Chemistry of Peptide Synthesis

Content: FUNDAMENTALS OF PEPTIDE SYNTHESIS    Chemical and Stereochemical Nature of Amino Acids    Ionic Nature of Amino Acids    Charged Groups in Peptides at Neutral pH   Side-Chain Effects in Other Amino Acids    General Approach to Protection and Amide-Bond Formation   N-Acyl and Urethane-Forming N-Substituents    Amide-Bond Formation and the Side Reaction of Oxazolone Formation   Oxazolone Formation and Nomenclature   Coupling, 2-Alkyl-5(4H)-Oxazolone Formation and Generation of Diastereoisomers from Activated Peptides    Coupling of N-Alkoxycarbonylamino Acids without Generation of   Diastereoisomers: Chirally Stable 2-Alkoxy-5(4H)-Oxazolones   Effects of the Nature of the Substituents on the Amino and Carboxyl Groups of the Residues that are Coupled to Produce a Peptide   Introduction to Carbodiimides and Substituted Ureas   Carbodiimide-Mediated Reactions of N-Alkoxycarbonylamino Acids    Carbodiimide-Mediated Reactions of N-Acylamino Acids and Peptides   Preformed Symmetrical Anhydrides of N-Alkoxycarbonylamino Acids   Purified Symmetrical Anhydrides of N-Alkoxycarbonylamino Acids   Obtained Using a Soluble Carbodiimide    Purified 2-Alkyl-5(4H)-Oxazolones from N-Acylamino and N-Protected Glycylamino Acids   2-Alkoxy-5(4H)-Oxazolones as Intermediates in Reactions of   N-Alkoxycarbonylamino Acids   Revision of the Central Tenet of Peptide Synthesis   Strategies for the Synthesis of Enantiomerically Pure Peptides   Abbreviated Designations of Substituted Amino Acids and Peptides    Literature on Peptide Synthesis     METHODS FOR THE FORMATION OF PEPTIDE BONDS   Coupling Reagents and Methods and Activated Forms    Peptide-Bond Formation from Carbodiimide-Mediated Reactions of N-Alkoxycarbonylamino Acids   Factors Affecting the Course of Events in Carbodiimide-Mediated Reactions of N-Alkoxycarbonylamino Acids   Intermediates and Their Fate in Carbodiimide-Mediated Reactions of N-Alkoxycarbonylamino Acids   Peptide-Bond Formation from Preformed Symmetrical Anhydrides of N-Alkoxycarbonylamino Acids   Peptide-Bond Formation from Mixed Anhydrides of N-Alkoxycarbonylamino Acids   Alkyl Chloroformates and Their Nomenclature   Purified Mixed Anhydrides of N-Alkoxycarbonylamino Acids and Their Decomposition to 2-Alkoxy-5(4H)-Oxazolones   Peptide-Bond Formation from Activated Esters of N-Alkoxycarbonylamino Acids   Anchimeric Assistance in the Aminolysis of Activated Esters    On the Role of Additives as Auxiliary Nucleophiles: Generation of Activated Esters    1-Hydroxybenzotriazole as an Additive that Suppresses N-Acylurea Formation by Protonation of the O-Acylisourea   Peptide-Bond Formation from Azides of N-Alkoxycarbonylamino Acids   Peptide-Bond Formation from Chlorides of N-Alkoxycarbonylamino Acids: N-9-Fluorenylmethoxycarbonylamino-Acid Chlorides    Peptide-Bond Formation from 1-Ethoxycarbonyl-2-Ethoxy-1,2-Dihydroquinoline-Mediated Reactions of N-Alkoxycarbonylamino Acids   Coupling Reagents Composed of an Additive Linked to a Charged Atom Bearing Dialkylamino Substituents and a Nonnucleophilic Counter-Ion   Peptide-Bond Formation from Benzotriazol-1-yl-Oxy-tris(Dimethylamino)Phosphonium Hexafluorophosphate-Mediated Reactions of N-Alkoxycarbonylamino Acids   Peptide-Bond Formation from O-Benzotriazol-1-yl-N,N,N\',N\' TetramethyluroniumHexafluorophosphate- and Tetrafluoroborate-Mediated Reactions of N-Alkoxycarbonylamino Acids    