Explicit goals of this research include: 1. To complete a highly convergent, relatively short total synthesis of the anticancer agent halichondrin B, which is potently active against several resistant human solid tumor xenografts, but is limited by scarcity from further advancement in NCI preclinical studies. 2. To further develop a powerful synthesis of 6,8-dioxabicyclo(3.2.1)octanes by intermolecular acetalization/intramolecular diene metathesis, for application to sialic acid syntheses (KDN, N-acetylneuraminic acid (Neu5Ac), and KDO). The last of these targets will require development of a means to distinguish between enantiotopic vinyl groups in the metathesis desymmetrization. 3. To explore the conversion of bridged 6,8-dioxabicyclo(3.2.1)octane derivatives to 1,7-dioxaspiro(5.5)decane spiroketals, which are ubiquitous structural components in insect pheromones, anticancer and antibiotic natural products. 4. To develop a new synthetic approach to the annonaceous acetogenins using catalytic ring closing metathesis to construct the bis(tetrahydrofuran) core, exemplified by a total synthesis of squamotacin. Quick access to the enantiomerically pure, C2-symmetric core will provide ready access to several additional potent antitumor agents in this class, which show potency ten to the 8th power to ten to the 10th power times that of adriamycin against several tumor cell lines. 5. To exploit, at the strategic level, symmetry and novel strategies for symmetry-breaking to simplify complex targets and to provide short and efficient syntheses thereof.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074394-07
Application #
6603723
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
1997-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
7
Fiscal Year
2003
Total Cost
$238,410
Indirect Cost
Name
University of Wisconsin Madison
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Dilger, Andrew K; Gopalsamuthiram, Vijay; Burke, Steven D (2007) A two-directional approach to a (-)-dictyostatin C11-C23 segment: development of a highly diastereoselective, kinetically-controlled Meerwein-Ponndorf-Verley reduction. J Am Chem Soc 129:16273-7
Wysocki, Laura M; Dodge, Matthew W; Voight, Eric A et al. (2006) Stereochemically general approach to adjacent bis(tetrahydrofuran) cores of annonaceous acetogenins. Org Lett 8:5637-40
Keller, Valerie A; Kim, Ikyon; Burke, Steven D (2005) Synthetic efforts toward the C22-C36 subunit of halichondrin B utilizing local and imposed symmetry. Org Lett 7:737-40
Lucas, Brian S; Luther, Laura M; Burke, Steven D (2005) A catalytic enantioselective hetero Diels-Alder approach to the C20-C32 segment of the phorboxazoles. J Org Chem 70:3757-60
Lambert, William T; Hanson, Gregory H; Benayoud, Farid et al. (2005) Halichondrin B: synthesis of the C1-C22 subunit. J Org Chem 70:9382-98
Lucas, Brian S; Luther, Laura M; Burke, Steven D (2004) Synthesis of the C1-C17 segment of phorboxazole B. Org Lett 6:2965-8
Voight, Eric A; Roethle, Paul A; Burke, Steven D (2004) Concise formal synthesis of the bryostatin southern hemisphere (C17-C27). J Org Chem 69:4534-7
Jiang, Yueheng; Hong, Jian; Burke, Steven D (2004) Stereoselective total synthesis of antitumor macrolide (+)-rhizoxin D. Org Lett 6:1445-8
Lucas, Brian S; Burke, Steven D (2003) Palladium(0)-mediated desymmetrization of meso tetraols: an approach to the C3-C17 bis-oxane segment of phorboxazoles A and B. Org Lett 5:3915-8
Jiang, Lei; Martinelli, Joseph R; Burke, Steven D (2003) A practical synthesis of the F-ring of halichondrin B via ozonolytic desymmetrization of a C(2)-symmetric dihydroxycyclohexene. J Org Chem 68:1150-3

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