Disulfide bond formation using the silyl chloride-sulfoxide system for the synthesis of a cystine peptide

Abstract

An efficient method for disulfide bond formation in peptides by the silyl chloride-sulfoxide system is described. Methyltrichlorosilane in trifluoroacetic acid, in the presence of diphenyl sulfoxide, is found to cleave various S-protecting groups of cysteine to form cystine directly within 10-30 min. No side reactions were observed with nucleophilic amino acids such as Met, His, or Tyr, except for Trp, under the reaction conditions of the silyl chloride-sulfoxide treatment. A chlorination of the indole moiety of unprotected Trp, rather than sulfur-sulfur bond formation, is a dominant reaction when the peptide containing unprotected Trp is treated with the chlorosilane-sulfoxide. However, the disulfide bond can be formed efficiently with no modification at the indole ring by treatment of the peptide having a formyl-protect ed Trp residue with the silyl chloride-sulfoxide system. The formyl group is removed by a brief treatment at basic pH without affecting the disulfide bond formed by the silyl chloride-sulfoxide treatment. This new disulfide bond forming reaction in trifluoroacetic acid is successfully applied to the syntheses of oxytocin, human brain natriuretic peptide, and somatostatin without any solubility problem.