+
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:

Multisite modifications of arenes using ketones as removable handles enabled by Pd and norbornene cooperative catalysis

Nature Synthesis volume 4, pages 209–218 (2025)Cite this article

Subjects

Abstract

Natural products serve as crucial sources for new drugs and play an indispensable role in drug discovery. Late-stage functionalization of natural products is an efficient method for diversifying their structures, fine-tuning their biological properties and rapidly constructing molecular libraries. Polysubstituted arenes serve as structural cores in pharmaceuticals derived from natural products. However, programmable multisite arene modification remains a largely unmet challenge. Here, using commercially available and easy-to-synthesize aryl ketones as substrates, we present the programmable multifunctionalization of natural products via a palladium- and norbornene-catalysed Catellani-type reaction. Given the ease of installing an acyl group and using it as a relay, this protocol enables the incorporation of a variety of bioactive molecules into natural products via successive acylation and deacylation processes. Furthermore, this strategy was applied to the construction of a molecular library based on dehydroabietic acid. Multiple molecules with substantially increased activity were obtained through antimicrobial activity screening.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Multisite modifications of natural products.
Fig. 2: Exploration of reaction conditions.
Fig. 3: Substrate scope investigation of ketone difunctionalization.
Fig. 4: Synthetic applications.
Fig. 5: Construction of polysubstituted aromatics and multisite modifications of natural products.

Similar content being viewed by others

Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information files. The crystallographic data for compound 5u have been deposited at the Cambridge Crystallographic Data Centra (CCDC 2371740). These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

References

  1. Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod. 83, 770–803 (2020).

    CAS  PubMed  Google Scholar 

  2. Hong, B., Luo, T. & Lei, X. Late-stage diversification of natural products. ACS Cent. Sci. 6, 622–635 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krskab, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).

    CAS  PubMed  Google Scholar 

  4. Terrier, F. Modern Nucleophilic Aromatic Substitution (Wiley-VCH, 2013).

  5. Ruiz-Castillo, P. & Buchwald, S. L. Applications of palladium-catalyzed C–N cross-coupling reactions. Chem. Rev. 116, 12564–12649 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Guillemard, L., Kaplaneris, N., Ackermann, L. & Johansson, M. J. Late-stage C–H functionalization offers new opportunities in drug discovery. Nat. Rev. Chem. 5, 522–545 (2021).

    CAS  PubMed  Google Scholar 

  7. Lam, N. Y. S., Wu, K. & Yu, J.-Q. Advancing the logic of chemical synthesis: C–H activation as strategic and tactical disconnections for C–C bond construction. Angew. Chem. Int. Ed. 60, 15767–15790 (2021).

    CAS  Google Scholar 

  8. Yamaguchi, J., Yamaguchi, A. D. & Itami, K. C–H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals. Angew. Chem. Int. Ed. 51, 8960–9009 (2012).

    CAS  Google Scholar 

  9. Liang, Y.-F. et al. Carbon–carbon bond cleavage for late-stage functionalization. Chem. Rev. 123, 12313–12370 (2023).

    CAS  PubMed  Google Scholar 

  10. Zhang, Z., Tanaka, K. & Yu, J. Q. Remote site-selective C–H activation directed by a catalytic bifunctional template. Nature 543, 538–542 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Fan, Z. et al. Molecular editing of aza-arene C–H bonds by distance, geometry and chirality. Nature 610, 87–93 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Shi, H. et al. Differentiation and functionalization of remote C–H bonds in adjacent positions. Nat. Chem. 12, 399–404 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Xia, Y., Lu, G., Liu, P. & Dong, G. Catalytic activation of carbon–carbon bonds in cyclopentanones. Nature 539, 546–550 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kingsbury, W. D. et al. Synthesis of water-soluble (aminoalkyl) camptothecin analogs: inhibition of topoisomerase I and antitumor activity. J. Med. Chem. 34, 98–107 (1991).

    CAS  PubMed  Google Scholar 

  15. Catellani, M. Novel methods of aromatic functionalization using palladium and norbornene as a unique catalytic system. Top. Organomet. Chem. 14, 21–53 (2005).

    CAS  Google Scholar 

  16. Martins, A., Mariampillai, B. & Lautens, M. Synthesis in the key of Catellani: norbornene-mediated ortho C–H functionalization. Top. Curr. Chem. 292, 1–33 (2009).

