Advanced Organic Reactions Carmelo J. Rizzo

Advanced Organic Reactions
(Lecture notes)
Carmelo J. Rizzo
Associate Professor of Chemistry, Vanderbilt University
Nashville, Tennessee, USA
Source:
http://www.vanderbilt.edu/AnS/Chemistry/Rizzo/chem223/chem223.htm

SELECTIVITY
Science 1983, 219, 245
Chemoselectivity
preferential reactivity of one functional group (FG) over another
- Chemoselective reduction of C=C over C=O:
O
H 2,
Pd/C
- Chemoselective reduction of C=O over C=C:
O
NaBH 4
- Epoxidation:
Regioselectivity
- Hydration of C=C:
O
MCPBA
NaBH 4, CeCl 3
O
OH O
OH
only
+
SELECTIVITY 1
OH
O
OH
O
OH
(2 : 1)
OH
- Friedel-Crafts Reaction:
R
SiMe 3
VO(acac) 2 ,
tBuOOH
RCOCl,
AlCl 3
1) B 2H 6
2) H 2O 2, NaOH
1) Hg(OAc) 2, H 2O
2) NaBH 4
O
O
RCOCl,
AlCl3 R
R
O
R
R
+
OH
+
OH
OH
exclusively
O
R

- Diels-Alder Reaction:
R O
O H
O H
O
O
+
+
R O
+
R
major minor
O
R
R R
O
O
+
+
OAc
SPh
Change in mechanism:
O H
O
O
major
OAc
OAc O OAc
R
O H
PhSH, H +
O
PhSH, (PhCO 2) 2
SPh
O
+
Raney Ni, H 2
SELECTIVITY 2
Stereochemistry:
Relative stereochemistry: Stereochemical relationship between two or more stereogenic centers
within a molecule
HO
H H
cholesterol
syn: on the same side ( cis)
anti: on the opposite side (trans)
enantiomers
same relative stereochemistry
- differences in relative stereochemistry lead to diastereomers.
Diastereomers= stereoisomers which are not mirror images; usually have different physical
properties
R
R
SPh
SPh
H
H
O
minor
O
O H
OH
O
O
OAc

SELECTIVITY 3
Absolute Stereochemistry: Absolute stereochemical assignment of each stereocenter (R vs S)
Cahn-Ingold-Prelog Convention (sequence rules)
- differences in absolute stereochemistry (of all stereocenters within the molecule) leads to
enantiomers.
- Reactions can "create" stereocenters
MeMgBr
Ph
O
H
MeMgBr
O MeMgBr
Ph H
HO CH 3
Ph H
H 3C OH
Ph H
HO CH 3
Ph H
Diastereomeric transition states- not necessarily equal in energy
Diastereoselectivity
R
Ph CHO
Me Me
N
O Zn
H 3C
CH 3
Zn
HO CH 3
Ph H
O Ph
CH 3
H
CH 3MgBr
Cram Model (Cram's Rule): empirical
O
L
M
S
M
R
O
L
S
Nu
Ph
HO H
syn
CH 3
Me Me
N
O Zn
H 3C
+
CH3 CH3 Zn
HO CH 3
H Ph
Ph
Diastereomers
enantiomers
(racemic product)
O H
Ph
CH 3
H OH
anti
O
H 3C H
CH 3MgBr CH 3MgBr
H
Ph
favored

Felkin-Ahn Model
Chelation Control Mode
R
TBSO
O
S
M
OR
H
O
OBn
O
L
O M
R
S
favored
CH 3MgBr
favored
MgBr
S
Nu
M
O
R
OR
TBSO
M
Nu
H
HO
S
O
M R
CH 3MgBr
O
OBn
disfavored
L
SELECTIVITY 4
HO
Nu
R
M
S
OR
relative stereochemical control
Stereospecific
Stereochemictry of the product is related to the reactant in a mechanistically defined manner; no
other stereochemical outcome is mechanistically possible.
i.e.; SN2 reaction- inversion of configuration is required
Br 2
Br 2
H 3C
Br
H
Br
H
CH 3
Br
H
CH 3
Br
H
CH 3
meso
Br
H
enantiomers (racemic)
Stereoselective
When more than one stereochemical outcome is possible, but one is formed in excess (even if that
excess is 100:0).
O
N
S
O
O
α-pinene
LDA, CH 3I
H 2, Pd/C
O
N
O
CH 3
H
H
H
only isomer
O
+
+
+
O
CH 3
H
CH 3
H
Br
H
not observed
S S
(96 : 4)
Diasteromers
N
O
O
CH 3
H
Diastereoselective
Enantiospecific

OXIDATIONS 5
Oxidations
Carey & Sundberg: Chapter 12 problems: 1a,c,e,g,n,o,q; 2a,b,c,f,g,j,k; 5; 9 a,c,d,e,f,l,m,n; 13
Smith: Chapter 3 March: Chapter 19
I. Metal Based Reagents
1. Chromium Reagents
2. Manganese Rgts.
3. Silver
4. Ruthenium
5. other metals
II Non-Metal Based Reagents
1. Activated DMSO
2. Peroxides and Peracids
3. Oxygen/ ozone
4. others
III. Epoxidations
Metal Based Reagents
Chromium Reagents
- Cr(VI) based
- exact stucture depends on solvent and pH
- Mechanism: formation of chromate ester intermediate
Westheimer et al. Chem Rev. 1949, 45, 419 JACS 1951, 73, 65.
R 2CH-OH
HCrO 4 -
R
C
R
H
HO
O Cr
+ H 2O
Jones Reagent (H2CrO4, H2Cr2O7, K2Cr2O7)
J. Chem. Soc. 1946 39
Org. Syn. Col. Vol. V, 1973, 310.
- CrO3 + H2O → H2CrO4 (aqueous solution)
K2Cr2O7 + K2SO4
- Cr(VI) → Cr(III)
(black) (green)
H +
- 2°- alcohols are oxidized to ketones
R 2 CH-OH
O -
O -
Jones
reagent
acetone
- saturated 1° alcohols are oxidized to carboxylic acids.
RCH 2-OH
Jones
reagent
acetone
O
R H
hydration
R
R
HO OH
R H
R
R
O
O
Jones
reagent
acetone
+ HCrO 3 - + H +
O
R OH
- Acidic media!! Not a good method for H + sensitive groups and compounds

Me 3 Si
H 17C 8
O
O
SePh
O
OH
OH
Jones
acetone
1) Jones,
acetone
2) CH 2N 2
Me 3Si
H 17C 8
O
O
O
O
SePh
OXIDATIONS 6
CO 2 CH 3
JACS 1982, 104, 5558
JACS 1975, 97, 2870
Collins Oxidation (CrO3•2pyridine)
TL 1969, 3363
- CrO3 (anhydrous) + pyridine (anhydrous) → CrO3•2pyridine↓
- 1° and 2° alcohols are oxidized to aldehydes and ketones in non-aqueous solution (CH2Cl2)
without over-oxidation
- Collins reagent can be prepared and isolated or generated in situ. Isolation of the reagent
often leads to improved yields.
- Useful for the oxidation of H + sensitive cmpds.
- not particularly basic or acidic
- must use a large excess of the rgt.
ArO
O
O
OH
CrO 3•(C 5H 5N) 2
CH 2Cl 2
ArO
O
H
O
O
JACS 1969, 91, 44318.
CrO3 catalyzed (1-2 mol % oxidation with NaIO6 (2.5 equiv) as the reozidant in wet aceteonitrile.
oxidized primary alcohols to carboxylic acids.
Tetrahedron Lett. 1998, 39, 5323.
Pyridinium Chlorochromate (PCC, Corey-Suggs Oxidation)
TL 1975 2647
Synthesis 1982, 245 (review)
CrO3 + 6M HCl + pyridine → pyH + CrO3 Cl - ↓
- Reagent can be used in close to stoichiometric amounts w/ substrate
- PCC is slighly acidic but can be buffered w/ NaOAc
HO
O
O
OH
PCC, CH 2 Cl 2
PCC, CH 2 Cl 2
OHC
O
O
CHO
JACS 1977, 99, 3864.
TL, 1975, 2647

- Oxidative Rearrangements
Me OH
Me
Me
OH
PCC, CH 2 Cl 2
PCC, CH 2Cl 2
- Oxidation of Active Methylene Groups
PCC, CH 2Cl 2
Me
O O O
PCC, CH2Cl2 O O
- PCC/Pyrazole PCC/ 3,5-Dimethylpyrazole
JOC 1984, 49, 550.
- selective oxidation of allylic alcohols
HO
H H
OH
N NH
PCC, CH 2 Cl 2
3,5-dimethyl
pyrazole
O
O
N NH
Pyridinium Dichromate (PDC, Corey-Schmidt Oxidation)
TL 1979, 399
- Na2Cr2O7•2H2O + HCl + pyridine → (C5H5N)2CrO7 ↓
PDC
CHO CH2Cl2 DMF
OH
1° alcohol
O
PDC
-allylic alcohols are oxidized to α,β-unsaturated aldehydes
O
JOC 1977, 42, 682
JOC 1976, 41, 380
JOC 1984, 49, 1647
H H
OXIDATIONS 7
CO 2H
OH
(87%)

- Supported Reagents Comprehensive Organic Synthesis 1991, 7, 839.
PCC on alumina : Synthesis 1980, 223.
- improved yields due to simplified work-up.
PCC on polyvinylpyridine : JOC, 1978, 43, 2618.
CH2 CH
cross-link CrO3, HCl
N N
CH 2
CH
N
Cr(VI)O3 •HCl
R 2CH-OH
to remove Cr(III)
1) HCl wash
2) KOH wash
3) H2O wash
R 2C=O
OXIDATIONS 8
CrO3/Et2O/CH2Cl2/Celite
Synthesis 1979, 815.
- CrO3 in non-aqueous media does not oxidized alcohols
- CrO3 in 1:3 Et2O/CH2Cl2/celite will oxidized alcohols to ketone and aldehydes
HO
C 8H 17
H2CrO7 on Silica
- 10% CrO3 to SiO2
- 2-3g H2CrO3/SiO2 to mole of R-OH
- ether is the solvent of choice
CrO 3
Et 2O/CH 2Cl 2/celite
(69%)
Manganese Reagents
Potassium Permanganate KMnO4/18-Crown-6 (purple benzene)
JACS 1972 94, 4024.
O
O
O O
K +
O
O
O
MnO 4 -
C 8H 17
CH 2
CH
Synthesis 1979, 815
N
Cr(III)
partially
spent
reagent
- 1° alcohols and aldehydes are oxidized to carboxylic acids
- 1:1 dicyclohexyl-18-C-6 and KMnO4 in benzene at 25°C gives a clear purple solution as high
as 0.06M in KMnO4.
O
CHO
CHO
CO 2 H
JACS 1972, 94, 4024
Synthesis 1984, 43
CL 1979, 443

OXIDATIONS 9
Sodium Permanganate
TL 1981, 1655
- heterogeneous reaction in benzene
- 1° alcohols are oxidized to acids
- 2° alcohols are oxidized to ketones
- multiple bonds are not oxidized
Barium Permanganate (BaMnO4)
TL 1978, 839.
- Oxidation if 1° and 2° alcohols to aldehydes and ketones- No over oxidation
- Multiple bonds are not oxidized
- similar in reactivity to MnO2
Barium Manganate
BCSJ 1983, 56, 914
Manganese Dioxide
Review: Synthesis 1976, 65, 133
- Selective oxidation of α,β-unsatutrated (allylic, benzylic, acetylenic) alcohols.
- Activity of MnO2 depends on method of preparation and choice of solvent
- cis & trans allylic alcohols are oxidized at the same rate without isomerization of the double
bond.
HO
HO
OH
MnO 2, CHCl 3
(62%)
- oxidation of 1° allylic alcohols to α,β-unsaturated esters
OH
OH
MnO 2,
ROH, NaCN
MnO 2, Hexanes
MeOH, NaCN
Manganese (III) Acetate α-hydroxylation of enones
Synthesis 1990, 1119 TL 1984 25, 5839
O
O
Mn(OAc) 3, AcOH
CO 2R
HO
CO 2 Me
AcO
O
OH
J. Chem. Soc. 1953, 2189
JACS 1955, 77, 4145.
JACS1968, 90, 5616. 5618
Ruthenium Reagents
Ruthenium Tetroxide
- effective for the conversion of 1° alcohols to RCO2H and 2° alcohols to ketones
- oxidizes multiple bonds and 1,2-diols.

Ph OH
O
RuO 4, NaIO 4
CCl 4, H 2O, CH 3CN
Ph
O
CO 2H
OH
RuO4, NaIO4 Ph OH Ph CO2H CCl4, H2O, CH3CN H CH H
3
CH
96% ee
3 94%ee
HO
O
O
RuO 2, NaIO 4
CCl 4, H 2O
O
O
O
OXIDATIONS 10
JOC 1981, 46, 3936
TL 1970, 4003
Tetra-n-propylammonium Perruthenate (TPAP, nPr4N + RuO4 - )
Aldrichimica Acta 1990, 23, 13.
Synthesis 1994, 639
- mild oxidation of alcohols to ketones and aldehydes without over oxidation
MeO 2C
OH
OSiMe 2tBu
TPAP
O
N +
- O Me
MeO 2C
O
OSiMe 2tBu
TL 1989, 30, 433
(Ph3P)4RuO2Cl3 RuO2(bipy)Cl2
- oxidizes a wide range of 1°- and 2°-alcohols to aldehydes and ketones without oxidation of
multiple bonds.
H
OH
OH
H
CHO
CHO
Ba[Ru(OH)2O3]
-oxidizes only the most reactive alcohols (benzylic and allylic)
(Ph3P)3RuCl2 + Me3SiO-OSiMe3
- oxidation of benzylic and allylic alcohols TL 1983, 24, 2185.
JCS P1 1984, 681.
Silver Reagents
Ag2CO3 ( Fetizon Oxidation) also Ag2CO3/celite Synthesis 1979, 401
- oxidation of only the most reactive hydroxyl
O
O
O
OH
OH
OH
OH
Ag 2 CO 3
Ag 2CO 3, C 6H 6
O
O
O
O
OH
O
O
JACS 1981, 103, 1864.
mechanism: TL 1972, 4445.

- Oxidation of 2° alcohol over a 1° alcohol
OH
OH Ag 2CO 3, Celite
(80%) O
Silver Oxide (AgO2)
- mild oxidation of aldehyde to carboxylic acids
AgO
RCHO
2 , NaOH RCO2H Ph
CHO
Prevost Reaction Ag(PhCO2)2, I2
Other Metal Based Oxidations
Osmium Tetroxide OsO4
review: Chem. Rev. 1980, 80, 187.
-cis hydroxylation of olefins
old mechanism:
OsO 4, NMO
- use of R3N-O as a reoxidant
TL 1976, 1973.
O
O
Stereoselectivity:
OH
RO
R 2
AgO 2
OsO 4, NMO
H
OsO 4
R 3
R 4
Ag(PhCO 2) 2, I 2
AcOH
Ag(PhCO2) 2, I2 AcOH, H2O O O
Os
O O
osmate ester
intermediate
O
Ph
O
OsO 4, NMO
AcO
OH
OH
AcO
OH
RO
CO 2H
OAc
OH
R 2
OXIDATIONS 11
JCS,CC 1969, 1102
JACS 1982, 104, 5557
OH
OH
OH
cis stereochemistry
TL 1983, 24, 2943, 3947
HO H
H
HO
R3 R4

- new mechanism: reaction is accelerated in the presences of an 3° amine
O
O
Os
O
O
R 1
[3+2]
[2+2]
R 2
O
O
Os
O
R 1
O
O
O
Os O
O
O
R 2
R1 R2 R 3N
[O]
hydrolysis
- Oxidative cleavage of olefins to carboxylic acids.
JOC 1956, 21, 478.
- Oxidative cleavage of olefins to ketones & aldehydes.
O
O
OAc
OsO4, NMO
O
O
OAc
OH
OH
NaIO 4
CHO
CHO
Substrate directed hydroxylations: Chem. Rev. 1993, 93, 1307
-by hydroxyl groups
- by amides
HO
HO
TMSO
CH 3
CH 3
MeS
O
O
AcO
HN
OsO 4,
pyridine
OsO 4,
pyridine
OsO 4, Et 2O
O
OAc
HO
HO
HO
HO
HO
TMSO
OsO 4
HO
CH 3
O
OH
CH 3
O
O
O
+
3:1
OAc
OH +
MeS
OXIDATIONS 12
R 1
O
O
Os O
O
R 1
HO
NR 3
H 2O
R 2
OH
R 2
+
O
JACS 1984, 105, 6755.
(86 : 14)
AcO
HN
HO
HO
HO
O
OAc
HO
OH
OH
CH 3
O
OH
CH 3
OsO 2
OsO 4
O
OH
[O]
O
O
OH

- by sulfoxides
- by sulfoximines
Ph
O
S
MeN
- By nitro groups
••
O
S
HN O
OH
O
S
OMe
••
••
O
OsO4 S
1) OsO 4
2) Ac 2O
AcO
OAc
HN
OMe
O
S
O
OH
OXIDATIONS 13
OH
••
(2 : 1)
(20 : 1)
Ph
O
S OH
O
OsO4, R3NO MeN
OH Δ OH
OH
OH
H 3C
CH 3
Raney nickel
OH
OH
OH
PhO2S O2N N
N
NHR
1) OsO4 2) acetone, H
PhO2S O2N N
N N
O O
+
HO N
N
N
N
NHR
CH 3
- OsO4 bis-hydroxylation favors electon rich C=C.
- Ligand effect:
OH
X
OsO 4
HO N
O O
+
N
N
N
N
N
N
NHR
NHR
X X
OH OH
OH OH
X= OH 80 : 20 (directing effect ?)
= OMe 98 : 2
= OAc 99 : 1
= NHSO2R 60 : 40 (directing effect ?)
OsO 4
K 3Fe(CN) 6, K 2CO 3
MeSO 2NH 2, tBuOH/H 2O
+
X OH
OH OH
OH OH
OsO4 (no ligand) 4 : 1
Quinuclidine 9 : 1
DHQD-PHAL > 49 : 1

Sharpless Asymmetric Dihydroxylation (AD) Chem. Rev. 1994, 94, 2483.
- Ligand pair are really diastereomers!!
R 1
R 3
Mechanism of AD:
O
dihydroquinidine ester
"HO OH"
"HO OH"
dihydroquinine ester
R 2
Ar
Ar
H
H
First Cycle
(high enantioselectivity)
O
O
Os
O
L
R 3 N
HO
OH
N
H
OR'
OR'
N
O
O
H2O
O
Os
[O]
O
Os
O
L
HO
0.2-0.4% OsO 4
acetone, H2O, MNO
O
O
O
O
OH
MeO
Ar =
R'= p-chlorobenzoyl
L
R 1
N
OXIDATIONS 14
R 3 OH
OH
Second Cycle
(low enantioselectivity)
H2O, L
O
O
O
O
O
Os
O
R 2
O
Os
O
O
O
O
80-95 % yield
20-80 % ee
- K3Fe(CN)6 as a reoxidant gives higher ee's- eliminates second cycle
TL 1990, 31, 2999.
- Sulfonamide effect: addition of MeSO2NH2 enhances hydrolysis of Os(VI) glycolate
(accelerates reaction)
- New phthalazine (PHAL) ligand's give higher ee's
MeO
H
N
N
O
Et
N
N
Et
O
(DHQD) 2-PHAL
N
N
H
OMe
JOC 1992, 57, 2768.
MeO
Et
H
N
N
O
N N
(DHQ) 2-PHAL
O
N
N
H
[O]
Et
OMe

O
O
N
- Other second generation ligands
MeO
H
N
N
Et
Ph
N N
Et
O O
Ph
PYR
Proposed catalyst structure:
O
Os
N
O
H
O
H
OMe
N N
MeO
Corey Model: JACS 1996, 118, 319
Enzyme like binding pocket;
[3+2] addition of OsO 4 to olefin.
R L
O
H
DHQL
N
N
R s RM
DHQ
H
N
H
N
OMe
OMe
N
Os
O
N
O
Et
IND
O
OXIDATIONS 15
N
Asymmetric
Binding
Cleft
O
O
Os
O
N
O
N
N O
N N
O O
N
Phthalazine
Floor
OMe
H
H
N
OMe
RL large and flat,
i.e Aromatics work particularly well
N
"Bystander
quinoline
(side wall)

R 1
R 1
R 1
R 1
R 1
R 1
Olefin Preferred Ligand
R 2
R 2
R 2
H
R 4
R 2
R 2
R 3
R 3
PYR, PHAL
PHAL
IND
PHAL
PHAL
PHAL, PYR
+ MeSO 2NH 2
ee's
30 - 97 %
70 - 97 %
20 - 80 %
90 - 99.8 %
90 - 99 %
20 - 97 %
OXIDATIONS 16
"AD-mixes" commercially available pre-mix solutions of Os, ligand and reoxidant
AD-mix α (DHQ)2PHAL, K3Fe(CN)6, K2CO3, K2OsO4 (0.4 MOL % Os to C=C)
AD-mix β (DHQD)2PHAL, K3Fe(CN)6, K2CO3, K2OsO4
OMe
N O
AD
(DHQD) 2PYR
94 % ee
N
HO
N
OMe
O
O
O
N O
OH
OH
Campthothecin
OMe
N O
- Kinetic resolution (not as good as Sharpless asymmetric epoxidation)
Ph
tBu
tBu
H
AD mix α
30% conversion
tBu
H
Ph
OH
tBu
H
OH
Ph
H tBu
Ph
H
OH
+ +
(4 : 1)
Ph
H
olefins with axial
dissymmetry
OH
O
OH
Ph
tBu
enriched

OXIDATIONS 17
Asymmetric Aminohydroxylation TL 1998, 39, 2507; ACIEE 1996, 25, 2818, 2813,
preparation of α-aminoalcohols from olefin. Syn addition as with the dihydroxylation
regiochemistry can be a problem
Ph
CO 2Me
O
Ph O N Cl
Na
K 2OsO 6H 4 (cat)
Ligand
Ph
O
O
Ph
NH
OH
CO 2Me
Ligand= PHAL 4:1
AQN 1:4
Molybdenum Reagents
MoOPH [MoO5•pyridine (HMPA)]
JOC 1978, 43, 188.
- α-hydroxylation of ketone, ester and lactone enolates.
R
O -
R'
+
O
O O
Mo
O O
L L
THF, -78°C
Palladium Reagents
Pd(0) catalyzed Dehydrogenation (oxidation) of Allyl Carbonates (Tsuji Oxidation)
Tetrahedron 1986, 42, 4361
R
H
R
OH
HO
H
O CO
2
Pd(OAc) 2,
CH 3CN, 80° C
H
O
OH
OH
R
H
R
O
O
O
O CO
2
Pd 2(DBA) 3•CHCl 3,
CH 3CN, 80° C
R
+
O
Ph
OH
R'
OH
N
CO 2Me
Pd(0)
- CO2 TL 1984, 25, 2791
R
H
R
O Pd
-
R
R
O
Tetrahedron 1987, 43, 3903
HO
H
H
O
OH
O
O
O
JACS 1989, 111, 8039.
Oxidation of silylenol ethers and enol carbonates to enones
O OTMS Pd(OAc) 2,
CH3CN O
Ph
O
O
OTIPS
O Pd(OAc) 2 ,
O
CH3CN (NH 4) 2Ce(NO 3) 6
DMF, 0°C
Ph
O
TL 1995, 36, 3985
Ph

Oppenauer Oxidation Synthesis 1994, 1007 Organic reactions 1951, 6, 207
OiPr
O Al
O
+ Al
OiPr
OiPr
R1R2CHOH H +
(CH3) 2C=O
R O
1 OiPr
R2 Nickel Peroxide
Chem Rev. 1975, 75, 491
Thallium Nitrate (TNN, Tl(NO3)3•3H2O
R 1
O
R 2
OXIDATIONS 18
+ Al(OiPr) 3
Pure Appl. Chem. 1875, 43, 463.
Lead Tetraacetrate Pb(OAc)4 Oxidations in Organic Chemistry (D), 1982, pp 1-145.
Non-Metal Based Reagents
Activated DMSO Review: Synthesis 1981, 165; 1990, 857. Organic Reactions 1990, 39, 297
S
Me
+
Me
S
Me
+
O- + E
Me
E
O
Nu:
S +
Me
Nu + E-O
E= (CF3CO)2O, SOCl2, (COCl)2, Cl2, (CH3CO)2O, TsCl, MeCl, SO3/pyridine, F3CSO2H,
PO5, H3PO4, Br2
Nu:= R-OH, Ph-OH, R-NH2, RC=NOH, enols
Swern Oxidation
- trifluoroacetic anhydride can be used as the activating agent for DMSO
S
Me
+
Me
O -
R 2CH-OH
O
S
Me
+
Me
(COCl) 2
CH 2Cl 2, -78°C
OH
O
H
R R
S
Me
+
Me
B:
O
Et 3N:
DMSO, (COCl) 2
CH 2Cl 2, Et 3N
Moffatt Oxidation (DMSO/DCC) JACS 1965, 87, 5661, 5670.
S +
Me
O- Me
C 6 H 11 N C N C 6 H 11
O
+
CF 3 CO 2 H,
Pyridine
OH
CO 2 Me
S +
Me
Me
SO3/Pyridine JACS 1967, 89, 5505.
CO 2 Me
HO H
H
OH
OH
S
CONH 2
NH
O C
N
DCC/ DMSO
CF 3 CO 2 H,
Pyridine
C 6 H 11
C 6 H 11
O
O
Cl
Cl
R 2 CH-OH
O
CO2Me HO H
SO3, pyridine,
DMSO, CH2Cl2 H
HO
O
Cl -
O
R
R
S
Me
+
Me
CHO
O
-CO, -CO 2
O
O
H
CO 2 Me
S
CONH 2
+
R R
Me
S +
Me
Me
Me
S
Me
Cl
TL 1988, 29, 49.
B:
R
R
JACS 1978, 100, 5565
JACS 1989, 111, 8039.
O

Corey-Kim Oxidation (DMS/NCS) JACS 1972, 94, 7586.
Me
S:
Me
+
O
N
Cl
O
N-Chlorosuccinimide
(NCS)
S +
Me
Oxygen & Ozone
Singlet Oxygen Acc. Chem. Res. 1980, 13, 419 Tetrahedron 1981, 37, 1825
O
H
• •
• O
• •
• •
O •
• •
hν
O O
triplet singlet
"ene" reaction
O O O
H
1) O 2 , hν, Ph 2 CO
2) reduction
Ozone Comprehensive Organic Synthesis 1991, 7, 541
O 3, CH 2Cl 2
-78°C
O
O O
Other Oxidations
Mukaiyama Oxidation BCSJ 1977, 50, 2773
MeO
Cl
CH 3
NH
R
CH
R
OH
MeO
OH
O
PrMgBr
THF
O
SEt
SEt
OEt
R
CH
R
O
N
O
O O
O MgBr
O
N N
• •
• •
• •
• •
Ph 3P:
Me
Tetrahedron 1981, 1825
Jones
RCOOH
O
tBuMgBr, THF
(70%)
HO
Ph 3P:
NaBH 4
O
N N
N N
O
N O
MeO
Cl
H
OXIDATIONS 19
Cl
OH
R
R
OH
O + O
O
OHC
CH3 O
NH
MeO
JACS 1979, 101, 7104
SEt
O
SEt
OEt

O
OH
tBuMgBr, THF
O
N
N
N
N
O O
Dess-Martin Periodinane JOC 1983, 48, 4155. JACS 1992, 113, 7277.
- oxidation conducted in CHCl3, CH3CN or CH2Cl2
- excellent reagent for hindered alcohols
- very mild
RO
AcO OAc
HO
I
OAc
O
O
• •
R 2CH-OH
Dess-Martin
(99%)
Chlorite Ion
-oxidation of α,β-unsaturated aldehydes to α,β−unsaturated acids.
Tetrahedron 1981, 37, 2091
CHO
OBn
NaClO 2,
NaH 2PO 4
tBuOH, H 2O
R
R
- O-Cl-O
Selenium Dioxide
- Similar to singlet oxygen (allylic oxidation)
Phenyl Selenium Chloride
OLi
PhSeCl
THF
OAc
O
SePh
RO
1) SeO 2
2) NaBH 4
H 2O 2
O
OBn
OH
H
+
O
- HClO 2
O
OH
H
Se
OAc
I
O
O
OXIDATIONS 20
O
+ 2 AcOH
JOC 1991, 56, 6264
O -
OAc
OBn
CO 2H
Ph O
- PhSeOH
- PhS-SPh will do similar chemistry however a sulfoxide elimination is less facile than a
selenoxide elinimation.
Peroxides & Peracids
- R3N: → R3N-O
- sulfides → sulfoxides → sulfones
-Baeyer-Villiger Oxidation- oxidation of ketones to esters and lactones via oxygen insertion
Organic Reactions 1993, 43, 251 Comprehensive Organic Synthesis 1991, vol 7, 671.

