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An enantioselective ambimodal cross-Diels–Alder reaction and applications in synthesis

Nature Catalysis volume 4, pages 892–900 (2021)Cite this article

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Abstract

Compared with the conventional Diels–Alder reaction, the development of selective cross-Diels–Alder reactions between two different conjugated dienes, especially in a catalytic asymmetric manner, has been neglected. We now report a peri- and enantioselective cross-Diels–Alder reaction of 3-alkoxycarbonyl-2-pyrones with unactivated conjugated dienes catalysed by a copper(II)–bis(oxazoline) complex, leading to formal inverse-electron-demand adducts with high enantioselectivity under mild reaction conditions. Computational studies showed that this reaction proceeds through an ambimodal transition state: post-transition-state bifurcation leads to [2+4] and [4+2] adducts with the same enantioselectivity, followed by a facile Cope rearrangement to provide a single observed thermodynamic [2+4] product. This reaction occurs with a wide variety of cyclopentadienes, fulvenes and cyclohexadienes, providing a highly efficient and enantioselective approach to densely functionalized cis-bicyclic scaffolds. The synthetic value of this reaction is demonstrated by the asymmetric synthesis of two biologically important natural products, artemisinic acid and coronafacic acid.

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Fig. 1: Cross-Diels–Alder reactions and ambimodal transition states.
Fig. 2: The discovery of an enantioselective cross-Diels–Alder reaction via an ambimodal transition state.
Fig. 3: DFT calculations of the reaction between 2-pyrone 1a and cyclopentadiene.
Fig. 4: Substrate scope of the enantioselective cross-Diels–Alder reaction.
Fig. 5: Synthetic applications of the enantioselective cross-Diels–Alder reaction.

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Data availability

The data generated or analysed during this study are included in the published article and Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2039052 (3a), 2039053 (4a), 2039054 (3ac), 2039055 (4ac) and 2039056 (4ac′). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data are available from the authors upon reasonable request.

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Acknowledgements

We acknowledge the National Natural Science Foundation of China (grant nos. 21801043 and 22071030 to Q.C.), the “1000-Youth Talents Plan” (to Q.C.), Fudan University (start-up grant to Q.C.), the National Science Foundation of the USA (CHE-1764328 to K.N.H) and the Natural Science Foundation of Zhejiang Province (grant no. LY20B020010 to L.Y.) for financial support. L.Y. is grateful for additional funding from the China Scholarship Council.

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Author notes

  1. These authors contributed equally: Meng-Meng Xu, Limin Yang.

Authors and Affiliations

  1. Department of Chemistry, Research Center for Molecular Recognition and Synthesis, Fudan University, Shanghai, China

    Meng-Meng Xu, Kui Tan, Qi-Tao Lu & Quan Cai

  2. College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou, China

    Limin Yang

  3. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Limin Yang, Xiangyang Chen & K. N. Houk

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Contributions

M.-M.X. developed the ambimodal cross-Diels−Alder reaction, optimized the reaction conditions, conducted the control experiments, evaluated the scope of the reaction and applied this reaction to the synthesis of the natural products artemisinic acid and coronafacic acid; L.Y. and X.C. performed the DFT calculations; K.T. helped to evaluate the scope of the reaction; Q.-T.L. helped in the synthesis of coronafacic acid; K.N.H. supervised the computational studies; Q.C. conceived and directed the project.

Corresponding authors

Correspondence to K. N. Houk or Quan Cai.

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The authors declare no competing interests.

Additional information

Peer review information Nature Catalysis thanks Luis Domingo, Aurélien de la Torre 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 Methods, Mechanistic Studies, Tables 1–4, Figs. 1 and 2, references and spectra.

Supplementary Data 1

Crystallographic data of compound 3a (CCDC 2039052).

Supplementary Data 2

Crystallographic data of compound 4a (CCDC 2039053).

Supplementary Data 3

Crystallographic data of compound 3ac (CCDC 2039054).

Supplementary Data 4

Crystallographic data of compound 4ac (CCDC 2039055).

Supplementary Data 5

Crystallographic data of compound 4ac′ (CCDC 2039056).

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Xu, MM., Yang, L., Tan, K. et al. An enantioselective ambimodal cross-Diels–Alder reaction and applications in synthesis. Nat Catal 4, 892–900 (2021). https://doi.org/10.1038/s41929-021-00687-x

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