Expedient Access to Enantioenriched 1‐Azaspiro Cyclobutanones Enabled by Modified Heyns Rearrangement

Abstract

AbstractLeveraging the unexplored regions of chemical space, the integration of spirocyclic cyclobutane in a molecular scaffold opens up a new vista in modern drug discovery. Despite recent advancements in achieving the synthesis of such motifs, strategies for their asymmetric construction have not been well‐recognized and remain a formidable challenge. Herein, for the first time, we have demonstrated a chiral Brønsted acid‐catalyzed enantioselective synthesis of 1‐azaspiro cyclobutanone enabled by an unusual reactivity of enamine that explore the potentiality of Heyns rearrangement upon electrophilic modification. This design strategy offers viable access to a wide range of cyclobutanone containing spiroindoline and spiropyrrolidine derivatives in good yields with excellent stereoselectivities (up to >99 % ee, >20 : 1 dr). Furthermore, the practicality of this methodology has been shown by a scale‐up synthesis of spirocyclic products and their facile post‐synthetic modifications.