Peptide Carbocycles: From −SS– to −CC– via a Late-Stage “Snip-and-Stitch”

Abstract

One way to improve the therapeutic potential of peptides is through cyclization. This is commonly done using a disulfide bond between two cysteine residues in the peptide. However, disulfide bonds are susceptible to reductive cleavage, and this can deactivate the peptide and endanger endogenous proteins through covalent modification. Substituting disulfide bonds with more chemically robust carbon-based linkers has proven to be an effective strategy to better develop cyclic peptides as drugs, but finding the optimal carbon replacement is synthetically laborious. We report a new late-stage platform wherein a single disulfide bond in a cyclic peptide can serve as the progenitor for any number of new carbon-rich groups, derived from organodiiodides, using a Zn:Cu couple and a hydrosilane. We show that this platform can furnish entirely new carbocyclic scaffolds with enhanced permeability and structural integrity and that the stereochemistry of the new cycles can be biased by a judicious choice in silane.