A method for the one-pot regioselective formation of the two disulfide bonds of α-conotoxin SI

A one-pot method for the regioselective formation of the disulfide bridges of α-conotoxin SI employing temperature-controlled orthogonal protecting groups is reported. The pairing of t-butyl and 4-methylbenzyl side-chain protecting groups was chosen for the four cysteine residues. Cleavage of the peptide from a solid support afforded a fully S-protected crude product. The first disulfide bridge was formed directly from the crude material by simultaneous cleavage and oxidation of the t-butyl groups in TFA:DMSO:anisole (97.9:2:0.1) at room temperature. The subsequent heating of this solution resulted in the cleavage of the 4-methylbenzyl groups with simultaneous oxidation yielding the desired bicyclic product.