Signposts to chiral drugs: organic synthesis in action/ Vitomir Sunjic, Michael J. Parnham
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TextPublication details: New York : Springre, 2011Description: 252p. : 24cmISBN: 9783034801249Subject(s): Drug Discovery -- methods | Pharmaceutical Preparations -- chemistry | Structure-Activity RelationshipDDC classification: 540.5 | Item type | Current library | Call number | Status | Date due | Barcode | Item holds |
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General Books
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Central Library, Sikkim University General Book Section | 540.5 SUN/ (Browse shelf(Opens below)) | Available | P40233 |
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| 540 WIN/D D-block Chemistry | 540.2457 FIS/C Chemistry for Biologists/ | 540.5 LIP/P Principles of Bioinorganic Chemistry | 540.5 SUN/ Signposts to chiral drugs: organic synthesis in action/ | 540.78 ELI /C A Collection of Interesting General Chemistry Experiments | 540.954 BAS/C Chemical science in colonial India: the science in social history/ | 541 ATK/A Atkin's Physical Chemistry |
Includes index.
1 Organic Synthesis in Drug Discovery and Development 1
1.1 Introduction 1
1.2 Synthetic Organic Chemistry in Pharmaceutical R&D 2
1.3 New Concepts in the Drug Discovery Process 5
1.3.1 The Impact of Natural Products on Modern Drug Discovery 6
1.3.2 Biologically Orientated Synthesis in Drug Discovery 8
1.3.3 Incorporation of Genomics and DNA-templated Synthesis into Drug Discovery 9
1.4 Conclusion 11
Reference 11
2 Aliskiren Fumarate 13
2.1 Introduction 13
2.2 Renin and the Mechanism of Aliskiren 14
2.3 Structural Characteristics and Synthetic Approaches to Aliskiren 16
2.3.1 Strategy Based on Visual Imagery, Starting from Nature's Chiral Pool: A Dali-Like Presentation of Objects 18
2.3.2 Fine-Tuning of the Chiral Ligand for the Rh Complex: Hydrogenation of the Selected Substrate with Extreme Enantioselectivities 21
2.4 Conclusion 26
References 26
3 (R)-K-13675 29
3.1 Introduction 29
3.2 Peroxisome Proliferator-Activated Receptor α Agonists 29
3.2.1 β-Phenylpropionic Acids 30
3.2.2 α-Alkoxy-β-Arylprionic Acids 31
3.2.3 α-Aryloxy-β-Phenyl Propionic Acids 33
3.2.4 Oxybenzoylglycine Derivatives 34
3.3 Non-hydrolytic Anomalous Lactone Ring-Opening 35
3.4 Mitsunobu Reaction in the Ether Bond Formation 38
3.5 Conclusion 42
References 42
4 Sitagliptin Phosphate Monohydrate 45
4.1 Introduction 45
4.2 Endogenous Glucoregulatory Peptide Hormones and Dipeptidoyl Peptides IV (DPP4) Inhibitors 46
4.3 Synthesis with C-acyl Meldrum's Acid as the N-Acylating Agent 47
4.4 Highly Enantioselective Hydrogenation of Unprotected β-Enamino Amides and the Use of Josiphos-Ligands 50
4.5 Ammonium Chloride, an Effective Promoter of Catalytic Enantioselective Hydrogenation 52
4.6 Conclusion 53
References 53
5 Biaryl Units in Valsartan and Vancomycin 55
5.1 Introduction 55
5.2 Angiotension AT Receptor, a G-Protein-Coupled Receptor 56
5.3 Cu-Promoted Catalytic Decarboxylative Biaryl Synthesis, a Biomimetic Type Aerobic Decarboxylation 59
5.4 Streiselective Approach to the Axially Chiral Biaryl System; the Case of Vancomycin 63
5.5 Conclusion 67
References 67
6 3-Amino-1,4-Bezodiazepines 69
6.1 Introduction 69
6.2 3-Amino-1,4-Benzodiazepine Derivatives as γ-Secretase Inhibitors 70
6.3 Configurational Stability: Racemization and Enantiomerization 71
6.4 Crystallization Induced Asymmetric Transformation 74
6.5 Asymmetric Ireland-Claisen Rearrangement 74
6.6 Hydrobroation of the Terminal C=C Bond: Anti-Markovnikov Hydratation 76
6.7 Crustallization-Induced Asummetric Transformation in the Synthesis of L-768,673 79
6.8 Conclusion 81
References 81
7 Sertraline 83
7.1 Introduction 83
7.2 Synaptosomal Serotonin Uptake and Its Selective Inhibitors (SSRI) 84
7.3 Action of Sertraline and Its Protein Target 85
7.4 General Synthetic Route 86
7.5 Stereoselective Reduction of Ketones and Imines Under Kinetic and Thermodynamic Control 87
7.5.1 Diastereoselectivity of Hudrogenation of rac-tetralone-Methylimine: The Old (MeNH2/TiCl4/Toluence) Method Is Improved by Using MeNH2/EtOH-Pd/CaCO3, 60-65°C in a Telescoped Process 87
7.5.2 Kinetic Resolution of Racemic Methylamine: Hydrosilylation by (R,R)-(EBTHI)TiF2/PhSiH3 Catalytic System 88
7.5.3 Catalytic Epimerization of the Trans- to the Cis-Isomer of Sertralilne 90
