Synthesis and Antiviral Evaluation of 3'-Fluoro-5'-norcarbocyclic Nucleoside Phosphonates Bearing Uracil and Cytosine as Potential Antiviral Agents

Abstract

Carbocyclic nucleoside analogues are an essential class of antiviral agents and are commonly used in the treatment of viral diseases (hepatitis B, AIDS). Recently, we reported the racemic synthesis and the anti-human immunodeficiency virus activities (HIV) of 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing purines as heterocyclic base. Based on these results, the corresponding racemic norcarbocyclic nucleoside phosphonates bearing pyrimidine bases were synthesized. The prepared compounds were evaluated against HIV, but none of them showed marked antiviral activity compared to their purine counterparts.

Keywords: antiviral; carbocyclic; nucleoside analogues; phosphonates.

Figure 1

Example of antiviral carbocyclic nucleosides and structures of the target compounds.

Scheme 1

Reagents and conditions: (a) DPPA, DIAD, PPh₃, THF/CH₂Cl₂, 0 °C, 30 min, 67%. (b) LiAlH₄, THF, 0 °C to RT, 30 min, 84%. (c) (E)-3-ethoxyacryloyl chloride, AgOCN, toluene, reflux, 30 min; then (±)-5, DMF, −20 °C to RT, 5 h, 98%. (d) HCl (2N), EtOH, reflux, 12 h, 78%.

Scheme 2

Reagents and conditions: (a) (i) BzOH, DIAD, PPh₃, THF, RT, 1 h; (ii) K₂CO₃, MeOH, RT, 4 h, 93% over two steps. (b) (EtO)₂P(O)CH₂OTs, NaH, DMF, RT, 3 days. (c) TMSBr, DMF, RT, 24 h, 24% from (±)-8.

Scheme 3

Reagents and conditions: (a) Ac₂O, DMAP, NEt₃, THF, RT, 1 h, 77%. (b) (i) Lawesson’s reagent, 1,2-dichloroethane, 83 °C, 20 h; (ii) methanolic ammonia, 100 °C, 4 h, 78% over two steps. (c) (i) BzOH, DIAD, PPh₃, THF, RT, 2 h; (ii) K₂CO₃, MeOH, RT, 2 h, 60% over two steps. (d) Bz₂O, DMF, RT, 24 h, 44%. (e) (i) (EtO)₂P(O)CH₂OTs, LiOtBu, DMF, 40 °C, 1 h; (ii) TMSBr, DMF, RT, 24 h; (iii) methanolic ammonia, 50 °C, 4 h, 67% over three steps.