Diastereoselective synthesis of 5,5-Difluoroisoxazolidine via [3 + 2] cycloaddition between Nitrones and Difluoroacrylates

Abstract

The incorporation of difluoromethylene (CF₂) group into the backbone of biomolecules is an appealing strategy in the drug development. We describe herein a diastereoselective synthesis of 5,5-difluoroisoxazolidine via dipolar [3 + 2] cycloaddition between nitrones and unsymmetric tetra-substituted difluoroacrylates under catalyst-free conditions. This reaction features mild conditions, moderate to good yield as well as excellent regio- and diastereo-selectivities. DFT calculations showed that a spontaneous inversion of the configuration of nitrogen center was involved.