Asymmetric Synthesis

243 Pages·1992·15.76 MB·English

by  R. A. Aitken (auth.)

Asymmetric Synthesis
Asymmetric Synthesis
Edited by
R. A. AITKEN
Department of Chemistry
University of St Andrews
UK
and
S. N. KILENYI
Sanofi Research
Bruxelles
Belgium
SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.
First edition 1992
Paperback edition 1994
© 1992 Springer Science+Business Media Dordrecht
Originally published by Chapman & Hall in 1992
Softcover reprint of the hardcover 1s t edition 1992
ISBN 978-94-010-4587-2 ISBN 978-94-011-1346-5 (eBook)
DOI 10.1007/978-94-011-1346-5
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Foreword
Very few fields in science have shown. such an acceleration from
theory to practice as the field of asymIfletric synthesis. When one
considers that the phrase 'asymmetric synthesis' was just a
mechanistic curiosity in 1965 with no one seriously believing that
this could someday be an important part of molecular synthesis,
the rate of progress has been quite remarkable. In just over twenty
years the organic chemist has transformed this virtually unknown
aspect of synthesis into a serious route to virtually every class of
chiral organic compounds in greater than 90% enantiomeric
purity. It is presently still enjoying significant growth and our
understanding of many of the guiding principles makes it
necessary to introduce the subject to students at a stage just after
the initial introduction to traditional organic chemistry. It can now
be safely stated that asymmetric synthesis may take its place
among other, more traditional, methods for reaching enantiomeri
cally pure compounds (resolution, microbiological processes,
enzyme catalyzed reactions).
This monograph does an admirable job of bringing all the
aspects of stereochemical principles and their application to a
variety of asymmetric processes, to the young student of organic
chemistry. Although not exhaustive in its coverage, it lays out the
foundation in excellent form, with sufficient examples, so that the
student can gain an appreciation of the progress made to date.
The authors, one of whom (Dr Aitken) has served as a
postdoctoral fellow in my laboratory and has seen first hand the
excitement of developing new asymmetric reactions, have done a
fine job in outlining the principles, definitions, analytical
techniques, and chemical behavior which surround this endeavor.
The authors are to be congratulated for creating this monograph,
for it will bring a new excitement to students in organic chemistry
and it will hopefully point the way for them to pursue more
advanced texts and literature compendia which will only serve to
enhance their knowledge of one of the most important fields of
modern chemistry.
Colorado State University A. I. Meyers
Fort Collins, Colorado, USA
Preface
This book has its origin in an eight lecture course on asymmetric
synthesis given to final year B.Sc. students at the University of St
Andrews since 1985. While there are many excellent monographs
and reviews available covering specific topics, these are generally
aimed at the research level, and none seemed entirely suitable as
an introductory text for students new to the area. At the same
time, the standard organic textbooks generally treat the subject in
an outdated way, very briefly, or not at all. We have therefore
attempted to fill this gap by providing an intermediate level book
which assumes little more than an elementary knowledge of
organic reactivity and stereochemical principles. We hope that it
will prove useful as an introduction to the area for advanced
undergraduate and postgraduate students in the UK and overseas,
and also for chemists in industry who are not familiar with the
area.
The first two chapters cover the aim and importance of
asymmetric synthesis, as well as the sometimes complex
terminology necessary for an understanding of the subject. The
terminology associated with organic stereochemistry is a rapidly
developing and often controversial area and we make no apology
for trying to straighten out some common misconceptions here
and provide the reader with a simple, up-to-date and self
consistent vocabulary for the rest of the book. Chapter 3 provides
an account of the sophisticated methods now available to judge
the degree of selectivity achieved in an asymmetric synthesis. In
chapter 4 the general strategy of asymmetric synthesis is examined
including the chiral starting materials available and a classification
of the known methods. The heart of the book is chapters 5 and 6
in which we have tried to present and explain what we feel to be
some of the most important asymmetric reactions. Here we faced
an almost impossible task due to the sheer volume of material.
Even concentrating on the best established and understood
methods, there has only been space for a brief treatment of each
and wherever possible we have included references to the most
recent reviews so that the interested reader can get more
information. We apologise in advance to anyone who finds that
PREFACE
their favourite method is not included. It is worth noting that the
subject is still developing rapidly and the mechanistic details of
some of the newer methods are not yet fully understood. In the
final chapter some examples of total syntheses are presented to
