Principles of Peptide Synthesis

A look at the shelves of a major library awakens doubts in the author of this small volume about the importance of writing a new introduction to peptide synthesis. This rather narrow area of bio-organic chemistry already has received considerable attention. A whole series of books deals with the synthesis of peptides. Some of these are textbooks written to support lecture courses on peptide synthesis. Others try to help the beginner, otherwise well versed in organic chemistry, to embark on some experimental project that requires the construction of peptide chains. Not less useful are the monographs which were compiled to aid the adept practitioner and to provide him with references to the growing literature of a very active field. Is there any need for a new book on peptide synthesis? Should we add a new volume to an already impressive and certainly useful series? The answer is not obvious. The author has already participated in two similar en­ deavors. The first edition! of "Peptide Synthesis", with M. A. Ondetti as coauthor, was meant to serve as an introduction for the beginner. It was rather well received by researchers who joined the field of peptide chemistry and were looking for initiation. While working on the 2 second edition with Drs. Klausner and Ondetti, we became painfully aware of the impossibility of the task.

Contenu

I. Introduction.- References of Chapter 1.- II. Activation and Coupling.- A. Activation.- B. Coupling.- C. Coupling Methods.- 1. The azide procedure.- 2. Anhydrides.- 3. Active esters.- 4. Coupling Reagents.- 5. Auxiliary Nucleophiles.- 6. Enzyme-catalyzed Formation of the Peptide Bond.- 7. A Comparison Between Various Coupling Methods.- References of Chapter II.- III. Reversible Blocking of Amino and Carboxyl Groups.- A. General Aspects.- 1. The Need for Protecting Groups.- 1. Minimal Versus Global Protection.- 3. Easily Removable Protecting Groups and Methods Used for Their Removal.- a. Reduction and Oxidation.- b. Acidolysis-Carbocation Formation.- c. Proton Abstraction (Carbanion Formation).- d. Nucleophilic Displacement.- e. Photolysis.- f. Enzyme-Catalyzed Hydrolysis.- B. Protection of the Carboxyl Group.- 1. Benzyl Esters and Substituted Benzyl Esters.- 2. Methyl Esters and Substituted Methyl Esters.- 3. Ethyl Esters and Substituted Ethyl Esters.- 4. tert. Butyl Esters and Related Compounds.- 5. Aryl Esters.- 6. Hydrazides.- C. Protection of the Amino Group.- 1. Alkyl and Alkylidene Protecting Groups..- 2. Protection by Acylation.- 3. Protection of the Amino Group in the Form of Urethanes.- a. Urethane-type Protecting Groups.- b. Introduction of Urethane-type Protecting Groups.- c. Removal of Urethane-type Protecting Groups.- 4. Protecting Groups Derived from Sulfur and Phosphorus.- References of Chapter III.- IV. Semipermanent Protection of Side Chain Functions.- A. Carboxyl Groups of Aspartyl and Glutamyl Residues.- B. Side Chain Amino Groups of Lysine and Ornithine.- C. Hydroxyl Groups in Serine, Threonine and Tyrosine.- D. The Sulfhydryl Group in Cysteine.- E. The Guanidino Group of Arginine.- F. Imidazole in Histidine.- G. The Thioether in Methionine.- H. The Indole Nitrogen in Tryptophan.- I. The Carboxamide Groups in Asparagine and Glutamine.- References of Chapter IV.- V. Side Reactions in Peptide Synthesis.- A. Side Reactions Initiated by Proton Abstraction.- 1. Racemization.- a. Mechanisms of Racemization.- b. Models for the Study of Racemization.- c. Detection of Raeemization. (Examination of Synthetic Peptides for the Presence of Diastereo-isomers.- d. Conservation of Chiral Purity.- 2. Undesired Cyclization.- 3. O-Acylation.- B. Side Reactions Initiated by Protonation.- 1. Raeemization.- 2. Undesired Cyclization.- 3. Alkylation..- 4. Chain Fragmentation.- C. Side Reactions Due to Overactivation.- D. Side Reactions Related to Individual Amino Acid Residues.- References of Chapter V.- VI. Tactics and Strategy in Peptide Synthesis.- A. Tactics.- 1. Combinations of Protecting Groups.- 2. Final Deprotection.- B. Strategies.- 1. Segment Condensation.- 2. Stepwise Synthesis Starting with the N-terminal Residue (N?C Strategy)..- 3. Stepwise Synthesis Starting with the C-terminal Residue (C?N Strategy)..- C. Disulfide Bridges.- D. Synthesis of Cyclic Peptides.- 1. Homodetic Cyclopeptides.- 2. Heterodetic Cyclopeptides.- E. Sequential Polypeptides.- F. Partial Synthesis (Semisynthesis).- References of Chapter VI.- VII. Techniques for the Facilitation of Peptide Synthesis.- A. Solid Phase Peptide Synthesis (SPPS).- 1. The Insoluble Support.- 2. The Bond Between Peptide and Polymer.- 3. Protection and Deprotection.- 4. Methods of Coupling in SPPS.- 5. Separation of the Completed Peptide Chain from the Polymeric Support.- 6. Problems in Solid Phase Peptide Synthesis.- B. Synthesis in Solution.- 1. Peptides Attached to Soluble Polymers.- 2. The "handle" Method.- 3. Synthesis "in situ".- 4. Synthesis without Isolation of Intermediates.- References of Chapter VII.- VIII. Recent Developments and Perspectives.- A. Formation of the Peptide Bond.- B. Protection.- 1. Carboxyl Groups.- 2. Temporary Protection of Amino Groups.- 3. Semipermanent Protection of Side Chain Functions.- 4. Removal of Protecting Groups.- C. Side Reactions.- D. Solid Phase Peptide Synthesis.- E. Catalysis..- References of Chapter VIII.- Author Index.