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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Lees, Robert G
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University of Maryland College Park
Schools of Earth Sciences/Natur
College Park
United States
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Cheng, Qing-Qing; Deng, Yongming; Lankelma, Marianne et al. (2017) Cycloaddition reactions of enoldiazo compounds. Chem Soc Rev 46:5425-5443
Sha, Qiang; Arman, Hadi; Doyle, Michael P (2016) Asymmetric synthesis of 1H-pyrrol-3(2H)-ones from 2,3-diketoesters by combination of aldol condensation with benzilic acid rearrangement. Chem Commun (Camb) 52:108-11
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Xu, Xinfang; Zavalij, Peter Y; Doyle, Michael P (2013) Highly enantioselective dearomatizing formal [3+3] cycloaddition reactions of N-acyliminopyridinium ylides with electrophilic enol carbene intermediates. Angew Chem Int Ed Engl 52:12664-8
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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

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