Comparison with the Mannich Reaction

The Mannich reaction is a close relative of the aldol, whereby an imine replaces the aldehyde acceptor. Proline has been demonstrated to be an excellent catalyst of the Mannich reaction, inducing high enantiomeric excess, as shown in Table 6.13. ° Pertinent to this discussion is that the stereochemical outcome of the proline-catalyzed Mannich reaction is opposite to that of the proline-catalyzed aldol reaction. 

Houk and Bahmnyar located the TSs for the Mannich reaction of the enamine of acetone and proline with A-ethyUdine-A-phenylamine (Reaction 6.27) at B3LYP/6-31G. They looked only for the TSs that allowed for proton transfer from 

TABLE 6.13 Comparison of the Proline-Catalyzed Mannich and Aldol Reactions 

The lowest energy TS 72a does correspond with the experimentally observed major product, and the energy differences with the other TSs are consistent with the typically large ee found in experiment. These computations are consistent with List s mechanistic proposal for the proline-catalyzed Mannich reaction. Further confirmation was provided by a computational smdy of Reaction 6.28. 

Two important aspects of the mechanism of this reaction were probed in detail using MP2/6-31-H-G(d,p)//B3LYP/6-31-H-G(d,p) computations. The first 

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