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Direct stereoselective C(sp3)–H alkylation of saturated heterocycles using olefins

Nature Chemistry volume 17, pages 344–355 (2025)Cite this article

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Abstract

Despite cross-coupling strategies that enable the functionalization of aromatic heterocycles, the enantioselective C(sp3)–H alkylation of readily available saturated hydrocarbons to construct C(sp3)–C(sp3) bonds remains a formidable challenge. Here we describe a nickel-catalysed enantioselective C(sp3)–H alkylation of saturated heterocycles using olefins, providing an efficient strategy for the stereoselective construction of C(sp3)–C(sp3) bonds. Using readily available and stable olefins and simple saturated nitrogen and oxygen heterocycles as prochiral nucleophiles, the coupling reactions proceed under mild conditions and exhibit broad scope and high functional group tolerance. Furthermore, the enantio- and diastereoselective C(sp3)–H alkylation of saturated hydrocarbons with alkenyl boronates has been achieved, enabling the synthesis of versatile alkyl boronates containing 1,2-adjacent C(sp3) stereocentres. Application of this approach to the late-stage modification of natural products and drugs, as well as to the enantioselective synthesis of a range of chiral building blocks and natural products, is demonstrated.

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Fig. 1: Stereoselective construction of C(sp3)–C(sp3) bonds via C(sp3)–H alkylation.
Fig. 2: Applications of the protocol to the asymmetric synthesis of biologically active natural products.
Fig. 3: Mechanistic studies and proposed mechanism for the C(sp3)–H alkylation of saturated heterocycles.

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Data availability

The data that support the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers 2344836 (5) and 2360607 (66). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Newton, C. G., Wang, S., Oliveira, C. C. & Cramer, N. Catalytic enantioselective transformations involving C–H bond cleavage by transition metal complexes. Chem. Rev. 117, 8908–8976 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. He, J., Wasa, M., Chan, K. S. L., Shao, Q. & Yu, J.-Q. Palladium-catalyzed transformations of alkyl C–H bonds. Chem. Rev. 117, 8754–8786 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. Zhang, C., Li, Z., Gu, Q. & Liu, X.-Y. Catalytic enantioselective C(sp3)–H functionalization involving radical intermediates. Nat. Commun. 12, 475 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Golden, D. L., Suh, S.-E. & Stahl, S. S. Radical C(sp3)–H functionalization and cross-coupling reactions. Nat. Rev. Chem. 6, 405–427 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rouquet, G. & Chatani, N. Catalytic functionalization of C(sp2)–H and C(sp3)–H bonds by using bidentate directing groups. Angew. Chem. Int. Ed. 52, 11726–11743 (2013).

    Article  CAS  Google Scholar 

  6. Saint-Denis, T. G., Zhu, R.-Y., Chen, G., Wu, Q.-F. & Yu, J.-Q. Enantioselective C(sp3)–H bond activation by chiral transition metal catalysts. Science 359, eaao4798 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Davies, H. M. L. & Liao, K. Dirhodium tetracarboxylates as catalysts for selective intermolecular C–H functionalization. Nat. Rev. Chem. 3, 347–360 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cao, H., Tang, X., Tang, H., Yuan, Y. & Wu, J. Photoinduced intermolecular hydrogen atom transfer reactions in organic synthesis. Chem Catal. 1, 523–598 (2021).

    Article  CAS  Google Scholar 

  9. Capaldo, L., Ravelli, D. & Fagnoni, M. Direct photocatalyzed hydrogen atom transfer (HAT) for aliphatic C–H bonds elaboration. Chem. Rev. 122, 1875–1924 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Twilton, J. et al. The merger of transition metal and photocatalysis. Nat. Rev. Chem. 1, 0052 (2017).

    Article  CAS  Google Scholar 

  11. Lipp, A., Badir, S. O. & Molander, G. A. Stereoinduction in metallaphotoredox catalysis. Angew. Chem. Int. Ed. 60, 1714–1726 (2021).

    Article  CAS  Google Scholar 

  12. Chan, A. Y. et al. Metallaphotoredox: the merger of photoredox and transition metal catalysis. Chem. Rev. 122, 1485–1542 (2022).

    Article  CAS  PubMed  Google Scholar 

  13. Holmberg-Douglas, N. & Nicewicz, D. A. Photoredox-catalyzed C–H functionalization reactions. Chem. Rev. 122, 1925–2016 (2022).

