Sulfilimine, a privileged class of −S(IV)=N− functional group found in nature, have been exploited as valuable building blocks in organic synthesis and as pharmacophores in drug discovery, and have aroused significant interests for chemical community. Nevertheless, the 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 sulfilimines fragment into peptides by an intermolecular sulfur atom transfer cascade reaction, utilizing hydroxylamine condensed with their acid moieties and varied diaryl disulfides. It provides a convenient, efficient, metal-free and widely applicable method for late-stage peptide modification and functionalization at their acid sites both in the homogeneous phase and on-resins in SPPS. Moreover, the modified peptides with sulfilimines have been demonstrated as a cleavable linker for peptide conjugates under reducible conditions, providing unique opportunities in peptide therapeutics development and drug discovery.

This article is Open Access

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