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.

Powering the Future: How Can Electrochemistry Make a Difference in Organic Synthesis?

“…81 The merger of electrosynthesis and asymmetric catalysis features the unique future possibilities of chiral solvents, 82 chiral electolytes, 83 or chiral electrodes. 84 However, despite key advances in asymmetric electrocatalysis, 85,86 major challenges remain. For instance, decomposition or electrodeposition of the key chiral catalyst represents key obstacles.…”

New Redox Strategies in Organic Synthesis by Means of Electrochemistry and Photochemistry

“…These reactions employ anodically coupled electrolysis (ACE) strategy and combine two parallel oxidative processes with similar oxidation potentials. Strategic reaction design allows the simultaneous generation of a pair of persistent and transient open-shell intermediates, which then add across an alkene in a regio- and chemoselective fashion under the direction of transition metal catalysts (e.g., Mn, 36 Co, 22b Cu; 22 for an example; see Figure 4 F). 21 Recently, Rovis and Lehrherr described a similar strategy for the reductive synthesis of hindered primary amines, wherein cathodically coupled electrolysis (CaCE) enables the concurrent formation of a transient α-amino radical ( 9 - 4 ) and a persistent heteroaryl radical ( 9 - 5 ) via proton-coupled electron transfer (PCET) prior to their cross coupling ( Figure 9 ).…”

Tailoring radicals by asymmetric electrochemical catalysis

“…Enantioselective hydrocyanation of alkenes is a fundamental, yet challenging transformation in asymmetric catalysis with respective to both scope and stereoselectivity. 12 Previous examples have mainly utilized Ni-H processes, 13 and an enantioselective radical approach was unknown. Lin and coworkers elegantly combined metal-hydride hydrogen-atom transfer catalysis with Co(III)-salen and the copper-radical catalysis with similar sBOX (L2) to achieve asymmetric radical hydrocyanation in an electrochemical setting (Scheme 3, right).…”