Regio‐ and Diastereoselective One‐pot Double Cascade Hybrid Formation/[3+3] Spirocyclization for the Synthesis of 3‐Spiropiperidines Under Phase Transfer Conditions

Abstract Herein, we report an efficient approach to synthesizing hybrid 3‐spiropiperidine heterocycles that incorporate both 3‐isochromanone and 3‐isoindolinone units through a one‐pot, double cascade reaction facilitated by an economical K 2 CO 3 /TBAB catalytic system. By examining the nucleophilicity of the lactone 3‐isochromanone, we developed a cascade reaction pathway that first generates a bi‐nucleophilic hybrid intermediate, which then undergoes [3+3] spirocyclization with α,β‐unsaturated aldehydes. The regioselectivity of the spirocyclization strongly depends on the substitution pattern of lactam ring.The process exhibits high diastereoselectivity, even with the formation of three or four stereocenters, including two contiguous tetra‐substituted carbons. These sequential cascade reactions were successfully scaled up, and the subsequent reactivity was readily analyzed, enabling the transformation of existing functional groups into valuable new functionalities.