Dual Electrocatalysis Enables Enantioselective Hydrocyanation of Conjugated Alkenes

Abstract

Chiral nitriles and their derivatives are prevalent in pharmaceuticals and bioactive compounds. Enantioselective alkene hydrocyanation represents a convenient and efficient approach for synthesizing these molecules. However, a generally applicable method featuring a broad substrate scope and high functional group tolerance remains elusive. Here, we address this long-standing synthetic problem using an electrocatalytic strategy. Electrochemistry allows for the seamless combination of two classic radical reactions—cobalt-mediated hydrogen-atom transfer and copper-promoted radical cyanation—to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidant. We harness electrochemistry’s unique feature of precise potential control to optimize the chemoselectivity of challenging substrates. Computational analysis sheds light on the origin of enantioinduction, for which the chiral catalyst imparts a combination of attractive and repulsive non-covalent interactions that direct the enantio-determining C–CN bond formation. This discovery demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent challenges in synthetic chemistry.

Catalyzing Electrosynthesis: A Homogeneous Electrocatalytic Approach to Reaction Discovery

“…We recently disclosed a dual electrocatalytic approach for the asymmetric hydrocyanation of conjugated alkenes (Scheme ). Our mechanistic design principle entails two distinct catalytic cycles operating simultaneously and synergistically on the anode, providing H • and CN • equivalents that are subsequently added to the alkene under catalyst control. This reaction design was inspired by recent literature on metal-hydride hydrogen-atom transfer catalysis, in which a catalytically generated metal-hydride species could enable HAT to an alkene to initiate diverse hydrofunctionalization reactions .…”