Dioxolane nucleoside

A)-Peniciclovir phosphates, (I), prepared by Vere Hodge (1) and N4-acylcytosine-1,3-dioxolane nucleoside derivatives, (II), prepared by Du (2) and Watanabe (3) were effective in the treatment of both HIV-1 and hepatitis B virus infections in mammals. 

Giles FJ, Garcia-Manero G, Cortes JE, et al. Phase 11 study of troxac-itabine, a novel dioxolane nucleoside analog, in patients with refractory leukemia. J Clin Oncol 2002 20 656-664. 

The dioxolane nucleoside phosphonates (50) and (51) have been prepared from... 

It was determined that the dioxolane ring system of a 1,6-anhydrohexose would serve well as a chiral template for the dioxolane nucleosides. Thus l,6-anhydromannoseii-i2 was chosen for its ease of large-scale preparation and the configuration of its hydroxyl groups at 2,3 and 4 ( 2 and 3 cis, and 3 and 4 trans) which allows for selective protection prior to oxidative cleavage (Fig. 4). 

In the search for an L-sugar that would serve as a chiral template for the synthesis of both the oxathiolane as well as dioxolane nucleosides, L-mannose was consid ed. L-mannose, however, suffers from several disadvantages in that it is not readily available or easily... 

The prevalence of diols in synthetic planning and in natural sources (e.g., in carbohydrates and nucleosides) has led to the development of a number of protective groups of valuing stability to a substantial array of reagents. Dioxolanes and diox-anes are the most common protective groups for diols. The ease of formation follows the order ... 

New applications of dioxolanes include evaluation of compounds such as 27 in perfumery <99MI77>, synthesis of N-hydroxypyrimidine derived nucleoside analogues such as 28 as potential antiviral agents <00CC2311> and use of 29 as a fungicide <00MIP43390>. 

Two approaches that have been validated for HIV inhibitors, nucleoside 5 -phosphonates [48] and 1,3-dioxolane analogs [49] have proven unsuccessful when applied to HCV inhibitors. Phosphonodiphosphates have been synthesized and are incorporated by NS5B RdRp, but Vmax/Km for these chain terminators is 10-100-fold less than for ATP, and potency must be greatly improved for analogs of this type to have utility [50]. A small series of 1,3-dioxolanes also failed to afford active inhibitors of HCV, or HIV, despite the addition of a 5-methyl substituent to impose the desired conformational preference [51]. Ring expanded nucleobases [52,53] and AICAR analogs have also been synthesized as HCV inhibitors which provide only weak replicon activity [54]. 

Optically active icco-nucleosides of type 1.1 of 2-nitromidazole were prepared from tartaric acid ester by conversion to the dioxolan followed by reduction and acylation to give 1154, which was converted to 1155. Its coupling and deacylation gave 1156 (94MIP1). All the optically active isomers showed a radiation-sensitization effect equivalent to that of the racemate. 

As part of an investigation into new synthetic routes to the important acyclic nucleoside class of antiviral drugs, the cross metathesis of 9-allyl-6-chloropurine with 2,2-dimethyl-4-vinyl-l,3-dioxolane was attempted <2003TL9177>. The reaction was confounded by the coordination of the ruthenium metathesis catalyst with the purine heterocyclic nitrogens. This was overcome to some extent by using the /i-toluenesulfonic acid or hydrogen chloride salts of the... 

Siddiqui, M. A., Marquez, V. E., Driscoll, J. S. and Barchi, J. J., Jr. (1994) A diastereo-selective synthesis of (S,5 )-a-fluoro-2,2-dimethyl-l,3-dioxolane-4-propanoic acid methyl ester, a key intermediate for the preparation of anti-HIV effective fluorodideoxy nucleosides. Tetrahedron Lett., 35, 3263-3266. 

The lipophilic effect of cyclopropyl explains why abacavir, a nucleoside reverse transcriptase inhibitor, has an improved absorption in the CNS compared to diaminop-urine dioxolane (DAPD) (Figure 20.14). ... 

Ceric ammonium nitrate, MeOH, 0 C, 15 min, 82-95% yield. Dioxolanes and some THP ethers are not affected, but in general, with extended reaction times, THP ethers are cleaved. Silica gel-supported CAN was found to be advantageous for the deprotection of nucleosides and nucleotides with primary TBS groups cleaved in preference to secondary derivatives. The TIPS group can also be cleaved by this method. This method was found effective where more traditional methods failed. ... 

Dioxolane analogues of thiazole nucleosides have been prepared starting from the thiazole derivative (439) which in turn is readily available from 2,2-diethoxyacetamide in a one-pot reaction (Scheme 108) <95TL378i>. 

Later, some of these C-nucleosides (e.g., 261) were synthesized by free radical C—C bond formation between the free radical 260, generated from the D-ribouronic acid derivative 259, and lepidinium trifluroacetate. Stereo-selectively of this coupling was attributed to the dominance of the steric bulk of the 1,3-dioxolane ring in 260 (92TL7575) (Scheme 78). 

The characterization and crystal structure of bis(ferrocenyl)dioxolane 17, produced by the reaction of ferrocenecarbaldehyde and the 4,5-dimethyl-l,3,2-dioxaphosphole 16 (13JOM(739)40), and the synthesis, characterization, and in vitro antineoplastic activity evaluation of the diastereomeric ferrocene acetals 18 and 19 (13S1853) have been reported. Accounts on the synthesis and evaluation for anti-HIV-1 activity of a series of dioxolane pyrimidine nucleosides 20-22 (13T10884) and the synthesis of the natural product trichodermatide A 23 (13AGE3646) have been published. The crystal structure of asarinin 24, which was isolated from the shrub Zanthoxylum datum, has been reported (13AXCo87). 

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