Chemistry of Peptide Sythesis is a complete overview of how peptides are synthesized and what techniques are likely to generate the most desirable reactions.

Features:

• Uses straightforward language with minimal abbreviations that is suitable for non-English speaking readers
• Includes more than 200 schematic representations of chemical reactions
• Contains abundant references to further knowledge of developments of the field
• Examines the protection of functional groups on the basis of the methods employed to remove the protectors
• Provides a simple understanding of steroisomerization, employing only the precise terms of enantiomerization and epimerization

Contents

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 Nµ-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

Index

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