Diastereodivergent synthesis of enantioenriched α,β-disubstituted γ-butyrolactones via cooperative N-heterocyclic carbene and Ir catalysis

Nature Catalysis volume 3, pages48–54(2020)Cite this article

Subjects

Abstract

The stereodivergent synthesis of natural product frameworks via a single transformation using simple starting materials is a significant challenge. The prevalence of γ-butyrolactones in biologically active natural products has long motivated the development of enantioselective strategies towards their synthesis. Herein, we report an enantio- and diastereodivergent [3 + 2] annulation reaction for the synthesis of α,β-disubstituted γ-butyrolactones through cooperative N-heterocyclic carbene organocatalysis and iridium catalysis. This method overcomes the challenges of merging N-heterocyclic carbene organocatalysis with iridium catalysis by the appropriate choice of ligands. The use of two chiral catalysts allowed control over the relative and absolute configuration of the two formed stereocentres, thereby providing selective access to all four possible stereoisomers of the γ-lactone products. The transformation could be extended to the synthesis of δ-lactams via [4 + 2] annulation. The synthetic utility of this methodology was illustrated in the concise synthesis of the naturally occurring lignan (−)-hinokinin.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

Fig. 1: Examples of γ-butyrolactones and their synthesis by NHC organocatalysis.
Fig. 2: Scope of the cis-selective [3 + 2] annulation reaction.
Fig. 3: Diastereodivergent synthesis of all four isomers of γ-butyrolactone 3a.
Fig. 4: Diastereodivergent [3 + 2] annulation reaction and isomerization of cis-lactones.
Fig. 5: Scope of the [4 + 2] annulation for the formation of cis-δ-lactams.
Fig. 6: Application of the [3 + 2] annulation to the synthesis of (−)-hinokinin.
Fig. 7: Mechanistic insights into the [3 + 2] annulation.

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers 1907670 ((R,S)-3c′) and 1907671 ((R,S)-6ab). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data supporting the findings of this study are available within the article and its Supplementary Information, or from the corresponding author upon reasonable request.

References

  1. 1.

    Enders, D., Niemeier, O. & Henseler, A. Organocatalysis by N-heterocyclic carbenes. Chem. Rev. 107, 5606–5655 (2007).

    CAS  PubMed  Google Scholar 

  2. 2.

    Marion, N., Díez-González, S. & Nolan, S. P. N-Heterocyclic carbenes as organocatalysts. Angew. Chem. Int. Ed. 46, 2988–3000 (2007).

    CAS  Google Scholar 

  3. 3.

    Izquierdo, J., Hutson, G. E., Cohen, D. T. & Scheidt, K. A. A continuum of progress: applications of N-hetereocyclic carbene catalysis in total synthesis. Angew. Chem. Int. Ed. 51, 11686–11698 (2012).

    CAS  Google Scholar 

  4. 4.

    Flanigan, D. M., Romanov-Michailidis, F., White, N. A. & Rovis, T. Organocatalytic reactions enabled by N-heterocyclic carbenes. Chem. Rev. 115, 9307–9387 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Hopkinson, M. N., Richter, C., Schedler, M. & Glorius, F. An overview of N-heterocyclic carbenes. Nature 510, 485–496 (2014).

    CAS  PubMed  Google Scholar 

  6. 6.

    Zhang, C., Hooper, J. F. & Lupton, D. W. N-heterocyclic carbene catalysis via the α,β-unsaturated acyl azolium. ACS Catal. 7, 2583–2596 (2017).

    CAS  Google Scholar 

  7. 7.

    Cardinal-David, B., Raup, D. E. A. & Scheidt, K. A. Cooperative N-heterocyclic carbene/Lewis acid catalysis for highly stereoselective annulation reactions with homoenolates. J. Am. Chem. Soc. 132, 5345–5347 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Raup, D. E. A., Cardinal-David, B., Holte, D. & Scheidt, K. A. Cooperative catalysis by carbenes and Lewis acids in a highly stereoselective route to γ-lactams. Nat. Chem. 2, 766–771 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Mo, J., Chen, X. & Chi, Y. R. Oxidative γ-addition of enals to trifluoromethyl ketones: enantioselectivity control via Lewis acid/N-heterocyclic carbene cooperative catalysis. J. Am. Chem. Soc. 134, 8810–8813 (2012).

