CATALYTIC ENANTIOSELECTIVE OLEFIN METATHESIS REACTIONS

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Enantioselective chemical reactions that are reliable, catalytic, selective (high regio- and stereoselectivity) can significantly expedite the large scale production and availability of important therapeutics. This proposal outlines experiments that will lead to the design, development and characterization of a various new catalysts that can effect asymmetric metathesis reactions with high efficiency and enantioselectivity. The catalysts developed here are unique in their ability to promote asymmetric metathesis. Furthermore, these catalysts will be utilize to develop new reaction technologies which afford products that are not otherwise accessible by any other metal-catalyzed or enzymatic process. The following specific goals will be pursued: I. Synthesis and Development of New Chiral, Optically Pure Mo-based Metathesis Catalysts. We have already identified that several chiral Mo complexes can effect highly enantioselective metathesis reactions. These chiral complexes easily lend themselves to steric and electronic modifications. We have also demonstrated that certain enantioselective reactions operate best with a specific variant of the chiral catalyst, whereas other transformations afford optimal results with a related analog. We will design, synthesize and fully characterize Mo-based chiral complexes that can effect enantioselective synthesis of a wider range of compounds. Such versatility will allow us to find a "best match" for a particular substrate, significantly expand the scope and utility of catalytic asymmetric metathesis and enhance our understanding of the mechanism of Mo-catalyzed metathesis. II. Enantioselective Synthesis through Catalytic Ring-Closing Metathesis. We will utilize the new Mo-based chiral complexes to synthesize chiral molecules from readily available achiral starting materials. We will develop reliable, catalytic and asymmetric methods for the synthesis of various carbo- and heterocycles, many of which bear quaternary carbon stereogenic centers (an example shown above). We will probe the utility of the new chiral Mo catalysts from part I, while carefully examining the validity of mechanistic models. III. Enantioselective Synthesis through Catalytic Ring-Opening Metathesis. Chiral Mo catalysts will be used in the development of asymmetric ring-opening metatheses as a new and unique catalytic enantioselective process. Recent preliminary data clearly indicate that our chiral Mo-based complexes are capable of effecting AROM with exceptional enantioselection. Both AROM followed by RCM, and AROM followed by intermolecular cross- metathesis, will be developed as efficient methods for catalytic enantioselective synthesis.