The Synthesis of Novel 5′‐Deoxy‐3′,5′,5′‐trifluoro‐apiosyl Nucleoside Phosphonic Acid Analogs as Antiviral Agents

Abstract

Racemic syntheses of novel 5′‐deoxy‐3′,5′,5′‐trifluoro‐apiose nucleoside phosphonic acid analogs were carried out from 1,3‐dihydroxyacetone, to be used as antiviral agents. Nucleophilic displacement of the triflate intermediate with diethyl (lithiodifluoromethyl)phosphonate was performed to yield the corresponding (α,α‐difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor under Vorbrüggen conditions to yield the nucleoside phosphonate analogs. Ammonolysis and hydrolysis of the phosphonates yielded the corresponding nucleoside phosphonic acid analogs. Furthermore, the lipophilic prodrug of the adenine derivative was synthesized to increase cellular uptake. The synthesized nucleoside analogs were screened for their antiviral activity against human immunodeficiency virus (HIV)‐1. The bis(SATE) prodrug of the adenine analog exhibited significant in vitro activity against HIV‐1.