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 construction of remote tertiary carbon–fluorine bonds

Nature Chemistry volume 11, pages 710–715 (2019)Cite this article

Subjects

Abstract

The carbon–fluorine bond engenders distinctive physicochemical properties and significant changes to general reactivity. The development of catalytic, enantioselective methods to set stereocentres that contain a benzylic C–F bond is a rapidly evolving goal in synthetic chemistry. Although there have been notable advances that enable the construction of secondary stereocentres that contain both a C–F and a C–H bond on the same carbon, significantly fewer strategies are defined to access stereocentres that incorporate a tertiary C–F bond, especially those remote from pre-existing activating groups. Here we report a general method that establishes C–F tertiary benzylic stereocentres by forging a C–C bond via a Pd-catalysed enantioselective Heck reaction of acyclic alkenyl fluorides with arylboronic acids. This method provides a platform to rapidly incorporate significant functionality about the benzylic tertiary fluoride by virtue of the diversity of both reaction partners, as well as the ability to install the stereocentres remotely from pre-existing functional groups.

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: Constructing chiral, non-racemic tertiary fluorides.
Fig. 2: Evaluation of alkene substrates to establish remote stereocentres and mechanistic studies.

Similar content being viewed by others

Data availability

All the characterization data and experimental protocols are provided in this article and its Supplementary Information. Data are also available from the corresponding author upon request.

References

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J. & Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 58, 8315–8359 (2015).

    Article  CAS  Google Scholar 

  4. Zhu, Y. et al. Modern approaches for asymmetric construction of carbon−fluorine quaternary stereogenic centers: synthetic challenges and pharmaceutical needs. Chem. Rev. 118, 3887–3964 (2018).

    Article  CAS  Google Scholar 

  5. Ma, J.-A. & Cahard, D. Asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions. Chem. Rev. 104, 6119–6146 (2004).

    Article  CAS  Google Scholar 

  6. Brunet, V. A. & O’Hagan, D. Catalytic asymmetric fluorination comes of age. Angew. Chem. Int. Ed. 47, 1179–1182 (2008).

    Article  CAS  Google Scholar 

  7. 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 

  8. Differding, E. & Lang, R. W. New fluorinating reagents—I. The first enantioselective fluorination reaction. Tetrahedron Lett. 29, 6087–6090 (1988).

    Article  CAS  Google Scholar 

  9. Shibata, N., Suzuki, E., Asahi, T. & Shiro, M. Enantioselective fluorination mediated by cinchona alkaloid derivatives/selectfluor combinations: reaction scope and structural information for N-fluorocinchona alkaloids. J. Am. Chem. Soc. 123, 7001–7009 (2001).

    Article  CAS  Google Scholar 

  10. Mohar, B., Baudoux, J., Plaquevent, J.-C. & Cahard, D. Electrophilic fluorination mediated by cinchona alkaloids: highly enantioselective synthesis of α-fluoro-α-phenylglycine derivatives. Angew. Chem. Int. Ed. 40, 4214–4216 (2001).

    Article  CAS  Google Scholar 

  11. Marigo, M., Fielenbach, D., Braunton, A., Kjærsgaard, A. & Jørgensen, K. A. Enantioselective formation of stereogenic carbon−fluorine centers by a simple catalytic method. Angew. Chem. Int. Ed. 44, 3703–3706 (2005).

    Article  CAS  Google Scholar 

  12. Steiner, D. D., Mase, N. & Barbas, C. F. Direct asymmetric α-fluorination of aldehydes. Angew. Chem. Int. Ed. 44, 3706–3710 (2005).

    Article  CAS  Google Scholar 

  13. Shibatomi, K., Kitahara, K., Okimi, T., Abe, Y. & Iwasa, S. Enantioselective fluorination of α-branched aldehydes and subsequent conversion to α-hydroxyacetals via stereospecific C−F bond cleavage. Chem. Sci. 7, 1388–1392 (2016).

    Article  CAS  Google Scholar 

  14. You, Y., Zhang, L. & Luo, S. Reagent-controlled enantioselectivity switch for the asymmetric fluorination of β-ketocarbonyls by chiral primary amine catalysis. Chem. Sci. 8, 621–626 (2017).

    Article  CAS  Google Scholar 

  15. Shibata, N. et al. Highly enantioselective catalytic fluorination and chlorination reactions of carbonyl compounds capable of two-point binding. Angew. Chem. Int. Ed. 44, 4204–4207 (2005).

