Organic chemistry Books

Book SynopsisTerpenes belong to the diverse class of chemical constituents isolated from materials found in nature. They play a very important role in human health and have significant biological activities, including anticancer, antimicrobial, anti-inflammatory, and antioxidant effects. This book provides an overview and highlights recent research in the phytochemical and biological understanding of terpenes and terpenoids, examining the most essential functions of these kinds of secondary metabolites.

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Book SynopsisThis textbook provides a simple approach to understand the various complex aspects of stereochemistry. It deals with basic static stereochemistry and gives an overview of the different isomeric forms and nomenclatures. With simple writing style and many examples, this book covers the topics such as stereochemistry of hydrocarbons, alkenes, cycloalkenes, optically active compounds, trivalent carbon, fused, bridged and caged rings and related compounds. This textbook also covers the additional topics such as optical rotatory dispersion and circular dichroism, steroechemistry of elimination reactions, substitution reactions, rearrangement reactions and pericyclic reactions. The book includes pedagogical features like end-of-chapter problems and key concepts to help students in self-learning. The textbook is extremely useful for the senior undergraduate and postgraduate students pursuing course in chemistry, especially organic chemistry. Besides, this book will also be a useful reference book for professionals working in various chemical industries, biotechnology, bioscience and pharmacy.Table of Contents1. Introduction 2.- Stereochemistry of Organic Compounds Containing Carbon- Carbon Single Bonds (Hydrocarbons) 3.- Stereochemistry of Organic Alicyclic Compounds Containing Carbon-Carbon Double Bonds (Alkenes and Cycloalkenes) 4.- Stereochemistry of Organic Compounds containing Asymmetric Carbon 5.- Symmetry Elements 6.- Stereochemistry of Optically Active Compounds having no Asymmetric Carbon Atoms 7.- Stereochemistry of Trivalent Carbon 8.- Stereochemistry of Fused, Bridged and Caged Rings and Related Compounds 9.- Optical Rotatory Dispersion and Circular Dichroism 10.- Stereochemistry of Addition Reactions 11.- Stereochemistry of Elimination Reactions 12.- Stereochemistry of Substitution Reactions 13.- Stereochemistry of Rearrangement Reactions 14.- Stereochemistry of Pericyclic Reactions 15.- Stereochemistry of Some Compound Containing Heteroatoms 16.- Stereochemistry of Some Heterocyclic Compounds 17.- Stereochemistry of Some Biomolecules 18.- Stereoselective Synthesis 19.- Enantioselective– Stereoselective Organic Reactions.

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Book SynopsisAuthored by one of the world's leading organic chemists, this authoritative reference provides an overview of basic strategies in directed evolution and introduces common gene mutagenesis, screening and selection methods. Throughout the text, emphasis is placed on methodology development to maximize efficiency, reliability and speed of the experiments and to provide guidelines for efficient protein engineering. Professor Reetz highlights the application of directed evolution experiments to address limitations in the field of enzyme selectivity, substrate scope, activity and robustness. He critically reviews recent developments and case studies, takes a look at future applications in the field of organic synthesis, and concludes with lessons learned from previous experiments.Table of ContentsPreface IX 1 Introduction to Directed Evolution 1 1.1 General Definition and Purpose of Directed Evolution of Enzymes 1 1.2 Brief Account of the History of Directed Evolution 4 1.3 Applications of Directed Evolution of Enzymes 16 References 17 2 Selection versus Screening in Directed Evolution 27 2.1 Selection Systems 27 2.2 Screening Systems 44 2.3 Conclusions and Perspectives 52 References 53 3 Gene Mutagenesis Methods 59 3.1 Introductory Remarks 59 3.2 Error-Prone Polymerase Chain Reaction (epPCR) and Other Whole-Gene Mutagenesis Techniques 60 3.3 Saturation Mutagenesis: Away from Blind Directed Evolution 70 3.4 Recombinant Gene Mutagenesis Methods 85 3.5 Circular Permutation and Other Domain Swapping Techniques 91 3.6 Solid-Phase Combinatorial Gene Synthesis for Library Creation 92 3.7 Computational Tools 96 References 101 4 Strategies for Applying Gene Mutagenesis Methods 115 4.1 General Guidelines 115 4.2 Rare Cases of Comparative Studies 118 4.3 Choosing the Best Strategy when Applying Saturation Mutagenesis 130 4.3.1 General Guidelines 130 4.3.2 Choosing Optimal Pathways in Iterative Saturation Mutagenesis (ISM) 135 4.3.3 Systematization of Saturation Mutagenesis 142 4.3.4 Single Code Saturation Mutagenesis (SCSM): Use of a Single Amino Acid as Building Block 149 4.3.5 Triple Code Saturation Mutagenesis (TCSM): A Viable Compromise when Choosing the Optimal Reduced Amino Acid Alphabet 151 4.4 Techno-Economical Analyses of Saturation Mutagenesis Strategies 154 4.5 Combinatorial Solid-Phase Gene Synthesis: An Alternative for the Future? 159 References 160 5 Selected Examples of Directed Evolution of Enzymes with Emphasis on Stereo- and Regioselectivity, Substrate Scope, and/or Activity 167 5.1 Explanatory Remarks 167 5.2 Collection of Selected Examples from the Literature 2010 up to 2016 189 References 189 6 Directed Evolution of Enzyme Robustness 205 6.1 Introduction 205 6.2 Application of epPCR and DNA Shuffling 207 6.3 B-FIT Approach 211 6.4 Iterative Saturation Mutagenesis (ISM) at Protein–Protein Interfacial Sites for Multimeric Enzymes 215 6.5 Ancestral and Consensus Approaches and their Structure-Guided Extensions 216 6.6 Computationally Guided Methods 219 6.6.1 SCHEMA Approach 219 6.6.2 FRESCO Approach 221 6.6.3 FireProt Approach 223 6.6.4 Constrained Network Analysis (CNA) Approach 224 6.6.5 Alternative Approaches 226 References 227 7 Directed Evolution of Promiscuity: Artificial Enzymes as Catalysts in Organic Chemistry 237 7.1 Introductory Background Information 237 7.2 Tuning the Catalytic Profile of Promiscuous Enzymes by Directed Evolution 245 7.3 Conclusions and Perspectives 259 References 260 8 Learning from Directed Evolution 267 8.1 Background Information 267 8.2 Case Studies Featuring Mechanistic, Structural, and/or Computational Analyses of the Source of Evolved Stereo- and/or Regioselectivity 269 8.2.1 Epoxide Hydrolase 269 8.2.2 Ene-Reductase of the Old Yellow Enzyme (OYE) 273 8.2.3 Esterase 279 8.2.4 Cytochrome P450 Monooxygenase 282 8.3 Additive versus Non-additive Mutational Effects in Fitness Landscapes 287 References 296 Index 303

