Comprehensive Chirality

Comprehensive Chirality

1st Edition - September 5, 2012

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  • Editors-in-Chief: Hisashi Yamamoto, Erick Carreira
  • eBook ISBN: 9780080951683
  • Hardcover ISBN: 9780080951676

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Although many books exist on the subject of chiral chemistry, they only briefly cover chiral synthesis and analysis as a minor part of a larger work, to date there are none that pull together the background information and latest advances in one comprehensive reference work. Comprehensive Chirality provides a complete overview of the field, and includes chiral research relevant to synthesis, analytic chemistry, catalysis, and pharmaceuticals. The individual chapters in each of the 9 volumes provide an in depth review and collection of references on definition, technology, applications and a guide/links to the related literature. Whether in an Academic or Corporate setting, these chapters will form an invaluable resource for advanced students/researchers new to an area and those who need further background or answers to a particular problem, particularly in the development of drugs.

Key Features

  • Chirality research today is a central theme in chemistry and biology and is growing in importance across a number of disciplinary boundaries. These studies do not always share a unique identifying factor or subject themselves to clear and concise definitions. This work unites the different areas of research and allows anyone working or researching in chiral chemistry to navigate through the most essential concepts with ease, saving them time and vastly improving their understanding.
  •  The field of chirality counts several journals that are directly and indirectly concerned with the field. There is no reference work that encompasses the entire field and unites the different areas of research through deep foundational reviews. Comprehensive Chirality fills this vacuum, and can be considered the definitive work. It will help users apply context to the diverse journal literature offering and aid them in identifying areas for further research and/or for solving problems.
  • Chief Editors, Hisashi Yamamoto (University of Chicago) and Erick Carreira (ETH Zürich) have assembled an impressive, world-class team of Volume Editors and Contributing Authors. Each chapter has been painstakingly reviewed and checked for consistent high quality. The result is an authoritative overview which ties the literature together and provides the user with a reliable background information and citation resource.


Graduate students and researchers working in organic, medicinal, and biological chemistry, as well as pharmacologists and toxicologists

Table of Contents

  • Editors in Chief

    Volume Editors


    Permission Acknowledgments

    Volume 1: Biological Significance: Pharmacology, Phamaceutical Agrochemical

    1.1 Introduction: The Importance of Chirality in Drugs and Agrochemicals


    1.1.1 Drugs

    1.1.2 Agrochemicals


    1.2 Importance of Chirality in the Field of Anti-infective Agents


    1.2.1 Introduction

    1.2.2 Antiinfectives from Natural Origin

    1.2.3 Antiinfectives from Nonnatural Origin

    1.2.4 Conclusion



    1.3 Chirality in Antibacterial Agents


    1.3.1 Introduction

    1.3.2 Membrane Synthesis Inhibitors

    1.3.3 Antibacterial Agents Acting on DNA

    1.3.4 Protein Synthesis Inhibitors

    1.3.5 Molecules Acting on New Targets

    1.3.6 Antibacterial Agents as Chiral Selectors


    1.4 Diastereomers, Enantiomers and Bioactivity. TMC207: A New Candidate for the Treatment of Tuberculosis


    1.4.1 Introduction

    1.4.2 Inhibition of ATP Synthase by TMC207

    1.4.3 Chemistry

    1.4.4 In Vitro Antimycobacterial Activity of TMC207

    1.4.5 Conformational Analysis of TMC207

    1.4.6 Molecular Basis and Stereospecificity

    1.4.7 Conclusion



    1.5 Fluorine in Medicinal Chemistry: Importance of Chirality

    1.5.1 Introduction

    1.5.2 Pharmaceuticals and Molecules of Biological Interest Bearing Fluorine and Trifluoromethyl Groups at an sp3-Hybridized Carbon


    1.6 Peptides and Chirality Effects on the Conformation and the Synthesis of Medicinally Relevant Peptides


    1.6.1 Introduction

    1.6.2 Chirality in Peptides from Amino Acids to Secondary Structures

    1.6.3 Chirality in Peptide Turn Geometry and Nucleation of β-Sheets

    1.6.4 Alternating Chirality in Peptide Helical Geometry and Cyclic Peptide Nanotubes

    1.6.5 Enantiomeric and Retro-enantio Peptide Analogs of Biologically Active Peptides

    1.6.6 Systematic Study of the Effects of Amino Acid Configuration on Conformation and Activity by D-Amino Acid Scanning of Peptide Hormones

    1.6.7 Maintaining Configurational Integrity in Peptide Synthesis by Overcoming the Pitfall of Racemization during Amide Bond Formation

    1.6.8 Industrial Synthesis of Chiral Peptides

    1.6.9 Conclusion


    1.7 Stereochemical Lability in Drug Molecules: Cases Where Chirality May Not Be Critical for Drug Development


    1.7.1 Introduction

    1.7.2 Chiral Drug Candidates that are Stereochemically Labile

    1.7.3 Methods for Assessing Stereomutation

    1.7.4 Conclusion



    1.8 Chirality in Agrochemicals

    1.8.1 Introduction

    1.8.2 Chiral Fungicides

    1.8.3 Chiral Insecticides

    1.8.4 Chiral Herbicides


    1.9 The use of New Phosphines as Powerful Tools in Asymmetric Synthesis of Biologically Active Compounds


    1.9.1 General Comments on the Importance of Chirality in Biologically Active Compounds

    1.9.2 New Phosphines in the Synthesis of Drug Candidates

    1.9.3 Phosphines in the Synthesis of Pharmacophores

    1.9.4 New Phosphines in Selected Total Syntheses

    1.9.5 Summary


    1.10 Chirality and Combinatorial Libraries for Drug Discovery, an Overview

    Volume 2: Synthetic Methods I: Chiral Pool and Diastereoselective Methods

    2.1 Introductory Remarks: Chiral Pool Syntheses and Diastereoselective Reactions



    2.2 General Principles of Diastereoselective Reactions: Rigid Templates


    2.2.1 Introduction

    2.2.2 Rigid Templates


    2.3 General Principles of Diastereoselective Reactions: Diastereoselectivity via Substrate-Directable Reactions (Internal Delivery) and Heterocyclizations


    2.3.1 Introduction

    2.3.2 Internal Delivery

    2.3.3 Heterocyclization


    2.4 General Principles of Diastereoselective Reactions: Acyclic Control of Diastereoselectivity

    2.4.1 Introduction

    2.4.2 Simple Diastereoselectivity

    2.4.3 Induced Diastereoselectivity

    2.4.4 Differentiation of Diastereotopic Groups in Diastereoselective Synthesis

    2.4.5 Thermodynamic Control of Diastereoselectivity


    2.5 General Principles of Diastereoselective Reactions: Diastereoselective Domino Reactions

    2.5.1 Introduction

    2.5.2 Domino Reactions Involving Pericyclic Processes

    2.5.3 Transition Metal-Catalyzed Domino Reactions

    2.5.4 Domino Reactions Involving 1,4-Addition

    2.5.5 Miscellaneous Domino Reactions

    2.5.6 Conclusion


    2.6 Chiral Pool Synthesis: From α-Amino Acids and Derivatives


    2.6.1 Introduction

    2.6.2 Alanine

    2.6.3 Valine: Malyngamide X (Scheme 5)

    2.6.4 Cysteine Ecteinascidin Et 583(6.8) (Scheme 6)

    2.6.5 Proline

    2.6.6 Trans-4-Hydroxy-L-Proline

    2.6.7 (+)-(R)-Pipecolinic Acid

    2.6.8 Serine

    2.6.9 Aspartate: Cyclomarin A (Scheme 25)

    2.6.10 L-Glutamic Acid

    2.6.11 Pyroglutamate (Scheme 28)

    2.6.12 Allysine

    2.6.13 D-Homotyrosine

    2.6.14 Tryptophan


    2.7 Chiral Pool Synthesis: Starting from Terpenes


    2.7.1 Introduction

    2.7.2 Acyclic Monoterpenes: Citronellol, Citronellal, and Citronellene

    2.7.3 Cyclic Monoterpenes

    2.7.4 Bi- and Tricyclic Terpenes: Nepetalactone and Santonin


    2.8 Chiral Pool Synthesis: Chiral Pool Syntheses Starting from Carbohydrates

    2.8.1 Introduction

    2.8.2 Background

    2.8.3 Synthesis of Macrocyclic and Polycyclic Compounds

    2.8.4 Synthesis of Heterocyclic Compounds

    2.8.5 Synthesis of Carbocyclic Compounds


    2.9 Chiral Pool Synthesis: Chiral Pool Syntheses from cis-Cyclohexadiene Diols


    2.9.1 Introduction

    2.9.2 Discovery of the Degradation Pathway of Aromatics by Soil Bacteria

    2.9.3 Isolation and Accessibility of Metabolites

    2.9.4 Advantages of cis-Cyclohexadiene Diols in Synthesis

    2.9.5 Microbiology Meets Chemistry – First Contact of Cyclohexadiene Diols with Chemists

    2.9.6 Chiral Pool Syntheses from cis-Cyclohexadiene Diols

    2.9.7 Conclusion



    2.10 Chiral Pool Synthesis: Chiral Pool Synthesis from Hydroxy Acids: Lactic Acid, Tartaric Acid, Malic Acid, and 2-Methyl-3-hydroxypropionic Acid



    2.10.1 Background

    2.10.2 3-Hydroxybutyric Acid in Total Synthesis

    2.10.3 Lactic Acid in Total Synthesis

    2.10.4 Roche Ester in Total Synthesis

    2.10.5 Mandelic Acid in Total Synthesis

    2.10.6 Malic Acid in Total Synthesis

    2.10.7 Tartaric Acid in Total Synthesis


    2.11 Chiral Pool Synthesis: Chiral Pool Synthesis from Quinic Acid

    2.11.1 Introduction

    2.11.2 Transformations of Quinic Acid

    2.11.3 Conversion of Quinic Acid to Shikimic Acid and Its Derivatives

    2.11.4 Applications of Quinic Acid in Natural Product Synthesis

    2.11.5 Concluding Remarks


    2.12 Selected Diastereoselective Reactions: Additions of Achiral Carbanions to Chiral Aldehydes and Ketones


    2.12.1 Introduction and Theoretical Models

    2.12.2 Addition of Polar Organometallic Reagents to Chiral Aldehydes and Ketones


    2.13 Selected Diastereoselective Reactions: Aldoltype Additions


    2.13.1 Introduction

    2.13.2 Aldol Reactions with Preformed Enolates

    2.13.3 Catalytic Aldol Additions


    2.14 Selected Diastereoselective Reactions: Enolate Alkylation


    2.14.1 Introduction

    2.14.2 Alkylation of Ketone and Aldehyde Enolates

    2.14.3 Alkylation of Ester and Lactone Enolates

    2.14.4 Alkylation of Amide and Lactam Enolates


    2.15 Selected Diastereoselective Reactions: Substrate Controlled Stereoselective Conjugate Addition Reactions with Organocopper Reagents


