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Catalytic enantio- and diastereoselective domino halocyclization and spiroketalization

Abstract

Asymmetric domino electrophilic halocyclizations are highly useful in the synthesis of structurally complex and pharmaceutically important compounds. Although some studies aimed at catalytic and enantioselective polyene cyclizations are documented, the chiral products have been limited to fused rings. Here, we report an efficient and highly enantio- and diastereoselective halocyclization and spiroketalization of olefinic keto-acids. Instead of electron-deficient thiourea, in this study electron-rich thiourea catalysts are crucial for high enantioselectivity. The resulting spiro compounds are privileged cores of many drugs and natural products. Our experimental and computational studies revealed that the reaction proceeded via a double dynamic–kinetic resolution mechanism. We anticipate that this work will stimulate the synthesis of other multifunctional compounds via electrophilic halocyclization.

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Fig. 1: Asymmetric domino halocyclization.
Fig. 2: Optimization of asymmetric halocyclization and spiroketalization of olefinic keto-acid.
Fig. 3: Substrate scope of stereoselective domino bromo- and iodocyclization–spiroketalization.
Fig. 4: Substrate scope of stereoselective domino chlorocyclization–spiroketalization.
Fig. 5: Enantio- and diastereoselective chlorocyclization–bis-spiroketalization of 5.
Fig. 6: Mechanistic study.
Fig. 7: DFT calculation for stereoselective domino bromocyclization–spiroketalization.

Data availability

The findings of this study are available within the paper and its Supplementary Information. Crystallographic parameters for compounds 3a, 4a-Br, 5 and 6 are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 1978126 (3a), CCDC 1978123 (4a-Br), CCDC 1978125 (5) and 1978124 (6). All data are available from the authors upon reasonable request.

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Acknowledgements

This work was supported by Hong Kong Special Administrative Region General Research Funding (grant number CUHK14304918), the Chinese University of Hong Kong Direct Grant (grant number 4053329) and Innovation and Technology Commission to the State Key Laboratory of Synthetic Chemistry (GHP/004/16GD). We thank Professor B. List (Max-Planck-Institut für Kohlenforschung) for a helpful discussion.

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Contributions

Y.-Y.Y. conceived of and directed the project. T.Z. performed the experimental works. W.-H.N. assisted the preparation of some starting materials. Y.-L.S.T. directed the DFT calculations and mechanism analysis. X.W. performed the DFT calculations. T.Z., X.W., Y.-L.S.T. and Y.-Y.Y. co-wrote the manuscript.

Corresponding authors

Correspondence to Ying-Lung Steve Tse or Ying-Yeung Yeung.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–16, Tables 1–4, Methods, References

Supplementary Data

Supplementary Data for DFT

Supplementary Data 1

CIF file for the crystallographic data of compound 3a.

Supplementary Data 2

CIF file for the crystallographic data of compound 4a-Br.

Supplementary Data 3

CIF file for the crystallographic data of compound 5.

Supplementary Data 4

CIF file for the crystallographic data of compound 6.

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Zheng, T., Wang, X., Ng, WH. et al. Catalytic enantio- and diastereoselective domino halocyclization and spiroketalization. Nat Catal 3, 993–1001 (2020). https://doi.org/10.1038/s41929-020-00530-9

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