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Book SynopsisThis useful reference focuses on the currently available toolbox of bio-catalysed reductions of C=O, C=C and formal C=N bonds to show which transformations can be reliably used in manufacturing processes and which still require improvements. Following an introductory chapter, chapters 2-4 present the synthetic strategies that are currently available for the reduction of C=C and C=O bonds and for reductive amination, by means of whole-cell catalysts and isolated enzymes. Chapters 5-7 go on to describe the improvements achieved thus far, illustrating the current versatility of enzymes in organic synthesis. Chapters 8-12 present the improvements brought about by the optimization of reaction conditions, and the use of particular synthetic sequences. The final chapter describes practical applications of bio-reductions for the synthesis of active pharmaceutical ingredients. With its excellent and comprehensive overview, this book will be of great interest to those working in academia and industry. From the contents: * Development of Sustainable Biocatalyzed Reduction Processes for Organic Chemists * Reductases: From Natural Diversity to Biocatalysis and Emerging Enzymatic Activities. * Synthetic Strategies Based on C=C Bioreductions * Synthetic Strategies Based on C=O Bioreductions * Development of Novel Enzymes for the Improved Reduction of C=C Double Bonds * Development of Novel Enzymes for the Improved Reduction of C=O Double Bonds * Synthetic Applications of Aminotransferases * Strategies for Cofactor Regeneration in Biocatalyzed Reductions * Effects of Solvent System and Substrate Loading in Bioreduction * Perspectives in the Use of In-Situ Product Removal (ISPR) Techniques in Bioreductions * Multi-Enzymatic Cascade Reactions Based on Reduction Processes * Relevant Practical Applications of Bioreduction Processes in the Synthesis of Active Pharmaceutical IngredientsTable of ContentsPreface DEVELOPMENT OF SUSTAINABLE BIOCATALYTIC REDUCTION PROCESSES FOR ORGANIC CHEMISTS Introduction Biocatalytic Reductions of C=O Double Bonds Biocatalytic Reductions of C=C Double Bonds Biocatalytic Reductions of Imines to Amines Biocatalytic Reductions of Nitriles to Amines Biocatalytic Deoxygenation Reactions Emerging Reductive Biocatalytic Reactions Reaction Engineering for Biocatalytic Reduction Processes Summary and Outlook REDUCTASES: FROM NATURAL DIVERSITY TO ESTABLISHED BIOCATALYSIS AND TO EMERGING ENZYMATIC ACTIVITIES Reductases: Natural Occurrence and Context for Biocatalysis Emerging Cases of Reductases in Biocatalysis Concluding Remarks SYNTHETIC STRATEGIES BASED ON C=C BIOREDUCTIONS FOR THE PREPARATION OF BIOLOGICALLY ACTIVE MOLECULES Introduction Bioreduction of Alpha,Beta-Unsaturated Carbonyl Compounds Bioreduction of Nitroolefins Bioreduction of Alpha,Beta-Unsaturated Carboxylic Acids and Derivatives Bioreduction of Alpha,Beta-Unsaturated Nitriles Concluding Remarks SYNTHETIC STRATEGIES BASED ON C=O BIOREDUCTIONS FOR THE PREPARATION OF BIOLOGICALLY ACTIVE MOLECULES Introduction Synthesis of Biologically Active Compounds through C=O Bioreduction Other Strategies to Construct Biologically Active Compounds Summary and Outlook PROTEIN ENGINEERING: DEVELOPMENT OF NOVEL ENZYMES FOR THE IMPROVED REDUCTION OF C=C DOUBLE BONDS Introduction The Protein Engineering Process and Employed Mutagenesis Methods Examples of Rational Design of Old Yellow Enzymes Evolving Old Yellow Enzymes (OYEs) Conclusions and Perspectives PROTEIN ENGINEERING: DEVELOPMENT OF NOVEL ENZYMES FOR THE IMPROVED REDUCTION OF C=O DOUBLE BONDS Introduction Detailed Characterization of PAR Detailed Characterization of LSADH Engineering of PAR for Increasing Activity in 2-Propanol/Water Medium Application of Whole-Cell Biocatalysts Possessing Mutant PARs and LSADH Engineering of Beta-Keto Ester Reductase (KER) for Raising Thermal Stability and Stereoselectivity New Approach for Engineering or Obtaining Useful ADHs/Reductases SYNTHETIC APPLICATIONS OF AMINOTRANSFERASES FOR THE PREPARATION OF BIOLOGICALLY ACTIVE MOLECULES Introduction Applications Challenges Future Research Needs Conclusions STRATEGIES FOR COFACTOR REGENERATION IN BIOCATALYZED REDUCTIONS Introduction: NAD(P)H as the Universal Reductant in Reduction Biocatalysis The Most Relevant Cofactor Regeneration Approaches - and How to Choose the Most Suitable One Coupling the Reduction Reaction to a Regeneration Reaction Producing a Valuable Compound Avoiding NAD(P)H: Does it Also Mean Avoiding the Challenge? Conclusions SOLVENT EFFECTS IN BIOREDUCTIONS Introduction Solvent Systems for Biocatalytic Reductions Solvent Control of Enzyme Selectivity Concluding Remarks APPLICATION OF IN SITU PRODUCT REMOVAL (ISPR) TECHNOLOGIES FOR IMPLEMENTATION AND SCALE-UP OF BIOCATALYTIC REDUCTIONS Introduction Process Requirements for Scale-Up Bioreduction Process Engineering In situ Product Removal Biocatalyst Format Selected Examples Future Outlook Conclusions BIOREDUCTIONS IN MULTIENZYMATIC ONE-POT AND CASCADE PROCESSES Introduction Coupled Oxidation and Reduction Reactions Consecutive and Cascade One-Pot Reductions Cascade Processes, Including Biocatalyzed Reductive Amination Steps Other Examples of Multienzymatic Cascade Processes, Including Bioreductive Reactions DYNAMIC KINETIC RESOLUTIONS BASED ON REDUCTION PROCESSES Introduction Cyclic Compounds Acyclic Alpha-Substituted-Beta-Keto Esters and 2-Substituted-1,3-Diketones Acyclic Ketones and Aldehydes Conclusions RELEVANT PRACTICAL APPLICATIONS OF BIOREDUCTION PROCESSES IN THE SYNTHESIS OF ACTIVE PHARMACEUTICAL INGREDIENT Introduction Ketoreductases Ene Reductases Others Bioreduction-Supported Processes Outlook Index

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Book SynopsisThe follow-up to the successful "Domino Reaction in Organic Synthesis", this ready reference brings up to date on the original concept. The chapters have been arranged according to the name of well-known transformations of the first step and in combination with the formed products. Each chapter is written by an internationally renowned expert, and the book is edited by L. F. Tietze, who established the concept of domino reactions. The one-stop source for all synthetic chemists to improve the synthetic efficiency and allow an ecologically and economically beneficial preparation of every chemical compound.Table of ContentsPreface Introduction TRANSITION METAL-CATALYZED CARBONYLATIVE DOMINO REACTIONS Introduction Transition Metal-Catalyzed Carbonylative Domino Reactions Outlook METATHESIS REACTIONS IN DOMINO PROCESSES Domino Processes Featuring Solely Metathesis Events Domino Processes Featuring Metathesis and Non-Metathesis Events Conclusion and Outlook C-H ACTIVATION REACTIONS IN DOMINO PROCESSES Heck Reactions/C-H Activations Carbopalladations and Aminopalladations of Alkynes/C-H Activations Palladium-Catalyzed/Norbornene-Mediated ortho C-H Activations Domino Reactions Involving Heteroatom-Directed C-H Activations Conclusions DOMINO REACTIONS INITIATED BY NUCLEOPHILIC SUBSTITUTION Domino SN/Michael Addition and Related Reactions Domino Reactions Initiated by Nucleophilic Ring Opening of Aziridines, Epoxides and Activated Cyclopropanes Domino