Disulfuration of Azlactones: A Versatile Entry to Unnatural, Disulfide-Linked Amino Acids and Peptides

We have developed a base-catalyzed disulfuration reaction of azlactones using N-dithiophthalimides for the preparation of the hitherto unexplored SS-linked amino acid/peptide derivatives. This reaction proceeds under mild conditions, yielding disulfurated azlactones in excellent yields across a variety of N-dithiophthalimides and diverse azlactones derived from various amino acids and peptides. Leveraging the ready availability of N-dithiophthalimides from several bilateral disulfurating reagents, this method allows for the modular integration of functional molecules and azlactones into SS- linkage in two-step operations. Furthermore, due to the transformability of the azlactone moiety through ring-opening with various nucleophiles, our method provides a wide variety of functional molecule-tagged amino acids and oligopeptides bearing SS-linkages in a modular and time-efficient manner, serving as a valuable tool for linker chemistry and peptide chemistry.