The synthesis of a novel nucleoside phosphonate constructed on a branched-threo-tetrofuranose scaffold, as a potential antiviral agent, is described. The pseudosugar moiety served as the nucleoside skeleton was produced starting from 2-butyne-1,4-diol in 10-steps. Glycosylation with the pseudosugar involved stereoselective neighboring group participation of p-anisyl group and gave the nucleoside derivative in 94% yield. After manipulating the protecting group and introduction of a methylenephosphate unit, the synthesis of the target novel cytidine phosphonate was achieved. The resulting nucleoside, a synthetic intermediate of the nucleoside phosphonate, would also be expected to serve as a useful building block for the synthesis of novel antisense/antigene derivatives.

As a part of our ongoing efforts to identify new anti-HIV agents, a 5′-thiopyrano-nucleoside derivative 4, designed based on 4′-thioD4C 1 and cyclohexenylnucleoside 3, was synthesized. The dihydrothiopyran skeleton of 4 was constructed by the ring closing metathesis of 21 which was synthesized from but-2-yne-1,4-diol. After converting the protecting group from MOM to TBS followed by oxidation, a Pummerer-type thioglycosylation reaction of 24 with persilylated uracil gave the desired 5-thiodihydrothiopyranyluracils 25 and 26 as a mixture of anomers. The conversion of 25 to a cytosine derivative and subsequent deprotection gave a 5-thiodidehydropyranosylcytosine derivative 4 in good yield. The anti-HIV activity of 4 was also evaluated.

We have identified a selective SN2′ reaction triggered by iodide ion that leads to the ring-opening of 2,2′-anhydro-α-nucleosides. By applying the method, we have synthesized α-d-2′,3′-didehydro-2′,3′-dideoxy-3′-C-hydroxymethyl nucleosides, designed as potential antiviral agents.A series of α-d-2′,3′-didehydro-2′,3′-dideoxy-3′-C-hydroxymethyl nucleosides were synthesized and evaluated for their in vitro antiviral activities (HSV, HCMV, HIV) and cytotoxicities.