    2.15.1 Introduction

    2.15.2 Organocopper Reagents in Total Synthesis

    2.15.3 Conclusion


    2.16 Selected Diastereoselective Reactions: Free Radical Additions and Cyclizations


    2.16.1 Introduction

    2.16.2 General Comments on Radicals and Their Reactivity

    2.16.3 Substrate-Controlled Intermolecular Reactions

    2.16.4 Substrate-Controlled Intramolecular Reactions

    2.16.5 Conclusion


    2.17 Selected Diastereoselective Reactions: Intramolecular Diels–Alder Reactions


    2.17.1 Introduction

    2.17.2 Synthetic Studies of Zoanthamine Alkaloids

    2.17.3 Synthetic Studies of Symbioimine and Neosymbioimine

    2.17.4 Synthetic Studies of Platensimycin and Platencin

    2.17.5 Synthetic Studies of Vinigrol

    2.17.6 Synthetic Studies of Other Natural Products Featured by Intramolecular Diels–Alder Reactions


    2.18 Selected Diastereoselective Reactions: Diastereoselective Intra- and Intermolecular 1,3-Dipolar Cycloadditions in Natural Product Synthesis


    2.18.1 Introduction

    2.18.2 General Rules (Charts 1 and 2)


    2.19 Selected Diastereoselective Reactions: Electrocyclizations


    2.19.1 Introduction

    2.19.2 2π Electrocyclizations

    2.19.3 4π Electrocyclizations

    2.19.4 6π Electrocyclizations

    2.19.5 8π Electrocyclizations


    2.20 Selected Diastereoselective Reactions: Ionic and Zwitterionic Cyclizations

    2.20.1 Introduction

    2.20.2 Nazarov-Initiated Diastereoselective Cyclization

    2.20.3 Construction of Polycyclic Compounds Through the Interrupted Nazarov Reaction

    2.20.4 Prins Reaction and Related Cationic Rearrangements

    2.20.5 Polyaromatic Natural Products

    2.20.6 Polyene/Epoxide Cyclization

    2.20.7 Donor–Acceptor (D–A) Cyclopropanes

    2.20.8 Internal Redox

    2.20.9 Pot-Pourri

    2.20.10 Conclusion


    2.21 Selected Diastereoselective Reactions: Diastereoface-Differentiating Claisen, Cope, and [2,3]-Wittig Rearrangements in Contemporary Natural Product Synthesis

    2.21.1 Introduction

    2.21.2 Claisen Rearrangements

    2.21.3 Cope Rearrangements

    2.21.4 [2,3]-Wittig Rearrangements

    2.21.5 Conclusion


    2.22 Selected Diastereoselective Reactions: Heck Type Cyclizations


    2.22.1 Introduction

    2.22.2 Cyclizations Onto Cyclic Alkenes

    2.22.3 Cyclizations onto Acyclic and Exocyclic Alkenes

    2.22.4 Conclusion


    2.23 Selected Diastereoselective Reactions: Gold Catalyzed Cyclizations

    2.23.1 Introduction

    2.23.2 Asymmetric Aldol Reaction

    2.23.3 Intrinsic Diastereoselectivity Based on Geometrical Restraints

    2.23.4 Diastereoselective Formation of E/Z Isomers

    2.23.5 sp3-Stereocenters from Enyne Substrates

    2.23.6 sp3-Stereocenters from Enallene Substrates

    2.23.7 sp3-Stereocenters from Alkyne Substrates

    2.23.8 sp3-Stereocenters from Allenes

    2.23.9 sp3-Stereocenters from Nucleophilic Additions to Alkenes

    2.23.10 sp3-Stereocenters from Reactions with 1,3-Dipoles

    2.23.11 sp3-Stereocenters from Nazarov-Like Cyclizations

    2.23.12 sp3-Stereocenters from Wagner–Meerwein Shifts

    2.23.13 sp3-Stereocenters from Indoles

    2.23.14 Conclusion


    2.24 Selected Diastereoselective Reactions: C–H Insertions

    Volume 3: Synthetic Methods II: Chiral Auxiliaries

    3.1 Amino Acid Derived Auxiliaries: Amino Acids as Chiral Auxiliaries


    3.1.1 Introduction

    3.1.2 Reductions

    3.1.3 C-C Bond-Forming Reactions

    3.1.4 Resolutions

    3.1.5 Concluding Remarks


    3.2 Amino Acid Derived Heterocyclic Chiral Auxiliaries: The use of Oxazolidinones, Oxazolidinethiones, Thiazolidinethiones, and Imidazolidinones

    3.2.1 Introduction

    3.2.2 Asymmetric Addition to C–O Bonds

    3.2.3 Asymmetric Alkylation and Related Reactions

    3.2.4 Asymmetric Addition to C–C Bonds

    3.2.5 Miscellaneous Reactions

    3.2.6 Cleavage of Chiral Auxiliaries

    3.2.7 Conclusion


    3.3 Terpene Derived Auxiliaries: Camphor and Pinene Derived Auxiliaries

    3.3.1 Introduction

    3.3.2 Camphor

    3.3.3 C-2 Functionalization

    3.3.4 C1-C2 Functionalized Camphor-Derived Auxiliaries

    3.3.5 C2–C3 Functionalized Camphor-Derived Auxiliaries

    3.3.6 Auxiliaries Derived from Camphor-10-Sulfonic Acid

    3.3.7 Aza-Camphor Class of Auxiliaries

    3.3.8 Auxiliaries Derived from Pinene

    3.3.9 Concluding Remarks


    3.4 Terpene Derived Auxiliaries: Menthol and Pulegone Derived Auxiliaries

    3.4.1 Menthol

    3.4.2 Menthone

    3.4.3 Pulegone

    3.4.4 Phenylmenthol

    3.4.5 Miscellaneous 8-(substituted)-menthol Derivatives


    3.5 Terpene Derived Auxiliaries: Miscellaneous Terpene Derived Auxiliaries


    3.5.1 Miscellaneous Terpene Derived Chiral Auxiliaries

    3.5.2 Fenchone Derivatives

    3.5.3 Limonene Derivatives

    3.5.4 Verbenone Derivatives

    3.5.5 Longifolene Derivatives

    3.5.6 Cedrene Derivatives

    3.5.7 Carvone Derivatives


    3.6 Acetogenin (Polypriopionate) Derived Auxiliaries: Tartaric Acid

    3.6.1 Introduction

    3.6.2 Use of Tartaric Acid and its Acid Derivatives for Asymmetric Reactions

    3.6.3 Tartaric Acid Esters

    3.6.4 Asymmetric Reactions Promoted by Tartramide–Metal Complexes

    3.6.5 Miscellaneous

    3.6.6 Conclusion


    3.7 Acetogenin (Polypriopionate) Derived Auxillaries: Hydroxyacids


    3.7.1 Introduction

    3.7.2 Background

    3.7.3 Nucleophilic 1,2-Additions

    3.7.4 Control of Chiral Centers in α- or β-Position of Carbonyl and Carboxylic Compounds

    3.7.5 Cyclopropanations

    3.7.6 Aziridinations

    3.7.7 Cycloadditions

    3.7.8 Miscellaneous Reactions


    3.8 Acetogenin (Polypriopionate) Derived Auxillaries: Hydroxyacid Derivatives


    3.8.1 Introduction

    3.8.2 Background

    3.8.3 Access to Pantolactams

    3.8.4 Enantioselective Reactions

    3.8.5 Diastereoselective Reactions


    3.9 Alkaloid Derived Auxiliaries: Cinchona Alkaloids and Derivatives


    3.9.1 Introduction

    3.9.2 Chiral Auxiliaries

    3.9.3 Metal-Mediated Reactions

    3.9.4 Organocatalysis and Phase-Transfer Catalysis

    3.9.5 Summary


    3.10 Alkaloid-Derived Auxiliaries: Ephedra Alkaloids

    3.10.1 History

    3.10.2 Biosynthesis


    3.11 Alkaloid Derived Auxiliaries: Miscellaneous Alkaloids

    3.11.1 Asymmetric Aldol Addition Reaction

    3.11.2 Asymmetric Aldol Addition Reaction: Application with (−)-Brucine

    3.11.3 Nitroaldol (Henry) Reaction: (−)-Brucine

    3.11.4 Enantioselective Reduction

    3.11.5 Friedel–Crafts Alkylation of Indole

    3.11.6 Cycloaddition Reactions

    3.11.7 Cycloaddition Reactions

    3.11.8 CarboLithiation: Conjugate Addition

    3.11.9 Intramolecular Conjugate Addition

    3.11.10 Synthesis and Application of Nicotine Derivatives via ortho-Lithiation

    3.11.11 Kinetic Resolution


    3.12 Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

    3.12.1 Introduction

    3.12.2 Asymmetric Cycloaddition Reactions

    3.12.3 Stereocontrolled Addition and Substitution Reactions

    3.12.4 Rearrangement Reactions

    3.12.5 Radical Reactions

    3.12.6 Oxidation Reactions

    3.12.7 Reduction Reactions

    3.12.8 Miscellaneous Application of Carbohydrate Auxiliaries

    3.12.9 Conclusions



    3.13 Carbohydrate Derived Auxiliaries: Amino Sugar and Glycosylamine Auxiliaries

    3.13.1 Introduction

    3.13.2 Aminosugar-Derived Oxazolidinones

    3.13.3 Glycosylamines as Auxiliaries

    3.13.4 Glycosylamine-Derived Organocatalysts

    3.13.5 Conclusion and Outlook


    3.14 Synthetically Derived Chiral Auxiliaries: Uses of Derivatives of Non-Carbohydrate Aldehydes and Ketones in Asymmetric Synthesis


