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.

Approaching sub-ppm-level asymmetric organocatalysis of a highly challenging and scalable carbon–carbon bond forming reaction

Nature Chemistry volume 10, pages 888–894 (2018)Cite this article

Subjects

Abstract

The chemical synthesis of organic molecules involves, at its very essence, the creation of carbon–carbon bonds. In this context, the aldol reaction is among the most important synthetic methods, and a wide variety of catalytic and stereoselective versions have been reported. However, aldolizations yielding tertiary aldols, which result from the reaction of an enolate with a ketone, are challenging and only a few catalytic asymmetric Mukaiyama aldol reactions with ketones as electrophiles have been described. These methods typically require relatively high catalyst loadings, deliver substandard enantioselectivity or need special reagents or additives. We now report extremely potent catalysts that readily enable the reaction of silyl ketene acetals with a diverse set of ketones to furnish the corresponding tertiary aldol products in excellent yields and enantioselectivities. Parts per million (ppm) levels of catalyst loadings can be routinely used and provide fast and quantitative product formation in high enantiopurity. In situ spectroscopic studies and acidity measurements suggest a silylium ion based, asymmetric counteranion-directed Lewis acid catalysis mechanism.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Fig. 1: Representative examples of tertiary aldol-containing natural products and catalytic asymmetric routes to these moieties.
Fig. 2: Reactivity comparison of DSI C-1 and IDPi C-2 in the Mukaiyama aldol reaction of ketone as electrophile under identical reaction conditions.
Fig. 3: Mukaiyama aldol reaction of ketones on a preparative scale with catalyst loadings between 0.9 and 25 ppm.
Fig. 4: Study of the reaction mechanism.

References

  1. List, B. et al. A Catalytic enantioselective route to hydroxy-substituted quaternary carbon centers: resolution of tertiary aldols with a catalytic antibody. J. Am. Chem. Soc. 121, 7283–7291 (1999).

    Article  CAS  Google Scholar 

  2. Nelson, S. G. Catalyzed enantioselective aldol additions of latent enolate equivalents. Tetrahedron: Asymmetry 9, 357–389 (1998).

    Article  CAS  Google Scholar 

  3. Mahrwald, R. Diastereoselection in Lewis-acid-mediated aldol additions. Chem. Rev. 99, 1095–1120 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Machajewski, T. D. & Wong, C.-H. The catalytic asymmetric aldol reaction. Angew. Chem. Int. Ed. 39, 1352–1375 (2000).

    Article  CAS  Google Scholar 

  5. Mahrwald, R. Modern Aldol Reactions (Wiley-VCH, Weinheim, 2004).

  6. Mahrwald, R. Modern Methods in Stereoselective Aldol Reactions (Wiley-VCH, Weinheim, 2013).

  7. Cozzi, P. J., Hilgraf, R. & Zimmermann, N. Enantioselective catalytic formation of quaternary stereogenic centers. Eur. J. Org. Chem. 2007, 5969–5994 (2007).

    Article  CAS  Google Scholar 

  8. Hatano, M. & Ishihara, K. Recent progress in the catalytic synthesis of tertiary alcohols from ketones with organometallic reagents. Synthesis 2008, 1647–1675 (2008).

    Article  CAS  Google Scholar 

  9. Adachi, S. & Harada, T. Catalytic enantioselective aldol additions to ketones. Eur. J. Org. Chem. 2009, 3661–3671 (2009).

    Article  CAS  Google Scholar 

  10. Elliott, M. L., Urban, F. J. & Bordner, J. Synthesis and absolute configuration of (R)- and (S)-ethyl 3-(4-oxocyclohex-2-enyl)propionate. J. Org. Chem. 50, 1752–1755 (1985).

