Origin of enantioreversal in the rhodium-catalyzed asymmetric hydrogenation of prochiral enamides and the effect of the α-substituent

The enantioselectivity of prochiral enamide hydrogenation depends on the structure of the enamide, with particular sensitivity to the nature of the a-substituent. Recently, Burk has reported a spectacular example of structure sensitivity for [Rh(DuPHOS)](+)-catalyzed enamide hydrogenations: although enamides containing either carboxyl or tert-butyl cl-substituents hydrogenate to greater than or equal to 99% enantiomeric excess, the sense of enantioselection for the two substrate classes is reversed. Why should the magnitude and sense of enantioselectivity depend so strongly on the enamide alpha -substituent? We report the application of QM/MM (ONIOM) computations to address this long-standing issue in asymmetric catalysis. Specifically, we demonstrate that computational methods reproduce the alpha -substituent effect in enamide hydrogenation catalysis and probe how the interaction of the enamide C-C bond and the catalyst varies with the structure of the substrate. The picture that emerges emphasizes the complex confluence of both electronic effects (i.e., those effects that do not depend on the size of the model system) and steric effects in controlling the stereochemistry of enamide hydrogenation reactions.