SN/Brook Rearrangements RADICAL REACTIONS IN DOMINO PROCESSES Introduction Radical/Cation Domino Processes Radical/Anionic Domino Processes Domino Radical/Radical Process Radical/Pericyclic Domino Processes Asymmetric Radical Domino Processes Conclusion and Outlook PERICYCLIC REACTIONS IN DOMINO PROCESSES Introduction Cycloadditions Sigmatropic Rearrangements Electrocyclizations Mixed Transformations Concluding Remarks MODERN DOMINO REACTIONS CONTAINING A MICHAEL ADDITION REACTION Introduction Formation of Acyclic Products Formation of Carbocycles Formation of O-Heterocycles Formation of N-Heterocycles Formation of S-Heterocycles Formation of Heterocycles Containing Nitrogen and Oxygen ALDOL REACTIONS IN DOMINO PROCESSES Introduction Domino Processes with the Aldol Reaction as First Step Domino Processes with the Aldol Reaction as Subsequent Step Conclusion and Outlook OXIDATIONS AND REDUCTIONS IN DOMINO PROCESSES Introduction Domino Reactions Initiated by Oxidation or Reduction Reaction Domino Reactions Having Oxidation in Middle of the Sequence Domino Reactions Terminated by Oxidation or Reduction Reaction Conclusion ORGANOCATALYSIS IN DOMINO PROCESSES Introduction One and Two-Component Domino Reactions Multicomponent Reactions Conclusions METAL-CATALYZED ENANTIO- AND DIASTEREOSELECTIVE C-C BOND FORMING REACTIONS IN DOMINO PROCESSES Domino Reaction Initiated by C-C Bond Formation Domino Reaction Initiated by C-H Bond Formation Domino Reaction Initiated by C-N Bond Formation Domino Reaction Initiated by C-O Bond Formation Domino Reaction Initiated by C-B and C-Si Bond Formation Conclusion and Outlook DOMINO PROCESSES UNDER MICROWAVA IRRADIATION, HIGH PRESSURE, AND IN WATER Introduction Microwave-Assisted Domino Reactions Aqueous Domino Reactions High-Pressure-Promoted Domino Reactions Conclusion and Outlook DOMINO REACTIONS IN LIBRARY SYNTHESIS Introduction Domino Reactions in Natural-Product-Inspired Compound Collection Syntheses Domino Approaches Targeting Scaffold Diversity Solid-Phase Domino Syntheses of Compound Collections Conclusion DOMINO REACTIONS IN THE TOTAL SYNTHESIS OF NATURAL PRODUCTS Cationic Domino Reactions Anionic Domino Reactions Radical Domino Reactions Pericyclic Domino Reactions Transition-Metal-Catalyzed Domino Reactions Domino Reactions Initiated by Oxidation or Reduction Conlcusion MULTICOMPONENT DOMINO PROCESS: RATIONAL DESIGN AND SERENDIPITY Introduction Basic Considerations of MCRs Substrate-Design Approach in the Development of Novel MCRs Conclusion Index

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Book SynopsisFilling the gap for an up-to-date reference that presents the field of organophosphorus chemistry in a comprehensive and clearly structured way, this one-stop source covers the chemistry, properties, and applications from life science and medicine. Divided into two parts, the first presents the chemistry of various phosphorus-containing compounds and their synthesis, including ylides, acids, and heterocycles. The second part then goes on to look at applications in life science and bioorganic chemistry. Last but not least, such important practical aspects as 31P-NMR and protecting strategies for these compounds are presented. For organic, bioinorganic, and medicinal chemists, as well as those working on organometallics, and for materials scientists. The book, a contributed work, features a team of renowned scientists from around the world whose expertise spans the many aspects of modern organophosphorus chemistry.Table of Contents1 Phosphines and Related Tervalent Phosphorus Systems 1Piet W. N. M. van Leeuwen 1.1 Introduction 1 1.2 Synthesis of Phosphorus Ligands 3 1.3 Ligand Properties 18 1.4 Rhodium-Catalyzed Hydroformylation with Xantphos-Type Ligands 29 1.5 Cross-Coupling Catalysis with Mono- and Bidentate Phosphines 33 2 Recent Developments in Phosphonium Chemistry 59Mathieu Berchel and Paul-Alain Jaffrès 2.1 Introduction 59 2.2 Synthesis of Phosphonium Salts 60 2.3 Phosphonium Salts as a Tool for Organic Synthesis 70 2.4 Phosphonium Salts for Biological and Medical Applications 84 2.5 Conclusion 102 3 Phosphorus Ylides and Related Compounds 113Alejandro Presa Soto and Joaquín García-Álvarez 3.1 Introduction 113 3.2 Preparation of Phosphorus Ylides 115 3.3 Applications of Phosphorus Ylides in Organic Synthesis 130 3.4 Conclusions 148 Acknowledgments 148 References 148 4 Low-Coordinate Phosphorus Compounds with Phosphaorganic Multiple Bond Systems 163Dietrich Gudat 4.1 Introduction 163 4.2 General Considerations on Structure and Bonding of PC Multiple Bond Systems 165 4.3 Synthetic Approaches 171 4.4 Reactivity 177 4.5 Applications of Phosphorus–Carbon Multiple Bond Systems 184 References 209 5 Pentacoordinate Phosphorus Compounds 219Masaaki Yoshifuji 5.1 History of Pentacoordinate Phosphorus Compounds 219 5.2 Preparation of Pentacoordinate Phosphorus Compounds 221 5.3 Structure of Trigonal Bipyramid and Square Pyramid 228 5.4 Interconversion of Pentacoordinate Phosphorus Compounds 229 5.5 Apicophilicity 232 5.6 Hydrolysis of Phosphate Esters 233 References 235 6 Hexacoordinate Phosphorus Compounds 239Masaaki Yoshifuji 6.1 Preparation and Structure of Hexacoordinate Phosphorus Compounds 239 6.2 Stereochemistry of Hexacoordinate Phosphorus Compounds 241 6.3 Hexacoordinate Compounds with Intramolecular Coordination 242 6.4 Theoretical Studies on Hexacoordinate Phosphorus Compounds 245 6.5 Hexacoordinate Phosphates as Counter Anions for Complex Ligands 245 References 247 7 Methods for the Introduction of the Phosphonate Moiety into Complex Organic Molecules 249Wouter Debrouwer, IrisWauters, and Christian V. Stevens 7.1 Introduction 250 7.2 P—C (sp3) Bond Formation 252 7.3 P—C (sp2) Bond Formation 261 7.4 P—C (sp) Bond Formation 278 7.5 Conclusion 285 References 286 8 Phosphorus Heterocycles 295Viktor Iaroshenko and SatenikMkrtchyan 8.1 Introduction 295 8.2 Five-Membered Phosphorus Heterocycles 296 8.3 Five-Membered Phosphorus Heterocycles with One Phosphorus Atom: 1H-Phospholes and Fused Aromatic Systems Containing Phosphole Ring 296 8.4 Aromaticity of 1H-Phospholes and 1H-Phosphole-Containing Heterocyclic Systems 303 8.6 Synthesis of 1H-Phospholes Following [4+1] and [2+2+1] Synthetic Strategies 307 8.7 Synthesis of Phospholes by [3+2] Cyclization Reaction 312 8.8 Synthesis of 1H-Phospholes by Intramolecular Cyclization Reactions 312 8.9 Synthesis of Phosphorus-Containing Porphyrin Hybrids 316 8.10 Fused Heterocycles with 1H-Phosphole Structural Fragment 317 8.11 Synthesis-Fused 1H-Phospholes Following [4+1] and [2+2+1] Synthetic Strategies 320 8.12 Synthesis of Fused Phospholes Following [3+2] Synthetic Strategies 324 8.13 Synthesis of Fused Phospholes Following Intramolecular Cyclization Strategies 329 8.14 Application of C—H Bond Activation Protocols for the Synthesis of Benzo[b]phosphindoles via Intramolecular Cyclization 339 8.15 Synthesis of π-Conjugated Benzo[b]phosphindoles Following [2+2+2] Cycloaddition Synthetic Strategy 