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

Abstract

We have developed a DABCO-catalyzed disulfuration reaction of azlactones using N-dithiophthalimides for the preparation of the SS-linked amino acid 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. Leveraging the ready availability of N-dithiophthalimides from several bilateral disulfurating reagents and the transformability of the azlactone moiety through ring-opening with various nucleophiles, our method offers a wide variety of disulfide–peptide conjugation in a modular and time-efficient manner, serving as a valuable tool for linker chemistry and peptide chemistry.