Organic Synthesis Strategy and Control

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vi Contents 28. Kinetic Resolution 627 29. Enzymes: Biological Methods in Asymmetric Synthesis 30. New Chiral Centres from Old — Enantiomerically Pure 651 Compounds & Sophisticated Syntheses — 681 31. Strategy of Asymmetric Synthesis 717 E: Functional Group Strategy 32. Functionalisation of Pyridine 749 33. Oxidation of Aromatic Compounds, Enols and Enolates 34. Functionality and Pericyclic Reactions: Nitrogen Heterocycles by 777 Cycloadditions and Sigmatropic Rearrangements 35. Synthesis and Chemistry of Azoles and other Heterocycles with Two 809 or more Heteroatoms 835 36. Tandem Organic Reactions 863 General References 893 Index 895
Page 2: Organic Synthesis
Page 8: Copyright © 2007 John Wiley & Sons
Page 14: Preface We would like to thank thos
Page 22: 1 Planning Organic Syntheses: Tacti
Page 26: groups, rings, double bonds, and ch
Page 30: complex. The vinyl metal derivative
Page 34: 2 Chemoselectivity Defi nitions Int
Page 38: Proviso (iii) is more obvious and y
Page 42: and 33 is a good choice for startin
Page 46: H R HO OH The alternative, more int
Page 50: Formation of specifi c enol equival
Page 54: the dilithium derivative of the aci
Page 58: TiCl 4. The aldehydes 105 and 108,
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MeO 2C TsO OH t-BuMe2SiCl OTBDMS CO
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formate. The chemoselectivity requi
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28 3 Regioselectivity: Controlled A
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44 4 Stereoselectivity: Stereoselec
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56 5 Alternative Strategies for Eno
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6 Choosing a Strategy: The Synthesi
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this a good strategy, particularly
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Modern versions of these strategies
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The Nazarov Reaction In addition to
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If iron carbonyl is used to generat
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Intramolecular Pauson-Khand reactio
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Other recent developments include a
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medicinal chemists 43 to make analo
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6 References 87 15. P. E. Eaton and
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7 The Ortho Strategy for Aromatic C
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Derivatives of meta cresol 10 are e
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ond under the reaction conditions s
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Firstly, let us consider the substi
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would simply undergo a lithium - ha
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Et2N O O In the same way, direct co
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eacted with BuLi followed by solid
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115 ii) Dilithiations OCONEt 2 1. s
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The aldehyde 129 is attacked using
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Benzyne Formation—A different aro
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The lactone 168 is lithiated at the
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8 σ-Complexes of Metals Introducti
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R Br 5 8 Introduction The structure
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Chiral Grignard reagents It has lon
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43 Me R FGA Transition Metal Comple
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complex with the two π-electrons o
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more stable than Mg(0), as in the m
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Just occasionally a Pd reaction wit
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9 Controlling the Michael Reaction
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Where direct (1,2-) addition is nec
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9 Using Copper (I) to Achieve Micha
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O OLi Me2CuLi 57 58 PhCHO 59; 1:2 s
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81; β-panasinene Wittig 2 + 2 O O
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Do not suppose that the regioselect
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10 Specifi c Enol Equivalents Intro
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O 16 CO2t-Bu 15 cat t-BuOK t-BuOH O
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Alkylation with simple alkyl halide
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HO + OMe HO OMe This time the lithi
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Aldehydes 88 do not form stable lit
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The second 119 clearly came from th
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now that the simple enols and enola
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of the ketone 152 with an aldehyde
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156 11 Extended Enolates R O O O O
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158 11 Extended Enolates There is n
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160 11 Extended Enolates The PhS gr
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162 11 Extended Enolates acrylate g
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164 11 Extended Enolates cleanly in
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166 11 Extended Enolates The Baylis
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168 11 Extended Enolates A Baylis-H
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170 11 Extended Enolates Conclusion
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12 Allyl Anions Introduction: Allyl
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If neither the halides nor their me
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Similar compounds 56 can be made 13
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see 21 and 23, from which a mixture
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Me 3Si Et 2O.BF 3 There are many re
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OH Co(dmgH) 2py SiMe3 (S)-138 0.3 e
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R 1 The best candidates are phospho
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12 References 187 13. H. Mattes and
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190 13 Homoenolates B B Direct homo
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192 13 Homoenolates MeO OSiMe 3 Con
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194 13 Homoenolates MeO I 57 NHBoc
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196 13 Homoenolates Sulfones Possib
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198 13 Homoenolates react α (or wh
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200 13 Homoenolates N Li An open ch
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202 13 Homoenolates 5. Disconnectio
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204 14 Acyl Anion Equivalents O R C
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206 14 Acyl Anion Equivalents An op
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208 14 Acyl Anion Equivalents Dithi
