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Electrolytic deuteration of unsaturated bonds without using D2

Nature Catalysis volume 3, pages 719–726 (2020)Cite this article

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Abstract

Site-selective deuteration of C–H bonds increases the lifetime and efficacy of drug molecules. Although effective methods to form C(sp2)–D bonds are known, processes for making C(sp3)–D bonds often have low site selectivity, require expensive and unrecoverable D2 gas, or use stoichiometric reagents. Here we report cost-efficient and site-selective reductive deuteration using a tandem electrochemical chemical palladium membrane reactor. This architecture mediates the chemical reaction of deuterium atoms (derived from reusable D2O in an electrochemical compartment) with alkynes, aldehydes and imines. The formation of C(sp3)–D and C(sp2)–D bonds in the isolated chemical compartment is made possible by the deuterium-selective permeability of the membrane that partitions the electrochemical compartment from the chemical compartment. We have utilized the reactor for the deuteration step in the construction of a common drug, cinacalcet, to demonstrate that this method can be used to incorporate deuterium atoms in a pharmaceutical.

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Fig. 1: Deuteration methodologies for the formation of C(sp3)–D bonds.
Fig. 2: Deuterium incorporation and yield by palladium membrane deuteration of alkynes.
Fig. 3: Deuterium incorporation and yield by palladium membrane deuteration of aldehydes and imines.
Fig. 4: Deuteration chemoselectivity and reaction rates with applied current.
Fig. 5: Synthesis of compound 18.

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The data supporting the findings in this study are available either within the paper or its Supplementary Information, or from the corresponding author on reasonable request.

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Acknowledgements

We thank Y. Ling and J. Zhu at the UBC Mass Spectrometry Centre for assistance with gas chromatography–mass spectrometry and liquid-chromatography–mass spectrometry, M. Ezhova at the nuclear magnetic resonance laboratory and M. Soon at the Pacific Centre for Isotopic and Geochemical Research for ICP–OES experiments. We are grateful to the Canadian Natural Science and Engineering Council (RGPIN-2018-06748), Canadian Foundation for Innovation (229288), Canadian Institute for Advanced Research (BSE-BERL-162173) and Canada Research Chairs for financial support. This research was undertaken thanks in part to funding from Canada First Research Excellence Fund, Quantum Materials and Future Technologies Program.

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Authors and Affiliations

  1. Department of Chemistry, The University of British Columbia, Vancouver, British Columbia, Canada

    Aiko Kurimoto, Rebecca S. Sherbo, Yang Cao, Nicholas W. X. Loo & Curtis P. Berlinguette

  2. Stewart Blusson Quantum Matter Institute, The University of British Columbia, Vancouver, British Columbia, Canada

    Yang Cao & Curtis P. Berlinguette

  3. Department of Chemical and Biological Engineering, The University of British Columbia, Vancouver, British Columbia, Canada

    Curtis P. Berlinguette

  4. Canadian Institute for Advanced Research (CIFAR), Toronto, Ontario, Canada

    Curtis P. Berlinguette

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Contributions

A.K. and C.P.B. devised the concept. A.K., R.S.S. and N.W.X.L. performed deuteration experiments. A.K and Y.C. performed characterizations. A.K. and Y.C. performed the deuterated drug synthesis. A.K., R.S.S. and C.P.B. wrote the manuscript. C.P.B. supervised the project.

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Correspondence to Curtis P. Berlinguette.

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Supplementary Figs. 1–12 and Methods 1–9.

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Kurimoto, A., Sherbo, R.S., Cao, Y. et al. Electrolytic deuteration of unsaturated bonds without using D2. Nat Catal 3, 719–726 (2020). https://doi.org/10.1038/s41929-020-0488-z

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