Chirality in Drug Research, Vol. 33 Book

Preface     XIII
List of Contributors     XV
Introduction
Chiral Drugs from a Historical Point of View   Joseph Gal     3
Introduction     3
A Word About Words     3
Old Chiral Drugs: Natural Remedies 3000BC-1900     4
Recognition of Chirality in Drugs     13
Enantioselectivity in Drug Action and Drug Metabolism: The Beginnings     16
Drug Chirality in the 20th Century     18
References     24
Synthesis
Stereoselective Synthesis of Drugs - An Industrial Perspective   Hons-Jurgen Federsel     29
Introduction: Historical Overview     29
Asymmetry from an Industrial Scale Perspective     32
Stereoselective Processes in Drug Manufacture - Drivers and Blockers     38
The Metal - Friend and Foe     41
Ligand Development - At the Core of Catalytic Chemistry     43
Asymmetric Reactions - A Rich Reservoir     45
Reductions     48
Oxidations     51
Carbon-Carbon Bond Formation     55
Retrospect and Prospect     59
References     62
Aspects of Chirality in Natural Products Drug Discovery   Philipp Krastel   Frank Petersen   Silvio Roggo   Esther Schmitt   Ansgar Schuffenhauer     67
Introduction     67
Stereochemical Aspects of Natural Products     71
Chirality Analysis of Natural Products versus Drugs and Synthetics     71
Determination of the Relative and Absolute Stereochemistry of Natural Products     74
NMR Spectroscopy     74
Chiroptical Methods     75
X-ray Crystallography     75
Total Synthesis and Degradation Reactions     76
Mechanisms of Stereochemical Control in Natural Product Biosynthesis     77
Origin of D-Amino Acids in Non-ribosomal Peptides     77
Control of Chirality in Modular Polyketide Synthesis     79
Modes of Stereodifferentiating Cyclization     80
Terpene Biosynthesis in Plants     82
Biological Activity of Natural Products Related to Stereochemistry     83
Natural Products Active on the Nervous System     84
Gossypol, a Racemic Natural Product     86
Epimerization of Natural Products in vivo     87
Tubuline Stabilizing Agents     88
References     90
Biotransformation Methods for Preparing Chiral Drugs and Drug Intermediates   Michael Muller   Marcel Wubbolts      95
Introduction     95
Examples of Established Applications of Biocatalysts in the Synthesis of Pharmaceuticals     96
Ephedrine Synthesis     96
Amino Acids     99
Amines     100
Penicillins/Cephalosporins     101
Racemic Resolution Using Hydrolytic Enzymes     103
Oxidoreductases     106
Oxynitrilases     108
Comparison of Nonenzymatic and Biocatalytic Transformations     108
Some Special Aspects of Biocatalysts, Recent Developments     111
Dynamic and Parallel Kinetic Resolution     111
Different Biocatalytic Approaches to One Building Block     112
Multipurpose Small Chiral Building Blocks     114
Optimization/New Access Using Molecular Biology Methods     116
Metabolic Engineering     116
Reaction Engineering     118
Conclusions and Outlook     119
References     120
Separations
Resolution of Chiral Drugs and Drug Intermediates by Crystallisation   Kazuhiko Saigo     127
Introduction     127
Physical Enantioseparation - Preferential Crystallization     127
Chemical Enantioseparation - Diastereomeric Salt Formation      133
The Bridge Between Preferential Crystallization and Diastereomeric Salt Formation     141
Process Research on the Enantioseparation of Racemates by Diastereomeric Salt Formation     143
The Role of Water in the Stabilization of Less-soluble Diastereomeric Salts - A Key Intermediate for the Synthesis of Duloxetine, 3-(Methyl-amino)-1-(2-thienyl)propan-1-ol     143
Reciprocal Enantioseparation - A Key Intermediate for ACE Inhibitors, 2-Hydroxy-4-phenylbutyric Acid, and 1-(4-Methyl-phenyl)ethylamine     146
Solvent Switch - A Key Intermediate for Lysine Production, [alpha]-Amino-[epsilon]-caprolactam     147
Examples of Enantioseparations in the Pharmaceutical Industry     149
References     152
Isolation and Production of Optically Pure Drugs by Enantioselective Chromatography   Eric Francotte     155
Introduction     155
General Considerations Regarding the Preparation of Single Stereoisomers of Chiral Drugs     156
The Different Approaches     156
Enantioselective Chromatography     157
Preparative Chiral Stationary Phases     158
Classification of Chiral Stationary Phases     158
Polymeric Phases     161
Polysaccharide-based CSPs     161
Polyacrylamide CSPs     164
Polymeric CSPs Derived from Tartaric Acid     164
Brush-type CSPs     165
[pi]-Acidic and [pi]-Basic Phases     165
Cyclodextrin-based CSPs     166
Chirobiotic CSPs     166
Chiral Ion-exchange Stationary Phases     167
Strategies for Performing Enantioselective Separations     168
Selecting the Right CSP     168
Selecting the Racemic Solute     170
Selecting the Right Synthetic Step     170
Preparative Enantioselective Resolution of Chiral Drugs     172
Laboratory-scale Separations     172
Pilot-scale Separations     176
Process-scale Separations     177
Production-scale Separations     178
Other Enantioselective Chromatographic Techniques     179
Gas Chromatography     179
Membranes     180
Centrifugal Partition Chromatography     180
Electrophoretic Methods     181
Conclusion     181
References     182
Stereoselective Chromatographic Methods for Drug Analysis   Norbert M. Maier   Wolfgang Lindner     189
