Recycling in Asymmetric Catalysis

Cyclic reaction networks consisting of an enantioselective product-forming step and a reverse reaction of the undesired enantiomer back to starting reactant are important for the generation of compounds with high enantiomeric purity. In order to avoid an equilibrium racemic state, a unidirectional cyclic process where product formation and regeneration of starting reactant proceed through different mechanistic pathways is required. Such processes must necessarily include a thermodynamically unfavorable step, since the product of the forward reaction is the reactant of the reverse reaction and vice versa. Thermodynamically uphill processes are ubiquitous to the function of living systems. Such systems gain the required energy by coupling to thermodynamically downhill reactions. In the same way, artificial cyclic reaction networks can be realized in systems open to mass or energy flow, and an out-of equilibrium nonracemic steady state can be maintained as long as the system is supplied with energy. In contrast to a kinetic resolution, a recycling process where the minor enantiomer is converted to starting reactant can result in a quantitative yield, but the enantiomeric purity of the product is limited by the selectivity of the catalysts used for the reactions. On the other hand, in a kinetic resolution, the slowly reacting enantiomer can always be obtained in an enantiomerically pure state, although the yield will suffer. In cyclic reaction systems which use chiral catalysts for both the forward and the reverse processes, a reinforcing effect results, and selectivities higher than those achieved by a single chiral catalyst are observed. A dynamic kinetic resolution can in principle also lead to a quantitative yield, but lacks the reinforcing effect of two chiral catalysts. Most examples of cyclic reaction networks reported in the literature are deracemizations of racemic mixtures, which proceed via oxidation of one enantiomer followed by reduction to the opposite enantiomer. We have developed cyclic reaction networks comprising a carbon-carbon bond formation. In these processes, the product is generated by the addition of a cyanide reagent to a prochiral aldehyde. This is followed by hydrolysis of the minor enantiomer of the product to generate the starting aldehyde. A unidirectional cycle is maintained by coupling to the exergonic transformation of the high potential cyanide reagent to a low potential compound, either a carboxylate or carbon dioxide. The products, which are obtained with high enantiomeric purity, serve as valuable starting materials for a variety of biologically and pharmaceutically active compounds.