Electrochemical Late‐Stage Stitching of Tryptophan Peptides via N─S Bond Formation

Late-stage diversification of peptides via selective modification of endogenous amino acid side chains provides a powerful strategy to access analogues with enhanced bioactivity and tailored physicochemical properties, thereby facilitating peptide-based drug discovery. However, precise manipulation of short peptides comprising canonical amino acids-particularly control over backbone conformation-remains a formidable challenge. Herein, we present a robust electrochemical strategy for constructing macrocyclic peptides through direct incorporation of diverse aryl sulfur linkers. This method enables tryptophan (Trp)-selective crosslinking via electrochemical reaction with aryl thiosulfonates, leading to efficient formation of S─N bonds. The resulting sulfur-bridged multi-aryl macrocycles act as conformationally adaptive scaffolds that reshape the peptide backbone architecture. This conformational remodeling grants access to previously inaccessible structural spaces that are critical for modulating biological activity.