Chirality in Drug Research

Abstract

Preface. List of Contributors. Introduction. 1 Chiral Drugs from a Historical Point of View (Joseph Gal). 1.1 Introduction. 1.2 A Word About Words. 1.3 Old Chiral Drugs: Natural Remedies 3000BC-1900. 1.4 Recognition of Chirality in Drugs. 1.5 Enantioselectivity in Drug Action and Drug Metabolism: The Beginnings. 1.6 Drug Chirality in the 20th Century. References. Synthesis. 2 Stereoselective Synthesis of Drugs - An Industrial Perspective (Hans-Jurgen Federsel). 2.1 Introduction: Historical Overview. 2.2 Asymmetry from an Industrial Scale Perspective. 2.3 Stereoselective Processes in Drug Manufacture - Drivers and Blockers. 2.4 The Metal - Friend and Foe. 2.5 Ligand Development - At the Core of Catalytic Chemistry. 2.6 Asymmetric Reactions - A Rich Reservoir. 2.7 Retrospect and Prospect. References. 3 Aspects of Chirality in Natural Products Drug Discovery (Philipp Krastel, Frank Petersen, Silvio Roggo, Esther Schmitt, and Ansgar Schuffenhauer). 3.1 Introduction. 3.2 Stereochemical Aspects of Natural Products. 3.3 Mechanisms of Stereochemical Control in Natural Product Biosynthesis. 3.4 Biological Activity of Natural Products Related to Stereochemistry. References. 4 Biotransformation Methods for Preparing Chiral Drugs and Drug Intermediates (Michael Muller and Marcel Wubbolts). 4.1 Introduction. 4.2 Examples of Established Applications of Biocatalysts in the Synthesis of Pharmaceuticals. 4.3 Some Special Aspects of Biocatalysts, Recent Developments. 4.4 Conclusions and Outlook. References. Separations. 5 Resolution of Chiral Drugs and Drug Intermediates by Crystallisation (Kazuhiko Saigo). 5.1 Introduction. 5.2 Physical Enantioseparation - Preferential Crystallization. 5.3 Chemical Enantioseparation - Diastereomeric Salt Formation. 5.4 The Bridge Between Preferential Crystallization and Diastereomeric Salt Formation. 5.5 Process Research on the Enantioseparation of Racemates by Diastereomeric Salt Formation. 5.6 Examples of Enantioseparations in the Pharmaceutical Industry. References. 6 Isolation and Production of Optically Pure Drugs by Enantioselective Chromatography (Eric Francotte). 6.1 Introduction. 6.2 General Considerations Regarding the Preparation of Single Stereoisomers of Chiral Drugs. 6.3 Preparative Chiral Stationary Phases. 6.4 Strategies for Performing Enantioselective Separations. 6.5 Preparative Enantioselective Resolution of Chiral Drugs. 6.6 Conclusion. References. 7 Stereoselective Chromatographic Methods for Drug Analysis (Norbert M. Maier and Wolfgang Lindner). 7.1 Introduction. 7.2 The Role of Enantioselective Analysis in Drug Development. 7.3 Separation Techniques in Enantiomer Analysis. 7.4 Principle of Enantiomer Separation. 7.5 Molecular Requirements for Chiral Recognition. 7.6 Thermodynamic Principles of Enantiomer Separation. 7.7 Role of Mobile Phase in Enantiomer Separation. 7.8 Chiral Selectors and Chiral Stationary Phases Employed in Liquid Chromatographic Enantiomer Separation. 7.9 Conclusions. References. 8 Capillary Electrophoresis Coupled to Mass Spectrometry for Chiral Drugs Analysis (Serge Rudaz and Jean-Luc Veuthey). 8.1 Introduction. 8.2 Capillary Electrophoresis (CE). 8.3 CE-MS Coupling. 8.4 Chiral Separation Strategies. 8.5 Partial Filling. 8.6 Partial Filling - Counter Current Technique. 8.7 Chiral Micellar Electrokinetic Chromatography. 8.8 Quantitative Aspects in CE-MS and Parameters for CE-ESI-MS Coupling. 8.9 Capillary Electrochromatography Coupled to Mass Spectrometry. 8.10 Discussion and Conclusion. References. 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 (Nobuyuki Harada). 9.1 Introduction. 9.2 Methodologies for Determining Absolute Configuration. 9.3 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 9.4 A Novel Chiral Molecular Tool, 2-Methoxy-2-(1-naphthyl)propionic Acid (MalphaNP Acid (S)-(+)-3), Useful for Enantioresolution of Alcohols and Simultaneous Determination of Their Absolute Configurations by the 1H NMR Aisotropy Method. 9.5 Absolute Configuration of the Thyroid Hormone Analog KAT-2003 as Determined by the 1H NMR Anisotropy Method with MalphaNP Acid. 9.6 Conclusion. References. 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 (Gerd Folkers, Mine Yarim, and Pavel Pospisil). 10.1 Introduction. 10.2 Chirality in QSAR. 10.3 Molecular Modeling in Chiral Chromatography. 10.4 Chirality of Protein Residues, Homology Modeling. 10.5 Chiral Selective Binding, MDS methods. 10.6 Docking of Chiral Compounds. 10.7 Molecular Modeling Software Dealing with Chirality and Some References to Its Successful Application. References. Subject Index.