    CAS  PubMed  Google Scholar 

  10. 10.

    Zhao, X., DiRocco, D. A. & Rovis, T. N-heterocyclic carbene and Brønsted acid cooperative catalysis: asymmetric synthesis of trans-γ-lactams. J. Am. Chem. Soc. 133, 12466–12469 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Xu, J. et al. Aminomethylation of enals through carbene and acid cooperative catalysis: concise access to β2-amino acids. Angew. Chem. Int. Ed. 54, 5161–5165 (2015).

    CAS  Google Scholar 

  12. 12.

    Jin, Z., Xu, J., Yang, S., Song, B.-A. & Chi, Y. R. Enantioselective sulfonation of enones with sulfonyl imines by cooperative N-heterocyclic-carbene/thiourea/tertiary-amine multicatalysis. Angew. Chem. Int. Ed. 52, 12354–12358 (2013).

    CAS  Google Scholar 

  13. 13.

    Wang, M. H., Cohen, D. T., Schwamb, C. B., Mishra, R. K. & Scheidt, K. A. Enantioselective β-protonation by a cooperative catalysis strategy. J. Am. Chem. Soc. 137, 5891–5894 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Zhuo, S. et al. Access to all-carbon spirocycles through a carbene and thiourea cocatalytic desymmetrisation cascade reaction. Angew. Chem. Int. Ed. 58, 1784–1788 (2019).

    CAS  Google Scholar 

  15. 15.

    Wu, X. et al. Sulfinate and carbene co-catalyzed Rauhut–Currier reaction for enantioselective access to azepino[1,2-a]indoles. Angew. Chem. Int. Ed. 58, 477–481 (2019).

    CAS  Google Scholar 

  16. 16.

    DiRocco, D. A. & Rovis, T. Catalytic asymmetric α-acylation of tertiary amines mediated by a dual catalysis mode: N-heterocyclic carbene and photoredox catalysis. J. Am. Chem. Soc. 134, 8094–8097 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Namitharan, K. et al. Metal and carbene organocatalytic relay activation of alkynes for stereoselective reactions. Nat. Commun. 5, 3982 (2014).

    CAS  PubMed  Google Scholar 

  18. 18.

    Chen, J., Yuan, P., Wang, L. & Huang, Y. Enantioselective β-protonation of enals via a shuttling strategy. J. Am. Chem. Soc. 139, 7045–7051 (2017).

    CAS  PubMed  Google Scholar 

  19. 19.

    Allen, A. E. & MacMillan, D. W. C. Synergistic catalysis: a powerful synthetic strategy for new reaction development. Chem. Sci. 3, 633–658 (2012).

    CAS  Google Scholar 

  20. 20.

    Wang, M. H. & Scheidt, K. A. Cooperative catalysis and activation with N-heterocyclic carbenes. Angew. Chem. Int. Ed. 55, 14912–14922 (2016).

    CAS  Google Scholar 

  21. 21.

    Liu, K., Hovey, M. T. & Scheidt, K. A. A cooperative N-heterocyclic carbene/palladium catalysis system. Chem. Sci. 5, 4026–4031 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Guo, C., Fleige, M., Janssen-Müller, D., Daniliuc, C. G. & Glorius, F. Cooperative N-heterocyclic carbene/palladium-catalyzed enantioselective umpolung annulations. J. Am. Chem. Soc. 138, 7840–7843 (2016).

    CAS  PubMed  Google Scholar 

  23. 23.

    Guo, C. et al. Mechanistic studies on a cooperative NHC organocatalysis/palladium catalysis system: uncovering significant lessons for mixed chiral Pd(NHC)(PR3) catalyst design. J. Am. Chem. Soc. 139, 4443–4451 (2017).

    CAS  PubMed  Google Scholar 

  24. 24.

    Singha, S., Patra, T., Daniliuc, C. G. & Glorius, F. Highly enantioselective [5 + 2] annulations through cooperative N-heterocyclic carbene (NHC) organocatalysis and palladium catalysis. J. Am. Chem. Soc. 140, 3551–3554 (2018).

    CAS  PubMed  Google Scholar 

  25. 25.

    Yasuda, S., Ishii, T., Takemoto, S., Haruki, H. & Ohmiya, H. Synergistic N-heterocyclic carbene/palladium-catalyzed reactions of aldehyde acyl anions with either diarylmethyl or allylic carbonates. Angew. Chem. Int. Ed. 57, 2938–2942 (2018).

