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

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.

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.

References

  1. 1.

    Diels, O. & Alder, K. Syntheses in the hydroaromatic series [in German]. Justus Liebigs Ann. Chem. 460, 98–122 (1928).

    CAS  Article  Google Scholar 

  2. 2.

    Hoffmann, R. & Woodward, R. B. The conservation of orbital symmetry. Acc. Chem. Res. 1, 17–22 (1968).

    CAS  Article  Google Scholar 

  3. 3.

    Corey, E. J. Catalytic enantioselective Diels–Alder reactions: methods, mechanistic fundamentals, pathways and applications. Angew. Chem. Int. Ed. 41, 1650–1667 (2002).

    CAS  Article  Google Scholar 

  4. 4.

    Nicolaou, K. C., Snyder, S. A., Montagnon, T. M. & Vassilikogiannakis, G. The Diels–Alder reaction in total synthesis. Angew. Chem. Int. Ed. 41, 1668–1698 (2002).

    CAS  Article  Google Scholar 

  5. 5.

    Ose, T. et al. Insight into a natural Diels–Alder reaction from the structure of macrophomate synthase. Nature 422, 185–189 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Chou, T. & Hung, S.-C. Selective cross Diels–Alder reaction of 2-(phenylsulfonyl) 1,3-dienes. J. Org. Chem. 53, 3020–3027 (1988).

    CAS  Article  Google Scholar 

  7. 7.

    Barco, A. et al. Generation and cycloaddition reactions of 3-substituted-2-nitro-1,3-dienes. Tetrahedron 52, 9275–9288 (1996).

    CAS  Article  Google Scholar 

  8. 8.

    Teyssot, M.-L., Lormier, A.-T., Chataigner, I. & Piettre, S. R. Cross-Diels–Alder reaction of 6-oxo-1-sulfonyl-1,6-dihydropyridine-3-carboxylates. J. Org. Chem. 72, 2364–2373 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Chou, S.-S. P. & Chen, P.-W. Cycloaddition reaction of 4-sulfur-substituted dihydro-2-pyridones and 2-pyridones with conjugated dienes. Tetrahedron 64, 1879–1887 (2008).

    CAS  Article  Google Scholar 

  10. 10.

    Pham, H. V. & Houk, K. N. Diels–Alder reactions of allene with benzene and butadiene: concerted, stepwise, and ambimodal transition states. J. Org. Chem. 79, 8968–8976 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Caramella, P., Quadreil, P. & Toma, L. An unexpected bispericyclic transition structure leading to 4+2 and 2+4 cycloadducts in the endo dimerization of cyclopentadiene. J. Am. Chem. Soc. 124, 1130–1131 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Hare, S. R. & Tantillo, D. J. Post-transition state bifurcations gain momentum – current state of the field. Pure Appl. Chem. 6, 679–698 (2017).

    Article  CAS  Google Scholar 

  13. 13.

    Ussing, B. R., Hang, C. & Singleton, D. A. Dynamic effects on the periselectivity, rate, isotope effects, and mechanism of cycloadditions of ketenes with cyclopentadiene. J. Am. Chem. Soc. 128, 7594–7607 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Thomas, J. B., Waas, J. R., Harmata, M. & Singleton, D. A. Control elements in dynamically determined selectivity on a bifurcating surface. J. Am. Chem. Soc. 130, 14544–14555 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Hong, Y. J. & Tantillo, D. J. A potential energy surface bifurcation in terpene biosynthesis. Nat. Chem. 1, 384–389 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Katori, T., Itoh, S., Sato, M. & Yamataka, H. Reaction pathways and possible path bifurcation for the Schmidt reaction. J. Am. Chem. Soc. 132, 3413–3422 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Garayalde, D., Gómez-Bengoa, E., Huang, X., Goeke, A. & Nevado, C. Mechanistic insights in gold-stabilized nonclassical carbocations: gold-catalyzed rearrangemement of 3-cyclopropyl propargylic acetates. J. Am. Chem. Soc. 132, 4720–4730 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Wang, Z. J., Benitez, D., Tkatchouk, E., Goddard, W. A. III & Toste, F. D. Mechanistic study of gold(I)-catalyzed intermolecular hydroamination of allenes. J. Am. Chem. Soc. 132, 13064–13071 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Hansen, J. H. et al. On the mechanism and selectivity of the combined C−H activation/Cope rearrangement. J. Am. Chem. Soc. 133, 5076–5085 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Nieves-Quinones, Y. & Singleton, D. A. Dynamics and the regiochemistry of nitration of toluene. J. Am. Chem. Soc. 138, 15167–15176 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Çelebi-Ölçüm, N., Ess, D. H., Aviyente, V. & Houk, K. N. Lewis acid catalysis alters shapes and products of bis-pericyclic Diels–Alder transition states. J. Am. Chem. Soc. 129, 4528–4529 (2007).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  22. 22.