    Article  CAS  PubMed  Google Scholar 

  14. Cheung, K. P. S., Sarkar, S. & Gevorgyan, V. Visible light-induced transition metal catalysis. Chem. Rev. 122, 1543–1625 (2022).

    Article  PubMed  Google Scholar 

  15. Zhang, Z., Chen, P. & Liu, G. Copper-catalyzed radical relay in C(sp3)–H functionalization. Chem. Soc. Rev. 51, 1640–1658 (2022).

    Article  CAS  PubMed  Google Scholar 

  16. Zhang, J. & Rueping, M. Metallaphotoredox catalysis for sp3 C–H functionalizations through hydrogen atom transfer (HAT). Chem. Soc. Rev. 52, 4099–4120 (2023).

    Article  PubMed  Google Scholar 

  17. Chen, X. & Kramer, S. Photoinduced transition-metal-catalyzed enantioselective functionalization of non-acidic C(sp3)–H bonds. Chem Catal. 4, 100854 (2024).

    Article  CAS  Google Scholar 

  18. Zhang, W. et al. Enantioselective cyanation of benzylic C–H bonds via copper-catalyzed radical relay. Science 353, 1014–1018 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li, J. et al. Site-specific allylic C–H bond functionalization with a copper-bound N-centred radical. Nature 574, 516–521 (2019).

    Article  CAS  PubMed  Google Scholar 

  20. Zhang, Z., Zhang, X. & Nagib, D. A. Chiral piperidines from acyclic amines via enantioselective, radical-mediated δ C–H cyanation. Chem 5, 3127–3134 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ahneman, D. T. & Doyle, A. G. C–H functionalization of amines with aryl halides by nickel-photoredox catalysis. Chem. Sci. 7, 7002–7006 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Heitz, D. R., Tellis, J. C. & Molander, G. A. Photochemical nickel-catalyzed C–H arylation: synthetic scope and mechanistic investigations. J. Am. Chem. Soc. 138, 12715–12718 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Perry, I. B. et al. Direct arylation of strong aliphatic C–H bonds. Nature 560, 70–75 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shen, Y., Gu, Y. & Martin, R. sp3 C–H arylation and alkylation enabled by the synergy of triplet excited ketones and nickel catalysts. J. Am. Chem. Soc. 140, 12200–12209 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Cheng, X., Lu, H. & Lu, Z. Enantioselective benzylic C–H arylation via photoredox and nickel dual catalysis. Nat. Commun. 10, 3549 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhang, W., Wu, L., Chen, P. & Liu, G. Enantioselective arylation of benzylic C–H bonds by copper-catalyzed radical relay. Angew. Chem. Int. Ed. 58, 6425–6429 (2019).

    Article  CAS  Google Scholar 

  27. Rand, A. X. et al. Dual catalytic platform for enabling sp3 α C–H arylation and alkylation of benzamides. ACS Catal. 10, 4671–4676 (2020).

    Article  CAS  Google Scholar 

  28. Sakurai, S., Matsumoto, A., Kano, T. & Maruoka, K. Cu-catalyzed enantioselective alkylarylation of vinylarenes enabled by chiral binaphthyl-BOX hybrid ligands. J. Am. Chem. Soc. 142, 19017–19022 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Shu, X., Zhong, D., Lin, Y., Qin, X. & Huo, H. Modular access to chiral α-(hetero)aryl amines via Ni/photoredox catalyzed enantioselective cross-coupling. J. Am. Chem. Soc. 144, 8797–8806 (2022).

    Article  CAS  PubMed  Google Scholar 

  30. Xu, S. et al. Enantioselective C(sp3)–H functionalization of oxacycles via photo-HAT/nickel dual catalysis. J. Am. Chem. Soc. 145, 5231–5241 (2023).

    Article  CAS  PubMed  Google Scholar 

  31. Xu, S. et al. Stereoselective and site-divergent synthesis of C-glycosides. Nat. Chem. 16, 2054–2065 (2024).

    Article  CAS  PubMed  Google Scholar 

  32. Xu, J., Li, Z., Xu, Y., Shu, X. & Huo, H. Stereodivergent synthesis of both Z- and E-alkenes by photoinduced, Ni-catalyzed enantioselective C(sp3)–H alkenylation. ACS Catal. 11, 13567–13574 (2021).

