Theoretical Mechanistic Study of the TBD-Catalyzed Intramolecular Aldol Reaction of Ketoaldehydes

The intramolecular aldol reaction of acyclic ketoaldehydes catalyzed by 1,5,7-triazabicyclo-[4.4.0]dec-5-ene (TBD) is investigated using density functional theory calculations. Compared to the proline-catalyzed aldol reaction, the use of TBD provides a unique and unusual complete switch of product selectivity. Three mechanistic pathways are proposed and evaluated. The calculations provide new insights into the activation mode of bifunctional guanidine catalysts. In the favored mechanism, TBD first catalyzes the enolization of the substrate and then the C-C bond formation through two concerted proton transfers. In addition, the computationally predicted stereochemical outcome of the reaction is in agreement with the experimental findings.