Enantioselective synthesis of the four isomers of the biologically active metabolite of the 2-arylpropanoic acid NSAID, ximoprofen, and assessment of their inhibitory activity on human platelet cyclo-oxygenase in vitro

The four stereoisomers of the parent keto acid of the oximino drug ximoprofen have been prepared in high enantiomeric purity. The stereochemistry in the propionic acid chain was established by the combination of Sharpless epoxidation followed by stereoselective hydrogenolysis of the benzylic carbon-oxygen bond with inversion of configuration. The stereochemistry of the centre in the cyclohexanone ring was controlled by the stereoselective conjugate addition of the arylpropanoic acid moiety to the enantiomers of 5-(trimethylsilyl)-2-cyclohexenone with subsequent removal of the trimethylsilyl group. The pharmacological activity of each of the four isomers of the keto acid parent of ximoprofen were assessed by their in vitro inhibition of human platelet cyclo-oxygenase. As expected, the (S) configuration of the propionic acid chain was essential for activity but it was also found that the stereochemistry in the cyclohexanone moiety was important. Attempts to separate the (E) and (Z) isomers of the oxime derivative from one of the stereoisomers were unsuccessful.