Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Synthesis of tri- and tetrasubstituted stereocentres by nickel-catalysed enantioselective olefin cross-couplings

Abstract

Asymmetric transition-metal catalysis has had a far-reaching impact on chemical synthesis. However, non-precious metal-catalysed strategies that provide direct entry to compounds with enantioenriched trisubstituted and fully substituted stereogenic centres are scarce. Here we show that a sterically encumbered chiral N-heterocyclic carbene-Ni(0) catalyst, in conjunction with an organotriflate and a metal alkoxide as hydride donor, promotes 1,2-hydroarylation and hydroalkenylation of diverse alkenes and 1,3-dienes. Replacing the metal alkoxide with an organometallic reagent allows installation of two different carbogenic motifs. These multicomponent reactions proceed through regio- and enantioselective carbonickelation followed by carbon–nickel bond transformation, providing a streamlined pathway towards enantioenriched carbon- or heteroatom-substituted tertiary or quaternary stereogenic centres. Through selective carbofunctionalizations, enantiodivergent access to opposite enantiomers may be achieved using the same catalyst antipode. The method enables practical access to complex bioactive molecules and other medicinally valuable but synthetically challenging building blocks, such as those that contain deuterated methyl groups.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The importance of developing enantioselective olefin cross-coupling reactions using non-precious metal catalysis.
Fig. 2: Reaction design and mechanistic studies.
Fig. 3: Exploration of olefin scope.
Fig. 4: Exploration of electrophile and nucleophile scope.

Similar content being viewed by others

Data availability

All data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2128517 (8), 2149572 (95) and 2173668 (Ni-1). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Lin, G.-Q., You, Q.-D. & Cheng, J.-F. Chiral Drugs: Chemistry and Biological Action (Wiley, 2011).

  2. Mori, K. Bioactive natural products and chirality. Chirality 23, 449–462 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Crossley, R. The relevance of chirality to the study of biological activity. Tetrahedron 48, 8155–8178 (1992).

    Article  CAS  Google Scholar 

  5. Noyori, R. Asymmetric catalysis: science and opportunities (Nobel Lecture). Angew. Chem. Int. Ed. 41, 2008–2022 (2002).

    Article  CAS  Google Scholar 

  6. Trost, B. M. Asymmetric catalysis: an enabling science. Proc. Natl Acad. Sci. USA 101, 5348–5355 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu, Y., Han, S.-J., Liu, W.-B. & Stoltz, B. M. Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules. Acc. Chem. Res. 48, 740–751 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tombo, G. M. R. & Belluš, D. Chirality and crop protection. Angew. Chem. Int. Ed. 30, 1193–1215 (1991).

    Article  Google Scholar 

  9. McDonald, R. I., Liu, G. & Stahl, S. S. Palladium(II)-catalysed alkene functionalization via nucleopalladation: stereochemical pathways and enantioselective catalytic applications. Chem. Rev. 111, 2981–3019 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Crisenza, G. E. M. & Bower, J. F. Branch selective Murai-type alkene hydroarylation reactions. Chem. Lett. 45, 2–9 (2016).

    Article  CAS  Google Scholar 

  11. Chen, J. & Lu, Z. Asymmetric hydrofunctionalization of minimally functionalized alkenes via earth abundant transition metal catalysis. Org. Chem. Front. 5, 260–272 (2018).

    Article  CAS  Google Scholar 

  12. Oxtoby, L. J., Gurak, J. A., Wisniewski, S. R., Eastgate, M. D. & Engle, K. M. Palladium-catalysed reductive Heck coupling of alkenes. Trends Chem. 1, 572–587 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zweig, J. E., Kim, D. E. & Newhouse, R. T. Methods utilizing first-row transition metals in natural product total synthesis. Chem. Rev. 117, 11680–11752 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Zhang, M., Ji, Y. & Zhang, C. Transition metal catalysed enantioselective migratory functionalization reactions of alkenes through chain-walking. Chin. J. Chem. 40, 1608–1622 (2022).