show the methods in action.
It is a pleasure for us to thank all the contributors for their
valuable work. We must also thank Kit Finlay, Margaret Shand, lona
Hutchison and Lesley Amott for typing the bulk of the manuscript
and Shaun Mesher for drawing the structures for chapter 6.
R. A. Aitken
S. N. Kilenyi
Contents
1 Chirality 1
R. A. AITKEN
1.1 The phenomenon of chirality I
1.2 The biological significance of chirality: the need for asymmetric synthesis 2
1.3 The selective synthesis of enantiomers 5
1.4 The enantiomeric purity of natural products 7
1.5 The stereogenic unit and types of chiral compound 8
1.6 Centrally chiral compounds of carbon and silicon 9
1.7 Centrally chiral compounds of nitrogen and phosphorus 10
1.8 Centrally chiral compounds of sulphur 12
1.9 Axially chiral compounds 13
1.1 0 Chiral molecules with more than one stereo genic unit: diastereomers 15
1.11 The selective synthesis of diastereomers 18
1.12 Prochirality: enantotopic and diastereotopic groups 19
1.13 Absolute configuration 20
Reference and notes 21
2 The description of stereochemistry 23
R. A. AITKEN
2.1 Compounds with one stereo genic centre 23
2.2 Axially chiral compounds 24
2.3 Compounds with more than one stereogenic unit 25
2.4 The topicity of enantioselective reactions 27
2.5 The relative topicity of diastereose1ective reactions 28
2.6 Further points on correct terminology 30
References and notes 31
3 Analytical methods: determination of enantiomeric
purity 33
D. PARKER and R. J. TAYLOR
3.1 Polarimetric methods 33
3.2 Gas chromatography methods 36
3.3 Liquid chromatographic methods 39
3.4 NMR spectroscopy 42
3.4.1 Chiral derivatising agents (CDAs) 44
3.4.2 Chiral solvating agents (CSAs) 50
3.4.3 Chiral lanthanide shift reagents (CLSRs) 57
3.5 Concluding remarks 60
References and notes 62
4 Sources and strategies for the formation of chiral
compounds 64
R. A. AITKEN and J. GOPAL
4.1 Chiral starting materials 64
4.1.1 Amino acids and amino alcohols 64
4.1.2 Hydroxy acids 66
x
CONTENTS
4.1.3 Alkaloids and other amines 67
4.1.4 Terpenes 68
4.1.5 Carbohydrates 69
4.2 Methods for the formation of chiral compounds 70
4.2.1 Use of naturally occurring chiral compounds as building blocks 70
4.2.2 Resolution 71
4.2.3 Methods of asymmetric synthesis 73
4.2.4 Special methods 77
4.3 Mechanistic considerations 80
References and notes 82
5 First- and second-generation methods: chiral starting
materials and auxiliaries 83
S. N. KILENYI
5.1 Non-stereodifferentiating methods 83
5.1.1 Classical resolution ((IR)-cis-permethric acid) 83
5.1.2 Resolution using a chiral auxiliary 85
5.1.3 Sulphoximines 87
5.1.4 Methods using enantiomerically pure building blocks 90
5.2 First-generation methods 92
5.2.1 Sugars 93
5.2.2 Amino acids 96
5.2.3 Terpenoids 96
5.2.4 Hydroxy acids 98
5.3 Second-generation methods: nucleophiles bearing a chiral auxiliary 102
5.3.1 General principles 102
5.3.2 Chiral enolate and aza-enolate equivalents 102
5.3.3 Asymmetric aldol reactions 109
5.3.4 Asymmetric ex-amino anions 118
5.3.5 Chiral sulphoxides 119
5.4 Electrophiles bearing chiral auxiliaries 123
5.4.1 Asymmetric Michael additions 123
5.4.2 Chiral acetals 130
5.4.3 Asymmetric additions to carbonyl compounds 132
5.5 Chiral auxiliaries in concerted reactions 135
5.5.1 Diels-Alder cycloaddition 135
5.5.2 The Claisen-Cope rearrangement 139
References 140
6 Third- and fourth-generation methods: asymmetric
reagents and catalysts 143
S. N. KILENYI and R. A. AITKEN
6.1 C-C bond-forming reactions 143
6.1.1 Asymmetric alkylation 143
6.1.2 Asymmetric Michael reaction 145
6.1.3 Asymmetric nucleophilic additions to carbonyl compounds 149
6.1.4 Asymmetric [2 + 2] cycloadditions 150
6.1.5 Asymmetric Diels-Alder reaction 152
6.1.6 Crotylboranes 153
6.1.7 Asymmetric formation of alkene double bonds 155
6.2 Chiral acids and bases 156
6.3 Asymmetric oxidation methods 160
6.3.1 Asymmetric epoxidation of alkenes 160
6.3.2 Asymmetric oxidation of sulphides 162
6.3.3 Asymmetric dihydroxylation 163
6.3.4 Chiral oxaziridines and their uses 165
CONTENTS Xl
6.4 Asymmetric reduction, double bond isomerisation and hydroboration 167
6.4.1 Catalytic hydrogenation with chiral transition metal complexes 167
6.4.2 Asymmetric double bond isomerisation 173
6.4.3 Asymmetric hydroboration of alkenes 174
6.4.4 Asymmetric reduction using chiral boranes and borohydrides 176
6.4.5 Chirally modified LiAIH4 179
6.5 Enzymatic and microbial methods 181
6.5.1 Enzymatic reduction 181
6.5.2 Enantioselective microbial oxidations 185
6.5.3 Esterases and lipases 188
References 189
7 Asymmetric total synthesis 192
S. N. KILENYI
7.1 First-generation methods 192
7.1.1 (R)-( + )-Frontalin 192
7.1.2 (-)-Prostaglandin E1 193
7.1.3 The Merck synthesis of (+ )-thienamycin 196
7.2 Second-generation methods 200
7.2.1 Prelog-Djerassi lactone 200
7.2.2 (R)-Muscone 203
7.2.3 (-)-Podophyllotoxin 203
7.2.4 (-)-Steganone 206
7.2.5 (+)-a-Allokainic acid 213
7.2.6 Leiobunum defence secretion 215
7.3 Third-generation methods 216
7.3.1 Carbocyclic iododeoxyuridine 216
7.4 Fourth-generation methods 218
7.4.1 A tricyclic analogue of indacrinone 218
7.4.2 (S)-H-Propranolol 220
7.4.3 Takasago (-)-menthol synthesis 222
7.4.4 (-)-Prostaglandin E1 222
7.4.5 Compactin and mevinolin analogues 224
References 227
Index 231