Alkenylation of cys-containing peptides with thianthrenium salts via thio-addition-migration

Peptide modification and stapling are widely recognized as effective strategies for improving the metabolic stability and enhancing cellular permeability of peptides. Alkenylthio units, which naturally occur in various peptides and proteins, play crucial roles in improving their stability and bioactivity. Herein, we present a mild, metal-free protocol for the rapid and efficient alkenylation of cysteine residues to build stable alkenylthio units in peptides and proteins. This method facilitates both the modification and macrocyclization of thiol-containing peptides and proteins by a formal C-S bond formation with a library of alkenyl thianthrenium salts. Mechanistic studies indicate that this alkenylation process involves the β-addition of alkenyl thianthrenium salts with thiolate and subsequent 1,2-thio-migration. Various protected/unprotected peptides and proteins can be conjugated with a range of alkenylthio units and fluorescent tags. Moreover, by incorporating the pentafluoroaryl ring into the alkenyl thianthrenium salts, this protocol enables the stapling and macrocyclization of bioactive and therapeutic peptides.