Applications of TRANSITION METAL CATALYSIS in Drug Discovery and Development -- Contents -- Preface -- Contributors -- About the Authors -- 1 Transition Metal Catalysis in the Pharmaceutical Industry -- 1.1 Overview of Catalysis -- 1.2 Transition Metal Catalysis in the Pharmaceutical Industry -- 1.2.1 Cross-Couplings for the Formation of Carbon-Carbon Bonds -- 1.2.2 Cross-Couplings for the Formation of Carbon-Heteroatom Bonds -- 1.2.3 Asymmetric Hydrogenation -- 1.2.4 Oxidative Catalysis -- 1.2.5 Asymmetric Addition Reactions -- 1.2.6 Metathesis -- 1.3 Challenges in Taking Catalysis to Industrial Scales -- 1.4 Summary and Future Outlook -- References -- 2 Selected Applications of Transition Metal-Catalyzed Carbon-Carbon Cross-Coupling Reactions in the Pharmaceutical Industry -- 2.1 Introduction -- 2.2 Carbon-Carbon Cross-Couplings -- 2.2.1 Suzuki Coupling -- 2.2.1.1 sp2 (Aryl)-sp2 (Aryl) Coupling -- 2.2.1.2 sp2 (Aryl)-sp2 (Heteroaryl) Coupling -- 2.2.1.3 sp2 (Heteroaryl)-sp2 (Heteroaryl) Coupling -- 2.2.1.4 sp2 (Aryl)-sp2 (Vinyl) Coupling -- 2.2.1.5 sp2 (Vinyl)-sp3 Coupling -- 2.2.1.6 sp2 (Aryl)-sp3 Coupling -- 2.2.2 Negishi Coupling -- 2.2.2.1 sp2 (Aryl)-sp2 (Heteroaryl) Coupling -- 2.2.2.2 sp2 (Heteroaryl)-sp2 (Heteroaryl) Coupling -- 2.2.3 Kumada Coupling -- 2.2.4 Stille Coupling -- 2.2.5 Heck Coupling -- 2.2.5.1 Intermolecular Heck Coupling -- 2.2.5.2 Intramolecular Heck Coupling -- 2.2.6 Sonogashira Coupling -- 2.2.6.1 Aryl Alkynyl Coupling -- 2.2.6.2 Vinyl Alkynyl Coupling -- 2.2.7 Trost-Tsuji Coupling -- 2.2.8 α-Arylation -- 2.2.9 C-H Activation/Direct Arylation -- 2.2.10 Sequential Cross-Coupling Reactions -- 2.2.11 Cyanation -- 2.2.12 Carbonylation -- 2.2.13 New Technology Enabled C-C Cross-Coupling Reactions -- 2.2.13.1 Microwave-Promoted Cross-Coupling Reactions -- 2.2.13.2 Cross-Coupling Reactions Catalyzed by Immobilized Catalysts.

2.2.13.3 Automated High-Throughput Reaction Condition Screening -- 2.2.13.4 Cross-Coupling Reactions in Supercritical CO2 -- 2.2.13.5 Catalyst Screening Using Calorimetry -- 2.2.13.6 Continuous Microflow Synthesis -- 2.3 Conclusion and Prospects -- References -- 3 Selected Applications of Pd- and Cu-Catalyzed Carbon-Heteroatom Cross-Coupling Reactions in the Pharmaceutical Industry -- 3.1 Introduction -- 3.2 Carbon-Heteroatom Cross-Couplings -- 3.2.1 Pd-Catalyzed C-N Couplings -- 3.2.1.1 Introduction -- 3.2.1.2 Pd-Catalyzed C-N Couplings in the Synthesis of Approved Drugs and Clinical Candidates -- 3.2.1.3 Pd-Catalyzed C-N Couplings in Drug Discovery -- 3.2.2 Cu-Catalyzed C-N Couplings -- 3.2.2.1 Introduction -- 3.2.2.2 Cu-Catalyzed C-N Coupling to Make Approved Drugs and Clinical Candidates -- 3.2.2.3 Cu-Catalyzed C-N Coupling in Drug Discovery -- 3.2.2.4 Other C-N Couplings -- 3.2.3 Pd- or Cu-Catalyzed C-O Coupling -- 3.2.3.1 Introduction -- 3.2.3.2 C-O Coupling in the Synthesis of Approved Drugs and Clinical Candidates -- 3.2.3.3 C-O Coupling in Drug Discovery -- 3.2.4 Pd- or Cu-Catalyzed C-S Coupling -- 3.2.4.1 Introduction -- 3.2.4.2 C-S Coupling in the Synthesis of Approved Drugs and Clinical Candidates -- 3.2.4.3 C-S Coupling in Drug Discovery -- 3.2.5 Pd- or Cu-Catalyzed C-SO2R Coupling -- 3.2.6 Cu-Mediated Oxidative Coupling of Boronic Acids and Heteroatoms -- 3.2.7 Pd- or Cu-Catalyzed C-B Coupling -- 3.2.7.1 Introduction -- 3.2.7.2 C-B Coupling in the Synthesis of Approved Drugs and Clinical Candidates -- 3.2.7.3 C-B Coupling in Drug Discovery -- 3.2.7.4 C-H Activation for C-B Coupling -- 3.2.8 Pd- or Cu-Catalyzed C-P Coupling -- 3.3 Conclusions and Outlook -- References -- 4 Asymmetric Cross-Coupling Reactions -- 4.1 Introduction -- 4.2 Carbon-Carbon Coupling Reactions -- 4.2.1 Addition to C=O Bonds -- 4.2.2 Addition to C=N Bonds.

