Science ofSynthesis

Volume Editors

Authors

Biocatalysis in Organic Synthesis 2

Reference Library 2014/6

ICFaber

W.-D. Fessner

N.J. Turner

S. K. Au U. Hanefeld M. Pohl

S. Bartsch S. Hussain D. Pressnitz

D.Beecher A.Uari V. Resch

A.Boffi D. B. Janssen N. Richter

A. S. Bommarius G. N. Kaluderovic J. P. N. Rosazza

A. Bonamore W. Kroutil H. F. Schreckenbach

G. Brown A. S. Lamm R. C. Simon

E. Busto F. Leipold K.Steiner

P. Clapes R. Lewin W. SzymanskiK. Faber A.T. Li M. L. Thompson

E.-M. Fischereder Z.Li N.J.TurnerS. P. France M. Majeric Elenkov P. Venkitasubra-

C. S. Fuchs J. Micklefleld manian

E. M. Geertsema T. S. Moody A. Vogel

A. Glieder S.Mix C. Wechsler

M. Gruber-Khadjawi M. Miiller L. A. Wessjohann

M. Hall G. J. Poelarends R. Wohlgemuth

2015

Georg Thieme Verlag KG

Stuttgart • New York

XXIII

Biocatalysis in Organic Synthesis 2

Preface V

Volume Editors' Preface IX

Abstracts XIII

Table of Contents XXV

2.1 C—C Bond Formation 1

2.1.1 Cyanohydrin Formation/Henry Reaction

K. Steiner, A. Clieder, and M. Gruber-Khadjawi 1

2.1.2 Aldol Reactions

P. Clapes 31

2.1.3 Acyloin, Benzoin, and Related Reactions

M. Pohl, C. Wechsler, and M. Muller 93

2.1.4 Enzymatic Carboxylation and Decarboxylation

R. Lewin, M. L. Thompson, and J. Micklefield 133

2.1.5 Addition to C=N Bonds

A. Ilari, A. Bonamore, and A. Boffi 159

2.2 Enzymatic C-Alkylation of Aromatic Compounds

L. A. Wessjohann, H. F. Schreckenbach, and C. N. Kaluderovic 177

23 Addition to C=C Bonds 213

2.3.1 Addition of Hydrogen to C=C Bonds: Alkene Reduction

K. Faber and M. Hall 213

2.3.2 Addition of Water to C=C Bonds

V. Resch and U. Hanefeld 261

2.3.3 Addition of Ammonia and Amines to C=C Bonds

S. Bartsch and A. Vogel 291

2.3.4 Enzymatic Carbon—Carbon Bond-Forming Michael-Type Additions

E. M. Ceertsema and C. J. Poelarends 313

XXIV Overview

2.4 Transamination and Reductive Amination 335

2.4.1 Amino Acid and Amine Dehydrogenases

A. S. Bommarius and S. K. Au 335

2.4.2 Imine Reductases

F. Leipold, S. Hussain, S. P. France, and N. J. Turner 359

2.4.3 co-Transaminases

R. C. Simon, E. Busto, E.-M. Fischereder, C. S. Fuchs, D. Pressnitz, N. Richter,

and W. Kroutil 383

23 Carbonyl Reduction 421

2.5.1 Ketone and Aldehyde Reduction

T. S. Moody, S. Mix, C. Brown, and D. Beecher 421

2.5.2 Carboxylic Acid Reductase

A. S. Lamm, P. Venkitasubramanian, and J. P. N. Rosazza 459

2.6 Epoxide Conversions 479

2.6.1 Asymmetric Synthesis of Enantiopure Epoxides Using Monooxygenases

A. T. Li and Z. Li 479

2.6.2 Reactions Catalyzed by Halohydrin Dehalogenases

