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:

Enantioselective macrocyclization via catalytic metallic dipole relay

Nature Catalysis volume 8, pages 368–377 (2025)Cite this article

Subjects

Abstract

Chiral macrocycles play critical roles across medicinal chemistry and materials science, yet their catalytic asymmetric synthesis remains challenging. Existing methods predominantly rely on intramolecular cyclization of linear precursors and asymmetric resolution of racemic macrocycles, often requiring complex synthesis while offering limited structural diversity. Here, inspired by non-ribosomal cyclopeptide biosynthesis, we present a catalytic metallic dipole relay strategy for the construction of axially chiral macrolactones. This approach enables concise enantioselective synthesis through stepwise strain release in biaryl lactones and dynamic kinetic resolution mediated by π-allyl-Pd dipoles. The method demonstrates broad applicability to medium (up to 91% yield with 93% enantiomeric excess) and large (up to 93% yield with 99% enantiomeric excess and >19:1 diastereomeric ratio) ring systems under mild conditions. By establishing stereochemical control during both medium-ring formation and subsequent macrocyclization, this strategy overcomes traditional limitations in the generation of axial chirality while extending the methodology of transition-metal-catalysed asymmetric cyclization.

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: Synthesis plan of chiral macrocycles.
Fig. 2: Results of Pd-catalysed asymmetric (6 + 4) cyclizations.
Fig. 3: Representive chiral 20-membered macrocycles and mechanism studies.
Fig. 4: Representive results of other chiral macrocycles.
Fig. 5: DFT computational studies and control experiments.

Similar content being viewed by others

Data availability

The data that support the findings in this work are available within this article and its Supplementary Information or from the authors upon reasonable request. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2271260 (3a), 2271264 (4a), 2325057 (6a), 2325060 (8a) and 2362166 (11g). Copies of the data can be obtained free of charge at https://www.ccdc.cam.ac.uk/structures/.

References

  1. Driggers, E. M., Hale, S. P., Lee, J. & Terrett, N. K. The exploration of macrocycles for drug discovery—an underexploited structural class. Nat. Rev. Drug Discov. 7, 608–624 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Seiple, I. B. et al. A platform for the discovery of new macrolide antibiotics. Nature 533, 338–345 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Morimoto, M. et al. Advances in supramolecular host-mediated reactivity. Nat. Catal. 3, 969–984 (2020).

    Article  CAS  Google Scholar 

  4. Wu, Q. et al. Poly[n]catenanes: synthesis of molecular interlocked chains. Science 358, 1434–1439 (2017).

    Article  CAS  PubMed  Google Scholar 

  5. Levine, D. P. Vancomycin: a history. Clin. Infect. Dis. 42, 5–12 (2006).

    Article  Google Scholar 

  6. Li, Y. et al. Iron catalyzed asymmetric hydrogenation of ketones. J. Am. Chem. Soc. 136, 4031–4039 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Mortensen, K. T., Osberger, T. J., King, T. A., Sore, H. F. & Spring, D. R. Strategies for the diversity-oriented synthesis of macrocycles. Chem. Rev. 119, 10288–10317 (2019).

    Article  CAS  PubMed  Google Scholar 

  8. Lv, X.-K. et al. Carbene organic catalytic planar enantioselective macrolactonization. Nat. Commun. 15, 958 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang, G., He, Y., Wang, T., Li, Z. & Wang, J. Atroposelective synthesis of planar-chiral indoles via carbene catalyzed macrocyclization. Angew. Chem. Int. Ed. 63, e202316739 (2024).

    Article  CAS  Google Scholar 

  10. Yu, S.-Z., Shen, G.-S., He, F.-Q. & Yang, X.-Y. Asymmetric synthesis of planar-chiral macrocycles via organocatalyzed enantioselective macrocyclization. Chem. Commun. 58, 7293–7296 (2022).

