Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Total synthesis of structurally diverse pleuromutilin antibiotics

Nature Chemistry volume 14, pages 1270–1277 (2022)Cite this article

Subjects

An Author Correction to this article was published on 25 October 2022

This article has been updated

Abstract

The emergence of drug-resistant bacterial pathogens has placed renewed emphasis on the total chemical synthesis of novel antibacterials. Tetracyclines, macrolides, streptogramins and lincosamides are now accessible through flexible and general synthetic routes. Pleuromutilins (antibiotics based on the fungal metabolite pleuromutilin) have remained resistant to this approach, in large part due to the difficulties encountered in the de novo construction of the decahydro-3a,9-propanocyclopenta[8]annulene skeleton. Here we present a platform for the total synthesis of pleuromutilins that provides access to diverse derivatives bearing alterations at previously inaccessible skeletal and peripheral positions. The synthesis is enabled by the serendipitous discovery of a vinylogous Wolff rearrangement, which serves to establish the C9 quaternary centre in the targets, and the development of a highly diastereoselective butynylation of an α-quaternary aldehyde, which forms the C14 secondary alcohol. The versatility of the route is demonstrated through the synthesis of seventeen structurally distinct derivatives, with many possessing potent antibacterial activity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The structures of (+)-pleuromutilin and clinically relevant derivatives, and a past synthetic route.
Fig. 2: An unexpected vinylogous Wolff rearrangement provided access to the C9 quaternary stereocentre and formed the basis for a synthetic route to C12 normethyl pleuromutilins.
Fig. 3: Scope of the butynylation reaction, completion of a fully derivatized analogue and synthesis of a C7-substitued pleuromutilin.
Fig. 4: Preparation of pleuromutilin derivatives, including ring contractions in the six- and eight-membered rings.
Fig. 5: Seventeen structurally distinct derivatives were prepared and evaluated against a panel of Gram-positive and -negative bacteria.

Similar content being viewed by others

Data availability

All data are available in the main text or the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre under deposition nos. CCDC 2114513 (S3), 2114514 (19), 2114515 (26), 2114516 (S20) and 2114517 (S37). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

Change history

References

  1. Fazakerley, N. J. & Procter, D. J. Synthesis and synthetic chemistry of pleuromutilin. Tetrahedron 70, 6911–6930 (2014).

    Article  CAS  Google Scholar 

  2. Goethe, O., Heuer, A., Ma, X., Wang, Z. & Herzon, S. B. Antibacterial properties and clinical potential of pleuromutilins. Nat. Prod. Rep. 36, 220–247 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Davidovich, C. et al. Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity. Proc. Natl Acad. Sci. USA 104, 4291–4296 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Thirring, K. et al. Preparation of 12-epi-pleuromutilin derivatives as antimicrobial agents. AT Patent WO2015110481A1 (2015).

  5. Berner, H. V., Schulz, G. H. & Schneider, H. Inversion of configuration of the vinylgroup at carbon 12 by reversible retro-en-cleavage. Monatsh. Fuer Chem. 117, 1073 (1986).

    Article  CAS  Google Scholar 

  6. Wicha, W. et al. Efficacy of novel extended spectrum pleuromutilins against E. coli in vitro and in vivo. In 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) (Nabriva, 2015).

  7. Paukner, S. et al. In vitro activity of the novel pleuromutilin BC-3781 tested against bacterial pathogens causing sexually transmitted diseases (STD). In 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (Nabriva, 2013).

  8. Paukner, S. & Riedl, R. Pleuromutilins: potent drugs for resistant bugs—mode of action and resistance. Cold Spring Harb. Perspect. Med. 7, a027110 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gentry, D. R., Rittenhouse, S. F., McCloskey, L. & Holmes, D. J. Stepwise exposure of Staphylococcus aureus to pleuromutilins is associated with stepwise acquisition of mutations in rplC and minimally affects susceptibility to retapamulin. Antimicrob. Agents Chemother. 51, 2048–2052 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Springer, D. M. et al. Synthesis and activity of a C-8 keto pleuromutilin derivative. Bioorg. Med. Chem. Lett. 13, 1751–1753 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Lykkeberg, A. K., Halling-Sorensen, B. & Jensen, L. B. Susceptibility of bacteria isolated from pigs to tiamulin and enrofloxacin metabolites. Vet. Microbiol. 121, 116–124 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Sun, F. et al. Unraveling the Metabolic Routes of Retapamulin: Insights into Drug Development of Pleuromutilins. Antimicrob. Agents Chemother. 62, e02388–17 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Daum, R. S., Kar, S. & Kirkpatrick, P. Retapamulin. Nat. Rev. Drug Discov. 6, 865–866 (2007).

