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

Abstract

The synthesis of phosphonates of methylenecyclopropane nucleoside analogues 15a– 18a , 15b– 18b and 15c– 18c by alkylation–elimination approach is described. In a foreshortened series, methanesulfonate 19 was transformed by Michaelis–Becker reaction with diethyl or diisopropyl phosphite to methylenecyclopropane phosphonates 20a or 20b . The latter were converted to vicinal dibromides 21a and 21b which were then used for alkylation–elimination of nucleic acid bases (adenine) or precursors (2-amino-6-chloropurine and N 4-acetylcytosine). The intermediary Z+ E-isomers 22a + 23a and 22b + 23b were dealkylated with bromo- of iodotrimethylsilane to free phosphonic acids 15a , 16a and phosphonate with an open cyclopropane ring 25 which were separated by ion exchange chromatography on Dowex 1. Phosphonate diesters 22c and 23c were separated by chromatography on silica gel, they were hydrolyzed to guanine derivatives 22d and 23d which were then dealkylated to give target analogues 15b , 16b and products of addition of hydrogen bromide or iodide across the double bond 26a or 26b . The E+ Z-isomers 22e + 23e were converted to cytosine phosphonates 15c + 16c and cyclic phosphonate with an open cyclopropane ring 27a . In a homologous series of phosphonates, dibromocyclopropane 34 was converted to intermediate 31 by reaction with diisopropyl methyl phosphonate and subsequent β-elimination. Compound 31 was transformed to vicinal dibromide 36 , 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 17a , 17b , E-isomers 18a , 18b and E+ Z-isomers 17c + 18c as the final products. All methylenecyclopropane phosphonates were devoid of antiviral activity with the exception of guanine derivative 15b which inhibited the replication of varicella zoster virus (VZV) and it was non-cytotoxic.