Chemistry of Peptide Synthesis: 1st Edition (Hardback) book cover

Chemistry of Peptide Synthesis

1st Edition

By N. Leo Benoiton

CRC Press

304 pages | 187 B/W Illus.

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Description

Chemistry of Peptide Synthesis is a complete overview of how peptides are synthesized and what techniques are likely to generate the most desirable reactions. Incorporating elements from the author’s role of Career Investigator of the Medical Research Council of Canada and his extensive teaching career, the book emphasizes learning rather than memorization. The text uses clear language and schematics to present concepts progressively, carefully excluding unnecessary details and providing a historical context in which to appreciate the development of the field.

The author first outlines the fundamentals of peptide synthesis, focusing on the intermediates in aminolysis reactions. Gradually the text builds into discussions of the applicability of coupling reactions, stereomutation, methods of deprotection, solid-phase synthesis, side-chain protection and side reactions, and amplification on coupling methods. The book clarifies the differences between oxazolones from amino-acid derivatives and segments and the implications of their formation on the chiral integrity of products. The author offers a critical analysis of the mechanisms of coupling reactions and the desirability of preactivation. The text explains hindrance and the nucleophilicity of tertiary amines and rationalizes their use. The book also explores mechanisms of acidolysis and the dual role of nucleophiles as reactants and scavengers.

Chemistry of Peptide Synthesis supplies a broad, yet straightforward approach that appeals to those with limited knowledge of organic chemistry or chemists from other fields as well as in-depth coverage that can be appreciated by experienced peptidologists.

Reviews

”This book provides the mechanistic basis for developing rational strategies in peptide synthesis. …The author’s unpretentious writing style belies the authoritative and sophisticated textual content. Over the course of well cross-referenced chapters, this treatise quickly transitions from offering a novice the principles of peptide science to engaging expert biochemists. The narrative flows unerringly as it guides the reader through 207 mechanism-based figures. Many such figures brilliantly superimpose the complex realities of deviant side reaction pathways onto the intended reaction course. In so doing, the study allows for the development of predictive skills in identifying a priori dead-end pathways.”

“Benoiton, in the fashion of a true scholar, relishes communicating the science of peptide synthesis, a field that he has pioneered. He understands the peptide bond as only an enzyme might and, in the course of this text, has ascribed explicit personalities to amino acids, their quirks notwithstanding. This extraordinary book belongs in all academic and research environments involved in peptide chemistry.”

— Kennerly S. Patrick, South Carolina College of Pharmacy, Medical University of South Carolina, in the Journal of Medicinal Chemistry, Vol. 49, No. 8 (2006)

”Leo Benoiton is an experienced peptide chemist who has made fundamental contributions to the chemistry of peptide synthesis. …The publication of such a book is timely, and could make an important contribution to the field … useful chemistry related to peptide synthesis is well discussed in this book, particularly in highly specialized or advanced topics such as partial epimerization (racemization), coupling methods/activation, and the molecular origins of the aggregation/insolubility of protected peptides. …”

— Stephen Kent, Institute for Biophysical Dynamics, University of Chicago, in Angewandte Chemie, Int’l Edition, Vol. 45, No. 26 (2006)

“ Despite its apparent simplicity as depicted in most textbooks, the synthesis of peptides in the many structural manifestations has many problems and pitfalls that often befuddle the synthetic chemist who has never made a peptide before. Having watched over 300 undergraduate and graduate students, postdoctoral associates, and more senior scientists, struggle with doing peptide synthesis and then having to send them to the library to read the primary literature so that they would finally “get it”, the appearance of N. Leo Benoiton’s Chemistry of Peptide Synthesis is a godsend. In fewer than 300 pages Professor Benoiton has distilled the essence of peptide synthesis—the strategies; the tactics; the pitfalls; the mechanisms; and so forth, as has done so in the “simple” language of synthetic and mechanistic organic chemistry. Of course one can always quibble with this point or that, argue that more could have been said or discussed about some aspect of peptide synthesis, but if you are new in peptide synthesis and want to get the “full picture” or are a more experienced peptide synthetic chemist and are branching into new aspects, there is no better place either to start your education in peptide synthesis or to become introduced to and familiar with some unfamiliar aspects of synthetic peptide chemistry than this book.

“The book consists of 8 chapters in what might be called a classical organization of the field. Chapter 1 is a short but masterful exposition of the properties of amino acids and of how these properties impact in peptide synthesis and synthetic tactics. Make sure you read this chapter before you proceed. Chapters 2, 3, and 4 carefully discuss the basic strategies and tactics in peptide synthesis primarily as developed in solution phase synthesis. Chapter 2 discusses methods for peptide bond formation; Chapter 3, protecting groups and methods of deprotection and Chapter 4, problems in chirality in peptide synthesis, how to study it, how to quantify, etc. and how to minimize side reactions. I particularly enjoyed Chapter 4—not only because the author and his group have had a major impact on our understanding of issues of chirality that arise in peptide synthesis, but also because these issues are rarely discussed in any detail in current synthetic peptide chemistry chapters. Chirality nonetheless appears as a problem more often than admitted in most peptide synthesis papers. So when it does, here is the place to read all about it. Chapter 5 provides a basic introduction to the use of solid phase peptide synthesis. It concentrates very much on the fundamentals of preparing linear peptides on a solid support. Chapter 6 provides an excellent discussion of the reactivity, protection, deprotection, and side reactions which result from the presence of the several function groups that are found in the 20 standard amino acids that make up proteins and related polypeptides. A clear exposition is given of the side reactions that can result and how they can be eliminated or minimized. This chapter is a must-read for neophytes in peptide synthesis even if they already have considerate experience in other areas of synthetic chemistry. A careful read of this chapter will prevent many problems of this chapter will prevent many problems that can arise in peptide synthesis. Chapters 7 and 8, the last two chapters in the book, discuss a number of issues that can arise in the synthesis of peptides dealing with coupling reagents, activated esters, anhydrides, mixed anhydrides, etc. These chapters contain many useful ideas and thoughts of the author that are invaluable for their usefulness and for their careful considerations.

Perhaps more could have been said about cyclic peptides: disulfides, lactams, head-to-tail cyclic peptides, lactones, etc., and the difficulties that can occur in their synthesis. And virtually nothing is said about peptide ligation chemistry or synthesis of peptide conjugates. In all fairness, however, as the author clearly states in his introduction, this book was written to expose the fundamentals of peptide synthesis.  In this respect, the author has produced a superb, scholarly treatment of the subject. This book will be very useful for many years to come, and I highly recommend it to those with a need to apply peptide synthesis, or those who wish to educate themselves to the field of peptide synthesis. All readers will learn a wealth of information and obtain many useful insights along the way. It is essential reading for all of my students.”

 —Victor J. Hruby, Regents Professor of Chemistry, Department of Chemistry, University of Arizona, Tucson, USA, written in PeptideScience, Vol. 88, No. 6 (November 2007)

Table of 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

APPENDICES

Useful Reviews

Year, Location and Chairmen of the Major Symposia

On the "Primary Sequence" of Peptides and Proteins

Index

Subject Categories

BISAC Subject Codes/Headings:
MED008000
MEDICAL / Biochemistry
SCI010000
SCIENCE / Biotechnology
SCI013040
SCIENCE / Chemistry / Organic