    3.14.1 Introduction

    3.14.2 Background

    3.14.3 Diastereomer Resolutions

    3.14.4 Desymmetrizations of meso Compounds

    3.14.5 Stereocontrolled Enolate Alkylations Involving Acetals

    3.14.6 Stereocontrolled Enolate Alkylations Involving Ketals

    3.14.7 Stereocontrolled 1,2-Additions to Carbonyl

    3.14.8 Alkylations of Imines Derived from Chiral Aldehydes or Ketones

    3.14.9 Stereocontrol of Radical Reactions Using Chiral Aldehydes or Ketones

    3.14.10 Cycloaddition Reactions Involving Ketals, Hemiaminals, and Aminals Derived from Chiral Ketones

    3.14.11 Miscellaneous Uses of Aldehydes and Ketones as Chiral Auxiliaries

    3.14.12 Conclusion


    3.15 Non-Chiral Pool Derived Synthetic Auxiliaries: Use of C2-Symmetric Chiral Diols

    3.15.1 Introduction

    3.15.2 C2-Symmetric Chiral 1,2- and 1,3-Diols

    3.15.3 BINOL and BINOL-Derivatives

    3.15.4 Conclusion


    3.16 Synthetically Derived Auxiliaries: Amines (including Diamines), Hydrazines and Hydroxylamines, and Amino Alcohols

    3.16.1 Introduction

    3.16.2 Amines (Including Diamines)

    3.16.3 Hydrazines and Hydroxylamines

    3.16.4 Aminoalcohols


    3.17 Synthetically Derived Auxiliaries: Phosphorus Derivatives


    3.17.1 Introduction

    3.17.2 Preparation by Resolving Racemates

    3.17.3 Stereoselective Synthesis Based on Alcohols as Chiral Auxiliaries

    3.17.4 Stereoselective Synthesis Based on Diols as Chiral Auxiliaries

    3.17.5 Stereoselective Synthesis Based on Aminoalcohols as Chiral Auxiliaries

    3.17.6 Stereoselective Synthesis Based on Thiols as Chiral Auxiliaries

    3.17.7 Stereoselective Synthesis Based on Amines as Chiral Auxiliaries

    3.17.8 Stereoselective Synthesis Based on Diamines as Chiral Auxiliaries

    3.17.9 Stereoselective Synthesis Based on Terpenoids as Chiral Auxiliaries

    3.17.10 Conclusion


    3.18 Synthetically Derived Auxiliaries: Sulfur Derivatives (including Sulfilamines and Sulfoximines)

    3.18.1 Introduction

    3.18.2 Synthesis of Chiral Sulfur Derivatives

    3.18.3 Chiral Sulfur Derivatives as Auxiliaries in Asymmetric Synthesis

    3.18.4 Applications of Chiral Sulfur Derivatives to the Synthesis of Biologically Active Substrates

    3.18.5 Conclusions


    3.19 Synthetically Derived Auxiliaries: Organometallic Derivatives (Main Group and Transition Metals)

    3.19.1 Introduction

    3.19.2 Main Group Organometallic Derivatives as Chiral Auxiliaries

    3.19.3 Transition Metal Organometallic Derivatives as Chiral Auxiliaries



    3.20 Stoichiometric Auxiliary Ligands for Metals and Main Group Elements: Ligands for Lithium


    3.20.1 Introduction

    3.20.2 Background: Structure of Organolithiums in Solution

    3.20.3 Ligands Connected to a Reactant by a Covalent Bond

    3.20.4 Ligands without a Covalent Bond with a Reactant

    3.20.5 Conclusions


    3.21 Stoichiometric Auxiliary Ligands for Metals and Main Group Elements: Ligands for Magnesium and Calcium

    3.21.1 Introduction

    3.21.2 General Properties of Magnesium and Calcium Metal Salts

    3.21.3 Enantioselective Diels–Alder Reactions

    3.21.4 Enantioselective 1.3-Dipolar Cycloadditions

    3.21.5 Lewis Acid-Mediated Radical Reactions

    3.21.6 Enantioselective Nucleophilic Addition to CO and CN Double Bonds

    3.21.7 Enantioselective Conjugate Additions

    3.21.8 Miscellaneous

    3.21.9 Conclusions


    3.22 Chiral Ligation for Boron and Aluminum in Stoichiometric Asymmetric Synthesis

    3.22.1 Introduction

    3.22.2 Asymmetric Hydroboration

    3.22.3 Asymmetric Reduction

    3.22.4 Asymmetric Allylboration

    3.22.5 Asymmetric Allenylboration

    3.22.6 Asymmetric Propargylboration

    3.22.7 Michael Additions to Unsaturated Substrates

    3.22.8 Matteson Chain Extensions and Related Chemistry

    3.22.9 Asymmetric Enolboration

    3.22.10 Asymmetric Diels–Alder Cycloadditions

    3.22.11 Chapter Summary and Concluding Remarks


    3.23 Stoichiometric Auxiliary Ligands for Metals and Main Group Elements: Ligands for Silicon


    3.23.1 Introduction

    3.23.2 Chiral Ligand-Modified Enolsilanes and Allylsilanes

    3.23.3 Chiral Ligand-Modified Silanes as Stoichiometric Lewis Acids

    3.23.4 Chiral Ligand-Modified Silanes as Lewis Acid Catalysts

    3.23.5 Conclusion


    3.24 Stoichiometric Auxiliary Ligands for Metals and Main Group Elements: Ligands for Tin and Stannanes


    3.24.1 Introduction

    3.24.2 Chiral Organotin Reagents with Sn-Centered Chirality

    3.24.3 Chiral Organotin Reagents with Sn-C-Linked Chiral Ligands

    3.24.4 Chiral Organotin Reagents with Sn-Heteroatom-Linked Chiral Ligands

    3.24.5 Conclusion


    3.25 Stoichiometric Auxiliary Ligands for Metals and Main Group Elements: Ligands for Zinc


    3.25.1 Introduction

    3.25.2 Addition to Carbonyl Compounds

    3.25.3 Addition to Imine Derivatives

    3.25.4 Conjugate Addition

    3.25.5 Cyclopropanation

    3.25.6 Miscellaneous Reactions


    3.26 Stoichiometric Auxiliary Ligands for Metals and Main Group Elements: Ligands for Chromium

    3.26.1 Introduction

    3.26.2 Preparation of Planar Chiral Arene Chromium Complexes

    3.26.3 Reactions of Arene Chromium Complexes

    3.26.4 Fisher-Type Chromium Carbene Complexes


    3.27 Stoichiometric Auxiliary Ligands for Metals and Main Group Elements: Ligands for Titanium and Zirconium Complexes

    Volume 4: Synthetic Methods III: Catalytic Methods: C–C Bond Formation

    4.1 Introduction: General Concepts

    4.2 C–C Bond-Forming Reactions via the Heck Reaction

    4.2.1 General Introduction

    4.2.2 Heck Reactions


    4.3 C–C Bond-Forming Reactions via Cross-Coupling

    4.3.1 General Introduction

    4.3.2 Cross-Coupling Reactions,


    4.4 C-C Bond Formation (Metathesis)

    4.4.1 Introduction

    4.4.2 Diastereoselective Metathesis Reactions

    4.4.3 Enantioselective Metathesis Reactions

    4.4.4 Conclusions



    4.5 C-C Bond Formation by Metal-Catalyzed Asymmetric Allylic Alkylation

    4.5.1 Introduction

    4.5.2 Palladium-Catalyzed Asymmetric Allylic Alkylation

    4.5.3 Other Metal-Catalyzed Asymmetric Allylic Alkylations


    4.6 C-C Bond Formation (Metal-Catalyzed Reductive Aldol Coupling)

    4.6.1 Introduction

    4.6.2 Rhodium

    4.6.3 Cobalt

    4.6.4 Iridium

    4.6.5 Ruthenium

    4.6.6 Palladium

    4.6.7 Nickel

    4.6.8 Platinum

    4.6.9 Copper

    4.6.10 Indium

    4.6.11 Conclusion



    4.7 C–C Bond Formation (Transition Metal-Catalyzed Michael)

    4.7.1 Introduction

    4.7.2 Conclusion


    4.8 C-C Bond Formation (Metal-Carbene Catalyzed)

    4.8.1 Introduction

    4.8.2 Cyclopropanation

    4.8.3 C–H Insertion Reactions

    4.8.4 Reactions Involving Ylide Formation

    4.8.5 Aromatic Addition and Substitution Reactions

    4.8.6 Concluding Remarks


    4.9 C-C Bond Formation using Lewis Acids and Silicon Enolates

    4.9.1 Introduction

    4.9.2 Asymmetric Lewis Acid-Catalyzed Mukaiyama Aldol Reactions

    4.9.3 Asymmetric Lewis Acid-Catalyzed Mannich-Type Reactions using Silicon Enolates and Related Compounds

    4.9.4 Asymmetric Lewis Acid-Catalyzed Michael Reactions with Silicon Enolates

    4.9.5 Asymmetric Hetero-Diels–Alder Cycloadditions of Carbonyl Compounds and Imines with Silicon Enolates

    4.9.6 Aza-Diels–Alder Cycloadditions

    4.9.7 Summary


    4.10 Enantioselective Aldol Reactions Catalyzed by Chiral Lewis Bases


    4.10.1 Introduction: Activation of Silyl Enol Ethers by Lewis Bases

    4.10.2 Enantioselective Aldol Reactions of Trichlorosilyl Enol Ethers Catalyzed by Lewis Bases

    4.10.3 Enantioselective Aldol Reactions Promoted by Lewis Base-activated Lewis Acids

    4.10.4 Enantioselective Reductive Aldol Reactions

    4.10.5 Enantioselective Direct Aldol-Type Reactions Via In Situ Generation of Silyl Enol Ethers

    4.10.6 Enantioselective Aldol Reaction of Trimethoxysilyl Enol Ethers Catalyzed by Chiral Phenoxides

    4.10.7 Aldol Reactions of Trimethylsilyl Enol Ethers Catalyzed by Phenoxides

    4.10.8 Conclusion


    4.11 C-C Bond-Forming Reactions via Transmetallation using Silyl Enol Ethers


    4.11.1 General Reaction Mechanism

    4.11.2 Representative Examples


    4.12 Direct C–C Bond Formation (Henry, aza-Henry)


    4.12.1 Introduction

    4.12.2 Asymmetric Metal Catalysis for Henry Reaction and aza-Henry Reaction

    4.12.3 Organocatalytic Henry Reaction and aza-Henry Reaction

    4.12.4 Stereocontrol in Asymmetric Henry Reaction and aza-Henry Reaction

    4.12.5 Outlook


    4.13 Direct C-C Bond Formation (Michael, Aldol, and Mannich)



    4.13.1 Metal-Catalyzed Direct Asymmetric Michael Reaction

    4.13.2 Metal-catalyzed Direct Asymmetric Aldol Reaction

    4.13.3 Metal-catalyzed Direct Asymmetric Mannich-type Reaction

    Table Summary of Transformations


    4.14 Reactions using Thioamide and Allylic Cyanide

    4.14.1 Introduction

    4.14.2 C-C Bond-Forming Reactions Using Thioamides

    4.14.3 Direct Catalytic Asymmetric Mannich-Type Reaction of Thioamides

    4.14.4 Direct Catalytic Asymmetric Aldol Reaction of Thioamides

    4.14.5 Direct Catalytic Asymmetric Conjugate Addition of Terminal Alkynes to α,β-Unsaturated Thioamides


    4.15 C-C Bond Formation

    4.15.1 Reactions Using Chiral Lewis Acids

    4.15.2 Reaction Using Chiral Metal Catalyst

    4.15.3 Reaction Using Chiral Organocatalysts


    4.16 Enantioselective Cyanation of Carbonyls and Imines


    4.16.1 Introduction

    4.16.2 Background

    4.16.3 Asymmetric Addition of Cyanide to Aldehydes and Ketones

    4.16.4 Asymmetric Addition of Cyanide to Imines and Related Species


    4.17 Asymmetric 1,2-Addition of Organometallics to Carbonyl and Imine Groups

    4.17.1 Introduction

    4.17.2 Zinc

    4.17.3 Magnesium

    4.17.4 Lithium

    4.17.5 Other Metals

    4.17.6 Outlook


    4.18 C-C Bond Formation (1,2-Alkenylation)

    4.18.1 Introduction

    4.18.2 Catalytic Asymmetric Alkenylation using Alkenylzinc Reagents

    4.18.3 Catalytic Asymmetric Alkenylation using Alkenylsilicon and Alkenylboron Reagents

    4.18.4 Catalytic Asymmetric Nozaki–Hiyama–Kishi Reactions

    4.18.5 Catalytic Asymmetric Morita–Baylis–Hillman Reactions and Their Aza Variants

    4.18.6 Catalytic Asymmetric Reductive and Alkylative Coupling Reactions

    4.18.7 Other Conditions


