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Cyclolignan synthesis streamlined by enantioselective hydrogenation of tetrasubstituted olefins

Nature Synthesis volume 3, pages 986–997 (2024)Cite this article

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A Publisher Correction to this article was published on 27 June 2024

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Abstract

Natural products have long been valuable sources of inspiration for drug discovery. Unfortunately, the inherent limitations of direct semisynthetic derivatizations have become clear, and the need to overcome these limitations is now particularly urgent because the most valuable natural products tend to be isolated in minute amounts; de novo synthesis with ideal modularity and diversity is therefore a critical goal in drug discovery research. Herein we report a powerful, general platform for cyclolignan synthesis that involves challenging rhodium-catalysed enantioselective hydrogenation of tetrasubstituted 1,2-dihydronaphthalene esters (>40 examples; up to 99% yield, >99% e.e.). This unique platform allows ready access to various types of cyclolignans, as exemplified by the expedient and mostly protecting-group-free synthesis of over thirty cyclolignans, including many that have not previously been synthesized, such as 6-methoxy podophyllotoxin, cleistantoxin, picrobursenin, austrobailignan-4, (+)-lirionol, (+)-gaultherin C, ovafolinin D, fimbricalyxoid A, and aglacins D, F–H (with three revised structures). We expect this work to inspire modular, de novo syntheses of other important classes of natural products and thus to rejuvenate the role of natural products in drug discovery and development.

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Fig. 1: Strategies for de novo modular synthesis of cyclolignans.
Fig. 2: Scope of the rhodium-catalysed asymmetric hydrogenation of dihydronaphthalene α,β-unsaturated carboxylic acid esters.
Fig. 3: Total syntheses of podophyllotoxins.
Fig. 4: Synthesis of other types of cyclolignans via epimerization of 2p.
Fig. 5: Asymmetric total syntheses of various compounds from ent-2j′.
Fig. 6: Total syntheses of various compounds from 2j′.
Fig. 7: Total syntheses of compounds 84 and 85.

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Data availability

The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition nos. CCDC 2261541 (2p), 2232313 (9), 2236506 (16), 2236638 [(±)-47], 2236477 (71), 2289443 (81), 2236507 (S9) and 2272028 (S24). These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif. All other relevant data generated and analysed during this study, including experimental, spectroscopic and crystallographic data, are included in this Article and its Supplementary Information.

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Acknowledgements

We are grateful to the National Natural Science Foundation of China (grant no. 22271236) and the Natural Science Foundation of Zhejiang Province (grant no. LXZ22B020001) for support of this research. We sincerely thank T. J. Schmidt (University of Münster) and Y. S. Yun (Tokyo University of Pharmacy and Life Sciences) for kindly providing us with their original NMR spectra for 6-methoxypodophyllotoxin-7-O-n-hexanoate and ovafonin D, respectively. We acknowledge R. Shenvi (Scripps Research) for helpful discussions; J. Liu from the Chemistry Instrumentation Center at Zhejiang University for X-ray crystallographic analysis; and the Instrumentation and Service Centre for Molecular Sciences, and the Instrumentation and Service Centre for Physical Science at Westlake University, for help with other data analyses.

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Author notes

  1. These authors contributed equally: Wen-Xiu Xu, Zhuo Peng.

Authors and Affiliations

  1. Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, Westlake University, Hangzhou, China

    Wen-Xiu Xu, Zhuo Peng, Qing-Xiu Gu, Yao Zhu, Li-Han Zhao & Hai-Hua Lu

  2. Department of Chemistry, Zhejiang University, Hangzhou, China

    Wen-Xiu Xu, Zhuo Peng & Qing-Xiu Gu

  3. Instrumentation and Service Center for Physical Sciences, Westlake University, Hangzhou, China

    Fucheng Leng

  4. Institute of Natural Sciences, Westlake Institute for Advanced Study, Hangzhou, China

    Hai-Hua Lu

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Contributions

H.-H.L. conceived the project, guided the studies, and wrote the manuscript. Z.P. developed the asymmetric hydrogenation and completed the synthesis of podophyllotoxins and related cyclolignans. W.-X.X. completed the syntheses of lirionol, aglacins, gaultherin C, ovafolinin D and fimbricalyxoid A. Q.-X.G., Y.Z. and L.-H.Z. helped with the preparation of some intermediates. F.L. provided further X-ray crystallographic analysis and justifications. All of the authors contributed to the analysis and interpretation of the results.

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Correspondence to Hai-Hua Lu.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–16, Tables 1–25 and experimental details.

Supplementary Data 1

X-ray crystallographic data for compound 2p (CCDC 2261541).

Supplementary Data 2

X-ray crystallographic data for compound 9 (CCDC 2232313).

Supplementary Data 3

X-ray crystallographic data for compound 16 (CCDC 2236506).

Supplementary Data 4

X-ray crystallographic data for compound 47 (CCDC 2236638).

Supplementary Data 5

X-ray crystallographic data for compound 71 (CCDC 2236477).

Supplementary Data 6

X-ray crystallographic data for compound 81 (CCDC 2289443).

Supplementary Data 7

X-ray crystallographic data for compound S9 (CCDC 2236507).

Supplementary Data 8

X-ray crystallographic data for compound S24 (CCDC 2272028).

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Xu, WX., Peng, Z., Gu, QX. et al. Cyclolignan synthesis streamlined by enantioselective hydrogenation of tetrasubstituted olefins. Nat. Synth 3, 986–997 (2024). https://doi.org/10.1038/s44160-024-00564-y

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