7.5.4 Stereoselective Reduction of Tetralone by Chiral Diphenyloxazaborolidine 91
7.6 Desymmetrization of Oxabenzonorbornadiene, Suzuki Coupling of Arylboronic Acids and Vinyl Halides 92
7.7 Pd-Catalyzed (Tsuji-Trost) Coupling of Arylboronic Acids and Allylic Esters 94
7.8 Simulated Moving Bed in the Commercial Production of Sertaline 97
7.9 Conclusion 101
References 101
8 1,2-Dihydroquinolines 103
8.1 Introduction 103
8.2 Glucocorticoid Receptor 103
8.3 Asymmetric Organocatalysis: Introducing a Thiourea Catalyst for the Petasis Reaction 105
8.3.1 General Consideration of the Petasis Reaction 106
8.3.2 Catalytic, Enantioselective Petasis Reaction 109
8.4 Multi-component Reactions: General Concept and Examples 112
8.4.1 General Concept of Multi-component Reactions 112
8.4.2 Efficient, Isocyanide-Based Ugi Multi-component Reactions 113
References 115
9 (-) -Menthol 117
9.1 Introduction 117
9.2 Natural Sources and First Technological Production of (-) -Menthol 118
9.3 Enantioselective Allylic Amine-Enamine-Imine Rearrangement, Catalysed by Rh(I)-(-) -BINAP Complex 119
9.4 Production Scale Synthesis of Both Enantiomers 122
9.5 Conclusion 123
References 123
10 Fexofenadine Hydrochloride 125
10.1 Introduction 125
10.2 Histamine Receptors as Biological Targets for Anti-allergy Drugs 126
10.3 Absolute Configuration and "Racemic Switch" 127
10.4.1 ZnBr2-Catalyzed Rearrangement of α-Haloketones to Terminal Carboxylic Acids 131
10.4.2 Microbial Oxidation of Non-activated C-H Bond 135
10.4.3 Bioisosterism: Silicon Switch of Fexofenadine to Sila-Fexofenadine 137
10.5 Conclusion 139
References 139
11 Montelukast Sodium 141
11.1 Introduction 141
11.2 Leukotriene D4 Receptor (LTD4), CysLT-1 Receptor Antagonists 142
11.3 Hydroboration of Ketones with Boranes from α-Pinenes and the Non-linear Effect in Asymmetric Reactions 144
11.4 Ru(II) Catalyzed Enantioselective Hydrogen Transfer 148
11.5 Biocatalytic Reduction with Ketoreductase KRED (KetoREDuctase) 150
11.6 CeCl3-THF Solvate as a Promoter of the Grignard Reaction: Phase Transfer Catalysis 150
11.7 Conclusion 152
References 153
12 Thilactone Peptides as Antibacterial Peptidomimetics 155
12.1 Introduction 155
12.2 Virulence and Quououm-Sensing System of Stapyylococcus aureus 156
12.3 Development of Chemical Ligation in Peptide Synthesis 158
12.4 Development of Native Chemical Ligation: Chemoselectivity in Peptide Synthesis 160
12.5 Development of NCL in Thiolactone Petide Synthesis 163
12.6 Conclusion 167
References 167
13 Efavirenz 169
13.1 Introduction 169
13.2 HIV-1 Reverse Transcriptase Inhibitors 170
13.2.1 Setric Interactions at the Active Site 171
13.3 Asymmetric Addition of Alkyne Anion to C=O Bond with Formation of Chiral Li+ Aggregates 173
13.3.1 Mechanism of the Chirality Transfer 173
13.3.2 Equilibration of Lithium Aggregates and the Effect of Their Relative Stability on Enantioselectivity 175
13.4 Scale-up of Alkynylation Promoted by the Use fo Et2Zn 176
13.5 Conclusion 177
References 177
14 Paclitaxel 179
14.1 Introduction 179
14.2 Disturbed Dynamics of Cellular Microtubules by Binding to β-Tubulin 180
14.3 Three Selected Synthetic Transformations on the Pathway to Paclitaxel 181
14.3.1 Intramolecular Heck Reaction on the Synthetic Route to Baccatin III 182
14.3.2 Trifunctional Catalyst for Biomimetic Synthesis of Chiral Diols: Synthesis of the Paclitaxel Side-Chain 185
14.3.3 Zr-Complex Catalysis in the Reductive N-deacylation of Taxanes to the Primary Amine, the Key Precursor of Paclitaxel 192
14.4 Conclusion 194
References 194
15 Neoglycoconjugate 197
15.1 Introduction 197
15.2 Human, α-1,3-Fucosyltransferase IV (Fuc-T) 198
15.3 Click Chemistry: Energetically Preferred Reactions 200
15.4 Target-Guided Synthesis or Freeze-Frame Click Chemistry 202
15.5 Application of Click Chemistry to the Synthesis of Neoglycoconjugate 1 205
15.6 Conclusion 207
References 207
16 12-Aza-Epothilones 209
16.1 Introduction 209
16.2 Epothilones: Mechanism of Action and Structure-Activity Relationships 210
16.3 Extensive vs. Peripheral Structure Modifications of Natural Products 212
16.4 Ring Closure Metathesis: An Efficient Approach to Macrocyclic "Non-natural Natural Products" 213
16.5 Diimide Reduction of the Allylic C=C Bond 220
16.6 Conclusion 222
References 222
Synthetic Methods and Concepts Discussed in the Chapters 225
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