    Google Scholar 

  17. Ye, J. & Lautens, M. Palladium-catalysed norbornene-mediated C–H functionalization of arenes. Nat. Chem. 7, 863–870 (2015).

    CAS  PubMed  Google Scholar 

  18. Cheng, H.-G., Chen, S.-Q., Chen, R.-M. & Zhou, Q.-H. Palladium(II)-initiated Catellani-type reactions. Angew. Chem. Int. Ed. 58, 5832–5844 (2019).

    CAS  Google Scholar 

  19. Wang, J.-C. & Dong, G. B. Palladium/norbornene cooperative catalysis. Chem. Rev. 119, 7478–7528 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Catellani, M., Frignani, F. & Rangoni, A. A complex catalytic cycle leading to a regioselective synthesis of o,o′-disubstituted vinylarenes. Angew. Chem. Int. Ed. 36, 119–122 (1997).

    CAS  Google Scholar 

  21. Lautens, M. & Piguel, S. A new route to fused aromatic compounds by using a palladium-catalyzed alkylation−alkenylation sequence. Angew. Chem. Int. Ed. 39, 1045–1046 (2000).

    CAS  Google Scholar 

  22. Mariampillai, B., Alliot, J., Li, M. & Lautens, M. A convergent synthesis of polysubstituted aromatic nitriles via palladium-catalyzed C−H functionalization. J. Am. Chem. Soc. 129, 15372–15379 (2007).

    CAS  PubMed  Google Scholar 

  23. Dong, Z., Liu, P. & Dong, G.-B. Complementary site-selectivity in arene functionalization enabled by overcoming the ortho constraint in palladium/norbornene catalysis. Nat. Chem. 10, 866–872 (2018).

    PubMed  Google Scholar 

  24. Lv, W.-W., Chen, Y.-H., Wen, S., Ba, D. & Cheng, G.-L. Modular and stereoselective synthesis of C-aryl glycosides via Catellani reaction. J. Am. Chem. Soc. 142, 14864–14870 (2020).

    CAS  PubMed  Google Scholar 

  25. Liu, Z.-S. et al. Construction of axial chirality via palladium/chiral norbornene cooperative catalysis. Nat. Catal. 3, 727–733 (2020).

    CAS  Google Scholar 

  26. Wang, J., Qin, C., Lumb, J.-P. & Luan, X.-J. Regioselective synthesis of polyfunctional arenes by a 4-component Catellani reaction. Chem. 6, 2097–2109 (2020).

    CAS  Google Scholar 

  27. Liu, X., Fu, Y., Chen, Z., Liu, P. & Dong, G. Ortho-C–H methoxylation of aryl halides enabled by a polarity-reversed N–O reagent. Nat. Chem. 15, 1391–1399 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Ertl, P. A. & Schuhmann, T. A. Systematic cheminformatics analysis of functional groups occurring in natural products. J. Nat. Prod. 82, 1258–1263 (2019).

    CAS  PubMed  Google Scholar 

  29. Nahm, S. & Weinreb, S. M. N-methoxy-N-methylamides as effective acylating agents. Tetrahedron Lett. 22, 3815–3818 (1981).

    CAS  Google Scholar 

  30. Sartori, G. & Maggi, R. Use of solid catalysts in Friedel–Crafts acylation reactions. Chem. Rev. 106, 1077–1104 (2006).

    CAS  PubMed  Google Scholar 

  31. Foley, D. J. & Waldmann, H. Ketones as strategic building blocks for the synthesis of natural product-inspired compounds. Chem. Soc. Rev. 51, 4094–4120 (2022).

    CAS  PubMed  Google Scholar 

  32. Huang, Z., Lim, H. N., Mo, F., Young, M. C. & Dong, G. Transition metal-catalyzed ketone-directed or mediated C–H functionalization. Chem. Soc. Rev. 44, 7764–7786 (2015).

    CAS  PubMed  Google Scholar 

  33. Zhou, P.-X. et al. Palladium catalyzed acylation/alkenylation of aryl iodide: a domino approach based on the Catellani–Lautens reaction. ACS Catal. 5, 4927–4931 (2015).

    CAS  Google Scholar 

  34. Huang, Y., Zhu, R., Zhao, K. & Gu, Z. Palladium-catalyzed Catellani ortho-acylation reaction: an efficient and regiospecific synthesis of diaryl ketones. Angew. Chem. Int. Ed. 54, 12669–12672 (2015).