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210 14 Acyl Anion Equivalents EEO C
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212 14 Acyl Anion Equivalents Lithi
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214 14 Acyl Anion Equivalents Synth
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216 14 Acyl Anion Equivalents A syn
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218 14 Acyl Anion Equivalents Catal
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220 14 Acyl Anion Equivalents 30. J
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15 Synthesis of Double Bonds of Def
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15 Control of Alkene Geometry by Eq
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Each of the following reactions giv
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at right angles to each other. Prot
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RCHO Br Ph3P MeCN PPh3 BuLi DMSO 71
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O (EtO) 2P O OEt EtO or NaH O (EtO)
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A more serious example is from John
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Ph3P R1 NaOH Ph2P R1 O BuLi Ph2P R1
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R2 R1 PhSiMe2 Me OH 142 KH 18-crown
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The Kocienski modifi cation of the
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MeO Ph O O TiCl3, Li MeO O naphthal
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A much simpler heterocyclic eight-m
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[2,3]-Sigmatropic rearrangements: T
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Stereospecifi c Methods for Z-Alken
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A synthesis of methoxatin Methoxati
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References 15 References 253 Genera
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16 Stereo-Controlled Vinyl Anion Eq
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Both the Grignard reagent 14 and vi
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The vinyl-lithium may be combined d
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hν Me H 2N NHTs CH2 CH2 MeOH 2. DM
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This example of the commoner thermo
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Hydroalumination of propargyl alcoh
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Here is an example from the McMurry
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Reactions of Vinyl Sn, B, Al, Si, a
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O CHO 173 Reactivity of vinyl alane
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Me 3Si E electrophilic attack O SiM
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17 Electrophilic Attack on Alkenes
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Chemoselectivity The commonest form
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HO Controlling Chemoselectivity 17
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‘Markovnikov’ Hydration Mercura
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The stereochemistry of all these st
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There is good stereoselectivity wit
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Me 3SiCl gives a stable silyl enol
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MeO2C Br H2O H Br H 150 O MeO O O O
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stereogenic centres around a six-me
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determined by the proximity of the
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OH O CO2Et from ethyl acetoacetate
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periodic table) and that gives the
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225 second CO migrationR R first B
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y the proximity of the right alkene
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17 References 305 5. A. Armstrong a
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308 18 Vinyl Cations: Palladium-Cat
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19 Allyl Alcohols: Allyl Cation Equ
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This can be useful when oxidation o
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in chapters 2-4 and summarised in c
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[2,3] Sigmatropic shifts in the all
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The [2,3] Wittig rearrangement Ethe
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Ph Ph CH 2I 2, Zn Ph Ph cat Cu cat
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By contrast, the diene 132 with one
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6 R 5 4 CO2Me 3 [3,3] CO 2Me 1 2 OS
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3 O 1 O 2 O OR O O OR O O OR O 4 5
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the ring) with the bulk of the side
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The scope of the Claisen-Cope rearr
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In three dimensions the reaction is
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Conjugating and electron-withdrawin
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Now for the stereochemistry. If a s
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19 References 367 4. B. M. Trost an
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20 Control of Stereochemistry - Int
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1 achiral If we just imagine the si
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1 achiral 5 achiral How to decide i
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What we draw What it means OH OH OH
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Achiral diastereomers You do not ne
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not convinced by this, make a tetra
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image at all. Since organic chemist
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e turned into an asymmetric synthes
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Step No. 3 Decide whether or not th
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addition of a nucleophile to ethyl
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this, your de could be 0% (which wo
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Since two asymmetric reactions are
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that chirotopicity (something that
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D D Cp 2Zr(H)Cl 93 D Ph 20 Popular
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21 Controlling Relative Stereochemi
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21 Formation of Cyclic Compounds vi
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18 Curtius CO 2H rearrangement 1. C
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Nomenclature Just before we go any
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Getting control - ketones It is all
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Getting control - esters With ester
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axial or equatorial leading to the
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21 Reactions of Cyclic Compounds: C
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Nu atoms move towards each other Nu
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will provide a barrier to incoming
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obvious cousin must be the bromolac
