Complex cyclohexanes and tetrahydropyrans via oxocarbenium ion cyclizations.
Item
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Title
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Complex cyclohexanes and tetrahydropyrans via oxocarbenium ion cyclizations.
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Identifier
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AAI3284380
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identifier
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3284380
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Creator
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Camara, Fatoumata.
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Contributor
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Adviser: David R. Mootoo
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Date
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2007
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Language
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English
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Publisher
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City University of New York.
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Subject
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Chemistry, Organic
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Abstract
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The synthesis and medicinal chemistry of highly oxygenated cyclohexanes and tetrahydropyrans have attracted considerable attention. Two examples of such compounds are fumagillin and C-glycoside of 2-amino-2-deoxy-galactose. Fumagillin, a natural product is known to inhibit angiogenesis and endothelial cell proliferation. Structure activity studies suggest that the C-4 side chain interacts with lipophilic amino acids on the proposed cellular target, the protein methionine aminopepetidase 2 (MetAP-2). As a result, there is interest in fumagillin analogues with different side chains. Galactosamine is an important subunit of many glycoconjugates that are involved in a number of biological processes. C-linked galactosamines are of interest as biochemical tools.;The work reported in this thesis involves the application of oxocarbenium ion cyclizations to the synthesis of side chain analogues of fumagillin and beta-C-glycoside of galactosamine. The initial plan, for the modified side chain analogue of fumagillin, involved the oxocarbenium cyclization on a precursor containing the pre-installed side chain. This plan was promising in a model study on a tetrahydropyran framework, but encountered problems in the synthesis of the cyclization precursor and the key cyclization step when applied to the real cyclohexane system. The eventual solution was to perform the oxocarbenium ion cyclization on a less complex substrate, followed by elaboration of the side chain via the Kocienski modification of the Julia reaction.;The key step in the synthesis of beta-C-glycoside of galactosamine was the formation of a C1-substituted glycal via an oxocarbenium ion-enol ether cyclization. The enol ether-thioacetal substrate for the cyclization step was obtained by DCC coupling of a thio-isopropilidene acetal (TIA) and an acid precursor, followed by Tebbe olefination of the ester. Attempts to convert the glycal intermediate using synthetic methodologies for the direct transformation of glycals to 2-aminosugars were not successful. The successful solution entailed conversion of the C1-substituted glycal to a 2-deoxy-2-oxime methyl ether followed by a stereoselective reduction, using Bu3SnH/BF3.OEt2. An attempt to apply this approach to the C-glycoside analogue of GalNAc1ManNAc was unsuccessful.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
