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Binary fluorous tagging enables the synthesis and separation of a 16-stereoisomer library of macrosphelides

Nature Chemistry volume 4, pages 124–129 (2012)Cite this article

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An Erratum to this article was published on 21 February 2012

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Abstract

Fluorous mixture synthesis minimizes the effort to synthesize small-molecule libraries by labelling the molecules rather than the reaction vessels. Reactants are labelled with fluorinated tags and products can later be demixed based on the fluorine content. A limit in the number of available tags can be overcome by using binary encoding so that a total of four tags can label uniquely a library of 16 compounds. This strategy, however, means that separation based on fluorine content alone is not possible. Here, we solve this problem by selectively removing one tag after an initial demixing step; a second demixing provides each individual compound. The usefulness of this strategy is demonstrated by the synthesis of a library that contains all 16 diastereomers of the natural products macrosphelides A and E. Macrosphelide D was not in this library, and so its assigned structure was incorrect. We determined its constitution by using NMR spectroscopy and its configuration by synthesizing four candidate stereoisomers.

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Figure 1: Single- and double-tagging strategies.
Figure 2: Binary tagging with four fluorous tags.
Figure 3: Fragments, tagged quasiisomers and mixture synthesis.
Figure 4: Double demixing illustrated with fraction 2.
Figure 5: Macrosphelide D structure candidates and syntheses.

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Change history

  • 18 January 2012

    In the version of this Article originally published, it erroneously stated the authors had no competing financial interests. This information has now been corrected in the HTML and PDF versions of the Article.

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Acknowledgements

We thank the National Institutes of Health for research support (National Institute of General Medical Sciences) and for a grant to purchase a 700 MHz NMR spectrometer. D-H.C. was supported by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2005-214-C00214). We thank K. Damodaran and S. Bowser for help with NMR spectra. We thank T. Yamada, Osaka University of Pharmaceutical Sciences, for providing copies of the spectra of macrosphelide M.

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  1. Department of Chemistry, 1101 Chevron Science Center, 219 Parkman Avenue, Pittsburgh, 15260, Pennsylvania, USA

    Dennis P. Curran, Mantosh K. Sinha, Kai Zhang, Jesse J. Sabatini & Dae-Hyun Cho

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  1. Dennis P. Curran
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  2. Mantosh K. Sinha
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Contributions

All authors conceived and designed the experiments and analysed the data. All authors, except D.P.C., performed the experiments: D-H.C. made the precursors and prepared a preliminary library, J.J.S. made the final library and carried out the demixing steps with K.Z., K.Z. purified and characterized the library members and M.K.S. made and characterized the macrosphelide D candidates. D.P.C wrote the paper. All authors commented on the manuscript.

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Correspondence to Dennis P. Curran.

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Competing interests

D.P.C. owns an equity interest in Fluorous Technologies, Inc., supplier of some reagents and HPLC columns used in this work. The other authors declare no competing financial interests.

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Chemical compounds table 1 (XLS 20 kb)

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Chemical compounds table 2 (XLS 32 kb)

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Curran, D., Sinha, M., Zhang, K. et al. Binary fluorous tagging enables the synthesis and separation of a 16-stereoisomer library of macrosphelides. Nature Chem 4, 124–129 (2012). https://doi.org/10.1038/nchem.1233

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