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

Abstract 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.