Enantioselective formation of an alpha,beta-epoxy alcohol by reaction of methyl 13(S)-hydroperoxy-9(Z),11(E)-octadecadienoate with titanium isopropoxide

Methyl 11(R),12(R)-epoxy-13(S)-hydroxy-9(Z)-octadecenoate (three isomer) was generated from linoleic acid by the sequential action of an enzyme and two chemical reagents. Linoleic acid was treated with lipoxygenase to yield its corresponding hydroperoxide [13(S)-hydroperoxy-9(Z),11(E)-octadecadienoic acid]. After methylation with CH2N2, the hydroperoxide was treated with titanium (IV) isopropoxide [Ti(O-i-Pr)(4)] at 5 degrees C for 1 h. The products were separated by normal-phase high-performance liquid chromatography and characterized with gas chromatography-mass spectrometry, infrared spectroscopy, and nuclear magnetic resonance spectroscopy. Approximately 30% of the product was methyl 13(S)-hydroxy-9(Z),11(E)-octadecadienoate. Over 60% of the isolated product was methyl 11(R),12(R)-epoxy-13(S)-hydroxy-9(Z)-octadecenoate. After quenching Ti(O-i-Pr)(4) with water, the spent catalyst could be removed from the fatty products by partitioning between CH2Cl2 and water. These results demonstrate that Ti(O-i-Pr)(4) selectively promotes the formation of an a-epoxide with the threo configuration. It was critically important to start with dry methyl 13(S)-hydroperoxy-9(Z),11(E)-octadecadienoate because the presence of small amounts of water in the reaction medium resulted in the complete hydrolysis of epoxy alcohol to trihydroxy products.