    Yu, P. et al. Mechanisms and origins of periselectivity of the ambimodal [6 + 4] cycloadditions of tropone to dimethylfulvene. J. Am. Chem. Soc. 139, 8251–8258 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Chen, S., Yu, P. & Houk, K. N. Ambimodal dipolar/Diels–Alder cycloaddition transition states involving proton transfers. J. Am. Chem. Soc. 140, 18124–18131 (2019).

    Article  CAS  Google Scholar 

  24. 24.

    Xue, X.-S. et al. Ambimodal trispericyclic transition state and dynamic control of periselectivity. J. Am. Chem. Soc. 141, 1217–1221 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Liu, F., Chen, Y. & Houk, K. N. Huisgen’s 1,3-dipolar cycloadditions to fulvenes proceed via ambimodal [6+4]/[4+2] transition states. Angew. Chem. Int. Ed. 59, 12412–12416 (2020).

    CAS  Article  Google Scholar 

  26. 26.

    Kim, K., Ruszczycky, M. W., Choi, S.-H., Liu, Y.-N. & Liu, H.-W. Enzyme-catalyzed [4+2] cycloaddition is a key step in the biosynthesis of spinosyn A. Nature 473, 109–112 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Partel, A. et al. Dynamically complex [6+4] and [4+2] cycloadditions in the biosynthesis of spinosyn A. J. Am. Chem. Soc. 138, 3631–3634 (2016).

    Article  CAS  Google Scholar 

  28. 28.

    Ohashi, M. et al. SAM-dependent enzyme-catalyzed pericyclic reactions in natural product biosynthesis. Nature 549, 502–506 (2016).

    Article  CAS  Google Scholar 

  29. 29.

    Zhang, B. et al. Enzyme-catalysed [6+4] cycloadditions in the biosynthesis of natural products. Nature 568, 122–126 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Zhang, Z. et al. Enzyme-catalyzed inverse-electron demand Diels–Alder reaction in the biosynthesis of antifungal ilicicolin H. J. Am. Chem. Soc. 141, 5659–5663 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Si, X.-G., Zhang, Z.-M., Zheng, C.-G., Li, Z.-T. & Cai, Q. Enantioselective synthesis of cis-decalin derivatives by the inverse-electron-demand Diels–Alder reaction of 2-pyrones. Angew. Chem. Int. Ed. 59, 18412–18417 (2020).

    CAS  Article  Google Scholar 

  32. 32.

    Gregson, R. P. & Mirrington, R. N. Stereospecific total synthesis of (±)-α-amorphene. J. Chem. Soc. Chem. Commun. 598–599 (1973).

  33. 33.

    Markó, I. E. & Evans, G. R. Catalytic, enantioselective, inverse electron-demand Diels–Alder (IEDDA) reactions of 3-carbomethoxy-2-pyrone (3-CMP). Tetrahedron Lett. 35, 2771–2774 (1994).

    Article  Google Scholar 

  34. 34.

    Posner, G. H., Eydoux, F., Lee, J. K., Bull, D. S. & Dai, H. Binaphthol-titanium-promoted, highly enantiocontrolled, Diels−Alder cycloadditions of electronically matched 2-pyrones and vinyl ethers: streamlined asymmetric synthesis of an A-ring precursor to physiologically active 1α-hydroxyvitamin D3 steroids. Tetrahedron Lett. 35, 7541–7544 (1994).