    Article  CAS  Google Scholar 

  15. Huang, X. et al. Enantioselective intermolecular Heck and reductive Heck reactions of aryl triflates, mesylates and tosylates catalysed by nickel. Angew. Chem. Int. Ed. 60, 2828–2832 (2021).

    Article  CAS  Google Scholar 

  16. Chen, Y., Dang, L. & Ho, C.-Y. NHC–Ni catalysed enantioselective synthesis of 1,4-dienes by cross-hydroalkenylation of cyclic 1,3-dienes and heterosubstituted terminal olefins. Nat. Commun. 11, 2269 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ho, C.-Y., Chan, C.-W. & He, L. Catalytic asymmetric hydroalkenylation of vinylarenes: electronic effects of substrates and chiral N-heterocyclic carbene ligands. Angew. Chem. Int. Ed. 54, 4512–4516 (2015).

    Article  CAS  Google Scholar 

  18. Podhajsky, S. M., Iwai, Y., Cook-Sneathen, A. & Sigman, M. S. Asymmetric palladium-catalysed hydroarylation of styrenes and dienes. Tetrahedron 67, 4435–4441 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen, Y.-G. et al. Nickel-catalysed enantioselective hydroarylation and hydroalkenylation of styrenes. J. Am. Chem. Soc. 141, 3395–3399 (2019).

    Article  CAS  PubMed  Google Scholar 

  20. Lv, X.-Y., Fan, C., Xiao, L.-J., Xie, J.-H. & Zhou, Q.-L. Ligand-enabled Ni-catalysed enantioselective hydroarylation of styrenes and 1,3-dienes with arylboronic acids. CCS Chem. 1, 328–334 (2019).

    Article  CAS  Google Scholar 

  21. Tran, H. N., Burgett, R. W. & Stanley, L. M. Nickel-catalysed asymmetric hydroarylation of vinylarenes: direct enantioselective synthesis of chiral 1,1-diarylethanes. J. Org. Chem. 86, 3836–3849 (2021).

    Article  CAS  PubMed  Google Scholar 

  22. Marcum, J. S., Taylor, T. R. & Meek, S. J. Enantioselective synthesis of functionalized arenes by nickel-catalysed site-selective hydroarylation of 1,3-dienes with aryl boronates. Angew. Chem. Int. Ed. 59, 14070–14075 (2020).

    Article  CAS  Google Scholar 

  23. Friis, S. D., Pirnot, M. T. & Buchwald, S. L. Asymmetric hydroarylation of vinylarenes using a synergistic combination of CuH and Pd catalysis. J. Am. Chem. Soc. 138, 8372–8375 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schuppe, A. W., Knippel, J. L., Borrajo-Calleja, G. M. & Buchwald, S. L. Enantioselective hydroalkenylation of olefins with enol sulfonates enabled by dual copper hydride and palladium catalysis. J. Am. Chem. Soc. 143, 5330–5335 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. He, Y., Liu, C., Yu, L. & Zhu, S. Enantio- and regioselective NiH-catalysed reductive hydroarylation of vinylarenes with aryl iodides. Angew. Chem. Int. Ed. 59, 21530–21534 (2020).

    Article  CAS  Google Scholar 

  26. He, Y., Song, H., Chen, J. & Zhu, S. NiH-catalysed asymmetric hydroarylation of N-acyl enamines to chiral benzylamines. Nat. Commun. 12, 638 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cuesta-Galisteo, S., Schörgenhumer, J., Wei, X., Merino, J. & Nevado, C. Nickel-catalysed asymmetric synthesis of α-arylbenzamides. Angew. Chem. Int. Ed. 60, 1605–1609 (2021).

    Article  CAS  Google Scholar 

  28. Anthony, D., Lin, Q., Baudet, J. & Diao, T. Nickel-catalysed asymmetric reductive diarylation of vinylarenes. Angew. Chem. Int. Ed. 58, 3198–3202 (2019).

