Preface ...................................................... XIII
List of Contributors ........................................... XV
Introduction
1. Chiral Drugs from a Historical Point of View ................. 3
Joseph Cal
1.1. Introduction ............................................ 3
1.2. A Word About Words ...................................... 3
1.3. Old Chiral Drugs: Natural Remedies 3000BC-1900 .......... 4
1.4. Recognition of Chirality in Drugs ...................... 13
1.5. Enantioselectivity in Drug Action and Drug
Metabolism: The Beginnings ............................. 16
1.6. Drug Chirality in the 20th Century ..................... 18
References .................................................. 24
Synthesis
2. Stereoselective Synthesis of Drugs-An Industrial
Perspective ................................................. 29
Hans-Jürgen Federsel
2.1. Introduction: Historical Overview ...................... 29
2.2. Asymmetry from an Industrial Scale Perspective ......... 32
2.3. Stereoselective Processes in Drug Manufacture-
Drivers and Blockers ................................... 38
2.4. The Metal - Friend and Foe ............................. 41
2.5. Ligand Development - At the Core of Catalytic
Chemistry .............................................. 43
2.6. Asymmetric Reactions - A Rich Reservoir ................ 45
2.6.1. Reductions ...................................... 48
2.6.2. Oxidations ...................................... 51
2.6.3. Carbon-Carbon Bond Formation .................... 55
2.7. Retrospect and Prospect ................................ 59
References .................................................. 62
3. Aspects of Chirality in Natural Products Drug Discovery ..... 67
Philipp Krastel, Frank Petersen, Silvio Roggo,
Esther Schmitt, and Ansgar Schuffenhauer
3.1. Introduction ........................................... 67
3.2. Stereochemical Aspects of Natural Products ............. 71
3.2.1. Chirality Analysis of Natural Products
versus Drugs and Synthetics ..................... 71
3.2.2. Determination of the Relative and Absolute
Stereochemistry of Natural Products ............. 74
3.2.2.1. NMR Spectroscopy ....................... 74
3.2.2.2. Chiroptical Methods .................... 75
3.2.2.3. X-ray Crystallography .................. 75
3.2.2.4. Total Synthesis and Degradation
Reactions .............................. 76
3.3. Mechanisms of Stereochemical Control in Natural
Product Biosynthesis ................................... 77
3.3.1. Origin of D-Amino Acids in Non-ribosomal
Peptides ........................................ 77
3.3.2. Control of Chirality in Modular Polyketide
Synthesis ....................................... 79
3.3.3. Modes of Stereodifferentiating Cyclization ...... 80
3.3.4. Terpene Biosynthesis in Plants .................. 82
3.4. Biological Activity of Natural Products Related
to Stereochemistry ..................................... 83
3.4.1. Natural Products Active on the Nervous System ... 84
3.4.2. Gossypol, a Racemic Natural Product ............. 86
3.4.3. Epimerization of Natural Products in vivo ....... 87
3.4.4. Tubuline Stabilizing Agents ..................... 88
References .................................................. 90
4. Biotransformation Methods for Preparing Chiral Drugs and
Drug Intermediates .......................................... 95
Michael Müller and Marcel Wubbolts
4.1. Introduction ........................................... 95
4.2. Examples of Established Applications of Biocatalysts
in the Synthesis of Pharmaceuticals .................... 96
4.2.1. Ephedrine Synthesis ............................. 96
4.2.2. Amino Acids ..................................... 99
4.2.3. Amines ......................................... 100
4.2.4. Penicillins/Cephalosporins ..................... 101
4.2.5. Racemic Resolution Using Hydrolytic Enzymes .... 103
4.2.6. Oxidoreductases ................................ 106
4.2.7. Oxynitrilases .................................. 108
