Catalytic Enantioselective Olefin Metathesis Reactions

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DESCRIPTION (provided by applicant): The goal of this project is the design and development of new catalysts that efficiently promote enantioselective olefins metathesis reactions. Investigations will be focused on catalytic asymmetric methods that deliver products that can be used in the synthesis of biologically active molecules and cannot be easily accessed by any existing protocols. Design and development of new catalysts and catalytic asymmetric protocols for organic synthesis are compelling objectives. One of the most important and rapidly emerging classes of transformations in organic chemistry is catalytic olefin metathesis. Readily available unsaturated compounds, through ring-closing, ring-opening or cross-metathesis reactions, are converted into a wide range of cyclic or acyclic compounds. Asymmetric olefin metathesis provides access to molecules that cannot be easily prepared by reactions of enantiomerically pure substrates in the presence of achiral catalysts, partly because methods for preparation of the requisite enantiomerically enriched substrates do not yet exist. We will design and develop new classes of Mo- and W-based chiral olefin metathesis catalysts that can be prepared in situ by new practical and efficient methods from easily accessible precursors. We will utilize the mechanistic understanding, obtained during previous studies in this program, to introduce catalysts with one or more of the following unique attributes: stereogenic metal center, cationic metal center, monodentate chiral ligand. The catalysts developed in this program will be utilized in the development of new and unique catalytic diastereo- and enantioselective methods in olefin metathesis. Catalytic asymmetric reactions will be designed that deliver synthetically versatile products, such as cyclic amines and amides, which are otherwise difficult to access; the majority of products contain an all-carbon quaternary stereogenic center, an important and notoriously difficult-to-access moiety that is found in a variety of molecules of exceptional biological activity. Enantioselective total synthesis of biologically active alkaloids quebrachamine (adrenergic blocker) and rhazinilam (anti-cancer) will thus be accomplished through unique routes rendered feasible by the new chiral catalysts and catalytic asymmetric methods developed in this program. Efficient, practical and highly stereoselective methods for preparation of chiral organic molecules are critical to the availability of therapeutic agents. Design and development of new catalysts and catalytic asymmetric protocols for organic synthesis are compelling objectives. Easily prepared and highly active chiral olefin metathesis catalysts that furnish unique routes for the synthesis of heteroatom-containing compounds are the goals of this program and of notable significance in medicinal research.