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Concise, scalable and enantioselective total synthesis of prostaglandins

Nature Chemistry volume 13, pages 692–697 (2021)Cite this article

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Abstract

Prostaglandins are among the most important natural isolates owing to their broad range of bioactivities and unique structures. However, current methods for the synthesis of prostaglandins suffer from low yields and lengthy steps. Here, we report a practicability-oriented synthetic strategy for the enantioselective and divergent synthesis of prostaglandins. In this approach, the multiply substituted five-membered rings in prostaglandins were constructed via the key enyne cycloisomerization with excellent selectivity (>20:1 d.r., 98% e.e.). The crucial chiral centre on the scaffold of the prostaglandins was installed using the asymmetric hydrogenation method (up to 98% yield and 98% e.e.). From our versatile common intermediates, a series of prostaglandins and related drugs could be produced in two steps, and fluprostenol could be prepared on a 20-gram scale.

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Fig. 1: PGs and their synthetic methods.
Fig. 2: Our retrosynthetic analysis based on enyne cycloisomerization.
Fig. 3: Efficient synthesis of key intermediates 12 and 20.
Fig. 4: Highly efficient synthesis of the ω-chains of PGs.
Fig. 5: Completion of the total synthesis of PGs.

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Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition no. CCDC 2013314 (compound 21). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. The experimental procedures and characterization of all new compounds are provided in the Supplementary Information. All other data supporting the findings of this study are available within this Article and its Supplementary Information.

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Acknowledgements

X.Z. is indebted to the Southern University of Science and Technology (start-up fund), Shenzhen Science and Technology Innovation Committee (grant no. KQTD20150717103157174), Shenzhen Nobel Prize Scientists Laboratory Project (C17783101), Key-Area Research and Development Program of Guangdong Province (grant no. 2020B010188001), Innovative Team of Universities in Guangdong Province (grant no. 2020KCXTD016) and National Natural Science Foundation of China (grant no. 21991113). G.-Q.C. gratefully acknowledges the Youth Fund from the National Natural Science Foundation of China (grant no. 21901107).

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Authors and Affiliations

  1. Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China

    Fuhao Zhang, Jingwen Zeng, Mohan Gao, Linzhou Wang, Gen-Qiang Chen & Xumu Zhang

  2. Department of Chemistry, National University of Singapore, Singapore, Singapore

    Fuhao Zhang & Yixin Lu

  3. Medi-X, Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, China

    Gen-Qiang Chen & Xumu Zhang

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  1. Fuhao Zhang
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Contributions

F.Z. contributed to the conception and design of the experiments. F.Z. performed the experiments and analysed the data. F.Z. and J.Z. conducted the gram-scale preparation of fluprostenol. M.G. and L.W. synthesized several intermediates. Y.L. provided useful advice in the synthesis of PGE. F.Z. and G.-Q.C. co-wrote the manuscript. X.Z. and G.-Q.C. conceived and directed the investigations and composed the manuscript, with revisions provided by F.Z.

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Correspondence to Gen-Qiang Chen or Xumu Zhang.

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The authors declare no competing interests.

Additional information

Peer review information Nature Chemistry thanks Fener Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Characterization data, supplementary experimental data, synthetic procedures, Supplementary Figs. 1–7 and Tables 1–16.

Supplementary Data 1

Crystallographic data for compound 21. CCDC reference 2013314.

Supplementary Data 2

Structure factors file for compound 21. CCDC reference 2013314.

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Zhang, F., Zeng, J., Gao, M. et al. Concise, scalable and enantioselective total synthesis of prostaglandins. Nat. Chem. 13, 692–697 (2021). https://doi.org/10.1038/s41557-021-00706-1

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