341 8.16 Five-Membered Phosphorus Heterocycles with One Heteroatom 342 8.17 Synthesis of 1,2- and 1,3-Heterophospholes: General Overview 345 8.18 1,2-Azaphospholes 347 8.19 Synthesis of 1,2-Azaphospholes Following [3+2] Synthetic Strategies 351 8.20 Synthesis of Fused 1,2-Azaphospholes via Intramolecular Cyclization Strategy 353 8.21 Synthesis of 1,2-Oxophospholes, 1,2-Thiaphosphols, and 1,2-Selenophosphols 356 8.23 Synthesis of 1,3-Azaphospholes by Intramolecular Cyclization Reactions 362 8.24 Synthesis of 1,3-Oxaphospholes, 1,3-Thiaphospholes, and 1,3-Selenophospholes 365 8.25 Six-Membered Phosphorus Heterocycles 372 8.26 Phosphinines: General Overview 372 8.27 Synthesis of λ3- and λ5-Phosphenines: General Overview 376 8.28 Synthesis of Phosphenines Following [5+1] Synthetic Strategy 378 8.29 Synthesis of Phosphenines Following [4+2] Synthetic Strategy 381 8.30 Synthesis of Phosphenines from Phospholes 388 8.31 Synthesis of Phosphenines Following 1,6-Electrocyclization Strategy 393 8.32 Synthesis of Fused λ3- and λ5-Phosphenines: General Overview 396 8.33 Synthesis of Fused Phosphenines Following [4+2] Synthetic Strategy 397 8.34 Synthesis of Fused Phosphenines by Intramolecular Cyclization 400 8.35 Synthesis of Fused Phosphenines Following [5+1] Synthetic Strategy 401 8.36 Six-Membered Phosphorus Heterocycles with One Heteroatom 404 8.37 Synthesis 1,2-, 1,3-, and 1,4-Heterophosphinines 408 8.38 1,2-Azaphosphenines 408 8.39 Synthesis of 1,2-Azaphosphenines Following [3+1+1+1] Synthetic Strategy 409 8.40 Synthesis of 1,2-Azaphosphenines Following [3+3] Synthetic Strategy 414 8.41 Synthesis of 1,2-Azaphosphenines Following [3+2+1] Synthetic Strategies 414 8.42 Synthesis of 1,2-Azaphosphenines Following [5+1] Synthetic Strategies 414 8.43 Synthesis of 1,2-Azaphosphenines Following [4+2] Synthetic Strategies 415 8.44 Synthesis of 1,2-Azaphosphenines Following Intramolecular Cyclization Strategies 417 8.45 1,3-Azaphosphenines 419 8.46 Synthesis of 1,3-Azaphosphenines Following [5+1] Synthetic Strategy 419 8.47 Synthesis of 1,3-Azaphosphenines Following [4+2] Synthetic Strategies 419 8.48 1,4-Azaphosphenines 421 8.49 Oxygen- and Sulfur-Containing Heterophosphinines 424 8.50 Application and Synthesis of Phosphoborine Systems 429 8.51 Application and Synthesis of 1,4-Phosphasiline System 432 8.52 Synthesis of Germanium- and Tin-Containing Heterophosphinines 437 References 441 9 Modern Aspects of 31P NMR Spectroscopy 457David S. Glueck 9.1 Introduction 457 9.2 Chemical Shifts 459 9.3 Coupling Constants 464 9.4 Two-Dimensional (2D) 31P NMR Techniques 469 9.5 Analytical Methods 471 9.6 Diffusion-Ordered NMR Spectroscopy (DOSY) 476 9.7 Solid-State (SS) 31P NMR 479 9.8 Physical and Chemical Processes of Organophosphorus Compounds 483 9.9 Identification of Intermediates and Monitoring Their Reactivity 488 9.10 Conclusion 490 Acknowledgment 490 References 490 10 Phosphorus in Chemical Biology and Medicinal Chemistry 499Marlon Vincent V. Duro, Dana Mustafa, Boris A. Kashemirov, and Charles E.McKenna 10.1 Phosphorus and Life: An Introduction 499 10.2 Unnatural Nucleotides as Chemical Tools in Biology 500 10.3 Prodrugs of Nucleoside Phosphates and Phosphonates 516 10.4 Synthesis and Medical Applications of Bisphosphonates 522 10.5 Conclusion: The Future of Phosphorus in Chemical Biology and Medicinal Chemistry 531 References 531 11 Future Trends in Organophosphorus Chemistry 545Shin-ichi Kawaguchi and Akiya Ogawa 11.1 Introduction 545 11.2 Facile C—P Bond Formation Methods 545 11.3 Utilization of Organophosphorus Compounds 551 References 553 Index 557

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Book SynopsisAdopting a novel approach to the topic by combining theoretical knowledge and practical results, this book presents the most popular and useful computational and experimental methods applied for studying the stereochemistry of chemical reactions and compounds. The text is clearly divided into three sections on fundamentals, spectroscopic and computational techniques, and applications in organic synthesis. The first part provides a brief introduction to the field of chirality and stereochemistry, while the second part covers the different methodologies, such as optical rotation, electronic circular dichroism, vibrational circular dicroism, and Raman spectroscopy. The third section then goes on to describe selective examples in organic synthesis, classified by reaction type, i.e. enantioselective, chemoselective and stereoselective reactions. A final chapter on total synthesis of natural products rounds off the book. A valuable reference for researchers in academia and industry working in the field of organic synthesis, computational chemistry, spectroscopy or medicinal chemistry.Table of ContentsPreface IX Acknowledgments XI List of Abbreviations XIII Part I Fundamentals 1 1 Chirality 3 1.1 Introduction 3 1.2 Tetrahedron of Carbon 9 1.2.1 Terpenoids 9 1.2.2 Flavonoids 13 1.2.3 Alkaloids 14 1.2.4 Steroids 16 1.2.5 Glycosides 17 1.2.6 Others 18 1.3 Other Stereogenic Centers 19 1.4 Optical Characteristics 23 1.4.1 Measurement of OR 24 1.4.2 ECD and Its Definition 25 1.4.3 Outline of VCD 26 1.4.4 Outline of ROA 27 References 28 2 Non-optical Method in Configuration Study 31 2.1 13CNMR Spectra 31 2.1.1 NMR and Atomic Structure 31 2.1.2 13C NMR Calculation 32 2.1.3 1HNMR 34 2.1.4 13C NMR Prediction and Conformational Search 34 2.2 X-Ray Diffraction and Mosher Method 41 2.2.1 X-Ray Diffraction 41 2.2.2 Mosher Method 44 2.3 Transition State Energy and Chirality Selectivity 51 2.4 Separation of Chiral Compounds 53 2.4.1 Chiral Organic Bases 53 2.4.2 Chiral Organic Acids 53 2.4.3 Chiral Organic Alcohols 53 2.4.4 Others 54 References 55 Part II Techniques 57 3 Optical Rotation (Rotatory Dispersion, ORD) 59 3.1 Introduction 59 3.2 Quantum Theory 59 3.3 Matrix Model 63 3.3.1 Matrix Basis 65 3.3.2 Explanation of General OR Characteristics 68 3.3.2.1 Sample Calculations 68 3.3.2.2 Calculated Values in Same Series of Compounds 73 3.4 ORD 77 3.5 Application 77 3.5.1 AC Assignment for Mono-Stereogenic Center Compounds 79 3.5.2 Matrix Model Application 80 3.5.3 AC Assignment for Poly-Stereogenic Center Compounds 82 3.5.4 Using ORD Method 83 References 84 4 Electronic Circular Dichroism 87 4.1 Exciton Chirality CD 87 4.2 ECD Characteristics for Chiral Metallic Compounds 92 4.3 Quantum Theory Basis 94 4.4 Principle Using ECD 95 4.5 Application 97 4.5.1 Procedure to Do ECD 97 4.5.2 ECD Application 97 4.5.3 UV Correction 102 References 105 5 Vibrational Circular Dichroism and Raman Optical Activity 107 5.1 Exciton Chirality 108 5.2 Quantum Theory Basis 109 5.2.1 VCD and IR 109 5.2.2 ROA and Raman Scattering 110 5.3 Principles Using VCD and ROA 113 5.4 Application 115 5.4.1 VCD Application 115 5.4.2 ROA Application 124 References 126 6 Combinational Use of Different Methods 129 6.1 Tactics to Select Methods 129 6.1.1 13CNMRMethods 130 6.1.2 OR and ORD 131 6.1.3 Matrix 132 6.1.4 ECD 132 6.1.5 VCD Method 