-enthusiastic zinc-dependent enzymes known
as metalloproteinases. One possible therapy for arthritis is inhibition of these enzymes by compounds
such as ‘Trocade’ 70 and ‘Marimastat’ 71.
HO
N
H
O
HO 2C
H
OH
O
H 1. SiMe3 68; 71% yield
O
N
MgCl
LiAlH 4
H
(+)-65 (+)-63
N
Me
O
O
TPAP
NMO
N
2. SOCl 2
HO 2C
70; Ro 32-3555
'Trocade'
Cartilage
Protective
Agent
O
OH
65; 97% yield
1. NH2NH2
H
69; 81% yield
2. KOH
HO N
H
LiAlH4
Et 2O
O
67
H
HO
O
O
COCl
66; (1S)-(–)-camphanic
acid chloride
RuCl 3/NaIO4
t-BuOH/H 2O
H
(+)-34; 82% yield
OH O
H
N
O
71; BB-2516 'Marimastat'
Cartilage Protective Agent
NHMe

These drugs are clearly peptide mimics having a genuine amide portion to the right as drawn,
a hydroxamic acid to the left and a core that binds zinc and acts as a transition state mimic for the
peptide cleavage. They have a C–C bond instead of the amide linkage in the natural substrate so
that the drug cannot be hydrolysed by the metallopeptidase. This is easily seen if we disconnect
71a to show the amino acid tert-leucine 73 and a derivative of succinic acid (butanedioic acid) as
the core 72. A similar core is present in trocade 70. We shall discuss the asymmetric synthesis of
both core succinates.
HO N
H
O
OH
O
H
N
Asymmetric alkylation of Evans’s chiral enolates
O
NHMe
HO 2C
CO2H
The succinate core can be prepared by alkylation of a simple carboxylic acid (74a or b) with
a bromoacetate using the Evans oxazolidinone chiral auxiliary derived from phenylalanine
(chapter 27). The branched alkyl group must be present in the substrate for alkylation
and the second acid group added in the alkylation so that there is no competition between
two carbonyl groups during enolate formation. After hydrolysis (91% yield) the alkylated
succinic acid 77 has 95% ee. Notice that the two acid groups are differentiated by this
procedure. 10
2.
71a
1. NaHMDS
THF, –78 ˚C
Br CO 2t-Bu
31 A Disappointment and a Resolution 727
CO2H
2 x C–N
amides
74a 74b
t-BuO2C
O
N
O
Direct alkylation of the enolate of 77a; R cyclopentyl with the alkyl halide 78 was not
very diastereoselective so an alternative route was used to allow equilibration to the more stable
isomer. 11 Carboxylation of the enolate gave 79a and alkylation of this malonate gave a good yield
of 80. The benzyl esters were cleaved by hydrogenation and the malonate decarboxylated to give
the required anti isomer of 81 in a 4:1 ratio with its syn diastereoisomer. Conversion into ‘Trocade’
is straightforward.
OH
72; chiral succinate
derivative
CO 2H
O
LiOH
H 2O 2
t-BuO2C
+
Ph
75
Ph
76 77
H2N
O
O
NHMe
73; derivative
of tert-leucine
N
O
CO2H
O

728 31 Strategy of Asymmetric Synthesis
t-BuO 2C
t-BuO 2C
BnO 2C
77a or b
79a or b
R
CO 2H
R
CO 2Bn
1. 2.02 x LDA
2. ClCO2Bn
3. BnBr
Cs2CO 3
2. O
1. NaH
N
N
Me
78
O
Br
t-BuO2C BnO2C CO 2Bn
Asymmetric synthesis from an enantiomerically enriched hydroxy-acid
O
N
O
N
Me
80
t-BuO2C
1. H2, Pd/C
2. heat
O
N
O
N
Me
81
CO 2H
An alternative route to 79b involved nucleophilic displacement from an enantiomerically pure
hydroxy acid 82 with a malonate enolate. The OH group was activated as a trifl ate 83. This method
depends on the availability of optically pure hydroxyacid. 12 Notice that the ‘wrong’ enantiomer of
82 must be used as inversion occurs during the S N2 reaction leading to 79b.
HO
O
OH
82; 2-(R)-hydroxyacid
TfO
O
However intermediate 81 is made, the rest of the synthesis involves coupling the free acid
to piperidine using a carbodiimide to give 84, removing the t-butyl group to free the other acid,
coupling that acid with a protected (O-benzyl) hydroxylamine and removing the protecting
group.
81
HN
EDAC
(carbodiimide)
HOBt
1. BnBr, Et 3N
EtOAc, reflux
2. Tf 2O,
pyridine
83
t-BuO 2C N
O
N
N
Me
O
84
O
OBn
NaH
BnO2C
t-BuO 2C
1. Et 3N
Me3SiOTf
2. BnONH2
EDAC
HOBt
3. H 2, 5%Pd/C
BnO 2C
t-BuO 2C
79b
O
OBn
70
Ro 32-3555 'Trocade'
Cartilage Protective
Agent

PART V – CONFORMATIONAL CONTROL AND RESOLUTION:
KINETIC OR NOT?
A tetrahydropyran that inhibits leukotriene biosynthesis
The leukotrienes are implicated in various infl ammatory conditions such as rheumatoid arthritis and
inhibiting their biosynthesis is potentially a useful therapy. Some time ago ICI (AstraZeneca now)
found that some THPs (TetraHydroPyrans) inhibited the enzyme 5-lipoxygenase in the pathway to
leukotrienes and they concentrated on achiral compounds such as 85 (known as ICI D2138). However
it soon became clear that an extra methyl group, as in 86, enhanced activity. This small change makes
the molecule chiral by introducing two chiral centres. It was necessary to fi nd which diastereoisomer
(syn or anti) was more active and which enantiomer of that diastereoisomer was better. 13
O
N
Me
The synthesis of 85 had involved the addition of a suitable organo-Li or Grignard reagent made
from 87 to the heterocyclic ketone 88 and it seemed sensible to adopt the same strategy for 86. So
two questions were asked: would it be better to start with a single enantiomer of 90 and what was
the diastereoselectivity of RLi and/or RMgBr additions to 90?
ArO
F
Br
O
1. BuLi or Mg
2.
O
O
ArO
O
87 88 89 90
Answering the second question fi rst, they found that the close relative 91 added to racemic 90
to give predominantly the anti diastereoisomer of 92 (3:1) while the Grignard reagent gave more
of the syn isomer (2:1). The aryl-lithium prefers equatorial while the Grignard reagent prefers
axial addition.
BnO
F
OMe
F
N
Me
85; ICI D2138 86
F
91
31 A Disappointment and a Resolution 729
Br
1. BuLi or Mg
2. 90
Ar
O
Me
O
OH
O
BuLi - 1:3
Mg - 2:1
HO
OH
Ar
syn-92 anti-92
O
O
F
O
Me
O
OMe
Me
Me
O

730 31 Strategy of Asymmetric Synthesis
Asymmetric synthesis of 2-methyl-tetrahydropyran-4-one by kinetic resolution
Now it is worth making enantiomerically enriched 90. One method already in the literature 14
involved reduction of racemic 90 with horse liver alcohol dehydrogenase. This is an enzymatic
kinetic resolution (chapters 28 and 29) and at 50% reduction the products are 31% unreacted
ketone 90 in good ee, 33% of one enantiomer of the anti-alcohol 93 in perfect (100%) ee, and a
trace of the syn-alcohol 93.
90
Horse liver alcohol
dehydrogenase
NAD+, pH7, 20 ˚C
50% completion
O
O
Me HO
Oxidation of ()-anti-93 with PCC gave enantiomerically pure ()-92 and addition of the
organo-Li or -Mg compounds would give the two diastereoisomers in this series. As you see the
yield of enantiomerically pure 93 is only 33% and, as is often the case with a kinetic resolution,
the unreacted ketone has a lower ee.
An alternative and more ingenious method gave all the stereochemical information required. 13
The racemic dienol 94 was subjected to Sharpless asymmetric epoxidation (chapter 25). 15 This is
another kinetic resolution run to about 50% completion. Using an excess of di-isopropyl tartrate
(DIPT, 1.5 equivalents) one enantiomer of the alcohol (R)-94 remained (72% ee) and one enantiomer
of one diastereoisomer of the epoxide 95 (95% ee) was formed. Once again the unreacted
starting material 94 has a lower ee than the enantioselectively formed product 95.
Alternatively, the ‘wrong’ enantiomer of DIPT was used to give the ‘right’ enantiomer of unreacted
allylic alcohol (S)-()-94 (of course also in 72% ee) and this was epoxidised using a catalytic
amount (0.2 equivalents) of DIPT. This gave the ‘right’ enantiomer of the epoxide. By these
means, good yields of both enantiomers of 95 could be formed and both could then be converted
into the various stereoisomers of 86.
94
(S)-(+)-90
31% yield, 85% ee
+
O
(2R,4S)-(–)-anti-93
33% yield, 100% ee
Me HO
+
OH OH OH
94
t-BuOOH, Ti( i-OPr) 4
1.5 equivalents
(–)-di-isopropyl
tartrate, –20 ˚C
t-BuOOH, Ti(O i-Pr) 4
1.5 equivalents
(+)-di-isopropyl
tartrate, –20 ˚C
(+)-95
+
(R)-(+)-94
23-38% yield 72%ee
OH
(S)-(–)-94
23-38% yield 72%ee
+
O
Me
(2S,4S)-(+)-syn-93
2% yield, 36% ee
O
(–)-95
27-33% yield >95%ee
t-BuOOH, Ti( i-OPr) 4
0.2 equivalents
(+)-di-isopropyl
tartrate, –20 ˚C
(–)-95
75% yield
92%ee

The epoxide 95 was reduced with REDAL [NaAlH(OCH 2CH 2OMe) 2] to give the diol 96.
Further simple chemistry gave the same (S)-() enantiomer of 90 as was left unreacted in the
enzymatic kinetic resolution. This enantiomer was converted into the two tertiary ethers 86 in
this series.
The other enantiomer (R)-()-90 was obtained by resolution of racemic syn-93 via the
α-methylbenzylamine salt of the phthalate 98. After chiral HPLC (chapter 22) the ester was
hydrolysed and oxidation gave (R)-()-90 from which the two remaining stereoisomers of 86
could be made.
The purpose of this investigation was analytical rather than synthetic and it was established
that the (2S,4R) enantiomer of 86, one of the enantiomers with equatorial aryl and equatorial
methyl groups, was the most potent compound. 13
O
95
HO
N
Me
REDAL
OH
HO
96
PART VI – ASYMMETRIC DESYMMETRISATION
OF A DIELS-ALDER ADDUCT
O
rac-syn-93
31 A Disappointment and a Resolution 731
1. phthalic
anhydride
1. O 3, MeOH
2. EtOH, HCl
Ifetroban sodium: a thromboxane receptor antagonist
O
2. (R)-(+)amine
F
(2S,4R)-86
MeO
Me
Ph NH 3
Thromboxanes are human metabolites vital for blood clotting but too much of them is dangerous
for patients with heart, lung, or kidney disease. They are also very unstable and the search for
stable, orally available, thromoboxane antagonists at the Bristol-Meyers Squibb company revealed
the useful compound ifetroban 16 sodium 99. It contains three rings: an ortho-disubstituted benzene
ring, an oxazole, and a bicyclic ether.
OH
EtO O
97
O
Me
98
Q
CO2 O
1. Et 3SiH
Me 3SiOTf
O
2. CrO3
O
(S)-(+)-90
>95% ee
O
OMe
Me
O
(2S,4R)-86; Q = quinolone-5-yl

732 31 Strategy of Asymmetric Synthesis
A laboratory synthesis starting with a Diels-Alder reaction
The Diels-Alder reaction between furan and maleic anhydride is reversible and gives the more
stable exo-adduct 100 (also commercially available). This compound contains the bicyclic ring
system of ifetroban but is achiral and the key problem is to disrupt symmetry of the adduct 100
in a controlled way. The original synthesis used to make the drug 17 converted the adduct 100
into the menthyl acetal 101 as a single enantiomer in four steps and then into the carboxylic
acid 102 in another six steps. This strategy amounts to a resolution as each menthol adduct
could be isolated by crystallisation of a diastereoisomeric mixture in only about 30% yield.
O
Na
O2C
O
O
N
O
O
O
O
O O
O
100 101 102
The problem with this synthesis is its great length (23 steps altogether) caused by the repeated
changes of oxidation level of the functional groups. The overall yield is less than 3% but even so
it was used to make some 20 kg of ifetroban sodium. As the compound became a more likely drug
candidate, a more effi cient synthesis was clearly needed.
Desymmetrisation of a symmetrical anhydride with a chiral Grignard reagent
O
HN
99
Ifetroban sodium
orally bioavailable
thromboxane A2
receptor antagonist
CO2H
Since the starting material for all syntheses of ifetroban is bound to be the achiral Diels-Alder
adduct 100, one good strategy is to desymmetrise this compound or the saturated version 103
with a chiral nucleophile. One that works is the oxazolidinone 104 derived from ephedrine. 18
[You have seen ephedrine used as a chiral auxiliary in chapter 27]. Reaction occurs
predominantly at one of the enantiotopic carbonyl groups to give the keto-acid 105. This is
immediately reduced and the chiral auxiliary removed to give the lactone 106. Though only one
centre is marked, fi ve new stereogenic centres are formed in 106, one by the reduction and the
others by desymmetrisation. The sequence is very selective, giving lactone 106 in 99.2% ee
after recrystallisation. The aldehyde is used to add the side chain 107 by a Wittig reaction and
the carboxylic acid is used to add the oxazole. The problem is that the yield is not very good.
The lithium derivative of 104 gives only 50% yield and even the Grignard reagent gives 65%
at best.
Ar

100
O
O
An alternative approach 17 is to attach a chiral auxiliary, (phenyl ethylamine, available by
resolution, chapter 22, and used repeatedly in chapters 22–28, to the anhydride 100 in the form
of a chiral imide 108. This auxiliary is very close to the two carbonyl groups of the anhydride in
108 and directs the achiral Grignard reagent 109 to one of them to give adduct 110 immediately
reduced and hydrolysed to the lactone 106. One recrystallisation gives 106 in 98% ee. This time
a Horner-Wadsworth-Emmons reaction (chapter 15) adds the side chain as a conjugated unsaturated
acid reduced to the saturated side chain in 111, a common intermediate in most syntheses of
ifetroban. The formation of the oxazole and the rest of the synthesis is described by R. N. Misra
and the Bristol-Meyers Squibb team. 16
100
H 2N
1. NaBH 4
2. 1M NaOH
EtOH
3. 10% HCl
1. NaBH 4
Me
2. H +
Ph
Laboratory and process routes compared
O
O
O
BrMg
Ph
O N Me
Me
O CHO
O
O
106
O
O
107
CO2Me
A simple comparison between the laboratory route used by the medicinal chemists and the
route devised by the development chemists at Bristol-Meyers Squibb for the production of 99
Wittig
O
O
CO2H
103 104 105
O
31 A Disappointment and a Resolution 733
O
O
N
O
O Me
108; 80-95% yield
crystallised
O CHO
106; 89% yield, 88% ee crude
>98% ee recrystallised
Ph
+
BrMg
1. DBU
O
(MeO) 2P CO 2Me
HO 2C
O
Ph
O N Me
CO2H
Me
O O
N Ph
O
O Me
109 110
(99% yield)
2. H 2, Pearlman's
catalyst(86% yield)
O
111
O
OH

734 31 Strategy of Asymmetric Synthesis
shows how important is this effi cient asymmetric synthesis. The laboratory route used 23 steps
and gave 3% overall yield with the asymmetry coming from a resolution. The process route,
summarised below, has 12 steps, gives 28% overall yield and derives asymmetry from a substrate-attached
chiral auxiliary. You may notice that the oxazole is assembled from the chiral
pool (serine, see chapter 25) even though the chirality is lost: serine is just a convenient starting
material.
H2N
HO
H 2N
HO
O
O
N
H
OH
(S)-L-serine
3 steps
Na
O2C
PART VII – ASYMMETRIC SYNTHESIS OF A BICYCLIC β-LACTONE
Lactacystin: a natural proteasome inhibitor
O
O O
O
N
O
4 steps
MeO2C
Proteins in the human body have a limited lifetime. They are earmarked for degradation with a
marker ‘ubiquitin’ and hydrolysed by proteasomes. Though this is a natural and necessary sequence
of events it can get out of hand and proteasome inhibitors could provide treatments for heart diseases,
asthma, and arthritis. Lactacystin 112 is a proteasome inhibitor from a soil micro-organism.
O
O
1 step
O
HN
N
O
H2N
O Me
O
Ph
Me
Ph
CO2H
Br
Br
108 109
3 steps
99;
Ifetroban
sodium
O O
CHO
1 step

It works by the spontaneous hydrolysis of the thiol ester to give N-acetyl cysteine 114 and the true
inhibitor, the β-lactone 113. This β-lactone has been the target of many syntheses using diverse
strategies and these form the last section of this chapter. Notice that the stereochemistry of the OH
and CO groups in the β-lactone is the same as that in lactacystin itself since the β-lactone is both
formed from 112 and reacts with 114 to give 112 by nucleophilic attack at the carbonyl group. The
biology and chemistry of these compounds is summarised in an excellent review. 19 There are many
syntheses - some very long - and we shall concentrate on the origin of chirality in each.
112
(+)-Lactacystin
proteasome
inhibitor
(inhibits protein
degradation)
O
NH
H
HO OH
O S
Strategies used in the synthesis of lactacystin, the β-lactone, and analogues
The thiolester portion is always derived from natural cysteine so there is a chiral pool element present
in all syntheses. Because there are four consecutive chiral centres in the main portion of the molecule,
just about every strategy has been employed by someone: more chiral pool, chiral reagents and
catalysts, chiral auxiliaries attached to substrate or reagent, and sometimes combinations of these.
A chiral pool synthesis of lactacystin from glucose
H
N
CO2H O
An early synthesis of lactacystin, not via the β-lactone, used glucose as starting material. 20
Disconnection to 115 (the vinyl group can be converted into CO 2H and the benzyl ether into CHO)
gives a structure that can be redrawn as 116 and then, with incorporation of an extra C atom (to be
removed in the synthesis by diol oxidation) derived from 117.
112/113
thiolester
hydrolysis
Me
HO
OH
N
R
OBn
NH
spontaneously
in vivo H
OH +
O
O
113
(+)-Lactacystin β-lactone:
the active proteasome
inhibitor
1
CHO
2 HN
It was already known that glucose could be converted into the cyclic ether 118 and a [3,3]
sigmatropic rearrangement (Overman style, see chapter 19) on the allylic imidate ester 119 should
give 120, a derivative of 117. The ‘should’ has to be there because it is not possible to forecast the
stereochemical outcome with certainty.
O
Me
O OH
O
OBn
115
?
31 A Disappointment and a Resolution 735
O
O
O
Me
Me
HO
OBn
3
O
R
OBn
HO
HO
1
O
SH
Me
116 117
118 119
120
O
NH
CCl 3
?
O
O
O
2
3
H
N
CO2H O
114
N-acetyl
cysteine
HN R
Me
OBn
HN COCCl3 OBn

736 31 Strategy of Asymmetric Synthesis
In the event, a 1:1 mixture of E:Z isomers of 119 gave a 4.8:1 mixture of 120 and its diastereoisomer
at the new centre in 60% yield. This is a remarkable level of control but later syntheses do
better. Deprotection, oxidative cleavage and cyclisation gave the pyrrolidine 121.
1. TFA, H 2O
120
2. NaIO4, MeOH
115; R = COCCl 3
1. Jones
oxidation
2. NaBH4 There was a further problem in the addition of i-PrMgBr to the aldehyde (R t-BuMe 2Si-) derived
from 121. The chemo- and stereoselectivity were poor and the product contained 35% 123a, 30% 123b,
and 21% alcohol from the reduction of 122. Though the unwanted products could be recycled: 123a by
oxidation and re-reduction and the alcohol by oxidation to 122 it is clearly possible to do better.
121
Me
RO
O
122
Chiral pool syntheses of lactacystin from amino acids
NH
CHO
Me
Amino acids are attractive starting materials for lactacystin and there are several published syntheses
using this type of chiral pool strategy. Baldwin 21 used glutamic acid 124 with the idea of
using the known Seebach-style intermediate 125 (chapter 24) with a relay chiral centre and
destroying the original centre to give a pyrrole 126 that is also an extended enolate. An aldol
reaction of 126 with i-PrCHO might be controlled to give the correct aldol product 127.
H
O OH
124
glutamic acid
i-PrMgBr
OR
The conversion of 125 into the pyrrole 126 uses reactions from earlier chapters. Methylation
is not stereoselective but that doesn’t matter as selenenylation, oxidation, and elimination gives a
single internal alkene – this chemistry will be explained in chapter 33. Now silylation destroys the
original chiral centre from glutamic acid but keeps the relay centre.
125
O
OH
NH2
O
H
N
O
Ph
Me
RO
N
O
123a
O
NH
Me
HO
OH
+
O
121
NH
Me
RO
OBn
O
123b
NH
OH
O
Ph Ph
? Me
N
aldol reaction of
extended enolate
HO
125 126
127
O
1. LDA
2. MeI
Me
N
Ph
1. LDA
2. PhSeBr
Me
O 3. O3, heat
H
128; 95% yield
O
H
N
O
Ph
t-BuMe2SiOTf Me
base, CH 2Cl 2
N
O
OSiMe2t-Bu
Ph
129; 79, 87% yields 130; 89% yield
O

The aldol reaction proved diffi cult but a Lewis acid (SnCl 4) catalysed reaction at low temperature
gave a 9:1 ratio of aldols in favour of 127 which could be isolated in 55% yield after
chromatography. Notice that the aldehyde has added to the same face as that ‘blocked’ by the
phenyl group, as we should expect from chapter 24. The alkene in 127 must now be removed, the
remaining OH group introduced, and the last two chiral centres in the pyrrolidine ring controlled.
These all present problems but the extra OH is the worst. Baldwin found an ingenious solution: two
OHs were introduced diastereoselectively by a racemic dihydroxylation of the acetate 131. The
two OHs go on the right side, opposite the Ph and aldol groups, and the diol 132 is cyclised to the
thiocarbonate 133 (Im imidazole).
O
O
Me
Ac2O 127
pyridine
room AcO
temperature
N
Ph
OsO4 O NMO
acetone
H2O Me
HO
HO
AcO
N
Ph
Im2CS O THF S
131; 99% yield
O
AcO
The thiocarbonate is used to get rid of the unwanted OH group in a radical reaction using
Bu 3SnH to initiate a radical chain The methyl centre is epimerised in this operation but treatment
with base gives the right diastereoisomer 135 and also hydrolyses the acetate. The original chiral
auxiliary can now be removed by hydrogenation and 136 should be close enough to lactacystin for
you to see that the synthesis can be completed.
133
O
Ph
Bu3SnH Me
N
NaOH
AIBN
toluene
reflux
HO
AcO
O
MeOH
134; 94% yield
Me
Corey’s earlier synthesis 22 uses a related strategy from serine involving a Seebach-style relay
chiral centre and two stereoselective aldol reactions. The aldol reaction with i-PrCHO is carried out
fi rst and the pyrrolidine ring assembled later with the second aldol reaction. Serine 137 is converted
to the cyclic t-BuCHO derivative 138. An aldol reaction with the enolate of 138 and i-PrCHO gives
mostly the wanted aldol 139. The aldehyde adds to the face opposite to the t-butyl group.
HO
NH 2
CO 2H
137; (S)-serine
31 A Disappointment and a Resolution 737
This oxazolidine ring is hydrolysed to give an open chain diol that can be selectively protected
with the large t-BuMe 2Si group 140. Treatment with formaldehyde now gives a different oxazolidine
Me
O
132; 87% yield 133; 91% yield
HO
HO
O
N
135; 94% yield
Ph
O
N
1. LDA, LiBr
2. i-PrCHO
CO2Me
138; 9:1 cis:trans
O
Ph
O
H 2, Pd/C
HCl, MeOH
N
MeO 2C
Ph
Me
OH
HO
HO
O
O
N
NH
O
Ph
136; 87% yield
139
77% yield
>98% this
isomer
OH

738 31 Strategy of Asymmetric Synthesis
141 and hence the aldehyde 142 ready for the next aldol reaction. This aldehyde cannot be enolised
so it is a good electrophile.
139
1. TfOH, MeOH
91% yield
2. TBDMSCl
97% yield
TBDMSO
HN
MeO2C
140
Ph
OH
(CH 2O) n
Heathcock’s diastereoselective aldol method (chapter 4) gave the required anti-aldol 144 but
only in low yield. Removal of the N-benzyl group allowed the amine to cyclise onto the aryl ester
and the bicyclic compound 145 of fi xed conformation is formed. Notice that all the substituents
are on the outside (exo face) of the folded molecule (chapter 21). The further development of 145
into lactacystin can be found in the paper. 22
O
O
1. LDA
2. 142 ArO2C
Ph
OH
N
OR
143 anti-144; 48% yield
O
The reagent strategy: asymmetric epoxidation and asymmetric allylboration
TsOH
MeO2C
We move into approaches that are more sophisticated in several ways. The synthesis by Omura
and Amos B. Smith 23 was partly inspired by the biosynthesis of lactacystin and partly by an
attempt to make other diastereoisomers. Their key intermediate is the non-proteinogenic amino
acid hydroxyleucine 147 and they were able to make both enantiomers of both diastereoisomers of
this compound by asymmetric synthesis.
Sharpless asymmetric epoxidation (chapter 27) of the allylic alcohol 148 with cumyl hydroperoxide
and ()-di-isopropyl tartrate (DIPT) gave the epoxide 149 in excellent yield and enantiomeric
purity. The other enantiomer could be made simply by using the other enantiomer of DIPT.
The problem is now: how to react the epoxide regiospecifi cally with a nitrogen nucleophile?
HO
O
Ph
N
O
TBDMSO
141; 96% yield
H2, Pd/C
EtOH
23 ˚C
Me
NH
amide
and aldol
H2N H
OH
HO OH O OH
O OH
146
O
HO
N
1. LiBH4
2. Swern
OR
O
145; 87% yield
OHC
Ph
N
O
TBDMSO
142; 85% yield
O
Me
HO
H
Ph O OH HO
? HO2C
148
Ti(Oi-Pr) 4
(+)-DIPT
O
149; 82% yield, >97% ee
OH
(2R,3S)-(+)-147
=
HO2C
NH 2
OH
(2R,3S)-(+)-147
3-Hydroxyleucine
H
N
OR
H
O
conformation of 145
NH2

A cunning solution was to attach the nucleophile to the OH as an isocyanate and to use the
anion 150 to react intramolecularly with the epoxide 149. Initially the anion must cyclise to the
nearer end of the epoxide to give 151 but even under the reaction conditions 151 starts to isomerise
to 152. This isomer 152 is not the alternative product from 150: it is formed by attack of the
secondary alcohol on the CO group of 151. Further treatment with NaH completes the isomerisation
to 152.
149
NaH
PhNCO
O
O
Ph
N
O
150
O
Ph
N
NaH
O
THF
heat
OH
151 (5:1 with 152)
Oxidation and esterifi cation give one diastereoisomer of protected 3-hydroxyleucine 153 and
epimerisation in base gives another 154. It is the latter that is required for the synthesis of lactacystin
but either enantiomer of either diastereoisomer can be made by this sequence. The overall
yield of natural 3-hydroxyleucine 147 is about 50% from the allylic alcohol 148.
152
MeO2C 1. Jones
(100% yield)
2. CH2N2 (87% yield)
Ph
N
O
KOH
EtOH
O
153
Ph
A few small changes give the oxazoline needed for the stereoselective aldol reaction with
formaldehyde. There is no syn/anti aldol question here: the electrophile simply adds to the face of
the more or less planar enolate opposite the isopropyl group. Now there was a severe diffi culty in an
apparently trivial reaction: oxidising the primary alcohol 156 to the aldehyde 157. The advantage
that the aldehyde is not enolisable is a disadvantage too as nucleophiles may attack and remove the
CHO group. The problem was solved by careful choice of reagents (Moffat oxidation with DMSO,
DCC and CF 3CO 2H). The aldehyde 157 was not isolated but used immediately in the next step.
147
1. HCl, MeOH
(100% yield)
2. PhC(OMe) 3
MeO 2C
N
Ph
31 A Disappointment and a Resolution 739
Brown’s crotyl borane 158 (chapter 24) provides reagent control through a chair-like sixmembered
ring in the formation of 159. Oxidation of the alkene (ozone with oxidative workup)
gives the free acid marked in 160 and on removal of the benzylic group the freed amine (circled)
cyclises to it to give the pyrrolidone required (147 as its methyl ester). The synthesis can easily be
completed from there.
N
O
O
anti-154; 96% yield
Ph
HO
N
O
O
152; 75% yield from 149
HO 2C HO 2C
OH
CO2Me 1. KOH
2. H2 Pd(OH)2
?
1. LHMDS
N
O
2. CH2O
O
155
Ph
156; 85% yield
>98% this diastereoisomer
H2N
OHC
OH
(2R,3S)-(+)-147
98% yield
N
Ph
CO 2Me
O
157

740 31 Strategy of Asymmetric Synthesis
Ipc2B
158
157
OH
CO2Me HO2C OH
CO2Me HCO2H Pd, NH3 O
NH
N
Ph
O
N
Ph
O
H
HO OH
CO2Me 159 160
(2R,3S)-(+)-147
(methyl ester)
Enzymes as reagents in the synthesis of lactacystin analogues
Many developments have come from Corey’s laboratories in the lactacystin area since the synthesis
described above. 24 One strategy we have not mentioned before is the use of an enzyme,
pig liver esterase (chapter 29) in the selective hydrolysis of one of two enantiotopic ester groups
in the malonate 161. An MeS group is used to block enolisation and prevent racemisation of the
product 162. The mono ester 162 is initially formed in 67% ee improved by one crystallisation of
the quinine salt to 95% ee. The pyrrolidine ring 164 is made in an unusual way by fi rst forming
the amide 163 and then cyclising the diester by carbonyl condensation. The new chiral centre in
164 is not controlled but disappears in the next step.
O
Me
MeS
CO2Me CO2H
1. PLE, pH 7.3 Me
1. (COCl) 2
2. crystallise MeS
2. RNH2 CO2Me quinine salt CO2Me 161
162; 62% yield
95% ee
O PMB
N
LDA
Me
CO2Me MeS
CO2Me 163; 99% yield
Me
PMB
MeS
N
O CO2Me
164; 93% yield
1:1 diastereoisomers
Now a remarkably simple aldol reaction with formaldehyde (compare 156 to 165) needing only
DBU as base gives mostly (9:1) the correct diastereoisomer 165. Easier to explain is the stereoselective
reduction of the ketone with acetoxy borohydride to give 166: the primary alcohol replaces
one of the acetates and directs the H atom to the bottom face of the ketone. Juggling the
protecting groups gives 167 ready for the introduction of the remaining chiral centres.
O
DBU
164
CH2O, H 2O
Me
MeS
N
PMB
OH
NaBH(OAc)3
–78 ˚C
MeS
O CO2Me HO CO2Me TBDMSO CO2Me 165; 90% yield 166; 95% yield, 99% ee 167
First, the MeS group was removed with Raney nickel giving the correct stereochemistry at the new
centre in 168. The stereochemistry actually comes from the protonation step and presumably arises
because EtOH donates an H atom to the less hindered side of the desulfurised enolate opposite the
OTBDMS group. Then oxidation with the Dess-Martin periodinane gives the vital aldehyde 169.
167
Raney Ni
EtOH
Me
H
TBDMSO
O
N
PMB
OH
CO2Me
168 (10:1 diastereoselectivity)
Me
O
Dess-Martin
periodinane
N
PMB
OH
Me
H
TBDMSO
O
MeS
N
Me
PMB
CHO
CO2Me
169; 78% yield from 167
O
N
PMB
OH

In previous syntheses this last centre has usually been added in an aldol reaction and here too
a carbon-carbon bond is made as the centre is introduced. But this time it is the addition of isopropenyl
Grignard reagent in the presence of Me 3SiCl that is required to give 171. The high stereochemical
control suggests a chair-like intermediate 170 with both carbonyl groups coordinated to
a magnesium atom and the isopropenyl group being transferred to the top face of the CHO group
as drawn. Further adjustments lead to the hydroxyacid 172 which was, in this synthesis, transformed
into the β-lactone 113 on the way to lactacystin 112. The isopropenyl Grignard was used
as isopropyl Grignard annoyingly reduced the aldehyde rather than adding to it, as in the reaction
of 122.
169
BrMg
Me3SiCl
O
Me
PMB
N
H
OMe
O Mg
O
OR
This synthesis includes the formation of the β-lactone using a phosphorus-based coupling reagent
‘BOP-Cl’ 173 bis(2-oxo-3-oxazolidinyl)phosphinic chloride. Notice the preferential formation
of the fused rather than the spirocyclic β-lactone and that cyclisation occurs with retention so
the phosphorus reagent 173 must activate the CO 2H group. The p-methoxybenzyl (PMB) group is
removed by oxidation with Ce(IV) to give 113. This approach from the enantiomerically pure 165
is ideally suited for the production of analogues and Corey has made many analogues to probe the
origin of the biological activity. 24
O Cl
O O
O
N P N
O
173; BOP-Cl
bis(2-oxo-3-oxazolidinyl)
phosphinic chloride
31 A Disappointment and a Resolution 741
Syntheses of 3-hydroxyleucine by other strategies
A leading group in lactacystin research is led by Panek at Boston University. They have produced
two further approaches to a key intermediate, 3-hydroxyleucine 147. One uses a chiral auxiliary
strategy. 25 Phenylglycinol 175 is available as either enantiomer. It can be alkylated chemoselectively
on nitrogen to give the amino ester 176. Trapping this with Ph 2CHCHO produces the Seebach-style
oxazoline 177 with a cis relationship between the old and the new (relay) chiral centres in 100%
yield. The key step is a stereoselective aldol of the lithium enolate of 177 with i-PrCHO. Reaction
occurs entirely on the face of the enolate opposite the two large groups (as drawn in 178) and very
much in favour of the anti-aldol product 178. In this aldol reaction, the original chiral centre is
not removed and the relay centre reinforces the stereoselectivity while holding the molecule in a
fi xed conformation. The rest of the synthesis is simply the removal of the various auxiliaries and
protecting groups.
Me
H
O
TBDMSO
MeO2C
N
PMB
OSiMe3
Me
H
O
HO
HO2C
170 171
172
172
Et3N, CH2Cl2 Me
H
O
N
PMB
O
O
OH
174; 90% yield
Ce(NH4) 2(NO 3) 6
MeCN, H 2O
Me
H
O
NH
O
O
OH
113; 62% yield
N
PMB
OH

742 31 Strategy of Asymmetric Synthesis
Ph
Ph
O
N
OH
NH 2
175 (S)-phenylglycinol
Ph
Ph
MeO2C OH
178; 90% yield
>30:1 anti:syn aldol
MeO 2C Br
MeO2C 176; 92% yield
The other uses a catalytic process, Sharpless’s aminohydroxylation 26 (chapter 25). By skilful
choice of the esterifying group, the amino hydroxylation of the unsaturated ester 181 could be
controlled to give the required regioisomer 182 in high ee after two recrystallisations from aqueous
ethanol (it was initially 87%).
The methyl ester of the ‘wrong’ diastereoisomer of 3-hydroxyleucine 183 required merely
deprotection of 182 and ester exchange best catalysed by Ti(IV). Incorporation into the oxazoline
184 prepares the way for the aldol reaction with formaldehyde that inverts the stereochemistry at
the ester centre and leads to their lactacystin synthesis. 27
182
Br
1. MeOH
Ti(OPr-i) 4
2. H 2, Pd/C
MeOH
Et 3N, THF, 0 ˚C
O
A large-scale synthesis of lactacystin analogues using AD
and an asymmetric aldol reaction
Ph
OH
OH
NH
HCO2H THF/H2O Ph
MeO2C NH
OH
179; 90% yield
O
Ph
O Ph
OHC
Ph
MgSO4, CH2Cl2 Ph
MeO2C N Ph
177; 100% yield
H 2, Pd/C
5 mol% K2[OsO2(OH) 4]
CbzNCl.Na, PrOH, H2O
MeO 2C
We end with a large scale synthesis by LeukoSite Inc. of Cambridge Mass. 28 designed to be used
for analogues of natural lactacystin. They started with the asymmetric dihydroxylation (chapter
25) of the unsaturated ester 186 (cf. compounds 148 and 181). This gave a 94% yield on a small
scale with AD-mix-α but could not easily be adapted to a larger scale because of the excessive
quantities of salts in over large volumes of solvent. They preferred a modifi cation from Pharmacia-
Upjohn at Uppsala using the organic re-oxidant N-methylmorpholine-N-oxide (NMO) instead of
potassium ferricyanide, no potassium carbonate and a more concentrated solution. 29 This gave 187
in only 60% yield but 99% ee after two recrystallisations. All three Sharpless methods have now
been used in lactacystin synthesis.
NH 2
OH
(2R,3S)-(+)-180
3-Hydroxyleucine
methyl ester
181 182; 60% yield, >99% ee
MeO 2C
NH 2
OH
5 mol% (DHQ) 2AQN = 1,4-bis-
(dihydroquininyl)anthraquinone
PhC(OMe) 3
TsOH
Ph
N
O
Br
CO 2Me
183; 100% yield 184; 85% yield
O
CbzNH
O
1. LHDMS
2. CH2O
THF, –78 ˚C Ph
1. LDA, –78 ˚C
2. i-PrCHO
(2R,3S)-(+)-147
3-Hydroxyleucine
HO
N
OH
O
CO 2Me
185; 85% yield

MeO2C 186
1 mol% K2OsO2(OH)4
1 mol% (DHQ) 2PHAL
1.6 equiv NMO
H2O/t-BuOH MeO 2C
Now one of the two OH groups must be replaced by NH 2 with retention of confi guration. This
can be achieved by the ortho-ester method like that summarised in chapter 23 for propylene oxide.
The intermediates 188 and 189 can be isolated but the process works better if 189 is hydrogenated
to give the oxazoline 184 in 89% yield over the three steps. Note that the stereochemistry of 189,
and hence 184, comes from a double inversion at the position α to the ester group.
187
1. PhC(OMe) 3
BF 3.OEt 2
2. MeCOBr
Et 3N, 0 ˚C
MeO2C
Br
OCOPh
NaN3
DMSO
MeO2C
The formation of 184 from 189 needs some explanation. Hydrogenation converts the azide into
an amino group to give 190 and this is in equilibrium with 192 by transfer of the benzoyl group from
O to N via the tetrahedral intermediate 191. Dehydration of 191 gives the stable heterocycle 184.
The oxazoline 184 provides an attractive approach to lactacystin as it is a protected form of
3-hydroxyleucine. The other half of the molecule was made in the LeukoSite synthesis by a very
different method: the alkylation of an Evans’ chiral auxiliary. This was chosen partly because
they wished to vary the alkyl group on the pyrrolidone ring and we use the propyl compound
as example. The phenylalanine derived oxazolidinone 193 (chapter 27) was acylated and then
the titanium enolate of 194 was alkylated to give 195 with very high selectivity and the chiral
auxiliary removed to give the simple acid 196.
O
Coupling with Et 2N using TBTU [2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafl uoroborate], removal of the benzyl group and oxidation with the Dess-Martin periodinane
N 3
OH
OH
OCOPh
188 (98% yield) 189 (85% yield)
187
60% yield
after recrystallisation
>99% ee
H 2
Pd(OH) 2/C
NH2 MeO2C Ph
189
H2 Pd(OH)2/C
MeO2C O O
Ph
HN
Ph
O
OH
O
MeO2C NH
OH
190 191
192
Ph
O
193
NH
Ph
31 A Disappointment and a Resolution 743
1. BuLi
2. BuCOCl
O N
1. TiCl 4
i-Pr2NEt 2. BOMCl
(BnOCH2Cl) O N
OBn
O O
O O
194; 97% yield 195; 85% yield pure
after recystallisation
Ph
MeO2C
N
LiOH.H2O H2O2 HO2C
O
Ph
184; 89% yield
TsOH
184
toluene
OBn
196; 90% yield

744 31 Strategy of Asymmetric Synthesis
gave the aldehyde 199 in good yield. This sequence from 193 gave optically pure aldehyde 199 in
70% yield without any chromatography.
196
Et2NH i-Pr2NEt Et2N OBn
TBTU
O
197; 98% yield
H2, Pd(OH) 2/C
Et2N OH Dess-Martin Et2N O
O
O H
198; 100% yield 199; 96% yield
Now the two parts, 184 and 199, must be linked in a controlled aldol reaction. The lithium
enolate 200 reacts with the aldehyde in 199 in the presence of excess Lewis acid Me 2AlCl to give
one diastereoisomer of 201 as the only product. Presumably the aluminium coordinates the tertiary
amide and aldehyde oxygen atoms to hold the aldehyde in one Felkin conformation while it is
attacked by the lithium enolate from one face only as sketched in 202.
184
1. LiHMDS
–80 ˚C
LiO
OMe
2. Me 2AlCl
2.2-2.4 equiv
N
O
1.25 x 199 Et2NOC
N
OH
O
Ph
Ph
200 201; E = CO2Me Al
O
O LiO
NR2
Any attempts to purify 201 by chromatography led to reverse aldol reactions and it was better
not to isolate 201 but just to wash it with aqueous bisulfi te before removing the oxazoline and
allowing the amine 203 to cyclise to form the pyrrolidine 204. An X-ray structure of 204 confi rmed
that the stereochemistry was correct.
201
washed
with
NaHSO3 55 psi H 2
Pd(OH)2/C
1:10 AcOH/H2O
room temp
Et 2N
O
E
OH
NH2 OH
203; E = CO 2Me
Hydrolysis of the ester with NaOH and β-lactone formation gave the propyl analogue 206 of
113 in 20% yield from simple starting materials over ten steps.
203
O
NaOH NH
Et3N NH
H2O H
O
H
4 ˚C
HO
OH
CO2H
Cl O
O
O
205 206
E
O
Pr
H
O
H
NH
202
H
OH
HO
CO2Me 204; 79% yield from184
recrystallised, X-ray
OH
N O
Ph
75% yield
recrystallised
10 steps
from i-PrCHO
>20% yield
OMe

References
31 References 745
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Section E:
Functional Group Strategy
32. Functionalisation of Pyridine ............................................................................................ 749
33. Oxidation of Aromatic Compounds, Enols and Enolates ............................................... 777
34. Functionality and Pericyclic Reactions: Nitrogen Heterocycles by
Cycloadditions and Sigmatropic Rearrangements ......................................................... 809
35. Synthesis and Chemistry of Azoles and other
Heterocycles with Two or more Heteroatoms .................................................................. 835
36. Tandem Organic Reactions ............................................................................................... 863

32
Functionalisation of Pyridine
This chapter examines functionalisation strategy - the addition of functional groups to a pre-formed
carbon skeleton. It revises previous sections in the context of some diffi cult reactions.
Introduction
PART I – THE PROBLEM
Low reactivity of pyridine compared with benzene at carbon
Reaction at nitrogen prevails
Formation of stable complexes with electrophiles
N-Nitro Heterocycles as Nitrating Agents
PART II – TRADITIONAL SOLUTIONS: ADDITION OF ELECTRON-DONATING SUBSTITUENTS
Amino and alkoxy groups: synthesis of fl upirtene
Regioselectivity in Electrophilic Substitution with Electron-Donating Groups
The Anti-Tumour Antibiotic Kedarcidin
Halogenation and Metallation
Pyridine N-Oxides in Electrophilic Substitution
Synthesis of nifl uminic acid and omeprazole
Ortho-Lithiation of Pyridines
Diazines
The Halogen Dance
Tandem Double Lithiation: The asymmetric synthesis of camptothecin
Tandem Lithiation of Pyridine N-Oxides and Nucleophilic Substitution
PART III – SURPRISINGLY SUCCESSFUL DIRECT ELECTROPHILIC SUBSTITUTIONS
Sulfonation and halogenation at the 3-position in strong sulfuric acid
The reaction with SOCl2: reaction at the 4-position, synthesis of DMAP
PART IV – SUCCESSFUL NITRATION OF PYRIDINE
Nitration in the 3-position with N2O5 and a sulfur nucleophile
Scope, limitations and mechanism
Sulfonation of Pyridines
Extension by Vicarious Nucleophilic Aromatic Substitution
Synthesis of Imidazo[4,5-c]pyridines
PART V – APPLICATIONS
The Baeyer anti-cancer drug BAY 43-9006
Anatoxin analogues
Epibatidine analogues
Polycyclic compounds
Katritzky’s improvement of Bakke nitration
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

750 32 Functionalisation of Pyridine
Introduction
A theme of this section is making reactions work. Usually that means making reactions that
already work quite well work much better. But we start with a reaction - electrophilic aromatic
substitution on pyridines and related heterocycles - that doesn’t really work at all. We shall see
why not and how the reaction can be successfully realised. This involves some serious mechanistic
thinking and questions of regioselectivity are vital to the solution. This is new chemistry with a
great future.
PART I – THE PROBLEM
Because it is such a familiar reaction, it can be forgotten that attack by electrophiles on benzene 1
is diffi cult because it gives an intermediate cation 2 which has lost the aromaticity of the starting
material. This is, after all, why Lewis acids are needed for many such reactions. The product 3 has
regained aromaticity but this is no help to the rate-determining step, the attack of the electrophile
and the formation of 2. That the reaction occurs at all is because 2 is a delocalised pentadienyl
cation and has some intrinsic stability as a cation. Successful electrophilic substitution of benzene
by HNO 3/H 2SO 4, fuming H 2SO 4, RCOCl and AlCl 3, or halogens with various Lewis acids is also
testimony to the extreme reactivity of these combinations of reagents.
E
1 2
H
E
slow fast
Pyridine has all the disadvantages of benzene plus some special ones of its own. Attack at the
2- or 4-positions 4 gives intermediate cations such as 5 which have part of the positive charge
delocalised onto nitrogen 5c. This would be no bad thing if the nitrogen atom were tetravalent like
stable NH 4 , but it is actually divalent like the unknown, electron-defi cient, and presumably very
unstable NH 2 .
Attack at the 3-position 6 is not so bad as the intermediate cation 7 is no longer delocalised
onto the electron-defi cient nitrogen atom but is not as stable as the benzene intermediate 5 and
the slow step is very slow because the HOMO of pyridine is lower in energy than the HOMO of
benzene.
3
E
E = NO 2; HNO 3 + H 2SO 4
E = Cl, Br, I; Hal 2 + Lewis acid
E = COR; RCOCl + AlCl 3
E
H
H
N N
N
N
E
E
4 5a 5b
5c
E
H
E
slow
N N
N
N
6 7a 7b 7c
H
E
E
H
H
E

So far electrophilic attack on pyridines sounds only a bit more diffi cult than that on benzenes
but there is worse to come. The reagents for nitration, halogenation and so on all require strong
protic or Lewis acid catalysts and these go for the pyridine nitrogen atom fi rst. Attempted
nitration would have to occur on the cation 8, making the intermediate an impossibly unstable
dication 9.
HNO3
NO 2
N
H2SO4
N
N
H
H
8 9
N-Nitro Heterocycles as Nitrating Agents
In fact, nitration of pyridine in the absence of protic or Lewis acid catalysts occurs at nitrogen. 1
The reagent has to be the rather unstable and moisture sensitive salt NO 2 BF4 . This is commercially
available, though expensive. The product is also not very stable but can be isolated as the
tetrafl uoroborate salt 11 as BF 4 is non nucleophilic. This compound 11 is itself a nitrating agent
and can be used to nitrate benzenes (but obviously not pyridine) simply by mixing in acetonitrile.
The products 12 have the usual substitution pattern for electrophilic substitution. Olah has called
this process ‘transfer nitration’.
N
32 N-Nitro Heterocycles as Nitrating Agents 751
NO 2 BF 4
A better method for the same reaction (nitration of benzenes) is to use the product of nitration
of pyrazole 2 13. When the nitration is carried out in the absence of strong acid, the product is the
N-nitro compound 14, a stable neutral molecule because a proton can be lost from the other nitrogen
atom. This compound is stable but reacts with the Lewis acid BF 3 to give an intermediate 15
that nitrates benzene effi ciently. It is probable that the C-nitration of pyrazoles also takes place via
such an intermediate as 15, see below.
Pyridine can also be used as an effi cient catalyst for the bromination of benzene (see Vogel,
page 860) through reaction at the nitrogen atom 16 while the crystalline reagent pyridinium
H
NO 2
?
N
10
NO 2
NO2 N
+ R
MeCN
R
NO2
BF4 11; 91% yield 12; >90% yield
N
N
HNO3, Ac2O HOAc N
N
BF3 N
N
BF3 benzene
NO2 H
NO2 NO2 13 14 15
89% yield

752 32 Functionalisation of Pyridine
bromide perbromide 17 is a convenient way of brominating alkenes. These are convincing illustrations
that pyridine does not react with bromine at carbon.
N
Br 2
Direct electrophilic substitution of pyridines is not, in general, a useful reaction. Only
3-substitution is remotely possible as the intermediate 7 at least does not attempt to put the positive
charges on the same atoms! The maximum yield of 3-nitro-pyridine by direct nitration is
5%, normally 3% is expected. If we want to carry out nitration on the pyridine ring, some means
must be found better than normal electrophilic substitution. We shall now explore various ways
in which this simple reaction can be achieved either by subterfuge or mechanistic ingenuity. The
same remarks apply to other electron-defi cient six-membered aromatic heterocycles such as
pyrimidine 20 and quinoline 22. Solutions to these problems are needed as many drugs and
natural products contain these rings. The Pharmacia-Upjohn anti-AIDS drug PNU-142721 19
contains pyridine and pyrimidine rings while the coenzyme methoxatin 21, that allows bacteria
to live off methane as their sole carbon source, contains an oxidised quinoline ring. All three
rings are heavily substituted and preparation of these compounds needs regiochemically controlled
substitution around the rings.
O
N
Me H
S
N
HBr
PART II – TRADITIONAL SOLUTIONS: ADDITION
OF ELECTRON-DONATING SUBSTITUENTS
Br2
pyridine
catalyst
N Cl
N
H
N
N
17
Br
16
Br Br Br
The analgesic Flupirtine 23 is a simple pyridine with three substituents at the 2, 3, and 6 positions.
Removal of the amide shows the core 24. The 4-fl uorobenzylamine 25 could be added by
nucleophilic substitution (easier in pyridines than in benzenes) and we shall delay the choice
of the leaving group (X in 26) for the moment. The only amino group we could conceivably
add by nitration is the one in the 3-position so we might continue by FGI (reduction) and CN
disconnection 27.
N
HO 2C
cyclohexene
NH2
O
19; PNU-142721 20; pyrimidine 21; methoxatin 22; quinoline
O
NH
CO2H
N
18
Br
CO 2H
Br
Br
N

