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A new template of C-4'-truncated phosphonated nucleosides (TPCOANs) has been obtained in good yields according to two different routes which exploit the reactivity of a phosphonated nitrone. The one-step procedure based on the 1,3-dipolar cycloaddition of a phosphonated nitrone with vinyl nucleobases leads to the unnatural alpha-nucleosides as the main adducts. On the other hand, the target beta-anomers have been obtained in high yield by a two-step procedure based on the 1,3-dipolar cycloaddition of a phosphonated nitrone with vinyl acetate followed by nucleosidation reaction. The reactivity of the phosphonated nitrone has been investigated trough quantum mechanical DFT calculations at the B3LYP/D95+(d,p) theory level. Preliminary biological assays show that beta-anomers of TPCOANs are able to inhibit the reverse transcriptase of different retroviruses at concentrations in the nanomolar range, with a potency comparable with that of tenofovir.

The first synthetic route of novel 2'(beta),3'(beta)-C-dimethyl carbodine analogues is described. The key intermediate cyclopentenyl alcohol 11(beta) prepared from Weinreb amide 4 via ring-closing metathesis (RCM) and vicinal dihydroxylation. Coupling of 12 with nucleosidic bases via the Pd(0) catalyzed reaction followed by stereoselective dihydoxylation and deprotection afforded the target carbocyclic nucleoside analogues. The synthesized compounds were evaluated as inhibitors of the hepatitis C virus (HCV) in Huh-7 cell line in vitro. However, the nucleosides failed to inhibit HCV RNA replication in the cell-based replicon assay (EC(50) > microM).

An efficient synthesis for racemic cyclopent-3-en-1-yl nucleoside analogues has been developed starting from cyclopentadiene. The key step is the regioselective hydroboration of a mixture of intermediate alkylatede cyclopentadienes to give one cyclopentenol.