133 6.2 Examples and Discussion 133 6.3 Revised Structures 138 6.3.1 ORD Method 139 6.3.2 Combinational Use of OR and ECD 144 6.3.3 VCD and ECD 146 6.3.4 Comprehensive Use of OR, ECD, and VCD 147 References 160 Part III Reactions 163 7 Enantioselective Reaction 165 7.1 Enantioselective Addition 165 7.1.1 Organic Zn- or Zn-Ti Reagent 165 7.1.2 Organic Cu–Zn, Cu–Li Reagent 169 7.1.3 Organo-Fe Complexes 173 7.1.4 Other Organo-Metallic Complexes 175 7.1.5 Organo-Si Reagents 178 7.2 Enantioselective Reduction 178 7.2.1 Green Chemistry 181 7.3 Enantioselective Oxidation 184 7.4 Prediction of ee Using Calculations 185 7.5 Catalyst Types 189 7.5.1 Amino Alcohols 189 7.5.2 Chiral Ligands Containing N–O Group 190 7.5.3 Chiral Axial Catalysts 191 7.5.4 Solid-Supported Chiral Compounds 192 7.5.5 Spiral Chiral Compounds 193 7.5.6 Asymmetric-Axle-Supported Chiral Catalyst 194 7.5.7 Chiral Shiff-Base Ligands 195 7.5.8 Some Asymmetric Lewis Acids 196 7.5.9 Organic P-Containing Ligands 197 7.6 Three Phenomena 198 7.6.1 Chirality Amplification (Nonlinear Effect) 198 7.6.2 Auto-Self Catalysis 199 7.6.3 Odd–Even Carbon Effect 199 References 201 8 Chemoselective Reaction 205 8.1 Chemoselective Additions 205 8.1.1 Addition to C=O or C=C Groups 205 8.2 Chemoselective Reduction 210 8.3 Chemoselective Oxidation 225 8.4 Other Chemoselective Reactions 231 References 237 9 Stereoselective Reaction 241 9.1 Conformational Study 241 9.2 Effect of Conformation on Reactions 247 9.3 Regioselective Reactions 251 9.4 Diastereoselective Reactions 260 9.4.1 Diastereoselective Additions 260 9.4.2 Other Diastereoselective Reactions 270 9.5 Calculation Using Theoretical Protocol 272 References 277 10 Total Organic Synthesis 279 10.1 Introduction 279 10.2 Retrosynthesis Strategies 279 10.3 Examples in Synthesis 285 10.3.1 (+)-Hirsutene 285 10.3.2 (2R,3S)-Rubiginone A2 and Its Analog 287 10.3.3 (+)-Brefeldin A 290 10.3.4 Malyngamide U and Its AC Reassignment 292 10.3.5 Taxol Derivatives 296 10.3.6 Amphidinolide T2 and Its Derivatives 298 10.3.7 (+)-Vindoline 303 10.4 Calculation in Total Synthesis 306 References 309 Index 313

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Book SynopsisWritten by a well-respected and experienced author, this textbook fills the gap for a concise introduction to the key concepts of organic stereochemistry and the most important classical and modern methods in stereoselective synthesis. The concepts are extensively illustrated in color, with practical examples and question-answer sets to help consolidate the reader's knowledge. In addition, animations are available from the Wiley website. A must-have for students in chemistry, biochemistry, and life sciences, as well as researchers in pharmaceutical and agrochemical companies in need of a quick introduction to the field.Trade ReviewReceived a review published in ‘l’actualité chimique - février 2017 - n° 415’"Das Buch ist sehr schön und auf den Punkt aufbereitet und eignet sich gut als Begleitwerk für organische Chemie bzw. Stereochemie Basisvorlesungen (...). Die Beispiele sind gut gewählt und decken alle relevanten Bereiche des Faches ab (...)." Prof. Dr. Mario Waser, Johannes Kepler Universität Linz, Österreich.Table of ContentsBASIC PRINCIPLES AT THE MOLECULAR LEVEL 1.) Structure and Properties 2.) Concepts of Stereochemistry PROPERTIES AT THE LEVEL OF MOLECULAR SETS 3.) Time Scales, Conformational Changes 4.) Tautomerism 5.) Absolute Configuration 6.) Enantiomeric Composition GENERAL CHARACTERISTICS OF SELECTIVE REACTIONS 7.) Main Types of Selectivities 8.) Classification of Selectivities 9.) Stereospecific and Stereoselective Reactions 10.) Applications of Stereoselective Reactions 11.) Stoichiometric Methods 12.) Catalytic Methods

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Book SynopsisThis book on click reactions to focus on organic synthesis, this reference work describes the click concept and underlying mechanisms as well as the main applications in various fields. As such, the chapters cover green chemical synthesis, metal-free click reactions, synthesis of pharmaceuticals, peptides, carbohydrates, DNA, macrocycles, dendrimers, polymers, and supramolecular architectures. By filling a gap in the market, this is the ultimate reference for synthetic chemists in academia and industry aiming for a fast and simple design and synthesis of novel compounds with useful properties.Table of ContentsList of Contributors XI Preface XV 1 Click Chemistry:Mechanistic and Synthetic Perspectives 1Ramesh Ramapanicker and Poonam Chauhan 1.1 Cycloaddition Click Reactions 2 1.1.1 Azide–Alkyne Huisgen 1,3-Dipolar Cycloaddition 2 1.1.2 Copper-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) Click Reaction 2 1.1.2.1 Mechanism of CuAAC Click Reactions 5 1.1.2.2 Catalysts used for CuAAC Click Reactions 6 1.1.2.3 Ligands used for CuAAC Click Reactions 7 1.1.3 Ruthenium-Catalyzed Azide–Alkyne Cycloaddition (RuAAC) Click Reactions 7 1.1.3.1 Mechanism of RuAAC Click Reactions 8 1.1.4 Strain-Promoted Azide–Alkyne Cycloaddition (SPAAC) Reactions 8 1.1.5 Organocatalytic Triazole Formation 10 1.2 Thiol-Based Click Reactions 12 1.2.1 Radical Click Reactions of Thiols 12 1.2.1.1 Thiol–Ene Radical Click Reaction 12 1.2.1.2 Thiol–Yne Radical Click Reaction 14 1.2.2 Nucleophilic Addition Click Reactions ofThiols 15 1.2.2.1 Thiol–Epoxide Click Reactions 17 1.2.2.2 Thiol–Isocyanate Click Reactions 17 1.2.2.3 Thiol–Michael Addition Click Reactions 18 1.2.2.4 Thiol–Halogen Nucleophilic Substitution Reaction 20 1.3 Miscellaneous Click Reactions 21 References 22 2 Applications of Click Chemistry in Drug Discovery and Development 25Balasubramanian Gopalan and Kalpattu Kuppusamy Balasubramanian 2.1 Introduction 25 2.2 Part A: Application of Click Chemistry to Drug Discovery and Development 25 2.2.1 Carbonic Anhydrase Inhibitors 30 2.2.2 Targeting Onchocerca Volvulus Chitinase-1 (OvCHT1) using the Hydroxytriazole Moiety within a Scaffold Hopping Approach 32 2.2.3 1,2,3-Triaole-Derived Anticancer Agents 34 2.2.3.1 Topoisomerase II Inhibitors 34 2.2.3.2 Histone Deacetylase Inhibitors 36 2.2.3.3 Protein Tyrosine Kinase Inhibitors 38 2.2.3.4 Antimicrotubule Agents 39 2.2.3.5 HSP 90 Inhibitors 40 2.2.3.6 Autophagy-Dependent Apoptosis in CancerTherapy 41 2.2.3.7 Anticancer Activity of 4β-Triazole-Podophyllotoxin 42 2.2.3.8 1,2,3-Triazole-Substituted Oleanolic Acid Derivatives as Anticancer Agents 42 2.2.3.9 Anti-Infective Agents 43 2.2.3.10 1,2,3-Triazole Nucleoside 44 2.2.3.11 1,2,3-Triazole Carbonucleosides 45 2.2.3.12 β-Lactamase Inhibitors as Antibacterial Agents 47 2.2.3.13 1,2,3-Triazole-Linked Carbazoles as Antitubercular Agents 48 2.2.3.14 1,4-Diaryl-Substituted 1,2,3-Traizoles as Antimycobacterial (Mtb) Agents 48 2.2.3.15 1,2,3-Triazole-Adamantylacetamide Hybrids as Antitubercular Agents 50 2.2.3.16 Non-Nucleoside HIV Integrase Inhibitors 50 2.2.3.17 MiscellaneousTherapeutic Segments: 1,2,3-Triazole-Linked Dopamine D3 Receptor (D3R) 53 2.2.3.18 Peptidomimetics: 