Synthesis of a Series of Purine 2′,3′-Dideoxy-L-Nucleoside Analogues as Potential Antiviral Agents

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Abstract
Various 2′,3′-dideoxy-L-nucleoside analogues, 6-amino-9-(2,3-dideoxy-β-L-ribofuranosyl) purine (19), 2-chloro-6-amino-9-(2,3-dideoxy-β-L-ribofuranosyl)-purine (20), 2-chloro-6-amino-9-(2,3-dideoxy-4-thio-β-L-ribofuranosyl) purine (21), 2,6-diamino-9-(2,3-dideoxy-β-L-ribofuranosyl) purine (26), 2,6-diamino-9-(2,3-dideoxy-β-thio-β-L-ribofuranosyl)-purine (27), 2-amino-6-chloro-9-(2,3-dideoxy-β-L-ribofuranosyl) purine (28), 6-chloro-9-(2,3-dideoxy-4-thio-β-L-ribofuranosyl) purine (29), and 6-amino-9-(2,3-dideoxy-4-thio-β-L-ribofuran-osyl) purine (30) have been synthesized by coupling of the sodium salt of 2-amino-6-chloropurine (1), 6-chloropurine (2), and 2,6-dichloropurine (3) with 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (4) or 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-4-thio-L-ribofuranose (5) in anhydrous MeCN in the presence of either EtAlCl2 or Et2AlCl followed by separation of the α/β-anomers and deprotection of the blocking groups. However, the synthesis of 9-(2,3-dideoxy-β-L-ribofuranosyl) guanine (57, β-L-ddG) was not straightforward. Coupling of the silylated N 2-palmitoylguanine (48) with sugar 4 in anhydrous MeCN, using trimethylsilyl trifluoromethanesulfonate as a catalyst yielded N-9-β- and N-9-α-; N-7-β- and N-7-α-isomers, compounds 49–52, which were separated by silica gel column chromatography with two appropriate eluting solvent systems. Removal of the protecting groups gave compound 57 (β-L-ddG) and the other 3 related isomers (58–60). The 2′,3′-dideoxy-L-nucleoside analogues were tested in vitro against HIV-1, HBV, L1210, P388, S-180, and CCRF-CEM. 6-Amino-9-(2,3-dideoxy-β-L-ribofuranosyl) purine (19, β-L-ddA) was found to have antiviral activity against HBV with an ED50 value of 6 μM.

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