Chemoselective and Regioselective Synthesis of Disulfide Bonds in Peptides via Electrophilic Substitution and Oxidation Reactions with Benzeneselenyl Bromide (Chloride)

In this work, electrophilic substitution and oxidation reactions with benzeneselenyl bromide (BSB) and benzeneselenyl chloride (BSC) were applied in peptide synthesis. Using the electrophilic substitution reaction, BSB and BSC modified the cysteine (Cys) residue to generate a (phenylselenenyl)sulfide group in the peptide. This group then reacted with the Cys residue of another peptide, affording either an asymmetric or symmetric intermolecular disulfide bond. Furthermore, both BSB and BSC can react with either two acetamidomethyl (Acm)-protected Cys residues (Cys(Acm)) or one 1,3-thiazolidine-4-carbonyl (Thz) group and one Cys(Acm) residue in acidic media. This reaction proceeds via the electrophilic substitution to form two (phenylselenenyl)sulfide groups in the peptide. These groups subsequently disproportionated to form an intramolecular disulfide bond. By utilization of the oxidation reaction, a pair of free Cys residues were oxidized to generate the intramolecular disulfide bond in the peptide. By combining the electrophilic substitution and oxidation reaction, two disulfide bonds were chemoselectively and regioselectively constructed in a-conotoxin IMI, a-conotoxin SI, a methionine-containing peptide, and apamin via a one-pot manner. Excellent yields of these peptides were achieved. Moreover, no oxidation reactions occurred on tryptophan (Trp), methionine (Met), or tyrosine (Tyr) residues in peptides.