Catalytic Asymmetric 5-Enolexo Aldolizations. A Computational Study
ABSTRACT The diastereo- and enantioselectivity obtained experimentally by Enders in the amine- catalyzed intramolecular 5-enolexo aldolization of 1,6-dicarbonyl compounds were fully rationalized using density functional theory methods. A polarizable continuum model was used to describe solvent effects. While 6-enolexo aldolizations are well described by Houk’s model on the basis of steric and electrostatic contacts, the main factors conditioning the final selectivity in 5-enolexo processes are calculated to be quite different. Thus, the selectivity results from the summation of several small electrostatic contacts with an unexpected HOMO electronic overlapping plus the ring strain of the 5-membered ring, while steric effects seem to be unimportant. Our results indicate, in contrast with 6-enolexo processes, that high selectivities aren’t expected in this type of reaction and that the experimental selectivity shall be very dependent on the reaction conditions, as known experimental results seem to suggest. 7-enolendo products are not expected, as they are predicted to be formed by higher energetic transition states. Variable reaction rates, experimentally observed with different catalysts, are suggested to be mainly a result of different catalyst solubility.