4.2.8. Comparison of Nonenzymatic and Biocatalytic
Transformations ................................ 108
4.3. Some Special Aspects of Biocatalysts, Recent
Developments .......................................... 111
4.3.1. Dynamic and Parallel Kinetic Resolution ........ 111
4.3.2. Different Biocatalytic Approaches to One
Building Block ................................. 112
4.3.3. Multipurpose Small Chiral Building Blocks ...... 114
4.3.4. Optimization/New Access Using Molecular
Biology Methods ................................ 116
4.3.5. Metabolic Engineering .......................... 116
4.3.6. Reaction Engineering ........................... 118
4.4. Conclusions and Outlook ............................... 119
References ................................................. 120
Separations
5. Resolution of Chiral Drugs and Drug Intermediates
by Crystallisation ......................................... 127
Kazuhiko Saigo
5.1. Introduction .......................................... 127
5.2. Physical Enantioseparation - Preferential
Crystallization ....................................... 127
5.3. Chemical Enantioseparation - Diastereomeric Salt
Formation ............................................. 133
5.4. The Bridge Between Preferential Crystallization
and Diastereomeric Salt Formation ..................... 141
5.5. Process Research on the Enantioseparation of
Racemates by Diastereomeric Salt Formation ............ 143
5.5.1. The Role of Water in the Stabilization of
Less-soluble Diastereomeric Salts -A Key
Intermediate for the Synthesis of
Duloxetine,3-(Methyl-amino)-l-(2-
thienyl)propan-l-ol ............................ 143
5.5.2. Reciprocal Enantioseparation - A Key
Intermediate for ACE Inhibitors, 2-Hydroxy-
4-phenylbutyric Acid, and l-(4-Methyl-phenyl)
ethylamine ..................................... 146
5.5.3. Solvent Switch - A Key Intermediate for
Lysine Production, π-Amino-ε-caprolactam ....... 147
5.6. Examples of Enantioseparations in the
Pharmaceutical Industry ............................... 149
References ................................................. 152
6. Isolation and Production of Optically Pure Drugs by
Enantioselective Chromatography ............................ 155
Eric Francotte
6.1. I ntroduction ......................................... 155
6.2. General Considerations Regarding the Preparation
of Single Stereoisomers of Chiral Drugs ............... 156
6.2.1. The Different Approaches ....................... 156
6.2.2. Enantioselective Chromatography ................ 157
6.3. Preparative Chiral Stationary Phases .................. 258
6.3.1. Classification of Chiral Stationary Phases ..... 158
6.3.2. Polymeric Phases ............................... 161
6.3.2.1. Polysaccharide-based CSPs ............. 161
6.3.2.2. Polyacrylamide CSPs ................... 164
6.3.2.3. Polymeric CSPs Derived from
Tartaric Acid ......................... 164
6.3.3. Brush-type CSPs ................................ 165
6.3.3.1. π-Acidic and π-Basic Phases ........... 165
6.3.3.2. Cyclodextrin-basedCSPs ................ 166
6.3.3.3. Chirobiotic CSPs ...................... 166
6.3.3.4. Chiral Ion-exchange Stationary
Phases ................................ 167
6.4. Strategies for Performing Enantioselective
Separations ........................................... 168
6.4.1. Selecting the Right CSP ........................ 168
6.4.2. Selecting the Racemic Solute ................... 170
6.4.3. Selecting the Right Synthetic Step ............. 170
6.5. Preparative Enantioselective Resolution of Chiral
Drugs ................................................. 172
6.5.1. Laboratory-scale Separations ................... 172
6.5.2. Pilot-scale Separations ........................ 176
6.5.3. Process-scale Separations ...................... 177
6.5.4. Production-scale Separations ................... 178
6.5. Other Enantioselective Chromatographic Techniques ..... 179
6.5.1. Gas Chromatography ............................. 179
