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 enable 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.