The overall objective of this proposal is the development of new strategies for the construction of carbocyclic or heterocyclic systems. This new methodology will facilitate the synthesis of biologically active compounds, and moreover, provide routes to previously unsynthesized compounds. Two strategies will be examined. In the first strategy we will study application of the intramolecular Diels-Alder reaction in the synthesis of the potent hypocholesterolemic agents mevinolin and dihydromevinolin. These compounds cause a marked decrease in serum cholesterol in man by inhibiting the rate-limiting enzymatic step (HMG-CoA reductase) in the cholesterol biosynthetic pathway. It is hoped that these agents will be useful for the treatment of atherosclerosis. The exploitation of the Claisen-rearrangement-mediated approach to hetero- and carbocycles in natural product synthesis is the second major topic of the program. The targeted compounds are primarily comprised of medium-sized rings. For example, this reaction will play a fundamental role in the construction of: the seven-membered ring of antitumor guaianolides (desacetoxymatricarin); as well as the eight-membered ring of both steganicin, which possesses antileukemic activity, and the cytotoxic taxane class of compounds, specifically, taxinine. A novel entry to the cyclodecane framework of the germacranes, a class of sesquiterpenes with a wide range of biological activities, will be demonstrated in the synthesis of costunolide and tulipinolide. Utilization of this process in the synthesis of the heterocyclic, neuronal excitatory compound, Alpha-kainic acid, will also be examined. Also, extension of this methodology to the bridged bicycloalkane class of compounds with possible application to clovene, the antitumor compound quadrone and an alternate taxane strategy will be pursued.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM028663-08
Application #
3275911
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1987-09-01
Project End
1988-11-30
Budget Start
1987-09-01
Budget End
1987-11-30
Support Year
8
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Type
Schools of Arts and Sciences
DUNS #
City
University Park
State
PA
Country
United States
Zip Code
16802
Belmar, Johannes; Funk, Raymond L (2012) Total synthesis of (±)-communesin F via a cycloaddition with indol-2-one. J Am Chem Soc 134:16941-3
Funk, Raymond L; Belmar, Johannes (2012) Total synthesis of (±)-isophellibiline. Tetrahedron Lett 53:176-178
Huntley, Raymond J; Funk, Raymond L (2011) Total synthesis of (±)-?-lycorane via the electrocyclic ring closure of a divinylpyrroline. Tetrahedron Lett 52:6671-6674
Nilson, Mark G; Funk, Raymond L (2011) Total synthesis of (±)-cortistatin J from furan. J Am Chem Soc 133:12451-3
Nilson, Mark G; Funk, Raymond L (2010) Total synthesis of (-)-nakadomarin A. Org Lett 12:4912-5
He, Yong; Funk, Raymond L (2006) Total syntheses of (+/-)-beta-erythroidine and (+/-)-8-oxo-beta-erythroidine by an intramolecular Diels-Alder cycloaddition of a 2-amidoacrolein. Org Lett 8:3689-92
Greshock, Thomas J; Funk, Raymond L (2006) An approach to the total synthesis of welwistatin. Org Lett 8:2643-5
Crawley, Seth L; Funk, Raymond L (2006) Generation of aza-ortho-xylylenes via ring opening of 2-(2-acylaminophenyl)aziridines: application in the construction of the communesin ring system. Org Lett 8:3995-8
Huntley, Raymond J; Funk, Raymond L (2006) A strategy for the total synthesis of dragmacidin E. Construction of the core ring system. Org Lett 8:4775-8
Greshock, Thomas J; Funk, Raymond L (2006) Synthesis of indoles via 6pi-electrocyclic ring closures of trienecarbamates. J Am Chem Soc 128:4946-7

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