INTRODUCTION TO STEREOCHEMISTRY AND CONFORMATIONAL ANALYSIS

EUSEBIO JUARISTI Professor of Chemistry Departamento de Quimica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, MEXICO

A Wüey-Interscience Publication

JOHN WILEY & SONS, INC.

New York • Chichester • Brisbane • Toronto • Singapore

CONTENTS

1 Chirality 1

1.1 Molecular Structure 1 1.2 The Origin of Chirality in Organic Compounds 7 1.3 Stereogenic Atoms 10 1.4 Stereogenic Atoms Other than Carbon 11 1.5 Chiral Methyl Groups (R-CHDT) 14 1.6 Chiral Polymers 15 References 15

2 Absolute Configuration 18

2.1 Determination of Absolute Configuration in Chiral Compounds 18

2.2 Fischer Projections 20 2.3 The D, L System of Nomenclature 21 2.4 The R, S System of Nomenclature 23 2.5 Correlation of Absolute Configuration 26 2.6 Nuclear Magnetic Resonance Methods for the

Establishment of Absolute Configuration 32 2.6.1 Proton Magnetic Resonance (PMR) Spectra of

Menthyl Phosphinates 32 2.6.2 Nuclear Magnetic Resonance (NMR) Chemical

Shifts of Diastereomeric a-Methoxy-a-trifluoro-methyl-phenylacetate Esters 32

x CONTENTS

2.6.3 Use of the Methylmandelate Ester for the Establishment of Absolute Configuration of Secondary Alcohols 34

References 35

3 Stereochemical and Conformational Descriptors 36

3.1 Introduction 36 3.2 Descriptors for Configurations of Chiral

Molecules 36 3.2.1 The (R) and (5) Symbols 36 3.2.2 Axes and Planes of Chirality 38 3.2.3 The (re) and (si) Descriptors 42 3.2.4 Helicity (P or M) 42

3.3 Descriptors Used to Specify the Configuration of Double Bonds 43 3.3.1 The eis and trans Descriptors 43 3.3.2 The (£) and (Z) Descriptors 45

3.4 The c and t Symbols 46 3.5 Descriptors Used to Specify Relative

Configurations 47 3.5.1 The erythro and threo Descriptors 47 3.5.2 The meso Descriptor 48 3.5.3 The rac Descriptor 48

3.6 Descriptors Used to Specify the Relative Orientation of Substituents 49 3.6.1 The D and L Symbols 49 3.6.2 The endo and exo Descriptors 49 3.6.3 The syn and anti Descriptors 50 3.6.4 The a and ß Symbols 51

3.7 The Like, Unlike Nomenclature 52 3.8 Descriptors Used to Specify the Conformation in Ethane

Segments. 54 3.8.1 Eclipsed and Staggered Conformations 54 3.8.2 Gauche and anti Conformations 54

3.9 Descriptors Used to Specify the Stereochemistry of Six-Membered Rings 54 3.9.1 Axial and Equatorial Substituents 54 3.9.2 Pseudoaxial, Pseudoequatorial, and Flagpole

Substituents 55 3.9.3 Anancomeric Rings 56

References 56

CONTENTS xi

4 Chiroptic Properties in Chiral Molecules 58

4.1 Optical Activity 58 4.2 Optical Rotatory Dispersion 63 4.3 The Octant Rule 65 4.4 The Quasi-Racemate Method 68 References 70

5 Stereochemistry of Organic Reactions 72

5.1 Stereoselective and Stereospecific Reactions 72 5.2 Bimolecular Nucleophilic Substitution (Sjy2) 73 5.3 Internal Nucleophilic Substitution (S^i) 75 5.4 Bimolecular Electrophilic Substitution (S£2) 77 5.5 Bimolecular Elimination (E2) 78 5.6 syn Elimination (Esyn) 83 5.7 syn Additions 85 5.8 anti Additions 85 5.9 Sigmatropic Rearrangements 87 References 89

