Skip to main content

Thank you for visiting nature.com. 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:

Divergence of catalytic systems in the zinc-catalysed alkylation of benzaldehyde mediated by chiral proline-based ligands

Nature Synthesis (2024)Cite this article

Subjects

Abstract

Asymmetric catalysis has expanded the range of chiral products readily accessible through increasingly efficient synthetic catalysts. The development of these catalysts often starts with a result obtained by systematic screening of known privileged chiral structures and assumes that the active species would be an isolated monomolecular species. Here we report the study of three proline-derived ligands, diphenyl-N-methyl-prolinol, diphenylprolinol and 5-(hydroxydiphenylmethyl)-2-pyrrolidinone, in the zinc-catalysed alkylation of benzaldehyde. The three ligands exhibit different system-level behaviour, characterized by multiple levels of aggregation that may be catalytically active simultaneously. While diphenyl-N-methyl-prolinol behaves as expected from a mechanistic point of view, diphenylprolinol shows enantiodivergence during the reaction due to an asymmetric autoinduction process. With 5-(hydroxydiphenylmethyl)-2-pyrrolidinone, we were able to establish the possibility of at least trimeric active species in equilibrium with less aggregated active species. Simulations using a mathematical model confirm the possibility of such systems-level behaviour. Parallel study of the three systems reveals three distinct system-level behaviours that are central to the efficiency of the catalytic reaction.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: General figure for the systems-level behaviour in asymmetric catalysis.
Fig. 2: Enantioselective addition of dialkylzinc to benzaldehyde catalysed by three chiral diphenylprolinol derivatives.
Fig. 3: DPMP-catalysed addition of ZnEt2 to benzaldehyde (0.15 M) at 20 °C in toluene as solvent.
Fig. 4: DPP (2)-catalysed addition of ZnEt2 to benzaldehyde (0.4 M) at 20 °C in toluene as solvent.
Fig. 5: DPPy (3)-catalysed addition of ZnEt2 to benzaldehyde (0.25 M) at 20 °C in toluene as solvent.
Fig. 6: Developed scheme of the monomer–dimer–trimer competition model.
Fig. 7: Simulations of NLE and e.e.P versus catalyst-loading curves.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available in the Supporting Information. Source data are provided with this paper.

References

  1. Yoon, T. P. & Jacobsen, E. N. Privileged chiral catalysts. Science 299, 1691–1693 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Jacobsen, E. N., Pfaltz, A. & Yamamoto, H. (eds) Comprehensive Asymmetric Catalysis Vols 1–3 (Springer, 1999).

  3. Ojima, I. (ed.) Catalytic Asymmetric Synthesis (Wiley, 2010).

  4. Ma, L., Abney, C. & Lin, W. Enantioselective catalysis with homochiral metal–organic frameworks. Chem. Soc. Rev. 38, 1248–1256 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Huang, S., Yu, H. & Li, Q. Supramolecular chirality transfer toward chiral aggregation: asymmetric hierarchical self-assembly. Adv. Sci. 8, 2002132 (2021).

    Article  Google Scholar 

  6. Puchot, C. et al. Nonlinear effects in asymmetric synthesis. Examples in asymmetric oxidations and aldolization reactions. J. Am. Chem. Soc. 108, 2353–2357 (1986).

    Article  CAS  PubMed  Google Scholar 

  7. Guillaneux, D., Zhao, S.-H., Samuel, O., Rainford, D. & Kagan, H. B. Nonlinear effects in asymmetric catalysis. J. Am. Chem. Soc. 116, 9430–9439 (1994).

    Article  CAS  Google Scholar 

  8. Girard, C. & Kagan, H. B. Nonlinear effects in asymmetric synthesis and stereoselective reactions: ten years of investigation. Angew. Chem. Int. Ed. 37, 2922–2959 (1998).

    Article  Google Scholar 

  9. Satyanarayana, T., Abraham, S. & Kagan, H. B. Nonlinear effects in asymmetric catalysis. Angew. Chem. Int. Ed. 48, 456–494 (2009).

    Article  CAS  Google Scholar 

  10. Klussmann, M. et al. Thermodynamic control of asymmetric amplification in amino acid catalysis. Nature 441, 621–623 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Kalek, M. & Fu, G. C. Caution in the use of nonlinear effects as a mechanistic tool for catalytic enantioconvergent reactions: intrinsic negative nonlinear effects in the absence of higher-order species. J. Am. Chem. Soc. 139, 4225–4229 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ali, C., Blackmond, D. G. & Burés, J. Kinetic rationalization of nonlinear effects in asymmetric catalytic cascade reactions under Curtin–Hammett conditions. ACS Catal. 441, 5776–5785 (2022).

