Synthesis of 3-substituted Isoxazolidin-4-ols Using Hydroboration-oxidation Reactions of 4,5-unsubstituted 2,3-dihydroisoxazoles

Isoxazolidines represent a very important class of N/O-containing heterocycles used as the key intermediates in the synthesis of more complex cyclic and acyclic compounds, including various biologically active molecules. Here, we present a fast and highly stereoselective approach towards both C-3/4- and C-3/4- isomers of 3-substituted isoxazolidin-4-ols. The strategy relies on a highly regio- and -stereoselective hydroboration-oxidation reaction of the 4,5-unsubstituted 2,3-dihydroisoxazoles with basic hydrogen peroxide. The consecutive oxidation/reduction route, sequentially employing Dess-Martin periodinane and ʟ-selectride, is used for the inversion of the C-3/4- relative configuration of the isoxazolidine ring. The significance of the method lies in its variability and applicability to a concise synthesis of various 4-hydroxyisoxazolidines, starting from the readily available -alkyl/aryl-nitrones. The resemblance to 3-hydroxypyrrolidines certainly makes the 4-hydroxyisoxazolidines important and valuable structural fragments in drug discovery.