Palladium-catalysed [2σ + 2π] cycloaddition reactions of bicyclo[1.1.0]butanes with aldehydes

Abstract

Cycloaddition reactions of bicyclo[1.1.0]butanes (BCBs) with 2π components are a powerful tool for preparing C(sp3)-rich arene bioisosteres. Despite enormous progress in this field, catalytic enantioselective cycloadditions of BCBs that produce enantioenriched three-dimensional bioisosteres are underdeveloped. Here we report a palladium-catalysed [3 + 2] cycloaddition reaction of vinyl-carbonyl-BCBs with carbonyl compounds, including formaldehyde, activated ketones, and aliphatic and aromatic aldehydes. This approach provides quick access to a wide variety of 2-oxabicyclo[2.1.1]hexanes. Density functional theory calculations indicate that the reaction occurs through a zwitterionic mechanism involving σ-bond cleavage, nucleophilic addition and allylic substitution. When (R,R)-ANDEN-phenyl Trost ligand is used, the stereoselectivity of the addition of palladium-zwitterionic enolates to carbonyl can be controlled to achieve enantioselective [3 + 2] cycloadditions. We further demonstrate the practicality of the method by carrying out several downstream transformations of cycloaddition products. Palladium catalysis enables the cycloaddition reaction between vinyl-carbonyl-bicyclo[1.1.0]butanes and aldehydes or ketones for the synthesis of 2-oxabicyclo[2.1.1]hexanes, an arene bioisotere. Enantiocontrol over the zwitterionic [2σ + 2π] cycloaddition process can be achieved using the commercially available (R,R)-ANDEN-phenyl Trost ligand.