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i-Pr OH i-Pr (±)-139 Me resolution
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But fi rst consider the yield of th
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other. With a kinetic diastereosele
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molecule 184. The butyl group does
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21 Open Chain Chemistry - in its Mo
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Cl 211a 21 Open Chain Chemistry - i
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Reaction with electrophiles can be
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22 Resolution Resolution Introducti
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The amine 2 is made by a chemical r
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One of the functional groups now sh
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The resolving agent must now be rem
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Resolution of Diastereoisomers When
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Resolution with half an equivalent
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malaria, but that it also had fewer
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Racemic Compounds Each crystal cont
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Finding a differential crystallisat
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When the N-acetyl derivative of the
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oom temperature by equilibration wi
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The only chiral intermediate is the
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(±)-129 OH OAc Pseudomonas lipase
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At 50% conversion, the product cont
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H O It should not be assumed that a
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23 The Chiral Pool — Asymmetric S
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R O OH Ph If you are manufacturing
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Valinol 27 and phenylalaninol 29 ar
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Derivatives of these aminoalcohols
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Formaldehyde introduces one carbon
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OH OBn OTBDMS TBDMSO OBn OH 108; pr
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The synthesis of captopril The fi r
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Normal peptide coupling (N-Boc-Ala
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The synthesis of ()-laurencin Some
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The next few steps including the vi
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That leaves just one nucleophile to
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231 O 2N The New Chiral Pool Glycid
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O HN Ph NH O When they wanted a sin
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Ph O H H O Me H O N N Me Ph (EtO) P
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The synthesis of crixivan (Indinavi
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O While 319 could be converted into
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Now the terminal OH group can be de
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Derived from them and from other ch
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HO The only C 3 sugar is the rather
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23 References 503 J. Capiello, Tetr
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506 24 Asymmetric Induction I Reage
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25 Asymmetric Induction II Asymmetr
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hydroperoxides can be used), a cata
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O 10a Mesylate was chosen as the le
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carbon, that is C-1 in 25. The mino
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H H H NHCHO O Cl 45; kalihinene X H
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64 py HCl HCl Ar OH CO2Me Summary o
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Osmium tetroxide is very expensive
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R R step A R O O OH O R O O Os O O
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Recommended ligands for different c
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ecause the secondary alcohols are t
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Note that to keep a straight carbon
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25 Dihydroxylating Compounds with M
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25 Dihydroxylating Compounds with M
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The reaction in the box below shows
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The synthesis of diltiazem 42 start
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MeCN H 2SO 4 SO 3 3 mol% 203 N O Me
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We have seen much of quinine and qu
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Consider, for example, a hypothetic
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Me OH 257 2. 1. SnCl 4, (CH 2O) n 2
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25 References 565 10. H. Miyaoka, H
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26 Asymmetric Induction III Asymmet
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Horner 4 at Mainz in Germany and Kn
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26 Hydrogenation with C 2-Symmetric
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When asymmetric reduction of the ke
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Corey’s CBS Reduction of Ketones
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Nowadays much less catalyst is need
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This was an extraordinary result wh
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CO2H O Me N Ph CHO Bn Bn NH2 phenyl
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Ph CHO More recent developments inc
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Cyclopropanation Historically one o
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N Ph Ph *Mo R 154 155 156 Mo* Examp
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Synthesis of enalapril The ACE (Ang
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Recent improvements include the rep
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O NR 2 N CHO i-Pr 2Zn O NR 2 Non-li
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Enantioselectivity with open chain
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26 References 597 22. T. D. Machaje
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600 27 Asymmetric Induction IV Subs
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28 Kinetic Resolution Types of Reac
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Starting Materials A selective whee
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Other symbols used in the realm of
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11 N R R OH 12 99% ee at 55% conver
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With the fast-reacting enantiomer t
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Dynamic Kinetic Resolutions The big
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MeO 2C S OAc (±)-40 OEt OEt 28 Dyn
