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Chirality retention in Friedel–Crafts spiroannulation for iterative synthesis of spiro-bridged conjugated carbocycles

Nature Synthesis (2025)Cite this article

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Abstract

The formation of chiral organic molecules from Friedel–Crafts reactions of chiral alcohols has been deemed impractical due to racemization via carbocation formation. Here we demonstrate the preservation of stereochemistry in intramolecular Friedel–Crafts alkylation reactions, expanding the boundaries of accessible chiral chemistry. Mechanistic investigations show that the retention of stereochemistry stems from the chirality memory of transient, axially chiral carbocation intermediates. This finding allows the synthesis of axially chiral spirocarbon-bridged conjugated carbocycles. Leveraging a rhodium-catalysed regioselective C–H activation–annulation approach, the reaction of thiobenzamide with phenylethynyl tertiary alcohol is a crucial step in expanding the spiro-bridged skeleton. We used this approach to develop an iterative synthetic sequence to construct enantiopure spirocarbon-bridged pure-hydrocarbon oligo(trans-stilbene) compounds. Notably, in the concluding step of the iterative synthesis, all chiral tertiary alcohol units undergo a stereospecific one-shot conversion to form multiple spirocyclic structures, resembling a ‘zipping up’ process. This synthetic strategy facilitates both the longitudinal and lateral extension of spiro-bridged conjugated structures, with promising applications in circularly polarized lasers.

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Fig. 1: Synthetic challenges towards optically active, multiple spirocarbon-bridged conjugated pure-hydrocarbon carbocycles and our solution.
Fig. 2: Rhodium-catalysed C–H annulation and iterative synthetic routes to spirocarbon-bridged conjugated carbocycles ((n+1)SpiroCnTS).
Fig. 3: Discovery and verification of the retention of stereochemistry in Friedel–Crafts spiroannulation.
Fig. 4: Free-energy profiles for intramolecular Friedel–Crafts alkylation in reactions of (S)-32 and (S,S)-34.
Fig. 5: Stereoselective iterative synthesis of spirocarbon-bridged conjugated pure-hydrocarbon carbocycles.
Fig. 6: Longitudinal and lateral extensions of spiro-bridged conjugated structures and their applications.

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Data availability

The data that support the findings of this study are available within the Article and its Supplementary Information. Data are also available from the corresponding authors upon reasonable request. The X-ray crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers 2291836 (5), 2289728 (9), 2294270 (11), 2294275 (rac-13), 2303144 ((R,R)-14 and (S,S)-14), 2294277 (rac-15), 2294278 ((R)-15), 2294279 ((R,S)-17 and (S,R)-17), 2294280 ((R,S)-19), 2294281 ((R,S,R)-21 and (S,R,S)-21), 2294282 ((R,S,R)-21), 2291829 (27), 2291826 (30) and 2294290 ((S,S)-34). These data can be obtained free of charge from the Cambridge Crystallographic Data Centre (CCDC) via www.ccdc.cam.ac.uk/data_request/cif. Source data are provided with this paper.

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Acknowledgements

We acknowledge financial support from the National NSF of China (22031007, 22371196, 22171130 and 22071162), the Natural Science Foundation of Sichuan, China (2022NSFSC0029), Guangdong Provincial Key Laboratory of Catalysis (2020B121201002), the New Cornerstone Science Foundation through the XPLORER PRIZE and Fundamental Research Funds for the Central Universities. Computational work was supported by the Center for Computational Science and Engineering and the CHEM High-Performance Supercomputer Cluster (CHEM-HPC) of the Department of Chemistry, Southern University of Science and Technology. We also thank P. Deng and D. Luo from the Analytical and Testing Center of Sichuan University for high-temperature NMR spectroscopy and crystal-structure analysis, respectively.

