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Asymmetric dearomatization catalysed by chiral Brønsted acids via activation of ynamides

Nature Chemistry volume 13, pages 1093–1100 (2021)Cite this article

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Abstract

Chiral Brønsted acid-catalysed asymmetric synthesis has received tremendous interest over the past decades, and numerous efficient synthetic methods have been developed based on this approach. However, the use of chiral Brønsted acids in these reactions is mostly limited to the activation of imine and carbonyl moieties, and the direct activation of carbon–carbon triple bonds has so far not been invoked. Here we show that chiral Brønsted acids enable the catalytic asymmetric dearomatization reactions of naphthol-, phenol- and pyrrole-ynamides by the direct activation of alkynes. This method leads to the practical and atom-economic construction of various valuable spirocyclic enones and 2H-pyrroles that bear a chiral quaternary carbon stereocentre in generally good-to-excellent yields with excellent chemo-, regio- and enantioselectivities. The activation mode of chiral Brønsted acid catalysis revealed in this study is expected to be of broad utility in catalytic asymmetric reactions that involve ynamides and the related heteroatom-substituted alkynes.

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Fig. 1: Chiral Brønsted acid-catalysed asymmetric synthesis.
Fig. 2: Preparative-scale synthesis and further transformations.
Fig. 3: DFT computations on the catalytic cycle and enantioselectivity-determining C–C bond formation transition states of CADA reactions of pyrrole-ynamides.

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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 numbers CCDC 2024759 (2c), 2055962 (2aw), 2024761 (6), 2024762 (8) and 2024763 (9). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data that support the findings of this study, which include experimental procedures and compound characterization, are available within the paper and its Supplementary Information.

References

  1. Zhang, Y.-C., Jiang, F. & Shi, F. Organocatalytic asymmetric synthesis of indole-based chiral heterocycles: strategies, reactions, and outreach. Acc. Chem. Res. 53, 425–446 (2020).

    Article  CAS  PubMed  Google Scholar 

  2. Schreyer, L., Properzi, R. & List, B. IDPi catalysis. Angew. Chem. Int. Ed. 58, 12761–12777 (2019).

    Article  CAS  Google Scholar 

  3. Maji, R., Mallojjala, S. C. & Wheeler, S. E. Chiral phosphoric acid catalysis: from numbers to insights. Chem. Soc. Rev. 47, 1142–1158 (2018).

    Article  CAS  PubMed  Google Scholar 

  4. Wang, Y.-B. & Tan, B. Construction of axially chiral compounds via asymmetric organocatalysis. Acc. Chem. Res. 51, 534–547 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Min, C. & Seidel, D. Asymmetric Brønsted acid catalysis with chiral carboxylic acids. Chem. Soc. Rev. 46, 5889–5902 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Akiyama, T. & Mori, K. Stronger Brønsted acids: recent progress. Chem. Rev. 115, 9277–9306 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Parmar, D., Sugiono, E., Raja, S. & Rueping, M. Complete field guide to asymmetric BINOL-phosphate derived Brønsted acid and metal catalysis: history and classification by mode of activation; Brønsted acidity, hydrogen bonding, ion pairing, and metal phosphates. Chem. Rev. 114, 9047–9153 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Terada, M. & Sorimachi, K. Enantioselective Friedel–Crafts reaction of electron-rich alkenes catalyzed by chiral Brønsted acid. J. Am. Chem. Soc. 129, 292–293 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Terada, M., Tanaka, H. & Sorimachi, K. Enantioselective direct aldol-type reaction of azlactone via protonation of vinyl ethers by a chiral Brønsted acid catalyst. J. Am. Chem. Soc. 131, 3430–3431 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Terada, M., Moriya, K., Kanomata, K. & Sorimachi, K. Chiral Brønsted acid catalyzed stereoselective addition of azlactones to 3-vinylindoles for facile access to enantioenriched tryptophan derivatives. Angew. Chem. Int. Ed. 50, 12586–12590 (2011).

    Article  CAS  Google Scholar 

  11. Čorić, I. & List, B. Asymmetric spiroacetalization catalysed by confined Brønsted acids. Nature 483, 315–319 (2012).

