The catalytic generation of asymmetry in organic compounds is a major focus of modern synthetic organic chemistry. While many advances have been made along these lines in the past decades, the problem of creating any given stereocenter in optically pure form is far from being solved. Metal-mediated asymmetric catalysis has created countless methods for the enantioselective synthesis of small molecules, but the metals involved can be costly, hazardous, and difficult to remove on a large scale. Asymmetric organocatalysis provides a sustainable and highly useful alternative specifically in the realm of hydrogen-bonding catalysis. Chiral urea and thiourea hydrogen bond donors have shown broad utility in catalyzing a number of asymmetric carbon-carbon bond forming reactions, due in part to their ability to bind and activate a variety of Lewis-basic and ionic substrates. An underdeveloped use of such catalysis is its application to asymmetric oxidation and reduction reactions. Flavoproteins are a diverse class of enzymes that utilize a flavin cofactor to perform oxidative transformations. A less explored (as compared to hydrogen-bonding catalysis) but surprisingly powerful arena of organocatalysis involves using non-enzyme-bound flavins to activate hydrogen peroxide or hydrazine for respective oxidation or reduction reactions. Few methods have applied flavin catalysis to enantioselective reactions. This proposal seeks to combine the two concepts of asymmetric hydrogen-bonding catalysis and flavin catalysis into a hybrid catalytic system that would be capable of achieving enantioselective oxidative and reductive transformations on a wide variety of substrates. A library of thiourea or urea and flavin catalysts will be synthesized based on established methods and combined in application to the asymmetric Baeyer-Villiger reaction, the asymmetric epoxidation of electron-deficient olefins, and the asymmetric hydrogenation of electron-deficient olefins. In all of the proposed reactions dinitrogen and/or water are the sole byproducts. Small-molecule therapeutics are arguably medicine's best tools for combating health-related problems. Therefore, there is an ever-present need for the rapid, inexpensive, and environmentally friendly production of potential drugs. Since this proposal seeks to create new methods for the selective synthesis of small molecules with no hazardous byproducts it is of particular relevance to public health.
| Burns, Noah Z; Witten, Michael R; Jacobsen, Eric N (2011) Dual catalysis in enantioselective oxidopyrylium-based [5 + 2] cycloadditions. J Am Chem Soc 133:14578-81 |
