The nucleophilic addition of nitrones to carbonyl compounds:: insights on the nature of the mechanism of the L-proline induced asymmetric reaction from a DFT analysis

The mechanism of the L-proline induced asymmetric nitrone-aldol reaction of N-methyl-C-ethylnitrone with dimethyl ketomalonate has been Studied by using density functional theory at B3LYP/6-31G** level. The reaction was initialized by the addition Of L-proline to the nitrone to form an aminal, which by elimination of the hydroxylamine gave a chiral enamine. The nucleophilic addition of this chiral enamine to dimethyl ketomalonate corresponds to stereoselective C-C bond-formation step. Further nucleophilic addition of hydroxylamine to the zwitterionic intermediate formed in the enamine addition gave a second aminal, which by L-proline elimination afforded the corresponding beta-hydroxynitrone. The B3LYP/6-31G** results are in acceptable agreement with previous experiments, allowing Lis to explain the stereoselectivity on the C-C bond-formation step. (C) 2004 Elsevier Ltd. All rights reserved.