UC San Diego

Sulfur-based reactivity and peptide macrocyclization provide complementary opportunities for controlling molecular structure and function. In this work, we report a unified investigation spanning electrophilic aromatic sulfenylation, regioselective Lewis base catalysis, and the development of a tryptophan-directed peptide stapling platform. We first describe a mild and general Lewis Base/Brønsted acid system that promotes rapid C–H sulfenylation of arenes using N-thiosuccinimide reagents. Kinetic analysis reveals that electron-rich sulfide products enable autocatalysis, whereas electron-poor systems require exogenous Lewis base catalysis. These findings inform the design of chiral indane-derived selenide catalysts that overcome innate para preference and deliver enhanced ortho selectivity, establishing that C–S bond formation can be directed through rational Lewis base tuning. Building on this mechanistic foundation, we next explore the unique chemical behavior of tryptophan, an electronically rich, structurally privileged, and interface-enriched amino acid, as a site-selective anchor for biomolecular modification. Leveraging its inherent C2 nucleophilicity, we introduce a metal-free Lewis base/Brønsted acid-catalyzed tryptophan sulfenylation strategy using PEG-based N-thiosuccinimide linkers to achieve i,i+4 macrocyclization. This Trp–Trp stapling platform exhibits broad compatibility, preserves native cysteine and lysine residues, and effectively stabilizes α-helical structure across both established and unexplored peptide–protein interaction targets. Together, these studies provide new insights into electrophilic sulfenylation mechanisms, regioselective Lewis base catalysis, and the underused potential of tryptophan as a covalent handle, culminating in a versatile new approach for peptide stapling and molecular design.