In the synthesis of large, complex biologically active molecules, carbon-carbon bond formation is of fundamental importance. Associated with carbon-carbon bond formation is the problem of controlling the stereochemistry on which biological activity depends to a large degree. Thus, the development of new methodologies for stereo-controlled carbon-carbon bond formation is of crucial importance in the health field. This proposal is directed at refining one of the most powerful carbon-carbon forming reactions, the Diels-Alder reaction. The Diels-Alder reaction is remarkable in that it can generate up to 4 concatenated chiral centers in a single step with control of the relative stereochemistries of the 4 centers. As such, it has been used extensively in natural product synthesis. Although many of the aspects of Diels-Alder reaction have been solved to a large degree, there remains a major challenge; that it be catalytic and asymmetric. This proposal is directed at developing chiral catalysts of the elements boron, aluminum, titanium, and tin for the catalytic asymmetric Diels-Alder reaction. The proposed chiral catalysts are readily made and, on the basis of previous experience, are likely to be successful. Initially, we propose to investigate the classical Diels-Alder partners, alpha-beta- unsaturated esters, aldehydes and ketones with butadienes and cyclopentadiene. The emphasis is on the nature of the catalysis. This will involve equilibrium and kinetic studies of the catalysis and the isolation of dienophile-catalyst adducts in order to understand the origins of catalysis and of the enantioselection. A mechanistic understanding of the asymmetric catalysis will provide a basis for developing new, more refined, asymmetric catalysts. We believe that the development of effective asymmetric catalytic Diels-Alder catalysts will have a broad impact on synthetic strategies which will ultimately lead to the more efficient production of biologically active molecules.
