Bioinspired Copper/Amine Cooperative Catalysis Enables Asymmetric Radical Azidation

Asymmetric radical transformations (ARTs) are vital for constructing chiral drugs and materials, while the highly reactive nature of radicals often imposes a challenge in selectivity control of these processes. Inspired by the principles of enzyme-cofactor cooperation to enhance stereochemical induction in enantioselective radical transformations, we developed an enantioselective asymmetric radical azidation <i>via</i> cooperative organo- and transition metal catalysis. This approach enables the efficient synthesis of heavily functionalized tertiary azides from readily available aldehydes. The key to this enantioselective process is the use of both chiral organocatalysts to transiently convert aldehydes to the corresponding chiral radical cationic species upon oxidation along with a detailed screening of chiral metal-azide catalysts to cooperatively enhance stereoinduction in carbon-azide bond formation. DFT studies suggest a favorable stereocontrol model and validate the crucial roles of chirality pairing of both catalytic schemes. We envision that this copper/amine cooperative catalysis could offer a useful strategy of constructing tetrasubstituted stereogenic carbon in asymmetric radical transformation development.