    4.19 To Catalytic Asymmetric 1,2-Alkynylation


    4.19.1 Introduction

    4.19.2 Alkynylation of Aldehydes

    4.19.3 Alkynylation of Ketones

    4.19.4 Alkynylation of Imines

    4.19.5 Concluding Remarks


    4.20 Other C-C Bond Formations including Au

    Volume 5: Synthetic Methods IV – Asymmetric Oxidation Reduction, C–N

    5.1 Asymmetric Baeyer–Villiger Oxidation


    5.1.1 Introduction

    5.1.2 Mechanism of Baeyer–Villiger Oxidation

    5.1.3 Asymmetric Reactions

    5.1.4 Conclusions


    5.2 Oxidation: C-O Bond Formation by C-H Activation


    5.2.1 Introduction

    5.2.2 Enantioselective Benzylic Oxidation

    5.2.3 Asymmetric Desymmetrization by C-H Oxidation

    5.2.4 Enantioselective Allylic C-H Oxidation

    5.2.5 Enantioselective Propargylic Oxidation

    5.2.6 Other Stereoselective Oxidation Systems for Activated C-H Bonds

    5.2.7 Selective Oxidation of Nonactivated C-H Bonds


    5.3 Oxidation: Epoxidation (Allylic Alcohol, Homoallylic Alcohol, Simple C–C, Electron Deficient C–C)


    5.3.1 General

    5.3.2 Epoxidation of Allylic Alcohols

    5.3.3 Epoxidation of Homoallylic Alcohol

    5.3.4 Epoxidation of Simple Carbon--Carbon Double Bonds

    5.3.5 Epoxidation of Electron-Deficient Carbon–Carbon Double Bonds


    5.4 Oxidation: α-hydroxylation of Carbonyls


    5.4.1 Introduction

    5.4.2 Stoichiometric Enantioselective α-Hydroxylation of Carbonyls and their Equivalents

    5.4.3 Catalytic Enantioselective α-Hydroxylation of Carbonyls and their Equivalents

    5.4.4 Summary and Conclusion


    5.5 Oxidation: C–N Bond Formation by Oxidation: C–H Bond Activation


    5.5.1 Introduction

    5.5.2 Metal–Nitrene-Mediated Enantioselective C–H Amination

    5.5.3 Stereoselective Allylic Amination Actuated by C–H Abstraction

    5.5.4 Catalytic C–H Amination with Azides as Nitrene Precursors


    5.6 Oxidation: C-N Bond Formation by Oxidation (Aziridines)


    5.6.1 Introduction

    5.6.2 Hypervalent Iodine Reagents as Nitrene Sources for Aziridination

    5.6.3 Haloamine and Other Amine Compounds as Nitrene Sources for Aziridination

    5.6.4 Azides as Nitrene Sources for Aziridination

    5.6.5 Conclusions

    Table Summary of Transformations


    5.7 Oxidation: C-N Bond Formation by Oxidation: Dinitrogen Addition to Double Bond (Diamino)

    5.7.1 Introduction

    5.7.2 1,2-Diamination of Alkenes by Stoichiometric Reactions

    5.7.3 1,2-Diamination of Alkenes by Catalytic Reactions

    5.7.4 Diamination of Butadienes by Catalytic Reactions

    5.7.5 Conclusion


    5.8 Asymmetric S–O Bond Formation by Oxidation


    5.8.1 Introduction

    5.8.2 Homogeneous Catalysts for Enantioselective S–O Bond Formation

    5.8.3 Enantioselective Sulfoxidation with Heterogeneous Catalysts

    5.8.4 Contribution of the Kinetic Resolution of Sulfoxide to Enantioselectivity

    5.8.5 Conclusions


    5.9 Oxidation: C-X Bond Formation (X–Halogen, S, Se)


    5.9.1 Introduction

    5.9.2 Enantioselective Electrophilic Fluorination

    5.9.3 Enantioselective Electrophilic Chlorination

    5.9.4 Enantioselective Electrophilic Bromination

    5.9.5 Enantioselective Electrophilic Iodination

    5.9.6 Enantioselective Electrophilic Sulfenylation

    5.9.7 Enantioselective Electrophilic Selenenylation

    5.9.8 Conclusion and Outlook


    5.10 Reduction – Hydrogenation: C–C; Chemoselective


    5.10.1 Introduction

    5.10.2 Homogenous Catalytic Hydrogenation of Olefins

    5.10.3 Conclusion


    5.11 Reduction – Hydrogenation: C–O; Chemoselective


    5.11.1 Introduction

    5.11.2 Background

    5.11.3 Asymmetric Hydrogenation of Functionalized Ketones

    5.11.4 Asymmetric Hydrogenation of Nonfunctionalized Ketones

    5.11.5 Asymmetric Hydrogenation of Ketones with Dynamic Kinetic Resolution


    5.12 Asymmetric Hydrogenation of Prochiral C–N Bonds

    5.12.1 Introduction

    5.12.2 Survey of Imine Substrates in Asymmetric Hydrogenation

    5.12.3 Concluding Remarks


    5.13 Reduction: Hydrosilylation

    5.13.1 Introduction

    5.13.2 Asymmetric Hydrosilylation of Ketones

    5.13.3 Asymmetric Hydrosilylation of Imines and Related C–N Bonds


    5.14 Reduction: Hydroformylation C–H and C–C

    5.14.1 Introduction

    5.14.2 Mechanism

    5.14.3 Asymmetric Hydroformylation of Vinylarenes

    5.14.4 Asymmetric Hydroformylation of Vinyl Acetate and Allyl Cyanide

    5.14.5 Asymmetric Hydroformylation of Other Substrates

    5.14.6 Synthetic Application to Larger Molecules

    5.14.7 Catalysts that can be Recovered


    5.15 Reduction: Hydrocyanation of C–C

    5.15.1 Introduction

    5.15.2 Scope of Asymmetric C–C-double Bond Hydrocyanation

    5.15.3 Mechanistic Considerations

    5.15.4 Practical Aspects on Laboratory Scale


    5.16 Reduction: Enantioselective Hydrovinylation of Alkenes

    5.16.1 Introduction

    5.16.2 Hydrovinylation Reactions

    5.16.3 Enantioselective Hydrovinylation Reactions

    5.16.4 Hemilabile Ligands, Highly Dissociated Counter Ions, and Design of New Ligands for Asymmetric Hydrovinylation of Vinylarenes

    5.16.5 Generation of All-Carbon Quaternary Centers

    5.16.6 Hydrovinylation of 1,3-Dienes

    5.16.7 Asymmetric Hydrovinylation of Norbornene and Other Strained Alkenes

    5.16.8 Applications of Asymmetric Hydrovinylation Reactions

    5.16.9 Conclusions and Future Prospects


    5.17 Reduction: Pinacol Coupling


    5.17.1 Introduction

    5.17.2 Pinacol Coupling

    5.17.3 Imino-Pinacol Coupling

    5.17.4 Carbonyl–Imine Reductive Coupling


    5.18 Addition Reaction: Kinetic Resolution



    5.18.1 Introduction

    5.18.2 Background

    5.18.3 Hydrolytic Kinetic Resolution (HKR) of Epoxides

    5.18.4 Kinetic Resolution of Alcohols by Acylation

    5.18.5 Kinetic Resolution of Alcohols by Silylation

    5.18.6 Alcoholysis of Chiral Cyclic Acid Unhydrides and Related Compounds

    5.18.7 Alcoholysis of Azlactones

    5.18.8 Alcoholysis of Vinyl Ethers

    5.18.9 Conclusion


    5.19 Addition Reaction: 1,4 Addition Heteroatom

    5.19.1 Introduction

    5.19.2 Asymmetric Aza-Michael Reactions

    5.19.3 Asymmetric Thio-Michael Reactions

    5.19.4 Asymmetric Conjugate Phosphination and Silylation

    5.19.5 Conclusion


    5.20 Addition Reaction: Cycloaddition Involving Oxidation (N–N, N–O; No C–C Bond Formed)

    5.20.1 Introduction

    5.20.2 [4+2] Cycloaddition of Nitroso Compounds and Acyl Diazenes

    5.20.3 [2+2] Cycloaddition of Nitroso Compounds and Diazenes

    5.20.4 Stepwise Formation of Pyrazolidine Using a Azodicarboxylate


    5.21 Desymmetrization of meso Diols



    5.21.1 Introduction

    5.21.2 Acylation and Related Reactions of meso Diols and Hydrolysis of meso-Diesters

    5.21.3 Oxidations of meso Diols

    5.21.4 Desymmetrization of Diol Derivatives


    5.22 Desymmetrization of meso Epoxide


    5.22.1 Introduction

    5.22.2 Background

    5.22.3 Desymmetrization via Ring-Opening with Nitrogen Based Nucleophile

    5.22.4 Desymmetrization via Ring-Opening with Oxygen Based Nucleophiles

    5.22.5 Desymmetrization via Ring-Opening with Thiols and Selenols

    5.22.6 Desymmetrization via Ring-Opening with Halogens

    5.22.7 Desymmetrization via Ring-Opening with Carbon Nucleophiles

    5.22.8 Desymmetrization via Deprotonation and Rearrangement

    5.22.9 Desymmetrization of meso Aziridines


    5.23 Desymmetrization of meso Anhydride

    Volume 6: Synthetic Methods V – Organocatalysis

    6.1 C–C Bond Formation: Alkylation

    6.1.1 Introduction

    6.1.2 Under Biphasic Phase-Transfer Conditions

    6.1.3 Enamine Catalysis

    6.1.4 Utilization of Radical Intermediate

    6.1.5 Electrophilic Trifluoromethylation

    6.1.6 Other Alkylation


    6.2 C-C Bond Formation: Michael Reaction

    6.2.1 Introduction

    6.2.2 α,β-Unsaturated Aldehydes and Ketones as Michael Acceptors

    6.2.3 Nitroolefins as Michael Acceptors

    6.2.4 α,β-Unsaturated Acid Derivatives as Michael Acceptors

    6.2.5 Other Michael Acceptors

    6.2.6 Conclusion and Outlook


    6.3 C-C Bond Formation: Mannich Reaction

    6.3.1 Introduction

    6.3.2 Proline and Proline Derivatives Catalyzed Reactions

    6.3.3 Brønsted Base Catalyzed Reactions

    6.3.4 Brønsted Acid Catalyzed Reactions

    6.3.5 Conclusion


    6.4 C–C Bond Formation: Aldol Reaction with Proline Derivatives


    6.4.1 Introduction

    6.4.2 Proline Organocatalysts

    6.4.3 Supported Organocatalysts

    6.4.4 Mechanistic Studies

    6.4.5 Application to Natural Product Syntheses

    6.4.6 Conclusions


    6.5 C–C Bond Formation: Aldol Reaction with Non-Proline Derivatives


    6.5.1 Introduction

    6.5.2 Enamine Mechanism

    6.5.3 Nonenamine Mechanism

    6.5.4 Conclusions


    6.6 Henry and aza-Henry Reactions

    6.6.1 Introduction

    6.6.2 Organocatalytic Henry (Nitroaldol) Reaction

    6.6.3 Organocatalytic aza-Henry (Nitro-Mannich-type) Reaction


    6.7 C–C Bond Formation: Cyanation

    6.7.1 Cyanohydrin Synthesis

    6.7.2 Strecker Reaction


    6.8 Allylations of C–O and C–N Double Bonds and Related Reactions


    6.8.1 Introduction

    6.8.2 Allylation and Related Reactions Catalyzed by Chiral Lewis Bases

    6.8.3 Allylation with Allylboronates Catalyzed by Chiral Diols or Chiral Brønsted Acids

    6.8.4 Allylation with Allylmetals Catalyzed by Chiral Organic Molecules

    6.8.5 Aminoallylation of Aldehydes via a 2-Aza-Cope Rearrangement

    6.8.6 Outlook and Perspective


    6.9 C-C Bond Formation: (aza) Morita–Baylis–Hillman Reaction


    6.9.1 Introduction

    6.9.2 Mechanism

    6.9.3 Chiral Lewis Base Catalysts

    6.9.4 Chiral Acid Catalysts

    6.9.5 Chiral Acid–Base Catalysts

    6.9.6 Enantioselective Domino Process Based on MBH Reactions

    6.9.7 Conclusion


    6.10 C–C Bond Formation: Diels–Alder Reaction


    6.10.1 Catalysis Using a Chiral Secondary Ammonium Salt

    6.10.2 Catalysis Using a Chiral Primary Ammonium Salt

    6.10.3 Catalysis Using Hydrogen Bonding

    6.10.4 Hetero-Diels–Alder Reaction Using Organocatalysts


    6.11 Cyclopropanation Reactions

    6.11.1 Introduction to Chiral Cyclopropanes

    6.11.2 Background to Cyclopropane Synthesis

    6.11.3 Asymmetric Cyclopropanation Reactions through Organocatalytic Iminium Ion Activation of α,β-Unsaturated Aldehydes and Ketones

