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Nickel-catalysed asymmetric heteroarylative cyclotelomerization of isoprene

Abstract

Monoterpenoids are a class of isoprenoids produced from geranyl diphosphate by various monoterpene synthases. Nature has evolved over millions of years to produce various cyclic monoterpenoids. Herein, we present a serendipitous creation of an unnatural monoterpene skeleton through heteroarylative telomerization of isoprene with heterocycles. Under nickel catalysis, a series of cyclic monoterpene derivatives bearing quaternary carbon stereocentre are constructed with up to 98% yield and 97% enantiomeric excess. Preliminary mechanistic studies suggest this atom-economic reaction proceeds through an enantioselective dimerization of isoprene and a sequential C–H alkylation of heterocycles pathway. This work not only contributes an efficient enantioselective transformation of bulk chemical isoprene, but also provides a guide to create an unnatural monoterpene framework that may exhibit different biological activities.

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Fig. 1: Catalytic synthesis of monoterpenoids.
Fig. 2: Substrate scope of purines, adenines and imidazoles.
Fig. 3: Substrate scope of other conjugated dienes and transformation of chiral telomers.
Fig. 4: Proposed mechanism and calculated transition states.
Fig. 5: Mechanistic studies.

Data availability

Data relating to the characterization data of materials and products, general methods, optimization studies, experimental procedures, mechanistic studies, mass spectrometry, high-performance liquid chromatography, NMR spectra and computational studies are available in the Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2127531 (3a). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Oldfield, E. & Lin, F. Y. Terpene biosynthesis: modularity rules. Angew. Chem. Int. Ed. 51, 1124–1137 (2012).

    Article  CAS  Google Scholar 

  2. Brill, Z. G., Condakes, M. L., Ting, C. P. & Maimone, T. J. Navigating the chiral pool in the total synthesis of complex terpene natural products. Chem. Rev. 117, 11753–11795 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tu, H.-F., Zhang, X., Zheng, C., Zhu, M. & You, S.-L. Enantioselective dearomative prenylation of indole derivatives. Nat. Catal. 1, 601–608 (2018).

    Article  CAS  Google Scholar 

  4. Sacchettini, J. C. & Poulter, C. D. Creating isoprenoid diversity. Science 277, 1788–1789 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Hyatt, D. C. et al. Structure of limonene synthase, a simple model for terpenoid cyclase catalysis. Proc. Natl Acad. Sci. USA 104, 5360–5365 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gao, Y., Honzatko, R. B. & Peters, R. J. Terpenoid synthase structures: a so far incomplete view of complex catalysis. Nat. Prod. Rep. 29, 1153–1175 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chang, W. C., Song, H., Liu, H. W. & Liu, P. Current development in isoprenoid precursor biosynthesis and regulation. Curr. Opin. Chem. Biol. 17, 571–579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nishimura, T., Ebe, Y. & Hayashi, T. Iridium-catalyzed [3 + 2] annulation of cyclic N-sulfonyl ketimines with 1,3-dienes via C-H activation. J. Am. Chem. Soc. 135, 2092–2095 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Nishimura, T., Nagamoto, M., Ebe, Y. & Hayashi, T. Enantioselective [3 . 2] annulation via C-H activation between cyclic N-acyl ketimines and 1,3-dienes catalyzed by iridium/chiral diene complexes. Chem. Sci 4, 4499–4504 (2013).

    Article  CAS  Google Scholar 

  10. Perry, G. J. P., Jia, T. & Procter, D. J. Copper-catalyzed functionalization of 1,3-dienes: hydrofunctionalization, borofunctionalization, and difunctionalization. ACS Catal. 10, 1485–1499 (2019).

    Article  CAS  Google Scholar 

  11. Smutny, E. J. Oligomerization and dimerization of butadiene under homogeneous catalysis. Reaction with nucleophiles and the synthesis of 1,3,7-octatriene. J. Am. Chem. Soc. 89, 6793–679 (1967).

    Article  CAS  Google Scholar 

  12. Takahashi, S., Shibano, T. & Hagihara, N. The dimerization of butadiene by palladium complex catalysts. Tetrahedron Lett. 8, 2451–2453 (1967).

    Article  Google Scholar 

  13. Faßbach, T. A., Vorholt, A. J. & Leitner, W. The telomerization of 1,3-dienes - a reaction grows up. Chem. Cat. Chem. 11, 1153–1166 (2019).

