(243a) New Developments in the Catalytic Cycle of L-Proline-Promoted Aldol-Type Reactions

The formation of carbon-carbon and carbon-heteroatom bonds is among the fundamental industrial processes that allows for the production of complex and unique species. While nature can catalyze bond formation with high efficiency, such processes in industrial and lab conditions are still very challenging, wasteful and costly. The current catalyst range for these reactions extends from the traditional strong acids and bases, transition metals, and heterogeneous materials to the environmentally friendly enzymes and catalytic antibodies. While conventional methods are plagued by harsh reaction conditions, corrosive reagents and costly protective groups, enzymes and catalytic antibodies have high substrate specificity and are costly to engineer. L-proline, an amino acid, represents a class of biomimetic catalytic materials called organocatalysts. Under homogeneous conditions, L-proline promotes a variety of reactions, such as aldol addition, α-aminoxylation, Michael addition, etc., which lead to the formation of new bonds. These reactions proceed at low temperatures and are associated with a high yield, enantioselectivity and atom efficiency. Nevertheless, a practical limitation to the use of L-proline as a catalyst stems from long reaction times and a low turnover number. Recently, auto-inductive behavior has been observed in L-proline-assisted α-aminoxylation and α-amination reactions. As a consequence, these processes occur on a much shorter time scale. Unfortunately, experimental kinetics techniques are unable to pinpoint definitively the nature of the rate-enhancing interactions in the catalytic cycle. To date, all L-proline-assisted aldol-type reactions are considered to proceed via the same biomimetic catalytic cycle involving the formation of an enamine intermediate. Therefore, to understand the origin of the unusual kinetic behavior in certain L-proline-catalyzed reactions, we used high-level quantum mechanical (QM) methods to map the reaction coordinates of aldol addition and α-aminoxylation reactions. All stable intermediates and transition states along the reaction coordinates were located at the B3LYP/6-31+G(d,p) level of theory in the presence of solvent, and single point energies were calculated at the M05-2X/MG3S level of theory. Our study discovered that the evolution of a certain type of reaction intermediate, called oxazolidinones, as well as a difference in the rate-limiting elementary step along the reaction coordinate for the different L-proline-catalyzed reactions, are most likely the cause of the experimentally observed autoacceleration. In order to identify the rate-determining step in each process, microkinetic models were developed employing rate parameters calculated from the quantum chemical results and standard statistical thermodynamics methods.