    Article  CAS  Google Scholar 

  11. Rodriguez, M. J. Process for performing retro-aldol reactions. US patent 5,677,423 (1996).

  12. Matovic, R., Ivkovic, A., Manojlovic, M., Tokic-Vujosevic, Z. & Saicic, R. N. Ring closing metathesis/fragmentation route to (Z)-configured medium ring cycloalkenes. Total synthesis of (±)-periplanone C. J. Org. Chem. 71, 9411–9419 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Hatano, M., Takagi, E. & Ishihara, K. Sodium phenoxide−phosphine oxides as extremely active Lewis base catalysts for the Mukaiyama aldol reaction with ketones. Org. Lett. 9, 4527–4530 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Kobayashi, S., Fujishita, Y. & Mukaiyama, T. The efficient catalytic asymmetric aldol-type reaction. Chem. Lett. 19, 1455–1458 (1990).

    Article  Google Scholar 

  15. Kan, S. B. J., Ng, K. K. H. & Paterson, I. The impact of the Mukaiyama aldol reaction in total synthesis. Angew. Chem. Int. Ed. 52, 9097–9108 (2013).

    Article  CAS  Google Scholar 

  16. Matsuo, J.-I & Murakami, M. The Mukaiyama adol reaction: 40 years of continuous development. Angew. Chem. Int. Ed. 52, 9109–9118 (2013).

    Article  CAS  Google Scholar 

  17. Denmark, S. E. & Fan, Y. Catalytic, enantioselective aldol additions to ketones. J. Am. Chem. Soc. 124, 4233–4235 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Denmark, S. E., Fan, Y. & Eastgate, M. D. Lewis base catalyzed, enantioselective aldol addition of methyl trichlorosilyl ketene acetal to ketones. J. Org. Chem. 70, 5235–5248 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Oisaki, K., Zhao, D., Kanai, M. & Shibasaki, M. Catalytic enantioselective aldol reaction to ketones. J. Am. Chem. Soc. 128, 7164–7165 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Moreau, X., Bazán-Tejeda, B. & Campagne, J.-M. Catalytic and asymmetric vinylogous Mukaiyama reactions on aliphatic ketones: formal asymmetric synthesis of taurospongin A. J. Am. Chem. Soc. 127, 7288–7289 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Kaib, P. S. J., Schreyer, L., Lee, S., Properzi, R. & List, B. Extremely active organocatalysts enable a highly enantioselective addition of allyltrimethylsilane to aldehydes. Angew. Chem. Int. Ed. 55, 13200–13203 (2016).

    Article  CAS  Google Scholar 

  22. Xie, Y. et al. Catalytic asymmetric vinylogous Prins cyclization: a highly diastereo- and enantioselective entry to tetrahydrofurans. J. Am. Chem. Soc. 138, 14538–14541 (2016).

    Article  CAS  PubMed  Google Scholar 

  23. Lee, S., Kaib, P. S. J. & List, B. Asymmetric catalysis via cyclic, aliphatic oxocarbenium ions. J. Am. Chem. Soc. 139, 2156–2159 (2017).

    Article  CAS  PubMed  Google Scholar 

  24. Liu, L. et al. Catalytic asymmetric [4+2]-cycloaddition of dienes with aldehydes. J. Am. Chem. Soc. 139, 13656–13659 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Gatzenmeier, T., Kaib, P. S. J., Lingnau, J. B., Goddard, R. & List, B. The catalytic asymmetric Mukaiyama–Michael reaction of silyl ketene acetals with α,β-unsaturated methyl esters. Angew. Chem. Int. Ed. 57, 2464–2468 (2018).

    Article  CAS  Google Scholar 

  26. Mahlau, M. & List, B. Asymmetric counteranion-directed catalysis: concept, definition, and applications. Angew. Chem. Int. Ed. 52, 518–533 (2013).

    Article  CAS  Google Scholar 

  27. García-García, P., Lay, F., García-García, P., Rabalakos, C. & List, B. A powerful chiral counteranion motif for asymmetric catalysis. Angew. Chem. Int. Ed. 48, 4363–4366 (2009).

    Article  CAS  Google Scholar 

  28. Ratjen, L., Garcia-Garcia, P., Lay, F., Beck, M. E. & List, B. Disulfonimide-catalyzed asymmetric vinylogous and bisvinylogous Mukaiyama aldol reactions. Angew. Chem. Int. Ed. 50, 754–758 (2011).

