Skip to main content

Thank you for visiting 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.

Enantio- and diastereoselective construction of vicinal C(sp3) centres via nickel-catalysed hydroalkylation of alkenes


In drug discovery, the proportion of aliphatic carbons (C(sp3)) and the presence of chiral carbons in organic molecules are positively correlated to their chance of clinical success. Although methods exist for the synthesis of chiral C(sp3)-rich molecules, they often are limited in scope, have poor modularity or are unsuitable for stereoselective synthesis using racemic reagents. The stereocontrol of vicinal C(sp3) centres is a particular challenge. Here we describe nickel-catalysed enantio- and diastereoselective hydroalkylation of internal alkenes with racemic alkyl bromides to selectively form one of the four possible stereoisomers. Because of its general and modular character, and its high functional group tolerance, we expect this approach to have wide applications in the stereoselective synthesis of C(sp3)-rich molecules.

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

Access options

Rent or buy this article

Get just this article for as long as you need it


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

Fig. 1: Stereoselective C(sp3)–C(sp3) cross-coupling.
Fig. 2: Scope of nickel-catalysed enantio- and diastereoselective hydroalkylation.
Fig. 3: Synthetic applications and diversification of the chiral products.
Fig. 4: Mechanistic studies.

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2165076 (3aa), 2165081 (3ab), 2118223 (3ad) and 2118224 (3af). Copies of the data can be obtained free of charge via All other data supporting the findings of this study, including experimental procedures and compound characterization, NMR, HPLC and X-ray analyses, are available within the Article and its Supplementary Information or from the authors. Raw NMR and HPLC data are also freely available in Zenodo:


  1. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  Google Scholar 

  2. Ritchie, T. J. & Macdonald, S. J. The impact of aromatic ring count on compound developability—are too many aromatic rings a liability in drug design? Drug Discov. Today 14, 1011–1020 (2009).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  4. Fu, G. C. Transition-metal catalysis of nucleophilic substitution reactions: a radical alternative to SN1 and SN2 processes. ACS Cent. Sci. 3, 692–700 (2017).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  6. 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 

  7. Sun, S. Z., Borjesson, M., Martin-Montero, R. & Martin, R. Site-selective Ni-catalyzed reductive coupling of α-haloboranes with unactivated olefins. J. Am. Chem. Soc. 140, 12765–12769 (2018).

    Article  CAS  Google Scholar 

  8. 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 

  9. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. He, S. J. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Yang, P.-F. et al. Regio- and enantioselective hydroalkylations of unactivated olefins enabled by nickel catalysis: reaction development and mechanistic insights. ACS Catal. 12, 5795–5805 (2022).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. 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  Google Scholar 

  21. Liu, S. Y. & Stephan, D. W. Contemporary research in boron chemistry. Chem. Soc. Rev. 48, 3434–3435 (2019).

    Article  CAS  Google Scholar 

  22. Leonori, D. & Aggarwal, V. K. Stereospecific couplings of secondary and tertiary boronic esters. Angew. Chem. Int. Ed. 54, 1082–1096 (2015).

    Article  CAS  Google Scholar 

  23. Sandford, C. & Aggarwal, V. K. Stereospecific functionalizations and transformations of secondary and tertiary boronic esters. Chem. Commun. 53, 5481–5494 (2017).

    Article  CAS  Google Scholar 

  24. Plescia, J. & Moitessier, N. Design and discovery of boronic acid drugs. Eur. J. Med. Chem. 195, 112270 (2020).

    Article  CAS  Google Scholar 

  25. Trippier, P. C. & McGuigan, C. Boronic acids in medicinal chemistry: anticancer, antibacterial and antiviral applications. Med. Chem. Commun. 1, 183–198 (2010).

    Article  CAS  Google Scholar 

  26. Caruano, J., Muccioli, G. G. & Robiette, R. Biologically active γ-lactams: synthesis and natural sources. Org. Biomol. Chem. 14, 10134–10156 (2016).

    Article  CAS  Google Scholar 

  27. Ye, L.-W., Shu, C. & Gagosz, F. Recent progress towards transition metal-catalyzed synthesis of γ-lactams. Org. Biomol. Chem. 12, 1833–1845 (2014).

    Article  CAS  Google Scholar 

  28. Matsuo, J.-i, Kobayashi, S. & Koga, K. Enantioselective alkylation of lactams and lactones via lithium enolate formation using a chiral tetradentate lithium amide in the presence of lithium bromide. Tetrahedron Lett. 39, 9723 (1998).

    Article  CAS  Google Scholar 

  29. Rauniyar, V. & Hall, D. G. Lewis acids catalyze the addition of allylboronates to aldehydes by electrophilic activation of the dioxaborolane in a closed transition structure. J. Am. Chem. Soc. 126, 4518–4519 (2004).

    Article  CAS  Google Scholar 

  30. Liu, J., Gao, S. & Chen, M. Asymmetric syntheses of (E)‑δ-hydroxymethyl-anti-homoallylic alcohols via highly enantio- and stereoselective aldehyde allylation with α‑borylmethyl‑(E)‑crotylboronate. Org. Lett. 23, 7808–7813 (2021).

    Article  CAS  Google Scholar 

  31. Fagnou, K. & Lautens, M. Halide effects in transition metal catalysis. Angew. Chem. Int. Ed. 41, 26–47 (2002).

    Article  CAS  Google Scholar 

  32. Liang, Y. & Fu, G. C. Nickel-catalyzed alkyl–alkyl cross-couplings of fluorinated secondary electrophiles: a general approach to the synthesis of compounds having a perfluoroalkyl substituent. Angew. Chem. Int. Ed. 54, 9047–9051 (2015).

    Article  CAS  Google Scholar 

  33. Roth, B. D. Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis. US patent 4,681,893 (1987).

  34. Magnus, N. A. et al. Additives promote Noyori-type reductions of a β‑keto-γ-lactam: asymmetric syntheses of serotonin norepinephrine reuptake inhibitors. J. Org. Chem. 78, 5768–5774 (2013).

    Article  CAS  Google Scholar 

  35. Zhang, C.-S., Zhang, B.-B., Zhong, L., Chen, X.-Y. & Wang, Z.-X. DFT insight into asymmetric alkyl–alkyl bond formation via nickel-catalysed enantioconvergent reductive coupling of racemic electrophiles with olefins. Chem. Sci. 13, 3728–3739 (2022).

    Article  CAS  Google Scholar 

Download references


This work is supported by the Swiss National Science Foundation (200021_181977). We thank R. Scopelliti (EPFL) and F. Fadaei Tirani (EPFL) for the determination of the X-ray crystal structure of compounds 3aa, 3ab, 3ad and 3af.

Author information

Authors and Affiliations



S.B. and X.H. conceived the project. S.B. designed, optimized and studied the scope and mechanism of the synthetic method. C.F. contributed to the study of synthetic applications and to some characterization of the compounds. S.B. and X.H. prepared the manuscript, with input from C.F.

Corresponding author

Correspondence to Xile Hu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Catalysis 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 Methods, Tables 1–8, Figs. 1–10 and references.

Supplementary Data 1

Crystallographic data for compound 3aa.

Supplementary Data 2

Crystallographic data for compound 3ab.

Supplementary Data 3

Crystallographic data for compound 3ad.

Supplementary Data 4

Crystallographic data for compound 3af.

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

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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