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

The enantioselectivity of prochiral enamide hydrogenation depends on the st ructure 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 hydrogen ate to greater than or equal to 99% enantiomeric excess, the sense of enant ioselection for the two substrate classes is reversed. Why should the magni tude and sense of enantioselectivity depend so strongly on the enamide alph a -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 eff ect in enamide hydrogenation catalysis and probe how the interaction of the enamide C-C bond and the catalyst varies with the structure of the substra te. The picture that emerges emphasizes the complex confluence of both elec tronic effects (i.e., those effects that do not depend on the size of the m odel system) and steric effects in controlling the stereochemistry of enami de hydrogenation reactions.