title: [A novel synthetic approach of tryptophan-containing cystine peptides by regioselective disulfide bond-forming reaction using the silyl chloride-sulfoxide system].
abstract: A general scheme for the efficient synthesis of Trp-containing cystine peptide by the successive treatment with methyltrichlorosilane-diphenylsulfoxide in trifluoroacetic acid (TFA) and trifluoromethanesulfonic acid (TFMSA)-thioanisole in TFA, is described. A disulfide bond-forming reaction by silyl chloride-sulfoxide system is completed within 10-15 min without modifications at sensitive residues (Tyr, His, Met) in peptide chain, except for a Trp residue. In order to synthesize a Trp-containing cystine peptide using silyl chloride, the indole moiety of Trp has to be protected since the chlorination of the indole ring proceeded predominantly. A formyl group has been the only protecting group employed for this purpose in practical syntheses of cystine peptides, although it was clarified that a side reaction derived from the formyl group migration was inevitable in the synthesis of somatostatin. Firstly, we examined the application of the following Nin-protecting groups, mesitylene-2-sulfonyl (Mts), cyclohexyloxycarbonyl (Hoc), and 2,4-dimethylpent-3-yloxycarbonyl(Doc) for an efficient synthesis of the Trp-containing cystide peptide by the silyl chloride method. In order to find a feasible scheme of the successive treatment with CH3SiCl3-PhS(O)Ph/TFA and TFMSA-thianisole in TFA, we synthesized somatostatin using Trp(Mts), Trp(Hoc) or Trp(Doc) derivative. The Doc group was found to be the most suitable as an indole protecting group, since the protecting group was cleaved under mild conditions (4 degrees C, 30 min) via the corresponding Nin-carboxylic acid intermediate. We then applied the above procedure to the synthesis of endothelin-1 (ET-1), a peptide containing 21-amino acid residues having a C-terminal Trp residue and two disulfide bonds, by regioselective disulfide formation. The combination of the silyl chloride method with iodine oxidation using S-acetamidomethyl (Acm) and S-tBu groups for the regioselective double disulfide formation was successfully applied to give a highly purified ET-1. These results also show that the Nin-Doc group would be useful for the efficient syntheses of complex cystine-peptides by the silyl chloride method.
authors.affiliation: Kyoto Pharmaceutical University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Fujiwara
mesh_terms: D000595:Amino Acid Sequence; D001555:Benzene Derivatives; D002625:Chemistry, Organic; D003553:Cystine; D004220:Disulfides; D019332:Endothelin-1 / Q000138:chemical synthesis / Q000737:chemistry; D008698:Mesylates; D008969:Molecular Sequence Data; D055601:Organic Chemistry Phenomena; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D012821:Silanes; D013004:Somatostatin / Q000138:chemical synthesis / Q000737:chemistry; D014269:Trifluoroacetic Acid; D014364:Tryptophan
chemical_list: D001555:Benzene Derivatives; D004220:Disulfides; D019332:Endothelin-1; D008698:Mesylates; D010455:Peptides; D012821:Silanes; D003553:Cystine; C048860:diphenyl sulfoxide; D013004:Somatostatin; D014364:Tryptophan; D014269:Trifluoroacetic Acid; C012077:trifluoromethanesulfonic acid; C049552:methyltrichlorosilane