Diversity-Oriented Synthesis of CF ₃ -Functionalized Polycyclic Spiroisoxazolones via Organobase-Promoted Vinylogous Michael Addition Cascade Reactions

An organobase-controlled regiodivergent approach for the synthesis of CF₃-containing polycyclic spiro-fused and -caged isoxazolone scaffolds is described. This is the first report demonstrating the reactivity of 4-alkylidene isoxazolones in VMA-based cascade reactions in combination with COCF₃-tethered enediones. Additionally, the asymmetric variant of the spiro-fused isoxazolone scaffolds was also achieved using a bifunctional squaramide catalyst. Control experiments confirmed the reversibility and stability of the hemiketal and ketal groups in spiroisoxazolones. Gram-scale synthesis and derivatization further demonstrated the synthetic utility.