Synthesis of oligonucleotide analogues.
Item
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Title
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Synthesis of oligonucleotide analogues.
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Identifier
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AAI8820865
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identifier
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8820865
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Creator
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Gandhi, Rajendrakumar Chimanlal.
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Contributor
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Adviser: Robert Engel
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Date
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1988
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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 research project concerns with the synthesis of the isosteric analogues of uridine nucleotides in which a 5{dollar}\sp\prime{dollar}-Oxygen atom has been replaced by a methylene group. In the pursuit of this goal, various uridine nucleosides were synthesized. Among these, the synthesis of 2{dollar}\sp\prime{lcub},{rcub}3\sp\prime{dollar}-O-isopropylideneuridine-6{dollar}\sp\prime{dollar}-phosphonic acid by several routes, was investigated.;The first strategy involved the simultaneous protection of the 2{dollar}\sp\prime{dollar}- and 3{dollar}\sp\prime{dollar}-hydroxyl groups in the form of an isopropylidene group, allowing further derivatization at the 5{dollar}\sp\prime{dollar}-position. This derivatization included oxidation followed by Horner-Emmons reaction to afford the 6{dollar}\sp\prime{dollar}-diphenyl-2{dollar}\sp\prime{lcub},{rcub}3\sp\prime{dollar}-O-isopropylideneuridine phosphonate. Hydrogenation of this ester with Adam's catalyst resulted in the simultaneous reduction of the double bond and the diphenyl phosphonate ester to yield the desired aforementioned phosphonic acid. Hydroboration followed by reduction of the aforementioned diphenyl phosphonate ester yielded the corresponding {dollar}\alpha{dollar}-hydroxyphosphonic acid.;The second strategy involved the conversion of the 5{dollar}\sp\prime{dollar}-hydroxyl group of 2{dollar}\sp\prime,3\sp\prime{dollar}-O-isopropylideneuridine into the corresponding 5{dollar}\sp\prime{dollar}-iodo compound via the tosylate derivative. The nucleophilic substitution of the 5{dollar}\sp\prime{dollar}-iodo group by the preformed dimethyl {dollar}\alpha{dollar}-lithiomethylphosphonate afforded the 6{dollar}\sp\prime{dollar}-dimethyl-{dollar}2\sp\prime{lcub},{rcub}3\sp\prime{dollar}-O-isopropylideneuridine phosphonate and a cyclic compound as a minor product. Dealkylation attempts on this dimethyl phosphonate with trimethylsilyl bromide--which, if successful, would have produced the aforementioned 6{dollar}\sp\prime{dollar}-phosphonic acid--remained unsuccessful.;Model studies involving the {dollar}\alpha{dollar}-lithiation of bis-trimethylsilyl chloromethyl phosphonic acid and its {dollar}\alpha{dollar}-alkylation using simple halides remained unsuccessful.;Several 2{dollar}\sp\prime{lcub},{rcub}5\sp\prime{dollar}-O-protected uridine derivatives were synthesized for the coupling experiments. In particular, the 2{dollar}\sp\prime{lcub},{rcub}5\sp\prime{dollar}-di-O-trityluridine by tritylation of uridine in pyridine and 2{dollar}\sp\prime{dollar}-tetrahydropyranyl-5{dollar}\sp\prime{dollar}-dimethoxytrityluridine in thee steps from uridine, were synthesized and employed in the coupling experiments with the 2{dollar}\sp\prime{lcub},{rcub}3\sp\prime{dollar}-isopropylideneuridine-6{dollar}\sp\prime{dollar}-phosphonic acid. After several unsuccessful coupling attempts the DCC coupling between the aforementioned phosphonic acid and the 2{dollar}\sp\prime{lcub},{rcub}5\sp\prime{dollar}-di-O-trityluridine followed by the acetic acid treatment afforded the isosteric dinucleotide UCH{dollar}\sb{lcub}\rm 2P{rcub}{dollar}U.
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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.
