Acid catalyst enantioselective aldol condensations

The mechanism and energetics of amine-catalyzed aldol reactions involving enamine intermediates have been extensively studied using various techniques including DFT. One specific class of these reactions that have not received adequate study is acid-catalyzed systems involving tertiary enamine intermediates. If examined first in the gas phase, which is common in DFT simulations, the reactants proceed directly to products seemingly barrierlessly. Houk and Bahmanyar have obtained almost identical results with similar systems1. The major flaw in this method of thinking is the assumption that the gas phase information translates directly to the solvated systems. In the gas phase H3O+ is a very strong acid, and immediately protonates the free aldehyde making it more reactive toward the enamine and thus proceeding directly to products without a barrier. When examined in solution however, H3O+ is stabilized by solvation, which in turn allows for the calculation of the reaction barrier. Both closed and open transition states are currently being examined for these systems.

Picture provided by Ian Mangion

Personnel: Jason Keith

This project is in collaboration with Ian Mangion and Prof. David MacMillan (Caltech)