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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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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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.
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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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DOI: https://doi.org/10.1038/s41557-023-01264-4
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