F
F
32 Regioselectivity in Electrophilic Substitution with Electron-Donating Groups 753
25
N
H
NH2 +
N
23; Flupirtene
H
N OEt
O
NH2 NH 2
C–N
amide
FGI
The nitro group will help the nucleophilic aromatic substitution so now we must choose
the leaving group X in 27. It need not be a good leaving group - the slow step in nucleophilic
aromatic substitution is the addition of the nucleophile -so as long as X is a tolerable leaving
group, it will do. It should promote electrophilic attack by NO 2 in the 3-position and 28; X
OMe should be available commercially. Putting X OMe fulfi ls all these conditions. Here is
the synthesis. 3
HNO 3
Nitration of 28; X OMe is successful because both electron-donating OMe and NH 2 groups
activate the 3-position and the intermediate cation 31 is delocalised over both N and O atoms. We
could have used lone pairs on either the OMe or NH 2 groups to draw the mechanism 30. The reaction
occurs in spite of the pyridine ring rather than because of it. The position of attack - C3 or C5 - is not
easily predicted and searching the literature or trial and error is needed.
Regioselectivity in Electrophilic Substitution with Electron-Donating Groups
You might think that nowadays there would be no doubt about the results of such reactions as
the nitration of 28 since NMR would quickly distinguish the possible products. This is not so as
a notorious case shows. Though it was known that reaction of 33 with iodine in aqueous sodium
carbonate gave the 2-iodo compound 34 in good yield, it was claimed in 1990 that a more complex
reagent gave the 6-iodo isomer 32. Reinvestigation showed that 34 was the only product though
the alternative 32 could be formed in moderate yield at higher temperature. It was also known
that chlorination gives the 2-chloro compound 35. The preference for the site next to nitrogen
(and therefore para to the OH group) may be due to steric crowding of the solvated oxyanion in
water. 4
F
NO2
N
H
N
NH2
NH 2
X N NH2 X N NH2 X N NH2
26
27
28
24
nitration
MeO N NH2H2SO4 MeO N NH2 Ar N
H
N NH2 28; X = OMe 27; X = OMe 29; Ar = 4-F-C6H4 NO 2
NO 2
H
25
NO2
NO2
NO2
MeO N NH2MeO N NH2MeO
(+)
N NH2 (+)
30
31a 31b
(+)
H
C–N
1. H 2
Raney Ni
2. ClCO 2Et
27
23

754 32 Functionalisation of Pyridine
I
N
32 (6-iodo)
OH
?
NaI, NaOCl
MeOH, H2O
OH
I 2
N
K2CO3 H2O N I
33 34 (2-iodo)
The synthesis of the drug PNU-142721 19 required a series of electrophilic substitutions on
3-hydroxy pyridine 5 33. Iodination of the chloride 35 went in the previously inaccessible 6position
to give 36. Now iodine-lithium exchange and reaction with acetaldehyde gave the secondary
alcohol 37 and fi nally iodination gave the tetrasubstituted pyridine 38. Each new substituent is
added as an electrophile in a specifi c position. Only the acetaldehyde had no choice.
35
I 2, H 2O
K2CO 3
Installation of the furan ring requires two extra carbons provided by a Sonagashira coupling
with trimethylsilyl acetylene to give 39. Cu(I)-catalysed closure of the furan ring follows and now
the role of the chlorine atom on the pyridine ring is revealed. It is there to block the most reactive
position and, its job complete, it can now be removed by hydrogenation.
35
Completion of the synthesis of PNU-142721 19 requires introduction of asymmetry and
coupling with a pyrimidine thiol. Asymmetry was introduced in two ways. The alcohol 41 was
enantioselectively acylated with trifl uoroethyl butyrate catalysed by porcine pancreatic lipase
(chapter 29) or else a Swern oxidation gave the ketone that could be enantioselectively reduced with
()-Dip chloride (chapter 24). Clean inversion from (S)-41 to the chloride (R)-42 was achieved
only with the Mitsunobu-like reagent Ph 3P/CCl 4. Finally, coupling with the thiolate anion of the
pyrimidine 43 gave a second clean inversion. 5 One recrystallisation improved the ee of the drug
19 from 97.6% to over 99%.
O
Me 3Si
(Ph 3P) 2PdCl 2
CuI, Et 3N
CH 2Cl 2, THF
N
OH
33
Cl 2
K2CO 3
H 2O
I
HO
1. LiH
2. BuLi
HO
I2, H2O HO
Cl N I
3. MeCHO
Cl N
OH K2CO3 Cl N
OH
Me
Me
36; 71% yield
37; 62% yield 38; 62% yield
Me H
(S)-41
SiMe 3
CuI
Et3N HO
EtOH
OH
Cl N
Me
39; 81% yield
OH
Ph3P
CCl 4
O
N
Me H
(R)-42; >97% ee
75–89% yield
Cl
Cl
O
HS
OH
N
Me
40; 86% yield
N
N
NH2
43
Cl
cyclohexene
20%
Pd(OH) 2
MeOH
reflux
1. NaH, DMF
2. (R)-42
O
N
N
35
Me
OH
Cl
41; 77% yield
(–)-(S)-19
97.6% ee
89% yield
OH

The Anti-Tumour Antibiotic Kedarcidin
Another incorrect structure was revealed by synthetic work aimed at structure 44, alleged to be
a part structure (the ‘chromophore’) of the antitumour antibiotic kedarcidin. The synthesis was
successful but revealed that the structure was wrong as the compound is a β-amino acid and not
an α-amino acid as had been assumed. 6
i-PrO
MeO
OMe
Cl
N
OH
O
HN CO2Me
The obvious compounds to make are the pyridine amines for coupling to the undisputed
naphthalene fragment. Both were made from the same pyridine 35 that featured in the last section.
Iodination and protection gave two iodo-pyridines 46; RTBDMS and MOM. The fi rst was combined
with Jackson’s d 3 reagent 47 (chapter 13) in a Negishi coupling to give 48 and the second in a
Heck reaction to give the unsaturated ester 49 to which Davies’s chiral lithium amide (chapter 24)
could be added to give a 97:3 ratio of 50 and its diastereoisomer.
35
Deprotection of 48 gave the amine needed for the synthesis of 44: this proved not to be the
natural product. The synthesis of the correct structure 6 45 had a curious twist: removal of the
benzyl groups from 50 resulted in dechlorination 51 and the chlorine was reinstated 52 with another
electrophilic substitution having the same regioselectivity as that of 35.
i-PrO
MeO
OMe
HN
OH
N
O
CO2Me
HO
Cl
44; alleged kedarcidin chromophore (1993)
OH
45; kedarcidin chromophore (1997)
1. t-BuOCl, NaI
H2O, MeCN
2. TBDMSCl
imidazole
46
R = MOM
75% yield
from 35
50
R = MOM
Cl
RO
N I
IZn
NHBoc
CO2Me 46; R = TBDMS
71% yield
47; d3 +
1. PdCl2(PPh3) 2
MeCONMe2 2. HF, NaF, pH5
reagent
Cl N
NHBoc
HO
BnN
CO2Me
CO2t-Bu Cl N
CO2t-Bu BnN
Li
Cl N
CO2t-Bu Pd(OAc) 2, Et 3N
DMF, 60 ˚C
1. H2, Pd(OH)2/C
MeOH, HOAc, H 2O
2. CF3CO2Et Et3N, MeOH
3. t-BuOH, TsOH
32 The Anti-Tumour Antibiotic Kedarcidin 755
RO
THF, –80 ˚C
RO
49; R = MOM; 90% yield 50; R = MOM; 83% yield
HO
N
NHCOCF3
51; 68% yield
CO 2t-Bu
Ph
NCS
DMF
Cl
HO
N
48; 73% yield
Ph
NHCOCF3
52; 82% yield
CO 2t-Bu

756 32 Functionalisation of Pyridine
Halogenation and Metallation
To summarise these last two examples: with even one electron-donating group on the pyridine
ring, halogenation becomes a useful reaction. Metallation with lithium or palladium-catalysed
couplings with alkenes (Heck), organo-zinc compounds, including those with β-hydrogens (Negishi),
or boronic acids (Suzuki) make new CC bonds while Buchwald-Hartwig chemistry makes
new bonds to O or N atoms. These are obviously very versatile sequences.
Pyridine N-Oxides in Electrophilic Substitution
This is all very well if your target molecule happens to have electron-donating substituents on
the pyridine ring, but what if it hasn’t? The traditional solution is to use a pyridine N-oxide 53
which simultaneously blocks the lone pair on nitrogen and provides a strongly electron-donating
substituent. Pyridines are easily oxidised to N-oxides with H 2O 2 (another instance of electrophilic
attack at N) and the substituted N-oxides 54 are easily reduced back to the pyridines 55 with trivalent
phosphorus compounds such as PCl 3.
E
N
H2O2 O
N
E
O
N
PCl3 N
53 54 55
Nitration can be carried out with the usual reagents and occurs in the 4-position (the 2- and
6-positions being sterically hindered by the solvated oxido group). The electrons from oxygen are
used in the reaction 56 and the nitrogen atom retains its positive charge throughout but the intermediate
57 is only a mono-cation unlike 9. This is a good synthesis of 4-nitropyridine 59.
O
N
O
N
H
NO2
NO2
PCl3 56
O
O
N
57
O
N
58
N
59
The deoxygenation of the product can be developed in synthetically useful ways. If there
is an electron-withdrawing group at the 3-position and PCl 3 is used, deoxygenation is accompanied
by chlorination at the 2-position 62. This new chlorine is activated towards
nucleophilic aromatic substitution both by its position on the pyridine ring and by the electronwithdrawing
group at the 3-position and can be replaced by O, N, S, or P nucleophiles 63. Pyridines
such as 61 are easily made from available nicotinic acid, pyridine-3-carboxylic acid 60.
N
O
OH
60; nicotinic acid
N
O
O
61
R
PCl3
This result suggests that the initial interaction of the N-oxide with PCl 3 is nucleophilic attack by
O 64. The intermediate can then either lose POCl 3 65 or add chloride. When nucleophilic attack
N
62
O
R
Nu
Cl N
E
63
O
Nu
R
NO 2

y chloride 67 occurs, it is the most electrophilic atom which is attacked - the one between the
pyridine nitrogen and the electron-withdrawing group. Aromaticity is restored by the loss of a proton
from the 2-position 68. This is a sort of nucleophilic substitution occurring after electrophilic
substitution. The leaving group (Cl 2PO ) is not at the site of nucleophilic attack.
E E
N
O
N
O
PCl3
PCl3
64 65
55
O
N
O
PCl3
R
66 67
Good use is made of this chemistry in the synthesis of nifl uminic acid 69, an analgesic with a
pyridine ring. Disconnection of the CN bond suggests a 2-chloropyridine 70 starting material
easily derived from nicotinic acid 60 and a simple aromatic amine 72 available by functionalisation
of trifl uorobenzene 74. 69 Is actually available as nifl umic acid from Aldrich.
CO 2H
N NH
CF 3
N
NH2
CO 2H
Cl N
The only mild surprise in the synthesis is that the PCl 3 reaction turns the acid into an acid chloride
75 which must be hydrolysed before the amine is added, otherwise an amide would be formed. 7
74
69
nifluminic
acid
These N-oxides can also be used to functionalise side chains in pyridines 76. The reaction is
rather similar to the PCl 3 reaction in that acetic anhydride attacks the oxygen atom of the N-oxide
and the released acetate ion can deprotonate 77 at an alkyl group in the 2-position. The resulting
enamine 78 can sacrifi ce the weak NO bond between the now neutral heteroatoms and form a
much stronger CO bond by a [3,3] sigmatropic rearrangement to give 79.
N
O
1. HNO 3
H 2SO 4
2. H2/Pd/C
HOAc
76
32 Pyridine N-Oxides in Electrophilic Substitution 757
C–N
72 60
H 2O 2
O
R
N Cl
O
PCl2
NO2
CO2H
O
H
N Cl
O
PCl2
CF3
CF3 CF3 72 73 74
N
68
70 O 71
60
71
PCl 3
Ac2O N
H OAc
O O
N
COCl
1. H2O Cl
75
2. 72
R
CO2H
TM69
nifluminic
acid
N
[3,3]
N
O O OAc
77 78 79
62

758 32 Functionalisation of Pyridine
This chemistry, preceded by an electrophilic substitution on the N-oxide, fi nds a most important
application in the synthesis of omeprazole, Astra(Zeneca)’s anti-ulcer drug and one of the best
selling medicines of recent years. Omeprazole 80 is a sulfoxide and has a 2,3,4,5-tetrasubstituted
pyridine linked through the sulfur atom to a benzimidazole. 8
The sulfoxide 80 can be made from the sulfi de 81 and an obvious CS disconnection suggests
two much simpler heterocyclic starting materials, a pyridine 82 and a benzimidazole 83. It is the
pyridine 82 which concerns us now.
Omeprazole: Analysis 1
80
FGI
oxidation
OMe
Me Me
N
Using the chemistry we have just described, the CH 2Cl group in the 2-position could be introduced
by functionalisation of the trimethyl pyridine N-oxide 86 since only the methyl group in the
2-position should be affected. The group in the 4-position might be introduced by electrophilic
attack on the N-oxide but there is no good reagent for “MeO ” as we shall see in the next chapter.
Nitration of the N-oxide 86 works well, however, and nucleophilic substitution is so good on pyridine
N-oxides that this is a reasonable strategy.
Omeprazole: Analysis 2
N
Me Me
O
S
HN
81
N
OMe
N
80
omeprazole
C–S
S
HN
OMe
Me Me
3,5-Dimethylpyridine 88 is available and the methyl group in the 2-position can be added by
the remarkable reaction in which MeLi appears to displace a hydride ion. It is not obvious that the
nitration of 86 will occur in the 4- rather than the 6-position but O is a bigger substituent than it
appears to be because of solvation. The published synthesis gives only “NO 2 ” as the reagent and
does not say how it was formed.
N
OMe
N
OMe
+ HS
Cl
N
N
H
82 83
OMe
NO2
Me Me FGI Me Me Me
C–N
Me Me
FGA
Me Me
C–C
Me
O
84
Me
N
Me
N
Me
O
O
85 86 87 88
N
Me N
OMe

Omeprazole: Synthesis 1
The diffi cult nucleophilic displacement of the NO 2 group by methoxide must be carried out
while the N-oxide is still present. The leaving group in this reaction is nitrite ion, NO 2 , which
is reasonably stable but you will recall that merely tolerable leaving groups are acceptable in a
reaction in which the addition step is rate-determining providing that they accelerate that step. The
nitro group certainly does that. The N-oxide has now completed its duties and functionalisation of
the side chain (2-Me) by the acetic anhydride reaction follows to give 89.
88
Me
MeLi
Me
1. H2O2 Me Me
MeO
Me Me Me
Ac2O
Me
THF
N Me 2. NO2 N
MeOH
Me
N Me
N
O
O
OAc
87 85
84 89
Acetate is not a good enough leaving group for an S N2 displacement (note the difference between
S N2 and aromatic nucleophilic substitution) so it must be transformed into the chloride 82 before
reaction with the thiolate anion of 58.
Omeprazole: Synthesis 2
89
SOCl2
OMe
Me Me
The fi nal oxidation of achiral sulfi de 62 to sulfoxide 80 with achiral mCPBA must of course
produce racemic omeprazole. Omeprazole is actually a pro-drug - it is transformed enzymatically
into the active compound - and in this process the chirality at sulfur is lost. The two enantiomers
have nearly the same biological effects though the more readily absorbed (S)-omeprazole is now
marketed as esomeprazole.
Ortho-Lithiation of Pyridines
N
62
32 Ortho-Lithiation of Pyridines 759
83
NaOH
Cl
NO2
81
mCPBA
Halogenation and replacement of halogen (Br or I) by a metal is a useful way to extend the scope
of electrophilic substitution on pyridines already having an electron-donating substituent
( usually based on O or N). Another valuable way is ortho-lithiation (chapter 7), that is replacement
of a hydrogen atom by lithium ortho to a similar substituent. The requirements are not quite the
same. The substituent must be an ortho-director: it must acidify the ortho proton and/or direct
the base (usually BuLi) to the ortho position. The simplest ortho directors are F and OMe but
the best are oxazolines, amides, and carbamates. There are more details of these processes on
benzene rings in chapter 7. If one of these groups is in the 4-position 90 or 93 lithiation 91 is
unambiguous and any electrophile (E ) that reacts with an aryl lithium reacts in the 3-position
92 and 94.
N
OMe
OMe
Me Me
O
80
omeprazole
S
HN
N
OMe
OMe

760 32 Functionalisation of Pyridine
OMe
H
BuLi
OMe
Li
E
2. E
N
N
N
N
N
90 91 92 93 94
The relative acidities of the positions around the pyridine ring 9 without any assistance from an
ortho-director are 700:72:1 for positions 4:3:2. It may seem odd that the position next to nitrogen
is least acidic but the sp 2 lone pair on nitrogen has an antibonding interaction with the C-Li bond
97. Though BuLi may be directed by the nitrogen 96 to C-2 the unstable product 97 soon equilibrates
to the more stable C-4 Li derivative 98.
700
H
N
H
H
95; acidity ratios
72
1
Regiospecifi city demands ortho-direction. A surprisingly effective group is a carboxylic acid
CO 2H that acts as its lithium derivative CO 2Li. One equivalent of BuLi is used to make this 100
from, say picolinic acid 99, and three equivalents of LiTMP to make the C-Li derivative 101.
Reaction with electrophiles such as CO 2 or carbonyl compounds occurs at C-3 102.
Iso-nicotinic acid 103 must also react at C-3 but nicotinic acid 105, R H shows the regioselectivity
expected from the relative acidity of C-1 and C-4 and gives substitution at C-4 whether
C-1 is substituted 105, R Cl, or unsubstituted 105, R H. The same result is found for amides
or oxazolines as ortho-directors. 10
This behaviour also occurs with quinolines, e.g. 107 and 109. BuLi cannot be used as it attacks
quinolines as a nucleophile. This problem is also found with other heterocycles, particularly those
with more than one heteroatom. 11
OMe
E
CONR2
1. BuLi
N H
N Li
Li Bu
anti-bonding
96 97
CONR2
BuLi
3 x
LiTMP
Li
CO2
CO2H O
N CO2H N CO2Li N
N CO2H 99 100
OLi
101 102; 85% yield
CO2H CO2H 1. BuLi
CO2H 1. BuLi
2. LiTMP
2. LiTMP
N
3. CO2
65% yield N
3. CO2
73% yield N
103 104 105
Li
N
98
CO2H CO2H 1. BuLi
2. LiTMP
3. CO2 CO2H R 69% yield
N Cl
106
E

N
107
Diazines
CO 2H
1. LiTMP
2. CO2
The three diazines, pyridazine, pyrimidine and pyrazine, are metallated well providing there is
good ortho-direction to prevent nucleophilic addition. The pyridazine (OMe as ortho-director)
111 and pyrazine 113 derivatives can be metallated 12 and their zinc derivatives coupled with
aromatic rings (Negishi coupling) to give 112 and 114. It is unusual to see Cl in 113 acting as such
an effi cient ortho-director.
OMe
N-Formyl amines such as DMF make good electrophilic CHO donors and in reaction with the
pyrimidine provide a tandem double coupling of electrophilic formylation followed by nucleophilic
substitution by the released amine anion. 13 The OMe group is the ortho-director.
Cl
The Halogen Dance
CO2H
N
108; 80% yield
OMe
N
1. BuLi
2. ZnCl2 N
N
N
3. 2-bromo
pyridine
N
OMe
4% Pd(PPh3) 4
OMe
111 112; 77% yield
N
OMe
N
OMe
Li
CO 2H
OHC
N
The iodo-fl uoro-pyridine 119 is lithiated by LDA to give the only possible lithium derivative 120.
But iodine is a poor ortho-director and the compound equilibrates by the ‘halogen dance’ to put
the Li atom next to one of the best ortho-directors: fl uorine. 14 Presumably one molecule of 120
removes I from 119 to give 123 from which the 3-I atom is removed by another molecule of 120
initiating a chain.
O
N
OMe
N
109
N Cl
1. LiTMP
CO 2. CO2 2H
1. BuLi
2. ZnCl2 3. PhI
4% Pd(PPh 3) 4
N
OMe
N
110; 60% yield
N Cl
113 114; 99% yield
N
OMe
CHO N
N
Cl N
Cl N
N N
O
115 116
117 118
I
N F
1. LiTMP
LDA
Li
I
N F
N F
119 120 121
32 The Halogen Dance 761
I
Li
MeI
I
Me
N F
OMe
I
N F
122 123
I
CO 2H
CO 2H
CHO

762 32 Functionalisation of Pyridine
This product was used by Comins in his synthesis of mappicine. The antiviral alkaloid is the
alcohol formed by borohydride reduction of mappicine ketone 124. Strategic disconnections
124 split the molecule into a quinoline 125 and a pyridone 126 and correspond to a simple S N2
and a Heck reaction. If the Heck reaction is performed last it will be intramolecular and hence
regioselective.
N
O
N O
124; mappicine ketone
Each component is made by lithiation of a heterocycle. Chlorine-directed lithiation of the commercially
available quinoline 127 goes at C-3 and reaction with formaldehyde gives the primary
alcohol 15 128. Reaction with PBr 3 replaces both OH and Cl with Br to give 125.
N
The pyridine 122 reacts with BuLi by I/Li exchange: capture of the lithium derivative with
propanal and oxidation gives the ketone 130 in the heterocyclic equivalent of a Friedel-Crafts
acylation. The fl uorine atom that was originally present to initiate the halogen dance from 120 to
121 can now be hydrolysed to give the pyridone 126.
The quinoline 125 and the pyridone 126 are coupled by a base-catalysed S N2 reaction. Formation
of the anion of the pyridone ensures attack at nitrogen (chapter 35). It only remains to close
the ring by a Heck reaction. 16
126
I
N Cl
1. LDA
2. CH2O
127 128
N F
122
t-BuOK
Me
O
1. BuLi
2. EtCHO
Me
HO
N F
129; 84% yield
125
N
Br
125
the quinoline
Cl
OH
O
Heck reaction
Br
PBr 3
nucleophilic
substitution
Me
Me
PCC HCl
N
O
N O
H
126
the pyridone
N
125
Br
Me
N F
H2O
N
H
O
130; 84% yield 126; 92% yield
Br
N O
O
131 132; 81% yield
O
N
O
Pd(OAc) 2
KOAc
Bu4N Br
MeCN
Br
124
57% yield

Tandem Double Lithiation: The asymmetric synthesis of camptothecin
The closely related camptothecin 133 is more complicated because it is chiral. Close analogues
(topotecan and irinotecan) are in use as anti-cancer drugs. As these compounds differ only by
substitution on the quinoline, synthesis of the enantiomerically pure pyridone 135 is obviously of
prime importance.
N
HO
O
O
N O
133; (S)-camptothecin
Comins , synthesis of 135 uses an ingenious double lithiation strategy. Treatment of
2-methoxy-pyridine 137 with the very hindered lithiating agent mesityl-lithium 136 gives
clean ortho-lithiation 138. Addition of Me 2NCHO would give the 3-aldehyde but Comins uses
the N-formyl diamine 139 to give, before work-up, the lithium alkoxide 140 with the diamine
still attached.
A molecule of BuLi is now guided to C-4 of 140 by the chelating diamine to give 141. Reaction
with iodine, reduction, demethylation and acetal formation give 143 in reasonable overall yield
after a short sequence from 137.
Now the asymmetric addition of the TCC 145 ester of 2-keto butyric acid (substrate strategy,
see chapter 27) to the lithium derivative of 143, prepared by I/Li exchange, gave the alkoxide 144
and hence, on work up in acidic solution, the pyridone 17 135. Coupling to the quinoline 134 was
achieved by the same S N2-Heck sequence used in the synthesis of 124.
N
134
the quinoline
I
Heck reaction
Cl
nucleophilic
substitution
HO
O
O
N O
H
135
the pyridone
Li
Me2N Me
Me
Me
+
N OMe
137
N
Li
+
OMe
Me2N Me
N
CHO
Me
N
OLi
136; mesityl 2-methoxy
N OMe
-lithium pyridine 138 139 140
140
32 Tandem Double Lithiation: The asymmetric synthesis of camptothecin 763
BuLi
Me 2N
Li
N
Me
OLi
N OMe
141
1. I 2
2. H 2O
NaBH 4
CeCl3
I
N OMe
OH
142; 46% yield
Me3SiCl
NaI
(CH 2O) n
MeCN
I
N O
O
143; 87% yield

764 32 Functionalisation of Pyridine
143
2.
1. BuLi
O
OTCC
LiO
O
N O
144
OTCC
O
Tandem Lithiation of Pyridine N-Oxides and Nucleophilic Substitution
We have seen how pyridine N-oxides can be used to promote electrophilic oxidation at C-2,4,
and 6. They also promote ortho-lithiation and nucleophilic substitution making them very versatile
intermediates. This is well illustrated in Quéguiner’s synthesis of the antibiotic caerulomycins.
2,2’-Bipyridyl, available as a ligand for many metals, is easily oxidised to its monoxide 146.
The synthesis starts with two electrophilic substitutions. Lithiation occurs ortho to the N-oxide:
quenching with BrCN gives a good yield of the bromide 147 and a conventional electrophilic nitration
occurs para to the N-oxide.
Next a nucleophilic substitution: the displacement of the poorish leaving group nitrite by methoxide
to give 149. The N-oxide had done its work so it is removed with PBr 3 and a Negishi coupling
with MeZnCl completes the skeleton of the caerulomycins 18 151. Oxidation of the methyl
group to an aldehyde with SeO 2 or phenyl seleninic anhydride gives caerulomycin E: its oxime is
caerulomycin A.
145
N
O
MeONa
MeOH
146
Br
N
OMe
N
O
1. LDA
2. BrCN
149; 84% yield
N
Br
PBr 3
CHCl 3
reflux
N
O
A limited use of direct electrophilic substitution combined with halogen/lithium exchange or
ortho-lithiation allows us to make a variety of pyridines and quinolines. When the N-oxides are
used as well, the scope is even wider. Nucleophilic substitution extends this still further. In the
next chapter (33) we shall see that electrophilic oxygen can also be added to pyridines. What is
missing is the direct formation of 3-substituted pyridines: this is dealt with in the next section.
HCl
H2O
i-PrOH
147; 70% yield
Br
N
OMe
N
135
60% yield
93% ee
KNO3 H2SO4 80 ˚C
20 hours
N
Br
MeZnCl
Pd(PPh3) 4
THF
reflux
OH
145
TCC alcohol
NO 2
N
O
148; 66% yield
Me
OMe
N
N
Ph
150; 90% yield 151; 90% yield
N

PART III – SURPRISINGLY SUCCESSFUL DIRECT ELECTROPHILIC
SUBSTITUTIONS
When, as in the omeprazole and caerulomycin syntheses, an N-oxide has a number of functions,
it is worth building in this extra functionality. Only 4-substituted pyridines can be made from the
N-oxide: the 3-isomers must be made available by direct electrophilic substitution on pyridines
themselves and fortunately some direct methods do work, though it is not immediately clear why
they do! Direct sulfonation 19 and bromination 20 both work well in very strong sulfuric acid, giving
the 3-sulfonic acid 152 and 3-bromopyridine 153 in good yield.
SO2OH
very concentrated
H 2SO 4
Br 2, 130 ˚C
N
catalytic HgSO4 220 ˚C, 24 hours N
very concentrated
H2SO4 N
152; 70% yield 153; 86% yield
It seems strange that reactions are successful under very strongly acidic conditions when the
pyridine will be completely protonated: one clue to this mystery is that “very strong sulfuric acid”
is made by adding SO 3 to concentrated sulfuric acid. Another is the mechanism of an important
reaction of pyridine with SOCl 2 which gives a double pyridinium salt 21 158. Initial electrophilic
attack at nitrogen 154 is followed by nucleophilic attack by a second pyridine at the 4-position
155. Loss of a proton 158 then re-aromatises the fi rst pyridine and the remains of the SOCl 2 must
disappear as SO(?) and chloride ions.
N
32 Tandem Lithiation of Pyridine N-Oxides and Nucleophilic Substitution 765
1. SOCl 2
2. EtOH
N
N
Cl S O
Cl
O
N
S
Cl O
N
S
Cl
N
N
H
154 155 156 157 158
The fi nal product 158 is useful because the pyridinium group can be displaced by nucleophiles.
An important example is the reaction with DMF which gives 22 the acylation catalyst DMAP (pronounced
‘D-map’, 4-DiMethylAminoPyridine) 159, and, presumably CO and HCl.
N
1. SOCl2
2. EtOH
158
Me2N-CHO
140–160 ˚C
If the double salt 158 is heated with sodium sulfi te (Na 2SO 3) in water, aromatic nucleophilic
substitution 160 leads to the sodium salt of pyridine-4-sulfonic acid 162 or to the sulfonic acid
itself 163 after acidifi cation. These are nucleophilic substitutions following electrophilic attack at
nitrogen.
N H
NMe 2
N
N
159
DMAP
DiMethyl
Amino
Pyrdidine
N
Br
2Cl

766 32 Functionalisation of Pyridine
N
N
H
O
O S O
O O
N S O
N
N
H
160 161 162
The products of many of the reactions in this section, e.g. 152, 153, and 163, look as though
they have been made by straightforward electrophilic substitution on the pyridine ring. But they
haven’t. In the next section we explore electrophilic substitutions that really work.
PART IV – SUCCESSFUL NITRATION OF PYRIDINE
SO2O
SO2OH
We now come to the successful nitration of pyridines in the 3-position by an indirect procedure. 23
The reagent is N 2O 5, dinitrogen pentoxide, a kind of “nitric acid anhydride”, a white crystalline
molecular solid 164 that ionises in polar solvents such as nitromethane to NO 2 and NO3 . Treatment
of pyridine with N 2O 5 in nitromethane followed by aqueous work-up with any of a variety
of sulfi tes (SO 2, Na 2SO 3 or NaHSO 3) gives high yields of 3-nitro-pyridine 165. The contrast with
previous methods could hardly be greater. The maximum yield from direct nitration is 5% - here
we get 77% of 3-nitro pyridine 165.
O N O N O O
N
O
O N O O
NO2
1. N2O5, MeNO2 O
2. NaHSO3, H2O O
164 N
N N
2O5 white crystalline solid in polar solvents
165; 77% yield
Reaction at pyridine is actually preferred to reaction at benzene - easily illustrated by the fate
of 4-phenyl pyridine 167 under the two sets of conditions. Traditional nitration occurs only on
the benzene ring 166 with the (presumably protonated) pyridine ring acting as a meta-directing
deactivating substituent. With N 2O 5, nitration of the (presumably unprotonated) pyridine ring is
preferred and occurs in the 3-position 168.
N
NO 2
HNO 3
H 2SO 4
166 167
N
1. N 2O 5, MeNO 2
2. NaHSO 3, H 2O
You may have partly guessed what is actually happening from the earlier parts of the chapter.
Electrophilic attack occurs at nitrogen and the N-nitro pyridinium salt 169 is the product from the
fi rst stage. If the reaction is carried out at low temperature, this salt, similar to the fl uoroborate 11
already known from the work of Olah, can be isolated. 24 The role of the bisulfi te ion is as nucleophile.
Attack actually occurs reversibly in the 2- and 4-positions but it is the former intermediate
171 that leads to the fi nal product 165. If bisulfi te ion is added to the salt 169 in D 2O, the proton
N
N
163
NO2 168

NMR of compound 171 can be seen. You may already have guessed that the role of bisulfi te was
as a nucleophile, but what happens next?
N 2O 5
MeNO 2
N N
NO2
NO3 N
NO2
169 170
HO S O
The bond between the nitro group and the pyridine nitrogen atom in 171 is a weak NN σbond
and it is advantageous for this to be transformed into a stronger CN σ-bond. Intermediate
172 cannot easily achieve this but intermediate 171 can undergo a favourable [1,5] sigmatropic
NO 2 shift 173. Loss of bisulfi te 174 then gives the product 165.
3
2
4
5
1N
NO2
173
SO 2OH
[1,5]
NO 2
shift
The [1,5] sigmatropic shift may look unlikely at fi rst but it should be compared with the [1,5]
shifts familiar from cyclopentadiene chemistry. The nitro group passes suprafacially across the
gap in the delocalised π-system of 173. It is quite likely that the nitration of many pyrazoles goes
through a similar sigmatropic rearrangement. If nitration occurs fi rst at nitrogen 14, the nitro
group can then be transferred to carbon 175 (or to the other nitrogen atom!) by a [1,5]NO 2 shift to
give 176 and this gives the product 177 by a [1,5]H shift. Even the tautomerism of pyrazoles, such
as the interconversion of 177 and 178, could be a [1,5]H shift. 25
This mechanism via 173 and 174 explains some puzzling results. Nitration of 4-acyl pyridines
179 occurs in excellent yield though electrophilic substitution would be disfavoured. Both the
nucleophilic addition of NaHSO 3 (181 to 182) and the [1,5] shift (182 to 183) are probably accelerated
by the presence of a ketone in the 4-position.
O
H
NO 2
N SO 2OH
SO 2OH
N
NO2 SO
+
2OH
N
NO2 171 172
N
174 165
N
N
NO2
[1,5]NO2
N
N
NO2 [1,5]NO2
N
NO2
H
N
[1,5]H
N
NO2 NH
[1,5]H
N
H
NO2 N
14 175 176 177
178
O O
1. N2O5
MeNO 2
N
2. H2O NaHSO3 N
179
32 Tandem Lithiation of Pyridine N-Oxides and Nucleophilic Substitution 767
NO 2
180; 75% yield
O
O
NO2
NO 2
N
NO2 N
NO2
SO2OH N SO2OH
181 182 183
O
H

768 32 Functionalisation of Pyridine
No reaction at all occurs with 3-acyl pyridines 26 86. With this substitution pattern, we already
know that nucleophilic attack occurs between the carbonyl group and the nitrogen atom to give
186 and hence 187 by a [1,5]NO 2 shift. No elimination of bisulfi te would now be possible and this
is a dead end.
N
O
184; no reaction
This work opens up important developments.
Simple 3-nitro-pyridines and, by reduction, 3-amino pyridines are now readily available as
starting materials.
Nitration of compounds having pyridine and benzene rings can be controlled to give chemoselective
reaction at either ring.
There will obviously be many applications in the future as the key reagent, N 2O 5, can be
manufactured on a 100 tonne scale from N 2O 4 and nitric acid (HNO 3).
Sulfonation of Pyridines
O
N
NO2 N
NO2 SO2OH N SO2OH 185 186 187
Some reactions thought of as normal electrophilic substitution may in fact proceed by this mechanism.
One example might be the sulfonation of 2-hydroxy-nicotinic acid used in the synthesis of a
component 27 190 of Pfi zer’s successor to Viagra 188.
MeO
O
HN
O
N N
N
N
O
S
O
N
N
Et
188; Pfizer′s UK-357,903
N
2 x
C–N
Sulfonation of 2-hydroxy-nicotinic acid 191 with sulfuric acid does not work but 30% oleum,
that is sulfuric acid containing a 30% excess of SO 3, gives a 90% yield of 190. This might easily
occur by N-sulfonation 192, addition of some nucleophile 193, [1,5] shift 194 and elimination.
Note that the position between CO 2H and N in 192 is blocked by the OH group so addition must
occur on the other side in contrast to 184. This compound will also be discussed in chapter 33.
MeO
O
O
[1,5]
OH
N O
C–O
N–S
O 2N
O
S
O
N
N
Et
SO2OH 189 190
O
OH
OH
N O

N
OH
CO2H
OO 2S
Extension by Vicarious Nucleophilic Aromatic Substitution
Vicarious nucleophilic substitution is the addition of nucleophiles carrying their own leaving group
at an unsubstituted position on an aromatic ring. Since the Bakke nitration makes 3-nitropyridines
available, reactions with amine nucleophiles X–NH 2, where X is a leaving group, at unsubstituted
positions become possible. 28 One such nucleophile is hydroxylamine. Attack occurs next to nitrogen,
but para to the nitro group 195. Dehydration 196 and protonation of the anion 197 at the imine nitrogen
gives the amine products 198. A base (KOH is best) is also needed and R can be H, Alk, or Ar.
OH
NH2 An alternative nucleophile is the amino-triazole 200 and this works better in some cases,
notably the isoquinoline 199. Amination again occurs para to the nitro group 201.
Synthesis of Imidazo[4,5-c]pyridines
N
OH
CO 2H
OO 2S
Nu
191 192 193
If, on the other hand, an amino group can be introduced ortho to the nitro group, reduction of 202
or 203 makes available the starting materials for fused heterocycles. One example is the synthesis
of imidazo[4,5-c]pyridines 205 from diamino pyridines such as 204.
A published synthesis of 3,4-diaminopyridine 29 204 starts with nitration of ‘4-hydroxypyridine’
207. This is a diffi cult reaction in spite of the electron-donating OH group because the compound
is mostly a pyridone 206. Nevertheless a 74% yield of 208 can be achieved with a mixture of
fuming nitric and sulfuric acids.
N
OH
CO 2H
Nu
N
OH
SO2OH
194
R O
R O
R O
R
CO2H
N
O H
N
O
N
O
N
HO
N
H
N
HN N
H2N N
195 196 197
198
N
202
NO2
N
+
N
N
199 200
NH2 or
N
NO2 32 Synthesis of Imidazo[4,5-c]pyridines 769
N NH 2
NO 2
[H]
t-BuOK
DMSO
NH 2
N
NH2 NH2 203 204
?
NO 2
NH 2
N
N
201
65% yield
205
H
N
N
R
190
NO 2

770 32 Functionalisation of Pyridine
HN
O
OH
fuming
HNO 3
N
fuming N
HN
H2SO NO2
NO2
4
206 207 208
209
The product 208 may be as drawn or it too may be a pyridone 209 but in any case it reacts with
POCl 3 to give the chloro-compound 210 and then by nucleophilic substitution with amines such
as benzylamine to give, after reduction, the diamine 212 from which the benzyl group could be
removed to give 204.
208
or
209
H
H
POCl3
Cl
BnNH2
N Ph H2
5% Pt/C
N Ph
[H]
N
NO2 N
NO2
N
NH2
210; 94% yield
211 212
Another method 30 uses nitration of available 4-aminopyridine 213 to give unstable 214 and then
by thermal rearrangement, the nitro compound 202 that can be reduced to 204 in good yield.
N
NH2 HNO3 H2SO4 N
H
N
NO2
heat
N
NH2
NO2 H2, 5% Pd/C
MeOH
213 214
202; 72% yield
Neither of these methods is suitable for large scale production but the Bakke method 31 works
well with a signifi cant modifi cation. The amino group in 213 must be protected as an amide 215
to prevent formation of 214. Then nitration and reduction to give 217 (half-protected 204) work
very well.
213
Ac 2O
Et 3N
MeCN
N
If the diamine 204 is wanted, hydrolysis of the amide in 217 is the answer. But if the more
interesting imidazolo-pyridine 205 is wanted, acid catalysed cyclisation of the amine onto the
amide gives the imidazole 205; R Me directly. Of course if R needs to be something else, the
original acylation of 213 should be done with that anhydride (RCO) 2O.
N
N
H
N
O
215; 97% yield
NH 2
NH 2
2M HCl
5 hours
70 ˚C
1. N 2O 5
MeNO 2
2. H 2O
NaHSO3
204; 96% yield 217
N
The previous synthesis 29 ended at the half-protected diamine 212. The N-benzyl group can of
course be removed by hydrogenation to give 204 but cyclisation of 212 with an acid anhydride
gives 218, a part-protected version of 205.
H
N
O
NO2
216; 72% yield
H
N
O
NH2
37% HCl
1-butanol
reflux
1 hour
OH
H 2, MeOH
5% Pd/C
room
temperature
20 hours
N
O
204
98% yield
H
N
O
NH2
217; 97% yield
H
N
Me
N
N
205; R = Me; 90% yield
204

N
204
NH 2
NH 2
H 2
catalyst
N
H
N
NH2
212
The type of molecule to be made from these compounds is illustrated by ABT-491, Abbott
laboratories inhibitor 32 of platelet aggregation factor 219. The imidazolo-pyridine segment is the
very one we have been discussing (205; R Me) with the added complication that the rest of the
molecule must be added to one of the two nitrogen atoms of the imidazole and not to the other.
N
O
CONMe2
F
The complete synthesis starts with a Friedel-Crafts reaction between a benzoyl chloride 220
and an indole 221. Replacement of the chloride in 222 by an amino group is achieved by S N2 with
azide and reduction with Ph 3P. Nucleophilic substitution on the chloro pyridine 224 gives an intermediate
225 having imidazole connectivity problem solved. All that was needed was the correct
nitro pyridine, easily made by Bakke nitration on 4-chloropyridine. The imidazole is closed by
reduction and acetylation and a Sonigashira coupling inserts the acetylene. This is an impressively
short and convergent synthesis with only one protecting group - the Me 3Si on the acetylene.
Cl
O
Br
Br
N
O
CONMe 2
F
226
N
N
Ph
N
Br
Ac2O
AcOH
N
N
N
N
218
219
ABT-491
(Abbott
Laboratories)
+
AlCl3
CH2Cl2 1. NaN3
DMF
N
room
temperature
N
2. Ph3P
THF, H 2O
F Cl
CONMe2
CONMe2 F Cl
220 221 222
O
Br O
N
+
Cl
NO2
N
Et3N MeCN
N
H
N
CONMe2 F NH2 CONMe2 F
223 224 225
1. H2, Pt/C
2. Ac2O
AcOH
Br
32 Synthesis of Imidazo[4,5-c]pyridines 771
N
N
Me 3Si
O
1. Pd(PPh3)4, toluene
SnMe 3
2. KF, H 2O, DMF
Ph
Me
219
ABT-491
NO 2
N

772 32 Functionalisation of Pyridine
PART V – APPLICATIONS
In this section we discuss the synthesis of various substituted pyridines by methods from earlier in
the chapter and their applications in the synthesis of larger drug molecules.
The Baeyer anti-cancer drug BAY 43-9006
This relatively simple compound 231 requires the 4-Cl picolinic acid chloride 227 easily made
in high yield by the SOCl 2 reaction described earlier. This has the advantage of simultaneously
turning the acid into the acid chloride. Formation of the amide 228 and then the diaryl ether is
followed by coupling with an isocyanate 230 to make the unsymmetrical urea 231. This large
scale synthesis is planned for manufacture. 33
CO2H
N
Anatoxin analogues
The heterocycles may be pyridine, pyridazine, pyrimidine (positional isomers) and the organozinc
reagents 233 were made from the bromo-compounds. Six compounds such as 234 were made
by Negishi coupling. 34
O
SOCl 2
O
N
COCl
OTf
BrZn
232 233
Epibatidine analogues (anti-smoking)
N
DMF MeOH
Cl
THF
+
MeNH 2
Cl
CONHMe
99 227; 89% yield 228; 88% yield
229 +
F 3C
Cl
230
The starting materials were prepared by electrophilic and nucleophilic substitution on activated
pyridines such as 235. The essential boronic acid 238 needed lithiation. 35
I 2, H 5IO 6
NCO
CH 2Cl 2
F 3C
Cl
N NH2
H2SO4 H2O, AcOH
N NH2 235
236
I
Suzuki coupling of such boronic acids with the trifl ate 240 of the protected ketone 239 gives
bicyclic compounds such as 241 easily reduced to epibatidine analogues such as 242.
N
N
H
N
O
p-aminophenol
t-BuOK
K2CO 3
DMF
H
N
1. Pd(PPh 3) 4
2. HCl, H 2O
H 2N
O
231; BAY 43-9006, 92% yield
NaNO 2
HF
pyridine
I
229; 87% yield
CONHMe
H
N
N
O
CONHMe
N
N
234; anatoxin analogue
1. BuLi
(HO) 3B
N F
2. (i-PrO) 3B
3. NaOH
N F
237 238

Boc
N
239
O
Alternatively, coupling of the boronic acid from 236 gives 242 that can be modifi ed by electrophilic
substitution afterwards and further Suzuki coupling used to give analogues 36
H
N
242
Polycyclic derivatives
Lateral lithiation of 244 and intramolecular electrophilic substitution with iminium ions derived
from the partly reduced phthalimide 247 in acidic solution leads to the polycyclic derivatives 37
such as 248. The 4-Me compound cyclises with some regioselectivity favouring para to OMe.
1. BuLi
Katritzky’s improvement of Bakke nitration
32 Synthesis of Imidazo[4,5-c]pyridines 773
1. (Me 3Si) 2NNa
2. PhNTf2
N
NH2
Boc
N
1. Br 2, HOAc
2. PhB(OH)2
Pd(OAc) 2
etc.
The main problem with the Bakke procedure is the need to prepare N 2O 5. Katritzky’s group has
avoided this by making N 2O 5 in situ from trifl uoroacetic anhydride and nitric acid. Pyridine gives
83% yield of 165, better than 77% by Bakke. Substituted pyridines such as 249 (76% rather than
15) and 251 (86% rather than 70) also give better yields, much better with 249.
OTf
238
Pd(PPh 3) 4
Boc
LiCl, Na 2CO 3
240 241
H
N
Ph
N
N
X 243
epibatidine
analogues:
X = F, NH 2, NMe2 MeO N
2. CH2O MeO N
Ph3P, DEAD
OH MeO N
N
244
245; 60% yield 246; 90% yield
1. LiEt 3BH
2. HCl, H 2O
N
1 part
N
249
MeO N
N
O
247; 90% yield
O
O N + +
OH
2.5 parts
conc. nitric
Cl
O 2N
F 3C
O
N
250; 76% yield
15% Bakke
OH
O
phthalimide
TsOH
benzene
N
MeO N
248; 70% yield
O
O
NO 2
O CF32.
Na2S2O5 H2O, 0 ˚C
N
6 parts 165; 83% yield
Cl
1. mix, 0-24 ˚C
Me Me
NO 2
N N
251
252; 86% yield
70% Bakke
N
O
F

774 32 Functionalisation of Pyridine
References
General references are given on page 893
1. G. A. Olah, S. C. Narang, J. A. Olah, R. L. Pearson and C. A. Cupas, J. Am. Chem. Soc., 1980, 102,
3507.
2. G. A. Olah, S. C. Narang and A. P. Fung, J. Org. Chem., 1981, 46, 2706.
3. W. Orth, J. Engel, P. Ernig, G. Scheffer and H. Pohle, Ger. Pat., 3,608,762; Chem. Abstr., 1987, 106,
50057.
4. P. W. Sheldrake, L. C. Powling and P. K. Slaich, J. Org. Chem., 1997, 62, 3008.
5. D. G. Wishka, D. R. Graber, E. P. Seest, L. A. Dolak, F. Han, W. Watt and J. Morris, J. Org. Chem.,
1998, 63, 7851.
6. S. Kawata, S. Ashizawa and M. Hirama, J. Am. Chem. Soc., 1997, 119, 12012.
7. E. C. Taylor and A. J. Crovetti, J. Org. Chem., 1954, 19, 1633; C. Hoffmann and A. Faure, Bull. Soc.
Chim. Fr., 1966, 2316.
8. Saunders, Top Drugs, chapter 5, page 37.
9. J. Clayden, Lithium, pages 61–70.
10. F. Mongin, F. Trécourt and G. Quéguiner, Tetrahedron Lett., 1999, 40, 5483.
11. A.-S. Rebstock, F. Mongin, F. Trécourt and G. Quéguiner, Tetrahedron Lett., 2002, 43, 767.
12. A. Turck, N. Plé, A. Leprêtre-Gaquère and G. Quéguiner, Heterocycles, 1998, 49, 205.
13. N. Plé, A. Turck, F. Bardin and G. Quéguiner, J. Heterocycl. Chem., 1992, 29, 467.
14. P. Rocca, C. Cochennec, F. Marsais, L. Thomas-dit-Dumont, M. Mallet, A. Godard and G. Quéguiner,
J. Org. Chem., 1993, 58, 7832.
15. D. L. Comins, M. F. Baevsky and H. Hong, J. Am. Chem. Soc., 1992, 114, 10971.
16. D. L. Comins and J. K. Saha, J. Org. Chem., 1996, 61, 9623.
17. D. L. Comins and J. M. Nolan, Org. Lett., 2001, 3, 4255; D. L. Comins and J. M. Salvador J. Org. Chem.,
1993, 58, 4656.
18. F. Trécourt, B. Gervais, O. Mongin, C. Le Gal, F. Mongin and G. Quéguiner, J. Org. Chem., 1998, 63,
2892.
19. S. M. McElvain and M. A. Goese, J. Am. Chem. Soc., 1943, 65, 2233.
20. H. J. den Hertog, L. van der Does and C. A. Landheer, Rec. Trav. Chim., 1962, 81, 864.
21. R. F. Evans, H. C. Brown and H. C. van der Plas, Org. Synth. Coll., 1973, V, 977.
22. G. Höfl e, W. Steglich and H. Vorbrüggen, Angew. Chem., Int. Ed., 1978, 17, 569.
23. J. Bakke, I. Hegborn, E. Øvreeide and K. Aaby, Acta Chem. Scand., 1994, 48, 1001.
24. J. M. Bakke and E. Ranes, J. Chem. Soc., Perkin Trans. 2, 1997, 1919; J. M. Bakke, H. Svensen and
E. Raines, J. Chem. Soc., Perkin Trans. 2, 1998, 2477.
25. J. W. A. M. Janssen, C. L. Habraken and R. Louw, J. Org. Chem., 1976, 41, 1758.
26. J. M. Bakke and E. Ranes, Synthesis, 1997, 281.
27. D. J. Dale, J. Draper, P. J. Dunn, M. L. Hughes, F. Hussain, P. C. Levett, G. B. Ward and A. S. Wood,
Org. Process Res. Dev., 2002, 6, 767.
28. J. M. Bakke, H. Svensen and R. Trevisan, J. Chem. Soc., Perkin Trans. 1, 2001, 376.
29. G. C. Wright, J. Heterocycl. Chem., 1976, 13, 601 modifi ed by D. M. Houston, E. K. Dolence, B. T. Keller,
U. Patel-Thombre and R. T. Borchardt, J. Med. Chem., 1985, 28, 471; M. F. Reich, P. F. Fabio, V. J. Lee,
N. A. Kuck and R. T. Testa, J. Med. Chem., 1989, 32, 2474.
30. H. Dvorakova, A. Holy, I. Votruba, and M. Masojidkova, Coll. Czech. Chem. Commun., 1993, 58, 629.
31. J. M. Bakke and J. Riha, J. Heterocycl. Chem., 1999, 36, 1143.
32. M. L. Curtin, S. K. Davidsen, H. R. Heyman, R. B. Garland, G. S. Sheppard, A. S. Florjancic, L. Xu,
G. M. Carrera, D. H. Steinman, J. A. Trautmann, D. H. Albert, T. J. Magoc, P. Tapang, D. A. Rhein, R.
G. Conway, G. Luo, J. F. Denissen, K. C. Marsh, D. W. Morgan and J. B. Summers, J. Med. Chem., 1998,
41, 74.
33. D. Bankston, J. Dumas, R. Natero, B. Reidl, M.-K. Monahan and R. Sibley, Org. Process Res. Dev.,
2002, 6, 777.
34. C. G. V. Sharples, G. Karig, G. L. Simpson, J. A. Spencer, E. Wright, N. S. Millar, S. Wonnacott and
T. Gallagher, J. Med. Chem., 2002, 45, 3235.

