Specific Aim I. Total Synthesis of Bryostatin 2. We propose to expand the utility of our recently developed method for the rapid construction of the 6,8-dioxabicyclo[3.2.1]octane ring system in the total synthesis of bryostatin 2, a clinically promising anticancer agent. In this context, we will: 1. Further develop our intermolecular ketalization/intramolecular ring-closing metathesis bond construction strategy to access the 6,9-dioxabicyclo[3.3.1]nonane ring system. 2. Use this desymmetrization strategy to accomplish efficient assembly of the C1-C16 and C17-C27 fragments of the bryostatins using (R,R)-1,6-heptadiene-3,5-diol as a common starting material for both fragments.
Specific Aim II. Total Synthesis of Phorboxazoles A and B. Based upon new preliminary results in Pd[0]- mediated desymmetrization, we will focus on these goals: 1. To develop and apply symmetry and novel strategies for symmetry-breaking to simplify a complex target and to provide a short, efficient synthesis. In this context we will investigate palladium-mediated, ligand-controlled double cyclization as a desymmetrization tactic. 2. To develop a regioselective differentiation of two vinyl appendages on the C5-C15 bis-pyran for converging subunits through the C 16-C 18 oxazole.
Specific Aim III. 6,8-Dioxabicyclo[3.2.1loctane and 1,7-Dioxaspiro[5.5]undecane Pharmacophore Libraries. Based upon our powerful ketalization/ring-closing metathesis route to bicyclic acetals and their demonstrated rearrangement to spiroketals, we intend: 1. To further demonstrate the utility of the intermolecular ketalization/intramolecular ring-closing metathesis protocol in a short synthesis of the didemniserinolipids. 2. To employ the 6,8-dioxabicyclo[3.2.1]octane skeleton as a scaffold for diversity-oriented synthesis. 3. To effect skeletal diversification via partitioning between 6,8-dioxabicyclo[3.2.1]octane and 1,7- dioxaspiro[5.5]undecane structures upon cleavage from solid support. 4. To prepare a pilot library of 2,600 pure compounds with these natural product-like scaffolds with three side-chain diversity elements and screen for a broad range of biological activities in the Keck Center for Chemical Genomics in our Department, and with collaborators on the campus of the UWMadison.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108488-02
Application #
6858826
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
2004-03-01
Project End
2008-02-29
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$229,414
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
Marvin, Christopher C; Voight, Eric A; Suh, Judy M et al. (2008) Synthesis of (+)-didemniserinolipid B: application of a 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis. J Org Chem 73:8452-7
Marvin, Christopher C; Clemens, Alexander J L; Burke, Steven D (2007) Synthesis of thromboxane B2 via ketalization/ring-closing metathesis. Org Lett 9:5353-6
Marvin, Christopher C; Voight, Eric A; Burke, Steven D (2007) Synthesis of (+)-didemniserinolipid B via ketalization/ring-closing metathesis. Org Lett 9:5357-9
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
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
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; Seradj, Hassan; Roethle, Paul A et al. (2004) Synthesis of the bryostatin 1 northern hemisphere (C1-C16) via desymmetrization by ketalization/ring-closing metathesis. Org Lett 6:4045-8