Reversal of Regioselectivity of Nitrone Cycloadditions by Lewis Acids

The regio- and stereoselectivity of cycloadditions of the nitrone 1a and the chiral, sugar-derived nitrones 13a and 13b with 3-(prop-2-enoyl)-1,3-oxazolidin-2-one (2) depends on the nature of the Lewis acid catalyst used. Addition of Lewis acid reverses the regioselectivity of the cycloaddition, and improves the anti-diastereoselectivity in the case of chiral nitrones. The sterically favored isoxazolidin-5-yl-substituted adducts 3, 4, and 14–17 are produced as the major products in the absence of Lewis acid, while the electronically favored regioisomers with isoxazolidin-4-yl substituents (5, 6, and 18–21, respectively) are obtained as major products in the [Ti(OⁱPr)₂Cl₂] catalyzed reactions. The reactions of nitrone 13b with 2 in the presence of other Lewis acids such as ZnCl₂, ZnBr₂, ZnI₂ and MgI₂/I₂ gave both regioisomeric pairs of the diastereoisomers, favoring the 4-substituted congeners. The diastereoisomeric isoxazolidines 3a–6a were reduced with NaBH₄ in THF/H₂O with subsequent desilylation to yield the separable diols 9–12. Reduction of the diastereoisomeric isoxazolidines 19a and 18a afforded the chiral alcohols 23 and 22, the latter of which was analyzed by X-ray crystallography.