Insights into the Synergistic Interplay of Ligand and Base Effects in Palladium-Catalyzed Enantioselectivity Hydrofunctionalization of Dienes

Transition-metal-catalyzed enantioselective C-O bond constructions via hydrofunctionalization involving the use of O-based nucleophiles are an important topic in synthetic chemistry. Herein, density functional theory calculations were conducted to unveil the mechanism and enantioselectivity of Pd-catalyzed asymmetric hydrofunctionalization of conjugated dienes. We found that the base-assisted 4,3-activation model of the ligand-to-ligand hydrogen transfer (LLHT) mechanism is the most preferred one among all the cases, which could be ascribed to the favorable C-H···O interactions and the electrostatic interactions. For the enantioselective C-O bond formation process, the orientation of the substrate in the chiral pocket plays a significant role in controlling the enantioselectivity by contributing different noncovalent interactions. On the basis of the distortion/interaction model and energy decomposition analysis, the distortion energy is identified as the dominant factor controlling the product chemoselectivity. BnOH acts as the substrate, proton shuttle, and stabilizer to facilitate the H-transfer process in both LLHT and the C-O bond formation process. This study provides molecular-level insights into the collaborative effect of the base and <i>P</i>,<i>N</i>-ligand to perform the catalytic activity in the asymmetric hydrofunctionalization of conjugated dienes, which might open a new avenue for designing more efficient base-assisted enantioselective hydrofunctionalization by Pd catalysis.