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.

Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols

Nature volume 532, pages 353–356 (2016)Cite this article

Subjects

An Addendum to this article was published on 23 May 2018

This article has been updated

Abstract

The chirality, or ‘handedness’, of a biologically active molecule can alter its physiological properties. Thus it is routine procedure in the drug discovery and development process to prepare and fully characterize all possible stereoisomers of a drug candidate for biological evaluation1,2. Despite many advances in asymmetric synthesis, developing general and practical strategies for obtaining all possible stereoisomers of an organic compound that has multiple contiguous stereocentres remains a challenge3. Here, we report a stereodivergent copper-based approach for the expeditious construction of amino alcohols with high levels of chemo-, regio-, diastereo- and enantioselectivity. Specifically, we synthesized these amino-alcohol products using sequential, copper-hydride-catalysed hydrosilylation and hydroamination of readily available enals and enones. This strategy provides a route to all possible stereoisomers of the amino-alcohol products, which contain up to three contiguous stereocentres. We leveraged catalyst control and stereospecificity simultaneously to attain exceptional control of the product stereochemistry. Beyond the immediate utility of this protocol, our strategy could inspire the development of methods that provide complete sets of stereoisomers for other valuable synthetic targets.

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

Figure 1: Varying biological activity of some different stereoisomers, and our strategy for constructing all stereoisomers of amino alcohols.
Figure 2: Asymmetric hydrosilylation/hydroamination of enals.
Figure 3: All stereoisomers of amino alcohols from enals.
Figure 4: Asymmetric hydrosilylation/hydroamination of enones.
Figure 5: All eight stereoisomers of amino alcohols synthesized from enones.

Change history

  • 23 May 2018

    A small modification to the procedure for handling dimethoxymethylsilane (DMMS)—rather than evaporation of volatiles before workup, the excess DMMS is quenched with ammonium fluoride—is described in the Supplementary Information to the accompanying Addendum (http://doi.org/10.1038/s41586-018-0112-4).

References

  1. Jozwiak, K., Lough, W. J. & Wainer, I. W. Drug Stereochemistry: Analytical Methods and Pharmacology 3rd edn (Informa, 2012)

  2. Wermuth, C. G. The Practice of Medicinal Chemistry 3rd edn (Elsevier, 2008)

  3. Jacobsen, E. N., Pfaltz, A. & Yamamoto, H. (eds) Comprehensive Asymmetric Catalysis Vol. I–III, Suppl. I–II (Springer, 1999)

  4. Tian, X. et al. Diastereodivergent asymmetric sulfa-Michael additions of α-branched enones using a single chiral organic catalyst. J. Am. Chem. Soc. 133, 17934–17941 (2011)

    Article  CAS  Google Scholar 

  5. McInturff, E. L., Yamaguchi, E. & Krische, M. J. Chiral-anion-dependent inversion of diastereo- and enantioselectivity in carbonyl crotylation via ruthenium-catalyzed butadiene hydrohydroxyalkylation. J. Am. Chem. Soc. 134, 20628–20631 (2012)

    Article  CAS  Google Scholar 

  6. Wang, B., Wu, F., Wang, Y., Liu, X. & Deng, L. Control of diastereoselectivity in tandem asymmetric reactions generating nonadjacent stereocenters with bifunctional catalysis by cinchona alkaloids. J. Am. Chem. Soc. 129, 768–769 (2007)

    Article  CAS  Google Scholar 

  7. Yan, X.-X. et al. Highly diastereoselective switchable enantioselective Mannich reaction of glycine derivatives with imines. J. Am. Chem. Soc. 130, 14362–14363 (2008)

    Article  CAS  Google Scholar 

  8. Luparia, M. et al. Catalytic asymmetric diastereodivergent deracemization. Angew. Chem. Int. Edn 50, 12631–12635 (2011)

    Article  CAS  Google Scholar 

  9. Lu, G., Yoshino, T., Morimoto, H., Matsunaga, S. & Shibasaki, M. Stereodivergent direct catalytic asymmetric mannich-type reactions of α-isothiocyanato ester with ketimines. Angew. Chem. Int. Edn 50, 4382–4385 (2011)

    Article  CAS  Google Scholar 

  10. Mechler, M. & Peters, R. Diastereodivergent asymmetric 1,4-addition of oxindoles to nitroolefins by using polyfunctional nickel-hydrogen-bond-azolium catalysts. Angew. Chem. Int. Edn 54, 10303–10307 (2015)

    Article  CAS  Google Scholar 

  11. Lee, E. C., Hodous, B. L., Bergin, E., Shih, C. & Fu, G. C. Catalytic asymmetric Staudinger reactions to form β-lactams: an unanticipated dependence of diastereoselectivity on the choice of the nitrogen substituent. J. Am. Chem. Soc. 127, 11586–11587 (2005)

    Article  CAS  Google Scholar 

  12. Huber, J. D. & Leighton, J. L. Highly enantioselective imine cinnamylation with a remarkable diastereochemical switch. J. Am. Chem. Soc. 129, 14552–14553 (2007)

    Article  CAS  Google Scholar 

  13. Huang, Y., Walji, A. M., Larsen, C. H. & MacMillan, D. W. C. Enantioselective organo-cascade catalysis. J. Am. Chem. Soc. 127, 15051–15053 (2005)

