Chiral Acylation with N-(Protected α-Aminoacyl)benzotriazoles for Advantageous Syntheses of Peptides and Peptide Conjugates

Abstract

N-(Protected α-aminoacyl)benzotriazoles are efficient intermediates for N- and O-aminoacylation. These intermediates enable fast preparations of biologically relevant peptides and peptide conjugates in high yields and purity, under mild reaction conditions, with full retention of the original chirality. The developed methodology allows simple solution- and solid-phase preparative techniques to generate complex peptides and peptide conjugates and serves as a platform for generating diverse medicinal chemistry building block libraries involving amino acid and heterocyclic moieties crucial for drug development. 1 Introduction 1.1 Background to Peptide Synthesis 1.2 Preparation of N-(Protected α-Aminoacyl)benzotriazoles 2 Peptide Coupling with Chiral N-(Protected α-Amino-acyl)benzotriazoles 2.1 Preparation of Dipeptides 2.2 Preparation of Tripeptides 2.2.1 Tripeptides by the Fragment-Coupling Procedure 2.2.2 Peptides by the Stepwise-Coupling Procedure 2.3 Preparation of Dipeptides Involving Sterically Hindered Amino Acids 2.4 Microwave-Assisted Solid-Phase Peptide Synthesis Utilizing N-(Protected α-Aminoacyl)benzotriazoles 3 Other N-Acylations Using Benzotriazole-Activated Intermediates 3.1 Glyco-Amino-Acids and Glycopeptides 3.2 Fluorescent Amino Acids and Peptides 3.3 Monosaccharide-Based Water-Soluble Fluorescent Tags 3.4 Chiral Peptide Nucleic Acid (PNA) Monomers with Modified Backbones 3.5 Heterocyclic Amines 4 O-Aminoacylation with Chiral N-(Protected α-Aminoacyl)benzotriazoles 4.1 Steroid Esters of α-Amino Acids 4.2 Terpene Esters of α-Amino Acids and Esters Derived from Long-Chain Alcohols 4.3 O-(Aminoacyl)sugar Conjugates 5 Conclusion.