Author information

Author notes

  1. These authors contributed equally: Xingwen Pu, Yi Lu, Zhonghao Zhou.

Authors and Affiliations

  1. Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, China

    Xingwen Pu, Yudong Yang, Cheng Zhang, Jingbo Lan & Jingsong You

  2. Department of Chemistry and Shenzhen Grubbs Institute, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, China

    Yi Lu & Peiyuan Yu

  3. Key Laboratory of Photochemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China

    Zhonghao Zhou & Yong Sheng Zhao

  4. Anhui Provincial Key Laboratory of Magnetic Functional Materials and Devices, School of Materials Science and Engineering, Anhui University, Hefei, China

    Zhonghao Zhou

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Contributions

X.P. performed the experiments and analysed the data. Y.L. performed the DFT calculations. Z.Z. performed the optically pumped lasing measurements under the guidance of Y.S.Z. J.Y. and J.L. designed and directed the project. P.Y. directed the DFT calculations and analysed the computational data. X.P., J.L., Y.Y., P.Y., C.Z. and J.Y. wrote the paper. All authors contributed to discussions.

Corresponding authors

Correspondence to Peiyuan Yu, Yong Sheng Zhao, Jingbo Lan or Jingsong You.

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Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks Koki Ikemoto and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Sections 1–16, Tables 1–72, Figs. 1–104 and experimental details.

Supplementary Data 1

Crystallographic data for compound 5, CCDC 2291836.

Supplementary Data 2

Structure factors for compound 5, CCDC 2291836.

Supplementary Data 3

Crystallographic data for compound 9, CCDC 2289728.

Supplementary Data 4

Structure factors for compound 9, CCDC 2289728.

Supplementary Data 5

Crystallographic data for compound 11, CCDC 2294270.

Supplementary Data 6

Structure factors for compound 11, CCDC 2294270.

Supplementary Data 7

Crystallographic data for compound 13, CCDC 2294275.

Supplementary Data 8

Structure factors for compound 13, CCDC 2294275.

Supplementary Data 9

Crystallographic data for compound 14, CCDC 2303144.

Supplementary Data 10

Structure factors for compound 14, CCDC 2303144.

Supplementary Data 11

Crystallographic data for compound (R)-15, CCDC 2294278.

Supplementary Data 12

Structure factors for compound (R)-15, CCDC 2294278.

Supplementary Data 13

Crystallographic data for compound rac-15, CCDC 2294277.

Supplementary Data 14

Structure factors for compound rac-15, CCDC 2294277.

Supplementary Data 15

Crystallographic data for compound 17, CCDC 2294279.

Supplementary Data 16

Structure factors for compound 17, CCDC 2294279.

Supplementary Data 17

Crystallographic data for compound 19, CCDC 2294280.

Supplementary Data 18

Structure factors for compound 19, CCDC 2294280.

Supplementary Data 19

Crystallographic data for compound rac-21, CCDC 2294281.

Supplementary Data 20

Structure factors for compound rac-21, CCDC 2294281.

Supplementary Data 21

Crystallographic data for compound (R,S,R)-21, CCDC 2294282.

Supplementary Data 22

Structure factors for compound (R,S,R)-21, CCDC 2294282.

Supplementary Data 23

Crystallographic data for compound 27, CCDC 2291829.

Supplementary Data 24

Structure factors for compound 27, CCDC 2291829.

Supplementary Data 25

Crystallographic data for compound 30, CCDC 2291826.

Supplementary Data 26

Structure factors for compound 30, CCDC 2291826.

Supplementary Data 27

Crystallographic data for compound 34, CCDC 2294290.

Supplementary Data 28

Structure factors for compound 34, CCDC 2294290.

Supplementary Data 29

Statistical source data for supplementary figures.

Source data

Source Data Fig. 6

Source data for Fig. 6c–e.

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Pu, X., Lu, Y., Zhou, Z. et al. Chirality retention in Friedel–Crafts spiroannulation for iterative synthesis of spiro-bridged conjugated carbocycles. Nat. Synth (2025). https://doi.org/10.1038/s44160-025-00817-4

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