6 Prochirality 91

6.1 Heterotopicity 91 6.2 Criteria Employed for the Identification of Heterotopic

Ligands 92 6.3 Analogy Between Heterotopicity and Isomerism 94 6.4 Heterotopic Faces 94 6.5 Conclusions 98 6.6 Consequences of Heterotopicity 98 6.7 Analogy of Enantiotopic Ligands and Faces with the

Doors of a Cabinet 104 References 105

7 Asymmetrie Organic Synthesis: Principles 106

7.1 The Importance of Asymmetrie Synthesis 106 7.2 Historical Aspects 110 7.3 Conditions for an Efficient Asymmetrie Synthesis 113 7.4 Energetic Considerations 114 7.5 Synthetic Methodology 117

7.5.1 Microbial and Enzymatic Methods 117 7.5.2 Biomimetic Methods 120 7.5.3 Racemate Resolution 123

CONTENTS

7.5.4 Catalytic Kinetic Resolution 124 7.5.5 Catalytic Asymmetrie Synthesis 124 7.5.6 The Use of Chiral Auxiliaries 124 7.5.7 The "Chiral Pool" 125

References 127

Enantiomeric Purity 129

8.1 Introduction 129 8.2 Evaluation of Optical Rotation 130 8.3 Chromatographie Methods 132 8.4 Determination of Enantiomeric Purity by Means of

Nuclear Magnetic Resonance Spectroscopy 136 8.4.1 Preparation of Diastereomers 136 8.4.2 Use of Chiral Solvents 139 8.4.3 Use of Chiral Lanthanide Shift Reagents 140

References 142

Resolution of Racemates 144

9.1 Introduction 144 9.2 Resolution via the Manual Separation of Enantiomeric

Crystals 144 9.3 Resolution via the Separation of Diastereomers 146

9.3.1 Resolution of Racemic Acids with Enantiomerically Pure Amines 149

9.3.2 Resolution of Racemic Amines with Chiral Acids 149 9.3.3 Resolution of Racemic Alcohol with

Enantiomerically Pure Acids 150 9.3.4 Resolution of Racemic Ketones 151

9.4 Enzymatic Resolution 152 9.5 Preparative Chromatographie Resolution 158 References 159

Asymmetrie Synthesis via a Chiral Catalyst 161

10.1 Introduction 161 10.2 Chiral Catalytic Hydrogenation 162 10.3 Industrial Production of L - D O P A 164 10.4 Mechanism of the Knowles Reaction 165 10.5 Homogeneous Catalysis in the Synthesis of

Trimoprostil 166 10.6 Catalytic Asymmetrie Synthesis of (S)-Malic Acid 169 10.7 Heterogeneous Catalytic Hydrogenation 170

CONTENTS XIII

10.8 Enantioselective Catalytic Hydrogenation with Semicorrin Metal Complexes 172

10.9 Asymmetrie Michael Additions 174 References 177

11 Asymmetrie Syntheses with Chiral Substrates 178

11.1 Introduction 178 11.2 The Cram and Prelog Reactions 178 11.3 Eliel's Chiral Oxathianes—Asymmetrie Syntheses of

Chiral Tertiary Alcohols 184 11.4 Addition of Chiral Enolates Derived from Glycine

to Aldehydes and Ketones in the Preparation of Enantiomerically Pure Amino Acids 186

11.5 Evans' Chiral oe,ß-Unsaturated iV-Acyloxazolidinones— Asymmetrie Diels-Alder Cycloaddition Reactions 192

11.6 Asymmetrie Alkylation of Secondary Amines 193 11.7 Asymmetrie Cyclopropanation 194 References 196

12 Asymmetrie Reactions Between Achiral Substrates and Chiral Reagents 199

12.1 Introduction 199 12.2 Synthesis of Enantiomerically Pure Compounds via

Chiral Organoboranes 199 12.3 Asymmetrie Reductions with Chiral Derivatives of

Lithium Aluminum Hydride 205 12.4 C2 Symmetrie Chiral Auxiliaries 208 12.5 Asymmetrie Induction in the Conjugate Addition of

