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Separation of Enantiomers: Synthetic Methods

Matthew H. Todd (Editor)
ISBN: 978-3-527-33045-4
312 pages
July 2014
Separation of Enantiomers: Synthetic Methods (3527330453) cover image

In one handy volume this handbook summarizes the most common synthetic methods for the separation of racemic mixtures, allowing an easy comparison of the different strategies described in the literature.
Alongside classical methods, the authors also consider kinetic resolutions, dynamic kinetic resolutions, divergent reactions of a racemic mixture, and a number of "neglected" cases not covered elsewhere, such as the use of circularly polarized light, polymerizations, "ripening" processes, dynamic combinatorial chemistry, and several thermodynamic processes.
The result is a thorough introduction to the field plus a long-needed, up-to-date overview of the chemical, biological, and physical methods and their applications. Newcomers to the field, students as well as experienced synthetic chemists will benefit from the highly didactic presentation: Every method is presented in detail, from relatively simple separation problems to advanced complex resolution methods.

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List of Contributors IX

1 Introduction: A Survey of How and Why to Separate Enantiomers 1
Matthew Todd

1.1 Classical Methods 2

1.2 Kinetic Resolution (‘KR’) 3

1.3 Dynamic Kinetic Resolution (‘DKR’) 5

1.4 Divergent Reactions of a Racemic Mixture (‘DRRM’) 7

1.5 Other Methods 8

Acknowledgments 9

References 9

2 Stoichiometric Kinetic Resolution Reactions 13
Mahagundappa R. Maddani, Jean-Claude Fiaud, and Henri B. Kagan

2.1 Introduction 13

2.2 Kinetic Treatment 14

2.2.1 Reactions First-Order in Substrate 14

2.2.1.1 Scope and Validity of Equation 2.6 18

2.2.1.2 Equivalent Formulations of the Basic Equation 2.6 19

2.2.2 Reactions Zero- or Second-Order in Substrate 19

2.2.3 Improvement of Kinetic Resolution Processes 20

2.2.4 Use of Enantio-Impure Auxiliaries 21

2.3 Chiral Reagents and Racemic Substrates 22

2.3.1 Esterification 22

2.3.2 Amide and Peptide Formation 30

2.3.3 Cycloaddition Reactions 35

2.3.4 Conjugate Additions 39

2.3.5 Borane-Involving Reactions 41

2.3.6 Kinetic Resolution of Allenes 43

2.3.7 Olefination Reactions 45

2.3.8 Deprotonation Reactions 48

2.3.9 Miscellaneous 49

2.4 Enantiodivergent Formation of Chiral Product 51

2.4.1 Introduction 51

2.4.2 Creation of a Stereogenic Unit 52

2.4.3 Formation of Regioisomers 54

2.5 Enantioconvergent Reactions 55

2.6 Diastereomer Kinetic Resolution 56

2.7 Some Applications of Kinetic Resolution 58

2.7.1 Organometallics and Analogues 58

2.7.2 Racemic Catalysts 61

2.7.3 Enantiomeric excess’s and Stereoselectivity Factor Measurements by Mass Spectrometry 63

2.7.4 Mechanistic Studies. The Hoffmann Test 66

2.7.5 Miscellaneous 69

2.8 Conclusion 70

2.A Table of s Factors Higher than 10 for Some Reactions 70

References 71

3 Catalytic Kinetic Resolution 75
H´el`ene Pellissier

3.1 Introduction 75

3.2 Kinetic Resolution of Alcohols 76

3.2.1 KR of Alcohols Using Chiral Acylation Catalysts 76

3.2.2 Oxidative KR of Alcohols 81

3.2.3 Miscellaneous Kinetic Resolutions 87

3.3 Kinetic Resolution of Epoxides 88

3.3.1 Hydrolytic Kinetic Resolution 88

3.3.2 Ring Opening of Epoxides by Nucleophiles Other than Water 92

3.4 Kinetic Resolution of Amines 93

3.5 Kinetic Resolution of Alkenes 97

3.6 Kinetic Resolution of Carbonyl Derivatives 101

3.7 Kinetic Resolution of Sulfur Compounds 102

3.8 Kinetic Resolution of Ferrocenes 103

3.9 Conclusions 105

Abbreviations 105

References 107

4 Application of Enzymes in Kinetic Resolutions, Dynamic Kinetic Resolutions and Deracemization Reactions 123
Cara E. Humphrey, Marwa Ahmed, Ashraf Ghanem, and Nicholas J. Turner