    Article  PubMed  CAS  Google Scholar 

  12. Shapiro, N. D., Rauniyar, V., Hamilton, G. L., Wu, J. & Toste, F. D. Asymmetric additions to dienes catalysed by a dithiophosphoric acid. Nature 470, 245–249 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tsuji, N. et al. Activation of olefins via asymmetric Brønsted acid catalysis. Science 359, 1501–1505 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Kikuchi, J. & Terada, M. Enantioselective addition reaction of azlactones with styrene derivatives catalyzed by strong chiral Brønsted acids. Angew. Chem. Int. Ed. 58, 8458–8462 (2019).

    Article  CAS  Google Scholar 

  15. Yang, J. et al. Organocatalytic enantioselective synthesis of tetrasubstituted α-amino allenoates by dearomative γ-addition of 2,3-disubstituted indoles to β,γ-alkynyl-α-imino esters. Angew. Chem. Int. Ed. 59, 642–647 (2020).

    Article  CAS  Google Scholar 

  16. Liu, X. et al. Catalytic asymmetric multiple dearomatizations of phenols enabled by a cascade 1,8-addition and Diels–Alder reaction. Chem. Sci. 11, 671–676 (2020).

    Article  CAS  Google Scholar 

  17. Qian, D., Wu, L., Lin, Z. & Sun, J. Organocatalytic synthesis of chiral tetrasubstituted allenes from racemic propargylic alcohols. Nat. Commun. 8, 567 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Wang, Y.-B. et al. Rational design, enantioselective synthesis and catalytic applications of axially chiral EBINOLs. Nat. Catal. 2, 504–513 (2019).

    Article  CAS  Google Scholar 

  19. Lynch, C. C., Sripada, A. & Wolf, C. Asymmetric synthesis with ynamides: unique reaction control, chemical diversity and applications. Chem. Soc. Rev. 49, 8543–8583 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen, Y.-B., Qian, P.-C. & Ye, L.-W. Brønsted acid-mediated reactions of ynamides. Chem. Soc. Rev. 49, 8897–8909 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. Evano, G., Theunissen, C. & Lecomte, M. Ynamides: powerful and versatile reagents for chemical synthesis. Aldrichim. Acta 48, 59–70 (2015).

    CAS  Google Scholar 

  22. Wang, X.-N. et al. Ynamides in ring forming transformations. Acc. Chem. Res. 47, 560–578 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Kaldre, D., Klose, I. & Maulide, N. Stereodivergent synthesis of 1,4-dicarbonyls by traceless charge–accelerated sulfonium rearrangement. Science 361, 664–667 (2018).

    Article  CAS  PubMed  Google Scholar 

  24. Minko, Y., Pasco, M., Lercher, L., Botoshansky, M. & Marek, I. Forming all-carbon quaternary stereogenic centres in acyclic systems from alkynes. Nature 490, 522–526 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Das, J. P., Chechik, H. & Marek, I. A unique approach to aldol products for the creation of all-carbon quaternary stereocentres. Nat. Chem. 1, 128–132 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Zhou, B. et al. Stereoselective synthesis of medium lactams enabled by metal-free hydroalkoxylation/stereospecific [1,3]-rearrangement. Nat. Commun. 10, 3234 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Hong, F.-L. & Ye, L.-W. Transition-metal catalyzed tandem reactions of ynamides for divergent N-heterocycle synthesis. Acc. Chem. Res. 53, 2003–2019 (2020).

    Article  CAS  PubMed  Google Scholar 

  28. Xia, Z.-L., Xu-Xu, Q.-F., Zheng, C. & You, S.-L. Chiral phosphoric acid-catalyzed asymmetric dearomatization reactions. Chem. Soc. Rev. 49, 286–300 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Zheng, C. & You, S.-L. Catalytic asymmetric dearomatization (CADA) reaction-enabled total synthesis of indole-based natural products. Nat. Prod. Rep. 36, 1589–1605 (2019).

