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Stereodefined rhodium-catalysed 1,4-H/D delivery for modular syntheses and deuterium integration

Nature Catalysis volume 4, pages 586–594 (2021)Cite this article

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Abstract

Deuterium-incorporated compounds are of high interest owing to their importance in the pharmaceutical industry, organic synthesis and materials science. So far, the integration of deuterium into the inert, saturated magic methyl or methylene groups of covalent molecules remains challenging. Here, we present a 1,4-H delivery of allylic metallic species to provide a highly stereoselective and straightforward approach to 3-methyl-2(E)-enals or -enones from readily available 2,3-allenols and organoboronic acids. The reaction accommodates many synthetically versatile functional groups as well as multi-pharmacophores, and is not limited to the formation of 3-methyl derivatives. By applying 1,4-H or D delivery, deuterium atom(s) from differently deuterated allenols can be edited into the methyl or methylene groups of versatile organic skeletons, resulting in the efficient formation of 4-monodeuterated, 1,4- and 4,4-doubly deuterated, and 4,4,4-triply deuterated 2(E)-enals or -enones. These powerful platform molecules can provide straightforward paths to other deuterated compounds for different purposes.

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Fig. 1: The importance of deuterated compounds, the magic methyl effect and strategies for deuteration.
Fig. 2: Scope of the reaction of allenols 1 with organoboronic acids 2.
Fig. 3: Modular incorporation of pharmacophores.
Fig. 4: Divergent syntheses of deuterated compounds.
Fig. 5: Mechanistic studies.

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Data availability

Experimental procedures, characterization of the compounds and density functional theory calculations are available in the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 1939682 (E-3ak) and 1939713 (E-3ed). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data are available from the corresponding authors upon reasonable request.

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Acknowledgements

Financial support from the National Natural Science Foundation of China (grant numbers 21690063 and 21988101 for S.M. and grant no. 21801041 for H.Q.) is acknowledged. We thank H. Xu for reproducing the results for compounds E-3am, E-3fd and E-3iv presented in Fig. 2.

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  1. These authors contributed equally: Weiyi Wang, Yibo Yu.

Authors and Affiliations

  1. Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, Shanghai, P. R. China

    Weiyi Wang, Yibo Yu, Bao Cheng, Hui Qian & Shengming Ma

  2. Department of Chemistry, Fudan University, Shanghai, P. R. China

    Huayi Fang

  3. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, P. R. China

    Xue Zhang & Shengming Ma

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Contributions

S.M., H.Q. and W.W. designed the experiments. W.W., Y.Y. and H.Q. performed the experiments. X.Z. and H.F. performed the density functional theory calculations. W.W., H.Q., X.Z., B.C. and S.M. wrote the manuscript.

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Correspondence to Xue Zhang, Hui Qian or Shengming Ma.

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The authors declare no competing interests.

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Peer review information Nature Catalysis thanks Jie An, Yu Lan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Methods, Figs. 1–14, Table 1, References and spectra of the products.

Supplementary Data 1

Crystallographic data of compound E-3ak.

Supplementary Data 2

Crystallographic data of compound E-3ed.

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Wang, W., Yu, Y., Cheng, B. et al. Stereodefined rhodium-catalysed 1,4-H/D delivery for modular syntheses and deuterium integration. Nat Catal 4, 586–594 (2021). https://doi.org/10.1038/s41929-021-00643-9

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