Principles of Peptide Synthesis

Principles of Peptide Synthesis is a very successful book by one of the pioneers of contemporary bioorganic synthesis. Its first edition proved a valuable source that is kept close to the work bench for frequent consulting. Any researcher planning the formation of the peptide bond, be it for the synthesis of a peptide chain or a cyclic peptide, benefits from the author's experience. The concise and critical treatment of the steps involved: protection, activation and bond formation require careful planning to avoid racemization and undesired side reactions. The second edition has been completely revised and updated. New procedures that have been developed since the first edition was published and that did not fit into the original are added in a separate chapter. This separation of old and new make it possible to assess new ideas and discern novel trends.

I. Introduction.- References.- II. Activation and Coupling.- 1 Activation.- 2 Coupling.- 3 Coupling Methods.- 3.1 The Azide Procedure.- 3.2 Anhydrides.- 3.3 Active Esters.- 3.4 Coupling Reagents.- 3.5 Auxiliary Nucleophiles.- 3.6 Enzyme-Catalyzed Formation of the Peptide Bond.- 3.7 Comment on Various Coupling Methods.- References.- III. Reversible Blocking of Amino and Carboxyl Groups.- 1 General Aspects.- 1.1 The Need for Protecting Groups.- 1.2 Minimal Versus Global Protection.- 1.3 Easily Removable Protecting Groups and Methods Used for Their Removal.- 1.3.1 Reduction and Oxidation.- 1.3.2 Acidolysis ― Carbocation Formation.- 1.3.3 Proton Abstraction (Carbanion Formation).- 1.3.4 Nucleophilic Displacement.- 1.3.5 Photolysis.- 1.3.6 Enzyme Catalyzed Hydrolysis.- 2 Protection of the Carboxyl Group.- 2.1 Benzyl Esters and Substituted Benzyl Esters.- 2.2 Methyl Esters and Substituted Methyl Esters.- 2.3 Ethyl Esters and Substituted Ethyl Esters.- 2.4 tert-Butyl Esters and Related Compounds.- 2.5 Aryl Esters.- 2.6 Hydrazides.- 3 Protection of the Amino Group.- 3.1 Alkyl and Alkylidene Protecting Groups.- 3.2 Protection by Acylation.- 3.3 Protection of the Amino Group in the Form of Urethanes.- 3.3.1 Urethane Type Protecting Groups.- 3.3.2 Introduction of Urethane Type Protecting Groups.- 3.3.3 Removal of Urethane-Type Protecting Groups.- 3.4 Protecting Groups Derived from Sulfur and Phosphorus.- References.- IV. Semipermanent Protection of Side Chain Functions.- 1 Carboxyl Groups of Aspartyl and Glutamyl Residues.- 2 Side Chain Amino Groups of Lysine and Ornithine.- 3 Hydroxyl Groups in Serine, Threonine and Tyrosine.- 4 The Sulfhydryl Group in Cysteine.- 5 The Guanidino Group of Arginine.- 6 Imidazole in Histidine.- 7 The Thioether in Methionine.- 8 The Indole Nitrogen in Tryptophan.- 9 The Carboxamide Groups in Asparagine and Glutamine.- References.- V. Side Reactions in Peptide Synthesis.- 1 Side Reactions Initiated by Proton Abstraction.- 1.1 Racemization.- 1.1.1 Mechanisms of Racemization.- 1.1.2 Models for the Study of Racemization.- 1.1.3 Detection of Racemization (Examination of Synthetic Peptides for the Presence of Unwanted Diastereoisomers).- 1.1.4 Conservation of Chiral Purity.- 1.2 Undesired Cyclization.- 1.3 O-Acylation.- 2 Side Reactions Initiated by Protonation.- 2.1 Racemization.- 2.2 Undesired Cyclization.- 2.3 Alkylation.- 2.4 Chain Fragmentation.- 3 Side Reactions Due to Overactivation.- 4 Side Reactions Related to Individual Amino Acid Residues.- References.- VI. Tactics and Strategy in Peptide Synthesis.- 1 Tactics.- 1.1 Combinations of Protecting Groups.- 1.2 Final Deprotection.- 2 Strategies.- 2.1 Segment Condensation.- 2.2 Stepwise Synthesis Starting with the N-Terminal Residue (N?C Strategy).- 2.3 Stepwise Synthesis Starting with the C-Terminal Residue (C?W Strategy).- 3 Disulfide Bridges.- 4 Synthesis of Cyclic Peptides.- 4.1 Homodetic Cyclopeptides.- 4.2 Heterodetic Cyclopeptides.- 5 Sequential Polypeptides.- 6 Partial Synthesis (Semisynthesis).- References.- VII. Techniques for the Facilitation of Peptide Synthesis.- 1 Solid Phase Peptide Synthesis (SPPS).- 1.1 The Insoluble Support.- 1.2 The Bond Between Peptide and Polymer.- 1.3 Protection and Deprotection.- 1.4 Methods of Coupling in SPPS.- 1.5 Separation of the Completed Peptide Chain from the Polymeric Support.- 1.6 Problems in Solid Phase Peptide Synthesis.- 2 Synthesis in Solution.- 2.1 Peptides Attached to Soluble Polymers.- 2.2 The “Handle” Method.- 2.3 Synthesis “in situ”.- 2.4 Synthesis Without Isolation of Intermediates.- References.- VIII Recent Developments, New Trends.- 1 Formation of the Peptide Bond.- 1.1 Acid Chlorides and Fluorides.- 1.2 Anhydrides.- 13 Active Esters.- 1.4 Coupling Reagents.- 1.5 Non-Conventional Formation of the Peptide Bond.- 1.6 Enzyme-Catalyzed Formation of the Peptide Bond.- 1.7 Cyclization and Formation of Disulfide Bridges.- 2 Protecting Groups.- 2.1 Blocking of the Carboxyl Function.- 2.2 Amine Protecting Groups.- 2.3 Masking of Functional Groups in the Side Chains of Amino Acids.- 2.4 Methods for the Introduction and Removal of Protecting Groups.- 3 Solid Phase Peptide Synthesis.- 4 Undesired Reactions in Peptide Synthesis.- 5 New Trends and Perspectives.- References.