    Article  CAS  Google Scholar 

  33. Cheng, X., Li, T., Liu, Y. & Lu, Z. Stereo- and enantioselective benzylic C–H alkenylation via photoredox/nickel dual catalysis. ACS Catal. 11, 11059–11065 (2021).

    Article  CAS  Google Scholar 

  34. Fu, L., Zhang, Z., Chen, P., Lin, Z. & Liu, G. Enantioselective copper-catalyzed alkynylation of benzylic C–H bonds via radical relay. J. Am. Chem. Soc. 142, 12493–12500 (2020).

    Article  CAS  PubMed  Google Scholar 

  35. Liu, L. et al. Copper-catalyzed intermolecular enantioselective radical oxidative C(sp3)–H/C(sp)–H cross-coupling with rationally designed oxazoline-derived N,N,P(O)-ligands. Angew. Chem. Int. Ed. 60, 26710–26717 (2021).

    Article  CAS  Google Scholar 

  36. Shu, X., Huan, L., Huang, Q. & Huo, H. Direct enantioselective C(sp3)–H acylation for the synthesis of α-amino ketones. J. Am. Chem. Soc. 142, 19058–19064 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Cuesta-Galisteo, S., Schörgenhumer, J., Hervieu, C. & Nevado, C. Dual nickel/photoredox-catalyzed asymmetric carbamoylation of benzylic C(sp3)–H bonds. Angew. Chem. Int. Ed. 63, e202313717 (2024).

    Article  CAS  Google Scholar 

  38. Shu, X., Zhong, D., Huang, Q., Huan, L. & Huo, H. Site- and enantioselective cross-coupling of saturated N-heterocycles with carboxylic acids by cooperative Ni/photoredox catalysis. Nat. Commun. 14, 125 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xu, P., Fan, W., Chen, P. & Liu, G. Enantioselective radical trifluoromethylation of benzylic C–H bonds via cooperative photoredox and copper catalysis. J. Am. Chem. Soc. 144, 13468–13474 (2022).

    Article  CAS  PubMed  Google Scholar 

  40. Murphy, J. J., Bastida, D., Paria, S., Fagnoni, M. & Melchiorre, P. Asymmetric catalytic formation of quaternary carbons by iminium ion trapping of radicals. Nature 532, 218–222 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Li, Y., Lei, M. & Gong, L. Photocatalytic regio- and stereoselective C(sp3)–H functionalization of benzylic and allylic hydrocarbons as well as unactivated alkanes. Nat. Catal. 2, 1016–1026 (2019).

    Article  CAS  Google Scholar 

  42. Fan, L., Liu, R., Ruan, X., Wang, P. & Gong, L.-Z. Asymmetric 1,2-oxidative alkylation of conjugated dienes via aliphatic C–H bond activation. Nat. Synth. 1, 946–955 (2022).

    Article  CAS  Google Scholar 

  43. Tahara, Y., Michino, M., Ito, M., Kanyivab, K. S. & Shibata, T. Enantioselective sp3 C–H alkylation of γ-butyrolactam by a chiral Ir(I) catalyst for the synthesis of 4-substituted γ-amino acids. Chem. Commun. 51, 16660–16663 (2015).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  45. Cordier, C. J., Lundgren, R. J. & Fu, G. C. Enantioconvergent cross-couplings of racemic alkylmetal reagents with unactivated secondary alkyl electrophiles: catalytic asymmetric Negishi α‑alkylations of N‑Boc-pyrrolidine. J. Am. Chem. Soc. 135, 10946–10949 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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 

  47. Vasilopoulos, A., Krska, S. W. & Stahl, S. S. C(sp3)–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling. Science 372, 398–403 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gong, Y., Su, L., Zhu, Z., Ye, Y. & Gong, H. Nickel-catalyzed thermal redox functionalization of C(sp3)–H bonds with carbon electrophiles. Angew. Chem. Int. Ed. 61, e202201662 (2022).

    Article  CAS  Google Scholar 

  49. Cheng, L., Liu, J., Chen, Y. & Gong, H. Nickel-catalysed hydrodimerization of unactivated terminal alkenes. Nat. Synth. 2, 364–372 (2023).

    Article  CAS  Google Scholar 

  50. Chen, M. et al. Oxidative cross dehydrogenative coupling of N‑heterocycles with aldehydes through C(sp3)–H functionalization. J. Am. Chem. Soc. 145, 20176–20181 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Breitenfeld, J., Scopelliti, R. & Hu, X. Synthesis, reactivity, and catalytic application of a nickel pincer hydride complex. Organometallics 31, 2128–2136 (2012).

