SYNTHESIS OF SEVERAL PYRIMIDINE L-NUCLEOSIDE ANALOGS AS POTENTIAL ANTIVIRAL AGENTS

beta-L-5-Iodo-2'-deoxyuridine (beta-L-IUdR, 7) and 1-[(beta-L-arabinofuranosyl)-E-5-(2-bromovinyl)]uracil (beta-L-BV-ara-U, 10) have been synthesized via a multi-step synthesis from L-arabinose. 2',3'-Dideoxy-beta-L-5-azacytidine (18), 2',3'-dideoxy-beta-L-2-thiocytidine (20) and their respective a-anomers, compounds 19 and 21, also were synthesized by direct coupling of 1-O-acetyl-5-O-(tert-butyldimethyfsilyl) (13) with the corresponding silylated bases, in the presence of EtA1Cl(2) in CH2Cl2, followed by separation of the alpha- and beta-isomers and deblocking of the 5'-protecting groups. In addition, 2',3'-dideoxy-beta-L-5-fluorocytidine (34), a potent anti-HIV and anti-HBV agent, was synthesized by an alternative methodology from 2',3'-dideoxy-beta-L-5-fluorouridine (31) via a 4-triazolylpyrimidinone intermediate. These L-nucleoside analogues were tested in vitro against HIV, HBV, HSV-1, and HSV-2. Among these compounds, 2',3'-dideoxy-beta-L-5-azacytidine (18) was found to show significant activity against HBV in vitro at approximately the same level as 2',3'-dideoxy-beta-D-cytidine (ddC), which is a known potent anti-HBV agent.