Zinc-Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes.

Abstract

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)-rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza-BCHs) by an enantioselective zinc-catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2-acyl imidazole group and a diverse array of alkynyl- and aryl-substituted imines. The target aza-BCHs, which consist of α-chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94% yield and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring-opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid-catalyzed cycloadditions of BCBs.