    CAS  Article  Google Scholar 

  35. 35.

    Markó, I. E., Warriner, S. L. & Augustynes, B. Radical-initiated, skeletal rearrangements of bicyclo[2.2.2]lactones. Org. Lett. 2, 3123–3125 (2000).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  36. 36.

    Burch, P. et al. Total synthesis of gelsemiol. Chem. Eur. J. 19, 2589–2591 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Zhou, Y., Zhou, Z., Du, W. & Chen, Y. Asymmetric inverse-electron-demand Diels–Alder reaction of 2-pyrone and 2,5-dienones via HOMO-activation. Acta Chim. Sin. 76, 382–386 (2018).

    CAS  Article  Google Scholar 

  38. 38.

    Liang, X.-W. et al. Enantioselective synthesis of arene cis-dihydrodiols from 2-pyrones. Angew. Chem. Int. Ed. 58, 14562–14567 (2019).

    CAS  Article  Google Scholar 

  39. 39.

    Cole, C., Fuentes, L. & Snyder, S. A. Asymmetric pyrone Diels–Alder reactions enabled by dienamine catalysis. Chem. Sci. 11, 2175–2180 (2020).

    CAS  Article  Google Scholar 

  40. 40.

    Liao, S., Sun, X.-L. & Tang, Y. Side arm strategy for catalyst design: modifying bisoxazolines for remote control of enantioselection and related. Acc. Chem. Res. 47, 2260–2272 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Evans, D. A., Johnson, J. S. & Olhava, E. J. Enantioselective synthesis of dihydropyrans. Catalysis of hetero Diels–Alder reactions by bis(oxazoline) copper(II) complexes. J. Am. Chem. Soc. 122, 1635–1649 (2000).

    CAS  Article  Google Scholar 

  42. 42.

    Yang, Z. et al. Relationships between product ratios in ambimodal pericyclic reactions and bond lengths in transition structures. J. Am. Chem. Soc. 140, 3061–3067 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Corey, E. J. & Loh, T.-P. First application of attractive intramolecular interactions to the design of chiral catalysts for highly enantioselective Diels–Alder reactions. J. Am. Chem. Soc. 113, 8966–8967 (1991).

    CAS  Article  Google Scholar 

  44. 44.

    Houk, K. N. & Luckus, L. J. Cycloadditions of dienes to fulvenes. J. Org. Chem. 38, 3836–3843 (1973).

    CAS  Article  Google Scholar 

  45. 45.

    Turconi, J. et al. Semisynthetic artemisinin, the chemical path to industrial production. Org. Process Res. Dev. 18, 417–422 (2014).

    CAS  Article  Google Scholar 

  46. 46.

    Barluenga, J., Fernández-Simón, J. L., Concellón, J. M. & Yu, M. Facile one-pot transformation of carboxylic acid chlorides into 2-substituted allyl alcohols or epichlorohydrins. Chem. Soc. Perkin Trans. 1 77–80 (1989).

  47. 47.

    Littleson, M. M. et al. Synthetic approaches to coronafacic acid, coronamic acid, and coronatine. Synthesis 48, 3429–3448 (2016).

    CAS  Article  Google Scholar 

  48. 48.

    Nara, S., Toshima, H. & Ichihara, A. Asymmetric total synthesis of (+)-coronafacic acid and (+)-coronatine, phytotoxins isolated from Pseudomonas syringae pathovars. Tetrahedron 53, 9509–9524 (1997).

    CAS  Article  Google Scholar 

  49. 49.

    Arai, T., Sasai, H., Yamaguchi, K. & Shibasaki, M. Regioselective catalytic asymmetric reaction of Horner-Wadsworth-Emmons reagents with enones: the odyssey of chiral aluminum catalysts. J. Am. Chem. Soc. 120, 441–442 (1998).

    CAS  Article  Google Scholar 

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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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Authors

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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