1,2,3-Triazole as a Disulfide Bond Mimetic 53 2.3 Part B: Synthesis of Triazole-Based Drugs Currently in use 54 2.2.1 Tazobactam 54 2.3.1.1 Synthesis of tazobactam from intermediate 102 55 2.3.1.2 Other reports on Tazobactam synthesis 55 2.3.2 Solithromycin 56 2.3.2.1 Synthesis of Solithromycin 57 2.3.3 Cefatrizine 60 2.3.4 Radezolid 61 2.3.5 Molidustat 63 2.3.5.1 Synthesis of Molidustat 63 2.3.6 Tradipitant 63 2.3.7 Carboxyamidotriazole 66 2.3.8 Rufinamide 66 2.3.8.1 Rufinamide–Novartis Process 66 2.3.8.2 An Efficient Synthesis of Rufinamide 68 2.3.8.3 Continuous-Flow Total Synthesis of Rufinamide 68 References 70 3 Green Chemical Synthesis and Click Reactions 77Maria José Arévalo, Óscar López, and Maria Victoria Gil 3.1 Introduction 77 3.2 Huisgen 1,3-Dipolar Cycloaddition 77 3.2.1 Green Perspectives on Reaction Conditions 78 3.2.1.1 Copper(I) Catalysts 78 3.2.1.2 Copper(I) Complexes with Nitrogen- and Phosphorous-Donating Ligands 79 3.2.1.3 Metalated Reagents as Catalysts 82 3.2.1.4 Immobilized Copper Species 82 3.2.1.5 Copper Nanocatalysis 83 3.2.1.6 Other Metals as Catalysts 84 3.2.1.7 Nonconventional Energy Sources 85 3.2.2 Applications to Synthesis 85 3.2.2.1 Regioselectivity of the Alkyne–Azide Cycloaddition 85 3.2.2.2 Different Substitution Patterns on Triazole 86 3.2.2.3 Strain-Promoted Cycloadditions 87 3.2.2.4 Sulfonyl Azides in Huisgen Cycloaddition 87 3.2.2.5 Synthesis of Vinyl-1,2,3-Triazoless 87 3.2.2.6 Triazole Derivative Ligands for Coordination Chemistry 88 3.2.2.7 Tetrazole Synthesis 88 3.2.2.8 Synthesis of Chiral Triazoles 88 3.2.2.9 Synthesis of Triazoles with Luminescent Properties 89 3.2.2.10 Synthesis of Triazole Libraries 89 3.2.2.11 Synthesis of Phosphorylated Triazoles 89 3.3 Other 1,3-Dipolar Cycloadditions 90 3.4 Atom Economy and Simplicity of Procedures in Multicomponent Reactions 90 3.4.1 Reaction Conditions 91 3.4.1.1 Copper Compounds as Catalysts 91 3.4.1.2 Copper Complexes with Nitrogen- and Phosphorous-Donating Ligands 91 3.4.1.3 Immobilized Copper Species 91 3.4.1.4 Copper Nanocatalysis 92 3.5 Summary and Conclusions 92 References 93 4 Synthesis of Substituted 1,2,3-Triazoles through Organocatalysis 99Kengadarane Anebouselvy and Dhevalapally B. Ramachary 4.1 Introduction 99 4.2 Preformed-Enolate-Based Synthesis of Substituted 1,2,3-Triazoles 101 4.3 Preformed-Enamine-Based Synthesis of Substituted 1,2,3-Triazoles 106 4.4 Synthesis of Substituted 1,2,3-Triazoles via Catalytic Enolate Intermediates 109 4.5 General Mechanistic Aspects of Enolate Route 113 4.6 Synthesis of Substituted 1,2,3-Triazoles via Enamine Intermediates 114 4.7 General Mechanistic Aspects of Enamine Route 123 4.8 Synthesis of Substituted 1,2,3-Triazoles via Iminium Intermediate 123 4.9 Miscellaneous Routes for the Synthesis of 1,2,3-Triazoles 124 4.10 Conclusions 136 Acknowledgments 136 References 137 5 Applications of the Cu-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) in Peptides 141Freek A. B. M. Hoogstede and Floris P. J. T. Rutjes 5.1 Introduction 141 5.2 CuAAC-Mediated Peptide Conjugation Strategies 142 5.3 CuAAC-Mediated Peptide Backbone Modification Strategies 148 5.4 Conclusions 157 References 157 6 Synthesis of Diverse Carbohydrate-Based Molecules using Click Chemistry 161Anoop S. Singh, Kunj B.Mishra, AmritaMishra, and Vinod K. Tiwari 6.1 Introduction 161 6.2 Cu-Catalyzed Click Chemistry in the Synthesis of Diverse Glycoconjugates 162 6.3 Synthesis of Carbohydrate-Based Simple to Complex Macrocycles 181 6.4 Click-Inspired Synthesis of Diverse Neoglycoconjugates 185 6.5 Conclusion and Future Perspective 195 Acknowledgment 196 References 196 7 Azide–Alkyne Click Reaction in Polymer Science 203Joydeb Mandal and S. Ramakrishnan 7.1 Introduction 203 7.2 Linear, Dendritic, and Hyperbranched Polymers 205 7.3 Telechelic and Block Copolymers 220 7.4 Star and Star-Block Polymers 226 7.5 Cyclic Polymers 230 7.6 Side-Chain Clickable Polymers 235 7.7 Cross-linked Polymeric Systems 238 7.8 Porous Organic Polymers 242 7.9 Surface Modification using CuAAC Reaction 244 7.10 Strain-Promoted Click Reaction 247 7.11 Topochemical Azide–Alkyne Cycloaddition (TAAC) Reactions 249 7.12 Summary and Outlook 251 References 251 8 Thiol-Based “Click” Chemistry for Macromolecular Architecture Design 255Weidong Zhang, Kui Chen, and Gaojian Chen 8.1 Introduction 255 8.2 Thiol Chemistry for Macromolecular Architecture Design 256 8.2.1 Linear Polymers 256 8.2.2 Graft and Comb Polymers 258 8.2.3 Star Polymers 261 8.2.4 Cyclic Polymers 263 8.2.5 Dendritic and Hyperbranched Polymers 265 8.2.6 Conjugated and Hybrid Polymers 270 8.3 Conclusion 276 Acknowledgments 284 References 284 9 Synthesis of Macrocycles and Click Chemistry 287Dario Pasini 9.1 Introduction 287 9.1.1 Peptide- and Sugar-Containing Click Macrocycles 289 9.1.2 Click Macrocycles for Anion Binding and Supramolecular Recognition 297 9.1.3 Clicking Macrocycles to form Mechanical Bonds 300 9.1.4 Cyclic Polymers Obtained by the CuAAC Click Reaction 302 9.2 Summary and Conclusions 304 References 304 10 Modifications of Nucleosides, Nucleotides, and Nucleic Acids using Huisgen’s [3+2] Azide–Alkyne Cycloaddition: Opening Pandora’s Box 309Franck Amblard, Ozkan Sari, Sebastien Boucle, Ahmed Khalil, and Raymond F. Schinazi 10.1 Introduction 309 10.1.1 Nucleoside Modifications 309 10.1.1.1 Nucleoside Analogs as Potential Drugs 309 10.1.1.2 Nucleoside Bioconjugates 311 10.2 Nucleotide and Nucleic Acid Modifications 316 10.2.1 “Artificial” DNA 316 10.2.2 Presynthetic Modification DNA 316 10.2.3 Postsynthetic Modification 318 10.3 Conclusion 331 Acknowledgments 332 References 332 Index 337

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Book SynopsisAuthored by one of the leading experts in the field, this is the only comprehensive overview of chiral organophosphorus compounds, from asymmetric synthesis to catalysis and pharmacological applications. As such, this unique reference covers the chemical background as well as spectroscopical analysis of phosphorus compounds, and thoroughly describes all the various synthetic strategies for these substances. Metal-, organo- and biocatalyzed reactions for the introduction of phosphorus are explained as are asymmetric oxidation and reduction methods for the preparation of all possible oxidation states of phosphorus. The text also includes industrial applications for these compounds. Of particular interest to chemists working in the field of asymmetric synthesis, as well as to the pharmaceutical industry due to the increasing number of phosphorous-containing drugs.Table of ContentsPreface xi Abbreviations xiii 1 Fundamentals of the Stereochemistry of Organophosphorus Compounds 1 1.1 Historical Background 1 1.2 Some Common Definitions in Stereochemistry 4 1.3 Determination of Enantiomer Composition 7 1.3.1 Method of Nuclear Magnetic Resonance 8 1.3.1.1 Chiral Solvating Agents 8 1.3.1.2 Complexes of Metals (Shift Reagents) 10 1.3.1.3 Chiral Derivatizing Agents for NMR 11 1.3.2 Chromatographic