Most small, bioactive organic compounds interact specifically with a particular enzyme through a series of oxygen- and nitrogen-containing "functional groups." The specificity and strength of this interaction depends on the overall shape of the molecule and on the arrangement of its functional groups in space (i.e., its "stereochemistry"). The discovery of new compounds with the ability to fight disease or otherwise modulate the behavior of a biological system thus relies on the existence of methods for the synthesis of densely functionalized, well-defined organic molecules. In this regard, a particularly important goal of synthetic organic chemistry is the discovery of new transformations that convert simple, widely available hydrocarbon starting materials into complex, functionalized molecules with high levels of control over their stereochemistry. We are investigating the utility of small, oxygen- and nitrogen-rich compounds called "oxaziridines" in new organic reactions. We hypothesize that (1) transition metal catalysts will increase the reactivity of oxaziridines, (2) fundamentally different reactions will be observed using different catalysts, and (3) these catalysts will have the ability to control the stereochemistry of the resulting value-added products. The proposed research will test these hypotheses in the context of two Specific Aims. First, we will develop copper-catalyzed reactions of oxaziridines for the construction of stereochemically well-defined 1,2- aminoalcohol structures ("aminohydroxylation reactions"). Second, we will develop titanium-catalyzed reactions of oxaziridines for the construction of 1,3-aminoalcohol-containing structures with similarly high levels of stereochemical fidelity ("nitrone cycloadditions"). Successful realization of our project goals will constitute a significant contribution to the field of synthetic organic chemistry and provide a set of powerful tools for the discovery of new drugs, new biological probes, and new materials.

Public Health Relevance

Most drugs are small organic molecules that fight disease by using a series of oxygen- and nitrogen- containing "functional groups" to interact with an enzyme in a pathogen or in a human cell. The ability of a drug to specifically recognize one target enzyme out of thousands and control the progress of a disease depends critically on the overall shape of the molecule and the arrangement of its functional groups in space. We are developing new methods for the rapid, shape-selective construction of well-defined nitrogen- and oxygen-rich molecules, which will enable the discovery and manufacture of the next generation of potent disease-fighting drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084022-05
Application #
8247782
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2008-06-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$266,740
Indirect Cost
$80,521
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
Williamson, Kevin S; Michaelis, David J; Yoon, Tehshik P (2014) Advances in the chemistry of oxaziridines. Chem Rev 114:8016-36
Deporter, Sandra M; Jacobsen, Ashley C; Partridge, Katherine M et al. (2010) N-Nosyl Oxaziridines as Terminal Oxidants in Copper(II)-Catalyzed Olefin Oxyaminations. Tetrahedron Lett 51:5223-5225
Partridge, Katherine M; Guzei, Ilia A; Yoon, Tehshik P (2010) Carbonyl imines from oxaziridines: generation and cycloaddition of N-O=C dipoles. Angew Chem Int Ed Engl 49:930-4
Benkovics, Tamas; Guzei, Ilia A; Yoon, Tehshik P (2010) Oxaziridine-mediated oxyamination of indoles: an approach to 3-aminoindoles and enantiomerically enriched 3-aminopyrroloindolines. Angew Chem Int Ed Engl 49:9153-7
Williamson, Kevin S; Yoon, Tehshik P (2010) Iron-catalyzed aminohydroxylation of olefins. J Am Chem Soc 132:4570-1
Benkovics, Tamas; Du, Juana; Guzei, Ilia A et al. (2009) Anionic halocuprate(II) complexes as catalysts for the oxaziridine-mediated aminohydroxylation of olefins. J Org Chem 74:5545-52
Allen, Charles P; Benkovics, Tamas; Turek, Amanda K et al. (2009) Oxaziridine-mediated intramolecular amination of sp(3)-hybridized C-H bonds. J Am Chem Soc 131:12560-1
Michaelis, David J; Williamson, Kevin S; Yoon, Tehshik P (2009) Oxaziridine-mediated enantioselective aminohydroxylation of styrenes catalyzed by copper(II) bis(oxazoline) complexes. Tetrahedron 65:5118-5124