Transition states of amine-catalyzed aldol reactions involving enamine intermediates: Theoretical studies of mechanism, reactivity, and stereoselectivity

The mechanisms, transition states, relative rates, and stereochemistries of amine-catalyzed aldol reactions involving enamine intermediates have been explored with density functional theory (B3LYP/6-31G*) and CPCM solvation m odels. Primary enamine-mediated aldol reactions involve half-chair transiti on states with hydrogen bonding leading to proton transfer. This leads to c harge stabilization and low activation energies as compared to secondary en amine-mediated aldol reactions. Oxetane intermediates can be formed when C- C bond formation occurs without H-transfer in the transition state. The ste reoselectivities of reactions of ketone enamines with aldehydes, including the facial stereoselectivity involving chiral aldehydes, were modeled and c ompared with experimental results. Transition states for the intramolecular aldol reactions leading to the formation of hydrindanone-beta -ketol and d ecalone-beta -ketol aldol products showed a preference for the formation of the cis-fused rings, in agreement with experimental results.