Michael D. Mosher, Ph.D.
- Chair and Professor
- Department of Chemistry and Biochemistry
- University of Northern Colorado
- Greeley, CO 80639
- Office: (970) 351-2559
- Fax: (970) 351-2533
- E-mail: Michael.Mosher@unco.edu
Novel Routes to 2-Isoxazoline Synthesis
ISO-1, an inhibitor of the proinflammatory cytokine MIF, has been shown to exhibit preventative properties toward Type 1 Diabetes in transgenic mice. The R-isomer, the eutomer, has been shown to interact well with the active site in MIF. This compound, and derivatives examined in those studies, were prepared via the typical 1,3-dipolar cycloaddition of a substituted nitrile oxide with an appropriately substituted alkene. While this method for isoxazoline synthesis can be useful, regiochemical and stereochemical concerns limit the utility of the method in some cases.
We have recently shown that palladium(II)-mediated nucleometalation / methoxy-carbonylation of a beta,gamma-unsaturated oxime gives rise to ISO-1 and related analogs. During the exploration of this route to the isoxazoline ring system, we noticed an interesting tandem reaction. Cyclization can occur directly from the unsaturated ketones upon treatment with hydroxylamine hydrochloride and strong base. Detailed studies, including trapping the intermediate anion developed in the reaction, indicate that the mechanism of the reaction involves a rearrangement of the alkene into conjugation with the carbonyl followed by Michael addition of the oxime hydroxyl group to close the isoxazoline ring.
The first stereoselective preparation of 3,5-disubstituted ?2-isoxazolines was also identified in our laboratory. While enantiomeric excess using chiral bis-oxazoline-based palladium(II) ligands was modest (57%ee), modification of the chiral ligands used promises further improvement in this cyclization.
Alternative approaches to developing stereochemical preference in the ring closure at C5 are currently being explored. And the conversion of these compounds to the straight-chained diols and triols by reduction of the O-N bond will give rise to novel routes to molecules typically prepared by less direct methods. This methodology is currently being applied to a total synthesis of the natural isomer of gingerol, the upper half of the statins, and related compounds.