15 Synthesis of Unnatural Amino Acids

395 Pages·2003·2.05 MB·English

Handbook of
CHIRAL
CHEMICALS
edited by
D a v i d J. A g e r
NSC Technologies
Mount Prospect, lllinois
MARCEL
-
MARCEDLE KKEIRN,C . NEWY ORK BASEL
DEKKER
ISBN: 0-8247-1058-4
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Preface
Thepurposeofthisbookistohighlighttheproblemsassociatedwiththeproduc-
tionofchiralcompoundsonacommercialscale.Withthemovementbypharma-
ceutical companies to develop single enantiomers as drug candidates, the focus
has turned to problems associated with this subclass of organic synthesis. The
majorclassesofnaturalproducts arealsodiscussed sincethestereogenic center
can be derived from nature through the use of ‘‘chiral pool’’ starting materials.
Despitetheexplosionofasymmetric methodsoverthepast20years,very
few can be performed at scale due to limitations in cost, thermodynamics, or
equipment.Themajorreactionsthathavebeenusedarecoveredinthisvolume.
Resolution, whether chemical or enzymatic, still holds a key position. This is
highlighted by a short discussion of the best-selling compounds of 1996. Many
are obtained either by resolution or by fermentation methods.
Themostmaturechemicalmethodisasymmetricreductionsandhydroge-
nations.Thisishighlightedbychaptersontheusesofnewligandsforhydrogena-
tionandhydride-reducingagents.Althoughwehavemadeconsiderableadvances
inthisarea,thegeneralcatalystisstillelusive.Thestrugglegoesontoidentifythe
ultimatehydrogenationcatalyst;forexample,theuseofenzymesandbiological
systemsfortheproductionofchiralcompoundscontinuestoincreaseatanalmost
explosive rate. Now that we have learned to manipulate nature’s catalysts, this
area will continue to grow and become more important.
Thechapteronaminoacidderivativesistheresultofaconsiderableamount
ofresearchonthenewmethodsforthepreparationofunnaturalaminoacidsand
derivatives at scale. Their findings carry over into other classes of compounds,
but the principles are highlighted exclusively within this field.
The chapters are grouped by topic. The first three are an introduction and
discussionoftherequirementsofsourcingchiralintermediates.Anotherchapter
presentsanoverviewofthecurrentlarge-volumechiralcompoundsandhowthey
are synthesized.
The next three chapters discuss how the key subclasses of the chiral pool
i
ii PREFACE
are obtained. The amino acid chapter is specific to the chiral pool materials as
therearemoreexamplesofaminoacidsynthesescontainedwithinotherchapters.
The next eight chapters cover methods that can be used to introduce or
control stereogenic centers. In some cases, such as asymmetric hydrogenations,
theapproachiswellestablishedandhasbeenemployedforthelarge-scalesynthe-
sis of a number of commercially important compounds. In other cases, such as
pericyclicreactions, thepotential exists,but hasnot yetbeen used.One chapter
covers enzymatic methods, an area that seems to be becoming more important
aswelearnhowtomanipulateenzymesbyallowingthemtocatalyzenewreac-
tions or take new substrates. The rush to market for pharmaceutical companies
is forcing the chemical development time to be minimized. This is leading to
large-scale usage of chiral auxiliaries.
Thechapteronresolutionshasanumberofexamplesasillustrationsshow-
ingthatthismethodologyisstillimportanttoobtainchiralcompounds.Although,
ultimately,itmaynotbethemostcost-effectivemethod,itcanprovidematerial
inarapidmanner,and canusuallybe scaledup.The introductionoflarge-scale
chromatographictechniques,aswell astheavailabilityofa large numberofen-
zymesthatcanbeusedtoperformreactionsononlyoneenantiomer,willensure
that this approach remains a useful tool in the future.
The remaining chapters discuss various examples and topics to augment
other chapters and provide a perspective of the different methods available.
Iwouldliketothankalltheauthorswhocontributedtothisbookandwho
have worked on it with me for the past few years. I would especially like to
thankmy colleagues at NSC Technologies for writing a numberof the chapters
and for having supplied numerous suggestions and ideas. Not only have they
developed new methodology, but they have also proceeded to use it at scale
within a very short timeframe. They continue to inspire me, as do many others
working in the arena of asymmetric synthetic methodology.