O
m-Chloroperbenzoic Acid, Peracetic Acid, Hydrogen peroxide
R 1
O
HO
R 2
O
O
Ar
Cl
O
H
O O
R 1
O
O
C
H
O
O
Ar
R 2
O 2N
NO 2
O H
O O
R 1
O
O
R 2
OXIDATIONS 21
+ ArCO 2H
- Concerted R-migration and O-O bond breaking. No loss of stereochemistry
- Migratory aptitude roughly follows the ability of the group to stabilize positive charge:
3° > 2° > benzyl = phenyl > 1° >> methyl
JACS 1971, 93, 1491
O
O
mCPBA O
O
O
CH 3
CH 3
O O HO
mCPBA
(80 %)
HO
O
O
CH 3
CO 2H
Oxone (postassium peroxymonosulfate) Tetrahedron 1997, 54, 401
RCHO
oxone
acetone (aq)
RCOOH
CH 3
CHO
Oxaziridines
reviews: Tetrahedron 1989, 45, 5703; Chem. Rev. 1992, 92, 919
R
- hydroxylation of enolates
O
R'
Base
R
O _
R
R'
PhSO 2
+
O _
R'
O
N
Ph
PhSO 2N=CHPh
O
R 3
N C
R R2 R
O
O
Ph
R'
_
NSO2Ph R
Ph
O
HO
Tetrahedron Lett. 1977, 2173
Tetrahedron Lett. 1978, 1385
O
R'
NHSO 2Ph
R
HO
O
R'
+
OH
By-product
supresed by using
bulkier oxaziradine
such as camphor
oxaziradine
PGE 1
CO 2H
PhSO 2N=CHPh

Asymmetric hydroxylations
MeO
MeO
O
MeO 2C
CO 2Me
O
OMe
KN(SiMe 3) 2
SO 2
N
O
NaN(SiMe 3) 2, THF
Ar
N
SO2O MeO
MeO
O
MeO 2C
OH
CO2Me (>95% ee)
HO
O
(67% ee)
OMe
- hydroxylation of organometallics
R-Li or R-Mg → R-OH JACS 1979, 101, 1044
- Asymmetric oxidation of sulfides to chiral sulfoxides.
JACS 1987, 109, 3370.
Synlett, 1990, 643.
OXIDATIONS 22
Tetrahedron 1991, 47, 173
MeO O
O OH
Remote Oxidation (functionalization) Comprehensive Organic Synthesis 1991, 7, 39.
Barton Reaction
•NO
OH
NOCl, CH 2Cl 2
pyridine
NO
OH
O NO
ketone
oxidation state
hν
- NO
•
N
HO
OH
O
•
H
N
C 5H 11
OH OH
•
OH
O
OH
perhydrohistricotoxin
OH
JACS 1975, 97, 430
Epoxidations
Peroxides & Peracids
- olefins → epoxides Tetrahedron 1976, 32, 2855
- α,β-unsaturated ketones, aldehydes and ester → α,β-epoxy- ketones, aldehydes and esters
(under basic conditions).
(CH 2) n
O
tBuOOH
triton B, C 6H 6
(CH 2) n
O
O
JACS 1958, 80, 3845

O
O
H
CO 2Me
mCPBA, NaHPO 3
Henbest Epoxidation- epoxidation directed by a polar group
Ph
O
OH
OAc
NH
O
H
H
O
H
mCPBA
mCPBA
mCPBA
Ar
O
O
Ph
O
OH
OAc
O
O
O
O
NH
H
+
O
CO 2Me
OH
OXIDATIONS 23
TL 1988, 23, 2793
O
10:1 diastereoselection
OH
+
O
1:4 diastereoselection
O
proposed transition state:
-OH directs the epoxidation
"highly selective"
- for acyclic systems, the Henbest epoxidation is often less selective
Rubottom Oxidation: JOC 1978, 43, 1588
O
LDA, TMSCl
OTMS
mCPBA
TMSO O
Sharpless Epoxidation tBuOOH w/ VO(acac)2, Mo(CO)6 or Ti(OR)4
Reviews: Comprehensive Organic Synthesis 1991, vol 7, 389-438
Asymmetric Synthesis 1985, vol. 15, 247-308
Synthesis, 1986, 89. Org. React. 1996, 48, 1-299.
Aldrichimica Acta 1979, 12, 63
review on transition mediated epoxidations: Chem. Rev. 1989, 89, 431.
- Regioselective epoxidation of allylic and homo-allylic alcohols
- will not epoxidize isolated double bonds
- epoxidation occurs stereoselectively w/ respect to the alcohol.
H 2O
O
OH

- Catalysts: VO(acac)2; Mo(CO)6; Ti(OiPr)4
- Oxidant: tBuOOH; PhC(CH3)2OOH
Acyclic Systems:
(CH 2) n
OH
OH
VO(acac) 2
tBuOOH
(CH 2) n
OH
O
O
OXIDATIONS 24
ring size VO(acac)2 MoO2(acac)2 mCPBA
5 >99% -- 84
6 >99 98 95
7 >99 95 61
8 97 42

OH
SiMe 3
OH
VO(acac) 2,
tBuOOH
VO(acac) 2,
tBuOOH
O
L
M
L
H3C O
H
CH 3
OH
tBu
O
O
SiMe 3
O
OH
H
H
+ O
(19 : 1)
H 3C
H 3C
L
H
O
M
OXIDATIONS 25
OH
+ O
(> 99 : 1)
- Careful conformational analysis of acyclic systems is needed.
Homoallylic Systems
Titanium Catalyst structure:
RO
O
Ti
O
OR
OR
CO2R O
O
OH OH
CO 2R
O
Ti
O
Disfavored
tBu
O
RO
O
O
CO 2R
Ti
O
OR
O
OR
CO2R O
O
RO 2C
OR
Ti
O
RO
O
O
H
H
O
L
O
tBu
SiMe 3
L
O
V
L
O
OH
OtBu
dominent stereocontrol element
OR
OR
Ti
O
OR
OR
CO2R O
O
Favored
CO 2R
O
Ti O
CO
O 2R
O
tBu

Asymmetric Epoxidation
tBuOOH, Ti(OiPr), (+) or (-) Diethyl Tartrate, 3Å molecular sieves
Empirical Rule
R 1
R 2
R 3 OH
(+)- DET epoxidation from the bottom
(-)- DET epoxidation from the top
OXIDATIONS 26
Catalytic system: addition of molecular sieves to "soak" up any water with 3A sieves, 5-10 mol %
catalyst is used.
Preparation of Allylic Alcohols:
R CHO
R
R
CO 2R'
CO 2R'
[(CH 3) 2CHCH 2] 2AlH
(DIBAL)
[(CH 3) 2CHCH 2] 2AlH
R OH
"In situ" derivatization of water soluble epoxy-alcohol
O
OH
OH
(-)-DIPT
(+)-DIPT
O
R
O
OH
O
O
OH
(R)-glycidol
OH
(S)-glycidol
O
Alkoxide opening of epoxy-alcohol product
reduced by use of Ti(OtBu)4 and catalytic conditions
Stoicheometric vs Catalytic epoxidation:
R
O
OH
O -
S
O
from
Ti(OiPr) 4
O
R
Na (MeOCH 2CH 2O) 2AlH 2
NO 2
(REDAL)
H 2, Lindlar's Catalyst
OH
OH
OH
(+)-DET
Ti(OiPr) 4
tBuOOH
O
OH
water soluble
organic soluble
stoicheometric: 85% ee
catalytic (6-7 mol %) 47% yield >95% ee
in situ deriv. with PNB 78% yield 92 % ee >98 %ee after 1 recrystallization
(+)-DET
R Ti(OiPr) 4 R
tBuOOH
O
OH OH
yields: 50 - 100 %
ee: > 95%
R C C CH 2OH

Ring Opening of Epoxy-Alcohols
Two dimensional amplification
AE
O
R OH R OH
OH
OH
(+)-DIPT, Ti(OiPr) 4,
tBuOOH, 3A sieves
(90 % ee)
Kinetic Resolution of Allylic Alcohols
R
OH
O
O
OH
OH
OH
+
REDAL
DIBAL
OXIDATIONS 27
OH
O
OH
95 : 5
O
OH
major minor
major minor
major
90 %
(>99.5 % ee)
(+)-DIPT, Ti(OiPr) 4,
tBuOOH, 3A sieves
RO
O
Ti
O
OR
OR
95 : 5
CO2R O
O
R
CO 2R
O
OH
O
OH
R OH
1,3-Diol
R OH
OH
1,2-Diol
OH
minor
95 : 5
O
OH
O
OH
meso
9.75%
+
Ti O
CO
O 2R
O
tBu
H
O
R
O
0.25 %
OH
OH

R 3
R 2
R 4
R 1
OH
kinetic resolution
-20 °C, 0.5 - 6 days
Reiterative Approach to the Synthesis of Carbohydrate
OR
OR
OR
O
CHO
O
OH
O
SPh
(MeO) 2 P(O)CH 2 CO 2 Me
OAc
NaH
HO -
PhS -
DIBAL
OR
PhS -
OH
O
OR
O
OR
CO 2Me
R 3
R 2
DIBAL
OR
HO
R 4
R 1
OH
40 - 50 % yield
> 99 % ee
OH
SPh
OR
+
acetone, H +
Jacobsen Aysmmetric Epoxidation
JACS 1990, 112, 2801; JACS 1991, 113, 7063; JOC 1991, 56, 2296.
- Reaction works best for cis C=C conjugated to an aromatic ring
H
N
N
O Cl O
H
tBu tBu
O
Mn
O
CHO
NaOCl
5 mol % Cat. ,NaOCl,
H 2O, CH 2Cl 2
86% ee
Methyltrioxoruthenium (MTO) Ru(VII)
Sharpless et al. JACS 1997, 117, 7863, 11536.
Ph
OR
O
0.5 mol % MTO Ru (VII),
pyridine, CH 2 Cl 2
1.5 eq. 30% H 2O 2 (aq.)
O
O
O
O
CHO
OH
H
N
R 3
R 2
OXIDATIONS 28
R 4
O
R 1
OH
40 - 50 % yield
high ee
OR
O
(+)-DET, Ti(OiPr) 4,
tBuOOH, 3A sieves
N
O O
O
H
O
tBu tBu
O
O
Mn
Ph
O
SPh
(98% ee)
HO
HO
mCPBA, Ac 2O
Pummerer
CHO
H
H
HO H
HO H
CH 2OH
L-glucose

Oxaziridines
- Asymmetric epoxidation of olefins Tetrahedron 1989 45 5703
Ph
Ph
CH 3
*
N
O 2
S
N
*
O
*
C 6F 5
OXIDATIONS 29
Dioxiranes (Murray's Reagent) Reviews: Chem. Rev. 1989, 89, 1187; ACR 1989, 27, 205
Org. Syn. 1996, 74, 91
- epoxidation of olefins
TBSO
TBSO
O
OTBS
O
O
O
CH 2Cl 2, acetone
(100%)
KHSO 5
"oxone"
TBSO
TBSO
- Asymmetric epoxidation JACS 1996, 118, 491.
- oxidation of sulfides to sulfoxides and sulfones
- oxidation of amines to amine-N-oxides
- oxidation of aldehydes to carboxylic acids
- hydroxylation of enolates
O
1) LDA
2) Cp 2TiCl 2
- bis-trifluoromethyldioxirane, much more reactive
JACS 1991, 113, 2205.
3)
O
O
F 3C O
F 3C
O
O
OH
H
O
O
O
OTBS
O
JOC 1990, 55, 2411
JOC 1994, 59, 2358
- oxidation of alcohols to carbonyl compounds. 1° alcohols give a mixture of aldehydes and
carboxylic acids.
- Insertion into 3° C-H bonds to give R3C-OH
DCC-H2O2 JOC 1998, 63, 2564
R N C N R H2O2 , MeOH
H
R
N
C O
N O
R
H R
R
O
+
H
O
C H
N N
R R

Carey & Sundberg Chapter 5 problems: 1a,b,c,d,f,h,j; 2; 3a-g, n,o; 4b,j,k,l; 9; 11;
Smith: Chapter 4 March: Chapter 19
Reductions
1. Hydrogenation
2. Boron Reagents
3. Aluminium Reagents
4. Tin Hydrides
5. Silanes
6. Dissolving Metal Reductions
Hydrogenations
Heterogeneous Catalytic Hydrogenation
Transition metals absorbed onto a solid support
metal: Pd, Pt, Ni, Rh
support: Carbon, alumina, silica
solvent: EtOH, EtOAc, Et2O, hexanes, etc.
REDUCTIONS 30
- Reduction of olefins & acetylenes to saturated hydrocarbons.
- Sensitive to steric effects and choice of solvent
- Polar functional groups, i.e. hydroxyls, can sometimes direct the delivery of H2.
- Cis addition of H2.
- Catalyst can be "poisoned"
- Directed heterogeneous hydrogenation
MeO
MeO
R 1
R 2
R 1
R 2
O
O
OH
O
O
CO 2Me
H 2 , Pd/C
H 2, Pd/C
H 2, Pd/C
H
R1 R2 MeO
MeO
H
R1 R2 H
H
O
O
OH
O
O
CO2M2 (86 : 14)
Lindlar Catalyst ( Pd/ BaSO4/ quinoline)- partially poisoned to reduce activity; will only
reduce the most reactive functional groups.
acetylenes + H2, Pd/BaSO4/ quinoline → cis olefins (Lindlar Reduction)
Acid Chlorides + H2, Pd/BaSO4 → Aldehydes (Rosemund Reduction)
Org. Rxn. 1948, 4, 362
R SiMe 3
O
CO 2 Me
H 2 , Pd/BaSO 4 , Quinoline
H 2 , Pd/BaSO 4 , pyridine
O
R
CO 2 Me
SiMe 3
TL 1976, 1539
JOC 1982, 47, 4254

HO
8π e -
conrotatory
HO OH HO OH
OH
H 2, Lindlar Catalyst
CH 2Cl 2: MeOH: Quinoline
6π e -
disrotatory
(90:9.5:0.5)
H
H
HO
H OH
REDUCTIONS 31
JACS 1982, 104, 5555
Ease of Reduction: (taken from H.O. House Modern Synthetic Reactions, 2nd edition)
R COCl
R NO 2
R R'
R CHO
R CH CH R'
O
R R'
Ar O
R
R C N
O
R OR'
O
R'
R N
R'
R CO 2 - Na +
R CHO
R NH 2
R
R'
R CH 2-OH
R CH 2 CH 2 R'
HO H
R R'
Ar CH3 + HO R
R CH 2 NH 2
R CH2-OH + HO R'
R CH2 R'
N
R'
no reaction
requires high
temperature & pressure
Raney Nickel Desulfuriztion ,
Reviews: Org. Rxn. 1962, 12, 356; Chem. Rev. 1962, 62, 347.
R
R S R H
O
(CH2) n
R R S
R H
Raney Nickel

S
HO
S
H
O O O
Raney Nickel
EtOH
(74%)
HO
H
O O O
Homogeneous Catalytic Hydrogenation
- catalyst is soluble in the reaction medium
- catalyst not "poisoned" by sulfur
- very sensitive to steric effects
- terminal olefins faster than internal; cis olefins faster than trans
REDUCTIONS 32
JOC 1987, 52, 3346
R
R
R
R
R > >
R R > R > R >> R
R
R
R
- (Ph3P)3RhCl (Wilkinson's Catalyst); [R3P Ir(COD)py] + PF6 - (Crabtree's Catalyst)
OH (Ph3P) 3RhCl, H2 OH
C 6 H 6
(92%)
R
JOC 1992, 57, 2767
Directed Hydrogenation
Review: Angew. Chem. Int. Ed. Engl. 1987, 26 , 190
- Diasterocontrolled hydrogenation of allylic alcohols directed by the -OH group
MeO
O - K +
(Ph 3 P) 3 RhCl, H 2
Rh +
Ph Ph
P
P
Ph Ph
Brown's Catalyst
BF4 -
PPh3 O PPh3 Rh H
H
Ir +
P(C6H11 ) 3
N
(Crabtree's Ctalyst)
JACS 1983, 105 , 1072
Regioselective Hydrogenation- allylic and homoallylic alcohols are hydrogenated faster than
isolated double bonds
MeO 2 C
OH
MeO 2C
OH
PF 6 -
MeO
H
O - K +

mechanism:
L +
H2 M
L
lose
H
H
OH
L
L
H
M
HO
L
M S
+
S
L
reductive
elimination
S
OH
migratory
insertion
L
L
H
L
REDUCTIONS 33
M
H
M
L
O
H
H 2
(oxidative
addition)
Diastereoselective Hydrogenation: since -OH directs the H2, there is a possibility for control of
stereochemistry
- sensitive to: H2 pressure
catalyst conc.
substrate conc.
solvent.
Regioselective Hydrogenation- allylic and homoallylic alcohols are hydrogenated faster than
isolated double bonds
OMe
O
HO
O
"Ir"
(20 mol %)
HO
OH H2 (640 psi), CH2Cl2 OH
H
OMe
Me
OH
Brown's Catalyst
Brown's Catalyst
H 2 (1000 psi)
OMe
O
H
OMe
H
Me
Selectivity is often higher with lower catalyst concentration:
OH OH
OH OH
OH
20 mol %
Catalyst
O
(24 : 1)
O
H
+
+
JACS 1984, 106, 3866
TL 1987, 28 , 3659
2.5 mol %
Catalyst
50 : 1 150 : 1
33 : 1 52 : 1

Olefin Isomerization:
OH
olefin
isomerization
OH
CH 3
OH
O
REDUCTIONS 34
(3 : 1)
major
product
- Conducting the hydrogenation at high H2 pressures supresses olefin isomerization and often
gives higher diastereoselectivity.
Other Lewis basic groups can direct the hydrogenation. (Ir seems to be superior to Rh for
these cases)
O
OMe
O
O
Ir +
Acyclic Examples
Me
OH
L
OMe
O
O
O
99 : 1
CO 2Me
CO 2H
N O
CO 2Me
CO 2H
> 99 : 1 Ir + 7 : 1
Rh + 1 : 1
1 : 1
Rh + (2 mol %)
H 2 (15 psi)
H
Ph
H
H3C H
H
H
L
L
M
H
M
L
H
O
O
H
CH 3
Ph
1,2-strain
Me
Ph
Ph
OH
CH 3
OH
OH
(97:3)
N O
Ir + > 99 : 1
Rh + 32 : 1
130 : 1
JCSCC 1982, 348
anti
syn

R 3
R 2
OH
R 1
L
R3 H
R3 H
L
L
M
R 1
H
M
L
H
O
O
H
H
R 2
R1 R2 favored
disfavored
1,2-strain
- Supression of olefin isomerization is critical for acyclic stereocontrol !
R 2
R 2
CH 3
OH
R 1
olefin
isomerization
OH
R 1
L
L
M
R2 CH3 H
H
R 1
R 1
H
O
CH2R2 H
- Rh + catalyst is more selective than Ir + for acyclic stereoselection.
Acyclic homoallylic systems:
E
R 2
A
O
H
M
R 3
L
L
L
H
H
L
M
R 1
H
O
HO
R 2
R 3
relative
stereochemistry
is critical
E
1,2-strain
R 2
A
R 2
R 2
REDUCTIONS 35
R 3
R 3
1,3-strain
O
H
R 3
R 2
M
R 2
R 2
R 2
OH
OH
R 1
OH
L
L
R 1
OH
R 1
R 1
anti
syn
syn
anti

TBSO
OH
TBSO
OH
OBz
OBz
Rh + (20 mol %)
H 2 (15 psi)
Rh + (20 mol %)
H 2 (15 psi)
TBSO
OH
TBSO
Asymmetric Homogeneous Hydrogenation
- Chiral ligands for homogeneous hydrogenation of olefins and ketones
MeO
PPh 2
NORPHOS
P
P
DUPHOS
P
P
DIPAMP
PPh 2
O
OMe
Ph
O
HN
O
CAMPHOS
CO 2H
O
Ph
NHAc
H
O
H
DIOP
PPh2 PPh2 DIPHEMP
CO 2Me
PPh 2
PPh 2
PPh2 PPh2 X
OH
PPh 2
PPh 2
CHIRAPHOS
PPh 2
PPh 2
X= CH 2 DPCP
X= N-R PYRPHOS
Rh (I) L*, H 2
DIOP 85% ee
DIPAMP 96% ee
PPPFA 93% ee
BINAP 100% ee
NORPHOS 95% ee
BPPM 91% ee
HO
BINAP
Ph
(95% ee)
OH
OBz
32 : 1
OBz
8 : 1
PPh 2
PPh 2
R= -CH 3 PROPHOS
= -Ph PHENPHOS
= -C 6H 11 CYCPHOS
Ph 2P
PPh2 PPh2 HN
N
CO2tBu BPPM
CO 2H
O
NH 2
L-DOPA
Ph
CO 2H
REDUCTIONS 36
Tetrahedron Lett. 1985, 26, 6005
PPh 2
DBPP
Fe
PPPFA
PPh 2
PPh 2
ACR 1983, 16, 106.
PPh 2
PPh 2
NMe 2

REDUCTIONS 37
General Mechanism: J. Halpern Science 1982, 217, 401 Asymmetric Synthesis 1985, vol 5, 41.
Detailed Mechanism:
Ph
P
*
P
H
P
*
CO 2 Me
NHAc
MeO 2 C
Rh
O
P
P
P
P
Ph
H 2
(slow)
Rh
NH
major complex
MeO2C H
Rh
P
O
Ph
NH
H
Rh
S
S
S
Ph
P
*
P
O
CH 3
CH 3
P
*
H
O
Rh
P
S
NH
CO2Me Ph
H 3 C
O
CH 3
H
N CO 2 Me
Ph
(R)
Minor product
Rh
Ph
CO 2 Me
NH
CH 3
S
S
CO 2 Me
NHAc
(fast equilibrium)
+
Ph
S
(fast)
P
P
CO 2 Me
NHAc
H 3 C
H 3 C
Rh
rate
limiting
P
P
HN
Ph
H
Rh
O
O
Ph
CO2Me NH
O
CH3 H 2
(slow)
Ph
H
Rh
NH
CH 3
CO 2 Me
minor complex
NH
Ph
O
H 2
(slow)
CO2Me H
S S
HN
MeO 2 C
Ph
Ph
S
CH 3
O
Rh
P
P
CO 2 Me
P
*
P
Rh H
P
*
P
*
H
H
N
MeO 2 C CH 3
O
(S)
Major product

MeO
MeO
O
O
Free Energy
H3C
Rh
P
P
HN CO2Me
Ph
O
*
MeO2C
minor complex
NH
P
*
P
Rh
O
Ph
major complex
(BINAP)RuAc 2 ,
H 2 (100 atm)
50 °C, CH 2 Cl 2
MeO
NAc
OMe
OMe
CH3
+
+
BINAP
CO 2 H
(BINAP)RuAc 2 ,
H 2 (4 atm)
Directed Asymmetric Hydrogenation
OH
HO
O
O
(94 % ee)
(BINAP)Ru (II), H2
(96 - 99 % ee)
O
Ph Ph
O
P O
Ru
P O
O
Ph Ph
Ru(AcO) 2 (BINAP),
H 2 (135 atm), MeOH
(97% ee)
MeO
MeO
(95 - 100 % ee)
Reaction Coordinate
O
O
ACR 1990, 23, 345.
MeO
NAc
OH
R
(S)-naproxen
OMe
OMe
REDUCTIONS 38
MeO2C
H NH
H
Rh Ph
P
* P
O CH3
H 3 C
(BINAP)RuAc2,
H 2 (100 atm)
50 °C, CH 2 Cl 2
CO 2 H
MeO
MeO
Rh
P
H
NH
CO2Me H
Ph
O
P
*
O
O
97 % ee
+
+
R
(95 - 98 % ee)
NH
Tetrahydropapaverine
OH OH
Vitamin E
CHO
J. Am. Chem. Soc. 1987, 109, 1596
OMe
OMe

Kinetic Resolution by Directed Hydrogenation
MeO 2C
Hydrogenation of Carbonyls
1,3-diketones:
MeO 2C
R 1
R 1
O O
O O
MeO
R
Ph
CO 2Me
Rh +
P P
Ph
OMe
H 2 (15 psi), L*Rh +
0 °C
(~60% conversion)
CF3SO3 -
MeO 2C
R = Et > 96 % ee
Ph 82 %
OMe 93 %
R 2
R 2
Ru (II)
H 2 (700 psi)
R 1
OH O
R 1
R 2
OH OH
anti
R 2
R
R 1
REDUCTIONS 39
CO 2Me
O
OH
OH OH
R 2
+ R1 R 2
R1= -CH3 R2= -CH3 anti : syn= 99 : 1
-CH3 -CH2CH3 16 : 1 (90 % ee)
-CH2CH3 -iPr 32 : 1
-CH2CH3 -CH2CH3 49 : 1
R 1
Decarbonylations
O
O O
O
R H
R 2
M
O
R 2
H 2
H
O
anti
H
R 1
Ru 2Cl 4(BINAP)
Et 3N, H 2 (100 atm)
(98% ee)
R 1
O OH
MeO 2C
R 2
H
O
M
OH
Directed
Reduction
O
H
syn
R2 R1 (Ph3P) 3RhCl
R H
O (Ph3P) 3RhCl
- CO R Cl - CO
syn
R 1
OH OH
R 2
JACS 1988, 110 , 6210
R Cl

OHC
Fe Fe
(Ph 3 P) 3 RhCl
PhCH3, Δ
Diimide HN=NH
Review: Organic Reactions 1991, 40J. Chem. Ed. 1965, 254
- Only reduces double bonds
- Syn addition of H2
- will selectivley reduce the more strained double bond
- Unstable reagent which is generated in situ
K + O2C-N=N-CO2K + + AcOH → H-N=N-H
H2N-NH2 + Cu 2+ + H2O2 → H-N=N-H
O
CO2MeK + - - +
O2C N N CO2 K
NO 2
HN
HN
O
O
S
HN=NH
(76%)
AcOH, MeOH
(95%)
O
hν (254 nm) NH
S
O O
N
H N H
hν, 16 hr
(96%)
NH
Fe
NO 2
CO 2 Me
Fe
+ COS + CO
REDUCTIONS 40
JOC 1990, 55, 3688
ACIEE 1965, 271
JACS 1986, 108 , 5908
TL 1993, 34, 4137
Metal Hydrides
Review on Metal Hydride Selectivity: Chem Soc Rev. 1976, 5 , 23
Comprehensive Organic Synthesis 1991, vol 8, 1.
Boron Hydrides Review: Chem. Rev. 1986, 86 , 763.
NaBH4
reduces ketones and aldehydes
LiBH4
reduces ketones, aldehydes, esters and epoxides. THF soluble
LiBH4/TMSCl stronger reducing agent. ACIEE 1989, 28, 218.
Zn(BH4)2 reduces ketones and aldehydes
R4N BH4
organic soluble (CH2Cl2) borohydrides. Synth Commun. 1990, 20, 907
LiEt3BH reduces ketones, aldehydes, esters, epoxides and R-X
Li s-Bu3BH reduces ketones, aldehydes, esters and epoxides (hindered borohydride)
Na(CN)NH3 reduces iminium ions, ketones and aldehydes
Na(AcO)3BH reduces ketones and aldehydes (less reactive)
NaBH2S3 reduces ketones and aldehydes

Sodium Borohydride NaBH4
- reduces aldehydes and ketones to alcohols
- does not react with acids, esters, lactones, epoxides or nitriles.
- Additives can increase reactivity.
REDUCTIONS 41
Sodium Cyanoborohydride Na (CN)BH3
Reviews: Synthesis 1975, 136; OPPI 1979, 11 , 201
- less reactive than NaBH4
- used in reductive aminations (Borch Reduction)
Na(CN)BH3 reduces iminium ions much more quickly than ketones or aldehydes
R
R
N
O
R"- 2 NH, MeOH,
AcO - NH 4 + , pH~ 8
O
CHO
R
R
N +
R'
R'
R"- 2 NH, MeOH,
AcO - NH 4 +
Na(CN)BH 3
- Related to Eschweiler-Clark Reaction
R NH 2
H 2CO, HCO 2H
H 2CO, H 2/Pd
Na(CN)BH 3
N
R
N
H
H
R N
R NH
- Reduction of tosylhydrazones gives saturated hydrocarbon
H
O
H
1) TsNHNH 2, H +
2) Na(CN)BH 3
(90%)
HO
1) TsNHNH2, H
HO
O
+
2) Na(CN)BH3 (100%)
- migration of the olefin occurs w/ α,β-unsaturated ketones
- Epoxide opening
O
O
OH
(75%)
or
NaBH 3CN,
BF 3•OEt 2, THF OH
H
HO
H
R'
R'
Me
JACS 1971, 93 , 2897
TL 1978, 1991
JOC 1977, 42 , 3157
JACS 1978, 100 , 7352
JOC 1994, 59, 4004

REDUCTIONS 42
NaBH2S3 Lalancette Reduction Synthesis 1972, 526 Can. J. Chem. 1970, 48 , 735.
NaBH4/ NiCl2
Chem. Pharm. Bull. 1981, 29 , 1159; Chem. Ber. 1984, 117 , 856.
Ar-NO2 → Ar-NH2
Ar-NO → Ar- NH2
R2C=N-OH → R2CH-NH2
NaBH4 / TiCl4
Synthesis 1980, 695.
R-COOH → R-CH2-OH
R-COOR' → R-CH2-OH
R-CN → R-CH2-NH2
R-CONH2 → R-CH2-NH2
R2C=N-OH → R2CH-NH2
R-SO2-R' → R-S-R'
NaBH4 / CeCl3 Luche Reduction
reduced α,β-unsaturated ketones in a 1,2-fashion
R
O
OH
R
R
NaBH 4/ CeCl 3
OH
C 5H 11
R
CO 2Me
O
R
R
NaBH 4
NaBH 4/ CeCl 3
MeOH
- selective reduction of ketones in the presence of aldehydes.
O
CHO
CeCl 3
H 2O
CO 2Me
NaBH4/ CeCl3 EtOH, H2O O
R
OH
OH
R
OH
R
OH
R
OH
+
R
OH
CHO
O
R
C 5 H 11
1) NaBH 4 , CeCl 3
2) work-up
R
H
O CHO OH CHO
NaBH4/ CeCl3 EtOH, H2O (78%)
JCSCC 1978, 601
JACS 1978, 100 , 2226
CO 2Me
CO 2Me
JACS 1979, 101 , 5848

Zinc Borohydride Zn(BH4)2 Synlett 1993, 885.
ZnCl2 (ether) + NaBH4 → Zn(BH4)2
- Ether solution of Zn(BH4)2 is neutral- good for base sensitive compounds
- Chelation contol model
R 1
O
O
R 2
OR
OH
H
Me
R
H -
R 1
Zn(BH 4) 2,
Et 2O, 0°C
RO
O
O
O
Zn
R 2
Zn
H
H B
H H
H
OH
OH
REDUCTIONS 43
R 1
OH
R 2
OR
TL 1983, 24 , 2653, 2657, 2661
Na + (AcO)3BH , Me4N + (AcO)3BH
Review: OPPI 1985, 17 , 317
- used in Borch reductive amination TL 1990, 31 , 5595; Synlett 1990, 537
- selective reduction of aldehydes in the presence of ketones
Ph
O
O
CHO
Bu4N (AcO) 3BH
C6H6, ↑↓
(77%)
O
CHO
Bu 4N (AcO) 3BH
C 6H 6, ↑↓
Ph
AcO OAc
B
H
O O
-hydroxyl-directed reduction of ketones
TL 1983, 24 , 273; TL 1984, 25 , 5449
OH
Me
O
Me
O
O
N
R
Me
O
Ph
H OAc
O
O
B
OAc
H
R
major
OH O
Me 4 N (AcO) 3 BH,
CH 3 CN, AcOH, −40°C
R
Na + BH(OAc) 3
OH
Me
OH
Me
H OAc
R
O
B
OAc
H
O
minor
(98:2)
OH
OH
OH
Ph OH
O
O
N
OH
Me
O
Ph
50 : 1
TL 1983, 24 , 4287
TL 1986, 27 , 5939
JACS 1988, 110 , 3560

MeO
OH
O
O
O
BnO
Me OH
O
Me
CO 2 R
OBn
Na + BH(OAc) 3
OBn
Me 4 N (AcO) 3 BH,
CH 3 CN, AcOH, −40°C
MeO
OH
O
OH
BnO
Me OH
O
CO 2R
Na + BH(OAc) 3
(Ph3P)2Cu BH4
reduction of acid chlorides to aldehydes JOC 1989, 45, 3449
reduction of alkyl and aryl azides to amines J. Chem. Res. (S) 1981, 17
R4N BH4 organic soluble borohydride (CH2Cl2)
R4N= BnEt3N or Bu4N Heterocylces 1980, 14, 1437, 1441
reduction of amides to amines
reduction of nitriles to amines
OH
Me
OBn
OBn
HO
MeO
REDUCTIONS 44
N
O
HO
O
OH
O
O
O
Me
OH
OH
Me OH
FK-506
TL 1989, 30 , 1037
BnEt3N BH4 / Me3SiCl
reduction of carbolxylic acids to alcohols Synth. Commun. 1990, 20, 907
LiBH4/ Me3SiCl ACIEE 1989, 28, 218.
Alkyl Borohydrides
Selectrides
Li + M
HB
+ HB M
LS-selectride
3
+ = Li (L-selectride)
K (K-selectride)
3
- hindered reducing agent
increased selectivity based on steric considerations
HO
O
OH
R
CO 2H
L-selectride
THF
HO
OH
OH
R
CO 2H
OH
JACS 1971, 93, 1491
OH
Me
O
CO 2R

