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:

Three-component reaction discovery enabled by mass spectrometry of self-assembled monolayers

Nature Chemistry volume 4, pages 45–51 (2012)Cite this article

Subjects

Abstract

Multicomponent reactions are employed extensively in many areas of organic chemistry. Despite significant progress, the discovery of such enabling transformations remains challenging. Here, we present the development of a parallel, label-free reaction-discovery platform that can be used in the identification of new multicomponent transformations. Our approach is based on parallel mass spectrometric screening of interfacial chemical reactions on arrays of self-assembled monolayers. This strategy enabled the identification of a simple organic phosphine that can catalyse a previously unknown condensation of siloxyalkynes, aldehydes and amines to produce 3-hydroxyamides with high efficiency and diastereoselectivity. The reaction was further optimized using solution-phase methods.

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: Discovery of a new three-component reaction by SAMDI.
Figure 2: Proposed mechanism of the phosphine-catalysed three-component reaction of siloxyalkynes with amines and aldehydes.
Figure 3: Other representative phosphine-catalysed reactions of siloxyalkynes.

Similar content being viewed by others

References

  1. Menger, F. M., Eliseev, A. V. & Migulin, V. A. Phosphatase catalysis via combinatorial organic chemistry. J. Org. Chem. 60, 6666–6661 (1995).

    CAS  Google Scholar 

  2. Liu, G. & Ellman, J. A. A general solid-phase synthesis strategy for the preparation of 2-pyrrolidinemethanol ligands. J. Org. Chem. 60, 7712–7713 (1995).

    CAS  Google Scholar 

  3. Burgess, K., Lim, H-J., Porte, A. M. & Sulikowski, G. A. New catalysts and conditions for a C–H insertion reaction identified by high-throughput catalyst screening. Angew. Chem. Int. Ed. Engl. 35, 220–222 (1996).

    CAS  Google Scholar 

  4. Cole, B. M. et al. Discovery of chiral catalysts through ligand diversity: Ti-catalyzed enantioselective addition of TMSCN to meso epoxides. Angew. Chem. Int. Ed. Engl. 35, 1668–1671 (1996).

    CAS  Google Scholar 

  5. Francis, M. B., Finney, N. S. & Jacobsen, E. N. Combinatorial approach to the discovery of novel coordination complexes. J. Am. Chem. Soc. 118, 8983–8984 (1996).

    CAS  Google Scholar 

  6. Taylor, S. J. & Morken, J. P. Thermographic selection of effective catalysts from an encoded polymer-bound library. Science 280, 267–270 (1998).

    CAS  PubMed  Google Scholar 

  7. Reetz, M. T., Becker, M. H., Kühling, K. M. & Holzwarth, A. Time-resolved IR-thermographic detection and screening of enantioselectivity in catalytic reactions. Angew. Chem. Int. Ed. 37, 2647–2650 (1998).

    CAS  Google Scholar 

  8. Senkan, S. M. High-throughput screening of solid-state catalyst libraries. Nature 394, 350–353 (1998).

    CAS  Google Scholar 

  9. Reddington, E. et al. Combinatorial electrochemistry: a highly parallel, optical screening method for discovery of better electrocatalysts. Science 280, 1735–1737 (1998).

    CAS  PubMed  Google Scholar 

  10. Sigman, M. S. & Jacobsen, E. N. Schiff base catalysts for the asymmetric Strecker reaction identified and optimized from parallel synthetic libraries. J. Am. Chem. Soc. 120, 4901–4902 (1998).

    CAS  Google Scholar 

  11. Cooper, A. C., McAlexander, L. H., Lee, D-H., Torres, M. T. & Crabtree, R. H. Reactive dyes as a method for rapid screening of homogeneous catalysts. J. Am. Chem. Soc. 120, 9971–9972 (1998).

    CAS  Google Scholar 

  12. Shaughnessy, K. H., Kim, P. & Hartwig, J. F. A fluorescence-based assay for high-throughput screening of coupling reactions. Application to Heck chemistry. J. Am. Chem. Soc. 121, 2123–2132 (1999).

