Computational Insights into Privileged Stereocontrolling Interactions Involving Chiral Phosphates and Iminium Intermediates.

The precise design of a catalyst for a given reaction is extremely difficult, often requiring a significant empirical screening campaign to afford products in high yields and enantiomeric excess. Design becomes even more challenging if one requires a catalyst that performs well for a diverse range of substrates. Such "privileged" catalysts exist, but little is known why they operate so generally. We report the results of computations which show that when substrate and catalyst features are conserved between significantly different mechanistic regimes, similar modes of activation can be invoked. As a validating case study, we explored a Hantzsch ester hydrogenation of α,β-unsaturated iminiums involving BINOL-derived chiral phosphates and find they impart asymmetric induction in an analogous fashion to their acid counterpart. Specifically, DFT calculations at the IEFPCM(1,4-dioxane)-B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level predicted enantioselectivity to be close to the experimental value (82% ee calculated, 96% ee experimental) and showed that the reaction proceeds via a transition state involving two hydrogen-bonding interactions from the iminium intermediate and nucleophile to the catalyst. These interactions lower the energy of the transition structure and provide extra rigidity to the system. This new model invokes "privileged" noncovalent interactions and leads to a new explanation for the enantioselectivity outcome, ultimately providing the basis for the development of general catalyst design principles and the translation of mechanistically disparate reaction profiles for the prediction of enantioselectivity outcomes using statistical models.