- selective 1,4-reductions of α,β-unsaturated carbonyl cmpds.
JOC 1975, 40 , 146; JOC 1976, 41 , 2194
O O
K-selectride, THF
(99%)
- 1,4-reduction generates an enolate which can be subsequently alkylated.
O
a) K-selectride, THF
b)
Br
O
REDUCTIONS 45
K + HBPh3
Syn. Comm. 1988, 18 , 89.
- even greater 1,4-selectivity
Li + HBEt3 (Super Hydride)
- very reactive hydride source
- reduces ketones, aldehydes, esters, epoxides and C-X (alkyl halides and sulfonates)
HO
HO
Boranes
Hydroboration
H
R
R
H
HO
O
R'
H
OH
1) TsCl, pyridine
2) Li Et 3BH, THF
B 2 H 6
B 2H 6
B 2 H 6
Li Et 3BH, THF
R
R
H
HO
HO
H
H
HO
HO
CH 3
B H HO H
B H
R'
B
H 2O 2, NaOH
H 3O +
H 2O 2, NaOH
R
H
HCA 1983, 66 , 760
HCA 1988, 71 , 872
R'
H
R-CH 2CHO
- BH3 reduces carboxylic acids to 1° alcohols in the presence of esters, nitro and cyano groups.
- BH3 reduces amides to amines
HO 2C
O
O
BH 3•SMe 2
- Boranes also reduce ketones and aldehydes to the corresponding alcohols.
THF
HO
O
O

Hindered Boranes
9-BNN
Disiamyl Borane (Sia 2BH)
Catecholborane
Pinylborane
Alpine Borane
IPC 2BCl (DIP-Cl)
Thexyl Borane
Borolane
Oxazaborolidine
B
H
B
H
O
BH
O
BH
H
B
B
H
B
H
=
REDUCTIONS 46
B
H
2 2
2
BCl
B
H
Ph Ph
O
N
BH
Asymmetric Reduction of Unsymmetrical Ketones Using Chiral Boron Reagents
Review: Synthesis 1992, 605.
Alpine Borane Midland Reduction
JACS 1979, 111 , 2352; JACS 1980, 112 , 867
review: Chem. Rev. 1989, 89 , 1553.
O alpine-borane
THF, 0°C
OH
(94% ee)
B
BH
2
BCl
Tetrahedron 1984, 40 , 1371

α-pinene
B
H
Mechanism:
9-BBN
B
H
9-BBN
R s
O
RL - works best for aryl- and acetylenic ketones
- because of steric hindrance, alpine-borane is fairly unreactive
Chloro Diisopinylcamphenylborane (DIP-Cl, Ipc2BCl) H.C. Brown
Review: ACR 1992, 25 , 16. Aldrichimica Acta 1994, 27 (2), 43
=
B
B
R s
REDUCTIONS 47
2
- Cl increases the Lewis acidity of boron making it a more reactive reagent
- saturated ketones are reduced to chiral alcohols with varying degrees of ee.
I
PrO
OMe
O
CO 2tBu
Ipc 2B-Cl,
THF
Borolane (Masamune's Reagent)
JACS 1986, 108 , 7404; JACS 1985, 107, 4549
Asymmetric Hydroboration:
O
a)
B
H
I
PrO
B
H
MeSO 3H, pentane
B
H
b) H 2O 2, NaOH
BCl
OMe
OH
OH
(90 % ee)
OH
(99.5% ee)
CO 2tBu
OH
(80% ee)
R L
B
JOC 1992, 57, 7044
(99.5% ee)

Oxazaborolidine (Corey)
JACS 1987, 109 , 7925; TL 1990, 31, 611l ; TL 1992, 33 , 4141
I
Ph Ph
O
N
BH
O
O
O
R
O OH
O O
N OH
BMe
O
BzO
Ph Ph
BH 3 •THF, -0°C
Aluminium Hydrides
1. LiAlH4
2. AlH3
3. Li (tBuO)3AlH
4. (iBu)2AlH DIBAL-H
5. Na (MeOCH2CH2O)2AlH2
O
Cl
O
O
OH
94 % ee
REDAL
I
(90% ee)
Cl
BzO
Ph Ph
O
N
B
CH 3
Catalytic
OH
O
R
OH
OH
+ BH 3
> 90 % ee
REDUCTIONS 48
92 % ee
86 % ee
93 % ee
TL 1988, 29 , 6409
O
O
N
H
Fluoxetine (Prozac)
OH
90 : 10
CF 3
CH 3
• HCl

REDUCTIONS 49
Lithium Aluminium Hydride LiAlH4 (LAH) Chem. Rev. 1986, 86, 763 Org. Rxn. 1951, 6, 469.
- very powerful reducing agent
- used as a suspension in ether or THF
- Reduces carbonyl, carboxylic acids and esters to alcohols
- Reduces nitrile, amides and aryl nitro groups to amines
- opens epoxides
- reduces C-X bonds to C-H
- reduces acetylenic alcohols trans-allylic alcohols
R
OH
H 2 N N H NH2
O
O
H
O CO2 Me
LAH
LAH, THF, ↑↓
(100%)
LAH, THF
(62%)
Lindlar/ H 2
O
O
R OH
H 2 N N H
H 2 N
H
HO
N
H
OH
NH 2
NH 2
TL 1988, 29 , 2793.
BINAL-H (Noyori)
- Chiral aluminium hydride for the asymmetric reduction of prochiral ketones
BINOL
O O
OH
OH
BINAL-H,THF
-100 to -78°C
1) LiAlH 4
2) ROH
R= Me, Et, CF 3CH 2-
HO
O
(94% ee)
O
BINAL-H
H
O Al OR
Li +
Tetrahedron 1990, 46 , 4809
Intermediate for 3-Component Coupling Strategy to Prostaglandins
O
RO Li + RCu
O
RO
OTBS
OTBS
CO 2Me
Li + O -
RO
I
OTBS
O
HO
OH
CO 2Me
CO 2H
PGE 2

REDUCTIONS 50
Alane AlH3
LiAlH4 + AlCl3 → AlH3
- superior to LAH for the 1,2-reduction of α,β-unsaturated carbonyls to allylic alcohols
Ph
OMe
O
O
Me
O
O
O
1) AlH 3, ether, 0°C
2) H 3O +
Diisobutyl Aluminium Hydride DIBAL or DIBAL-H
H
- Reduces ketones and aldehydes to alcohols
- reduces lactones to hemi-acetals
O
(CH 2) n
O
DIBAL
O Al
O
(CH2) n
(stable complex)
Al
work up
HO
Me
O
OH
CHO
OH
(CH2) n
JACS 1989, 111 , 6649
OH
O
(CH2) n
lactol
- reduces esters to alcohols
- under carefully controlled reactions conditions, will partially reduce an ester to an aldehyde
Al
O
DIBAL
R CO2Me R C OMe
HO
O
HO
O
iPrO 2C
O
OH
R OH
OBn
OBn
O
OBn O
OBn
CO 2iPr
O
TMS-Cl, Et 3N
O
H
if complex
is stable
R CHO
DIBAL, CH 2Cl 2
CH 2Cl 2 R OSiMe 3
Reduction of O-Methyl hydroxamic acids
R
O
R'
R'-M
O
O
R N OMe
Me
DIBAL, CH 2 Cl 2
if complex
is unstable
OHC
DiBAl-H
HO
CH 2 Cl 2 , -78°C
DIBAL or LAH
fast
R CHO R CH2 OH
O
OBn
HO OH
OBn
OH
OBn
H OBn
CHO
O
R H
O
R H
JACS 1990, 112 , 9648
TL 1998, 39, 909
TL 1981, 22 , 3815

Sodium Bis(2-Methoxyethoxy)Aluminium Hydride REDAL
Organic Reactions 1988, 36, 249 Organic Reactions 1985, 36, 1.
MeO
MeO
Na +
- "Chelation" directed opening fo allylic epoxides
OH
R OH
O
O
Al
H
H
REDUCTIONS 51
REDAL O DIBAL-H R OH TL 1982, 23 , 2719
R OH
OH
1,3-diol
Sharpless
epoxidation
O
Ph OH Ph OH
HO
Me
Me
O
BnO
O
Me
O
O
OH
OH OH OH
Amphotericin B
OH
REDAL
DME
OH
+
LiAlH 4 2 : 98
AlH 3 95 : 5
BnO
OH
REDAL 150 : 1
DIBAL 1 : 13
OH
OH O
O
HO
OH
O Me
OH
NH 2
1,2-diol
OH
Ph OH
OH
OH + BnO
OH
JOC 1988, 53 , 4081
OH
O
Me
HO OH
Me
OH
Me
O
Me
O sugar
O O
Me
Erythromycin A
Lithium Tri(t-Butoxy)aluminium Hydride Li + (tBuO)3AlH
- hindered aluminium hydride, will only react with the most reactive FG's
R-CO 2H
Cl
H
N +
Me
Me
pyridine, -30°C
O
R Cl
O
R O
H
Li(tBuO) 3AlH
Me
N +
Me
O
R H
Li(tBuO) 3AlH
CuI (cat), -78°C
Meerwein-Ponndorf-Verley Reduction: opposite of Oppenauer oxidation
Synthesis 1994, 1007 Organic Reactions 1944, 2, 178
O
O
O
H
O AcHN
O
Al(O-Pr) 3, iPrOH
O
O
R H
H
O AcHN
OH
sugar
TL 1983, 24 , 1543

Asymmetric M-P-V Reduction
X O
Ph
O
Bn
N
Sm
I
O
iPrOH, THF
Ph
X OH
X= H, Cl, OMe
yield: 83-100 %
96% ee
JACS 1993, 115, 9800
Dissolving Metal Reductions
Birch Reductions reduction of aromatic rings Organic Reactions 1976, 23, 1.
Tetrahedron 1986, 42, 6354. Comprehensice Organic Synthesis 1991, vol. 8, 107.
- Li, Na or K metal in liquid ammonia
M, NH 3
R R R
_•
H H
•
H
REDUCTIONS 52
H H
R
H H
- position of the double bond in the final product is dependent of the nature of the substituent
R
R R
R= ERG
R= EWG
- ketones and nitro groups are also reduced but esters and nitrile are not.
- α,β-unsaturated carbonyl cmpds are reduced in a 1,4-fashion to give an enolate which can be
subsequently used to trap electrophiles
Other Metals
- Mg
HO
O
Me
EtO 2C
O
H
O
Me
O O
Me
Me
O
K, NH 3,
MeOH, -78°C
(92%)
a) Li, NH 3, tBuOH
b) CH 2O
Mg, MeOH
X X
Mg, MeOH
(98%)
- Zn reduction of α-halocarbonyls
O
Br
Zn, PhH,
DMSO, MeI
HO
O
HO
Me
EtO 2C
O
H
O
Me
O O
Me
Me
OH
X- CN, CO 2R, CONR' 2
O
Me
JOC 1991, 56 , 6255
JOC 1984, 59 , 3685
TL 1987, 28 , 5287
JACS 1967, 89, 5727

R O
O
Cl
Zn
R-OH
X Y
R
R'
Zn, AcOH
X= Cl, Br, I
Y= X, OH
"Copper Hydrides"
LAH or DIBAL-H + MeCu → "CuH"
- selective 1,4-reduction of α,β-unsaturated ketones (even hindered enones)
O
O
H
H
O
1) MeCu, DIBAL,
HMPA, THF, -50°C
2) MeLi
3)
Br
MeCu, DIBAL, HMPA
THF, -50°C
(85%)
O
O
H
H H
O
REDUCTIONS 53
R
CH
JOC 1987,52 , 439
CH R'
JOC 1986,51 , 537
[(Ph3P)CuH]6 Stryker Reagent
JACS 1988, 110 , 291 ; TL 1988, 29 , 3749
- 1,4-reduction of α,β-unsaturated ketones and esters; saturated ketones are not reduced
- halides and sulfonates are not reduced
- 1,4-reduction gives an intermediate enolate which can be trapped with electrophiles.
O Br O
[(Ph 3 P)CuH] 6 , THF
TL 1990, 31 , 3237
Silyl Hydrides
- Hydrosilylation
Et3SiH + (Ph3P)3RhCl (cat)
- selective 1,4-reduction of enones, 1,2-reduction of saturated ketones to alchohols.
O O SiEt3 H3O O
+
Et3SiH, (Ph3P) 3RhCl (cat)
O
O
O
iPr 3SiH, Et 2O
Si O Pt
2 2
O
O
OSi(iPr) 3
(87%)
TL 1972, 5085
J. Organomet. Chem. 1975, 94 , 449
JOC 1994, 59, 2287
- Buchwald Reduction
JACS 1991, 113 , 5093
- catalytic reagent prepared from Cp2TiCl2 + nBuLi and stoichometric (Et)3SiH in THF will
reduce ester, ketones and aldehydes to alcohols under very mild conditions.
- α,b− unsaturated esters are reduced to allylic alcohols
- free hydroxyl groups, aliphatic halides and epoxides are not reduced

Clemmensen Reduction Organic Reactions 1975, 22, 401
Comprehensive Organic Synthesis 1991, vol 8, 307.
- reduction of ketones to saturated hydrocarbons
O
Zn(Hg), HCl
Wolff-Kishner Reduction Organic Reactions 1948, 4, 378
Comprehensive Organic Synthesis 1991, vol. 8, 327.
- reduction of ketones to saturated hydrocarbons
O
H 2N-NH 2, KOH
H
H
H
H
REDUCTIONS 54
Radical Deoxygenation
Review: Tetrahedron 1983, 39 , 2609 Chem. Rev. 1989, 89, 1413.
Comprehensive Organic Synthesis 1991, vol. 8, 811
Tetrahedron 1992, 48, 2529
W. B. Motherwell, D. Crich Free Radical Chain Reactions in Organic Synthesis
(Academic Press: 1992)
- free radical reduction of halide, thio ethers, xanthates, thionocarbanates by a radical chain
mechanism.
R 3C-X
X= -Cl, -Br, -I, -SPh,
nBu 3Sn-H, AIBN
Ph-CH 3 ↑↓
S
O Ph
R 3C-H
S
S
, O SMe , O N
Barton-McCombie Reduction
JCS P1 1975, 1574
R3C-X → R3C-H X= -OC(=S)-SMe, -OC(=S)-Im, -OC(=S)Ph
HO
Ph
O
O
HO
O
O
O
HO
AcHN
O
O
O
OBn
R
NaH, imidazole,
THF, CS2, MeI
Cl
a) Ph NMe2 , THF
+
b) H 2 S, pyridine
N
(90%)
S
N N
(CH 2 Cl) 2
59%
N
Ph
S
N
O
Ph
O
O
N
O
S
O
O
O
O
AcHN
S
O
SMe
Xanthate
Thionobenzoates
O
O
OBn
Thiocarbonyl Imidazolides
N
nBu 3 SnH, AIBN
PhCH 3 , reflux
(85%)
N
N
CN CN
AIBN
R R
nBu 3 SnH, AIBN
PhCH 3 , reflux
(73%)
nBu 3 SnH, AIBN
PhCH 3 , reflux
(57%)
Ph
O
O
O
O
O
AcHN
O
O
O
OBn

- Cyclic Thionocarbonates: deoxygenation of 1,2- and 1,3-diols to alcohols
HO
MeO
MeO
OH
O
OMe
S
REDUCTIONS 55
N N S
nBu3SnH, AIBN
O
HO
N N O O PhCH O
3 , reflux
JCS P1 1977, 1718
MeO
MeO
MeO
(61%)
MeO
OMe
OMe
- Thionocarbonate Modification (Robbins)
JACS 1981, 103 , 932; JACS 1983, 105 , 4059.
iPr O
Si
iPr
O
O
B
Si O OH
iPr iPr
HO
O
O
O
PhOC(S)Cl,
pyridine, DMAP
> 90%
O
S
O
O
OAr
nBu3SnH,
AIBN, PhCH3 88-91%
iPr O
Si
iPr
O
O
B
Si O O
iPr iPr
S
Ar= 2,4,6-trichlorophenyl,
4-fluorophenyl
O
O CH3
O
O
O
OPh
- N-Phenyl Thionocarbamates Tetrahedron 1994, 34, 10193.
iPr O
Si
iPr
O
Si O
O
U
O
S
PhNCS
NaH, THF
(78%)
iPr iPr NHPh
- Methyl oxylates
OC
O
CO 2 Me
OAc
MeO 2CCOCl
THF
iPr O
Si
iPr
O
O
U
Si O O
iPr iPr
O
MeO 2C O
OC
Thiocarbamates
O
CO 2Me
Methyl Oxylate Esters
nBu 3SnH, AIBN
PhCH 3, reflux
(58-78%)
Tetrahedron 1991, 47, 8969
Best method for deoxygenation
of primary alcohols
S
NHPh
OAc
(TMS) 3SiH, AIBN
PhH, reflux
(93%)
nBu 3SnH, AIBN
PhCH 3, reflux
iPr O
iPr
Si
O
Si O
iPr iPr
O
iPr O
Si
iPr
O
O
U
Si O
iPr iPr
OC
O
CO 2Me
- Water Soluble Tin Hydride: [MeO(CH2)2O(CH2)3]3SnH / 4,4'-Azo(bis-4-cyanovaleric acid)
TL 1990, 31 , 2957
- Silyl Hydride Radical Reducing Agents
- replacement for nBu3SnH
(Me3Si)3SiH Chem Rev. 1995, 95, 1229.
JOC 1991, 56 , 678; JOC 1988, 53 , 3641; JACS 1987, 109 , 5267
Ph2SiH2 / Et3B / Air
TL 1990, 31 , 4681; TL 1991, 32 , 2569
- hypophosphorous acid as radical chain carrier
JOC 1993, 58, 6838
B
OAc

REDUCTIONS 56
- Photosensitized electron transfer deoxygenation of m-trifluoromethylbenzoates
JACS 1986, 108, 3115, JOC 1996, 61, 6092, JOC 1997, 62, 8257
iPr O
Si
iPr
O
O
U
Si O O
iPr iPr
O
N-methylcarbazole,
hν, iPrOH, H 2O
CF 3
Dissolving Metal : JACS 1972, 94, 5098
O
O
H
OH
nBuLi,
(Me 2N) 2P(O)Cl
Radical Decarboxylation: Barton esters
Aldrichimica Acta 1987, 20 (2), 35
Radical Deamination
N
S R
hn or Δ
O
O
(85%)
N
O
H
S
O
P(NMe 2 ) 2
O
O
R
iPr O
Si
iPr
O
O U
Si O
iPr iPr
Li, EtNH 2,
THF, tBuOH
nBu 3SnH, Δ
- CO 2
Comprehensive Organic Synthesis 1991, vol. 8, 811
Reduction of Nitroalkanes JOC 1998, 63, 5296
O
O
NO 2
Bu 3SnH, PhSiH 3
initiator, PhCH 3 (reflux)
(75%)
O
O
O
O
R H
CH 3
H

Carey & Sundberg Chapter 13.1 problems # 1; 2; 3a, b, c ;
Smith: Chapter 7
PROTECTING GROUPS 57
Protecting Groups
T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis (2nd edition) J.
Wiley & Sons, 1991.
P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994
1. Hydroxyl groups
2 Ketones and aldehydes
3. Amines
4. Carboxylic Acids
- Protect functional groups which may be incompatible with a set of reaction
conditions
- 2 step process- must be efficient
- Selectivity a. selective protection
b. selective deprotection
Hydroxyl Protecting Groups
Ethers
Methyl ethers
R-OH → R-OMe difficult to remove except for on phenols
Formation: - CH2N2, silica or HBF4
- NaH, MeI, THF
Cleavage: - AlBr3, EtSH
- PhSe -
- Ph2P -
- Me3SiI
O
O
OMe
OBz
AlBr 3, EtSH
Methoxymethyl ether MOM
R-OH → R-OCH2OMe stable to base and mild acid
Formation: - MeOCH2Cl, NaH, THF
- MeOCH2Cl, CH2Cl2, iPr2EtN
Cleavage - Me2BBr2 TL 1983, 24 , 3969
O
O
OH
OBz
TL 1987, 28 , 3659

PROTECTING GROUPS 58
Methoxyethoxymethyl ethers (MEM)
R-OH → R-OCH2OCH2CH2OMe stable to base and mild acid
Formation: - MeOCH2CH2OCH2Cl, NaH, THF
- MeOCH2CH2OCH2Cl, CH2Cl2, iPr2EtN TL 1976, 809
Cleavage - Lewis acids such as ZnBr2, TiCl4, Me2BBr2
MEM-O
C 5H 11
O
O-Si(Ph) 2tBu
S
B
S
Cl
C 5H 11
- can also be cleaved in the presence of THP ethers
HO
O
O-Si(Ph) 2tBu
Methyl Thiomethyl Ethers (MTM)
R-OH → R-OCH2SMe Stable to base and mild acid
Formation: - MeSCH2Cl, NaH, THF
Cleavage: - HgCl2, CH3CN/H2O
- AgNO3, THF, H2O, base
Benzyloxymethyl Ethers (BOM)
R-OH → R-OCH2OCH2Ph Stable to acid and base
Formation: - PhOCH2CH2Cl, CH2Cl2, iPr2EtN
Cleavage: - H2/ PtO2
- Na/ NH3, EtOH
Tetrahydropyranyl Ether (THP)
R-OH
O
H + , PhH
R
O
O
Stable to base, acid labile
Formation - DHP (dihydropyran), pTSA, PhH
Cleavage: - AcOH, THF, H2O
- Amberlyst H-15, MeOH
Ethoxyethyl ethers (EE)
JACS 1979, 101 , 7104; JACS 1974, 96 , 4745.
R-OH
O
H +
R
O
Benzyl Ethers (R-OBn)
R-OH → R-OCH2Ph stable to acid and base
O
TL 1983, 24 , 3965, 3969
(R-OEE) base stable, acid labile
Formation: - KH, THF, PhCH2Cl
- PhCH2OC(=NH)CCl3, F3CSO3H JCS P1 1985, 2247
Cleavage: - H2 / PtO2
- Li / NH3

2-Napthylmethyl Ethers (NAP) JOC 1998, 63, 4172
formation: 2-chloromethylnapthalene, KH
cleavage: hydrogenolysis
BnO
OH O ONAP H 2, Pd/C
(86%)
BnO
PROTECTING GROUPS 59
OH O OH
p- Methoxybenzyl Ethers (PMB)
Formation: - KH, THF, p-MeOPhCH2Cl
- p-MeOPhCH2OC(=NH)CCl3, F3CSO3H TL 1988, 29 , 4139
Cleavage: - H2 / PtO2
- Li / NH3
- DDQ
- Ce(NH4)2(NO3)6 (CAN)
- e -
o-Nitrobenzyl ethers
Review: Synthesis 1980, 1; Organic Photochemistry, 1987, 9 , 225
R-OH
NaH, THF
NO 2
Cl R O
O 2N
Cleavage: - photolysis at 320 nm
HO
O
HO
O
HO
OH
NO 2
hν, 320 nm,
pyrex, H 2O
HO
O
HO
OH
HO
OH
p-Nitrobenzyl Ether TL 1990, 31 , 389
-selective removal with DDQ, hydrogenolysis or elctrochemically
9-Phenylxanthyl- (pixyl, px) TL 1998, 39, 1653
Formation:
ROH +
Removal:
Ph OR
Trityl Ethers -CPh3 = Tr
R-OH → R-OCPh3
O
Ph Cl
O
hν (300 nm)
CH 3CN,H 2O
formation: - Ph3C-Cl, pyridine, DMAP
- Ph3C + BF4 -
Cleavage: - mild acid
pyridine
ROH +
JOC 1972, 37 , 2281, 2282.
Ph OR
O
O
Ph OH
- selective for 1° alcohols
- removed with mild acid; base stable

Methoxytrityl Ethers
JACS 1962, 84 , 430
- methoxy group(s) make it easier to remove
R 2
R 1
C O R
R 3
(p-Methoxyphenyl)diphenylmethyl ether
4'-methoxytrityl MMTr-OR
PROTECTING GROUPS 60
Di-(p-methoxyphenyl)phenylmethyl ether
4',4'-dimethoxytrityl DMTr-OR
Tri-(p-methoxyphenyl)methyl ether
4',4',4'-trimethoxytrityl TMTr-OR
Tr-OR < MMTr-OR < DMTr-OR

PROTECTING GROUPS 61
Silyl Ethers Synthesis 1985, 817 Synthesis 1993, 11 Synthesis 1996, 1031
R-OH → R-O-SiR3
formation: - R3Si-Cl, pyridine, DMAP
- R3Si-Cl, CH2Cl2 (DMF, CH3CN), imidazole, DMAP
- R3Si-OTf, iPr2EtN, CH2Cl2
Trimethylsilyl ethers Me3Si-OR TMS-OR
- very acid and water labile
- useful for transiant protection
Triethylsilyl ethers Et3Si-OR TES-OR
- considerably more stable that TMS
- can be selectively removed in the presence of more robust silyl ethers with with F- or
mild acid
TESO
O
OTBS
H 2 O/ACOH/THF
(3:5:11), 15 hr O
(97%)
Triisopropylsilyl ethers iPr3Si-OR TIPS-OR
- more stabile to hydrolysis than TMS
Phenyldimethylsilyl ethers
J. Org. Chem. 1987, 52 , 165
OH
OTBS
Liebigs Ann. Chem. 1986, 1281
t-Butyldimethylsilyl Ether tBuMe2Si-OR TBS-OR TBDMS-OR
JACS 1972, 94 , 6190
- Stable to base and mild acid
- under controlled condition is selective for 1° alcohols
TBSO
t-butyldimethylsilyl triflate tBuMe2Si-OTf TL 1981, 22 , 3455
- very reactive silylating reagent, will silylate 2° alcohols
cleavage:
- acid
- F- (HF, nBu4NF, CsF, KF)
O
OTBS
CO 2Me
HF, CH 3CN
(70%)
HO
O
HO
CO 2Me
JCS Perkin Trans. 1 1981, 2055
t-Butyldiphenylsilyl Ether tBuPh2Si-OR TBDPS-OR ∑-OR
- stable to acid and base
- selective for 1° alcohols
- Me3Si- and iPr3Si groups can be selectively removed in the presence of TBS or TBDPS
groups.
- TBS can be selectively removed in the presence of TBDPS by acid hydrolysis.
TL 1989, 30 , 19

Esters
PROTECTING GROUPS 62
cleavage - F- - Fluoride sources: - nBu4NF (basic reagent)
- HF / H2O /CH3CN TL 1979, 3981.
- HF•pyridine Synthesis 1986, 453
- SiF4. CH2Cl2
TL 1992, 33 , 2289
Me
tBu
Me
O
Si
O
Si
O
Ph
tBu
Ph
OTHP
Me
Si tBu
Me
R-OH → R-O2CR'
AcOH / THF/ H 2O
PPTS / EtOH
Me
tBu
Me
O
Si
Si
O
OH
Ph
tBu
Formation: - "activated acid", base, solvent, (DMAP)
Ph
OH
JOC 1981, 46 ,1506
TL 1989, 30 , 19.
JACS 1984, 106 , 3748
Activated Acids Chem. Soc. Rev. 1983, 12, 129 Angew. Chem. Int. Ed. Engl. 1978, 17, 569.
RCO2H → "activated acid" → carboxylic acid derivative (ester, amide, etc.)
Acid Chlorides
O O
N N
R OH
1. SOCl2
2. PCl5
3. (COCl)2
Anhydrides
R Cl
Activating Agents:
Carbonyl Diimidazole
O
R OH
+
2
R OH
O
O
N N
N N
P 2O 5
O
+
R N
N
acyl pyridinium ion
(more reactive)
O
R O
O
R N
O
R
N
Acyl Imidazole
O
R N
+ CO +
N
N +
NH

O
R OH
O
Dicyclohexylcarbodiimide
+
R OH
+
N C N
O
R O
C 6H 11
NH
C
N
C 6H 11
PROTECTING GROUPS 63
Nu:
R
O
Nu
+
C 6 H 11 NH
Ketene formation is a common side reaction- scambling of chiral centers
R
H
O
O
C
N
C 6 H 11
NH
C 6H 11
R
C O
"ketene"
Hydroxybenzotriazole (HOBT) - reduces ketene formation
O
R O
C 6H11 NH
C
N
C 6H 11
N-Hydroxysuccinimide (NHS)
O
R O
C 6H 11
NH
C
N
C 6H 11
+
+
HO
N
O
O
N
N
N
OH
O
R O
O
R O
2,2'-Dipyridyl Disulfide (Aldrithiol, Corey Reagent)
Aldrichimica Acta 1971, 4 , 33
Ph 3 P:
N S S N R S
O
+
N
N N
N
O
O
N N SH
Mukaiyama's Reagent (2-Chloro-1-methyl pyridinium Iodide or 2-Fluoro-1methyl
pyridinium p-toulenesulfonate)
Aldrichimica Acta 1987, 20 , 54
Chem. Lett. 1975, 1045; 1159; 1976, 49; 1977, 575
O
R OH
+
O
TsO
F N
R O
-
+
Me
+
N
Me
I -
+
O
N
H
Ph 3P=O
Acetates
R-OH → R-O2CCH3
- stable to acid and mild base
- not compatable with strong base or strong nucleophiles such as organometallic
reagents
Formation: - acetic anhydride, pyridine
- acetyl chloride, pyridine
C 6 H 11

Chloroacetates
PROTECTING GROUPS 64
Cleavage: - K2CO3, MeOH, reflux
- KCN, EtOH, reflux
- NH3, MeOH
- LiOH, THF, H2O
- enzymatic hydrolysis (Lipase) Org. Rxns. 1989, 37, 1.
Cl
Cl
O
OAc
OAc
Porcine Pancreatic
Lipase
OAc
OH
TL 1988, 30 , 6189
(96% ee)
- can be selectively cleaved with Zn dust or thiourea.
O
AcO
O Me
O
O
OAc
O
Me O
O
O
OR
Cl
H 2NNHCOSH
HO
AcO
Me
HO
O
OAc
O
Me O
OH
OR
JCS CC 1987, 1026
Trifluoroacetates
Formation: - with trifluoroacetic anhydride or trifluoroacetyl chloride
Cleavage: - K2CO3, MeOH
Pivaloate (t-butyl ester)
- Fairly selective for primary alcohols
Formation: - tbutylacetyl chloride or t-butylacetic anhydride
Cleavage: - removed with mild base
Benzoate (Bz)
- more stable to hydrolysis than acetates.
Formation: - benzoyl chloride, benzoic anhydride, benzoyl cyanide (TL 1971, 185) ,
benzoyl tetrazole (TL 1997, 38, 8811)
Cleavage: - mild base
- KCN, MeOH, reflux
1,2 and 1,3- Diols Synthesis 1981, 501 Chem. Rev. 1974, 74, 581
R
OH
Isopropylidenes (acetonides)
R
OH
OH
OH
R 1
R 1
R 2
R 2
R 3
O
R3 O O
H
R R1 + , -H2O H +
acetone or
MeO OMe
or
OMe
Me Me
O O
R R 1
- in competition between 1,2- and 1,3-diols, 1,2-acetonide formation is usually favored
- cleaved with mild aqueous acid