Methods of Analysis 14 1.3.2.1 Gas Chromatography 15 1.3.2.2 Liquid Chromatography 16 1.4 Determination of the Absolute Configuration 17 1.4.1 X-ray Crystal Analysis 17 1.4.2 Method of Chemical Correlation 19 1.4.3 The Assignment of Absolute Configuration by NMR 19 1.5 Asymmetric Induction and Stereochemistry 24 1.5.1 Asymmetric Induction 24 1.5.2 Asymmetric Synthesis 25 1.5.3 Asymmetric Transformation 25 1.5.4 An Enantioselective Reaction 25 1.5.5 Enantioselective Synthesis 25 1.6 Summary 26 References 26 2 Asymmetric Synthesis of P-Chirogenic Phosphorus Compounds 35 2.1 Introduction 35 2.2 Low-Coordinated Phosphorus Compounds 36 2.3 Trivalent Tricoordinated Phosphorus Compounds 41 2.3.1 Configuration Stability of P(III)-Compounds 41 2.3.2 Asymmetric Nucleophilic Substitution at P (III) 43 2.3.2.1 Secondary Alcohols as Chiral Auxiliaries 45 2.3.2.2 Optically Active Amines as Chiral Auxiliaries 54 2.3.2.3 Ephedrine as Inductor of Chirality at P(III) 58 2.3.3 Asymmetric Oxidation of P(III) Compounds 67 2.3.4 Asymmetric Electrophilic Substitution at P(III) 68 2.3.4.1 Asymmetric Michaelis–Arbuzov Reaction 70 2.4 Pentavalent P(IV)-Phosphorus Compounds 71 2.4.1 Introduction 71 2.4.2 Nucleophilic Substitution Reactions 72 2.4.2.1 Nucleophilic Substitution at P(IV) with Chiral Alcohol 74 2.4.2.2 Nucleophilic Substitution at P(IV) with Chiral Amines 78 2.5 Chiral P(V) and P(VI) Phosphorus Compounds 80 2.6 Summary 86 References 87 3 Phosphorus Compounds with Chiral Side-Chain Centers 101 3.1 Introduction 101 3.2 Asymmetric Induction in Side Chains 102 3.2.1 Transfer of Chirality from Phosphorus to Other Centers 103 3.2.1.1 Chiral Phosphorus-Stabilized Anions 103 3.2.1.2 1,2-Asymmetric Induction 105 3.2.1.3 1,4-Asymmetric Induction 107 3.3 Enantioselective Olefination 113 3.4 Stereoselective Addition of Phosphorous Nucleophiles to C=X Bonds 117 3.4.1 Phospha-Aldol Reaction 119 3.4.2 Phospha-Mannich Reaction 130 3.4.3 Phospha-Michael Reaction 142 3.5 Asymmetric Reduction 147 3.6 Asymmetric Oxidation 152 3.7 C-Modification 156 3.8 Asymmetric Cycloaddition 157 3.9 Multiple Stereoselectivity 159 3.10 Summary 169 References 170 4 Asymmetric Catalysis with Metal Complexes 187 4.1 Introduction 187 4.2 Asymmetric Catalytic Hydrogenation and Other Reactions of Reduction 188 4.2.1 Hydrogenation of C=C Phosphorus Compounds 188 4.2.2 Hydrogenation of C=O Phosphorus Compounds 200 4.3 Asymmetric Reduction and Oxidation 203 4.3.1 Reduction of C=O, C=N, and C=C bonds 204 4.3.2 Asymmetric Oxidation 210 4.4 Electrophilic Asymmetric Catalysis 211 4.4.1 Catalytic Electrophilic Substitution at the Phosphorus Atom 212 4.4.1.1 Alkylation and Arylation of P(III) Compounds 213 4.4.2 Catalytic Electrophilic Substitution in a Side Chain 217 4.4.2.1 Alkylation 217 4.4.2.2 Halogenation 219 4.4.2.3 Amination 221 4.5 Nucleophilic Asymmetric Catalysis 223 4.5.1 Asymmetric Addition of Phosphorus Nucleophiles to Multiple Bonds 223 4.5.1.1 Phospha-Aldol Reaction 224 4.5.1.2 Phospha-Mannich Reaction 229 4.5.1.3 Phospha-Michael Reaction 232 4.6 Cycloaddition Reactions 237 4.7 Summary 240 References 241 5 Asymmetric Organocatalysis 253 5.1 Introduction 253 5.2 Modes for Catalytic Activation of Substrates in Asymmetric Organocatalysis 254 5.3 Phospha-Aldol Reaction 258 5.3.1 Catalysis with Cinchona Alkaloids 258 5.3.2 Catalysis with Cinchona-Thiourea 259 5.3.3 Catalysis by Other Organocatalysts 260 5.4 Phospha-Mannich Reactions 262 5.4.1 Organocatalysis by Cinchona Alkaloids 262 5.4.2 Organocatalysis by Imines 263 5.4.3 Organocatalysis by Iminium salts 265 5.4.4 Organocatalysis by Chiral Brønsted acids 265 5.5 Phospha-Michael Reaction 269 5.5.1 Organocatalysis by Cinchona Alkaloids 269 5.5.2 Organocatalysis by Thiourea 270 5.5.3 Organocatalysis by Iminium salts 272 5.5.4 Organocatalysis by N-Heterocyclic Carbenes 274 5.5.5 Organocatalysis Using Proline Derivatives 274 5.6 Organocatalytic Addition to Ketophosphonates 282 5.6.1 Proline, Amino Acids, andTheir Derivatives 282 5.6.2 Organocatalysis by Thiourea 288 5.7 Phospha-Henry Reaction 288 5.8 OrganocatalyticModification of P-ylids 290 5.9 Asymmetric Catalysis with Chiral Diamines 292 5.10 Miscellaneous 303 References 305 6 Asymmetric Biocatalysis 315 6.1 Introduction 315 6.2 Enzymatic Synthesis of Organophosphorus Compounds 315 6.2.1 Kinetic Resolution of Hydroxyphosphonates 316 6.2.2 Resolution of α-Hydroxyphosphonates by Biocatalytic Transesterification 317 6.2.3 Resolution of α-Hydroxyphosphonates by Biocatalytic Hydrolysis 319 6.2.4 Dynamic Kinetic Resolution of α-Hydroxyphosphonates 323 6.2.5 Resolution of β- and ω-Hydroxyphosphonates 323 6.2.6 Dynamic Kinetic Resolution of β-Hydroxyphosphonates 331 6.2.7 Resolution of Aminophosphonates 332 6.3 Biosynthesis of Compounds with C–P Bond 335 6.4 Resolution of P-Chiral Phosphorus Compounds 337 6.5 Microbiological Synthesis of Chiral Organophosphorus Compounds 349 6.5.1 Yeast-Catalyzed Synthesis 349 6.5.2 Synthesis Using Unicellular Fungi 354 6.5.3 Synthesis Using Bacteria 356 6.6 Summary 358 References 358 Index 369

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Book SynopsisProvides, in one handbook, comprehensive coverage of one of the hottest topics in stereoselective chemistry Written by leading international authors in the field, this book introduces readers to C-H activation in asymmetric synthesis along with all of its facets. It presents stereoselective C-H functionalization with a broad coverage, from outer-sphere to inner-sphere C-H bond activation, and from the control of olefin geometry to the induction of point, planar and axial chirality. Moreover, methods wherein asymmetry is introduced either during the C-H activation or in a different elementary step are discussed. Presented in two parts?asymmetric activation of C(sp3)-H bonds and stereoselective synthesis implying activation of C(sp2)-H bonds?CH-Activation for Asymmetric Synthesis showcases the diversity of stereogenic elements, which can now be constructed by C-H activation methods. Chapters in Part 1 cover: C(sp3)-H bond insertion by metal carbenoids and nitrenoids; stereoselective C-C bond and C-N bond forming reactions through C(sp3)?H bond insertion of metal nitrenoids; enantioselective intra- and intermolecular couplings; and more. Part 2 looks at: C-H activation involved in stereodiscriminant step; planar chirality; diastereoselective formation of alkenes through C(sp2)?H bond activation; amongst other methods. -Covers one of the most rapidly developing fields in organic synthesis and catalysis -Clearly structured in two parts (activation of sp3- and activation of sp2-H bonds) -Edited by two leading experts in C-H activation in asymmetric synthesis CH-Activation for Asymmetric Synthesis will be of high interest to chemists in academia, as well as those in the pharmaceutical and agrochemical industry. Table of ContentsForeword xi Part I Asymmetric Activation of C(sp3)—H Bonds 1 Part I.A C(sp3)—H Bond Insertion by Metal Carbenoids and Nitrenoids 