M. Majeric Elenkov, W. Szymariski, and D. B. Janssen 507

2.6.3 Epoxide HydrolysisR. Wohlgemuth 529

Keyword Index 557

Author Index 591

Abbreviations 629

XXV

Table of Contents

2.1.1 Cyanohydrin Formation/Henry Reaction

K. Steiner, A. Clieder, and M. Gruber-Khadjawi

2.1.1 Cyanohydrin Formation/Henry Reaction 1

2.1.1.1 Hydroxynitrile Lyases Used in Synthesis 2

2.1.1.1.1 Applications of (R)-Selective Hydroxynitrile Lyases 4

2.1.1.1.1.1 Hydrogen Cyanide Addition to Aldehydes 4

2.1.1.1.1.2 Hydrogen Cyanide Addition to Ketones 6

2.1.1.1.1.3 Transhydrocyanation 7

2.1.1.1.1.4 Nitroalkane Addition to Aldehydes (Henry Reaction) 8

2.1.1.1.2 Applications of (S)-Selective Hydroxynitrile Lyases 9

2.1.1.1.2.1 Hydrogen Cyanide Addition to Aldehydes 9

2.1.1.1.2.2 Hydrogen Cyanide Addition to Ketones 11

2.1.1.1.2.3 Transhydrocyanation 12

2.1.1.1.2.4 Nitroalkane Addition to Aldehydes (Henry Reaction) 12

2.1.1.1.2.5 Resolution of Racemic 2-Nitro Alcohols 14

2.1.1.1.3 Resolution of Racemic Cyanohydrins 14

2.1.1.1.4 Mechanistic Aspects 15

2.1.1.1.5 Optimization of the Reaction Systems 20

2.1.1.1.5.1 Enzyme Engineering 20

2.1.1.1.5.2 Reaction Engineering 22

2.1.1.2 Conclusions and Outlook 25

2.1.2 Aldol Reactions

P. Clapes

2.1.2 Aldol Reactions 31

2.1.2.1 Aldol Addition of 1,3-Dihydroxyacetone Phosphate to Aldehydes 32

2.1.2.1.1 Methods of 1,3-Dihydroxyacetone Phosphate Synthesis 33

2.1.2.1.2 Aldol Addition of 1,3-Dihydroxyacetone Phosphate 35

2.1.2.1.2.1 Aldol Addition of 1,3-Dihydroxyacetone Phosphate to Aliphatic and

Haloaliphatic Aldehydes 35

2.1.2.1.2.2 Aldol Addition of 1,3-Dihydroxyacetone Phosphate to Hydroxy-Containing

Aldehydes 36

2.1.2.1.2.3 Aldol Addition of 1,3-Dihydroxyacetone Phosphate toThiol-Containing

Aldehydes 41

2.1.2.1.2.4 Aldol Addition of 1,3-Dihydroxyacetone Phosphate to Nitrogen-Containing

Aldehydes 42

2.1.2.1.2.5 Aldol Addition of 1,3-Dihydroxyacetone Phosphate to

Dialdehydes ("Tandem" Aldolization) 55

XXVI Table of Contents

2.1.2.1.2.6 Aldol Addition of 1,3-Dihydroxyacetone Phosphate to Other Aldehydes 56

2.1.2.1.2.7 Aldol Addition of 1,3-Dihydroxyacetone Phosphate Analogues to Aldehydes • 58

2.1.2.2 Aldol Addition of 1-Hydroxyalkan-2-ones to Aldehydes 59

2.1.2.2.1 Aldol Addition of 1,3-Dihydroxyacetone, Hydroxyacetone,

and 1-Hydroxybutan-2-one to Nitrogen-Containing AldehydesCatalyzed by D-Fructose 6-Phosphate Aldolase and Variants 59

2.1.2.2.2 Aldol Addition of 1,3-Dihydroxyacetone, Hydroxyacetone,and 1 -Hydroxybutan-2-one to Other Aldehydes Catalyzed by