Pyrrolidino Instead of Dimethylamino Substituents for the Environmental Acceptability of Phosphonium and Carbenium Salt-Based Reagents    Intermediates and Their Fate in Benzotriazol-1-yl-Oxyphosphonium and Carbenium Salt-Mediated Reactions   1-Hydroxybenzotriazole as Additive in Couplings of N-Alkoxycarbonylamino Acids Effected by Phosphonium and Uronium Salt-Based Reagents    Some Tertiary Amines Used as Bases in Peptide Synthesis   The Applicability of Peptide-Bond Forming Reactions to the Coupling of N-Protected Peptides Is Dictated by the Requirement to Avoid Epimerization: 5(4H)-Oxazolones from Activated Peptides   Methods for Coupling N-Protected Peptides   On the Role of 1-Hydroxybenzotriazole as an Epimerization Suppressant in Carbodiimide-Mediated Reactions   More on Additives   An Aid to Deciphering the Constitution of Coupling Reagents from Their Abbreviations    PROTECTORS AND METHODS OF DEPROTECTION   The Nature and Properties Desired of Protected Amino Acids   Alcohols from which Protectors Derive and Their Abbreviated Designations   Deprotection by Reduction: Hydrogenolysis    Deprotection by Reduction: Metal-Mediated Reactions   Deprotection by Acidolysis: Benzyl-Based Protectors    Deprotection by Acidolysis:tert-Butyl-Based Protectors    Alkylation due to Carbenium Ion Formation during Acidolysis    Deprotection by Acid-Catalyzed Hydrolysis   Deprotection by Base-Catalyzed Hydrolysis   Deprotection by beta-Elimination    Deprotection by beta-Elimination: 9-Fluorenylmethyl-Based Protectors   Deprotection by Nucleophilic Substitution by Hydrazine or Alkyl Thiols    Deprotection by Palladium-Catalyzed Allyl Transfer    Protection of Amino Groups: Acylation and Dimer Formation   Protection of Amino Groups: Acylation without Dimer Formation    Protection of Amino Groups: tert-Butoxycarbonylation   Protection of Carboxyl Groups: Esterification    Protection of Carboxyl, Hydroxyl, and Sulfhydryl Groups by tert-Butylation and Alkylation    Protectors Sensitized or Stabilized to Acidolysis   Protecting Group Combinations     CHIRALITY IN PEPTIDE SYNTHESIS    Mechanisms of Stereomutation: Acid-Catalyzed Enolization    Mechanisms of Stereomutation: Base-Catalyzed Enolization    Enantiomerization and Its Avoidance during Couplings of N-Alkoxycarbonyl-L-Histidine    Mechanisms of Stereomutation: Base-Catalyzed Enolization of Oxazolones Formed from Activated Peptides    Mechanisms of Stereomutation: Base-Induced Enolization of Oxazolones Formed from Activated N-Alkoxycarbonylamino Acids    Stereomutation and Asymmetric Induction    Terminology for Designating Stereomutation    Evidence of Stereochemical Inhomogeneity in Synthesized Products   Tests Employed to Acquire Information on Stereomutation   Detection and Quantitation of Epimeric Peptides by NMR Spectroscopy    Detection and Quantitation of Epimeric Peptides by HPLC    External Factors that Exert an Influence on the Extent of Stereomutation During Coupling   Constitutional Factors that Define the Extent of Stereomutation During Coupling: Configurations of the Reacting Residues    Constitutional Factors that Define the Extent of Stereomutation During Coupling: The N-Substituent of the Activated Residue or the Penultimate Residue   Constitutional Factors that Define the Extent of Stereomutation During Coupling: The Aminolyzing Residue and its Carboxy Substituent   Constitutional Factors that Define the Extent