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.

  • Article
  • Published:

Asymmetric hydrogenation of ketimines with minimally different alkyl groups


Asymmetric catalysis enables the synthesis of optically active compounds, often requiring the differentiation between two substituents on prochiral substrates1. Despite decades of development of mainly noble metal catalysts, achieving differentiation between substituents with similar steric and electronic properties remains a notable challenge2,3. Here we introduce a class of Earth-abundant manganese catalysts for the asymmetric hydrogenation of dialkyl ketimines to give a range of chiral amine products. These catalysts distinguish between pairs of minimally differentiated alkyl groups bound to the ketimine, such as methyl and ethyl, and even subtler distinctions, such as ethyl and n-propyl. The degree of enantioselectivity can be adjusted by modifying the components of the chiral manganese catalyst. This reaction demonstrates a wide substrate scope and achieves a turnover number of up to 107,800. Our mechanistic studies indicate that exceptional stereoselectivity arises from the modular assembly of confined chiral catalysts and cooperative non-covalent interactions between the catalyst and the substrate.

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

Access options

Buy this article

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

Fig. 1: The distinction between two minimally differentiated alkyl groups.
Fig. 2: Optimization of reaction parameters.
Fig. 3: Mechanistic studies and DFT calculations.
Fig. 4: Substrate scope of imines with primary, secondary and tertiary alkyl and primary alkyl groups.

Similar content being viewed by others

Data availability

All data are available in the main text or the supplementary materials.


  1. Walsh, P. J. & Kozlowski, M. C. Fundamentals of Asymmetric Catalysis (Univ. Science Books, 2010).

  2. Zhang, F.-H., Zhang, F.-J., Li, M.-L., Xie, J.-H. & Zhou, Q.-L. Enantioselective hydrogenation of dialkyl ketones. Nat. Catal. 3, 621–627 (2020).

    Article  CAS  Google Scholar 

  3. Zhou, H. et al. Organocatalytic stereoselective cyanosilylation of small ketones. Nature 605, 84–89 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. McDaniel, D. H. & Brown, H. C. An extended table of Hammett substitutent constants based on the ionization of substituted benzoic acids. J. Org. Chem. 23, 420–427 (1958).

    Article  CAS  Google Scholar 

  5. Tolman, C. A. Steric effects of phosphorus ligands in organometallic chemistry and homogeneous catalysis. Chem. Rev. 77, 313–348 (1977).

    Article  CAS  Google Scholar 

  6. McFord, A. W., Butts, C. P., Fey, N. & Alder, R. W. 3× Axial vs 3× equatorial: the ΔGGA value is a robust computational measure of substituent steric effects. J. Am. Chem. Soc. 143, 13573–13578 (2021).

    Article  CAS  PubMed  Google Scholar 

  7. Bell, S. et al. Asymmetric hydrogenation of unfunctionalized, purely alkyl-substituted olefins. Science 311, 642–644 (2006).

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Li, C., Wang, C., Villa-Marcos, B. & Xiao, J. Chiral counteranion-aided asymmetric hydrogenation of acyclic imines. J. Am. Chem. Soc. 130, 14450–14451 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Li, C., Villa-Marcos, B. & Xiao, J. Metal−Brønsted acid cooperative catalysis for asymmetric reductive amination. J. Am. Chem. Soc. 131, 6967–6969 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Tang, W. et al. Cooperative catalysis: combining an achiral metal catalyst with a chiral Brønsted acid enables highly enantioselective hydrogenation of imines. Chem. Eur. J. 19, 14187–14193 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Schramm, Y., Barrios-Landeros, F. & Pfaltz, A. Discovery of an iridacycle catalyst with improved reactivity and enantioselectivity in the hydrogenation of dialkyl ketimines. Chem. Sci. 4, 2760–2766 (2013).

    Article  CAS  Google Scholar 

  12. Bae, H. Y. et al. Approaching sub-ppm-level asymmetric organocatalysis of a highly challenging and scalable carbon-carbon bond forming reaction. Nat. Chem. 10, 888–894 (2018).

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Wang, Z., Yang, X.-Y., Xu, Y. & Zhou, Q.-L. Iridium-catalyzed asymmetric hydrogenation of dialkyl imines. CCS Chem. 6, 905–911 (2024).

    Article  CAS  Google Scholar 

  14. Yasukawa, T., Masuda, R. & Kobayashi, S. Development of heterogeneous catalyst systems for the continuous synthesis of chiral amines via asymmetric hydrogenation. Nat. Catal. 2, 1088–1092 (2019).

