Large-scale computational modeling of [Rh(DuPHOS)](+)-catalyzed hydrogenation of prochiral enamides: Reaction pathways and the origin of enantioselection

The potential energy surface for the [Rh((R,R)-Me-DuPHOS)](+)-catalyzed asy mmetric hydrogenation of a prochiral enamide, alpha -formamidoacrylonitrile , has been computed using a three-layer hybrid quantum mechanics/molecular mechanics method (ONIOM). The bond-breaking and bond-forming region is mode led using a nonlocal density functional method (B3LYP), whereas HF theory a nd molecular mechanics (UFF) are used to describe the electronic and steric impact of the outer coordination sphere of the catalyst. Intermediates and transition states were calculated along four isomeric pathways of two dias tereomeric manifolds. The starting point for each manifold is a square plan ar catalyst-enamide complex. Binding of the re enantioface of the enamide t o the catalyst generates the more stable, major diastereomer, favored by 3. 6 kcal/mol over the minor diastereomer, which has the si face bound. Howeve r, the net free energy barrier for the reaction is 4.4 kcal/ mol lower for the minor diastereomer than for the major diastereomer, making the minor di astereomer considerably more reactive and reproducing the "anti-lock-and-ke y'' behavior observed experimentally in rhodium-catalyzed asymmetric hydrog enations. The difference in transition-state energies corresponds to an ena ntiomeric excess of 99.9% (R), within the range of experimental enantiosele ctivities of [Rh((R,R)-Me-DuPHOS)](+) hydrogenations. The stability and rea ctivity differences of the two diastereomers are explained using simple ste ric and electronic arguments. The sequence of elementary steps, as well as the relative orderings of intermediates and transition states, is very simi lar to that found in our previous work on the achiral model system [Rh(PH3) (2)(alpha -formamidoacrylonitrile)](+). We find oxidative addition to be th e turnover-limiting step of the catalytic cycle. Our results are consistent with available empirical data for rhodium-catalyzed asymmetric hydrogenati ons, although more detailed experimental studies are needed on the specific model system studied herein.