of Stereomutation During Coupling: The Nature of the Activated Residue    Reactions of Activated Forms of N-Alkoxycarbonylamino Acids in the Presence of Tertiary Amine   Implications of Oxazolone Formation in the Couplings of N-Alkoxycarbonlyamino Acids in the Presence of Tertiary Amine    Enantiomerization in 4-Dimethylaminopyridine-Assisted Reactions of N-Alkoxycarbonylamino Acids   Enantiomerization During Reactions of Activated N-Alkoxycarbonylamino Acids with Amino Acid Anions   Possible Origins of Diastereomeric Impurities in Synthesized Peptides   Options for Minimizing Epimerization during the Coupling of Segments   Methods for Determining Enantiomeric Content   Determination of Enantiomers by Analysis of Diastereoisomers   Formed by Reaction with a Chiral Reagent    SOLID-PHASE SYNTHESIS   The Idea of Solid-Phase Synthesis    Solid-Phase Synthesis as Developed by Merrifield    Vessels and Equipment for Solid-Phase Synthesis    A Typical Protocol for Solid-Phase Synthesis    Features and Requirements for Solid-Phase Synthesis    Options and Considerations for Solid-Phase Synthesis    Polystyrene Resins and Solvation in Solid-Phase Synthesis    Polydimethylacrylamide Resin    Polyethyleneglycol-Polystyrene Graft Polymers   Terminology and Options for Anchoring the First Residue    Types of Target Peptides and Anchoring Linkages   Protecting Group Combinations for Solid-Phase Synthesis    Features of Synthesis Using Boc/Bzl Chemistry    Features of Synthesis Using Fmoc/tBu Chemistry    Coupling Reagents and Methods for Solid-Phase Synthesis    Merrifield Resin for Synthesis of Peptides Using Boc/Bzl Chemistry    Phenylacetamidomethyl Resin for Synthesis of Peptides Using Boc/Bzl Chemistry   Benzhydrylamine Resin for Synthesis of Peptide Amides Using Boc/Bzl Chemistry   Resins and Linkers for Synthesis of Peptides Using Fmoc/tBu Chemistry    Resins and Linkers for Synthesis of Peptide Amides Using Fmoc/tBu Chemistry    Resins and Linkers for Synthesis of Protected Peptide Acids and Amides    Esterification of Fmoc-Amino Acids to Hydroxymethyl Groups of Supports    2-Chlorotrityl Chloride Resin for Synthesis Using Fmoc/tBu Chemistry    Synthesis of Cyclic Peptides on Solid Supports      REACTIVITY, PROTECTION, AND SIDE REACTIONS   Protection Strategies and the Implications Thereof   Constitutional Factors Affecting the Reactivity of Functional Groups    Constitutional Factors Affecting the Stability of Protectors    The e-Amino Group of Lysine    The Hydroxyl Groups of Serine and Threonine    Acid-Induced O-Acylation of Side-Chain Hydroxyls and the O-to-N Acyl Shift   The Hydroxyl Group of Tyrosine    The Methylsulfanyl Group of Methionine    The Indole Group of Tryptophan    The Imidazole Group of Histidine    The Guanidino Group of Arginine    The Carboxyl Groups of Aspartic and Glutamic Acids   Imide Formation from Substituted Dicarboxylic Acid Residues   The Carboxamide Groups of Asparagine and Glutamine   Dehydration of Carboxamide Groups to Cyano Groups During Activation   Pyroglutamyl Formation from Glutamyl and Glutaminyl Residues   The Sulfhydryl Group of Cysteine and the Synthesis of Peptides Containing Cystine   Disulfide Interchange and Its Avoidance during the Synthesis of Peptides Containing Cystine   Piperazine-2,5-Dione Formation from Esters of Dipeptides   N-Alkylation during Palladium-Catalyzed Hydrogenolytic Deprotection and Its Synthetic