    Article  CAS  Google Scholar 

  14. Simmons, B., Walji, A. M. & MacMillan, D. W. C. Cycle-specific organocascade catalysis: application to olefin hydroamination, hydro-oxidation, and amino-oxidation, and to natural product synthesis. Angew. Chem. Int. Edn 48, 4349–4353 (2009)

    Article  CAS  Google Scholar 

  15. 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  ADS  CAS  Google Scholar 

  16. Schindler, C. S. & Jacobsen, E. N. A new twist on cooperative catalysis. Science 340, 1052–1053 (2013)

    Article  ADS  CAS  Google Scholar 

  17. Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications (Wiley VCH, 2010)

  18. Zhu, S., Niljianskul, N. & Buchwald, S. L. Enantio- and regioselective CuH-catalyzed hydroamination of alkenes. J. Am. Chem. Soc. 135, 15746–15749 (2013)

    Article  CAS  Google Scholar 

  19. Shi, S.-L. & Buchwald, S. L. Copper-catalyzed selective hydroamination reactions of alkynes. Nature Chem. 7, 38–44 (2015)

    Article  ADS  CAS  Google Scholar 

  20. Zhu, S. & Buchwald, S. L. Enantioselective CuH-catalyzed anti-Markovnikov hydroamination of 1, 1-disubstituted alkenes. J. Am. Chem. Soc. 136, 15913–15916 (2014)

    Article  CAS  Google Scholar 

  21. Yang, Y., Shi, S.-L., Niu, D., Liu, P. & Buchwald, S. L. Catalytic asymmetric hydroamination of unactivated internal olefins to aliphatic amines. Science 349, 62–66 (2015)

    Article  ADS  CAS  Google Scholar 

  22. Niu, D. & Buchwald, S. L. Design of modified amine transfer reagents allows the synthesis of α-chiral secondary amines via CuH-catalyzed hydroamination. J. Am. Chem. Soc. 137, 9716–9721 (2015)

    Article  CAS  Google Scholar 

  23. Bandar, J. S., Pirnot, M. T. & Buchwald, S. L. Mechanistic studies lead to dramatically improved reaction conditions for the Cu-catalyzed asymmetric hydroamination of olefins. J. Am. Chem. Soc. 137, 14812–14818 (2015)

    Article  CAS  Google Scholar 

  24. Miki, Y., Hirano, K., Satoh, T. & Miura, M. Copper-catalyzed intermolecular regioselective hydroamination of styrenes with polymethylhydrosiloxane and hydroxylamines. Angew. Chem. Int. Edn 52, 10830–10834 (2013)

    Article  CAS  Google Scholar 

  25. Hannedouche, J. & Schulz, E. Asymmetric hydroamination: a survey of the most recent developments. Chemistry 19, 4972–4985 (2013)

    Article  CAS  Google Scholar 

  26. Deutsch, C., Krause, N. & Lipshutz, B. H. CuH-catalyzed reactions. Chem. Rev. 108, 2916–2927 (2008)

    Article  CAS  Google Scholar 

  27. Barker, T. J. & Jarvo, E. R. Developments in transition-metal-catalyzed reactions using electrophilic nitrogen sources. Synthesis 24, 3954–3964 (2011)

    Google Scholar 

  28. Lipshutz, B. H., Noson, K., Chrisman, W. & Lower, A. Asymmetric hydrosilylation of aryl ketones catalyzed by copper hydride complexed by nonracemic biphenyl bis-phosphine ligands. J. Am. Chem. Soc. 125, 8779–8789 (2003)

    Article  CAS  Google Scholar 

  29. Chen, J.-X. et al. Highly chemoselective catalytic hydrogenation of unsaturated ketones and aldehydes to unsaturated alcohols using phosphine-stabilized copper(I) hydride complexes. Tetrahedron 56, 2153–2166 (2000)

    Article  CAS  Google Scholar 

  30. Moser, R., Boskovic, Z. V., Crowe, C. S. & Lipshutz, B. H. CuH-catalyzed enantioselective 1,2-reductions of α,β-unsaturated ketones. J. Am. Chem. Soc. 132, 7852–7853 (2010)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the National Institutes of Health (grant GM-58160 to S.L.B.). The content of this paper is solely our responsibility and does not necessarily represent the official views of the National Institutes of Health. We thank Y.-M. Wang and M. T. Pirnot for help preparing the manuscript. The departmental X-ray diffraction instrumentation was purchased with the help of funding from the National Science Foundation (CHE-0946721). We thank P. Müller for X-ray crystallographic analysis of compound 5a.

Author information

Authors and Affiliations

  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Shi-Liang Shi, Zackary L. Wong & Stephen L. Buchwald

Authors
  1. Shi-Liang Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zackary L. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen L. Buchwald
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.-L.S. and S.L.B. conceived the idea and designed the research. S.-L.S. and Z.L.W. performed the experiments. S.-L.S. and S.L.B. wrote the manuscript. All authors commented on the final draft of the manuscript and contributed to the analysis and interpretation of the data.

Corresponding author

Correspondence to Stephen L. Buchwald.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data – see contents page for details. (PDF 11324 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, SL., Wong, Z. & Buchwald, S. Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols. Nature 532, 353–356 (2016). https://doi.org/10.1038/nature17191

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature17191

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