Racemic Synthesis of Novel 6'-Methylene-5'-norcarbocyclic Purine Phosphonic Acid Analogues via Mitsunobu Reaction

Abstract

Novel 5'-norcarbocyclic adenine and guanine phosphonic acid analogues with 6'-electronegative moiety such as unsaturated C-C bond were designed and synthesized from commercially available 2-methylene-propane-1,3-diol (4). Regioselective Mitsunobu reaction successfully proceeded from an allylic functional group (±)-12b at low reaction temperature in polar cosolvent (DMF/1,4-dioxane) to give purine phosphonate analogues (±)-13 and (±)-20. The purine nucleoside phosphonate and phosphonic acid analogues were subjected to antiviral screening against HIV-1. Guanine analogue (±)-23 shows significant anti-HIV activity in PBM cell lines (EC 50 = 8.1 µM).