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Practical synthesis of C1 deuterated aldehydes enabled by NHC catalysis

Nature Catalysis volume 2, pages 1071–1077 (2019)Cite this article

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Abstract

The recent surge in applications of deuterated pharmaceutical agents has created an urgent demand for synthetic methods that efficiently generate deuterated building blocks. Here, we show that N-heterocyclic carbenes promote a reversible hydrogen–deuterium exchange reaction with simple aldehydes, which leads to a practical approach to synthetically valuable C1 deuterated aldehydes. The reactivity of the well-established N-heterocyclic carbene-catalysed formation of Breslow intermediates from aldehydes is reengineered to overcome the overwhelmingly kinetically favourable benzoin condensation reaction and achieve the critical reversibility to drive the formation of desired deuterated products when an excess of D2O is employed. Notably, this operationally simple and cost-effective protocol serves as a general and truly practical approach to all types of 1-D-aldehydes including aryl, alkyl and alkenyl aldehydes, and enables chemoselective late-stage deuterium incorporation into complex, native therapeutic agents and natural products with uniformly high levels (>95%) of deuterium incorporation for a total of 104 tested substrates.

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Fig. 1: Methods for the synthesis of deuterated aldehydes.
Fig. 2: Exploration and the scope of NHC-catalysed HDE with aromatic aldehydes (61 examples).
Fig. 3: Scope of NHC-catalysed HDE with enals (20 examples) and aliphatic aldehydes (23 examples).
Fig. 4: Gram-scale synthesis, recycling and reuse of D2O and a synthetic application.

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Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

Financial support was provided by the NIH (5R01GM125920-03), the National Natural Science Foundation of China (21702058 and 21202112), East China University of Science and Technology, the ‘111’ Project and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).

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Author notes

  1. These authors contributed equally: Huihui Geng and Xiaobei Chen.

Authors and Affiliations

  1. State Key Laboratory of Bioengineering Reactor, and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai, China

    Huihui Geng, Xiaobei Chen, Zuyuan Shen, Pengfei Qian, Junwei Chen & Wei Wang

  2. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China

    Jingjing Gui & Shilei Zhang

  3. Department of Pharmacology and Toxicology, College of Pharmacy and BIO5 Institute, University of Arizona, Tucson, AZ, USA

    Yueteng Zhang & Wei Wang

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Contributions

H.G. and X.C. made equal contributions to this work. H.G., J.G., Y.Z., Z.S., P.Q. and J.C. conducted and analysed the experiments. X.C., S.Z. and W.W. planned, designed and directed the project and S.Z. and W.W. wrote the manuscript.

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Correspondence to Xiaobei Chen, Shilei Zhang or Wei Wang.

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Supplementary methods, Supplementary Fig. 1, Supplementary Tables 1–5 and Supplementary references.

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Geng, H., Chen, X., Gui, J. et al. Practical synthesis of C1 deuterated aldehydes enabled by NHC catalysis. Nat Catal 2, 1071–1077 (2019). https://doi.org/10.1038/s41929-019-0370-z

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