32 References 775
35. F. I. Carroll, F. Liang, H. A. Navarro, L. E. Brieaddy, P. Abraham, M. I. Damaj and B. R. Martin, J. Med.
Chem., 2001, 44, 2229.
36. F. I. Carroll, J. R. Lee, H. A. Navarro, L. E. Brieaddy, P. Abraham, M. I. Damaj and B. R. Martin, J. Med.
Chem., 2001, 44, 4039 and F. I. Carroll, J. R. Lee, H. A. Navarro, W. Ma, L. E. Brieaddy, P. Abraham,
M. I. Damaj and B. R. Martin, J. Med. Chem., 2002, 45, 4755.
37. M. A. Brodney and A. Padwa, Tetrahedron Lett., 1997, 38, 6153.
38. A. R. Katritzky, E. F. V. Scriven, S. Majumder, R. G. Akhmedova, A. V. Vakulenko, N. G. Akhmedov,
R. Murugan and K. A. Abboud, Org. Biol. Chem., 2005, 3, 538.

33
Oxidation of Aromatic Compounds, Enols
and Enolates
This chapter examines the addition of functional groups to aromatic rings and to carbonyl groups via
enols or enolates. It revises previous sections.
Introduction
PART I – ELECTROPHILIC SUBSTITUTION BY OXYGEN ON BENZENE RINGS
The Diazotisation Approach
Synthesis of a successor to Viagra
The Friedel-Crafts and Baeyer-Villiger Route
Avoidance by choice of oxygenated starting materials
Oxidation through Lithiation and Ortho-Lithiation
Hydroxylation of Pyridines by ortho-Lithiation
Synthesis of Atpenin B
Introducing OH by Nucleophilic Substitution
PART II – OXIDATION OF ENOLS AND ENOLATES
Direct Oxidation without Formation of a Specifi c Enol
Selenium dioxide
Nitrosation with nitrites
Nitrosation with stable nitroso compounds
Indirect Oxidation with Formation of a Specifi c Enol: Enone Formation
Pd(II) oxidation of silyl enol ethers
Bromination of enols in enone formation
Sulfur and selenium compounds in enone formation
Asymmetric Synthesis of Cannabispirenones
Oxidation of Enones: Epoxides and the Eschenmoser Fragmentation
PART III – ELECTROPHILIC ATTACK ON ENOL(ATE)S BY OXYGEN
The Problem
Competition with Baeyer-Villiger rearrangement and oxidative cleavage
Unexpected Success with the “Obvious” Reagents
Unique successful hydroxylations with ozone and mCPBA
First Successful Method: Epoxidation of Silyl Enol Ethers (Rubottom Oxidation)
Method, mechanism, and isolation of intermediates
Chemo- regio- and stereoselectivity: synthesis of fused γ-lactones
Hydroxylation of Amino-ketones via Silyl Enol Ethers
Synthesis of vinca alkaloids and model compounds
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

778 33 Oxidation of Aromatic Compounds, Enols and Enolates
Second Successful Method: Hydroxylation with MoOPH
The reagent: hydroxylation of lithium enolates
Stereoselectivity (substrate control)
Hydroxylation of steroids and amino acids
Third Successful Method: Hydroxylation with N-Sulfonyl Oxaziridines
The reagents and the mechanism
Hydroxylation of sodium and potassium enolates: side reaction with lithium
Substrate controlled stereoselectivity: asymmetric hydroxylation
Asymmetric hydroxylation with camphor sultam derivatives
Asymmetric synthesis of tetracycline precursors
Synthesis of a calcium channel opening drug
Asymmetric synthesis of buproprion
Summary
Introduction
This chapter is also about functionalisation. But it deals with the addition of a diffi cult
electrophile (‘RO ’) to familiar nucleophiles: aromatic compounds, including the pyridines
of chapter 32, and enols and enolates. As well as the diffi culties of creating suitable reagents
that control chemo- and regioselectivity, stereoselectivity and asymmetric induction are
important.
PART I – ELECTROPHILIC SUBSTITUTION BY OXYGEN ON BENZENE RINGS
The one large gap in electrophilic substitution reactions on benzene rings 1 is the absence of
simple methods to introduce oxygen with an electrophilic reagent 2. You were advised in the
Disconnection Textbook (page 21) to have the oxygen atom present in the starting material 3 and
achieve the same result by adding an electrophile 4.
[HO ]
The Diazotisation Approach
OH
?
R R
E
1 2 3
4
The traditional approach was a nitration, reduction, diazotisation and hydrolysis sequence of four
reactions. Though the OH group is actually added by a nucleophilic substitution on the diazonium
salt 7 the nitrogen atom was originally added as an electrophilic nitro group 5.
1
HNO3
H 2SO 4
R
5
NO2 H2, Pd/C
R
OH
E
NH2 NaNO2 HCl
R
6 7
OH
N2 H2O 2

You might think such an apparently cumbersome approach is now no longer used but it is. In
a synthesis of biologically active compounds related to epibatidine, the nitropyridine 9, available
by chemistry described in chapter 32, was converted into the key intermediate 14 by a sequence
of reactions including the removal of the OH group already present and the introduction of a new
one by diazotisation and so on. 1
HNO 3
O 2N
N O
H2SO4 N OH
K2CO3
DMF
N
quinoline
OH
N Cl
H
8 9 10; 45% yield 11; 78% yield
Fe
powder
H 2O
AcOH
H2N I
N Cl
12; 68% yield
Synthesis of a successor to Viagra
1. NaNO 2
HBF 4, H 2O
2. Ac 2O
I2
O 2N I
AcO I
2M KOH
N Cl
H2O
N Cl
13; 72% yield 14; 63% yield
In the large scale synthesis of the successor to Viagra described in the last chapter a short synthesis
of the pyridine 23 replaced a much longer laboratory synthesis that used a similar sequence. The
amino group in available 2-aminopyridine 15 directed sulfonation and bromination to give 17 and
then, its work done, was replaced by the OH group 18.
N
NH2
SO3 H2SO4 N
NH2
Br 2
N
NH2
The conversion of the sulfonic acid to the sulfonyl chloride 19, necessary for the formation
of the piperazine amide 20, also replaced the OH group by Cl. This was turned to advantage
in introducing the OEt group by nucleophilic substitution before Pd(0)-catalysed carbonylation
gave the carboxylic acid 23. This eight step route 2 giving 11% yield, and containing a hazardous
high temperature reaction with carbon monoxide, contrasts with the fi ve step large scale route
described in chapter 32 giving 50% yield.
Br
NaNO 2
POCl3
O 2N I
HO I
140 ˚C
O
S
O
H2O OH
O
S
O
OH
HCl
H2O O
S
O
OH
POCl3 O
S
O
Cl
15 16; 80% yield 17; 70% yield 18; 82% yield 19; 48% yield
Cl
OEt
Et3N N
Br
N
Br
19
CH2Cl2 HN
O
NEt S
O
N
NaOEt
EtOH
NEt
O
S
O
N
CO, Pd(0)
EtOH, Et3N
120 ˚C
NEt
20; 90% yield
33 The Diazotisation Approach 779
21; 66% yield
N
N
O
O
OH
OEt
S N
Br
PCl 5
CO 2Et
22; 95% yield
NaOH
EtOH
NEt
N
N
Cl
OEt
Br
CO 2H
O
S
O
N
NEt
23; 88% yield

780 33 Oxidation of Aromatic Compounds, Enols and Enolates
The Friedel-Crafts and Baeyer-Villiger Route
About the only simple way to introduce an oxygen atom by electrophilic substitution is to follow a
Friedel-Crafts acylation of 1 using, say acetyl chloride to give 24, with a Baeyer-Villiger oxidation
with a peroxyacid. The aromatic ring will normally migrate in preference to the methyl group and
the product 25 will be formed by the overall introduction of an acetate with the regioselectivity of
an electrophilic substitution.
R
O
O
OAc
Cl
mCPBA
NaOH
AlCl3
R
R
H2O
R
1 24 25 26
Avoidance by choice of oxygenated starting materials
You are usually advised when making a complex aromatic compound to have any oxygen atoms
(directly joined to the benzene ring) already present at the start. In their synthesis of the lichen
metabolite dechlorolecideoidin 27, McEwen and Sargent 3 chose the fully substituted benzene 29
as precursor for the right hand ring.
Cl
HO
Me
O
O
Cl
OH
Cl
HO
OH
2 x C–O B-V
O
Me
CO2Me HO
Me
CO2Me OHC
Me
27; dechlorolecideoidin 28 29
A search for available starting materials with both oxygen atoms present revealed methyl
orsellinate 31 so the chlorine could be disconnected next to give 30. Regioselectivity was confi ned
to the formylation of 31 and they did indeed have diffi culty with that step.
Me
Me
29a 30
Methyl orsellinate 31 was differentially protected and formylated to give 33 after removal of
the isopropyl group with TiCl 4. Benzylation and oxidation gave the benzoic acid 34 ready for a
surprising conclusion to the synthesis.
31
HO
OHC
i-PrO
i-PrBr
K2CO 3
Cl
OH
CO 2Me
OH
Me
32; 75% yield
CO 2Me
C–Cl
SEAr
1. (MeO) 2SO 4
K 2CO 3
2. SnCl 4
Cl 2CHOMe
3. TiCl 4
HO
OHC
HO
OHC
OH
CO 2Me
OMe
Me
33; 53% yield
CO 2Me
C–C
S EAr
1. BnBr
K 2CO 3
HO
2. NaClO 2
NH 2SO 2OH
H2O, dioxan
HO
BnO
HO 2C
Cl
Me
31
OH
OH
OH
CO 2Me
CO 2Me
Me
34
OMe
CO 2Me

Friedel-Crafts acylation of 35 with 34 was brought about with trifl uoroacetic anhydride and the
benzyl groups removed to give 36. The last oxygen was now introduced by an interesting oxidation
with K 3Fe(CN) 6. The spirolactone 37 was formed in good yield and, on heating and removal of
the OMe group, gave dechlorolecideoidin 27. The interesting chemistry as well as the selectivity
in this synthesis is explored in the workbook.
Cl
Me
1. 34
(CF 3CO) 2O
CH 2Cl, 0 ˚C
Cl
Oxidation through Lithiation and Ortho-Lithiation
Probably the best modern method for introduction of OH by electrophilic aromatic substitution is lithiation,
reaction with a boronate ester, and oxidation. 4 These are the same boron compounds that are used
in Suzuki coupling (chapter 18) and are made the same way. In this example, selective mono-lithiation
by Br/Li exchange on available tribromoanisole 39 (easily prepared by bromination of anisole or phenol)
occurs ortho to the MeO group and reaction of aryl-lithium 39 with trimethyl borate gives the
boronic ester 40. Peroxyacids such as peracetic acid are usually used for the fi nal oxidation.
The oxidation is very similar to that used after hydroboration to make alcohols (chapter 17) and
involves a migration of the aryl group from B to O as the weak OO bond of the peroxy group is
broken. It also closely resembles a Bayer-Villiger oxidation. The boronic acids are as good as the
esters: PhMgBr reacts with B(OMe) 3 followed by 10% HCl to give PhB(OH) 2 oxidised without
isolation to phenol 5 by H 2O 2 in 78% yield.
Hydroxylation of Pyridines by ortho-Lithiation
Me
O Me
CO2Me Fe(III) Cl
The basic ortho-lithiation strategy for electrophilic substitution on pyridines was explained in
the last chapter. Now we need to explore the more powerful methods available when we add
this boron-mediated oxidation. An example of control by ortho-lithiation in the synthesis of
caerulomycin should reveal the possibilities. The pyridine 42 is lithiated in the 2-position because
Me
O Me
2. H2, HCl
H2O BnO
Pd/C
OBn EtOAc HO O O OMe
K2CO3 HO
O
H H
O
35
36 37
Br
OMe
ArB(OMe) 2
33 Hydroxylation of Pyridines by ortho-Lithiation 781
Br
Br
OMe
Br
Br
Br
38 39 40
Li
Br
OMe
B(OMe)2
BuLi B(OMe) 3 MeCO 3H
MeCO 3H
R
MeO OMe
B
O O
O
R
O
Br
B(OMe)2
OMe
Br
41; 87% yield
H 2O
CO 2Me
OH
ArOH
OMe

782 33 Oxidation of Aromatic Compounds, Enols and Enolates
an amide is a stronger ortho-director than a simple ether. Negishi coupling (chapter 18) of the Zn
derivative with 2-bromo-pyridine gives the dipyridine 43 in good yield. A second ortho-lithiation
must now occur at the 5-position and bromination gives 44.
OMe
N
OCONi-Pr 2
42
1. s-BuLi
2. ZnCl 2
3. 2-Br-pyridine
1 mol% Pd(PPh 3) 4
OMe
N
OCONi-Pr2 1. PhLi
N
2. BrCN
43; 77% yield
Treatment of 44 with BuLi would lead to Br/Li exchange, but treatment with LDA lithiates the
remaining position (C-6) on the ring 45 then the halogen dance (chapter 32) gives the more stable
lithium derivative 46 with Li ortho to the OMe group. Protonation gives 47 in good yield. 6
44 LDA
Br
OMe
OCONi-Pr 2
N
Li N
Br N
Li
OCONi-Pr 2
Completion of the synthesis of caerulomycin C starts with a very effi cient second Negishi
coupling to give 48, but then requires oxidation to an aldehyde, oxime formation, and removal of
the original ortho-directing amide. The yield of 49 was unsatisfactory.
47
The successful sequence used the boron method to introduce one of the OMe groups and
started with the di-iodo pyridine 50. ortho-Lithiation with the very hindered LiTMP (lithium tetramethylpiperidide)
to prevent I/Li exchange, reaction with a borate and oxidation gave the pyridone
51. Methylation of the hydroxypyridine tautomer gave 52 and selective I/Li exchange of the iodine
ortho to an MeO group followed by Negishi coupling gave the bipyridine 53. The difference now
is that a second I/Li exchange (BuLi - no choice now), reaction with DMF and oxime formation
gave caerulomycin C 49 in good yield. 7
H
MeZnCl
1 mol%
Pd(PPh3) 4
1. LiTMP
OMe
2. B(OMe) 3
3. MeCO3H I N I
I N
H
OMe
N
Br
H 2O
OMe
N
OCONi-Pr 2
N
44; 81% yield
H
Br
OMe
45 46 47; 85% yield
H
OMe
OCONi-Pr 2
1. amide
hydrolysis
OMe
Me N
N
2. DDQ
3. NH2OH
H
N
N
N
HO
48; 100% yield
49;

Synthesis of Atpenin B
A dramatic example of this strategy is the synthesis of atpenin B 54 from 2-chloropyridine with
the introduction of four oxygen atoms round the pyridine ring, three of them by electrophilic substitution.
Far from being an ‘impossible’ reaction, electrophilic aromatic substitution by oxygen
has become a favoured strategy. The fi rst disconnection is easy: the alkyl side chain 56 can be
added to the pyridine 55 by some kind of Friedel-Crafts acylation or via lithiation between two
ortho-directors. This synthesis is on the cover of Clayden, Organolithiums: Selectivity for Synthesis,
Pergamon, 2002.
MeO
MeO
OH O
OH
O
MeO
X
+
N OH
MeO N OH
54; Atpenin B 55 56
The ‘clockwise’ strategy chosen by Quéguiner and his group was to introduce the OH groups
in turn from 2-chloropyridine 57 mainly by lithiation and reaction with a borate ester. With LDA
or PhLi chlorine acts as an ortho-director 58 so the fi rst OH group goes in easily 59. Methylation
and nucleophilic substitution by MeO puts in the two methoxy groups 60.
1. LDA
or PhLi
Li
2. B(OMe) 3
Cl N
Cl N
3. MeCO3H Cl N
2. MeONa
57
58
59; 65% yield
The third OH group can now be introduced in the same way 61. The next stages are tricky as
the fourth OH group is not on the next atom round the ring. The C-4 OH group must be made into a
good ortho-director but not by MeO - a carbamate was chosen 62 - and some group must be placed
at C-5 that can be used later to differentiate this position from C-6. Bromine was chosen 63.
60
MeO
O
MeO N
H
61; 64% yield
MeO
MeO
Now comes the clever bit. Lithiation of 63 with LDA occurs next to Br at the only remaining
free position 64 but the ‘halogen dance’ (chapter 32) exchanges Br and Li so that Li is next to the
excellent ortho-directing carbamate 65. Protonation with EtOH gives 66 ready for introduction of
the fourth and last OH group.
63 LDA
1. LDA or PhLi
2. B(OMe) 3
3. MeCO3H MeO
MeO
OCO2Ni-Pr 2
N
33 Synthesis of Atpenin B 783
Br
ClCO 2Ni-Pr 2
Ag 2CO 3
MeO
HO
Li MeO N
OCO 2Ni-Pr 2
N
62; 71% yield
OCO 2Ni-Pr 2
Li
1. MeI
1. BuLi
2. BrCN
EtOH
MeO
MeO
MeO N
60; 58% yield
OCO 2Ni-Pr 2
Br
MeO N
63; 93% yield
MeO
Br MeO N
OCO 2Ni-Pr 2
64 65 66; 73% yield
H
Br

784 33 Oxidation of Aromatic Compounds, Enols and Enolates
Lithiation with BuLi by Br/Li exchange and oxidation by the borate method inserts the C-6
OH group 67. This is promptly protected as a labile 2-silylethyl ether 68 in readiness for the last
lithiation and introduction of the side chain.
66
1. BuLi
2. B(OMe)3
MeO
OCO2Ni-Pr 2
Lithiation promoted mainly by the carbamate and reaction with the required aldehyde 65
followed by oxidation turned out to be the best way to introduce the ketone. All that remained was
to remove the two protecting groups and atpenin A 50 was formed in good yield. 8
Introducing OH by Nucleophilic Substitution
This last sequence suggests that the introduction of OMe, or of course OH, could be done by
displacement of activated halide. That is simple enough in a pyridine but is also possible in
benzenes as halogens are ortho, para-directing and sequences such as 1 to 72 do a similar job.
PART II – OXIDATION OF ENOLS AND ENOLATES
NaH
Since the carbonyl group is so important in synthesis and enolisation can now be well controlled
(chapters 3-5, 10 and 11) it makes sense to prepare other molecules by controlled functionalisation
of enols and enolates. As this involves replacement of hydrogen atoms by functional groups, these
processes are all oxidations of some kind. We shall start with the introduction of a second carbonyl
or hydroxyl group and progress to the introduction of an alkene, both being next to a carbonyl
group already in the molecule. Two of the products have stereochemistry: asymmetry in the one
and geometry (E or Z ) in the other.
MeO
OCO2Ni-Pr 2
3. MeCO3H MeO N
H
O Cl
SiMe3
MeO N O
67; 63% yield 68
68
1. BuLi
2. RCHO
3. PCC
1. X 2 (Hal 2)
Lewis acid
2. HNO3 R R
H2SO4 1
i-Pr 2NCOO
MeO
MeO
70
N
O
O
R
69; 80% yield
X
NO 2
RO
R
SiMe3
1. KOH, MeOH
2. HCl, MeOH
OH
H 2
54
atpenin A
78% yield
NO2
Pd/C
R
71 72
O
R2 O
R2 R
OH
1 R1 R1 O
R2 R
O
1
or
?
?
SiMe3
O
OH
NH 2
R 2

Direct Oxidation without Formation of a Specifi c Enol
Selenium dioxide
Direct oxidation of carbonyls to 1,2-dicarbonyls can be carried out with selenium dioxide (SeO 2)
though there are selectivity problems. The reaction starts with an ‘ene’ reaction 73 forming the
enol derivative 74. This undergoes a [2,3] sigmatropic shift 74 to form the C-O bond and loss of
selenium and water 75 gives the fi nal product 76.
O
Se
O O O
R
H
R
Se OH
O [2,3]
R
O
O
Se
73 74
H
75
OH
There is little control over enolisation as the enol derivative is formed in the fi rst stage of the
reaction. Two examples from Vogel 9 are the formation of ninhydrin 78 in poor yield and the more
useful synthesis of the α-ketoaldehyde 80. In both cases, enolisation has occurred at the only
possible site.
O
SeO 2
O
O
As an example we shall choose the cyclic 1,2-dione 82. Ring contraction is a commonly
used strategy for ring synthesis especially for the formation of fi ve- from six-membered
rings and three- from four-membered rings but is almost never used for the formation of
four- from fi ve-membered rings as the increased strain makes the reaction unfavourable.
Nevertheless, the ring contraction of 82 to the acid 81 (by the benzilic acid rearrangement) did
seem possible as the dione 82 is already strained. To test this idea, 82 had to be made. The chosen
route was by functionalisation of the mono-ketone 83 as this could be made from the diol 84 and
hence by hydration of the known adduct 85 of acetylene and two molecules of acetone.
HO CO 2H
33 Direct Oxidation without Formation of a Specifi c Enol 785
Hydration of 85 catalysed by acid and Hg(II) gave the cyclic ether 83 directly 10 and oxidation
with selenium dioxide gave the cyclic dione 82 which was stable as its crystalline dihydrate 86.
There is again no ambiguity of enolisation.
R
O
76
O + Se + H2O O
O
77 78; 34% yield 79 80; 72% yield
O
O
O
C–O
OH OH
HO
81 82 83
84 85
O
SeO 2
O O
O
O
? ? ? ?
O
CHO
OH

786 33 Oxidation of Aromatic Compounds, Enols and Enolates
85
Hg(II), H
H2O
The ring contraction was surprisingly successful. 11 The best yields of 81 were with sodium
bicarbonate though KOH can be used. Presumably only one ketone is necessary 87 for even such a
weak base to promote the rearrangement from the monohydrate 88. Under the reaction conditions
the product is the stable carboxylate anion 90.
86
O
O
87
OH
OH
Nitrosation with nitrites
O
O
83; yield 80% 86
Another method is nitrosation with nitrous acid or, preferably, an alkyl nitrite in acidic solution.
The enol of the carbonyl compound 91 reacts 92 with NO , formed from RONO in acid, to give
the unstable nitroso compound 93 that tautomerises to the stable oxime 94. If the dicarbonyl
compound 95 is wanted, the oxime is easily hydrolysed.
R
O
H
R
OH
N O
As the reaction is carried out in acidic solution, we can expect modest regioselectivity for
enolisation on the more substituted side of the carbonyl group. An example from Vogel 12 is the
oxidation of butanone 96 to give the monoxime 98 via the nitroso compound 97. The dioxime
(a useful ligand for metals) 99, the diketone, or the monoxime 98 can be made by this route.
Reduction of the oximes gives primary amines.
Nitrosation with stable nitroso compounds
O
O
SeO2
O
OH
HO
OH
OH
Nitroso compounds that cannot enolise are forced to keep the reactive NO bond. Chlorination
of the oxime 100 of cyclohexanone gives the bright blue α-chloro nitroso compound 101 stable
enough to be isolated. 13 Enolates attack the nitroso group at nitrogen 102 to give, after elimination
of chloride 103, a nitrone 104 that can be hydrolysed to the hydroxylamine 105 and then reduced
to the α–amino compound 106, stable only as a salt.
HO
O CO2H
NaHCO3
boiling
water
81
89% yield
HO CO 2
O
O
O
88 89 90
R
O
H
N
O
R
O
O
N
OH
H2O R
91 92 93; nitroso compound 94; oxime 95; α-dicarbonyl
O O
O
BuONO
cat. HCl
NH2OH.HCl NaOH
NOH
NO
NOH
NOH
96 97 98
99; 47% yield
O
81

OH
N
R
O O
N
Cl
Cl2
Cl
ON
R
R
O
100 101; bright blue 91
102
O O
N
1. NaN(SiMe3)2
2. 101
Oppolzer developed this chemistry into an asymmetric synthesis of α-amino acids 110 using
enolates of amides 107 derived from his chiral sultam 109. The hydroxylamines 108 are isolated
in perfect diastereomeric purity which translates into high ees in the fi nal products 14 110.
An ingenious application was in the asymmetric synthesis of coniine 15 114, the alkaloid in
hemlock by which Socrates met his death. The sultam amide 111 incorporates a protected ketone
so that acidic hydrolysis forms the cyclic nitrone 112 by capture of that ketone. Reduction and
base-catalysed cleavage of the amide gives coniine 114.
Much simpler, though not enantioselective, examples have been reported recently by Hisashi
Yamamoto. 16 Lithium or tin enolates 116 react with nitrosobenzene to give good yields of
hydroxylamines 117.
R
R
O
O
N
Cl
O OH
103 104
105
N
SO2 O
107
SO 2
H 2, Pd/C
Ph
33 Direct Oxidation without Formation of a Specifi c Enol 787
N
O
O
R
1. NaN(SiMe 3) 2
2. 101
3. HCl, H 2O
111
O
N
HCl
H 2O
HONH
SO2 O
108; >99% de
O
N
SO2 O
N
OH
113; 92% yield
Ph
OM
115 116; M = Li or SnBu 3
R
1. NaN(SiMe3)2
2. 101
3. HCl, H2O
Ph N
1. Zn, HCl
H 2O, AcOH
0 ˚C
2. LiOH
3. ion
exchange
1. NaH, toluene
2 hours reflux
2. i-Bu2AlH O
Ph
NH
Zn
HCl
H2O
AcOH
SO2 109
R
O
N
SO2 O
N
O
112; 72% yield
109
83%
yield
O OH
N
+
Ph
106
NH 2.HCl
NH +
HO2C NH2
R
110
N
H
114; (–)-coniine
56% overall yield
117; M = Li
70% yield
M = SnBu3
96% yield

788 33 Oxidation of Aromatic Compounds, Enols and Enolates
One interesting aspect of this reaction is that the acid-catalysed variant using silyl enol ethers
118 and Lewis acids provides a good way to oxidise the enol as the electrophilic end of the nitroso
group switches to the oxygen atom. The product 120 is an N,O-disubstituted hydroxylamine. As
the NO single bond is rather easily cleaved reductively, this route promises to be a good way to
make α-hydroxyketones. 17
Indirect Oxidation with Formation of a Specifi c Enol: Enone Formation
Pd(II) oxidation of silyl enol ethers
O OSiMe 3 O
O N
H
118 119
120; 94% yield
More regioselective methods are available if a specifi c enol equivalent (often the silyl enol ether
122) can be used in the oxidation. These methods are usually used to introduce a conjugated
alkene next to the carbonyl group. Oxidation of a silyl enol ether with Pd(II) does this job
well. 18
R 1
Regioselective oxy-palladation of the enol derivative gives 124 or 125, either of which
might lose palladium in a β-elimination that can only go one way. The problem is that the
palladium comes out as Pd(0) but must go in as Pd(II) so the reaction is not intrinsically
catalytic. The answer is to add a stoichiometric oxidant, such as a quinone, to complete the
cycle.
122
Pd(OAc) 2
oxypalladation
An excellent example is the synthesis of mevinolin 126, an HMG-CoA reductase inhibitor that
lowers the cholesterol level, by Hirama and Iwashita. 19 Their idea was to use a Diels-Alder reaction
to close both rings in one step and they therefore disconnected various peripheral fragments to
leave the simpler ketone 127. Reversing the Diels-Alder reveals 128 and the starting material was
actually one diastereoisomer to ensure stereochemical control in the ring closure.
PhNO
Et 3SiOTf
O
R1 OSiMe3 R1 O
R2 R2 R2 Pd(OAc) 2
121 122
123
AcO
R 1
OSiMe 3
R 2
R 1
PdOAc
PdOAc
124 125
O
H
R 2
β-elimination
123
H Pd OAc
Ph
Pd(0)

O
O
HO
O
1
O
5
The Diels-Alder was successful 20 129 but now the methyl group in the SW corner needs to
be added by conjugate addition and that requires an enone. Oxidation of the silyl enol ether 130,
prepared by kinetic enolate formation with LDA, with catalytic Pd(OAc) 2 and benzoquinone as
the stoichiometric oxidant gave the required enone 131 in 57% yield. Addition of Me 2CuLi was
stereoselective to give 132 and the synthesis of mevinolin completed.
128 heat
33 Indirect Oxidation with Formation of a Specifi c Enol: Enone Formation 789
Bromination of enols in enone formation
H
3
126; mevinolin
O R
H
128
OTBDMS
129
=
FGI
O H
X
OTBDMS
The oldest but still occasionally useful method for enone formation from saturated ketones
involves bromination and elimination of HBr from the bromoketone 133. The problem here is
that the proton to be removed (H b in 133) in the elimination is not the most acidic proton in the
molecule: H a is much more acidic.
R 1
1. LDA
2. t-BuMe 2SiCl
TBDMSO R
H
OTBDMS
130
Nevertheless this method can work well if hindered or non-nucleophilic bases (such as DBN
and DBU) are used. The dienone 134 was needed for a study of migrating groups in the dienonephenol
rearrangement. 21 The bold proposal was that double elimination from dibromoketone 135
O
O
O
Pd(OAc) 2
quinone
5
127
3
1
Diels-
Alder
OBn
O
O R
H
OTBDMS
131
O
O
X
Me 2CuLi
O
R1 O
R1 O
R2 R2 R2 H
H
Br
b
Ha Br2 base
121 133 123
Me
128
OBn
R
O R
H
OTBDMS
132; 91% yield

790 33 Oxidation of Aromatic Compounds, Enols and Enolates
would allow the ketone 136 to be used and that this might in turn be made by double conjugate
addition of a cuprate to dienone 137. Direct oxidation by a quinone or SeO 2 would give this from
the enone 138, easily made by Robinson annelation.
O O
O O O
FGI
Br Br
FGA? 2 x C-C
FGI
The enone 138 could be oxidised to dienone 137 with the quinone DDQ 139. Bromination
of 136 rather surprisingly gave a single crystalline isomer 140 in 90% yield: NMR revealed the
stereochemistry shown. The double dehydrobromination was carried out with calcium carbonate
in DMF.
This synthesis was well worthwhile as the dienone-phenol rearrangement of 134 gave the phenol
144 showing that the ethyl group migrates better than methyl. The dienone rearranges to 142 and a
second migration is needed before a cation is formed 143 that can give an aromatic compound by
loss of a proton. In each rearrangement there is a choice between a methyl and an ethyl group.
Sulfur and selenium compounds in enone formation
conjugate
addition
134 135 136 137 138
O
Cl CN
DDQ Me2CuLi
138
137 136
139
Cl
134
O
139; DDQ
H
CN
Br2 CaCO3 136 140 134
HOAc
DMF
OH OH OH H
141
O
Br Br
140; 90% yield
Probably the most popular method to introduce an alkene is by regioselective functionalisation
with a sulfur or selenium reagent, oxidation, and elimination. The α-RS or α-RSe compound 145
is made by sulfenylation or selenenylation of a specifi c enol equivalent. Oxidation requires only
mild reagents such as H 2O 2, and the elimination follows a cyclic syn mechanism 146 so the lack
of acidity in H b is unimportant. The elimination (a reverse ene reaction) is highly E-selective as
the substituents R 1 CO and R 2 prefer an anti conformation in the transition state. This resembles
the high E-selectivity in the [3,3]-sigmatropic rearrangements discussed in chapter 15. S(e) means
either Se or S.
OH
142 143 144

121
33 Indirect Oxidation with Formation of a Specifi c Enol: Enone Formation 791
R 1
O
R2 R
RS(e)
1
O
Hb R
RS(e)
2
R
O
1
O
R2 [O]
heat
+ PhS(e)OH
145 146
(E)-123
Sulfenylation of lithium enolates with PhS-SPh or of silyl enol ethers with PhS-Cl allows any
α-PhS carbonyl compound to be made regioselectively, e.g. 149 and 152 from 147 (see chapter 5).
Oxidation with sodium periodate gives the sulfoxide without over-oxidation to the sulfone, but
elimination requires reasonably high temperatures (about 120 C for MeSO but only about 50 C
for PhSO). Together with the unpleasant by-products, the results of disproportionation of unstable
PhSOH, this has led to a preference for the selenium version of the reaction, though we must admit
that the by-products are even more offensive. 22
O
OSiMe3
O
SPh
PhS-SPh NaIO4
The selenium version of this reaction offers the advantages that over-oxidation is no problem and
that the elimination of the selenoxides occurs at room temperature or below so that the oxidation
and elimination normally occur as a single step. 23 A simple example is the preparation of another
starting material 158 for a dienone-phenol rearrangement. 24 The lithium enolate of spirocyclic
ketone 155 reacts with PhSeCl to give 156 and oxidation with H 2O 2 gives the dienone 158 directly,
with the selenoxide 157 as an intermediate. The overall yield is 83%.
155
LDA
147
151
OLi
Me 3SiCl
Et 3N
O O
1. LDA
2. PhSeCl
PhSCl
A general problem that is neatly solved by these methods is that of making exo-methylene
lactones such as 167. These compounds are cytotoxic and both carcinogenic and anti-cancer compounds
are found in this class. If the cis-fused lactone 159 is converted into its lithium enolate
160 we have a classic case of a folded molecule and attack by an electrophile occurs on the exo
face, that is the same face as the ring-junction hydrogen atoms. Methylation gives 161. The lithium
enolate of this molecule 162 again has a fl at fi ve-membered ring and a second electrophile also
adds on the exo face, say to give 163. In this compound the PhSe group and the ring junction H are
syn to each other so elimination on the selenoxide tends to give the more stable but less interesting
unsaturated lactone 164.
PhS
148 149
O
O
1. NaIO 4
2. heat
O
150
O O
SPh
heat
152 153 154
SePh
H 2O 2
156 157
O
SePh
O
158
O

792 33 Oxidation of Aromatic Compounds, Enols and Enolates
H
LDA
O
O
O
H
H
159 160
H
If we want the exomethylene lactone 167, we must simply add the electrophiles in the reverse
order. 25 The PhSe group is therefore anti to the ring junction H atom 166 and elimination on the
selenoxide must give 167.
159
Asymmetric Synthesis of Cannabispirenones
H
O
H
161
O
OLi
PhSe-SePh
or PhSeCl
O
O
O
H
162
H
163 164
H
O
H
165
SePh
O
H
SePh
The selenium oxidation can even be a source of asymmetry. Both enantiomers of cannabispirenones
170 occur naturally in different plants and the racemic enone is made in two steps from the achiral
ketone 168. You will see that 170 is chiral only by virtue of the alkene in the ring.
Hydrogenation of 170 gives the achiral saturated ketone 171 that can be desymmetrised by
a chiral base. The lithiated diamine 172 gives mostly the lithium enolate 173 and hence, by
addition of selenium and oxidative elimination, the enone (R)-170. Different bases give the other
enantiomer. 26
MeO
MeO
1. LDA
2. PhSe-X
MeO
MeO
O
1. LDA
2.MeI
MeO
OLi
H
O
H
166
MeI
CHO
H2O 2
SePh
O
H
H 2O 2
MeO
MeO
MeO
168 169 170
171
O
Me
Ph
N Li
Me
172
N
MeO
MeO
173
OLi
1. PhSeBr
O
MeO
H
LDA
O
O
H
167
O
2. H2O2 MeO
(R)-170; 84% ee
O
O

Oxidation of Enones: Epoxides and the Eschenmoser Fragmentation
Once the enone is prepared, further oxidation becomes easier. The epoxide can be formed at the
alkene with the nucleophilic oxidant H 2O 2/NaOH. The mechanism involves a discrete enolate
intermediate 176 so the stereochemistry of the alkene is lost and E- and Z-enones 174 usually both
give the anti-epoxide 177.
R 1
O
(E)-174
R 2
H2O2
NaOH
R 1
O
R
175
2
O OH
This reaction gives some stereoselectivity with pulegone 178 as the epoxide 179 is formed in
an approximately 2:1 anti:syn ratio, 27 and chemo-selectivity as carvone 180 gives just one epoxide
181 as a mixture of diastereoisomers: the electron-rich alkene is not epoxidised. 28
H 2O 2
Further reactions on these compounds lead to other oxidised products in which the lack of
stereochemical control in the epoxidation is unimportant, so, for example isophorone oxide
rearranges with various catalysts to the cyclopentanone 182 (80% yield) while both isomers of
pulegone oxide 179 gives the cycloheptadione 29 183 (78% yield). Exhaustive methylation of the
extended enolate produced by reduction of 181 gives 184 in good yield. 28
The most dramatic of all these reactions is the Eschenmoser fragmentation 30 - a general route to
alkynyl aldehydes 189 and ketones. The tosylhydrazone 186 of an epoxyketone 185 gives an anion
on treatment with base that fragments once 187 to give an alkene and again 188 in the reverse
direction 188 to give the alkyne.
R 1
O
176
O OH
O
NaOH
O
O
O
NaOH
O
178; (R)-(+)-pulegone 179; 2:1 anti:syn 180; (R)-(+)-carvone 181; 92% yield
H 2O 2
NaOH
O
O
O
OHC
isophorone isophorone oxide 182
O
33 Oxidation of Enones: Epoxides and the Eschenmoser Fragmentation 793
O
TsNH.NH 2
N
NHTs
O
base
O
N
179
NTs
O
R 2
H 2O 2
181
O O
183
N N
185 186 187
188
Ts
O
Li
MeI
NH 3(l)
THF
R 1
O
O
177
O
R 2
184; 80% yield
189
CHO
O

794 33 Oxidation of Aromatic Compounds, Enols and Enolates
The ‘disconnection’ corresponding to a fragmentation must of course be a reconnection and
there is a choice here 191 when reconnecting the alkyne to the aldehyde 190 or ketone 192.
Whether you draw the intermediates or not you should get back to the same two enones as potential
starting materials. In this case either method works and you may choose the enone you prefer, or
that you fi nd easier to make.
The rest of this chapter is about attempts to introduce electrophilic oxygen onto enolates. The
option of acylation followed by Baeyer-Villiger rearrangement is not available as the starting
materials themselves contain carbonyl groups and react with peroxy acids. The alternative
solutions will lead us into interesting chemistry. We shall omit unreliable older solutions involving
oxygen gas, Pb(OAc) 4 etc.
PART III – ELECTROPHILIC ATTACK ON ENOL(ATE)S BY OXYGEN
The Problem
O
H
b
reconnect
Eschenmoser
fragmentation
Competition with Baeyer-Villiger rearrangement and oxidative cleavage
b
The idea is to be able to react a carbonyl compound 193 (or some specifi c enol derivative of it)
with some reagent for the synthon “HO ” so that a new CO bond is formed on the next atom
192. Sometimes no stereochemistry will be involved but we should also like to be able to create
single enantiomers.
The most obvious thing to do is to react the carbonyl compound with a peroxyacid. After
all, double bonds react to give epoxides and enols are more nucleophilic than double bonds.
Unfortunately, peroxyacids are nucleophilic as well as electrophilic and form hemiacetals with
carbonyl compounds which decompose by the C to O migration 195 known as the Baeyer-Villiger
rearrangement.
CHO
H
a
a reconnect
Eschenmoser
fragmentation
190 191 192
O OH
O
193
O
ArCO 3H
?
OH
R R
OH
194 195 196
O
O
Ar
O
O
O
H
O
OH
O
R

Electrophilic oxygen is introduced at the carbon atom next to the old carbonyl group but the
CC bond linking these atoms is lost so the result is not α-hydroxylation. Oxidative cleavage of
the enol alkene bond is going generally to be a problem in this section and is best illustrated by
the useful ozonolysis of silyl enol ethers 198 and 199 of the same ketone 194. The regiospecifi c
formation of silyl enol ethers is described in chapter 3.
HO2C O R
1. O3 MeOH
OSiMe3
R
O
R
OSiMe3 R
1. O3 MeOH
HO HO2C R
2. Me2S
2. NaBH4
197; R = Me
90% yield
198
194
Reduction and cyclisation of ketoacid 197 would give lactone 196 while cyclisation of 200
would give the isomeric lactone. This second method is therefore controllable whereas in the
Baeyer-Villiger rearrangement, only the more highly substituted group migrates. However, the
Baeyer-Villiger does go with retention at the migrating group whereas there is no stereochemical
control in the ozone reactions.
Unexpected Success with the “Obvious” Reagents
Unique successful hydroxylations with ozone and mCPBA
200; R = Me
94% yield
Two remarkable observations need discussion at this stage as they show that the two methods we
have dismissed sometimes work. Attempted ozonolysis of the silyl enol ether 202 derived from
camphor 201 gave instead a quantitative yield of the silyl ether of hydroxycamphor 31 203.
Though the product 203 is a mixture of diastereoisomers, it does at least show that even
ozone sometimes attacks an enol as an oxygen electrophile. The second example is even more
remarkable. Attempted epoxidation of the tricyclic ketone 204 gave a mixture of four compounds:
two epoxides 205 in a 7:1 ratio from mCPBA attack at the alkene and two regioisomeric lactones
206 from the Baeyer-Villiger rearrangement of the ketone.
199
O OSiMe3 O3 O
201; camphor 202
O
O
33 Unexpected Success with the “Obvious” Reagents 795
204
H
O
MeOH
mCPBA
CH2Cl2 room
H
+
temperature
O
205; 59% yield
7:1 diastereoisomers
O
OSiMe3
203
100% yield
H
O
O
206; 25% yield
mixture of lactones

796 33 Oxidation of Aromatic Compounds, Enols and Enolates
This compound was intended to be a model compound for a more complex ketone 207 to be used
in the synthesis of the quassinoid natural products, some of which have anti-cancer properties, but,
mindful perhaps of Woodward’s dictum that the only reliable model compound is the enantiomer
of the real thing 32 they tried the reaction with 207. With one equivalent of mCPBA they got just
one diastereoisomer of the epoxide.
O
O
H
207
O
CO 2Me
CO 2Bu-t
For the purposes of this chapter, the more exciting result was that treatment with an excess of
mCPBA converted 207 into 209 in quantitative yield: epoxidation is totally stereoselective and
hydroxylation has also occurred at the easily enolised position between the ketone and the ester
to give a single diastereoisomer of the alcohol 209. The stereoselectivities are remarkable enough
but the mere fact the hydroxylation occurs so effi ciently gives hope for the development of a more
general method. Inspection of the structure of bruceantin 210, the most promising of the anticancer
quassinoids, shows just how valuable this reaction turned out to be. The diffi cult tertiary
alcohol has been inserted in exactly the right place with the right stereochemistry.
207
excess
mCPBA
CH2Cl2 room
temperature
O
O
mCPBA
CH 2Cl 2
room
temperature
First Successful Method: Epoxidation of Silyl Enol Ethers
(Rubottom Oxidation)
Method, mechanism, and isolation of intermediates
O
H
O
OH
CO2Me CO 2Bu-t
209; only product; 100% yield
208; only product; 88% yield
It is a small logical step from the last section to attempt the epoxidation of silyl enol ethers 211.
The result is slightly surprising: hydroxylation is successful but the product is the silyl ether 212
of the α-hydroxyketone. 33,34
O OSiMe 3 O
mCPBA
193 211
212
?
O
O
O
O
HO
H
O
H
OH
O
CO 2Me
CO 2Bu-t
CO2Me
H
HO O O
H H
OSiMe 3
210; bruceantin
O
OCOR
OH

The immediate product is presumably the epoxide 213 which opens in acetal fashion to give
214 and transfers silicon intramolecularly to give 212. The reaction 214 is formally a 5-endo-tet
reaction and would not occur if carbon were being transferred. As silicon is the atom under attack,
a pentacovalent intermediate can be formed and the requirement for a linear S N2 transition state
no longer applies.
OSiMe3
mCPBA
Me 3Si
O
O
Support for this mechanism came from an unexpected quarter. In a synthesis of sterpuric acid
215, Paquette planned to put in the alkene at the end by a Julia olefi nation. 35 Addition of MeLi
to the ketone 216 and non-stereospecifi c elimination (chapter 15) looked a good strategy. The
1,2-relationship between OH and ketone in 216 is awkward and the decision was made to try a
hydroxylation on the silyl enol ether of the parent ketone 217.
HO2C
Me
33 First Successful Method: Epoxidation of Silyl Enol Ethers (Rubottom Oxidation) 797
This decision was to have sensational results as treatment of the silyl enol ether 218 with buffered
(NaHCO 3) mCPBA gave an 86% yield of a crystalline compound whose structure, determined by
X-ray, was 219 - the fi rst stable epoxide of a silyl enol ether had been isolated.
When the epoxide 219 was treated with even weak acid, or when the silyl enol ether 218 was
epoxidised with unbuffered mCPBA, no epoxide could be found. Instead a 76% yield of the silyl
ether 220 of the hydroxylated ketone 216 was formed. The stereochemistry of 220 is of course
determined by that of 219 and the requirement for cis-fused four- and fi ve-membered rings.
Sterpuric acid 215 has the same stereochemistry.
O
SiMe 3
211 213 214
212
H
Me
OH
Me
215; sterpuric acid
MeO2C
Me
217
1. NaN(SiMe 3) 2
PhO 2S
219
2. Me 3SiCl
H
Me
O
OSiMe3 FGI
Julia
olefination
MeO 2C
Me
PhCO 2H
CH 2Cl 2
20 ˚C
HO2C
Me
H
PhO 2S
H
PhO 2S
216
Me
OSiMe 3
218; 91% yield
MeO2C
Me
O
H
Me
OH
mCPBA
NaHCO 3
CH 2Cl 2
20 ˚C
Me
O
C–O
enol
oxidation
PhO2S
O
OSiMe3 220; 76% yield
MeO2C
Me
MeO2C
Me
H
O
PhO 2S
217
OSiMe 3
H
Me
PhO2S O
OSiMe3
219; 86% yield
HO 2C
Me
H
PhO2S
216
O
O
Me
H
Me
OH

798 33 Oxidation of Aromatic Compounds, Enols and Enolates
This approach can use the inherent regioselectivity of silyl enol ether formation (chapter 3)
using kinetic or thermodynamic enolisation. Hence kinetic enolisation of enones (chapter 11)
occurs on the α’ side leading to 2-Me 3SiO-butadienes such as 222. Epoxidation of this silyl enol
ether gives the unstable silyloxy ketone 223 which can be desilylated by fl uoride ion and hence
transformed into the hydroxyketone 225 or acetoxy ketone 224. These transformations are useful
because the hydroxy ketones can be unstable 34 (see below).
221
O OSiMe 3 O
O
1. LDA
2. Me3SiCl 224; 74% yield
OAc
222; 85% yield
Et 3NHF
Et 3N, Ac 2O
mCPBA
Chemo- regio- and stereoselectivity: synthesis of fused γ-lactones
223
Et 3NHF
OSiMe3
A dramatic example of selectivity comes in the approach to helenolides by Lansbury and Vacca. 36
Many sesquiterpenoids, such as 226, have fi ve-membered lactones fused onto larger rings and
conjugation with an exomethylene group gives some anti-cancer properties. The exomethylene
group can be added by Wittig and other reactions (see selenium chemistry earlier in the chapter).
Lansbury and Vacca decided to explore the strategy of adding the lactone to a protected
hydroxyketone having all the rest of the stereochemistry in place. They wanted methods for the
disconnection 227 to 228.
HO
H
Wittig
O
etc.
O
HO
226 227
H
The idea was that the lactone 227 could come from 228 by the sequence: (i) stereo- and
regioselective α-hydroxylation 229, (ii) Wittig style reaction on the ketone to add the extra two
carbon atoms 230, (iii) stereoselective conjugate reduction of the double bond with the OH group
directing the reagent to the bottom face of the alkene, and (iv) lactonisation.
CH 2Cl 2
O
O
223
O
225; 83% yield
H H
H
H
(i) ?
OH
(ii) ?
OH
(iii) +
(iv) ?
O
O
COR
228 229
230
227
?
RO
OH
H
228
O
O
O

The reasons for the choice of reagent for each reaction are instructive. Epoxidation of a silyl
enol ether was chosen for the hydroxylation for two reasons. It was known that the potentially
diffi cult (the α-atom on both sides is primary) regioselectivity of enolisation of ketones 228 could
be solved by using LDA and HMPA. The lithium enolate is formed away from the quaternary
ring junction. Then epoxidation of related alkenes was known to go on the bottom face and the
stereochemistry of the epoxidation determines the stereoselectivity of the hydroxylation 232.
H
1. LDA, HMPA
2. Me3SiCl
t-BuO
O t-BuO
OSiMe3 t-BuO
O
228; R = t-Bu 231 232; 75% yield
The unstable silyl ether in 232 was replaced by a more stable acetoxy ketone 233 which was not
isolated. A Horner-Wadsworth-Emmons reaction was used for the Wittig-style olefi nation (chapter
15). A nitrile 234 replaced the carbonyl group in 230 as it was found easier to reduce nitriles in
conjugative fashion.
t-BuO
H
232
O
OSiMe3
Ac2O Et3N
DMAP
CH2Cl2 t-BuO
The reduction step was stereoselective with either LiAlH 4 or LiBH 4. In both cases, the hydride
reducing agent fi rst cleaved the acetate ester and then an intermediate “ate” complex transferred
hydride ion intramolecularly in a cis fashion 235 to the unsaturated nitrile to give the correct
stereochemistry 236. Finally cyclisation of the alcohol onto the nitrile to give the trans fused
lactone 227 occurred in much the same way that nitriles are converted directly to ethyl esters with
ethanol in acid solution. The overall yield of 227 was a respectable 40%.
234
1.3 x
LiAlH4 or 3-4 x
LiBH4 t-BuO
33 Hydroxylation of Amino-ketones via Silyl Enol Ethers 799
H
235
NC
Hydroxylation of Amino-ketones via Silyl Enol Ethers
Synthesis of vinca alkaloids and model compounds
H
H
233
3. mCPBA
CH2Cl2 0 ˚C
It would be a limitation of any of these methods if they could not be used with heterocyclic nitrogen
compounds. This is a serious matter because amines are easily converted into N-oxides as we saw
in the last chapter. The synthesis of the alkaloid vindoline 237 by Langlois raised this question.
O
OAc
H
OSiMe 3
O
H
(EtO) 2P CN
OAc
NaH, DME
t-BuO
CN
234; 90% yield
H
H
O
B
H
H
OH
1. NaOH
EtOH
2. H
O
H
t-BuO
CN t-BuO
227; R = t-Bu
O
236; 92% yield
40% (over six steps)

