Photocatalytic synthesis of 2-oxabicyclo[2.1.1]hexanes: cobalt-enhanced efficiency

Abstract

Development of new synthetic strategies to prepare C(sp³)-rich arene bioisosteres, especially their heteroatom incorporating analogs, is less explored, but highly in demand. Here we report a photocatalytic [2π + 2σ] cycloaddition reaction between bicyclo[1.1.0]butanes and aldehydes enabled by cobalt under visible light irradiation. The key step is that bicyclo[1.1.0]butanes could be oxidized to generate radical cation intermediates which could be promoted by cobalt, facilitating a nucleophilic addition to the aldehydes. This unprecedented strategy exhibits broad functional group tolerance and efficiently constructs complex molecular architectures and derivatives of natural products with good to excellent yields. Detailed mechanistic studies and product manipulation have demonstrated the viability of this open-shell approach. The desired 2-oxa-BCH motif demonstrated excellent acidity tolerance and significantly enhanced lipophilicity potentially leading to enhanced metabolic properties and in vitro bioactivities compared to its parent phenyl-type bioisostere.