Aminocatalytic enantioselective [2 + 2] cycloaddition of Bicyclo[1.1.0]butanes and α,β-unsaturated aldehydes

Abstract

Bicyclo[1.1.0]butanes have opened a new area of chemical space for construction of bicyclo[2.1.1]hexanes – a scaffold showing promise as ortho- and meta-aryl bioisosteres. Herein, we present the first aminocatalytic concept that enables the enantioselective [2 + 2] cycloaddition of bicyclo[1.1.0]butanes with α,β-unsaturated aldehydes. The reaction is general for α,β-unsaturated aldehydes, substituted at the γ-position with aromatic functionalities, esters and ketones, by applying a secondary aminocatalyst and Yb(OTf)₃ as a Lewis acid to activate the bicyclo[1.1.0]butane. For cinnamaldehydes, bicyclo[2.1.1]hexane cycloadducts are obtained in moderate to good yields, and up to 96.5 : 3.5 e.r. Pleasingly, α,β-unsaturated aldehydes containing ester and ketone functionalities in the γ-position provided high yields and enantioselectivities up to 98.5 : 1.5 e.r. For all three classes of [2 + 2] cycloadditions, a range of α,β-unsaturated aldehydes and bicyclo[1.1.0]butanes were successfully tolerated. Several transformations adding further complexity to the bicyclo[2.1.1]hexane scaffolds are disclosed. Finally, a reaction mechanism is proposed.