Development of Axially Chiral Phosphoramidite Ligands and Their Application in Pd-Catalyzed Asymmetric Synthesis of Spiro-Pyrazolone–Pyrrolidinones via [2 + 3] Cycloaddition

Pyrrolidinone, pyrazolone, and spiro pyrazolone derivatives possess significant and unique pharmaceutical activities. However, asymmetric synthesis of chiral spiro-pyrazolone-pyrrolidinones with potential pharmaceutical activity has not been reported thus far. Therefore, it is highly desirable to develop a concise and efficient approach to chiral spiro-pyrazolone-pyrrolidinones with high reactivity and stereoselectivity. Here, we describe a palladium-catalyzed asymmetric [2 + 3] cycloaddition of α,β-unsaturated pyrazolones with vinyloxazolidine-2,4-diones, and diverse and highly functionalized chiral spiro-pyrazolone-pyrrolidinones were synthesized in high yields (64-77%), excellent diastereoselectivity (>20:1 dr), and high to excellent enantioselectivity (84-98% ee). The results showed that our newly developed axially chiral phosphoramidite ligand significantly enhanced the reactivity and stereoselectivity of this [2 + 3] cycloaddition reaction. Further modification of the obtained chiral spiro-pyrazolone-pyrrolidinone afforded some new and valuable chiral spiro N-heterocycles.