4.2.3 Addition to C=C and CHC=C Bonds -- 4.2.3.1 Conjugate Addition -- 4.2.3.2 Cycloaddition -- 4.2.3.3 Allylic Alkylation -- 4.2.4 Insertion -- 4.3 Carbon-Heteroatom Coupling Reactions -- 4.3.1 Addition of Nitrogen Nucleophiles -- 4.3.1.1 Aziridine Ring Opening -- 4.3.1.2 N-Allylation -- 4.3.1.3 Conjugate Addition -- 4.3.2 Addition of Nitrogen Electrophiles -- 4.3.3 Addition of Oxygen Nucleophiles -- 4.3.4 Insertion -- 4.4 Emerging Technologies -- 4.5 Conclusion -- References -- 5 Metathesis Reactions -- 5.1 Introduction -- 5.2 Catalyst Systems -- 5.3 Applications in Medicinal Chemistry -- 5.3.1 Synthesis of Standard Ring Sizes (5-7) by RCM -- 5.3.2 Synthesis of Medium-Sized Rings (8-9) by RCM -- 5.3.3 Synthesis of Large-Sized Rings by RCM -- 5.3.4 RCM in the Synthesis of Natural Products and Analogues -- 5.3.5 Formation of Olefins by Cross Metathesis -- 5.3.6 Metathesis Applications in Solid-Phase Synthesis -- 5.4 Applications in Process Chemistry -- 5.5 Summary and Outlook -- References -- 6 Transition Metal-Catalyzed Synthesis of Five- and Six-Membered Heterocycles -- 6.1 Introduction and Background -- 6.2 Heck Cyclization -- 6.3 Cyclization Induced by Cross-Coupling -- 6.4 Migratory Insertion-Induced Cyclization -- 6.5 Cyclization via Carbon-Heteroatom Coupling -- 6.6 Cycloisomerization -- 6.7 Ring-Closing Metathesis -- 6.8 Other Cyclizations of Interest -- 6.9 Conclusion -- References -- 7 Oxidative Catalysis -- 7.1 Introduction -- 7.2 Carbon-Oxygen Bond Oxidation -- 7.3 Allylic Oxidation (Carbon-Hydrogen Bond) -- 7.4 Carbon-Carbon Double Bond Oxidation -- 7.4.1 Epoxidation -- 7.4.2 Dihydroxylation -- 7.5 Conclusion -- References -- 8 Industrial Asymmetric Hydrogenation -- 8.1 Introduction -- 8.2 The Art of Process Development -- 8.2.1 Outlining and Assessing Synthetic Routes -- 8.2.2 Chemical Feasibility of the Enantioselective Catalytic Step.

8.2.3 Optimization and Scale-Up: Piloting the Catalytic Reaction -- 8.3 Selected Case Histories -- 8.3.1 L-Dopa (Monsanto, VEB Isis-Chemie) -- 8.3.2 (R)-HPB Ester (Ciba-Geigy, Ciba SC/Solvias) -- 8.3.2.1 Route C: Heterogeneous Hydrogenation of Ethyl 2-Oxo-4- phenylbutyrate -- 8.3.2.2 Route D: Heterogeneous Hydrogenation of Ethyl 2,4-Dioxo-4- phenylbutyrate -- 8.3.2.3 Comparison of Processes A-D -- 8.3.3 Sitagliptin (Merck) -- 8.4 Selected Effective Hydrogenation Processes -- 8.4.1 Production Processes for Penem Antibiotics and Ofloxacin Intermediates (Takasago) -- 8.4.2 Pilot Processes for Building Blocks and Intermediates (Roche) -- 8.4.3 Pilot Processes for (R)-3,5-Bis-trifluoromethylphenyl Ethanol (Solvias/Rohner, Merck) -- 8.4.4 Pilot Processes for Taranabant Intermediates (Merck) -- 8.4.5 Bench-Scale Processes for Pregabalin Intermediate (Pfizer) -- 8.4.6 Production Processes for Aliskiren Building Block (Solvias, DSM, BASF) -- 8.4.7 Production Processes for Adrenaline and Phenylephrine (Boehringer Ingelheim) -- 8.4.8 Intermediates for Biotin Synthesis (Lonza, DSM/Solvias) -- 8.4.9 Production Process for (S)-Metolachlor (Ciba-Geigy/Novartis/Solvias/Syngenta) -- 8.4.10 Processes for Citronellol Production (Takasago, Roche) -- 8.4.11 Production Process for ( + )-cis-Methyl Dihydrojasmonate (Firmenich) -- 8.5 Conclusions and Future Developments -- References -- Index.