Cycloalkylidene Ketals
- Cyclopentylidene are slightly easier to cleave than acetonides
- Cyclohexylidenes are slightly harder to cleave than acetonides
Benzylidene Acetals
R
R
OH
OH
OH
OH
R 1
R 1
O
MeO OMe
(CH2) n -or- (CH2) n
H + , -H 2O
PhCHO
-or-
PhCH(OMe) 2
H + , -H 2O
PROTECTING GROUPS 65
(CH2) n
O O
R R 1
Ph
O O
R R 1
- in competition between 1,2- and 1,3-diols, 1,3-benzylidene formation for is usually
favored
- benzylidenes can be removed by acid hydrolysis or hydrogenolysis
- benzylidene are usually hydrogenolyzed more slowly than benzyl ethers or olefins.
p-Methoxybenzylidenes
- hydrolyzed about 10X faster than regular benzylidenes
- Can be oxidatively removed with Ce(NH4)2(NO3)6 (CAN)
BnO
MeO
OBn
O
O
O
OMe
Ce(NH 4) 2(NO 3) 6
CH 3CN, H 2O
(95%)
Other Reactions of Benzylidenes
- Reaction with NBS (Hanessian Reaction)
MeO
H
Ph
O
HO
O O
HO OMe
NBS, CCl 4
Ph
O
Br
O O
HO
HO
OMe
BnO
MeO
- if benzylidene of a 1° alcohol, then 1° bromide
- Reductive Cleavage
MeO 2C
O
O O
O
Ph
O
CO 2Me
O
Ph
Na(CN)BH 3,
TiCl 4,CH 3CN
TMS-CN
BF 3 •OEt 2
MeO 2C
MeO
O
O
OH
OBn
OH
CO 2 Me
O
Ph
H CN
OBn
O
OH
OH
Org. Syn. 1987, 65, 243
Synthesis 1988, 373.
Tetrahedron 1985, 41, 3867

Carbonates
Ph
O O
O
R
OH
OMe
OH
R 1
DIBAL-H
(Im) 2CO
- stable to acid; removed with base
- more difficult to hydrolyze than esters
BnO OH
PROTECTING GROUPS 66
O
O
OMe
O O
R R 1
TL 1988, 29 , 4085
Di-t-Butylsilylene (DTBS) TL 1981, 22 , 4999
- used for 1,3- and 1,4-diols; 1,2-diols are rapidly hydrolyzed
- cleaved with fluoride (HF, CH3CN -or- Bu4NF -or- HF•pyridine)
- will not fuctionalize a 3°-alcohol
OH
OH
(t-Bu) 2SiCl 2, Et 3N
CH 3CN, HOBT
O tBu
Si
O tBu
1,3-(1,1,3,3)-tetraisopropyldisiloxanylidene (TIPDS) TL 1988, 29 , 1561
- specific for 1,3- and 1,4-diols
- cleaved with fluoride or TMS-I
HO
HO
O
HN
O
OH
O
N
iPr 2Si(Cl)-O-Si(Cl)iPr 2
pyridine
Ketones and Aldehydes
- ketones and aldehydes are protected as cyclic and acyclic ketals and acetals
- Stable to base; removed with H3O +
R
R 1
O
MeOH, H +
(CH 2OH) 2, H +
PhH, -H2O
-or-
(CH 2OSiMe 3) 2,
TMS-OTf, CH 2Cl 2
CH 2(CH 2OH) 2,
H + , PhH, -H 2O
R
R 1
OMe
OMe
R
R 1
O
O
1,3-dioxolanes
R
O
R1 O
1,3-dioxanes
Si
O
O
Si
O
O
HN
O
OH
TL 1980, 21 , 1357
O
N

Cleavage rate of substituted 1,3-dioxanes:
Chem. Rev. 1967, 67 , 427.
R
R 1
O R O
R
>
>>
O
O
R 1
PROTECTING GROUPS 67
- Ketal formation of α,β-unsaturated carbonyls are usually slower than for the
saturated case.
Fluoride cleavable ketal:
Me 3Si
O
Base cleavable ketal:
R 1
O
R 2
HO
O
OH
pTSA, C 6H 6
O
SO 2Ph
O
O
R 1
O
O
O
LiBF 4
(88%)
R 2
CH 2 (CH 2 OH) 2 ,
H + , PhH, -H 2O
SO 2Ph
O
O
DBU, CH 2Cl 2
R 1
O
O
O
O
O
O
R 1
TL 1997, 38, 1873
Carboxylic Acids Tetrahedron 1980, 36, 2409. Tetrahedron 1993, 49, 3691
Nucelophilic Ester Cleavage: Organic Reactions 1976, 24, 187.
Esters
Alkyl Esters
formation: - Fisher esterification (RCOOH +R'OH + H + )
- Acid Chloride + R-OH, pyridine
- t-butyl esters: isobutylene and acid
- methyl esters: diazomethane
Cleavage: - LiOH, THF, H2O
- enzymatic hydrolysis Org. Rxns. 1989, 37, 1.
- t-butyl esters are cleaved with aqueous acid
- Bu2SnO, PhH, reflux (TL 1991, 32, 4239)
MeO 2C CO 2Me
O
R OR'
OH
Bu 2SnO, PhH, ↑↓
R= Me, Et, tBu
Pig Liver Esterase
pH 6.8 buffer
R OH
9-Fluorenylmethyl Esters (Fm)
TL 1983, 24 , 281
- cleaved with mild base (Et2NH, piperidine)
RCO 2H
+
OH
O
DCC
OH
O
R 2
MeO 2C CO 2H
TL 1991, 32, 4239
O
R O
TL 1998, 39, 2401

2-Trimethylsilyl)ethoxymethyl Ester (SEM)
HCA 1977, 60 , 2711.
- Cleaved with Bu4NF in DMF
RCO 2H +
HO O
SiMe 3
DCC
- Cleaved with MgBr2•OEt2 TL 1991, 32, 3099.
2-(Trimethylsilyl)ethyl Esters
JACS 1984, 106 , 3030
- cleaved with Fluoride ion
Haloesters
RCO 2H
+
HO
SiMe 3
DCC
- cleaved with Zn(0) dust or electrochemically
RCO 2H +
Benzyl Esters
RCO2H + PhCH2OH → RCO2Bn
PROTECTING GROUPS 68
R
O
R
O O
O
O
SiMe 3
DCC
HO CCl3 R O CCl3 Formation: - DCC
- Acid chloride and benzyl alcohol
Cleavage: - Hydrogenolysis
- Na, NH3
Diphenylmethyl Esters
RCO 2H +
Cleavage: - mild H3O +
- H2, Pd/C
- BF3•OEt2
HO CHPh2
DCC
o-Nitrobenzyl Esters
- selective removed by photolysis
Orthoesters Synthesis 1974, 153 Chem. Soc. Rev. 1987, 75
TL 1983, 24 , 5571
RCOCl +
O
OH
R O
- Stable to base; cleaved with mild acid
O
O
R
O
O
BF 3•OEt 2
O CHPh2
R
O
SiMe 3
O
O

PROTECTING GROUPS 69
Amines
Carbamates
9-Fluorenylmethyl Carbamate (Fmoc)
Acc. Chem. Res. 1987, 20 , 401
- Cleaved with mild base such as piperidine, morpholine or dicyclohexylamine
R 2 NH
2,2,2-Trichloroethyl Carbamate
EtO 2C
+
O
Cl O
O
Cl 3C O Cl
NaHCO 3
H 2O, dioxane
R 2NH, pyridine
- Cleaved with zinc dust or electrochemically.
S
N
O
O
CCl 3
2-Trimethylsilylethyl Carbamate (Teoc)
- cleaved with fluoride ion.
MeO
Me 3Si
O O
Cl
N CH3
O
O O
SiMe 3
t-Butyl Carbamate (BOC)
O
H
N
O
O
O
SEt
SEt
R 2NH
OTBS
OEt
tBuO
S Te Te S
+
NaBH 4
R 2 NH
Bu 4NF, THF
(100%)
O OtBu
O
Cl 3C O N
EtO 2C
MeO
Cl
S
O
R 2N O
R
R
NH
Me 3Si
H
N CH3
R 2N OtBu
Cleavage: - with strong protic acid (3M HCl, CF3COOH)
- TMS-I
-
O
B
O
Cl
O
O
TL 1985, 26 , 1411
O
O
H
TL 1986, 27 , 4687
O
OH
O
SEt
SEt
Allyl Carbamate (Alloc) TL 1986, 27 , 3753
O
N R
R
OEt
JACS 1979, 101 7104

R 2NH
O
O O
O
O
PROTECTING GROUPS 70
O
R 2N O
- removed with Pd(0) and a reducing agent (Bu3SnH, Et3SiH, HCO2H)
O
HN O
CO 2Me
Benzyl Carbanate (Cbz)
R 2NH
Cleavage: - Hydrogenolysis
- PdCl2, Et3SiH
- TMS-I
- BBr3
- hν (254 nm)
- Na/ NH3
m-Nitrophenyl Carbamate
JOC 1974, 39 , 192
Amides
Formamides
Acetamides
- removed by photolysis
1) Pd(OAc) 2 , Et 3 N, Et 3 SiH
2) H 3 O +
O
BnO Cl
- removed with strong acid
R 2NH
- removed with strong acid
R 2NH +
+
O
R 2N O
HCO 2Et
Ac 2O
Trifluoroacetamides
Cleavage: - base (K2CO3, MeOH, reflux)
- NH3, MeOH
Sulfonamides
p-Toluenesulfonyl (Ts)
R 2NH +
R 2NH
pTsCl, pyridine
(CF 3CO) 2O
NO 2
NH 2
O
R 2N O
R 2N SO 2
CO 2Me
O
Ph
R 2N H
O
R 2N CH 3
O
R 2N CF 3
TL 1986, 27 , 3753

Cleavage: - Strong acid
- sodium Naphthalide
- Na(Hg)
Ts Ts
N
N
N
Ts
Trifluoromethanesulfonyl
Tf Tf
N N
Tf
N
N
Tf
Na(Hg), MeOH
Na 2HPO 4
(65%)
Na, NH 3
Trimethylsilylethanesulfonamide (SES)
TL 1986, 54 , 2990; JOC 1988, 53, 4143
- removed with CsF, DMF, 95°C
R 2NH
Me 3 Si
Et 3N, DMF
tert-Butylsulfonyl (Bus) JOC 1997, 62, 8604
R-NH 2
tBuSOCl,
Et 3N, CH 2Cl 2
R2N O
S
tBu
H H
N
N
SO 2Cl
NH
NH
mCPBA
-or-
RuCl 3, NaIO 4
N
H
HN
HN
R 2 N S
PROTECTING GROUPS 71
O O
R 2N SO 2tBu
JOC 1992, 33, 5505
SiMe 3
JOC 1989, 54 , 2992
CF 3SO 3H,
CH 2Cl 2, anisole
R-NH 2

C-C BOND FORMATION 72
Carbon- Carbon Bond Formation
1. Alkylation of enolates, enamines and hydrazones
C&S: Chapt. 1, 2.1, 2.2 problems Ch 1: 1; 2; 3, 7; 8a-d; 9; 14 Ch. 2: 1; 2; 4)
Smith: Chapt. 9
2. Alkylation of heteroatom stabilized anions C&S :Chapt. 2.4 - 2.6)
3. Umpolung Smith: Chapt. 8.6
4. Organometallic Reagents
C&S: Chapt. 7, 8, 9 problems ch 7: 1; 2; 3, 6; 13 Ch. 8: 1; 2
Smith: Chapt. 8
5. Sigmatropic Rearrangements . C&S Chapt. 6.5, 6.6, 6.7 # 1e,f,h,op
Smith Chapt. 11.12, 11.13
Enolates Comprehensive Organic Synthesis 1991, vol. 2, 99.
- α-deprotonation of a ketone, aldehyde or ester by treatment with a strong nonnucleophillic
base.
- carbonyl group stabilizes the resulting negative charge.
H
H H
O
R
B:
H
H
-
O
- Base is chosen so as to favor enolate formation. Acidity of C-H bond must be greater
(lower pKa value) than that of the conjugate acid of the base (C&S table 1.1, pg 3)
H 3 C CH 3
O
O
H 3 C CH 2
O
OEt
pK a = 20
pK a = 10
R
MeO - pK a = 15
tBuO - pK a = 19
H
H
O -
R
unfavorable enolate
concentration
more favorable
enolate concentration
- Common bases: NaH, EtONa, tBuOK, NaNH2, LiNiPr2, M N(SiMe3)2,
Na CH2S(O)CH3
Enolate Formation:
- H + Catalyzed (thermodynamic)
O
- Base induced (thermodynamic or kinetic)
O
H
:B
H +
Regioselective Enolate Formation Tetrahedron 1976, 32, 2979.
- Kinetic enolate- deprotonation of the most accessable proton (relative rates of
deprotonation). Reaction done under essentially irreversible conditions.
O
LDA, THF, -78°C
O -
OH
+ B:H
O - Li +

C-C BOND FORMATION 73
typical conditions: strong hindered (non-nucleophilic) base such as LDA
R2NH pKa= ~30
N Li
Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be
problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide)
R
R
O
O
OR'
OR'
LDA, THF, -78°C
E +
N
Li
THF, -78°C
- Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate:
more highly substituted C=C of the enol form
O - K +
O
R
O
R
N
tBuO - K + , tBuOH
O - Li +
OR'
O - K +
kinetic thermodynamic
typical conditions: RO - M + in ROH , protic solvent allows reversible enolate
formation. Enolate in small concentration (pKa of ROH= 15-18 range)
- note: the kinetic and thermodynamic enolate in some cases may be the same
- for α,β-unsaturated ketones
Trapping of Kinetic Enolates
- enol acetates
Ph
O
thermodynamic
site
1) NaH, DME
2) Ac 2O
kinetic
Regiochemically
pure enolates
Ph
Ph
O
O
O
kinetic
site
+
Ph
isolatable
separate & purify
CH 3Li, THF CH 3Li, THF
O - Li +
Ph
O
O
O - Li +

- silyl enolethers Synthesis 1977, 91. Acc. Chem. Res. 1985, 18, 181.
Ph
O
1) LDA
2) Me 3SiCl
kinetic
Geometrically
pure enolates
Ph
Ph
OTMS
O - M +
+
C-C BOND FORMATION 74
Ph
isolatable
separate & purify
CH 3Li, THF
-or-
Bu 4 NF -or- TiCl 4
Ph
OTMS
O - M +
CH 3Li, THF
- tetraalkylammonium enolates- "naked" enolates
- TMS silyl enol ethers are labile: can also use Et3Si-, iPr3Si- etc.
- Silyl enol ether formation with R3SiCl+ Et3N gives thermodyanamic silyl
enol ether
- From Enones
O
OSiMe 3
1) Li, NH 3
2) TMS-Cl
- From conjugate (1,4-) additions
O
TMSO
H
O
1) MeLi
2) E +
TMS-Cl, Et 3N TMS-OTf
Et 3N
O OSiMe3 Li, NH3, tBuOH
(CH 3) 2CuLi
TMS-Cl
- From reduction of α-halo carbonyls
O
Br
O - Li +
Trap or use directly
Zn or Mg
E +
O - M +
O
O
E
H
OSiMe 3
Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides)
Comprehensive Organic Synthesis 1991, vol. 3, 1.
1° alkyl halides, allylic and benzylic halides work well
2° alkyl halides can be troublesome
3° alkyl halides don't work
E

O
a) LDA, THF, -78°C
b) MeI
O
C-C BOND FORMATION 75
- Rate of alkylation is increased in more polar solvents (or addition of additive)
(Me 2N) 3P O
HMPA
O
R NMe2 R= H DMF
R-CH3 DMA
O
H3C S CH3 DMSO
CH 3N
O
Me
O
CH 3N NCH 3
Me 2N
TMEDA
Mechanism of Enolate Alkylation: SN2 reaction, inversion of electrophile stereochemistry
M + - O
Alkylation of 4-t-butylcyclohexanone:
O
equitorial anchor
tBu
R
H
E
E
A
B
O - M +
R
A
favored
B
X
C
tBu
tBu
180 °
H
H
O
E
E
R
E
R
O
R
O
Chair
Twist Boat
on cyclohexanone enolates, the electrophile approaches from an "axial" trajectory. This
approach leads directly into a chair-like product. "Equitorial apprach leads to a higher
energy twist-boat conformation.
Alkylation of α,β-unsaturated carbonyls
R 1
H
O
H
R 2
R 1
R 1
O - M +
O - M +
Kinetic
H
R 2
H
Thermodynamic
R 2
E
E
R 1
R 1
H
E
O
O
E
NMe 2
H
R 2
R 2

O
Stork-Danheiser Enone Transposition:
- overall γ-alkylation of an α,β-unsaturated ketone
OMe
LDA
PhCH 2 OCH 2 Cl
PhO
O
OMe
CH 3 Li
Chiral enolates- Chiral auxilaries.
D.A. Evans JACS 1982, 104 , 1737; Aldrichimica Acta 1982,15 , 23.
Asymmetric Synthesis 1984, 3, 1.
- N-Acyl oxazolidinones
R
R
O
N
O
O
Me Ph
O
O
N O
LDA, THF
Et-I
LDA, THF
Et-I
R
R
R
R
O
N
O
O
Me Ph
O
O
N
N
O
O
O
O
Me Ph
major product
(96:4)
O O
N O
major product
(96:4)
Enolate Oxidation Chem. Rev. 1992, 92, 919.
R
O
N
O
O
NaN(SiMe 3) 2,
THF, -78°C
O
Ph
N
SO2Ph LDA, THF
O
N OtBu
tBuO N
O
R
Boc
R
PhO
LiOH, H 2O, THF
LiOH, H 2O, THF
OH
N
HN
Boc
O
O
N
N
O
O
O
O
HO
C-C BOND FORMATION 76
CH 3
OMe
H 2 N OH
Me Ph
norephedrine
H 2N OH
valinol
R
R
(88 - 98 % de)
(94 - 98 % de)
O
O
1) HO -
OH
OH
2) CH 2N 2
3) TFA
4) Raney Ni
H 3 O +
PhO
CH 3
J. Org. Chem. 1995, 60, 7837.
Complimentary Methods
for enantiospecific alkylations
Diastereoselectivity: 92 - 98 %
for most alkyl halides
R
O
NH 2
OMe
O

R
R
O
N
O
Ph
O
N
O
O
Ph
R
O
N 3
Bu 2BOTf, Et 3N
O
N
O
Ph
O
KN(SiMe 3) 2, THF
SO 2N 3
R
1) LiOH
2) H 2, Pd/C
R
Bu Bu
B
O O
N 3
N
Ph
O
N
O
O
Ph
R
NBS
O
NH 2
OH
D- amino acids
Oppolzer Camphor based auxillaries Tetrahedron, 1987, 43, 1969.
diastereoselectivities on the order of 50 : 1
O
O
SO2N(C6H11) 2
SO2Ph N
O
O
Ar
R
Ar
N
SO2Ph
O
O
Et 2Cu•BF 3
Asymmetric Acetate Aldol
O
N
S
O
1) Br
R
O
O
SO2N(C6H11) 2
O
H
Sn(OTf) 2, CH 2Cl 2,
R 3 N, -40°C
2) TIPS-OTf, pyridine
3) NH 3
Chiral lithium amide basess
MeO
OMe
CH 3
CO 2Et
H
Br
O
LDA, NBS
TIPSO
O
O
R
SO 2N(C 6H 11) 2
O
85 %, 19:1 de
Ph N OMe
Li
THF, -78°C
(CH 3) 2C=O
NH 2
MeO
C-C BOND FORMATION 77
O
H
R
O
SO 2N(C 6H 11) 2
Br
Br
O
N
S
O 2
O
Ph
N
O
O
R
HO
J. Am. Chem. Soc. 1998, 120, 591
J. Org. Chem. 1986, 51, 2391
CH 3
O
OMe O
(72% ee)
N 3 -
H
O
NH 2

O
tBu
N
N
Ph
N
Li
THF, HMPA
TMSCl
But
H
O
H
N
Li
N
N
Me
Ph
C-C BOND FORMATION 78
OTMS
Lewis Acid Mediated Alkylation of Silyl Enolethers- SN1 like alkylations
OTMS tBu-Cl, TiCl 4,
CH 2Cl 2, -40°C
OTMS
(79%)
SPh
R Cl
TiCl 4, CH 2Cl 2, -40°C
(78%)
O CH3
O
C(CH 3) 3
SPh
R
note: alkylation with a
3° alkyl halide
Raney Ni
(95 %)
O
R
tBu
(97 % ee)
ACIEE1978, 17, 48
TL 1979, 1427
Enamines Gilbert Stork Tetrahedron 1982, 38, 1975, 3363.
- Advantages: mono-alkylation, usually gives product from kinetic enolization
O
O
N
H
H + , (-H 2 O)
-Chiral enamines
O O
N N
"Kinetic"
O
••
N
enamine
Imines Isoelectronic with ketones
Ph
N
OMe
LDA, THF, -20°C
N
Li
Me
O
N
R-I
"Thermodynamic"
Ph
1) E
2) H 3 O +
can not become coplanar
O
+
N
O
E
R
O
H 2 O
E
O
E
E = -CH 3 , -Et, Pr,
PhCH 2 -, allyl-
ee 87 - 99 %

C-C BOND FORMATION 79
Hydrazones isoelectronic with ketones Comprehensive Organic Synthesis 1991, 2, 503
O
Me 2 N-NH 2
H + , (-H 2 O)
N
+ E N
N N
E
hydrolysis
LDA, THF
- Hydrazone anions are more reactive than the corresponding ketone or aldehyde
enolate.
- Drawback: can be difficult to hydrolyze.
- Chiral hydrazones for asymmetric alkylations (RAMP/SAMP hydrazones- D. Enders
"Asymmetric Synthesis" vol 3, chapt 4, Academic Press; 1983)
N
N
E (C,C)
OMe
N N
N
LDA
NH 2
OMe
MeO
O
N
H 2 N
SAMP RAMP
I OTBS
OMe
Li ••
R1 N N
R 2 H
E
Me
O
TBSO
1) LDA
2) Ts-CH 3 , THF
-95 - -20 °C
3) MeI, 2N HCl
Z (C,N)
N
N
(95 % de)
O
N N
E
OMe
CH 3
-
O 3
(100 % ee)
R1 N N
Aldol Condensation Comprehensive Organic Synthesis 1991, 2, 133, 181.
H
O
R
a) LDA, THF, -78°C
b R'CHO
H
O
R
OH
R'
R 2
E
H
MeO
TBSO
-
β-hydroxyl aldehyde
(aldol)
- The effects of the counterion on the reactivity of the enolates can be important
Reactivity Li + < Na + < K + < R4N + addition of crown ethers
N N
O
H

C-C BOND FORMATION 80
- The aldol reaction is an equilibrium which can be "driven" to completion.
R
O - M +
R'
+ RCHO H
O
M
O
R
R'
work-up
In the case of hindered enolates, the equillibrium favors reactants. Mg 2+ and Zn 2+
counterions will stabilize the intermediate β-alkoxycarbonyl and push the equillibrium
towards products. (JACS 1973, 95, 3310)
O - M +
PhCHO, THF
O
OH
Ph
H
O
R
OH
M= Li 16% yield
M= MgBr 93% yield
- Dehydration of the intermediate β-alkoxy- or β-hydroxy ketone can also serve to drive
the reaction to the right.
O
O
H
O
tBuO - Na + , tBuOH
Enolate Geometry
- two possible enolate geometries
O
O
LDA, THF, -78°C
O
O
H
O
O - Li + O - Li +
E - enolate
- enolate geometry plays a major role in stereoselection.
Z -enolate
E -enolate
R 1
R 1
OM
OM
R 2
R 3 CHO
H
R 1
+
H R 2
R 2
H
R 3 CHO
- Zimmerman-Traxler Transition State : Ivanov condensation
JACS 1957, 79 , 1920.
O
Ph H
+
-
+
MgBr
+
PHCHCO 2 MgBr
-
R 1
Ph
O
O
H
R 2
O
OH
Ph
OH
R 3
R 3
"pericyclic" T.S.
R'
JACS 1979, 101 , 1330
H
Z - enolate
erythro
(syn)
threo
(anti)
H Br
O
Mg
OMgBr

Analysis of Z-enolate stereoselectivity
R 3
H
H
O
H
O
R 2
R 2
M
M
R 1
H
3
R R1
O
R 3
H
R 2
H
R 2
H O
H R 3
Analysis of E-enolate stereoselectivity
H
R 3
H
R 2
O
R 1
R 2 H
O M
R 1
R 1
R 1
M
O
O
R 3
H
H
R 3
O
H
C-C BOND FORMATION 81
R 2
M
R 1
erythro (syn)
favored
O
H
R 2
M
threo (anti)
disfavored
R H 3 H
H O M
O
O O
R M
M
O
3
O
H
M
R
3
R R1
2
O
O M
Analysis of Boat Transition State for Z-Enolates
R 3
H
R 3
O
O
H
R 2
R 2
M
H
H
Favored Chair
M
R 1
R 1
O
Disfavored Chair
O
H
R 2
H
R 3
R 1
R 1
R 1
O
O
O
R 2
R 2
HO
HO
R 3
R 3
H
H
R 2
R 1
R 1
threo (anti)
favored
O
H
M
R
R3 R1
erthro (syn)
disfavored
2
O
O
O
O
H
staggered
R 2
R 3
R3 R2 R 1
O
R 1 R 3
O
R 2
R 2
OH
OH
R 1 R 3
R 1
O
O
R 2
R 2
O
O M
H
Boat
H
R 1
OH
OH
O
R 1
R 3
R 3
O M
H
Boat: R1-R2 1,3-interaction is gone

Analysis of Boat Transition State for E-Enolates
R 3
H
H
R 3
O
O
H
R 2
H
R 2
M
Favored Chair
M
R 1
R 1
Disfavored Chair
O
O
R 1
R 1
O
O
R 2
R 2
HO
HO
R 3
R 3
C-C BOND FORMATION 82
H
staggered
H
R 3
R 3
R2
O
O M
Boat
H
H
R2
R 1
O
O M
R 1
Boat: R 1-R 2
1,3-interaction is gone
Summary of Aldol Transition State Analysis:
1. Enolate geometry (E- or Z-) is an important stereochemical aspect. Z-Enolates
usually give a higher degree of stereoselection than E-enolates.
2. Li + , Mg 2+, Al3+ = enolates give comparable levels of diastereoselection for kinetic
aldol reactions.
3. Steric influences of enolate substituents (R1 & R2) play a dominent role in kinetic
diastereoselection.
R 1
R 1
O - M +
H
R 2
O- M +
H
R 2
Path A
Path
B
Path A
When R1 is the dominent steric influence, then path A proceeds. If R2 is the dominent
steric influence then path B proceeds.
4. The Zimmerman-Traxler like transition state model can involve either a chair or boat
geometry.
Noyori "Open" Transition State for non-Chelation Control Aldols
Absence of a binding counterion. Typical counter ions: R4N + , K + /18-C-6, Cp2Zr 2+
- Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols
regardless of enolate geometry.
Z- Enolates:
R 3
R 1
O
R 1
H
H
H
H R3
O
O -
R 2
O -
R 2
Favored
Disfavored
R 1
R H
3 H R2 O
R 1
O
O -
O -
H H
R R
3 2
H
R 3
H
R 1
R 1
R 1
O
O -
O
O
H
O -
Favored
R1 H
O
Disfavored
R 3
R 2
R 2
R 2
R 2
HO
HO
R 3
R 3
R 1
R 1
O
R 2
HO
Syn Aldol
O
R 2
HO
Anti Aldol
R 3
R 3

E- Enolate:
R 3
- O
- O
H
H
O
H
H R3 O
R 1
R 2
R 1
R 2
favored
disfavored
- O
R1
R3 H
O
H R2 - O R1
H H
O
R R
3 2
R 3
- O
R 1
H
O
favored
H
- O
R 1
H
O
disfavored
R 3
H
R 2
R 2
C-C BOND FORMATION 83
NMR Stereochemical Assignment.
Coupling constants (J) are a weighted average of various conformations.
O
H
O
R 1
O
H
O
R 1
H A
R 3
H A
H B
R 2
60 °
H B
R 3
R 2
R 1
R 1
O
O
R 2
H
H
R 1
O
H A
60 °
R 2 HA
R 1
H B
HB R3 O
H
O HB
R 3
R 3
O
H
H A
O
H A
O
R 3
R 2
Syn Aldol
JAB = 2 - 6 Hz
O
R 3
R 1
Anti Aldol
JAB = 1 - 10 Hz
R 2
60 ° 60 °
H B
O
H A
H B
OH
R 2
non H-bonded
H B
R 1
H A
R 3
R 2
non H-bonded
OH
R 1
R 1
O
O
R 2
HO
Syn Aldol
R 2
HO
Anti Aldol
Boron Enolates: Comprehensive Organic Synthesis 1991, 2, 239. Organic Reactions 1995, 46, 1;
Organic Reactions 1997, 51, 1. OPPI 1994, 26, 3.
- Alkali & alkaline earth metal enolates tend to be aggregates- complicates
stereoselection models.
- Boron enolates are monomeric and homogeneous
- B-O and B-C bonds are shorter and stronger than the corresponding Li-O abd Li-C
bonds (more covalent character)- therefore tighter more organized transition state.
Generation of Boron Enolates:
O R 2 B-X OBR 2
iPrEtN
X= OTf, I
R= Bu, 9-BBN
R 3
R 3

R
R 3N:
R 3N:
O
R 1
H
R1 R2 OSiMe 3
O
N 2
H
H
+
O
R 2
+
O
H
R 3 B
R 2 B-X
R' 3B
_
BL 2OTf
_
BL 2OTf
R
R
OBR 2
OBR' 2
OBR 2
Diastereoselective Aldol Condensation with Boron Enolates
Ph
O
R 1
OBEt2 R2 Z-enolate
R 1
OBEt 2
R 2
E-enolate
R 3 CHO
OBEt 2
Ph
pure
Z-enolate
R 3CHO
R 1
R 1
O
O
R 2
R'
RCHO
R 2
OH
OH
R 1
C-C BOND FORMATION 84
OBL2 R2 Z-enolate
R 1
OBEt 2
R2 E-enolate
+ Me 3Si-X
Asymmetric Aldol Condansations with Chiral Auxilaries-
D.A. Evans et al. Topics in Stereochemistry, 1982, 13 , 1-115.
- Li + enolates give poor selectivity (1:1)
- Boron and tin enolates give much improved selectivity
Me
Me
1) Bu 2BOTf,
EtNiPr 2, -78°
2) RCHO
Bu
Bu
R 3
R 3
Hooz Reaction
O OBEt 2
Ph R
100% Syn Aldol
generally
> 95 : 5
syn : anti
generally
~ 75 : 25
anti : syn
O O
B
OH O O
Bu2BOTf, O - O +
EtNiPr2, -78°
RCHO
N O
R
N O
N O
Me
O
O
N O
Ph
R
OH
Me
O
X
> 99:1 erythro

