Superfast Protein Desulfurization Triggered by Low‐Energy Visible Light

The combination of transthioesterification‐based ligation of thiol‐derived amino acids and the post‐ligation desulfurization has greatly expanded the scope of modern chemical protein synthesis. Here, we report a new strategy of low‐energy visible light‐induced desulfurization (LEnVLD) that enables superfast and clean protein desulfurization (half life = 1.7 s) with improved reaction selectivity compared to the previous methods. The LEnVLD method can be easily carried out under very mild conditions using only a catalytic amount of fluorescent dye and household flashlight (ca. 5 W) irradiation, eliminating the need for any pyrophoric reagent, thiol additives, or excessive radical initiators, and its practicality was demonstrated by the fast and high‐yielding desulfurization of more than 30 peptide and protein substrates bearing a variety of sensitive functional groups (e.g., Thz, N‐alkylated maleimide, and thioester). Moreover, the convenience and robustness of LEnVLD enables its extension to versatile reaction scenarios (e.g., solid‐supported desulfurization and flow chemistry‐based desulfurization) that would enhance the practical capability of chemical protein synthesis.