Computational Insights Into Enantioselectivity Differences in Pseudoenantiomeric Cinchona Alkaloid‐Catalyzed Imine Umpolung Michael Additions

ABSTRACT Pseudoenantiomeric cinchona alkaloid‐derived organocatalysts offer one of the most widely applied approaches to synthesize both enantiomers of target products. Although the catalyst pairs differ only subtly in the position of the vinyl group, various studies have revealed the uneven chiral induction ability between them. This phenomenon remains unexplained by current computed stereochemical models. We herein report DFT calculations on the imine umpolung Michael addition reaction between a trifluoromethyl imine and an α,β‐unsaturated N‐acyl pyrrole, which is catalyzed by catalysts quinidinium QD and its pseudoenantiomeric catalyst quininium Q . New stereochemical models are established to elucidate the weak bonding interactions governing substrate‐catalyst binding, including π–π stacking and N + –CH···O ion‐pairing interactions. The calculated ΔΔ G ‡ values successfully reproduce the change in enantioselectivity associated with the different vinyl positions in the pseudoenantiomeric catalysts. These models successfully rationalize the long‐standing “vinyl effect” observed in cinchona alkaloid‐derived pseudoenantiomeric catalysts.