The goal of this program is to define new strategies and methods for the synthesis of bioactive natural products that contain a seven-membered ring. The molecules we make will provide tools to study many biological processes and may ultimately be used to develop new therapeutics, especially for cancer. Specifically, we intend to develop a general strategy for the synthesis of the rearranged steroidal compounds cortistatin A and alkaloids in the Lycopodium family. The cortistatins are potent angiogenesis inhibitors and should find use in combating tumor cell metastasis. We present a strategy to synthesize these natural products using cycloheptadiene precursors. These cycloheptadienes are in turn generated from novel metal-mediated methods. It is our expectation that these new methodological developments for seven-membered ring formation will streamline the synthesis of complex molecules. The total synthesis of the cortistatins and Lycopodium alkaloids will drive new developments, which will in turn, be applied to the synthesis of other molecules of biological and structural interest. These contributions will aid advances in human medicine and chemical biology using small molecules.

Public Health Relevance

Finding new and more efficient ways to construct small organic molecules is an important pursuit that will provide new tools for chemical biology as well as medicine and lead to improvements in human health. Our goals are to develop new strategies and methods that efficiently build small molecules including natural products that are of pharmaceutical importance. In this regard, we are especially interested in new seven- membered ring forming reactions using transition metals.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086374-04
Application #
8323939
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$308,287
Indirect Cost
$94,523
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
Mercado-Marin, Eduardo V; Sarpong, Richmond (2015) Unified Approach to Prenylated Indole Alkaloids: Total Syntheses of (-)-17-Hydroxy-Citrinalin B, (+)-Stephacidin A, and (+)-Notoamide I. Chem Sci 6:5048-5052
Beng, Timothy K; Takeuchi, Hironori; Weber, Manuel et al. (2015) Stereocontrolled synthesis of vicinally functionalized piperidines by nucleophilic β-addition of alkyllithiums to α-aryl substituted piperidine enecarbamates. Chem Commun (Camb) 51:7653-6
de Jesus Cortez, Felipe; Lapointe, David; Hamlin, Amy M et al. (2013) Synthetic studies on the icetexones: enantioselective formal syntheses of icetexone and epi-icetexone. Tetrahedron 69:
Jeffrey, Jenna L; Bartlett, Emily S; Sarpong, Richmond (2013) Intramolecular C(sp3)-N coupling by oxidation of benzylic C,N-dianions. Angew Chem Int Ed Engl 52:2194-7
Mundal, Devon A; Sarpong, Richmond (2013) Synthetic studies toward the citrinadin A and B core architecture. Org Lett 15:4952-5
García-Reynaga, Pablo; Zhao, Chunqing; Sarpong, Richmond et al. (2013) New GABA/glutamate receptor target for [³H]isoxazoline insecticide. Chem Res Toxicol 26:514-6
Newton, James N; Fischer, Daniel F; Sarpong, Richmond (2013) Synthetic studies on pseudo-dimeric Lycopodium alkaloids: total synthesis of complanadine B. Angew Chem Int Ed Engl 52:1726-30
Murphy, Rebecca A; Sarpong, Richmond (2012) Direct methoxypyridine functionalization approach to magellanine-type Lycopodium alkaloids. Org Lett 14:632-5
Leal, Raul A; Beaudry, Danial R; Alzghari, Saeed K et al. (2012) Synthesis of the pentacyclic skeleton of the indole alkaloid arboflorine. Org Lett 14:5350-3
Gruver, Jocelyn M; West, Scott P; Collum, David B et al. (2010) Experimental characterization and computational study of unique C,N-chelated lithium dianions. J Am Chem Soc 132:13212-3

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