o-Fructose 6-Phosphate Aldolase and Transaldolase B Variants 63

2.1.2.3 Aldol Addition of Pyruvate to Aldehydes 67

2.1.2.3.1 Aldol Addition of Pyruvate to N-Acetyl-D-mannosamine and Analogues 69

2.1.2.3.2 Aldol Addition of Pyruvate to D-Arabinose and Analogues 72

2.1.2.3.3 Aldol Addition of Pyruvate to Aldehydes 73

2.1.2.4 Aldol Addition of Glycine to Aldehydes 75

2.1.2.5 Self- and Cross-Aldol Reactions of Acetaldehyde 78

2.1.2.5.1 Aldol Addition of Acetaldehyde, Acetone, and Fluoroacetone to Aldehydes • • 79

2.1.2.5.2 Sequential Two-Step Aldol Additions of Acetaldehyde to Aldehydes 80

2.1.2.6 Self- and Cross-Aldol Reactions of 2-Hydroxyacetaldehyde 80

2.1.2.7 Aldol Addition Reactions Catalyzed by Catalytic Antibodies 82

2.1.2.8 Outlook 86

2.1.3 Acyloin, Benzoin, and Related Reactions

M. Pohl, C. Wechsler, and M. Muller

2.1.3 Acyloin, Benzoin, and Related Reactions 93

2.1.3.1 Enzymatic Transformations 93

2.1.3.2 Reaction and Substrate Engineering 94

2.1.3.3 Enzyme Engineering 95

2.1.3.4 Further Modification of Benzoin Products 97

2.1.3.5 Retrosynthetic Potential of Thiamine Diphosphate Dependent Enzymes in

Benzoin and Stetter Reactions 98

2.1.3.6 Synthetic Applications 99

zi.3.6.1 Benzoin Reactions To Give Secondary Alcohols 99

2.1.3.6.1.1 (R)-1-Hydroxy-1-phenylpropan-2-one Derivatives 99

2.1.3.6.1.1.1 Variation of the Donor Substrate 100

2.1.3.6.1.1.2 Variation of the Aromatic Acceptor Substrate 101

2.1.3.6.1.2 (S)-1-Hydroxy-1-phenylpropan-2-one Derivatives 102

2.1.3.6.1.3 (R)-2-Hydroxy-1-phenylpropan-1-one Derivatives 103

2.1.3.6.1.4 (S)-2-Hydroxy-1-phenylpropan-1-one Derivatives 105

2.1.3.6.1.5 Acetoin 107

2.1.3.6.1.6 Aliphatic Acyloins 108

2.1.3.6.1.7 (R)-Benzoins 112

2.1.3.6.1.8 (S)-Benzoins 115

Table of Contents XXVII

2.1.3.6.2 Benzoin Reactions Resulting in 1-Hydroxyalkan-2-ones 116

2.1.3.6.3 Benzoin Reactions Resulting in a,a-Disubstituted Acyloins 118

2.1.3.6.4 Reactions To Give Alkenic Products 121

2.1.3.6.5 Stetter Reaction To Give 1,4-Diketones 123

2.1.3.7 Conclusions 126

2.1.4 Enzymatic Carboxylation and Decarboxylation

R. Lewin, M. L. Thompson, and J. Micklefield

2.1.4 Enzymatic Carboxylation and Decarboxylation 133

2.1.4.1 Biocatalytic Carboxylation 133

2.1.4.1.1 Regioselective Biocatalytic Carboxylation of Phenols 134

2.1.4.1.2 Biocatalytic Carboxylation of Hydroxystyrene Derivatives 138

2.1.4.1.3 Biocatalytic Carboxylation of Heteroaromatic Compounds 139

2.1.4.1.4 Biocatalytic Carboxylation of Epoxides 141

2.1.4.1.5 Carboxylation of Aliphatic Compounds in Biosynthesis 142

2.1.4.2 Biocatalytic Decarboxylation 144