Chiral Organocuprates 210 12.6 Enantioselective Deprotonation by Chiral Lithium

Amide Bases 212 References 214

13 Miscellaneous Methods for the Control of Stereochemistry 216

13.1 Introduction 216 13.2 Stereocontrol in Aldol Reactions 217 13.3 Stereochemical Control by Double Asymmetrie

Induction 222 13.4 Effect of Cation on Diastereofacial Selectivity in Aldol

Reactions 227

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13.5 Stereochemistry of the Addition of Dithianyl Lithiums to Cyclohexanones 231

References 235

14 The Conformational Analysis of Acyclic and Cycloalkanes 237

14.1 Introduction 237 14.2 Development of Conformational Analysis 238 14.3 The Conformation of Acyclic Molecules 239 14.4 Cyclohexane Conformations 243 14.5 The Conformation of Other Cycloalkanes 248

14.5.1 Cyclopropane 248 14.5.2 Cyclobutane 248 14.5.3 Cyclopentane 248 14.5.4 Cycloheptane 249 14.5.5 Cyclooctane 250 14.5.6 Other Cycloalkanes 250

14.6 Molecular Mechanics Computations on Hydrocarbons 250 References 251

15 Applications of Dynamic NMR Spectroscopy in Conformational Analysis 253

15.1 Fundamentals 253 15.2 Study of the Ring Inversion in Cyclohexane 255 15.3 Study of Ring Inversion in ds-Decalin 256 15.4 Ring Inversion in Cyclohexane Derivatives 257 15.5 Axial and Equatorial Conformers ofChlorocyclohexane 258 15.6 The A Values of Deuterium and Tritium 260 15.7 Conformational Analysis of Aminocyclohexane Using

1 5NNMR at Low Temperature 263 15.8 Conformational Preference of the Diphenylphosphinoyl

Group in Cyclohexane 263 15.9 Conformational Analysis of 1-Methyl-1-phenyl-

cyclohexane—Lack of Additivity of A Values 265 15.10 Direct Observation of Axial Phenylcyclohexane 266 15.11 Barrier to Pyramidal Inversion in Azetidine 267 15.12 Dynamic NMR Study of Phenyl Thiolformate 268 References 269

16 Conformational Analysis of Heterocycles 271

16.1 Introduction 271 16.2 Monosubstituted Tetrahydropyrans 272

CONTENTS XV

16.3 1,3-Dioxane 273 16.4 1,5-Benzodioxepins 279 16.5 Sulfur-Containing Heterocycles 280 16.6 Conformational Preference of Dithia[3.3]meta-

cyclophanes 283 16.7 Conformational Preference of the N-H Bond in

Piperidine 283 References 285

17 The Anomeric Effect 286

17.1 Historical Aspects 286 17.2 Rationalizations of the Anomeric Effect 287 17.3 Study of the Anomeric Effect in 2-Substituted

1,3-Dithianes 288 17.4 The Enthalpie Anomeric Effect 291 17.5 S-C-P Anomeric Interactions 293 17.6 The Effect of para-Substituents on the Conformational

Behavior of 2-Aryl-l,3-dithianes 295 References 298

18 The Attractive and Repulsive Gauche Effects 299

18.1 Introduction 299 18.2 The Attractive gauche Effect 300

18.2.1 1,2-Heterosubstituted Ethanes 300 18.2.2 5-Heterosubstituted-l,3-dioxanes 301 18.2.3 1,2-Diheterosubstituted Cyclohexanes 302

18.3 The Repulsive gauche Effect 305 18.3.1 2-Substituted-l,4-oxathianes 306 18.3.2 1,2-frans-Disubstituted Cyclohexanes 306 18.3.3 5-Substituted-l,3-dithianes 307

References 310

Author Index 313

Subject Index 323