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.

Simple organic molecules as catalysts for enantioselective synthesis of amines and alcohols

Nature volume 494, pages 216–221 (2013)Cite this article

Subjects

Abstract

The discovery of catalysts that can be used to synthesize complex organic compounds by enantioselective transformations is central to advances in the life sciences1; for this reason, many chemists aim to discover catalysts that allow for preparation of chiral molecules as predominantly one mirror-image isomer2. The ideal catalyst should not contain precious elements3 and should bring reactions to completion in a few hours through operationally simple procedures. Here we introduce a set of small organic molecules that can catalyse reactions of unsaturated organoboron reagents with imines and carbonyls; the products of the reactions are enantiomerically pure amines and alcohols, which might serve as intermediates in the preparation of biologically active molecules. A distinguishing feature of this catalyst class is the presence of a ‘key’ proton embedded within their structure. Catalysts are derived from the abundant amino acid valine and are prepared in large quantities in four steps with inexpensive reagents. Reactions are scalable, do not demand stringent conditions, and can be performed with as little as 0.25 mole per cent catalyst in less than six hours at room temperature to generate products in more than 85 per cent yield and ≥97:3 enantiomeric ratio. The efficiency, selectivity and operational simplicity of the transformations and the range of boron-based reagents are expected to render this advance important for future progress in syntheses of amines and alcohols, which are useful in chemistry, biology and medicine.

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

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: The significance of homoallylic amines and alcohols illustrated by three approaches to their catalytic enantioselective synthesis.
Figure 2: Chiral amino alcohols as candidates for catalyst precursors.
Figure 3: Efficient and enantioselective catalytic allyl additions to aldimines.
Figure 4: Practical, scalable and highly α-selective catalytic enantioselective allyl additions to imines.
Figure 5: Catalytic enantioselective additions to isatins and reactions with an allenylboron reagent.

References

  1. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009)

    Article  CAS  Google Scholar 

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

  3. Nakamura, E. & Sato, K. Managing the scarcity of chemical elements. Nature Mater. 10, 158–161 (2011)

    Article  ADS  CAS  Google Scholar 

  4. Yus, M., González-Gómez, J. C. & Foubelo, F. Catalytic enantioselective allylation of carbonyl compounds and imines. Chem. Rev. 111, 7774–7854 (2011)

    Article  CAS  Google Scholar 

  5. Borzilleri, R. M. et al. A novel application of a Pd(0)-catalyzed nucleophilic substitution reaction to the regio- and stereoselective synthesis of lactam analogues of the epothilone natural products. J. Am. Chem. Soc. 122, 8890–8897 (2000)

    Article  CAS  Google Scholar 

  6. Sirasani, G. & Andrade, R. B. Total synthesis of (–)-leuconicine A and B. Org. Lett. 13, 4736–4737 (2011)

    Article  CAS  Google Scholar 

  7. Xie, W., Zhou, B., Pei, D. & Ma, D. Total synthesis of cyclic tetrapeptide FR235222, a potent immunosuppressant that inhibits mammalian histone deacetylases. Org. Lett. 7, 2775–2777 (2005)

    Article  CAS  Google Scholar 

  8. Kim, S. J. & Jang, D. O. Indium-mediated catalytic enantioselective allylation of N-benzoylhydrazones using a protonated chiral amine. J. Am. Chem. Soc. 132, 12168–12169 (2010)

    Article  CAS  Google Scholar 

  9. Tan, K. L. & Jacobsen, E. N. Indium-mediated asymmetric allylation of acylhydrazones using a chiral urea catalyst. Angew. Chem. Int. Edn 46, 1315–1317 (2007)

    Article  CAS  Google Scholar 

  10. Kargbo, R. et al. Readily accessible, modular, and tunable BINOL 3,3′-perfluoroalkylsulfones: highly efficient catalysts for enantioselective In-mediated imine allylation. J. Am. Chem. Soc. 129, 3846–3847 (2007)

