Stereocenters adjacent to heterocycles are prevalent in natural products and pharmaceuticals. However, their synthesis is challenging due to the sensitivity of heterocycles to reaction conditions. A BINOL-catalyzed enantioselective conjugate addition of vinyl boronic acids to heterocycle-appended enones was developed by May and co-workers (Org. Lett. 2012, 14, 6104-6107) to increase the scope of synthetically accessible α-chiral heterocycles. The selectivity and rate of the reaction were found to be strongly dependent on the 3,3′-substituents of the BINOL. We first used the open-source computational toolkit AARON (An Automated Reaction Optimizer for New catalysts) to quantum mechanically screen a virtual library of 28 BINOL-derived catalysts, identifying one substituted BINOL predicted to offer improved activity and selectivity com-pared to previously-known catalysts for this reaction. We then used these computational data to derive a multivariate linear model of the electronic and geometric factors that control the activity and selectivity of catalysts for this reaction. Contrary to the common assumption that only the energy difference in barrier heights between the (R) and (S) pathways must be considered, we found that the enantioselectivity of these reactions is primarily based on the ability of the catalyzed reaction to out-compete the racemic background reaction. Finally, we experimentally tested the most promising new catalysts and confirmed their predicted performance.

Catalyst optimization through quantum mechanical screening and multivariate linear regressions

ACS Fall 2021

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