The goal of this program is to define new strategies and methods for the synthesis of bioactive molecules in the diterpenoid alkaloid family. The complex molecules that we construct can provide tools to study ion channels and may ultimately be used to develop new therapeutics. Our synthetic studies should also lead to a better understanding of organic functional group reactivity since our targets possess a multitude of functional groups in a congested setting. Specifically, we intend to develop strategies to synthesize different structural classes of diterpenoid alkaloids including coryphine, kobusine and cossonidine. We expect our unique strategies and methods for synthesis to streamline access to unique ion channel potentiators.

Public Health Relevance

Finding new and more efficient ways to construct complex small molecules derived from natural products is an important pursuit that may lead to improvements in human health. Our goals are to develop new strategies and methods that efficiently build complex natural products in the diterpenoid alkaloid family and their associated derivatives of pharmaceutical relevance that would positively address neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084906-07
Application #
8655545
Study Section
Special Emphasis Panel (ZRG1-BCMB-R (02))
Program Officer
Lees, Robert G
Project Start
2008-08-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
7
Fiscal Year
2014
Total Cost
$288,473
Indirect Cost
$90,473
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
Kou, Kevin G M; Pflueger, Jason J; Kiho, Toshihiro et al. (2018) A Benzyne Insertion Approach to Hetisine-Type Diterpenoid Alkaloids: Synthesis of Cossonidine (Davisine). J Am Chem Soc 140:8105-8109
Kou, Kevin G M; Kulyk, Svitlana; Marth, Christopher J et al. (2017) A Unifying Synthesis Approach to the C18-, C19-, and C20-Diterpenoid Alkaloids. J Am Chem Soc 139:13882-13896
Pflueger, Jason J; Morrill, Louis C; deGruyter, Justine N et al. (2017) Magnesiate Addition/Ring-Expansion Strategy To Access the 6-7-6 Tricyclic Core of Hetisine-Type C20-Diterpenoid Alkaloids. Org Lett 19:4632-4635
Kou, Kevin G M; Li, Beryl X; Lee, Jack C et al. (2016) Syntheses of Denudatine Diterpenoid Alkaloids: Cochlearenine, N-Ethyl-1?-hydroxy-17-veratroyldictyzine, and Paniculamine. J Am Chem Soc 138:10830-3
Weber, Manuel; Owens, Kyle; Sarpong, Richmond (2015) Atropurpuran - Missing Biosynthetic Link Leading to the Hetidine and Arcutine C20-Diterpenoid Alkaloids or an Oxidative Degradation Product? Tetrahedron Lett 56:3600-3603
Marth, C J; Gallego, G M; Lee, J C et al. (2015) Network-analysis-guided synthesis of weisaconitine D and liljestrandinine. Nature 528:493-8
Schultz, Erica E; Lindsay, Vincent N G; Sarpong, Richmond (2014) Expedient synthesis of fused azepine derivatives using a sequential rhodium(II)-catalyzed cyclopropanation/1-aza-Cope rearrangement of dienyltriazoles. Angew Chem Int Ed Engl 53:9904-8
Heller, Stephen T; Kiho, Toshihiro; Narayan, Alison R H et al. (2013) Protic-solvent-mediated cycloisomerization of quinoline and isoquinoline propargylic alcohols: syntheses of (±)-3-demethoxyerythratidinone and (±)-cocculidine. Angew Chem Int Ed Engl 52:11129-33
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:
Lebold, Terry P; Wood, Jessica L; Deitch, Josh et al. (2013) A divergent approach to the synthesis of the yohimbinoid alkaloids venenatine and alstovenine. Nat Chem 5:126-31

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