Application    Catalytic Transfer Hydrogenation and the Hydrogenolytic Deprotection of Sulfur-Containing Peptides    Mechanisms of Acidolysis and the Role of Nucleophiles    Minimization of Side Reactions during Acidolysis    Trifunctional Amino Acids with Two Different Protectors    VENTILATION OF ACTIVATED FORMS AND COUPLING METHODS   Notes on Carbodiimides and Their Use    Cupric Ion as an Additive that Eliminates Epimerization in Carbodiimide-Mediated Reactions    Mixed Anhydrides: Properties and Their Use   Secondary Reactions of Mixed Anhydrides: Urethane Formation    Decomposition of Mixed Anhydrides: 2-Alkoxy-5(4H)-Oxazolone Formation and Disproportionation   Activated Esters: Reactivity   Preparation of Activated Esters using Carbodiimides and Associated Secondary Reactions    Other Methods for the Preparation of Activated Esters of N-Alkoxycarbonylamino Acids   Activated Esters: Properties and Specific Uses   Methods for the Preparation of Activated Esters of Protected Peptides, Including Alkyl Thioesters   Synthesis using N-9-Fluorenylmethoxycarbonylamino Acid Chlorides    Synthesis using N-Alkoxycarbonylamino-Acid Fluorides    Amino-Acid N-Carboxyanhydrides: Preparation and Aminolysis   N-Alkoxycarbonylamino-Acid N-Carboxyanhydrides    Decomposition during the Activation of Boc-Amino Acids and Consequent Dimerization   Acyl Azides and the Use of Protected Hydrazides    O-Acyl and N-Acyl N\'-Oxide Forms of 1-Hydroxybenzotriazole Adducts and the Uronium and Guanidinium Forms of Coupling Reagents    Phosphonium and Uronium/Aminium/Guanidinium Salt-Based Reagents: Properties and Their Use    Newer Coupling Reagents    To Preactivate or not to Preactivate: Should That Be the Question?    Aminolysis of Succinimido Esters by Unprotected Amino Acids or Peptides    Unusual Phenomena Relating to Couplings of Proline    Enantiomerization of the Penultimate Residue During Coupling of an N -Protected Peptide    Double Insertion in Reactions of Glycine Derivatives: Rearrangement of Symmetrical Anhydrides to Peptide-Bond-Substituted Dipeptides   Synthesis of Peptides by Chemoselective Ligation   Detection and Quantitation of Activated Forms    MISCELLANEOUS   Enantiomerization of Activated N-Alkoxycarbonylamino Acids and Esterified Cysteine Residues in the Presence of Base    Options for Preparing N-Alkoxycarbonylamino Acid Amides and 4-Nitroanilides    Options for Preparing Peptide Amides   Aggregation during Peptide-Chain Elongation and Solvents for its Minimization    Alkylation of Peptide Bonds to Decrease Aggregation: 2-Hydroxybenzyl Protectors    Alkylation of Peptide Bonds to Decrease Aggregation: Oxazolidines and Thiazolidines (Pseudo-Prolines)   Capping and the Purification of Peptides   Synthesis of Large Peptides in Solution   Synthesis of Peptides in Multikilogram Amounts   Dangers and Possible Side Reactions Associated with the Use of Reagents and Solvents    Organic and Other Salts in Peptide Synthesis   Reflections on the Use of Tertiary and Other Amines   Monomethylation of Amino Groups and the Synthesis of N-Alkoxycarbonyl-N-Methylamino Acids   The Distinct Chiral Sensitivity of N-Methylamino Acid Residues and Sensitivity to Acid of Adjacent Peptide Bonds    Reactivity and Coupling at -Methylamino Acid Residues    APPENDICES   Useful Reviews   Year, Location and Chairmen of the Major Symposia   On the \"Primary Sequence\" of Peptides and Proteins    Index