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

Abstract

Peptide macrocyclization is often as lowp rocess, plagued by epimerization and cyclodimerization. Herein, we describe an ew method for peptide macrocyclization employing the Ag I -promoted transformation of peptide thioamides. The Ag I has ad ual function:c hemoselectively activating the thioamide and tethering the N-terminal thioamide to the Cterminal carboxylate.Extrusion of Ag 2 Sgenerates an isoimide intermediate,w hichu ndergoes acyl transfer to generate the native cyclic peptide,r esulting in ar apid, traceless macrocylization process.Cyclic peptides are furnished in high yields within 1hour,free of epimerization and cyclodimerization.

A Bottom-Up Approach To Preserve Thioamide Residue Stereochemistry during Fmoc Solid-Phase Peptide Synthesis

“…6−8 Thioamides can also be employed in photochemical schemes as photoswitches 9,10 or as fluorescent quenchers to study conformational changes in peptides. 11−15 In view of the importance of thioamides in peptide chemistry, 16 methods for their incorporation into peptides with robust stereochemical integrity are highly desirable. Activated thioamide precursors can be prepared from Fmocprotected amino acids 17,18 and introduced into peptides following standard solid-phase peptide synthesis (SPPS) protocols.…”