This grant application addresses the chemical synthesis problems of two architecturally complex natural products, kendomycin and garsubellin A. The broad objectives of the research program are to develop innovative strategies for the efficient synthesis of molecular agents possessing therapeutic potential for the treatment of diseases and to develop powerful chemical methods of broad utility in the production of the compounds required in biomedical investigations.
The specific aims of the present proposal are: 1) the achievement of an efficient total synthesis of kendomycin, a potent endothelin receptor antagonist and calcitonin receptor agonist that exhibits pronounced antibacterial, antitumor, and anti-osteoporotic activities, using a novel macroglycosylation approach; 2) the development of innovative strategies based on a mechanistically degenerative tandem approach that are appropriate for the expeditious synthesis of the core skeleton of kendomycin; 3) the establishment of a chemical model to gain insights into the biosynthesis of kendomycin through a total synthesis using a biomimetic cascade approach based on novel internal redox and macro-Michael addition processes; and 4) the achievement of a concise total synthesis of garsubellin A, a potent neurotrophic agent that induces the biosynthesis of neurotransmitters, using a multicomponent tandem approach that allows for rapid assembly of the core structure of hyperforin natural products. The proposed synthetic investigations take advavantage of multicomponent cascade approaches which most efficiently address the problem of constructing complex molecular structures. Thus, the chemistry we seek to develop through this grant application can be extended in many ways to bring significant advances in the chemical synthesis of bioactive compounds. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073065-03
Application #
7184317
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2005-02-05
Project End
2010-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$241,506
Indirect Cost
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Joo, Jung Min; David, Ramoncito A; Yuan, Yu et al. (2010) Concise synthesis of the Erythrina alkaloid 3-demethoxyerythratidinone via combined rhodium catalysis. Org Lett 12:5704-7
Yuan, Yu; Lai, Amy J; Kraml, Christina M et al. (2006) A highly enantio- and diastereoselective 1,3-dimethylallylation of aldehydes. Tetrahedron 62:11391-11396
Joo, Jung Min; Yuan, Yu; Lee, Chulbom (2006) Tandem cyclization of alkynes via rhodium alkynyl and alkenylidene catalysis. J Am Chem Soc 128:14818-9
Yuan, Yu; Men, Hongbin; Lee, Chulbom (2004) Total synthesis of kendomycin: a macro-C-glycosidation approach. J Am Chem Soc 126:14720-1