    Article  CAS  Google Scholar 

  16. Reddy, D. S. et al. Desymmetrization-like catalytic enantioselective fluorination of malonates and its application to pharmaceutically attractive molecules. Angew. Chem. Int. Ed. 47, 164–168 (2008).

    Article  CAS  Google Scholar 

  17. Jiao, Z. et al. Palladium-catalyzed enantioselective α-arylation of α-fluoroketones. J. Am. Chem. Soc. 138, 15980–15986 (2016).

    Article  CAS  Google Scholar 

  18. Bélanger, É., Cantin, K., Messe, O., Tremblay, M. & Paquin, J.-F. Enantioselective Pd-catalyzed allylation reaction of fluorinated silyl enol ethers. J. Am. Chem. Soc. 129, 1034–1035 (2007).

    Article  Google Scholar 

  19. Liang, Y. & Fu, G. C. Catalytic asymmetric synthesis of tertiary alkyl fluorides: Negishi cross-couplings of racemic α,α-dihaloketones. J. Am. Chem. Soc. 136, 5520–5524 (2014).

    Article  CAS  Google Scholar 

  20. Han, X., Kwiatkowski, J., Xue, F., Huang, K. W. & Lu, Y. Asymmetric Mannich reaction of fluorinated ketoesters with a tryptophan-derived bifunctional thiourea catalyst. Angew. Chem. Int. Ed. 48, 7604–7607 (2009).

    Article  CAS  Google Scholar 

  21. Xie, C., Wu, L., Han, J., Soloshonok, V. A. & Pan, Y. Assembly of fluorinated quaternary stereogenic centers through catalytic enantioselective detrifluoroacetylative aldol reactions. Angew. Chem. Int. Ed. 54, 6019–6023 (2015).

    Article  CAS  Google Scholar 

  22. Ishimaru, T. et al. Cinchona alkaloid catalyzed enantioselective fluorination of allyl silanes, silyl enol ethers, and oxindoles. Angew. Chem. Int. Ed. 47, 4157–4161 (2008).

    Article  CAS  Google Scholar 

  23. Wu, J. et al. A combination of directing groups and chiral anion phase-transfer catalysis for enantioselective fluorination of alkenes. Proc. Natl Acad. Sci. USA 110, 13729–13733 (2013).

    Article  CAS  Google Scholar 

  24. Lozano, O. et al. Organocatalyzed enantioselective fluorocyclizations. Angew. Chem. Int. Ed. 50, 8105–8109 (2011).

    Article  CAS  Google Scholar 

  25. Wolstenhulme, J. R. & Gouverneur, V. Asymmetric fluorocyclizations of alkenes. Acc. Chem. Res. 47, 3560–3570 (2014).

    Article  CAS  Google Scholar 

  26. Rauniyar, V., Lackner, A. D., Hamilton, G. L. & Toste, F. D. Asymmetric electrophilic fluorination using an anionic chiral phase-transfer catalyst. Science 334, 1681–1684 (2011).

    Article  CAS  Google Scholar 

  27. Shunatona, H. P., Früh, N., Wang, Y.-M., Rauniyar, V. & Toste, F. D. Enantioselective fluoroamination: 1,4-addition to conjugated dienes using anionic phase-transfer catalysis. Angew. Chem. Int. Ed. 52, 7724–7727 (2013).

    Article  CAS  Google Scholar 

  28. Egami, H. et al. Dianionic phase-transfer catalyst for asymmetric fluoro-cyclization. J. Am. Chem. Soc. 140, 2785–2788 (2018).

    Article  CAS  Google Scholar 

  29. Butcher, T. W. & Hartwig, J. F. Enantioselective synthesis of tertiary allylic fluorides by iridium-catalyzed allylic fluoroalkylation. Angew. Chem. Int. Ed. 57, 13125–13129 (2018).

    Article  CAS  Google Scholar 

  30. Mei, T.-S., Patle, H. H. & Sigman, M. S. Enantioselective construction of remote quaternary stereocentres. Nature 508, 340–344 (2014).

    Article  CAS  Google Scholar 

  31. Mei, T.-S., Werner, E. W., Burckle, A. J. & Sigman, M. S. Enantioselective redox-relay oxidative Heck arylations of acyclic alkenyl alcohols using boronic acids. J. Am. Chem. Soc. 135, 6830–6833 (2013).

    Article  CAS  Google Scholar 

  32. Amii, H. & Uneyama, K. C–F bond activation in organic synthesis. Chem. Rev. 109, 2119–2183 (2009).

    Article  CAS  Google Scholar 

  33. Heitz, W. & Knebelkamp, A. Synthesis of fluorostyrenes via palladium-catalyzed reactions of aromatic halides with fluoroolefins. Macromol. Chem. Rapid Commun. 12, 69–75 (1991).