800 33 Oxidation of Aromatic Compounds, Enols and Enolates
Vindoline belongs to the vinca alkaloids, an important class of indole alkaloids whose dimers
(such as vincadifformine) are anti-cancer compounds. The most diffi cult functionality in this
compound is the tertiary α-hydroxyester and Langlois 37 proposed to make this by hydroxylation
of the related keto-ester 238.
MeO
N
O
H
Me CO2Me 237; vindoline
There were two related questions of chemoselectivity to be answered here: would the amino
groups in 238 be too reactive to survive the oxidation with mCPBA and would the rather stable
silyl enol ether of the β-ketoester be reactive enough to be epoxidised? Langlois decided to conduct
a trial experiment with the simple amino-β-ketoester 239 that contains all these features. If
this is successful, there will still be the question of stereoselectivity. The silyl enol ether 240 was
duly formed in the most stable position between the two carbonyl groups and epoxidation with an
excess of mCPBA gave a good yield of the required α-hydroxyester 243 via the epoxide 241 and
the silyl ether 242 which was desilylated in aqueous base without isolation.
Me
N
239
O
CO2Me
Me
N
240
OSiMe 3
CO 2Me
The same conditions were applied to the vindoline precursor 238 and the α-hydroxyester 237
was formed in an even better 89% yield as a single diastereoisomer with the hydroxyl group going
in syn to the nearer ring junction hydrogen atom. This puts it on the exo face of the locally folded
molecule. The synthesis of vindoline was completed from here. 38
The epoxidation of silyl enol ethers is the oldest of the methods in this chapter but it works well
and is still very much in use today. The reagents are simple and easy to use, rather unlike the one
we are now going to meet.
Second Successful Method: Hydroxylation with MoOPH
The reagent: hydroxylation of lithium enolates
N
OH
H
2.5 x
mCPBA
0 ˚C
CH2Cl2 Me
N
?
MoOPH [pronounced “moof” and more correctly oxidoperoxymolybdenum(aqua)-(hexamethylphosphoric
triamide)] is a molybdenum peroxide complex 245 that hydroxylates lithium
enolates. 39
O
MeO
OSiMe3
CO2Me 241
Me
N
N
H
N
O
H
Me CO2Me
238
O
Na 2CO 3
H2O CO2Me OSiMe3 242
Me
N
O
CO2Me OH
243; 80% yield
O
HMPA
Me
Hexa-
2N
Methyl Me2N P
Phosphor- Me2N Amide
O
MoOPH O O
Molybdenum Mo
Oxido
O O
O N
Peroxy
HMPA
(Me2N) 3P
Me
N
O
N
DMPU
Me Di
Methyl
Propylene
Urea
244 245 246

It can be made by a simple process but unfortunately has to contain a molecule of carcinogenic
HMPA 244 for stability. Versions with the safer DMPU 246 instead are not so effective. The crystals
are best prepared just before use and are pale yellow when pure. 40
MoO 3 + 30% H 2O 2
HMPA
Stereoselectivity (substrate control)
In a typical reaction, the lithium enolate of the carbonyl compound 247 is prepared in the usual
way and reacted with yellow MoOPH to give the hydroxylated product 248 and blue molybdenum
compounds so that the reaction is self-indicating. The best feature of the method is that it uses
lithium enolates since the regioselective preparation of these intermediates is much easier to
control than that of other metal enolates. Hence 2-phenylcyclohexanone 249 gives a single
regioisomer of the hydroxyketone 250 from kinetic enolisation with good stereoselectivity.
R
O
247
OEt
1. LDA
THF, –78 ˚C
2. MoOPH
–78 ˚C
We have hinted in this chapter at the instability of some of these α-hydroxy carbonyl compounds
and the hydroxylation of 249 unfolded some details of this problem. Compound 250 had
been reported in 1960 from the hydrolysis of the ester 251 but the compounds produced by the
two routes had different NMR spectra. The hydrolysis of the ester 251 actually gave a rearranged
hydroxyketone 252. The same product was formed on treatment of 250 with KOH. The instability
arises if the carbon atom with the OH group also has a hydrogen atom and can therefore enolise
255. The intermediate ene-diol (or its anion 254 or 253) can re-protonate at either end of the
double bond to give different ketones.
AcO
O
Ph O
KOH
MeOH
Hydroxylation of steroids and amino acids
1. dry in vacuum
MoO5.H2O.HMPA yellow crystals, 67% 2. pyridine
OH
OH
OEt
R
O
248
58-85% yield
Ph
MoO5.pyridine.HMPA
245; MoOPH, yellow crystals
The message is that you should not treat α-hydroxy carbonyl compounds with base if they can
enolise on the hydroxyl side. Because MoOPH is not an epoxidising agent, there is good chemoselectivity
if the molecule also contains alkenes. This steroid example 256 shows that good yields
and high stereoselectivity can be obtained.
256
251
33 Second Successful Method: Hydroxylation with MoOPH 801
H
H
252
Me
H
O
1. LDA,
THF, –78 ˚C
2. MoOPH,
–78 ˚C
OH
253
THPO THPO
O
O
Ph
249
HO
Ph 1. LDA
2. MoOPH
O
254
H
HO
O
Ph
250; 100% yield
7:1 anti:syn
Ph HO
KOH
MeOH
H
Me
O
HO
O
255
H OH 257
75% yield
H
Ph

802 33 Oxidation of Aromatic Compounds, Enols and Enolates
There is stereoselectivity here, as in the last example, and both are determined by the substrate, that
is the molecule being hydroxylated. The reagent MoOPH is large and it attacks the less hindered side
of the substrate under kinetic control. Some control can be achieved in the interesting hydroxylation
of aspartic acid enolates. 41 The lithium enolate of the dimethyl ester of N-protected aspartic acid 259
gives high syn selectivity in hydroxylation next to only one of the two ester groups 260.
258
HO
aspartic
2C
acid
259
NH 2
CO2H
1. LHMDS, THF,
HMPA, –78 ˚C
2. MoOPH, –78 ˚C
259
OH
CO2Me MeO2C
NHR
260; 95% yield, 11:1 syn:anti
MeO2C
If 259 is fi rst treated with BuLi and then turned into the lithium enolate and reacted with
MoOPH, a good yield of the other diastereoisomer, anti-261 is formed. The fi rst result is probably
hydroxylation opposite the very large NHR group in a Houk conformation of the enolate
(chapter 21) while anti-selective hydroxylation probably results from chelation control.
MeO 2C
NHR
259
CO2Me
1. BuLi, THF, –78 ˚C
2. LHMDS
3. MoOPH, –78 ˚C
The popularity of MoOPH has waned with the discovery of the next type of reagents for
hydroxylations. These N-sulfonyl oxaziridines should now probably be your fi rst choice. In the
1986 volume of Organic Syntheses three recipes for hydroxylation of enolates stand side by
side. Rubottom 42 describes the formation of the kinetic lithium enolate of the enone 262 and the
oxidation of the silyl enol ether 263 with mCPBA to give the α’ product 264 (see chapter 11 for the
regioselectivity of such extended enolates).
O OSiMe 3
1. LDA,
DME, –15 ˚C
2. Me3SiCl Vedejs and Larsen 43 describe the preparation of MoOPH and the hydroxylation of the lithium
enolate of camphor 265 to give a good yield of a 5:1 ratio of endo:exo alcohols 266 while Moriarty
44 gives an example of a method we have not discussed, the hydroxylation of potassium enolates
with o-iodosobenzoic acid.
O
HN
Ph
CO 2Me
259, N-protected aspartic
acid dimethyl ester
OH
CO2Me
MeO2C NHR
261; 70% yield, 1:20 syn:anti
1. mCPBA,
hexane, –15 ˚C
2. Et3NHF CH2Cl2 262 263; 88-91% 264; 69-74%
1. LDA
2. MoOPH
OH
265; camphor 266; 77% yield
5:1 endo:exo
O
Ph
O
KOH, MeOH
5-10 °C
IO
CO 2H
Ph
HO
MeO OMe
OH
267
65% yield
O
5% H2SO4
CH 2Cl 2 Ph
O
OH
268
83% yield

MoOPH is less effective than the boron method for oxidation of aromatic enolates too. In a
similar comparison the pyridine 269 was lithiated and treated with oxygen, MoOPH, or the boronate
sequence to give the hydroxypyridine 271. The results are very clear. 45
N
269
OMe
PhLi
Third Successful Method: Hydroxylation with N-Sulfonyl Oxaziridines
The reagents and the mechanism
N
OMe
1. B(OMe) 3
OMe
reagent O2 MoOPH
Li
270
2. AcO3H N
OH
271; 65% yield
yield
of 271
29% 25%
These reagents contain a three-membered ring made up of C, N, and O atoms - an oxaziridine.
The nitrogen atom must be a sulfonamide (usually a benzene sulfonamide) and the carbon atom
usually has some substituent. The simplest such reagent 273 is formed by epoxidation of N-phenylsulfonyl
benzaldehyde imine 272 with mCPBA or Oxone®, a persulfate potassium salt 2KHSO 5.
KHSO 4.K 2SO 4.
O O
Ph S N Ph
272
mCPBA
or Oxone ® , K 2CO 3
O O
Ph S N Ph
O
273
This compound 273 is a single diastereoisomer and one of the two stereogenic centres is
the nitrogen atom. Nitrogen normally inverts too quickly to be stereogenic but in a threemembered
ring and with an electronegative substituent, inversion through the unfavourable
trigonal nitrogen atom is very slow. It reacts with sodium or potassium enolates to give products
of α-hydroxylation. 46
R 1
O
274
R 2
1. Na or KHMDS
2. oxaziridine 273
R 1
OH Me3Si N SiMe 3
O
275
The enolate attacks the oxygen atom of 273 in an unusual S N2 reaction at oxygen 276. The leaving
group is the sulfonamide anion, which is why a sulfonamide is necessary. The anion returns
277 to form the original imine 272 and ejects the anion 278 of the α-hydroxy-carbonyl compound
275.
O O
33 Third Successful Method: Hydroxylation with N-Sulfonyl Oxaziridines 803
Ph S N Ph
O
R1 276
R 2
O
R 2
[Na or K]
NaHMDS or KHMDS
R1 R2 O O Ph
Ph
S
N O
R
O
1
R2 272 O
277
O
278
275

804 33 Oxidation of Aromatic Compounds, Enols and Enolates
Hydroxylation of sodium and potassium enolates: side reaction with lithium
Lithium enolates 279 do give α-hydroxy-carbonyl compounds but there is a signifi cant side reaction
that is a kind of aldol reaction on the imine product 272 through a six-membered cyclic transition
state 280 like those we used to explain the stereoselectivity of aldol reactions in chapter 4.
Hence the Na or K disilazide bases NaHMDS or KHMDS are usually used.
R 1
R 2
279
OLi
273
PhO2S
Li
N
R1 Ph
Ph
280 281
Substrate controlled stereoselectivity: asymmetric hydroxylation
Though the reagent 273 does have stereochemistry it does not transmit it to the product and the
stereoselectivity of the reaction is under substrate control. Folded molecules like the lactone 282
react on the outside as expected to give the exo-product 283.
Good asymmetric induction occurs with the Evans valine-derived chiral auxiliary (as in 284,
see chapter 27) which reacts in alkylation style on the face of the enolate away from the i-Pr group.
The products 285 give α-hydroxy-acids 286 on hydrolysis.
Ph
O
O
Asymmetric hydroxylation with camphor sultam derivatives
O
O
For asymmetric hydroxylation of enolates it is necessary to provide more permanent asymmetry
than is found in 273. The most successful reagents so far have been the (camphorsulfonyl) oxaziridines
such as ()-CSO 288. Since both enantiomers of camphor are available and the formation
of Oppolzer’s chiral sultam (chapter 27) makes chemistry such as 265 → 287 familiar, these
are reagents of some appeal. Derivatives with extra chlorine 289 or methoxy substituents are also
available. Epoxidation of the imine 287 occurs exclusively on the lower face to give 288 and hence
creates two new stereogenic centres (C and N in the oxaziridine ring) but it is the chirality of the
bicyclic camphor system supported by the asymmetric position of the polar sulfone group that
leads to successful induction. Hydroxylation of the simple ketone 290 with the chlorosultam 289
gives 291 with high ee.
R 2
PhO2S
Li
N
O O
1. KHMDS
2. 273 O
O
H
H
N
i-Pr
284
O
O
282
1. NaHMDS
2. 273
Ph
O
N
O
O
O
OH
i-Pr
285; 85% yield
95:5 diastereoisomers
283
HO
1. purify by
crystallisation
2. LiOH
Ph
O
O
R 1
OH
286
R 2
O
OH

S
O O
287
33 Third Successful Method: Hydroxylation with N-Sulfonyl Oxaziridines 805
N
S
O O
Asymmetric synthesis of tetracycline precursors
O
N
S
O O
Cl
Cl
N
(+)-CSO 288 (+)-chlorosultam 289
O
Strategies for producing optically active α-hydroxy-carbonyl compounds by hydroxylation with
oxaziridines depend on whether enantio- or diastereo-selectivity is required. The synthesis of
precursors for the antibiotic tetracyclines is a good illustration. These compounds, e.g. 292, have
four rings A-D, hence “tetracyclines”. Ring D is usually aromatic but rings A–C have a variety of
oxygenated functionality and stereochemistry. These two features come together at the A/B ring
junction where there is a diffi cult tertiary α-hydroxy-carbonyl unit.
One strategy for tetracycline synthesis is to build a B/C precursor with suitable functionality
for extension to ring A and with the tertiary α-hydroxy-carbonyl unit already in place. Two
potential starting materials for different tetracyclines are 293 and 295 and both might be made by
α-hydroxylation of enolates.
Both precursors 294 and 296 are chiral but the chirality of 296 lies at an enolisable centre
between two carbonyl groups and the enolate, the intermediate in hydroxylation, is only prochiral.
It makes sense therefore to use racemic 296 with the correct optically active sultam 297 to make
295 by asymmetric hydroxylation 47 but to use optically active precursor 294 with racemic sultam
273 in diastereoselective hydroxylation 48 (54% yield).
Ph
O
290
Ph
1. NaHMDS
2. (+)-289
BnO H O
OH
BnO H O OMe O
OH
CO2Me
OMe O
H
C B
?
C B
?
OMe
OMe
OMe
OMe
293 294 295
296
1. NaHMDS
294 293
2. O O
Ph S N Ph
O
273
OH
OH
296
2. 297
1.KHMDS
O O
OH
D C B A
OMe O
OH
CO2Me OMe
O
OH
H H
Me OH OH NMe2 292; oxytetracycline
NH 2
295; 70% yield, >95% ee
Ph
O
OH
291; 84% yield
95.4% ee
OMe
OMe
N
Ph
CO2Me
S O
O O
(+)-dimethoxy-sultam 297

806 33 Oxidation of Aromatic Compounds, Enols and Enolates
Synthesis of a calcium channel opening drug
The Bristol-Meyers Squibb calcium channel opener 298 can clearly be made by addition of
some protected organometallic derivative 300 to the isatin 299. In fact this is easily done with a
Grignard reagent from 301 with an OMe group at the phenolic position. In the synthesis (below) a
preliminary treatment of 299 with NaH was needed before addition of the Grignard reagent
CF 3
H
N
OH
OH
The chemists at B-MS were faced with the problem of determining the biological activity of
both enantiomers of the drug. The availability of both enantiomers (from both enantiomers of
camphor) of the Davies oxaziridine 288 made it worthwhile to remove the OH group from 302
and put it back again. 49 Protected 302 was reduced with Et 3SiH and TFA, a reagent that reduces
alcohols that easily form cations, to 303. Then this was enantiospecifi cally hydroxylated with
each enantiomer of 288 to give, after deprotection with BBr 3, the two enantiomers of the drug
298.
Asymmetric synthesis of buproprion
O
C–C
CF 3
298 Cl
299
CF3
1. Mg
301
2. 299
+ NaH
Cl
H
N
CF 3
O
Et3SiH
OH
CF3CO2H
OMe
Cl
302 303
H
N
While a drug is being evaluated, it is necessary to prepare both enantiomers. When you know
which enantiomer you want, you need an asymmetric (and preferably catalytic) synthesis.
GlaxoSmithKline’s anti-depressant drug buproprion 50 305 provides an excellent example. This
simple compound is needed as the (R)-enantiomer and can obviously be made by S N2 displacement
(with inversion) on some derivative of the (S)-alcohol 306. Asymmetric hydroxylation of the
enolate of the simple aryl ketone 307 should answer.
Buproprion – Analysis
O
Cl
(R)-305
C–N
inversion
NHt-Bu
Cl
H
N
O
O
O +
Cl
CF 3
1. KHMDS
H
OMe 2. (+)-288
(S)-306
O
OH
M
300
protect
OH
OH
H
N
Cl
(–)-304
asymmetric
hydroxylation
of enolate
Cl
=
Cl
O
Br
301
BBr3
OH
CH2Cl2 OMe
307
O
OMe
(+)-298
>95% ee

A chiral oxaziridine could have been used but the company prefers a catalytic method: the
asymmetric dihydroxylation (chapter 25) of the silyl enol ether 308. Presumably the diol 309 is
formed but the hemiacetal collapses on workup and the mesylate of (R)-306 allows displacement
with t-BuNH 2 and the synthesis of buprion 307.
Buproprion – Asymmetric Synthesis
OSiMe3 Me3SiCl AD
307 Cl
base
Summary
Electrophilic substitution of pyridines (chapter 32) and the hydroxylation of aromatic compounds
and enol(ate)s (this chapter) are now useful and fl exible reactions that can be made to work on a
variety of compounds with all the necessary selectivity. Functionalisation as a strategy - that is the
removal of functionality during analysis - can be diffi cult to fi nd during the disconnection process
as one naturally tends to be thinking of making rapid progress in simplifi cation by carbon–
carbon disconnections. The secret is to keep it in the mind alongside the FGA strategy and ask the
question: would this synthesis be easier if I either removed (functionalisation strategy) or added
(FGA strategy) a functional group to the target molecule? A comprehensive review 51 of this topic
appeared in 2003.
References
Cl
308 309
33 References 807
HO OSiMe3
General references are given on page 893
1. LaV. L. Brown, S. Kulkarni, O. A. Pavlova, A. O. Koren, A. G. Mukhin, A. H. Newman, and A. G. Hortl,
J. Med. Chem., 2002, 45, 2841.
2. D. J. Dale, J. Draper, P. J. Dunn, M. L. Hughes, F. Hussain, P. C. Levett, G. B. Ward and A. S. Wood,
Org. Process Res. Dev., 2002, 6, 767.
3. P. M. McEwen and M. V. Sargent, J. Chem. Soc., Perkin Trans. 1, 1981, 883.
4. K. Green, J. Org. Chem., 1991, 56, 4325.
5. M. F. Hawthorne, J. Org. Chem., 1957, 22, 1001.
6. See for example F. Mongin and G. Quéguiner, Tetrahedron, 2001, 57, 4059.
7. F. Mongin, F. Trécourt, B. Gervais, O. Mongin and G. Quéguiner, J. Org. Chem., 2002, 67, 3272.
8. F. Trécourt, M. Mallet, O. Mongin and G. Quéguiner, J. Org. Chem., 1994, 59, 6173.
9. Vogel, p. 629.
10. M. S. Newman and W. R. Reichele, Org. Syn. Coll., 1973, V, 1024.
11. B. L. Murr, G. B. Hoey and C. T. Lester, J. Am. Chem. Soc., 1955, 77, 4430; J. L. Harper and C. T. Lester,
J. Org. Chem., 1961, 26, 1294.
12. Vogel, p. 630.
13. E. Müller, H. Metzger and D. Fries, Chem. Ber., 1954, 87, 1449.
14. W. Oppolzer, O. Tamura and J. Deerberg, Helv. Chim. Acta, 1992, 75, 1965.
15. W. Oppolzer, C. G. Bochet and E. Merifi eld, Tetrahedron Lett., 1994, 35, 7015.
16. N. Momiyama and H.Yamamoto, Org. Lett., 2002, 4, 3579.
17. N. Momiyama and H. Yamamoto, Angew. Chem. Int. Ed., 2002, 41, 2986; there is a correction on page
3313.
OH
work-up 1. MsCl
(S)-306
2. t-BuNH2 (R)-305
buproprion

808 33 Oxidation of Aromatic Compounds, Enols and Enolates
18. Y. Ito, T. Hirao and T. Saegusa, J. Org. Chem., 1978, 43, 1011; B. M. Trost, Y. Nishimura, K. Yamamoto and
S. S. McElvain, J. Am. Chem. Soc., 1979, 101, 1328; M. R. Roberts and R. H. Schlessinger, J. Am. Chem.
Soc., 1979, 101, 7626; J. Tsuji, Palladium Reagents and Catalysts, Wiley, Chichester, 1995, page 104.
19. M. Hirama and M. Iwashita, Tetrahedron Lett., 1983, 24, 1811.
20. M. Hirama and M. Uei, J. Am. Chem. Soc., 1982, 102, 4251.
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22. B. M. Trost, T. N. Salzmann and K. Hiroi, J. Am. Chem. Soc., 1976, 98, 4887.
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25. P. A. Grieco and M. Miyashita, J. Org. Chem., 1974, 39, 120.
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27. W. Reusch and C. K. Johnson, J. Org. Chem., 1963, 28, 2557.
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Schlecht and T. Utawanit, J. Org. Chem., 1984, 49, 3264.
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34. G. M. Rubottom and J. M. Gruber, J. Org. Chem., 1978, 43, 1599.
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37. R. Z. Andriamialisoa, N. Langlois and Y. Langlois, Tetrahedron Lett., 1985, 26, 3563.
38. R. Z. Andriamialisoa, N. Langlois and Y. Langlois, J. Org. Chem., 1985, 50, 961.
39. E. Vedejs, D. A. Engler and J. E. Telschow, J. Org. Chem., 1978, 43, 188.
40. E. Vedejs and S. Larsen, Org. Synth., 1986, 64, 127.
41. F. J. Sardina, M. M. Paz, E. Fernández-Megía, R. F. de Boer and M. P. Alvarez, Tetrahedron Lett., 1992,
33, 4637.
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34
Functionality and Pericyclic Reactions:
Nitrogen Heterocycles by Cycloadditions
and Sigmatropic Rearrangements
This chapter considers the effect of nitrogen atoms on Diels-Alder reactions, [3,3]-sigmatropic
rearrangements such as the Aza-Cope, group transfer reactions such as the Alder Ene reaction
and other pericyclic processes
PART I–INTRODUCTION
The Effects of Functionality on Pericyclic Reactions
Cycloadditions: The Diels-Alder and the Alder ‘ene’ reactions
[3,3] and [2,3]Sigmatropic rearrangements: the aza Cope rearrangement
Other pericyclic processes giving nitrogen heterocycles
PART II– CYCLOADDITIONS TO MAKE NITROGEN HETEROCYCLES
Diels-Alder Reactions with Azadienes
Problems with the Diels-Alder reactions with azadienes
Stable 1-azadienes
Stable nucleophilic 1-azadienes (HOMO used in cycloadditions)
Stable electrophilic 1-azadienes (LUMO used in cycloadditions)
Diels-Alder reactions with 2-azadienes
Diels-Alder Reactions with Imines
Intramolecular Diels-Alder Reactions with Azadienes
Intramolecular Diels-Alder Reactions with Imines
Intramolecular Diels-Alder Reactions with a Nitrogen Tether
PART III–‘ENE’ REACTIONS TO MAKE NITROGEN HETEROCYCLES
Intramolecular Alder ‘Ene’ Reactions with a Nitrogen Tether
Intermolecular ‘Ene’-style Reactions with Oximes
PART IV– [3,3] SIGMATROPIC REARRANGEMENTS
The ‘Aza-Cope’ Rearrangement
The Anionic ‘Aza-Cope’ Rearrangement
PART V– OTHER REACTIONS
Electrocyclic Reactions
Ring Closing Olefi n Metathesis
The Pauson-Khand Reaction
Metal-Catalysed Alkyne Trimerisation
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

810 34 Functionality and Pericyclic Reactions
PART I – INTRODUCTION
The Effects of Functionality on Pericyclic Reactions
Cycloadditions: The Diels-Alder and the Alder ‘ene’ reactions
Our understanding of pericyclic reactions is ultimately based on Woodward and Hoffmann’s
analysis of orbital symmetry. This chapter considers the consequences of inserting functionality
into a pericyclic reaction so that the symmetry of at least one component is perturbed. For example,
a nitrogen atom could be part of the diene in a Diels-Alder reaction in two ways: we could have
a 1- or a 2- ‘azadiene’ (1 or 3). If the reaction is successful the product in both cases (2 or 4) would
be a nitrogen heterocycle. Alternatively, we could use an imine 5 as the dienophile. Again, assuming
that the reaction works, the product is a nitrogen heterocycle. In fact, as we shall see later, the
infl uence of the added nitrogen atom is pernicious and none of these three reactions works very
well with these simple compounds. This chapter will discuss what effects such functionality has
on pericyclic reactions and how the diffi culties can be overcome. 1
R
N
R
R
R ? N R
N
R ?
To limit the scope of the discussion and also to give it a useful synthetic focus, we shall consider
only those reactions that lead to heterocyclic nitrogen compounds. These products may be aromatic
but will more usually be partly saturated so there will be a good deal of stereochemistry and some
asymmetric synthesis. We shall therefore also discuss reactions in which the nitrogen atom is not
part of the pericyclic process as such but infl uences it strongly by being part of a tether. The regio-
and stereo-selectivity in Diels-Alder reactions such as the cyclisation of 7 is largely controlled by
the length and position of the tether so the functional group does infl uence the pericyclic process.
The Alder ‘ene’ reaction 9 is a ‘group transfer’ reaction closely related to the Diels-Alder reaction
but with a C–H bond in place of one of the alkenes in the diene. This reaction does not of itself
close a ring so once again a nitrogen tether will be necessary if a heterocycle 10 is to be formed.
R
1 2 3 4 5
6
R
NR
?
R
R
7 8
[3,3] and [2,3]Sigmatropic rearrangements: the aza Cope rearrangement
NR
Typical [3,3] sigmatropic rearrangements include the Claisen and Cope rearrangements. The
‘aza-Cope’ is a [3,3] sigmatropic rearrangement with a nitrogen atom in one of two possible positions
11 or 13. In neither case is a ring of any kind formed in this reaction but in both cases the
product is a rather unstable imine and further ionic reactions may lead to heterocycles.
N
R
R
H
R
R
N
R
R
?
H
NR
R
9 10
R
?
R
N
R
NR

R
N
The tandem reactions in which the aza-Cope is followed by an ionic C–C bond-forming second
step are often carried out on anions or cations. Here is an anionic example 15 to 16 we shall be
discussing later in the chapter. Some of the most dramatic [2,3] sigmatropic rearrangements have
been of nitrogen ylids undergoing ring expansion to give medium rings. We shall discuss the ring
expansion of 17 to give a nine-membered cyclic amine 18 by [2,3] rearrangement of an ylid later.
Other pericyclic processes giving nitrogen heterocycles
The chapter ends with a rather miscellaneous collection of reactions such as one example of
an electrocyclic ring closure 19 . There are more important examples of ring closing olefi n
metathesis (RCM) and other organometallic reactions such as the Pauson-Khand reaction and
co-trimerisation.
PART II– CYCLOADDITIONS TO MAKE NITROGEN HETEROCYCLES
Diels-Alder Reactions with Azadienes
R R N
R N
[3,3] [3,3]
N
11 12
13
14
H
N
O
R
R
H
N
R
R
R
N
O
CO2R
R
N
CO KH
18-crown-6
DBU
2R
15 16
17
18
R
N
electrocyclic
R
N
RCM
N
N
R
R
19 20 21 22
Problems with the Diels-Alder reactions with azadienes
1-Azadienes 24 are easily made from amines and enals such as 23 . The Diels-Alder reaction of
24 with maleic anhydride looks very attractive 25 and you might expect 26 to be the product.
O
PhNH2
34 Diels-Alder Reactions with Azadienes 811
Ph
N
O
23
R
24
R
R
25
26
R
Ph
N
O
O
Ph
N
O
O
O

812 34 Functionality and Pericyclic Reactions
Unfortunately the nitrogen atom lowers the HOMO energy of the diene 24 and it is not a good
match with the LUMO of maleic anhydride. Instead the imine 24 is in equilibrium with the enamine
27 and, in conformation 27b, this has a high energy HOMO and so the product 2 of the reaction
is 28. The tautomerism between 24 and 27 may be especially easy as it can be drawn as a [1,5]H
sigmatropic shift. This confl ict between weakly electrophilic imines and their tautomers, the
nucleophilic enamines, is one of the themes of this chapter. 1
24
Ph
N
R
One solution to the imine/enamine equilibrium is to load the nitrogen atom with a removable
acyl group. Popular choices are urethanes and sulfonamides. If the nitrogen atom is unsubstituted
32, the imine 33 is favoured by conjugation but if the nitrogen is substituted 31, it is forced to give
the enamine 29.
There is a further disadvantage in using simple Diels-Alder reaction of azadienes to make heterocycles.
The products, e.g. 2 and 4 are themselves either imines or enamines and are inherently
unstable and it is also necessary to stabilise them to make isolation of the heterocycle possible.
Stable 1-azadienes
Ph
NH
NHPh
R
R
O
R
27a 27b 28
CO2R enamine
H
imine enamine imine
N
R ClCO2R N
R
N
R
NH2 NH
NHPh
R
R
R
R
R
R
29 30 31 32 33 34
Among the few examples of simple 1-azadiene Diels-Alder reactions is a dihydropyridine synthesis
using the stable azadiene 39 (prepared from cinnamaldehyde and aniline) with the dienophile
38 prepared from the isoxazole 35 by elimination. This is a reverse-electron-demand cycloaddition,
the HOMO of the dienophile 38 combining with the LUMO of the azadiene 39 to give the cycloadduct
40 and hence the dihydropyridine 41 with complete regioselectivity and in very high yield. 3
H
N
O
NC
H
Ph
O
O
ClCO 2R
Li
H
H NC H
NC H
LDA
N
Me3SiCl Ph
–78 ˚C O Ph O Ph
–78 ˚C
Me3SiO Ph
35 36 37 38; 92% yield
80 ˚C
Me3SiO Ph N
Ph
Me3SiO N
Ph
Ph
Ph N
Ph
38 39
40 41; 98% yield
NC
H
Ph
NC
Ph
N
O
O
O
CO2R

Other dienes, even cyclopentadiene, perform poorly with this dienophile 38 but the azadiene
39 that does so well here is a very special case. It is stabilised by the phenyl groups at both ends of
the molecule and it cannot tautomerise into an enamine. More generally useful 1-azadienes must
be stabilised by conjugating substituents that are defi nitely electron-donating or withdrawing so
that the HOMO or the LUMO is unambiguously selected for cycloaddition.
Stable nucleophilic 1-azadienes (HOMO used in cycloadditions)
Ghosez used hydrazones 35 for this purpose. The regioselectivity shows that the NMe 2 group
dominates the HOMO of the diene in reaction with the LUMO of dienophiles such as acrylonitrile.
The arrows on the mechanism 44 show the nucleophilic end of the diene 43 interacting with the
electrophilic end of acrylonitrile. The cycloaddition may or may not be concerted. 4
CHO NH 2
42
NMe 2
N
N CN
N CN
NMe2
43
NMe2 44
NMe2 45
Though the NMe 2 group can be reductively removed from 45, it has generally been more
valuable to convert the products into pyridines by elimination and oxidation. Reaction of the same
diene 43 with the unsymmetrical naphthaquinone 46 gave a single regioisomer of 48 after treatment
of the unstable adduct 47 with refl uxing ethanol. 5
O
O
OMe
43
room
temperature
O
24 hours
NMe2 O
O
46 47 48
If the substituent is OH instead of OMe, hydrogen bonding to one of the carbonyl groups of
the naphthaquinone 49 reverses the coeffi cients in the LUMO and the opposite regioselectivity is
found in the product 50.
HOMO
43
N
34 Diels-Alder Reactions with Azadienes 813
NMe2
O
LUMO
In all these examples the 1-azadiene is stabilised by being a hydrazone, but most published
examples cannot tautomerise to enamines as they do not have proton-bearing substituents in the
right position.
Stable electrophilic 1-azadienes (LUMO used in cycloadditions)
N
room
temperature
Sulfonamides are the most widely used electrophilic 1-azadienes, e.g. 51, and they react with
electron-rich dienophiles such as enol ethers in reverse electron demand Diels-Alder reactions. 6
OMe
air
EtOH
24 hours
N
O
H
O
O
49 50
O
N
O
OH
OMe

814 34 Functionality and Pericyclic Reactions
The LUMO of the diene 51, activated by the imine, interacts 52 with the high energy HOMO of
the enol ether to accelerate the reaction and determine the regioselectivity of the cycloadduct 53.
LUMO
O
NH2 N
N OEt 48 hours
N OEt
SO2Ph SO2Ph SO2Ph
SO2Ph 51
52
53; 73% yield
Addition of another electron-withdrawing group to the azadiene (the ester in 54) lowers the
LUMO energy even more and the reaction 55 can now be run at room temperature (though pressure
helps) with perfect regioselectivity 57 and good endo:exo stereoselectivity from the interaction of
the OEt group with the back of the diene 56.
EtO 2C
54
Ph
N
SO2Ph EtO 2C
Ph
More impressively, azadienes, such as 59, that could tautomerise to enamines 58 also give good
yields of adducts 60 with high regioselectivity and endo stereoselectivity. 1-Azadienes are still not
easy to use but enough methods are now available to make heterocycle synthesis by this route a
practical proposition.
H
N SO2Ph
58; enamine not formed
Diels-Alder reactions with 2-azadienes
EtO 2C
HOMO
Ph
H H
H
The same problems arise with 2-azadienes and Ghosez 7 has solved them by loading the dienes
with strongly electron-donating or withdrawing groups. The imide 61 was doubly silylated to give
a 2-aza-diene 62 that cannot tautomerise to an enamine. It adds regioselectively to an acetylenic
ester to give a pyridone 64 after an acidic work-up that hydrolyses the silyl-imino ether of 63 and
catalyses the aromatisation by loss of the other silyl ether.
O
HN H
O
61
TBDMSOTf
Et 3N
RO
N OEt
SO2Ph O
Et
H
N
SO2Ph
55 56
´
N
OR
62; R=TBDMS
86% yield
reflux
CHCl3
59
CO 2Me
OEt
N SO2Ph
RO
N
110 ˚C
48 hours
toluene
115 ˚C
CO2Me
25 ˚C
24 hours
1M HCl
EtO2C
H
Ph
H
H
N OEt
SO2Ph 57; 80% yield
>20:1 endo:exo
OEt
N SO2Ph
60; 79%, >20:1 endo:exo
HN
OR
63; R=TBDMS 64; 64% yield
O
CO 2Me

The regioselectivity of the addition is determined by the HOMO of the azadiene 62 which is
dominated by the two electron-donating silyloxy groups. The nitrogen atom is almost irrelevant.
The LUMO of the unsaturated ester is typical for any Diels-Alder reaction.
For a reverse electron-demand Diels-Alder with azadienes, Barluenga 8 reacted stable silylated
imines 65 of unenolisable aldehydes (R Ar or cinnamyl) with acetylene dicarboxylic esters to
give the 2-azadienes 67.
CO 2Me
Me 3Si
toluene
25 ˚C
CO 2Me 65
N R
MeO2C
N
R
66
CO2Me
SiMe3
MeO2C
The imine nitrogen must attack the acetylene 68 and the resulting enolate desilylate the imine
cation 69 to trap the diene as 70. No tautomerism to an enamine is possible. This intermediate is
desilylated with fl uoride to give the diene 67 in remarkably good yield.
These dienes 70 have three electron-withdrawing groups, the imine and two esters, and react
with electron-donating enamines, e.g. 71, to give pyridines 74, again in excellent yield, after an
acidic work-up that tautomerises the initially formed imine 72 to the stable conjugated enamine
73 and then eliminates the amine used to make the enamine. The fi nal oxidative aromatisation is
spontaneous in air.
N
71
MeO 2C
R
N
MeO2C
67
25 ˚C
CH 2Cl 2
34 Diels-Alder Reactions with Azadienes 815
HOMO
of azadiene
62
O
OMe
MeO2C
SiMe 3 N SiMe3
R
68 69
MeO2C
N
R
TBDMSO
H
N
N
MeO2C
OTBDMS
O
MeO 2C
HN
R
CO2Me
OMe
H
N
CsF
MeOH
LUMO of
acetylenic
ester
N
CO2Me
R
67; 94-97% yield
MeO 2C
2M HCl
THF
50 ˚C
N
70
MeO 2C
CO2Me
R
MeO 2C
SiMe3
72 73
74; 95% yield
N
R

816 34 Functionality and Pericyclic Reactions
The regiochemistry of the cycloaddition is curious. The imine and the terminal ester groups
direct to one end but the middle ester group dominates and directs the enamine to the other end.
The diene LUMO evidently has its largest coeffi cient as shown, and seems again to ignore the
imine, though whether this is a concerted cycloaddition or a two-step ionic reaction is uncertain.
LUMO of 70
MeO 2C
Diels-Alder Reactions with Imines
N
CO2Me
R
The other side of the coin is a Diels-Alder reaction between an ordinary diene and an imine. 9
Here the problem is the instability of the imine. An ingenious solution was found by Kraus 10 who
distilled a THF solution of the trimer 75 into a fl ask cooled to 78 C. The imine 76 was stable at
that temperature and could be converted into the stable acylated enamine 77.
N
N N
75
distil with THF
N
When Danishefsky 11 set out to synthesise ipalbidine 83, a Diels-Alder reaction of this imine
77 was an obvious approach. To get effi cient reaction, it was necessary to use a diene 79 activated
by two electron-donating ethers and to activate the imine with a Lewis acid. The orientation of 81
is as expected from the LUMO of the imine reacting with the HOMO of the diene.
MeO
O
OEt
Conversion into ipalbidine 83 required reduction of the lactam 81 and demethylation of the aryl
methyl ether 82. Though the yield in the cycloaddition was poor, this is a short synthesis.
Ar
78
O
81
N
1. LDA
HMPA
77
2. t-Bu-
Me2SiCl Ar
OEt BF3
CH2Cl2 Ar
OTBDMS
79; 100% yield
LiAlH 4
AlCl 3
MeO
82; 73% yield
N
ClCO 2Me
Et 3N
–78 ˚C
HOMO of 71
MeO 2C
76 77
N
N
EtO OTBDMS MeO
80 81; 40-45% yield
BBr 3
CH 2Cl 2
HO
N
O
83; 78% yield
N
N

Even simple imines can be used if the diene is activated enough and Danishefsky’s diene 84
is nucleophilic enough to combine with simple imines with Lewis acid catalysis. This example
85 could tautomerise to an enamine but the imine, especially as its ZnCl 2 complex, reacts better
with such a nucleophilic diene. 12
Me 3SiO
84
OMe
Me 3SiO
OMe
N Ph
From the many examples of reactions with imines activated in various ways, we select the asymmetric
synthesis of pipecolic acids by double diastereomeric induction using an activated imine
87 with two chiral auxiliaries - α-methylbenzylamine on the nitrogen atom and 8-phenylmenthol
as esterifying group. Both these auxiliaries were discussed in earlier chapters (22 and 27). Acidcatalysed
cycloaddition with normal dienes gives excellent asymmetric induction and reasonable
yield. We show the matched case - the mismatched case is obviously worse. 13
Ph N
Me
O
O
Intramolecular Diels-Alder Reactions with Azadienes
Ph
85
ZnCl 2, THF
excess of imine
room temperature
36-48 hours
CF3CH2OH, CF3CO2H 24 hours
room temperature
N Ph
One sure way to make the hetero Diels-Alder reaction go well and with regio-and stereoselectivity
is to make it intramolecular. 14 The highly reactive diene 90 is formed by elimination
with fl uoride ion from 89. The cycloaddition is rapid because it restores aromaticity. The regioselectivity
is as expected from HOMO of dienophile plus LUMO of diene but is probably controlled
by the tether. 15 The stereochemistry certainly is: the azadiene is attached to the bottom face of
the fi ve-membered ring and is delivered to the bottom face of the dienophile to give the all-trans
‘aza-oestrone’ 91.
F
SiMe3
N
NMe 3
34 Intramolecular Diels-Alder Reactions with Azadienes 817
H
87
RO OR
CsF
MeCN
reflux
89 90
N
Heathcock has used a remarkable cascade of reactions, including an intramolecular Diels-Alder
reaction of a protonated 2-aza-diene, in the synthesis of Daphniphyllum alkaloids. We give one
example. The diol 92 gives the unstable dialdehyde 93 by Swern oxidation and hence the protonated
H
RO OR
then H
H2O O
86; 69% yield
OR*
N
O
Ph Me
88; 53% yield
>95% de
N
91
H
H
O

818 34 Functionality and Pericyclic Reactions
azadiene 94 by reaction with ammonia. As one of the aldehydes in 93 is joined to a quaternary
centre and cannot form an enamine, only one such azadiene can be formed. But now that you can
see the side chain ‘R 1 ’, what happens to 94? Several pericyclic reactions are possible.
OH
R H
R1 OH
(COCl) 2
DMSO
Et 3N
CH 2Cl 2
OHC
OHC
R H
The product is the cage amine 97. The azadiene must cycloadd to the nearer of the two
unactivated alkenes in the conformation 95 (mechanism not shown for clarity). Though the regioselectivity
is what we should expect from the HOMO of the dienophile and the LUMO of the
protonated 2-azadiene, the short tether (two saturated carbon atoms) is probably responsible. It
is certainly responsible for the stereochemistry as the tether delivers the dienophile to the top
face of the diene. 16 The product 96 cyclises by addition of the remaining alkene to the immonium
ion to give 97. We shall see more of these tandem sequences later in the sections on sigmatropic
rearrangements.
Intramolecular Diels-Alder Reactions with Imines
R 1
1. NH 3
CH 2Cl 2
2. HOAc
Simple imines give good yields of intramolecular Diels-Alder reactions providing always that the
second ring formed is stable and that usually means fi ve- or six-membered. Grieco has developed
a simple method whereby an aldehyde, also containing a remote diene, is combined with an amine
in acidic solution. The immonium ion cannot usually be isolated as cycloaddition 99 is rapid. A
simple example 98 gives the tricyclic amine 17 101
This reaction is obviously useful for the synthesis of hydroquinolines and compounds such as
pumiliotoxin C 102. The aza-Diels-Alder disconnection 103 requires a preliminary FGA. The
required aldehyde 105 was made from the known enantiomerically pure 106.
HN
R H
92 93
94
H
N
95
R H
aza-Diels-
Alder
Me
Me
CHO MeNH N
H
2.HCl
N
H2O, EtOH
98 99
H
N
R
HN
96 97
H
Me
R
N
100 101
?

Me
H
8a
N
H H H
102; pumilotoxin C
FGA
Me
H
aza-
Diels-
Alder
imine CHO
N Pr
NH Pr
H H H
103 104 105
When the reaction was carried out by treating the aldehyde ()-105 with ammonium chloride,
the cycloaddition took place under quite mild conditions (75 C in aqueous ethanol) with complete
regiochemical control but gave a mixture of two diastereoisomers 108 and 109 in a 70:30 ratio but
none of the right isomer for the pumiliotoxin synthesis. 17 The major product 108 has three of the
chiral centres correct but is epimeric with pumiliotoxin C 102 at C-8a. Grieco has used this
reaction successfully for other alkaloids. 18
Me
NH 4Cl
Me
This result shows both the strengths and the weaknesses of such intramolecular aza-Diels-Alder
reactions. The stereochemical outcome is controlled by the tether and such considerations as endo/exo
selectivity matter very little. The molecule must fold 110 so that the preferred transition state 111 has
the newly formed carbocyclic ring (not the ring formed by the cycloaddition itself) in the best chair
conformation 112. The reaction is useful only if you want the stereochemistry it naturally gives.
Intramolecular Diels-Alder Reactions with a Nitrogen Tether
The last example shows how intramolecular Diels-Alder reactions can produce two rings simultaneously.
A simple Diels-Alder reaction (i.e. not ‘aza’) with a nitrogen atom in the tether simply
switches the two rings round: now two new bonds in the carbocyclic ring are made by the
cycloaddition while one of them also completes the heterocyclic ring. In simple examples both the
regio- and stereochemistry is controlled by the tether: the carbamate-stabilised enamine 113 gives
only the cis ring junction 116 via an endo-like transition state 115. This time the relative stereochemistry
is correct for pumiliotoxin C 102 though the yield is poor. 19
Me
Me
H
C–N
Me
Me
H
CHO
H2O, EtOH
Pr 75 ˚C
NH2 Pr
8a
H
N
H H
Pr
H
N
H H
(–)-105 107 108 2.2:1 108:109 109
Me
113
H
34 Intramolecular Diels-Alder Reactions with a Nitrogen Tether 819
N
CO2Me H
Me
H
H
NH2 H
H
NH2 H
H
NH2 110 111 112
Me
H
H
OR OH
Pr
106
H
N
CO2Me N
H
N
CO2Me CO2Me
H H
190 ˚C
toluene
24 hours
114 115
116; 25% yield
Me
Pr

820 34 Functionality and Pericyclic Reactions
There are many examples of such reactions being used in synthesis. Often many new chiral
centres are established in one step as in the lycorine synthesis of Boeckmann. 20 The starting
material 118 is prepared by elimination on the spirocyclic ammonium salt 117 and contains no 3D
stereochemistry.
O
O
MeO 2C
N
117
OAc
Cycloaddition gives a single diastereoisomer of adduct 120 with four new chiral centres. The
molecule 118 must fold 119 so that the ester group is indeed endo to the diene but that, and the
regioselectivity, are mainly due to the very short tether - just one CH 2 group between two rigid
rings. The product 120 is a late intermediate in a synthesis of lycorane.
O
O
118
CO2Me
N
OAc
PART III – ‘ENE’ REACTIONS TO MAKE NITROGEN HETEROCYCLES
Intramolecular Alder ‘Ene’ Reactions with a Nitrogen Tether
O
O
DBU
The Alder ‘ene’ reaction is like a Diels Alder reaction in which one π-bond in the diene has been
replaced by a C–H bond 121. It does not therefore form a ring and does not fi t easily into any of the
three classes of pericyclic reaction (cycloaddition, electrocyclic, and sigmatropic). Since a hydrogen
atom is transferred from one component to the other it is best described as a ‘group transfer’
reaction. 21 The regioselectivity is determined by the interaction 123 with the π-bond of the ‘ene’
(the HOMO) with the LUMO of the ‘enophile.’
‘ene’ ‘enophile’
110 ˚C
4 hours
toluene
The ‘ene’ reaction forms a heterocyclic ring if the two components are tethered by a nitrogen
atom. Simple examples described by Oppolzer and Snieckus show that there is some kinetic preference
for the ‘endo’ product. After 24 hours at 150 C, the syn product 126 is the only one from
the intramolecular ‘ene’ reaction 22 125.
O
O
118
CO2Me
H
H
H
OAc
CO2Me
H
O
MeO2C H
N
O
119 120
N
HOMO
H CO2Me H CO2Me H
121 122 123
OAc
OAc
H
N
LUMO
CO2Me

SiMe 3
N
O
H CO2Me 124
150 ˚C
24 hours
N
SiMe 3
If the reaction mixture, or compound 124 alone, is heated to 250 C, the more stable anti isomer
129 is the only product. Though there are two carbonyl groups conjugated with the ‘enophile’
only the amide carbonyl can interact with the π-bond of the ‘ene’ so that the endo transition state
127 leads to the syn product 126. The exo transition state 128 leads to the anti product 129 and
equilibration is presumably by reverse ‘ene’ reaction.
Me 3Si
O
N
34 Intramolecular Alder ‘Ene’ Reactions with a Nitrogen Tether 821
If the carbonyl group responsible for the endo secondary orbital overlap is not there, as in
130, the exo product 131 is formed at lower temperatures. This was just as well as the reaction was
used to make allokainic acid 132 having the stereochemistry of 131.
Recognising an ‘ene’ disconnection of this sort is not easy but the relationship between
the π-bond and the carbonyl group in the product (126, 129, or 131) is a help. Of course the
reaction could also be used to make saturated compounds by subsequent hydrogenation and
then even that clue is no longer there. What makes this chemistry all the more useful is that
an asymmetric version has been devised and used to make a single enantiomer of allokainic
acid. 23 Initial results were not promising: the menthyl ester 133 gave anti 135 with less than
18% ee. However, the 9-phenylmenthyl ester 134 (see chapter 27) gave much better results.
Regioselectivity and anti-stereoselectivity were unimpaired but asymmetric induction depended
both on the geometry of the dienophile (E or Z-134) and the conditions. Thermal cycloaddition
gave a 50:50 mixture of the two diastereoisomers anti-136 and anti-138 but with Lewis acid
catalysis at lower temperatures a sensitivity to the geometry of the dienophile (E or Z-134)
could be used to make either diastereoisomer and hence, after hydrolysis, either enantiomer of
allokainic acid 132.
O
H CO2Me
125 126
SiMe3 N
SiMe3 N
H
H
H
O
H
H
H O
H CO2Me
CO2Me MeO2C H
N
SiMe 3
O
CO2Me
127 (endo) 126
128 (exo) 129
CF 3
N
H CO2Et
130
O
CO 2Et
CO2Et
80 ˚C
16 hours
CF3
N
O
CO2Et
CO 2Et
CO2Et
131; 97% yield
H
H
N
N
SiMe 3
O
H
CO2H
CO 2H
132; (+)-α-allokainic
acid
CO2Me

