Synthesis of phosphonate derivatives of methylenecyclopropane nucleoside analogues by alkylation–elimination method and unusual opening of cyclopropane ring

The synthesis of phosphonates of methylenecyclopropane nucleoside analogues , and by alkylation–elimination approach is described. In a foreshortened series, methanesulfonate was transformed by Michaelis–Becker reaction with diethyl or diisopropyl phosphite to methylenecyclopropane phosphonates or . The latter were converted to vicinal dibromides and which were then used for alkylation–elimination of nucleic acid bases (adenine) or precursors (2-amino-6-chloropurine and N4-acetylcytosine). The intermediary Z+E-isomers + and + were dealkylated with bromo- of iodotrimethylsilane to free phosphonic acids , and phosphonate with an open cyclopropane ring which were separated by ion exchange chromatography on Dowex 1. Phosphonate diesters and were separated by chromatography on silica gel, they were hydrolyzed to guanine derivatives and which were then dealkylated to give target analogues , and products of addition of hydrogen bromide or iodide across the double bond or . The E+Z-isomers + were converted to cytosine phosphonates + and cyclic phosphonate with an open cyclopropane ring . In a homologous series of phosphonates, dibromocyclopropane was converted to intermediate by reaction with diisopropyl methyl phosphonate and subsequent β-elimination. Compound was transformed to vicinal dibromide , a key component for alkylation–elimination of nucleic acid bases. The rest of the synthetic sequence followed the scheme described for the series of lower homologues to give the Z-isomeric phosphonates , , E-isomers , and E+Z-isomers + as the final products. All methylenecyclopropane phosphonates were devoid of antiviral activity with the exception of guanine derivative which inhibited the replication of varicella zoster virus (VZV) and it was non-cytotoxic.