    Article  CAS  Google Scholar 

  11. Ding, Q., Wang, Q.-Y., He, H. & Cai, Q. Asymmetric synthesis of (−)-pterocarine and (−)-galeon via chiral phase transfer-catalyzed atropselective formation of diarylether cyclophane skeleton. Org. Lett. 19, 1804–1807 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. Tong, S. et al. Catalytic enantioselective synthesis and switchable chiroptical property of inherently chiral macrocycles. J. Am. Chem. Soc. 142, 14432–14436 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Araki, T., Noguchi, K. & Tanaka, K. Enantioselective synthesis of planar-chiral carba-paracyclophanes: rhodium-catalyzed [2+2+2] cycloaddition of cyclic diynes with terminal monoynes. Angew. Chem. Int. Ed. 52, 5617–5621 (2013).

    Article  Google Scholar 

  14. Kanda, K., Koike, T., Endo, K. & Shibata, T. The first asymmetric Sonogashira coupling for the enantioselective generation of planar chirality in paracyclophanes. Chem. Commun. 2009, 1870–1872 (2009).

    Article  Google Scholar 

  15. Wang, D., Shao, Y.-B., Chen, Y., Xue, X.-S. & Yang, X. Enantioselective synthesis of planar-chiral macrocycles through asymmetric electrophilic aromatic amination. Angew. Chem. Int. Ed. 61, e202201064 (2022).

    Article  CAS  Google Scholar 

  16. Dong, Z., Li, J., Yao, T. & Zhao, C. Palladium-catalyzed enantioselective C–H olefination to access planar-chiral cyclophanes by dynamic kinetic resolution. Angew. Chem. Int. Ed. 62, e202315603 (2023).

    Article  CAS  Google Scholar 

  17. Gagnon, C. et al. Biocatalytic synthesis of planar chiral macrocycles. Science 367, 917–921 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. Zou, S., Yu, B. & Huang, H. Enantioselective ring-closing aminomethylamination of aminodienes enabled by modified Trost ligands. Chem. Catal. 2, 2034–2048 (2022).

    Article  CAS  Google Scholar 

  19. Xiong, Q., Xiao, L., Dong, X.-Q. & Wang, C.-J. Asymmetric synthesis of chiral aza-macrodiolides via iridium-catalyzed cascade allylation/macrolactonization. Org. Lett. 24, 2579–2584 (2022).

    Article  CAS  PubMed  Google Scholar 

  20. López, R. & Palomo, C. Planar chirality: a mine for catalysis and structure discovery. Angew. Chem. Int. Ed. 61, e202113504 (2022).

    Article  Google Scholar 

  21. Marsault, E. & Peterson, M. L. Macrocycles are great cycles: applications, opportunities and challenges of synthetic macrocycles in drug discovery. J. Med. Chem. 54, 1961–2004 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Iyoda, M., Yamakawa, J. & Rahman, M. J. Conjugated macrocycles: concepts and applications. Angew. Chem. Int. Ed. 50, 10522–10553 (2011).

    Article  CAS  Google Scholar 

  23. Kopp, F. & Marahiel, M. A. Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis. Nat. Prod. Rep. 24, 735–749 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Xu, X. & Doyle, M. P. The [3+3]-cycloaddition alternative for heterocycle syntheses: catalytically generated metalloenolcarbenes as dipolar adducts. Acc. Chem. Res. 47, 1396–1405 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang, M.-M., Qu, B.-L., Shi, B., Xiao, W.-J. & Lu, L.-Q. High-order dipolar annulations with metal-containing reactive dipoles. Chem. Soc. Rev. 51, 4146–4174 (2022).

    Article  CAS  PubMed  Google Scholar 

  26. Zhang, J. et al. Transition metal-catalyzed asymmetric cyclizations involving allyl or propargyl heteroatom-dipole precursors. Chin. J. Org. Chem. 42, 3051–3101 (2022).