    Article  CAS  Google Scholar 

  11. Aydin, J., Kumar, K.-s., Sayah, M. J., Wallner, O. A. & Szabó, K. J. Synthesis and catalytic application of chiral 1,1′-bi-2-naphthol and biphenanthrol-based pincer complexes: selective allylation of sulfonimines with allyl stannane and allyl trifluoroborate. J. Org. Chem. 72, 4689–4697 (2007)

    Article  CAS  Google Scholar 

  12. Wada, R. et al. Catalytic enantioselective allylation of ketoimines. J. Am. Chem. Soc. 128, 7687–7691 (2006)

    Article  CAS  Google Scholar 

  13. Lou, S., Moquist, P. N. & Schaus, S. E. Asymmetric allylboration of acyl imines catalyzed by chiral diols. J. Am. Chem. Soc. 129, 15398–15404 (2007)

    Article  CAS  Google Scholar 

  14. Chakrabarti, A., Konishi, H., Yamaguchi, M., Schneider, U. & Kobayashi, S. Indium(I)-catalyzed asymmetric allylation, crotylation, and α-chloroallylation of hydrazones with rare constitutional and high configurational selectivities. Angew. Chem. Int. Edn 49, 1838–1841 (2010)

    Article  CAS  Google Scholar 

  15. Naodovic, M., Wadamoto, M. & Yamamoto, H. Enantioselective Ag-catalyzed allylation of aldimines. Eur. J. Org. Chem. 2009, 5129–5131 (2009)

    Article  Google Scholar 

  16. Ferraris, D. et al. Catalytic, enantioselective alkylation of α-imino esters: the synthesis of nonnatural α-amino acid derivatives. J. Am. Chem. Soc. 124, 67–77 (2002)

    Article  CAS  Google Scholar 

  17. Vieira, E. M., Snapper, M. L. & Hoveyda, A. H. Enantioselective synthesis of homoallylic amines through reactions of (pinacolato)allylborons with aryl-, heteroaryl-, alkyl-, or alkene-substituted aldimines catalyzed by chiral C1-symmetric NHC–Cu complexes. J. Am. Chem. Soc. 133, 3332–3335 (2011)

    Article  CAS  Google Scholar 

  18. Hamada, T., Manabe, K. & Kobayashi, S. Catalytic asymmetric allylation of hydrazono esters in aqueous media by using ZnF2–chiral diamine. Angew. Chem. Int. Edn 42, 3927–3930 (2003)

    Article  CAS  Google Scholar 

  19. Peddibhotla, S. 3-Substituted-3-hydroxy-2-oxindole, an emerging new scaffold for drug discovery with potential anti-cancer and other biological activities. Curr. Bioact. Compd 5, 20–38 (2009)

    Article  CAS  Google Scholar 

  20. Coste, A., Couty, F. & Evano, G. TMC-95A–D and analogues: chemistry and biology. C.R. Chimie 11, 1544–1573 (2008)

    Article  CAS  Google Scholar 

  21. Yamamoto, D. et al. Design, synthesis, and biological activities of madindoline analogues. Bioorg. Med. Chem. Lett. 16, 2807–2811 (2006)

    Article  CAS  Google Scholar 

  22. Hanhan, N. V., Sahin, A. H., Chang, T. W., Fettinger, J. C. & Franz, A. K. Catalytic asymmetric synthesis of 3-hydroxy-2-oxindoles. Angew. Chem. Int. Edn 49, 744–747 (2010)

    Article  CAS  Google Scholar 

  23. Itoh, J., Han, S. B. & Krische, M. J. Enantioselective allylation, crotylation, and reverse prenylation of substituted isatins: iridium-catalyzed C–C bond-forming transfer hydrogenation. Angew. Chem. Int. Edn 48, 6313–6316 (2009)

