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Microwave-assisted preparation of the quorum-sensing molecule 2-heptyl-3-hydroxy-4(1H)-quinolone and structurally related analogs

Nature Protocols volume 7, pages 1184–1192 (2012)Cite this article

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Abstract

An optimized procedure for the efficient preparation of 2-heptyl-3-hydroxy-4(1H)-quinolone (Pseudomonas quinolone signal or PQS) and a diverse range of structurally related 2-alkyl-4-quinolones with biological activity is presented. The two-step synthesis begins with the formation of α-chloro ketones by the coupling of a Weinreb amide (2-chloro-N-methoxy-N-methylacetamide) and an appropriate Grignard reagent. The resulting α-chloro ketones can be reacted with commercially available anthranilic acids under microwave irradiation conditions to furnish the desired 2-alkyl-4-quinolone products. As a typical example, the synthesis of PQS, a molecule involved in quorum sensing in the pathogenic bacterium Pseudomonas aeruginosa, is described in detail. The first step of this process (α-chloro ketone formation) takes ∼10 h in total to complete from commercially available bromoheptane and 2-chloro-N-methoxy-N-methylacetamide. The second step (microwave-assisted reaction with anthranilic acid) takes ∼14 h in total to complete (the reaction typically proceeds in ∼30 min, with work-up and purification requiring ∼13 h).

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Figure 1
Figure 2: Outline of the synthetic route to PQS developed by Pesci et al.9.
Figure 3
Figure 4: Synthesis of PQS.
Figure 5: PQS analogs successfully generated using this protocol2,3.
Figure 6
Figure 7
Figure 8

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Acknowledgements

We gratefully acknowledge financial support from the Engineering and Physical Sciences Research Council, the Biotechnology and Biological Sciences Research Council, the Medical Research Council and the Newman Trust.

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Authors and Affiliations

  1. Department of Chemistry, University of Cambridge, Cambridge, UK

    James T Hodgkinson, Warren R J D Galloway & David R Spring

  2. Department of Biochemistry, University of Cambridge, Cambridge, UK

    James T Hodgkinson & Martin Welch

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  1. James T Hodgkinson
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  2. Warren R J D Galloway
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  3. Martin Welch
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  4. David R Spring
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Contributions

J.T.H., M.W. and D.R.S. conceived the experiments. M.W. and D.R.S. supervised the work. J.T.H. performed the experiments and analyzed the data. W.R.J.D.G. assisted with data analysis and wrote the paper.

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Correspondence to David R Spring.

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Hodgkinson, J., Galloway, W., Welch, M. et al. Microwave-assisted preparation of the quorum-sensing molecule 2-heptyl-3-hydroxy-4(1H)-quinolone and structurally related analogs. Nat Protoc 7, 1184–1192 (2012). https://doi.org/10.1038/nprot.2012.054

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