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A stereoselective reductive cross-coupling reaction with kinetic control

Nature Catalysis volume 8, pages 1241–1249 (2025)Cite this article

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Abstract

Substituted cyclohexanes are ubiquitous motifs in bioactive molecules. Thermodynamically disfavoured substituted cyclohexane scaffolds can significantly enhance both the biological activity and pharmacokinetic properties of potential drugs. However, achieving stereoselective cross-coupling for the synthesis of these structures with precise kinetic control remains a challenge. Here we present a modular reductive cross-coupling reaction that enables the stereoselective synthesis of thermodynamically disfavoured substituted cyclohexanes, employing simple alkenes as coupling partners. Mechanistically, the exceptional stereochemistry of this reaction is governed by a Heck-type migratory insertion step. The utility of this method is also demonstrated through the concise synthesis of bioactive molecules.

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Fig. 1: A stereoselective cross-coupling reaction with kinetic control.
Fig. 2: Optimization of the reaction conditions.
Fig. 3: Substrate scope.
Fig. 4: Late-stage functionalization and comparative study.
Fig. 5: Synthetic applications.
Fig. 6: Plausible mechanism and mechanistic investigation.

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Data availability

All information relating to optimization studies, experimental procedures, DFT calculations, NMR spectra and high-resolution mass spectrometry are available in the Supplementary Information. All other data are available from the corresponding authors upon request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers CCDC 2242056 (15), 2239184 (18), 2242054 (23), 2239177 (30), 2226452 (46) and 2242066 (61). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Aldeghi, M., Malhotra, S., Selwood, D. L. & Chan, A. W. E. Two- and three-dimensional rings in drugs. Chem. Biol. Drug. Des. 83, 450–461 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tsien, J., Hu, C., Merchant, R. R. & Qin, T. Three-dimensional saturated C(sp3)-rich bioisosteres for benzene. Nat. Rev. Chem. 8, 605–627 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lovering, F. Escape from Flatland 2: complexity and promiscuity. MedChemComm 4, 515–519 (2013).

    Article  CAS  Google Scholar 

  4. Cherney, E. C. et al. Conformational-analysis-guided discovery of 2,3-disubstituted pyridine IDO1 inhibitors. ACS Med. Chem. Lett. 12, 1143–1150 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brameld, K. A., Kuhn, B., Reuter, D. C. & Stahl, M. Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis. J. Chem. Inf. Model 48, 1–24 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Subbaiah, M. A. M. & Meanwell, N. A. Bioisosteres of the phenyl ring: recent strategic applications in lead optimization and drug design. J. Med. Chem. 64, 14046–14128 (2021).

    Article  CAS  PubMed  Google Scholar 

  7. Staszewski, M. et al. Guanidine derivatives: how simple structural modification of histamine H3R antagonists has led to the discovery of potent muscarinic M2R/M4R antagonists. ACS Chem. Neurosci. 12, 2503–2519 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Hekking, K. F. W. et al. Development of potent Mcl-1 inhibitors: structural investigations on macrocycles originating from a DNA-encoded chemical library screen. J. Med. Chem. 67, 3039–3065 (2024).

    Article  CAS  PubMed  Google Scholar 

  9. Simonin, C. et al. Optimization of TRPV6 calcium channel inhibitors using a 3D ligand-based virtual screening method. Angew. Chem. Int. Ed. 54, 14748–14752 (2015).

    Article  CAS  Google Scholar 

  10. Li, Y., Shi, H. & Yin, G. Synthetic techniques for thermodynamically disfavoured substituted six-membered rings. Nat. Rev. Chem. 8, 535–550 (2024).

    Article  CAS  PubMed  Google Scholar 

  11. Wiesenfeldt, M. P., Nairoukh, Z., Li, W. & Glorius, F. Hydrogenation of fluoroarenes: direct access to all-cis-(multi)fluorinated cycloalkanes. Science 357, 908–912 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. Wiesenfeldt, M. P., Knecht, T., Schlepphorst, C. & Glorius, F. Silylarene hydrogenation: a strategic approach that enables direct access to versatile silylated saturated carbo- and heterocycles. Angew. Chem. Int. Ed. 57, 8297–8300 (2018).

    Article  CAS  Google Scholar 

  13. Ling, L., He, Y., Zhang, X., Luo, M. & Zeng, X. Hydrogenation of (hetero)aryl boronate esters with a cyclic (alkyl)(amino)carbene–rhodium complex: direct access to cis-substituted borylated cycloalkanes and saturated heterocycles. Angew. Chem. Int. Ed. 58, 6554–6558 (2019).