    6.11.4 Asymmetric Cyclopropanation Reactions through Organocatalytic Hydrogen Bond Activation of Electron-deficient Olefin Derivatives

    6.11.5 Asymmetric Cyclopropanation Reactions through Organocatalytic Activation of Ylides

    6.11.6 Organocatalytic Asymmetric Cyclopropanation through Chiral Phase-transfer Catalysis

    6.11.7 Conclusion and Outlook

    Table Summary of Transformations


    6.12 Benzoin and Stetter Reactions


    6.12.1 Introduction

    6.12.2 Asymmetric Benzoin Reaction

    6.12.3 Asymmetric Stetter Reaction

    6.12.4 Conclusion


    6.13 C-C Bond Formation: Cascade or Domino Reaction

    6.13.1 Introduction

    6.13.2 Double Cascade Reactions

    6.13.3 Triple Cascade Reactions

    6.13.4 Quadruple Cascade Reactions

    6.13.5 Conclusions


    6.14 C–N Bond Formation: α-Amination and α-Hydrazination of Carbonyl Compounds with DEAD and Related Compounds


    6.14.1 Introduction

    6.14.2 Background

    6.14.3 α-Amination of Carbonyl Compounds


    6.15 C–N Bond Formation: Aziridine Formation

    6.15.1 Introduction

    6.15.2 Asymmetric Synthesis of Aziridines from Chiral Sulfonylimines

    6.15.3 Iodine Catalyst

    6.15.4 Aza-Darzens Reaction

    6.15.5 Aziridination of Unsaturated Carbonyl Compounds

    6.15.6 Aziridination by Organocatalytic Reduction of α-Haloimines

    6.15.7 By Quaternary Salts of Cinchona Alkaloids

    6.15.8 Conclusions


    6.16 C–O Bond Formation: α-Oxygenation

    6.16.1 α-Oxygenation of Carbonyl Compounds Introduction

    6.16.2 α-Oxygenation from 1,2-Diol Introduction

    6.16.3 α-Oxygenation via Oxidative Dearomatization of Phenols Introduction

    6.16.4 α-Oxygenation via Oxidative Cyclyzation Introduction


    6.17 C–O Bond Formation: Acylation of meso Diols


    6.17.1 Introduction

    6.17.2 Background

    6.17.3 Phosphine Catalysts

    6.17.4 DMAP-Related Catalysts

    6.17.5 Imidazole Catalysts

    6.17.6 NHC Catalysts

    6.17.7 Tertiary Amine Catalysts

    6.17.8 Amidine Catalysts

    6.17.9 Enzymatic Asymmetric Acylation

    Table Summary of Transformations


    6.18 C-O Bond Formation: Desymmetrization of Acid Anhydride


    6.18.1 Introduction

    6.18.2 Enantioselective Desymmetrization of Acid Anhydride Using Cinchona Alkaloids

    6.18.3 Enantioselective Desymmetrization of Acid Anhydride Using Nonalkaloid Catalysts

    6.18.4 Mechanistic Studies

    6.18.5 Conclusions


    6.19 C–O Bond Formation: Epoxide Formation

    6.19.1 Introduction

    6.19.2 Catalytic Cycle via Sulfide Alkylation and Deprotonation

    6.19.3 Ylide Formation from a Carbene Source

    6.19.4 Diastereoselectivity

    6.19.5 Enantioselectivity

    6.19.6 Application in Synthesis

    6.19.7 Other Ylide-Catalyzed Epoxidation

    6.19.8 Summary


    6.20 C–X Bond Formation: α-Halogenation of Carbonyl Compounds


    6.20.1 Introduction

    6.20.2 Asymmetric Halogenation via Enamine Catalysis

    6.20.3 Asymmetric Halogenation by Chiral tert-Amine Catalysts

    6.20.4 Asymmetric Halogenation by Chiral Phase-transfer Catalysts

    6.20.5 Asymmetric Halogenation by Chiral N-oxide

    6.20.6 Conclusions


    6.21 C–X Bond Formation: Organocatalytic Enantioselective Halogenation of meso Epoxides


    6.21.1 Introduction: Classical Halogenation of meso Epoxides

    6.21.2 Chlorination of meso Epoxides by Silicon Tetrachloride and Chiral Lewis Bases as Organocatalysts

    6.21.3 Mechanistic Scope of the Chlorination Reaction by Silicon Tetrachloride and Chiral Lewis Bases

    6.21.4 Fluorination of the meso Epoxides by Chiral Amines as Co-Organocatalysts

    6.21.5 Conclusion


    6.22 C–X Bond Formation: Organocatalytic α-Sulfenylation and α-Selenenylation

    6.22.1 Introduction

    6.22.2 Organocatalytic α-Sulfenylation

    6.22.3 Organocatalytic α-Selenenylation

    6.22.4 Conclusions


    6.23 Oxidation: Organocatalyzed Asymmetric Epoxidation of Alkenes

    6.23.1 Introduction

    6.23.2 Chiral Ketone-Catalyzed Epoxidation

    6.23.3 Iminium Salt-Catalyzed Epoxidation

    6.23.4 Other Asymmetric Epoxidation Reagents

    6.23.5 Conclusion


    6.24 Oxidation: Epoxidation of Enones


    6.24.1 General Introduction

    6.24.2 Epoxidation of Enones

    6.24.3 Epoxidation of Enals

    6.24.4 Epoxidation of Enoates and Enamides

    6.24.5 Epoxidation of Miscellaneous Electron-Deficient Alkenes: Vinyl Sulfones

    6.24.6 Summary and Conclusions

    Table Summary of Transformations


    6.25 Reduction: Asymmetric Transfer Hydrogenation with Hantzsch Esters

    Volume 7: Synthetic Methods VI – Enzymatic and Semi-Enzymatic

    7.1 Introduction and General Concepts


    7.1.1 Biocatalysis in Organic Synthesis

    7.1.2 The Current Biocatalysis Toolbox

    7.1.3 New Synthetic Transformations using Biocatalysts

    7.1.4 Future Trends


    7.2 Screening Methods for Enzymes

    7.2.1 Introduction

    7.2.2 Screening Enzymes in Living Cells

    7.2.3 Screening in Microtiter Plates

    7.2.4 Screening with Multiple Substrates

    7.2.5 Screening with Analytical Instrumentation

    7.2.6 Conclusion



    7.3 Directed Evolution and (Semi-) Rational Design Strategies for the Creation of Synthetically useful, Stereoselective Biocatalysts


    7.3.1 Introduction

    7.3.2 Library Design and Construction

    7.3.3 Screening and Selection


    7.4 Cofactor Recycling for Enzyme Catalyzed Processes


    7.4.1 Introduction

    7.4.2 Nicotinamide Cofactor Regeneration

    7.4.3 Flavin Regeneration

    7.4.4 PLP Regeneration

    7.4.5 ATP/NTP Regeneration

    7.4.6 Sugar Nucleotide Regeneration

    7.4.7 PAPS Regeneration

    7.4.8 Acetyl-Coenzyme a Regeneration

    7.4.9 Conclusions


    7.5 Reaction Engineering of Biotransformations


    7.5.1 Introduction

    7.5.2 Important Process Properties of Enzymes

    7.5.3 Enzyme Stabilization

    7.5.4 Typical Reactors

    7.5.5 Current and Future Developments in Enzyme Technology

    7.5.6 Summary


    7.6 Hydrolysis and Reverse Hydrolysis: Hydrolysis and Formation of Amides


    7.6.1 Introduction

    7.6.2 Background

    7.6.3 Production of Nonchiral Amides and Amines

    7.6.4 Asymmetric Synthesis of Optically Active Amides


    7.7 Hydrolysis and Reverse Hydrolysis: Selective Nitrile Hydrolysis using Nitrilase and its Related Enzymes


    7.7.1 Background

    7.7.2 Distribution of Nitrilases

    7.7.3 Nitrilase Mechanism, Structure, and Properties

    7.7.4 Strategies for Screening Nitrilase-Producing Microorganisms

    7.7.5 Strategies to Access Biodiversity for Synthetic Applications

    7.7.6 Approaches to Improve the Catalytic Potential of Nitrilases

    7.7.7 Opportunities and Future Outlook


    7.8 Hydrolysis and Reverse Hydrolysis: Halohydrin Dehalogenases

    7.8.1 Introduction

    7.8.2 Biochemical Properties of Halohydrin Dehalogenases

    7.8.3 Biocatalytic and Environmental Applications

    7.8.4 Engineering Studies

    7.8.5 Conclusions and Outlook


    7.9 Hydrolysis and Reverse Hydrolysis: Dynamic Kinetic Resolution

    7.9.1 Introduction

    7.9.2 Fundamentals for Dynamic Kinetic Resolution

    7.9.3 Dynamic Kinetic Resolution of Alcohols

    7.9.4 Dynamic Kinetic Resolution of Amines and Amino Acids

    7.9.5 Synthetic Applications of Metalloenzymatic DKR

    7.9.6 Summary


    7.10 Reduction: Asymmetric Biocatalytic Reduction of Ketones

    7.10.1 Introduction

    7.10.2 Types of ADHs

    7.10.3 Sources of ADHs Useful for Biocatalysis

    7.10.4 Selected ADHs Useful for Preparative Applications

    7.10.5 Biocatalytic Ketone Reduction Process Concepts

    7.10.6 Enantioselective Biocatalytic Ketone Reductions with a Focus on the Synthesis of Alcohols Used as Drug Intermediates