L
O
L
B
_ +
_ _
N
O
L
O
B
L
O
Oppolzer Sultam
1) LDA
2) Bu 3SnCl
O
S
O
O
O
O
N
O
RCHO
H
R 2
O
R
R 3
H
H
+
L
O
H
R O
+
L
B
L
O
O
N O
L
L
B
_
O
O
B
_
O
N
O
preferred conformation
C-C BOND FORMATION 85
R
R
L
O
B
O
H
L O R3 B
Favored Disfavored
S
O 2
R 3
N
Sn
O
N
N
O
O
R 2
R 2
R 2
OH
R 3
R 3CHO
L 2B
N
S
O2 O
N
S
O2 O
R 2
L
O
R 2
O
N
R 3CHO
OH
R 3
O
R 3
N
O
R 2
R 2
OH
O
R 3
L
O
+
L
O
S
O 2
O
+
O
N O
N
N
O
R 2
O
OH
R 3

Chiral Boron
R
O
BOTf
StBu
iPrEt2N, PhCHO,-78°C
when large,
higher E-enolate
selectivity
Ph Ph
O
SPh
Ph
OH
O
StBu
+
1 : 33
(> 99 % ee)
C-C BOND FORMATION 86
Ph
ArO2SN NSO
B
2Ar OH O
Br
Ph
SPh +
Ph
iPrEt2N, PhCHO,-78°C
R
> 95 : 5
(> 95 % ee)
• In general, syn aldol products are achievable with high selectivity, anti aldols are
more difficult
Mukaiyama-Aldol- Silyl Enol Ethers as an enolate precursors.
Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with
aldehydes: proceeds via "open" transition state to give anti aldols starting from either
E- or Z- enolates.
OSiMe 3
OEt
OSiMe 3
OEt
RCHO, TiCl 4,
CH 2Cl 2, -78°C
RCHO, TiCl 4,
CH 2Cl 2, -78°C
Asymmetric Mukiayama Aldol:
Ph
H 3C
O
NMe 2
OSiMe 3
RCHO, TiCl 4,
CH 2Cl 2, -78°C
R
OH
CH 3
CO 2Et
+
R
OH
OH
R
OH
R= iPr (anti : syn) = 100 : 0
C 6H 11 94 : 6
Ph 75 : 25
R
OH
CH 3
CO 2Et
R= iPr (anti : syn) = 52 : 48
C 6H 11 63 : 37
Ph 67 : 33
OH O
R R c
(90-94% de)
+
+
R
OH
O
O
CH 3
CH 3
OH O
StBu
SPh
CO 2 Et
CO 2Et
R R c
syn : anti = 85 : 15
selectivity insenstivie to enolate geometry

Ph
N SO2Ph O OSitBuMe 2
O
OSitBuMe 2
SO 2 N(C 6 H 11 ) 2
iPrCHO, TiCl 4,
CH 2Cl 2, -78°C
RCHO, TiCl 4,
CH 2Cl 2, -78°C
R c
R c
O
O
HO
CH 3
HO
CH 3
C-C BOND FORMATION 87
96 % de
anti : syn = 93 : 7
+ Syn product
E-Enolate
R= Ph % de= 90 anti : syn = 91 : 19
nPr 85 94 : 6
iPr 85 98 : 2
Z-Enolate
R= iPr % de= 87 anti : syn = 97 : 7
Mukaiyama-Johnson Aldol- Lewis acid promoted condensation of silyl enol ethers with acetals:
O
OSiMe 3
O
Cl 4Ti
O
O
O +
Ph
TiCl 4 or SnCl 4
RCHO or RCH(OR') 2
CH 2Cl 2, -78°C
O
OTMS
OTMS
O
TiCl 4, CHCl 2, -78 °C
TiCl 4,
(CH 3) 2C(OEt) 2
(78 %)
Cl 4Ti
OH
R
HO
+
O
Ph
Mukaiyama-Johnson Aldol
via Ti or Sn enolate
O
O
O
O
O
O OEt
OSiMe 3
Fluoride promoted alkylation of silyl enol ethers Acc. Chem. Res. 1985, 18, 181
OSiMe 3
nBu 4NF, THF, MeI
O

Meyer's Oxazolines:
N
O
Ester
equiv.
(ipc) 2BOtf
iPrEt 2N, Et 2O
Anti-Aldols by Indirect Methods:
PhSe C 6H 11
1) TBS-Cl
2) DiBAl-H
O
3) TsCl
4) Ba(CN)BH 3
MeO
O
N
MeO
O
O
OTBS
chiral
auxillary
N
R
1) (C 5H 7) 2BOTf
R 3N
2) RCHO
OTBS
CO 2Me
N
(ipc) 2B R
HO
O
SePh
syn
aldol
CH 3 O 3
1) LDA, THF,
-78 °C
2) RCOCl
Syn Aldols by Indirect Methods:
O
O O
N
1) LDA, THF,
-78 °C
2) RCOCl
1) LDA, THF,
-78 °C
2) RCHO
MOMO
O
O O
N
N
O
O
OMOM
CH 3
O
N
1) RCHO
2) 3N H2SO4 3) CH2N2 (~ 30%)
OTBS
O
CH 3
R
C 6H 11
R
C-C BOND FORMATION 88
H 3C
OH
CO 2Me
+
R
H 3C
OH
R= nPr %ee (anti) = 77 anti : syn = 91 : 9
C 6H 11 84 95 : 5
tBu 79 94 : 6
1) HF
2) [O]
3) NaIO 4
4) CH 2 N 2
CH 3
R
CHO
OTBS
O
O
CH 3
CH 3
R
KBEt 3H, Et 2O,
-78 °C
Zn(BH 4) 2
Zn(BH 4) 2
R
HO
Anti Aldol
Product
CO 2Me
1) HIO 6
2) CH 2N 2 MeO2C
O
MOMO
MOMO
O O
N
N
CH 3
O
OMOM
N
OH
O
CH 3
OH
R
Anti Aldol
HO
CH 3
OMOM
R
HO
CH 3
CH 3
CO 2Me
R
CH 3
HO
CO 2Me
syn : anti
1 : 99
syn : anti
97 : 3
syn : anti = 100 : 1

Aldol Strategy to Erythromycin:
O
O
O
O
15
N
O O
N
Ph
O O
N
Ph
EtMgBr
86%
11
O
9
10
12
13 O
14 1
O 2
8
OH
3
7
Erythromycin
aglycone
5
4
6
OH
O LDA,
CH 3 CH 2 COCl
Ph
O O
3
83%, (96:4)
OH
syn
aldol
CHO
O
O Sn(OTf) 2 ,
Et 3 N, CH 2 Cl 2
8
5
CH 3 CH 2 CHO
84% (> 96:4)
O OH OTBS
11
N
OH
+
O O
Ph
1) 9-BBN, THF
2) Swern oxid.
73% (85:15)
13
O
1
HO2C 1
CHO
4
O O
N
CHO
4 3 2 1
OH OH O OH OH
[O] [O]
syn
aldol 3
O
O TiCl 4 , iPr 2 EtN,
CH 2 Cl 2
9
O
OH
O O
N
Ph
CHO
90% (> 99:1)
O OH
Ph
1) PMBC(NH)CCl3 TfOH
2) (PhMe2Si) 2NLi, TMS-Cl
48 %
OH
O
O O
C-C BOND FORMATION 89
O OH
O
syn
aldol
N
CHO
O O
Ph
CHO
CO 2H
O OH OH
syn
aldol 1
+
CHO
2
O OH
1) Na BH(OAc) 3
2) TBS-OTf, 2,6-lutidine
3) AlMe 3 , (MeO)MeNH•HCl
TMSO PMBO
OH
OH
3 5 9 11 13
11
13
72% (>99:1)
OTBS
5
+
CHO
MeO
N
CH 3
Erythromycin
seco acid
CO 2 H
CO 2H
1) Zn(BH 3 ) 2
2) (H 3 C) 2 C(OMe) 2
CSA
(100%)
O OH OTBS

O
O O
N
Ph
1) Zn(BH 3 ) 2
2) DDQ
O
95%
O O
N
Ph
L
Sn
L O
X
H3C H O
H
O
H
CH3 CH3 X
O
H
H L
CH3 H Sn
O
O L
H3C Disfavored
CH3 O
O
OH
X R
CH3 CH3 O
anti-syn
O
OH
X R
CH3 CH3 anti-syn
C-C BOND FORMATION 90
X
H
L O
CH
L
3
Ti H
O
L
O
Disfavored
H
CH3 CH3 X
H3C J. Am. Chem. Soc.
O L 1990,112, 866
H
H Ti L
O
O L
H
H3C CH3 O O
TMSO
CHO
PMBO
OTBS BF3•OEt2 ,
O O O O O
CH2Cl2 , -78 °C
+
O N
PMBO
OH
OTBS
3 5 7 11 13 83% (95:5)
3 5 7 9 11 13
8
O
O O
N
Ph
p-MeOC6H 4
O O O O OTBS
p-MeOC 6 H 4
13
O
11
p-MeOC 6 H 4
O O OH O O OTBS
O
10
9
12
O
1
2
O
8
3
7
5
4
O
6
O
1) LiOOH
2) TBAF
Ph
1) NaH, CS 2 , MeI
2) nBu 3 SnH, AIBN
70%
p-MeOC 6 H 4
O O O O O OH
HO
63% 13
1) Pd(OH) 2 , iPrOH
2) PCC
3) 1M HCl, THF
58 %
O
9
11
OH
5
13 O OH
1 3
O OH
Cl 3 C 6 H 2 COCl
iPr 2 EtN, DMAP
Michael Addition
- 1,4-addition of an enolate to an α,β-unsaturated carbonyl to give 1,5-dicarbonyl
compounds
Organometallic Reagents
Grignard reagents:
R-MgBr
Ph
O - M +
R
O
Mg(0)
R-Br R-MgBr
THF
O
THF
R
OH
+
O
Ph
O
O O
R
R
R
OH
often a mixture of
1,2- and 1,4-addition
(86%

R-MgBr
R-MgBr
O
THF, CeCl3 O
CuI,THF, -78C
R
OH
O
R
C-C BOND FORMATION 91
1,2-addition
1,4-addition
Organolithium reagents
- usually gives 1,2-addition products
- alkyllithium are prepared from lithium metal and the corresponding alkyl halide
- vinyl or aryl- lithium are prepared by metal-halogen exchange from the
corresponding vinyl or aryl- haidide or trialkyl tin with n-butyl, sec-butyl or t-
butyllithium.
X= Br, I, Bu3Sn
R-Br
Li(0)
Et2O R-Li
X Li
nBu-Li
Organocuprates
Reviews: Synthesis 1972, 63; Tetrahedron 1984, 40 , 641; Organic Reactions 1972, 19 , 1.
- selective 1,4-addition to α,β-unsaturated carbonyls
2 R-Li
O
CuI, THF
R 2 CuLi
Et 2 O
O
R 2CuLi
- curprate "wastes" one R group- use non transferable ligand
_
R-Li
MeO
Cu
MeO
R
Cu R
non-transferable
ligand
Other non transferable ligands
_
Bu3P Cu R Li +
_
Me2S Cu R Li + _
NC Cu R Li + _
F3B Cu R Li +
S
Cu
CN
R
2-
2Li +
Li +
Mixed Higher Order Cuprate
B. Lipshutz Tetrahedron 1984, 40 , 5005
Synthesis 1987, 325.
Addition to Acetals Tetrahedron Asymmtetry 1990, 1, 477.
H 3 C
O
R
R
O
R
O O CH 3
(n-C 6 H 13 ) 2 CuLi
BF3•OEt2
H CH3 Nu: H
R
n-C 6 H 13
O O
LA
O
CH 3
OH
R
1) PCC
2 NaOEt
OH
Chiral axulliary is destroyed 99 % ee
LA
O
H
O
Nu
n-C 6 H 13
CH 3
TL 1984, 25, 3087

O
O
TMS
1) TiCl 4
2) [O]
3) TsOH
OH
98 % ee
C-C BOND FORMATION 92
JACS 1984, 106, 7588
Stereoselective Addition to Aldehydes
- Aldehydes are "prochiral", thus addition of an organometallic reagent to an aldehydes
may be stereoselective.
- Cram's Rule JACS 1952, 74 , 2748; JACS 1959, 84 , 5828.
empirical rule
R 1
O
*
L
M
S
-
2) "H + 2 - "
1) "R
"
R1 R2 OH
L
M
S
O
OH
M S
M S
L R 1
2 -
R
- Felkin-Ahn TL 1968, 2199; Nouv. J. Chim. 1977, 1 , 61.
based on ab initio calculations of preferred geometry of aldehyde which considers the
trajectory of the in coming nucleophile (Dunitz-Burgi trajectory).
L
O
R 1
M
S
vs.
R 2 - R
2 -
R 1
L
R 2
better worse
- Chelation Control Model- "Anti-Cram" selectivity
- When L is a group capable of chelating a counterion such as alkoxide groups
R 1
O
M +
*
M +
S
O OR'
R 1
M S
OR'
M
2 -
R
R2 R 1
OH
OR'
OR'
HO R 2
R1 M S
S
M
S
M
O
R 1
L
"Anti-Cram" Selectivity
Umpolung - reversal of polarity Aldrichimica Acta 1981, 14, 73; ACIIE 1979, 18, 239.
i.e: acyl anion equivalents are carbonyl nucleophiles (carbonyls are usually electophillic)
PhCHO
R
O
-
usually
Benzoin Condensation Comprehensive Organic Synthesis 1991, 1, 541.
KCN
Ph
O -
CN H
Ph
OH
-
Cyanohydrin anion
PhCHO
HO
CN Ph
R
CN
O
+
O -
Ph Ph
- O
CN
OH
O OH
Ph Ph Ph
Benzoin

C-C BOND FORMATION 93
Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions
H3C
N
NH 2
+
N S
N
H3C
Thiamin pyrophosphate
CHO
H OH
H OH
H OH
H2C
OPO3
D-ribose-5-P
(C 5 aldose)
Trimethylsilycyanohydrins
OMs
O O
Dithianes
CN
R H
OEE
S S
R H
+
H
O TMS-CN
NaHMDS,
THF, -60°C
(72%)
Aldehyde Hydrazones
N
H
R H
N tBu
B:, THF
E +
H 2 C
OPO3PO3
O
H OH
H OH
H2C
OH
OPO3
D-ribulose-5-P
(C 5 ketose)
TMSO CN
R H
O O
NC
S S
R
-
thiamin-PP
OEE
H3C
H
LDA, THF
R'-I
N
CHO
NH2
N
OH
H2C OPO3
glyceraldehyde-3-P
(C 3 aldose)
CSA, tBuOH
N
R E
H
N tBu
TMSO CN
R
_
S S
R R'
Heteroatom Stabilized Anions (Dithiane anion is an example)
Sulfones
R S
O O
Ph
Sulfoxides
R S
O
Ph
LDA, THF
B:
_
R S
O O
LDA, THF R S
_
O
Ph
Ph
O
R' R'
O
R' R'
R'
R'
R S
R'
R'
OH
O O
OH
R S
O
Ph
H 3 C
+
Ph
_
+
N S
H2C
OH
O
HO H
H OH
H OH
H
OH
H2C OPO3
sedohepulose-7-P
(C 7 ketose)
O O
acyl anion
equivalent
Hg(II)
O
Al(Hg)
O
R E
Raney Ni
OPO3PO3
Tetrahedron Lett. 1997, 38, 7471
O
R R'
R'
R'
R'
R
R'
R
OH
OH

Epoxide Opening Asymmetric Synthesis 1984, 5, 216.
Ph
BnO
S
O
S
_
Basic (SN2) Condition
R
O
Acid (SN1-like) Condition
+
OH
R
Nu
O
H
O +
Nu:
BnO
OH
OH
Nu
R Nu
HO
R OH
Me2CuLi 6 : 1
AlMe3 1 : 5
O
Me3Al OH
O
1) TBS-Cl
2) MeI, CaCO 3, H +
S S
_
Ph
O
(69 %)
OH
+
Ph
OH
BnO
S
S
C-C BOND FORMATION 94
Steric Approach Control
Nu: attachs site that best
stabilizes a carbocation
Cyclic Sulfites and Sulfates (epoxide equivalents) Synthesis 1992, 1035.
R 1
OH
OH
O
S
O O
R 1
O O
S
O O
R 1
R 2
R 2
R 2
SOCl2, Et3N O
O
S
O
Nu:
Nu:
O
O
O S
O
R 1
R 1
S
O
R 1
O -
sulfite
O -
H
Nu
H
Nu
R 2
R 2
R 2
S
S
OH
RuCl 3, NaIO 4
H 2O
H 2O
Nu:
OH
OH
JACS 1981, 103, 7520
JOC 1974, 3645
TL 1983, 24, 1377
Tetrahedron Lett. 1992, 33, 931
HO
R 1
H
O O
S
O O
R 1
Nu2 R1 sulfate
H
Nu
R 2
H
R 2
R2 Nu1

O
MeO
O
R 1
O
SO 2
O
R 2
SO2 1) (CH OTBS
3) 2CuLi
CO2Me O
OBn
meso
SO 2
O
MeO
BnO
2) TBS-Cl
OBn
OMe
H3C HO
H
N
NCH 3
OAc
Δ
OMe
OBn
Irreversible Payne Rearrangement
O
O
SO 2
O
OH
OTBS
CO 2Me
CO 2Me
NaH
OMe
CH 3
OMe
CO 2Me
MeO
Bu 4NF
OBn
MeO 2C
R 1
1) H 2, Rh
2) HF
MeO OMe
NCH 3
OH
C-C BOND FORMATION 95
CO 2Me
OH
R 2
OBn
MeO
BnO
OH
O
O
O
OMe
O
1) Ac 2O
2) HCl
NCH 3
Payne Rearrangement of 2,3-epoxyalcohols Aldrichimica Acta 1983, 16, 60
Sigmatropic Rearrangements Asymmetric Synthesis 1984, 3, 503.
Nomenclature:
σ bond
that breaks
1
2 3
R
1 3 R
1 3
2
2
Δ
1
2 3
3
3
2
1
R H
1
4
5
Δ
2
1
R H
1
σ bond
that breaks
R
R
4
5
σ bond
that forms
σ bond
that forms
carpenter Bee
pheromone
OBn
[3,3]-rearrangement
[1,5]-Hydogen migration
3,3-sigmatropic Rearrangements
Cope Rearrangemets- requires high temperatures Organic Reaction 1975, 22, 1
R
Δ
R
OMe

Chair transition state:
"Chirality Transfer"
Ph
H 3C
R
Ph
H 3C
CH 3
Ph
R
R
CH 3
Ph
R
E
H H
3C
H
CH 3
220 °C
C-C BOND FORMATION 96
H 3C
E,Z (99.7 %) E,E (0.3 %) Z,Z (0 %)
Z
H3C H3C H 3C
H 3 C
H
H
E
E
HH
H 3C
CH 3
E
CH 3
CH 3
CH 3
E,Z (0 %) E,E (90 %) Z,Z (10 %)
Z
E
Ph
H 3 C
CH 3
E
Ph
H 3C
Ph
Z
CH 3
Ph
Z
H
S
CH 3
R
H
CH 3
CH 3
R
H
(87 %)
(13 %)
H
S
CH 3
Z
Z
Z
Diastereomers
Diastereomers
- anion accelerated (oxy-) Cope- proceeds under much milder conditions (lower
temperature) JACS 1980, 102 , 774; Tetrahedron 1978, 34, 1877; Organic Reactions 1993, 43,
93; Comprehensive Organic Synthesis 1991, 5, 795. Tetrahedron 1997, 53, 13971.

OH
OH OMe
KH
Ring expansion to medium sized rings
OH
KH, DME, 110°C
KH, Δ
O -
O
C-C BOND FORMATION 97
O
OMe
9-membered
ring
Claisen Rearrangements - allyl vinyl ether to an γ,δ-unsaturated carbonyl
Chem. Rev. 1988, 88, 1081.; Organic Reactions 1944, 2, 1.; Comprehnsive Organic Synthesis
1991, 5, 827.
O
O
H
OH
O
Hg(OAc) 2
Chair Transition State for Claisen
R O X
old stereogenic
center
R
H
O
O
R
H
O
H
R
O
O
H
Δ
X
1,3-diaxial
interaction
X
O
X
O
O
220 °C
R
O
R
O
E-olefin
O
R
O
H
X
CHO
O
Z-olefin
X
O
JACS 1979, 101 , 1330
X=H E/Z = 90 : 10
X= OEt, NMe 2, etc E/Z = > 99 : 1
X
new stereogenic
centers

C-C BOND FORMATION 98
- Chorismate Mutase catalyzed Claisen Rearrangement- 105 rate enhancement over
non-enzymatic reaction
CO2H OH
Chorismate
O CO 2H
Chorismate
mutase
HO 2C
OH
O
Prephenate
CO 2H
- Claisen rearrangement usually proceed by a chair-like T.S.
HO 2C
OH
H
O
OH
H
H
O CO2H H
CO2H CO2H Chair
T.S
Boat
T.S
HO 2C
O
OH
H
OH
H
H
H
CO 2H
O
CO2H J. Knowles
JACS 1987, 109, 5008, 5013
Opposite
stereochemistry
OH OH
OH
J. Org. Chem. 1976, 41, 3497, 3512
J. Org. Chem. 1978, 43, 3435
CH 3
O
H
CH 3
CH 3
R
R
H
O
O
s
O
CH 3
hydrophobically accelerated Claisen - JOC 1989, 54, 5849
OH
OH
H
CH3
CH 3
+
+
OH
OH
CH 3
O
R
R
H
H
O
O
O
H
s
CH 3
CH 3
Tocopherol
94 - 99 % ee
CH 3
CO 2 R

Johnson ortho-ester Claisen:
OH
H 3C-C(OEt) 3
H +
EtO OEt
O
Δ
- EtOH
Ireland ester-enolate Claisen. Aldrichimica Acta 1993, 26, 17.
Eschenmoser
O
O
O
O
Me Me
OH
"Chirality Transfer"
R
N
O
Ph
R= Et, Bn, iPr, tBu
OBn
R
EtO OEt
BF 3
LDA, THF
TMS-Cl
LDA, THF
TMS-Cl
NMe 2
Ph
O
Me
R
OTMS
O
Me
NMe 2
O
[3.3]
OBn
CO 2H
Δ
C-C BOND FORMATION 99
OEt
O
[3.3]
OH
O
JOC 1983, 48, 5221
[2,3]-Sigmatropic Rearrangement Comprehensive Organic Synthesis 1991, 6, 873.
H Z
R
:X Y
R
H
H
R
X Y:
X Y:
R 1
N
O
R
H
R
N
R
O
Ph
O
OEt
NMe 2
X Y: R R :X Y
H
aldehyde
oxidation state
(86 - 96 % de)
-Wittig Rearrangement Organic Reactions 1995, 46, 105 Synthesis 1991, 594.
O
O
_
SnR 3
base
BuLi
R 1
O
:X
HO
_
Y
R
E

TBDPSO
MeO
O
H
OH
KH, 18-C-6,
Me 3 SnCH 2 I
TBDPSO
MeO
H 3 C
O
(58%)
H
TBDPSO
MeO
O
H
CH 3
Sulfoxide Rearrangement
R
H
O -
S
O
O
O
OH
H
+
O
SnMe 3
nBuLi
TBDPSO
MeO
O
(42%)
H
TBDPSO
MeO
CH3 Ph
_
H3C CH3 Ph OH
_
Ph
CH3 Ph
CO2Et
S
O -
R
S
O
(MeO) 3 P
H3C Ph
(MeO) 3 P
O
O
CH 3
OH
C-C BOND FORMATION 100
H
O
HO
CO 2 Et
HO
Li
(87 %)
(13 %)
J. Am. Chem. Soc.
1997, 119, 10935
Ene Reaction Comprehensive Organic Synthesis 1991, 5, 1; Angew. Chem. Int. Ed. Engl. 1984, 23,
876; ; Chem. Rev. 1992, 28, 1021.
H H
- Ene reaction with aldehydes is catalyzed by Lewis Acids (Et2AlCl)
Ph
O
O
CHO
H
O
H
R
H
O
Et2AlCl
CH 2 Cl 2 -78°C
SnCl4
SnCl 4
R
Ph
O
O
H
OH
Ph
O
O
H 3 C
O
OH
JOC 1992, 57, 2766
OH
99.8 % de
+ syn isomer
(94 : 6)

PhS
+
O
H CO 2 Me
O
O TiCl 2
OH
C-C BOND FORMATION 101
CO 2 Me
(97% ee)
Tetrahedron Lett.
1997, 38, 6513
O
OH
OH
R
+
H CO2Me PhS
R
CO2Me +
(9 : 1)
PhS
R
CO2Me anti (99 % ee) syn (90 % ee)
- Metallo-ene Reaction Angew. Chem. Int. Ed. Engl. 1989, 28, 38
Cl
intramolecular
CHO
MgBr
1)
Li
CH 3
MgCl
C 6 H 13
2) SOCl 2 Cl
O
1) PCC
2) MeLi
3) O 3
CH 3
H
MgCl
CH 3
CHO
OH
BrMg
BrMg
+
H 3 C
1) Mg(0), Et 2 )
2) 60 °C
4) KOH
5) H 2
6) Ph 3 P=CH 2
SOCl 2
CH 3
H
H 3 C
CH 3
ClMg
ClMg
MgCl
O Capnellene
H
C 6 H 13
C 6 H 13
CH 3
H 2 O
H 2 O
MgCl
O 2
+
H 3 C
CH 3
H 3 C
H 3 C
(11 : 1)
CH 3
Cl 1) Mg(0), Et2)
2) 60 °C
CH 3
H
C 6 H 13
C 6 H 13
(10 %)
(> 1%)
MgCl
OH

C-C BOND FORMATION 102
Synthesis of Phyllanthocin A. B. Smith et al. J. Am. Chem. Soc. 1987, 109, 1269.
O O
O N
Ph CH 3
BnO
1)
-
BnO
O
O
2) H 3 O +
3) Swern
HO 2C
BnO
O
O
H
BnO
O
O
O
O
H
O
CH 3
MEMO
O
O
O
CH 3
O
(Me 3Si) 2NLi
O
O
Br
BnO
1) LDA, TMSCl
2) BnMe 3NF, MeI
O O
O N
Ph CH 3
1) O 3
2) H 2, Lindlar's BnO
1) ZnCl 2
2) H +
OH
BnO
MeO 2C
BnO
O
CHO
1) MEM-Cl
2) O 3 BnO
O
O
O
O
O
O
O
O
O
O
O
CH 3
CH 3
O
1) LAH
2) BnBr
Ph
MeAlCl
CHO
OMEM
(CH 3) 2S(O)CH 2 -
1) DBU
2) H 2, Pd/C
3) RuO 4
Phyllanthocin

C=C Bond Formation C&S Chapt. 2 # 5,6,8,9,12
C=C BOND FORMATION 103
1. Aldol Condensation
2. Wittig Reaction (Smith, Ch. 8.8.A)
3. Peterson Olefination
4. Julia-Lythgoe Olefination
5. Carbonyl Coupling Reactions (McMurry Reaction) (Smith Ch. 13.7.F)
6. Tebbe Reagent
7. Shapiro and Related Reaction
8. β−Elimination and Dehydration
9. From Diols and Epoxides
10 From Acetylenes
11. From Other Alkenes-Transition Metal Catalyzed Cross-Coupling and Olefin
Metathesis
Aldol Condensation -Aldol condensation initially give β-hydroxy ketones which under
certain conditions readily eliminated to give α,β-unsaturated carbonyls.
OMe
OMe OR
O
LDA, THF, -78°C
O
O
-78C → RT
CHO
OMe
OMe OR
O
O
O
Tetrahedron
1984, 40, 4741
Robinson Annulation : Sequential Michael addition/aldol condensation between
a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-1one
JOC 1984, 49 , 3685 Synthesis 1976, 777.
O
O
O
L-proline
O
O
Weiland-Mischeler Ketone
(chiral starting material)
Mannich Reaction - α,β-unsaturated carbonyls (α-methylene carbonyls)
O
H 2 C=O, Me 2 NH•HCl
H2C N Me
+ Me
Mannich Reaction
Cl -
O

C=C BOND FORMATION 104
Wittig Reaction review: Chem. Rev. 1989, 89, 863.
mechanism and stereochemistry: Topic in Stereochemistry 1994, 21, 1
- reaction of phosphonium ylide with aldehydes, ketones and lactols to give
olefins
R X
R 1
O
R 2
Ph 3P
- Olefin Geometry
+
Ph3P R
+
R PPh3 O -
betaine
X -
R 2
R 1
Ph 3P
L
Ph 3P
S
L S
O
O
S
L S
L
strong
base
Ph 3P
R
O
_
+
R PPh3 ylide
R 2
R 1
oxaphosphetane
Z- olefin
E- Olefin
- Ph 3P=O
R PPh3 phosphorane
- With "non-stabilized" ylides the Wittig Reaction gives predominantly Z-olefins.
Seebach et al JACS
L
O
S
S
L
PPh 3
+
O
L S
Ph3P L
L
L S
S
L
O
PPh 3
+
PPh 3
S
S
- "Stabilized ylides" give predominantly E-olefins
O
+
_
L S
Ph3P CO2Me O
L
S
L
- Ph 3P=O
S
CO 2Me
R
S
S
+
R 1
R 2
- O
L S
L
PPh 3
S
L L
Z-olefins

C=C BOND FORMATION 105
- Betaine formation is reversible and the reaction becomes under thermodynamic
control to give the most stable product.
- There is NO evidence for a betaine intermediate.
- Vedejs Model:
Ph
Ph
Ph
Ph
O
P
Ph
P
Ph
H
R
H
R
O
H
R
R
H
Cis
Trans
Phosphonate Modification (Horner-Wadsworth-Emmons)
R X
(EtO) 3P R P(OEt) 2
Arbazov Reaction O
Pukered (cis)
oxaphosphetane
(kinetically favored)
Planar (trans)
oxaphosphetane
(thermodynamically favored)
_
R P(OEt) 2
O
- R is usually restricted to EWG such as CO2H, CO2Me, CN, SO2Ph etc. and the
olefin geometry is usually E.
- Still Modification TL 1983, 24, 4405.
(CF 3CH 2O) 2P
O
CO 2Me
- CF3CH2O- groups make the betaine less stable, giving more Z-olefin.
Me CHO (CF CO
3Si 3CH2O) 2P 2Me O
(Me 3Si) 2N - K + , THF,
18-C-6
Me 3Si
Z:E = 25:1
CO 2Me
JACS 1988,
110, 2248
Peterson Olefination review: Synthesis 1984, 384 Organic Reactions 1990, 38 1.
LDA, THF
Me3Si CO Me
2Me 3Si CO2Me _
MeO 2C
Me 3Si
R 1
O
H
R 2
Silicon can stabilize
an α- negative charge
- Me 3Si-O
R 1
R 2
R 1
O
CO 2 Me
R 2
MeO 2C
Me 3Si
R 1
usually a mixture
of E and Z olefins
- O
H
R 2

