Binding Modes and Origins of Enantioselectivity in the Phase-Transfer-Catalyzed Conjugate Cyanation of β-Trifluoromethylated Chalcones

Despite their importance in industrial applications, enantioselective phase-Transfer catalyzed reactions are poorly understood, especially for anionic nucleophiles other than enolates. In this context, we have studied the quinidinium-catalyzed phase-Transfer cyanation of trifluoromethylated chalcones, reported by Shibata in 2012 and patented by Syngenta in 2016, using density functional theory (DFT) calculations. To efficiently sample the conformational space available to the noncovalently bound systems, we have designed a multistage procedure involving interrupted constrained optimizations, which identifies the most relevant conformers while sparing computational resources. A full study of the mechanism with a model catalyst confirmed that the 1,4-Addition step is enantiodetermining in this reaction. Our calculations predict a 97:3 e.r. favoring the (R) enantiomer at the B3LYP-D3(BJ)/Def2TZVPP/SMD(i-Pr₂O) level of theory, in excellent agreement with the experimental results. A complete analysis of the available binding modes of the substrates with the catalyst demonstrates that the strong stabilization of the two reaction partners by the ammonium α-hydrogens in the transition structure is critical to lower the activation barrier for the conjugate addition and that-stacking interactions are not the main drivers of the selectivity as previously thought. These discoveries allowed us to propose a model of selectivity for the conjugate cyanation of chalcones, which mirrors the previously reported model for phase-Transfer-catalyzed enolate alkylations.