    Google Scholar 

  14. Keim, W. & Roper, M. Terpene amine synthesis via palladium-catalyzed isoprene telomerization with ammonia. J. Org. Chem. 46, 3702–3707 (1981).

    Article  CAS  Google Scholar 

  15. Hidai, M. et al. Palladium-catalyzed asymmetric telomerization of isoprene - preparation of optically-active citronellol. J. Organomet. Chem. 232, 89–98 (1982).

    Article  CAS  Google Scholar 

  16. Keim, W., Kurtz, K.-R. & Röper, M. Palladium catalyzed telomerization of isoprene with secondary amines and conversion of the resulting terpene amines to terpenols. J. Mol. Catal. 20, 129–138 (1983).

    Article  CAS  Google Scholar 

  17. Maddock, S. M. & Finn, M. G. Palladium-catalyzed head-to-head telomerization of isoprene with amines. Organometallics 19, 2684–2689 (2000).

    Article  CAS  Google Scholar 

  18. Leca, F. & Reau, R. 2-Pyridyl-2-phospholenes: new P,N ligands for the palladium-catalyzed isoprene telomerization. J. Catal. 238, 425–429 (2006).

    Article  CAS  Google Scholar 

  19. Jackstell, R., Grotevendt, A., Michalik, D., El Firdoussi, L. & Beller, M. Telomerization and dimerization of isoprene by in situ generated palladium-carbene catalysts. J. Organomet. Chem. 692, 4737–4744 (2007).

    Article  CAS  Google Scholar 

  20. Gordillo, A., Pachón, L. D., de Jesus, E. & Rothenberg, G. Palladium-catalysed telomerisation of isoprene with glycerol and polyethylene glycol: a facile route to new terpene derivatives. Adv. Synth. Catal. 351, 325–330 (2009).

    Article  CAS  Google Scholar 

  21. Maluenda, I. et al. Room temperature, solventless telomerization of isoprene with alcohols using (N-heterocyclic carbene)-palladium catalysts. Catal. Sci. Technol. 5, 1447–1451 (2015).

    Article  CAS  Google Scholar 

  22. Colavida, J. et al. Regioselectivity control in Pd-catalyzed telomerization of isoprene enabled by solvent and ligand selection. ACS Catal. 10, 11458–11465 (2020).

    Article  CAS  Google Scholar 

  23. Ackermann, L., Vicente, R. & Kapdi, A. R. Transition-metal-catalyzed direct arylation of (hetero)arenes by C-H bond cleavage. Angew. Chem. Int. Ed. 48, 9792–9826 (2009).

    Article  CAS  Google Scholar 

  24. Hartwig, J. F. Regioselectivity of the borylation of alkanes and arenes. Chem. Soc. Rev. 40, 1992–2002 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Gandeepan, P. et al. 3d Transition metals for C-H activation. Chem. Rev. 119, 2192–2452 (2019).

    Article  CAS  PubMed  Google Scholar 

  26. Clement, N. D. & Cavell, K. J. Transition-metal-catalyzed reactions involving imidazolium salt/N-heterocyclic carbene couples as substrates. Angew. Chem. Int. Ed. 43, 3845–3847 (2004).

    Article  CAS  Google Scholar 

  27. Nakao, Y., Kashihara, N., Kanyiva, K. S. & Hiyama, T. Nickel-catalyzed hydroheteroarylation of vinylarenes. Angew. Chem. Int. Ed. 49, 4451–4454 (2010).

    Article  CAS  Google Scholar 

  28. Shih, W. C. et al. The regioselective switch for amino-NHC mediated C-H activation of benzimidazole via Ni-Al synergistic catalysis. Org. Lett. 14, 2046–2049 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Wang, Y. X. et al. Enantioselective Ni-Al bimetallic catalyzed exo-selective C-H cyclization of imidazoles with alkenes. J. Am. Chem. Soc. 140, 5360–5364 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Diesel, J., Grosheva, D., Kodama, S. & Cramer, N. A bulky chiral N-heterocyclic carbene nickel catalyst enables enantioselective C-H functionalizations of indoles and pyrroles. Angew. Chem. Int. Ed. 58, 11044–11048 (2019).