2.1.4.2.1 Thiamine Diphosphate Dependent Decarboxylases 144

2.1.4.2.2 Arylmalonate Decarboxylases: Decarboxylation of Malonic Acids 148

2.1.4.2.3 Acetolactate Decarboxylases 151

2.1.4.2.4 A Postulated Malonic Semi-Aldehyde Decarboxylase 153

2.1.5 Addition to C=N Bonds

A. Ilari, A. Bonamore, and A. Boffi

2.1.5 Addition to C=N Bonds 159

2.1.5.1 Pictet-Spenglerases 159

2.1.5.1.1 Biosynthesis of Benzylisoquinoline and Indole Alkaloids 160

2.1.5 1.2 Structural Basis of Norcoclaurine and Strictosidine Synthases 162

2.1.5.1.3 Other Pictet-Spenglerases 163

2.1.5.2 Norcoclaurine Synthase Catalyzed Pictet-Spengler Reactions 163

2.1.5.2.1 One-Pot Preparation of (S)-Norcoclaurine 164

2.1.5 2.2 Biocatalyzed Synthesis of 1-Substituted Tetrahydroisoquinolines 166

2.1.5.3 Strictosidine Synthase Catalyzed Pictet-Spengler Reactions 168

2.1.5.3.1 Synthesis of Strictosidine Analogues with Substituents on the Indole Unit ••• 168

2.1.5 3.1.1 Synthesis of Piperazinoindoles 170

2.1.5.3.1.2 Synthesis of Azaindole-Containing Strictosidine Analogues 171

2.1.5.3.2 Biocatalyzed Synthesis of P-Carbolines Using Substituted Aldehydes 173

2.1.5.3.2.1 Synthesis of Tetrahydro-P-carbolines Using Secologanin Aglycone Analogues 173

2.1.5.3.2.2 Synthesis of Tetrahydro-P-carbolines Using Achiral Aliphatic and

Aromatic Aldehydes 174

XXVIII Table of Contents

2.2 Enzymatic C-Alkylation of Aromatic Compounds

L. A. Wessjohann, H. F. Schreckenbach, and C. N. Kaluderovic

2.2 Enzymatic C-Alkylation of Aromatic Compounds 177

2.2.1 5-Adenosyk-methionine-Dependent C-Methylation 180

2.2.1.1 Vitamin E Complex 181

2.2.1.2 C-Methylation of Nucleic Acids 185

2.2.1.3 C-Methylation of Other Aromatic Compounds 187

22.2 Aromatic C-Prenylation 190

2.2.2.1 Phenolic Prenyltransferases 192

2.2.2.2 Indole Prenylation 197

2.2.3 C-Clycosyltransferases 199

2.2.4 S-Adenosyk-methionine-lndependent C-Methylation 203

2.2.4.1 Thymidylate Synthases 203

2.2.5 Conclusions and Future Perspectives 205

23 Addition to C=C Bonds

23.1 Addition of Hydrogen to C=C Bonds: Alkene Reduction

K. Faberand M. Hall

23.1 Addition of Hydrogen to C=C Bonds: Alkene Reduction 213

23.1.1 Substrate Scope 215

23.1.1.1 Enals 215

23.1.1.2 Enones 217

23.1.1.3 Carboxylic Acid Derivatives 220

23.1.1.3.1 Carboxylic Acids 220

23.1.1.3.2 Carboxylic Acid Esters 222

23.1.1.3.3 Cyclic Imides 224

2.3.1.1.4 Nitroalkenes 225

23.1.1.5 a,(5-Unsaturated Nitriles 227

23.1.1.6 a,(3-Unsaturated Alkynes 229

23.1.2 Stereocontrol Strategies 229

23.1.2.1 Enzyme-Based Stereocontrol 230

23.1.2.2 Substrate-Based Stereocontrol 231

23.1.2.2.1 Via Substrate Configuration 231

