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Asymmetric dearomatization catalysed by chiral Brønsted acids via activation of ynamides

Nature Chemistry volume 13, pages 1093–1100 (2021)Cite this article

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Abstract

Chiral Brønsted acid-catalysed asymmetric synthesis has received tremendous interest over the past decades, and numerous efficient synthetic methods have been developed based on this approach. However, the use of chiral Brønsted acids in these reactions is mostly limited to the activation of imine and carbonyl moieties, and the direct activation of carbon–carbon triple bonds has so far not been invoked. Here we show that chiral Brønsted acids enable the catalytic asymmetric dearomatization reactions of naphthol-, phenol- and pyrrole-ynamides by the direct activation of alkynes. This method leads to the practical and atom-economic construction of various valuable spirocyclic enones and 2H-pyrroles that bear a chiral quaternary carbon stereocentre in generally good-to-excellent yields with excellent chemo-, regio- and enantioselectivities. The activation mode of chiral Brønsted acid catalysis revealed in this study is expected to be of broad utility in catalytic asymmetric reactions that involve ynamides and the related heteroatom-substituted alkynes.

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Fig. 1: Chiral Brønsted acid-catalysed asymmetric synthesis.
Fig. 2: Preparative-scale synthesis and further transformations.
Fig. 3: DFT computations on the catalytic cycle and enantioselectivity-determining C–C bond formation transition states of CADA reactions of pyrrole-ynamides.

Data availability

Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2024759 (2c), 2055962 (2aw), 2024761 (6), 2024762 (8) and 2024763 (9). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data that support the findings of this study, which include experimental procedures and compound characterization, are available within the paper and its Supplementary Information.

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Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (92056104 and 21772161 for L.-W.Y., and 21702182 and 21873081 for X.H.), the Natural Science Foundation of Fujian Province of China (2019J02001), NFFTBS (J1310024) and the Science & Technology Cooperation Program of Xiamen (3502Z20183015). Fundamental Research Funds for the Central Universities (2020XZZX002-02), the State Key Laboratory of Clean Energy Utilization (ZJUCEU2020007) and the Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University, is greatly appreciated. Calculations were performed on the high-performance computing system at the Department of Chemistry, Zhejiang University.

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Author notes

  1. These authors contributed equally: Ying-Qi Zhang, Yang-Bo Chen.

Authors and Affiliations

  1. State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China

    Ying-Qi Zhang, Yang-Bo Chen, Xin-Yang Fan, Zhi-Xin Zhang & Long-Wu Ye

  2. Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University, Hangzhou, China

    Ji-Ren Liu, Shao-Qi Wu & Xin Hong

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

    Long-Wu Ye

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Contributions

Y.-Q.Z., Y.-B.C., X.-Y.F. and Z.-X.Z. performed the experiments. X.H. designed the DFT calculations. J.-R.L. and S.-Q.W. performed the DFT calculations. L.-W.Y. conceived and directed the project and wrote the paper. All the authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Xin Hong or Long-Wu Ye.

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The authors declare no competing interests.

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Peer review information Nature Chemistry thanks Christian Wolf 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 Tables 1–19, Figs. 1–8, experimental methods and data, crystallography data, computational studies, NMR, IR, HPLC spectra and references

Supplementary Data 1

Crystallographic data for compound 2c; CCDC reference 2024759.

Supplementary Data 2

Crystallographic data for compound 2aw; CCDC reference 2055962.

Supplementary Data 3

Crystallographic data for compound 6; CCDC reference 2024761.

Supplementary Data 4

Crystallographic data for compound 8; CCDC reference 2024762.

Supplementary Data 5

Crystallographic data for compound 9; CCDC reference 2024763.

Supplementary Data 6

Cartesian Coordinates for Computed Species.

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Zhang, YQ., Chen, YB., Liu, JR. et al. Asymmetric dearomatization catalysed by chiral Brønsted acids via activation of ynamides. Nat. Chem. 13, 1093–1100 (2021). https://doi.org/10.1038/s41557-021-00778-z

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