Additional Information
Book Details
Abstract
Synthetic Methods in Drug Discovery Volume 1 focusses on the hugely important area of transition metal mediated methods used in industry. Current methods of importance such as the Suzuki-Miyaura coupling, Buchwald-Hartwig couplings and CH activation are discussed. In addition, exciting emerging areas such as decarboxylative coupling, and the uses of iron and nickel in coupling reactions are also covered. This book provides both academic and industrial perspectives on some key reactions giving the reader an excellent overview of the techniques used in modern synthesis. Reaction types are conveniently framed in the context of their value to industry and the challenges and limitations of methodologies are discussed with relevant illustrative examples. Edited and authored by leading scientists from both academia and industry, this book will be a valuable reference for all chemists involved in drug discovery as well as postgraduate students in medicinal chemistry.
Contains contributions from many distinguished synthetic chemists andprovides both academic and industrial perspectiveson key reactions giving the readeranexcel-lent overview of the techniques used in modernsynthesis.
Prof. Gianluca Sbardella
This book is a must-have handbook and a highly valuable reference for all chemists involved in drug discovery as well as postgraduate students in medicinal chemistry.
Prof. Gianluca Sbardella
David Blakemore has spent his entire career in the pharmaceutical industry. Following his post-docs in Cambridge and Paris, he joined Warner-Lambert as a Group Leader in the Discovery Chemistry group. In 2001, he joined Pfizer in Sandwich and is currently the Synthesis Lead for the World-Wide Medicinal Chemistry Group at Pfizer Neusentis. Part of David’s role is in liaising with academics to highlight key areas of chemistry that could be of real value to the pharmaceutical industry and to develop interactions in those areas.
Paul Doyle has spent his entire career at the interface of chemistry and biology in the service of drug discovery. After his first degree in chemistry at Oxford, Paul completed his D.Phil. at the University of Sussex studying bio-organic synthetic chemistry. He spent a 15-year early career in a wide variety of therapeutic discovery programmes at the Wellcome Foundation before establishing one of the first UK discovery CROs, Biofocus. In 2008, Paul joined Peakdale as CEO.
Yvette Fobian has spent the majority of her career in the pharmaceutical industry. After completing her PhD and spending a year in Monsanto’s Corporate Research, she joined the Medicinal Chemistry Group in Searle/Monsanto in 1997 and ultimately Pfizer in 2003 following a series of mergers and acquisitions. In her most current role, Yvette is in an excellent position to see first-hand the needs and impact of synthetic enablement for both small and large scale delivery within the discovery team.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Contents | ix | ||
| Preface | vii | ||
| Chapter 1 Suzuki–Miyaura Coupling | 1 | ||
| 1.1 Introduction | 1 | ||
| 1.2 The Catalytic Cycle of the SMC | 3 | ||
| 1.3 The Impact of the Ligand | 4 | ||
| 1.4 Electron-rich, Sterically Hindered Phosphine Ligands | 6 | ||
| 1.5 N-Heterocyclic Carbene Ligands | 9 | ||
| 1.6 The Boronate Species | 10 | ||
| 1.7 Base and Solvent | 19 | ||
| 1.8 Optimal Reaction Conditions | 20 | ||
| 1.9 Examples of Process-scale SMC Reactions | 23 | ||
| 1.10 Side Reactions in SMC Reactions | 29 | ||
| 1.10.1 Oxidation and Homo-coupling | 29 | ||
| 1.10.2 Protodeboronation | 32 | ||
| 1.11 SMC Reactions of Dihalogenated Aromatic Systems | 51 | ||
| 1.12 SMC Reactions of Aryl Tosylates, Mesylates and Diazonium Species | 58 | ||
| 1.13 Generation of Vinyl, Cyclopropyl and Benzyl Derivatives | 59 | ||
| 1.14 Conclusion | 62 | ||
| References | 63 | ||
| Chapter 2 Negishi Coupling | 70 | ||
| 2.1 Introduction | 70 | ||
| 2.2 Mechanism | 71 | ||
| 2.3 Formation of Organozinc Reagents | 72 | ||
| 2.4 Applications in Drug Discovery | 74 | ||
| 2.4.1 sp3–sp3 Carbon Bond Formation | 75 | ||
| 2.4.2 sp3–sp2 Carbon Bond Formation | 75 | ||
| 2.4.3 sp2–sp2 Carbon Bond Formation | 82 | ||
| 2.5 Conclusion | 99 | ||
| References | 100 | ||
| Chapter 3 Hiyama Coupling | 104 | ||