    Article  CAS  Google Scholar 

  34. Patrick, T. B., Agboka, T. Y. & Gorrell, K. Heck reaction with 3-fluoro-3-buten-2-one. J. Fluor. Chem. 129, 983–985 (2008).

    Article  CAS  Google Scholar 

  35. Rousée, K., Bouillon, J.-P., Couve-Bonnaire, S. & Pannecoucke, X. Stereospecific synthesis of tri- and tetrasubstituted α-fluoroacrylates by Mizoroki–Heck reaction. Org. Lett. 18, 540–543 (2016).

    Article  Google Scholar 

  36. Hirotaki, K. & Hanamoto, T. Mizoroki–Heck reaction of (1-fluorovinyl)methyldiphenylsilane with aryl iodides. J. Org. Chem. 76, 8564–8568 (2011).

    Article  CAS  Google Scholar 

  37. Thornbury, R. T. & Toste, F. D. Palladium-catalyzed defluorinative coupling of 1-aryl-2,2-difluoroalkenes and boronic acids: stereoselective synthesis of monofluorostilbenes. Angew. Chem. Int. Ed. 55, 11629–11632 (2016).

    Article  CAS  Google Scholar 

  38. Yang, J., Zhao, H.-W., He, J. & Zhang, C.-P. Pd-catalyzed Mizoroki–Heck reactions using fluorine-containing agents as the cross-coupling partners. Catalysts 8, 23–57 (2018).

    Article  Google Scholar 

  39. Werner, E. W., Mei, T.-S., Burckle, A. J. & Sigman, M. S. Enantioselective Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy. Science 338, 1455–1458 (2012).

    Article  CAS  Google Scholar 

  40. Wada, S. & Jordan, R. F. Olefin insertion into a Pd–F bond: catalyst reactivation following β-F elimination in ethylene/vinyl fluoride copolymerization. Angew. Chem. Int. Ed. 56, 1820–1824 (2017).

    Article  CAS  Google Scholar 

  41. Lee, S. H. & Schwartz, J. Stereospecific synthesis of alkenyl fluorides (with retention) via organometallic intermediates. J. Am. Chem. Soc. 108, 2445–2447 (1986).

    Article  CAS  Google Scholar 

  42. Furuya, T. & Ritter, T. Fluorination of boronic acids mediated by silver(i) triflate. Org. Lett. 11, 2860–2863 (2009).

    Article  CAS  Google Scholar 

  43. O’Connor, T. J. & Toste, F. D. Gold-catalyzed hydrofluorination of electron-deficient alkynes: stereoselective synthesis of β‐fluoro Michael acceptors. ACS Catal. 8, 5947–5951 (2018).

    Article  Google Scholar 

  44. Jana, R., Pathak, T. P. & Sigman, M. S. Advances in transition metal (Pd,Ni,Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners. Chem. Rev. 111, 1417–1492 (2011).

    Article  CAS  Google Scholar 

  45. Hilton, M. J. et al. Relative reactivity of alkenyl alcohols in the palladium-catalyzed redox-relay Heck reaction. Tetrahedron 71, 6513–6518 (2015).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge financial support from the National Institutes of Health (NIGMS RO1 GM063540). J.L. thanks the Shanghai institute of Organic Chemistry, Chinese Academy of Sciences (SIOC), for a postdoctoral fellowship. Q.Y. acknowledges Shanghai Jiao Tong University for a postdoctoral fellowship.

Author information

Authors and Affiliations

  1. Department of Chemistry, The University of Utah, Salt Lake City, UT, USA

    Jianbo Liu, Qianjia Yuan & Matthew S. Sigman

  2. Department of Chemistry, University of California, Berkeley, CA, USA

    F. Dean Toste

Authors
  1. Jianbo Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qianjia Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Dean Toste
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthew S. Sigman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.L. and Q.Y. performed the experiments and analysed the data. J.L, F.D.T. and M.S.S. designed the experiments. M.S.S. prepared this manuscript with feedback from F.D.T. and J.L.

Corresponding author

Correspondence to Matthew S. Sigman.

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 details and compound characterization data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, J., Yuan, Q., Toste, F.D. et al. Enantioselective construction of remote tertiary carbon–fluorine bonds. Nat. Chem. 11, 710–715 (2019). https://doi.org/10.1038/s41557-019-0289-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-019-0289-7

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