    Article  CAS  Google Scholar 

  14. Kaithal, A. et al. cis-Selective hydrogenation of aryl germanes: a direct approach to access saturated carbo- and heterocyclic germanes. J. Am. Chem. Soc. 145, 4109–4118 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liang, Y. et al. Selective 1,4-syn-addition to cyclic 1,3-dienes via hybrid palladium catalysis. ACS Cent. Sci. 10, 1191–1200 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Miyaura, N. & Buchwald, S. L. Cross-coupling Reactions: A Practical Guide (Springer, 2002).

  17. Jana, R., Pathak, T. P. & Sigman, M. S. Advances in transition metal (Pd,Ni,Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners. Chem. Rev. 111, 1417–1492 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cherney, A. H., Kadunce, N. T. & Reisman, S. E. Enantioselective and enantiospecific transition-metal-catalyzed cross-coupling reactions of organometallic reagents to construct C–C bonds. Chem. Rev. 115, 9587–9652 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Choi, J. & Fu, G. C. Transition metal–catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Diccianni, J. B. & Diao, T. Mechanisms of nickel-catalyzed cross-coupling reactions. Trends Chem. 1, 830–844 (2019).

    Article  CAS  Google Scholar 

  21. Kotesova, S. & Shenvi, R. A. Inner- and outer-sphere cross-coupling of high Fsp3 fragments. Acc. Chem. Res. 56, 3089–3098 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nakamura, M., Matsuo, K., Ito, S. & Nakamura, E. Iron-catalyzed cross-coupling of primary and secondary alkyl halides with aryl Grignard reagents. J. Am. Chem. Soc. 126, 3686–3687 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Thaler, T. et al. Highly diastereoselective Csp3–Csp2 Negishi cross-coupling with 1,2-, 1,3- and 1,4-substituted cycloalkylzinc compounds. Nat. Chem. 2, 125–130 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Mu, X., Shibata, Y., Makida, Y. & Fu, G. C. Control of vicinal stereocenters through nickel-catalyzed alkyl–alkyl cross-coupling. Angew. Chem. Int. Ed. 56, 5821–5824 (2017).

    Article  CAS  Google Scholar 

  25. Matier, C. D., Schwaben, J., Peters, J. C. & Fu, G. C. Copper-catalyzed alkylation of aliphatic amines induced by visible light. J. Am. Chem. Soc. 139, 17707–17710 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Komeyama, K., Michiyuki, T. & Osaka, I. Nickel/cobalt-catalyzed C(sp3)–C(sp3) cross-coupling of alkyl halides with alkyl tosylates. ACS Catal. 9, 9285–9291 (2019).

    Article  CAS  Google Scholar 

  27. Li, J., Ren, Q., Cheng, X., Karaghiosoff, K. & Knochel, P. Chromium(II)-catalyzed diastereoselective and chemoselective Csp2–Csp3 cross-couplings using organomagnesium reagents. J. Am. Chem. Soc. 141, 18127–18135 (2019).

    Article  CAS  PubMed  Google Scholar 

  28. Górski, B., Barthelemy, A.-L., Douglas, J. J., Juliá, F. & Leonori, D. Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer. Nat. Catal. 4, 623–630 (2021).

    Article  Google Scholar 

  29. Takeuchi, D., Watanabe, K., Sogo, K. & Osakada, K. Polymerization of methylenecyclohexanes catalyzed by diimine–Pd complex. Polymers having trans- or cis-1,4- and trans-1,3-cyclohexylene groups. Organometallics 34, 3007–3011 (2015).

    Article  CAS  Google Scholar 

  30. Zhu, D. et al. Asymmetric three-component Heck arylation/amination of nonconjugated cyclodienes. Angew. Chem. Int. Ed. 59, 5341–5345 (2020).

    Article  CAS  Google Scholar 

  31. Li, Y. et al. Modular access to substituted cyclohexanes with kinetic stereocontrol. Science 376, 749–753 (2022).

    Article  CAS  PubMed  Google Scholar 

  32. Chen, C., Guo, W., Qiao, D. & Zhu, S. Synthesis of enantioenriched 1,2-cis disubstituted cycloalkanes by convergent NiH catalysis. Angew. Chem. Int. Ed. 62, e202308320 (2023).

