ENANTIOSELECTIVE SYNTHESIS OF THE 4 ISOMERS OF THE BIOLOGICALLY-ACTIVE METABOLITE OF THE 2-ARYLPROPANOIC ACID NSAID, XIMOPROFEN, AND ASSESSMENT OF THEIR INHIBITORY ACTIVITY ON HUMAN PLATELET CYCLOOXYGENASE IN-VITRO

The four stereoisomers of the parent keto acid of the oximino drug xim oprofen have been prepared in high enantiomeric purity. The stereochem istry in the propionic acid chain was established by the combination o f Sharpless epoxidation followed by stereoselective hydrogenolysis of the benzylic carbon-oxygen bond with inversion of configuration. The s tereochemistry of the centre in the cyclohexanone ring was controlled by the stereoselective conjugate addition of the arylpropanoic acid mo iety to the enantiomers of 5-(trimethylsilyl)-2-cyclohexenone with sub sequent removal of the trimethylsilyl group. The pharmacological activ ity of each of the four isomers of the keto acid parent of ximoprofen were assessed by their in vitro inhibition of human platelet cyclo-oxy genase. As expected, the (S) configuration of the propionic acid chain was essential for activity but it was also found that the stereochemi stry in the cyclohexanone moiety was important. Attempts to separate t he (E) and (Z) isomers of the oxime derivative from one of the stereoi somers were unsuccessful.