Development of Water‐soluble 3‐Nitro‐2‐pyridinesulfenate for Disulfide Bond Formation of Peptide under Aqueous Conditions

Establishing an efficient method for the synthesis of disulfide bonds in peptides is an important challenge for the further development of several research fields, including peptide‐based medicinal chemistry and biochemistry. Herein, we report the development of a novel highly water‐soluble 3‐nitro‐2‐pyridine (Npy) sulfenate that efficiently forms intramolecular disulfide bonds in reduced peptides. Moreover, Npy‐sulfenate formed a disulfide bond in a thiol‐containing peptide prepared by thiol‐additive‐free native chemical ligation (NCL), as demonstrated by the one‐pot synthesis of adrenomedullin, which contains 52 amino acid residues. This study provides a new one‐pot synthetic methodology for preparing mid‐sized cyclic disulfide peptides via sulfenate‐mediated oxidation.