Synthesis and Anti‐Retroviral Activity of Novel 5′‐Deoxy‐5′,5′‐difluoro‐threosyl Nucleoside Phosphonic Acid Analogs

Abstract

Novel 5′‐deoxy‐5′,5′‐difluoro‐threose purine phosphonic acid analogs were designed and synthesized from 2‐propanone‐1,3‐diacetate. Direct displacement of the triflate intermediate 12 with diethyl (lithiodifluoromethyl)phosphonate provided the corresponding (α,α‐difluoroalkyl) phosphonate 13. Condensation successfully proceeded from a glycosyl donor 14 under Vorbrüggen conditions to provide the nucleoside phosphonate analogs 15α, 15β, 18α, and 18β, respectively. Ammonolysis and hydrolysis of the phosphonates 15β and 18β yielded the nucleoside phosphonic acid analogs 16, 17, 19b, and 20. Also, synthesis of prodrugs of adenine derivative was performed to increase cellular uptake. The synthesized nucleoside analogs were subjected to antiviral screening against human immunodeficiency virus (HIV)‐1. Bis(SATE) prodrug 22 of the adenine analog exhibited significant in vitro activity against HIV‐1.