Computational Evidence for the Enamine Mechanism of Intramolecular Aldol Reactions Catalyzed by Proline

A comparison of previously proposed models of the CC bond-forming step of the title reaction with density functional methods indicate that the most favored one involves an enamine intermediate undergoing a concerted aldol cyclization with proton transfer from the proline carboxylic acid group (see structure). This step is equal in energy to the intramolecular deprotonation leading to the enamine, and both are partially rate-determining steps.