Complex natural products remain one of the great sources of inspiration and innovation in the development of novel therapeutic treatments. However, their complexity presents synthetic challenges when generating analogs or quantities necessary for biological testing. One structural motif that creates a particular challenge is the enantioselective synthesis of carbocyclic structures containing quaternary stereocenters. In the current proposal, synthetic chemistry tools are described which will allow the efficient, enantioselective construction of carbocyclic structures with two quaternary stereocenters, vicinal quaternary- tertiary stereocenters and contiguous quaternary-tertiary-quaternary stereocenters. The synthetic tools will extend the recently developed Birch-Cope sequence in a valuable, new direction. Furthermore, the project describes a strategy to apply these tools to the enantioselective synthesis of trigonochinene D, a diterpene natural product with antimicrobial properties. The development of a synthesis of trigonochinene D and the tools to generate other complex molecules with antibiotic properties will assist in addressing the escalating crisis of antibiotic resistance.

Public Health Relevance

Complex natural products remain one of the great sources of inspiration and innovation in the development of novel therapeutic treatments, especially antibiotic therapy. Trigonochinene D is a recently reported diterpene natural product which, with its unique chemical architecture and antibiotic activity, is representative of the riches found in natural product chemistry. The proposed project will develop synthetic chemistry tools to permit the efficient and specific synthesis of trigonochinene D, thereby facilitating its development as a new antibiotic treatment. With modern medicine facing a burgeoning crisis in antibiotic resistance, the tools developed here have the potential to facilitate important advances in the search for improved therapeutic treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM087291-01A1
Application #
7779192
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2010-01-01
Project End
2014-12-31
Budget Start
2010-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2010
Total Cost
$211,052
Indirect Cost
Name
Bryn Mawr College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
067398420
City
Bryn Mawr
State
PA
Country
United States
Zip Code
19010
Malachowski, William P; Winters, Maria; DuHadaway, James B et al. (2016) O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1. Eur J Med Chem 108:564-76
Burke, Sarah J; Malachowski, William P; Mehta, Sharan K et al. (2015) The enantioselective construction of tetracyclic diterpene skeletons with Friedel-Crafts alkylation and palladium-catalyzed cycloalkenylation reactions. Org Biomol Chem 13:2726-44
Ross, Tina Morgan; Burke, Sarah; Malachowski, Wlliam P (2014) Enantioselective synthesis of decalin structures with all-carbon quaternary centers via one-pot sequential Cope/Rauhut-Currier reaction. Tetrahedron Lett 55:4616-4618