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Asymmetric dearomative single-atom skeletal editing of indoles and pyrroles

Nature Chemistry volume 17, pages 215–225 (2025)Cite this article

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Abstract

Heterocycle skeletal editing has recently emerged as a powerful tactic for achieving heterocycle-to-heterocycle transmutation without the need for multistep de novo heterocycle synthesis. However, the enantioselective skeletal editing of heteroarenes through single-atom logic remains challenging. Here we report the enantiodivergent dearomative skeletal editing of indoles and pyrroles via an asymmetric carbon-atom insertion, using trifluoromethyl N-triftosylhydrazones as carbene precursors. This strategy provides a straightforward methodology to access enantiomerically enriched six-membered N-heterocycles containing a trifluoromethylated quaternary stereocentre from planar N-heteroarenes. The synthetic utility of this enantiodivergent methodology was demonstrated by a broad evaluation of reaction scope, product derivatization and concise syntheses of drug analogues. Mechanistic studies reveal that the excellent asymmetric induction arises from the initial cyclopropanation step. The asymmetric single-atom insertion strategy is expected to have a broad impact on the field of single-atom skeletal editing and catalytic asymmetric dearomatization of aromatic compounds.

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Fig. 1: CADA of indoles and related N-heteroarenes.
Fig. 2: Evaluation of reaction conditions.
Fig. 3: Gramme-scale synthesis and synthetic applications.
Fig. 4: CADA reactions of pyrroles and further synthetic transformations.
Fig. 5: Reaction mechanism studies.
Fig. 6: DFT calculations for the origin of enantioselectivities.

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Data availability

The data that support the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2261312 for (S)-34, 2266339 for (R)-34, 2281736 for (2R,3S)-43, 2281629 for (2R,3S)-44, 2350998 for (R)-64, 2311749 for (5S,6S)-76 and 2350447 for 82. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. DFT-optimized structures, Cartesian coordinates and energies have been deposited online and are freely available at https://doi.org/10.6084/m9.figshare.26820343.

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Acknowledgements

Research reported in this publication was supported by NSFC (22331004 to X.B. and 22371035 to Z.L.), the Department of Science and Technology of Jilin Province (20230508054RC to Z.L. and 20240305092YY to Z.L.) and the Royal Society (Newton Advanced Fellowship NAF\R1\191210 to X.B. and E.A.).

Author information

Author notes

  1. These authors contributed equally: Xiaolong Zhang, Qingmin Song, Shaopeng Liu.

Authors and Affiliations

  1. Department of Chemistry, Northeast Normal University, Changchun, China

    Xiaolong Zhang, Qingmin Song, Shaopeng Liu, Paramasivam Sivaguru, Zhaohong Liu, Yong Yang, Yongyue Ning & Xihe Bi

  2. Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK

    Edward A. Anderson

  3. Schulich Faculty of Chemistry, Technion – Israel Institute of Technology, Technion City, Haifa, Israel

    Graham de Ruiter

  4. State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, China

    Xihe Bi

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Contributions

X.Z., S.L., Y.Y. and Y.N. performed and analysed the experiments. Q.S. carried out the DFT calculations. Z.L. and X.B. conceived the concept, and together with E.A., G.R. and P.S. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Zhaohong Liu or Xihe Bi.

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Nature Chemistry thanks Yu-hong Lam, Guang-Jian Mei and the other, anonymous, reviewer for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information (download PDF )

Materials and methods, Supplementary Figs. 1–289, Tables 1–10 and spectral data for all new compounds.

Supplementary Data 1

Crystallographic data for compound S-34; CCDC reference 2261312.

Supplementary Data 2

Crystallographic data for compound R-34; CCDC reference 2266339.

Supplementary Data 3

Crystallographic data for compound 2R,3S-43; CCDC reference 2281736.

Supplementary Data 4

Crystallographic data for compound 2R,3S-44; CCDC reference 2281629.

Supplementary Data 5

Crystallographic data for compound 5S,6S-76; CCDC reference 2311749.

Supplementary Data 6

Crystallographic data for compound R-64; CCDC reference 2350998.

Supplementary Data 7

Crystallographic data for compound 82; CCDC reference 2350447.

Supplementary Data 8 (download ZIP )

The xyz coordinates of DFT calculations.

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Zhang, X., Song, Q., Liu, S. et al. Asymmetric dearomative single-atom skeletal editing of indoles and pyrroles. Nat. Chem. 17, 215–225 (2025). https://doi.org/10.1038/s41557-024-01680-0

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