    Article  CAS  Google Scholar 

  24. Vieira, E. M., Haeffner, F., Snapper, M. L. & Hoveyda, A. H. A robust, efficient and highly enantioselective method for synthesis of homopropargyl amines. Angew. Chem. Int. Edn 51, 6618–6621 (2012)

    Article  CAS  Google Scholar 

  25. Barnett, D. S., Moquist, P. N. & Schaus, S. E. The mechanism and an improved asymmetric allylboration of ketones catalyzed by chiral biphenols. Angew. Chem. Int. Edn 48, 8679–8682 (2009)

    Article  CAS  Google Scholar 

  26. Weinreb, S. M. & Orr, R. K. N-Phosphinoylimines: an emerging class of reactive intermediates for stereoselective organic synthesis. Synthesis 8, 1205–1227 (2005)

    Article  Google Scholar 

  27. Fujita, M., Nagano, T., Schneider, U., Hamada, T. & Kobayashi, S. Zn-catalyzed asymmetric allylation for the synthesis of optically active allylglycine derivatives. Regio- and stereoselective formal α-addition of allylboronates to hydrazono esters. J. Am. Chem. Soc. 130, 2914–2915 (2008)

    Article  CAS  Google Scholar 

  28. Guzman-Martinez, A. & Hoveyda, A. H. Enantioselective synthesis of allylboronates bearing a tertiary or quaternary B-substituted stereogenic carbon by NHC–Cu-catalyzed substitution reactions. J. Am. Chem. Soc. 132, 10634–10637 (2010)

    Article  CAS  Google Scholar 

  29. Itoh, T., Ishikawa, H. & Hayashi, Y. Asymmetric aldol reaction of acetaldehyde and isatin derivatives for the total syntheses of ent-convolutamydine E and CPC-1 and a half fragment of madindoline A and B. Org. Lett. 11, 3854–3857 (2009)

    Article  CAS  Google Scholar 

  30. Cravotto, G. et al. Convolutamydine A: the first authenticated absolute configuration and enantioselective synthesis. Tetrahedr. Asymm. 17, 3070–3074 (2006)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the US National Institutes of Health, Institute of General Medical Sciences (grant GM-57212). S.T. was a Swiss National Science Foundation Postdoctoral Fellow; E.M.V. was an AstraZeneca Graduate Fellow. We thank B. Li for assistance in securing X-ray structures, S. J. Meek, S. J. Malcolmson and K. L. Tan for discussions, Boston College for providing access to computational facilities and Frontier Scientific for gifts of various organoboron reagents.

Author information

Authors and Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, 02467, Massachusetts, USA

    Daniel L. Silverio, Sebastian Torker, Tatiana Pilyugina, Erika M. Vieira, Marc L. Snapper, Fredrik Haeffner & Amir H. Hoveyda

Authors
  1. Daniel L. Silverio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sebastian Torker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tatiana Pilyugina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erika M. Vieira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marc L. Snapper
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fredrik Haeffner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Amir H. Hoveyda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.L.S. and T.P. were involved in the discovery, design and development of the catalysts; D.L.S., S.T. and T.P. worked on applications to enantioselective additions to imines; D.L.S. and E.M.V. developed the enantioselective allyl and allene additions to isatins, respectively; D.L.S., S.T., T.P. and F.H. carried out mechanistic and computational studies. A.H.H. conceived, designed and directed the investigations and wrote the manuscript with revisions provided by D.L.S. and E.M.V. This work is part of a collaborative programme between A.H.H. and M.L.S. involving the development of amino acid-derived chiral catalysts.

Corresponding author

Correspondence to Amir H. Hoveyda.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Information sections A-D – see contents in file for details. (PDF 23287 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Silverio, D., Torker, S., Pilyugina, T. et al. Simple organic molecules as catalysts for enantioselective synthesis of amines and alcohols. Nature 494, 216–221 (2013). https://doi.org/10.1038/nature11844

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11844

This article is cited by

Comments

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.

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