Stereogenic and Conformational Diversity in Multicomponent Ir-Catalyzed Borylation of Arenes: Unveiling the Origin of Enantioselectivity by Conformational Sampling

To date, multicomponent transition-metal-catalyzed asymmetric reactions have led to pivotal breakthroughs in modern catalysis. However, investigations on the mechanism of these reactions are inherent challenges due to the coeffect of the complicated stereostructures and multiple noncovalent interactions. Here, we proposed a stepwise computational workflow combining density functional theory (DFT) calculations and molecular dynamics (MD) simulations to investigate a multicomponent Ir-catalyzed asymmetric borylation of arenes induced by chiral cations. Based on a definite rate-determining step investigated by DFT calculations, we employed MD simulations with constrained harmonic potential for coordinate bonds to completely sample the conformations of enantioselectivity-determining transition-state ensembles. Interestingly, results reproduce well the experimental enantioselectivity (ee value) and clearly reveal that both quantity and energy of conformations are responsible for the enantioselectivity. Systematical analysis on the conformations suggests that the advantages of <i>tert</i>-butyl group substitution at the <i>meta</i> position of the outer chiral cation for enantioselective C-H borylation do not arise from steric repulsion of the <i>tert</i>-butyl group destabilizing the unfavorable <i>R</i>-forming transition states but other two factors: (i) the limited conformational freedom due to the bulky <i>tert</i>-butyl group and (ii) the dispersion interactions between the <i>tert</i>-butyl group and the methyl group of the Bpin ligand stabilize the <i>S</i>-forming transition state more than <i>R</i>-one. This work underscores the fundamental significance and importance of conformational space accessibility and multiple noncovalent interactions for elucidating the origin of asymmetry induction.