One-Pot Cyclization and Cleavage of Peptides with N-Terminal Cysteine via the N,S-Acyl Shift of the N-2-[Thioethyl]glycine Residue

We developed a one-pot method for peptide cleavage from a solid support via the N,S-acyl shift of N-2-[thioethyl]glycine and transthioesterification using external thiols to produce cyclic peptides through native chemical self-ligation with the N-terminal cysteine. The feasibility of this methodology is validated by the syntheses of model short peptides, including a tetrapeptide, the bicyclic sunflower trypsin inhibitor SFTI-1, and rhesus Θ-defensin RTD-1. Synthesis of the whole peptide precursor can be fully automated and proceeds without epimerization or dimerization.