23.1.2.2.2 Via Substituent Effects 232

2.3.1.2.3 Protein Engineering 233

23.1.3 Cofactor Recycling Strategies 236

23.1.3.1 Coupled-Enzyme Approach 236

2.3.1.3.1.1 Proteins Expressed Separately 237

23.1.3.1.2 Designer Cells 239

Table of Contents XXIX

2.3.1.3.2 Nicotinamide-lndependent Systems 240

23.1.3.2.1 Disproportionation: Coupled-Substrate Approach 240

23.2.2 Electro-and Photochemical Methods 242

23.1.3.3 Synthetic-Nicotinamide-Based Approach 243

23.1.4 Synthetically Relevant Examples 244

23.1.5 Conclusions 256

23.2 Addition of Water to C=C Bonds

V. Resch and U. Hanefeld

23.2 Addition ofWater to C=C Bonds 261

23.2.1 Addition of Water to Electron-Rich Double Bonds 267

23.2.1.1 Reaction Using Oleate Hydratases 267

23.2.1.2 Reaction Using Carotenoid Hydratases and

Linalool Dehydrogenase-lsomerases 270

23.2.1.3 Reaction Using Kievitone Hydratases and Phaseollidin Hydratases 271

23.2.1.4 Reaction Using Limonene Hydratases 272

23.2.1.5 Reaction Using Acetylene Hydratases 273

23.2.2 Addition of Water to Electron-Deficient Double Bonds 274

23.2.2.1 Reaction Using Fumarases 274

23.2.2.2 Reaction Using Maleases and Citraconases 276

23.2.2.3 Reaction Using Aconitases 276

23.2.2.4 Reaction Using Urocanases 277

23.2.2.5 Reaction Using Hydratase-Tautomerase Bifunctionality 278

23.2.2.6 Reaction Using Enoyl-CoA Hydratases 279

23.2.2.7 Reaction Using Carnitine Dehydratases 281

23.2.2.8 Reaction Using Hydroxycinnamoyl-CoA Hydratase Lyases 281

23.2.2.9 Reaction Using Michael Hydratases 283

2.3.2.2.10 Reaction Using Phenolic Acid Decarboxylases 284

23.2.2.11 Reaction Using Artificial Hydratases 285

23.3 Addition of Ammonia and Amines to C=C Bonds

S. Bartsch and A. Vogel

23.3 Addition of Ammonia and Amines to C=C Bonds 291

23.3.1 Addition of Amines to Fumarate and Mesaconate 292

23.3.1.1 Aspartase 293

23.3.1.2 Adenylosuccinate Lyase 295

23.3.1.3 Argininosuccinate Lyase 296

23.3.1.4 (S,S)-Ethylenediamine-N,N'-disuccinate and Iminodisuccinate Lyases 296

23.3.1.5 3-Methylaspartate Ammonia Lyase 298

23.3.2 Aromatic Amino Acid Ammonia Lyases and Aminomutases 301

23.3.2.1 Synthesis of L-a-Amino Acids 302

23.3.2.2 Synthesis of (3-Amino Acids 306

XXX Table of Contents

23.4 Enzymatic Carbon—Carbon Bond-Forming Michael-Type Additions

E. M. Ceertsema and C. J. Poelarends

23.4 Enzymatic Carbon-Carbon Bond-Forming Michael-Type Additions 313

23.4.1 a.p-Unsaturated Carbonyl Acceptors 315

23.4.1.1 a,P-Unsaturated Carbonyl Acceptors and 1,3-Dicarbonyl Donors 315

23.4.1.2 a,p-Unsaturated Carbonyl Acceptors and 4-Hydroxybenzopyran-2-one Donors 317

