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 π-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.