    Article  CAS  Google Scholar 

  15. Bahamonde, A., Al Rifaie, B., Martín-Heras, V., Allen, J. R. & Sigman, M. S. Enantioselective Markovnikov addition of carbamates to allylic alcohols for the construction of α-secondary and α-tertiary amines. J. Am. Chem. Soc. 141, 8708–8711 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Xi, Y. et al. Application of Trimethylgermanyl-substituted bisphosphine ligands with enhanced dispersion interactions to copper-catalyzed hydroboration of disubstituted alkenes. J. Am. Chem. Soc. 142, 18213–18222 (2020).

    Article  CAS  PubMed  Google Scholar 

  17. Knowles, R. R. & Jacobsen, E. N. Attractive noncovalent interactions in asymmetric catalysis: links between enzymes and small molecule catalysts. Proc. Natl Acad. Sci. USA 107, 20678–20685 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  18. Drauz, K., Gröger, H. & May, O. (eds) Enzyme Catalysis in Organic Synthesis (Wiley, 2012).

  19. Savile, C. K., & Janey, J. M. Biocatalytic asymmetric synthesis of chiral amines from ketones applied to Sitagliptin manufacture. Science 329, 305–309 (2010).

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Reetz, M. T. Laboratory evolution of stereoselective enzymes: a prolific source of catalysts for asymmetric reactions. Angew. Chem. Int. Ed. 50, 138–174 (2011).

    Article  CAS  Google Scholar 

  21. Renata, H., Wang, Z. J. & Arnold, F. H. Expanding the enzyme universe: accessing non-natural reactions by mechanism-guided directed evolution. Angew. Chem. Int. Ed. 54, 3351–3367 (2015).

    Article  CAS  Google Scholar 

  22. Wang, Q.-Q. et al. Self-assembled nanospheres with multiple endohedral binding sites pre-organize catalysts and substrates for highly efficient reactions. Nat. Chem. 8, 225–230 (2016).

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Leenders, S. H. A. M., Gramage-Doria, R., de Bruin, B. & Reek, J. N. H. Transition metal catalysis in confined spaces. Chem. Soc. Rev. 44, 433–448 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Mitschke, B., Turberg, M. & List, B. Confinement as a unifying element in selective catalysis. Chem 6, 2515–2532 (2020).

    Article  CAS  Google Scholar 

  25. Hou, G. et al. Enantioselective hydrogenation of N−H imines. J. Am. Chem. Soc. 131, 9882–9883 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Zuo, W., Lough, A. J., Li, Y. F. & Morris, R. H. Amine(imine)diphosphine iron catalysts for asymmetric transfer hydrogenation of ketones and imines. Science 342, 1080–1083 (2013).

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Li, B., Chen, J., Liu, D., Gridnev, I. D. & Zhang, W. Nickel-catalysed asymmetric hydrogenation of oximes. Nat. Chem. 14, 920–927 (2022).

    Article  CAS  PubMed  Google Scholar 

  28. Mas-Roselló, J., Smejkal, T. & Cramer, N. Iridium-catalyzed acid-assisted asymmetric hydrogenation of oximes to hydroxylamines. Science 368, 1098–1102 (2020).

    Article  ADS  PubMed  Google Scholar 

  29. Oates, C. L., Goodfellow, A. S., Bühl, M. & Clarke, M. L. Manganese catalysed enantioselective hydrogenation of in situ-synthesised imines: efficient asymmetric synthesis of amino-indane derivatives. Green Chem. 25, 3864–3868 (2023).

    Article  CAS  Google Scholar 

  30. Chen, J.-J. et al. Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines. Nature 618, 294–300 (2023).

    Article  ADS  CAS  PubMed  Google Scholar 

  31. Xi, Y., Ma, S. & Hartwig, J. F. Catalytic asymmetric addition of an amine N-H bond across internal alkenes. Nature 588, 254–260 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yang, Y., Shi, S.-L., Niu, D., Liu, P. & Buchwald, S. L. Catalytic asymmetric hydroamination of unactivated internal olefins to aliphatic amines. Science 349, 62–66 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. Friedfeld, M. R., Zhong, H., Ruck, R. T., Shevlin, M. & Chirik, P. J. Cobalt-catalyzed asymmetric hydrogenation of enamides enabled by single-electron reduction. Science 360, 888–893 (2018).

    Article  ADS  CAS  PubMed  Google Scholar 

  34. Wang, Y. et al. Structure, reactivity and catalytic properties of manganese-hydride amidate complexes. Nat. Chem. 14, 1233–1241 (2022).

