The long-term objective of this research is the effective and efficient synthesis of single isomers of biologically important compounds in high yields and selectivities using asymmetric catalysis. Focus is on the unique capabilities of chiral dirhodium(ll) carboxamidates to cause high stereocontrol together with exceptional regio- and chemoselectivity at high turnover numbers (TONs). Originally developed for catalytic metal carbene transformations, these catalysts are now known to be effective for Lewis acid-catalyzed transformations, and this proposal incorporates both in its applications. Plans are described for the catalytic enantioselective syntheses of the stegane and isostegan series of lignan lactones, for a key bicyclic lactone intermediate in prostaglandin syntheses, and to control diastereoselectivity for formation of the less stable cis-disubstituted isomer in cyclopropanation reactions. However, the principal focus of our efforts is in new developments from ylide chemistry and Lewis acid-catalyzed transformations that we have recently discovered. Highly stereoselective syntheses of epoxides and aziridines, dihydrofurans and dihydropyrroles, and dihydroazepines directly from vinyldiazoacetates and aldehydes or imines via ylide intermediates are now possible, and major efforts will be directed to enantiocontrol in their formation. Bicyclic pyrroles and their analogues are prepared in a one-step catalytic process whose advantages will be further developed. Asymmetric Lewis acid catalyzed approaches to highly stereoselective hetero-Diels-Alder reactions, [2+2]-cycloadditions, and 1,3-dipolar additions using chiral dirhodium(ll) carboxamidate catalysts offer potentially significant advantages, especially with TONs up to 10,000 from commonly reported values of less than 50. These studies take advantage of our large stock of chiral dirhodium(ll) carboxamidate catalysts, since their steric and electronic features conducive to high reactivity and selectivity differ greatly among catalytic metal carbene and Lewis acid transformation.

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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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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University of Maryland College Park
Schools of Earth Sciences/Natur
College Park
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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, 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
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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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