This program will investigate fundamental aspects of heterocycle activation and coupling in the context of a synthetic program designed to prepare potent cytotoxic agents. The targets include FK317 metabolites, N-methylaziridinomitosene B, diazonamide A, and structures containing hindered peptide subunits such as hemiasterlin, an inhibitor of tubulin polymerization. Selected synthetic intermediates will be submitted to the NCI Drug Screening Program, and specific targets in the FK317 and N-methylaziridinomitosene B project will be evaluated for DNA alkylation and crosslinking ability in collaboration with Prof. P. Hopkins (Univ. of Washington). Synthetic efforts in the aziridinomitosene area will exploit recently developed methods for anionic cyclization to prepare FK317 metabolites and to test their role in the activation cascade. Advances in oxazole lithiation will be used to synthesize N-methylaziridinomitosene B and the corresponding hydroquinone. Solvolysis products of the hydroquinone will be identified under controlled pH conditions to resolve mechanistic issues. The Diazonamide A project will focus on synthetic methodology, including the introduction of quaternary carbon with control of absolute configuration in a benzofuranone, ring closure of a hindered peptide in a relatively rigid polycyclic environment, and assembly of an oxazole- and indole-containing biaryl macrocycle. The oxazole activation technology will also be used to assemble heterocyclic structures containing di-oxazoles, tri-oxazoles, and oxazolylindoles. Similar structures often appear in marine natural products. Methodology for high yield coupling of hindered peptides has been developed as part of the diazonamide A project and will be extended to the synthesis of the exceptionally hindered hemiasterlins and related structures.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA017918-30
Application #
6747304
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
1978-07-01
Project End
2005-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
30
Fiscal Year
2004
Total Cost
$300,163
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Peris, Gorka; Vedejs, Edwin (2015) Enantiocontrolled synthesis of a tetracyclic aminal corresponding to the core subunit of diazonamide A. J Org Chem 80:3050-7
Wiedner, Susan D; Vedejs, Edwin (2012) Reactivity of aziridinomitosene derivatives related to FK317 in the presence of protic nucleophiles. J Org Chem 77:1045-55
Wiedner, Susan D; Vedejs, Edwin (2010) Aziridinomitosanes via lactam cyclization. Org Lett 12:4030-3
Nelson, John M; Vedejs, Edwin (2010) Metalated aziridines for cross-coupling with aryl and alkenyl halides via palladium catalysis. Org Lett 12:5085-7
Duffey, Trisha A; Mackay, James A; Vedejs, Edwin (2010) Catalytic parallel kinetic resolution under homogeneous conditions. J Org Chem 75:4674-85
Duffey, Trisha A; Shaw, Scott A; Vedejs, Edwin (2009) AcOLeDMAP and BnOLeDMAP: conformationally restricted nucleophilic catalysts for enantioselective rearrangement of indolyl acetates and carbonates. J Am Chem Soc 131:14-5
Peris, Gorka; Vedejs, Edwin (2008) Diastereoselective carboxyl migrations of 3-arylbenzofuranones. J Org Chem 73:1158-61
Bobeck, Drew R; Warner, Don L; Vedejs, Edwin (2007) Internal azomethine ylide cycloaddition methodology for access to the substitution pattern of aziridinomitosene A. J Org Chem 72:8506-18
Warner, Don L; Hibberd, Amber M; Kalman, Monica et al. (2007) N-silyl protecting groups for labile aziridines: application toward the synthesis of N-H aziridinomitosenes. J Org Chem 72:8519-22
Shaw, Scott A; Aleman, Pedro; Christy, Justin et al. (2006) Enantioselective TADMAP-catalyzed carboxyl migration reactions for the synthesis of stereogenic quaternary carbon. J Am Chem Soc 128:925-34

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