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Dual electrocatalysis enables enantioselective hydrocyanation of conjugated alkenes

Nature Chemistry volume 12, pages 747–754 (2020)Cite this article

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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 dual electrocatalysis. Using this strategy, we leverage electrochemistry to seamlessly combine two canonical radical reactions—cobalt-mediated hydrogen-atom transfer and copper-promoted radical cyanation—to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidants. We also harness electrochemistry’s unique feature of precise potential control to optimize the chemoselectivity of challenging substrates. Computational analysis uncovers the origin of enantio-induction, for which the chiral catalyst imparts a combination of attractive and repulsive non-covalent interactions to direct the enantio-determining C–CN bond formation. This work demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent challenges in synthetic chemistry.

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Fig. 1: Enantioselective hydrocyanation: synthetic significance and proposed strategy.
Fig. 2: Reaction design, discovery and optimization.
Fig. 3: Product derivatization.
Fig. 4: Electrochemical tuning of reaction chemoselectivity and comparison with chemical methods.
Fig. 5: Computational stereochemical model.

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Data availability

The data that support the findings of this study are included in this published article and its Supplementary Information files. Crystallographic data for compound 4 has been deposited at the Cambridge Crystallographic Data Centre under deposition number 1978310 and can be obtained free of charge (http://www.ccdc.cam.ac.uk/data_request/cif).

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Acknowledgements

Financial support to S.L. was provided by NIGMS (R01GM130928) and Eli Lilly. Financial support to B.G.E. and R.A.D. was provided by start-up funding from Cornell University. This study made use of the NMR facility supported by the NSF (CHE-1531632) and resources of the National Energy Research Scientific Computing Center (NERSC), a US Department of Energy Office of Science User Facility operated under contract no. DE-AC02-05CH11231. We thank K. Moeller for helpful discussions, A. Condo for gas chromatography mass spectrometry analysis, Y. Shen and J. Liu for providing some of the substrates and IKA for donation of the ElectraSyn 2.0.

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Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA

    Lu Song, Niankai Fu, Brian G. Ernst, Wai Hang Lee, Robert A. DiStasio Jr. & Song Lin

  2. Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, IN, USA

    Michael O. Frederick

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Contributions

S.L. conceived of the project. L.S., N.F., M.O.F. and S.L. designed the experiments. L.S., N.F. and W.H.L. carried out the experiments. B.G.E. and R.A.D. designed and carried out all DFT calculations. B.G.E., R.A.D and S.L. analysed the DFT data. All authors contributed to writing the manuscript.

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Correspondence to Robert A. DiStasio Jr. or Song Lin.

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Extended data

Extended Data Fig. 1 Methods for electrochemical hydrocyanation of alkenes.

a, Electrochemical hydrocyanation of alkenes using a custom-made cell58 (0.20 mmol scale). b, Electrochemical hydrocyanation of alkenes using ElectraSyn 2.0 (0.30 mmol scale). c, Electrolysis using a commercial three-necked flask (2.0 mmol scale). d, Electrolysis using a commercial three-necked flask (5.0 mmol scale). Detailed experimental procedures can be found in the Methods section.

Extended Data Fig. 2 Methods for product derivatization.

a, Derivatization of product 15 to naproxen methyl ester 56 (analogue of naproxen). b, Derivatization of product 15 to benzoindoline 57 (analogue of duocarmycin). c, Derivatization of product 18 to dihydroisoquinolone 58 (analogue of palonosetron). Detailed experimental procedures can be found in Methods section.

Supplementary information

Supplementary Information

Supplementary information including general information and general procedures for enantioselective electrocatalytic hydrocyanation of conjugated alkenes, suboptimal and unsuccessful substrates, possible mechanistic scenarios, procedure for control experiments using chemical oxidants, product derivatization, DFT computational data, cyclic voltammetry data of Cu complexes, relevant references on electrochemical hydrofunctionalization, DFT rationale for reaction regioselectivity with phenylallene, X-ray crystallography, references, spectral data for products and Supplementary Figs. 1–14.

Supplementary Data 1

Crystallographic data for compound 4. CCDC reference 1978310.

Supplementary Data 2

Raw DFT output files for the computational data.

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Song, L., Fu, N., Ernst, B.G. et al. Dual electrocatalysis enables enantioselective hydrocyanation of conjugated alkenes. Nat. Chem. 12, 747–754 (2020). https://doi.org/10.1038/s41557-020-0469-5

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