    Article  CAS  Google Scholar 

  27. Trost, B. M., Huang, Z. & Murhade, G. M. Catalytic palladium-oxyallyl cycloaddition. Science 362, 564–568 (2018).

    Article  CAS  PubMed  Google Scholar 

  28. Yang, L.-C. et al. Stereoselective access to [5.5.0] and [4.4.1] bicyclic compounds through Pd-catalysed divergent higher-order cycloadditions. Nat. Chem. 12, 860–868 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Ohmatsu, K., Imagawa, N. & Ooi, T. Ligand-enabled multiple absolute stereocontrol in metal-catalysed cycloaddition for construction of contiguous all-carbon quaternary stereocentres. Nat. Chem. 6, 47–51 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Cheng, Q., Zhang, H.-J., Yue, W.-J. & You, S.-L. Palladium-catalyzed highly stereoselective dearomative [3+2] cycloaddition of nitrobenzofurans. Chem 3, 428–436 (2017).

    Article  CAS  Google Scholar 

  31. Zheng, Y., Qin, T. & Zi, W.-W. Enantioselective inverse electron demand (3+2) cycloaddition of palladium-oxyallyl enabled by a hydrogen-bond-donating ligand. J. Am. Chem. Soc. 143, 1038–1045 (2021).

    Article  CAS  PubMed  Google Scholar 

  32. Peng, Y., Huo, X., Luo, Y., Wu, L. & Gong, L.-Z. Enantio- and diastereodivergent synthesis of spirocycles through dual-metal-catalyzed [3+2] annulation of 2-vinyloxiranes with nucleophilic dipoles. Angew. Chem. Int. Ed. 60, 24941–24949 (2021).

    Article  CAS  Google Scholar 

  33. Ding, W.-W., Zhou, Y., Han, Z.-Y. & Gong, L.-Z. Asymmetric cascade carbonylation/annulation of benzyl bromides, CO, and vinyl benzoxazinanones enabled by Pd/chiral Lewis-base relay catalysis. J. Org. Chem. 88, 5187–5193 (2023).

    Article  CAS  PubMed  Google Scholar 

  34. Yu, C., Huang, H., Li, X., Zhang, Y. & Wang, W. Dynamic kinetic resolution of biaryl lactones via a chiral bifunctional amine thiourea-catalyzed highly atropo-enantioselective transesterification. J. Am. Chem. Soc. 138, 6956–6959 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Beleh, O. M., Miller, E., Toste, F. D. & Miller, S. J. Catalytic dynamic kinetic resolutions in tandem to construct two-axis terphenyl atropisomers. J. Am. Chem. Soc. 142, 16461–16470 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ruan, L.-X., Sun, B., Liu, J.-M. & Shi, S.-L. Dynamic kinetic asymmetric arylation and alkenylation of ketones. Science 379, 662–670 (2023).

    Article  CAS  PubMed  Google Scholar 

  37. Reyes, R. L., Iwai, T. & Sawamura, M. Construction of medium-sized rings by gold catalysis. Chem. Rev. 121, 8926–8947 (2021).

    Article  CAS  PubMed  Google Scholar 

  38. Cheng, J. K., Xiang, S.-H., Li, S., Ye, L. & Tan, B. Recent advances in catalytic asymmetric construction of atropisomers. Chem. Rev. 121, 4805–4902 (2021).

    Article  CAS  PubMed  Google Scholar 

  39. Carmona, J. A., Rodríguez-Franco, C., Fernández, R., Hornillos, V. & Lassaletta, J. M. Atroposelective transformation of axially chiral (hetero)biaryls. From desymmetrization to modern resolution strategies. Chem. Soc. Rev. 50, 2968–2983 (2021).

    Article  CAS  PubMed  Google Scholar 

  40. Xiao, Y.-Q. et al. Taming chiral quaternary stereocenters via remote H-bonding stereoinduction in palladium-catalyzed (3+2) cycloadditions. Angew. Chem. Int. Ed. 62, e202212444 (2023).

    Article  CAS  Google Scholar 

  41. Wang, B.-C. et al. Synthesis of S(IV)-stereogenic chiral thio-oxazolidinones via palladium-catalyzed asymmetric [3+2] annulations. Angew. Chem. Int. Ed. 63, e202319728 (2024).

