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Pharmaceutical Book from C.H.I.P.S.

Chemistry of Peptide Sythesis
by N. Leo Benoiton

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 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

Index

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Chemistry of Peptide Sythesis
by N. Leo Benoiton
2005 304 pages $148.95 + shipping
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