    Article  Google Scholar 

  13. Geiger, Y., Achard, T., Maisse-François, A. & Bellemin-Laponnaz, S. Hyperpositive nonlinear effects in asymmetric catalysis. Nat. Catal. 3, 422–426 (2020).

    Article  CAS  Google Scholar 

  14. Geiger, Y., Achard, T., Maisse‐François, A. & Bellemin‐Laponnaz, S. Observation of hyperpositive non-linear effect in catalytic asymmetric organozinc additions to aldehydes. Chirality 32, 1250–1256 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. Geiger, Y., Achard, T., Maisse-François, A. & Bellemin-Laponnaz, S. Hyperpositive non-linear effects: enantiodivergence and modelling. Chem. Sci. 11, 12453–12463 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Geiger, Y., Achard, T., Maisse‐François, A. & Bellemin‐Laponnaz, S. Absence of non‐linear effects despite evidence for catalyst aggregation. Eur. J. Org. Chem. 2021, 2916–2922 (2021).

    Article  CAS  Google Scholar 

  17. Thierry, T., Geiger, Y. & Bellemin-Laponnaz, S. Observation of hyperpositive non-linear effect in asymmetric organozinc alkylation in presence of N-pyrrolidinyl norephedrine. Molecules 27, 3780 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhou, Q.-L. (ed.) Privileged Chiral Ligands and Catalysts (Wiley, 2011).

  19. Kitamura, M., Okada, S., Suga, S. & Noyori, R. Enantioselective addition of dialkylzincs to aldehydes promoted by chiral amino alcohols. Mechanism and nonlinear effect. J. Am. Chem. Soc. 111, 4028–4036 (1989).

    Article  CAS  Google Scholar 

  20. Kitamura, M., Suga, S., Oka, H. & Noyori, R. Quantitative analysis of the chiral amplification in the amino alcohol-promoted asymmetric alkylation of aldehydes with dialkylzincs. J. Am. Chem. Soc. 120, 9800–9809 (1998).

    Article  CAS  Google Scholar 

  21. Pu, L. & Yu, H.-B. Catalytic asymmetric organozinc additions to carbonyl compounds. Chem. Rev. 101, 757–824 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Noyori, R. Asymmetric Catalysis in Organic Synthesis (Wiley, 1994).

  23. Soai, K., Ookawa, A., Ogawa, K. & Kaba, T. Complementary catalytic asymmetric induction in the enantioselective addition of diethylzinc to aldehydes. Chem. Commun. 7, 467–468 (1987).

    Article  Google Scholar 

  24. Soai, K., Ookawa, A., Kaba, T. & Ogawa, K. Catalytic asymmetric induction. Highly enantioselective addition of dialkylzincs to aldehydes using chiral pyrrolidinylmethanols and their metal salts. J. Am. Chem. Soc. 109, 7111–7115 (1987).

    Article  CAS  Google Scholar 

  25. Geiger, Y. & Bellemin‐Laponnaz, S. Non‐linear effects in asymmetric catalysis: impact of catalyst precipitation. ChemCatChem 14, e202200165 (2022).

    Article  CAS  Google Scholar 

  26. Burés, J. A simple graphical method to determine the order in catalyst. Angew. Chem. Int. Ed. 55, 2028–2031 (2016).

    Article  Google Scholar 

  27. Burés, J. Variable time normalization analysis: general graphical elucidation of reaction orders from concentration profiles. Angew. Chem. Int. Ed. 55, 16084–16087 (2016).

    Article  Google Scholar 

  28. Nielsen, C. D.-T. & Burés, J. Visual kinetic analysis. Chem. Sci. 10, 348–353 (2019).

    Article  CAS  PubMed  Google Scholar 

  29. Gesslbauer, S., Hutchinson, G., White, A. J. P., Burés, J. & Romain, C. Chirality-induced catalyst aggregation: insights into catalyst speciation and activity using chiral aluminum catalysts in cyclic ester ring-opening polymerization. ACS Catal. 11, 4084–4093 (2021).

    Article  CAS  Google Scholar 

  30. Alamillo-Ferrer, C., Hutchinson, G. & Burés, J. Mechanistic interpretation of orders in catalyst greater than one. Nat. Rev. Chem. 7, 26–34 (2023).

