Synthesis and antiviral activity of phosphonate derivatives of enantiomeric dihydro-2H-pyranyl nucleosides

A synthetic approach to phosphonate derivatives of 2,5-cis-substituted dihydro-2H-pyranyl nucleosides has been developed and both series of enantiomers (3 and 4) have been prepared. The key step in the synthetic pathway was the introduction of the phosphonomethoxy moiety on pentopyranosyl glycals through a Ferrier-type rearrangement. The heterocyclic base was then incorporated under Mitsunobu conditions. The resulting nucleoside derivatives were more stable towards acidic degradation than their natural isomers. However, they were found to be inactive against the replication of human immunodeficiency virus (HIV), herpes simplex virus (HSV) and other herpes viruses [i.e. varicella-zoster virus (VZV), cytomegalovirus (CMV)] in cell culture, which could at least partially be ascribed to an inefficient phosphorylation by cellular enzymes (i.e. GMP kinase).