Synthesis and Antiviral Evaluation of 3'‐C‐Hydroxymethyl‐3'‐O‐Phosphonomethyl‐β‐D‐5'‐deoxyxylose Nucleosides

Abstract

L‐2'‐deoxythreose nucleoside phosphonates PMDTA and PMDTT possess potent anti‐HIV activity. Herein, a novel class of 3'‐C‐branched‐l‐threose nucleoside phosphonate analogs, 5'‐deoxy‐3'‐C‐hydroxymethyl‐3'‐O‐phosphonomethyl‐d‐xylose nucleosides, were synthesized and biologically evaluated. The key sugar intermediate 3‐C‐benzyloxymethyl‐3‐O‐diethylphosphonomethyl‐1,2‐O‐isopropylidene‐α‐d‐5‐deoxyxylose (8) was firstly synthesized, which may be an interesting scaffold for access to diverse 3'‐C‐branched l‐threosyl nucleoside phosphonate derivatives. And the key synthesis involved Wittig olefination of 1,2‐O‐isopropylidene‐3‐oxo‐α‐d‐5‐deoxyxylose, stereoselective dihydroxylation of alkenes by aqueous KMnO4, selective benzylation of hydroxymethyl group under activation of dibutyltin oxide, and introduction of phosphonate group by nucleophilic substitution. Eventually, glycosylation under Vorbrüggen conditions provided 3'‐C‐hydroxymethyl‐3'‐O‐phosphonomethyl‐β‐d‐5'‐deoxyxylose nucleoside analogs in satisfying yield.