Carboxamide

Abstract: 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.