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Organocatalytic olefin C–H functionalization for enantioselective synthesis of atropisomeric 1,3-dienes

Nature Catalysis volume 7, pages 185–194 (2024)Cite this article

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Abstract

The availability of structurally and stereochemically diverse chemical scaffolds is important to support continual development of drug discovery, functional materials and asymmetric synthesis. Axially chiral 1,3-dienes, particularly acyclic ones, are potentially valuable yet underutilized skeletons due to concerns about chiral stability and the absence of suitable synthetic conditions. Here we show an organocatalytic strategy for the direct functionalization of alkenyl C–H bonds, enabling the challenging atroposelective construction of a broad range of acyclic chiral 1,3-dienes in a modular manner. Intensive studies on the reaction mechanism show that the current strategy not only bypasses the traditional indirect process for olefinic C–H functionalization but also represents a departure from transition-metal-catalysed C(sp2)–H activation. These findings are expected to open avenues for research on olefin chemistry and to inspire investigation into the organocatalytic activation of other inert structures.

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Fig. 1: Background of atropisomeric 1,3-dienes and our design.
Fig. 2: Reaction development.
Fig. 3: Substrate generality.
Fig. 4: One-pot asymmetric transformation of 1,3-dienes with other electrophiles.
Fig. 5: Transformations and applications of atropisomeric dienes.
Fig. 6: Control experiments.
Fig. 7: Computational investigation of the reaction mechanism.

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Data availability

The X-ray crystallographic coordinates for the structure of 2w reported in this Article have been deposited at the CCDC under deposition number CCDC 2184813. These data can be obtained free of charge from the CCDC via http://www.ccdc.cam.ac.uk/data_request/cif. The data supporting the findings of this work are provided in the Supplementary Information, including experimental procedures, the characterization of new compounds and data of the DFT calculations, or are available from the authors upon reasonable request.

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Acknowledgements

We are grateful for financial support from the National Key R&D Program of China (2022YFA1503703 to B.T. and 2021YFF0701604 to B.T.), National Natural Science Foundation of China (22231004 to B.T., 22371113 to Y.-B.W., 22271135 to S.-H.X. and 21825105 to B.T.), Guangdong Innovative Program (2019BT02Y335 to B.T.) and Shenzhen Science and Technology Program (JCYJ20220818100604009 to Y.-B.W., JCYJ20210324105005015 to S.-H.X., JCYJ20210324104212035 to Y.-B.W. and KQTD20210811090112004 to B.T.). Computational work was supported by the resources from the Center of Computational Science and Engineering at SUSTech.

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Author notes

  1. These authors contributed equally: Quan-Hao Wu, Meng Duan, Yu Chen.

Authors and Affiliations

  1. School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, China

    Quan-Hao Wu

  2. Shenzhen Grubbs Institute, Department of Chemistry, Southern University of Science and Technology, Shenzhen, China

    Quan-Hao Wu, Yu Chen, Peiyuan Yu, Yong-Bin Wang, Jun Kee Cheng, Shao-Hua Xiang & Bin Tan

  3. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Meng Duan & Kendall N. Houk

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Contributions

B.T. and Y.-B.W. conceived and directed the project. Q.-H.W. and Y.-B.W. designed and performed the experiments. K.N.H. directed the DFT calculations and mechanism analysis. M.D. and Y.C. performed the DFT calculations and mechanism analysis. J.K.C. and S.-H.X. helped with the collection of some compounds and data analysis. B.T., K.N.H., Y.-B.W., Q.-H.W., P.Y., J.K.C. and S.-H.X. wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Yong-Bin Wang, Kendall N. Houk or Bin Tan.

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Nature Catalysis thanks Yan Li 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 Figs. 1–6, Tables 1–6, Methods and references.

Supplementary Data 1

Checkcif file of 2w.

Supplementary Data 2

Cif file of 2w.

Supplementary Data 3

Structure factors of 2w.

Supplementary Data 4

Structure factors of 2w.

Supplementary Data 5

Data of DFT Calculations Coordinates

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Wu, QH., Duan, M., Chen, Y. et al. Organocatalytic olefin C–H functionalization for enantioselective synthesis of atropisomeric 1,3-dienes. Nat Catal 7, 185–194 (2024). https://doi.org/10.1038/s41929-023-01097-x

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