6.5.2. Membranes ...................................... 180
6.5.3. Centrifugal Partition Chromatography ........... 180
6.5.4. Electrophoretic Methods ........................ 181
6.6. Conclusion ............................................ 181
References ................................................. 182
7. Stereoselective Chromatographic Methods for Drug
Analysis ................................................... 189
Herbert M. Maier and Wolfgang Lindner
7.1. Introduction .......................................... 189
7.2. The Role of Enantioselective Analysis in Drug
Development ........................................... 191
7.3. Separation Techniques in Enantiomer Analysis .......... 192
7.4. Principle of Enantiomer Separation .................... 194
7.4.1. Indirect Enantiomer Separation ................. 195
7.4.2. Direct Enantiomer Separation ................... 196
7.4.2.1. Chiral Mobile Phase Additives
(CMPA) ................................ 196
7.4.2.2. Chiral Stationary Phases .............. 197
7.5. Molecular Requirements for Chiral Recognition ......... 198
7.6. Thermodynamic Principles of Enantiomer Separation ..... 199
7.7. Role of Mobile Phase in Enantiomer Separation ......... 202
7.8. Chiral Selectors and Chiral Stationary Phases
Employed in Liquid Chromatographic Enantiomer
Separation ............................................ 205
7.8.1. CSPs Derived from Polymers ..................... 207
7.8.1.1. CSPs Derived from Natural Polymers .... 207
7.8.1.1.1. Polysaccharide-type CSPs ... 207
7.8.1.1.2. Protein-type CSPs .......... 215
7.8.1.2. CSPs Derived from Synthetic
Polymers .............................. 218
7.8.1.2.1. Helical Poly
(methacrylates) ............ 218
7.8.1.2.2. Chiral Poly
(methacrylamides) .......... 218
7.8.1.2.3. Tartardiamide-network
Polymers ................... 219
7.8.1.2.4. Poly(diaminocyclohexane-N,
N-diacrylamide) ............ 219
7.8.1.2.5. Molecularly Imprinted
Polymers ................... 221
7.8.2. Macrocyclic CSPs ............................... 224
7.8.2.1. Cyclodextrin-type CSPs ................ 224
7.8.2.2. Glycopeptide-type CSPs ................ 226
7.8.2.3. Crown Ether-type CSP .................. 231
7.8.3. CSPs Based on Low-Molecular-Weight Molecules ... 233
7.8.3.1. Donor-Acceptor-type CSPs .............. 233
7.8.3.2. Ion-exchange-type CSPs ................ 237
7.8.3.2. Ligand-exchange-type CSPs ............. 240
7.8.4. CSPs Based on Target-specific Bioaffinity
Systems ........................................ 240
7.8.4.1. Antibody-type CSPs .................... 241
7.8.4.2. Aptamer-type CSPs ..................... 242
7.9. Conclusions ........................................... 244
References ................................................. 245
8. Capillary Electrophoresis Coupled to Mass Spectrometry
for Chiral Drugs Analysis .................................. 261
Serge Rudaz and Jean-Luc Veuthey
8.1. Introduction .......................................... 261
8.2. Capillary Electrophoresis (CE) ........................ 262
8.3. CE-MS Coupling ........................................ 263
8.3.1. CE-ESI-MS ...................................... 263
8.3.2. Other CE-MS Coupling ........................... 265
8.4. Chiral Separation Strategies .......................... 265
8.5. Partial Filling ....................................... 268
8.5.1. Partial Filling with Crown Ethers .............. 268
8.5.2. Partial Filling with Neutral Derivatized CD .... 268
8.6. Partial Filling - Counter Current Technique ........... 270
8.6.1. Anionic Analytes - Positively Charged Chiral
Selectors ...................................... 271
8.6.2. Cationic Analytes - Negatively Charged
Chiral Selectors ............................... 271
8.7. Chiral Micellar Electrokinetic Chromatography ......... 274
8.8. Quantitative Aspects in CE-MS and Parameters for
CE-ESI-MS Coupling .................................... 276
8.9. Capillary Electrochromatography Coupled to Mass
