SYNTHESIS OF A SERIES OF PURINE 2',3'-DIDEOXY-L-NUCLEOSIDE ANALOGS ASPOTENTIAL ANTIVIRAL AGENTS

Various 2',3'-dideoxy-L-nucleoside analogues, 6-amino-9-(2,3-dideoxy-b eta-L-ribofuranosy))purine (19), -amino-9-(2,3-dideoxy-beta-L-ribofura nosyl)-purine (20), -9-(2,3-dideoxy-4-thio-beta-L-ribofuranosyl)purine (21), 2,5- diamino 9-(2,3-dideoxy-beta-L-ribofuranosyl)purine (26), 9 -(2,3-dideoxy-4-thio-beta-L-ribofuranosyl)-purine (27), -chloro-9-(2,3 -dideoxy-beta-L-ribofuranosyl)purine (28), -9-(2,3-dideoxy-4-thio-beta -L-ribofuranosyl)purine (29), and -9-(2,3-dideoxy-4-thio-beta-L-ribofu ranosyl)purine (30) have been synthesized by coupling of the sodium sa lt of 2-amino-6-chloropurine (1), 6-chloropurine (2), and 2,6-dichloro purine urine (3) with ert-butyldimethylsilyl)-2,3-dideoxy-L-ribofurano se (4) or yldiphenylsilyl)-2,3-dideoxy-4-thio-L-ribofuranose (5) in an hydrous MeCN in the presence of either EtAlCl(2) or Et(2)AlCl followed by separation of the alp-anomers and deprotection of the blocking gro ups. However, the synthesis of 9-(2,3-dideoxy-beta-L-ribofuranosyl)gua nine (57, beta-L-ddG) was not straightforward. Coupling of the silylat ed N-2-palmitoylguanine (48) with sugar 4 in anhydrous MeCN, using tri methylsilyl trifluoromethanesulfonate as a catalyst yielded N-9-beta- and N-9-alpha-; N-7-beta- and N-7-alpha-isomers, compounds 49-52, whic h were separated by silica gel column chromatography with two appropri ate eluting solvent systems. Removal of the protecting groups gave com pound 57 (beta-L-ddC) 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-beta-L-r ibofuranosyl)purine (19, beta-L-ddA) was found to have antiviral activ ity against HBV with an ED(50) value of 6 mu M.