    CAS  Google Scholar 

  26. 26.

    Hoffmann, H. M. R. & Rabe, J. Synthesis and biological activity of α-methylene-γ-butyrolactones. Angew. Chem. Int. Ed. 24, 94–110 (1985).

    Google Scholar 

  27. 27.

    Koch, S. S. C. & Chamberlin, A. R. in Studies in Natural Products Chemistry Vol. 16 (ed Rahman, A.-U.) 687-725 (Elsevier Science, 1995).

  28. 28.

    Seitz, M. & Reiser, O. Synthetic approaches towards structurally diverse γ-butyrolactone natural-product-like compounds. Curr. Opin. Chem. Biol. 9, 285–292 (2005).

    CAS  PubMed  Google Scholar 

  29. 29.

    Mao, B., Fañanás-Mastral, M. & Feringa, B. L. Catalytic asymmetric synthesis of butenolides and butyrolactones. Chem. Rev. 117, 10502–10566 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Sohn, S. S., Rosen, E. L. & Bode, J. W. N-heterocyclic carbene-catalyzed generation of homoenolates: γ-butyrolactones by direct annulations of enals and aldehydes. J. Am. Chem. Soc. 126, 14370–14371 (2004).

    CAS  PubMed  Google Scholar 

  31. 31.

    Burstein, C. & Glorius, F. Organocatalyzed conjugate umpolung of α,β-unsaturated aldehydes for the synthesis of γ-butyrolactones. Angew. Chem. Int. Ed. 43, 6205–6208 (2004).

    CAS  Google Scholar 

  32. 32.

    Murauski, K. J. R., Jaworski, A. A. & Scheidt, K. A. A continuing challenge: N-heterocyclic carbene-catalyzed syntheses of γ-butyrolactones. Chem. Soc. Rev. 47, 1773–1782 (2018).

    CAS  PubMed  Google Scholar 

  33. 33.

    Burstein, C., Tschan, S., Xie, X. & Glorius, F. N-Heterocyclic carbene-catalyzed conjugate umpolung for the synthesis of γ-butyrolactones. Synthesis 2006, 2418–2439 (2006).

    Google Scholar 

  34. 34.

    Douglas, J., Churchill, G. & Smith, A. D. NHCs in asymmetric organocatalysis: recent advances in azolium enolate generation and reactivity. Synthesis 44, 2295–2309 (2012).

    CAS  Google Scholar 

  35. 35.

    Cheng, Q. et al. Iridium-catalyzed asymmetric allylic substitution reactions. Chem. Rev. 119, 1855–1969 (2019).

    CAS  PubMed  Google Scholar 

  36. 36.

    Krautwald, S., Sarlah, D., Schafroth, M. A. & Carreira, E. M. Enantio- and diastereodivergent dual catalysis: α-allylation of branched aldehydes. Science 340, 1065–1068 (2013).

    CAS  PubMed  Google Scholar 

  37. 37.

    Krautwald, S. & Carreira, E. M. Stereodivergence in asymmetric catalysis. J. Am. Chem. Soc. 139, 5627–5639 (2017).

    CAS  PubMed  Google Scholar 

  38. 38.

    Beletskaya, I. P., Nájera, C. & Yus, M. Stereodivergent catalysis. Chem. Rev. 118, 5080–5200 (2018).

    CAS  PubMed  Google Scholar 

  39. 39.

    Waldeck, B. Biological significance of the enantiomeric purity of drugs. Chirality 5, 350–355 (1993).

    CAS  PubMed  Google Scholar 

  40. 40.

    Teichert, J. F. & Feringa, B. L. Phosphoramidites: privileged ligands in asymmetric catalysis. Angew. Chem. Int. Ed. 49, 2486–2528 (2010).

    CAS  Google Scholar 

  41. 41.

    Defieber, C., Ariger, M. A., Moriel, P. & Carreira, E. M. Iridium-catalyzed synthesis of primary allylic amines from allylic alcohols: sulfamic acid as ammonia equivalent. Angew. Chem. Int. Ed. 46, 3139–3143 (2007).

    CAS  Google Scholar 

  42. 42.

