Small cell-permeable natural products and their analogs play a crucial role in the treatment of disease. This proposal addresses the syntheses of several biologically active molecules relevant to the treatment of cancer, HIV, stroke and heart disease through """"""""The Synthesis and Application of Chiral Cyclohexadienones."""""""" Optically enriched chiral cyclohexadienones are relatively inaccessible chemical entities. Their fragile nature coupled with the lack of enantioselective access has hampered their widespread synthetic applications. We intend to show that robust cyclohexadienones can be constructed to undergo a myriad of diastereoselective reactions including 1,2-, 1,4- and 1,6-additions, along with various rearrangements and cycloadditions. We intend to prove that these cyclohexadienones can be easily constructed in enantiopure form. We will establish the usefulness of these adducts as non-racemic cyclohexyl synthons through short syntheses to ascertain the subtleties of the surrounding synthetic chemistry. Each proposed synthesis addresses a target that is (or has proven to be) difficult to construct by current technologies and is highly relevant to national public health. It should become evident that the synthetic method proposed has eventual greater application in the assembly of future prospective drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM064831-03
Application #
6699027
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2002-01-01
Project End
2006-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
3
Fiscal Year
2004
Total Cost
$271,668
Indirect Cost
Name
University of California Santa Barbara
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
094878394
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106
Weaver, Marisa G; Bai, Wen-Ju; Jackson, Stephen K et al. (2014) Diels-Alder construction of regiodifferentiated meta-amino phenols and derivatives. Org Lett 16:1294-7
David, Jonathan G; Bai, Wen-Ju; Weaver, Marisa G et al. (2014) A general diastereoselective catalytic vinylogous aldol reaction among tetramic acid-derived pyrroles. Org Lett 16:4384-7
Bai, Wen-Ju; David, Jonathan G; Feng, Zhen-Gao et al. (2014) The domestication of ortho-quinone methides. Acc Chem Res 47:3655-64
Bai, Wen-Ju; Jackson, Stephen K; Pettus, Thomas R R (2012) Mild construction of 3-methyl tetramic acids enabling a formal synthesis of palau'imide. Org Lett 14:3862-5
Cohn, Elysia P M T; Wu, Kun-Liang; Pettus, Thomas R R et al. (2012) A new strategy for detection and development of tractable telomerase inhibitors. J Med Chem 55:3678-86
Green, Jason C; Burnett 4th, G Leslie; Pettus, Thomas R R (2012) New strategies for natural products containing chroman spiroketals. Pure Appl Chem 84:1621-1631
Cha, Jacob Y; Burnett 4th, G Leslie; Huang, Yaodong et al. (2011) A strategy for the late-stage divergent syntheses of scyphostatin analogues. J Org Chem 76:1361-71
Wenderski, Todd A; Marsini, Maurice A; Pettus, Thomas R R (2011) A diastereoselective formal synthesis of berkelic acid. Org Lett 13:118-21
Wu, Kun-Liang; Mercado, Eduardo V; Pettus, Thomas R R (2011) A convergent total synthesis of (±)-?-rubromycin. J Am Chem Soc 133:6114-7
Wenderski, Todd A; Hoarau, Christophe; Mejorado, Lupe et al. (2010) Dearomatization applications of I((III)) reagents and some unusual reactivity amongst resorcinol derived cyclohexadienones. Tetrahedron 66:5873-5883

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