The long term objectives of this grant application are focused on the total syntheses of natural products with promising biological profiles and the development of new synthetic methods. The development of new synthetic methods that are simple, efficient and general in scope continues to be an essential scientific pursuit. Such methods serve many needs of basic science and enable the development of new pharmaceuticals and other essential chemical structures. Natural products have greatly impacted public health over the last sixty years by serving as the source or lead structures for new drugs. A large percentage of currently used antibiotics and cancer therapeutics are natural products or derivatives of natural products. This proposal describes efforts to design and execute efficient synthetic blueprints towards several natural product diterpenoids with unique and promising biological modes of action. These synthetic blueprints will provide access to collections of unique natural product hybrid structures. These otherwise inaccessible compound collections will help unravel and shed light on the biological significance each one of these natural product structural features play, which is expected to be critical for further advancement and applications. The efficiency of the proposed synthetic routes detailed herein are enabled by strategic use of an underdeveloped oxidative dearomatization protocol. The mecahnism and scope of this powerful oxidative dearomatization protocol will be rigorously evaluated in order to enable development of asymmetric variants as well as to provide a blueprint for future applications. The reactivity of the synthons generated using this method will be established during the grant period. The goal of this grant application is to complete total syntheses of three different classes of bicyclic natural products. In all proposed synthetic approaches a perfectly suited dearomatization protocol, which we plan to study and advance during the grant period, serves as the cornerstone. Our efficient synthetic routes will be used to create unique natural product hybrid collections that will prove invaluable in decoding these natural products molecular mechanisms, which in turn should help advance their development. The new synthetic method proposed will benefit chemists both in academia and the pharmaceutical industry thus directly or indirectly impacting the discovery, study, development and production of new drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086584-05
Application #
8307410
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2008-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$293,339
Indirect Cost
$97,319
Name
University of Arizona
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Yang, Qingliang; Draghici, Cristian; Njardarson, Jon T et al. (2014) Evolution of an oxidative dearomatization enabled total synthesis of vinigrol. Org Biomol Chem 12:330-44
Mack, Daniel J; Njardarson, Jon T (2013) Syntheses and structural confirmations of members of a heterocycle-containing family of labdane diterpenoids. Angew Chem Int Ed Engl 52:1543-7
Yang, Qingliang; Njardarson, Jon T; Draghici, Cristian et al. (2013) Total synthesis of vinigrol. Angew Chem Int Ed Engl 52:8648-51
McGrath, Nicholas A; Binner, Joshua R; Markopoulos, Georgios et al. (2011) An efficient oxidative dearomatization-radical cyclization approach to symmetrically substituted bicyclic guttiferone natural products. Chem Commun (Camb) 47:209-11
Morton, Jason G M; Draghici, Cristian; Kwon, Laura D et al. (2009) Rapid assembly of vinigrol's unique carbocyclic skeleton. Org Lett 11:4492-5
McGrath, Nicholas A; Bartlett, Emily S; Sittihan, Satapanawat et al. (2009) A concise ring-expansion route to the compact core of platensimycin. Angew Chem Int Ed Engl 48:8543-6