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Total synthesis of marinomycin A using salicylate as a molecular switch to mediate dimerization

Abstract

Antibiotics play a significant role in human health because of their ability to treat life-threatening bacterial infections. The growing problems with antibiotic resistance have made the development of new antibiotics a World Health Organization priority. Marinomycin A is a member of a new class of bis-salicylate-containing polyene macrodiolides, which have potent antibiotic activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Herein, we describe a triply convergent synthesis of this agent using the salicylate as a novel molecular switch for the chemoselective construction of the macrodiolide. This strategy raises new questions regarding the biosynthetic role of the salicylate and its potential impact on the mechanism of action of these types of agents. For instance, in contrast to penicillin, which enhances the electrophilicity of the cyclic amide through ring strain, salicylates reduce the electrophilicity of the aryl ester through an intramolecular resonance-assisted hydrogen bond to provide an amide surrogate.

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Figure 1: Proposed role of salicylate as a molecular switch for macrolide construction and synthetic plan for marinomycin A.
Figure 2: Synthesis of fragments 4, 5 and 6.
Figure 3: Synthesis of differentially protected monomer 21.
Figure 4: Salicylate molecular switch-mediated dimerization.
Figure 5: Completion of the total synthesis of marinomycin A.

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Acknowledgements

The authors acknowledge the National Institutes of Health (GM54623) and the National Science Foundation (CHE-0316689) for generous financial support, and the Royal Society for a Wolfson Research Merit Award (to P.A.E.). The authors are also grateful to the EPSRC National Mass Spectrometry Service Centre (Swansea, UK) for high-resolution mass spectrometry. This Article is dedicated to Professor Robert H. Grubbs on the occasion of his 70th birthday.

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P.A.E. managed the project, analysed data and prepared the manuscript with M-H.H. and S.M. M.J.L. and M-H.H. devised the synthesis of the monomer and performed the laboratory experiments. M-H.H. identified the significance of the salicylate molecular switch and performed the laboratory work to complete the total synthesis of the natural product. S.M. conducted key control experiments on the salicylates and identified the major side product from the macrolactonization.

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Correspondence to P. Andrew Evans.

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The authors declare no competing financial interests.

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Evans, P., Huang, MH., Lawler, M. et al. Total synthesis of marinomycin A using salicylate as a molecular switch to mediate dimerization. Nature Chem 4, 680–684 (2012). https://doi.org/10.1038/nchem.1330

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