822 34 Functionality and Pericyclic Reactions
COCF3
CO
N
2Et
CO2Et O O R
E- or Z-133; R = i-Pr
E- or Z-134; R = CMe2Ph Z-134
E-134
Natural ()-α-allokainic acid 132 comes from anti-136 by two simple steps in 73% yield. The
stereochemistry of the fi nal centre is under thermodynamic control.
N
COCF3
CO2Et
CO2Et CO2R* anti-136
Intermolecular ‘Ene’-style Reactions with Oximes
Nitrogen can be incorporated as an oxime into a different kind of ‘ene’ reaction that has been
explored by Grigg and his group. The ‘ene’ component now bears no resemblance to a diene: one
pair of electrons comes from the lone pair on nitrogen and the other from the OH bond of the
oxime 140. The enophile is a more conventional enone and the initial product is a nitrone 141.
No nitrogen heterocycle is formed in this step, but, if the enophile contains a second alkene, a
1,3-dipolar cycloaddition gives a bicyclic structure. The simplest reagent for this job is the rather
unstable divinyl ketone (penta-1,4-dien-3-one, 143). Fortunately this can be released from the
dichloroketone 142 with base and distilled with the solvent THF into the reaction mixture. 24
R 1
The oximes are easily made but only the Z-oxime reacts. The temperature must be high enough
for the isomers to equilibrate. With alkyl oximes 144 this is easy enough: equilibration occurs at
81 C in MeCN. The ‘ene’ reaction forms the nitrone 146 under the same conditions.
RCHO
+
NH 2OH
O H
N
140
R
O
R 2
N
E-144
N
COCF 3
CO2Et CO2Et CO 2R*
anti-135; R = i-Pr
anti-136; R = CMe 2Ph
N
COCF 3
CO2Et CO2Et CO 2R*
anti-137; R = i-Pr
anti-138; R = CMe 2Ph
70 ˚C, 80 hours 50: :50
Et2AlCl, –35 ˚C
95:
:5
Et2AlCl, –35 ˚C 15: :85
O H
NaOH
R 1
81 ˚C
MeCN
H
N
CO2H
CO2H
CO2H
anti-139
pH 3
H 2S
H 2O
H
N
132
CO 2H
CO 2H
R2 O
N
H
H H
K2CO3 THF O
O
Cl O Cl
141 142 143
R
O H
N
Z-144
O
145
146
R
O
N
O

The 1,3-dipolar cycloaddition follows with the regiochemistry shown 146a and the product is a
bicyclic compound 147 with an N–O single bond that is easily reduced to give a seven-membered
cyclic aminoketone 148 with stereochemistry.
R
O
N
O
146 146a
Oximes of aromatic aldehydes 149 do not equilibrate under these conditions but the Lewis acid
catalyst HfCl 4 both allows oxime equilibration and reverses the regioselectivity of the 1,3-dipolar
cycloaddition 150 so that the fi nal product is a piperidine 152. The regiochemical reversal is probably
because the LUMO of the nitrone and the HOMO of the enone are used in 146a but, by lowering
the LUMO energy of the enone, HfCl 4 switches to the HOMO of the nitrone in 150.
PART IV – [3,3] SIGMATROPIC REARRANGEMENTS
The ‘Aza-Cope’ Rearrangement
R
O
N
O
OH O
O
OH HfCl4 Ar OH
145
HfCl4 O HfCl4
O O
N
Ar
E-149
N
Z-149
66 ˚C
THF
Ar N
150
Ar N
151
Ar N
H
152
The aliphatic Claisen (or oxy-Cope) rearrangement is a familiar [3,3] sigmatropic rearrangement
154, typically requiring temperatures of 200 C or so. The reaction is driven by the formation of
a carbonyl group 155.
The ‘aza-Cope’ rearrangement 157 has no special name and, at fi rst sight, no special utility as
it requires at least as high a temperature and the products are imines 158 very easily hydrolysed to
the products 155 of the Claisen rearrangement.
R
R
R
O
34 The ‘Aza-Cope’ Rearrangement 823
heat
>200 ˚C
R
O
The reaction is of value only if the products can be trapped with the nitrogen still in place. Stille
achieved this by (i) forming the starting materials by forcing the imine to enamine conversion
R
[3,3]
O
N
147
153 154 155
heat
R
N
>200 ˚C
R
N
R
N
O
156 157 158 155
[3,3]
R
R
O
O
H 2O
[H]
R
R
HN
148
OH
O

824 34 Functionality and Pericyclic Reactions
by acylation of the imine 160 followed by reduction 162, (ii) accelerating the aza-Cope step by
protonation of the amine 163, and (iii) trapping the imine products 164 by a second reduction 165.
The enamine 162 can be isolated in 95% yield if the imine 160 is not isolated on the way. 25 Other
catalysts also effective in reducing the temperature for the sigmatropic rearrangement from >200
to about 100 C include TiCl 4, Me 3Al, and BF 3.
NH 2
159
0.3-0.8 x HCl
reflux in dioxane
[100-102 ˚C]
10 hours
CHO
N
COCl
Et3N N
160; 74% yield
O
161; 94% yield
N
H
[3,3]
163 164
This sequence does not of course produce a nitrogen heterocycle. For that to happen we must
have further reactions that make a second C–N bond. One of the earliest and most interesting is
a pyridine synthesis 26 using a variety of pericyclic steps starting with propargyl amine 167 and a
1,3-diketone 166.
The stable enaminone 168 undergoes an aza-Cope reaction 170 at nearly 200 C in nitrobenzene.
It may seem odd that a linear alkyne should take part in such a reaction but in fact
this is not unusual. The product is an allene 171 that undergoes tautomerism to the more stable
enaminone 172 then a [1,5] sigmatropic H shift before cyclising to a dihydropyridine 174. The
cyclisation is formally a six electron disrotatory electrocyclic reaction 173. The solvent PhNO 2
oxidises 174 to the pyridine 169.
O
170
N
H
O
O H 3N
166 167
[3,3]
O
H
NaOH
benzene
reflux
O
Though dramatic, this is an unusual example of such processes. Much more has been made of
tandem aza-Cope and Mannich reactions, particularly by Overman. A typical sequence begins
with the addition of a vinyl-lithium, e.g. 176, to a protected α-aminoketone 177 to give, in this
case, the product 178 from Felkin-like attack (chapter 21) on the side of the ketone anti to the
amino group. 27
N
H
195 ˚C
PhNO 2
LiAlH4
LiAlH 4
0 ˚C
N
162; 98% yield
N
H
N
168; 74% yield 169; 50% yield
O
N H
N
H
H
171 172
[1,5]H
O
O
N
H
N
H
165; 83% yield
O
173 174
N
H

Br
O
O
t-BuLi
O
Li
Ph
175 176 177
O
+
O
N CN
Ar
OH
N CN
H
Ph
178
14:1 diastereoisomers
67% anti
isolated
The cyanide group can be eliminated with silver(I) catalysis to give the starting material
179 for an aza-Cope rearrangement. The product 182, however, has a new heterocyclic ring and
has also rearranged. The old fi ve-membered carbocyclic ring is now six-membered. The fi rst step
is indeed a [3,3] sigmatropic rearrangement on the immonium ion 179. The product 180 is another
immonium salt and is also an enol. Mannich cyclisation 181 gives the product 182. This is the
tandem aza-Cope (or azonia-Cope) rearrangement/Mannich ring closure sequence.
178
1.1 x
AgNO 3
EtOH
2 hours
50 ˚C
Ar
OH
H
N
179
Ph
[3,3]
Ar
OH
H
180
N
N
H
Ph
182; 94% yield
The stereochemistry can be predicted from the way the starting material 179 folds. Transition
states for [3,3] sigmatropic rearrangements prefer a chair-like conformation, in this case 184. The
dotted bonds in 184 show that minimal change is needed to form the new σ-bond and break the old.
The anti relationship between H and OH in 179 should be clear in 184. The chair six-membered
ring in 184 leads to the syn relationship between Ar and the same H in 185.
R
H
N
OH
Ar
R
H
Such effi cient transmission of stereochemical information suggest that asymmetric versions of
this reaction should be possible. Using a single enantiomer of 1-phenylethylamine, a single enantiomer
of the aminoketone 186 was prepared and converted into the starting material 187 for the
aza-Cope reaction. 28 The tandem reaction sequence is the same as that for 178 to 182 but gives a
single enantiomer of 188 in 94% yield and 99% ee.
Ph
=
N
OH
OH
Ar
Ar
N
181
Mannich
Ph
R
H
O
N
OH
183 184
185
O
N CN
O
Ph
Li
186 176
34 The ‘Aza-Cope’ Rearrangement 825
+
O
Ar
OH
Ag(I)
Ar
Ar
Ar
H
N CN
Ph
H
N
Ph
187; 91% yield 188; 94% yield
O

826 34 Functionality and Pericyclic Reactions
There is more to this chemistry than meets the eye. A simpler route to the [3,3] precursor,
avoiding the need for stoichiometric silver, is set out in the chart below.
HO
Me
O
NH 2
189; alanine
O
Me
Treatment of 192 with acid releases the immonium salt 193 that undergoes the tandem
aza-Cope/Mannich sequence. The fi nal product is a single diastereoisomer of the substituted
pyrrolidine 195.
O
Ph
Ph
N Me
Me
192
camphor
sulfonic
acid
toluene
60 ˚C
1.5 hours
However, though 195 is a single diastereoisomer, it is completely racemic. 29 The intermediate
194 is achiral though it is formed in a chiral conformation 194a that can give only one enantiomer
195a of the product. The problem is that, if the intermediate 194a is long lived enough for
bond rotation, it may fl ip to the enantiomeric conformation 194b that gives the enantiomeric
product 195b.
Racemisation occurs because the intermediate 194 is achiral and long lived enough for bond
rotation. This does not apply to the corresponding intermediate in the previous example 185. This
compound is a cyclononadiene containing two E-alkenes. Such compounds are chiral and bond
rotation is not possible because of the medium ring. Even if the chiral auxiliary is absent, a single
enantiomer of 185 should, and does, rearrange to a single enantiomer of 182.
The Anionic ‘Aza-Cope’ Rearrangement
Ph
Li
Ph
NHCO2Et excess
Me NHCO2Et 191; 80% yield
N
Me
Me
190 20:1 diastereoisomers
192
HO
Me
Ph
Ph
N
[3,3]
Alternatively, the aza-Cope rearrangement can be greatly accelerated by an oxyanion rather in the
style of the Cope rearrangement itself. The N/O acetal 196, easily prepared from cyclohexanone
and an amino alcohol, undergoes a rearrangement in strong base to give the spirocyclic
pyrrolidine 30 198.
HO
HO
Me
Ph
Ph
Ph
Ph
N
Me
Me
193 194
Mannich
Ph
O
O Ph
Ph
Ph
Me N
195
Me
79% yield
Ph
O
Ph
Ph
Me
OH
Me
N
ring
flip
OH
Me
N
Ph
Me
O
Ph
Ph
Me N
Me
195a
Ph
H
194a
Ph
H
194b
N Me
Me
195b

O
NH
KH
18-crown-6
O
196 197
198
The strong base removes the proton from the nitrogen atom and opens the ring 199 to give the
starting material 197 for an anion-accelerated aza-Cope rearrangement at 25 C in conformation
197a. The product is an enolate, rather than the enols we have been seeing up to now, and it
cyclises 200 in Mannich style onto the imine to give the anion of the product 198.
196
KH
O
N
O
199 197a
N
If the molecule is too rigid for the Mannich cyclisation to occur easily, it is possible to carry
it out as a separate step. Overman’s approach to gelsemine, a very diffi cult target, involves an
anionic aza-Cope rearrangement on 201 and the trapping of the enolate. 31 The resulting ketone
202 is cyclised in acidic solution. Evidently the addition of the enol to the protonated imine
goes better than the cyclisation of the enolate onto the neutral imine when the fi nal product is as
strained as 203.
R
The fi rst step is treatment of 201 with an excess of KH. Both the OH and the NH lose their protons
and cyanide is eliminated 204 to give the starting material for the aza-Cope 205. The product
is initially formed in a twisted conformation 206 that opens out to give the simple cis-fused imine
enolate 206a. Trapping the enolate with ClCO 2Me also converts the imine into the acylated enamine
207 and the enol ester is easily hydrolysed to give the ketone 202.
201
N
OH
1. KH
N
[3,3]
O
H2C
R
MeO2C O
N
HCO2H HN CN
2. ClCO2Me
3. KOH,
MeOH, H2O H
reflux
MeO2C
N
201 202 203
1. KH
R
R
34 The Anionic ‘Aza-Cope’ Rearrangement 827
O
204
O
N CN R
2. ClCO 2Me
MeO 2C
O
N
CH2 205
R
H
H
206a 207
N
[3,3]
R
O
200
OCO2Me
N
206
3. KOH
MeOH
H 2O
O
R
N
NH
202
198

828 34 Functionality and Pericyclic Reactions
In formic acid, the enamine is protonated on carbon to give the very electrophilic immonium
ion 208 which cyclises in conformation onto the enol 208a in an intramolecular Mannich reaction
to give the bicyclic skeleton 203 required for gelsemine.
202
R
MeO2C OH
HCO2H N
=
PART V – OTHER REACTIONS
This part contains one genuine pericyclic reaction and a collection of near relatives that all give
nitrogen heterocycles by the combination of various unsaturated molecules.
Electrocyclic Reactions
H
208
MeO 2C
There are few useful examples of electrocyclic reactions giving nitrogen heterocycles and we shall
give just one - a photochemical six electron electrocyclic reaction that closes a ring in a synthesis
of lysergic acid 211. The fi rst step is the acylation of the imine 209 and its regioselective conversion
into the more conjugated enamine 32 210.
BzN
NMe
O
COCl
The electrocyclic step is a photochemical cyclisation of 210 under reducing conditions to give
a mixture of diastereoisomers of 212 in about a 7:1 ratio. These were further reduced and the
N-benzoyl group replaced to give a separable mixture of amines: the required diastereoisomer 213
was isolated in 61% yield.
BzN
Et3N
The electrocyclic step can be drawn on the amide 210a but is perhaps more convincing when
drawn on the delocalised version 210b. In either case this is a photochemical six electron electrocyclic
reaction and therefore conrotatory. This determines the trans stereochemistry at two of the
N
R
208a
O O
OH
N Me
MeO2C
BzN
HN
209 210; 96% yield 211; Lysergic acid
O O
210
N Me
hν
NaBH 4
10:1
benzene:
MeOH
O
H
O
H H
N
H
Me
1. LiAlH4 2. PhCOCl
3. crystallise
H
BzN
212; 81% yield
O
N
R
203
CO 2H
NH
H
H
H H
N
Me
H
H
BzN
213; 61% yield

new centres in the product 214: the ringed hydrogen atoms must both have rotated in the same
sense (clockwise or anticlockwise).
BzN
O O
Under the reaction conditions, the enolate is protonated by methanol 215 to give the more
favourable cis ring junction 216 and borohydride reduces the immonium group stereoselectively
to give the major diastereoisomer 217 of the fi nal product.
BzN
Ring Closing Olefi n Metathesis
O O
O O
N
Me
N
Me
hν
six electron
conrotatory
electrocyclic
H H
N
Me
BzN
BzN
H
210a 210b 214
OMe
H
O O
H H
N Me
34 Ring Closing Olefi n Metathesis 829
MeOH
H
O O
H
N Me
O
H
O
H H
N
H
Me
H
BzN
H
BzN
H
215 216 217
In principle ring closing metathesis (RCM, chapter 15) offers a simple route to unsaturated nitrogen
heterocycles. The fi rst disconnection is across an alkene inside the ring and normally two alkenes
are created by the addition of a CH 2 group at each end. Further disconnection might have simple
alkylation at nitrogen in mind. A special problems in making nitrogen heterocycles this way might
well be complexation of the metal by nitrogen so the nature of R might be important.
Though any group could be added in theory, the addition of a CH 2 group ensures that the other
product will be gaseous ethylene so the thermodynamics are favourable. The Grubbs’ catalyst
(Cy cyclohexyl) is greatly to be preferred because of its stability and wide scope. This is not
strictly a pericyclic reaction but in concept it is very like a cycloaddition followed by a reverse
cycloaddition.
H
NaBH 4
Ring
X
Closing 2 x C–N
R N
R N R NH2 Metathesis
Grubbs
PCy3
catalyst
Cl
R N R N + CH2 CH2 Ru
Cl
Ph
PCy3 X
Grubbs
catalyst
Cy = cyclohexyl

830 34 Functionality and Pericyclic Reactions
We shall discuss just the application of RCM to the asymmetric synthesis of pyrrolidine and
piperidine derivatives. The asymmetry comes from an enantiomerically pure sulfi nyl imine
218 that accepts a lithiated sulfone as nucleophile to give one diastereoisomer of adduct 219;
R SO 2Ph. The chiral auxiliary is removed with acidic methanol and allylation on the nitrogen
gave a potential RCM substrate 221. In the event this compound failed to cyclise with the Grubbs’
catalyst so the nitrogen was acetylated to make it a worse ligand. Now RCM was successful and
the cyclic amide 223 formed in good yield. The amide can be hydrolysed quite easily to give the
free amine 224 as a single enantiomer of the anti diastereoisomer. 33
SO 2Ph
SO2Ph = R
R
N Ar
H
221; 72-79%
yield
1. LDA
R
TFA
R
2. O
O
MeOH
p-Tol
S
N Ar p-Tol
S
N
H
Ar
0 ˚C
H2N Ar
218 219; 85-100% yield 220; 62-88% yield
MeCOCl
R
5 mol%
Grubbs catalyst
The stereoselectivity in the formation of 219 can be explained by a combination of the imine
with the lithiated sulfone 225 in an intramolecular mechanism 225 with a chair transition state
226. The vinyl group goes axial to avoid a clash with the large groups around the sulfone.
p-Tol
The synthesis of pyrrolidines demands fi rst of all the movement of one of the alkenes closer
to the nitrogen atom. This can be done by equilibration of the allyl sulfone in 227 to the more
stable conjugated vinyl sulfone 228 with catalytic base. Then allylation at nitrogen gave a possible
metathesis substrate 229. In this series neither the amine 229, nor the corresponding benzamide
would undergo metathesis.
The problem is the sulfone. The trisubstituted alkene in 229 is too hindered. Reductive removal
of the sulfone and acylation gave a good metathesis substrate 231 and hence the pyrrolidine
R
40% aqueous
H2SO 4
K 2CO3
DMF
Et3N benzene N Ar
CH2Cl2 room temperature
N Ar
MeOH
100 ˚C N Ar
Ac
2-3 hours Ac
H
222; 73-83% yield
223; 80-89% yield 224; 60-74% yield
S
Ar
O N Ar
O S
N
O
Li
O
S
O
S
Li S
p-Tol
p-Tol N
O O
Ph
Ph
H
225 226 219
SO2Ph
cat. KOBu t
SO 2Ph
H2N Ar
THF, 0 ˚C
H2N Ar
K2CO3 MeCN
227 228; 73-85% yield
Br
Ar
Br
SO 2Ph
SO 2Ph
N Ar
H
229; 72-83% yield
R

232. That the product was enantiomerically pure was demonstrated by chiral HPLC of the N-Boc
compound and comparison of rotation with the known pyrrolidine 233.
229
SmI 2
THF/
HMPA
–20 ˚C
N Ar
H
230; 59-65% yield
PhCOCl
Et3N CH2Cl2 N Ar
COPh
231; 75-100% yield
5 mole%
Grubbs
catalyst
CH2Cl2 room
temp.
Ar
N
COPh
232
85-94% yield
The Pauson-Khand Reaction
In chapter 6 we described the use of the remarkable Pauson-Khand reaction for the synthesis of
cyclopentenones. If the components (CO, alkene and alkyne) are tethered by a nitrogen atom, a
heterocycle will also be formed. The fi rst stage in this process is to couple the cobalt carbonyl
complex, e.g. 236, of a halo-alkyne with an amine containing the alkene in the side chain. The best
way to do this is to react 234 with Co 2(CO) 9 to give 235 and then 236 and to capture this complex
with the amine without isolation of intermediates. 34
If the secondary amine is an allylic amine, the complex 239 rearranges with the incorporation
of a molecule of carbon monoxide (see chapter 6) to give the cyclopentenone 240 with simultaneous
formation of a pyrrolidone. This might be easier to see when you realise that 239 is the Co
complex of 238. The yields are not wonderful (48–64%) but are reasonable for a reaction that does
so much in one step.
A recent Organic Syntheses procedure 35 describes a much higher yielding version using a cobalt
complex formed from 241 by treatment with Et 3SiH and cyclohexylamine. Only catalytic amounts
(5 mol%) are needed to cyclise the sulfonamide 242 to the pyrrolidine 243.
N
H
Ph
233; >99.9% ee
Ph
Cl
Co2(CO) 9
0 ˚C
(CO) 3Co
Ph
Co(CO) 3
Cl
25 ˚C
CO
(CO) 3
Co
(CO) 3Co
Ph
O
Cl
R2NH (CO)3Co
Ph
Co(CO) 3
O
NR2 234 235 236
237
Ph
(CO)3Co
238
N
O
R
Co(CO)3
241
34 The Pauson-Khand Reaction 831
OH
(CO) 3Co
Ts
Ph
Co(CO)3
O
239
N
N
R
45 ˚C
CO, 241
67 ˚C
O
Ph
240
O
N
R
Ts N
O
242 243; 86-93% yield

832 34 Functionality and Pericyclic Reactions
Metal-Catalysed Alkyne Trimerisation
In the same vein but more in the style of Vollhardt’s co-trimerisation is a remarkable series of
reactions that combine three alkynes. One is propargyl alcohol and the other two are tethered by
a sulfonamide. 36 In the simple case 245, trimerisation with the Grubbs’ catalyst (see above) gives
one positional isomer 244 of a benzo-pyrroline while Wilkinson’s catalyst [(Ph 3P) 3RhCl] gives the
other possible isomer 246.
TsN
Even more remarkably, moving the nitrogen atom in the tether so that it is conjugated with
one of the alkenes 248, reduces the yield a little but doesn’t alter the regioselectivity at all. The
CH 2OH end of the propargyl alcohol reacts with the less hindered end of the amine when Grubbs’
catalyst is used 249 but the other way round with Wilkinson’s catalyst 247. With Grubbs’ catalyst
the reaction is presumably a series of metatheses starting on the less hindered alkene. It is not yet
understood how Wilkinson’s catalyst reverses this selectivity.
References
Me OH
244; 90% yield
Me
N
Ts
247; 67% yield
5 mole%
Wilkinson's
catalyst
25 ˚C
toluene
OH
5 mole%
Wilkinson's
catalyst
25 ˚C
toluene
OH
TsN
OH
TsN
245
248
General references are given on page 893
1. General Reference: D. L. Boger and S. M. Weinreb, Hetero Diels-Alder Methodology in Organic
Synthesis, Academic Press, San Diego, 1987.
2. H. R. Snyder, R. B. Hasbrouck and J. F. Richardson, J. Am. Chem. Soc., 1939, 61, 3560; H. R. Snyder and
J. C. Robinson, J. Am. Chem. Soc., 1941, 63, 3279.
3. A. Alberola, A. M. González, B. González, M. A. Laguna, and F. J. Pulido, Tetrahedron Lett., 1986, 27,
2927.
4. B. Serckx-Poncin, A.-M. Hesbain-Frisque and L. Ghosez, Tetrahedron Lett., 1982, 23, 3261.
5. K. T. Potts, E. B. Walsh, and D. Bhattacharjee, J. Org. Chem., 1987, 52, 2285.
6. D. L. Boger, W. L. Corbett, T. T. Curran, and A. M. Kaspar, J. Am. Chem. Soc., 1991, 113, 1713.
7. F. Sainte, B. Serckx-Poncin, A.-M. Hesbain-Frisque and L. Ghosez, J. Am. Chem. Soc., 1982, 104,
1428.
8. J. Barluenga, M. Thomás, A. Ballasteros and V. Gotor, J. Chem. Soc., Chem. Commun., 1987, 1195.
9. General Reviews: S. M. Weinreb and J. I. Levin, Heterocycles, 1979, 12, 949; S. M. Weinreb and R. R.
Staib, Tetrahedron, 1982, 38, 3087; G. R. Heinzelman, I. R. Meigh, Y. R. Mahajan and S. M. Weinreb,
Org. React., 2005, 65, 141.
10. G. A. Kraus and K. Neuenschwander, J. Org. Chem., 1981, 46, 4791.
11. S. J. Danishefsky and C. Vogel, J. Org. Chem., 1986, 51, 3915.
12. J. F. Kerwin and S. Danishefsky, Tetrahedron Lett., 1982, 23, 3739.
Me
H
Me
H
OH
OH
5 mole%
Grubbs'
catalyst
40 ˚C
CH2Cl 2
5 mole%
Grubbs'
catalyst
40 ˚C
CH2Cl 2
TsN
Me
246; 81% yield
Me
OH
N
Ts
249; 70% yield
OH

34 References 833
13. P. D. Bailey, D. J. Londesbrough, T. C. Hancox, J. D. Heffernan and A. B. Holmes, J. Chem. Soc., Chem.
Commun., 1994, 2543.
14. General Review: E. Ciganek, Org. React., 1984, 32, 1.
15. Y. Ito, S. Miyata, M. Nakatsuka, and T. Saegusa, J. Am. Chem. Soc., 1981, 103, 5250.
16. R. B. Ruggieri, M. M. Hansen, and C. H. Heathcock, J. Am. Chem. Soc., 1988, 110, 8734.
17. P. A. Grieco and D. T. Parker, J. Org. Chem., 1988, 53, 3658.
18. P. A. Grieco and D. T. Parker, J. Org. Chem., 1988, 53, 3325; P. A. Grieco and A. Bahsas, Tetrahedron
Lett., 1988, 29, 5855.
19. W. Oppolzer and W. Fröstl, Helv. Chim. Acta, 1975, 58, 590; W. Oppolzer W. Fröstl and H. P. Weber,
Helv. Chim. Acta, 1975, 58, 593.
20. R. K. Boeckman, J. P. Sabatucci, S. W. Goldstein, D. M. Springer and P. F. Jackson, J. Org. Chem., 1986,
51, 3740.
21. I. Fleming, Pericyclic Reactions, Oxford University Press, 1999.
22. W. Oppolzer and V. Snieckus, Angew. Chem., Int. Ed., 1978, 17, 476.
23. W. Oppolzer, C. Robbiani, and K. Bättig, Helv. Chim. Acta, 1980, 63, 2015.
24. I. S. Saba, M. Frederickson, R. Grigg, P. J. Dunn and P. C. Levett, Tetrahedron Lett., 1997, 38, 6099;
P. J. Dunn, A. B. Graham, R. Grigg, P. Higginson and I. S. Saba, Chem. Commun., 2000, 2033, P. J.
Dunn, A. B. Graham, R. Grigg and P. Higginson, Chem. Commun., 2000, 2035.
25. G. R. Cook and J. R. Stille, J. Org. Chem., 1991, 56, 5578; G. R. Cook, N. S. Barta and J. R. Stille,
J. Org. Chem., 1992, 57, 461.
26. K. Berg-Nielsen and L. Skattebøl, Acta Chem. Scand., 1978, B32, 553.
27. L. E. Overman, L. T. Mendelson and E. J. Jacobsen, J. Am. Chem. Soc., 1983, 105, 6629.
28. L. E. Overman and S. Sugai, Helv. Chim. Acta, 1985, 68, 745.
29. E. J. Jacobsen, J. Levin, and L. E. Overman, J. Am. Chem. Soc., 1988, 110, 4329.
30. M. Kakimoto and M. Okanawa, Chem. Lett., 1979, 1171.
31. W. G. Earley, E. J. Jacobsen, G. P. Meier, T. Oh and L. E. Overman, Tetrahedron Lett., 1988, 29, 3781;
W. G. Earley, T. Oh and L. E. Overman, Tetrahedron Lett., 1988, 29, 3785.
32. T. Kiguchi, C. Hashimoto, T. Naito and I. Ninomiya, Heterocycles, 1982, 19, 2279.
33. R. Kumareswaran, T. Balasubramanian and A. Hassner, Tetrahedron Lett., 2000, 41, 8157.
34. J. Balsells, A. Moyano, A. Riera and M. A. Pericàs, Org. Lett., 1999, 1, 1981.
35. M. C. Patel, T. Livinghouse and B. L. Pagenkopf, Org. Synth., 2003, 80, 93.
36. B. Witulski, T. Stengel and J. M. Fernández-Hernández, Chem. Commun., 2000, 1965.

35
Synthesis and Chemistry of Azoles
and other Heterocycles with Two
or more Heteroatoms
This chapter considers how aromatic heterocyclic compounds with two or more nitrogen
(or other heteroatoms, chiefl y O and S) atoms can be made. In particular it deals with the addition
of new C-C and C-X bonds to previously prepared heterocycles of this kind.
PART I – INTRODUCTION
Azoles: Heterocyclic Compounds with More than One Nitrogen Atom
Names for a selection of these heterocycles: mainly 5- and 6-membered aromatic rings
PART II – BUILDING THE RING
a. The Simplest Disconnections
The synthesis of allopurinol
The synthesis of thiazoles
b. Routes to Isoxazoles
The synthesis of isoxazoles from dicarbonyl compounds
The synthesis of isoxazoles by 1,3-dipolar cycloaddition
c. Tetrazoles
The synthesis of tetrazoles by 1,3-dipolar cycloaddition
PART III – DISCONNECTIONS OUTSIDE THE RING
a. N–C Disconnections: Azole Anions
How to get reaction at nitrogen using azole anions
The problem of tautomerism in azoles
How to get reaction at nitrogen using silyl derivatives in acid solution
b. C–X Disconnections
Using electrophilic and nucleophilic aromatic substitution in fi ve- and six-membered
heterocycles. Chemo- and regioselectivity
The synthesis of pyridazines
c. C–C Disconnections
The few reactions that work well with heterocycles. The Heck reaction, Friedel-Crafts
acylation and a mention of lithiation
d. Examples: An Anti-Ulcer Drug and Pentostatin
An isocytosine-based drug with three heterocyclic rings
Pentostatin: an example with fused fi ve- and seven-membered rings
A Designed Enzyme Inhibitor
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

836 35 Synthesis and Chemistry of Azoles
PART I – INTRODUCTION
Azoles: Heterocyclic Compounds with More than One Nitrogen Atom
Most important drug molecules are heterocycles and most of those heterocycles contain more than
one heteroatom yet the chemistry of these systems is neglected and even despised by many organic
chemists. 1 A few examples should convince you that neglect of this area is quite unjustifi ed for any
serious organic chemist. The very fi rst synthetic drug, antipyrine 1, is an aromatic pyrazolone with
two adjacent nitrogens in a fi ve-membered ring. Perhaps the most famous drug of all, penicillin
2, has a saturated fi ve-membered ring with a nitrogen and a sulfur atom and of course the vital
β-lactam used to disrupt bacteria cell wall synthesis.
In more modern times, the fi rst successful anti-ulcer drug, cimetidine 3, with its ability to block
histamine synthesis in the stomach, is an imidazole and the classical anti-depressant valium 4 has
a seven-membered ring heterocycle that is not (quite) aromatic.
3
Cimetidine
(Tagamet)
(1970s)
N
S
N Me
H
imidazole
H
N NHMe
N CN
Coming more up to date, Viagra 5, Pfi zer’s impotence treatment that hit the headlines at the end
of the last century has three heterocyclic rings - a saturated piperazine and two aromatic rings that
separately make a pyrimidone and a pyrazole and together imitate a purine. The most successful
drug to date, Omeprazole 6, is another anti-ulcer drug but with a unique action that inhibits the
proton pump. It has a pyridine ring and a benzimidazole.
5
Viagra
(Sildenafil)
1
Antipyrine
(1887)
EtO
O
S
N
O
O
N
N
Ph
pyrimidone
HN
O
N
Me
Me
N
N
Pr
Me
piperazine
N
Me
pyrazole
Ph
These rings are from four- to seven-membered, but fi ve- and six-membered dominate. They
may be saturated, partly saturated, or fully aromatic and they may contain one or more heteroatom.
The heteroatoms may be nitrogen, oxygen, or sulfur but nitrogen dominates. In this chapter
Me
O
H
N
O
H
Cl
OMe
N
pyridine
H
N
S
Me
O
S
CO 2H
HN
Me
Ph
N
N
2
penicillin G
(1940)
N
O
benzimidazole
4
Diazepam
(Valium)
6
Omeprazole
(Losec)
OMe

we shall be looking at the synthesis of fi ve- and six-membered rings, mostly aromatic, and mostly
containing two or more nitrogen atoms. The chemistry will be very varied.
It is worthwhile introducing these ring systems with a brief survey highlighting the main
features of the various systems. All are based either on pyrrole 7 or pyridine 8. The distinction
between the two types of nitrogen atoms present in these rings is an extremely important part of
understanding aromatic heterocyclic chemistry.
7
pyrrole
N
H
N
H
N
H
p lone pair
Pyrrole 7 has only two π-bonds so it needs the lone pair on the nitrogen atom to complete the
aromatic sextet and the lone pair has to be in a p-orbital and delocalised round the ring. Pyridine
8 has three π-bonds so the lone pair on nitrogen is not needed. Besides, it is in an sp 2 orbital in the
plane of the ring and cannot be delocalised as it is orthogonal to the p-orbitals in the ring. Pyrroles
are therefore nucleophilic and react with electrophiles at nitrogen or at carbon while pyridines
react with electrophiles only at nitrogen and the ring itself is electrophilic (chapter 32).
Adding an extra nitrogen atom (in thought only!) to the pyridine ring system creates three new
heterocycles, pyridazine 9, pyrimidine 10, and pyrazine 11, and in all three the extra nitrogen is of
the pyridine type with localised lone pairs on both nitrogen atoms. These three heterocycles are
more electrophilic and even less nucleophilic than pyridine.
9
pyridazine
Adding more nitrogen atoms to pyrrole gives a series of diazoles 12 and 13, triazoles 14 and 15 and
tetrazole 16 but each has two π-bonds and so needs the lone pair of only one of the nitrogen atoms for
aromaticity. Each extra nitrogen atom is of the pyridine sort with an sp 2 lone pair. These heterocycles
become less nucleophilic as more nitrogen atoms are added. In the diagrams below, the pyrrole-like
lone pairs are marked in the ring and the pyridine-like lone pairs in sp 2 orbitals outside the ring.
N
N
N
N
N
N N
N
When sulfur or oxygen atoms are present in a fi ve-membered ring, they provide the pyrrole-like
lone pair and any nitrogen atoms are necessarily pyridine-like. The four most important systems
are oxazole 17 and thiazole 18 with 1,3-related heteroatoms and isoxazole 19 and isothiazole 20
with an N-O or N-S bond.
With fused heterocyclic rings, the situation can be quite complicated but it is really necessary
only to decide whether each nitrogen atom is pyrrole- or pyridine-like. You can count electrons in
N
N
N
8
pyridine
N
sp2 lone pair
12; pyrazole 13; imidazole 14 triazoles 15
16; tetrazole
17
oxazole
35 Azoles: Heterocyclic Compounds with More than One Nitrogen Atom 837
H H H 1,2,3- H 1,2,4-
H
O
N
N
N
18
thiazole
10
pyrimidine
S
N
N
N
19
isoxazole
O
N
11
pyrazine
N
N
N
N
N
20
isothiazole
N
S
N

838 35 Synthesis and Chemistry of Azoles
each ring or in both rings together, whichever you prefer though in the case of the azaindolizine
21, it is more convincing to count the ten electrons in the periphery as the pyrrole-like nitrogen
belongs to both rings. The three unmarked nitrogens in the purine 22 are all pyridine-like.
21
imidazo
[1,2-a]pyridine
(aza-indolizine)
The rest of the chapter is divided into two parts. We shall fi rst consider how the rings themselves
may be formed and then how new bonds (either C-X or C-C) may be built onto a previously
formed ring. Both methods are important.
PART II – BUILDING THE RING
a. The Simplest Disconnections
N
N
pyridine
-like
pyrole
-like
22
purine
The fi rst disconnection to be considered is breaking all the C–X bonds in the ring. This is an obvious
strategy for a pyrazole since one C–N bond is part of an enamine and the other is an imine
23. Both functional groups are made from amines and carbonyl compounds. Here hydrazine is the
diamine that emerges from an easily made 1,3-dicarbonyl compound 24.
23
pyrazole
R1 enamine
R 2 R 3
N
H
N
imine
2 x C-N
O
24
An example is the pyrazole 25 needed for the synthesis of Viagra. Double C–N disconnection
reveals a diketoester 26 with a convenient 1,3-diCO relationship that can be disconnected to a
ketone 27 and unenolisable, reactive, and symmetrical diethyl oxalate.
EtO 2C
The Claisen condensation is regioselective because the most stable enolate 28 of the product 26
is formed under the reaction conditions and it is more stable than the alternative 29. Reaction with
hydrazine occurs at the two keto groups rather than at the less electrophilic ester.
CO2Et 27
CO2Et diethyl
oxalate
EtO
R 1
N
R 2 R 3
O
N N
+
N
H
pyrole
-like
H 2N NH 2
hydrazine
Pr
N
H
25
N
2 x C-N
EtO2C 1
2
O
26
Pr
3
O
1,3-diCO
Claisen
ester
OEt
EtO2C
O
diethyl oxalate
+
Pr
O
27
EtO2C
O
28
Pr
O
EtO2C
O
26
Pr
O
H 2N NH 2
H2O
25
EtO2C
O
29
O

The synthesis of allopurinol
Many heterocycles were made by simple procedures of this kind and the syntheses were designed by
breaking the molecule into reasonable pieces. Putting these aromatic molecules together generally
relied on thermodynamics rather than kinetic selectivity. A good example is allopurinol 30, a treatment
for gout that works by inhibiting xanthene 31 oxidase and thus preventing the deposition of painful
crystalline uric acid 32 in the joints. Allopurinol imitates purine 22; the main change being the movement
of a nitrogen atom in the right hand ring so that a pyrazole replaces the imidazole in purine.
O
O
H
HN
N
HN
N
N N
H
H2N N N
H
30; allopurinol 31; xanthine
Disconnection of hydrazine 30a from allopurinol leaves a diamide with an extra aldehyde
group 33. Disconnection of that aldehyde leaves a simple and available symmetrical heterocycle
that exists in the dihydroxy tautomer 34 and will require a one-carbon electrophile corresponding
to the synthon 35. We shall meet reagents for this synthon soon.
HN
O
N
30a
N
N
H
2 x C-N
HN
O
N
33
No doubt such a synthesis could be carried out. We might also explore the alternative disconnection
of the six-membered ring. Opening up the amidine 30b at fi rst looks unpromising but
tautomerism between 36 and 37 reveals an amidine and an excellent disconnection to a nitrile 38
from which hydrazine can be removed to give the much simpler 39. Now we must use the same
disconnection as 33 to give the same synthon 35 and the even simpler 40.
OHC
HN
N
H
O
N
30b
O
N
N
H
C=N
imine
N
38 39
35 The Simplest Disconnections 839
H
O
O
The synthesis is typical of old heterocyclic methods but has a delightful twist at the end. The
one carbon electrophile corresponding to CHO is triethyl orthoformate CH(OEt) 3. The other
starting materials are very simple: formamide, cyanoacetic acid, and hydrazine and the synthesis
is very short. Intermediate 40 is crystalline but need not be isolated as 34 g of cyanoacetic acid can
O
O
CHO
xanthine
oxidase
N
O
OH
HN
N
34
±H
N
H
N
H N
H
H2N
36
N
H
HN
37
O
O
H
N
N N
H H
32; uric acid
OH
C-N OHC
OHC
C-N
NH
N
35+
N
NH
H
H
2
N
X
O
O
O
+
?
O
CHO
35
NH
N
H
CHO X
+
NH2 C–N
amidine
O
N
N
40 41

840 35 Synthesis and Chemistry of Azoles
be converted directly into 15 g of 42. The twist is that the last reaction is carried out by heating the
dry yellow crystalline 38 at 150 C. No visible change occurs, but water is lost and the compound
is entirely converted into allopurinol 2 30.
The synthesis of thiazoles
The most obvious disconnection (1,1-diX) of a thiazole 43 reveals an acid derivative but the other
starting material 44 is an impossible compound requiring NH 2 and SH groups to be cis substituted
on an alkene. Neither of these functional groups (primary enamine or thioenol) is stable and
control of the geometry would also be impossible. The thiol 44 is also the thioenol of an α-amino
thioketone 45: these are equally unknown.
N R
S
2
R1 R3 H2N R
HS
2
R1 R3 O
H2N R
X
S
2
R3 1,1-diX
+
C-S and C=N
43; thiazole 44; does not exist 45; does not exist
The most productive disconnection is to keep the two heteroatoms in the same starting material,
recognising that this can be redrawn as a thioamide. We start by disconnecting the C–N bond
43a of the enamine and then 46 the C–S bond to reveal a simple α-haloketone 48 and a compound
47 that may look strange at fi rst but can be redrawn as a thioamide 49.
R 1
O
N R
S
2
R3 R2 R3 O
R S 1
NH
O
R SH X
1
C-N C-S NH
+
enamine
43a 46
47 48
The synthesis of thiazoles 43 adds an element of regioselectivity as the thioamide has soft
(S; orbital controlled) and hard (N; charge controlled) nucleophilic sites and it is essential to differentiate
equally clearly between the two electrophilic centres on the carbonyl part of the molecule. We need
to know that a thioamide will react with an α-haloketone 48; X Cl, Br so that the hard nitrogen
atom attacks the ketone and the soft sulfur atom attacks the saturated carbon atom. Thus the simple
non-steroidal anti-infl ammatory drug Fentiazac 50 is made from thiobenzamide 51 and the simple
bromoketone 52, made in turn by bromination of the ketoacid. The synthesis is just that. 3
Fentiazac: Analysis
HCONH 2
formamide
HO
CN Ac2O, 70 ˚C
cyanoacetic acid
40
Cl
HC(OEt)3
Ac2O
N
C-N
NH O
2
Ph Ph
+
CO
S
2H C-S
CO2H
S Br
50 51 52
H
O
N
H
O
42
CN
OEt
NH 2NH 2
AcOH
R 2
R 3
47
38
Cl
150 ˚C
R 1
NH 2
49
30
S

. Routes to Isoxazoles
The synthesis of isoxazoles from dicarbonyl compounds
The disconnection of isoxazoles is easier because there is obviously a molecule of hydroxylamine
(NH 2OH) waiting to be removed so that isoxazole 53 is ‘obviously’ made from 1,3-diketone 54
and hydroxylamine. That is all very well until we realise that we should also like to make isoxazole
55 from the same two starting materials!
R 1
R 2
O
O
N
R O 1
R1 C–O
C=N
enol ether
imine
53
C=N
imine
54
C–O
enol ether
55
Regioselectivity is not so straightforward here. Both N and O are good nucleophiles for carbonyl
groups. There has been some success in controlling the reaction by conditions. Thus chemists at Wyeth
making ‘glucose lowering agents for obese diabetic mice’ reacted hydroxylamine with the ketoesters
57 in acetic acid at room temperature overnight to give mainly isomer 58 while in concentrated HCl
at lower temperatures for shorter times, isomer 56 predominated. It looks as though 56 is the kinetic
and 58 the thermodynamic product but the yield of either isomer was poor 4 (30–40% at best).
Ar
It is better to differentiate the two electrophilic sites more sharply. The bromoenones 59 give
some regioselectivity at different pHs. Hydroxylamine is usually added as the crystalline hydrochloride
and base is needed to release the free amine. Carbonate does this and with K 2CO 3 in
EtOH, isoxazole 60 is the product. It appears that conjugate addition of the nitrogen atom 61 occurs
fi rst. 5
Ph
With the stronger base NaOEt in the same solvent, the isomeric isoxazole 62 is the main product.
Presumably the hydroxylamine anion is the nucleophile and now the oxyanion does conjugate
addition 64 in the fi rst step. Attractive and rational though this method may be, the average yields
of either isomer are only 25–50%. This type of approach relies too much on delicate choices between
similar groups and a better way is needed.
Ph
R 2
R 2
N
O
R
OH
N
O
1. NH2OH 2. conc HCl
cold, 1 hour
Ar
R
CO2Et O
1. NH2OH 2. AcOH
room temperature
overnight
Ar
R
56 57 58
R
O
Br
K 2CO 3/EtOH
Ph
R
N
O
Ph
R Br
59 60 61
R
Br
NH 2OH.HCl
NH 2OH.HCl
NaOEt/EtOH
O
Ph
59 62
35 Routes to Isoxazoles 841
R
O
N
Ph
O
NH
OH
R Br
O
Ph
R
O
R
Br
Br
O
NH2 Ph O
63 64
O
O
N
H
NH 2
OH
O
NH2

842 35 Synthesis and Chemistry of Azoles
The synthesis of isoxazoles by 1, 3-dipolar cycloaddition
And this is it! Alkynes add to nitrile oxides in a concerted π4 s π2 s cycloaddition 65 to give an isoxazole
66 in one step. 6 The alkyne provides the two electrons and the nitrile oxide provides four (a lone pair
on the oxyanion and one of the π-bonds in the alkyne). The nitrile oxide is an example of a ‘1,3-dipole’
being nucleophilic at one end and electrophilic at the other. It provides the four π-electrons from three
atoms. The alkyne is a ‘dipolarophile’. You may guess that nitrile oxides are inherently unstable. In fact
they do 1,3-dipolar cycloadditions on themselves to produce strange heterocycles 67 called furoxans.
They must therefore be released in the presence of the dipolarophile and the dipolarophile must live up
to its name and be better than the nitrile oxide at accepting the 1,3-dipole.
R 1
R 2
R 3
1,3-dipolar
R 2
N O
R1 cycloaddition
65 66
R 3
O
N
cycloaddition
There are two good ways to do this. Dehydration of alkyl nitrocompounds 68, either with
PhNCO or with Ph 3P and DEAD (EtO 2C-NN-CO 2Et) in a Mitsunobu elimination gives nitrile
oxides 69, as does the 1,3-elimination of HCl from chloro-oximes 70. In the next section we shall
show only the nitrile oxide but you should recall that it is generated in the reaction mixture by one
of these reactions.
R N O
H H
O
68
The problem of regioselectivity remains. Monosubstituted alkynes usually react cleanly using
the HOMO of the alkyne and the LUMO of the nitrile oxide. The product is exactly that type of
isoxazole (72 or 73) that was so diffi cult to make from dicarbonyl compounds and hydroxylamine.
Here regioselectivity is controlled because the two substituents (R 1 and R 2 ) are on different
reagents. Conditions are very mild.
R 2
The disconnection for this reaction is extremely simple 66a - just remove the nitrile oxide.
However, if a fully substituted isoxazole is required, the disubstituted alkyne is no longer a satisfactory
dipolarophile as it usually does not show enough regioselectivity.
R 2
R 1
PhNCO
or Ph 3P
DEAD
N O
66a
R 1
R 3
O
N
R
stand at
room
temperature
N O
R
N
O
Cl
69 70
R 2
R 1
R 2
72
R
N
O
Et3N Cl2 R NOH
R 1
O
N
N O
R 3
R 1
R 2
O
N
73
1,3-dipolar
R NOH
H
71
stand at
room
temperature
66 +
R 3
R 1
R 1
R R
N
N
O
67
NH 2OH
R 2
O
N
74
O
N O
R O
R 2
H

Better results are often obtained by using, as a latent alkyne, an alkene 77 with a substituent X
that can be eliminated and that directs the regioselectivity of the cycloaddition. This means that a
preliminary FGI on the isoxazole 75 (alkene to alkyl X) is required before the 1,3-dipolar disconnection
76.
Analysis:
R
R
R
FGI
R
R
X
1,3-dipolar
O
O
R
N
75
R N
76
cycloaddition
77
N O
If X is electron-withdrawing, and the best example is X Cl, the LUMO of the dipolarophile
reacts with the HOMO of the nitrile oxide, i.e. O attacks the electrophilic end of the alkene, and
the intermediate isoxazoline eliminates HCl 78 (not necessarily by an E2 reaction) to give the
aromatic isoxazole 79.
Synthesis:
Cl
R
R
N O
If on the other hand the substituent X is electron-donating, and various examples such as OAc,
NR 2, OSiMe 3, or SR can be used, the regioselectivity is reversed with the HOMO of the dipolarophile
attacking the LUMO of the nitrile oxide at the carbon end of the dipole. Elimination
80 gives the isomeric isoxazole 81.
The three approaches can be compared with the same isoxazoles. 1,3-Dipolar cycloaddition
with the alkyne 82 gives a mixture of regioisomers 83 and 84. If the chloroalkene 85 is used
instead, only 84 is formed while the enamine 86 gives 83 only. 7
82
85
86
Synthesis:
X = OAc, NR 2
OSiMe 3, SR
Ph
O
O
R
R
H
Ph Cl
O
Ph NMe 2
35 Routes to Isoxazoles 843
X
N O
Ph
Ph
Ph
N O
N O
N O
Cl
R
R
H
R
Ph
O
Ph
78
R
H
O
N
X
R
X
+
R
R
79
R
O
N
O
O
N
R N
80 81
83; 12% yield
83 only
O
N
Ph
R
84; 70% yield
O
Ph
O
N
84 only

844 35 Synthesis and Chemistry of Azoles
c. Tetrazoles
The synthesis of tetrazoles by 1, 3-dipolar cycloaddition
One group of heterocycles made almost exclusively by 1,3-dipolar cycloadditions is the tetrazoles
87. They have four nitrogen atoms in the fi ve-membered ring and therefore only one carbon atom
and, inevitably, no C–C bonds. Tetrazoles are as acidic as carboxylic acids (pK a about 5) and disconnection
of the anion 88 into a nitrile and azide ion is the usual approach.
Tetrazoles:
Analysis
R
N
FGI
N
N
N
N
N
N
H
87 88
R
There are many ways to make the reaction work well, one of the most popular using sodium
azide buffered with ammonium chloride with LiCl in DMF. The product is the tetrazole anion 88
and the tetrazole 87 is released on acidifi cation. The example 91 shows that the yields are excellent
and that functionality can be included in the side chain. 8
MeO
89
1. NaN3, LiCl, NH4Cl MeO
N
CN DMF, 100 ˚C
N
N
N
That the reaction occurs as expected between the HOMO of azide (which is, after all, an
anion) and the LUMO of the electrophilic nitrile is confi rmed by reactions with aryl nitriles
ArCN with sodium azide. The yields are all close to quantitative but the reaction is faster when
R is an electron-withdrawing group. Not everyone agrees that the reaction is concerted as the
approach of the two linear molecules looks very hindered. However, a stepwise addition of azide
ion 92 followed by cyclisation 93 looks, if anything, worse as two negatively charged atoms
must attack each other in the cyclisation 93. However, this too is pericyclic (electrocyclic) and
not ionic.
one step
mechanism
R
N
RCN
N
N
N
NaN 3, LiCl
NH4Cl, DMF, 100 ˚C
86
90
This disconnection should of course be followed by others as the need arises. Thus the antihypertensive
zolterine 94 containing a second heterocyclic ring - a piperazine - can be made from
nitrile 95 and that comes from conjugate addition of the piperazine to acrylonitrile.
N
1,3-dipolar
cycloaddition
acid
88 87
work-up
two step mechanism
R
N
N
N
N
92
2. acid work-up
N
R
N
N
N
N
MeO
N
N
N
N
H
91; 100% yield
R N N N
93
86