    CAS  Google Scholar 

  35. Dong, Z., Wang, J., Ren, Z. & Dong, G. Ortho C-H acylation of aryl iodides by palladium/norbornene catalysis. Angew. Chem. Int. Ed. 54, 12664–12668 (2015).

    CAS  Google Scholar 

  36. Jun, C.-H. Transition metal-catalyzed carbon–carbon bond activation. Chem. Soc. Rev. 33, 610–618 (2004).

    CAS  PubMed  Google Scholar 

  37. Chen, F., Wang, T. & Jiao, N. Recent advances in transition-metal-catalyzed functionalization of unstrained carbon–carbon bonds. Chem. Rev. 114, 8613–8661 (2014).

    CAS  PubMed  Google Scholar 

  38. Song, F.-J., Guo, T., Wang, B.-Q. & Shi, Z.-J. Catalytic activations of unstrained C–C bond involving organometallic intermediates. Chem. Soc. Rev. 47, 7078–7115 (2018).

    CAS  PubMed  Google Scholar 

  39. Yu, X.-Y., Chen, J.-R. & Xiao, W.-J. Visible light-driven radical-mediated C–C bond cleavage/functionalization in organic synthesis. Chem. Rev. 121, 506–561 (2021).

    CAS  PubMed  Google Scholar 

  40. Deng, L. & Dong, G.-B. Carbon–carbon bond activation of ketones. Trends Chem. 2, 183–198 (2020).

    CAS  Google Scholar 

  41. Huang, H.-W., Ji, X.-C., Wu, W.-Q. & Jiang, H.-F. Transition metal-catalyzed C–H functionalization of N-oxyenamine internal oxidants. Chem. Soc. Rev. 44, 1155–1171 (2015).

    CAS  PubMed  Google Scholar 

  42. Wang, Z.-Y. et al. Palladium-catalyzed deuteration of arylketone oxime ethers. Angew. Chem. Int. Ed. 65, e202319773 (2024).

    Google Scholar 

  43. Wang, Z.-Y. et al. Dual ligands relay-promoted transformation of unstrained ketones to polyfluoroarenes and nitriles. Sci. China Chem. 66, 2037–2045 (2023).

    CAS  Google Scholar 

  44. Li, H. et al. Transformations of aryl ketones via ligand-promoted C–C bond activation. Angew. Chem. Int. Ed. 59, 14388–14393 (2020).

    CAS  Google Scholar 

  45. Liu, X., Zhu, Q. & Dong, G. Beyond tertiary amines: introducing secondary amines by palladium/norbornene-catalyzed ortho amination. Angew. Chem. Int. Ed. 63, 2024 (2024).

    Google Scholar 

  46. Krossing, I. & Raabe, I. Noncoordinating anions—fact or fiction? A survey of likely candidates. Angew. Chem. Int. Ed. 43, 2066–2090 (2004).

    CAS  Google Scholar 

  47. Liu, X., Wang, J. & Dong, G. Modular entry to functionalized tetrahydrobenzo(β)azepines via the palladium/norbornene cooperative catalysis enabled by a C7-modified norbornene. J. Am. Chem. Soc. 143, 9991–10004 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang, M.-L. et al. Mizoroki–Heck reaction of unstrained aryl ketones via ligand-promoted C–C bond olefination. Org. Lett. 23, 2147–2152 (2021).

    CAS  PubMed  Google Scholar 

  49. Schoenherr, H. & Cernak, T. Profound methyl effects in drug discovery and a call for new C–H methylation reactions. Angew. Chem. Int. Ed. 52, 12256–12267 (2013).

    CAS  Google Scholar 

  50. Talele, T. T. The ‘cyclopropyl fragment’ is a versatile player that frequently appears in preclinical/clinical drug molecules. J. Med. Chem. 59, 8712–8756 (2016).

    CAS  PubMed  Google Scholar 

  51. Morrison, K. C. & Hergenrother, P. J. Natural products as starting points for the synthesis of complex and diverse compounds. Nat. Prod. Rep. 31, 6–14 (2014).

    CAS  PubMed  Google Scholar 

  52. Tietze, L. F., Bell, H. P. & Chandrasekhar, S. Natural product hybrids as new leads for drug discovery. Angew. Chem. Int. Ed. 42, 3996–4028 (2003).

    CAS  Google Scholar 

  53. González, M. A. et al. Synthesis and biological evaluation of dehydroabietic acid derivatives. Eur. J. Med. Chem. 45, 811–816 (2010).