    Article  CAS  Google Scholar 

  33. Gurak, J. A.Jr, Yang, K. S., Liu, Z. & Engle, K. M.Directed, regiocontrolled hydroamination of unactivated alkenes via protodepalladation. J. Am. Chem. Soc. 138, 5805–5808 (2016).

    Article  CAS  PubMed  Google Scholar 

  34. Li, Y. & Yin, G. Nickel chain-walking catalysis: a journey to migratory carboboration of alkenes. Acc. Chem. Res. 56, 3246–3259 (2023).

    Article  CAS  PubMed  Google Scholar 

  35. Shen, Z. et al. Creating glycoside diversity through stereoselective carboboration of glycals. Nat. Commun. 15, 10167 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yu, S., Berner, O. M. & Cook, J. M. General approach for the synthesis of indole alkaloids via the asymmetric Pictet–Spengler reaction: first enantiospecific total synthesis of (−)-corynantheidine as well as the enantiospecific total synthesis of (−)-corynantheidol, (−)-geissoschizol, and (+)-geissoschizine. J. Am. Chem. Soc. 122, 7827–7828 (2000).

    Article  CAS  Google Scholar 

  37. Yang, F., Jin, Y. & Wang, C. Nickel-catalyzed asymmetric intramolecular reductive Heck reaction of unactivated alkenes. Org. Lett. 21, 6989–6994 (2019).

    Article  CAS  PubMed  Google Scholar 

  38. Xiao, X. & Liu, J. Progress in the synthesis of C(sp2)–C(sp3) bond by reductive Heck reactions of alkenes. Chin. J. Org. Chem. 41, 3349–3365 (2021).

    Article  CAS  Google Scholar 

  39. Xie, J.-Q., Liang, R.-X. & Jia, Y.-X. Recent advances of catalytic enantioselective Heck reactions and reductive-Heck reactions. Chin. J. Chem. 39, 710–728 (2021).

    Article  CAS  Google Scholar 

  40. Zhang, L. et al. Nickel-catalyzed enantioselective reductive conjugate arylation and heteroarylation via an elementary mechanism of 1,4-addition. J. Am. Chem. Soc. 144, 20249–20257 (2022).

    Article  CAS  PubMed  Google Scholar 

  41. Wang, X.-X., Lu, X., Li, Y., Wang, J.-W. & Fu, Y. Recent advances in nickel-catalyzed reductive hydroalkylation and hydroarylation of electronically unbiased alkenes. Sci. China Chem. 63, 1586–1600 (2020).

    Article  CAS  Google Scholar 

  42. Wang, Y., He, Y. & Zhu, S. NiH-catalyzed functionalization of remote and proximal olefins: new reactions and innovative strategies. Acc. Chem. Res. 55, 3519–3536 (2022).

    Article  CAS  PubMed  Google Scholar 

  43. Zhang, Z., Bera, S., Fan, C. & Hu, X. Streamlined alkylation via nickel-hydride-catalyzed hydrocarbonation of alkenes. J. Am. Chem. Soc. 144, 7015–7029 (2022).

    Article  CAS  PubMed  Google Scholar 

  44. Perez Garcia, P. M., Di Franco, T., Orsino, A., Ren, P. & Hu, X. Nickel-catalyzed diastereoselective alkyl–alkyl Kumada coupling reactions. Org. Lett. 14, 4286–4289 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Lu, Z. & Fu, G. C. Alkyl–alkyl Suzuki cross-coupling of unactivated secondary alkyl chlorides. Angew. Chem. Int. Ed. 49, 6676–6678 (2010).

    Article  CAS  Google Scholar 

  46. Aragón, J., Sun, S., Pascual, D., Jaworski, S. & Lloret-Fillol, J. Photoredox activation of inert alkyl chlorides for the reductive cross-coupling with aromatic alkenes. Angew. Chem. Int. Ed. 61, e202114365 (2022).

    Article  Google Scholar 

  47. Yang, Y. et al. Practical and modular construction of C(sp3)-rich alkyl boron compounds. J. Am. Chem. Soc. 143, 471–480 (2021).

