Studies on the decomposition pathways of diastereoisomeric mixtures of aryl nucleoside α-hydroxyphosphonates under hydrolytic conditions. Synthesis of α-hydroxyphosphonate monoesters

Abstract

Decomposition pathways of nucleoside α-hydroxyphosphonates 1 (diastereomeric mixtures) bearing different aryl groups, both in the ester and the hydroxymethine fragment, were investigated under various hydrolytic conditions. We found that in aqueous basic media, the stability and decomposition pathways of these compounds were governed by the electronic features of the aryl group in the hydroxymethine moiety (hydroxyphosphonate ⇌ H-phosphonate diester + aldehyde equilibria) and the nature of attacking nucleophiles (α-nucleophiles, e.g. hypoiodite or peroxide anions). The significant differences observed in the rates of hydrolysis of hydroxyphosphonates 1vs. their O-acylated derivatives point to the importance of an intramolecular acid catalysis exerted by the adjacent hydroxyl function. Based on these findings, an efficient synthetic protocol for otherwise difficult to access hydroxyphosphonate monoesters of type 7 has been developed.