Synthesis of a Bridged Bicyclic Natural Product Using Allenyl Esters

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DESCRIPTION (provided by applicant): This proposal sets forth a research program for the development of new organic reactions for the facilitated synthesis of a medicinally-relevant natural product (vitisinol D). The synthesis plan will involve the application of relatively new an underutilized building blocks in organic chemistry (chiral allenyl esters) exploiting the high degree of unsaturation and unique juxtaposition of functional groups present. Thus vitisinol D, a natural product that inhibits blood clotting, will be synthesized (for the first time) in 14 steps using these new building blocks and a new cyclization sequence (reductive aldol). Importantly, the planned synthesis will make available sufficient quantities of vitisinol D to allow for biochemical studies to determine the mechanism of action for this structurally unique, and virtually inaccessible, natural product. The project will also expand methods to prepare more complex allenyl esters as single isomers (non-racemic). These methods entail the development of unique catalysts to afford a high degree of control in bond formation leading to the allenyl ester products. With these allene building blocks in hand, a series of vitisinol D derivatives will be efficiently synthesized (3-5 steps). Through collaboration with nearby Torrey Pines Institute for Molecular Studies, the activity of vitisinol D and its derivatives against blood clotting will e examined. These biological studies, enabled by the synthesis methods developed as part of this project, are aimed at determining the enzymatic target of vitisinol D ultimately serving as a starting point for future medicinal chemistry investigations of blood clotting diseases.