Abstract

The goal of this program is to develop new strategies for the synthesis of diterpenoid alkaloid natural products. These compounds and their unique derivatives, which can only be accessed using our approach, will provide small molecules that will serve as novel small molecules to combat pain by modulating voltage-gated sodium ion channels. Our synthetic studies should also lead to new variants of [4+2] cycloadditions to achieve regioselectivity and enantioselectivity. Specifically, we intend to develop strategies to synthesize different structural classes of diterpenoid alkaloids including the aconitine- type, the arcutine type and the hetisine type.

Public Health Relevance

Finding new and more efficient ways to build complex, bioactive, secondary metabolites (natural products) is important as it may lead to improvements in human health, for example to find new alternatives to existing pain medications. Our goals are to develop new strategies to efficiently construct complex secondary metabolites in the diterpenoid alkaloid family and derivatives. These small molecules will positively address the treatment of pain.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM084906-10
Application #
9257084
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
2008-08-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

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

  Publications

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

Showing the most recent 10 out of 23 publications