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Computational investigations on the phosphine-ligated CuH-catalyzed conjugate reduction of α-β unsaturated ketones: regioselectivity and stereoselectivity

Computational investigations on the phosphine-ligated CuH-catalyzed conjugate reduction of α-β unsaturated ketones were performed with the DFT method. Two phosphine-ligated CuH catalysts, Ph3P–CuH and (R)-SEGPHOS–CuH, were employed to probe the reaction mechanism with the emphasis on regioselectivity and stereoselectivity. The calculations on the Ph3P–CuH system indicate that there exist two competing reaction pathways: the 1,4- and 1,2-path. The 1,4-path is predicted to be energy-favoured among these reaction paths. The mechanism of the 1,4-path includes two steps: (1) the first step is predicted to be the rate-determining step (RDS), corresponding to the delivery of the hydrogen atom of the CuH catalyst to the β-carbon atom of the substrate, with the formation of the enolate; (2) in the second step, the enolate undergoes a σ-bond metathesis with the hydride source to liberate the final product and regain the catalysts. In the chiral (R)-SEGPHOS–CuH system, the first step of CuH to the unsaturated bond is vital for the distribution of products and therefore responsible for the stereoselectivity of the 1,4-addition. The calculations on the (R)-SEGPHOS–CuH system reproduce the major product in the R-configuration, which is consistent with the experimental observation. The steric hindrance between the bulky substituent moiety of the substrate and the P-phenyl ring of the SEGPHOS–CuH catalyst is identified as the origin of the stereoselectivity for the titled reaction.