In Silico Screening of P,N-Ligands Facilitates Optimization of Au(III)-Mediated S-Arylation

Abstract

Metal-mediated cysteine S-arylation is an emerging bioconjugation technique due to its high chemoselectivity, rapid kinetics, and aqueous compatibility. We have previously demonstrated that by altering the sterics of the ligand and aryl groups of an Au(III) oxidative addition complex, one can modulate the kinetics of the bimolecular coordination and induce rate constants up to 16,600 m⁻¹s⁻¹. To further enhance the rate of coordination, density functional theory (DFT) calculations were performed to investigate the steric properties of the P,N-ligated Au(III) oxidative addition complex as well as the thermodynamics of the S-arylation reaction. This allowed for the accelerated screening of 13 new Au(III) oxidative addition complexes. Three of these more sterically promising, synthetically available P,N-ligands were synthesized, incorporated into Au(I) and Au(III) complexes, and the rates studied experimentally. The comprehensive mechanistic insights from the DFT calculations led to the development of new reagents with bimolecular coordination rate constants as fast as 20,200 m⁻¹s⁻¹. Further experimental characterization of these reagents’ efficacy as S-arylation reagents led to a proposed switch in selectivity-determining step for the fastest reagent, which was further confirmed by profiling the reductive elimination kinetics. This work provides a concise workflow for the screening of metal-mediated cysteine S-arylation reagents and new fundamental insights into the coordination chemistry behavior of Au(III) systems.