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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Arias, C. A. & Murray, B. E. Antibiotic-resistant bugs in the 21st century—a clinical super-challenge. N. Engl. J. Med. 360, 439–443 (2009).
von Nussbaum, F., Brands, M., Hinzen, B., Weigand, S. & Häbich D. Antibacterial natural products in medicinal chemistry—exodus or revival? Angew. Chem. Int. Ed. 45, 5072–5129 (2006).
Fleming, A. On the antibacterial action of cultures of a Penicillium, with special reference to their use in the isolation of B. influenzae. Br. J. Exp. Pathol. 10, 226–236 (1929).
Eichner, S., Floss, H. G., Sasse, F. & Kirschning A. New, highly active nonbenzoquinone geldanamycin derivatives by using mutasynthesis. ChemBioChem 10, 1801–1805 (2009).
Goss, R. J. M. et al. An expeditious route to fluorinated rapamycin analogues by utilising mutasynthesis. ChemBioChem 11, 698–702 (2010).
Staunton, J. & Weissman, K. J. Polyketide biosynthesis: a millennium review. Nat. Prod. Rep. 18, 380–416 (2001).
Hertweck, C. The biosynthetic logic of polyketide diversity. Angew. Chem. Int. Ed. 48, 4688–4716 (2009).
Tsai, S.-C. et al. Crystal structure of the macrocycle-forming thioesterase domain of the erythromycin polyketide synthase: versatility from a unique substrate channel. Proc. Natl Acad. Sci. USA 98, 14808–14813 (2001).
Akey, D. L. et al. Structural basis for macrolactonization by the pikromycin thioesterase. Nature Chem. Biol. 2, 537–542 (2006).
Zhou, H., Qiao, K., Gao, Z., Vederas, J. C. & Tang, Y. Insights into radicicol biosynthesis via heterologous synthesis of intermediates and analogs. J. Biol. Chem. 285, 41412–41421 (2010).
Forouhar, F. et al. Structural and biochemical studies identify tobacco SABP2 as a methyl salicylate esterase and implicate it in plant innate immunity. Proc. Natl Acad. Sci. 102, 1773–1778 (2005).
Grabowski, S. L. Hydrogen Bond — New Insights (Springer, 2006).
Kwon, H. C., Kauffman, C. A., Jensen, P. R. & Fenical, W. Marinomycins A–D, antitumor-antibiotics of a new structure class from a marine actinomycete of the recently discovered genus ‘Marinispora’. J. Am. Chem. Soc. 128, 1622–1632 (2006).
Chambers, H. F. & DeLeo, F. R. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nature Rev. Microbiol. 7, 629–641 (2009).
Murray, B. E. Vancomycin-resistant enterococcal infections. N. Engl. J. Med. 342, 710–721 (2000).
Matsumori, N., Yamaji, N., Matsuoka, S., Oishi, T. & Murata, M. Amphotericin B covalent dimers forming sterol-dependent ion-permeable membrane channels. J. Am. Chem. Soc. 124, 4180–4181 (2002).
Nicolaou, K. C. et al. Total synthesis of marinomycins A–C and of their monomeric counterparts monomarinomycin A and iso-monomarinomycin A. J. Am. Chem. Soc. 129, 1760–1768 (2007).
Amans, D., Bareille, L., Bellosta, V. & Cossy, J. Synthesis of the monomeric counterpart of marinomycin A. J. Org. Chem. 74, 7665–7674 (2009).
Hoffmann, R. W. Conformation design of open-chain compounds. Angew. Chem. Int. Ed. 39, 2054–2070 (2000).
Smith, A. B. III & Xian, M. Anion relay chemistry: an effective tactic for diversity oriented synthesis. J. Am. Chem. Soc. 128, 66–67 (2006).
Keck, G. E. & Wager, C. A. The first directed reduction of β-alkoxy ketones to anti-1,3-diol monoethers: Identification of spectator and director alkoxy groups. Org. Lett. 2, 2307–2309 (2000).
Bernet B. & Vasella A. Carbocyclische verbindungen aus Monosacchariden. I. Umsetzungen in der Glucosereihe. Helv. Chim. Acta. 62, 1990–2016 (1979).
Evans, P. A., Grisin, A. & Lawler, M. J. Diastereoselective construction of syn-1,3-dioxanes via a bismuth-mediated two-component hemiacetal/oxa-conjugate reaction. J. Am. Chem. Soc. 134, 2856–2859 (2012).
Michels, T. D., Rhee, J. U. & Vanderwal, C. D. Synthesis of δ-tributylstannyl-α,β,γ,δ-unsaturated aldehydes from pyridines. Org. Lett. 10, 4787–4790 (2008).
Uchiyama, M. et al. Regiocontrolled intramolecular cyclizations of carboxylic acids to carbon–carbon triple bonds promoted by acid or base catalyst. Org. Lett. 8, 5517–5520 (2006).
Chatterjee, A. K., Choi, T.-L., Sanders, D. P. & Grubbs, R. H. A general model for selectivity in olefin cross metathesis. J. Am. Chem. Soc. 125, 11360–11370 (2003).
Hassan, A. E. A., Nishizono, N., Minakawa, N., Shuto, S. & Matsuda A. Nucleosides and nucleotides. 151. Conversion of (Z)-2′-(cyanomethylene)-2′-deoxyuridines into their (E)-isomers via addition of thiophenol to the cyanomethylene moiety followed by oxidative syn-elimination reactions. J. Org. Chem. 61, 6261–6267 (1996).
Griffith, W. P., Ley, S. V., Whitcombe, G. P. & White, A. D. Preparation and use of tetra-n-butylammonium per-ruthenate (TBAP reagent) and tetra-n-propylammonium per-ruthenate (TPAP reagent) as new catalytic oxidants for alcohols. J. Chem. Soc. Chem. Commun. 1625–1627 (1987).
Bhattacharjee, A. & De Brabander, J. K. Synthesis of side chain truncated apicularen A. Tetrahedron Lett. 41, 8069–8073 (2000).
Smith, A. B. III, Dong, S., Brenneman, J. B. & Fox, R. J. Total synthesis of (+)-sorangicin A. J. Am. Chem. Soc. 131, 12109–12111 (2009).
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary information
Supplementary information (PDF 6278 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nchem.1330
This article is cited by
-
A brief history of antibiotics and select advances in their synthesis
The Journal of Antibiotics (2018)
-
Living GenoChemetics by hyphenating synthetic biology and synthetic chemistry in vivo
Nature Communications (2017)