    Article  CAS  Google Scholar 

  42. Trost, B. M., Machacek, M. R. & Aponick, A. Predicting the stereochemistry of diphenylphosphino benzoic acid (DPPBA)-based palladium-catalyzed asymmetric allylic alkylation reactions: a working model. Acc. Chem. Res. 39, 747–760 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Zhang, Y.-C., Zhang, X. & Ma, S.-M. Stretchable chiral pockets for palladium-catalyzed highly chemo- and enantioselective allenylation. Nat. Commun. 12, 2416 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang, L.-C. et al. Construction of nine-membered heterocycles through palladium-catalyzed formal [5+4] cycloaddition. Angew. Chem. Int. Ed. 56, 2927–2931 (2017).

    Article  CAS  Google Scholar 

  45. Li, M.-M. et al. Sequential visible-light photoactivation and palladium catalysis enabling enantioselective [4+2] cycloadditions. J. Am. Chem. Soc. 139, 14707–14713 (2017).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key R&D Program of China (2023YFA1507203 to W.-J.X. and L.-Q.L., and 2022YFA1506100 to Z.Z.), the National Natural Science Foundation of China (22471089 to L.-Q.L., 22271113 to L.-Q.L., 22203034 to Z.Z. and 92256301 to W.-J.X.) and Founding from Central China Normal University and Wuhan Institute of Photochemistry and Technology (L.-Q.L. and W.-J.X.). We thank F.-F. Pan (CCNU) for X-ray crystallographic analysis assistance. We acknowledge W.-B. Liu in Wuhan University for helpful discussions.

Author information

Author notes

  1. These authors contributed equally: Bao-Le Qu, Meng Xiao.

Authors and Affiliations

  1. Engineering Research Center of Photoenergy Utilization for Pollution Control and Carbon Reduction, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, China

    Bao-Le Qu, Meng Xiao, Lin He, Jun-Wei Shi, Zhihan Zhang, Wen-Jing Xiao & Liang-Qiu Lu

  2. Wuhan Institute of Photochemistry and Technology, Wuhan, China

    Wen-Jing Xiao & Liang-Qiu Lu

  3. State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, China

    Liang-Qiu Lu

  4. School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, China

    Liang-Qiu Lu

Authors
  1. Bao-Le Qu
    View author publications

    Search author on:PubMed Google Scholar

  2. Meng Xiao
    View author publications

    Search author on:PubMed Google Scholar

  3. Lin He
    View author publications

    Search author on:PubMed Google Scholar

  4. Jun-Wei Shi
    View author publications

    Search author on:PubMed Google Scholar

  5. Zhihan Zhang
    View author publications

    Search author on:PubMed Google Scholar

  6. Wen-Jing Xiao
    View author publications

    Search author on:PubMed Google Scholar

  7. Liang-Qiu Lu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

B.-L.Q. and L.-Q.L. conceived the work, B.-L.Q., L.H. and J.-W.S. designed and conducted the experiments, M.X. performed the DFT calculation under the supervision of Z.Z. W.-J.X. and L.-Q.L. supervised and directed the research, and all authors wrote the paper.

Corresponding authors

Correspondence to Zhihan Zhang or Liang-Qiu Lu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Catalysis thanks Rajarshi Samanta, Jian Wang, Yong Wang and Xiaoyu Yang 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 methods, discussion, references, Tables 1–9 and Figs. 1–14.

Supplementary Data 1

Crystallographic data for compound 3a.

Supplementary Data 2

Crystallographic data for compound 4a.

Supplementary Data 3

Crystallographic data for compound 6a.

Supplementary Data 4

Crystallographic data for compound 8a.

Supplementary Data 5

Crystallographic data for compound 11g.

Supplementary Data 6

Checkcif file for compound 3a.

Supplementary Data 7

Checkcif file for compound 4a.

Supplementary Data 8

Checkcif file for compound 6a.

Supplementary Data 9

Checkcif file for compound 8a.

Supplementary Data 10

Checkcif file for compound 11g.

Supplementary Data 11

The atomic coordinates of optimized structures.

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

Qu, BL., Xiao, M., He, L. et al. Enantioselective macrocyclization via catalytic metallic dipole relay. Nat Catal 8, 368–377 (2025). https://doi.org/10.1038/s41929-025-01322-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41929-025-01322-9

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