Theoretical Insight into the Mechanism, Selectivity, and Substituent Effects in Rh-Catalyzed Asymmetric Arylation of Cyclobutenone Ketals with Arylboronic Acids

Abstract

DFT calculations were conducted to elucidate the reaction mechanism, the origin of selectivities, and substituent effects in the rhodium-catalyzed asymmetric arylation of cyclobutenone ketals with arylboronic acids. The results reveal that both regioselectivity and enantioselectivity are determined by the carbometalation step. The strong preference for 1,2-carbometalation over 2,1-carbometalation arises from reduced steric repulsion and favorable electronic interactions. Enantioselectivity toward the (S)-configured product originates from a combination of minimized steric congestion and a stabilizing hydrogen-bonding interaction in the key transition state. The substituents on the arylboronic acids play a crucial role in governing the reaction selectivity. Electron‑withdrawing substituents preferentially stabilize the byproduct-forming transition state, thereby narrowing the energy gap and diminishing selectivity, whereas electron-donating substituents widen this gap, suppress the byproduct pathway, and enhance both selectivity and yield. This study provides quantitative, molecular-level insights into selectivity control and substituent effects that were not accessible from the previously proposed qualitative mechanism.