2 1 Stereoselective C—C Bond-Forming Reactions Through C(sp3)—H Bond Insertion of Metal Carbenoids 3 Aoife M. Buckley, Thomas A. Brouder, Alan Ford, and Anita R. Maguire 1.1 Introduction 3 1.2 Diazo Compounds 4 1.3 Mechanistic Understanding 5 1.4 Catalysts 7 1.4.1 Copper 7 1.4.1.1 Bisoxazoline and Schiff Base 7 1.4.2 Rhodium 8 1.4.2.1 Rhodium(II) Carboxylates 9 1.4.2.2 Rhodium(II) Carboxamidates 10 1.4.2.3 Ortho-metalated Complexes 11 1.4.3 Iridium and Ruthenium 11 1.5 Intramolecular C(sp3)—H Bond Insertion 11 1.5.1 Chemoselectivity 13 1.5.1.1 Catalyst Effects 13 1.5.1.2 Substrate Effects 14 1.5.2 Regioselectivity 16 1.5.2.1 Formation of Three-Membered Rings 17 1.5.2.2 Formation of Four-Membered Rings 18 1.5.2.3 Formation of Five-Membered Rings 20 1.5.2.4 Formation of Six-Membered Rings 20 1.5.3 Diastereoselectivity 23 1.5.3.1 Substrate Effects 23 1.5.3.2 Catalyst Effects 25 1.5.4 Enantioselectivity 25 1.6 Intermolecular C(sp3)—H Bond Insertion 30 1.6.1 Chemoselectivity 30 1.6.1.1 Diazo Compounds 32 1.6.1.2 Catalyst Effects 34 1.6.1.3 Substrate Functional Groups 35 1.6.2 Regioselectivity 36 1.6.2.1 Substrate Effects 36 1.6.2.2 Catalyst Effects 38 1.6.2.3 Diazo Compound Effects 39 1.6.3 Diastereoselectivity 39 1.6.3.1 Substrate Effects 39 1.6.3.2 Catalyst Effects 42 1.6.4 Enantioselectivity 43 1.7 Conclusion 45 References 45 2 Stereoselective C—N Bond-Forming Reactions Through C(sp3)—H Bond Insertion of Metal Nitrenoids 51 Philippe Dauban, Romain Rey-Rodriguez, and Ali Nasrallah 2.1 Introduction 51 2.2 Historical Background 52 2.2.1 Seminal Studies in Catalytic C(sp3)–H Amination 52 2.2.2 Mechanistic and Stereochemical Issues 56 2.3 Catalytic Stereoselective C(sp3)–H Amination Reactions with Iminoiodinanes 60 2.3.1 Catalytic Intermolecular Enantioselective Reactions (Chirality Only on the Metal Complex) 60 2.3.2 Catalytic Intramolecular Enantioselective Reactions 63 2.3.3 Catalytic Intermolecular Diastereoselective Reactions (Chirality on the Metal Complex and the Nitrene Precursor) 66 2.4 Catalytic Stereoselective C(sp3)–H Amination Reactions with Azides 67 2.4.1 Transition Metal-Catalyzed C(sp3)–H Amination Reactions 67 2.4.2 Enzymatic C(sp3)–H Amination Reactions 68 2.5 Catalytic Stereoselective C(sp3)–H Amination Reactions with N-(Sulfonyloxy)carbamates 70 2.6 Conclusion 72 References 72 Part I.B C(sp3)–H Activation as Stereodiscriminant Step 77 3 Enantioselective Intra- and Intermolecular Couplings 79 Qiaoqiao Teng and Wei-Liang Duan 3.1 Introduction 79 3.2 Enantioselective Intramolecular Couplings of Aliphatic Substrates 79 3.2.1 C–C Coupling 79 3.2.2 C–X Coupling 89 3.3 Enantioselective Intermolecular Couplings of Aliphatic Substrates 90 3.3.1 Pd Catalysis 91 3.3.2 Rh Catalysis 102 3.3.3 Ir Catalysis 102 3.4 Conclusion 104 References 105 4 Substrate-Controlled Transformation: Diastereoselective Functionalization 107 Sheng-Yi Yan, Bin Liu, and Bing-Feng Shi 4.1 Introduction 107 4.2 Diastereoselective Functionalizations of N-Phthaloyl-α-Amino Acids 108 4.2.1 Diastereoselective β-C(sp3)–H Functionalizations of N-Phthaloyl-α-Amino Acids 108 4.2.1.1 Bidentate Directing Group 108 4.2.1.2 Monodentate Directing Group 114 4.2.2 Diastereoselective γ-C(sp3)–H Functionalization of α-Amino Acid Derivatives 114 4.3 Diastereoselective C–H Activation Controlled by Chiral Auxiliary 116 4.4 Diastereoselective C(sp3)–H Functionalization of Conformationally Restricted Cyclic Substrates 121 4.5 Summary and Conclusions 127 References 128 Part II Stereoselective Synthesis Implying Activation of C(sp2)—H Bonds 131 5 Planar Chirality via C(sp2)–H Activation Involved in Stereodiscriminant Step 133 Qing Gu and Shu-Li You 5.1 Introduction 133 5.2 Diastereoselective Synthesis of Planar Chiral Ferrocenes 134 5.3 Enantioselective Synthesis of Planar Chiral Ferrocenes 134 5.3.1 Pd(II)-Catalyzed Direct C—H Bond Functionalization 134 5.3.2 Pd(0)-Catalyzed Direct C—H Bond Functionalization 140 5.3.3 Ir/Rh-Catalyzed Direct C—H Bond Functionalization 144 5.3.4 Au/Pt-Catalyzed Direct C—H Bond Functionalization 146 5.4 Conclusion 147 References 148 6 Axial Chirality via C(sp2)–H Activation Involved in Stereodiscriminant Step 151 Quentin Dherbassy, Joanna Wencel-Delord, and Françoise Colobert 6.1 Introduction 151 6.2 Asymmetric Coupling of Two Arenes by Oxidative Dimerization 152 6.2.1 Copper-Catalyzed Reactions 153 6.2.2 Vanadium-Catalyzed Reactions 154 6.2.3 Iron-Catalyzed Reactions 155 6.2.4 Application in the Synthesis of Natural Products 155 6.2.5 Conclusion 156 6.3 Stereoselective C–H Functionalization of Prochiral or Racemic Biaryls 158 6.3.1 Asymmetric C–H Alkylation of Naphthylpyridines 158 6.3.2 Diastereoselective C–H Functionalization Using a Chiral Directing Group 159 6.3.2.1 Sulfinyl as Chiral Directing Group 159 6.3.2.2 Phosphates as Chiral Directing Group 162 6.3.3 Enantioselective C–H Functionalization of Racemic Biaryl 163 6.3.4 Stereoselective C–H Functionalization Using a Transient Chiral Directing Group 165 6.3.5 Conclusion 167 6.4 Atroposelective Cross-Coupling of Two Moieties 167 6.4.1 Pd-Catalyzed C–H Arylation of Thiophene Derivatives 167 6.4.2 Pd-Catalyzed C–H Arylation of Biaryl Sulfoxides 169 6.4.3 Rh-Catalyzed C–H Arylation of Diazonaphthoquinones 171 6.4.4 Conclusion 172 6.5 General Conclusion 172 References 172 7 Central Chirality via Asymmetric C(sp2)–H Activation Implying Desymmetrization and Kinetic Resolution 175Soufyan Jerhaoui, Françoise Colobert, and Joanna Wencel-Delord 7.1 Synthesis of C-Stereogenic Molecules via C(sp2)–H Functionalization 175 7.1.1 Desymmetrization 175 7.1.2 Kinetic Resolution 182 7.2 Synthesis of P-Central Chiral Molecules via C(sp2)–H Functionalization 183 7.3 Synthesis of Chiral Organosilicon Molecules via C(sp2)–H Functionalization 187 7.4 Synthesis of S-Chiral Molecules via C(sp2)–H Functionalization 189 7.5 Conclusions 190 References 191 8 Non-stereoselective C(sp2)–H Activation Followed by Selective Functionalization of Metallacyclic Intermediate 193 Xiaohong Chen, Xue Gong, Bo Wang, and Guoyong Song 8.1 Introduction 193 8.2 Intramolecular Couplings 194 8.2.1 Palladium and Nickel Catalysis 194 8.2.2 Rhodium Catalysis 196 8.2.3 Iridium Catalysis 200 8.2.4 Enantioselective Hydroacylation 203 8.3 Intermolecular Couplings 210 8.3.1 Rhodium Catalysis 210 8.3.2 Iridium Catalysis 219 8.3.3 Other Metal Catalysis 226 8.4 Conclusion 231 Acknowledgments 231 References 231 9 Diastereoselective Formation of Alkenes Through C(sp2)—H Bond Activation 239 Parthasarathy Gandeepan and Lutz Ackermann 9.1 Introduction 239 9.2 C–H Activation with Alkenes 241 9.2.1 Nondirected C–H Alkenylation 241 9.2.2 Directed C–H Alkenylation 244 9.3 C–H Activation with Alkenyl (Pseudo)halides 250 9.4 Hydroarylation 252 9.4.1 Hydroarylation of Alkynes 252 9.4.2 Hydroarylation of Allenes 257 9.5 Hydroacylation 261 9.5.1 Hydroacylation of Alkynes 261 9.5.2 Hydroacylation of Allenes 263 9.6 Conclusion 264 References 265 Index 275

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