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Abstract

3'-Chloro and 3'-acetylsulfanyl derivatives of 1-(2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil were prepared by reaction of 2,3'-anhydro-1-{5'-O-benzoyl-4'-C-[(benzoyloxy)methyl]-2'-deoxy-α-L-erythro-pentofuranosyl}uracil (3) with hydrogen chloride and thioacetic acid, respectively. The reaction with hydrogen chloride gave a mixture of N-1 and N-3 substituted uracil derivatives 12 and 14. Reaction of 1-{3-O-benzoyl-4-C-[(benzoyloxy)methyl]-2-deoxy-α-L-threo-pentofuranosyl}uracil (7) with thionyl chloride and subsequent debenzoylation afforded 1-(4-C-chloromethyl-2-deoxy-β-D-erythro-pentofuranosyl)uracil (19). Nucleophilic substitution with lithium thioacetate, followed by deacylation, converted 1-{3-O-benzoyl-4-C-[(benzoyloxy)methyl]-2-deoxy-5-O-p-toluenesulfonyl-α-L-threo-pentofuranosyl}uracil (9) into 1-(2-deoxy-4-C-sulfanylmethyl-β-D-erythro-pentofuranosyl)uracil (21). The obtained thiols were oxidized with iodine or air to give 1,1'-[disulfandiylbis(2,3-dideoxy-4-hydroxymethyl-α-L-threo-pentofuranose-3,1-diyl]di(pyrimidine-2,4-(1H,3H)-dione) (17) and 1,1'-[disulfandiylbis(2,5-dideoxy-4-hydroxymethyl-α-L-threo-pentofuranose-5,1-diyl]di(pyrimidine-2,4(1H,3H)-dione) (22). Reaction of 1-{3-acetylsulfanyl-5-O-methanesulfonyl-4-C-[(benzoyloxy)methyl]-2,3-dideoxy-α-L-threo-pentofuranosyl)}uracil (24) with methanolic sodium methoxide afforded 1-(3,5-anhydro-2,3-dideoxy-4-C-hydroxymethyl-3-sulfanyl-α-L-threo-pentofuranosyl)uracil (25). The same reagent was used in the preparation of 1-(3,5-anhydro-2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil (26) from 1-{4-C-[(benzoyloxy)methyl]-2-deoxy-5-O-p-toluenesulfonyl-α-L-threo-pentofuranosyl}uracil (8). From the series of 4'-substituted 2'-deoxyuridine derivatives, synthesized in this study, solely the 4'-chloromethyl derivative 19 and the oxetane derivative 26 exhibited an appreciable activity against HIV-1 and HIV-2.

Keywords: 2'-Deoxy-4'-C-hydroxymethyluridine derivatives; Antivirals.