    Article  CAS  Google Scholar 

  29. Wei, X., Shu, W., García-Domínguez, A., Merino, E. & Nevado, C. Asymmetric Ni-catalysed radical relayed reductive coupling. J. Am. Chem. Soc. 142, 13515–13522 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Guo, L. et al. General method for enantioselective three-component carboarylation of alkenes enabled by visible-light dual photoredox/nickel catalysis. J. Am. Chem. Soc. 142, 20390–20399 (2020).

    Article  CAS  Google Scholar 

  31. Quasdorf, K. W. & Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516, 181–191 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sardini, S. R. et al. Ni-catalysed arylboration of unactivated alkenes: scope and mechanistic studies. J. Am. Chem. Soc. 141, 9391–9400 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Thomas, S. P. & Aggarwal, V. K. Asymmetric hydroboration of 1,1-disubstituted alkenes. Angew. Chem. Int. Ed. 48, 1896–1898 (2009).

    Article  CAS  Google Scholar 

  34. Mei, T.-S., Patel, H. H. & Sigman, M. S. Enantioselective construction of remote quaternary stereocentres. Nature 508, 340–344 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang, C., Santiago, C. B., Crawford, J. M. & Sigman, M. S. Enantioselective dehydrogenative heck arylations of trisubstituted alkenes with indoles to construct quaternary stereocenters. J. Am. Chem. Soc. 137, 15668–15671 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Patel, H. H. & Sigman, M. S. Enantioselective palladium-catalysed alkenylation of trisubstituted alkenols to form allylic quaternary centers. J. Am. Chem. Soc. 138, 14226–14229 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang, Z., Yin, H. & Fu, G. C. Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins. Nature 563, 379–383 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xiao, L.-J. et al. Nickel(0)-catalysed hydroarylation of styrenes and 1,3-dienes with organoboron compounds. Angew. Chem. Int. Ed. 57, 461–464 (2018).

    Article  CAS  Google Scholar 

  39. Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Franz, A. K. & Wilson, S. O. Organosilicon molecules with medicinal applications. J. Med. Chem. 56, 388–405 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Yoshikai, N., Matsuda, H. & Nakamura, E. Hydroxyphosphine ligand for nickel-catalysed cross-coupling through nickel/magnesium bimetallic cooperation. J. Am. Chem. Soc. 131, 9590–9599 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Tasker, S. Z., Gutierrez, A. C. & Jamison, T. F. Nickel-catalysed Mizoroki–Heck reaction of aryl sulfonates and chlorides with electronically unbiased terminal olefins: high selectivity for branched products. Angew. Chem. Int. Ed. 53, 1858–1861 (2014).

    Article  CAS  Google Scholar 

  43. Albright, A. et al. Design and synthesis of C2-symmetric N-heterocyclic carbene precursors and metal carbenoids. J. Org. Chem. 76, 7341–7351 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu, C.-F., Luo, X., Wang, H. & Koh, M. J. Catalytic regioselective olefin hydroarylation(alkenylation) by sequential carbonickelation-hydride transfer. J. Am. Chem. Soc. 143, 9498–9506 (2021).

    Article  CAS  PubMed  Google Scholar 

  45. Wang, H., Liu, C.-F., Martin, R. T., Gutierrez, O. & Koh, M. J. Directing-group-free catalytic dicarbofunctionalization of unactivated alkenes. Nat. Chem. 14, 188–195 (2022).

    Article  CAS  PubMed  Google Scholar 

  46. Würtz, S. & Glorius, F. Surveying sterically demanding N-heterocyclic carbene ligands with restricted flexibility for palladium-catalysed cross-coupling reactions. Acc. Chem. Res. 41, 1523–1533 (2008).

    Article  PubMed  Google Scholar 

  47. Harbeson, S. L. & Tung, R. D. Chapter 24 – Deuterium in drug discovery and development. Annu. Rep. Med. Chem. 46, 403–417 (2011).

    CAS  Google Scholar 

  48. Sun, Q. & Soulé, J.-F. Broadening of horizons in the synthesis of CD3-labeled molecules. Chem. Soc. Rev. 50, 10806–10835 (2021).