    PubMed  Google Scholar 

  54. Liu, W., Zell, D., John, M. & Ackermann, L. Manganese-catalyzed synthesis of cis-β-amino acid esters through organometallic C–H activation of ketimines. Angew. Chem. Int. Ed. 54, 4092–4096 (2015).

    CAS  Google Scholar 

  55. Wu, Q. et al. Pd-catalysed direct C(sp2)–H fluorination of aromatic ketones: concise access to anacetrapib. Chem. Commun. 57, 4544–4547 (2021).

    CAS  Google Scholar 

  56. Turner, N. A. et al. Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research. Nat. Rev. Microbiol. 17, 203–218 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Gu, W. & Wang, S. Synthesis and antimicrobial activities of novel 1H-dibenzo[a,c]carbazoles from dehydroabietic acid. Eur. J. Med. Chem. 45, 4692–4696 (2010).

    CAS  PubMed  Google Scholar 

  58. Zhang, W.-M. et al. The synthesis and antistaphylococcal activity of dehydroabietic acid. Eur. J. Med. Chem. 127, 917–927 (2017).

    CAS  PubMed  Google Scholar 

  59. Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007).

    PubMed  Google Scholar 

  60. Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).

    CAS  PubMed  Google Scholar 

  61. Otto, M. Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus. Annu. Rev. Microbiol. 64, 143–162 (2010).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

L.L. thanks the National Key Research and Development Program of China (2023YFD1800102). H.-X.D. and Y.Y. thank the National Natural Science Foundation of China (22171276, 21920102003). H.-X.D. and H.X. thank the Science and Technology Commission of Shanghai Municipality (17JC1405000, 21ZR1475400, 23ZR1474400 and 18431907100). H.-X.D. thanks the Program of Shanghai Academic Research Leader (19XD1424600). X.W. and Z.-Y.W. thank the Shanghai Postdoctoral Excellence Program (2023706 and 2022699) for financial support.

Author information

Author notes

  1. These authors contributed equally: Kai-Liang Tao, Xing Wang, Huan Liu.

Authors and Affiliations

  1. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China

    Kai-Liang Tao, Wen-Qing Chen, Yi Sun, Yang Ye & Hui-Xiong Dai

  2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Xing Wang, Huan Liu, Yun-Qian Zhang, Yu-Xi Li, Zhen-Yu Wang, Yang Ye, Hui Xu & Hui-Xiong Dai

  3. School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

    Huan Liu & Lefu Lan

  4. University of Chinese Academy of Sciences, Beijing, China

    Huan Liu, Yun-Qian Zhang, Yu-Xi Li, Yang Ye & Hui-Xiong Dai

  5. The First Affiliated Hospital of Anhui Medical University, Hefei, China

    Lefu Lan

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

    Hui-Xiong Dai

Authors
  1. Kai-Liang Tao
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Xing Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Huan Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Wen-Qing Chen
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Yi Sun
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Yun-Qian Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Yu-Xi Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Zhen-Yu Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Yang Ye
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Hui Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Lefu Lan
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Hui-Xiong Dai
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

K.-L.T. and X.W. discovered and developed these reactions. W.-Q.C., Y.S., Y.-Q.Z., Y.-X.L., Z.-Y.W. and H.X. helped perform the experiments determing the substrates’ scope and synthetic applications. H.L. and L.L. designed and conducted the antimicrobial evaluation. H.-X.D. conceived the concept and directed the project. H.-X.D. and H.X. prepared this paper. Y.Y. and H.-X.D. directed the research.

Corresponding authors

Correspondence to Hui Xu, Lefu Lan or Hui-Xiong Dai.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks the anonymous reviewers 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 1–23, material chart, discussion, antimicrobial evaluation, experimental procedures and NMR spectra.

Reporting Summary

Supplementary Data 1

Crystallographic data for compound 5u, CCDC 2371740.

Supplementary Data 2

Structure factors for compound 5u, CCDC 2371740.

Supplementary Data 3

Reflection intensities for compound 5u, CCDC 2371740.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) 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

Tao, KL., Wang, X., Liu, H. et al. Multisite modifications of arenes using ketones as removable handles enabled by Pd and norbornene cooperative catalysis. Nat. Synth 4, 209–218 (2025). https://doi.org/10.1038/s44160-024-00673-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44160-024-00673-8

Search

Advanced 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
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载