The proposed research combines methodology and total synthesis. The targets chosen for total synthesis are halichondrin and rhizoxin. Both natural products are relatively scarce and demonstrate potent antimitotic activity by binding to the vinca domain on tubulin. In vivo activity against vinblastine and vincristine resistant cell lines has led to the selection of rhizoxin for Phase II clinical evaluation, and halichondrin B is currently in preclinical development. As a key strategy in both syntheses, two-directional chain synthesis is being applied. Three new methods for the synthesis of polysubstituted hydropyrans are also proposed. Planned variations of the Claisen rearrangement include a tandem glycolate ester enolate Claisen/ring-closing metathesis sequence, a desymmetrization of C2-symmetric substrates via a dioxanone rearrangement, and asymmetric catalysis of the dioxanone Claisen rearrangement by cationic metal complexes. Based on the second method, a short synthesis of KDO, a membrane component of Gram-negative bacteria, is proposed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074394-03
Application #
2895970
Study Section
Special Emphasis Panel (ZRG3-BNP (01))
Program Officer
Lees, Robert G
Project Start
1997-07-01
Project End
2000-06-30
Budget Start
1999-07-07
Budget End
2000-06-30
Support Year
3
Fiscal Year
1999
Total Cost
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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