Enantiospecific synthesis of 3′-hetero-dideoxy nucleoside analogues as potential anti-HIV agents

Abstract

Bnovo**oH -11 10 9 * We thank J. M. Cameron, J. A. V. Coates, C. Penn, N. Cammack and H. Jenkinson of the Virology Department of Glaxo Group Research for the presentation of these data.

Antiviral activities of isometric dideoxynucleosides of D- and L-related stereochemistry

“…The mirror image of these compounds (R,R enantiomers) with D-related stereochemistry (Fig. 1) were reported by Huryn et al (36,37) and Jones et al (39).…”

“…The R,R-thiaisonucleosides (Fig. 1) have been prepared by an enantioselective synthesis beginning with diacetone-D-glucose (38,39). Unlike their oxygen counterparts, none of these thiaisonucleosides showed anti-HIV activity in whole-cell assays (MT-4 cells) at concentrations below 375 M.…”

A Fortuitously Straightforward Synthesis of 4-Acetoxy-2-Propyltetrahydrothiophene

“…Tetrahydrothiophenes occur widely as important building blocks of many biologically active molecules, such as 3´-heterodideoxy nucleoside analogues as potential anti-HIV agents, 1,2 modified dideoxy isonucleosides with antiviral activity, 3 the essential coenzyme biotin as a water-soluble vitamin with important biological functions, 4 so do their derivatives, such as the corresponding cyclic sulfonium salts, the potent a-glucosidase inhibitors salacinol, 5,6 kotalanol, 7 salaprinol and ponkoranol 8,9 isolated from several Salacia plant species, and the related cyclic sulfolanes as high-affinity P 2 ligands for HIV-1 protease inhibitors. 10 A comprehensive review about the methods for the synthesis of tetrahydrothiophenes, provided by Benetti et al, 11 included several different ways to produce chiral nonracemic tetrahydrothiophenes and some typical synthetic routes for the racemates.…”

“…As far as we know, there are only a few methods reported in the literature to prepare such analogues. One of the analogues, nonracemic 5-[(benzyloxy)methyl]tetrahydrothiophen-3-ol was prepared by starting from diacetone-D-glucose through a 12step route, 1,2 and the other one, 5-methyltetrahydrothiophene-3-ol was obtained by starting from ethyl 3-bromobutanoate and ethyl 2-mercaptoacetate through nucleophilic substitution, intramolecular Claisen condensation, hydrolysis and decarboxylation, and reduction. 10 In addition, 5-[(methoxycarbonyl)methylene]tetrahydrothiophen-3-ol was prepared by the reaction of d-chloromethyl a,b-unsaturated d-lactone with thioacetic acid followed by treatment with potassium carbonate.…”

Anti-Human Immunodeficiency Virus Activities of Nucleosides and Nucleotides: Correlation with Molecular Electrostatic Potential Data

“…Its triphosphate is one of the most powerful inhibitors of HIV RT known (K i ϭ 16 nM) (31). The enantiomer of this compound also shows some activity against HIV (14,15). In comparison, none of the other isomeric nucleosides of the (S,S), (R,R), or apio families were found to have significant anti-HIV activity (30).…”