Late-Stage Cysteine-Selective <i>S</i> -Sulfonylation and Penicillamine-Selective <i>S</i> -Sulfenylation: Peptide Functionalization via Thiosulfonate Chemistry

Peptide functionalization enables the attachment of functional groups to amino acid residues present in peptides to alter their physiochemical properties. In this study, we discovered the new reactivity of fluorinated 8-quinoline thiosulfonates, leading to the development of a straightforward, late-stage modification strategy for synthesizing cysteine thiosulfonates on native peptides. Comparison studies between cysteine and penicillamine peptides reveal that trifluoromethyl thiosulfonates act as electrophilic sulfenylating reagents with mercaptans. The key to achieving cysteine-selective S-sulfonylation lies in the formation of a reactive trifluoromethyl sulfenylating intermediate, which is subsequently attacked by sulfinic acid or sulfinate species on less sterically hindered cysteine peptides.