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:

Enantioselective aldol reactions with masked fluoroacetates

Nature Chemistry volume 8, pages 276–280 (2016)Cite this article

Subjects

Abstract

Despite the growing importance of organofluorines as pharmaceuticals and agrochemicals, the stereoselective introduction of fluorine into many prominent classes of natural products and chemotherapeutic agents is difficult. One long-standing unsolved challenge is the enantioselective aldol reaction of fluoroacetate to enable access to fluorinated analogues of medicinally relevant acetate-derived compounds, such as polyketides and statins. Herein we present fluoromalonic acid halfthioesters as biomimetic surrogates of fluoroacetate and demonstrate their use in highly stereoselective aldol reactions that proceed under mild organocatalytic conditions. We also show that the methodology can be extended to formal aldol reactions with fluoroacetaldehyde and consecutive aldol reactions. The synthetic utility of the fluorinated aldol products is illustrated by the synthesis of a fluorinated derivative of the top-selling drug atorvastatin. The results show the prospects of the method for the enantioselective introduction of fluoroacetate to access a wide variety of highly functionalized fluorinated compounds.

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

Figure 1: Fluorination of therapeutic agents.
Figure 2: Fluoromalonates as surrogates of fluoroacetate.
Figure 3: Derivatization of fluorinated aldol products.
Figure 4: Applications of fluorothioacetate aldol products.

Similar content being viewed by others

References

  1. Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology (Blackwell Publishing Ltd, 2009).

    Book  Google Scholar 

  2. Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007).

    Article  Google Scholar 

  3. Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).

    Article  CAS  Google Scholar 

  4. O'Hagan, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 37, 308–319 (2008).

    Article  CAS  Google Scholar 

  5. Wang, J. et al. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011). Chem. Rev. 114, 2432–2506 (2013).

    Article  Google Scholar 

  6. Fried, J. & Sabo, E. F. 9α-Fluoro derivatives of cortisone and hydrocortisone. J. Am. Chem. Soc. 76, 1455–1456 (1954).

    Article  CAS  Google Scholar 

  7. Walker, M. C. & Chang, M. C. Y. Natural and engineered biosynthesis of fluorinated natural products. Chem. Soc. Rev. 43, 6527–6536 (2014).

    Article  CAS  Google Scholar 

  8. Furuya, T., Kamlet, A. S. & Ritter, T. Catalysis for fluorination and trifluoromethylation. Nature 473, 470–477 (2011).

    Article  CAS  Google Scholar 

  9. Yang, X., Wu, T., Phipps, R. J. & Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 115, 826–870 (2015).

    Article  CAS  Google Scholar 

  10. Khosla, C., Herschlag, D., Cane, D. E. & Walsh, C. T. Assembly line polyketide synthases: mechanistic insights and unsolved problems. Biochemistry 53, 2875–2883 (2014).

    Article  CAS  Google Scholar 

  11. Mahrwald, R. Modern Methods in Stereoselective Aldol Reactions (Wiley-VCH Verlag GmbH & Co., 2013).

    Book  Google Scholar 

  12. Welch, J. T., Seper, K., Eswarakrishnan, S. & Samartino, J. Preparation of α-fluoro enolates and their use in the directed aldol reaction. J. Org. Chem. 49, 4720–4721 (1984).

    Article  CAS  Google Scholar 

  13. Welch, J. T. & Plummer, J. S. The stereoselective aldol condensation of α-fluoroacetates. Synth. Comm. 19, 1081–1090 (1989).

    Article  CAS  Google Scholar 

  14. Linderman, R. J. & Graves, D. M. Oxidation of fluoroalkyl-substituted carbinols by the Dess–Martin reagent. J. Org. Chem. 54, 661–668 (1989).

    Article  CAS  Google Scholar 

  15. Huang, X.-T. & Chen, Q.-Y. Ethyl α-fluoro silyl enol ether: stereoselective synthesis and its aldol reaction with aldehydes and ketones. J. Org. Chem. 67, 3231–3234 (2002).

    Article  CAS  Google Scholar 

  16. Saadi, J., Akakura, M. & Yamamoto, H. Rapid, one-pot synthesis of β-siloxy-α-haloaldehydes. J. Am. Chem. Soc. 133, 14248–14251 (2011).

    Article  CAS  Google Scholar 

  17. Walker, M. C. et al. Expanding the fluorine chemistry of living systems using engineered polyketide synthase pathways. Science 341, 1089–1094 (2013).

    Article  CAS  Google Scholar 

  18. Orlandi, S., Benaglia, M. & Cozzi, F. Cu(II)-catalyzed enantioselective aldol condensation between malonic acid hemithioesters and aldehydes. Tetrahedron Lett. 45, 1747–1749 (2004).

    Article  CAS  Google Scholar 

  19. Magdziak, D. et al. Catalytic enantioselective thioester aldol reactions that are compatible with protic functional groups. J. Am. Chem. Soc. 127, 7284–7285 (2005).

    Article  CAS  Google Scholar 

  20. Ricci, A. et al. Organocatalytic enantioselective decarboxylative addition of malonic half thioesters to imines. Adv. Synth. Catal. 349, 1037–1040 (2007).

    Article  CAS  Google Scholar 

  21. Lubkoll, J. & Wennemers, H. Mimicry of polyketide synthases—enantioselective 1,4-addition reactions of malonic acid half-thioesters to nitroolefins. Angew. Chem. Int. Ed. 46, 6841–6844 (2007).

