Synthesis of 3'-fluoro-2',3'-dideoxy-2',3'-didehydro-4'-ethynyl-D- and -L-furanosyl nucleosides

The Journal of Organic Chemistry
Xin ChenChung K Chu

Abstract

An efficient procedure has been developed for the synthesis of 3'-fluoro-2',3'-dideoxy-2',3'-didehydro-4'-ethynyl D- and L-furanosyl nucleosides (1 and 2) starting from 2,3-O-isopropylidene-d-glyceraldehyde. The key intermediate 1-O-benzoyl-3E-fluoro-3,4-unsaturated-5,6-di(tert-butyldimethylsilyloxy)-2-hexanone 8 was obtained in nine steps with the overall yield of 22%. The alpha,beta-unsaturated ketone 8 was then treated with ethynylmagnesium bromide in a typical Grignard reaction procedure to afford the two intermediates 9 and 10, which after deprotection, oxidation, and acetylation gave the corresponding 4-ethynyl-substituted D- and L-sugar moieties 15 and 16, respectively. A series of D- and L-pyrimidine and purine nucleosides were prepared by the coupling of the sugar moieties with various silylprotected bases. The anomeric mixtures were obtained after condensation. After separation, the beta-isomers were further deprotected to yield the target nucleosides. All the newly synthesized 4'-substituted nucleosides were tested for their activities against HIV, among which the D-adenine derivative showed moderate anti-HIV activity (EC(50) = 25.1 microM) without significant cytotoxicity.

References

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Citations

Dec 21, 2006·Antiviral Chemistry & Chemotherapy·Chung K ChuRobert W Sidwell
May 24, 2006·Chemistry : a European Journal·Hideyo TakahashiShiro Ikegami
Sep 4, 2009·Journal of Fluorine Chemistry·Peng LiuChung K Chu

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