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  • Perspective
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Copper-catalysed asymmetric radical cyanation

Nature Synthesis volume 1, pages 107–116 (2022)Cite this article

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Abstract

Catalytic asymmetric cyanation is a straightforward route to α-chiral nitriles that has previously relied on the enantioselective attack of cyanide on unsaturated electrophiles or the hydrocyanation of alkenes. More recently, such asymmetric cyanation reactions have entailed the reaction of cyanide with carbon radicals promoted by chiral copper catalysts via a radical relay process. In this Perspective, we discuss catalytic asymmetric cyanation reactions and the key carbon radicals involved, such as benzylic, allylic and propargylic radicals. In particular, we outline the control of selectivity by considering the mechanism of formation for the carbon radicals as well as the subsequent copper-catalysed radical cyanation step. The carbon radicals can be generated from a diverse range of precursors, which include C–H substrates, alkenes, esters, cyclopropanol and so on. As a consequence, copper-catalysed asymmetric radical cyanation has the potential to expand the scope of catalytic asymmetric cyanation and is expected to find broad utility in organic synthesis and the late-stage functionalization of complex molecules.

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Fig. 1: Chiral nitriles and their synthesis via copper-catalysed ARC.
Fig. 2: Access to α-chiral nitriles through the copper-catalysed ARC of C–H bonds.
Fig. 3: Different synthetic approaches to chiral nitriles through the copper-catalysed ARC of carbon radicals generated from the radical addition of alkenes and C–X bond cleavage.
Fig. 4: Mechanistic and computational studies on selectivity control during carbon radical formation and copper-catalysed cyanation.
Fig. 5: Mechanistic and computational studies on the asymmetric carbon radical cyanation.

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Acknowledgements

We are grateful for financial support from the National Key R&D Program of China (No. 2021YFA1500100), the National Nature Science Foundation of China (nos. 95956202, 21790330 and 21821002), the Science and Technology Commission of Shanghai Municipality (nos. 20JC1417000, 21520780100 and 19590750400), the Key Research Program of Frontier Science (QYZDJSSW-SLH055) and the International Partnership Program (no. 121731KYSB20190016), of the Chinese Academy of Sciences.

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  1. Fei Wang

    Present address: State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjing, China

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  1. State Key Laboratory of Organometallic Chemistry and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Fei Wang, Pinhong Chen & Guosheng Liu

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F.W., P. C. and G.L. co-wrote the manuscript with input and comments from all the authors.

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Correspondence to Guosheng Liu.

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Nature Synthesis thanks Xin-Yuan Liu, Song Lin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Thomas West was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Wang, F., Chen, P. & Liu, G. Copper-catalysed asymmetric radical cyanation. Nat Synth 1, 107–116 (2022). https://doi.org/10.1038/s44160-021-00016-x

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