    Article  CAS  Google Scholar 

  31. Loup, J., Muller, V., Ghorai, D. & Ackermann, L. Enantioselective aluminum-free alkene hydroarylations through C-H activation by a chiral nickel/JoSPOphos manifold. Angew. Chem. Int. Ed. 58, 1749–1753 (2019).

    Article  CAS  Google Scholar 

  32. Hu, Y. C., Ji, D. W., Zhao, C. Y., Zheng, H. & Chen, Q. A. Catalytic prenylation and reverse prenylation of indoles with isoprene: regioselectivity manipulation through choice of metal hydride. Angew. Chem. Int. Ed. 58, 5438–5442 (2019).

    Article  CAS  Google Scholar 

  33. Yang, J. et al. Cobalt-catalyzed hydroxymethylarylation of terpenes with formaldehyde and arenes. Chem. Sci. 10, 9560–9564 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kuai, C. S. et al. Ligand-regulated regiodivergent hydrosilylation of isoprene under iron catalysis. Angew. Chem. Int. Ed. 59, 19115–19120 (2020).

    Article  CAS  Google Scholar 

  35. Li, Y. et al. Acid-catalyzed chemoselective C- and O- prenylation of cyclic 1,3-diketones. Chin. J. Catal. 41, 1401–1409 (2020).

    Article  CAS  Google Scholar 

  36. Jiang, W. S. et al. Orthogonal regulation of nucleophilic and electrophilic sites in Pd-catalyzed regiodivergent couplings between indazoles and isoprene. Angew. Chem. Int. Ed. 60, 8321–8328 (2021).

    Article  CAS  Google Scholar 

  37. Zhao, C. Y. et al. Bioinspired and ligand-regulated unnatural prenylation and geranylation of oxindoles with isoprene under Pd catalysis. Angew. Chem. Int. Ed. 61, e202207202 (2022).

    CAS  Google Scholar 

  38. Janssen-Muller, D., Schlepphorst, C. & Glorius, F. Privileged chiral N-heterocyclic carbene ligands for asymmetric transition-metal catalysis. Chem. Soc. Rev. 46, 4845–4854 (2017).

    Article  PubMed  Google Scholar 

  39. Zhang, W. B., Yang, X. T., Ma, J. B., Su, Z. M. & Shi, S. L. Regio- and enantioselective C-H cyclization of pyridines with alkenes enabled by a nickel/N-heterocyclic carbene catalysis. J. Am. Chem. Soc. 141, 5628–5634 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Thongpaen, J., Manguin, R. & Basle, O. Chiral N-heterocyclic carbene ligands enable asymmetric C-H bond functionalization. Angew. Chem. Int. Ed. 59, 10242–10251 (2020).

    Article  CAS  Google Scholar 

  41. Duan, C.-L. et al. Acetic acid-promoted rhodium(III)-catalyzed hydroarylation of terminal alkynes. Synlett 30, 932–938 (2019).

    Article  CAS  Google Scholar 

  42. Saidi, O. et al. Ruthenium-catalyzed meta sulfonation of 2-phenylpyridines. J. Am. Chem. Soc. 133, 19298–19301 (2011).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Y.-G. Zhou (Dalian Institute of Chemical Physics) and Z.-S. Ye (Dalian University of Technology) for helpful discussions and manuscript revisions. Financial support from Dalian Institute of Chemical Physics (grant no. DICPI201902), Dalian Outstanding Young Scientific Talent (grant no. 2020RJ05) and the National Natural Science Foundation of China (grant no. 22071239) is acknowledged.

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Authors and Affiliations

Authors

Contributions

Q.-A.C. conceived and supervised the project. Q.-A.C. and G.Z. designed the experiments. G.Z., C.-Y.Z., X.-T.M., Y.L., X.-X.Z., H.L., D.-W.J. and Y.-C.H. performed the experiments and analysed the data. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Qing-An Chen.

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The authors declare no competing interests.

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Nature Catalysis thanks Mengchun Ye, Wei Guan 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 Figs. 1–7, Tables 1–10, Methods, Discussions, References and Copies of NMR and HPLC for products.

Supplementary Data 1

Compound 3a.

Supplementary Data 2

Structure factor of 3a.

Supplementary Data 3

Computational data.

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Zhang, G., Zhao, CY., Min, XT. et al. Nickel-catalysed asymmetric heteroarylative cyclotelomerization of isoprene. Nat Catal 5, 708–715 (2022). https://doi.org/10.1038/s41929-022-00825-z

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