CPA-catalyzed multicomponent reaction of anilines, aldehydes, and azetidinones: Rapid access to enantiopure-fused azetidines

The wide occurrence of enantiopure-fused azetidines in various bioactive molecules leads to a great demand for their efficient synthetic methods. However, so far, organocatalytic protocols have been rather limited. Here we develop a chiral phosphoric acid (CPA)-catalyzed multicomponent reaction of anilines, aldehydes, and azetidinones to access tetrahydroquinoline-fused azetidines with three contiguous stereocenters. Noteworthy features include complete diastereocontrol, high enantioselectivity, good yields, and broad functional group tolerance. Successful implementation of this strategy relies on dual activation of imine and enamine intermediates with CPA. This work not only contributes an efficient organocatalytic assembly of chiral fused azetidines but also provides a paradigm for designing other asymmetric multicomponent reactions.