Late-Stage Aromatic C-H Bond Functionalization for Cysteine/Selenocysteine Bioconjugation.

Bioconjugation of peptides and proteins has become an indispensable tool in fundamental biological research and drug development. Herein, we report a copper-mediated efficient cysteine/selenocysteine-specific bioconjugation through direct C-H functionalization of electron-rich arenes under biocompatible reaction conditions. In this method, a series of commercial electron-rich arenes, including natural products and drug molecules, are conjugated to cysteine/selenocysteine-containing peptides and proteins. Furthermore, we show that this new bioconjugation method allows the efficient stapling of peptides, as well as the cross-linking of different peptides to a single arene, all in high yields. The tunable electron density of small molecules enables the selective modification of selenocysteine in the presence of cysteine residues. Finally, mechanistic studies suggest that the conjugation proceeds via a proton-coupled electron transfer (PCET) process and substrate radical binding to the copper for C-Se/S bond formation. This approach provides an efficient strategy for the late-stage functionalization of complex small molecules to generate peptide/protein conjugates.