Mechanistic insights into the chiral phosphoramide-catalyzed, enantioselective crossed-aldol reactions of aldehydes.

[reaction: see text] The mechanism of the phosphoramide-catalyzed enantioselective aldol additions of trichlorosilyl enolate 1 to aldehydes has been studied. Natural abundance 12C/13C kinetic isotope analysis showed that the rate-determining step of the reaction is the aldolization. Arrhenius activation parameters for the aldol addition reaction were determined. The entropy of activation is large and highly negative, whereas the enthalpy of activation is relatively small. Despite the different trends in selectivity observed for electron-rich and electron-poor aldehydes, similar entropic and enthalpic contributions to the free energies of activation are found for both classes of substrates. The experimental results from the Arrhenius and the kinetic isotope effect studies allowed the formulation of an interpretation for the divergent selectivity trends in the aldol reaction.