SYNTHESIS AND BIOACTIVATION OF BIS(AROYLOXYMETHYL) AND MONO(AROYLOXYMETHYL) ESTERS OF BENZYLPHOSPHONATE AND PHOSPHONOACETATE

The bis(aroyloxymethyl) esters of benzylphosphonate 8 (X=Ph, Ar=Ph, 2-MeC6H4 or 2,4,6-Me3C6H2) and methoxycarbonylmethylphosphonate 8 (X=MeO2C, Ar=Ph, 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 (X=Ph, Ar=Ph, 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 (X=Ph or MeO2C, Ar=Ph, 2-MeC6H4 or 2,4,6-Me3C6H2) and the mono(aroyloxymethyl) salts 12 (X=Ph, Ar=Ph, 2-MeC6H4 or 2,4,6-Me3C6H2, M+=C6H11NH3+) were stable towards chemical hydrolysis at 37-degrees-C at physiological pH. In the presence of porcine liver carboxyesterase, the bis(aroyloxymethyl) esters of benzylphosphonate 8 (X=Ph, Ar=Ph or 2-MeC6H4) degraded to the mono(aroyloxymethyl) esters 12 (X=Ph, Ar=Ph or 2-MeC6H4), which showed slow hydrolysis to benzylphosphonate. For the bis(aroyloxymethyl) esters of methoxycarbonylmethylphosphonate 8 (X=MeO2C, Ar=Ph or 2-MeC6H4) there was competition between the esterase-catalysed hydrolyses of the aroyloxymethyl and methoxycarbonyl groups. For the triester 8 (X=MeO2C, Ar=2,4,6-Me3C6H2) cleavage of the methoxycarbonyl group was observed and hydrolysis of the sterically hindered 2,4,6-tri-methylbenzoyl group (Ar=2,4,6-Me3C6H2) was not detected for any compound.