Disulfide-paired regioisomers of α-conotoxin SI can be accessed by orthogonal schemes using the combination of S-9H-xanthen-9-yl (S-Xan) and S- acetamidomethyl (S-Acm) groups for cysteine protection. Following solid-phase assemblies of the linear precursors, the peptides were cleaved from the solid support concurrent with removal of S-Xan protecting groups. The first disulfide bridges were formed in solution, using either the traditional DMSO method or a recently introduced approach featuring a solid-phase Ellman's reagent. The second disulfide bridges were oxidized by three different methods: reactions mediated by thallium trifluoroacetate, iodine, or a sulfoxide/silyl mixture. In general, yields depended primarily on which regioisomer was the target, rather than the specific chemistry used for either disulfide-forming step. However, the selectivities towards the desired regioisomers were reproducibly better using the solid-phase Ellman's reagent, by comparison to the DMSO method. In the most favorable cases, complete selectivity was achieved, while even in cases where the net results using DMSO gave considerable scrambling, the corresponding experiments with the solid-phase Ellman's reagent were more selective. Possible reasons why choice of oxidation method for the first step affects the selectivity at the second step are discussed.
- Disulfide pairing
- Orthogonal cysteine protection
- Solid- phase Ellman's reagent
- α-conotoxin SI