    Article  CAS  Google Scholar 

  52. Lu, X. et al. Practical carbon–carbon bond formation from olefins through nickel-catalyzed reductive olefin hydrocarbonation. Nat. Commun. 7, 11129 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  53. He, Y. L., Cai, Y. L. & Zhu, S. L. Mild and regioselective benzylic C–H functionalization: Ni-catalyzed reductive arylation of remote and proximal olefins. J. Am. Chem. Soc. 139, 1061–1064 (2017).

    Article  CAS  PubMed  Google Scholar 

  54. Zhou, F., Zhu, J., Zhang, Y. & Zhu, S. NiH-catalyzed reductive relay hydroalkylation: a strategy for the remote C(sp3)–H alkylation of alkenes. Angew. Chem. Int. Ed. 57, 4058–4062 (2018).

    Article  CAS  Google Scholar 

  55. Wang, Z. B., Yin, H. L. & 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 

  56. Zhou, F., Zhang, Y., Xu, X. & Zhu, S. NiH-catalyzed remote asymmetric hydroalkylation of alkenes with racemic α-bromo amides. Angew. Chem. Int. Ed. 58, 1754–1758 (2019).

    Article  CAS  Google Scholar 

  57. He, S. et al. Nickel-catalyzed enantioconvergent reductive hydroalkylation of olefins with α-heteroatom phosphorus or sulfur alkyl electrophiles. J. Am. Chem. Soc. 142, 214–221 (2020).

    Article  CAS  PubMed  Google Scholar 

  58. Yang, Z. & Fu, G. C. Convergent catalytic asymmetric synthesis of esters of chiral dialkyl carbinols. J. Am. Chem. Soc. 142, 5870–5875 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Qian, D., Bera, S. & Hu, X. Chiral alkyl amine synthesis via catalytic enantioselective hydroalkylation of enecarbamates. J. Am. Chem. Soc. 143, 1959–1967 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Wang, J. W. et al. Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines. Nat. Commun. 12, 1313 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang, S. et al. Enantioselective access to chiral aliphatic amines and alcohols via Ni-catalyzed hydroalkylations. Nat. Commun. 12, 2771 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  63. Sun, S.-Z. et al. Enantioselective deaminative alkylation of amino acid derivatives with unactivated olefins. J. Am. Chem. Soc. 144, 1130–1137 (2022).

    Article  CAS  PubMed  Google Scholar 

  64. 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 

  65. 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 

  66. 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 

  67. Yang, H. & Ye, Y. Recent progress in NiH-catalyzed linear or branch hydrofunctionalization of terminal or internal alkenes. Top. Curr. Chem. 381, 23 (2023).

    Article  CAS  Google Scholar 

  68. Mao, R., Bera, S., Turla, A. C. & Hu, X. Copper-catalyzed intermolecular functionalization of unactivated C(sp3)–H bonds and aliphatic carboxylic acids. J. Am. Chem. Soc. 143, 14667–14675 (2021).

    Article  CAS  PubMed  Google Scholar 

  69. Huo, H., Gorsline, B. J. & Fu, G. C. Catalyst-controlled doubly enantioconvergent coupling of racemic alkyl nucleophiles and electrophiles. Science 367, 559–564 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bera, S. & Hu, X. Nickel-catalyzed regioselective hydroalkylation and hydroarylation of alkenyl boronic esters. Angew. Chem. Int. Ed. 58, 13854–13859 (2019).

    Article  CAS  Google Scholar 

  71. Zhang, Y., Han, B. & Zhu, S. Rapid access to highly functionalized alkyl boronates by NiH-catalyzed remote hydroarylation of boron-containing alkenes. Angew. Chem. Int. Ed. 58, 13860–13864 (2019).

    Article  CAS  Google Scholar 

  72. Bera, S., Mao, R. & Hu, X. Enantioselective C(sp3)–C(sp3) cross-coupling of non-activated alkyl electrophiles via nickel hydride catalysis. Nat. Chem. 13, 270–277 (2021).

    Article  CAS  PubMed  Google Scholar 

  73. Bera, S., Fan, C. & Hu, X. Enantio- and diastereoselective construction of vicinal C(sp3) centres via nickel-catalysed hydroalkylation of alkenes. Nat. Catal. 5, 1180–1187 (2022).

