The goal of this research program is the design and development of highly selective and efficient catalytic processes for the synthesis of biologically relevant compounds. Investigations will build upon our newest discoveries with unique catalytic uses of dirhodium carboxamidates. Breakthroughs in their applications for chemical oxidations and as chiral Lewis acids have demonstrated greatly enhanced versatility for these catalysts that will be further explored. The fixed stereodefined geometry of these catalysts provides access to highly enantioenriched products in metal carbene reactions of diazoacetates and, together with their low oxidation potentials, also provides capabilities for highly selective Lewis acid catalyzed reactions and efficient chemical oxidations. In all aims we seek high turnover numbers and high selectivities. In this funding period we will resolve limitations of chiral dirhodium carboxamidates for metal carbene transformations by novel processes for which preliminary results indicate that the aims will be achieved. We will develop diazo chemistry for catalytic stereoselective transformations to further enhance applicability of catalytic metal carbene chemistry in organic synthesis. New catalytic syntheses of multi-functional B-keto-a- diazoesters with subsequent catalytic metal carbene transformations provides highly efficient access to more complex carbon frameworks than previously possible through reactions with diazoacetates. We will use active Lewis acidic chiral dirhodium(ll,lll) carboxamidate catalysts to broaden the range of applicable carbon-carbon bond forming transformations. Reactivity and selectivity enhancement through chiral dirhodium(ll,lll) catalysts expands their utilization to Lewis acid catalyzed reactions for which chiral dirhodium(ll,ll) catalysts are ineffective, and initial focus will be given to those transformations for which preliminary results are most promising. We will develop and apply catalytic oxidative methodologies to compounds that are of biological significance. Newly discovered tert-butyl hydroperoxide oxidations catalyzed by dirhodium caprolactamate, based largely on its low oxidation potential and solubilities, offer a unique opportunity to develop a spectrum of oxidative transformations, compatible with water as a solvent, that are not easily achieved by other methods (especially allylic and benzylic oxidations). Applications encompass reactions with steroids, phenolic compounds, unsaturated fatty acids, amines, and other biologically relevant substrates.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM046503-22
Application #
8316122
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lees, Robert G
Project Start
1991-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
22
Fiscal Year
2012
Total Cost
$294,030
Indirect Cost
$98,010
Name
University of Maryland College Park
Department
Chemistry
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Xu, Xinfang; Doyle, Michael P (2014) The [3 + 3]-cycloaddition alternative for heterocycle syntheses: catalytically generated metalloenolcarbenes as dipolar adducts. Acc Chem Res 47:1396-405
Shanahan, Charles S; Truong, Phong; Mason, Savannah M et al. (2013) Diazoacetoacetate enones for the synthesis of diverse natural product-like scaffolds. Org Lett 15:3642-5
Xu, Xinfang; Zavalij, Peter Y; Hu, Wenhao et al. (2013) Vinylogous reactivity of enol diazoacetates with donor-acceptor substituted hydrazones. Synthesis of substituted pyrazole derivatives. J Org Chem 78:1583-8
Xu, Xichen; Qian, Yu; Zavalij, Peter Y et al. (2013) Highly selective catalyst-dependent competitive 1,2-CýýýC, -OýýýC, and -NýýýC migrations from ýý-methylene-ýý-silyloxy-ýý-amido-ýý-diazoacetates. J Am Chem Soc 135:1244-7
Qian, Yu; Zavalij, Peter J; Hu, Wenhao et al. (2013) Bicyclic pyrazolidinone derivatives from diastereoselective catalytic [3 + 3]-cycloaddition reactions of enoldiazoacetates with azomethine imines. Org Lett 15:1564-7
Xu, Xinfang; Hu, Wen-Hao; Doyle, Michael P (2011) Highly enantioselective catalytic synthesis of functionalized chiral diazoacetoacetates. Angew Chem Int Ed Engl 50:6392-5
Wang, Xiaochen; Weigl, Carolin; Doyle, Michael P (2011) Solvent enhancement of reaction selectivity: a unique property of cationic chiral dirhodium carboxamidates. J Am Chem Soc 133:9572-9
Xu, Xinfang; Ratnikov, Maxim O; Zavalij, Peter Y et al. (2011) Multifunctionalized 3-hydroxypyrroles in a three-step, one-pot cascade process from methyl 3-TBSO-2-diazo-3-butenoate and nitrones. Org Lett 13:6122-5
Wang, Xiaochen; Xu, Xinfang; Zavalij, Peter Y et al. (2011) Asymmeric formal [3 + 3]-cycloaddition reactions of nitrones with electrophilic vinylcarbene intermediates. J Am Chem Soc 133:16402-5
Truong, Phong; Xu, Xinfang; Doyle, Michael P (2011) An efficient methodology to substituted furans via oxidation of functionalized ?-diazo-?-ketoacetates. Tetrahedron Lett 52:2093-2096

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