Enantioselective Total Synthesis of Marcfortine B via SmI2-mediated C-C Bond Form

University Of California Berkeley, Berkeley CA

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Abstract

DESCRIPTION (provided by applicant): Helminths, especially parasitic nematodes, are known to cause significant health complications in humans and domestic animals. Macrocyclic lactones, benzimidazoles, and imidazothiazoles are at present being used for the eradication of gastrointestinal nematodes in veterinary medicine. Scientists at Merck have reported the potent antiparasitic activity of marcfortine A, paraherquamide A, VM55599, and their analogs. Because of their potential in treating various intestinal parasites, and due to their limited availability,the marcfortines and related compounds are prime targets for laboratory synthesis. Marcfortines A, B, and C are fungal metabolites of Penicillium roqueforti. To date, an enantioselective synthesis of the marcfortines has not been reported. The objective of this proposal is the enantioselective synthesis and biological testing of marcfortine B and related derivatives. The specific aims of the proposal are to develop methodology to establish a key C-C bond using an isocyanate, complete the total synthesis of marcfortine B using a key Diels-Alder and isocyanate C-C bond formation, and to investigate the biological activity of marcfortine and related derivatives. The key developments in this proposal will be the investigation of a new sp-sp2 direct C-C bond formation utilizing isocyanates and enamides as well as the application of the catalytic dynamic resolution of N-Boc-2- lithiopiperidine to a highly complex target. In addition, the synthesis will demonstrate the utility of the highly convergent Diels-Alder reactions between our proposed dienophile and 1,1-disubstituted dienes in the synthesis of prenylated indole alkaloids. Our proposed plan will mark the first enantioselective synthesis of any member of the marcfortine family. In addition, the sequence will provide many opportunities for the synthesis of analogs whose biological activity will be evaluated.