Asymmetric Aza-Michael/Michael/Mannich Domino Reaction of 2-Aminochalcones and 5-Alkenyl-Thiazolones: Access to Enantioenriched 1,4-Sulfur-Bridged Piperidinone Skeletons

Herein, we disclose a novel organocatalytic approach for the enantioselective synthesis of 1,4-sulfur-bridged piperidinone skeletons via sequential aza-Michael/Michael/Mannich domino reaction of 2-aminochalcones and 5-alkenyl-thiazolones. The one-pot approach catalyzed by a bifunctional squaramide catalyst furnishes bridged polycyclic compounds with five contiguous stereocenters (three tertiary, two heteroquaternary) in excellent yields (up to 95%) and stereochemical outcomes (up to 99% ee and up to >20:1 dr). The methodology offers outstanding control on regio- and chemoselectivity, showcasing broad substrate compatibility. Additionally, the reaction is scalable and postsynthetic transformation to a spirothiazolone-tetrahydroquinoline derivative further amplifies the synthetic utility of the methodology.