23.4.1.3 a,p-Unsaturated Carbonyl Acceptors and a-Cyano Carbonyl Donors 318

23.4.1.4 a.p-Unsaturated Carbonyl Acceptors and a-Nitro Carbonyl Donors 319

23.4.2 Nitroalkene Acceptors 320

23.4.2.1 Nitroalkene Acceptors and 1,3-Dicarbonyl Donors 320

23.4.2.2 Nitroalkene Acceptors and a-Nitro Carbonyl Donors 323

23.4.2.3 Nitroalkene Acceptors and Ketone Donors 324

23.4.2.4 Nitroalkene Acceptors and Aldehyde Donors 326

23.4.3 Cyanoalkene Acceptors 329

2.3.4.3.1 Dicyanoalkene Acceptors or ct-Cyano a.p-Unsaturated Carbonyl Acceptors

and 1,3-Dicarbonyl Donors 329

23.4.4 Conclusions and Future Outlook 330

2.4 Transamination and Reductive Amination

2.4.1 Amino Acid and Amine Dehydrogenases

A. S. Bommarius and S. K. Au

2.4.1 Amino Acid and Amine Dehydrogenases 335

2.4.1.1 Amino Acid Dehydrogenases 335

2.4.1.1.1 Physicochemical, Sequence, and Structure Comparison 336

2.4.1.1.2 Substrate Specificity 338

2.4.1.1.2.1 Specificity of Alanine Dehydrogenase 338

2.4.1.1.2.2 Specificity of Leucine Dehydrogenase 339

2.4.1.1.2.3 Specificity of Valine Dehydrogenase 340

2.4.1.1.2.4 Specificity of Glutamate Dehydrogenase 340

2.4.1.1.2.5 Specificity of Phenylalanine Dehydrogenase 341

2.4.1.1.2.6 Specificity of meso-Diaminopimelate Dehydrogenase 342

2.4.1.1.2.7 Specificity of Other Amino Acid Dehydrogenases 343

2.4.1.1.3 Synthetic Applications 344

2.4.1.1.3.1 Synthesis of (S)-tert-Leucine 344

2.4.1.1.3.2 Synthesis of (S)-L-6-Hydroxynorleucine 345

2.4.1.1.3.3 Synthesis of (5)-2-Amino-5-(l,3-dioxolan-2-yl)pentanoic Acid 346

2.4.1.1.3.4 Synthesis of (S)-3-Hydroxyadamantan-1-ylglycine 347

2.4.1.1.3.5 Synthesis of (S)-1-Cyclopropyl-2-methoxyethanamine 347

2.4.1.1.3.6 Synthesis of (R)-D-Cyclohexylalanine 348

2.4.1.1.3.7 Synthesis of [R)-5,5,5-Trifluoronorvaline 348

2.4.1.1.3.8 Synthesis of Free Amines from Ketones 349

2.4.1.1.3.9 Synthesis of Amino Acid Enantiomers from Racemic a-Hydroxy Acids 350

Table of Contents XXXI

2.4.1.2 Amine Dehydrogenases 350

2.4.1.2.1 Synthesis with a Leucine Dehydrogenase Derived Amine Dehydrogenase — 352

2.4.1.2.2 Synthesis with a Phenylalanine Dehydrogenase Derived

Amine Dehydrogenase 352

2.4.1.2.3 Synthesis with a Chimeric Amine Dehydrogenase 353

2.4.2 Imine Reductases

F. Leipold, S. Hussain, S. P. France, and N. J. Turner

2.4.2 Imine Reductases 359

2.4.2.1 NADPH Dependent Imine Reductases 363

2.4.2.1.1 Substrate Specificity 364

2.4.2.1.2 Whole-Cell Biotransformations 367

2.4.2.1.3 Kinetic Properties 370

2.4.2.2 NAD(P)H Dependent Imino Acid Reductases 373

2.4.2.3 F420 Dependent Imine Reductases 378

2.4.2.4 Conclusions 379

2.4.3 (o-Transaminases

R. C. Simon, E. Busto, E.-M. Fischereder, C. S. Fuchs, D. Pressnitz,

N. Richter, and W. Kroutil

2.4.3 (^Transaminases 383

2.4.3.1 Amination of Ketones 384

2.4.3.1.1 Amination of Linear Monoketones 384

2.4.3.1.1.1 Amination Employing Alanine as Amine Donor 384

2.4.3.1.1.1.1 Amination with Lactate Dehydrogenase 384

2.4.3.1.1.1.1.1 Preparation of Optically Pure (R)- and (S)-I-Phenylethylamine 385

2.4.3.1.1.1.1.2 Preparation of an (S)-Rivastigmine Precursor 386

2.4.3.I.U.o Chemoenzymatic Preparation of a Precursor for

the Dual Orexin Receptor Antagonist MK-6096 387

2.4.3.1.1.1.2 Amination with Alanine Dehydrogenase 388

2.4.3.1.1.1.2.1 (S)-Amination 388