Zolterine (anti-hypertensive) Analysis:
Ph
N
N
H
N
1,3-dipolar
Ph
N
1,3-diX
Ph
N
94; Zolterine
N
N
N
95
CN
This synthesis was carried out using the method we have described and is short and unambiguous. 9
Zolterine (anti-hypertensive) Synthesis:
Ph
N
96
NH
CN
95
NaN 3, LiCl
NH 4Cl, DMF, 100 ˚C
If there is functionality directly attached to the carbon atom of the tetrazole, a problem
may seem to arise. Thus many drugs are made from 5-aminotetrazole 97 and our disconnection
requires the unlikely looking molecule H 2N-CN. This is in fact ‘cyanamide’ available as a
mixture with water and ‘stabilisers’ to prevent dimerisation to ‘dicyandiamide’ 98. The dimer
is 50 times cheaper and can be used in the 1,3-dipolar cycloaddition under slightly different
conditions. 10
Many Tetrazole Drugs Made from 5-Aminotetrazole
Analysis:
Synthesis
H2N N
H
N
N
N
1,3-dipolar
NH2 N
N
N
N
NH2 N
97
cyanamide
A good example of a drug made from aminotetrazole is Merrell Dow’s anti-allergic agent MSD
427. You will notice that the drug 99 is actually the stable anion of the tetrazole. It makes sense to
disconnect the aminotetrazole immediately to reveal the N-formyl derivative 100 of o-aminobenzoic
acid (anthranilic acid) 101. 11
Analysis:
O
N
N
N
99; MSD 427
N
N
N
2 x C–N
35 Tetrazoles 845
O
Another fragment is a one carbon electrophile we have shown as ‘ CHO’. You will appreciate
that the more heteroatoms there are in the ring, the more necessary it is to use small carbon
fragments to make the rings. All that remains is to identify a reagent for 102 and to decide on the
order of events. The reagent chosen was triethyl orthoformate HC(OEt) 3 and the synthesis was
simplicity itself.
Ph
NH
N
CN
H2N N
H
98; dicyandiamide
N
96
+
NH
H
N
N
N
N
N
94; Zolterine
O
CN
HCl added
slowly
H2N
H
N
to NaN3
water
N
N
N
97; crystallises as
stable hydrate
N
H
OR
CHO
C–N
OH
NH2 [ CHO]
H2N 100 101 102
N
97
N
N
N
H

846 35 Synthesis and Chemistry of Azoles
Synthesis
97
HC(OEt) 3
O
O N
N
N
+
OMe
H N
H
N
H
NH2 103
104
PART III – DISCONNECTIONS OUTSIDE THE RING
a. N–C Disconnections: Azole Anions
Though tetrazole is the most dramatic example of a stable anion from an azole, all the azoles show
enhanced acidity when compared with simple cyclic amines. 12 Pyrrole (pK aH 3.4) is a much weaker
base than pyrrolidine (pK aH 11.3) and it is protonated at carbon 107, not at nitrogen, to give the dearomatised
ion 106 since the lone pair is delocalised round the ring. As an acid 108, it is much stronger
than simple amines since the anion 109 is aromatic, like the cyclopentadienyl anion, but more stable
because of the electronegative nitrogen atom. Pyrrole is about as strong an acid as a tertiary alcohol,
so bases that you might use to make t-BuO , such as NaH, are needed to make the anion.
Every additional nitrogen atom must be of the pyridine sort and this has the curious effect of
increasing both the acidity and the basicity. There is another difference. Protonation now occurs
on the pyridine-like nitrogen atom but both nitrogen atoms cooperate to deliver electrons in both
pyrazole 111 and imidazole 112. In this process the pyridine-like nitrogen atom becomes pyrrole-like
and vice versa but this is merely formal as the cations 110 and 113 are symmetrically
delocalised and the two nitrogen atoms are equivalent.
The action of pyrazole and imidazole as acids is simpler. In each case the anion (114 or 117) is
aromatic, symmetrical, and more stable than the pyrrole anion because of the extra nitrogen atom.
The two ‘diazoles’ pyrazole and imidazole are almost equal in acid strength.
As we add (this is a thought process and not a chemical reaction) more nitrogen atoms the trend
to greater acidity continues. The two triazoles 119 and 120 are stronger acids and, as we have seen,
O
N
H
OMe
105
N
N
N
N
N
H
H pKa as base –3.4
pKa as acid 16.5
N
H
H N
H
H
N
H
B
N
106 107 108
109
N
N
H
pKaH as base
2.5
N
N H
H
H
110 111; pyrazole
N
N
pKa
as acid
N
N pKa
as acid
N
N 14.2 N
N
14.4
H B
H
B
114a 114b 115 116
base
N
H
N
H
N
pKaH as base
7.0
N
H
H
112; imidazole 113
N
N
N
N
117a 117b
99

tetrazole 122 is about as strongly acidic as carboxylic acids. All this information seems rather dull
but it is essential to have a grasp of the trends when planning to make bonds to the nitrogen atoms
of the azoles.
N
N
118
N
1,2,3-triazole 1,2,4-triazole
pKa as acid
N pKa as acid
N N N
9.4 N
N 10.3
H
H
119
120
How to get reaction at nitrogen using azole anions
In a nutshell: if you want to make a bond to a nitrogen atom, use the anion. The simplest examples
are tetrazoles. The anti-infl ammatory broperamole is the piperidine amide of the acid 124 that
has a 1,3-relationship that can be disconnected fi rst to reveal a simple tetrazole 125 available by
1,3-dipolar cycloaddition.
Br
N
N
N
N
The tetrazole synthesis was done with azide and acetic acid and base-catalysed conjugate
addition followed by treatment with SOCl 2, to make the acid chloride, and piperidine completed
the synthesis. 13
The indole-based drug 129 is clearly made by acylating an indole 127 and this was the last
step in the synthesis, The problem here is chemoselectivity. The answer is the usual one of ‘last
in, fi rst out’. The anion of the indole will be needed to ensure reaction at nitrogen but the anion of
the tetrazole will be formed fi rst. Two molecules of NaH make the dianion 128 and the less stable
anion, that of the indole, reacts fi rst. 14
N
H
Br
124
126
CN
CO 2H
NaN 3
HOAc
35 N–C Disconnections: Azole Anions 847
N
NaH
N
HN DMF
N
N
Br
N
121
N
tetrazole
N
N N
N
H
122
N
N
NH
1,3-diX
+
N
1,3-dipolar
CO2H
Br
N
125
N
NH
N
N
CO 2H
N
N
N
N
pK a
as acid
5.5
N
N
123
N
N
+ NaN3 CN
Br
125 126
Br
ArCOCl
N
N
N
Cl
127 128 129
N
124
N
CO2H
O
N
N
HN
N

848 35 Synthesis and Chemistry of Azoles
In many cases where azole anions are used, problems of regioselectivity arise too. There are
many fungicidal drugs based on triazoles, usually 1,2,4-triazoles, and the anions of these compounds
may have two different sites to react. The ketone 131 is made by alkylation of the triazole
anion with the primary alkyl chloride 15 130 and is the basis for many anti-fungal acetals 132.
Cl
The anion of 1,2,4-triazole 133 might be alkylated elsewhere. Reaction at N-1 or N-2 leads to the
same product 134 but reaction at N-4 gives symmetrical 135 instead. It is not always easy to predict
where reaction will occur but reaction at N-1 or N-2 is usually wanted and there is at least a 2:1
statistical factor in favour of this regioselectivity. We shall explore this question in the next section.
2 N
4
N
1
N
RX
N
at N-1
N
N
R
at N-2
R
133
134
The problem of tautomerism in azoles
R
N
at N-4 N
N
Any azole is a tautomeric mixture. That is not always obvious as, say, the two tautomers of imidazole
itself are the same - they merely exchange protons in the way that a carboxylic acid does and
this has no effect on reactions or synthesis.
H
130
N
O
Cl
N
N N H
tautomerism of imidazole
But as soon as there is substitution (anywhere except at the carbon atom between the two nitrogens
136) the two tautomers become different and the sample contains both in equilibrium. Thus
nitration of 136 gives a tautomeric mixture of 137 and 138.
N N H
R
136a
Cl
N
N
H
N
base
H
Cl
N
N
O
Cl
131
NO2
There is no point in trying to separate these tautomers as each would rapidly equilibrate with
the other. If the next reaction is intended to occur at one of the nitrogen atoms and so the anion is
to be used, then all is well as both tautomers 137 and 138 give the same anion 139. To be precise,
the anion 139 is delocalised (139a and 139b are just two different ways to draw the same anion)
and protonation at either nitrogen atom gives one of the tautomers 137 or 138. With such an
H
N N
134
R
R
136b 137
N
N
N
N
135
O O
O O
H
R
R
tautomerism of a carboxylic acid
O 2N
H
HO OH
N
N
OR
O 2N
N
O
R
138
N
O
H
N
OR
N
N
Cl
Cl
132; antifungal drugs

unsymmetrical anion, reasonable regioselectivity is to be expected, and the product on reaction of
the anion 139 with an electrophile is isomer 140 rather than the other 141.
tautomers delocalised forms
O2N O2N
H
137
O 2N
N
138
N
R
R
N
N
H
base
base
O 2N
Why should that isomer 140 be formed? The real reason is that the largest coeffi cient in the
HOMO of the anion is at that nitrogen atom. This is not very helpful as it is not easy to work out
quickly the distribution of coeffi cients in such molecules. Fortunately there is an easy way to fi nd
the answer. Look for the isomer of the product with the longest conjugated system between the
pyrrole-like nitrogen and the functional group. Here the answer is clear-cut. The isomer formed
140 has conjugation from N lone pair to nitro group all round the ring as in 140a/b while the other
isomer 141 has that conjugation only round part of the ring 141a/b.
O
E
N
N
139a
139b
This chemistry is used in the synthesis of metronidazole 16 (Flagyl®) 143 a drug for the treatment
of parasitic infections of the urinary tract. The substituent R is just methyl and the electrophile is
ethylene oxide. The nitro group makes the imidazole NH in 137/8 even more acidic and NaOH is a
strong enough base for the N-alkylation. The yield of 143 shows that regioselectivity is complete.
HN
N
O
O
E
N
N
O
How to get reaction at nitrogen using silyl derivatives in acid solution
N
N
N
R
R
N
N
Not all reactions can be carried out in basic solution so we also need a method for adding electrophiles
to heterocyclic nitrogen atoms in acidic solution. This is an important problem in nucleoside synthesis,
E
O2N
E
O2N
N N N N
E
R
R
140 141
not formed
R
R
R
R
140a 140b
141a 141b
N
NO2
35 N–C Disconnections: Azole Anions 849
O2N
HN
Me
Me
Me
142 137; R = Me 138; R = Me
N
O2N
O
N
N
N
O
NH
N
O
E
NaOH
O
N
N
O
O 2N
N
E
N N
HO
Me
143; 100% yield

850 35 Synthesis and Chemistry of Azoles
especially when modifi ed nucleosides are needed for anti-viral compounds. A nucleoside consists of
a ‘base’, a purine or a pyrimidine, joined through a nitrogen atom to a sugar. If the sugar is ribose we
have an RNA-style nucleoside 145 and if deoxyribose, DNA-style 144.
144
a nucleoside
from DNA
HO
The obvious disconnection to make in any nucleoside is at the very strategic C–N bond between
the two rings. Here is a proposed synthesis of cytidine 146. It is also obvious to make the
nitrogen a nucleophile 147 and the sugar the electrophile 149 by the addition of a leaving group
150. The oxygen atom in the ring makes a cation at that position 149 rather favourable.
Cytidine
Analysis:
HO
O
NH2
N
N
HO OH
146; cytidine
O
O
N
1,1-diX
C–N
Synthons:
HO
HO
The leaving group on the sugar 150 could be a halide or acetate or even an alkoxide as we then
would have an acetal. But these compounds will react in acidic rather than basic solution and so
the problem is the structure of 148: what can be Y? The answer is an SiMe 3 group, attached to the
oxygen rather than the nitrogen and we have a famous silicon-directed nucleoside synthesis, the
Vorbrüggen coupling. 17 The silyl group can be added in a number of ways and it will be important
to protect all the OH groups.
Cytidine
Synthesis:
HO
O
NH2
Me
N
H
151
HO OH
153; ribose
N
HO
OH
O
O thymine–
a pyrimidine
NH
O
deoxyribose
(Me3Si)2NAc
BzO
NH 2
N
O
NHSiMe 3
N
N
HO
O
147
OH
N OSiMe3 152
O
OAc
BzO
154
OBz
149
adenine–
a purine
HO
O
N
N
Reagents:
HO
NH 2
N
N
ribose
OH
BzO
HO
145
a nucleoside
from RNA
O
NH 2
N
Y
O
N
N
O
148
X
OH
150
NHSiMe3
N
BzO OBz
155
protected cytidine
O

You may be surprised by the stereoselectivity of this coupling. The benzoate on the 2’ position actually
participates 157 after the acetate is lost 156 so that the silylated pyrimidine has to attack from
the top face 159. Silylated cytosine reacts rather like a silyl enol ether. This type of stereochemical
control applies only to ribonucleosides and is more diffi cult to achieve without the 2’ OH group.
BzO
BzO
O
O
O
O
BzO
BzO O
BzO O
BzO
156 Ph
157 Ph
158
BzO
O
NHSiMe3
N
N
O
O
O
SiMe 3
Ph
O
One synthesis of the important anti-viral drug AZT 163 (Azidothymidine, used in the treatment
of HIV) shows this. The doubly silylated thymine 161 combines with the azido-sugar 162
under Lewis acid catalysis to give AZT after work-up. Only 33% of the required diastereoisomer
163 can be isolated and about the same amount of the other is formed. 18
161
silylated
thymidine
Other synthetic anti-viral compounds, such as carbovir 169, lack the oxygen atom in the ring so
that a route based on an S N1 style stereoselective displacement appears impossible. Carbovir has
a double bond in the ring however so that an η 3 palladium allyl cation complex allows regio- and
stereo-selective displacement of an ester leaving group (chapter 19). The palladium attacks the
alkene 164 from the opposite side to the leaving group to give 165. The nucleophile then comes
in from the opposite side to the palladium and at the end of the allyl cation farthest from the other
substituent to give 166 with overall retention of confi guration.
BnO
162
159
TBDMSO
35 N–C Disconnections: Azole Anions 851
OSiMe 3
N
N3
N
O
OCO 2Et
OAc
OSiMe 3
OMe
Pd(PPh 3) 4
BzO
O
BzO
160
N
t-BuMe 2SiOTf
BnO
O
NHSiMe 3
N
OBz
O
HO
BzO
N3
O
BzO
O
O
O
N
O
N
BzO OBz
155
protected cytidine
PdL3
164 165
166
NuH
O
N
BnO
NH
Ph
NHSiMe3
O
163
AZT
AZido
Thymidine
Nu
O

852 35 Synthesis and Chemistry of Azoles
The starting material 164 can be made as a single enantiomer by the use of an oxazolidinone
chiral auxiliary (chapter 27). Treatment with the chloropurine 167 catalysed by Pd(0) gave only
the correct stereoisomer 168 in 63% yield - not a high yield but better than 33% - and deprotection
and hydrolysis gave the guanine-derived carbovir 19 169.
N
N
H
Cl
N
167
N
NH2
Pd(PPh3)4
165
b. C–X Disconnections
Using electrophilic and nucleophilic aromatic substitution in fi ve- and six-membered
heterocycles. Chemo- and regioselectivity
Cl
OBn
N
N
1. BCl3 OH
N
NH
N N NH2 2. NaOH
N N NH2 168
169
carbovir
Five-membered rings with two or more heteroatoms are usually good at electrophilic substitution
as one of the heteroatoms must be either O or S or a pyrrole-like nitrogen atom any of which
supply lone pair electrons. Pyrazole 12, imidazole 13, oxazole 17, thiazole 18, isoxazole 19 and
isothiazole 20 are examples. Multiple substitution can be a problem but is less so than for pyrrole
because there are fewer carbon atoms available and the pyridine-like nitrogen atoms deactivate
the ring.
12; pyrazole 13; imidazole 17; oxazole 18; thiazole 19; isoxazole 20; isothiazole
N
H
N
O
N
An example 20 is the antibiotic 171. The nitro group on the furan ring of 170 was originally put
in by nitration but now bromination is carried out in acetic acid. Furan is fundamentally more
reactive towards bromine than the thiazole ring. However, the furan is deactivated by the nitro
group while the thiazole is activated by the amino group. In fact bromination occurs exclusively at
the one remaining position on the thiazole.
O2N
N
H
N
O
N
S
Br2
HOAc
Six-membered rings with two or three nitrogens (they must all be pyridine-like) are very unreactive
towards electrophilic attack but good at nucleophilic attack if there is any remotely feasible
leaving group, even OR or better SR. The main ring systems are pyridazine, pyrimidine, pyrazine
and triazine and the places where nucleophilic substitution occurs best are marked with an ‘X’. We
shall see examples of these reactions in the next section.
S
N
O2N
NH2 NH2 170 171; 86% yield
O
O
N
N
Br
S
O
S
N

N N
X
X N
X N X X N X
pyridazine (X = H) pyrimidine (X = H) pyrazine (X = H) triazine (X = H)
When there is a nitrogen atom common to two rings, one ring may be good at electrophilic
and the other at nucleophilic substitution. In this example known as imidazo[1,5-b]pyridazine
172, bromination occurs in the fi ve-membered ring to give 173, while nucleophilic substitution
occurs if there are leaving groups X in the six-membered ring 174. It is inevitable that the nitrogen
common to both rings is of the pyrrole type and these systems are probably best considered as 10
electron aromatic compounds.
The synthesis of pyridazines
X
N N
N
Br 2
X
N
N N
N
The ‘most obvious’ disconnection depends on which Kekulé form of the pyridazine you happen
to draw. Disconnection of both C–N bonds reveals either 175 an encouraging 1,4-diketone 176
and a most discouraging molecule of diimide 177 or, by imine disconnection, 178 an encouraging
molecule of available hydrazine and a rather discouraging Z-enedione 179.
R 1
R 2
There is one useful case of the second disconnection. Maleic anhydride 180 has to have a Z
alkene because of its cyclic structure. Reaction with hydrazine gives a diamide 181 that prefers to
exist as 182 and is known as ‘maleic hydrazide’.
This product is useful because it gives the dichloride 182 with POCl 3. This compound reacts
cleanly once with ammonia to give 184 and then again with any nucleophile, including amines
under more vigorous conditions, to give 185; Nu NHR, OR, SR etc. 21
X
N
Br X
X
X
N N
172 173 174; X = Cl, SMe, OMe
R 2
H2N NH2
N N
HN NH
R1 O O
N N
R1 R1 O O
175 176
177
diimide 178
179 hydrazine
O
O
O
180
maleic anhydride
35 C–X Disconnections 853
H2N NH2
H2O
O
R 2
O N
NH
O N
N
H
H
181
N
N
X
R 2
OH
182; 85% yield
N

854 35 Synthesis and Chemistry of Azoles
O
N
N
H
182
OH
POCl3
A more general approach to pyrazines is based on an FGA strategy. Removal of the alkene also
removes all the problems. Disconnection 186 of hydrazine gives the same simple 1,4-diketone 177
we saw before and the most obvious ways to make that 187 are the d 1 a 3 or d 2 a 2 strategies,
both requiring some umpolung.
R 2
A simple example is the synthesis of Cyanamid’s broad leaf herbicide 193 by the d 1 a 3
strategy. m-Fluorobenzaldehyde combines with morpholine and cyanide to give the aminonitrile
188. The marked proton is acidic because of the cyanide group. The anion is good at conjugate
addition (these d 1 reagents were specifi cally designed by Stork for conjugate addition, chapter 9)
and adds well to the methacrylate ester to give the 1,4-dicarbonyl compound 189. Cyclisation with
hydrazine and aromatisation with bromine gives the pyridazolone 191 and nucleophilic aromatic
substitution by the POCl 3 and nucleophile (here methoxide) sequence gives the herbicide 193 in
good yield. 22
ArCHO
CF 3
c. C–C Disconnections
Cl
NH 3
NH2
Nu
N N
Cl N N
Cl N N
EtOH
Nu
FGA
183 184; 70% yield
185
N N
R1 N N
R1 R1 O O H2N NH2 R2 R2 R2 oxidation
imines
175
186
176
b
b
a
a
X
The few reactions that work well with heterocycles. The Heck reaction, Friedel-Crafts
acylation and a mention of lithiation
The ever-versatile Heck reaction (chapter 18) works well with most heterocycles providing one can
put the halide or trifl ate in the right place on the heterocyclic ring. This example shows that an
unprotected nucleoside 194, made by iodination of deoxyuridine, reacts cleanly with ethyl acrylate
R 2
R1 O O
R1 O
O
a3 d1 187
2 x C=N
R 1 O
d 2
R 2
O
a2 1.
HN
O
NC N
O 1. CO2R O CO2R NH2NH2 N
H
N O
2. KCN, H2O Ar
H
H
188
NaOMe
2. HOAc
Ar
189
EtOH, H2O Ar
190
N
N O
N
N Cl
N
N
POCl3 CF3 MeO
MeOH
CF3 191 192 193
NH2
Br 2
HOAc
OMe

in a typical Heck reaction without any protection of the OH or NH groups in the nucleoside. 23 The
reactions of nucleosides we have used so far have all required complete protection.
HO
I
O
N
The Heck reaction makes a C–C bond and adds a highly functionalised fragment that can be
elaborated into many other functional groups. The same is true of the Friedel-Crafts reaction that
generally works well with azoles or other heterocycles able to do electrophilic substitution. As
usual, it is best to have only one free position so that no regioselectivity problems arise. In the
Heck reaction, the site of attack is marked by the iodine atom, but the Friedel-Crafts can occur at
any free position. Our example is a pyrazole that acylates cleanly with Lewis acid catalysts to give
eventually the herbicide pyrazolate 196.
Cl
It turns out that it is better to acylate the pyrazolone in a standard Friedel-Crafts fashion to give
201. Whether you draw the pyrazole 200 as a pyrazolone 199 or not, there are plenty of electrons
from one of the nitrogen atoms to activate the remaining free position in the ring. Subsequent
tosylation fi xes the molecule in pyrazole form as pyrazolate.
d. Examples: an Anti-Ulcer Drug and Pentostatin
NH
O
EtO 2C
cat. Pd(OAc) 2
Ph3P, Et 3N
dioxan
85 ˚C, 3 hours
EtO 2C
We give two examples: an anti-ulcer drug with three heterocyclic rings and an anti-viral and antitumour
compound, pentostatin.
HO
HO
HO
194 195; 80% yield
Cl
TsO
O
N
Me
N
Me
196; pyrazolate (herbicide) 197
O
N
Me
199
NH
35 Examples: an Anti-Ulcer Drug and Pentostatin 855
Me
HO
C–C
Friedel-Crafts
Me
Cl
Ar
Cl
N
N
197
AlCl3 HO
N
N
Me
Me
200 201
O
O
Cl
Me
+
TsCl
O
N
TsO
NH
O
198
N
Me
Me
N
196
pyrazolate
(herbicide)

856 35 Synthesis and Chemistry of Azoles
An isocytosine-based drug with three heterocyclic rings
A series of anti-ulcer drugs such as cimetidine and ranitidine were the most successful drugs of
all time when they fi rst appeared. They work by inhibiting histamine action in the stomach. We
shall look at a more modern version, a drug from what was then SmithKline Beecham, another
H 2 receptor histamine antagonist 24 202. It is particularly appropriate for this chapter as it contains
three heterocyclic rings with two heteroatoms each: an imidazole, a pyrimidone, and a thiazole
and it allows us to revise material from other chapters as well as this.
202
former SKB
histamine receptor
H2 antagonist
imidazole
H
N
N
Me
Strategically it is best to disconnect somewhere in the middle of the molecule and the ease
of nucleophilic substitution on pyrimidones suggests the C–N bond exo to that ring 202a. This
gives us a relatively simple imidazole fragment 203 and a fragment with the other two rings
204. The leaving group on the pyrimidone 204 (X) could be Cl but need only be as good as
OMe.
Analysis
H
N Me
N
S
N
H
202a
N
O
N
H
N
S
The imidazole 203 can easily be disconnected 203a back to the simpler imidazole 205 and
H 2NCH 2CH 2SH. You may forecast selectivity problems in the combination of unactivated 205
and the unprotected aminothiol, but wait. Alcohol 205 can be made from the ester 206 and that
can be made from formamidine 207 and a suitably activated acetoacetate 208 (X is again a leaving
group).
H
N
N
Me
S
203a
NH2
C–S
H
N
N
205
Me
C–N
The remaining fragment can be disconnected 204a at the six-membered ring by removal of
some simple amidine derivative 209. The remainder 210 has a 1,3-diCO relationship so a Claisen
ester disconnection gives yet again a one-carbon electrophile and a simple ester 211. This is best
made from the unsaturated ester 212 and some sort of aldol reaction on 213.
S
nucleophilic
aromatic
substitution
OH
FGI
H
N
N
H
N
N
N
O
N N
H H
pyrimidone
206
N
S
thiazole
O
Me
S
NH2 +
N
X N
H
203 204
Me
CO 2Et
2 x
C–N
H
O
NH2 +
NH
X
N
207 208
S
CO2Et

X
N
O
N
H
CHO +
204a
EtO2C
N
211
S
N
2 x C–N
S
FGI EtO2C
S aldol
Now we must put the molecule together again. 2-Bromothiazole is available so lithiation and
carbonylation with DMF gives 213 and an aldol (Knoevenagel) reaction with malonic acid gives
214 without a separate decarboxylation step. The best one-carbon electrophile is ethyl formate
(HCO 2Et) and thiourea makes a suitable derivative of 209 for displacement.
Br S 1. BuLi
N 2. Me2N.CHO 2-bromothiazole
EtO2C
S
HCO2Et S NH2 Na, Et2O O
N
EtOH
reflux
215
The other half starts with formation of the imidazole by the Bredereck reaction. The leaving
group in 208 can be an acetate but more interestingly the nucleophile can be an excess of formamide
HCONH 2. The alcohol 205 reacts selectively in strongly acidic solution with the aminothiol
to give 218 without protection. After isolation as the HBr salt, 203 is liberated and reacted with
217 to give the complete molecule.
O
AcO
CO2Et
208; X = OAc
excess
HCONH 2
35 Examples: an Anti-Ulcer Drug and Pentostatin 857
206
213
61% yield
LiAlH4
NH 2
H
N
N
Pentostatin: an example with fused fi ve- and seven-membered rings
X
NH
Pentostatin 219 is clearly a modifi ed deoxynucleoside with a seven-membered ring instead of the
normal six-membered ring of a purine. 25 It is simplest to remove the stereochemistry in the sevenmembered
ring by FGI of the alcohol to a ketone 220. We can then disconnect the sugar, expecting
to use the sort of chemistry earlier in the chapter, maybe a silyl derivative of the purine analogue
221 and a derivative of the sugar 222, maybe with X OAc.
NH2
HO
CH2(CO 2C
2H) 2
pyridine
piperidine
205
S
Me
HN
+
RO
O
O H
209 210
HS
O
N
H
216
OH
48% HBr
OHC
N
N
212 213
NH 2
214
N
N
S
S
MeI
NaOH
EtOH
H 2O
N
EtOH
S
H 2SO 4
MeS
1,3-diCO
212
N
O
N
H
217
S
H 2/Pd/C
MeOH
45 ˚C
H
N Me 2Br
NH3 pH 11 217
N
H
S
218; 98% yield
K2CO3
H2O 203
as crystalline salt
N
211
S
202

858 35 Synthesis and Chemistry of Azoles
HO
HN
OH
N N
O
HO
N
219; pentostatin
FGI
HO
HN
O
N N
O
HO
220
N
1,1-diO
The sugar is available deoxyribose but the seven-membered ring heterocycle 221 must be made.
Disconnection of the one atom electrophile from between the two nitrogen atoms reveals a diamine
223 that can be made by reduction of a dinitro compound 224. Removal of nitromethane
from 224 gives a simple nitroimidazole carboxylic acid 225. Clearly the nitro group will be added
by direct nitration but we can take advantage of its presence to reconnect an alkene 226 to the
carboxylic acid with the idea of using the nitro group to activate the methyl group in 227. Nitration
of 4-methylimidazole would be expected to go where we want it as the only alternative, C-3, is
between the two nitrogen atoms and less reactive to electrophiles.
HN
H 2N
HO2C 1,3-diO N reconnect
C–C
N
O
N
N
H
O 2N
225
N
H
The synthesis starts with the routine nitration of available 228 and the base-catalysed reaction
of 227 with benzaldehyde to give 229 (226; RPh). It is necessary to protect this and benzylation
in base gives predominantly the isomer 230 with the longest conjugated system. Ozonolysis (ozonation)
reveals the stable crystalline carboxylic acid 232. After deprotection, both isomers give 225.
Me
N
221a
HNO 3
H
N
2SO4 H
228 (available)
1,1-diO
2 x C–N
Me
O2N
227
N
N
H
C–N
O
HN
N
N
O
221
N
N
H
+
HO
N
H2N
O2N
H
223 224
R
PhCHO
base
O2N
226
Ph
FGI
N
N
H
O 2N
O 2N
C–C
N
N
H
229, >80% yield
O
Me
O2N
Ph Cl
K 2CO 3
DMF
Ph
N
Ph
HO2C N
O
N
O
N
Ph
+
Ph
O2N N
N
H
1. O3 2. HCO3H N
O2N
Ph
232, 75% yield
230 >95% yield, 3:1 isomers 231
crystalline acid
HO
222
N
N
H
227
O
N
N
H
X

SnCl2
HCl
Now the seven-membered ring must be built up. Here an azole-based reagent, CDI, carbonyl
di-imidazole proves invaluable. Reaction with 232 gives the acylimidazole 233 and this acylates
the potassium ‘enolate’ of nitromethane in good yield to give 234 and hence, by reduction, the
diamine 235. The N-benzyl group can now be removed and the synthesis of the seven-membered
ring is completed with the one-carbon electrophile HC(OEt) 3.
N
N
H 2N
O
N
H2N
O
N
HO2C
+
N
N
O2N
Ph
235; crystalline
74% yield diHCl salt
The rest of the synthesis follows the methods already discussed. The purine analogue 221 was
silylated and coupled with the sugar derivative 236 to give a mixture of stereoisomers at the
anomeric position. Deprotection and not very stereoselective reduction gave pentostatin.
A Designed Enzyme Inhibitor
N
N
H2N
Ph
H2N
O
N
N
N
H
N
Modifi ed sugars are important sources of new drugs. Imidazoles such as 238 are glucosidase
inhibitors and Streith 26 and co-workers set out to develop more potent inhibitors by introducing
substituents R into the basic structure. Modifying a core structure introduces diversity quickly
from a single compound. The core structure 238 obviously comes from a sugar and the easiest
way to remove the imidazole is to expose it 239 and then use an imidazole synthesis from an
aldehyde 240 that is arabinose. How to add the substituent R regioselectively to 238 is not
obvious.
HO
CDI
N
R
OH
N
OH
?
THF
A protected form 241 of the aldehyde 240 was easily made from arabinose and the imidazole
inserted with glyoxal and ammonia. Removal of the trityl group with HCl and cyclisation via the
mesylate gave 244, a protected version of 238.
O
O2N
H2 HC(OEt)3
Pd/C
pH

860 35 Synthesis and Chemistry of Azoles
BnO
O H
OBn
241
Now comes the moment of truth. Can 244 be functionalised regiospecifi cally? Though the
imidazole portion is unsymmetrical, it is not a tautomeric mixture (in contrast to 136 and 137).
Iodination with NIS gives the wrong isomer 245, the one with the longer conjugated system. The
uncyclised imidazole 243 reacts twice to give 246 and hence by cyclisation and deiodination, 248.
BnO
N
OBn
N
Each isomer can be combined with a variety of electrophiles using Mg or Pd as the metal to
replace iodine by oxidative insertion, and the best inhibitor 250 was made by Sonagashira coupling
of 248 to phenyl acetylene and reduction of 249 to the saturated compound.
References
OBn
OTr
OBn
O
NH3 BnO
OBn BnO
OBn
MeOH HCl MsCl
O
H H
BnO
OBn
pyridine
N NH OTr N NH OH
N N
General references are given on page 893
1. The best general aromatic heterocyclic book is probably J. A. Joule and K. Mills, Heterocyclic Chemistry,
Blackwell Science, Oxford, Fourth Edition, 2000; but see Clayden Organic Chemistry chapters 43
and 44 for a mechanistic introduction.
2. B. G. Hildick and G. Shaw, J. Chem. Soc. (C), 1971, 1610.
3. K. Brown, D. P. Cater, J. F. Cavalla, D. Green, R. A. Newberry and A. B. Wilson, J. Med. Chem., 1974,
17, 1177.
4. K. L. Kees, T. J. Caggiano, K. E. Steiner, J. J. Fitzgerald, M. J. Kates, T. E. Christos, J. M. Kulishoff,
R. D. Moore and M. L. McCaleb, J. Med. Chem., 1995, 38, 617.
5. C. Kashima, S.-I. Shirai, N. Yoshiwara and Y. Omote, J. Chem. Soc., Chem. Commun., 1980, 826.
6. P. N. Confalone and E. M. Huie, Org. React., 1988, 36, 1; R. D. Little in Comp. Org. Synth., 5, 239.
7. C. Kashima, S.-I. Shirai, N. Yoshiwara and Y. Omote, J. Chem. Soc., Chem. Commun., 1980, 826.
OBn
BnO
OBn
242; 62% yield 243; 81% yield
244; 92% yield
OBn
OBn
N NH OH
I
I I
245; 57% yield 246; 91% yield
BnO
N
I
OBn
N
OBn
MsCl
pyridine
BnO
N
OBn
N
OBn
OBn
BnO
OBn
Ph H2, Pd(OH) 2/C
Pd(PPh3) 4
EtOH/AcOH
CuI, Et3N DMF
80 ˚C
N N
room
temperature
24 hours
1. EtMgBr
2. H 2O
BnO
I I
I
247; 57% yield 248; 87% yield
N
OBn
Ph
Ph
248 249; 62% yield
250; 56% yield
HO
N
OH
N
N
OH
OBn
OBn

35 References 861
8. R. N. Butler in Comprehensive Heterocyclic Chemistry, ed. A. R. Katritzky and C. W. Rees, Pergamon,
Oxford, 1984, volume 5, pages 791–838; W. G. Finnigan, R. A. Henry and R. Lofquist, J. Am. Chem.
Soc., 1958, 80, 3908.
9. W. G. Stryker and S. Hayao, Miles Laboratories, Belgian Patent 1965, 661,396; Chem. Abstr., 1965, 63,
18114e.
10. R. M. Herbst and J. A. Garrison, J. Org. Chem., 1953, 18, 941; W. L. Garbrecht and R. M. Herbst, J. Org.
Chem., 1953, 18, 1003.
11. N. P. Peet, L. E. Baugh, S. Sunder, J. E. Lewis, E. H. Matthews, E. L. Olberding and D. N. Shah, J. Med.
Chem., 1986, 29, 2403; A. P. Vinogradoff and N. P. Peet, J. Heterocycl. Chem., 1989, 26, 97.
12. J. Catalan, J. L. M. Abboud and J. Elguero, Adv. Het. Chem., 1987, 41, 187.
13. Miles Laboratories Inc., British Patent 1,319,357, Chem. Abstr., 1973, 79, 92231.
14. P. F. Juby and T. W. Hudyma, J. Med. Chem., 1969, 12, 396.
15. G. J. Tanoury, C. H. Senanayake, R. Hett, Y. Hong and S. A. Wald, Tetrahedron Lett., 1997, 38, 7839;
J. Heeres, L. J. J. Backx and J. Van Cutsem, J. Med. Chem., 1984, 27, 894. .
16. D. Lednicer and L. A. Mischer, Organic Chemistry of Drug Synthesis, vol 1, page 241.
17. H. Vorbrüggen and C. Ruh-Polenz, Org. React., 1999, 55, 1; R. T. Walker in Comprehensive Organic
Chemistry, 5, 53 (see p. 64ff.).
18. G. W. J. Fleet, J. C. Son and A. E. Derome, Tetrahedron, 1988, 44, 625.
19. B. Brown and L. S. Hegedus, J. Org. Chem., 2000, 65, 1865.
20. W. R. Sherman and D. E. Dickson, J. Org. Chem., 1962, 27, 1351.
21. B. Stanovik and M. Tisler, Tetrahedron, 1967, 23, 387.
22. J. D. Albright, F. J. McEvoy and D. B. Moran, J. Heterocycl. Chem., 1978, 15, 881.
23. P. Herdewijn, E. De Clercq, J. Balzarini and H. Vanderhaeghe, J. Med. Chem., 1985, 28, 550.
24. T. H. Brown, R. C. Blakemore, P. Blurton, G. J. Durrant, C. R. Ganellin, M. E. Parsons, A. C. Rasmussen,
D. A. Rawlings and T. F. Walker, Eur. J. Med. Chem., 1989, 24, 65.
25. D. C. Baker and S. R. Putt, J. Am. Chem. Soc., 1979, 101, 6127.
26. E. Dubost, T. Tschamber and J. Streith, Tetrahedron Lett., 2003, 44, 3667.

36 Tandem Organic Reactions
This fi nal chapter examines a strategy – combining two or more distinct reactions in a single operation.
The fi rst reaction gives an intermediate, usually one diffi cult to make, that does a different reaction
to make a product much larger than any starting material. Any type of chemistry may be used so this
chapter also revises material from the earlier parts of the book.
PART I – INTRODUCTION
What are Tandem Reactions?
Short historical background
Criteria for tandem reactions discussed in this chapter
Tandem Reactions We Shall Not Discuss
Radical chain reactions
Highly reactive intermediates
Polymerisation
PART II – CONJUGATE ADDITION AS THE FIRST STEP
Simple Enolate Capture by Electrophiles
Anti stereochemistry in six-membered rings
Conformational control from a chiral centre in the cyclohexenone
Remote stereochemical control in fi ve-membered rings: prostaglandins
Regio- and stereochemical control in open chain compounds
Asymmetric induction by a chiral auxiliary on the enolate
Tandem Michael-Michael Reactions: One Conjugate Addition Follows Another
Double Michael or Diels-Alder reaction?
Stereochemical control in the double conjugate addition
Tandem Reactions as Polymerisation Terminated by Cyclisation
The ‘MIMIRC’ sequence with vinyl phosphonium salts
Tuning the ‘MIMIRC’ sequence with different Michael acceptors
Heterocycles by Tandem Conjugate Additions
Tandem conjugate addition and Mannich reaction
Tandem Conjugate Addition and Aldol Reaction
Tandem conjugate addition of enolates and aldol reactions
Tandem conjugate addition of chiral amines and aldol reactions
PART III – INTERMEDIATE IS AN UNSTABLE IMINE OR ENAMINE
Intermediate Would Be Formed by Amide Condensation
The synthesis of a tricyclic amine by tandem amide condensation and Mannich reaction
Alternatives to amide condensations: use of sulfur
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd

864 36 Tandem Organic Reactions
Asymmetric Tandem Methods Involving Unstable Imines etc.
An asymmetric synthesis of pipecolic acids
Intermolecular trapping of alkenes by iminium ions
An Asymmetric Synthesis of ()-Pumiliotoxin B
Retrosynthetic analysis
Three enantiomerically pure starting materials ensure remote stereochemical control
Tandem iminium ion formation and vinyl silane cyclisation
PART IV – TANDEM PERICYCLIC REACTIONS
Electrocyclic Formation of a Diene for Diels-Alder Reaction
Tandem Ene Reactions
Tandem [3,3]-Sigmatropic Rearrangements
Tandem Aza-Diels-Alder and Aza-Ene Reactions
Completion of the synthesis of Daphniphyllum alkaloids
Tandem Reactions Involving 1,3-Dipolar Cycloaddition
Asymmetric synthesis of swainsonine
Tandem synthesis of 2-vinyl indoles
PART IV – OTHER TANDEM REACTIONS LEADING TO HETEROCYCLES
A Tandem Metallation Route to the Ellipticine Skeleton
Tandem Aza-Diels-Alder and Allyl Boronate Reactions
Tandem Beckmann Rearrangement and Allyl Silane Cyclisation
PART V – TANDEM ORGANOMETALLIC REACTIONS
Tandem Asymmetric Heck and Pd-Allyl Cation Reactions
Tandem Ring-Closing and Ring-Opening Metathesis
A Ru-Catalysed Four-Component Coupling
PART I – INTRODUCTION
What are Tandem Reactions?
Short historical background
Tandem reactions 1 were originally any pair of reactions that followed one another in a single
operation like the two people on a tandem. The most famous example still is conjugate addition
followed by trapping of the specifi c enolate with an electrophile. 2 Addition of a lithium cuprate
to the enone 1 gives the lithium enolate 2 and this combines with an electrophile to give the anti
disubstituted ketone 3. The point of making this a tandem process is that the enolate 2 could not
be easily made from the parent ketone 4.
O OLi
R2CuLi
E
R
R
R
1 2 3 4
Since tandem reactions fi rst appeared they have been given many diverse names such as cascade,
consecutive, and coupled processes, domino reactions, interrupted polymerisation, one-pot,
sequential and serial reactions, and tactical combinations. Some authors have tried to classify
E
O
O

tandem processes according to the lifetime of the intermediate, whether it is isolated, whether the
two reactions follow spontaneously or need some intervention by the chemist and so on. It seems
to us most helpful to call all these multi-step reactions carried out in one fl ask ‘tandem reactions’
and to prefer a discussion of their strategical signifi cance to any attempt at a formal classifi cation.
There is nothing new in reactions occurring in many steps all in the same pot. The Robinson
annelation is a classic where conjugate addition and intramolecular aldol reactions follow each
other without as break. An extreme example would be the reaction of a Mannich salt 5 with the
1,3-diketone 6 to give the enone 7 on treatment with base
Most chemists would consider that there are four separate steps in this reaction: elimination,
conjugate addition, aldol reaction and dehydration. Mechanistically we should double this number
as each step requires preliminary enolate ion formation.
Criteria for tandem reactions discussed in this chapter
In spite of all these steps, chemists do not usually consider the Robinson annelation a tandem
reaction. This is partly because it is an old reaction but partly because each intermediate would, if
isolated, give the same reaction as in the one-pot process. We shall describe as tandem reactions
only those that have
•
•
•
•
•
O
NR3
O O
O
At least two steps that form signifi cant bonds (C–C or C–X)
An intermediate produced in the fi rst step that would be tricky to make otherwise.
A second step that in some way depends on the fi rst.
Some advantage in running the steps in sequence such as regio- or stereoselectivity.
Some degree of surprise in the way the reaction works (not entirely serious).
Tandem Reactions We Shall Not Discuss
Radical chain reactions
5
enolate formation
and elimination
O
36 Tandem Reactions We Shall Not Discuss 865
NR 3
+
O
O
enolate formation
and aldol reaction
H O
Some reactions that undoubtedly meet all these criteria we shall nevertheless exclude to restrict
the chapter to a manageable size. Radical chain reactions, such as the synthesis of hirsutene 12
base
O
6 7
O
+
O
H O
OH
O
enolate formation and
conjugate addition
enolate formation
and elimination
O
O O
O
O
O

866 36 Tandem Organic Reactions
by Curran, are tandem processes. The initial radical 9 cyclises fi rst to a new tertiary radical 10 by
a 5-exo-trig process and this in turn forms a second ring 11 by a 5-exo-dig cyclisation. Neither
intermediate 10 nor 11 would be easy to make except by tandem reactions and there is excellent
regio- and stereochemical control. 3
H
Highly reactive intermediates
Nor shall we discuss reactions of highly reactive intermediates such as carbocations, carbanions,
ketenes (such as 14), or benzynes that are always prepared in the presence of the molecule with
which they are to react. This 2 2 ketene cycloaddition 15 actually involves three steps but the
ketene is very reactive and cyclopentadiene must be present when it is formed if a good yield of
the important adduct 16 is to be had.
Polymerisation
I
H
10
Bu 3SnH
8 9
We shall not discuss polymerisation nor reactions that can be made to occur in one pot but are
essentially independent processes except where there is an advantage in running them in tandem
fashion. Since the most important aspect of tandem reactions is the nature of the intermediate after
the fi rst reaction, the fi rst section has conjugate addition as the fi rst step and explores the way a
second reaction can use the enolate produced.
PART II – CONJUGATE ADDITION AS THE FIRST STEP
Simple Enolate Capture by Electrophiles
Anti stereochemistry in six-membered rings
H
Following our introduction, a simple example 4 of conjugate addition is a cuprate addition to cyclohexenone
followed by trapping of the lithium enolate 18 with MeI to give the anti product 19.
H
11
H
H SnBu 3
H
H H
12; hirsutene
O
O
O
O
H
H
Cl Cl
Cl
Et3N Cl
Cl
Cl
Cl
C
Cl
2 + 2
Cl
Cl H
13 14 15 16

O OLi
Bu 2CuLi MeI
Bu
Bu
17 18 anti-19
Conformational control from a chiral centre in the cyclohexenone
A more interesting situation arises with a substituent already on C-5 20. The cuprate then adds
anti to that substituent (the intermediate is here trapped as a silyl ether anti-21) and trapping with
electrophiles introduces a second anti relationship anti, anti-22. The stereoselectivity arises by
axial attack both during the conjugate addition and on the enolate (chapter 21).
O
OSiMe 3
R1 R1 R
R1 R
20 anti-21 anti,anti-22
Remote stereochemical control in fi ve-membered rings: prostaglandins
If the ring is not six-membered, conjugate addition occurs on the less hindered face, usually
opposite any substituent. An example 26 in prostaglandin synthesis also makes the point that
tandem reactions don’t automatically solve all problems. 5,6
TBDMSO
2.
O
I
36 Simple Enolate Capture by Electrophiles 867
+
LiCu
R 2CuLi
Me 3SiCl
CO 2Me
R
OTBDMS 2
TBDMSO
Addition of the enantiomerically pure cuprate 24 to the enantiomerically pure cyclopentenone
23 occurs stereoselectively on the face of the enone 23 opposite the large silyl ether to give the
lithium enolate 25. Reaction with an electrophile would be expected to occur on the bottom face as
the nearer (and larger) substituent is on the top face. And so it does, but it was not expected that the
lithium had to be exchanged for a Ph 3Sn group to make the rather crowded enolate reactive enough
for alkylation. The sequence round the ring is thus anti, anti. Notice that the allyl group is added
as an electrophile (chapter 19) but the vinyl group is added as a nucleophile (chapter 16) in both
cases with control over E/Z geometry. This is indeed, as Noyori calls his paper, 6 ‘An Extremely
Short Way to Prostaglandins.’
O
E
E
TBDMSO
O
O
OLi
23 24 25
1. Ph3SnCl, HMPA
OTBDMS
26
Me
R
OTBDMS
CO 2Me

868 36 Tandem Organic Reactions
Regio- and stereochemical control in open chain compounds
Simple stereoselective aldol reactions (chapter 3) can also be controlled by tandem conjugate addition.
Addition of Me 2CuLi to the simple unsaturated ketone 27 gives the lithium enolate 28. It would be
very diffi cult to produce this enolate from the parent ketone t-BuCO.Me with regio- or stereoselectivity.
The cyclic transition state 29 with zinc replacing lithium then shows the way to the anti-aldol 7 30.
O OLi OH O
O O
Zn
But Me2CuLi MeCHO
Me
H
–78 ˚C
ZnCl2
H
Me
27 28 29 30; 96% yield
all anti aldol
Asymmetric induction by a chiral auxiliary on the enolate
If no component has stereochemistry, asymmetric conjugate addition can be ensured by a C2 symmetric
chiral auxiliary attached to the enolate partner. Addition of the lithium enolate of the amide
31 to the unsaturated ester 32 gives the lithium enolate 33 with good stereochemical control at
both the new centres. 8
OBn
OBn
N
O
31
2.
1. LDA, –78 ˚C
MeO 2C
32
Alkylation with 34 now occurs to give mostly (11:1) the product 35 with the two new chains
attached trans (anti-) to the fi ve-membered ring. The yield is only moderate as is often the case
in tandem reactions. The advantages of combining three substantial fragments regioselectively
with the creation of three new stereogenic centres with absolute as well as relative stereochemical
control outweigh this low yield. After all, no stepwise process is likely to give as much of 35. The
minor diastereoisomer 36 has the same relative stereochemistry as 35 in the new portion but, on
amide hydrolysis, would give the other enantiomer of the product. Another way to put this is that
the initial induction during the conjugate addition is imperfectly controlled but that the second
step, the alkylation, is entirely stereoselective. See later for the next step.
HMPA, THF
–78 ˚C
O
33 MeO2C +
34
I
N
H
35; 64% yield
OBn
N
O
LiO
H
OMe
33
N
O
MeO2C H
36; minor product
OBn

36 Tandem Michael-Michael Reactions: One Conjugate Addition Follows Another 869
Tandem Michael-Michael Reactions: One Conjugate Addition
Follows Another
Double Michael or Diels-Alder reaction?
An important type of tandem reaction arises when both steps are conjugate additions (Michael
reactions, chapter 9). The most widely used case is the conjugate addition 38 of a kinetic α’ enolate
from an enone 37 (chapter 11) to a second enone. The resulting enolate than adds back 39 to
the fi rst compound in a second conjugate addition. The product 41 contains a six-membered ring
formed in the tandem process.
O
37
Li
R
O
O
38
first
conjugate
addition
There is an alternative interpretation of this sequence: that the kinetic enolate does a Diels-Alder
reaction 42 with the second enone. The regiochemistry is right: the more nucleophilic end of the
enolate (higher energy HOMO) adds to the more electrophilic end of the second enone (larger coeffi
cient in the LUMO). It is not possible to tell which mechanism is right in this example as there
is no stereochemistry in the product and in any case this is a simplifi ed example: most reported
cases are much more complex.
O
R
LDA
O
In one case the reaction was conducted as a genuine Diels-Alder reaction on the silyl enol ether
45 of the α’-enolate 44 to see what the result would be. 9 The Diels-Alder reaction 47 with the
enantiomerically pure enoate ester 46 required 160 C and gave a 40% yield of a 1:1 mixture of
diastereoisomers of 49.
R = MOM
MeOCH2O-
O
O
O
O
O R
second
conjugate
addition
Li
O
Li
O
O
O R
O
O R
39 40 41
R
R
42 40 41
43
OR
OSiMe 3
CO2Me
LDA
THF
OR
160 ˚C
OLi
OSiMe 3
OR
44 45
O
O
Me3SiCl
47 48
OSiMe 3
CO 2Me
OR
OR
+
O
O
O
O
O
46
O
O
CO 2Me
CO 2Me
OR
49; 40% yield, 1:1 mixture

