Gold-Promoted Biocompatible Selenium Arylation of Small Molecules, Peptides and Proteins.

A low pKa (5.2), high polarizable volume (3.8 angstrom), and proneness to oxidation under ambient conditions make selenocysteine (Sec, U) a unique, natural reactive handle present in most organisms across all domains of life. Sec modification still has untapped potential for site-selective protein modification and probing. Herein we demonstrate the use of a cyclometalated gold(III) compound, [Au(bnpy)Cl2], in the arylation of diselenides of biological significance, with a scope covering small molecule models, peptides, and proteins using a combination of multinuclear NMR (including 77Se NMR), and LC-MS. Diphenyl diselenide (Ph-Se)2 and selenocystine, (Sec)2, were used for reaction optimization. This approach allowed us to demonstrate that an excess of diselenide (Au/Se-Se) and an increasing water percentage in the reaction media enhance both the conversion and kinetics of the C-Se coupling reaction, a combination that makes the reaction biocompatible. The C-Se coupling reaction was also shown to happen for the diselenide analogue of the cyclic peptide vasopressin ((Se-Se)-AVP), and the Bos taurus glutathione peroxidase (GPx1) enzyme in ammonium acetate (2 mM, pH=7.0). The reaction mechanism, studied by DFT revealed a redox-based mechanism where the C-Se coupling is enabled by the reductive elimination of the cyclometalated Au(III) species into Au(I). Organometallic gold(III) compounds are introduced here as a valuable addition to the toolkit of metal-based systems apt at facilitating selenium arylation, with applications spanning from synthetic chemistry to selenoprotein modification. By combining multinuclear NMR, LC-MS and DFT we show that the compound [Au(bnpy)Cl2] enables the arylation of diselenides and selenols present in small molecules, peptides, and proteins via a redox-based mechanism.image