Reversible and Versatile On-Tether Modification of Chiral-Center-Induced Helical Peptides

Abstract

Modification of the cross-linker of constrained peptides has recently received considerable attention. Here, we present a versatile approach to modifing the cross-linking tether of chiral-center-induced helical (CIH) peptides via the S-alkylation reaction. The alkylation process displayed high conversion efficiency, selectivity, and substrate tolerance. Notably, although on-tether S-alkylation could lead to a pair of peptide epimers, the major alkylated product retained the helical structure of its helical precursor peptide. This S-alkylation was readily reversible under reductive conditions, which provides a simple method for traceless modification. In addition to expanding the chemical space of CIH peptides, this strategy is the first on-tether modification platform with known retention of the peptides' original helicity.