870 36 Tandem Organic Reactions
Stereochemical control in the double conjugate addition
The tandem Michael-Michael reaction gave a very different result. This time the lithium enolate
44 reacted with the unsaturated ester 46 at 78 to 40 C and gave an 86% yield of a single
adduct, endo-49. The most obvious conclusion is that the reaction does indeed go by a two-step
mechanism, especially as the stereochemistry can be convincingly explained by lithium coordination
to the two reagents 50. There is just a possibility that it is a Diels-Alder reaction showing
greater stereoselectivity because of the lower temperature.
OLi
44
OR
46
–78 to –40 ˚C
then aqueous
work-up
O
O
OR
H
MeO2C endo-49; 86% yield
50
OMe
O
H
H
OR
O
O
The stereochemistry is controlled by the fi rst conjugate addition represented mechanistically as
50a that gives the new lithium enolate in the right conformation for the second conjugate addition
51 giving the enolate 52 of endo-49. We shall assume that these reactions are tandem Michael-
Michael additions for the rest of this section.
O
OR
50a
O
O MeO O
Li
first
conjugate
addition
Tandem Reactions as Polymerisation Terminated by Cyclisation
O
O
O
O
second
conjugate
addition
O
O
MeO
OR
Li
O
O
MeO2C
51 52
We have just seen how one conjugate addition can be followed by a second leading to a sixmembered
ring. If instead the product 53 of the fi rst conjugate addition reacts with a second
molecule of the Michael acceptor, this could be the start of polymerisation.
X
first
conjugate
addition
CO 2Me
X
second
third
conjugate
conjugate
addition
X
addition
CO2Me
CO2Me MeO2C CO2Me CO2Me 53 54
We lose interest in the polymerisation but imagine that the original nucleophile was the enolate
of a carbonyl compound. Now the fi rst two adducts have an alternative: they could cyclise.
O
Li
etc.
OR

It is not likely that 55 will cyclise as it would give a four-membered ring 56, but 57 is very likely
to cyclise to the six-membered ring 58. If cyclisation is faster than the bimolecular addition of
another Michael acceptor, the polymerisation will be interrupted and an effi cient tandem process
invented.
R
O
55
LDA
second
conjugate
addition
CO 2Me
R
OLi
R
first
conjugate
addition
CO 2Me
The ‘MIMIRC’ sequence with vinyl phosphonium salts
O
R
O
MeO2C CO2Me 57
CO2Me
This is the basis of Posner’s ‘MIMIRC’ (Michael-Michael-Ring Closure) sequences. 10 In the fi rst
example, the electrophile is a vinyl phosphonium salt 59. The fi rst adduct 60 could cyclise, by the
Wittig reaction, only to a cyclobutene 62 so it prefers to add a second molecule of 59 but the next
intermediate 61 cyclises to a six-membered ring 63.
R
O
36 Tandem Reactions as Polymerisation Terminated by Cyclisation 871
first
conjugate
addition
R
O
R
The fi nal product 63 retains the Ph 3P group from the fi rst vinyl phosphonium salt 59 and in
the example below, using a boron enolate, this was hydrolysed to the stable phosphine oxide 11 66.
Note the creation of a quaternary carbon atom at a spiro centre.
55
cyclisation
second
conjugate
addition
MeO 2C
R
O
R
O
CO 2Me
56
58
R
O
CO 2Me
PPh3 PPh3 PPh3
PPh3 PPh3
59 60 61
Ph O
1. LiN(SiMe 3) 2
2. Et 3B
3.
PPh 3
Ph
62
64 65
PPh 3
4. KOH, H 2O
Ph
Wittig
R PPh3
63
O
66; 79% yield
PPh 2

872 36 Tandem Organic Reactions
Tuning the ‘MIMIRC’ sequence with different Michael acceptors
Fine tuning of the Michael acceptor led to better MIMIRC reactions. The combination of an ester
group and an ArS at one end of the vinyl group is ideal. 12 The tandem product 70 is isolated as a
single diastereoisomer in 55% yield, an average yield of 82% for the formation of each C–C bond.
The ArS groups can be removed by oxidation to the sulfoxide and thermal elimination (chapter
33). Spontaneous dehydration gives the benzene ring 71.
Li TolS CO2Me
O O
first
conjugate
LDA
addition
68
ring
closure
MeO2C
HO
STol STol
CO2Me
TolS
O
67 68
1. m-CPBA
2. heat
MeO2C
70 71
Heterocycles by Tandem Conjugate Additions
Tandem conjugate addition and Mannich reaction
CO 2Me
second
conjugate
addition
CO 2Me
This type of sequence should be ideal for the construction of heterocyclic systems too. The Sceletium
alkaloids have fused cyclohexane and pyrrolidine rings with a substituted benzene at the
ring junction. Sceletium A-4 72 also has a pyridine fused onto the cyclohexane ring. It looks as
though tandem conjugate additions of the cyclic enamine 73 to the vinyl pyridine 74 might be a
good synthesis of this compound but the vinyl pyridine is not electrophilic enough.
MeO
OMe
H
N
Me
72; Sceletium A-4
N
Diels-Alder
or tandem
conjugate
additions
MeO
The answer is to use a protected form of the unsaturated ketoaldehyde 75 instead and build the
pyridine afterwards. 13 The synthesis of the cyclic enamine 73 appears as a problem in the workbook.
Conjugate addition of the enamine 73 gives one enolate 77 that equilibrates with the other
78: cyclisation now gives 79. Deprotection reveals the aldehyde 80 that exists as a mixture with the
hemiacetal of its enol 81. The 6/5 ring junction is formed preferentially syn while the third chiral
centre is lost in equilibration with 81.
OMe
N
TolS
O
69
N
Me
73 74 75
CO 2Me
STol
CO2Me
O CHO

Ar
Ar
N Me
O
O
O
O
N
H
Me
O
79; 85% yield
The mixture of 80 and 81 reacts with hydroxylamine in another tandem conjugate addition to
give a heterocycle 82 that loses water to give Sceletium-A4 72 in one step from the mixture.
Tandem Conjugate Addition and Aldol Reaction
O
N
Me
Tandem conjugate addition of enolates and aldol reactions
Ar
Ar
Other fates are possible for the enolate formed in the initial conjugate addition and an obvious
possibility is an aldol reaction. With an asymmetric catalyst, the combination of three simple
molecules leads to one enantiomer of one diastereoisomer of the tandem Michael-aldol product 14
83. The catalyst 84 is based on a BINOL Al complex (see chapters 25, 26). It can be drawn either
as a lithium salt with an aluminium cation or, better, as a lithium aryloxide with a Lewis-acidic
aluminium atom. This is better because both basic ArO and Lewis acidity are necessary for
catalysis.
O
73 (as
HCl salt)
81
+
H
Ar
O
+
H
EtO 2C
36 Tandem Conjugate Addition and Aldol Reaction 873
76
H
N
Me
Me
80
Ph
CO 2Et
O
MeCN
reflux
CHO
10 mol%
catalyst
36 hours
room
temperature
TsOH
dioxan
H 2O
The conjugate addition 85 of the malonate to cyclopentenone creates asymmetry [exactly how
is not known] in the enolate which accepts the aldehyde on the face opposite the malonate 86. The
stereochemistry of the third centre is determined by the necessarily E-enolate (chapter 4).
O
77
H
N
Me
80
O
O
O
CHO
Ar
Ar
N
3 x NH2OH.HCl Ar
–H2O
O
H
OH
Me
Ph
EtO2C CO2Et 83; 64% yield 91% ee
H
N
Me
82
OH
Li
O
O
O
N
Me
78
Al
84
H
N
Me
81
O
O
72
Sceletium A-4
O
O
O
OH

874 36 Tandem Organic Reactions
O
EtO2C 85
Me
CO2Et
asymmetric
conjugate
addition
O
EtO 2C
Tandem conjugate addition of chiral amines and aldol reactions
This more dramatic reaction starts with the simple conjugate addition of the Davies chiral version
of LDA 89 to unsaturated esters fi rst given in chapter 24. The lithium amide gives the
Z-enolate of the product 90 and hence the adduct 91. The transition state 92 gives the correct
stereochemistry. 15
Ph N
H
Ph
BuLi
THF
–78 ˚C
Ph N
Li
Ph
1.
The tandem aldol reaction simply involves adding an aldehyde to the lithium enolate before
work-up. Since it is a Z-enolate we can expect a syn aldol. The ‘Z’-enolate 90 is indeed formed
(we are drawing the molecules in a different way to make the aldol stereochemistry clearer) and
it does give a syn-aldol with the added advantage that only one of the two possible syn-aldols 90
predominates. The two benzylic groups can be removed, the fi rst with ‘CAN’, ceric ammonium
nitrate, Ce(IV)(NH 4) 2(NO 3) 6 and the second by reduction, to give one enantiomer of 95.
PART III – INTERMEDIATE IS UNSTABLE IMINE OR ENAMINE
Intermediate Would Be Formed by Amide Condensation
Li
O
2. H , H 2O
O
R OEt
Me
CO2Et 86
Ph
In this section we shall look at (mostly) heterocyclic syntheses where a vital intermediate is an
unstable imine, iminium salt, or enamine that cannot be made stoichiometrically. The only way
to use such an intermediate is to prepare it in low concentration as part of a tandem process in the
presence of the third reagent. If the second step is fast enough, the unstable intermediate will be
removed from the equilibrium and the process continues.
Ph
N
diastereoselective
aldol reaction
Ph
OLi
R OEt
88 89 90; 'Z'-enolate
Ph
CO2Et
90' R'CHO
2.5 x CAN
R' N Ph
R'
Z' lithium
MeCN, H2O enolate
OH R
93; ~70% yield
this diastereoisomer
Ph
O
H
OLi
Me
EtO2C CO2Et
87
N
CO2Et
H
N Ph
H2, Pd(OH) 2/C
or Na, NH3(l)
OH R
Ph
O
R OEt
91; 92% yield; 95% de
Ph
R' NH 2
OH
94 95
CO2Et
R
R
H
O
H
H
Me
N
H Li
OEt
Ph
Ph
92

The synthesis of a tricyclic amine by tandem amide condensation and Mannich reaction
The tricyclic keto-amide 96 is at the core of the Daphniphyllum alkaloids. The 1,3-relationship between
the nitrogen atom and the ketone suggests a Mannich disconnection and the intermediate iminium ion
97 is simply derived from the diketoamide 98. However, the iminium ion would have to be formed by
attack of the amide nitrogen atom on one of the ketones and this is an unfavourable reaction. 16
O
N
H
1,3-diO O
C=N
N
Mannich imine
O
O
O
96 97
98
A protected version 99 of 98 is easily made and the tandem sequence works well. The unstable
iminium ion 100 is formed in low concentrations but cyclises under the acidic conditions to form
101, the protected version of 96.
It is initially puzzling that it is not necessary to hydrolyse the acetal before the Mannich reaction.
Under the acidic conditions, the acetal is in equilibrium with the enol ether and this is reactive enough
to combine with the very electrophilic iminium ion 102. The stereochemistry of the product is determined
in this cyclisation step and simply ensures that the two fi ve-membered rings are cis fused.
99
TsOH
toluene
O
NH O
O O
O
36 Intermediate Would Be Formed by Amide Condensation 875
TsOH O
TsOH
N
toluene toluene
O
Alternatives to amide condensations: use of sulfur
Unsaturated amide 103 looks as though it should cyclise cleanly when the enamine on the left
displaces the leaving group ‘X’. But how are we to make 103? Disconnection a is obvious but
the amide nitrogen will not react with the ketone. Disconnection b is more promising. The imine
nitrogen is not a good nucleophile but is a lot better than an amide while the acylating reagent can
be made as active as we like.
H
H
O
O
O
NH O
99 100
101
N
H
O
OH
O
N
H
O
H
OH
O
N
H
102
O
O
OH
N
N
H
O
H
O
O
OH
101

876 36 Tandem Organic Reactions
O
HN
There was a hidden agenda here too. A second cyclisation onto an electron-rich benzene ring
was planned to build up the skeleton of the Erythrina alkaloids and it occurred to Tamura 17 that a
sulfi de (X SMe below) might control both cyclisations. Therefore the anhydride 106 was combined
with an imine 105 already having the aromatic ring tethered to the nitrogen atom.
H 2N
+
OMe
Simple displacement of SMe will not do for the fi rst cyclisation as the SMe group must be
preserved for the second cyclisation. Oxidation to the sulfoxide and cyclisation by the Pummerer
rearrangement is the answer. The intermediate cation cyclises well 109 and creates a new cation
110 rather similar in style to 97. The aromatic ring cyclises 111 to this cation. The stereochemistry
is also well controlled. The 5/6 ring junction is cis, as expected since the two-carbon tether on the
nitrogen delivers the aromatic ring to one face of the fi ve-membered ring. The stereochemistry
of the SMe group is not important as SMe will be reductively removed once it has done its work
of controlling the cyclisations. The tandem aspect of this synthesis concerns the two successive
unstable intermediates 109 and 111.
Asymmetric Tandem Methods Involving Unstable Imines etc.
An asymmetric synthesis of pipecolic acids
R
X
O
O
a
N
X
b
+
a
N
b
O N Y
R
103
R
+
OMe
MeS
SMe
104 105 106 107
MeO
MeO
R
N
O
SMe
Even unactivated double bonds will cyclise onto reactive iminium salts as this synthesis of cis-4hydroxy
pipecolic acid 116; R H shows. This is like a Prins reaction but involves an iminium
ion instead of an aldehyde. 18
Ar
O O O
N
O
108 109 110
111
N
TsOH
O
SMe
R
N
O
SMe
MeO
MeO
R
N
N
112; 60% yield
H
O
SMe
O
SMe
X
O
Ar
O
SMe

NH
R
113
The stereochemistry comes from the intramolecular trapping of the intermediate cation 117
by the carboxylic acid to form a diaxial bridge. Hydrolysis of the lactone inevitably gives cis-116.
To make this an asymmetric synthesis, a chiral substituent was attached to the nitrogen atom
113. The tandem reaction then gave a not very high selectivity (60:40 diastereoisomeric mixture)
but the isomers could easily be separated by crystallisation of the salt of 115 with bromocamphor
sulfonic acid. Removal of the α-methylbenzyl group and lactone hydrolysis gave the pipecolic acid
117 as a single enantiomer. This was needed for the synthesis of an HIV protease inhibitor.
OH 2. NH2 NH
Ph
1. TsCl
Et 3N
Ph
119 120
Intermolecular trapping of alkenes by iminium ions
It is surprisingly also possible to trap an external electrophile in this kind of sequence. The amino
alcohol 122 from phenylglycine (chapter 23) was alkylated and the unsaturated amine 123 combined
with glyoxal. This gives an equilibrating mixture of various cations such as 124 and 125. If
a large excess of a nucleophile such as azide ion is present, bicyclic products like 126 are formed
in reasonable yield. 19
O
+ CHO
CO2H
114
glyoxylic
heat
H2O
MeCN N
R
O
6M HCl
reflux
N
R
CO2H
acid 115 116
CHO
CO2H HO O
H
O
NH
R
114
N
R
CO2H R
N
R
N
113 117 118
115
Ph
OH
NH2
ROTs
i-Pr2NEt,
MeCN
36 Asymmetric Tandem Methods Involving Unstable Imines etc. 877
Ph
OH
NH
114
heat
H2O
MeCN
N
O
Ph
121; 67-72% yield
60:40 diasts
CHO
CHO
H2O
THF
Ph
1. crystallise
sulfonate
salt
O
2. NH4OH
O
N
OH
(+)-121
41% yield
96.4% ee
122 123; 53% yield
124 125
Ph
O
N
OH
O
1. H 2/Pd(OH) 2
2. 6M HCl
reflux
3. ionexchange
resin
OH
H excess
NaN3 Me
HO 3S
O
bromocamphor
sulfonic acid
Ph
OH
N
H
H
Br
CO2H
116; 88% yield
99.8% ee
O
N
OH
H
Me
126
N3

878 36 Tandem Organic Reactions
The cyclisation of the alkene onto the iminium salt must be concerted with the attack of the
azide ion to some degree to account for the stereochemical control. Presumably the molecule folds
as 127 and azide attacks at the back of the alkene through a transition state like 128. In these diagrams
the OH group is drawn in the anomerically more stable axial conformation.
O
Ph
N
OH
127
An Asymmetric Synthesis of ()-Pumiliotoxin B
The family of pumiliotoxins, found in the poison-skinned frogs of South America, include pumiliotoxin
B 129. This polycyclic alkaloid has two alkenes: alkene a should be easy to control by Wittig
or Peterson methods but alkene b is exo to a ring and there is very little difference between one
side of the ring and the other. Some carefully controlled method will be needed. The stereogenic
centres fall into three families: 1 and 2 are adjacent on the six-membered ring and should be
simple. Centre 6 is entirely isolated and not functionalised. Centres 10 and 11 form a 1,2-diol and
again should be simple to control. There is a three carbon spacer between each family and, if that
were not bad enough, each spacer contains an alkene that holds the nearest chiral centres rigidly
away from each other. The only reasonable approach is to make three separate enantiomerically
pure pieces and join them together.
Retrosynthetic analysis
O
Ph
(–) N3 Disconnection at alkene a gives a fragment 130 with some functional group OR for the Wittig
or Peterson reaction. There is a unique carbon atom between the nitrogen atom and alkene b
so disconnection to an (unstable) iminium ion and a stereochemically controlled vinyl anion
synthon 131 (chapter 16) was chosen by Overman, 20 who rather specialises in this kind of
iminium ion.
129
alkene b
N
H OH
?
N3
N
alkene a
129; (+)-pumiliotoxin B
H OH
OH
OH
(+)
N
(+)
OH
Ph
N
OH
128 126
OR
?
N
1
H OH
130 131
2
6
N
O
H OH
10
OH
OH
11
pumiliotoxin B: stereogenic centres
N 3
OR

The reagent for the vinyl anion needs to be compatible with the conditions for imine formation
and the choice fell on a vinyl silane 132. The stereogenic centres in the ring can be controlled by
an epoxide 133 in combination with some other vinyl silane reagent 134.
N
H OH
131a
OR
Me3Si NH
H OH
132
Three enantiomerically pure starting materials ensure remote stereochemical control
The synthesis is necessarily long and we shall concentrate on the tandem aspects. The three enantiomerically
pure starting materials were the acetylenic silane 135 for C-6, prepared by resolution
(chapter 22), the epoxide 136, for C-1 and 2, prepared from proline (chiral pool strategy, chapter
23) and the Wittig reagent 137, prepared from ethyl lactate (chiral pool again), for C-11.
SiMe 3
OBn
N
CO 2Bn
H O
Hydroalumination of the alkyne in 135 gave the Z-vinyl aluminium 138. Treatment with MeLi
gave the ‘ate’ complex that reacted with the epoxide 136 to give 139. As the epoxide is opened, the
oxyanion produced cyclises onto the Cbz group on nitrogen. This product was entirely Z and there
was only a trace (7%) of one other diastereoisomer.
135
1. i-Bu 2AlH,
MeLi
Hydrolysis of the carbamate in base released the unstable alcohol 140 that could be trapped
with formaldehyde to give the new heterocycle 141. This compound contains the extra carbon
atom needed for the six-membered ring in pumiliotoxin B but this has yet to cyclise onto the vinyl
silane
139
1. KOH
EtOH
36 An Asymmetric Synthesis of (+)-Pumiliotoxin B 879
OR
Ph 3P
NH
H O
133
Me 3Si
135 136 137
Me3Si
i-Bu 2Al
O
134
OSiPh 2Bu-t
O
OBn
2. 136 N
O SiMe3
H
138
H
Me
139; 77% yield, all Z
Me3Si 2. CH2O NH
H2O H OH
140
OBn
N
H
Me
O
SiMe3
141
OBn
OBn
OR

880 36 Tandem Organic Reactions
Tandem iminium ion formation and vinyl silane cyclisation
Now comes the critical moment. Treatment of 141 with acid (camphor sulfonic acid is used, not
because it is enantiomerically pure, but because it is convenient) opens the heterocyclic ring to
give the unstable iminium ion that cyclises onto the vinyl silane 142 to give the β-silyl cation 143
with retention of confi guration at the alkene. The product 144 is formed in only moderate yield
(52% from 141) but contains no trace of the E-isomer.
141
camphor
sulfonic
acid
Me 3Si
N
OBn
H OH
H OH
H OH
142 β-silyl cation 143 144; 52% yield, all Z
Finally the benzyl group was removed, the primary alcohol oxidised to the aldehyde, and an
E-selective Wittig reaction performed with the enantiomerically pure stabilised ylid 137. No
racemisation of either partner occurred and the product was almost pure E at the new alkene. Stereoselective
reduction gave ()-pumiliotoxin B 129 identical to the natural product in all respects,
including biological effects.
144
We have spent some time over this synthesis as it is a beautiful example of convergent use of
enantiomerically pure starting materials brought together with a tandem Mannich/vinyl silane
cyclisation at its core.
PART IV – TANDEM PERICYCLIC REACTIONS
Pericyclic reactions are normally insensitive to conditions: they often require no acid or base
catalysis and are 100% atom effi cient with no by-products. There is no problem in running a
sequence of pericyclic reactions whether cycloaddition, electrocyclic, or sigmatropic, and almost
every combination has been tried. This section explores some of the more successful methods.
Electrocyclic Formation of a Diene for Diels-Alder Reaction
N
SiMe3
An early but important example of this style of tandem reaction is based on the benzocyclobutene
148, easily prepared from the nitrile 146 by cyclisation of the benzyne 19 147.
OBn
OSiPh 2Bu-t
1. Li, NH3(l) 2. Swern
3. ylid 137
N
O
LiAlH4 THF
129
(+)-pumiliotoxin B
74% yield, all Z,E
H OH
145; 71% yield,

Br
H
NH 2 NaNH2
NH3(l)
NC OMe
NC OMe
OMe
146 147 148; 65% yield
Alkylation with an unsaturated alkyl halide 149 gives an intermediate 150 ready for the tandem
sequence. Simple heating at around 200 C gives a single diastereoisomer of 151 with the creating
of two new chiral centres and a typical tandem yield.
148
1. NaNH 2, NH 3(l)
2.
HO2C
149
I
HO 2C
CN
180-230 ˚C
toluene
sealed tube
OMe
HO2C
The cyclobutene ring fi rst opens in an electrocyclic reaction 152. This must be conrotatory as
it is a four electron process but there is no stereochemistry at this stage. Then an intramolecular
Diels-Alder cycloaddition 153 closes the new six-membered ring. This is a particularly favourable
reaction as the formation of the alkene completes a benzene ring. It would not be possible to
prepare such an unstable diene so a tandem process is necessary.
R
CN
OMe
The stereochemistry suggests that the molecule folds up in the arrangement 154 with the
methyl group on top of the benzene ring as that gives all three centres correct including the cis ring
junction. 21 The reaction was designed as a route to ajmaline 155 and the bridging amine is formed
from the necessarily cis CO 2H and CN groups. The alternative folding 156 would put CN and H
trans. There is no endo overlap here as nothing is conjugated with the dienophile. Intramolecular
Diels-Alder reactions need no endo overlap as the two components are already tethered.
H
NC
36 Electrocyclic Formation of a Diene for Diels-Alder Reaction 881
NC
H
CN
150; 76% yield 151; 52% yield
4 electron
conrotatory
electrocyclic
HO 2C
152 153
CN
OMe
Diels-Alder
4 + 2
cycloaddition
CO2H H
N
Me
H
Me
151
H
HO2C NC
OMe
OMe
154 155; ajmaline
156
151
OMe
OMe

882 36 Tandem Organic Reactions
Tandem Ene Reactions
It is less common to fi nd two pericyclic reactions of the same kind coupled together but the Alder
‘ene’ reaction and the oxo ‘ene’ reaction can both be catalysed by Lewis acids under the same
conditions. A simple example is the combination of the exocyclic alkene 157 with acrolein. The
intermediate unsaturated aldehyde 158 cyclises stereoselectively to form a new carbocyclic ring
159. The intermediate 158 is perfectly stable so the tandem sequence is convenient rather than
necessary. 22
+
H
Me 2AlCl
0 ˚C, CH 2Cl2
O
157 158
The fi rst step is a straightforward ene reaction 160 with the LUMO of the aluminium complex
of acrolein attracting the HOMO of the reactive alkene. The circles indicate the largest coeffi cient
in each frontier orbital. The second step is an oxo-ene 161 with the oxygen atom of the aldehyde
capturing the allylic proton. The stereochemistry of the product 159 suggests that the reactive
conformation is 161.
H
Tandem [3,3]-Sigmatropic Rearrangements
Cope rearrangements, the all-carbon [3,3]-sigmatropic rearrangements, often have no particular
reason to go one way or the other. It may even be necessary in some syntheses to drive them in
the direction they dislike. Such an example is the formation of a ten-membered ring (an unfavourable
medium ring) from a six-membered ring. 23 The starting material 164 was prepared as a single
enantiomer from (S)-()-carvone 162.
O
162; (S)-(+)-carvone
Heating this silyl enol ether 164 at about 200 C gives the unstable silyl ester 165 isolated as
the stable methyl ester 166 in 30% yield. This is obviously not a good yield but enough has been
achieved to make the tandem process worthwhile. A ten-membered ring with two E-alkenes has
CHO
Me 2AlCl
0 ˚C, CH 2Cl2
H
OH
159; 63% yield
HOMO
H AlClMe2 HO
LUMO
O
AlClMe2
O
H
H
H
H
=
H
OH
160 161
159
O
1. LDA, HMPA
–78 ˚C
2. i-Pr3SiCl
O
i-Pr3SiO 163 164
O

een formed. Two new stereogenic centres have been controlled relative both to each other and to
what is now a remote centre - the isolated methyl group. Though the original centre on carvone
has disappeared, three others have appeared.
O
i-Pr3SiO 164
200 ˚C
dodecane
140 minutes
i-Pr3SiO 2C
In detail, the fi rst step is a Cope rearrangement - a [3,3]-sigmatropic rearrangement involving
nothing but carbon atoms 167. This step is unfavourable because it transforms a stable cyclohexane
into an unstable E,E-decadiene. The product 168 is a minor component in the equilibrium.
What drives the reaction forward is a favourable Claisen-Ireland rearrangement on the silyl enol
ether 168. This step is favourable because it creates a carbonyl group (the ester in 165) at the
expense of an alkene.
O
unfavourable Cope
[3,3] sigmatropic
rearrangement
The stereochemistry emerges from the reactive conformations of 165 and 168. The most stable
conformation 169 already has the two vinyl groups next to each other and the [3,3]-sigmatropic
rearrangement can go through the favoured chair transition state to give the two E-alkenes
in 170. The substituents on each alkene are already trans to each other in 169. Conformation
170 cannot do the next reaction but these ten-membered rings are very fl exible and conformation
171 is just right. Again the E-alkene in 165 is already so arranged in 171 and the two new
stereogenic centres develop without change from the Z-enol ether, the E-alkene, and the chair
transition state for the Claisen-Ireland rearrangement 171. This product was used to synthesise
sesquiterpenes.
RO
H
1. KF.2H 2O
HMPA
2. CH 2N 2
MeO 2C
165 166; 30% yield from 163
O
Favourable
Claisen-Ireland
[3,3] sigmatropic
rearrangement
i-Pr 3SiO 2C
i-Pr3SiO i-Pr3SiO 167 168 165
169
H
O
Me
H
36 Tandem [3,3]-Sigmatropic Rearrangements 883
E alkene
H
RO O H
O
Me
H
E alkene
H H
OR
170 171
H
H
H
H
anti
H atoms
H H
O
H
H
E alkene
= 165
OR
Me

884 36 Tandem Organic Reactions
Tandem Aza-Diels-Alder and Aza-Ene Reactions
Completion of the synthesis of Daphniphyllum alkaloids
We left compound 35 as the product of a tandem conjugate addition/alkylation and promised
further chemistry later in the chapter. In fact, 35 was used in another more remarkable tandem
sequence involving two pericyclic reactions and the creation of a polycyclic Daphniphyllum
alkaloid. The fi rst few steps are straightforward and give diol 173 in good yield. 8
N
O
MeO2C
35
H
OBn
1. DIBAL, –78 ˚C
2. KOH, 165 ˚C
HO
OH
O
O
Now the excitement begins. The diol 173 is oxidised to a rather unstable dialdehyde 174 that is
immediately combined with ammonia to give a dihydropyridine 175. The chiral centre that was
not controlled in the earlier sequence is lost in this step. This is again not isolated but treated with
acetic acid. A series of reactions ensues - this is the second tandem sequence in this synthesis - and
the molecule folds up to give 176.
173
The fi rst step is an aza-Diels-Alder reaction (chapter 34) with the (probably protonated) dihydropyridine
175 acting as the diene. Only the nearer of the two alkenes in the side chain can
reach the aza-diene and it approaches from the top face (as drawn 177) because it is tethered to the
diene by that face. The tether determines both the regio- and the stereoselectivity of the reaction.
N
Swern
H
R
175
H
OBn
LiAlH 4
Et 2O
HO
HO
172 173; 95% yield
OBn
OBn
H
H
OHC
NH3
HOAc
OHC
R
gas
N
R
HN
174 175 176; 77% yield
OBn
HOAc
H
R
N
H Me
OBn
intramolecular
aza-Diels-Alder
R
N
H
177 178
H
H
OBn
OBn
OBn

The second reaction amounts to an aza-ene reaction with the most remote alkene providing
the ‘ene’ partner and the imine. The molecule folds up 179 to give a chair conformation in the
developing six-membered ring and the product 176 is easily transformed into ()-methyl homosecodaphniphyllate
180.
R
N
H
178
H
OBn
Tandem Reactions Involving 1,3-Dipolar Cycloaddition
Asymmetric synthesis of swainsonine
H
N
179
H
A commoner way to make heterocycles by pericyclic reactions is to use 1,3-dipolar cycloadditions.
These often occur without catalysis and so are compatible with many other reactions. The
starting material 182 for this asymmetric synthesis of swainsonine was derived from a natural
sugar (chiral pool strategy, chapter 23). An exceptionally stereoselective Wittig reaction gave the
Z-alkene 183 (chapter 15) and the alcohol was converted into the azide 184 with diphenylphosphoryl
azide. 24
Ph 3P
181
Cl
2.
O
O
O
OH
The tandem sequence occurs when the azide is heated in a hydrocarbon solvent. A 5/6 fused
bicyclic ring system 186 is formed and the last reaction is known to be a simple cyclisation of the
intermediate 185 (though this is not isolated) by nucleophilic displacement.
O
O
N3
184
36 Tandem Reactions Involving 1,3-Dipolar Cycloaddition 885
1. KN(SiMe 3) 2
Cl
182
reflux
benzene
The fi rst step is a 1,3-dipolar cycloaddition of the azide onto the unactivated alkene 187. The
regioselectivity of the cycloaddition (and no doubt also its stereoselectivity, though this is lost in
the next reaction) is controlled by the short tether. The product 188 is not stable and rearranges,
perhaps by the concerted H shift and loss of nitrogen shown, into 189 which promptly cyclises to
give the product 186 by loss of a proton.
OBn
OH Cl
183; 86% yield; Z only
176
O
O
O (PhO)2P
O
O
N
N3
Ph3P
DEAD
THF, 23 ˚C
O
HN
180
O
H CO2Me
N3 Cl
184; 76% yield; Z only
Cl
185 186
O
O
N

886 36 Tandem Organic Reactions
O
O
The stereochemistry needed for swainsonine 192 is introduced by hydroboration – borane adds
to the face of the alkene opposite the acetal in 186 and the regioselectivity is determined by the
nitrogen atom since the alkene 186 is an enamine.
O
O
186
1. BH3.THF
2. H2O2,
NaOAc
Tandem synthesis of 2-vinyl indoles
N
O
H
N N N Cl
O
N
N
N
Cl O
N
Cl
O
N
187 188 189
190
O
Now an extraordinary sequence starting with a 1,3-dipolar cycloaddition but containing at least
seven reactions occurring sequentially. Reaction of PhNH.OH with an aldehyde R 1 CHO gives
the rather unstable nitrones 193 as the fi rst step in the tandem sequence. The 1,3-dipolar cycloaddition
with cyano-allenes 194 occurs regioselectively to give the unstable heterocycles 195 that
immediately undergo a [3,3]-sigmatropic rearrangement that breaks the weak N–O single bond.
Rearomatisation gives a benzo-azacycloheptanone 197 that eliminates the aromatic amine by an
E1cB mechanism 198 to give an open chain amino enone 199. This fi nally cyclises to the indole
200. It is amazing that the molecule fi nds its way through this maze of reactions and even more
amazing that the yields are quite good. 25
This sequence can be used to build polycyclic heterocycles very quickly from simple starting
materials. Even enolisable aldehydes with extra functionality such as 201 can be used in the
sequence; the more complex vinyl indole 202 is formed in very reasonable yield 25 (66%).
O
191
O
H OH
N
O
HO
H H
H OH
HO
N
192; 85% yield
swainsonine
Ph O
N
R1 R2 CN
R
N
H
2
OH
CN
R1 N
R1 O
R2 CN
R
NH2 2
O
CN
R1 H
N
R2
O
CN
R1 H
N
H
R1 R2 R
N
H
CN
2
O
H
CN
R1 1,3-dipolar
cycloaddition[3,3]-sigmatropicrearran-
193 194
195
gement
196 197
enolisation E1cB
imine formation
and aromatisation
198
199 200
186

OHC
Me N Me
1. PhNHOH
N
201
O
Clearly this indole 202 is destined for a Diels-Alder reaction and refl uxing in toluene gives an
excellent yield of one (endo-) diastereoisomer of the product 204.
202
reflux
toluene
N
H
PART IV – OTHER TANDEM REACTIONS LEADING TO HETEROCYCLES
A Tandem Metallation Route to the Ellipticine Skeleton
2.
H
O
N
CN
As we move from pericyclic reactions to other processes, we can consider a tandem metallation
route to the same basic skeleton, that of ellipticine 205, the basis of some important drugs. The
selectivity problem here is to relate the position of the two nitrogen atoms.
This process involves a straightforward directed ortho metallation (chapter 7) of the pyridine
amide 206 and capture by the indole aldehyde 208. Without work-up, the product 209 is lithiated
again and the ‘ellipticine quinone’ 210 is formed in good yield. 26
N
H
R
R
205
36 A Tandem Metallation Route to the Ellipticine Skeleton 887
The second lithiation must occur preferentially on the indole to give 211 (the alternative is a
second metallation on the pyridine ring). Cyclisation is by acylation and the product 212 oxidises
in air to give the ‘quinone’ 210.
Me
N
H
CN
202; 60%
N
H
CN
H H
CN
203 204; 80% yield
Li
N
O
NEt2 N 1 x s-BuLi
1 x TMEDA
Et2O, –78 ˚C
O
NEt2 N
+
N
Me
206 207 208
OLi
N
Me O
209
N
NEt 2
s-BuLi
–78 ˚C to
room
temperature
O
O
H
N
Me O
210; 76% yield
O
N
N
Me
CHO

888 36 Tandem Organic Reactions
209
s-BuLi
OLi
Tandem Aza-Diels-Alder and Allyl Boronate Reactions
N
N Li N
Me O NEt2
Me O
211 212
One last example of the aza-Diels-Alder reaction fi nishes this section. The diene 215 is a curious
hybrid of a dienyl boronate and the sort of aza-diene we met in chapter 33 and is easily prepared
by hydroboration of a suitable functionalised acetylene 213.
1. R2BH, DMF, 0 ˚C
O
EtO OEt
213
2. Me3NO.2H2O 3. pinacol
4. cat. HCl, dioxan
OHC
O
B
214
O
Me2N NH2 Me2N
N
215
B
O
Reaction with maleic imide 216 and an aldehyde gives a bicyclic product 217 with a new piperidine
ring and four new stereogenic centres. The yield is around 50% - entirely acceptable in such
a productive tandem process. 27
O
O
N
216
R
215
R'CHO
heat
dry toluene
The fi rst step is of course the aza-Diels-Alder reaction 218 with no regioselectivity but lots
of stereochemistry. The cis ring junction in 217 comes from the cis alkene in maleimide and the
endo transition state gives the remaining centre. The next step is an allyl boronate reaction 219
with the aldehyde. Coordination of the aldehyde oxygen with the boron ensures that the aldehyde
is delivered to the top face and the aldol stereochemistry comes from the six-membered cyclic
transition state. Snieckus comments that the reaction works well as a tandem process because the
4 2 cycloaddition is slower than the allyl boronate reaction so the unstable intermediate does not
accumulate. This comment has more general application.
R'
H O
OH
N
N
H
OH
H
NMe2 O
217; 42-52% yield
B(OR)2
N
NMe2
O
N
O
R
H
N
N
H
NMe2 O
R'
O
B(OR) 2
O
R R'
OH
H
N
H
NMe2 N
O
Aza-
Diels-
Alder
H
O
218 219
217
R
N
air
210
R

Tandem Beckmann Rearrangement and Allyl Silane Cyclisation
The Beckmann rearrangement 28 involves C to N migration of a group anti to the OH group on an
oxime. Such a cation might be trapped by a carbon nucleophile such as an allyl silane (chapter 12)
that is reactive but not destroyed under the Beckmann conditions. A condition for such a scheme
would be a stereoselective way of making oximes and the answer is a directed metallation of a
symmetrical oxime. 29 Lithiation of symmetrical cyclohexanone oxime 220 gives a lithium azaenolate
(221 or 222) that can be trapped with alkyl halides RX to give one isomer (Z-) of 223.
N
OH 1. 2 x BuLi
THF
N
O
Li
Li
or
N
O
Li
220 221 222
If the alkyl halide is a suitably functionalised allyl silane (Z-allyl silanes are easier to prepare)
the product Z,Z-224 can be activated by mesylation ready for the tandem procedure. 30
220
Rearrangement of Z,Z-226 now gives a cation 227 that reacts with the allyl silane to close a
second ring. Attack occurs at the end of the alkene away from the silicon atom so that a β-silyl
cation might be an intermediate.
N OMs
SiMe 3
N OH
SiMe3 MsCl
This product 228 is not very stable and the best conditions for the reaction turned out to be
DIBAL (i-Bu 2AlH) in CH 2Cl 2. DIBAL acts fi rst as a Lewis acid to initiate the rearrangement and
then reduces the imine 228 stereoselectively to the stable amine 229.
Et 3N
Li
2. RX
N OMs
Z,Z-224 Z,Z-225
N SiMe3
H
Z,Z-226 227 228
N OMs
36 Tandem Beckmann Rearrangement and Allyl Silane Cyclisation 889
SiMe 3 i-Bu 2AlH
CH2Cl2 –78 to 0 ˚C
H
Z,Z-225 228
N
i-Bu 2AlH
N
H
N
R
223
SiMe3
H
N OH
H
229; 45% yield

890 36 Tandem Organic Reactions
PART V – TANDEM ORGANOMETALLIC REACTIONS
Tandem Asymmetric Heck and Pd-Allyl Cation Reactions
Two important palladium-catalysed methods are the Heck reaction (chapter 18) and nucleophilic
attack on palladium allyl cation complexes (chapter 19). These two can be combined in a tandem
process and, with a suitable chiral ligand, made asymmetric. 31 The fi rst step is intramolecular
Pd(0)-catalysed addition of a vinyl trifl ate to a cyclopentadiene. Oxidative insertion of Pd(0) into
the vinyl trifl ate to give a palladium vinyl σ-complex 223 is followed by π-complex formation by
this Pd(II) species. The short tether directs the Pd to the cis face of the fl at ring. The Heck stage is
completed by coupling 224 of the vinyl group to the nearer end of the old π-bond to make a new
Pd(II) σ-complex 225. Notice how convenient it is that the Heck reaction gives the Pd(II) complex
needed to form the allyl cation while the loss of Pd(0) from the second step 226 provides the right
oxidation state for the next Heck reaction.
OTf
OTf Pd
Pd(0)
230 231 232 233
Now the second alkene comes into play as 234 is really an allyl σ-complex that prefers to exist
as an allyl η 3 cation complex 235. If a suitable nucleophile, such as a malonate enolate, is present
this will attack the allyl cation complex. It must attack from the opposite face to the palladium and
prefers to attack next to the H atom rather than the Me group giving 236.
X
H Pd
H
EtO 2C
Pd
The starting material is not chiral and chirality fi rst arises in the Heck reaction when the vinyl
Pd complex can attack one of two enantiotopic alkenes in the diene. In the presence of catalytic
BINAP, good asymmetric induction 237 can be achieved.
OTf
Pd
R
CO2Et
H PdX
EtO2C
H OR
CO2Et
234 235
236
OTf
230
116.8 mg
Cl
3.8 mg Pd Pd
Cl
16.25 mg (S)-(–)-BINAP
EtO2C
85 mg NaBr, DMSO
CO 2Et Na
OSiPh 2Bu-t
EtO2C CO2Et
H OSiPh2Bu-t
237
74% yield, 87% ee

Tandem Ring-Closing and Ring-Opening Metathesis
With two identical groups it might seem that tandem reactions have little value. This ingenious
double metathesis should convince you otherwise. The starting material 240 is made by Luche reduction
(the Luche method prevents reduction of the alkene) of cyclopentenedione 239. Allylation
of both alcohols gives the symmetrical (meso) starting material 241 for the double metathesis with
the Grubbs catalyst 238. The symmetrical product 242 is formed in excellent yield. 32
The metathesis starts with one of the less hindered allyl groups and it doesn’t matter which you
choose as the fi rst intermediate will always be 243. The Ru carbene complex can reach only the
central alkene so it completes the metathesis with this to give 244 and then 245. Now a second
metathesis with the remaining allyl group gives the product 242 via 246. The stereochemistry
remains unaltered even though the molecule is opened up and put together again.
O
O
O
RuLn RuLn LnRu LnRu 243 244 245 246
A Ru-Catalysed Four-Component Coupling
O
O
O O
More recently, chemists seem to be able to invent multi-component reactions almost at will. An
outstanding example is this four-component coupling catalysed by ruthenium. Three component,
surely, do we hear you say? The fourth component is the bromide ion. 33
R 1
PCy 3
Cl
Ru
Cl
PCy3
238
+
O
Ph
36 A Ru-Catalysed Four-Component Coupling 891
O
O
247
239
R2 +
O
O
R 3 CHO
NaBH 4, CeCl 3
MeOH, –78 ˚C
10 mol % catalyst:
Ru[NCMe] 3 PF 6
15% SnBr 4, DMF, 60 ˚C
The fi rst step is the formation of an alkyne-Ru π-complex 249 that adds bromide ion, presumably
transferred from Ru in view of the stereochemistry of 250. Now the enone 247 and the
vinyl-Ru complex 250 couple with retention of the stereochemistry of 250 and transfer of the Ru to
oxygen to make a Ru-enolate. This is known to be true as work-up in the absence of the aldehyde
gives the ketone 252.
N
HO
5 mol% Grubbs
Ru catalyst
240; 58% yield
Br
O
OH
2.
1. NaH, DMF
O O
60 ˚C, 2 hours
241; 60% yield 242; 90% yield
R 3 OH
Br
R 1 R 2
Br O
248; 40-70% yield
up to 6:1 Z:E, >10:1 syn:anti
242

892 36 Tandem Organic Reactions
R 1
RuCp
Br
If the aldehyde is present, a Ru-aldol reaction gives a single geometrical and diastereomeric
aldol product 248 and the Ru is lost as CpRu so it can catalyse the next cycle. There are quite
a few extra reagents needed to make the reaction go well: catalytic Sn(II)Br 2 and the curious
spirocyclic ammonium salt. This latter is essential.
References
R 1
Br
RuCp
247
R 1 R 2
Br ORuCp
R1 R2 RuCp
Br O
249 250 251 252
General references are given on page 893
1. T.-L. Ho, Tandem Organic Reactions, Wiley, New York, 1992.
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9. H. Nagaoka, K. Kobayashi, T. Okamura, and Y. Tamada, Tetrahedron Lett., 1987, 28, 6641.
10. G. H. Posner and S.-B. Lu, J. Am. Chem. Soc., 1985, 107, 1424.
11. G. H. Posner, J. P. Mallamo and A. Y. Black, Tetrahedron, 1981, 37, 3921.
12. G. H. Posner, S.-B. Lu, E. Asirvatham, E. F. Silversmith and E. M. Shulman, J. Am. Chem. Soc., 1986,
108, 511; G. H. Posner and E. M. Shulman-Roskes, J. Org. Chem., 1989, 54, 3514.
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T. van Ree, A. Wiechers and N. Woudenberg, Tetrahedron Lett., 1976, 935.
14. T. Arai, H. Sasai, K. Aoe, K. Okamura, T. Date, and M. Shibasaki, Angew. Chem., Int. Ed., 1996, 35, 104.
15. S. G. Davies, N. M. Garrido, O. Ichihara and I. A. S. Walters, J. Chem. Soc., Chem. Commun., 1993,
1153; S. G. Davies and D. R. Fenwick, J. Chem. Soc., Chem. Commun., 1995, 1109; N. Asao, N. Tsukada
and Y. Yamamoto, J. Chem. Soc., Chem. Commun., 1993, 1660; N. Asao, T. Uyehara and Y. Yamamoto,
Tetrahedron, 1990, 46, 4563.
16. C. H. Heathcock, S. K. Davidsen and S. Mills, J. Am. Chem. Soc., 1986, 108, 5650.
17. Y. Tamura, H. Maeda, S. Akai and H. Ishibashi, Tetrahedron Lett., 1982, 23, 2209.
18. S. J. Hays, T. C. Malone and G. Johnson, J. Org. Chem., 1991, 56, 4084.
19. C. Agami, F. Couty, M. Poursolis, and J. Vaissermann, Tetrahedron, 1992, 48, 431.
20. L. E. Overman, K. L. Bell, and F. Ito, J. Am. Chem. Soc., 1984, 106, 4192.
21. T. Kametani, Y. Kato, T. Honda, and K. Fukumoto, J. Am. Chem. Soc., 1976, 98, 8185.
22. B. B. Snider and E. A. Deutsch, J. Org. Chem., 1983, 48, 1822.
23. S. Raucher, K.-W. Chi, K.-J. Hwang, and J. E. Burks, J. Org. Chem., 1986, 51, 5503.
24. W. H. Pearson and K.-C. Lin, Tetrahedron Lett., 1990, 31, 7571.
25. S. Blechert, R. Knier, H. Schroers and T. Wirth, Synthesis, 1995, 592.
26. M. Watanabe and V. Snieckus, J. Am. Chem. Soc., 1980, 102, 1457.
27. J. Tailor and D. G. Hall, Org. Lett., 2000, 2, 3715.
28. Clayden, Organic Chemistry, page 997.
29. M. E. Jung, P. A. Blair, and J. A. Lowe, Tetrahedron Lett., 1976, 1439.
30. D. Schinzer and Y. Bo, Angew. Chem., Int. Ed., 1991, 30, 687.
31. T. Ohshima, K. Kagechika, M. Adachi, M. Sodeoka, and M. Shibasaki, J. Am. Chem. Soc., 1996, 118, 7108.
32. W. J. Zuercher, M. Hashimoto, and R. H. Grubbs, J. Am. Chem. Soc., 1996, 118, 6634.
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General References
Full details of important books referred to by abbreviated titles in the chapters to avoid repetition.
Clayden, Lithium: J. Clayden, Organolithiums: Selectivity for Synthesis, Pergamon, 2002.
Clayden, Organic Chemistry: J. Clayden, N. Greeves, S. Warren and P. Wothers, Organic Chemistry, Oxford
University Press, Oxford, 2000.
Collins, Chirality in Industry: eds. A. N. Collins, G. N. Sheldrake and J. Crosby, Chirality in Industry:
The Commercial Manufacture and Applications of Optically Active Compounds, Vol I, 1992, Vol II,
1997, Wiley, Chichester.
Comp. Org. Synth.: eds. Ian Fleming and B. M. Trost, Comprehensive Organic Synthesis, Pergamon, Oxford,
1991, six volumes.
Corey, Logic: E. J. Corey and X.-M. Cheng, The Logic of Chemical Synthesis, Wiley, New York, 1989.
Designing Syntheses: S. Warren, Designing Organic Syntheses, Wiley, Chichester, 1978.
Disconnection Textbook: S. Warren, Organic Synthesis, The Disconnection Approach, Wiley, Chichester,
1982.
Disconnection Workbook: S. Warren, Workbook for Organic Synthesis, The Disconnection Approach,
Wiley, Chichester, 1982.
Drauz and Waldmann: K. Drauz and H. Waldmann, Enzyme Catalysis in Organic Synthesis, VCH, Weinheim,
Two Volumes, 1995, ISBN 3-527-28479-6.
Eliel: E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley, New York, 1994.
Fieser, Reagents: L. Fieser and M. Fieser, Reagents for Organic Synthesis, Wiley, New York, 20 volumes,
1967–2000, later volumes by T.-L. Ho.
Fleming, Orbitals: Ian Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley, London,
1976.
Fleming, Syntheses: Ian Fleming, Selected Organic Syntheses, Wiley, London, 1973.
Houben-Weyl; Methoden der Organischen Chemie, ed. E. Müller, and Methods of Organic Chemistry,
ed. H.-G. Padeken, Thieme, Stuttgart, many volumes 1909–2004.
House: H. O. House, Modern Synthetic Reactions, Benjamin, Menlo Park, Second Edition, 1972.
Morrison: Asymmetric Synthesis, ed. J. D. Morrison, Academic Press, Orlando, 5 Volumes, 1983–5.
Nicolaou and Sorensen: K. C. Nicolaou and E. Sorensen, Classics in Total Synthesis: Targets, Strategies,
Methods. VCH, Weinheim, 1996. Second volume now published.
Ojima, Asymmetric: I. Ojima (ed.) Catalytic Asymmetric Synthesis, Second Edition, Wiley, New York,
2000.
Saunders, Top Drugs: J. Saunders, Top Drugs: Top Synthetic Routes, Oxford University Press, Oxford,
2000.
Vogel: B. S. Furniss, A. J. Hannaford, P. W. G. Smith, and A. R. Tatchell, Vogel’s Textbook of Practical
Organic Chemistry, Fifth Edition, Longman, Harlow, 1989.