    7.10.7 Integration of Biocatalytic Ketone Reduction in Multistep One-Pot Processes

    7.10.8 Summary and Outlook


    7.11 Reduction: Enantioselective Bioreduction of C–C Double Bonds


    7.11.1 Introduction

    7.11.2 Microorganisms as Biocatalysts

    7.11.3 Isolated Enzymes as Biocatalysts

    7.11.4 Biocatalytic Reduction of Asymmetric Alkenes

    7.11.5 Conclusions and Outlook


    7.12 Oxidation: Oxidases


    7.12.1 Introduction

    7.12.2 Oxidation of C-N Bonds

    7.12.3 Oxidation of C-O Bonds

    7.12.4 Summary and Outlook


    7.13 Oxidation: Stereoselective Oxidations with Cytochrome P450 Monooxygenases


    7.13.1 Introduction to Cytochrome P450 Enzymes

    7.13.2 Stereoselective Oxidations Catalyzed by Mammalian P450 Enzymes

    7.13.3 Stereoselective Hydroxylations and Epoxidations

    7.13.4 Conclusions and Outlook



    7.14 Oxidation: Asymmetric Enzymatic Sulfoxidation


    7.14.1 Introduction

    7.14.2 Occurrence and Uses of Optically Active Sulfoxides

    7.14.3 Early Studies on Biological Oxidation of Sulfur

    7.14.4 Asymmetric Sulfoxidation by Microbes

    7.14.5 Asymmetric Sulfoxidation by Isolated Enzymes

    7.14.6 Miscellaneous Biological and Biomimetic Asymmetric Oxidations of Sulfur

    7.14.7 Asymmetric Reductions of Racemic Sulfoxides

    7.14.8 Conclusions


    7.15 Oxidation: Haloperoxidases

    7.15.1 Introduction

    7.15.2 Halogenating Enzymes

    7.15.3 Enzyme Mechanisms

    7.15.4 Natural Halogenated Compounds

    7.15.5 Applications in Biotransformations


    7.16 C–X Bond Formation: Hydroxynitrile Lyases: From Nature to Application

    7.16.1 Introduction

    7.16.2 Biology of Hydroxynitrile Lyases

    7.16.3 Stereoselective Transformations

    7.16.4 Multistep and Cascade Reactions

    7.16.5 Process engineering

    7.16.6 Conclusions



    7.17 C–X Bond Formation: C–C Bond Formation using TDP-Dependent Enzymes


    7.17.1 TDP Enzymes Overview

    7.17.2 Transferases

    7.17.3 Lyases

    7.17.4 Outlook

    7.17.5 Conclusions


    7.18 C–X Bond Formation: Transaminases as Chiral Catalysts: Mechanism, Engineering, and Applications

    7.18.1 PLP-Dependent Enzymes

    7.18.2 Transaminase Nomenclature

    7.18.3 Reaction Mechanism

    7.18.4 Asymmetric Synthesis

    7.18.5 Kinetic Resolution

    7.18.6 Production of Amino Acids

    7.18.7 Production of Chiral Amines

    7.18.8 Enzyme Engineering

    7.18.9 Yield Improvement

    7.18.10 Other Solutions

    7.18.11 Conclusion



    7.19 C-X Bond Formation: Enzymatic Enantioselective Decarboxylative Protonation and C-C Bond Formation


    7.19.1 Introduction

    7.19.2 L-Aspartate-β-Decarboxylase

    7.19.3 Acetolactate Decarboxylase

    7.19.4 Malonic Semialdehyde Decarboxylase from Rhodococcus sp. KU1314

    7.19.5 The Arylmalonate Decarboxylases

    7.19.6 Serine Hydroxymethyltransferase (SHMT)

    7.19.7 Pyruvate, Phenylpyruvate, and Benzoylformate Decarboxylase

    7.19.8 Conclusion

    Summary of Transformations


    7.20 Multi-Enzyme Reactions


    7.20.1 Introduction

    7.20.2 Synthesis of Enantiomerically Pure Amino Acids

    7.20.3 Synthesis of Enantiomerically Pure Amines

    7.20.4 Preparation of Chiral Alcohols

    7.20.5 Stereoselective Formation of C–C Bonds

    7.20.6 From Multi-Enzyme Processes to Artificial Biosynthetic Pathways

    7.20.7 Multifunctional Enzymes



    7.21 Enzymatic Carbohydrate Synthesis

    7.21.1 Introduction

    7.21.2 Synthesis of Monosaccharides and Derivatives

    7.21.3 Formation of the Glycosidic Bond

    7.21.4 Enzymatic Modification of Oligo- and Polysaccharides

    7.21.5 Summary and Outlook


    7.22 Enzyme Catalytic Promiscuity: Expanding the Catalytic Action of Enzymes to New Reactions


    7.22.1 Introduction

    7.22.2 Discovery and Application of Existing Catalytically Promiscuous Enzymes

    7.22.3 New Reaction Design

    7.22.4 Future Prospects



    7.23 New Emerging Reactions


    7.23.1 Introduction

    7.23.2 C-X Bond Formation

    7.23.3 Asymmetric Hydrogenation

    7.23.4 C–C Cleavage

    7.23.5 N- and O-Demethylations

    7.23.6 Chiral Amines

    7.23.7 Hydroxylations

    7.23.8 Halogenation

    7.23.9 Peptide Synthesis

    7.23.10 Sugar Biochemistry

    7.23.11 Biocatalytic and Chemical Multicomponent Reactions

    7.23.12 Wish List

    7.23.13 Conclusion


    7.24 Enantioselective Hybrid Catalysts

    Volume 8: Separations and Analysis

    8.1 Perspective and Concepts: Chirality in Nineteenth Century Science

    8.1.1 Chirality Pre-1848

    8.1.2 Louis Pasteur

    8.1.3 Lord Kelvin

    8.1.4 Chirality Post-1848


    8.2 Perspective and Concepts: Biomolecular Significance of Homochirality: The Origin of the Homochiral Signature of Life

    8.2.1 Introduction

    8.2.2 Is Chirality an Essential Feature of Life?

    8.2.3 Is Homochirality an Essential Feature of Life?

    8.2.4 Diastereomeric Interactions

    8.2.5 Is Macroscopic Biological Handedness Fixed by Biomolecular Handedness?

    8.2.6 Origin of Biomolecular Chirality: Biotic or Abiotic?

    8.2.7 Mechanisms for Amplification of Enantiomeric Bias

    8.2.8 Is Prebiotic Homochirality of the Monomers Really a Precondition for Life?

    8.2.9 Crucial Issues in the Origin of Life

    8.2.10 At What Stage in the Origin of Life did Homochirality Arise?

    8.2.11 Is a Chiral Influence Really Needed?

    8.2.12 Possible Chiral Influences

    8.2.13 Circularly Polarized Light

    8.2.14 Parity-Violation by the Weak Force

    8.2.15 Calculation of the PVED

    8.2.16 Is the PVED too Small to be Amplified?

    8.2.17 Proposals to Measure the PVED

    8.2.18 Exochirality


    8.3 Perspective and Concepts: Overview of Techniques for Assigning Stereochemistry


    8.3.1 Practical Considerations

    8.3.2 Deciding on the Best Strategy

    8.3.3 Case Studies

    8.3.4 Summary


    8.4 Physical Separations: Solid-State Forms and Habits of Chiral Substances


    8.4.1 Introduction

    8.4.2 Background

    8.4.3 Practical Examples

    8.4.4 Morphology Prediction

    8.4.5 Habit Prediction


    8.5 Physical Separations: Chiral Discrimination of Enantiomers by Diastereomeric Complexation with Chiral Host Compounds

    8.5.1 Introduction

    8.5.2 General Methods for Resolution Experiments

    8.5.3 Enantiomer Resolution by Inclusion Complexation with Homochiral Host Compounds

    8.5.4 Conclusions


    8.6 Physical Separations: Behavior of Structurally Similar Molecules in the Resolution Processes

    8.6.1 Introduction

    8.6.2 Self-disproportionation

    8.6.3 Conclusions



    8.7 Chromatographic Separations and Analysis: Chromatographic Separations and Analysis of Enantiomers


    8.7.1 Overview of the Historical Development of Chromatography

    8.7.2 Chiral Separations: Chromatographic

    8.7.3 Derivatization in Chiral Chromatography

    8.7.4 Chiral Stationary Phases (CSPs) for High-Performance Liquid Chromatography (HPLC), Gas Chromatography (GC), and Supercritical Fluid Chromatography (SFC)


    8.8 Chromatographic Separations and Analysis: Chiral Ion and Ligand Exchange Stationary Phases


    8.8.1 Introduction

    8.8.2 Chiral Stationary Phases in LE Chromatography

    8.8.3 Chiral Stationary Phases in IE Chromatography


    8.9 Chromatographic Separations and Analysis: Protein and Glycoprotein Stationary Phases


    8.9.1 Introduction

    8.9.2 Preparation of Protein and Glycoprotein Stationary Phases

    8.9.3 Type of Protein and Glycoprotein Stationary Phases

    8.9.4 Chiral Recognition Mechanism on Protein and Glycoprotein Stationary Phases

    8.9.5 Conclusions


    8.10 Chromatographic Separations and Analysis: Cyclodextrin Mediated HPLC, GC and CE Enantiomeric Separations

    8.10.1 Introduction

    8.10.2 CD and CD Derivatives for Enantioselective HPLC

    8.10.3 Cyclodextrin-Based Chiral Stationary Phases for Gas Chromatography

    8.10.4 Cyclodextrins as Chiral Selectors in Capillary Electrophoresis


    8.11 Chromatographic Separations and Analysis: Cellulose and Polysaccharide Derivatives as Stationary Phases

    8.11.1 Introduction

    8.11.2 Characteristics of Polysaccharide-Based Chiral Stationary Phases and Packing Materials

    8.11.3 Chromatographic Separations Using Polysaccharide-Based Chiral Stationary Phases

    8.11.4 Preparative Separation

    8.11.5 Structure of Phenylcarbamate Derivatives of Cellulose and Amylose

    8.11.6 Chiral Recognition Mechanism

    8.11.7 Conclusions


    8.12 Chromatographic Separations and Analysis: Macrocyclic Glycopeptide Chiral Stationary Phases


    8.12.1 Introduction

    8.12.2 The Macrocyclic Glycopeptide Family

    8.12.3 Macrocyclic Glycopeptide Chiral Stationary Phases

    8.12.4 Chromatographic Enantioseparations on Macrocyclic Glycopeptide Selectors

    8.12.5 Conclusions



    8.13 Chromatographic Separations and Analysis: Chiral Crown Ether-Based Chiral Stationary Phases


    8.13.1 Introduction

    8.13.2 CSPs Based on (3,3′-Diphenyl-1,1′-Binaphthyl)-20-Crown-6 Ethers

    8.13.3 CSPs Based on (+)-(18-Crown-6)-2,3,11,12-Tetracarboxylic Acid

    8.13.4 CSPs Based on Phenolic Chiral Pseudo-18-Crown-6 Ethers

    8.13.5 Conclusion



    8.14 Chromatographic Separations and Analysis: New Stationary Phases

    8.14.1 Introduction

    8.14.2 Cyclodextrin

    8.14.3 Chemically Bonded CD-CSPs Based on Urethane Linkage

    8.14.4 Chemically Bonded CD-CSPs Based on Urea Linkage

    8.14.5 Chemically Bonded CD-CSPs Based on Amino Linkages

    8.14.6 Chemically Bonded CD-CSPs Based on Ether Linkages

    8.14.7 Chemically Bonded CD-CSPs Based on Triazolyl Linkages

    8.14.8 Conclusion


    8.15 Chromatographic Separations and Analysis: Diastereomeric Derivatization for Chromatography

    8.15.1 Introduction. The Role of Enantiomeric Separations Based on Diastereomeric Derivatization in the Era of Direct Methods

