Catalytic Asymmetric 5-enolexo Aldolizations. A Computational Study

Abstract

The diastereo- and enantioselectivity obtained experimentally by Enders et all. (Enders, D.; Niemeier, O.; Straver, S. Synlett 2006, 3399-3402) 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 five-membered ring, whereas steric effects seem to be unimportant. Our results indicate, in contrast with 6-enolexo processes, that high selectivities are not 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 solubilities.

Iterative Coupling of Two Different Enones by Nitromethane Using Bifunctional Thiourea Organocatalysts. Stereocontrolled Assembly of Cyclic and Acyclic Structures

“…Most importantly, the bifunctional organocatalysts were able to induce a Michael addition onto α,β-unsaturated aldehyde 8a and then promote a direct intramolecular aldol reaction to selectively furnish the ketocyclohexanol 13a . Accordingly, the bifunctional thiourea catalyst was not only capable of the activation of the ketone moiety of ( S )- 5a but also of inducing the proper alignment of the aldehyde moiety to afford the syn -ketol functionality . Using the opposite sequence of organocatalysts 1a and 2 (Scheme , route c) provided the ent - 13a cyclic ketol with the same selectivity but with lower yields (no side reaction was detected) as the applied pseudoenatiomeric catalysts are not enantiomers but diastereomers and the basicities of the quinuclidine nitrogen are also different in the two catalysts.…”