Prodrugs of phosphonoformate: the effect of para-substituents on the products, kinetics and mechanism of hydrolysis of dibenzyl methoxycarbonylphosphonate

Abstract

The para-substituted analogues of dibenzyl methoxycarbonylphosphonate (1; X = N₃, NO₂, CF₃) have been prepared in ca. 60% yield and their product and kinetic profiles of hydrolysis have been evaluated. Relative to the unsubstituted analogue 1(X = H) which has a half-life of 64 min, the para-substituted triesters of phosphonoformate undergo rapid hydrolysis at pH 7.4 and 36.4°C with half-lives of 2.5 min (X = N₃), 5.6 min (X = NO₂) and 15 min (X = CF₃). In contrast to 1(X = H), which on hydrolysis gives ca. 30% C–P bond cleavage with dibenzyl phosphite formation, the para-substituted analogues hydrolyse predominantly to the para-substituted benzyl methoxycarbonyl-phosphonate diesters (2). Triester 1(X = NO₂) hydrolyses to the diester 2(X = NO₂) with P–O bond cleavage, consistent with nucleophilic attack of water at phosphorus and identical to that observed for the unsubstitued analogue. In contrast, triester 1(X = N₃) hydrolyses to the diester 2(X = N₃) with C–O bond cleavage presumably via an intermediate with benzyl carbonium ion character.