Introduction     189
The Role of Enantioselective Analysis in Drug Development     191
Separation Techniques in Enantiomer Analysis     192
Principle of Enantiomer Separation     194
Indirect Enantiomer Separation     195
Direct Enantiomer Separation     196
Chiral Mobile Phase Additives (CMPA)     196
Chiral Stationary Phases     197
Molecular Requirements for Chiral Recognition     198
Thermodynamic Principles of Enantiomer Separation     199
Role of Mobile Phase in Enantiomer Separation     202
Chiral Selectors and Chiral Stationary Phases Employed in Liquid Chromatographic Enantiomer Separation     205
CSPs Derived from Polymers     207
CSPs Derived from Natural Polymers     207
Polysaccharide-type CSPs     207
Protein-type CSPs     215
CSPs Derived from Synthetic Polymers     218
Helical Poly(methacrylates)     218
Chiral Poly(methacrylamides)     218
Tartardiamide-network Polymers     219
Poly(diaminocyclohexane-N,N-diacrylamide)     219
Molecularly Imprinted Polymers     221
Macrocyclic CSPs     224
Cyclodextrin-type CSPs     224
Glycopeptide-type CSPs     226
Crown Ether-type CSP     231
CSPs Based on Low-Molecular-Weight Molecules      233
Donor-Acceptor-type CSPs     233
Ion-exchange-type CSPs     237
Ligand-exchange-type CSPs     240
CSPs Based on Target-specific Bioaffinity Systems     240
Antibody-type CSPs     241
Aptamer-type CSPs     242
Conclusions     244
References     245
Capillary Electrophoresis Coupled to Mass Spectrometry for Chiral Drugs Analysis   Serge Rudaz   Jean-Luc Veuthey     261
Introduction     261
Capillary Electrophoresis (CE)     262
CE-MS Coupling     263
CE-ESI-MS     263
Other CE-MS Coupling     265
Chiral Separation Strategies     265
Partial Filling     268
Partial Filling with Crown Ethers     268
Partial Filling with Neutral Derivatized CD     268
Partial Filling - Counter Current Technique     270
Anionic Analytes - Positively Charged Chiral Selectors     271
Cationic Analytes - Negatively Charged Chiral Selectors     271
Chiral Micellar Electrokinetic Chromatography     274
Quantitative Aspects in CE-MS and Parameters for CE-ESI-MS Coupling     276
Capillary Electrochromatography Coupled to Mass Spectrometry     277
Discussion and Conclusion     278
References     280
Powerful Chiral Molecular Tools for Preparation of Enantiopure Alcohols and Simultaneous Determination of Their Absolute Configurations by X-Ray Crystallography and/or [superscript 1]H NMR Anisotropy Methods   Nobuyuki Harada     283
Introduction     283
Methodologies for Determining Absolute Configuration     284
Nonempirical Methods for Determining Absolute Configurations of Chiral Compounds     284
Relative and/or Empirical Methods for Determining Absolute Configuration Using an Internal Reference of Absolute Configuration     285
CSDP Acid, Camphorsultam Dichlorophthalic Acid (-)-1, Useful for the Enantioresolution of Alcohols by HPLC and Simultaneous Determination of Their Absolute Configurations by X-ray Crystallography     287
A Novel Chiral Molecular Tool, 2-Methoxy-2-(1-naphthyl)propionic Acid (M[alpha]NP Acid (S)-(+)-3), Useful for Enantioresolution of Alcohols and Simultaneous Determination of Their Absolute Configurations by the [superscript 1]H NMR Anisotropy Method     295
Facile Synthesis of M[alpha]NP Acid (3) and Its Enantioresolution with Natural (-)-Menthol     298
The [superscript 1]H NMR Anisotropy Method for Determining the Absolute Configuration of Secondary Alcohols: the Sector Rule and Applications     399
Enantioresolution of Various Alcohols Using M[alpha]NP Acid and Simultaneous Determination of Their Absolute Configurations     304
Recent Applications of the M[alpha]NP Acid Method to Various Alcohols     307
Application of the M[alpha]NP Acid Method to Chiral meta-Substituted Diphenylmethanols     313
Absolute Configuration of the Thyroid Hormone Analog KAT-2003 as Determined by the [superscript 1]H NMR Anisotropy Method with M[alpha]NP Acid     314
Conclusion     319
References     319
Keywords in Chirality Modeling Molecular Modeling of Chirality - Software and Literature Research on Chirality in Modeling, Chirality in Docking, Chiral Ligand-Receptor Interaction and Symmetry   Gerd Folkers   Mine Yarim   Pavel Pospisil     323
Introduction     323
Chirality in QSAR     324
Molecular Modeling in Chiral Chromatography     325
Chirality of Protein Residues, Homology Modeling     326
Chiral Selective Binding, MDS methods     327
DNA     327
Topoisomerase II-DNA Crossover Recognition     328
Chiral Catalysis     328
Chiral Ligand-Receptor Interactions - Proteins     329
Docking of Chiral Compounds     331
Molecular Modeling Software Dealing with Chirality and Some References to Its Successful Application      332
ChemDraw 6.0 (CambridgeSoft) - an Example of the Classical Program     333
Chirano - Chirality of Nucleic Acid Chains     333
Corina - Chirality in 3D Structure Generator     334
Omicron from OpenEye Software - Chirality from 1D Formulas     334
Cache Software BioMedCache - Chirality Convention in Semiempirical Calculations     335
Accelrys     335
Schrodinger-Generation of Stereoisomers     335
Tripos - Stereochemistry Module StereoPlex     336
MOE - DAPPER     337
References     338
Subject Index     341