    Article  CAS  Google Scholar 

  29. Tap, A., Blond, A., Wakchaure, V. N. & List, B. Chiral allenes via alkynylogous Mukaiyama aldol reaction. Angew. Chem. Int. Ed. 55, 8962–8965 (2016).

    Article  CAS  Google Scholar 

  30. van Gemmeren, M., Lay, F. & List, B. Asymmetric catalysis using chiral, enantiopure disulfonimides. Aldrichimica Acta 47, 3–13 (2014).

    Google Scholar 

  31. James, T., van Gemmeren, M. & List, B. Development and applications of disulfonimides in enantioselective organocatalysis. Chem. Rev. 115, 9388–9409 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Giacalone, F., Gruttadauria, M., Agrigento, P. & Noto, R. Low-loading asymmetric organocatalysis. Chem. Soc. Rev. 41, 2406–2447 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Park, S. Y., Lee, J.-W. & Song, C. E. Parts-per-million level loading organocatalysed enantioselective silylation of alcohols. Nat. Commun. 6, 7512 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xu, W. et al. Metal-templated design: enantioselective hydrogen-bond-driven catalysis requiring only parts-per-million catalyst loading. J. Am. Chem. Soc. 138, 8774–8780 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Zhang, Z. & List, B. Kinetics of the chiral disulfonimide-catalyzed Mukaiyama aldol reaction. Asian J. Org. Chem. 2, 957–960 (2013).

    Article  CAS  Google Scholar 

  36. Zhang, Z. et al. Asymmetric counteranion-directed Lewis acid organocatalysis for the scalable cyanosilylation of aldehydes. Nat. Commun. 7, 12478 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Song, J. J. et al. N-Heterocyclic carbene-catalyzed silyl enol ether formation. Org. Lett. 10, 877–880 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Support from the Max Planck Society, the Deutsche Forschungsgemeinschaft (Leibniz Award to B.L. and Cluster of Excellence RESOLV, EXC 1069) and the European Research Council (Advanced Grant ‘C–H Acids for Organic Synthesis, CHAOS’) is acknowledged. The authors thank J.L. Kennemur for her suggestions during the preparation of this manuscript, P. Gupta for his assistance on the preparation of artwork, the technicians of our group, and the members of our NMR, MS and HPLC departments for their excellent service. The work of K.K. and I.L. was supported by grant IUT20-14 from the Estonian Ministry of Education and Research. This paper is dedicated to Prof. T. Mukaiyama in celebration of his 90th birthday (Sotsuju).

Author information

Authors and Affiliations

  1. Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany

    Han Yong Bae, Denis Höfler, Philip S. J. Kaib, Pinar Kasaplar, Chandra Kanta De, Arno Döhring, Sunggi Lee & Benjamin List

  2. University of Tartu, Institute of Chemistry, Tartu, Estonia

    Karl Kaupmees & Ivo Leito

Authors
  1. Han Yong Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Denis Höfler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip S. J. Kaib
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pinar Kasaplar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chandra Kanta De
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Arno Döhring
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sunggi Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Karl Kaupmees
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ivo Leito
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Benjamin List
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.Y.B. developed the reaction and investigated the substrate scope, derivatizations of the aldol products, and implemented in situ FT-IR study. D.H. first observed the high activity of IDPi catalysts in the described reaction. The IDPi catalysts were developed by H.Y.B., P.S.J.K. and B.L. H.Y.B., P.S.J.K., P.K. and S.L. synthesized the IDPi catalysts used in this study. H.Y.B., C.K.D. and A.D. investigated large-scale and low-catalyst loading experiments. K.K. and I.L. measured pKa values of acid catalysts. B.L. designed and oversaw the project. H.Y.B. and B.L. wrote the manuscript.

Corresponding author

Correspondence to Benjamin List.

Ethics declarations

Competing interests

The authors declare no competing interests.

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 experimental data, synthetic procedures and chemical compound characterization data

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bae, H.Y., Höfler, D., Kaib, P.S.J. et al. Approaching sub-ppm-level asymmetric organocatalysis of a highly challenging and scalable carbon–carbon bond forming reaction. Nature Chem 10, 888–894 (2018). https://doi.org/10.1038/s41557-018-0065-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-018-0065-0

This article is cited by

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