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Label-assisted mass spectrometry for the acceleration of reaction discovery and optimization

Nature Chemistry volume 5, pages 423–427 (2013)Cite this article

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Abstract

The identification of new reactions expands our knowledge of chemical reactivity and enables new synthetic applications. Accelerating the pace of this discovery process remains challenging. We describe a highly effective and simple platform for screening a large number of potential chemical reactions in order to discover and optimize previously unknown catalytic transformations, thereby revealing new chemical reactivity. Our strategy is based on labelling one of the reactants with a polyaromatic chemical tag, which selectively undergoes a photoionization/desorption process upon laser irradiation, without the assistance of an external matrix, and enables rapid mass spectrometric detection of any products originating from such labelled reactants in complex reaction mixtures without any chromatographic separation. This method was successfully used for high-throughput discovery and subsequent optimization of two previously unknown benzannulation reactions.

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Figure 1: Use of LA–LDI–TOF–MS to monitor the progress of a representative known reaction.
Figure 2: Reaction screen using LA–LDI–TOF–MS and identification of two catalytic benzannulations.
Figure 3: Mechanism and scope of gold-catalysed benzannulation of siloxy alkyne with 2-pyrones.
Figure 4: Mechanism and scope of gold-catalysed benzannulation siloxy alkynes with isoquinoline N-oxides.

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References

  1. 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).

    Article  CAS  Google Scholar 

  2. 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).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. Mueller, C. A., Markert, C., Teichert, A. M. & Pfaltz, A. Mass spectrometric screening of chiral catalysts and catalyst mixtures. Chem. Commun. 13, 1607–1618 (2009).

    Article  Google Scholar 

  6. Wassenaar, J. et al. Catalyst selection based on intermediate stability measured by mass spectrometry. Nature Chem. 2, 417–420 (2010).

    Article  CAS  Google Scholar 

  7. Ebner, C., Muller, C. A., Markert, C. & Pfaltz, A. Determining the enantioselectivity of chiral catalysts by mass spectrometric screening of their racemic forms. J. Am. Chem. Soc. 133, 4710–4713 (2011).

    Article  CAS  Google Scholar 

  8. 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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. McNally, A., Prier, C. K. & MacMillan, D. W. C. Discovery of an α-amino C–H arylation reaction using the strategy of accelerated serendipity. Science 334, 1114–1117 (2011).

    Article  CAS  Google Scholar 

  11. Friest, J. A., Broussy, S., Chung, W. J. & Berkowitz, D. B. Combinatorial catalysis employing a visible enzymatic reacon in real time: synthetically versatile (pseudo)halometalation/carbocyclizations. Angew. Chem. Int. Ed. 50, 8895–8899 (2011).

    Article  CAS  Google Scholar 

  12. Montavon, T. J., Li, J., Cabrera-Pardo, J. R., Mrksich, M. & Kozmin, S. A. Three-component reaction discovery enabled by mass spectrometry of self-assembled monolayers. Nature Chem. 4, 45–51 (2012).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Yoshino, K., Takao, T., Murata, H. & Shimonishi, Y. Use of the derivatizing agent, 4-aminobenzoic acid 2-(diethylamino)ethyl ester, for high-sensitivity detection of oligosaccharides by electrospray ionization mass spectrometry. Anal. Chem. 67, 4028–4031 (1995).

    Article  CAS  Google Scholar 

  15. Ahn, Y. H. & Yoo, J. S. Malononitrile as a new derivatizing reagent for high-sensitivity analysis of oligosaccharides by electrospray ionization mass spectrometry. Rapid Commun. Mass Spectrom. 12, 2011–2015 (1998).

    Article  CAS  Google Scholar 

  16. Szewczyk, J. W., Zuckerman, R. L., Bergman, R. G. & Ellman, J. A. A mass spectrometric labeling strategy for high-throughput reaction evaluation and optimization: exploring C–H Activation. Angew. Chem. Int. Ed. 40, 216–219 (2001).

    Article  CAS  Google Scholar 

  17. Bernad, P. L. Jr, Khan, S., Korshun, V. A., Southern, E. M. & Shchepinov, M. S. S(O)-Pixyl protecting group as efficient mass-tag. Chem. Commun. 3466–3468 (2005).

  18. Thuong, M. B. T. et al. Trimethoxyarene as highly ionizable tag for reaction analysis by atmospheric pressure photoionization mass spectrometry (APPI/MS): exploration of heterocylic synthesis. Eur. J. Org. Chem. 2012, 85–92.

  19. McCarley, T. D., McCarley, R. L. & Limbach, P. A. Electron-transfer ionization in matrix-assisted laser desorption/ionization mass spectrometry. Anal. Chem. 70, 4376–4379 (1998).

    Article  CAS  Google Scholar 

  20. Macha, S. F., McCarley, T. D. & Limbach, P. A. Influence of ionization energy on charge-transfer ionization in matrix-assisted laser desorption/ionization mass spectrometry. Anal. Chim. Acta 397, 235–245 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Turkmen, Y., Montavon, T. J., Kozmin, S. A. & Rawal, V. H. Silver-catalyzed inverse electron-demand Diels–Alder reaction of 1,2-diazines with siloxy alkynes. J. Am. Chem. Soc. 134, 9062–9065 (2012).

    Article  CAS  Google Scholar 

  27. Afarinkia, K., Vinader, V., Nelson, T. D. & Posner, G. H. Diels–Alder cycloadditions of 2-pyrones and 2-pyridones. Tetrahedron 48, 9111–9171 (1992).

    Article  CAS  Google Scholar 

  28. Danheiser, R. L. & Gee, S. K. A regiocontrolled annulation approach to highly substituted aromatic compounds. J. Org. Chem. 49, 1672–1674 (1984).

    Article  CAS  Google Scholar 

  29. Danheiser, R. L., Nishida, A. N., Savariar, S. & Trova, M. P. Trialkylsilyloxyalkynes: synthesis and aromatic annulation reactions. Tetrahedron Lett. 29, 4917–4920 (1988).

    Article  CAS  Google Scholar 

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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. The authors thank I. Steele for X-ray crystallographic analysis.

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Authors and Affiliations

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

    Jaime R. Cabrera-Pardo, David I. Chai, Song Liu & Sergey A. Kozmin

  2. Department of Chemistry (Chicago Tri-Institutional Centre for Chemical Methods and Library Development), Northwestern University, Evanston, 60208, Illinois, USA

    Milan Mrksich

Authors
  1. Jaime R. Cabrera-Pardo
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  3. Song Liu
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Contributions

J.R.C.-P. developed the reaction-screening platform, and performed and analysed all reactions using MS. D.I.C and S.L. carried out the reaction optimization and scope studies. M.M. provided assistance with instrumentation and data analysis. S.A.K. provided overall management of the project. The manuscript was written by S.A.K., M.M., J.R.C.-P. and D.I.C.

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Correspondence to Sergey A. Kozmin.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary information (PDF 5314 kb)

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Crystallographic data for compound 10a (CIF 10 kb)

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Crystallographic data for compound 10e (CIF 12 kb)

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Crystallographic data for compound 13a (CIF 12 kb)

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Crystallographic data for compound 13f (CIF 29 kb)

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Cabrera-Pardo, J., Chai, D., Liu, S. et al. Label-assisted mass spectrometry for the acceleration of reaction discovery and optimization. Nature Chem 5, 423–427 (2013). https://doi.org/10.1038/nchem.1612

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