2.4.3.1.1.1.2.2 (R)-Amination 390

2.4.3 1.1.2 Amination Employing Isopropylamine as Amine Donor 392

2.4.3.1.1.2.1 Amination Followed by Spontaneous Cyclization 394

2.4.3.1.1.2.2 Amination of In Situ Formed Ketones 396

2.4.3.1.1.3 Amination Employing 1-Phenylethylamine as Amine Donor 397

2.4.3.1.1.4 Amination in Organic Solvents 398

2.4.3.1.2 Amination of Diketones 400

2.4.3.1.2.1 Monoamination of 1,5-Diketones 400

2.4.3.1.3 Amination of Cyclic Monoketones 402

2.4.3.1.3.1 Amination of Unsubstituted and 3-Substituted Monocyclic Ketones 402

2.4.3.1.3.2 Amination of 2-Substituted Monocyclic Ketones via

Dynamic Kinetic Resolution 403

2.4.3.1.3.3 Amination of Bicyclic Ketones 404

XXXII Table ofContents

2.4.3.1.3.4 Amination of Multicyclic (Nonsteroidal) Ketones 406

2.4.3.1.3.5 Amination of Steroids and Related Compounds 408

2.4.3.2 Amination of Aldehydes 410

2.4.3.3 Amination of Alcohols 411

2.4.3.4 Resolution of a-Chiral Primary Amines 413

2.4.3.4.1 Kinetic Resolution via Deamination 413

2.4.3.4.2 Deracemization via Deamination/Transamination 414

2.5 Carbonyl Reduction

2.5.1 Ketone and Aldehyde Reduction

T. S. Moody, S. Mix, C. Brown, and D. Beecher

2.5.1 Ketone and Aldehyde Reduction 421

2j.i.i Industrial Bioreductions 425

2.5.1.1.1 Reduction in the Synthesis of (S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol •• 426

2.5.1.1.2 Reduction in the Synthesis of Lipitor 427

23.1.1.3 Reduction in the Synthesis of Montelukast 428

2.5.1.2 Microbial Bioreductions 429

23.1.3 Reduction of Aromatic Ketones 432

2.5.1.4 Reduction and Oxidation Involving Aliphatic and Cyclic Ketones 436

2.5.1.5 Reduction of Bulky Ketones 444

2.5.1.6 Reduction of Chiral Ketones Involving a Dynamic Kinetic Resolution 447

23.1.7 Reduction ofAldehydes 450

23.1.8 Immobilization of Carbonyl Reductase Enzymes and Membrane Applications 451

23.1.9 Ionic Liquids and Carbonyl Reductase Enzymes 452

2.5.1.10 Conclusions and Outlook 453

23.2 Carboxylic Acid Reductase

A. S. Lamm, P. Venkitasubramanian, and J. P. N. Rosazza

2.5.2 Carboxylic Acid Reductase 459

2.5.2.1 Isolation and Purification of Carboxylic Acid Reductase 460

23.2.1.1 Carboxylic Acid Reductase from Nocardia iowensis DSM 45197 460

2.5.2.1.2 Recombinant Carboxylic Acid Reductase from E. coli 462

2.5.2.2 Mechanism of Carboxylic Acid Reduction 462

2.5.2.3 Substrate Scope with Carboxylic Acid Reductase 465

23.2.4 Applications of Carboxylic Acid Reductase 469

23.2.4.1 Synthesis of Ibuprofen 469

23.2.4.2 Synthesis of Vanillin 470

2.5.2.4.3 Reduction of Ferulic Acid 473

2.5.2.4.4 Synthesis of 3-Hydroxytyrosol 475

2.5.2.4.5 Reduction of Fatty Acids 475

2.5.2.4.6 Hydrogenation of Fatty Acids 475

2.5.2.5 Conclusions 476

Table of Contents XXXIII

2.6 Epoxide Conversions

2.6.1 Asymmetric Synthesis of Enantiopure Epoxides Using Monooxygenases

A. T. Li and Z. Li

2.6.1 Asymmetric Synthesis of Enantiopure Epoxides Using Monooxygenases - 479

2.6.1.1 Asymmetric Epoxidation ofAlkenes with Styrene Monooxygenase 479

2.6.1.1.1 Epoxidation of Styrene and Substituted Styrenes 480

2.6.1.1.2 Epoxidation of 1-or 2-Substituted 1-Phenylethenes 482

2.6.1.1.3 Epoxidation of Non-styrene-Type Terminal Alkenes 484

2.6.1.1.4 Epoxidation of Cyclic Alkenes 486

