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The 4′ position modifications in carbocyclic nucleosides have not been investigated much as potential antiviral agents. Due to the higher ring strain and torsion of the cyclopentyl carbocyclic ring, it is not easy to carry out the modification at the 4′ position. Therefore, there is a need for a procedure that may tackle the synthesis of 4′ position substituted carbocyclic pentyl ring. In this communication, a stereoselective synthesis of 4′‐α‐fluoro‐methyl carbocyclic nucleosides has been reported. A stereoselective synthesis of the 4‐α‐fluoro‐methyl carbocyclic sugar moiety (16) was carried out via carbocyclic ketone 1. The oxidation of the 5‐methyl hydroxy of 9 followed by the aldol condensation gave a diol 11, which via selective protection followed by selective fluorination, yielded a MOM‐protected 4‐α‐fluoro‐methyl carbocyclic ring (16). Compound 16 served as a key intermediate for the synthesis of purines (21&24) and pyrimidine (28&31) nucleosides. The described synthesis may be utilized to construct the various 4′ position modified carbocyclic nucleos(t)ides for an elaborated structure‐activity relationship (SAR) as an antiviral and anticancer agent.

Varicella zoster virus (VZV) establishes lifelong infection after primary disease and can reactivate. Several drugs are approved to treat VZV diseases, but new antivirals with greater potency are needed. Previously, we identified), which had significant anti-VZV activity. In this communication, we report the synthesis and evaluation of numerous L-BHDU prodrugs: amino acid esters (14−26), phosphoramidates (33−34), long-chain lipids (ODE-L-BHDU-MP, 38, and HDP-L-BHDU-MP, 39), and phosphate ester prodrugs (POM-L-BHDU-MP, 41, and POC-L-BHDU-MP, 47). The amino acid ester L-BHDU prodrugs (L-phenylalanine, 16, and L-valine, 17) had a potent antiviral activity with EC 50 values of 0.028 and 0.030 μM, respectively. The phosphate ester prodrugs POM-L-BHDU-MP and POC-L-BHDU-MP had a significant anti-VZV activity with EC 50 values of 0.035 and 0.034 μM, respectively, and no cellular toxicity (CC 50 > 100 μM) was detected. Out of these prodrugs, ODE-L-BHDU-MP (38) and POM-L-BHDU-MP (41) were selected for further evaluation in future studies.