    Article  CAS  PubMed  Google Scholar 

  30. Wu, W.-T., Zhang, L. & You, S.-L. Catalytic asymmetric dearomatization (CADA) reactions of phenol and aniline derivatives. Chem. Soc. Rev. 45, 1570–1580 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Zheng, C. & You, S.-L. Catalytic asymmetric dearomatization by transition-metal catalysis: a method for transformations of aromatic compounds. Chem 1, 830–857 (2016).

    Article  CAS  Google Scholar 

  32. Brak, K. & Jacobsen, E. N. Asymmetric ion-pairing catalysis. Angew. Chem. Int. Ed. 52, 534–561 (2013).

    Article  CAS  Google Scholar 

  33. Ding, L., Wu, W.-T., Zhang, L. & You, S.-L. Construction of spironaphthalenones via gold-catalyzed intramolecular dearomatization reaction of β-naphthol derivatives. Org. Lett. 22, 5861–5865 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Ge, S. et al. Chiral N,N′-dioxide/Sc(OTf)3 complex-catalyzed asymmetric dearomatization of β-naphthols. Chem. Commun. 53, 11759–11762 (2017).

    Article  CAS  Google Scholar 

  35. Bai, L. et al. Palladium(0)-catalyzed intermolecular carbocyclization of (1,n)-diynes and bromophenols: an efficient route to tricyclic scaffolds. Angew. Chem. Int. Ed. 55, 6946–6950 (2016).

    Article  CAS  Google Scholar 

  36. Wu, W.-T., Xu, R.-Q., Zhang, L. & You, S.-L. Construction of spirocarbocycles via gold-catalyzed intramolecular dearomatization of naphthols. Chem. Sci. 7, 3427–3431 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zheng, J., Wang, S.-B., Zheng, C. & You, S.-L. Asymmetric dearomatization of naphthols via a Rh-catalyzed C(sp2)–H functionalization/annulation reaction. J. Am. Chem. Soc. 137, 4880–4883 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Yang, D. et al. Application of a C–C bond-forming conjugate addition reaction in asymmetric dearomatization of β-naphthols. Angew. Chem. Int. Ed. 54, 9523–9527 (2015).

    Article  CAS  Google Scholar 

  39. Zeng, X.-P., Cao, Z.-Y., Wang, Y.-H., Zhou, F. & Zhou, J. Catalytic enantioselective desymmetrization reactions to all-carbon quaternary stereocenters. Chem. Rev. 116, 7330–7396 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Christoffers, J. & Mann, A. Enantioselective construction of quaternary stereocenters. Angew. Chem. Int. Ed. 40, 4591–4597 (2001).

    Article  CAS  Google Scholar 

  41. Zhang, A.-H. et al. Sequestration of guest intermediates by dalesconol bioassembly lines in Daldinia eschscholzii. Org. Lett. 19, 2142–2145 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Kim, J.-Y., Lee, C.-W., Jang, J.-G. & Gong, M.-S. Orange phosphorescent organic light-emitting diodes using new spiro[benzoanthracene-fluorene]-type host materials. Dyes Pigm. 94, 304–313 (2012).

    Article  CAS  Google Scholar 

  43. Zhang, Y.-L. et al. Unprecedented immunosuppressive polyketides from Daldinia eschscholzii, a mantis-associated fungus. Angew. Chem. Int. Ed. 47, 5823–5826 (2008).

    Article  CAS  Google Scholar 

  44. Shao, L., Wang, Y.-H., Zhang, D.-Y., Xu, J. & Hu, X.-P. Desilylation-activated propargylic transformation: enantioselective copper-catalyzed [3+2] cycloaddition of propargylic esters with β-naphthol or phenol derivatives. Angew. Chem. Int. Ed. 55, 5014–5018 (2016).

    Article  CAS  Google Scholar 

  45. Rousseaux, S., García-Fortanet, J., Sanchez, M. A. D. A. & Buchwald, S. L. Palladium(0)-catalyzed arylative dearomatization of phenols. J. Am. Chem. Soc. 133, 9282–9285 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Khan, M. A. Spiro-lactam NMDA receptor modulators and uses thereof. World patent 2018026779 (2018).

  47. Giblin, G. M. P. et al. Spiro derivatives as voltage-gated sodium channel modulators. World patent 2013179049 (2013).

