MOLECULAR MECHANICS AND NOE INVESTIGATIONS OF THE SOLUTION STRUCTURESOF INTERMEDIATES IN THE [RH(CHIRAL BISPHOSPHINE)]-CATALYZED HYDROGENATION OF PROCHIRAL ENAMIDES()

In order to probe the structural features that give rise to the high e nantioselectivity observed for the hydrogenation of methyl (Z)-alpha-a cetamidocinnamate (MAC) as catalyzed by complexes containing the fragm ent [Rh(chiral bisphosphine)]+, we have utilized NOE spectroscopy comb ined with molecular mechanics computations. In addition to the olefini c substrate MAC, we have examined its isopropyl ester (PRAC) and the d iolefins norbornadiene and cyclooctadiene. Results are presented for t he chiral bisphosphines DIPAMP, CHIRAPHOS, and DIPH. We address the fo llowing questions. (1) How does the chirality of the chiral bisphosphi ne ligand give rise to enantiodifferentiating interactions when a proc hiral enamide is bound to the catalyst? (2) Are the solution structure s of the catalysts similar to the crystallographically determined soli d-state structures? (3) Can molecular mechanics computations account f or the diastereoselectivities observed for the binding of the pro-R vs pro-S faces of MAC to the catalyst and for the rates of reaction of t hese intermediates with dihydrogen? The primary analytical methods emp loyed are the SHAPES force field (for molecular mechanics computations ) and conformer population analysis (CPA, for multiconformational anal ysis of NOE data) that have been developed in our laboratory. The resu lts of these investigations demonstrate that these highly selective ca talysts exhibit significant conformational mobility and the structure cannot be considered a rigid, chiral template. Overall, the solution a nd solid-state structures are similar, although both molecular mechani cs and NOE investigations suggest that multiple conformers may be acce ssed. The principal enantiodiscriminating interaction appears to occur between the plane of the enamide ester function and the proximal aren e ring of the chiral bisphosphine. We conclude that molecular mechanic s computations can account for the binding diastereoselectivities of t he antipodal faces of MAC to the catalysts but not for the relative re activities of these intermediates with dihydrogen. As a result of the high steric energies computed by molecular mechanics, we cast doubt on the purported intermediacy of a six-coordinate dihydride in the catal ytic asymmetric hydrogenation of prochiral enamides.