Clarification of the role of water in proline-mediated aldol reactions.

The report by List, Lerner, and Barbas1 in 2000 of an intermolecular direct aldol reaction catalyzed by proline became an unexpected watershed for the field of organocatalysis.2-4 Pihko and co-workers4b,c were the first to observe significantly higher yields with addition of water to intermolecular aldol reactions, even allowing employment of stoichiometric substrate ratios in some cases. This finding has great potential to widen the scope of proline catalysis, which to date has not achieved practical levels of efficiency. Pihko suggested that in the absence of water the formation of oxazolidinones deactivates proline, concluding that water accelerates the reaction. As pointed out recently,5 however, rate acceleration by water is counter-intuitive in the generally accepted enamine mechanism. Seebach, Eschenmoser, and coworkers6 have recently provided an alternative view of the role of oxazolidinones within the aldol reaction network. In this report, kinetic and spectroscopic studies provide a coherent mechanistic rationalization of the role of water in the aldol reaction shown in eq 1. Our work highlights the importance of deconvoluting the intrinsic kinetic effect of water within the catalytic cycle from its effects off the cycle.