2.6.1.1.5 Epoxidation of Secondary Allylic Alcohols 487

2.6.1.2 Asymmetric Epoxidation of Alkenes with Xylene Monooxygenase 488

2.6.1.3 Asymmetric Epoxidation of Alkenes with Alkane Monooxygenase 489

2.6.1.4 Asymmetric Epoxidation of Alkenes with Alkene Monooxygenase 492

2.6.1.5 Asymmetric Epoxidation of Alkenes with Cytochrome P450 Monooxygenase 493

2.6.1.5.1 Wild-Type Cytochrome P450 Epoxidation of Styrene and Substituted Styrenes 494

2.6.1.5.2 Engineered Cytochrome P450 Epoxidation of Styrene and

Substituted Styrenes 495

2.6.1.5.3 Cytochrome P450 Epoxidation of Other Terminal Alkenes 496

2.6.1.5.4 Cytochrome P450 Epoxidation of Cyclic Alkenes 498

2.6.1.5.5 Cytochrome P450 Epoxidation of Long-Chain Unsaturated Fatty Acids 499

2.6.1.6 Conclusions 501

2.6.2 Reactions Catalyzed by Halohydrin Dehalogenases

M. Majeric Elenkov, W. Szymanski, and D. B. Janssen

2.6.2 Reactions Catalyzed by Halohydrin Dehalogenases 507

2.6.2.1 Epoxide-Ring-Opening Reactions 508

2.6.2.1.1 Synthesis of Azido Alcohols 509

2.6.2.1.2 Synthesis of p-Hydroxynitriles 513

2.6.2.1.3 Synthesis of Oxazolidin-2-ones 514

2.6.2.1 4 Other Epoxide-Ring-Opening Reactions Catalyzed by

Halohydrin Dehalogenases 515

2.6.2.2 Ring-Closure Reactions of Halohydrins 516

2.6.2.3 Cascade Reactions 518

2.6.2.3.1 Cascade Reactions Using a Single Enzyme 518

2.6.2.3.2 Cascade Reactions Using Multiple Enzymes 519

2.6.2.3.3 Cascade Involving Biocatalytic and Chemocatalytic Reactions 521

2.6.2.4 Dynamic Kinetic Resolution Strategy 523

2.6.2.4.1 Biocatalytic Racemization 524

2.6.2.4.2 Chemocatalytic Racemization 524

XXXIV Table ofContents

2.6.3 Epoxide Hydrolysis

R. Wohlgemuth

2.6.3 Epoxide Hydrolysis 529

2.6.3.1 Monosubstituted Epoxides Containing an Aromatic Group and

Their Vicinal Diols 533

2.6.3.1.1 Monosubstituted Epoxides Containing a Phenyl Croup and Their Vicinal Diols 533

2.6.3.1.1.1 Chiral Phenyloxiranes 534

2.6.3.1.1.2 Vicinal Diols Derived from Monosubstituted Epoxides Containing a

Phenyl Croup 536

2.6.3.1.2 Chiral Pyridyloxiranes 538

2.6.3.2 Glycidyl Ethers and Their Vicinal Diols 539

2.6.3.2.1 Enantioenriched Glycidyl Ethers 539

2.6.3.2.2 Vicinal Diols from Glycidyl Ethers 540

2.6.3.3 Monosubstituted Epoxides Containing Alkyl or Alkenyl Substituents and

Their Vicinal Diols 541

2.6.3.3.1 Monosubstituted Epoxides Containing Alkyl or Alkenyl Substituents 541

2.6.3.3.2 Diols from Monosubstituted Epoxides Containing Alkyl orAlkenyl Substituents 542

2.6.3.4 Other Monosubstituted Epoxides and Related Diols 543

2.6.3.4.1 Other Chiral Monosubstituted Epoxides 543

2.6.3.4.2 Other Chiral Monosubstituted Diols 544

2.6.3.5 Geminally Disubstituted Epoxides and Related Diols 544

2.6.3.5.1 Chiral 2,2-Disubstituted Epoxides 545

2.6.3.5.2 Chiral 2,2-Disubstituted Vicinal Diols 547

2.6.3.6 Vicinally Disubstituted Epoxides and Related Diols 547

2.6.3.6.1 Nonsymmetrical Vicinally Disubstituted Epoxides 548

2.6.3.6.2 Diols from Nonsymmetrical Vicinally Disubstituted Epoxides 549

2.6.3.6.3 Diols from Symmetrical Vicinally Disubstituted meso-Epoxides 550

2.6.3.7 Trisubstituted Epoxides and Related Diols 550

2.6.3.7.1 Chiral Trisubstituted Epoxides 551

2.6.3.7.2 Chiral Diols from Trisubstituted Epoxides 551

Keyword Index 557

Author Index 591

Abbreviations 629