Asymmetric conjugate addition of ketones to β-nitrostyrenes by means of 1,2-amino-alcohol-derived prolinamides as bifunctional catalysts

Different L-prolinamides 21, prepared from L-proline and chiral P-amino alcohols are active bifunctional catalysts for the direct nitro-Michael addition of ketones to beta-nitrostyrenes. In particular, catalyst 21e, prepared from L-proline and (1S,2R)-cis- 1-amino-2-indanol, exhibits the highest catalytic performance working in polar aprotic solvents such as NMP, especially in the presence of 20 mol-% of acid additives such as p-nitrobenzoic acid or under microwave heating. High syn diastereoselectivities (up to 94% de) and good enantio-selectivities (up to 80% ee) are obtained at room temp. Moreover, catalyst 21e can be easily recovered and reused. ESI-MS studies are used to characterize the intermediates as-sumed for the catalytic cycle. The stereochemical control attending Michael addition reactions between ketones and nitrostyrenes catalyzed by prolinamide derivatives 21 has been investigated with computational density functional methods. Transition-state energies for the rate-limiting C-C bond-forming step are calculated. Analysis of these structures indicates that hydrogen bonding plays an important role in catalysis, and that the energy barrier for Re-face attack to form syn-(4S,5R) products is lower than that for Si-face attack leading to syn-(4R,5S) products. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007).