A Practical Synthesis of Enantiopure 4,5-Dihydroisoxazole-5-carboxylic Acids

Abstract

The 1,3-dipolar cycloaddition of a variety of aromatic and aliphatic nitrile oxides to 2,5-trans-2,5-diphenylpyrrolidine ­derived acrylamide and cinnamamide efficiently affords the corresponding 4,5-dihydroisoxazole-5-carboxamides in a highly regio- and stereoselective manner. The cycloaddition of aliphatic nitrile oxides to the analogue methacrylamide proceeds also smoothly to afford the expected cycloadducts in moderate yields and very high regio- and stereoselectivity. In sharp contrast, aromatic nitrile ­oxides react with the same amide to afford 5-methyl-4,5-dihydroisoxazole-5-carboxamides in higher yields but as near 1:1 mixtures of diastereoisomers. Acid hydrolysis of these products afforded enantiopure 4,5-dihydroisoxazole-5-carboxylic acids.

asymmetric synthesis - cycloadditions - heterocycles - ­nitrile oxides - isoxazolines

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