David J. Ager
Contents
Preface i
Contributors ix
1. Introduction 1
David J. Ager
1.1. Chirality 1
1.2. Chiral Pool 2
1.3. Chiral Reagents 2
1.4. Chiral Catalysts 2
1.5. Stoichiometric Reagents 4
1.6. Resolution 5
1.7. Synthesis at Scale 5
1.8. Analysis 8
1.9. Summary 8
References 8
2. Sourcing Chiral Compounds for the Pharmaceutical
Industry 11
Graham J. Tucker
2.1. Introduction 11
2.2. Consideration of Sources 12
2.3. Major, Medium, and Minor Players 28
2.4. Technology 28
2.5. Available Chiral Compounds 32
2.6. Conclusion 32
iii
iv CONTENTS
3. Synthesis of Large-Volume Products 33
David J. Ager
3.1. Introduction 33
3.2. Pharmaceuticals 33
3.3. Food Ingredients 40
3.4. Agricultural Products 43
3.5. Summary 45
References 45
4. Synthesis of Phenylalanine by Fermentation and
Chemoenzymatic Methods 49
Ian G. Fotheringham
4.1. Introduction 49
4.2. l-Phenylalanine Overproducing Microorganisms 50
4.3. Biotransformation Routes to l-Phenylalanine 57
4.4. Resolution-Based l-Phenylalanine Synthesis 60
4.5. Conclusions 63
References 64
5. Carbohydrates in Synthesis 69
David J. Ager
5.1. Introduction 69
5.2. Disaccharides 70
5.3. Monosaccharides and Related Compounds 72
5.4. Glyceraldehyde Derivatives 75
5.5. Hydroxy Acids 76
5.6. Summary 79
References 79
6. Terpenes: Expansion of the Chiral Pool 83
Weiguo Liu
6.1. Introduction 83
6.2. Isolation 84
6.3. Monoterpenes 84
6.4. Reactions of Monoterpenes 92
6.5. Summary 99
References 100
CONTENTS v
7. Substitution Reactions 103
David J. Ager
7.1. Introduction 103
7.2. S 2 Reactions 103
N
7.3. Epoxide Openings 105
7.4. Cyclic Sulfate Reactions 107
7.5. Iodolactonizations 108
7.6. Allylic Substitutions 108
7.7. Summary 110
References 110
8. Resolutions at Large Scale: Case Studies 115
Weiguo Liu
8.1. Introduction 115
8.2. Chemical Resolution 116
8.3. Enzymatic Resolutions 128
8.4. Summary 138
References 138
9. Transition Metal Catalyzed Hydrogenations,
Isomerizations, and Other Reactions 143
Scott A. Laneman
9.1. Introduction 143
9.2. Homogeneous Catalysts 147
9.3. Asymmetric Heterogeneous Catalysts Implemented
in Industry 165
9.4. Asymmetric Hydrogen Transfer 168
9.5. Hydroformylation 169
9.6. Hydrosilylation 170
9.7. Asymmetric Cyclopropanations 171
9.8. Conclusions 171
References 173
10. Pericyclic Reactions 177
Michael B. East
10.1. Introduction 177
10.2. The Diels-Alder Reaction 177
10.3. Claisen-Type Rearrangements 187
vi CONTENTS
10.4 The Ene Reaction 190
10.5. Dipolar Cycloadditions 191
10.6. [2,3]-Sigmatropic Rearrangements 192
10.7. Other Pericyclic Reactions 194
10.8. Summary 195
References 196
11. Asymmetric Reduction of Prochiral Ketones Catalyzed
by Oxazaborolidines 211
Michel Bulliard
11.1. Introduction 211
11.2. Stoichiometric Reactions 211
11.3. The Catalytic Approach 212
11.4. Industrial Application in the Synthesis of
Pharmaceuticals 220
11.5. Conclusion 224
References 224
12. Asymmetric Oxidations 227
David J. Ager and David R. Allen
12.1. Introduction 227
12.2. Sharpless Epoxidation 227
12.3. Asymmetric Dihydroxylation 232
12.4. Jacobsen Epoxidation 236
12.5. Halohydroxylations 238
12.6. Enzymatic Methods 239
12.7. Summary 239
References 239
13. Biotransformations: ‘‘Green’’ Processes for the Synthesis
of Chiral Fine Chemicals 245
David P. Pantaleone
13.1. Introduction 245
13.2. Biocatalyst Classifications 246
13.3. Metabolic Pathway Engineering 272
13.4. Screening for Biocatalysts 276
13.5. Summary 278
References 278
CONTENTS vii
14. Industrial Applications of Chiral Auxiliaries 287
David R. Schaad
14.1. Introduction 287
14.2. Chiral Auxiliary Structures in Pharmaceuticals 289
14.3. Application of Chiral Auxiliaries in Industry 290
14.4. Potential Applications of Chiral Auxiliaries 293
14.5. Conclusions 298
References 298
15. Synthesis of Unnatural Amino Acids: Expansion of
the Chiral Pool 301
David J. Ager, David R. Allen, Michael B. East, Ian G.
Fotheringham, Scott A. Laneman, Weiguo Liu, David P.
Pantaleone, David R. Schaad, and Paul P. Taylor
15.1. Introduction 301
15.2. The Choice of Approach 302
15.3. Small-Scale Approaches 304
15.4. Intermediate-Scale Approaches 308
15.5. Large-Scale Methods 310
15.6. Summary 315
References 315
16. Synthesis of L-Aspartic Acid 317
Paul P. Taylor
16.1. Introduction 317
16.2. Commercial Production 317
16.3. General Properties of Aspartase 319
16.4. Biocatalyst Development 319
16.5. Future Perspectives 323
References 326
17. Synthesis of Homochiral Compounds: A Small
Company’s Role 329
Basil J. Wakefield
17.1. Introduction 329
17.2. Classical Resolution 329
17.3. The Chiral Pool 331
17.4. Enzyme-Catalyzed Kinetic Resolution 333
References 336