4.1 Introduction 123

4.2 Kinetic Resolutions Using Hydrolytic Enzymes 123

4.2.1 Lipases in Organic Synthesis 123

4.2.2 Structural Features of Lipases 124

4.2.3 Typical Substrates for Lipases and Esterases 125

4.2.4 Monitoring the Progress of Lipase-Catalysed Resolutions 126

4.2.5 Kazlauskas’ Rule 127

4.2.6 Activated Acyl Donors 128

4.2.7 Examples of Lipase-, Lipolase- and Hydrolase-Catalysed Reactions in Synthesis 129

4.2.7.1 Resolution of Secondary Alcohols 129

4.2.7.2 Resolution of Amines 131

4.2.7.3 Hydrolysis of Lactams and Nitriles 132

4.2.7.4 Epoxide Hydrolases 133

4.2.8 Strategies for Controlling and Enhancing the Enantioselectivity of Enzyme-Catalysed Reactions 134

4.2.8.1 Substrate Engineering 134

4.2.8.2 Solvent Engineering 135

4.2.8.3 Immobilization and Chemical Modification 136

4.2.8.4 Directed Evolution and Enzyme Libraries 137

4.3 Dynamic Kinetic Resolution 138

4.3.1 Non-Enzyme-Catalysed Racemization 139

4.3.1.1 In Situ Racemization via Protonation/Deprotonation 139

4.3.1.2 In Situ Racemization via Addition/Elimination 140

4.3.1.3 In Situ Racemization via Oxidation/Reduction 140

4.3.1.4 In Situ Racemization via Nucleophilic Substitution 141

4.3.1.5 In Situ Racemization via Free Radical Mechanism 141

4.3.2 Metal-Catalysed Racemization 141

4.3.2.1 Ruthenium-Based Catalysts 142

4.3.2.2 Non-Ruthenium Catalysts 145

4.3.3 Enzyme-Catalysed Racemization 147

4.4 Deracemization 148

4.4.1 Deracemization of Secondary Alcohols 148

4.4.2 Deracemization of Carboxylic Acids 150

4.4.3 Deracemization of Amino Acids and Amines 151

4.4.4 Deracemization of Enol Actates 152

4.5 Enantioconvergent Reactions 153

4.6 Conclusions 153

References 154

5 Dynamic Kinetic Resolution (DKR) 161
Keiji Nakano and Masato Kitamura

5.1 Introduction 161

5.2 Definition and Classification 162

5.3 Dynamic Kinetic Resolution (DKR) 164

5.3.1 Tautomerization 164

5.3.2 Pyramidal Inversion, Deformation and Rotation 181

5.3.3 Elimination–Addition and Addition–Elimination 184

5.3.4 Nucleophilic Substitution 193

5.3.5 Others 198

5.4 Mathematical Expression 201

5.5 DKR-Related Methods 204

5.5.1 DYKAT through a Single Enantiomeric Intermediate 205

5.5.2 DTR of Two Diastereomeric Intermediates 206

5.5.3 Stereoinversion 206

5.5.4 Cyclic Deracemization 207

5.5.5 Enantio-Convergent Transformation 207

5.6 Concluding Remarks 208

References 209

6 Enantiodivergent Reactions: Divergent Reactions on a Racemic Mixture and Parallel Kinetic Resolution 217
Trisha A. Russell and Edwin Vedejs

6.1 Introduction: The Conceptual Basis for Kinetic Resolution and Enantiodivergent Reactions 217

6.2 Divergent RRM Using a Single Chiral Reagent: Ketone Reduction 222

6.2.1 Racemic Ketones and Chiral Non-Enzymatic Hydride Donors 227

6.3 Divergent RRM under Oxidative Conditions 229

6.4 Organometallic Reagents and Regiodivergent RRM 237

6.5 Regiodivergent RRM in Selective Reactions of Difunctional Substrates 248

6.6 Divergent RRM Using Two Chiral Reagents: Parallel Kinetic Resolution (PKR) 252

6.7 Conclusion 262

Acknowledgement 262

References 262

7 Rare, Neglected and Potential Synthetic Methods for the Separation of Enantiomers 267
Matthew Todd

7.1 Resolution through the Selfish Growth of Polymers: Stereoselective Polymerization 267

7.2 Resolution through Photochemical Methods 271

7.3 Combinations of Crystallization and Racemization 274

7.3.1 Crystallization-Induced Dynamic Resolution (CIDR) 275

7.3.2 Ripening 277

7.4 Destruction Then Recreation of Stereocentres: Enantioselective Protonations 278

7.5 Dynamic Combinatorial Chemistry 280

7.6 Asymmetric Autocatalysis 282

7.7 Miscellaneous 283

7.8 Concluding Remarks 283

Acknowledgements 284

References 284

Index 291

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An Associate Professor at The University of Sydney's School of Chemistry, Matthew Todd gained his BA and PhD from Cambridge University, UK, where he later became a Fellow in Chemistry. Prior to taking up his current position, he was a Wellcome Trust postdoctoral fellow at the University of California, Berkeley, USA, from 1999 to 2000, and then became a lecturer in organic chemistry at the Department of Chemistry, Queen Mary, University of London from 2001 to 2005. Prof. Todd's research group is investigating synthetic methodology, responsive metal complexes, and asymmetric catalysis. He has received awards for his work in open science, most notably his creation of the Open Source Malaria consortium that is trialling a new model of drug discovery.
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