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Diastereodivergent construction of disubstituted cyclobutanes via electrochemical cobalt-catalysed reductive coupling

Nature Synthesis (2026)Cite this article

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Abstract

The configuration of cyclobutane-based drug molecules plays a critical role in their biological and pharmacological properties. Although substantial progress has been made in the chemoselective and diastereoselective construction of substituted cyclobutanes, achieving efficient diastereodivergent catalysis from the same set of starting materials remains challenging. In this work, an electrochemical cobalt-catalysed method for the reductive coupling of alkynes and cyclobutenes is reported, enabling the synthesis of a range of substituted cyclobutane diastereoisomers. Proton sources are used to generate cobalt–hydride intermediates through a sequence of cathodic reduction and protonation. By modulating the steric and electronic properties of the proton sources, the trans/cis ratio can be altered, offering a different approach for the efficient synthesis of two diastereoisomers of the desired cyclobutane product. Mechanistic studies support a Co(II)–H reaction pathway and suggest that diastereodivergence arises from distinct distortions of the proton source and differential interactions between the cyclobutyl cobalt intermediate and the respective proton sources.

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Fig. 1: Challenges and strategies for the diastereodivergent synthesis of cyclobutanes.
Fig. 2: Substrate scopes of alkynes and cyclobutenes.
Fig. 3: Enantioselective reductive coupling.
Fig. 4: Stereodivergent synthesis of cyclobutanes and its synthetic applications.
Fig. 5: Mechanistic studies.
Fig. 6: Catalytic cycle and DFT calculations.

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Data availability

All data are available in the main text or the Supplementary Information. The crystallographic data for the structures reported in this paper are freely available from the Cambridge Crystallographic Data Centre under the associated CCDC codes: 2401812 (rac-38), 2401813 (33-cis), 2401814 (38) and 2401815 (33-cis (S,R)). Copies of the data can be obtained free of charge from the CCDC via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Yang, P., Jia, Q., Song, S. & Huang, X. [2+2]-Cycloaddition-derived cyclobutane natural products: structural diversity, sources, bioactivities, and biomimetic syntheses. Nat. Prod. Rep. 40, 1094–1129 (2023).

    Article  PubMed  Google Scholar 

  2. Dembitsky, V. M. Naturally occurring bioactive cyclobutane-containing (CBC) alkaloids in fungi, fungal endophytes, and plants. Phytomedicine 21, 1559–1581 (2014).

    Article  PubMed  CAS  Google Scholar 

  3. Van der Kolk, M. R., Janssen, M. A. C. H., Rutjes, F. P. J. T. & Blanco-Ania, D. Cyclobutanes in small-molecule drug candidates. ChemMedChem 17, e202200020 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Genzink, M. J., Rossler, M. D., Recendiz, H. & Yoon, T. P. A general strategy for the synthesis of truxinate natural products enabled by enantioselective [2 + 2] photocycloadditions. J. Am. Chem. Soc. 145, 19182–19188 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Xu, Y., Conner, M. L. & Brown, M. K. Cyclobutane and cyclobutene synthesis: catalytic enantioselective [2 + 2] cycloadditions. Angew. Chem. Int. Ed. 54, 11918–11928 (2015).

    Article  CAS  Google Scholar 

  6. Poplata, S., Tröster, A., Zou, Y.-Q. & Bach, T. Recent advances in the synthesis of cyclobutanes by olefin [2 + 2] photocycloaddition reactions. Chem. Rev. 116, 9748–9815 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Xiong, P., Ivlev, S. I. & Meggers, E. Photoelectrochemical asymmetric dehydrogenative [2 + 2] cycloaddition between C–C single and double bonds via the activation of two C(sp3)–H bonds. Nat. Catal. 6, 1186–1193 (2023).

    Article  CAS  Google Scholar 

  8. Das, S. et al. Asymmetric counteranion-directed photoredox catalysis. Science 379, 494–499 (2023).

    Article  PubMed  CAS  Google Scholar 

  9. Guo, J. et al. Visible light-mediated intermolecular crossed [2 + 2] cycloadditions using a MOF-supported copper triplet photosensitizer. Nat. Catal. 7, 307–320 (2024).

    Article  CAS  Google Scholar 

  10. Goetzke, F. W., Hell, A. M. L., van Dijk, L. & Fletcher, S. P. A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes. Nat. Chem. 13, 880–886 (2021).

    Article  PubMed  CAS  Google Scholar 

  11. Liang, Z. et al. Cobalt-catalyzed diastereo- and enantioselective carbon–carbon bond forming reactions of cyclobutenes. J. Am. Chem. Soc. 145, 3588–3598 (2023).

    Article  PubMed  CAS  Google Scholar 

  12. Girvin, Z. C. et al. Asymmetric photochemical [2 + 2]-cycloaddition of acyclic vinylpyridines through ternary complex formation and an uncontrolled sensitization mechanism. J. Am. Chem. Soc. 144, 20109–20117 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Hu, L. et al. PdII-catalyzed enantioselective C(sp3)−H activation/cross-coupling reactions of free carboxylic acids. Angew. Chem. Int. Ed. 58, 2134–2138 (2019).

    Article  CAS  Google Scholar 

  14. Xiao, L.-J. et al. PdII-catalyzed enantioselective C(sp3)–H arylation of cyclobutyl ketones using a chiral transient directing group. Angew. Chem. Int. Ed. 59, 9594–9600 (2020).

    Article  CAS  Google Scholar 

  15. Lan, S. et al. Asymmetric transfer hydrogenation of cyclobutenediones. J. Am. Chem. Soc. 146, 4942–4957 (2024).

    Article  PubMed  CAS  Google Scholar 

  16. Wang, Y.-M., Bruno, N. C., Placeres, ÁL., Zhu, S. & Buchwald, S. L. Enantioselective synthesis of carbo- and heterocycles through a CuH-catalyzed hydroalkylation approach. J. Am. Chem. Soc. 137, 10524–10527 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Kim, D. K., Riedel, J., Kim, R. S. & Dong, V. M. Cobalt catalysis for enantioselective cyclobutanone construction. J. Am. Chem. Soc. 139, 10208–10211 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Chen, J., Zhou, Q., Fang, H. & Lu, P. Dancing on ropes—enantioselective functionalization of preformed four-membered carbocycles. Chin. J. Chem. 40, 1346–1358 (2022).

    Article  CAS  Google Scholar 

  19. Yasukawa, T., Gilles, P., Martin, J., Boutet, J. & Cossy, J. Enantioselective reduction of cyclobutenones using ene-reductases. Adv. Synth. Catal. 366, 3257–3261 (2024).

    Article  CAS  Google Scholar 

  20. Wang, Z., Zhu, J., Wang, M. & Lu, P. Palladium-catalyzed divergent enantioselective functionalization of cyclobutenes. J. Am. Chem. Soc. 146, 12691–12701 (2024).

    Article  PubMed  CAS  Google Scholar 

  21. Du, J., Skubi, K. L., Schultz, D. M. & Yoon, T. P. A dual-catalysis approach to enantioselective [2 + 2] photocycloadditions using visible light. Science 344, 392–396 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Jiang, Y., Wang, C., Rogers, C. R., Kodaimati, M. S. & Weiss, E. A. Regio- and diastereoselective intermolecular [2 + 2] cycloadditions photocatalysed by quantum dots. Nat. Chem. 11, 1034–1040 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Sherbrook, E. M., Jung, H., Cho, D., Baik, M.-H. & Yoon, T. P. Brønsted acid catalysis of photosensitized cycloadditions. Chem. Sci. 11, 856–861 (2020).

    Article  CAS  Google Scholar 

  24. Sherbrook, E. M. et al. Chiral Brønsted acid-controlled intermolecular asymmetric [2 + 2] photocycloadditions. Nat. Commun. 12, 5735 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Bower, J. F., Kim, I. S., Patman, R. L. & Krische, M. J. Catalytic carbonyl addition through transfer hydrogenation: a departure from preformed organometallic reagents. Angew. Chem. Int. Ed. 48, 34–46 (2009).

    Article  CAS  Google Scholar 

  26. Holmes, M., Schwartz, L. A. & Krische, M. J. Intermolecular metal-catalyzed reductive coupling of dienes, allenes, and enynes with carbonyl compounds and imines. Chem. Rev. 118, 6026–6052 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Doerksen, R. S. et al. Ruthenium-catalyzed cycloadditions to form five-, six-, and seven-membered rings. Chem. Rev. 121, 4045–4083 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Gandeepan, P. & Cheng, C.-H. Cobalt catalysis involving π components in organic synthesis. Acc. Chem. Res. 48, 1194–1206 (2015).

    Article  PubMed  CAS  Google Scholar 

  29. Kong, J.-R., Ngai, M.-Y. & Krische, M. J. Highly enantioselective direct reductive coupling of conjugated alkynes and α-ketoesters via rhodium-catalyzed asymmetric hydrogenation. J. Am. Chem. Soc. 128, 718–719 (2006).

    Article  PubMed  CAS  Google Scholar 

  30. Zbieg, J. R., Yamaguchi, E., McInturff, E. L. & Krische, M. J. Enantioselective C–H crotylation of primary alcohols via hydrohydroxyalkylation of butadiene. Science 336, 324–327 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Saxena, A., Choi, B. & Lam, H. W. Enantioselective copper-catalyzed reductive coupling of alkenylazaarenes with ketones. J. Am. Chem. Soc. 134, 8428–8431 (2012).

    Article  PubMed  CAS  Google Scholar 

  32. Wei, C.-H., Mannathan, S. & Cheng, C.-H. Regio- and enantioselective cobalt-catalyzed reductive [3 + 2] cycloaddition reaction of alkynes with cyclic enones: a route to bicyclic tertiary alcohols. Angew. Chem. Int. Ed. 51, 10592–10595 (2012).

    Article  CAS  Google Scholar 

  33. Bishop, H. D., Zhao, Q. & Uyeda, C. Catalytic asymmetric synthesis of zinc metallacycles. J. Am. Chem. Soc. 145, 20152–20157 (2023).

    Article  PubMed  CAS  Google Scholar 

  34. Liu, R. Y., Yang, Y. & Buchwald, S. L. Regiodivergent and diastereoselective CuH-catalyzed allylation of imines with terminal allenes. Angew. Chem. Int. Ed. 55, 14077–14080 (2016).

    Article  CAS  Google Scholar 

  35. Köpfer, A., Sam, B., Breit, B. & Krische, M. J. Regiodivergent reductive coupling of 2-substituted dienes to formaldehyde employing ruthenium or nickel catalyst: hydrohydroxymethylation via transfer hydrogenation. Chem. Sci. 4, 1876–1880 (2013).

    Article  Google Scholar 

  36. Geary, L. M., Woo, S. K., Leung, J. C. & Krische, M. J. Diastereo- and enantioselective iridium-catalyzed carbonyl propargylation from the alcohol or aldehyde oxidation level: 1,3-enynes as allenylmetal equivalents. Angew. Chem. Int. Ed. 51, 2972–2976 (2012).

    Article  CAS  Google Scholar 

  37. Sam, B., Breit, B. & Krische, M. J. Paraformaldehyde and methanol as C1 feedstocks in metal-catalyzed C−C couplings of π-unsaturated reactants: beyond hydroformylation. Angew. Chem. Int. Ed. 54, 3267–3274 (2015).

    Article  CAS  Google Scholar 

  38. Oda, S., Sam, B. & Krische, M. J. Hydroaminomethylation beyond carbonylation: allene–imine reductive coupling by ruthenium-catalyzed transfer hydrogenation. Angew. Chem. Int. Ed. 54, 8525–8528 (2015).

    Article  CAS  Google Scholar 

  39. Ortiz, E., Evarts, M. M., Strong, Z. H., Shezaf, J. Z. & Krische, M. J. Ruthenium-catalyzed C−C coupling of terminal alkynes with primary alcohols or aldehydes: α,β-acetylenic ketones (ynones) via oxidative alkynylation. Angew. Chem. Int. Ed. 62, e202303345 (2023).

    Article  CAS  Google Scholar 

  40. Cui, K., Li, Y.-L., Li, G. & Xia, J.-B. Regio- and stereoselective reductive coupling of alkynes and crotononitrile. J. Am. Chem. Soc. 144, 23001–23009 (2022).

    Article  PubMed  CAS  Google Scholar 

  41. Gu, Z.-Y., Li, W.-D., Li, Y.-L., Cui, K. & Xia, J.-B. Selective reductive coupling of vinyl azaarenes and alkynes via photoredox cobalt dual catalysis. Angew. Chem. Int. Ed. 62, e202213281 (2023).

    Article  CAS  Google Scholar 

  42. Cheng, X. et al. Recent applications of homogeneous catalysis in electrochemical organic synthesis. CCS Chem 4, 1120–1152 (2022).

    Article  CAS  Google Scholar 

  43. Malapit, C. A. et al. Advances on the merger of electrochemistry and transition metal catalysis for organic synthesis. Chem. Rev. 122, 3180–3218 (2022).

    Article  PubMed  CAS  Google Scholar 

  44. Leech, M. C. & Lam, K. A practical guide to electrosynthesis. Nat. Rev. Chem. 6, 275–286 (2022).

    Article  PubMed  Google Scholar 

  45. Yan, M., Kawamata, Y. & Baran, P. S. Synthetic organic electrochemical methods since 2000: on the verge of a renaissance. Chem. Rev. 117, 13230–13319 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Li, P., Wang, Y., Zhao, H. & Qiu, Y. Electroreductive cross-coupling reactions: carboxylation, deuteration, and alkylation. Acc. Chem. Res. 58, 113–129 (2025).

    Article  PubMed  Google Scholar 

  47. Zhu, C., Chen, H., Yue, H. & Rueping, M. Electrochemical chemo- and regioselective arylalkylation, dialkylation and hydro(deutero)alkylation of 1,3-enynes. Nat. Synth. 2, 1068–1081 (2023).

    Article  CAS  Google Scholar 

  48. Montgomery, C. L., Amtawong, J., Jordan, A. M., Kurtz, D. A. & Dempsey, J. L. Proton transfer kinetics of transition metal hydride complexes and implications for fuel-forming reactions. Chem. Soc. Rev. 52, 7137–7169 (2023).

    Article  PubMed  CAS  Google Scholar 

  49. Gnaim, S. et al. Cobalt-electrocatalytic HAT for functionalization of unsaturated C–C bonds. Nature 605, 687–695 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Derosa, J., Garrido-Barros, P., Li, M. & Peters, J. C. Use of a PCET mediator enables a Ni-HER electrocatalyst to act as a hydride delivery agent. J. Am. Chem. Soc. 144, 20118–20125 (2022).

    Article  PubMed  CAS  Google Scholar 

  51. Wang, T., He, F., Jiang, W. & Liu, J. Electrohydrogenation of nitriles with amines by cobalt catalysis. Angew. Chem. Int. Ed. 63, e202316140 (2024).

    Article  CAS  Google Scholar 

  52. Gao, S., Wang, C., Yang, J. & Zhang, J. Cobalt-catalyzed enantioselective intramolecular reductive cyclization via electrochemistry. Nat. Commun. 14, 1301 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Ai, W., Zhong, R., Liu, X. & Liu, Q. Hydride transfer reactions catalyzed by cobalt complexes. Chem. Rev. 119, 2876–2953 (2019).

    Article  PubMed  CAS  Google Scholar 

  54. Zhong, R., Wei, Z., Zhang, W., Liu, S. & Liu, Q. A practical and stereoselective in situ NHC–cobalt catalytic system for hydrogenation of ketones and aldehydes. Chem 5, 1552–1566 (2019).

    Article  CAS  Google Scholar 

  55. Liu, X., Rong, X., Liu, S., Lan, Y. & Liu, Q. Cobalt-catalyzed desymmetric isomerization of exocyclic olefins. J. Am. Chem. Soc. 143, 20633–20639 (2021).

    Article  PubMed  CAS  Google Scholar 

  56. Liu, B. et al. Ligand-controlled stereoselective synthesis of 2-deoxy-β-C-glycosides by cobalt catalysis. Angew. Chem. Int. Ed. 62, e202218544 (2023).

    Article  CAS  Google Scholar 

  57. Rong, X., Yang, J., Liu, S., Lan, Y. & Liu, Q. Remote stereocontrol of all-carbon quaternary centers via cobalt-catalyzed asymmetric olefin isomerization. CCS Chem 5, 1293–1300 (2023).

    Article  CAS  Google Scholar 

  58. Akutagawa, T., Takeda, S., Hasegawa, T. & Nakamura, T. Proton transfer and a dielectric phase transition in the molecular conductor (HDABCO+)2(TCNQ)3. J. Am. Chem. Soc. 126, 291–294 (2004).

    Article  PubMed  CAS  Google Scholar 

  59. Ess, D. H. & Houk, K. N. Distortion/interaction energy control of 1,3-dipolar cycloaddition reactivity. J. Am. Chem. Soc. 129, 10646–10647 (2007).

    Article  PubMed  CAS  Google Scholar 

  60. Ess, D. H. & Houk, K. N. Theory of 1,3-dipolar cycloadditions: distortion/interaction and frontier molecular orbital models. J. Am. Chem. Soc. 130, 10187–10198 (2008).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank S. Liu for helpful discussions. Financial support from the National Natural Science Foundation of China (22225103) and the Tsinghua University Initiative Scientific Research Program are greatly appreciated.

Author information

Author notes

  1. These authors contributed equally: Jie Yang, Hengxu Li.

Authors and Affiliations

  1. Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing, People’s Republic of China

    Jie Yang, Hengxu Li & Qiang Liu

  2. College of Chemistry, Shandong Normal University, Jinan, People’s Republic of China

    Qiong Wang

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  1. Jie Yang
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  2. Hengxu Li
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Contributions

J.Y. and Q.L. conceptualized the study. J.Y. contributed to the methodology. J.Y. and Q.W. did the investigation. H.L and Q.W. performed the DFT calculations. Q.L. was involved in funding acquisition, did the project administration and supervised the work. J.Y. and Q.L wrote the original draft. J.Y. and Q.L contributed to the writing, review and editing of the paper.

Corresponding authors

Correspondence to Qiong Wang or Qiang Liu.

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The authors declare no competing interests.

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Nature Synthesis thanks Jolene Reid, Wen-Jing Xiao, Junliang Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information (download PDF )

Experimental details, Supplementary Figs. 1–56 and Tables 1–26.

Supplementary Data 1

Crystallographic data for compound rac-38; CCDC reference 2401812.

Supplementary Data 2

Crystallographic data for compound 33-cis; CCDC reference 2401813.

Supplementary Data 3

Crystallographic data for compound 38; CCDC reference 2401814.

Supplementary Data 4

Crystallographic data for compound 33-cis (S,R); CCDC reference 2401815.

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Yang, J., Li, H., Wang, Q. et al. Diastereodivergent construction of disubstituted cyclobutanes via electrochemical cobalt-catalysed reductive coupling. Nat. Synth (2026). https://doi.org/10.1038/s44160-025-00947-9

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