    CAS  Google Scholar 

  13. Copeland, G. T. & Miller, S. J. A chemosensor-based approach to catalyst discovery in solution and on solid support. J. Am. Chem. Soc. 121, 4306–4307 (1999).

    CAS  Google Scholar 

  14. Berkowitz, D. B., Bose, M. & Choi, S. In situ enzymatic screening (ISES): a tool for catalyst discovery and reaction development. Angew. Chem. Int. Ed. 41, 1603–1607 (2002).

    CAS  Google Scholar 

  15. Stauffer, S. R. & Hartwig, J. F. Fluorescence resonance energy transfer (FRET) as a high-throughput assay for coupling reactions. Arylation of amines as a case study. J. Am. Chem. Soc. 125, 6977–6985 (2003).

    CAS  PubMed  Google Scholar 

  16. Yao, S., Meng, J-C., Siuzdak, G. & Finn, M. G. New catalysts for the asymmetric hydrosilylation of ketones discovered by mass spectrometry screening. J. Org. Chem. 68, 2540–2546 (2003).

    CAS  PubMed  Google Scholar 

  17. Chen, P. Electrospray ionization tandem mass spectrometry in high-throughput screening of homogeneous catalysts. Angew. Chem. Int. Ed. 42, 2832–2847 (2003).

    CAS  Google Scholar 

  18. Teichert, T. & Pfaltz, A. Mass spectrometric screening of enantioselective Diels–Alder reactions. Angew. Chem. Int. Ed. 47, 3360–3362 (2008).

    CAS  Google Scholar 

  19. Wassenaar, J. et al. Catalyst selection based on intermediate stability measured by mass spectrometry. Nature Chem. 2, 417–421 (2010).

    CAS  Google Scholar 

  20. Kanan, M. W., Rozenman, M. M., Sakurai, K., Snyder, T. M. & Liu, D. R. Reaction discovery enabled by DNA-templated synthesis and in vitro selection. Nature 431, 545–549 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Rozenman, M. M., Kanan, M. W. & Liu, D. R. Development and initial application of a hybridization-independent, DNA-encoded reaction discovery system compatible with organic solvents. J. Am. Chem. Soc. 129, 14933–14938 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen, Y., Kamlet, A. S., Steinman, J. B. & Liu, D. R. A biomolecule-compatible visible light-induced azide reduction from a DNA-encoded reaction discovery system. Nature Chem. 3, 146–153 (2011).

    Google Scholar 

  23. Beeler, A. B., Su, S., Singleton, C. A. & Porco, J. A. Jr Discovery of chemical reactions through multidimensional screening. J. Am. Chem. Soc. 129, 1413–1419 (2007).

    CAS  PubMed  Google Scholar 

  24. Goodell, J. R. et al. Development of an automated microfluidic reaction platform for multidimensional screening: reaction discovery employing bicyclo[3.2.1]octanoid scaffolds. J. Org. Chem. 74, 6169–6180 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Robbins, D. W. & Hartwig, J. F. A simple, multidimensional approach to high-throughput discovery of catalytic reactions. Science 333, 1423–1427 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Min, D-H., Yeo, W-S. & Mrksich, M. A method for connecting solution phase enzyme activity assays with immobilized format analysis by mass spectrometry. Anal. Chem. 76, 3923–3929 (2004).

    CAS  PubMed  Google Scholar 

  27. Min, D-H., Tang, W-J. & Mrksich, M. Chemical screening by mass spectrometry to identify inhibitors of anthrax lethal factor. Nature Biotechnol. 22, 717–720 (2004).

    CAS  Google Scholar 

  28. Su, J., Bringer, M. R., Ismagilov, R. F. & Mrksich, M. Combining microfluidic networks and peptide arrays for multi-enzyme assays. J. Am. Chem. Soc. 127, 7280–7281 (2005).

    CAS  PubMed  Google Scholar 

  29. Ban, L. & Mrksich, M. On-chip synthesis and label-free assays of oligosaccharide arrays. Angew. Chem. Int. Ed. 47, 3396–3399 (2008).

