Synthesis of Cystine-Stabilised Dicarba Conotoxin EpI: Ring-Closing Metathesis of Sidechain Deprotected, Sulfide-Rich Sequences

Recombinant peptide synthesis allows for large-scale production of peptides with therapeutic potential. However, access to dicarba peptidomimetics via sidechain-deprotected sequences becomes challenging exposed Lewis basicity presented by amine and sulfur-containing residues. Presented here is a combination strategies which can be used deactivate coordinative residues achieve high-yielding Ru-catalyzed ring-closing metathesis. The chemistry exemplified using α-conotoxin EpI, native bicyclic disulfide-containing sequence isolated from the marine conesnail Conus episcopatus. Replacement loop I disulfide E/Z–dicarba bridges was achieved high conversion solution-phase metathesis unprotected linear after simple chemoselective oxidation ion-exchange masking problematic functionality. Metathesis also attempted in green solvent choices further improve sustainability synthesis.