    He, M., Uc, G. J. & Bode, J. W. Chiral N-heterocyclic carbene catalyzed, enantioselective oxodiene Diels−Alder reactions with low catalyst loadings. J. Am. Chem. Soc. 128, 15088–15089 (2006).

    CAS  PubMed  Google Scholar 

  43. 43.

    Marcotullio, C. M., Pelosi, A. & Curini, M. Hinokinin, an emerging bioactive lignan. Molecules 19, 14862–14878 (2014).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Timple, J. M. V. et al. The lignan (−)-hinokinin displays modulatory effects on human monoamine and GABA transporter activities. J. Nat. Prod. 76, 1889–1895 (2013).

    CAS  PubMed  Google Scholar 

  45. 45.

    Gil, A., Albericio, F. & Álvarez, M. Role of the Nozaki–Hiyama–Takai–Kishi reaction in the synthesis of natural products. Chem. Rev. 117, 8420–8446 (2017).

    CAS  PubMed  Google Scholar 

  46. 46.

    Ye, K.-Y., Cheng, Q., Zhuo, C.-X., Dai, L.-X. & You, S.-L. An iridium(I) N-heterocyclic carbene complex catalyzes asymmetric intramolecular allylic amination reactions. Angew. Chem. Int. Ed. 55, 8113–8116 (2016).

    CAS  Google Scholar 

  47. 47.

    Yang, Z.-P., Jiang, R., Zheng, C. & You, S.-L. Iridium-catalyzed intramolecular asymmetric allylic alkylation of hydroxyquinolines: simultaneous weakening of the aromaticity of two consecutive aromatic rings. J. Am. Chem. Soc. 140, 3114–3119 (2018).

    CAS  PubMed  Google Scholar 

  48. 48.

    Bao, C.-C., Zheng, D.-S., Zhang, X. & You, S.-L. Iridium/N-heterocyclic carbene complex-catalyzed intermolecular allylic alkylation reaction. Organometallics 37, 4763–4772 (2018).

    CAS  Google Scholar 

  49. 49.

    Kaeobamrung, J., Kozlowski, M. C. & Bode, J. W. Chiral N-heterocyclic carbene-catalyzed generation of ester enolate equivalents from α,β-unsaturated aldehydes for enantioselective Diels–Alder reactions. Proc. Natl. Acad. Sci. USA 107, 20661–20665 (2010).

    CAS  PubMed  Google Scholar 

  50. 50.

    Bhaskararao, B. & Sunoj, R. B. Origin of stereodivergence in cooperative asymmetric catalysis with simultaneous involvement of two chiral catalysts. J. Am. Chem. Soc. 137, 15712–15722 (2015).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Support for this work was generously provided by the Deutsche Forschungsgemeinschaft (Leibniz Award) and the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 843349-H2020-MSCA-IF-2018 (E.S.). We also thank M. J. James, M. van Gemmeren, T. Patra and Z. Nairoukh (University of Münster) for helpful discussions and corrections during the preparation of the manuscript. M. Wollenburg, M. Wiesenfeldt, T. Wagener, K. Kronenberg and N. Radhoff (University of Münster) are acknowledged for experimental support.

Author information

Author notes

  1. These authors contributed equally: Santanu Singha, Eloisa Serrano.

Affiliations

  1. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany

    Santanu Singha, Eloisa Serrano, Shobhan Mondal, Constantin G. Daniliuc & Frank Glorius

Authors
  1. Santanu Singha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eloisa Serrano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shobhan Mondal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Constantin G. Daniliuc
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frank Glorius
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.S., E.S., S.M. and F.G. designed, performed and analysed the experiments. C.G.D. performed the crystallographic studies. S.S., E.S. and F.G. co-wrote the manuscript. All authors contributed to discussions.

Corresponding author

Correspondence to Frank Glorius.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary information

Supplementary methods, Tables 1–7, Figures 1–8, references

Compound (R,S)-3c

′ Crystallographic data for compound (R,S)-3c′

Compound (R,S)-6ab

Crystallographic data for compound (R,S)-6ab

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Singha, S., Serrano, E., Mondal, S. et al. Diastereodivergent synthesis of enantioenriched α,β-disubstituted γ-butyrolactones via cooperative N-heterocyclic carbene and Ir catalysis. Nat Catal 3, 48–54 (2020). https://doi.org/10.1038/s41929-019-0387-3

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing