Intermolecular sulfur atom transfer cascade enabled late-stage introduction of sulfilimines into peptides†

Abstract

Sulfilimines, a privileged class of –S(IV)N– functional groups found in nature, have been exploited as valuable building blocks in organic synthesis and as pharmacophores in drug discovery, and have aroused significant interest in the chemical community. Nevertheless, strategies for late-stage introduction of sulfilimines into peptides and proteins have still met with limited success. Herein, we have developed a method of introducing biological sulfilimine fragments into peptides by an intermolecular sulfur atom transfer cascade reaction, utilizing hydroxylamine condensed with the acid moieties of peptides and varied diaryl disulfides. It provides a convenient, efficient, metal-free and widely applicable method for late-stage modification and functionalization of peptides at their acid sites both in the homogeneous phase and on-resins in SPPS. Moreover, the modified peptides with sulfilimines have been demonstrated as cleavable linkers for peptide conjugates under reducible conditions, providing unique opportunities in peptide therapeutics development and drug discovery.