Synthesis of Novel 6′-Spirocyclopropyl-5′-Norcarbocyclic Adenosine Phosphonic Acid Analogues as Potent Anti-Hiv Agents

Abstract

Novel 5′-norcarbocyclic adenosine phosphonic acid analogues with 6′-electropositive moiety such as spirocyclopropane were designed and synthesized from the commercially available diethylmalonate 5. Regioselective Mitsunobu reaction proceeded in the presence of an allylic functional group at a low reaction temperature in polar cosolvent [dimethylformamide (DMF)/1,4-dioxane] to give purine analogue 15. To improve cellular permeability and enhance the anti-human immunodeficiency virus (HIV) activity of this phosphonic acid, a SATE phosphonodiester nucleoside prodrug 23 was prepared. The synthesized adenosine phosphonic acids analogues 18–21 and 23 were subjected to antiviral screening against HIV-1.

Keywords:

• Anti-HIV agents
• 6′-spirocyclopropyl nucleosides
• bis-SATE prodrug
• mitsunobu reaction