While redox processes are often utilized for protein modification processes, iridium hydride-based catalytic reductive alkylation remains the sole example of the catalytic reduction for protein bioconjugation purposes in this metal catalysis section (Scheme 9A, 9B). Analogous to the traditional protein modification strategy using aldehyde and cyanoborohydride reagents, 141 the iridium-based hydride reduction would occur through the Schiff base formation from the protein amines followed by the reduction of the Schiff base to amine. The catalytic system reported by Francis and co-workers utilized activation of a pro-catalyst, watersoluble iridium Cp* complex through reduction with sodium formate (Scheme 9B). Electron-rich bipyridine ligands were found to be particularly effective, which perhaps is an indication of importance of nucleophilicity of the metal hydride species. While this iridium catalysis has been used in other reports, there has not been other metal-catalyzed reductive approaches developed for protein bioconjugation. The lack of the development may be due to the challenges of retention of reduction-sensitive S-S bonds in proteins, although mild and/or bulky reductants such as ascorbate and triarylphosphine 144 have been successfully utilized in the protein labeling strategies. Reduction-based metal catalysis may grow dramatically for protein modification fields, as reductive metal catalysis (e.g., metal hydride chemistry) has been useful in many chemical biology applications. Scheme 9. Iridium-catalyzed reductive alkylation/amination. (A) General reaction scheme. (B) The structure of the procatalyst (left) and active catalyst after reduction with sodium formate (right).