    Article  CAS  PubMed  Google Scholar 

  31. Nakano, K., Nozaki, K. & Hiyama, T. Asymmetric alternating copolymerization of cyclohexene oxide and CO2 with dimeric zinc complexes. J. Am. Chem. Soc. 125, 5501–5510 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Nakano, K., Hiyama, T. & Nozaki, K. Asymmetric amplification in asymmetric alternating copolymerization of cyclohexene oxide and carbon dioxide. Chem. Commun. 6, 467–468 (2005).

    Google Scholar 

  33. Dreisbach, C., Wischnewski, G., Kragl, U. & Wandrey, C. Changes of enantioselectivity with the substrate ratio for the addition of diethylzinc to aldehydes using a catalyst coupled to a soluble polymer. J. Chem. Soc. Perkin Trans. 1, 875–878 (1995).

    Article  Google Scholar 

  34. Trost, B. M., Fettes, A. & Shireman, B. T. Direct catalytic asymmetric aldol additions of methyl ynones. Spontaneous reversal in the sense of enantioinduction. J. Am. Chem. Soc. 126, 2660–2661 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Bryliakov, K. P. Dynamic nonlinear effects in asymmetric catalysis. ACS Catal. 9, 5418–5438 (2019).

    Article  CAS  Google Scholar 

  36. Griffiths, G. J. & Warm, A. Proposed mechanism for the enantioselective alkynylation of an aryl trifluoromethyl ketone, the key step in the synthesis of efavirenz. Org. Process Res. Dev. 20, 803–813 (2016).

    Article  CAS  Google Scholar 

  37. Mayer, L. C., Heitsch, S. & Trapp, O. Nonlinear effects in asymmetric catalysis by design: concept, synthesis, and applications. Acc. Chem. Res. 55, 3345–3361 (2022).

    Article  CAS  PubMed  Google Scholar 

  38. Trapp, O. in Supramolecular Catalysis Ch. 4 (eds van Leeuwen, P. W. N. M. & Raynal, M.) 55–67 (Wiley, 2022).

  39. Storch, G. & Trapp, O. By-design enantioselective self-amplification based on non-covalent product–catalyst interactions. Nat. Chem. 9, 179–187 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. Scholtes, J. F. & Trapp, O. Design and synthesis of a stereodynamic catalyst with reversal of selectivity by enantioselective self-inhibition. Chirality 31, 1028–1042 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Menke, J.-M. & Trapp, O. Controlling the enantioselectivity in an adaptable ligand by biomimetic intramolecular interlocking. J. Org. Chem. 87, 11165–11171 (2022).

    Article  CAS  PubMed  Google Scholar 

  42. Torres, M., Maisse-François, A. & Bellemin-Laponnaz, S. Highly recyclable self-supported chiral catalysts for the enantioselective α-hydrazination of β-ketoesters. ChemCatChem 5, 3078–3085 (2013).

    Article  CAS  Google Scholar 

  43. Bissessar, D., Achard, T. & Bellemin-Laponnaz, S. Robust and recyclable self-supported chiral nickel catalyst for the enantioselective Michael addition. Adv. Synth. Catal. 358, 1982–1988 (2016).

    Article  CAS  Google Scholar 

  44. Enthaler, S. Rise of the zinc age in homogeneous catalysis? ACS Catal. 3, 150–158 (2013).

    Article  CAS  Google Scholar 

  45. Athavale, S. V., Simon, A., Houk, K. N. & Denmark, S. E. Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies. Nat. Chem. 12, 412–423 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Athavale, S. V., Simon, A., Houk, K. N. & Denmark, S. E. Structural contributions to autocatalysis and asymmetric amplification in the Soai reaction. J. Am. Chem. Soc. 142, 18387–18406 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Trapp, O. et al. In situ mass spectrometric and kinetic investigations of Soai’s asymmetric autocatalysis. Chemistry 26, 15871–15880 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Trapp, O. Efficient amplification in Soai’s asymmetric autocatalysis by a transient stereodynamic catalyst. Front. Chem. 8, 615800 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Soai, K., Shibata, T., Morioka, H. & Choji, K. Asymmetric autocatalysis and amplification of enantiomeric excess of a chiral molecule. Nature 378, 767–768 (1995).

    Article  CAS  Google Scholar 

  50. Soai, K., Kawasaki, T. & Matsumoto, A. Asymmetric autocatalysis of pyrimidyl alkanol and related compounds. Self-replication, amplification of chirality and implication for the origin of biological enantioenriched chirality. Tetrahedron 74, 1973–1990 (2018).

