Total Synthesis of Cytotoxic ent-Kauranoid Natural Products

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DESCRIPTION (provided by applicant): The complex molecular structure of medicinally important natural products has stimulated the development of new chemical reactions that quickly generate structural complexity from simple starting materials. Transition metal-catalyzed reactions are uniquely suited for this purpose because the chemoselectivity and stereoselectivity of a given process is quite often predictable and reliable. Vanadium catalysts have found widespread application in synthesis, most notably as catalysts for isomerization and asymmetric oxidation reactions. This research plan will focus on the development of a novel vanadium-catalyzed cascade reaction between propargylic alcohols and cyclopropyl aldehydes that generates highly functionalized 1,3-dienes. This tandem process represents a single pot, atom economic construction of highly functionalized dienes that are powerful, flexible intermediates towards more complex targets. After exploring the substrate scope of this cascade reaction, the utility of the 1,3-diene as an intermediate in synthesis will be demonstrated by performing selective inter- and intramolecular transformations to generate important natural product scaffolds. The vanadium-catalyzed cascade will then be used to carry out a concise total synthesis of nodosin and sculponin B of the ent-kauranoid family of natural products. Nodosin and other ent-kauranoids have recently received significant attention due to their potent anticancer activity. Nodosin in particular has shown potent inhibitory activity against K562 human chronic myelogenous leukemia cells. The synthesis of nodosin will represent a general strategy for accessing many of the ent-kauranoids, facilitating further development of this important class of compounds as cancer chemotherapeutic agents.