Synthesis of novel entecavir analogues having 4'-cyano-6''-fluoromethylenecyclopentene skeletons as an aglycone moiety as highly potent and long-acting anti-hepatitis B virus agent.

Encouraged by our recent findings that 4'-cyano-deoxyguanosine (2), entecavir analogues 4 and 5 are highly potent anti-hepatitis B virus (HBV) agents, we designed and synthesized 6 having a hybridized structure of 4 and 5. The chiral quaternary carbon portion at the 4'-position, which is substituted by cyano- and 5'-hydroxymethyl groups, was stereospecifically constructed by radical-mediated 5- exo-dig mode cyclization of 10. The introduction of the fluorine atom into the 6''-position was achieved by radical-mediated stannylation of sulfide ( E )-11 and subsequent electrophilic fluorination of ( E )-12. The desired ( E )-6 was obtained after the introduction of the guanine base into ( E )-18 under Mitsunobu conditions and following global deprotection. The stereoisomer ( Z )-6 was also prepared by the same procedure using ( Z )-12. Compound ( E )-6 showed highly potent anti-HBV activity (EC 50 = 1.2 nM) with favorable cytotoxicity (CC 50 = 93 μM).