Synthesis and bioactivation of bis(aroyloxymethyl) and mono(aroyloxymethyl) esters of benzylphosphonate and phosphonoacetate

Abstract

The bis(aroyloxymethyl) esters of benzylphosphonate 8(XPh, ArPh, 2-MeC₆H₄ or 2,4,6-Me₃C₆H₂) and methoxycarbonylmethylphosphonate 8(XMeO₂C, ArPh, 2-MeC₆H₄ or 2,4,6-Me₃C₆H₂) have been prepared by reaction of 2 equiv. of the appropriate aroyloxymethyl iodide with the disilver salt of either benzylphosphonate or methoxycarbonylmethylphosphonate. The cyclohexylammonium salts of the mono(aroyloxymethyl) esters of benzylphosphonate 12(XPh, ArPh, 2-MeC₆H₄ or 2,4,6-Me₃C₆H₂, M⁺C₆H₁₁NH₃⁺) were prepared by reaction of silver benzyl benzylphosphonate with the appropriate aroyloxymethyl iodide, with subsequent hydrogenolysis to remove the P-O-benzyl group. The bis(aroyloxymethyl) esters 8(XPh or MeO₂C, ArPh, 2-MeC₆H₄ or 2,4,6-Me₃C₆H₂) and the mono(aroyloxymethyl) salts 12(XPh, ArPh, 2MeC₆H₄ or 2,4,6-Me₃C₆H₂, M⁺C₆H₁₁NH₃⁺) were stable towards chemical hydrolysis at 37 °C at physiological pH. In the presence of porcine liver carboxyesterase, the bis(aroyloxymethyl) esters of benzylphosphonate 8(XPh, ArPh or 2-MeC₆H₄) degraded to the mono(aroyloxymethyl) esters 12(XPh, ArPh or 2-MeC₆H₄,), which showed slow hydrolysis to benzylphosphonate. For the bis(aroyloxymethyl) esters of methoxycarbonylmethylphosphonate 8(XMeO₂C, ArPh or 2MeC₆H₄) there was competition between the esterase-catalysed hydrolyses of the aroyloxymethyl and methoxycarbonyl groups. For the triester 8(XMeO₂C, Ar2,4,6-Me₃C₆H₂) cleavage of the methoxycarbonyl group was observed and hydrolysis of the sterically hindered 2,4,6-trimethylbenzoyl group (Ar2,4,6-Me₃C₆H₂) was not detected for any compound.