The design and development of organometallic methodology for the selective formation of five and six-membered carbocyclic rings is proposed. Carbon- carbon bond formation is planned using established reactivity of metal- carbon bonds for the insertion of alkene and alkyne functional groups. More specifically, the metal complex chosen to perform insertion of alkenes is a titanocene alkenyl chloride species. These complexes are known for their efficient olefin insertion as the Ziegler-Natta polypropylene catalysts. By performing this reaction in an intramolecular manner, with the metal-carbon bond tethered to the unit of unsaturation, ring-formation is achieved. There are a number of features we hope to address while designing an organometallic method to perform these cyclizations. Regioselective addition to unsaturated functionality, diastereoselective formation of asymmetric centers, and optimized conversion to cyclic products are all properties of these transformations which must be determined in order for these methods to be applied to the construction of complex organic molecules. This project will focus on the generation of carbocyclic products formed by exo cyclization to give five and six- membered rings. The size of the ring produced is modified by altering the length of the carbon chain binding the metal center to the unit of unsaturation. In order to determine the full capabilities of this ring- forming process, intramolecular insertion of alkenes, alkynes, and cyclopropanes into titanium-carbon bonds will be studied. Intramolecular insertion into alkyl, vinyl, and aryl titanocene chloride species would provide a structural variety of products. The advantages to this method are the ways in which different ring systems which can be constructed. Through intramolecular bond formation to an existing ring, fused or bridged bicyclic rings can be formed depending on the location of the alkene. Fused six-membered rings, such as those of mevinolin or steroids, fused six and five-membered rings (steroids), or fused five-membered rings of terpenes are all potential targets. Of added significance is the ability to generate quaternary carbons in the form of angular methyl groups. Such methodology has potential applications in the synthesis of steroid products in the formation of the C-D ring system with the C-18 angular methyl substituent. The synthesis of both angular methyl groups and geminal dimethyl configurations also provide a valuable means of constructing many of the terpenoid natural products.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Medicinal Chemistry Study Section (MCHA)
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Michigan State University
Schools of Arts and Sciences
East Lansing
United States
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