Julia-Lythgoe Olefination TL 1973, 4833 Tetrahedron 1987, 43, 1027
O
PhO 2 S
O
O
SO 2Ph
H
O
R
HO
O
OBz
+
OR
LDA, THF, -78°C
OH
TBSO
O
OSitBuPh 2
SO 2Ph
CHO
PhO 2S
OH
1) tBuLi, THF,
HMPA, -78°C
2) Na(Hg) NaHPO 4
THF, MeOH, -40°C
OTBDPS
Ramberg-Backlund Rearrangement
Cl
O
S
O
Br
Br
OR
OR
OSiPh 2tBu
OSiPh 2tBu
MeLi, THF
R
SmI 2,
HMPA/THF
R= H, Ac
1) Na 2S•Al 2O 3
2) mCPBA
O
S
O
OTBS
O
HO
O
O
O
S
O
C=C BOND FORMATION 106
1) MsCl, Et 3N
2) Na(Hg), MeOH
OH
O
OBz
O
OSitBuPh 2
thiiarane dioxide
OR
OR
OTBS
R
mixture
of olefins
Tetrahedron Lett. 1993, 34, 7479
OTBDPS
75 % yield
E:Z = 3 : 1
OSiPh 2 tBu
OSiPh 2tBu
- SO 2
O
O
HO
OH
TL 1991,
32, 495
O
O
O
Milbemycin α 1
Synlett 1994, 859
SOCl 2
OR
OR
JACS 1992, 114, 7360
Carbonyl Coupling Reactions (McMurry Reaction)
Reviews: Chem. Rev. 1989, 89, 1513.
- reductive coupling of carbonyls with low valent transition metals, Ti(0)
or Ti(II), to give olefins
R 1
O
R 2
"low-valent Ti"
R 1
R 2
R 1
R 2
+
R 1
R 2
R 2
R 1
usually a mixture
of E and Z olefins
excellent method for the preparation of strained (highly substituted) olefins
- Intramolecular coupling gives cyclic olefins

O
OHC
OMe
OMe
CHO
"low-valent Ti"
CHO
TiCl 4 , Zn,
pyridine
(86 %)
OH OH
C=C BOND FORMATION 107
OMe
JACS 1984, 106, 723
OMe
Tetrahedron Lett. 1993, 34, 7005
Tebbe Reagent Cp2Ti(CH2)ClAlMe2
- methylenation of ketones and lactones. The later gives cyclic enol ethers.
Cp
H2 C
O O Ti AlMe2 Cp Cl
O
200 °C
- Cp2TiMe2 will also do the methylenation chemistry
JACS 1990, 112, 6393.
Shapiro and Related Reactions Organic Reactions 1990, 39, 1 : 1976, 23, 405
- Reaction of a tosylhydrazone with a strong base to give an olefin.
Et
Me
NNHTs
2 eq. nBuLi
THF
Et
Me
_
N N Ts
_
Et
Me
N
N _
O
_
- N Et 2 E Et +
Bamford-Stevens Reaction- initial conversion of a tosylhydrazone to a diazo
intermediate
R1 R2 H
R 3
NNHTs
base
R1 R2 H
N
R 3
N Ts
_
a: aprotic- decomposition of the diazo intermediate under aprotic conditions
gives and olefin through a carbene intermediate.
R1 R2 H
+ N
_
N
R 3
- N 2
R1 R2 H
R3 ••
Carbene
b. protic- decomposition of the diazo intermediate under protic conditions an
olefin through a carbonium ion intermediate.
R1
R2 H
+ N
_
N
R 3
H + R R1
2
H
R3 H
+ N
N
- N 2
R1 R2 H
+
R3
H
R1 R2 R 2
Me
H
+ N
_
N
R1
- H +
R 3
R3
R 2
R 1
R 3
Me
E

C=C BOND FORMATION 108
β- Eliminations
Anti Eliminations
- elimination of HX from vicinal saturated carbon centers to give a olefin,
usually base promoted.
- base promoted E2- type elimination proceeds through an anti-periplanar
transition state.
B:
R 3
R 1
X
H
R 4
- typical bases: NaOMe, tBuOK, DBU, DBN, DABCO, etc.
R 2
N N N N
DBN DBU DABCO
- X: -Br, -I, -Cl, -OR, epoxides
R
O
O
R R'
"unactivated"
O
B:
R
O
R 1
R 3
N
AlEt2 R OH
- or -
TMS-OTf, DBU
R'
Syn Elimination
- often an intramolecular process
R 1
H
R2 X
R 3
R 4
R 1
R 3
R 2
R 4
N
N
R 2
R 4
OH
BCSJ 1979, 52, 1705
JACS 1979, 101, 2738
O
X= Se Ph
O
S Ph
Cope Elimination- elimination of R2NOH from an amine oxide
OLI
+
Me2N=CH2 THF, -78°C
I -
O
NMe 2 mCPBA
THF
O O NMe2 1) Me2CuLi +
2) Me2N=CH2 CF -
3CO2 O
JACS 1977,
99 , 944
Tetrahedron
1977, 35 , 613
O
N
Me2 - O
- Me2NOH

R
H 3CHN
Selenoxide Elimination Organic Reactions 1993, 44, 1.
OH
R'
N
O
N SePh
Bu
O
3P: R
- or -
NO2 SeCN
R'
SeAr
H3C O H3C O
PhSeO2H, PhH, 60 °C
O
N
Ph
(82%)
mCPBA
H
H 3CHN
R
C=C BOND FORMATION 109
R'
Se
O SeAr
H 3 C
O
O H3C N
- ArSeOH
N
O
R
Ph
R'
JACS 1979,
101, 3704
JOC 1995, 60, 7224
JCS P1 1985, 1865
Dehydration of Alcohols
- alcohols can be dehydrated with protic acid to give olefins via an E1
mechanism.
- other reactions dehydrate alcohols under milder conditions by first converting
them into a better leaving group, i.e. POCl3/ pyridine, P2O5
Martin sulfurane; Ph2S[OCPh(CF3)2]2 JACS, 1972, 94, 4997 dehydration
occurs under very mild, neutral conditions, usually gives the most stable olefin
BzO
H
OH
MSDA, CH 2 Cl 2
BzO
H
JACS 1989,
111 , 278
Burgess Reagent (inner salt) JOC, 1973, 38, 26 occurs vis a syn elimination
H
R1 R2 R 3
R 4
OH
_ +
MeO2CNSO2NEt3 PhH, reflux
_ +
MeO2CNSO2NEt3 MeO2C -N
H
Olefins from Vicinal Diols
Corey-Winter Reaction JACS 1963, 85, 2677; TL 1982, 1979; TL 1978, 737
R
OH
R'
Im 2 C=S
O
R1 R2 OH R R'
S
O
SO2 O
R4 R3 R 3 P:
R R'
R 1
R 2
R 4
R 3

C=C BOND FORMATION 110
- vic-diols can be converted to olefins with K2WCl6 JCSCC 1972, 370; JACS
1972, 94, 6538
- This reaction worked best with more highly substituted diols and give
predominantly syn elimination.
- Low valent titanium; McMurry carbonyl coupling is believed to go through
the vic-diol. vic-diols are smoothly converted to the corresponding olefins under
these conditions. JOC 1976, 41 , 896
Olefins from Epoxides
R1 H
O
H
R2 R1 H
NCO
R 1
O
NC-Se -
H
H
H
R2 R 1
H
Ph 2 P -
HO
PPh2Me R2 H
Se -
R 1
R 2
+
- O
H
H
R 1
R 2
SeCN
HO
H
H
R 2
PPh 2
-Ph 2 MeP=O
R1
R 1
MeI
R 1
R2
H H
NCSe
R2 - O
From Acetylenes
- Hydrogenation with Lindlar's catalyst gives cis-olefins
R R' Co2 (CO) 8 R R'
R 1
Co 2(CO) 6
H
Bu 3SnH
H SnBu 3
R R'
From Other Olefins
Sigmatropic Rearrangements
- transposition of double bonds
Se
R 2
H
H 2, Rh
H
HO
H
H
H
R 2
PPh2Me +
"inversion "
of R groups
R 1
R R'
H
NCO
R 1
H R 2
R 2
H
Se -
H
"retention"
of R groups
Tetrahedron Lett. 1998, 39, 2609
Birch Reduction Tetrahedron 1989, 45, 1579
OMe OMe O
H 3O +

C=C BOND FORMATION 111
Olefin Isomerization- a variety of transition metal (RhCl3•H2O) catalyst will
isomerize doubles bonds to more thermodynamically favorable configurations
(i.e. more substituted, trans, conjugated)
Cl Cl
Ti
OH
RhCl 3 •3H 2 O
EtOH
OH
Olefin Inversion Tetrahedron 1980, 557
- Conversion of cis to trans olefins
- Conversion of trans to cis- olefins
OH
OH
C5H11 OH
CO 2 Me
R R' hν, PhSSPh R
I 2 , CH 2 Cl 2
HO
C 5 H 11
+
up to 80% ee
R'
JOC 1987,
52 , 2875
OH
OH
JACS 1992
114 , 2276
CO 2 Me
JACS, 1984, 107, xxxx
Transition Metal Catralyzed Cross-Coupling Reactions
Coupling of Vinyl Phosphonates and Triflates to Organometallic Reagents
- vinyl phosphates review: Synthesis 1992, 333.
O
O
O
R 2 CuLi
(EtO) 2 PCl
O
OP(OEt) 2
R
OP(OEt) 2
Li, NH 3 ,
tBuOH
R 2 CuLi
- preparation of enol triflates Synthesis 1997, 735
O
O
LDA, THF, -78°C
Tf 2 NPh
Tf 2 O, CH 2 Cl 2
N
tBu tBu
OTf
OTf
kinetic
product
O
thermodynamic
product
R
R

HO
- reaction with cuprates. Acc. Chem. Res. 1988, 25, 47
tBu
OTf
Ph 2CuLi
tBu
C=C BOND FORMATION 112
Ph
TL 1980,
21 , 4313
- palladium (0) catlyzed cross-coupling of vinyl or aryl halides or triflates with
organostannanes (Stille Reaction)
Angew. Chem. Int. Ed. Engl. 1986, 25, 508.; Organic Reactions 1997, 50, 1-652
HO
CHO
1)
OH
TESO TESO
Bu 3Sn
O
O
O
(-)-Macrolactin A
2
MgBr
BOMe
2) TESOTf, 2,6-lutidine
(52%)
PdCl 2(MeCN) 2
TESO
Bu 3SnH, AIBN
(38%)
OPiv
O
O
O 3, NaBH 4
(77%)
TBSO
OH
TBSO
TESO
CHO Bu3SnCHBr2, CrCl2 (42%)
Bu 3Sn
TESO
SnMe 3
TBSO
I
TBSO
1)LDA, Tf 2NPh
2) Pd(PPh 3) 4
Bu 3Sn
TESO OTES
TESO
I
OTBS
Bu 3Sn
1) O 3, Me 2S
2) allyl bromide, Zn
3) Dess-Martin
Periodinane
(70%)
OPiv
CO 2H
OH
O
a) nBu3SnH, (Ph3P) 2PdCl2 b) I2 (83%
O
Bu 3Sn
1) Dess-Martin
Periodinane
2) Ph 3P + CH 2I, I -
NaHMDS
3) DIBAL
(50%)
SnBu 3
I
I
O
OH
TBSO OH
I
CO 2H
TBSO
PdCl 2(MeCN) 2
(65%)
I
OH
JOC 1986,
51 , 3405
TESO OTES
I
TBSO
TESO
J. Am. Chem. Soc.
1998, 120, 3935
1) HF, MeCN
2) Me4NBH(OAc) 3
3) TBSCl, imidazole
(76%)
OH
OH
CO 2H

Bu 3 Sn
Bu 3Sn
TESO
I
TESO
TESO
TESO
O
CO 2H
O
+
TESO
1) Pd 2(dba) 3
iPr 2NEt
2) TBAF
(35%)
I
TESO
C=C BOND FORMATION 113
HO
HO
OH
OH
(-)-Macrolactin A
Ph 3P, DEAD
palladium (0) catalyzed carbonylations- coupling of a vinyl triflate with a
organostanane to give α,b-unsaturated ketones.
But
OTf
Me 3SnPh
Pd(0), CO
tBu
O
Ph
JACS 1994,
106 , 7500
Nickel (II) Catalyzed Cross-Coupling with Grignard Reagents (Kumada
Reaction): Pure Appl. Chem. 1980, 52, 669 Bull Chem. Soc. Jpn. 1976, 49, 1958
AcO
Br OMe
N
H
X
Aryl or vinyl halide or triflate
OAc
R-MgBr
(dppp)NiCl 2
Br
1) Ni Ni
Br
(2 equiv), 65 °C
2) LiAlH 4, Et 2O
(72%)
O
R R= alkyl, vinyl or aryl
N
H
HO
(±)-Neocarazostatin B
OMe
OH
(50%)
O
Tetrahedron Lett.
1998, 39, 2537, 2947,
Olefin Metathesis Tetrahedron 1998, 54, 4413, Acc. Chem. Res. 1995, 25, 446.
R +
1 R2
(CH 2) n
(CH 2) n
catalyst
catalyst
olefin
metathesis
(CH 2) n
catalyst
(CH 2) n
n
R 1
R 2
Ring-Opening Metathesis
Polymerization (ROMP)
Ring-Closing Metathesis
(RCM)

Metathesis Catalysts:
H3C F3C F3C Mechanism:
iPr
F3C F3C N
O Mo
O
CH 3
iPr
Schrock' s Catalyst
R 1
R 1
R 2
Ph
(C 6H 11) 3P
Cl
Ru
Cl
(C6H11) 3P
Grubbs' Catalyst
C=C BOND FORMATION 114
Ph
Ph
+ [M]
R1 [M]
[M]
R 1
R2 +
[M]
(C6H11) 3P
Cl
Ru
Cl
(C6H11) 3P
R 2
Ph

C≡C Bond Formation
1. From other acetylenes
2. From carbonyls
3. From olefins
4. From Strained Rings
5. Eschenmosher Fragmentation
6. Allenes
C≡C BOND FORMATION 115
From Other Acetylenes
- The proton of terminal acetylenes is acidic (pKa= 25), thus they can be
deprotonated to give acetylide anions which can undergo substitution reactions
with alkyl halides, carbonyls, epoxides, etc. to give other acetylenes.
R 1
R H R
_
M +
R 1-X
O
Et 2AlCl
R 2
O
R R 1
- Since the acetylenic proton is acidic, it often needs to be protected as a
trialkylsilyl derivative. It is conveniently deprotected with fluoride ion.
R 3
R
R
OH
OH
R3 R2 F
R H R SiR3 R H
-
B:, R3SiCl Acetylide anions and organoboranes
_ Li +
R 3B
R 1
Palladium Coupling Reactions:
iPr 3Si SnBu 3
O
BR 3
O
_
Cl Cl
(Ph 3 P) 4 Pd
Li +
iPr 3Si
I 2
O
O
R 1 R
SiiPr 3
JOC 1974, 39 , 731
JACS, 1973, 95 , 3080
JACS 1990,
112, 1607

TBSO
HO
OTBS
OTBS
HO
CO 2Me
Copper Coupling- 1,3-diynes
R 1
+
R 2
Br C 5 H 11
OTBS
Pd(Ph 3P) 4, CuI
iPr 2NH, PhH
Cu(OAc) 2
R 1
OH
TBSO
OH
C≡C BOND FORMATION 116
C 5H 11
R 1
OTBS
OTBS
CO 2H
CO 2Me
JACS 1985,
107, 7515
Adv. Org. Chem.
1963,4 , 63
Nicholas Reaction
- acetylenes as their Co2(CO)8 complex can stabilize an α-positive charge,
which can subsequently be trapped with nucleophiles.
R 1
N CO 2 Me
Nu:
Co 2 (CO) 6
OR 4
R2 R3 R 1
Co 2(CO) 8
(CO) 6Co 2
Tf 2 O, CH 2 Cl 2 ,
MeNO 2 , -10°C
tBu N tBu
Nu
R2 R3 (OC)6Co2
(CO) 6Co 2
R 1
O
OR 4
R2 R3 oxidative
decomplexation
N CO2Me
Co2(CO)6-acetylene deocomplexation: JOC 1997, 62, 9380
From Aldehydes and Ketones
I 2
R 1
(CO) 6 Co 2
R 1
Nu
R2 R3 O
+
N CO 2 Me
R
RCHO
P3P, CBr4 R
Br
R
Li R
Br
+
R'-X
2 eq. nBuLi
_
ClCO2Et H2O R
R2 R3 JCSCC 1991, 544
R'
CO 2Et
H

OHC
OSitBuPh 2
OHC OSitBuPh 2
CBr 4 , Ph 3 P
Br 2 C
Br2C
OSitBuPh2
OSitBuPh 2
C≡C BOND FORMATION 117
a) nBuLi,
THF, -78°C
b) ClCO 2 Me
MeO 2 C
MeO2C
- by conversion of ketones to gem-dihalides followed by elimination
R
O
R'
PCl 5
Cl Cl tBuOK
R'
R
- HCl
R
Cl
R'
tBuOK
- HCl
OSitBuPh 2
OSitBuPh 2
JACS 1992, 114 , 7360
R R'
- by conversion of ketones to enol phosphates followed by elimination
R
O
R'
LDA, (EtO) 2P(O)Cl
R
O P(O)(OEt) 2 LiNH 2, NH 3
- Insertion reaction of a vinyl carbene (terminal acetylenes)
O
R R'
N 2
N2CHP(O)(OMe) 2
C
tBuOK R R'
O
Me3Si THF,
_
N2 -78°C → RT
R'
-N 2
+
C
••
R R'
R R'
R R'
Via Elimination Reactions of Vinyl Halides
- Treatment of vinyl halides with strong base gives acetylenes.
R
X
H
R'
X= Cl, Br, I, OTf, O 3SR, OP(O)R 2
Base
- HX
R R'
Base= LDA; tBuOK; NaNH 2, DBU
JOC 1987,
52 , 4885
JOC 1982,
47 , 1837
Synlett 1994, 107
- Addition of Grignard reagents to 1,1-difluoroethylene yields an acetylide anion
which can be subsequently trapped with electrophiles.
R-MgX
H 2 C=CF 2
R
_
E +
R E
TL 1982, 23 , 4325
JOC 1976, 41 , 1487
Strained Rings Topics in Current Chemistry 1983, 109, 189.
- Cyclopropenones and cyclobutendiones can be photolyzed or thermolyzed
(FVP) to give acetylenes.
O
O
hν (209 nm)
8 °K
C O
C
O
- CO - CO JACS 1973,
O
95 , 6134
Benzyne

R 2
R 1
Eschenmoser Fragmentation
O
O
R'
O
1) 370 °C
2) 12°K
- CO
FVP
(retro- D-A)
N
N
Ph
R R
tBuOOH,
triton B, C 6 H 6
Allenes Tetrahedron 1984, 40, 2805
- from dihalocyclopropanes
R
R
R'
Br
Br
R
R'
- From SN2' Reactions
Nu:
R
O
Br
O
O
R'
Ph
R 1 R 2 +
iPr
Base
-or-
heat
HN
iPr
NH2 iPr
AcOH, CH 2Cl 2
R
_ ••
X
R'
R'
C≡C BOND FORMATION 118
ACIEE 1988,27 , 398
JACS 1991, 113 , 6943
CL 1982, 1241
O
Nu
R
O
R
R'
HCA 1972,
55 , 1276
H
R'
H
R
JOC 1992, 57, 7052
- from sigmatropic rearrangements from propargyl sulfoxides and phosphine
oxides.
OH
R'
Ph 2PCl, Et 3N
R
Ph
Ph
:P
O
R'
O
Ph 2P
R
R'
H
R'
H
TL 1990, 31 , 2907
JACS 1990, 112 , 7825

Functional Group Interconversions
C&S Chapter 3 #1; 2; 4a,b, e; 5a, b, d; 6a,b,c,d; 8
1 sulfonates
2 halides
3 nitriles
4 azides
5 amines
6 esters and lactones
7 amides and lactams
FUNCTIONAL GROUP INTERCONVERSIONS 119
Sulfonate Esters
- reaction of an alcohols (1° or 2°) with a sulfonyl chloride
R'SO
O
2Cl
R OH R O S
O
R'
sulfonate ester
R'= mesylate
CH 3
CF 3
CH 3
triflate
tosylate
- sulfonate esters are very good leaving groups. Elimination is often a
competing side reaction
Halides
- halides are good leaving groups with the order of reactivity in SN2 reactions
being I>Br>Cl. Halides are less reactive than sulfonate esters, however
elimination as a competing side reaction is also reduced.
- sulfonate esters can be converted to halides with the sodium halide in acetone
at reflux. Chlorides are also converted to either bromides or iodides in the same
fashion (Finkelstein Reaction).
O
R O S
O
X
R' R X
-
R Cl
NaI, acetone
reflux
R I
X= Cl, Br, I
- conversion of hydroxyl groups to halides: Organic Reactions 1983, 29, 1
- R-OH to R-Cl
- SOCl2
- Ph3P, CCl4
- Ph3P, Cl2
- Ph3P, Cl3CCOCCl3
R OH R X

- R-OH to R-Br
- PBr3, pyridine
- Ph3P, CBr4
- Ph3P, Br2
- R-OH to R-I
- Ph3P, DEAD, MeI
FUNCTIONAL GROUP INTERCONVERSIONS 120
Nitriles
- displacement of halides or sulfonates with cyanide anion
- dehydration of amides
- POCl3, pyridine
- TsCl, pyridine
- P2O5
- SOCl2
R X
O
R NH 2
KCN, 18-C-6
DMSO
R C N
R C N
- Reaction of esters and lactones with dimethylaluminium amide
TL 1979, 4907
O
Me
O Ar
- Dehydration of oximes
R CHO
Me 2AlNH 2
H 2NOH•HCl
- Oxidation of hydrazones
N
NMe 2
H 3C
NC
Ar
N OH
R H
O
O
(97%)
- Reduced to aldehydes with DIBAL.
DIBAL
RC≡N
OH
P 2O 5
C
N
RCHO
JOC 1987, 52, 1309
R C N
Tetrahedron Lett.
1998, 39, 2009

FUNCTIONAL GROUP INTERCONVERSIONS 121
Azides
- displacement of halides and sulfonates with azide anion
O
O
SO 2 N(C 6 H 11 ) 2
LDA, THF
NBS
O
O
NH
SO2N(C6H11 ) 2
2
- activation of the alcohol
R OH
JOC 1993, 58, 5886
O
HO
+
(99.6 % ee)
+
N F
Me
TsO -
O
O
Br
SO2N(C6H11)2
R OH + EtO 2C N N CO 2Et
R-OH
(PhO) 2P(O)-N3 DBU, PhCH3 DEAD
R O
+
PPh3 - Photolyzed to aldehydes
Amines
- Gabriel Synthesis
O
O
N -
Ar
O
K + R X
- reduction of nitro groups
H2, Pd/C
Al(Hg), H2O
NaBH4
LiAlH4
Zn, Sn or Fe and HCl
H2NNH2
sodium dithionite
HO
+
N OR
Me
O P(OPh) 2
O
NaN 3
NH 2
Ph 3P, NaN 3
+ DBU-H + + N 3 -
O
O
N
R
O
O
SO2N(C6H11 ) N3 2
TL 1986, 27, 831
R N 3 +
EtO2C +
PPh3 N
_
N
CO2Et
activated alcohol
R N 3 + Ph 3P=O
H 2NNH 2
R NO 2 R NH 2
SN2
(91 %)
R NH 2
O
N O
Me
N 3
(97.5 % ee)

- reduction of nitriles
H2, PtO2/C
B2H6
NaBH4
LiAlH4
AlH3
Li, NH3
- reduction of azides
H2, Pd/C
B2H6
NaBH4
LiAlH4
Zn, HCl
(RO)3P
Ph3P
thiols
FUNCTIONAL GROUP INTERCONVERSIONS 122
R C N R CH2 NH2 R N 3 R NH 2
- reduction of oximes (from aldehydes and ketones)
H2, Pd/C
Raney nickel
NaBH4, TiCl4
LiAlH4
Na(Hg), AcOH
- reduction of amides
H2, Pd/C
B2H6
NaBH4, TiCl4
LiBH4
LiAlH4
AlH3
- Curtius rearrangement
O
R Cl
N OH
R R'
O
R N
NaN 3
R''
R'
R N O
isocyanate
O
••
R N N
+
N
H 2O
••••
NH 2
R R'
R N R'
Δ
- N 2
R''
R NH 2
O
••••
R N
nitrene

Tf
Tf
- reductive aminations of aldehydes and ketones
- Borsch Reaction
- Eschweiler-Clark Reaction
- alkylation of sulfonamides
N
N
HN
Tf
HN Tf
K 2 CO 3 , DMF
110°C
Br
- transaminiation
Br
FUNCTIONAL GROUP INTERCONVERSIONS 123
Tf Tf
N N
Tf
O N Ph
PhCH2NH2 H +
N
N
tBuOK
Tf
Na, NH 3
NH
NH
HN
HN
TL 1992, 33 , 5505
cyclam
N Ph NH 2
H 3O +
Esters and Lactones
- Reaction of alcohols with "activated acids"
- Baeyer-Villigar Reaction Organic Reactions 1993, 43, 251
- Pd(0) catalyzed carboylation of enol triflates
OTf CO, DMF
Pd(0), ROH
CO2R TL 1985, 26 , 1109
Can. J. Chem.
1970, 48, 570
- Arndt-Eistert Reaction Angew. Chem. Int. Ed. Engl. 1975, 15, 32.
O
R Cl
CH2N2 Et2O R
O
N2 diazo ketone
Wolff R
Rearrangement C O R'OH
H
ketene
O TsN3, Et3N R
CO2Me - Diazoalkanes: carbene precursors
R-CHO
1) NH 2NH 2
2) Pb(OAc) 4, DMF
H 2N
N
R 3N
R R
R-N 2
hν
ROH
R
O
••
R CH
R
O
TsN 3 N2
O
N 2
OR'
JOC 1995, 60, 4725
R R
- Halo Lactonizations review: Tetrahedron 1990, 46 , 3321
CO 2 H
I 2 -KI
H 2 O, NaHCO 3
O
H
I
+
O
I
O
O

CO 2H
- Selenolactonization
O
OH
PhSeCl, CH 2Cl 2
FUNCTIONAL GROUP INTERCONVERSIONS 124
Pd(OAc) 2
(5 mol %)
DMSO, air
(86%)
PhSe
O
O
O
H 2O 2
O
JOC 1993, 58, 5298
O
O
JACS 1985,
107 , 1148
- Mitsunobu Reaction Synthesis 1981 , 1; Organic Reactions, 1991, 42, 335
Mechanism: JACS 1988, 110 , 6487
OH
R R'
DEAD, Ph 3 P
O
O R''
R''CO 2 H R R'
Inversion of alcohol
stereochemistry
Amides and Lactams
- reaction of an "activated acid" with amines
- Beckman Rearrangement Organic Reactions 1988, 35, 1
O
R R'
- Schmidt rearrangement
- others
O
OTf
O
OTHP
O
R R'
CO, DMF
Pd(0), R 2NH
PhCH 2NH 2
AlMe 3
N OH
R R'
HN 3
PCl 5
O
H + R NR'
O NR 2
OH
O
-Weinreb amide Tetrahedron Lett. 1981, 22, 3815
O
R OR'
H 3CNH(OCH 3) •HCl
AlMe 3
O
R N
CH 3
OCH 3
N
H
OTHP
O
R NR'
TL 1985, 26 , 1109
Ph
DIBAL
R 1-M
TL 1977, 4171
O
R H
O
R R 1

3 Membered Rings
1. epoxides
a. peracids, hydroperoxides and dioxiranes
b. transition metal catalyzed epoxidations
c. halohydrins
d. Darzen's condensation
e. sulfur ylides
2. cyclopropanes
a. Simmons-Smith reactions
b. diazo compounds
c. sulfur ylides
d. SN2 displacements
3. aziridines
a. nitrenes
b. SN2 displacements
THREE-MEMBERED RING FORMATION 125
Epoxides
- peracid, hydroperoxide and dioxirane oxidation of alkenes
- transition metal catalyzed epoxidation of alkenes
- Sharpless epoxidation
- Metal oxo reagents (Jacobsen's reagent)
- from halohydrins
- Darzen's Condensation
BrCH 2 CO 2 Et
B:
NBS, H 2 O
O
_
BrCHCO2Et R R'
Br
OH
bromohydrin
- sulfur ylides Chem. Rev. 1997,97, 2421.
O
Me S +
+
CH - Me
Me
2SCH -
2
2
O
Ph S
NMe 2
R
R'
CH 2 -
Corey Johnson
sulfoximine
base
O -
Br
CO 2Et
O
_
+
SPh 2
Trost
R
R'
O
CO 2Et

THREE-MEMBERED RING FORMATION 126
- dimethylsulfoxonium methylide and dimethylsulfonium methylide
(Corey's reagent) review: Tetrahedron 1987, 43 , 2609.
O
R R'
O
R R'
DMSO, NaH
- O SMe 2
R R'
O
O
R R'
- cyclopropyldiphenylsulfonium ylide (Trost's reagent) ACR 1974, 7, 85.
+
_ SPh2 -
O SPh2 O BF3
R R'
- sulfoximine ylides (Johnson's reagent) ACR 1973, 6 , 341
O
O
-
Ph S CH2 NMe2 O
R R'
R R'
Cyclopropanes
- Simmons-Smith Reaction Org. Reactions 1973, 20, 1.
- sulfur ylides
ZnCu + CH 2 I 2
ICH 2 ZnI
- polar groups (-OH, -NR2- CO2R) can direct the cyclopropanation
OH OH
Ph
O
ZnCu, CH 2I 2
O
Ph
O
Me 2S
CH 2 -
O _
Ph S
NMe2 O
Ph
R
R'
JACS 1979, 101 , 2139
Tetrahedron
1987, 43 , 2609
O
Ph
R
ACR 1973,
6 , 341
O
R'