    Article  CAS  Google Scholar 

  74. Pezzetta, C., Bonifazi, D. & Davidson, R. W. M. Enantioselective synthesis of N-benzylic heterocycles: a nickel and photoredox dual catalysis approach. Org. Lett. 21, 8957–8961 (2019).

    Article  CAS  PubMed  Google Scholar 

  75. Maddocks, C. J., Ermanis, K. & Clarke, P. A. Asymmetric “clip-cycle” synthesis of pyrrolidines and spiropyrrolidines. Org. Lett. 22, 8116–8121 (2020).

    Article  CAS  PubMed  Google Scholar 

  76. Zhang, S., Chen, X., Zhang, J., Wang, W. & Duan, W. An enantioselective formal synthesis of (+)-(R)-α-lipoic acid by an l-proline-catalyzed aldol reaction. Synthesis 3, 383–386 (2008).

    Google Scholar 

  77. Yadav, J. S., Sridhar Reddy, M. & Prasad, A. R. Stereoselective syntheses of (–)-tetrahydrolipstatin via Prins cyclisations. Tetrahedron Lett. 47, 4995–4998 (2006).

    Article  CAS  Google Scholar 

  78. Sudau, A., Munch, W., Bats, J.-W. & Nubbemyer, U. Total synthesis of (–)-pumiliotoxin 251D. Eur. J. Org. Chem. 2002, 3315–3325 (2002).

    Article  Google Scholar 

  79. Becker, D. P. et al. Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists. J. Med. Chem. 49, 1125–1139 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Du, X. & Huang, Z. Advances in base-metal-catalyzed alkene hydrosilylation. ACS Catal. 7, 1227–1243 (2017).

    Article  CAS  Google Scholar 

  81. Wang, K., Ding, Z., Zhou, Z. & Kong, W. Ni-catalyzed enantioselective reductive diarylation of activated alkenes by domino cyclization/cross-coupling. J. Am. Chem. Soc. 140, 12364–12368 (2018).

    Article  CAS  PubMed  Google Scholar 

  82. Maity, B. et al. Mechanistic insight into the photoredox-nickel-HAT triple catalyzed arylation and alkylation of α‑amino Csp3–H bonds. J. Am. Chem. Soc. 142, 16942–16952 (2020).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This project was supported by the National Natural Science Foundation of China (22171215 to W.K. and 22301225 to Y.P.), the Cultivation Program of Wuhan Institute of Photochemistry and Technology (GHY2023KF007 to W.K.), Hubei Provincial Outstanding Youth Fund (2022CFA092 to W.K.), Hubei Provincial Natural Science Foundation (2023AFB034 to Y.P.), GuangDong Basic and Applied Basic Research Foundation (2023A1515110137 to Z.Z. and 2022A1515110113 to Y.P.) and the 75th China Postdoctoral Science Foundation (2024M752461 to Z.Z.). We thank the Core Facility of Wuhan University for X-ray single-crystal diffraction analysis.

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  1. These authors contributed equally: Zhijun Zhou, Yang Ke.

Authors and Affiliations

  1. The Institute for Advanced Studies, Wuhan University, Wuhan, China

    Zhijun Zhou, Yang Ke, Rui Miao, Fen Hu, Xiaoqin Wang, Yuanyuan Ping, Sheng Xu & Wangqing Kong

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

    Wangqing Kong

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Contributions

W.K. conceived and directed this project. Z.Z., Y.K., Y.P., R.M., F.H., X.W. and S.X. conducted the experimental investigations. Z.Z., Y.K. and Y.P. analysed and interpreted the experimental data. W.K. wrote the manuscript with feedback from the other authors. Z.Z., Y.P. and Y.K. prepared the Supplementary Information. All authors contributed to discussions.

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Correspondence to Yuanyuan Ping or Wangqing Kong.

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Nature Chemistry thanks Xi Lu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Tables 1–14, Figs. 1–194, experimental procedures, product characterization and X-Ray crystallographic analysis.

Supplementary Data 1

Crystallographic data for compound 5; CCDC 2344836.

Supplementary Data 2

Crystallographic data for compound 66; CCDC 2360607.

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Zhou, Z., Ke, Y., Miao, R. et al. Direct stereoselective C(sp3)–H alkylation of saturated heterocycles using olefins. Nat. Chem. 17, 344–355 (2025). https://doi.org/10.1038/s41557-025-01747-6

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