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 α,β-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.