    Article  CAS  PubMed  Google Scholar 

  49. Atzrodt, J., Derdau, V., Fey, T. & Zimmermann, J. The renaissance of H/D exchange. Angew. Chem. Int. Ed. 46, 7744–7765 (2007).

    Article  CAS  Google Scholar 

  50. Wang, Z.-C., Xie, P.-P., Xu, Y., Hong, X. & Shi, S.-L. Low-temperature nickel-catalysed C−N cross-coupling via kinetic resolution enabled by a bulky and flexible chiral N-heterocyclic carbene ligand. Angew. Chem. Int. Ed. 60, 16077–16084 (2021).

  51. Green, S. A., Matos, J. L. M., Yagi, A. & Shenvi, R. A. Branch-selective hydroarylation: iodoarene–olefin cross-coupling. J. Am. Chem. Soc. 138, 12779–12782 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Cheltsov, A. V. et al. Vaccinia virus virulence factor N1L is a novel promising target for antiviral therapeutic intervention. J. Med. Chem. 53, 3899–3906 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cai, Y. et al. Copper-catalysed enantioselective Markovnikov protoboration of α-olefins enabled by a buttressed N-heterocyclic carbene ligand. Angew. Chem. Int. Ed. 57, 1376–1380 (2018).

    Article  CAS  Google Scholar 

  54. Xiang, J. N. et al. Method for preparing diphenyl propane lignan compound. Chinese patent CN102060640A (2011).

  55. Weix, D. J. Methods and mechanisms for cross-electrophile coupling of Csp2 halides with alkyl electrophiles. Acc. Chem. Res. 48, 1767–1775 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Petruncio, G., Shellnutt, Z., Elahi-Mohassel, S., Alishetty, S. & Paige, M. Skipped dienes in natural product synthesis. Nat. Prod. Rep. 38, 2187–2213 (2021).

    Article  CAS  PubMed  Google Scholar 

  57. Hayashi, T., Konishi, M., Ito, H. & Kumada, M. Optically active allylsilanes. 1. Preparation by palladium-catalysed asymmetric Grignard cross-coupling and anti stereochemistry in electrophilic substitution reactions. J. Am. Chem. Soc. 104, 4962–4963 (1982).

    Article  CAS  Google Scholar 

  58. Hayashi, T., Konishi, M., Ito, H. & Kumada, M. Optically active allylsilanes. 2. High stereoselectivity in asymmetric reaction with aldehydes producing homoallylic alcohols. J. Am. Chem. Soc. 104, 4963–4965 (1982).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Ministry of Education of Singapore Academic Research Fund Tier 1 (A-0004139-00-00, M.J.K.) and by the National Key R&D Program of China (2021YFF0701600), the National Natural Science Foundation of China (91856111, 21871288, 21821002 and 22171280), the Science and Technology Commission of Shanghai Municipality (22XD1424900) and the CAS Youth Interdisciplinary Team (JCTD-2021-11, S.-L.S.). We thank G.K. Tan for X-ray crystallographic analysis.

Author information

Authors and Affiliations

Authors

Contributions

C.-F.L., Z.-C.W., X.L., J.L. and C.H.M.K. developed the catalytic method and conducted the mechanistic studies. M.J.K. and S.-L.S. directed the investigations. M.J.K. conceived the project and wrote the manuscript, with revisions provided by the other authors.

Corresponding authors

Correspondence to Shi-Liang Shi or Ming Joo Koh.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Catalysis thanks Chun Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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 Tables 1–8, Figs. 1–5, methods, note 1 and references.

Supplementary Data 1

Crystallographic data for compound 8.

Supplementary Data 2

Crystallographic data for compound 95.

Supplementary Data 3

Crystallographic data for compound Ni-1.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, CF., Wang, ZC., Luo, X. et al. Synthesis of tri- and tetrasubstituted stereocentres by nickel-catalysed enantioselective olefin cross-couplings. Nat Catal 5, 934–942 (2022). https://doi.org/10.1038/s41929-022-00854-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41929-022-00854-8

This article is cited by

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