    8.15.2 Conditions of the Applicability of Diastereomeric Derivatization in Enantiomeric Analysis

    8.15.3 Separation and Determination of Enantiomers Based on Diastereomeric Derivatization

    8.15.4 Achiral Derivatization Before the Separation on Chiral Stationary Phases


    8.16 Chromatographic Separations and Analysis: Chiral Separations by Thin Layer Chromatography


    8.16.1 Introduction

    8.16.2 Chiral Stationary Phases

    8.16.3 Stationary Phases Impregnated with a Chiral Selector

    8.16.4 Chiral Additives to Mobile Phase

    8.16.5 Indirect Separation of Enantiomers


    8.17 Chromatographic Separations and Analysis: Chiral Gas Chromatography


    8.17.1 Introduction and History

    8.17.2 Stationary Phases

    8.17.3 Techniques

    8.17.4 Applications

    8.17.5 Conclusion



    8.18 Chromatographic Separations and Analysis: Supercritical Fluid Chromatography for Chiral Analysis and Semi-Preparative Purification

    8.18.1 Introduction

    8.18.2 Chiral Stationary Phases (CSP)

    8.18.3 Effect of Physical Parameters on Retention, Resolution, and Efficiency

    8.18.4 Chiral Analytical SFC

    8.18.5 Validating a Method

    8.18.6 Analytical-Scale Instrumentation

    8.18.7 Introduction to Semi-Preparative SFC

    8.18.8 Issues Against Recycling-Phase Behavior

    8.18.9 CO2 Supply Issues-Issues Against not Recycling

    8.18.10 GDS

    8.18.11 The Chromatographic Hardware

    8.18.12 Summary


    8.19 Chromatographic Separations and Analysis: Chiral Detectors for Chromatography


    8.19.1 Introduction

    8.19.2 OR Detectors

    8.19.3 CD Detectors

    8.19.4 OR versus CD

    8.19.5 Application of Chiral Detectors

    8.19.6 Limitations

    8.19.7 Perspectives


    8.20 Spectroscopic Analysis: Polarized Light and Optics

    8.20.1 Linearly, Elliptically, and Circularly Polarized Light


    8.21 Spectroscopic Analysis: Polarimetry and Optical Rotatory Dispersion

    8.21.1 Introduction

    8.21.2 Historical Perspective

    8.21.3 Linearly and Circularly Polarized Light

    8.21.4 Molecular Aspects of Optical Rotations

    8.21.5 Instrumental Design

    8.21.6 Instrumental Operation

    8.21.7 Applications and Examples


    8.22 Spectroscopic Analysis: Electronic Circular Dichroism

    8.22.1 Historical Perspective

    8.22.2 Circularly and Elliptically Polarized Light

    8.22.3 Differential Absorption and Light Intensities

    8.22.4 Molecular Aspects of CD

    8.22.5 Instrumental Design

    8.22.6 Single Beam Design

    8.22.7 Dual Beam Design

    8.22.8 Instrumental Operation

    8.22.9 Applications and Examples

    8.22.10 Conformational Analysis

    8.22.11 Complex Mixtures and Hyphenated CD


    8.23 Spectroscopic Analysis: Synchrotron Radiation Circular Dichroism

    8.23.1 Introduction

    8.23.2 Results and Discussion

    8.23.3 Summary



    8.24 Spectroscopic Analysis: Exciton Circular Dichroism for Chiral Analysis


    8.24.1 Introduction and Outline of the CD Exciton Chirality Method

    8.24.2 CD and UV Spectra and their Rotational and Dipole Strengths

    8.24.3 Principles of the CD Exciton Chirality Method

    8.24.4 Consistency between X-ray Bijvoet and CD Exciton Chirality Methods

    8.24.5 Suitable Chromophores for the CD Exciton Chirality Method

    8.24.6 Application of the CD Exciton Chirality Method to Chiral Compounds

    8.24.7 Conclusion



    8.25 Spectroscopic Analysis: Vibrational Circular Dichroism


    8.25.1 Introduction

    8.25.2 Definitions

    8.25.3 VCD Instrumentation

    8.25.4 VCD Theory

    8.25.5 VCD Calculations

    8.25.6 Comparison of Measured and Calculated Spectra

    8.25.7 Applications of VCD

    8.25.8 Conclusions


    8.26 Spectroscopic Analysis: Raman Optical Activity

    8.26.1 Introduction

    8.26.2 Instrumentation

    8.26.3 ROA of Small Molecules

    8.26.4 Macromolecules and Biological Molecules

    8.26.5 Other Molecules

    8.26.6 Other Applications

    8.26.7 Calculation of ROA Spectra

    8.26.8 Outlook


    8.27 Spectroscopic Analysis: Ab initio Calculation of Chiroptical Spectra


    8.27.1 Introduction: Chiral Techniques and Interpretations of the Spectra

    8.27.2 Overview of Ab Initio and DFT Methods

    8.27.3 Optical Rotatory Dispersion

    8.27.4 Electronic Circular Dichroism

    8.27.5 Magnetic Circular Dichroism as a Chiral Method for Achiral Molecules

    8.27.6 Vibrational Circular Dichroism

    8.27.7 Raman Optical Activity

    8.27.8 Common Aspects of the Computational Approaches

    8.27.9 Conclusions


    8.28 Spectroscopic Analysis: NMR and Shift Reagents


    8.28.1 Introduction

    8.28.2 Chiral Solvating Agents

    8.28.3 Metal Complexes

    8.28.4 Liquid Crystals

    8.28.5 Chiral Derivatizing Agents

    8.28.6 Database Methods for Compounds with Multiple Stereocenters


    8.29 Spectroscopic Analysis: Diastereomeric Derivatization for Spectroscopy

    8.29.1 Introduction

    8.29.2 Amines

    8.29.3 Alcohols

    8.29.4 Diols and Polyols

    8.29.5 Amino Alcohols

    8.29.6 Carboxylic Acids

    8.29.7 Amino Acids

    8.29.8 Aldehydes and Ketones

    8.29.9 Natural Products

    8.29.10 Conclusions


    8.30 Spectroscopic Analysis: Chiroptical Sensors


    8.30.1 Introduction

    8.30.2 Structure and Enantiopurity Determinations for Chiral Analytes

    8.30.3 Chiroptical Sensors for Achiral Analytes

    8.30.4 Conclusion



    8.31 Physical and Spectrometric Analysis: An Overview of Chiral Physical Analysis

    8.31.1 Introduction

    8.31.2 Anomalous Scattering in Single-Crystal X-ray Diffraction

    8.31.3 Powder X-ray Diffraction

    8.31.4 Chiral Analysis using Synthetic Receptors

    8.31.5 Chiral Analysis using Electrochemical Phenomena

    8.31.6 Mass Spectrometry and Chiral Reporter Molecule

    8.31.7 Nano-Detection of Chirality

    8.31.8 Chirality Analysis using Fluorescence

    8.31.9 Conclusion


    8.32 Physical and Spectrometric Analysis: Anomalous Scattering Single Crystal X-ray Diffraction

    8.32.1 Introduction

    8.32.2 X-ray Diffraction – Theory Principles

    8.32.3 Anomalous Scattering

    8.32.4 Use of Anomalous Scattering in Absolute-Configuration Determination

    8.32.5 Examples

    8.32.6 Conclusion


    8.33 Physical and Spectrometric Analysis: Absolute Configuration Determination by X-ray Crystallography


    8.33.1 Introduction

    8.33.2 Single-Crystal X-ray Diffraction Techniques Using an Internal Chiral Reference

    8.33.3 Single-Crystal X-ray Diffraction Techniques Exploiting Resonant Scattering

    8.33.4 Powder X-ray Diffraction

    8.33.5 Characterization of Compounds and Crystals

    8.33.6 Technicalities

    8.33.7 Advanced Examples


    8.34 Physical and Spectrometric Analysis: Nano-Detection of Chirality

    Volume 9: Industrial Applications of Asymmetric Synthesis

    Industrial Applications of Asymmetric Synthesis: An Overview

    9.1 Introduction to Industrial Applications of Asymmetric Synthesis


    9.1.1 Introduction

    9.1.2 Scope

    9.1.3 Asymmetric Chemistry in the Pharmaceutical and Fine Chemical Industry

    9.1.4 Trends and Future Directions for Organic Chemistry in the Pharmaceutical and Fine Chemical Industry

    9.1.5 Summary


    9.2 Asymmetry in the Plant: Concepts and Principles for the Scale-Up of Asymmetric Organic Reactions


    9.2.1 Introduction

    9.2.2 Major Development Streams in the Twentieth Century

    9.2.3 In Search of the Best Methodology

    9.2.4 Green Chemistry as a Driver for Asymmetric Methodologies

    9.2.5 Outlook for the Future

    9.2.6 Summing-up and Conclusions


    9.3 Industrial Applications of Asymmetric Synthesis: Asymmetric Synthesis as an Enabler of Green Chemistry

    Industrial Applications of Metal-Catalyzed Asymmetric Synthesis

    9.4 Industrial Applications of Asymmetric Reduction of C–C Bonds


    9.4.1 Introduction

    9.4.2 Citronellol by Asymmetric Hydrogenation of Nerol or Geraniol

    9.4.3 (+)-cis-Methyl Dihydrojasmonate

    9.4.4 Menthol Via Asymmetric Hydrogenation

    9.4.5 Aliskiren

    9.4.6 Laropiprant

    9.4.7 Candoxatril

    9.4.8 Tipranavir

    9.4.9 Rozerem

    9.4.10 Conclusion


    9.5 Industrial Application of the Asymmetric Reduction of C–O and C–N Bonds, including Enamides and Enamines


    9.5.1 Introduction

    9.5.2 Reactions for Asymmetric Reduction

    9.5.3 Hurdles (Requirements) and Solutions in Industrialization

    9.5.4 Examples of Industrial Applications

    9.5.5 Concluding Remarks


    9.6 Industrial Applications of Asymmetric Oxidations

    9.6.1 Introduction

    9.6.2 Epoxidations

    9.6.3 Asymmetric Dihydroxylation

    9.6.4 Aminohydroxylation

    9.6.5 Halohydroxylations

    9.6.6 Heteroatom Oxidations

    9.6.7 Biological Methods

    9.6.8 Summary


    9.7 Industrial Applications of the Jacobsen Hydrolytic Kinetic Resolution Technology


    9.7.1 The Jacobsen Hydrolytic Kinetic Resolution Technology (HKR)

    9.7.2 Industrial Applications of the HKR and Related Technologies

    9.7.3 Future Directions and Conclusions



    9.8 Industrial Applications of Metal–Promoted C-C, C-N, and C-O Asymmetric Bond Formations



    9.8.1 Introduction

    9.8.2 Asymmetric C-C Bond Formation

    9.8.3 Asymmetric C-N Bond Formation

    9.8.4 Asymmetric C-O Bond Formation

    9.8.5 Conclusions



    9.9 Catalyst Recovery and Recycle: Metal Removal Techniques

    Industrial Applications of Organocatalyzed Asymmetric Synthesis

    9.10 Industrial Applications of Organocatalysis

    Industrial Applications of Biocatalysis in Asymmetric Synthesis

    9.11 Industrial Applications of Biocatalysis: An Overview


    9.11.1 Introduction

    9.11.2 Background – Why Biocatalysis?

    9.11.3 Examples from Different Enzyme Classes

    9.11.4 Some Practical Aspects

    9.11.5 Further Assistance and Information

    9.11.6 Conclusions


    9.12 Industrial Applications of Biocatalytic Hydrolysis (Esters, Amides, Epoxides, Nitriles) and Biocatalytic Dynamic Kinetic Resolution


