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
✍ Scribed by David P.G. Hamon; Peter J. Hayball; Ralph A. Massy-Westropp; Josephine L. Newton; Julie G. Tamblyn
- Publisher
- Elsevier Science
- Year
- 1996
- Tongue
- English
- Weight
- 450 KB
- Volume
- 7
- Category
- Article
- ISSN
- 0957-4166
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✦ Synopsis
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.
A paper on 2-[4'-(3"-{hydroxyimino}cyclohexyl)phenyl]propanoic acid (Ximoprofen) 1, reported that this experimental non-steroidal anti-inflammatory agent was significantly more potent than 2-[4'-(2"methylpropyl)phenyl]propanoic acid (Ibuprofen). 1 The active component was considered to be the precursor keto acid. Ximoprofen can exist as eight possible stereoisomers and the precursor keto acid can exist as four stereoisomers. No information has been reported either about the synthesis of the individual stereoisomers or of their pharmacological activity. It is assumed that a mixture of all possible stereoisomers has been used in these pharmacological studies. Because the importance of single enantiomers has now been recognised in the area of drug synthesis we have developed asymmetric syntheses which allow access to the four keto acid stereoisomers 2a, 2b, 3a and 3b. We present here the experimental details for a preliminary communication 2 concerning the enantioselective synthesis of these isomers and an attempt to isolate the pure (E) and (Z) oximes derived from one of them. Pharmacological aspects are discussed after the synthesis section.
Synthesis of the Isomers
Two particular challenges arise in the enantioselective synthesis of the isomeric keto acids: control of the stereochemistry at C-2 in the propionic acid chain and at the stereogenic center in the cyclohexanone unit. It was considered that the stereochemistry of these two centers could he controlled in the following way (see Scheme 1 263