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OH O 51 Hydrogenation Something tha
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9 OH Lipase 28 Parallel Kinetic Res
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N N Li Ph Me (R)-76 base 77 : 78 LD
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TfO OTf 82 N Ph Cl Pd Cl N 85 28 Do
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89 Triene 89 reacts to form the dio
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29 Enzymes: Biological Methods in A
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O 1; 40 g CO 2Et 200 g baker's yeas
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In some cases two different enzymes
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difference. One useful group is the
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This is a kinetic resolution that w
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the 2,3-bond in the ring. Bromobenz
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Br O O Epoxidation There are all so
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Whole cells of engineered E. coli B
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Enzymatically catalysed aldol react
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160 [O] Engineered aldolase O O O H
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RO 181 1. 9-BBN 2. 175; R = Ac [PdC
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The synthetic compounds are obvious
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Racemic 217 could readily be acetyl
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now Cbz derivatised, remains in the
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29 References 679 42. B. B. Corson,
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682 30 New Chiral Centres from Old
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31 Strategy of Asymmetric Synthesis
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Ph The racemic amino alcohol 2 was
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a Pd-catalysed coupling of a vinyl
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PART III - GRANDISOL AND SOME BICYC
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The remainder of the synthesis invo
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These drugs are clearly peptide mim
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PART V - CONFORMATIONAL CONTROL AND
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The epoxide 95 was reduced with RED
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100 O O An alternative approach 17
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It works by the spontaneous hydroly
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The aldol reaction proved diffi cul
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A cunning solution was to attach th
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In previous syntheses this last cen
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MeO2C 186 1 mol% K2OsO2(OH)4 1 mol%
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32 Functionalisation of Pyridine Th
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So far electrophilic attack on pyri
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F F 32 Regioselectivity in Electrop
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The Anti-Tumour Antibiotic Kedarcid
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y chloride 67 occurs, it is the mos
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Omeprazole: Synthesis 1 The diffi c
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N 107 Diazines CO 2H 1. LiTMP 2. CO
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Tandem Double Lithiation: The asymm
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PART III - SURPRISINGLY SUCCESSFUL
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NMR of compound 171 can be seen. Yo
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N OH CO2H OO 2S Extension by Vicari
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N 204 NH 2 NH 2 H 2 catalyst N H N
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Boc N 239 O Alternatively, coupling
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32 References 775 35. F. I. Carroll
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778 33 Oxidation of Aromatic Compou
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810 34 Functionality and Pericyclic
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35 Synthesis and Chemistry of Azole
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we shall be looking at the synthesi
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The synthesis of allopurinol Many h
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. Routes to Isoxazoles The synthesi
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Better results are often obtained b
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Zolterine (anti-hypertensive) Analy
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tetrazole 122 is about as strongly
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unsymmetrical anion, reasonable reg
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You may be surprised by the stereos
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N N X X N X N X X N X pyridazine (X
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in a typical Heck reaction without
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X N O N H CHO + 204a EtO2C N 211 S
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SnCl2 HCl Now the seven-membered ri
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35 References 861 8. R. N. Butler i
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864 36 Tandem Organic Reactions Asy
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866 36 Tandem Organic Reactions by
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868 36 Tandem Organic Reactions Reg
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870 36 Tandem Organic Reactions Ste
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872 36 Tandem Organic Reactions Tun
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874 36 Tandem Organic Reactions O E
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876 36 Tandem Organic Reactions O H
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878 36 Tandem Organic Reactions The
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880 36 Tandem Organic Reactions Tan
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886 36 Tandem Organic Reactions O O
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888 36 Tandem Organic Reactions 209
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890 36 Tandem Organic Reactions PAR
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892 36 Tandem Organic Reactions R 1
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Index Acetal, 195 Selective formati
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Bombykol, 232 Boranes, 256, 264, 29
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with azadienes, 811-814 with imines
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Erythrina alkaloid, 134, 876 Esomep
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Kalihinene X ()-α-Kainic acid, 357
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Nootkatone, 50 Norvir, 479 NOVRAD,
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Seebach, 55, 56, 600 Relay chiral u
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Vinyl alanes, 271 Vinyl anion equiv
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