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Synthesis Of Novel Anti-HIV N-O Bond Incorporated L-Nucleoside Analogs

Posted on:2005-10-19Degree:DoctorType:Dissertation
Country:ChinaCandidate:J C ChuFull Text:PDF
GTID:1101360122982236Subject:Applied Chemistry
Abstract/Summary:PDF Full Text Request
AIDS severely threatens all human beings. Therefore it is urgent to find potent anti-HIV medicines. Some of D-nucleoside analogs were proved as anti-HIV medicines, while, their L-isomers were also found to be promising compounds. This thesis reports the design and synthesis of a series of novel N-alkyl- hydroxylamine-modified L-nucleoside analogs, in which 40 novel compounds were obtained via a 13-step synthetic route in about 4% overall yields. These compounds are desirable for the studies of their biological activities and structure-activity relationships.Started from L-ascorbic acid, a diastereomeric mixture of L-gulono-1,4-lactone was obtained in 99.1% yield by Pd/C-catalyzed hydrogenation. The mixture was selectively protected by a ketal group under an acid condition to give 5,6-O-isopropylidene-L-gulono-1,4-lactone in 75.0% yield. L-(S)-glyceraldehyde acetonide was obtained after the lactone was submitted to NaIO4 oxidation. Since the glyceraldehyde can dissolve into both water and organic solvents, Wittig reaction was successively carried out at 0℃ in the mixture solvent of water and CH2Cl2 to give ethyl-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-acrylate with the cis-isomer as the main product. The mixture of the trans-isomer and the cis-isomer was hydrolyzed under an acid condition to give dialcohol and (R)-(+)-5-hydroxymethyl-2-(5H)-furanone, respectively. Separation and purification of the resulting mixture gave the furanone in 43.0% yield. The protected furanone was then submitted to a series of N-alkyl- hydroxylamines to give the corresponding Michael addition products in 86-89% yields. There was a five-membered ring intermediate in the Michael addition procedure and only one configuration was obtained by addittion of N-alkylhydroxylamines from the less hindered face of the furanone ring. Those compounds were protected, reduced, and acylated to give acetyl intermediates in 20-33% yield. These intermediates were turned into oxonium intermediates catalyzed by TMSOTf, and then glycosylated to give the protected nucleoside analogs in 70-85% yields. In order to separate the mixture of diastereo-isomers, these compounds were selectively deprotected and then separated. Most of them could be successively separated to give monomers and then submitted to another deprotected procedure to produce the final nucleoside analogs in 55-77% yields.The structures of the key intermediates and the novel target nucleoside analogs were confirmed by the analysis of NMR data.
Keywords/Search Tags:AIDS, HIV, Nucleoside analog, Michael addition, L-ascorbic acid, Wittig reaction.
PDF Full Text Request
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