Asymmetric synthesis is an integral part of synthetic organic chemistry. Some of the reactions in this book were known prior to 1980, while several new ones, particularly catalytic asymmetric reactions, have been discovered in the recent years. The impact of this new class of reactions has been impressively extensive―both on organic and medicinal chemistry. These reactions have been accepted whole-heartedly by synthetic organic chemists in developing shorter routes for complex natural targets as well as in the manufacture of a wide range of drug intermediates.

Preface iii

CHAPTER 1 Introduction 1

1.1 Synthesis of chiral molecules in living systems 2

1.2 Need for asymmetric synthesis 5

1.3 Synthesis of stereoisomers as racemic products 11

1.4 Selectivity in synthesis of stereoisomers 17

CHAPTER 2 Terms, definitions and concepts in asymmetric synthesis 24

CHAPTER 3 Achiral and chiral molecules and their properties 44

3.1 Introduction 44

3.2 Properties of enantiomers (E_1and E_2) 48

3.3 Properties of chiral diastereoisomers 67

CHAPTER 4 Prochirality 72

4.1 Introduction: Stereohomotopic and stereoheterotopic atoms/groups and faces 72

4.2 Stereohomotopic atoms/groups and faces 74

4.3 Stereoheterotopic atoms/groups and faces 77

41\4 Prochirality: Nomenclature 93

CHAPTER 5 Enantioselective and diastereoselective synthesis 101

5.1 Structure, symmetry and transition state energy requirements for enantioselectivity 101

5.2 Structure, symmetry and transition state energy requirements for (asymmetric) diastereoselective synthesis 109

CHAPTER 6 Methods for monitoring enantioselective and diastereoselective synthesis 118

6.1 Conventions for expressing enantioselectivity and diastereoselectivity 118

6.2 Determination of % op, % ee, % es in enantioselective reactions 121

6.3 Physical methods in the determination of absolute configuration 138

6.4 Determination of configuration from the established stereochemical pathway of asymmetric reactions 148

CHAPTER 7 Methods for inducing asymmetry 150

7.1 Methods for inducing enantioselectivity 150

7.2 Methods for inducing diastereoselectivity 156

7.3 Classification of asymmetric synthesis 165

CHAPTER 8 Chiral substrate controlled asymmetric reactions: Diastereoselection in acyclic systems 179

8.1 Asymmetric induction 179

8.2 1,2-Asymmetric induction (Cram, Felkin-Anh models) 181

8.3 1,3-Asymmetric induction (Reetz and Cram-Reetz models) 196

8.4 1,4-Asymmetric induction (Prelog's model) 198

CHAPTER 9 Chiral auxiliary controlled asymmetric reactions—asymmetric a-alkylations 202

9.1 Introduction to enolates 202

9.2 Chiral auxiliary controlled a-alkylations of enolates and azaenolates 212

CHAPTER 10 Chiral stoichiometric reagent controlled asymmetric synthesis: Chiral boron reagents 228

10.1 Introduction 228

10.2 Enantioselective hydroboration: Use of chiral boron hydrides 229

10.3 Chiral trialkyl boranes: Alpine borane (IPC.BBN, Midlands reagent) 234

CHAPTER 11 Chiral catalyst mediated asymmetric reactions: Enzymes 238

11.1 Introduction 238

11.2 Enzymes: Chiral biocatalysts 239

11.3 Enantioface Re and Si selective transformations of prochiral ketones, aldehydes and olefins 241

11.4 Enantiotopic and diastereotopic atom/group selective transformations 247

11.5 Enzymatic discrimination of enantiotopic groups of meso compounds: Meso trick 252

11.6 Enzymatic discrimination of diastereotopic atoms and groups 253

11.7 Kinetic resolutions of racemic esters and alcohols with lipases and esterases 254

CHAPTER 12 Chiral organometallic catalysed asymmetric reactions: Sharpless asymmetric epoxidations, dihydroxylations and aminohydroxylations 257

12.1 Introduction 257

12.2 Stoichiometric enantioselective nucleophilic epoxidation 259

12.3 Sharpless asymmetric epoxidation (AE) 260

12.4 Catalytic enantioselective oxidation of sulphides: Kagan's sulphoxidation 280

12.5 Sharpless asymmetric dihydroxylation (AD) 280

12.6 Sharpless asymmetric aminohydroxy lation 293

CHAPTER 13 Chiral organometallic catalysed asymmetric reactions 302

13.1 Jacobsens epoxidation: Catalytic asymmetric epoxidation of unfunctionalised olefins 302

13.2 Knowles catalytic homogeneous asymmetric hydrogenations 309

13.3 Noyoris catalytic homogeneous asymmetric hydrogenations 323

CHAPTER 14 Organocatalysts in asymmetric synthesis—chiral additive mediated reactions 336

14.1 Introduction 336

14.2 Shi epoxidation 336

14.3 (R, R)-tartaric acid catalysed enantioselective reductions 340

14.4 Enantioselective catalytic reduction of ketones by oxazaborolidines 341

14.5 Enantioselective cyclopropanation of allylic alcohols by dioxaboralanes 343

CHAPTER 15 Asymmetric aldol reaction 346

15.1 Introduction 347

15.2 Aldol reactions: Four classes 349

15.3 Mukaiyama aldol reaction 364

CHAPTER 16 Asymmetric Diels-Alder reactions 369

16.1 Introduction 369

16.2 Woodward-Hoffmann suprafacial-suprafacial stereoselectivity: Syn addition 370

16.3 Endo-exo selectivity and the role of Lewis acids 376

16.4 Regioselectivity in Diels-Alder reactions 381

16.5 Enantio- and diastereoselectivity in Diels-Alder reactions (asymmetric Diels-Alder reactions) 381

CHAPTER 17 Stereoselective synthesis and stereospecific synthesis 392

17.1 Stereoselective synthesis 393

17.2 Stereospecific synthesis 402

Annexure 1 Symmetry elements and symmetry operations 413

Annexure 2 Point groups 426

Annexure 3 Molecules with one chiral center 441

Annexure 4 Molecules with two or more chiral centers 448

Index 455

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