Enantioselective Synthesis of Spirocyclic Isoxazolones Using a Conia-Ene Type Reaction

Stereoselective synthesis of spirocyclic compounds containing heterocyclic motifs represents a formidable challenge in enantioselective synthesis. Here, we present a cascade reaction between alpha,beta-unsaturated aldehydes and isoxazolones under synergistic catalysis of a chiral secondary amine and a palladium(0) catalyst. This strategy allows access to chiral spiroisoxazolone derivatives with a large substrate scope tolerance and high levels of diastereoselectivity (dr up to 20:1) and enantioselectivity (up to 99% ee). Furthermore, the utility of this methodology is showcased by the transformation of chiral spiroisoxazolones into structurally attractive and enantiomerically enriched cyclopentene carboxylic acids with two stereogenic centers.