    CAS  Google Scholar 

  30. Gurard-Levin, Z. A., Kim, J. & Mrksich, M. Combining mass spectrometry and peptide arrays to profile the specificities of histone deacetylases. ChemBioChem 10, 2159–2161 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Su, J. & Mrksich, M. Using MALDI-TOF mass spectrometry to characterize interfacial reactions on self-assembled monolayers. Langmuir 19, 4867–4870 (2003).

    CAS  Google Scholar 

  32. Li, J., Thiara, P. S. & Mrksich, M. Rapid evaluation and screening of interfacial reactions on self-assembled monolayers. Langmuir 23, 11826–11835 (2007).

    CAS  PubMed  Google Scholar 

  33. Dömling, A. & Ugi, I. Multicomponent reactions with isocyanides. Angew. Chem. Int. Ed. 39, 3168–3210 (2000).

    Google Scholar 

  34. Touré, B. B. & Hall, D. G. Natural product synthesis using multicomponent reaction strategies. Chem. Rev. 109, 4439–4486 (2009).

    PubMed  Google Scholar 

  35. Guillena, G., Ramon, D. J. & Yus, M. Organocatalytic enantioselective multicomponent reactions (OEMCRs). Tetrahedron: Asymmetry 18, 693–700 (2007).

    CAS  Google Scholar 

  36. Zhang, L. & Kozmin, S. A. Brønsted acid-promoted cyclizations of siloxyalkynes with arenes and alkenes. J. Am. Chem. Soc. 126, 10204–10205 (2004).

    CAS  PubMed  Google Scholar 

  37. Zhang, L. & Kozmin, S. A. Gold-catalyzed cycloisomerizations of siloxy enynes to cyclohexadienes. J. Am. Chem. Soc. 126, 11806–11807 (2004).

    CAS  PubMed  Google Scholar 

  38. Sun, J. & Kozmin, S. A. Brønsted acid-promoted cyclizations of 1-siloxy-1,5-diynes. J. Am. Chem. Soc. 127, 13512–13513 (2005).

    CAS  PubMed  Google Scholar 

  39. Sun, J. & Kozmin, S. A. Silver-catalyzed hydroamination of siloxy alkynes. Angew. Chem. Int. Ed. 45, 4991–4993 (2006).

    CAS  Google Scholar 

  40. Sweis, R., Schramm, M. P. & Kozmin, S. A. Silver-catalyzed [2+2] cycloadditions of siloxyalkynes. J. Am. Chem. Soc. 126, 7442–7443 (2004).

    CAS  PubMed  Google Scholar 

  41. Sun, J., Keller, V. A., Meyer, S. T. & Kozmin, S. A. Silver-catalyzed aldehyde olefination using siloxy alkynes. Adv. Synth. Catal. 352, 839–842 (2010).

    CAS  Google Scholar 

Download references

Acknowledgements

This work was funded by the National Institutes of Health (P50 GM086145) and the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust. We thank Ian Steele for the X-ray crystallographic analysis of 5.

Author information

Author notes

  1. Timothy J. Montavon and Jing Li: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Chemistry, Chicago Tri-Institutional Center for Chemical Methods and Library Development, University of Chicago, Chicago, 60637, Illinois, USA

    Timothy J. Montavon, Jing Li, Jaime R. Cabrera-Pardo, Milan Mrksich & Sergey A. Kozmin

Authors
  1. Timothy J. Montavon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jaime R. Cabrera-Pardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Milan Mrksich
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sergey A. Kozmin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.J.M. and J.L. contributed equally to the work. J.L. performed and analysed all interfacial reactions on monolayers. T.J.M. carried out most of the solution-based studies. J.R.C-P. assisted with scope studies. M.M. and S.A.K. equally provided project management. The manuscript was written by T.J.M., J.L., S.A.K. and M.M.

Corresponding authors

Correspondence to Milan Mrksich or Sergey A. Kozmin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 4818 kb)

Supplementary information

Crystallographic data for compound 5 (CIF 20 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Montavon, T., Li, J., Cabrera-Pardo, J. et al. Three-component reaction discovery enabled by mass spectrometry of self-assembled monolayers. Nature Chem 4, 45–51 (2012). https://doi.org/10.1038/nchem.1212

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1212

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