SYNTHESIS OF RNA ANALOGUES.
Item
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Title
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SYNTHESIS OF RNA ANALOGUES.
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Identifier
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AAI8501157
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identifier
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8501157
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Creator
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MAZUR, WIESLAW ADAM.
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Contributor
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Robert Engel
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Date
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1984
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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 of nucleoside and nucleotide analogues in which the 3'-oxygen is replaced by a methylene group has been the object of this research program.;Various approaches to these substances have been evaluated and a general strategy has been developed which can be applied to the synthesis of 3'-modified nucleosides as well as isosteric nucleic acid analogues.;Two routes to these substances were used. The first began with specific protection of nucleosides at the 2'- and 5'-hydroxyls using silyl based reagents, thus exposing the 3'-carbon to selective transformations. Despite successful oxidations of the 3'-carbon in uridine and guanosine, all attempts to generate a new carbon-carbon bond in these positions failed.;The second strategy, which led to a development of synthetic routes to an isosteric trinucleotide (16 steps) and isomers of 3'-hydroxymethyluridine (9 steps), utilized 3-deoxy-1,2:5,6-diisopropylidene-3-C-methylene-(alpha)-D-glucofuranose (1) as a common substrate.;In the preparation of trinucleotide, the methylene group in (1) was converted stereospecifically to a 3-hydroxymethyl function and then to a 3-bromomethyl derivative. The bromination method involving bromine, triphenylphosphine and NBS was improved and now can be applied for substitution of hydroxyls with bromine in substances very sensitive to acids. Displacement of bromine by phosphorus was achieved by means of Arbuzov reaction with triisopropyl phosphite, following a conversion of the D-glucofuranose structure into an D-ribofuranose one. Further cleavage of the isopropyl functions, after introduction of the uracil ring at C-1, produced 3'-dihydroxyphosphonomethyl derivative of 3'-deoxyuridine. A required differentiation of the properties of the 2'- and 5'-hydroxyls in this nucleotide was achieved by protection of the 5'-hydroxyl, prior to the Arbuzov reaction, with the 3-benzoylpropionyl group while the 2'-hydroxyl was acetylated. This system proved to be stable in a wide range of reactions involving the 1- and 3- positions of the ribose ring. The 3-benzoylpropionyl group was selectively cleaved in the final steps giving access to isosteric trinucleotide analogue.;The same pattern of the hydroxyl protection was applied to the synthesis of 3-deoxy-3-methyleneuridine. Despite extensive efforts to epoxidize the 3'-olefinic bond in the latter, none were successful. However, this olefin reacted readily with osmium tetroxide giving a mixture of isomeric at C-3' 3'-hydroxymethyluridines.
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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.
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Program
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Chemistry
