Enantioselectivity in the synthesis of 3,5-disubstituted Δ2-isoxazolines

The R-isomer of ISO-1, a 3,5-disubstituted Δ2-isoxazoline, has been implicated as a potential therapeutic agent for the treatment of Type 1 Diabetes via the antagonism of macrophage migration inhibitory factor (MIF). Δ2-Isoxazolines can be prepared by the palladium(II)-mediated cyclization of substituted β,γ-unsaturated oximes. While this reaction results in racemic mixtures, we have developed a stereoselective variant of this method based on the incorporation of an enantiomeric palladium complex in the reaction mixture. The use of chiral bisoxazoline ligands in the palladium(II)-mediated ring closure reaction has been shown to enhance the enantiomeric excess due to chirality at C5 of the Δ2-isoxazoline.