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A bridged backbone strategy enables collective synthesis of strychnan alkaloids

Nature Chemistry volume 15, pages 1074–1082 (2023)Cite this article

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Abstract

Bridged frameworks are of high chemical and biological significance, being ubiquitous in pharmaceutical molecules and natural products. Specific structures are usually preformed to build these rigid segments at the middle or late stage in the synthesis of polycyclic molecules, resulting in decreased synthetic efficiency and target-specific syntheses. As a logically distinct synthetic strategy, we constructed an allene/ketone-equipped morphan core at the outset through an enantioselective α-allenylation of ketones. Experimental and theoretical results revealed that the high reactivity and enantioselectivity of this reaction are attributed to the cooperative effects of the organocatalyst and metal catalyst. The bridged backbone generated was employed as a structural platform to guide and facilitate the assembly of up to five fusing rings, and the allene and ketone groups thereon were used to precisely install various functionalities at C16 and C20 at the late stage, leading to a concise, collective total synthesis of nine strychnan alkaloids.

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Fig. 1: Representative clinical drugs and natural products bearing a bridged backbone and an outline of the synthetic design.
Fig. 2: DFT calculations.
Fig. 3: Synthesis of the shared intermediate 9.
Fig. 4: The collective access to strychnan alkaloids.

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Data availability

All relevant data supporting the findings of this study, including experimental procedures, compound characterizations and theoretical calculations are available within the Article 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 2195671 (9b), 2195676 (10h), 2195681 (15) and 2195680 (24). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (21922102, 21871033, 22271033), the Fundamental Research Funds for the Central Universities (2022CDJQY-001, 2020CDJQY-Z002) and Chongqing Science and Technology Commission (CSTB2022NSCQLZX0036) to M.Z. The numerical computations were performed at Hefei advanced computing centre. We are grateful to X. Gong from Analytical and Testing Center of Chongqing University for X-ray crystallographic analysis.

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Author notes

  1. These authors contributed equally: Wenqiang Zhou, Song Xi, Haohua Chen.

Authors and Affiliations

  1. Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Innovative Drug Research Center, School of Pharmaceutical Sciences, Chongqing University, Chongqing, China

    Wenqiang Zhou, Song Xi, Dan Jiang, Jiao Yang, Shuangwei Liu, Ling He, Hanyue Qiu & Min Zhang

  2. Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing, China

    Haohua Chen & Yu Lan

  3. College of Chemistry and Institute of Green Catalysis, Zhengzhou University, Zhengzhou, China

    Yu Lan

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Contributions

M.Z. and Y.L. conceived and directed the project. W.Z. and S.X. performed the experiments and analysed the experimental data with the help of D.J., J.Y. and S.L. Y.L. and H.C. conducted the theoretical studies. M.Z. and Y.L. wrote the manuscript with W.Z., S.X., H.C., H.Q. and L.H. W.Z., S.X. and H.C. prepared the Supplementary Information. All authors discussed the results and gave their approval of the final version.

Corresponding authors

Correspondence to Yu Lan or Min Zhang.

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The authors declare no competing interests.

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Nature Chemistry thanks Christoph Schneider, Sylvain Canesi 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 1–23, Figs. 1 and 2, experimental data, synthesis and characterization data, NMR spectra, X-ray crystallographic data and density functional theory calculation data.

Supplementary Data 1

Crystallographic data for compound 10h; CCDC reference 2195676.

Supplementary Data 2

Crystallographic data for compound 9b; CCDC reference 2195671.

Supplementary Data 3

Crystallographic data for compound 15; CCDC reference 2195681.

Supplementary Data 4

Crystallographic data for compound 24; CCDC reference 2195680.

Supplementary Data 5

Structure factors for compound 10h; CCDC reference 2195676.

Supplementary Data 6

Structure factors for compound 9b; CCDC reference 2195671.

Supplementary Data 7

Structure factors for compound 15; CCDC reference 2195681.

Supplementary Data 8

Structure factors for compound 24; CCDC reference 2195680.

Supplementary Data 9

Cartesian coordinates for all optimized structures.

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Zhou, W., Xi, S., Chen, H. et al. A bridged backbone strategy enables collective synthesis of strychnan alkaloids. Nat. Chem. 15, 1074–1082 (2023). https://doi.org/10.1038/s41557-023-01264-4

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