| 3.1 Introduction | 104 | ||
| 3.2 Development of the Hiyama Coupling Reaction | 105 | ||
| 3.3 Mechanistic Considerations | 106 | ||
| 3.4 Fluoride-free Hiyama Coupling | 109 | ||
| 3.5 Hiyama-Denmark Coupling | 114 | ||
| 3.6 Summary | 119 | ||
| References | 120 | ||
| Chapter 4 Sonogashira Coupling | 122 | ||
| 4.1 Introduction | 122 | ||
| 4.2 Development of the Sonogashira Reaction | 123 | ||
| 4.3 Mechanistic Aspects of the Reaction | 124 | ||
| 4.3.1 Typical Reaction Conditions | 126 | ||
| 4.4 Utility of the Sonogashira Reaction | 126 | ||
| 4.5 The Glaser–Hay Coupling Reaction | 136 | ||
| 4.6 The Copper-free Sonogashira Coupling Reaction | 136 | ||
| 4.7 Summary | 140 | ||
| Acknowledgments | 141 | ||
| References | 141 | ||
| Chapter 5 Heck Coupling | 143 | ||
| 5.1 Introduction | 143 | ||
| 5.2 Intermolecular Heck Couplings | 148 | ||
| 5.3 Intramolecular Heck Reactions | 158 | ||
| 5.4 Conclusion | 165 | ||
| References | 166 | ||
| Chapter 6 Palladium- and Copper-catalysed C–N Cross-coupling in Drug Discovery | 170 | ||
| 6.1 Introduction | 170 | ||
| 6.1.1 Overview of Pd-catalysed C–N Cross-coupling | 172 | ||
| 6.1.2 Overview of Cu-catalysed C–N Cross-coupling | 178 | ||
| 6.2 Primary and Secondary Aliphatic Amines | 180 | ||
| 6.3 Anilines and Amino Heterocycles | 197 | ||
| 6.4 Amides, Sulfonamides, and Other Weak N–H Nucleophiles | 207 | ||
| 6.5 Azoles | 214 | ||
| 6.6 Ammonia, Hydrazine, and their Surrogates | 222 | ||
| 6.7 Summary and Outlook | 229 | ||
| References | 232 | ||
| Chapter 7 Chan–Lam Coupling Reaction: Copper-promoted C–Element Bond Oxidative Coupling Reaction with Boronic Acids | 242 | ||
| 7.1 General Introduction | 242 | ||
| 7.2 C–N Oxidative Coupling with Arylboronic Acids | 244 | ||
| 7.2.1 Recent C–N Oxidative Coupling with Arylboronic Acids | 244 | ||
| 7.2.2 Intramolecular C–N Oxidative Coupling | 251 | ||
| 7.2.3 Recent Pharmaceutical Applications | 252 | ||
| 7.3 C–O Oxidative Coupling with Arylboronic Acids | 256 | ||
| 7.3.1 Intramolecular C–O Oxidative Coupling | 259 | ||
| 7.3.2 Pharmaceutical Applications | 260 | ||
| 7.4 C–N and C–O Oxidative Coupling with Alkenyl, Alkyl and Alknylboronic Acids | 261 | ||
| 7.4.1 Boron Reagents | 263 | ||
| 7.5 Other C–Element Oxidative Coupling (C–S, C–P, C–F, C–Cl, C–Br, C–I, C–Se, C–Te, C–F, C–C, C–H) | 264 | ||
| 7.6 Mechanistic Studies | 266 | ||
| 7.7 Future and Conclusions | 268 | ||
| Acknowledgments | 269 | ||
| References | 269 | ||
| Chapter 8 C–H Activation Approaches to Molecules | 274 | ||
| 8.1 Introduction | 274 | ||
| 8.2 C–H Arylation | 275 | ||
| 8.2.1 Intermolecular C(sp2)–H Arylation | 277 | ||
| 8.2.2 Intramolecular C(sp2)–H Arylation | 302 | ||
| 8.2.3 C(sp3)–H Arylation | 305 | ||
| 8.3 C–H Alkenylation and Alkylation | 307 | ||
| 8.3.1 C(sp2)–H Alkenylation and Alkylation | 307 | ||
| 8.3.2 C–H Insertion of Carbenes and Metal Carbenoids | 314 | ||
| 8.4 C–H Amination | 316 | ||
| 8.5 C–H Oxidation | 330 | ||
| 8.6 C–H Halogenation | 337 | ||
| 8.7 C–H Borylation | 349 | ||
| 8.7.1 Borylation of Arene C–H Bonds | 350 | ||
| 8.7.2 Borylation of Heteroarene C–H Bonds | 356 | ||
| 8.7.3 Directed C–H Borylation | 361 | ||
| 8.8 Summary and Outlook | 372 | ||
| References | 374 | ||
| Chapter 9 Palladium-catalyzed Decarboxylative Couplings | 384 | ||
| 9.1 Introduction | 384 | ||
| 9.2 Redox-neutral Decarboxylative Biaryl Syntheses | 386 | ||
| 9.2.1 Decarboxylative Couplings with Bimetallic Catalysts | 387 | ||
| 9.2.2 Decarboxylative Couplings with Pd-based Systems | 399 | ||
| 9.3 Decarboxylative Direct Arylation Processes | 402 | ||
| 9.4 State-of-the-Art in Decarboxylative Couplings | 403 | ||
| 9.5 Conclusions | 404 | ||
| Abbreviations | 405 | ||
| Acknowledgments | 405 | ||
| References | 405 | ||
| Chapter 10 New Frontiers with Transition Metals | 411 | ||
| 10.1 Introduction | 411 | ||
| 10.3 Iron Catalysed Synthesis of Biaryl Compounds | 421 | ||
| 10.4 Iron Catalysed Oxidative Functionalisation of Amines | 423 | ||
| 10.5 Nickel Transition Metal Catalysis | 427 | ||
| 10.6 Transition Metal Catalysed C–H C(sp2)–C(sp2) Coupling | 429 | ||
| 10.7 Transition Metal Catalysed Direct C–H C(sp2)-C(sp2) Coupling | 433 | ||
| 10.8 Conclusion | 439 | ||
| References | 439 | ||
| Subject Index | 443 |