Spectrometry .......................................... 277
8.10.Discussion and Conclusion ............................. 278
References ............................................ 280
9. Powerful Chiral Molecular Tools for Preparation of
Enantiopure Alcohols and Simultaneous Determination of
Their Absolute Configurations by X-Ray Crystallography
and/or 1H NMR Anisotropy Methods ........................... 283
Nobuyuki Harada
9.1. Introduction .......................................... 283
9.2. Methodologies for Determining Absolute
Configuration ......................................... 284
9.2.1. Nonempirical Methods for Determining
Absolute Configurations of Chiral Compounds .... 284
9.2.2. Relative and/or Empirical Methods for
Determining Absolute Configuration Using
an Internal Reference of Absolute
Configuration .................................. 285
9.3. CSDP Acid, Camphorsultam Dichlorophthalic Acid
(-)-l, Useful for the Enantioresolution of Alcohols
by H PLC and Simultaneous Determination of Their
Absolute Configurations by X-ray Crystallography ...... 287
9.4. A Novel Chiral Molecular Tool, 2-Methoxy-2-
(l-naphthyl)propionic Acid (MαNP Acid (S)-(+)-3),
Useful for Enantioresolution of Alcohols and
Simultaneous Determination of Their Absolute
Configurations by the 1H NMR Anisotropy Method ........ 295
9.4.1. Facile Synthesis of MaNP Acid (3) and Its
Enantioresolution with Natural (-)-Menthol ..... 298
9.4.2. The 1H NMR Anisotropy Method for Determining
the Absolute Configuration of Secondary
Alcohols: the Sector Rule and Applications ..... 399
9.4.3. Enantioresolution of Various Alcohols Using
MaNP Acid and Simultaneous Determination of
Their Absolute Configurations .................. 304
9.4.4. Recent Applications of the MαNP Acid Method
to Various Alcohols ............................ 307
9.4.5. Application of the MaNP Acid Method to
Chiral metα-Substituted Diphenylmethanols ...... 313
9.5. Absolute Configuration of the Thyroid Hormone
Analog KAT-2003 as Determined by the 1H NMR
Anisotropy Method with MaNP Acid ...................... 314
9.6. Conclusion ............................................ 319
References ................................................. 319
10.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 ................... 323
Cerd Folkers, Mine Yarim, and Pavel Pospisil
10.1.Introduction .......................................... 323
10.2.Chirality in QSAR ..................................... 324
10.3.Molecular Modeling in Chiral Chromatography ........... 325
10.4.Chirality of Protein Residues, Homology Modeling ...... 326
10.5.Chiral Selective Binding, MDS methods ................. 327
10.5.1.DNA ............................................ 327
10.5.2.Topoisomerase II-DNA Crossover Recognition ..... 328
10.5.3.Chiral Catalysis ............................... 328
10.5.4.Chiral Ligand-Receptor Interactions -
Proteins ....................................... 329
10.6.Docking of Chiral Compounds ........................... 331
10.7.Molecular Modeling Software Dealing with Chirality
and Some References to Its Successful Application ..... 332
10.7.1.ChemDraw 6.0 (CambridgeSoft) -an Example of
the Classical Program .......................... 333
10.7.2.Chirano - Chirality of Nucleic Acid Chains ..... 333
10.7.3.Corina - Chirality in 3D Structure
Generator ...................................... 334
10.7.4.Omicron from OpenEye Software - Chirality
from ID Formulas ............................... 334
10.7.5.Cache Software BioMedCache - Chirality
Convention in Semiempirical Calculations ....... 335
10.7.6.Accelrys ....................................... 335
10.7.7.Schrödinger - Generation of Stereoisomers ...... 335
10.7.8.Tripos - Stereochemistry Module StereoPlex ..... 336
10.7.9.МОЕ-DAPPER ..................................... 337
References ................................................. 338
Subject Index ................................................. 341
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