Ynamide-Mediated Synthetic Approach to Thioamide-Substituted Peptides

Abstract

A novel synthetic approach to thioamide-substituted peptides is reported. It provides a practical tool for the chemical biology study of peptides and proteins by replacing a carbonyl oxygen atom of an amide bond by an sp²-hybridized sulfur atom to precisely introduce a thioamide bond Ψ[CS-NH] into a peptide backbone. The α-thioacyloxyenamide intermediates, originating from ynamide coupling reagent and proteinogenic amino monothioacids, are proved to be novel effective thioacylating reagents in both the solution and solid phase peptide syntheses. Herein, we describe the detailed synthesis protocol for site-specifically incorporating a thioamide bond at 19 of 20 proteinogenic amino acid residues (except for His) of a peptide backbone in a racemization/epimerization-free manner.

Keywords: Racemization/epimerization-free; Thioacylating reagents; Thioamide bond; Thioamide-substituted peptide; Ynamide coupling reagent.