    Article  CAS  PubMed  Google Scholar 

  48. Lyon, W. L. & MacMillan, D. W. C. Expedient access to underexplored chemical space: deoxygenative C(sp3)–C(sp3) cross-coupling. J. Am. Chem. Soc. 145, 7736–7742 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dziechciejewski, W. J., Weber, R., Sowada, O. & Boysen, M. M. K. Cycloalkene carbonitriles in rhodium-catalyzed 1,4-addition and formal synthesis of vabicaserin. Org. Lett. 17, 4132–4135 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Higuchi, R. I. et al. 4-Alkyl- and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinolines: potent, nonsteroidal androgen receptor agonists. Bioorg. Med. Chem. Lett. 9, 1335–1340 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Ma, R. et al. Stereoselective synthesis of chiral hydrophenanthridines via a one-pot stepwise aza-Michael/Michael/Michael process. Org. Lett. 24, 4798–4803 (2022).

    Article  CAS  PubMed  Google Scholar 

  52. Hamilton, M. M. et al. Discovery of IACS-9779 and IACS-70465 as potent inhibitors targeting indoleamine 2,3-dioxygenase 1 (IDO1) apoenzyme. J. Med. Chem. 64, 11302–11329 (2021).

    Article  CAS  PubMed  Google Scholar 

  53. Beck, H. P. et al. Preparation of immunoregulatory agents. WO patent 2,016,073,774 (2016).

  54. Pang, X. et al. Regiocontrolled reductive vinylation of aliphatic 1,3-dienes with vinyl triflates by nickel catalysis. J. Am. Chem. Soc. 143, 4536–4542 (2021).

    Article  CAS  PubMed  Google Scholar 

  55. Zhu, S., He, Y., Xue, Y., Chen, J. & Song, P. Nickel-catalyzed regiodivergent reductive hydroarylation of styrenes. Synlett 32, 1647–1651 (2021).

    Article  Google Scholar 

  56. Lyu, X. et al. Intramolecular hydroamidation of alkenes enabling asymmetric synthesis of β-lactams via transposed NiH catalysis. Nat. Catal. 6, 784–795 (2023).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant no. 22122107 to G.Y. and grant no. 22401220 to Y.L.), the Fundamental Research Funds for the Central Universities (grant no. 413100070 to Y.L.), Guangdong Basic and Applied Basic Research Foundation (grant no. 2024A1515011689 to G.Y. and grant no. 2025A1515010310 to Y.L.), the National Key R&D Program of China (grant nos. 2022YFA1505100 and 2023YFA1508600 to X.Q.), the Scientific Research Innovation Capability Support Project for Young Faculty (grant no. ZYGXQNJSKYCXNLZCXM-H17 to G.Y.) and the supercomputing system in the Supercomputing Center of Wuhan University. We thank the Core Facility of Wuhan University for help with X-ray crystallographic analysis.

Author information

Author notes

  1. These authors contributed equally: Zhenpeng Shen, Hongjin Shi, Yangyang Li.

Authors and Affiliations

  1. The Institute for Advanced Studies, State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China

    Zhenpeng Shen, Hongjin Shi, Yangyang Li & Guoyin Yin

  2. College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, China

    Xiangyu Zhang & Xiaotian Qi

  3. Shenzhen Research Institute, Wuhan University, Shenzhen, China

    Guoyin Yin

Authors
  1. Zhenpeng Shen
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  2. Hongjin Shi
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  3. Yangyang Li
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  4. Xiangyu Zhang
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Contributions

G.Y. designed the project and directed the work. Z.S., H.S. and Y.L. performed all synthetic experiments. X.Z. and X.Q. performed all DFT calculations. G.Y., Y.L. and Z.S. wrote the paper.

Corresponding authors

Correspondence to Yangyang Li, Xiaotian Qi or Guoyin Yin.

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The authors declare no competing interests.

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Peer review information

Nature Catalysis thanks Rodrigo A Cormanich 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 Tables 1–9, Figs. 1–9, methods, characterization data, DFT calculations, mechanistic discussion and references.

Supplementary Data 1

CIF file of the crystal structure of compound 15.

Supplementary Data 2

CIF file of the crystal structure of compound 18.

Supplementary Data 3

CIF file of the crystal structure of compound 23.

Supplementary Data 4

CIF file of the crystal structure of compound 30.

Supplementary Data 5

CIF file of the crystal structure of compound 46.

Supplementary Data 6

CIF file of the crystal structure of compound 61.

Supplementary Data 7

Atomic coordinates of the optimized structures.

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Shen, Z., Shi, H., Li, Y. et al. A stereoselective reductive cross-coupling reaction with kinetic control. Nat Catal 8, 1241–1249 (2025). https://doi.org/10.1038/s41929-025-01440-4

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