    Article  CAS  Google Scholar 

  51. Geiger, Y. One Soai reaction, two mechanisms? Chem. Soc. Rev. 51, 1206–1211 (2022).

    Article  CAS  PubMed  Google Scholar 

  52. Xiang, S.-H. & Tan, B. Advances in asymmetric organocatalysis over the last 10 years. Nat. Commun. 11, 3786 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Han, B. et al. Asymmetric organocatalysis: an enabling technology for medicinal chemistry. Chem. Soc. Rev. 50, 1522–1586 (2021).

    Article  CAS  PubMed  Google Scholar 

  54. Aukland, M. H. & List, B. Organocatalysis emerging as a technology. Pure Appl. Chem. 93, 1371–1381 (2021).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Interdisciplinary Thematic Institute ITI-CSC via the IdEx Unistra (ANR-10-IDEX-0002) within the programme Investissement d’Avenir (T.T.) and the Ministère de l’Enseignement Supérieur et de la Recherche (MESR) for a PhD grant to Y.G. We thank the NMR department of CNRS FR2010 Strasbourg and in particular B. Vincent for his valuable studies. We also thank T. Achard, A. Maisse-François and E. Couzigné from IPCMS Strasbourg.

Author information

Author notes

  1. Yannick Geiger

    Present address: Institut de Science et d’Ingénierie Supramoléculaires, Université de Strasbourg–CNRS UMR 7006, Strasbourg, France

  2. These authors contributed equally: Thibault Thierry, Yannick Geiger.

Authors and Affiliations

  1. Institut de Physique et Chimie des Matériaux de Strasbourg, Université de Strasbourg–CNRS UMR 7504, Strasbourg, France

    Thibault Thierry, Yannick Geiger & Stéphane Bellemin-Laponnaz

Authors
  1. Thibault Thierry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yannick Geiger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stéphane Bellemin-Laponnaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.T. performed the synthetic experiments. Y.G. made the mathematical models and computed simulations. T.T., Y.G. and S.B.-L. performed the data analyses. S.B.-L. conceptualized and supervised the study, and wrote the manuscript with T.T. and Y.G.

Corresponding author

Correspondence to Stéphane Bellemin-Laponnaz.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks Oliver Trapp 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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

All details of syntheses, experimental procedures and mathematical treatments.

Supplementary Data 1

Spreadsheet program for ML models (Supplementary Information, sections 3.3 and 3.4).

Supplementary Data 2

Numerical experimental data for Supplementary Fig. 1.

Supplementary Data 3

Numerical experimental data for Supplementary Fig. 2.

Supplementary Data 4

Numerical experimental data for Supplementary Fig. 3.

Supplementary Data 5

Numerical experimental data for Supplementary Fig. 4.

Supplementary Data 6

Numerical experimental data for Supplementary Fig. 5.

Supplementary Data 7

Numerical experimental data for Supplementary Fig. 6.

Supplementary Data 8

Numerical experimental data for Supplementary Fig. 7.

Supplementary Data 9

Numerical experimental data for Supplementary Fig. 8.

Supplementary Data 10

Numerical experimental data for Supplementary Fig. 9.

Supplementary Data 11

Numerical experimental data for Supplementary Fig. 10.

Supplementary Data 12

Numerical experimental data for Supplementary Fig. 11.

Supplementary Data 13

Numerical simulation data for Supplementary Fig. 12.

Supplementary Data 14

Numerical experimental data for Supplementary Fig. 13.

Supplementary Data 15

Numerical experimental data for Supplementary Fig. 14.

Supplementary Data 16

Numerical experimental data for Supplementary Fig. 15.

Supplementary Data 17

Numerical experimental data for Supplementary Fig. 16.

Supplementary Data 18

Numerical experimental data for Supplementary Fig. 17.

Supplementary Data 19

Numerical simulation data for Supplementary Fig. 19.

Source data

Source Data Fig. 3

Numerical experimental data.

Source Data Fig. 4

Numerical experimental data.

Source Data Fig. 5

Numerical experimental data.

Source Data Fig. 7

Numerical simulation data.

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

Thierry, T., Geiger, Y. & Bellemin-Laponnaz, S. Divergence of catalytic systems in the zinc-catalysed alkylation of benzaldehyde mediated by chiral proline-based ligands. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00491-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s44160-024-00491-y

Search

Advanced search

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