(MeO) 2 HC
Ph
THREE-MEMBERED RING FORMATION 127
- diazo alkanes and diazo carbonyls Synthesis 1972, 351; 1985, 569
- cyclopropanation with diazoalkanes; olefin requires at least on electron
withdrawing group.
MeO 2 C
CO 2 Me
CH 2 N 2
MeO 2 C
(MeO) 2 HC
N
N
CO 2 Me
hν
(MeO) 2 HC
CO 2 Me
MeO 2 C JACS 1975,
97 , 6075
- diazoketones; photochemical or metal catalyzed decomposition of
diazoketones to carbenes followed by cyclopropanation of olefins.
Org. Rxns. 1979, 26, 361; Tetrahedron 1981, 37, 2407
N 2
O
O
O
N 2 CuSO4 , Δ
O
O
Rh 2(OAc) 2
Ph
Ph
O
Ph
O
JACS 1970, 92 , 3429
JACS 1969, 91 , 4318
O
O
91 % yield
O
89 % de
JACS 1993, 115, 9468
Asymmetric cyclopropanation: Doyle, Chem Rev. 1998, 98, 911
Aldrichimica Acta 1997, 30, 107
O
O CO2Et
- SN2 Reactions
CO 2Et TsN 3, Et 3N
O
O
Br
C 5H 11
- SPh
CO 2Et
C 5H 11
O
O
N 2
CO 2Et
O
C 5H 11
CO 2Et
SPh
DBU O
O
CO 2Et
C 5H 11
O
JACS 1978,
99 , 1940
JACS 1977,
99, 1940
- Electrophillic Cyclopropanes review: ACR 1979, 12 , 66
in many ways, cyclopropanes react silmilarly to double bonds
- homo-1,4-addition
Nu:
CO 2R
CO 2R
Nu
CO 2R
CO 2R
ACR 1979,12 , 66

Aziridines
OMe
THREE-MEMBERED RING FORMATION 128
Nu:= malonate anion, amines, thiolate anion, enamines, cuprates
(usually requires double activation of cyclopropane)
H
OH
H
MeO 2C
R 2
R 1
O
- hydrogenation
CO2Me CH2I2, Zn-Cu
H 2, PtO 2,
AcOH
- hydrolysis
CH 2I 2, Zn-Cu
R 3
H
MeO
Cu(acac) 2
PhN=ITs
Me 2CuLi
O
H
OH
R2 R1 CO 2Me
Ts
N
MeO 2C
CO 2Me
Me
O
H + , MeOH
R 3
ArCO 3H,
Na 2 HPO 4
TL 1982, 23 , 1871
O
TL 1976, 3875
OH
H
J. Org. Chem. .1991, 56, 6744
O
CO 2Me
JACS 1967
89 , 2507

4 Membered Rings
1. cyclobutanes & cyclobutenes
2. oxatanes
FOUR-MEMBERED RING FORMATION 129
Cyclobutanes
- [2+2] cycloadditions
- photochemical cycloadditions (2πs +2πs)
Acc. Chem. Res. 1968, 1, 50; Synthesis 1970, 287; Acc. Chem. Res. 1971, 4, 41;
Organic Photochemistry 1981, 5, 123; Angew. Chem. Int. Ed. Engl. 1982, 21, 820;
Acc. Chem. Res. 1982, 15, 135; Organic Photochemistry 1989, 10, 1
Organic Reactions 1993, 44, 297
- for synthetic purposes, cyclic α,β-unsaturated carbonyl are the most
useful.
O
O
+
- symmetry requirements
CH2 CH2 Hot Ground State?
O
H
N
+
CH 3
O
hν
CH 3
E
1 E*
intersystem
crossing
hν
2πs + 2πs O
~ 340 nm
HOMO
- enones with olefins
hν
hν
O
H 2C=CH 2
hν, CH 2Cl 2
O
Ph CH 3
LUMO
3 E*
O O O
O
(90%)
O
+ +
+
Base
H 2C=CH 2
O H
2πs + 2πa
thermal cyclization
H
N
CH 3
O
CH 3
O H
H
HO
O
*
O
H
Caryophellene
isomerization
JCSCC
1966, 423
E.J. Corey
JACS 1963,
85 , 362
cis
ring-fusion
CH 3 grandisol
JACS 1986,
108 , 306

H 3 C
O
hν
- enones with acetylenes
O H
H
FOUR-MEMBERED RING FORMATION 130
O H
O hν O O
O
- DeMayo Reaction
O
O
O
CH 3
O
O
O
O
R
O
hν, pyrex
hν
controls
conformation O
O
CH3 controls
addition
O
favored
O
O
O
disfavored
O
R
H
hν
O
+ JACS 1984
106 , 4038
2 : 1
O
H
pTSA, MeOH
reflux
70-80 % de
H 3 C
O
O
O
H 3 C
H
H
H
CH3 O
O
O
MeO 2C
- Photochemistry of Ketones (Norrish Type I and II reactions)
HO
O
hν
254, 307 nm
Yang
reaction
H
O•
•
OH
•
Norrish II
cleavage
•
Norrish I
cleavage
H
O
H
H
O
O
H
H 3 C
O
OH
H
• •
H
CO 2 Me
+
R
H 3 C
O
JACS 1982
104, 5070
O
O
O
JACS 1986,
108 , 6425
H
H
H
CH3 TL 1993, 34, 1425

FOUR-MEMBERED RING FORMATION 131
- filtering photchemical reaction to prevent Norrish reactions
quartz 180 nm
Vycor 200 nm
Pyrex 280 nm
Uranium glass 320 nm
MOMO
SEMO
- Yang Reaction
CH 3
O
hν (254 nm)
C6H6 MOMO
SEMO
- thermal cycloadditons (2πa + 2πs)
- symmetry requirements
- ketenes
2π a + 2π s
R
H
Cl
O
O
O
O
O
Cl
Cl
N 2
Δ
Et 3N
Zn
hν
R
H
H
H
CH 3
O HOMO
LUMO
O
O
O
O
OH
JACS 1987,
109 , 3017
- thermal cyclization of ketene with olefins
Tetrahedron 1986, 42, 2587; 1981, 37, 2949; Organic Reactions 1994, 45, 159.
p z
p y
LUMO
of ketene
2πa
O
HOMO
of olefin
2πs

H 3C
H 3C
O
O
N
Ph
O
N +
Ph O
CH 3
OMe
1)
CH 3
2) H 2O
CCl 3
O
Cl
Zn-Cu, Et 2O
H3C H3C FOUR-MEMBERED RING FORMATION 132
Cl
Cl
O
O CH 3
Ph
N +
-reaction of ketene with enamines
NR 2
H
H
O
R'
OMe
O
NR 2
O
O
R'
CH 3
O
NR 2
CH 2N 2
H
H
Cl
Cl
R*O
O
Ar
JACS 1987,
109 , 4753
CH 3
JACS 1982, 104, 2920
- reaction of ketene with imines to give β-lactams (Staudinger Reaction)
+
R H
N
Bn
R
N
CH 2Cl 2
-78°C → 0°C
H
H
Ph
O
O
N
O
H
H
R
O
O
N
Bn
- reaction of difluorodihaloethylene with olefins
Organic Reactions 1962, 12, 1
R
F 2C=CX 2
X= F, Cl
F
F X
R
NR
Ph
O
N
O
O
(90-96 % de)
- reaction of difluorodihaloethylene with acetylenes- biradical mechanism
R
F 2C=CX 2
X= F, Cl
F
X
F X
R
X
hydrolysis
O
R
O
R
NBn

O
- SN2 Reaction
CN
_
OR
O
OTs
KH, DMSO
HO
- acyloin reaction Organic Reactions 1976, 23, 259
(CH 2) n
CO 2Me
CO 2Me
R
R
Na, TMS-Cl
CO 2Me
CO 2Me
FOUR-MEMBERED RING FORMATION 133
CN
(CH 2) n
O
OR
OTMS
OTMS
JACS 1980,
102 , 1404
F -
(CH 2) n
OH
Grandisol
- benzocyclobutanes ACIEE 1984, 23, 539; Synthesis 1978, 793
benzocyclobutane o-quinodimethane
R
R
O
O O
- cyclotrimerization of 1,5-diyenes with an acetylenes
- sulfur ylides
O
R R'
SiMe 3
CpCo(CO) 2
+
_ SPh2 SiMe 3
O
R R'
Oxatanes Organic Photochemistry 1981, 5, 1
- [2+2] cycloaddition (Paterno-Buchi Reaction)
R R'
O
O
R R'
hν
hν (254 nm)
BF 3
R
Me 3Si
Me 3Si
R
O
R'
O
R'
O
OH
R
O
R'
O
OH
O
O
O
JACS 1974, 96,
5268, 5272

HO
Br
HO
O
- SN2 reaction
OH
OH
O
SiMe 3
O
O
hν
Me 2C CMe 2
OH NBS O
OTBS
C 5H 11
OH
- sulfur ylides
O
β-Lactones
R 2
O
R 1
BnO N H
H
H
O
O
SPh
OH
CO 2 H
SiMe 3
+
C5H11
H2C_ O
S
NTs
CO 2Me
CO2Me
Me
LDA, THF
O
R 3
R 4
DEAD, Ph 3P
OBn O
H
FOUR-MEMBERED RING FORMATION 134
Tf 2O, CH 2Cl 2
(MeO) 3 P, DEAD
O -
- O
O
Br
R4 SPh
R3 R2 R1 BnO
O
N
H
O
O
O
Br
O
O
NTs
S
O
CH3 O
1) MgBr 2•OEt 2
2) KF, H 2O, CH 3CN
R 2CuLi
O
O
SiMe 3
OBn
OH
C 5H 11
OH
O
TL 1975
1001
C 5 H 11
O
JCSCC 1979, 421
CO 2Me
O
O
R1 R4 R2 R3 R
BnO
O
O
96 % de
NH
CO 2 Me
CO 2H
TL 1980,21 , 445
JACS 1984,
107 , 6372
JACS 1979,
101 , 6135
JOC 1991,
56 , 1176
TL 1995, 36, 4159
JACS 1987,
109 , 4649

Baldwin's Rules (Suggestions) for Ring Closure
JOC 1977, 42 , 3846
JCSCC 1976, 734, 736, 738
BALDWIN'S RULES FOR RING CLOSURE 135
Approach Vector Analysis
- for an SN2 displacement at a tetrahedral center, the approach vector of the
entering nucleophile is 180° from the departing leaving group
Nu: L
Nu L
Nu :L
- for the addition of a nucleophile to an Sp2 center, the nucleophile approaches
perpendicular to the π-system.
Nu
Nomenclature
1. indicate ring size being formed
3 membered ring = 3
4 membered ring = 4
etc.
2. indicate geometry of electrophilic atom
if Y= Sp3 center; then Tet (tetrahedral)
if Y= Sp2 center; then Trig (trigonal)
if Y= Sp center; then Dig (digonal)
Y
X:
3. indicate where displaced electrons end up
- if the displaced electron pair ends up out side the ring being formed;
then Exo
- if the displaced electron pair ends up within the ring being formed;
then Endo
Exo
Y
X:
Z
Z
Nu
Z Y
Endo
X:

BALDWIN'S RULES FOR RING CLOSURE 136
4. Ring forming reaction is designated as Favored or Disfavored
disfavored does not imply the reaction can't or won't occur- it only means
the reaction is more difficult than favored reactions.
Rules (Suggestions) for Ring Closure
- All Exo-Tet reactions are favored
X: Y Z X: Y Z
X: Y
3- 4- 5- 6- 7-
- - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - -
- 5-Endo-Tet and 6-Endo-Tet are disfavored
X:
- All Exo-Trig reactions are favored
X: Y Z X: Y Z
Z
Y
Z
X:
5- 6-
- - - - -Disfavored- - - - -
X: Y
3- 4- 5- 6- 7-
- - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - -
Z
- 3-Endo-Trig, 4-Endo-Trig and 5-Endo-Trig are disfavored; 6-Endo-Trig, 7-
Endo-Trig, etc. are favored
Z
Z
Z
Y
X: Y X: Y
X:
3- 4- 5-
- - - - - - - - - - - - -Disfavored- - - - - - - - - - - -
X:
Z
Y
X:
Y
Y
Z
Z
Z
X: Y
6-
X:
X:
Y
Y
Z
X:
Z
Y
7-
Z
- - - - - -Favored- - - - - -

BALDWIN'S RULES FOR RING CLOSURE 137
- 3-Exo-Dig and 4-Exo-Dig are disfavored; 5-Exo-Dig, 6-Exo-Dig, 7-Exo-Dig, etc.
are favored
X: Y
Z
X: Y
Z
X: Y
X:
Z
Y
X:
Y
Z
3- 4- 5- 6- 7-
- - - - - -Disfavored- - - - - - - - - - - - - - - - - - -Favored- - - - - - - - - - - -
- All Endo-Dig are favored
Z
X: Y
Z
X:
Y
3- 4-
Z
X:
Y
Z
5- 6-
Z
X: Y
- - - - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - - - - - -
EXCEPTION:
There are many !!! (see March p 212-214)
X:
7-
Y
Z

5 Membered Rings
HO
HO
OH
PGF 2α
CO 2H
Me
H
Me Me
FIVE-MEMBERED RING FORMATION 138
Me
O
HO
OH
PGE 2
Hirsutene Isocumene
Modhephane
1. Intramolecular SN2 Reactions
2. Intramolecular Aldol Condensation and Michael Addition
3. Intramolecular Wittig Olefination
4. Ring Expansion and Contraction Reactions
a. 3 → 5
b. 4 → 5
c. 6 → 5
5. 1,3-Dipolar additions
6. Nazarov Cyclization
7. Arene-Olefin Photocyclization
8. Radical Cyclizations
9. Others
Synthesis 1973, 397; ACIEE 1982, 21 , 480;
Intramolecular SN2 Reaction 5-exo-tet: favored
O
O
Br
Br
CO 2Me
O
CN
LDA
O
O
CN OH
CO 2 Me
Me
Me
JCSCC 1973, 233
O
JACS 1974, 96 , 5268
CO 2H
Me
Me

RO 2C CO2R
TsO
O
O
O Cl
Cl
NaH, DMSO
Intramolecular Aldol Condensation 5-exo-trig: favored
intramolecular aldol condensation of 1,4-diketones
Br
O
O
O
O
CH 3
O
O
O
R'
CH 3
CO 2Me
O
O
R
NaOMe, MeOH
NaOH
Intramolecular Michael Addition 5-exo-tet: favored
Organic Reactions 1995, 47, 315-552
O
FIVE-MEMBERED RING FORMATION 139
O
O
CH 3
RO 2C CO 2R
O
CH 3
Br
R'
R
TL 1982,
29, 2237
O
CO 2Me
MeO 2C O O
O
O
O
JCSCC 1979, 817
JACS 1979,
101 , 5081
JACS 1980,
102 , 4262
JOC 1983,
48 , 1217
JACS 1979,
101 , 7107

Intramolecular Wittig Olefination Tetrahedron 1980, 36, 1717
THPO
O
base
O
C 5H 11
OTHP
THPO
1) (MeO) 2P(O)CH 2 -
2) Collins
O
C 5H 11
OTHP
THPO
O
FIVE-MEMBERED RING FORMATION 140
O
O
P(OMe) 2
C 5H 11
OTHP
HO
OH
CO 2 H
C 5H 11
JOC 1981, 46 , 1954
Ring Expansion Reactions
- 3 → 5: Vinyl Cyclopropane Rearrangement Organic Reactions 1985, 33, 247.
O
O
H
O
O
O
_
SPh 2
TMSO
H
O
O
H
O
JACS 1979, 101 , 1328
- 4 → 5: Reaction of cyclobutanones with Diazomethane
Me
Cl
Cl
Cl
O
Me
O
Cl
Cl
O
O CH 3
Ph
CH 2 N 2
CH 2 N 2
CH 3
Me Cl
Me
CH 2N 2
O
Cl Cl
O
Cl
Cl
O CH 3
Ph
O
Me
O
O
Me
CH 3
H
OTMS
TL 1980,
21 , 3059
JACS 1987,109 , 4752

FIVE-MEMBERED RING FORMATION 141
Ring Contraction Reactions
- 6 → 5: Favorskii Reaction Organic Reactions 1960, 11 , 261
Cl
O
_
O
_ OH - O OH
CO 2H
1,3-Dipolar Addition to Olefins 1,3-Dipolar Cycloaddition Chemistry , vol 1 & 2 (A.
Padwa ed.) (Wiley, NY 1984); ACIEE 1977, 16 , 10. Chem Rev. 1998, 98, 863.
a b +
_
c
1,3-Dipole (4π)
LUMO
4πs + 2πs
Alkene (2π)
HOMO
- trimethylenemethane (TMM) ACIEE 1986, 25 , 1. Synlett 1992, 107.
N
N
CO 2Me
Δ, MeCN
-N 2
high
temperature
MeO 2C
•
•
•
•
TMM
MeO 2C
note: TMM usually reacts poorly w/ electron defficient olefins
MeO 2C
O
- α,α'-dihaloketones
O
Br Br
Me 3Si OAc
O
Me 3Si OAc
Pd(0), 80°C
Ni(COD) 2, 35 °C
Fe(CO) 9
CO 2Me
OFeL n
+
Pd(0)
Ar
H
CO 2Me
•
O
•
_
PdLn
O
CO 2Me
+
TL 1986, 27 , 4137
ACIEE 1985, 24 , 316
TL 1983, 24 , 5847
O
Ar
ACR 1979, 12 , 61
H
CO 2Me
H
CH 3
JACS 1981,
103 , 2744

O
- nitrones ACR 1979, 12 , 396; Organic Reactions, 1988, 36 , 1
O
H
- nitrile oxides
O
N
O
Ph
N
O
OTHP
O
CO 2Et
N
OH
1) TBS-Cl, DMF,
imidazole
2) nBuLi, THF
Bu 3 Sn
(80%)
O
MeO 2C
ArNCO
S
- O
Bu 2 BOTf, iPr 2 EtN,
CH 2 Cl 2 , -78°C
O
H
O
N
R 1
+
O -
N R 2
R 3
Nitrone
MeNHOH,
EtONa
NH
NaOCl, H2O,
CH2Cl2
TBSO
(88%)
OTHP
(99%)
OH
Bn
N
O -
C 4H 9
N O- +
CO 2 Et
THPO
O
O
Me
H
OH
CH 3
N O
Me
O
N
H
Ph
O
+ _
N O
FIVE-MEMBERED RING FORMATION 142
MeO 2C
O
1) PPTS, EtOH, ↑↓
2) (CH 3 ) 2 C(OMe) 2 ,
PPTS
3) Swern
(48%)
O
N
R 1
1) MeI
2) H 2, Pd/C
N
NH
S
O
CO 2 Et
1) DHP, PPTS
CH 2 Cl 2 , ↑↓
2) LAH
TBSO
O
(60%)
O
N
R 2
Bn
N
O
C 4H 9
R 3
JACS 1964,
86 , 3756
Me 2N
H 2
OTHP
N
O
H
OH
Me
H
JACS 1983,
104 , 6460
O
OTHP
OH
OH
CO 2Et
H 2 , Raney Ni, H 2 O,
MeOH, B(OMe) 3
(88%)
HF•pyridine,
CH 3 CN, pyridine
O
O
(73%)
JOC 1984,
49 , 5021
JACS 1992,
104 , 4023
1) Swern
2) NH 2 OH•HCl
AcONa, MeOH
HO
O
(89%)
OTHP
O
OH
Cassiol
TL 1996, 37, 9292
OH
OH

OTBS
N +
O _
OTBS
O N
FIVE-MEMBERED RING FORMATION 143
LAH
OTBS
Arene -Olefin Photocyclization Organic Photochemistry 1989, 10 , 357
- the photochemistry of benzene is dominated by the singlet state
OMe
hν
hν
AcO hν
*
hν
*
AcO
hν
*
OMe
*
+
*
*
1
*
O
*
*
*
*
*
OAc
Me 2 CuLi O
Me
OMe
HO
H
+
OH
NH 2
OAc
JACS 1982,
104 , 5805
JCSCC, 1986 247
1) FVP
2) H 2, Pd/C
H +
cedrane
TL 1993, 34, 3017
isocume
Tetrahedron
1981,37 , 4445
JACS 1981,
103 , 688
TL 1982, 23 , 3983
TL 1983, 24 , 5325

Intramolecular Photochemical [2+2]
"Rule of Five"
O
O
O
O
hν
hν
FIVE-MEMBERED RING FORMATION 144
O
O
O
O
JOC 1975, 40 , 2702
JOC 1979, 44 , 1380
Nazarov Cyclization review: Synthesis 1983, 429 Organic Reaction 1994, 45, 1
- cyclization of allyl vinyl or divinyl ketones
- 1,4-hydroxy-acetylenes
HO
OH
H
O
O
OH
- Silicon-Directed Nazarov
O
Me
SiMe 3
H 3PO 4/HCO 2H
H 3PO 4/HCO 2H
H 2SO 4, MeOH
FeCl 3
- Tin -directed Nazarov TL 1986, 27 , 5947
Me
O
O
O
O
H
OH
Tetreahedron
1986, 42 , 2821
JOC 1989,
54 , 3449
Radical Cyclization
B. Giese Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds
(Pergamon Press; NY) 1986; Bull. Soc. Chim. Fr. 1990, 127 , 675; Tetrahedron 1981, 37 ,
3073; Tetrahedron 1987, 43, 3541; Advances in Free Radical Chemistry 1990, 1, 121.
Organic Reactions 1996, 48, 301-856.
Radical Addition to multiple bonds:
1. Free radical addition is a two stage process involving an addition step followed by an
atom transfer step.
2. In general, the preferred regioselectivity of the addition is in a manor to give the
most stable radical (thermodynamic control)

FIVE-MEMBERED RING FORMATION 145
Advantages of free radical reactions:
1. non-polar, little or no solvent effect
2. highly reactive- good for hindered or strained sysntems
3. insensitive to acidic protons in the substrates (i.e. hydroxyl groups do not
necessarily need to be protected
Mechanism of radical chain reactions
1. initiation
2. propagation
3. termination (bad)
Formation of carbon centered radicals:
tin hydride reduction of
alkyl, vinyl and aryl halides,
alcohol derivatives:
xanthates, thionocarbonate, thiocarbonylimidazolides
organosselenium & boron compounds
carboxylic acid derivatives (Barton esters)
reduction of organomercurials
thermolysis of organolead compounds
thermolysis or photolysis of azoalkanes.
Radical Ring Closure
For irreversible ring closure reaction, the kinetic product will predominate.
Both the 5-exo-trig and 6-endo trip are favored reactions, with the 6 exo-trig mode
producing the most stable radical. However, the 5-exo-trig is about 50 time faster
•
•
•
•
•
• •
kinetically
favored
k 1,5
•
•
•
•
•
+
k 1,6
100 : 0
• •
+
100 : 0
+
98:2
+
85:15
+
100 : 0
thermodynamically
favored
•
•
•
•
3-exo-trig
vs
4-endo-trig
4-exo-trig
vs
5-endo-trig
5-exo-trig
vs
6-endo-trig
6-exo-trig
vs
7-endo-trig
7-exo-trig
vs
8-endo-trig

•
and
•
FIVE-MEMBERED RING FORMATION 146
radicals open up fast and are not synthetically useful;
often used as probes for radical reaction
Effects of substituent on the regiochemistry of the 5-hexenyl radical cyclization
•
•
•
•
•
•
•
•
+
48:1
+
>200:1
+
2:3
+
< 1:100
Stereochemistry of 5-hexenyl radical cyclization
1-, or 3-substitued 5-hexenyl radicals give cis disubstituted cyclopentanes
2-, or 4-substituted 5-hexenyl radicals give trans disubstitued cyclopentanes
4
R
R
3
2
R
R
1
Br
Br
Br
Br
Bu 3 SnH
Bu 3 SnH
•
•
H
H
H
R
prefered transition state
•
R
•
H
H
H
H
R
R
•
•
•
•
R
R
+
65 : 35
+
75 : 25
83 : 17
R R
73 : 27
R R
+
+
R
R

THPO
OH
CN
Br
CO 2Me Br
Br
Si
O
Bu 3SnH
THPO
nBuSnH,
AIBN
Bu 3SnH,
AIBN
FIVE-MEMBERED RING FORMATION 147
OH CN
CO 2Me
H Si
O
JACS 1983,
105 , 3720
JACS 1990,
112, 5601
H 2O 2
THPO
multiple cyclizations: D. Curran Advances in Free Radical Chemistry 1990, 1, 121.
O OAc
1) NaBH4, CeCl3 2) Ac2O, Et3N PhSeCl, CH 2Cl 2
THPO
I
O
O
O
PhSe
HO
Bu 3SnH, AIBN
PhH, reflux
O
CO 2H
O
O
H 2O 2
1) PPTS, EtOH
2) LAH
3) (CF 3SO 2) 2O
pyridine
4) Bu 4NI, PhH
Bu 3SnH, AIBN
PhH, reflux
CH 3MgBr,
CuBr•SMe 2
O
•
1) LAH
2) CH 3SO 2Cl
3) NaI
4) Li
5) CrO3, H2SO4, H2O 1) LDA, THF
2) TBSCl
•
HO
I
O
CO 2Me
O
O
1) I 2
2) DBU
H 3 C
O
OTBS
H H
THPO
I
70 °C
CuSMe 2 Li +
1) Me3Si Li
(1.0 equiv)
2) CsF
1) CH 3 MgBr
(excess)
2) Me 3 SiBr
H
O
Me
H
H H
(±)-hirsutene
O
Br
O
O
(±)-capnellene
Tetrahedron Lett.
1985, 41, 3943
O
OTBS
JACS 1985,
107 , 1148
MgBr
CuBr•SMe 2, THF
OH
H
OH

adical trapping
RO
O
RO
O
CHO
OEt
O
I
O
Br
O
nBuSnH,
AIBN
nBuSnH,
AIBN
O SmI 2, THF
RO
O
•
FIVE-MEMBERED RING FORMATION 148
OEt
Me
Me
Me
OH
H
H
tBuNC
can also be trapped with acrylate esters or acrylonitrile.
OEt
Pd(OAc) 2,
CH 3CN
I
RO
O
nBuSnH,
AIBN
OEt
O
RO
O
C 5H 11
OEt
•
Me 3Si
1) (S)-BINAL-H
2) HCl, H 2O, THF
O
HO
C 5 H 11
RO
RO
O
OEt
OH
O
C 5H 11
O
Me
RO
O
O
SiMe3 C5H11 O
O
1) Wittig
2) deprotect
JACS 1986,
108, 1106
CN
JACS 1988,
110 , 5064
OEt
140°
Brook
rearrangement
HO
HO
JACS 1986,
108 , 6384
RO
O
OEt
(+)-PGF 2α
Paulson-Khand Reaction Tetrahedron 1985, 41 , 5855; Organic Reactions 1991, 40 , 1.
R R'
Co 2(CO) 6
O
O
R''
CHO
O
R R''
R'
Co 2(CO) 8, NMO
O
+
O
O
R
R'
O
R''
Organometallics
1982, 1 , 1560
JOC 1992,
57 , 5277
C 5H 11
OTMS
CO 2H

EtO 2C CO 2Et
Ph
Cp 2TiCl 2,
EtMgBr, CO
FIVE-MEMBERED RING FORMATION 149
O
Ph
CO 2Et
CO 2Et
JOC 1992,
57 , 5803
Ring-Closing Metathesis Tetrahedron 1998, 54, 4413, Acc. Chem. Res. 1995, 25, 446.
OH
O
O
N
Ph
N
Ph
O
O
O
O
Bu 2 BOTf,
CH 2Cl 2, -78°C
(82 %)
CHO
LiBH 4,
THF, MeOH
(78%)
P(C6H11) 3
OH O O
Cl
Cl
Ru
Ph
N O P(C6H11) 3
OH
OH
Ph
(97%)
J. Org. Chem. 1996, 61, 4192
Diazoketones Tetrahedron 1981, 37 , 2407; Organic Reactions 1979, 26 , 361
FVP of Acetylenic Ketones
R 1
R 2
O
H
R 1
R 2
R 3
O
FVP
N 2
R 1
R 2
BF 3
O
H
••
R 3
R 1
R 2
O
TL 1975, 4225
R 1
R 2
O
R 3
TL 1986,
27 , 19

Six Membered Rings
1. Diels-Alder Reaction
2. o-Quinodimethanes
3. Intramolecular ene reaction
4. Cation olefin cyclizations
5. Robinson annulation
6-MEMBERED RING FORMATION 150
Diels-Alder Reaction
ACIEE 1984, 23 , 876; ACIEE 1977, 16 , 10; Organic Reactions 1984, 32 , 1
W. Carruthers Cycloadditions Reactions in Organic Synthesis (Pergamon Press, Oxford) 1990
- reaction of a 1,3-diene with an olefin to give a cyclohexene.
- thermal symmetry allowed pericyclic reaction
- diene must reaction is an s-cis conformation
- highly stereocontrolled process- geometry of starting material is preserved in the
product
- possible control of 4 contiguous stereocenters in one step
B
B
A
A
+
X
X
Y
Y
- Alder Endo Rule: In order to maximize secondary orbital interactions, the endo TS is
favored in the D-A rxn. Tetrahedron 1983, 39, 2095
Orientation Rules
X
O
X Y
X Y
B
A
A
O
O
+
B
O
O
O
Y
exo
endo
X
B
B
A
A
B
B
H
H
Y
X
Y
Y
X
O
A
A
O
X
Y
Y
X
O
H H
O O
O
+
+
X
major minor
minor
major
Y
B
B
A
A
Y
X
X
Y

X
+
Y
X
6-MEMBERED RING FORMATION 151
Y
+
X
major minor
- when both the diene and dienophile are "unactivated" the D-A rxn is sluggish
- D-A rxns with electron rich dienes and electron defficient dienophiles work the best.
Some electron deficient dienophiles are quinones, maleic ahydride, nitroalkenes, α,βunsaturated
ketones, esters and nitriles.
- D-A rxns with electron deficient dienes and electron rich dienophiles also work well.
These are refered to as reverse demand D-A rxns.
- D-A rxns are sensitive to steric effects of the dienephiles, particularly at the 1- and 2postions.
Steric bulk at the 1-position may prevent approach of the dienophile while steric
bulk at the 2-position may prevent the diene from adopting the s-cis conformation.
- The D-A rxn is promoted by Lewis acids (TiCl4, BF3 AlCl3, AlEt2Cl, SnCl4,...)
- The D-A rxn is promoted by high pressure (1 kbar ~ 14200 psi) Synthesis 1985, 1.
OMe
+
O
OMe
H
O
Me
+
NHBOC
O
5 Kbar
20 kbars, 50°C
Eu(fod) 3
OMe
O
O
NHBOC
H
O
OMe
Me
+
Y
H
O
OMe
JACS 1986,
108 , 3040
NHBOC
Synthesis
1986, 928
- The D-A rxn is usually insenstive to solvent effects, except for water. ACR 1991, 24 , 159
+
CO 2 - Na +
O
H 2O
CHO
isooctane
k rel=1
H 2O
k rel= 700
OHC
endo
CO 2H
H
(70%)
O
+
4 : 1
20 : 1
+
OHC
H
exo
CO 2H
H
(15%)
O
JACS 1980, 102 , 7816
TL 1983, 24 , 1901
TL 1984 , 25 , 1239
JOC 1984, 49 , 5257
JOC 1985, 50 , 1309
Tetrahedron 1986, 42 , 2847

