Origin of Stereoselectivity in a Chiral N-Heterocyclic Carbene-Catalyzed Desymmetrization of Substituted Cyclohexyl 1,3-Diketones

The mechanism and stereoselectivity in a chiral N-heterocyclic carbene-catalyzed desymmetrization of a 1,3-diketone is established by using density functional theory computations. The Breslow intermediate formation is identified to involve Hunig's base-assisted proton transfer. The relative energies of stereoselectivity-determining intramolecular aldol cyclization transition states reveal that in the most preferred mode the re-face of enolate adds to the si-face of carbonyl leading to a tricyclic lactone with a configuration (2aS,4aS,8'S) in excellent agreement with previous experimental reports.