    Article  CAS  Google Scholar 

  22. Bae, H. Y., Sim, J. H., Lee, J.-W., List, B. & Song, C. E. Organocatalytic enantioselective decarboxylative aldol reaction of malonic acid half thioesters with aldehydes. Angew. Chem. Int. Ed. 52, 12143–12147 (2013).

    Article  CAS  Google Scholar 

  23. Nakamura, S., Sano, M., Toda, A., Nakane, D. & Masuda, H. Organocatalytic enantioselective decarboxylative reaction of malonic acid half thioesters with cyclic N-sulfonyl ketimines by using N-heteroarenesulfonyl cinchona alkaloid amides. Chem. Eur. J. 21, 3929–3932 (2015).

    Article  CAS  Google Scholar 

  24. Furutachi, M., Mouri, S., Matsunaga, S. & Shibasaki, M. A heterobimetallic Ni/La-salan complex for catalytic asymmetric decarboxylative 1,4-addition of malonic acid half-thioester. Chem. Asian J. 5, 2351–2354 (2010).

    Article  CAS  Google Scholar 

  25. Pan, Y. et al. Expanding the utility of Brønsted base catalysis: biomimetic enantioselective decarboxylative reactions. Chem. Eur. J. 17, 8363–8370 (2011).

    Article  CAS  Google Scholar 

  26. Rigo, B., Fasseur, D., Cauliez, P. & Couturier, D. Reaction of trimethylsilyl derivatives with Meldrum's acid: a new and easy monofunctionalization of malonic acid. Tetrahedron Lett. 30, 3073–3076 (1989).

    Article  CAS  Google Scholar 

  27. Pohl, N. L., Gokhale, R. S., Cane, D. E. & Khosla, C. Synthesis and incorporation of an N-acetylcysteamine analogue of methylmalonyl–CoA by a modular polyketide synthase. J. Am. Chem. Soc. 120, 11206–11207 (1998).

    Article  CAS  Google Scholar 

  28. Arakawa, Y., Fritz, S. P. & Wennemers, H. Organocatalytic stereoselective synthesis of acyclic γ-nitrothioesters with all-carbon quaternary stereogenic centers. J. Org. Chem. 79, 3937–3945 (2014).

    Article  CAS  Google Scholar 

  29. Bahlinger, A., Fritz, S. P. & Wennemers, H. Stereoselective metal-free synthesis of β-amino thioesters with tertiary and quaternary stereogenic centers. Angew. Chem. Int. Ed. 53, 8779–8783 (2014).

    Article  CAS  Google Scholar 

  30. Brak, K. & Jacobsen, E. N. Asymmetric ion-pairing catalysis. Angew. Chem. Int. Ed. 52, 534–561 (2013).

    Article  CAS  Google Scholar 

  31. Bordwell, F. G. Equilibrium acidities in dimethyl sulfoxide solution. Acc. Chem. Res. 21, 456–463 (1988).

    Article  CAS  Google Scholar 

  32. Krautwald, S., Sarlah, D., Schafroth, M. A. & Carreira, E. M. Enantio- and diastereodivergent dual catalysis: α-allylation of branched aldehydes. Science 340, 1065–1068 (2013).

    Article  CAS  Google Scholar 

  33. Kitagaki, J., Shi, G., Miyauchi, S., Murakami, S. & Yang, Y. Cyclic depsipeptides as potential cancer therapeutics. Anti-Cancer Drugs 26, 259–271 (2015).

    Article  CAS  Google Scholar 

  34. Oláh, G. & Kuhn, S. Darstellung und Untersuchung Organischer Fluorverbindungen XXI. Darstellung von Fluoracetaldehyd und Aliphatischen Fluormethylketonen. Chem. Ber. 89, 864–865 (1956).

    Article  Google Scholar 

  35. Tabernero, L., Bochar, D. A., Rodwell, V. W. & Stauffacher, C. V. Substrate-induced closure of the flap domain in the ternary complex structures provides insights into the mechanism of catalysis by 3-hydroxy-3-methylglutaryl–CoA reductase. Proc. Natl Acad. Sci. USA 96, 7167–7171 (1999).

    Article  CAS  Google Scholar 

  36. Wang, Z. et al. Molecular modeling studies of atorvastatin analogues as HMGR inhibitors using 3D-QSAR, molecular docking and molecular dynamics simulations. Bioorg. Med. Chem. Lett. 24, 3869–3876 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the Swiss National Science Foundation for financial support of this work. We thank N. Trapp and the SMoCC facility of D-CHAB at ETH Zurich for recording the X-ray crystal structure. We dedicate this article to Professor Albert Eschenmoser on the occasion of his 90th birthday.

Author information

Authors and Affiliations

  1. Laboratory of Organic Chemistry, ETH Zurich, Vladimir-Prelog-Weg 3, Zurich, CH-8093, Switzerland

    Jakub Saadi & Helma Wennemers

Authors
  1. Jakub Saadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helma Wennemers
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.S. conducted the experiments. J.S. and H.W. conceived and designed the project, analysed the data and prepared the manuscript.

Corresponding author

Correspondence to Helma Wennemers.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 6459 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saadi, J., Wennemers, H. Enantioselective aldol reactions with masked fluoroacetates. Nature Chem 8, 276–280 (2016). https://doi.org/10.1038/nchem.2437

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.2437

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