6-MEMBERED RING FORMATION 152
- The mechanism of the D-A rxn is believed to be a one-step, concerted, non-synchronous
process.
- concerted- bond making and bond breaking processes take place in a single kinetic step
(no dip in the transition state)
- synchronous- bond making and bond breaking take place at the same time and to the
same extent.
+
M.J.S. Dewar JACS
1984, 104 , 203, 209.
- study of secondary D-isotope effects have indicated a highly symmetrical T.S.
D D
H H
D D
D D
Diels Alder Reactions:
O
HO 2C
+
NHCO 2 Bn
O
CHO
trans
k 1
k 2
PhH, reflux
MeO
H
O
BnO 2 CHN
N
H
pumiliotoxin C
O
H
H MeO2C O CO2H reserpine
N
H
MeO 2 C
JACS 1978,
100 , 5179
N
+
H
+
OMe
H
O
D
H
D
D
O 2CAr
H
BnO 2 CHN
CH3
H
H
D
H
D
D
MeO 2C
Tetrahedron
1958, 2 , 1
JACS 1972,
94 , 1168
CHO
OMe
OAc
trans
CHO
NHCO 2 Bn

O
Me 3SiO
CO 2 Me
Me 3 SiO
MeO
+
OMe
Danishefsky's
Diene
OMe
SPh
+
O
MeO 2C
Hetero Diels-Alder Reactions
- Heterodienophiles
Me 3 SiO
CH(OMe) 2
CH 3
Me 3SiO
+
+
+
OMe
N
Ts
+
OMe
R
EtO 2C
CO 2 Me
O
N
CO2Bn
O
MeO OMe
O
Compactin
CO2Bn N
PhH, 5°C
MeO2C
PhS
Me 3 Si-O
O
O
R O
OMe
PhH, reflux
O
TsN
CO 2 Me
CH(OMe) 2
O
N
CH 3
6-MEMBERED RING FORMATION 153
JACS 1986,
108 , 5908
R
CO 2Bn
CO 2 Me
H
MeO 2 C
PhS
N
R
O
O CO 2Et
O
CO 2Bn
HO
HO
AcO
AcO
O
N
H
R
O
O
MeO 2 C
ACR 1981,
14 , 400
H
O
Vernolepin
JACS 1982,
102 , 1428
OAc
CH 3
NAc
OH
OH
R
SPh
OH
H
O
TL 1987,
28 , 813
TL 1985
27 , 4727

Me
Me
Me 3 SiO
Me
Me
+
Ph S
O
Me 3SiO
OMe
O
S
NTs
S Ph
+ H
M
- Heterodienes
MeO 2 C
O
OMe
O
O
Me
+
Ar
M(fod) 3
H O
O
OAc
+
Me O
OEt
PhS
OAc
+
C 3F 7
H
O
Me
Me
S
Ph H
OBn
Yb(fod) 3
3
Me
Me
S
O
NTs
Me 3 SiO
MeO 2 C
EtO
endo:exo
10 : 1
1) MgBr 2
2) H 3O +
Me
AcO
O
OAc
OMe
Me
6-MEMBERED RING FORMATION 154
O
H
O O
H
Me
SPh
Me
O
Ar
Ph
S
Me
O
HF,
Pyridine
+
endo: exo
1:2
O
M(hfc) 3
MeO 2 C
OBn
C 3F 7
O
HO
Me
Me
O
AcO
Me
3
NHTs
Me
Tetrahedron,
1983, 39 , 1487
OMe
Me
M
H
O O
H
O
OH
JACS 1985,
107 , 1256
O
Me
Me
OH
Ar
TL 1983,
24 , 987
JACS 1985,
107 , 6647
ACIEE 1983,
22 , 887
ACR 1986,
19 , 250

O
OR'
N
N
OR'
O
+
N
RO
AcO O
RO
O
OR
RO
O
RO N N
Intramolecular Diels-Alder Reactions (IDA)
- Type I IDA rxns
Δ
N
O
OR
O
CO 2 R'
6-MEMBERED RING FORMATION 155
OR' O
RO
RO NHAc
H
N
O
Fused bicyclc
Bridged Bicyclic
OR
OMe JACS 1987,
109 , 285
JOC 1985,
50 , 2719
- Generally, for E-dienes, the fused product is observed unless the connecting chain is
very long. For Z-dienes, either the fused or bicyclic products are possible.
EtO 2C
- Type II IDA rxns: gives bridgehead olefin
O
O
O
185°C
155°C
O
EtO 2C
O
395°C
O
O
Ph
O
NHBz O
OH
EtO 2C
O
JACS 1982,
104 , 5708, 5715
AcO
O
O
OH
H
BzO AcO
Taxol
OH
CO 2Et
O
JACS 1987,
109 , 447
ACIEE 1983,
24 , 419

O
6-MEMBERED RING FORMATION 156
- IDA reactions to give fused 6•5 (hydroindene) and 6•6 (hydronaphthalene) ring
systems are usually favorable reactions.
R
R'
(CH 2) n
n= 1 or 2
R
R'
(CH 2) n
- Intramolecular D-A rxns that give medium sized rings (7,8,9, 10) are much less
favorable.
- Intramolecular D-A rxn which form large rings are often favorable reactions with the
diene and olefin portions act as if they were seperate molecules
O
O
O
O
H
O
endo
H
O
O
+
O
H
O
exo
H
O
O
6.2 : 6.8 : 1 (77% combined yield)
+
H
O
H
O
O
O
JACS 1980,
102 , 1390
- Preference for endo or exo transition state depends on the substituition of the diene,
dieneophile and connecting chain.
- For intramolecular D-A rxns, geometric constraints can now reverse the normal
regiochemistry of the addition as compared to the intermolecular rxn.
R
+
CO 2R'
CO 2R'
- for intramolecular D-A reactions, we will use endo and exo to described the
disposition of the connecting chain
R
R'
(CH 2) n
R'
R
(CH2) n
endo
R
R'
(CH2) n
exo
R
R
CO 2R'
R
CO 2R'
R'
H
R'
H
H
H
(CH 2) n
(CH 2) n

6-MEMBERED RING FORMATION 157
- Lewis acids can greatly effect the endo/exo ratio of IDA reactions especially when the
olefin portion is E. The effects for Z-olefins is much more subtle
MeO 2 C
CO 2Me
150°C
(RO) 2AlCl 2, rt
180°C
EtAlCl 2, rt
MeO 2C
H
H
+
MeO 2C
H
H
75 : 25 (75% combined yield)
100 : 0 (72% combined yield)
MeO 2C
H
H
+
MeO 2C
H
H
75 : 25 (74% combined yield)
63 : 37 (60% combined yield)
JACS 1982,
104 , 2269
- the effect of substituents on the connectinng chain can influence the stereochemical
course of the IDA reaction
MeO 2C
HN
Intramolecular Diels-Alder Reactions:
TBSO
O
CO 2 Me
O
O
H
O
EtAlCl 2
rt
R
150°C
R
130°C
MeO 2C
H
TBSO
O
R R
O
MeO 2C H
O
H
O
HN
H
H
TL 1973,
4477
JOC 1981,
46 , 1506
JOC 1981,
46 , 1509

H
H
OTBS
OTBS CO2Me
CF 3CO 2H
EtAlCl 2
O
6-MEMBERED RING FORMATION 158
TBSO
H
H
H
H CO 2 Me
OTBS
JACS 1981,
103 , 4948
JOC 1982,
47 , 180
Asymmetric Diels-Alder Reactions
- Chiral Auxillaries Chem. Rev. 1992, 92 , 953; Tetrahedron 1987, 43 , 1969
O
H
M
O
Ph O
Ar O
H O
+
O
O
O
Me
O
OAc
OAc
O
O
O
O
O X
+
Ph
BF 3 •OEt 2 , -40°C
+
O
OTMS
O
+
OTMS
PhCHO
Eu(hfc) 3
OAc
OAc
Et 2AlCl
O
CH 2Cl 2, -80°C
Ph
H
OH
>98% d.e.
TiCl 4, 0°C
O
O
O
O
R*
O
Ph
O
w/ BF 3 •OEt 2
R*
O
Me
O
OR* +
8 : 92
OR*
Ph
HO
HO
OH
(-)- Shikimic Acid
(97:3)
CO 2R*
CO 2R*
+
18 : 82
92 : 8
O
O
O
O
CO2H JOC 1983, 48, 1137
JOC 1983, 43, 4441
ACIEE 1985, 24, 1
TL 1984,
25 , 2191
Δ = 4.5 %ee
TiCl 4 = 78% ee
iBu 2AlCl= 90% ee
O
OR*
Ph
d.e > 95%
up to 70% d.e.
Me
OR*
JOC 1989,
54 , 2209
Chem Lett. 1989, 2149
JACS 1986, 108, 7060

O
Ph O N
O
N
O
S
O
+
CH 3
R
O
SnCl4, -78C
R*
O N
O
O
H O
H
O
S
R
97% d.e.
(iPrO) 2TiCl 2,
CH 2Cl 2, 0°C
O O
SO2 N
X
EtAlCl2, -78°C
Oppolzer Auxillary
O
Evan's auxillaries
O
N
Me 2AlCl
O
O
_
Me 2ClAl
R
Me 2AlCl
+
O
N
O
O
6-MEMBERED RING FORMATION 159
O
PhMgBr
R*
O N
H
O S
O
N O
Me Ph
Ph
H
R
CO 2R *
endo/exo= 86:4
98% de
CO 2R*
+
R
endo (major) endo
exo
CO 2R* +
Tetrahedron
1987, 43 , 1969
exo
O
CO 2R*
O
R* OH
O N
TL 1989,
30 , 6963
O
N O
CO 2R*
1 equiv Me 2AlCl 2 equiv. Me 2AlCl
endo/exo 20:1 60:1
endo A/ endoB 4:1 20:1
k(rel) 1 100
O
Me 2AlCl
_
Me2AlCl2 + Al
O O
N
O
R
JCSCC , 1985 , 1449
TL 1986, 27 , 1853
H
N
O Al
O
O

R
Ph
O
Ph
O N
O
O
O N
Me
O
O
N O
O
Ph
- Chiral Dienes
O
O
O
O
OMe
OMe
Ph
Ph
+
EtAlCl 2, -100°C
Me 2AlCl
Me 2AlCl
CHO
O
O
OH
R*
OHC
O
R*
O
H
O
H
H
O
MeO
O
O
6-MEMBERED RING FORMATION 160
+
R*
15 : 85
95 : 5
Ph
OH
(R)-(+)-α-terpineol
O
H
H
OMe BF 3•OEt 2, -20°C 4:1
BF 3•OEt 2, -78°C 94:6
approach of
dienophile
π-stacking
arrangement
JACS 1984, 106, 4261
JACS 1988, 110 , 1238
TL 1984 , 25 , 4071
JACS 1988, 110 , 1238
Ph
O
OMe
O
H
O
OH
H
O
only product
- Chiral Catalysts Chem. Rev. 1992, 92 , 1007; Synthesis 1991, 1; OPPI 1994, 26, 129-
158
Me
TMSO
CHO +
OtBu
Me
+ PhCHO
OH
EtAlCl 2, -78°C
Eu(hfc) 3, -10°C O
O
Me
CHO
72% (ee)
Ph
JCSCC
1979, 437
TL 1983,
24 , 3451

Br CHO
CHO
+
+
OTBS
O
O O
O
OH O
N
Br CHO
Br
Br
O
+
O
O
O
O
O
+
+
N
O
O
OAc
H
N
N
Ts
O
Et
O
B
Ph
Me
Ph
Me
O
O
Ph Ph
OH
OH
Ph Ph
(iPrO) 2TiCl 2
Ph Ph
O OH
O OH
Ph Ph
(iPrO) 2TiCl 2
(30 mol % catalyst)
Ph
OH
OH
Ph
BH3, -78°C OH O
Ts
N
B
O
O
N
H
-78°C
CH 2Cl 2, -78 °C,
16 hrs
H 3 C
H
O
H
N
N
Ts
O
B
Bu
HO
O
H
CH 2 Cl 2 , PhCH 3
-78 °C, 42 hrs
OC
6-MEMBERED RING FORMATION 161
Br
O
CHO
Br (81%, 99% ee)
CO2H Gibberellic Acid
OTBS
CHO
(83%, 97% ee)
O
O
OH
O
O
O
Br
O
N
O
O N
H
H
O
OAc
CHO
1) NaBH 4
2) DDQ
3) F -
4) HCl
CL 1986, 1967
O
(> 99% ee)
70% yield
95% ee
JACS 1986,
108 , 3510
(98%)
JACS 1992,
114 , 8290
HO
O
O
H
N
N
Ts
Cassiol
O
B
H
O
Br
approach of diene
JACS 1994, 116, 3611
OH
OH

6-MEMBERED RING FORMATION 162
Ketene Equivalents in the D-A reaction
- ketenes undergo thermal [2+2] cycloaddition with dienes to give vinyl cyclobutanones.
- 2-chloroacrylonitrile as a ketene equiv. for D-A rxns.
AcO Cl CN
+ AcO
Cl
CN
KOH, tBuOH
70 °C
ortho-Quinodimathanes Synthesis 1978, 793; Tetrahedron 1987, 43 , 2873
Me 3 Si
Me 3 Si
O
1)
benzocyclobutane
MgBr
CuI, TMS-Cl
H
1) CF 3 CO 2 H, CCl 4 , -30°C
2) Pb(O 2 CCF 3 ) 4
O
O
HO
O
HN
O
170 °C
O
Me
N
O
Me
N
Me
N
N
N
OTMS
H
H H
Estrone
o-quinodimethane
Me 3 Si
Me 3 Si
155 °C
155 °C
LiNH 2 , NH 3 , THF
O
155 °C
O
I
O
H
HN
N
R
O
HO
R
ACIEE 1984, 23 , 539
JACS 1977, 99 , 5483
JACS 1979, 101 , 215
JACS 1980, 102 , 241
Me
OMe
N
OMe
O
Me
N
180 °C
O
O
Me
N
NH
H
O
O
Me 3 Si
Me 3 Si
JACS 1971,
93 , 3836
ACIEE 1971, 11 , 1031
ACIEE 1971, 11 , 1031
ACIEE 1971, 11 , 1031
Nature (London) 1994, 367, 630
ACIEE 1995, 34, 2079
R
R
Me 3 Si SiMe 3
CpCo(CO)2
H
H H
O

Photoenolization Tetrahedron 1976, 22, 405
R
R
O
H
R
•
hν O •
R
H
6-MEMBERED RING FORMATION 163
R
R
OH
MeO 2 C CO 2 Me
Intramolecular Ene Reactions ACIEE 1984, 23 , 876, Synthesis 1991, 1
Polyene Cyclization
BnO H
CHO
CHO
CHO
Binaphthol
Me 2 Zn
SnCl 4
Me 2 AlCl
R
R
OBn
OH
O
OH
H
H
90% ee)
Terpene Biosynthesis
terpenes C10 geraniol
sesquiterpenes C15 farnesol
diterpenes C20 geranylgeraniol
steroids C30 squalene
- isoprene- basic building block
OPP
geraniol-PP (C 10 )
+
OPP
isopentyl-PP
OPP
O
O
O
O
OH
O
OH
JOC 1985,
50, 4144
JACS 1991,
113 , 2071
Tetrahedron Lett. 1985, 26, 5535
+
isoprene unit
OPP
Farnesyl-PP (C 15 ) geranylgeraniol-PP (C20)
squalene (C 30 )
R
R
R
R
OH
CO2Me -H 2 O
CO2Me
CO 2 Me
CO 2 Me

O
Camphor α-Cedrane
Biosynthesis of camphor:
OPP
Biosynthesis of cedrane:
+
OPP
+
+
H
H
+
6-MEMBERED RING FORMATION 164
HO 2C
+
+
Abietic Acid
Stork-Eschenmoser Hypothesis- Olefin Geometry is preserved in the cyclization reaction, i.e.
trans olefin leads to a trans fused ring jucntion
A. Eschenmoser HCA 1955, 38, 1890; G. Stork JACS 1955, 77, 5068
H +
H
Me
R
H
Me
Biosynthesis of Abietic acid:
+
H
OPP
H
H
Me
+
Me
H
H
+
H +
H
OPP
R
H
Me
Me
H
H
Me
Me
H
HO 2 C
O
OPP
H

-Steroid Biosynthesis:
squalene
HO
squalene
epoxidase
H
H
+ O
H
H
+
squalene oxide
H
HO
squalene
cyclase
HO
H
H
Lanosterol
H
H
6-MEMBERED RING FORMATION 165
H
+
HO
HO
H
H
H
H
H
H
Protosterol
Cholesterol
- Polyene cyclization in synthesis ACR 1968, 1, 1; Bioorg. Chem. 1976, 5, 51; Asymmetric
Synthesis 1984, 3, 341-409; ACIEE 1976, 15, 9
O
MeO
O O
H
CO 2Me
OPO(OEt) 2
SnCl 4
CH 3 NO 2 , 0°C
(8%)
CHO
SnCl 4
pentane
(27%)
HO
SnCl 4
PhH, rt
(38%)
HO
1) Hg(O 2CCF 3) 2
2) NaCl
H
MeO
O
H
H
H
ClHg
H
δ- Amyrin
H
H
H
H
OH
CO 2Me
O
H +
H
H
E.E. van Tamelen
JACS 1972, 94 , 8229
JACS 1974,
96 , 3333
W.S. Johnson
JACS 1974, 96, 3979
JACS 1980,
102 , 7612

Robinson Annulation Synthesis 1976, 777; Tetrahedron 1976, 32, 3.
O
O
O
acid or base
(thermodynamic
conditions)
6-MEMBERED RING FORMATION 166
- unfavorable equillibium for the Michael addition under kinetic conditions
- O
O
base
(kinetic conditions)
- stabilizing the resulting enolate of the Michael Addition product can shift the
equilibrium as in the case of the vinyl silane shown below
OR
- O
Me 3 Si
O
base
(kinetic conditions)
OR
Me 3 Si
Me3SiO H
b)
Me3Si - Methyl Vinyl Ketone equivalents
O
O
Me 3 Si
I
+
I
- O
+ -
O
O
O
Me3Si
- O
a) MeLi
O
c) MeONa
Aldol
O
O
O
O
O
O
O
O
- O
O
O
O
mCPBA
O
O
Me 3 Si
O
O
O
H
OR
JACS 1974,
96 , 3862
O
H +
JACS 1974,
96 , 6181

Intramolecular Aldol Condensation of 1,5-Diketones
6-exo-trig; favored process
- DeMayo reaction to 1,5-diketones
Intramolecular Alkylations (SN2 reaction)
Radical Cyclizations
Acyloin Reaction
R
O
O
R'
base
- H 2O
Birch Reduction Organic Reactions 1992, 42, 1.
O
O
O
Aromatic Substitution (Carey & Sundberg, Chapter 11)
Intramolecular Wittig Reaction
Sigmatropic Rearrangements
hν
O
O
6-MEMBERED RING FORMATION 167
O
O
R'
R
DIBAL-H
H 3C
O
H
O

Medium Sized Rings
7-Membered Rings
7-MEMBERED RING FORMATION 168
[4+2] cycloadditions
- [4+2] cycloadditions between dienes and allylcations leads to cycloheptadienes
review: ACIEE 1984, 23 , 1; ACIEE 1973, 12 , 819
F 3 CCO 2
SiMe 3
O O O
mCPBA
R
OTMS
+
+
ZnCl 2 , -30°C
Br
O
O
+ +
+
OMe
+
O
ZnCl 2
I
+
CF 3CO 2Ag
SiMe3
-78°C
O
O
H
Me
O
ACIEE 1973, 12, 819
ACIEE 1984, 23, 1
+
+ JACS 1982,
104 , 1330
- Noyori [4+2] cycloaddition of α,α'-dibromoketones and dienes
review: ACR 1979, 12 , 61
O
Br Br
R
Fe 2(CO) 9
-or-
Zn-Cu
R
OM
+
R
HO
O
O
O
O
O
R R
H
JACS 1979, 101, 226
ACIEE 1982,
21, 442
O
O
ACR 1979, 61
Organic Reactions
1983, 29, 163

Me
O
HO
O O O
mCPBA
O
Br Br
O
Me
Br
Br
+
1)
O
Br Br
O
Br Br
O
Fe 2 (CO) 9
O
O
Br
O
O
Br
1)
OMe
+
O
OBn
Fe 2(CO) 9
O
CO2Me N
Fe2(CO) 9
2) Zn
O
O
1) H2, Pd/C
2) CF 3 CO 3 H
7-MEMBERED RING FORMATION 169
O
Br Br
MeO 2C
O
O
N
O
HO
O
O
O
O
O
O
Zn
O
O
O
JACS 1978, 100 , 1786
Tetrahedron 1985, 41, 5879
OH
JACS 1979, 101, 226
O
H H
CO2H O
O
JACS 1972, 94, 3940
JOC 1976, 41, 2075
O
Me Me Me
1) CF3CO3H OH
2) LDA, MeI
O
JCSCC 1985, 55
Me OBn
OH OH OBn
- [4+2] cycloaddition between pentadienyl cations and olefins
O
O
Δ
O
+ + +
- O
OH
+
O
O
O
Tetrahedron 1966, 22, 2387
JOC 1987, 52, 759

MeO OMe
O
OMe
7-MEMBERED RING FORMATION 170
O
SnCl4 JACS 1977, 99, 8073
JACS 1979, 101, 6767
O
OMe
JACS 1981, 103, 2718
Seven-Membered Rings from Funnctionalization of Tropone
Organic Reactions 1997, 49, 331-425
O
Cl
- [6+4] cycloadditions of tropones with dienes
O
O -
[6+4]
150°C
R
(88%)
O
O
O
HO HO
HO OH
Ingenol
- [4+2] cycloaddition between tropone and olefins
O
Radical Ring Expansion Reactions
- one carbon ring expansions
(CH 2 ) n
• O
O
(CH 2 ) n
CO 2 Me
n = 1,2,3
CO 2 Me
NaH, CH 2 Br 2
O
(CH 2 ) n
O
(CH 2 ) n
Br
[4+2]
150°C
(81%)
CO 2 Me
nBu 3 SnH,
AIBN
O
R
O
O
(CH 2 ) n
JOC 1988, 53, 4596
JACS 1987, 109, 3147
JACS 1986, 108, 4655
JOC 1986, 51, 2400
CO 2 Me
O
nBu3SnH JACS 1987,109, 3493
JACS 1987,109 , 6548
•
CO2Me (CH2 ) n
CO2Me •

O
CH 3
• O
Bu 3 SnLi
BrCH2SePh
SnBu 3
O
SePh
SnBu 3
- more than one carbon expansion
+
O
O R
X
(CH 2 ) n
SnBu 3
X= I, SePh
n= 1,2
Br
O
O
7-MEMBERED RING FORMATION 171
O
Br
+
O
(CH 2 ) n
R
•
SnBu 3
Bu 3 Sn•
Bu 3 SnH, AIBN,
C 6 H 6 , reflux
Tetrahedron 1989, 45, 909
Tetrahedron 1991, 47, 6795
Tetrahedron 1989, 45, 909
Tetrahedron 1991, 47, 6795
Eight-Membered Rings review:Tetrahedron 1992, 48 , 5757.
[4+4] Cycloaddition of Dienes
O
O
MeO2C
MeO 2 C
Ni(COD) 2, Ph 3P
60°C
Carbonyl Coupling Reactions
- Acyloin Reaction CO2Me
- McMurry Reaction
R
CO 2Me
O
Ni(COD) 2 , Ph 3 P
60°C
O
O
MeO 2 C
MeO 2 C
O
O
JACS 1986,
108 , 4678
O
H
H
O
Asteriscanolide
Na O
JACS 1971,
93 , 1673
CO 2Et
Ti (0)
R
OH
O
JOC 1992, 57, 7163
JACS 1988,
110 , 5904

CHO OHC
Aldol-like Condensations
tBuPh 2 SiO
O
O
OTMS
(CH 2) n
Me 3 Si Cl
O
OEt
Pinocol Rearrangement
Me 3SiO
SiMe 3
O
OTs
R
TiCl 3, Zn-Cu
H H
TiCl 4
O
n= 1,2
SnCl 4
OMe
tBuPh 2 SiO
Me 3 Si
7-MEMBERED RING FORMATION 172
O
Lewis Acid
O SiMe 3 O
OMe
OMe
SnCl 4
Me 3SiO
TiCl 4
O
O
Cl
(CH 2) n
OTs
OH
SiMe 3
O
O
R
JACS 1986,
108 , 3513
JCSCC 1983, 703
JACS 1986,
108 , 3516
O
Cl
Laurenyne
JOC 1988,
53 , 50
JACS 1988,
110 , 2248
+
OMe
JACS 1989,
111 , 1514
OMe
H
Tiffeneu-Demyanov Ring Expansion
- one carbon ring expansion for virtually any size ring
O HO NH2 1) Me3SiCN 2) LAH
HONO
N2
O H
O
JOC 1980,
45 , 185
- also see Beckman and Schmidt rearrangements as a one atom ring expansion
for the conversion of cyclic ketones to lactams.

DeMayo Reaction
O
O
O
O
OAc
+
hν, pyrex
O
O
O
O
O
7-MEMBERED RING FORMATION 173
O
hν
O O
Ring Expansion/Contraction via Sigmatropic Rearrangements
- Cope Rearrangement
O
O
SMe
- Anion Accelerated Cope
OH
- Claisen Rearrangement
O
O
O
55°C
O
O
AcO
O
O
JCSCC 1984, 1695
pTSA, MeOH
H
CO2Me reflux JACS 1986,
O
108 , 6425
O
O
H
O
TL 1991,
32 , 6969
KH, 18-C-6
115°C O
JACS 1989,
111, 8284
Tebbe
reagent
O
185°C
O
OCOCH 2OH
Pleuromutilin
O
H
TL 1990,
31 , 6799

- Ester Enolate Claisen- 4 carbon ring contractions
O
O
MOMO
O
O
1) LDA, TBS-Cl
2) 110°C
H
7-MEMBERED RING FORMATION 174
CO 2H
MOMO
H
H
CO2TBS JACS 1982, 104 , 4030
Tetrahedron 1986, 42 , 2831
1) LDA, TBS-Cl
2) 110°C JOC 1988, 53 , 4141

Exam 1

page 1 of 5
1. Give the reagent(s) necessary to carry out the following transformations. The stereochemistry of
the products and reactants is as shown. (20 pts)
HO
O
O
OH O
O
CO 2 H
OH
OH OH
O
OH
O
HO
O
O
O
OH OH
OH
N
OH
CO 2CH 3
O

page 2 of 5
2. Give the product of the following reactions. The stereochemistry of the reactant is as shown.
Give the proper sterochemistry of the major steroisomer of the product. (20 pts)
tBuMe 2 SiO
Ph
Ph
O
O
OCH 3
O
N
O
O
O
O
H
O
O
H 3 C Ph
2)
OsO 4 , MNO
(CH 3 ) 2 CuLi
mCPBA
1) LDA, THF
Ph
O SO2Ph N
CH 3 MgBr

3. What are the following reagents used for. Please be specific. (8 pts each)
Ir + P(C 6H 11) 3
N
H H
N N
O
Mn
O
O
tBu tBu
PF 6 -
Bu 2 BOTf, iPr 2 NEt
PPh2 PPh2 page 3 of 5
4. Give the reagent(s) needed to selectively deprotect the substrate below to the desired product.
(16 pts)
BnO O
AcO
OH
OH
OSitBuMe 2
BnO O
AcO
O
O
OH
BnO O
AcO
O
O
OSitBuMe 2
OH O
AcO
O
O
BnO O
OH
O
OSitBuMe 2
O
OSitBuMe 2

5. Provide the product and all intermediates for the following sequence of reactions. (20 pts)
O
O
1) LiAlH 4
2) MnO 2
3) tBuMe 2 SiCl, pyridine
4) pCH 3 C 6 H 3 SO 2 NHNH 2
H + , C 6 H 6 (- H 2 O)
5) NaCNBH 3
page 4 of 5

page 5 of 5
6. Starting from cyclohexanone, provide a feasible synthesis target shown. Give all reagents and
intermediates. (16 pts)
O
~ 4 steps

Exam 2

1. Give the product of the following reactions. The stereochemistry of the reactant is as shown.
Give the proper sterochemistry of the major stereoisomer of the product. (24 pts)
Ph
OH
_ +
Me MeO 2CNSO 2NEt 3
H
H
O
O
O
O
NNHTs
O
OTf
Cl
Cp2Ti
PhH, Δ
CH 2
Al(CH3)2
Cl
a) BuLi (2 equiv)
b) CH 3 I
1) LDA, TMS-Cl
2) Δ
Pd(0), CO, MeOH
1) CH 2 N 2
2) hν, MeOH
page 1 of 5.

page 2 of 5.
2. Give the reagent(s) necessary to carry out the following transformations. The stereochemistry of
the products and reactants is as shown. (24 pts)
H
O
H
CHO
O
OH
H
O O
H
H
O
O
H
H
H
CO 2Me
CO 2Me
H
O
O
H
O Ph

page 3 of 5.
3. Give the expected product from a thermal and photochemical [2+2] cycloaddition of
cycloheptenone with ethylene. Using MO's, clearly show why the photochemical and thermal
pathways give different stereochemical outcomes. (12 pts)
O
+

4. Provide the product and all intermediates for the following sequence of reactions. (20 pts)
O
O
O
1) cyclopentene, hν
2) DIBAL
3) tBuO - K +
4a) (CH 3 ) 2 CuLi
b) Tf2NPh
5) Ph 2 CuLi
page 4 of 5.

5. Complete the synthesis for the target shown. Give all reagents and intermediates. (20 pts).
OH
OH
~5 steps
O O
page 5 of 5.

Exam 3

1. Give the product of the following reactions. The stereochemistry of the reactant is as shown.
Give the proper sterochemistry of the major stereoisomer of the product. (20 pts)
NHBn
H
H
CO 2H
O
N
CH 3
O O
N
Ph
O
R
CpCo(CO) 2
CHO
I 2
R
H 2 , Pd/C
a) Bu 2 BOTf, Et 3 N
b) PhCHO
page 1 of 6.

page 2 of 6.
2. Give the reagent(s) necessary to carry out the following transformations. The stereochemistry of
the products and reactants is as shown. (20 pts)
Ph
O
OBn OBn
OMe OMe
O
CHO
O
O
O
OEt
Me
OH
I
Ph
OBn
O
O
OH
O
OH
CO 2 H
OEt
CN
CH 3
OMe
OH
OBn

3. Short Answers. (5 points each, 20 points total)
a. Define enantioselective and enantiospecific and give examples of each.
b. What is the Stork-Eschenmoser hypothesis?
page 3 of 6.

page 4 of 6.
c. What are Baldwin's Rules (be general, do not give each specific rule)? Be sure to explain what are
the basis of the rules and give one example each of a reaction that is favored and disfavored
according to Baldwin's rule.
d. Define umpolung and give an example.

4. Provide the product and all intermediates for the following sequence of reactions. (20 pts)
OH
OH
OH
1) (CH 3 ) 2 C(OCH 3 ) 2 , H +
2) MnO 2
3) (EtO) 2P(O)CH 2CO 2Me, base
4) AcOH, THF, H 2 O
5) tBuSiCl (1 equv), pyridine
6) TsCl, pyridine
7) Bu 4 NF
page 5 of 6.

5. Complete the synthesis for the target shown. Give all reagents and intermediates. (20 pts).
O
OBn
~ 6 steps
O
O
page 6 of 6.