Synthesis of methylenecyclopropane analogues of antiviral nucleoside phosphonates

Abstract

Synthesis of methylenecyclopropane analogues of nucleoside phosphonates 6a , 6b , 7a and 7b is described. Cyclopropyl phosphonate 8 was transformed in four steps to methylenecyclopropane phosphonate 16 . The latter intermediate was converted in seven steps to the key Z- and E-methylenecyclopropane alcohols 23 and 24 separated by chromatography. Selenoxide eliminations ( 15 → 16 and 22 → 23 + 24 ) were instrumental in the synthesis. The Z- and E-isomers 23 and 24 were transformed to bromides 25a and 25b , which were used for alkylation of adenine and 2-amino-6-chloropurine to give intermediates 26a , 26b , 26c and 26d . Acid hydrolysis provided the adenine and guanine analogues 6a , 6b , 7a and 7b . Phosphonates 6b and 7b are potent inhibitors of replication of Epstein-Barr virus (EBV).