  48. Sharma, S. K. et al. Identification of E2F-1/Cyclin A antagonists. Bioorg. Med. Chem. Lett. 11, 2449–2452 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Damour, D. et al. Synthesis and binding affinities of novel spirocyclic lactam peptidomimetics of somatostatin. Chem. Lett. 27, 943–944 (1998).

    Article  Google Scholar 

  50. Romano, C., Jia, M., Monari, M., Manoni, E. & Bandini, M. Metal-free enantioselective electrophilic activation of allenamides: stereoselective dearomatization of indoles. Angew. Chem. Int. Ed. 53, 13854–13857 (2014).

    Article  CAS  Google Scholar 

  51. Giacinto, P., Bottoni, A., Garelli, A., Miscione, G. P. & Bandini, M. Covalent or non-covalent? A mechanistic insight into the enantioselective Brønsted acid catalyzed dearomatization of indoles with allenamides. ChemCatChem 10, 2442–2449 (2018).

    Article  CAS  Google Scholar 

  52. Reid, J. P., Simón, L. & Goodman, J. M. A practical guide for predicting the stereochemistry of bifunctional phosphoric acid catalyzed reactions of imines. Acc. Chem. Res. 49, 1029–1041 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Proctor, R. S. J., Colgan, A. C. & Phipps, R. J. Exploiting attractive non-covalent interactions for the enantioselective catalysis of reactions involving radical intermediates. Nat. Chem. 12, 990–1004 (2020).

    Article  PubMed  CAS  Google Scholar 

  54. Falivene, L. et al. Towards the online computer-aided design of catalytic pockets. Nat. Chem. 11, 872–879 (2019).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (92056104 and 21772161 for L.-W.Y., and 21702182 and 21873081 for X.H.), the Natural Science Foundation of Fujian Province of China (2019J02001), NFFTBS (J1310024) and the Science & Technology Cooperation Program of Xiamen (3502Z20183015). Fundamental Research Funds for the Central Universities (2020XZZX002-02), the State Key Laboratory of Clean Energy Utilization (ZJUCEU2020007) and the Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University, is greatly appreciated. Calculations were performed on the high-performance computing system at the Department of Chemistry, Zhejiang University.

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Author notes

  1. These authors contributed equally: Ying-Qi Zhang, Yang-Bo Chen.

Authors and Affiliations

  1. State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China

    Ying-Qi Zhang, Yang-Bo Chen, Xin-Yang Fan, Zhi-Xin Zhang & Long-Wu Ye

  2. Center of Chemistry for Frontier Technologies, Department of Chemistry, Zhejiang University, Hangzhou, China

    Ji-Ren Liu, Shao-Qi Wu & Xin Hong

  3. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Long-Wu Ye

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Contributions

Y.-Q.Z., Y.-B.C., X.-Y.F. and Z.-X.Z. performed the experiments. X.H. designed the DFT calculations. J.-R.L. and S.-Q.W. performed the DFT calculations. L.-W.Y. conceived and directed the project and wrote the paper. All the authors discussed the results and commented on the manuscript.

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Correspondence to Xin Hong or Long-Wu Ye.

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The authors declare no competing interests.

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Peer review information Nature Chemistry thanks Christian Wolf 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 1–19, Figs. 1–8, experimental methods and data, crystallography data, computational studies, NMR, IR, HPLC spectra and references

Supplementary Data 1

Crystallographic data for compound 2c; CCDC reference 2024759.

Supplementary Data 2

Crystallographic data for compound 2aw; CCDC reference 2055962.

Supplementary Data 3

Crystallographic data for compound 6; CCDC reference 2024761.

Supplementary Data 4

Crystallographic data for compound 8; CCDC reference 2024762.

Supplementary Data 5

Crystallographic data for compound 9; CCDC reference 2024763.

Supplementary Data 6

Cartesian Coordinates for Computed Species.

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Zhang, YQ., Chen, YB., Liu, JR. et al. Asymmetric dearomatization catalysed by chiral Brønsted acids via activation of ynamides. Nat. Chem. 13, 1093–1100 (2021). https://doi.org/10.1038/s41557-021-00778-z

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