Disulfide bond‐forming reaction using a dimethyl sulfoxide/aqueous HCl system and its application to regioselective two disulfide bond formation

Disulfide bond formation in S‐acetamidomethyl (Acm) cysteine‐containing peptides by successive treatments with silver trifluoromethanesulfonate (AgOTf) and dimethyl sulfoxide (DMSO)/aqueous HCl is described. An S‐Acm cysteine was found to be quantitatively converted into cystine by deprotection of the Acm group with AgOTf followed by DMSO/aqueous HCl treatment. Under these reaction conditions, no significant side reactions were observed with oxidation‐sensitive amino acids such as Met, Tyr and Trp. Oxytocin and a Trp‐containing peptide, urotensin II, were prepared by this method. Furthermore, regioselective two disulfide bond formation was found to be feasible by the combination of air oxidation and the AgOTf‐DMSO/HCl system. This strategy has been successfully applied to the syntheses of tachyplesin I and endothelin I, which have two disulfide bonds and a Trp residue in the molecule.