    9.12.1 Introduction

    9.12.2 Enzymatic Asymmetric Hydrolysis

    9.12.3 Enzymatic Asymmetric Hydrolysis of Nitriles and Amides

    9.12.4 Enzymatic Acylation Reactions

    9.12.5 Enzymatic Transesterification/Esterification and Ammonolysis

    9.12.6 Enzymatic Hydrolysis for Preparation of Chiral Epoxides

    9.12.7 Enzymatic Dynamic Kinetic Resolution (DKR) and Deracemization

    9.12.8 Enzymatic Cleavage of Cbz Groups

    9.12.9 Conclusion


    9.13 Industrially Relevant Enzymatic Reductions


    9.13.1 Introduction: Industrial Enzyme Reactions

    9.13.2 Reduction Classes

    9.13.3 Sitagliptin Case Study: Development of a Transaminase Route to Sitagliptin

    9.13.4 Conclusion


    9.14 Industrial Applications of Asymmetric Biocatalytic C-C Bond Forming Reactions

    9.14.1 Introduction

    9.14.2 Thiamin Diphosphate Dependent Lyases

    9.14.3 Aldolases

    9.14.4 Hydroxynitrile Lyases

    9.14.5 Summary and Future Outlook


    9.15 Industrial Applications of Asymmetric Synthesis using Cross-Linked Enzyme Aggregates

    Industrial Applications: Enabling Technologies

    9.16 Crystallization as a Tool in Industrial Applications of Asymmetric Synthesis


    9.16.1 Introduction

    9.16.2 Classical Diastereomeric Resolutions

    9.16.3 Discovery of Resolution Methods

    9.16.4 Phase Diagrams of Racemates

    9.16.5 Phase Diagrams

    9.16.6 Dynamic Thermodynamic Asymmetric Transformations by Crystallization

    9.16.7 Resolutions without Resolving Agents

    9.16.8 Resolution of Racemizable Conglomerates by Attrition-Induced Grinding

    9.16.9 Conclusion



    9.17 Industrial Applications of Chiral Chromatography


    9.17.1 Introduction

    9.17.2 Principles of Preparative Chiral Chromatography

    9.17.3 Chiral Stationary Phases for Large-Scale Separations of Enantiomers by Chromatography

    9.17.4 Preparative and Process-Scale Chromatographic Technologies

    9.17.5 Chromatography Process Design Methodology

    9.17.6 Large-Scale Synthesis Using Chiral Chromatography: Benefits and Industrial Examples

    9.17.7 Conclusion


    9.18 Industrial Applications of Process Analytical Technology to Asymmetric Synthesis

    Industrial Applications of Asymmetric Synthesis: Case Studies

    9.19 Synthesis of the Leading HCV Protease Inhibitors

    9.19.1 Introduction

    9.19.2 Ciluprevir (BILN-2061)

    9.19.3 Boceprevir

    9.19.4 Telaprevir

    9.19.5 BI 201335

    9.19.6 Danoprevir

    9.19.7 Conclusions



    Author Index

Product details

  • No. of pages: 5648
  • Language: English
  • Copyright: © Elsevier Science 2012
  • Published: September 5, 2012
  • Imprint: Elsevier Science
  • eBook ISBN: 9780080951683
  • Hardcover ISBN: 9780080951676

About the Editors in Chief

Hisashi Yamamoto

Hisashi Yamamoto

Chemists' ability to perform syntheses on a routine basis is due in large part to the development of new methods for synthesizing organic molecules which would have been impossible just a few decades ago. The availability of such new methods of synthesis has increased not only the range of structures which can be assembled but also the ease and economy of synthesis. During the past 30 years of his research, Professor Hisashi Yamamoto has had a tremendous impact on the field of organic chemistry through his reports of dramatic new advances in organic synthesis. Yamamoto's publications are numerous (over 450), and almost every one of them has provided an innovative new development or idea. Applications of this original and versatile chemistry have allowed him and other scientists to realize truly efficient syntheses of organic molecules of both theoretical and practical importance.

Hisashi Yamamoto has uncovered novel aspects of Lewis and Brønsted acid catalysts in selective organic synthesis. During his career he has discovered a wide variety of powerful new synthetic reactions, reagents, and catalysts based on acid catalysis chemistry. Through his dedicated efforts, Lewis and Brønsted acid are now recognized as major tools in the synthesis of both simple and complex organic molecules. Among Yamamoto's many superb contributions the following are especially worthy of mention.

His research in the area of organoaluminum chemistry has had a great impact on synthetic organic chemistry. The strong Lewis acidity of organoaluminum compounds appears to account for their strong tendency to form a stable 1:1 complex. Thus, the coordination of molecules invariably causes a change of reactivity, and the coordinated group may be activated or deactivated depending upon the type of reaction. Furthermore, with coordination of organic molecules an auxiliary bond can become coupled to the reagent and promote the desired reaction. In short, the reagents make a combined Lewis acid - Lewis base attack on a substrate with less activation energy, a field opened by Yamamoto's early and highly original studies. His aluminum amide reagents for epoxide rearrangement, biogenetic-type terpene synthesis, and the Beckmann rearrangement-alkylation reaction sequence are notable examples.

He was intrigued by the chemistry of the carbonyl compound-Lewis acid complex and introduced the unusually bulky organoaluminum reagents, methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide) (MAD) and aluminum tris(2,6-diphenylphenoxide) (ATPH). These reagents were successfully utilized for the selective alkylation of cyclic ketones and aldehydes to generate equatorial alcohol and an anti-Cram type product, respectively, for trans- and cis-selective Claisen rearrangement, for regioselective Diels-Alder reaction, and for epoxide-aldehyde rearrangement. The ATPH - aromatic carbonyl complex reacts with nucleophiles selectively at the para-position of the aromatic ring to generate cyclohexadiene derivatives.

After these pioneering researches in Lewis acid chemistry, Yamamoto has become aware of the vast importance of chiral Lewis acids in modern asymmetric synthesis. In 1985, he first introduced binaphthol as a key ligand for chiral Lewis acid catalysts. This work was the forerunner of a vast quantity of present-day research on the binaththol based chiral Lewis acid catalyst. Based on his knowledge of organoaluminum chemistry, he designed a new and powerful organoaluminum catalyst for asymmetric hetero-Diels-Alder reaction. It was his Brønsted acid-Lewis acid combined system, however, which gave him a unique opportunity for the most efficient asymmetric Lewis acid catalyst for Diels-Alder reaction. A similar concept was employed for his catalytic asymmetric protonation under acidic conditions, which now creates a long sought proton induced asymmetric polyene cyclization.

His discovery of tartaric acid based catalyst (CAB catalyst) and amino acid based catalyst led to the first enantioselective Diels-Alder reaction of a broad range of dienes and dienophiles. The same catalyst was shown to be the first highly efficient catalyst for asymmetric aldol and ene type reactions. The reaction is simple, exceedingly stereoselective, and environmentally friendly.

Direct condensation of carboxylic acids by alcohols or amines is the most important transformation of organic synthesis. Yamamoto found Lewis acid catalyst could play an important role for such esterification and amidation processes. For example, his new hafnium catalyzed esterification and boron catalyzed amidation are now becoming increasingly important to the chemical industry.

More recently, he has developed new asymmetric oxidation processes based on an acid catalysis concept. His nitroso chemistry offers an entirely new access to selective organic synthesis and provides catalytic enantioselective reaction to introduce oxygen and/or nitrogen into the molecule. His pyridine based nitroso- and azo-hetero-Diels-Alder provides powerful tool for asymmetric synthesis. He also recently reported asymmetric epoxidation of homoallylic alcohols based on new vanadium catalyst, one of the most difficult asymmetric oxidations to date.

After moving to Chicago, he proposed the use of 8-hydroxyquinole based chiral Lewis acid catalysis. The catalyst is designed as a rigid metal complex of cis-b-configuation. The reagent turned out to be a brand-new "privileged ligand" for asymmetric synthesis. Catalytic asymmetric pinacol coupling, NH reaction, Mukaiyama-Michael addition, and Pudovik reactions are now able to proceed with complete enantioselectivities.

His laboratory is also noted for its introduction of metal reagents that allow highly selective SN2 cross coupling with carbonyl and allylic electrophiles. Allylic organobarium reagent, so-called "Yamamoto's reagent", reacts with a variety of electrophiles selectively at less substituted termini with complete stereospecificity, resolving a long-standing problem in terpene synthesis.

Affiliations and Expertise

The University of Chicago, Illinois, USA, Chubu University, Aichi, Japan

Erick Carreira

Erick Carreira

Erick M. Carreira was born in Havana, Cuba in 1963. He obtained a B.S. degree in 1984 from the University of Illinois at Urbana­Champaign under the supervision of Scott E. Denmark and a Ph.D. degree in 1990 from Harvard University under the supervision of David A. Evans. After carrying out postdoctoral work with Peter Dervan at the California Institute of Technology through late 1992, he joined the faculty at the same institution as an assistant professor of chemistry and subsequently was promoted to the rank of associate professor of chemistry in the Spring of 1996, and full professor in Spring 1997. Since September 1998, he has been full professor of Organic Chemistry at the ETH Zürich. He is the recipient of the American Chemical Society Award in Pure Chemistry, Nobel Laureate Signature Award, Fresenius Award, a David and Lucile Packard Foundation Fellowship in Science, Alfred P. Sloan Fellowship, Camille and Henry Dreyfus Teacher Scholar Award, Merck Young Investigator Award, Eli Lilly Young Investigator Award, Pfizer Research Award, National Science Foundation CAREER Award, Arnold and Mabel Beckman Young Investigator Award, and a Camille and Henry Dreyfus New Faculty Award. He is also the recipient of the Associated Students of the California Institute of Technology Annual Award in Teaching and a Richard M. Badger Award in Teaching.

His research program focuses on the asymmetric synthesis of biologically active, stereochemically complex, natural products. Target molecules are selected which pose unique challenges in asymmetric bond construction. A complex multistep synthesis endeavor provides a goal-oriented setting within which to engage in reaction innovation and design. Drawing from the areas of organometallic chemistry, coordination chemistry, and molecular recognition, Carreira's group is developing catalytic and stoichiometric reagents for asymmetric stereocontrol.

Affiliations and Expertise

ETH Zürich, Switzerland

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