    Article  PubMed  Google Scholar 

  35. Freitag, F., Irrgang, T. & Kempe, R. Mechanistic studies of hydride transfer to imines from a highly active and chemoselective manganate catalyst. J. Am. Chem. Soc. 141, 11677–11685 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Wen, J., Wang, F. & Zhang, X. Asymmetric hydrogenation catalyzed by first-row transition metal complexes. Chem. Soc. Rev. 50, 3211–3237 (2021).

    Article  CAS  PubMed  Google Scholar 

  37. Garbe, M. et al. Manganese(I)-catalyzed enantioselective hydrogenation of ketones using a defined chiral PNP pincer ligand. Angew. Chem. Int. Ed. 56, 11237–11241 (2017).

    Article  CAS  Google Scholar 

  38. Widegren, M. B., Harkness, G. J., Slawin, A. M. Z., Cordes, D. B. & Clarke, M. L. A highly active manganese catalyst for enantioselective ketone and ester hydrogenation. Angew. Chem. Int. Ed. 56, 5825–5828 (2017).

    Article  CAS  Google Scholar 

  39. Liu, C., Liu, X. & Liu, Q. Stereodivergent asymmetric hydrogenation of quinoxalines. Chem 9, 2585–2600 (2023).

    Article  CAS  Google Scholar 

  40. Yamashita, Y., Noguchi, A., Fushimi, S., Hatanaka, M. & Kobayashi, S. Chiral metal salts as ligands for catalytic asymmetric Mannich reactions with simple amides. J. Am. Chem. Soc. 143, 5598–5604 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Huang, H., Liu, X., Zhou, L., Chang, M. & Zhang, X. Direct Asymmetric reductive amination for the synthesis of chiral β-arylamines. Angew. Chem. Int. Ed. 55, 5309–5312 (2016).

    Article  CAS  Google Scholar 

  42. Murakami, M., Takahashi, K., Mase, T., Murase, K. & Ida, H. α-Aminomethylbenzyl alcohol derivatives. US patent 3,994,974 (1976).

  43. Kim, M.-S. et al. Heteroaryl compounds and their use as therapeutic drugs. Patent WO2017039331 (2017).

Download references


We thank Y. Xi from the National University of Singapore and J. Xiao from the University of Liverpool for helpful discussions and valuable revisions. Financial support from the National Key R&D Program of China (2021YFF0701600) and the National Natural Science Foundation of China (22225103 and 22171159) is greatly appreciated.

Author information

Authors and Affiliations



M.W., Y.L. and Q.L. did the conceptualization of the study. M.W., S.L. and H.L. contributed to the methodology. M.W., S.L. and H.L. did the investigation. Y.L. and Q.L. were involved in funding acquisition. Y.L. and Q.L. did the project administration. Y.L. and Q.L. supervised the work. M.W., S.L., Y.W. and Q.L. wrote the original draft. M.W., Y.L. and Q.L. contributed to the writing, review and editing of the paper.

Corresponding authors

Correspondence to Yu Lan or Qiang Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature thanks Rhett Kempe and the other, anonymous, reviewer(s) 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.

Extended data figures and tables

Extended Data Fig. 1 Comparison of free energy profiles.

Free energy profiles for the hydride transfer of 1a promoted by fac-Int4 and fac-Int5. Ar = o-bromophenyl.

Extended Data Fig. 2 Catalytic cycle.

Proposed mechanism for the Mn-Catalyzed asymmetric hydrogenation of ketimines.

Extended Data Fig. 3 Substrate scope of imines with primary/secondary/tertiary alkyl and methyl groups.

aReaction conditions: 1 (0.25 mmol), Mn-17 (2 mol%) and NaHMDS (5 mol%) in PhF (0.5 mL) at 5 °C for 20 h. Isolated yields (%) were given and enantioselectivities (%ee) were determined by chiral-phase HPLC. bMn-15 was used instead of Mn-17 at 25 °C. cMn-6 was used instead of Mn-17 at 25 °C. dMn-1 (2 mol%) and NaOtBu (10 mol%) in 1,4-dioxane (0.8 mL) at 60 °C for 20 h. eMn-1 (2 mol%) and KOtBu (20 mol%) in diethylene glycol dimethyl ether (0.8 mL) at 25 °C.

Extended Data Fig. 4 Synthetic applications.

a, Test of catalytic activity, TON experiment on a scale of grams. b, Deprotection of N-PG for the synthesis of primary amine. c, Preparation of (S)-Levdobutamine. d, Preparation of bioactive MER tyrosine kinase inhibitor (TCCA = trichloroisocyanuric acid; HATU = 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate).

Supplementary information

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

Wang, M., Liu, S., Liu, H. et al. Asymmetric hydrogenation of ketimines with minimally different alkyl groups. Nature 631, 556–562 (2024).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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