Catalytic asymmetric [4 + 1] cycloaddition to synthesize chiral pyrazoline-spirooxindoles

Abstract

An asymmetric formal [4 + 1] cycloaddition of N-unprotected oxindole 3-pyridinium salts and α-halo hydrazones to access chiral pyrazoline-spirooxindoles is realized by using a chiral N,N′-dioxide-Pr(OTf)₃ complex as a catalyst. The process includes base-promoted in situ formation of oxindole 3-pyridinium ylides and azoalkenes, followed by an asymmetric [4 + 1] annulation. The efficient enantiocontrol benefits from low temperature, which weakens the strong background reaction, and hydrogen bonding between the oxindole scaffold in the substrate and H₂O in the catalyst, which prevents the plane flip of the oxindole ring. A range of bioactive chiral pyrazoline-spirooxindole derivatives are obtained in good yields with excellent ee values.