Index
Acetal, 195
Selective formation under thermodynamic
control, 59, 61
Acifran, 207
Acorene, 67
Acyl anion equivalents, 67, 72, and see also
chapter 14
See also synthons, d 1
Aldol reaction of, 169, 695
Derivatives of cyclic vinyl ethers, 203, 210
Diketones synthesis, 216
Dithians, 205
Functionalised Wittig reagents, 203, 214
Intramolecular, 242, 266
Lithium derivatives of allenyl ethers,
203, 212
Modifi ed acetals, 203–205
Nitroalkanes, 203, 214
Ester d 1 synthon, 203, 209
Oxidative cleavage of allenes, 212
Vinyl ethers, 212
Yamamoto’s ROCH(CN) 2, 209
Acyloin reaction, 73, 178
Silicon modifi cation, 73
Agelastatin, 465, 493
AL-4862 (Azopt), 510, 511
Aldol reaction, 201
See also specifi c substrates
Acid catalysed, 214, 297, 314
anti-Selective of boron enolates, 611
of ester enolates, 18, 85
of lithium enolates, 778, 791
of silyl enol ethers, 795–796
Diastereoselective, 52, 332
E and Z nomenclature, 355, 405
Enone synthesis by, 58, 67, 621
Enzymatic, 436, 459
Equilibrating reaction, 19, 51, 73
Homoaldol reaction, 189, 194
1,5-Induction, 708
Organic Synthesis: Strategy and Control, Written by Paul Wyatt and Stuart Warren
Copyright © 2007 John Wiley & Sons, Ltd
1,3-anti Induction, 702
1,4-syn Induction, 706
Mukaiyama aldol reaction, 32
Of lithium enolates, see chapters 3–6, plus 778,
791, 800
Of enamines, 30
Of extended enolates, 155, 159
Of silyl enol ethers, 20, 163, 191
Of zirconium enolates, 49
Open transition state of silyl enol ethers, 48
Proline-catalysed, 579
Stereochemical control, 690
Stereoselective aldol reaction, 44, 51, 404, 670,
737, 739, 868
syn-Selective of boron enolates, 47
of phenylthio esters, 47
of ketone enolates, 48
of silyl enol ethers, 48
of zirconium enolates, 49
of thioester boron enolates, 611
Synthesis of ()-discodermolide, 709
Tandem Michael and aldol reaction, 869
Alkaloids, 475, 501
Ligands for the Sharpless asymmetric
dihydroxylation, 538
Alkenes, 277, 512, 543
See also Wittig and Horner-Wadsworth-Emmons
reactions, 155, 157
Amine catalysed isomerisation, 228
Control of geometry, see chapter 15
Epoxidation of, 224, 273
Markovnikov addition, 283
anti-Markovnikov addition, 284
Isomerisation, 353, 362
Intramolecular trapping of by iminium ions, 668,
877
Photochemical isomerisation, 250
Polyene cyclisations, 302
Radical isomerisation, 251
cis-Selective synthesis, 145

896 Index
Alkenes (Continued)
Stereospecifi c Z-alkene synthesis, 712
Stereospecifi c E-alkene synthesis, 252
Synthesis by selenoxide elimination, 213
trans-Selective synthesis, 232
Reaction with electrophiles, 256, 433
regioselective, 520, 531
chemoselective, 571, 604
Alkynes, 248, 262
Bromination of, 789
Hydroboration of, 263
Michael addition to, 130, 621
Reduction to alkenes, 248
E-Selective LiAlH 4 reduction of, 248
1,3-Allylic shift, 174
()-α-Allo-kainic acid, 821–822
Allopurinol, 839
Allyl anions equivalents, 173
See chapter 12, 315
Allylboration, asymmetric, 718, 738
Allyl dianion, 183
Allylic alcohols, 340, 343, 359
See chapter 19, 735
Chromium(VI) mediated rearrangement of, 7, 85
Directed Simmons-Smith cyclopropanation, 585
Heck reaction of, 854–855
Palladium-catalysed reaction of, 6, 267
Rearrangement of, 83
Reaction with nucleophiles, 109, 112, 115
Stereochemically controlled epoxidations of, 350
Synthesis
from aldehydes and ketones, 342
by enone reduction, 341
from iodolactonisation products, 341
by Wittig reaction, 342–343
Allylic alkylation, asymmetric, 685
Allylic phosphates, 343
Ambruticin, 563
Amino acids, see chapters 22 and 23
Diazotisation of, 467
Nucleophilic substitution of α-lactones, 513, 517
Conversion to, 321, 666
α-chloro acids, 467
epoxides, 350, 363
(R)-amino acids, 382, 449
Reduction of, 468
Synthesis from 2-acylamino acrylates, 568
Amino alcohols, 499
Synthesis of
quinolone antibiotics, 484
oxazolidinone antibiotics, 485
anti-viral nucleoside analogues, 486
Aminohydroxylation, 528, 552
Amino-nitriles, 199
Michael addition of, 228, 621
Hydrolysis of, 624, 744
Amlodipine, 439, 676, 677
(R) and (S)-Amino-1-phenylethanol, 718
Amopyroquine, 12–13
Amphotericin, 118
()-Anatoxin-A, 772
Anomeric effect, 46–47
Antheridic acid, 60
()-Aplysistatin, 689
Aspartame TM , 467, 570
Asperazine, 329
()-Aspicilin, 549
()-Astericanolide, 690
Asymmetric deprotonation, 522
Of tropinone, 522
With sparteine, 522
Asymmetric induction, 528, 533–534
Reagent based control, see chapter 24
Atpenin B, 783
Aza-enolates, 142–143, 145
See enolates
Azatyrosine, 193, 605
Aziridine, 696, 778
Reaction with azide, 844, 847
AZT (Azidothymidine), 851
Baeyer-Villiger rearrangement, 36
Of cyclohexanones, 35, 147, 471
Enzymatic, 487, 575
Regioselectivity, 593–594, 614
Reverse selectivity, 664
With engineered baker’s yeast, 664
()-Balanol, 533–534
Baker’s yeast, 652, 664
Reduction of ketones, 510
Mnemonic for ketone reduction, 530–531
Bakke nitration, 773
Katritzky’s improvement of, 773
BAY 43-9006, 772
Baylis-Hillman reaction, 166
Asymmetric, organic catalysis of, 161, 166
Beckmann rearrangement, 889
Tandem Beckmann rearrangement and allyl silane
cyclisation, 889
Benzyne, 866, 880
Formation using ortho-lithiation, 96–100
Bestatin, 480
Birch reduction, 622
Asymmetric, 622
Combined with iodolactonisation, 617, 682
Asymmetric of heterocycles, 751
Schultz’s asymmetric, 682
Synthesis of extended enolates, 161, 165
Blastmycin, 427
BMS 181100, 574

Bombykol, 232
Boranes, 256, 264, 299
See also hydroboration, 284
Asymmetric borane reduction of unsymmetric ketones, 507
Alpine-Borane®, 509
Ipc 2BCl (DIP-Chloride®) reduction with, 510
ketones, 507–510
β-keto-acids, 219
Reaction of chiral allylic boranes with imines, 513
Boronic acids, 756, 772
Synthesis from alkynes, 266
Vinyl boronic acids, synthesis, 330, 334
Boronic esters, 329
Vinyl boronic esters, synthesis, 330, 334
Bredereck reaction, 857
Brefeldin, 270
()-Brevicomin, 312, 667
Bromination, 333, 495
Of alkenes, 511–512
Of benzene, 622
Bromolactonisation, 293, 419
Brown’s crotyl borane, 739
()-Brunsvigine, 64
Buchwald-Hartwig coupling, 756
Buproprion, 778, 806
Bürgi-Dunitz angle, 695, 702
Cadinene, 66
(S)-Camptothecin, 763
Cannabispirenones, 777, 792
Captopril, 465, 476
Carboalumination, 267
Carbocupration, 268
Carbohydrates, 473
Synthesis of D-glyceraldehyde, 474
Carbo-metallation, 267
Carbonylation, 299
Of organo-zirconium reagents, 121
Of palladium σ-complexes, 122
Carboxylic Acids, 37, 63
Lithium enolate formation, 289
Reaction with vinyl-lithium reagents, 269
β-Carotene, 329
CBS reduction of ketones, 575
Synthesis of cetirizine, 576
Cecropia juvenile hormone, 279
Cedrene, 67
()-(R)-Cetrizine, 448
()-Chanoclavine, 595
Chelation control, 683, 696, 802
Of Grignard reagents, 13, 51, 113, 115–117
Of Zn(BH 4) 2 reduction, 427–428
Chiral auxiliaries, 466, 469, 613
See chapter 27, 763
See also specifi c auxiliary
Index 897
Asymmetric aldol with, 327–328
Conjugate (Michael) addition with, 613
Diels-Alder reaction with, 613–614
Chiral Pool, 676, 683
See chapter 23, 244, 514
New chiral pool, 588
amino-indanols, 491
C 2 symmetric diamines, 555
epichlorhydrin, 637
glycidol, 487
phenylglycine, 488–489
Tables of most common substrates, 497–501
Chloroenones, 261
Chloroquine, 446
Chrysanthemic acid, 460
trans-Chrysanthemic acid, 460
Cilastatin, 585
()-Cinatrin B, 358
(S)-()-Citronellol, 472, 571
Claisen ester condensation, 209, 224
Claisen(-Cope) Rearrangement, 224, 246
Aza-Claisen rearrangement, 823
Claisen-Ireland rearrangement, 355
Chirality transfer, 420, 432
Diastereoselectivity, 419–422
Palladium(II) catalysed, 283, 318
Regioselectivity, 320–322
Stereochemistry in, 354, 380
Claisen ester condensation, 209, 224
Conformational control, 410, 412
Concanamycin, 268
Conjugate addition, see chapter 9, plus 268–271
See Michael addition, 287, 309
Conjugate substitution, 310, 312
See Michael addition, 287, 309
Cope rearrangement, 352–353
Oxy-Cope rearrangement, 823
Aza-Cope, 823–825
anionic aza-Cope, 827
tandem aza-Cope and Mannich reactions,
824
Copper, 64, 119
Aryl-amine cross coupling, 124–125
Catalysed S NAr reaction, 484
Organo-copper reagents, 129, 137
Michael addition of, 148, 228
stereoselective, 228, 233
structure, 248
Organo-cuprates, 131, 316, 619, 708
acylation of, 237–238, 463
alkynyl cuprates, 269–270
lithium cuprates, 132, 147
Michael addition of, 148, 228
reaction with alkyl halides, 116
structure, 248

898 Index
Copper (Continued)
vinyl cuprates, 261, 270, 327, 486
Michael addition of, 148, 228
Cyanocuprates, 131
Michael addition of, 148, 228
Corey-Fuchs reaction, 322
Coriolin, 74, 284
CP-060S, 455
Crixivan (Indinavir), 491, 493
Crocacin C, 327
Crocacin D, 327
Cuprates, 314, 316, 327
See organo-copper reagents, 129
α-Curcumene, 18–19
Curtius rearrangement, 481, 586
Cyanohydrin, 655, 665
Enzymatic formation, 567, 670
Enzymatic reaction of, 632
Cycloadditions, 747, 809
See also Diels-Alder reaction and 1,3-dipolar
cycloaddition, 822, 885–886
22 Photochemical, 134
22 Ketene cycloadditions, asymmetric, 587
Synthesis of enalapril, 589
Cycloheptanones
Synthesis using oxyallyl cations, 71, 78
Cyclopentannelation, 195, 284
Cyclopentanones, 79, 664
Synthesis, 81
by oxidative rearrangement of tertiary allylic
alcohols, 83
by Pauson-Khand reaction, 71, 79
using chromium carbenes, 86
using oxyallyl cations, 71, 78–79
using ynoate(s), 85
Cyclopropanes, 192, 193, 240
See also Simmons-Smith reaction, 349, 351
Synthesis, 350
asymmetric, 355, 382
using Michael addition, 426, 577
using sulfoxonium ylids, 128
Danishefsky’s diene, 291–292, 561
DARVON, 454, 507
(S,S)-iso-ddA, 486
Decarboxylation, 140, 148, 250, 360
Dendrobine, 195
11-Deoxytetrodotoxin, 352
Deracemisation, 505, 517–518
Of arylpropionic acids, 654
Of α-halo acids, 515, 518
Desymmetrisation Reactions, 528, 558
Comparison with kinetic resolution, 560
Opening of anhydrides, 528
Of bis-allylic esters, 594
Opening epoxides, 399
Of immobilised enzymes, 675
Of a symmetrical Diels-Alder adduct, 677
Of a dihydropyridine, 677
Then kinetic resolution, 646
With lipases, 656
Mono esterifi cation of diols, 561
Diastereoselection of 1,3-diols, 424
Diazines, 761
Diazoketones, rearrangement to carboxylic acids,
844, 847
Diazotisation, 467
In the electrophilic substitution of benzene, 622
DIBAL, 666
Ester reduction, 653
Nitrile reduction, 23
1,3-Dicarbonyls, 785
Synthesis, 785
Alkylation of, 848
1,4-Dicarbonyls, 785
Synthesis by Stetter reaction, 220
1,5-Dicarbonyls, 785
Synthesis, 785
Diels-Alder reaction, 291, 315, 345
See also hetero-Diels-Alder reaction, 561–562
Asymmetric, 296
organic catalysis, 577
C 2-symmetric Lewis acid catalysis, 583
with box and pybox catalysts, 584
with Oppolzer’s chiral sultam, 615
with chiral auxiliaries attached to the diene, 617
Aza-Diels Alder reaction, 819, 884, 888
Tandem aza-Diels-Alder and allyl boronate reactions,
864, 884
Tandem Aza-Diels-Alder and aza-ene reactions, 864,
888
Danishefsky’s diene, 561–562, 617
Enantioselectivity in catalysed, 584
Endo-selectivity, 401–403, 425, 506
Hetero-Diels-Alder reaction, 345, 561
Asymmetric, 342, 355
auxiliary controlled, 614–618
copper bis-oxazoline catalysed, 584
chromium Salen catalysed, 562
Synthesis of ambruticin, 563, 564
Lewis acid catalysed, 169, 214
Of azadienes, 812
1-azadienes, 812
2-azadienes, 814
Of β-bromo alkynes, 315
Of β-sulfonyl alkynes, 315
Of imines, 687
Intramolecular, 686, 700, 739

with azadienes, 811–814
with imines, 812, 815
with a nitrogen tether, 819, 820
Stereoselectivity of, 224, 304, 851
Differential crystallisation (entrainment), 449
With racemisation, 451–453
Typical procedure, 449
4, 5-Dihydrostreptazolin, 244
Dihydroerythramine, 134
Dihydroxylation reaction, 282, 304
See also Sharpless asymmetric dihydroxylation reaction,
538
Of alkenes, 538, 542
Racemic dihydroxylation reaction, 737
()-cis-Diltiazem, 621
Synthesis using, 812
Sharpless asymmetric dihydroxylation reaction, 587
Jacobsen epoxidation, 663
Evans’ oxazolidinones, 621
1.2-Diols, 15
Conversion to epoxides, 38
1,3-Dipolar cycloaddition, 248, 658
Isoxazole synthesis, 841–843
Tetrazole synthesis, 847
Tandem reactions involving, 885
()-Discodermolide, 709
Large scale synthesis, 712, 742
()-Disparlure, 531–532
Dithians, 207
Acylation of, 237
Alkylation of, 247
Dithioacetal monoxides, 204, 209
Exchange, 209
Synthesis of, 257
Conversion to carbonyl compounds, 267
Dithioacetal monoxides, 204, 209
E1 reaction, 228
E1cB reaction, 228
E2 reaction, 232
Efavirenz, 515, 591
Electrocyclic reactions, 828
Electrophilic substitution, 807
Of benzene, 803
By oxygen on benzene, 778
Of pyridine, 812, 824
α-Eleostearic acid, 129
Enalapril, 478
Enamines, 19
See specifi c reactions also, 181
A 1,3 strain
Acylation of, 238, 621
Alkylation of, 30, 143, 159
Aldol reaction of, 158–159
Index 899
Extended, 158–159
Reaction with, 181
alkyl halides, 196–197
α-carbonyl halides, 142
α-halo carbonyls, 38
oxyallyl cations, 71, 78
Michael addition of, 136
Regioselective formation of, 142, 149
Robinson annulation of, 226
[3,3] Sigmatropic rearrangement of, 246
Synthesis of
1,4-dicarbonyls, 785
1,5-dicarbonyls, 785
Ene (Alder ene) reaction, 884
Oxo-ene reaction, 297, 299
Asymmetric, 304, 327
Asymmetric carbonyl ene, 590
Aza-ene reaction, 864, 884
Intramolecular, 890
with a nitrogen tether, 819, 820
with oximes, 822
Tandem ene reactions, 882
Enolates, 16–20
See also homo-and extended enolates, 158, 159
Acylation, 181
Alkylation of, 186
Aldol reaction of, see chapters 3–6, plus 695, 736
Aza-enolates, 143, 145
alkylation of, 186
alkylation of aldehydes, 145
alkylation and Michael, 146
extended, 155
metallated hydrazones, 139, 145
reaction with alkyl halide, 159, 162
reaction with epoxides, 180
Synthesis, 180
Alkylation of, 186
Alkylation of aldehydes, 145
Alkylation and Michael, 146
Capture by electrophiles, 863, 866
Chiral, 867–868
RAMP and SAMP, 469, 599, 601
Schöllkopf’s bislactim ethers, 603
Seebach’s relay chiral units, 606
from hydroxyl acids, 607
from Evans’ oxazolidinones, 609
William’s chiral glycine enolate equivalent, 605
cis-Boron enolate generation, 408–410
Conjugate substitution reaction of, 866–869
Electrophilic attack by oxygen, 602, 694
MoOPH hydroxylation of, 778, 800
N-Sulfonyl oxaziridine hydroxylation of, 802
Nitrosation with nitroso compounds, 786
Reaction of endocyclic enolates, 413

900 Index
Enolates (Continued)
Reaction of exocyclic enolates, equatorial vs axial
attack, 399
Reaction with epoxides, 38, 116
Of 1,3-Dicarbonyls, 785
“Naked” from silyl enol ethers, 146
Reaction with epoxides, 180
Regioselective formation of, 178, 260
trans-Boron enolate generation, 425
O-Acylation of, 425
Enols, 16, 29, 784
See also enolates and enolisation, 784
Specifi c enol equivalents, 17
Bromination of, 789
Selenium oxide oxidation of, 785–786
Nitrosation with nitrites, 786
Enol Ethers, 139, 796, 799
Synthesis from enols, 778
Asymmetric hydroboration of, 512
Enolisation, 189
Regioselectivity, 196
Under kinetic control, 606, 670
Under thermodynamic control, 668, 670
Under equilibrating conditions, 73, 75, 140
Enones, 163
Oxidation of, 281, 301
Synthesis, see chapter 5, also 286
by acid catalysed aldol reaction, 579
by acylation of vinyl metal reagents, 63
by aldol reaction, 71, 74
by base catalysed aldol reaction, 579
by bromination of enols, 789
by palladium(II) oxidation of silyl enol ethers, 777
using sulfur and selenium compounds, 790
E-Selective synthesis by Wittig style ‘aldol’ reaction,
208, 232, 236
Regioselective asymmetric hydrogenation of, 572
Enzymes, 636
Acylation of alcohols, 631
Desymmetrisation, 646, 627
with immobilised enzymes, 657
with lipases, 656
of a symmetrical Diels-Alder adduct, 677, 687
of a dihydropyridine, 812, 824
Effects of amines on lipases and esterases, 651, 659
Engineered aldolase, 669
Ester formation and hydrolysis, 651, 653
Kinetic resolution with, 655
as resolving agents, 456
by ester hydrolysis, 457
of secondary alcohols with lipases, 458
of α-acetoxysulfi des, 639
of amines, 659
of ibuprofen with esterases, 517, 654
of hemiacetals using lipase, 193, 794
with proteolytic enzymes, 459
with racemisation, 460
Nucleophilic addition to carbonyl groups, 665
Addition of cyanide to aldehydes, 665
Catalysed aldol reactions, 667
Acylating enzymes, 660
Oxidation with, 701, 739
asymmetric dihydroxylation of benzenes, 725, 742
Baeyer-Villiger rearrangement, 36, 794–795
Baeyer-Villiger rearrangement with engineered
baker’s yeast, 36, 118, 238
epoxidation, 224, 261
Polymer-supported reagents and enzymes, 658
Reduction of ketones using baker’s yeast, 652
Synthesis of, 658
prostaglandins, 661
syringolide, 667
Versus whole organisms, 656
(1R,2S)-()-Ephedrine, 470–471, 515
Epibatidine, 315, 749, 772, 779
Epichlorhydrin, 487–488, 499
As a chiral pool reagent, 465, 487
Nucleophilic attack on, 490, 505, 513
Reaction with α-naphthol, 530
Epothilone A, 669–670
Epoxidation, 670, 673
See also epoxides, Sharpless asymmetric and Jacobsen
epoxidations, 559, 663
Asymmetric epoxidation with chiral sulfur ylids, 516
With sulfur ylids, 128, 516
With sulfonium ylids, 333–334, 339
With mCPBA, 795–797
Epoxidation with VO(acac) 2/t-BuOOH, 281
Epoxidation with H 2O 2/base, 284, 289
Enzymatic, 436, 459
Epoxides, 467, 499
See also epoxidations, 350, 559
Chemoselective synthesis, 667, 741
Rearrangement to aldehydes, 62, 132
Reaction with
azide, 280, 309
enolates, 313–314
Grignard reagents, 591, 666
Me 3SiBr, 418
Regioselective reduction of, 277, 286
Regioselective synthesis, 30
Stereoselective synthesis, 48, 443
using allylic alcohols, 55, 63
Synthesis from
amino acids, 193
1,2-diols, 528, 538
trans-Di-axial product, 414, 416
Eschenmoser fragmentation, 793

Erythrina alkaloid, 134, 876
Esomeprazole, 524, 759
Ester, 18, 147
Lithium enolate formation, 146, 804
Alkylation of, 30, 143
Aldol reaction of, 225, 158–159
Reduction of, 223
Erythronolides, 292
Eucarvone, 128
Evans-Mislow rearrangement, 694
Evans’ oxazolidinones, 599, 609
Asymmetric alkylation with, 717
Asymmetric Michael addition with, 11, 13, 870
syn-Aldol reaction with boron enolates, 43, 47
anti-Aldol reaction by Lewis acid catalysis,
149, 160
Evans-Tishchenko reduction, 424
Extended enolates, see chapter 11
Alkylation, 154, 156
Generation of kinetic enols, 798
Ketones, 651, 652
Kinetic product, 155
Reaction at α-position, 157–158
Reaction at γ-position, 158–159
Synthesis using Birch reduction, 165
Thermodynamic generation, 155–157, 159
Thermodynamic product, 155
Felkin-Anh Selectivity, 237, 429–431, 666
Conformation, 681, 683
Control, 683
Fenarimol, 116
Fenfl uramine, 435, 451
Fentiazac, 840
Flexibilene, 5–7, 267
Fluconazole, 447
(S)-Fluoxetine (Prozac), 510
Flupirtine, 752
Flutriafol, 3, 447
Formylation, 564, 761
By ortho-lithiation, 763–764
Fosinopril, 476
()-FR900482, 696
FR-900848, 392
Friedel-Crafts reaction, 34, 38, 55
Acylation, 37
Alkylation, 34, 35
Aliphatic Friedel-Crafts reaction, 55, 64
intramolecular, 74
Regioselectivity, 77, 80
With heterocycles, 165
Fries rearrangement, 92
Anionic Fries rearrangement, 107
Regioselectivity, 107, 131
Index 901
()-Fumagillol, 64
Fusilade (Fluazifop butyl), 456
Geiparvirin, 19
Gibberellin, 257
()-Grandisol, 260–261, 723
Grignard reagents, 13, 51
Acylation of, 52
Alkylation of, 57
Allyl Grignard reagents, 173
Cerium-catalysed addition of, 313
Chelation-controlled addition, 247
Chiral Grignard reagents, 732
Desymmetrisation of a symmetrical anhydride using a
chiral Grignard, 732
Reaction with
aldehydes, 793, 815
CO 2, 827, 831
epoxides, 38
ketones, 43–44
nitriles, 117, 199
Reduction of aldehydes and ketones, 793
Structure, 200
Synthesis, 193
Vinyl Grignard, 256–257
addition to ketones, 258
synthesis, 260
Synthesis by exchange, 264
Gingerol, 32
Ginkgolide, 139, 148
Grandisol, 260–261
Half-chair, 247, 347
Halicholactone, 349
Halogen dance, 761
Halolactonisation, 289
See also bromo- and iodo-lactonisation, 290, 293
Hantszch pyridine synthesis, 439
Heck reaction, 317–323, 755, 762
Asymmetric, 763
Mechanism of, 317, 765
Intramolecular, 773, 797
Reaction of allylic alcohols, 346
Synthesis of
strychnine, 320
asperazine, 329
With heterocycles, 334, 587
Tandem asymmetric Heck and Palladium-allyl cation
reaction, 864, 890
Henry reaction, 225
Hetero-Diels-Alder reaction, 345
See Diels-Alder reaction, 393
Hexaconazole, 447
Hirsutene, 24–25

902 Index
Homoenolate, see chapter 13
Acetal derived, 193
Allyl carbamates, 201
Aryl coupling of, 193
Cyclopropyl, 194
Enantioselective generation, 193
From 3-membered rings, 467
Generation from 2-haloacids, 191
Generation from 2-chloroesters, 191
Heteroatom-substituted allyl anions, 189, 196
Michael addition of zinc homoenolates, 192–193
Of allyl amines, 198
Of allyl silanes, 197
Of allyl sulfi des, 197
Of carboxylic acid, addition to aldehydes and ketones,
190
Of sulfones, 186
acylation of, 183
synthesis of, 237
Reaction with ketones and aldehyde, 180
Reaction with electrophiles, 180
Synthesis of enantionmerically pure β-oxo-amino acids,
193
Zirconium, 192
Hoppe’s ‘defensive strategy’, 190
Houk conformation, 351, 400
Houk control, 697
Horeau principle, 391
Horner-Wadsworth-Emmons reaction, 62, 136, 233, 733
Still and Gennari modifi cation, 236
E-selective, 241
Z-selective, 342
β-Hydride elimination, 121–123
Hydantoin synthesis, 488
Hydroalumination, 263–265
Of alkynes, 263
Of propargyl alcohols, 265
Hydroboration, 263
Of alkenes, 263
Of alkynes, 263
Asymmetric hydroboration of alkenes, 512
Asymmetric hydroboration of enol ethers, 513
Carbonylation of alkyl boranes, 299
Ketone synthesis using cyanide, 301
Hydrogenation, 51, 122
Asymmetric hydrogenation of alkenes, 493
Asymmetric hydrogenation of carbonyl groups, 572
Catalytic asymmetric homogeneous hydrogenation,
568
With C 2 symmetrical phosphine Rh complexes, 572
With C 2 symmetrical BINAP Rh and Ru complexes, 572
With Raney nickel, 621
Reduction of 2-acylamino acrylates, 569
Regioselective asymmetric hydrogenation of enones, 572
Of alkynes, 80
Transfer hydrogenation, 320, 479, 640
Noyori’s synthesis of menthol, 574
Using Wilkinson’s catalyst, 568
Hydrometallation, 120
Of alkynes, 80
Hydrosilylation, 120
Intramolecular, 124, 128, 133
Metal catalysed, 120
Hydrostannylation, 262
Of terminal alkynes, 262
Hydroxylation, 781
Hydroxy acids
Synthesis of, 783
TADDOL, 469
propylene oxide, 470
streptazolin from tartaric acid, 475, 482
(2S,4R)-Hydroxypipecolic acid, 720
Hydrozirconation, 266
Of alkenes, 270
Imines, 601
Enamine tautomerism of, 848
Hydrogenation of, 478, 572
Tandem iminium ion formation and vinyl silane
cyclisation, 880
Imidazoles, 859
Nitration of, 858
Synthesis by Bredereck reaction, 857
Indicine, 543
Organo-indium reagents, 184
Allyl indiums, 184
synthesis of all-trans dienes, 184
Indolizomycin, 239
Iodo-etherifi cation, 674
Iodolactonisation, 682–683
Combined with Birch reduction, 165
Stereoselectivity, 168, 185
Ircinal A, 244
Iridomyrmecin, 287, 289
Isoxazoles, 841
Synthesis by 1,3 dipolar cycloaddition, 842
Itraconazole (Sporanox), 686
Jacobsen Epoxidation, 491, 528
Catalyst, 51
Synthesis, 51
of crixivan, 491
of ditiazem, 557
cis-Jasmone, 71–72, 211
Jones oxidation, 332
Julia reaction, 494–495, 241
Kocienski modifi cation, 241
Juvabione, 51

Kalihinene X
()-α-Kainic acid, 357
Kedarcidin, 755
Kendomycin, 135
Ketorolac, 460, 655, 656
Ketones, 11, 15, 18
Asymmetric borane reduction of unsymmetrical, 507
Asymmetric addition of carbon nucleophiles, 515
Baker’s yeast reduction of, 688
Corey’s CBS reduction of, 575
Ipc 2BCl (DIP-Chloride®) reduction of β-keto-acids,
510
Reduction of using;
Ipc 2BCl (DIP-Chloride®), 510
K-Selectride®, 721
REDAL, 731
Kinetic control, 28, 33
Of enolisation, 666
Kinetic resolution reactions, see chapter 28
See also enzymes, 635
Of diastereomeric mixtures, 384, 447
Double methods, 635
Dynamic kinetic resolutions, 636
reaction of epichlorhydrin, 637
of α-acetoxysulfi des, 639
of enzymes and metals together, 640
by hydrogenation, 640–641
Parallel kinetic resolution, 641
With racemisation, 655
Regiodivergent resoltuions, 644
S Values, 630
By Sharpless asymmetric epoxidation, 647
Synthesis of 2-methyl-tetrahydropyran-4-one, 730
With chiral DMAP, 631
Unwanted kinetic resolutions, 635
Knoevenagel reaction, 141, 857
()-Lactacystin, 718, 734
Lactonisation, 224, 289
See also halo- and sulfenyl-lactonisations, 292–293
Enantioselective lactonisation of achiral hydroxy
diacids, 521
LAF389, 495
Lamivudine, 638–639
()-Laurencin, 481
Lindlar’s catalyst, 248
Lipase, 358, 457–460
Kinetic resolution of hemiacetals, 193
Kinetic resolution of secondary alcohols, 458
Lipstatin, 22
Lipoic acid, 35
alpha-Lithiation, 108–110
Lateral lithiation, 111
Chemoselectivity, 111
Index 903
ortho-Lithiation, 91, 96
Anionic Fries rearrangement, 107, 112
Benzyne formation by, 110
Dilithiations, 106
Directing groups, 98, 99
containing oxygen, 98
containing nitrogen, 99
fl uorine, 103, 108
Multiple lithiations, 101
Multiple directed lithiations, 101
Of fl uoroanisoles, 103
Of pyridine, 750–751
Of quinolones, 484
Regioselectivity, 508, 513
Lithium, 17–19, 115
Organo-lithium reagents, 269, 514
acylation of, 628, 631
allyl lithium reagents, 175–176, 181
carbonylation of, 779, 857
conjugate substitution reaction of, 316
reaction with
alkyl halides, 115
carboxylic acids, 117
epoxides, 128
structure, 128
vinyl-lithium reagents, 269
synthesis, 270
Lithium amide addition, 17, 112, 522
Asymmetric, 522
Lithium-halogen exchange, 99
Longifolene, 15
Lotrafi ban, 676
Luche reaction, 260, 891
Lycorine, 683, 685
Lysergic acid, 828
()-Macbecin I, 699–700
Macrolactonisation, 150
Yamaguchi lactonisation, 670
Mannich reaction, 824, 828, 872, 875
Reverse Mannich reaction within chiral resolutions, 454
Tandem aza-Cope and Mannich reactions, 824
Tandem Michael and Mannich reactions, 869
Mannicone, 21
Mappicine, 762
Markovnikov addition, 283–284
Marimastat, 726
McMurry reaction, 242
Intramolecular, 242
Meldrum’s acid, 24, 141
Aldol reaction of, 161
()-Menthol, 499, 573
L-methyl DOPA, 450
Methyl shikimate, 418

904 Index
Mercuration, of alkenes, 283, 294, 440
Mercuration-reduction, 283
Metathesis, 243–244, 494
Asymmetric, 241
Cross, 247
Grubbs’ Catalysts, 243
Hoveyda-Grubbs catalyst, 494
Mechanism, 243
Molybdenum-catalysed, 800–801
Schrock’s molybdenum catalyst, 586
Ring closing, 829
tandem ring-closing and ring-opening, 864, 891
Methoxatin, 251
Methylation, 140, 249
Methylenation, 135
Methylenomycin, 81
O-Methyljoubertiamine, 204, 216
Metronidazole (Flagyl®), 849
Mevinolin, 788
MGS002836, 685
Michael (conjugate) addition, see chapter 9, also 39, 619
Asymmetric, 619
addition of lithium nucleophiles, 619
with chiral auxiliaries, 620
with chiral sulfoxides, 621
with Evans’ oxazolidinones, 600
with 8-phenylmenthyl esters, 619
induction by a chiral auxiliary, 868
Copper catalysed, 684
Conjugate substitution reaction, 316
Followed by reaction with electrophiles, 316,
319, 323
Fuctionalised Michael donors, 136
Intramolecular, 180
To alkynes, 261
Of alkynyl cuprates, 269–270
Of amino-nitriles, 199
Of anilines, 812
Of cuprates, 133
Of cyanocuprates, 131
Of 1,3-dicarbonyl compounds, 37, 141
Of organo-copper reagents, 129–131
Of enamines, 30, 35, 38
Of enolates, 35, 46
Of extended enolates, 159
Of heteroatom nucleophiles, 135
Of Grignard reagents, 178, 193
Of nitroalkanes, 204, 206, 218
Of nitroketones, 216
Of silyl cuprate, 217
Of silyl enol ethers, 777–778, 791, 796
Of sulfur ylids, 128, 516
Of sulfonium ylids, 128, 343
Of sulfoxonium ylids, 128
Of tetrazoles, 844
Organic catalysis of, 577, 582
Stereoselective, 563
copper catalysed, 562
Synthesis, 19
of 1,5-dicarbonyl compounds, 19, 34
of diketones, 38
Tandem, 863–864
Michael-Mannich reactions, 132
Michael-Michael additions, 869
stereochemical control in, 867
TiCl 4 catalysed, 48
Versus 1,2-addition, 39
Microscopic reversibility, 415
Milbemycin β3, 330, 332
‘MIMIRC’ sequence, 863, 871
Tuning with different Michael acceptors, 872
Mitsunobu reaction, 22, 208, 241
MK-0966, 84
Modhephene, 77
Monensin, 357, 419
Monomorine, 687, 688
MoOPH, 778, 800
Hydroxylation of enolates, 802, 804
Hydroxylation of steroids and amino acids, 801
Stereoselectivity, 801–802, 804
MSD 427, 845
Mukaiyama aldol reaction, 32
See also silyl enol ethers, 33
Multistriatin, 139, 143
Myxalamide A, 264
Nafuredin, 241
Nazarov reaction, 71, 77
Lewis acid catalysed, 169, 214
Regioselectivity, 245, 264
Effect of fl uorinated substituents, 595, 686
Effect of silyl substituents, 78
Negishi coupling, 755, 761, 764, 772
()-Neoplanocin, 136
Nickel,160
Catalysed butadiene dimerisation, 164
Organo-nickel reagents
allyl nickel complexes, 177
alkylation of, 186
cyclopentenone synthesis, 173, 178
synthesis of, 178
Nifl uminic acid, 749, 757
Nitration, 758, 764, 766
Of benzene, 759, 766
Of pyridine, 758
Nitroalkanes, 204, 218
Conversion to ketones, 208, 218
Synthesis of, 219
Mono-protected ketones, 219
Strigol, 204, 219

Nootkatone, 50
Norvir, 479
NOVRAD, 454, 507
N-Sulfonyl oxaziridines, 778, 802, 803
Asymmetric hydroxylation with camphor sultam
derivatives, 804
Hydroxylation of enolates, 804
Stereoselectivity, 778, 814
Nuciferal, 195, 144
Nucleophilic addition, 590
Asymmetric nucleophilic attack by chiral alcohols,
517
Asymmetric addition to carbonyls, 515
Enzymatic, to carbonyl groups, 521
Felkin-Anh model, 696
To cyclic ketones, 399, 410
Ofl oxacin, 484–485
Omeprazole, 524, 758
Organic catalysis, 577
Proline-catalysed aldol reaction, 579
Baylis-Hillman reaction, 581
Conjugate addition, 581
Diels-Alder reaction, 613–614
Robinson annelation, 790, 865
Reactions with hydroxy acetone, 579
Organo-copper reagents, 129, 137
See copper, 129
Organo-lithium reagents, 117
See lithium, 117
Organo-nickel reagents
See nickel
Organo-zinc reagents, 568, 591–592
See zinc, 592
Organo-zirconium reagents, 121
See zirconium, 121–122
Oxidation, 114, 118–119
Of aromatic compounds, 98
Asymmetric oxidation of sulfi des, 523
Of enolates, 39, 139, 802, 804, 806
Oxidation state, 114, 119
Oxidative insertion, 123, 177
Oxyallyl cations, 78–79
Synthesis of cycloheptanones, 886
Synthesis of cyclopentanones, 79
Oxy-mercuration, of alkynes, 283
oxypalladation, 360
Ozonolysis, 428, 697
Palladium, 6–7, 83, and see chapter 18
see Heck, Stille and Suzuki
Allylic substitution reaction, 340
asymmetric, 342
Aryl-amine cross coupling, 124–125
Carbonylation of σ-complexes, 97
Index 905
Catalysed, 124
cross coupling of vinyl aluminiums, 271
S NAr reaction, 484
tin hydride reduction, 322
Diene synthesis, 325
β-hydride elimination, 121–123
Lactone synthesis by carbonylation, 124
Oxidation of sily enol ethers, 725
Oxypalladation, 283, 360
Reaction with monoepoxides of dienes, 339, 363
β-Panasinene, 134
Papain, kinetic resolution with, 459
Pauson-Khand reaction, 71, 79
Asymmetric, 135
Intramolecular, 74–76
Regioselectivity, 77, 80
Rhodium(I) catalysed, 83
Payne rearrangement, 532
Pederin, 204, 213
Pentostatin, 855, 857, 859
Peptide coupling, 467, 477, 479–480
With DCC, 544, 739
With EDC, 480
()-Petasinecine, 691–692
(R)-()-Perilla alcohol, 348
Periodate diol cleavage, 614, 726
(1R,3R)-Permethrinic acid, 460–461
Peterson reaction, 726, 878
()-PF1163B, 704
8-Phenylmenthol, 684, 817
Asymmetric Michael additions with 8-phenylmethyl
esters, 619
2 2 Photochemical cycloaddition, 81
Phyllanthoside, 212
Pleraplysilin-1, 326
Pinacol rearrangement, 14–15
Chemoselectivity, 14
Lewis acid mediated, 15, 20
Selectivity of secondary versus tertiary alcohols, 14
Synthesis of longifolone, 15
Pipoxide, 350–351
PNU-142721, 753–754
()-podorhizon, 621
Prins Reaction, 295, 721, 876
Double Prins reaction, 298
Lewis acid catalysed, 217, 297, 169
Oxo-ene mechanism, 297
Stereoselectivity, 298
Tetrahydropyran syntheisis, 296
Propranolol, 487–488, 528, 530
Synthesis using
Sharpless asymmetric epoxidation, 647
Sharpless asymmetric dihydroxylation, 537
Prostacyclin (PGI 2), 365
Isocarbocyclin, 365

906 Index
Prostaglandins, 84
PGA 2, 84
Pseudo-asymmetric centres, 394
Pseudomeconin, 124
()-Pumiliotoxin B, 864, 878
Pumiliotoxin C, 402, 818
Pumiliotoxin 251D, 191
Pummerer oxidation, 314
Purinol, 839
Pyrazolate, 855
Pyrazole, 29, 315, 751
Synthesis from 1,3-dicarbonyls, 29, 37, 141
Synthesis of allopurinol, 839
Pyrenophorin, 204, 207–208, 211
Pyridazines, 853
Synthesis, 853
Pyridine, 12, 13, 85, 770–773
Bakke nitration of, 773
Katritzky’s improvement of, 773
Chlorination of, 786
Electrophilic substitution of, 750
direct electrophilic substitution, 752
Hydroxylation, by ortho-lithiation, 781
Iodination of, 754
N-oxides, 555
electrophilic substitution of, 750, 752, 807
tandem lithiation and nucleophilic substitution, 764
ortho-Lithiation of, 759
Nitration of, 751
Regioselectivity in electrophilic substitution of,
753
Sulfonation of, 768
Synthesis of imidazo[4,5-c]pyridines, 769
Vicarious nucleophilic substitution of, 769
Quercus lactones, 201
Radical cyclisation, 478, 683
RAMP, 469, 601
Raney nickel, 621
Reduction of alkenes, 670
Ramipril, 477
Reduction, 165, 248, 341, 342, 422, 507, 652
See also specifi c reagents and substrates, 713
Asymmetric
using aluminium hydrides, 507
using baker’s yeast, 652
using BINAL-H, 508
using boranes, 508–510
using DARVON-H, 507
of unsymmetrical ketones, 507, 652
anti-Selective, 533
of β-hydroxy ketones, 422
Evans’ reduction of hydroxy ketones, 422, 427
Of azide with PPh 3, 122, 235, 318–319
Of imines, 687
Borane, 299
Using DIBAL, 331, 589
Ester, 355
Evans 1,3-reduction, 670
Evans-Tishchenko reduction, 424
Using K-Selectride®, 721
Using L-Selectride®, 220, 411
Using LiAlH 4, 429, 488, 507
Using NaBH 4, 684, 688, 695
Of nitriles, 799
Using samarium(II) iodide, 82
syn-Selective, 120, 408
Of β-hydroxy ketones, 422, 424
Reductive amination, 402, 437
Reformatsky reaction, 427
Regiodivergent resolutions, 644
Remote induction, 704
1,4-Control by sigmatropic shifts, 707
1,4-syn Induction in the aldol reaction, 706
1,5-Induction in the aldol reaction, 708
Resolution, 435–446
Chiral chromatography, 446
Of a hydroxy-acid, 437
Of a hydroxy-amine, 438
Of an amino-acid, 438
Via covalent compounds, 439
Of diastereomers, 447
Synthesis of Jacobsen’s Mn(III) epoxidation catalyst,
444
With racemisation, 451
(R)-Reticuline, 545
Retinal, 160
Retinol, 173, 185
Ritter reaction, 492
Robinson annelation, 577
Organic catalysis of, 579
Roseophilin, 75
Rubrynolide, 9, 23
Rubottom oxidation, 777, 796
Ruthenium, 7, 243
Catalysed four component coupling, 864, 891
Catalysed hydrogenation, 572, 574
Catalysed metathesis, 243–245
Samarium(II) iodide, 82
See also Evans-Tishchenko reduction, 424
N-O bond cleavage, 837
Reductive removal of a sulfone, 321, 602
SAMP, 602, 623
Santalene, 177
Sceletium A-4, 872
Scopadulcin, 69

Seebach, 55, 56, 600
Relay chiral units, 606
Hydroxy ester alkylation, 602–603
Synthon nomenclature, 55–56
Selenenyl-lactonisation, 294
Selenium dioxide, 785
Enol oxidation, 785
Enone synthesis, 256, 621
Oxidation of enols, 784
Senepoxide, 164
Serricornine, 409–410
Sertraline, 443
Shapiro reaction, 255, 258–261
Sharpless asymmetric aminohydroxylation, 552
Sharpless asymmetric dihydroxylation, 537
Advanced dihydroxylation strategy, 551–552
Diastereoselectivity, 547, 551
Catalytic cycle, 540
Ligands for, 543
recommended ligands, 527
Methanesulfonamide, 542
Mnemonic device, 542
Regioselectivity, 547
Solvent dependence, 540
Synthesis of
aspicillin, 549
()-propranolol, 554
reticuline, 545
indicine, 543
Sharpless asymmetric epoxidation, 527, 647, 725, 730, 738
Catalyst structure, 529
Kinetic resolution using, 638
Ligands for, 543, 584
Mnemonic device, 530, 542
Propranolol synthesis, 530
Modifi cation after, 531
Synthesis of
()-propranolol, 530
()-disparlure, 532
Summary, 537
Shikimic acid, 350, 616
[1,5] Sigmatropic shift, 767
[1,5]H shift, 767
[1,5]NO 2 shift, 767–768
[2,3] Sigmatropic rearrangements, 247, 810
See also Wittig rearrangement
Of allylic phosphates, 192
Of allylic sulfoxides, 339, 343
In allylation of ketones, 345
Synthesis of allylic alcohol, 129
E-Alkene synthesis, 225, 227
[3,3] Sigmatropic rearrangement, 245, 823
See also Claisen and Cope rearrangements, 352
Of allylic sulfones, 186, 239
Index 907
Of chromate esters, 341
Stereochemical transmission, 691
Tandem [3,3] sigmatropic rearrangements, 823
Silanes, 178
See silicon, 178
Silicon, 183
See also silanes and siyl enol ethers, 182, 184
Cation stabilisation of, 182
Silanes, 182
allyl silanes, 182
alkylations, 284
asymmetric addition to adehydes, 515
asymmetric reaction with electrophiles, 30, 39
cobalt-stabilised cations, 182
deprotonation of, 521–522
electrophilic attack, 180, 256
heterocyclic synthesis, 181
Michael addition, 197
reaction with
acetals, 195
epoxides, 180
aldehydes, 180
S E2’ reaction of, 433
Synthesis
by Wittig reaction, 482
tandem Beckmann rearrangement and allyl silane
cyclisation, 889
Vinyl silanes, 197
‘ate’ complexes from, 274
conversion to carbonyl compounds, 197
reaction with electrophiles, 212
synthesis, 180
tandem iminium ion formation and vinyl silane
cyclisation, 880
E-vinyl silanes, 259
synthesis from alkynes, 261
Silyl enol ethers, 17, 20
O-Acylation of, 484
Aldehydes of, 16, 18–20
Aldol reaction of, 19–20
syn-selective, 47
anti-selective, 46
Addition to aldehydes, 19–20
Alkylation of, 16–17, 30
tertiary halides, 36
Conjugate addition of, 39
Diels-Alder reaction of, 52, 164
Lewis acid catalysed aldol reaction of, 169, 159
Mukaiyama aldol reaction, 32
Palladium(II) oxidation of, 283
Rubottom oxidation, 796
Thermodynamic formation of, 15, 16, 20
Synthesis under equilibrating conditions, 73, 75, 140
Simmons-Smith cyclopropanation reaction, 348

908 Index
Sonagashira coupling, 754, 860
Stannanes, 265, 327
See Tin and Stille coupling, 325
Stereochemical analysis, 385
Stereochemical descriptors, 381
Stereogenic centre, defi nition, 43
Stereoselectivity, defi nition, 43
Stereospecifi city, defi nition, 43
Sterpuric acid, 797
Stetter reaction, 204, 220
Stille coupling, 325
Double stille couplings, 328
Variations of, 604
Synthesis of β-carotene, 328
Synthesis of asperazine, 329
Strecker reaction, 199, 450
Asymmetric, 452
Streptazolin, 482
Strigol, 219
Strychnine, 320
Substitution reaction, 316, 778
S E2’ reaction, 433
S EAr reaction, see chapters 7, 32, 33
S NAr reaction, 484
S N1 reaction, 308–309, 376
S N2 reaction, 34, 38, 43
S N2’ reaction, 340
Sulfenyl-lactonisations, 294
SuperQuat, 618
Suzuki coupling, 329–335, 662, 669–670
Synthesis of milbemycin β3, 330–332
Synthesis of brevicomin, 332, 333
Swainsonine, 885
Swern oxidation, 63, 321, 473
Sydowic acid, 93
()-Syringolide, 668
Synthons, 56
a 1 , see chapters 3, 4, 5
a 3 , see chapter 9
d 1 , see chapter 14
d 2 , see chapter 10
d 3 , see chapter 11
Seebach nomenclature, 56
Tandem organic reactions, see chapter 36
Involving 1,3-dipolar cycloadditions, 248
Involving Heck reaction, 317
Involving Michael (conjugate) addition, 619
and aldol reaction, 667
of chiral amines and aldol reactions, 863
heterocycle synthesis, 887
‘MIMIRC’ sequence, 871
use of sulfur, 875
Involving pericyclic reactions, 880
[3,3] sigmatropic rearrangements, 34, 69
aza-Diels-Alder reaction, 819, 884, 888
Diels-Alder reaction, 24, 52, 157
aza-ene reaction, 885
ene reaction, 297, 882
Involving metallation, 887
Involving metathesis, 891
Iminium ion formation and vinyl silane cyclisation, 880
Polymerisation terminated by cyclisation, 870
Asymmetric synthesis of
pipecolic acids, 876
()-pumiliotoxin, 878
Synthesis of
tricyclic amine, 875
2-vinyl indoles, 886
Tautomerism, 848
In azoles, 848
Taxodione, 303
Terpenes, 472
Chiral auxiliary synthesis, 472
8-phenylmenthol synthesis, 619
Tetrazoles, 844
Michael addition of, 870
Synthesis by 1,3 dipolar cycloaddition, 842
Synthesis of zolterine, 844
Thermodynamic control
In formation of cyclic compounds, 686
Of double bond geometry, 227, 703
Of enolisation, 30, 785, 799
Thiazole, 840
Carbonylation of, 857
Synthesis, 840
Thienamycin, 520
Thyroxine, 476
Tin, 183
Organo-tin (stannane) reagents
vinyl stannanes, 265, 336
synthesis by Shapiro reaction, 259, 342
Z-vinyl stannanes, 265
synthesis from alkynes by hydroalumination,
271
trans-Di-axial ring opening, 414, 416
Transmetallation, 114, 323
1,2,4-triazoles, 848
Alkylation of, 848
U100766, 485–486
Umpolung, 56, 854
Vernolepin, 158, 291
Vertinolide, 168
Viagra TM (Sildenafi l), 779
()-Vincamine, 454

Vinyl alanes, 271
Vinyl anion equivalents, 255, 264 See chapter 16
Vinyl cation equivalents, 309–310 See chapter 18
Vinyl coupling, 313
Vinyl halides, 313
E-vinyl bromide, 332
from vinyl silane, 309
vinyl iodide, 260–261, 264
synthesis by Shapiro reaction, 258
E-vinyl iodides, 264, 318
synthesis from boronic acids, 330, 333
Vorbrüggen coupling, 850
Wacker oxidation, 283
Cyclopentannelation using, 284
Weinreb amides, 118
Reaction with organometallic reagents, 115, 195
Synthesis from esters, 196
Wittig reaction, 230
Alkene synthesis, 230
Diene synthesis, 232
E-selective enone synthesis, 232
Index 909
E-selective reaction of stabilised phosphonate ylids,
232–233
Horner-Wittig reaction, 236–237
Intramolecular reaction of phosphonium ylids, 579
‘MIMIRC’ sequence, 871
Schlosser modifi cation, 234–235
Unsaturated carboxylic acid synthesis, 76
Z-selective, of phosphonium salts, 157, 185, 196
Wittig rearrangement, 247
See also [2,3] Sigmatropic rearrangement, 247
Wittig Still rearrangement, 247
Yomogi alcohol, 344
Zimmermann-Traxler transition state, 45
Zinc, 568
Organo-zinc reagents, 568, 592
asymmetric addition to aldehydes, 592
Zirconium, 49
enolates, syn-selective aldol reaction, 49
Organo-zirconium reagents, 121
reaction with acid chlorides, 121, 181, 192
carbonylation of, 122