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.

Public Health Relevance

The goal of this proposal is to synthesize and evaluate the biological activity of marcfortine B and its derivatives, which have potential in treating various intestinal parasites such as nematodes, known to cause significant health complications in humans and domestic animals. Since all drugs are required to be enantiopure for FDA evaluation and since no enantioselective synthesis of marcfortine B has been reported to date, our undertaking will provide an entry into this important class of potential drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM103210-02
Application #
8554302
Study Section
Special Emphasis Panel (ZRG1-F04-K (09))
Program Officer
Barski, Oleg
Project Start
2012-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$52,190
Indirect Cost
Name
University of California Berkeley
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Beng, Timothy K; Wilkerson-Hill, Sidney M; Sarpong, Richmond (2014) Direct access to functionalized azepanes by cross-coupling with ?-halo eneformamides. Org Lett 16:916-9