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

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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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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The authors declare no competing financial interests.

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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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