Rapid, Traceless, Ag^I-Promoted Macrocyclization of Peptides Possessing an N-Terminal Thioamide

Peptide macrocyclization is often a slow process, plagued by epimerization and cyclodimerization. Herein, we describe a new method for peptide macrocyclization employing the Ag^I-promoted transformation of peptide thioamides. The Ag^I has a dual function: chemoselectively activating the thioamide and tethering the N-terminal thioamide to the C-terminal carboxylate. Extrusion of Ag₂S generates an isoimide intermediate, which undergoes acyl transfer to generate the native cyclic peptide, resulting in a rapid, traceless macrocylization process. Cyclic peptides are furnished in high yields within 1 hour, free of epimerization and cyclodimerization.