    Article  CAS  Google Scholar 

  14. Veve, M. P. & Wagner, J. L. Lefamulin: review of a promising novel pleuromutilin antibiotic. Pharmacotherapy 38, 935–946 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Liu, F. & Myers, A. G. Development of a platform for the discovery and practical synthesis of new tetracycline antibiotics. Curr. Opin. Chem. Biol. 32, 48–57 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Seiple, I. B. et al. A platform for the discovery of new macrolide antibiotics. Nature 533, 338–345 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li, Q. et al. Synthetic group A streptogramin antibiotics that overcome Vat resistance. Nature 586, 145–150 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mitcheltree, M. J., Stevenson, J. W., Pisipati, A. & Myers, A. G. A practical, component-based synthetic route to methylthiolincosamine permitting facile northern-half diversification of lincosamide antibiotics. J. Am. Chem. Soc. 143, 6829–6835 (2021).

    Article  CAS  PubMed  Google Scholar 

  19. Gibbons, E. G. Total synthesis of (±)-pleuromutilin. J. Am. Chem. Soc. 104, 1767–1769 (1982).

    Article  CAS  Google Scholar 

  20. Boeckman, R. K., Springer, D. M. & Alessi, T. R. Synthetic studies directed toward naturally occurring cyclooctanoids. 2. A stereocontrolled assembly of (±)-pleuromutilin via a remarkable sterically demanding oxy-cope rearrangement. J. Am. Chem. Soc. 111, 8284–8286 (1989).

    Article  CAS  Google Scholar 

  21. Fazakerley, N. J., Helm, M. D. & Procter, D. J. Total synthesis of (+)-pleuromutilin. Chem. Eur. J. 19, 6718–6723 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Murphy, S. K., Zeng, M. & Herzon, S. B. A modular and enantioselective synthesis of the pleuromutilin antibiotics. Science 356, 956 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zeng, M., Murphy, S. K. & Herzon, S. B. Development of a modular synthetic route to (+)-pleuromutilin, (+)-12-epi-mutilins, and related structures. J. Am. Chem. Soc. 139, 16377–16388 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Farney, E. P., Feng, S. S., Schafers, F. & Reisman, S. E. Total synthesis of (+)-pleuromutilin. J. Am. Chem. Soc. 140, 1267–1270 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nicholas, J. F. & Sergey, V. P. Synthesis of pleuromutilin. J. Am. Chem. Soc. 144, 10174–10179 (2022).

    Article  Google Scholar 

  26. Lotesta, S. D. et al. Expanding the pleuromutilin class of antibiotics by de novo chemical synthesis. Chem. Sci. 2, 1258–1261 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Nagata, W., Yoshioka, M. & Murakami, M. Hydrocyanation. VI. Application of the new hydrocyanation methods to conjugate hydrocyanation of α,β-unsaturated ketones, conjugated dienones, and conjugated enamines and to preparation of α-cyanohydrins. J. Am. Chem. Soc. 94, 4654–4672 (1972).

    Article  CAS  Google Scholar 

  28. Egger, H. & Reinshagen, H. New pleuromutilin derivatives with enhanced antimicrobial activity. II. Structure–activity correlations. J. Antibiot. 29, 923–927 (1976).

    Article  CAS  Google Scholar 

  29. Smith, A. B. A vinylogous Wolff rearrangement; copper sulphate-catalysed decomposition of unsaturated diazomethyl ketones. Chem. Commun. 695–696 (1974).

  30. Ireland, R. E. & Willard, A. K. The stereoselective generation of ester enolates. Tetrahedron Lett. 16, 3975–3978 (1975).

    Article  Google Scholar 

  31. Justicia, J., Sancho-Sanz, I., Álvarez-Manzaneda, E., Oltra, J. E. & Cuerva, J. M. Efficient propargylation of aldehydes and ketones catalyzed by titanocene(III). Adv. Synth. Catal. 351, 2295–2300 (2009).

    Article  CAS  Google Scholar 

  32. Bartolo, N. D., Read, J. A., Valentín, E. M. & Woerpel, K. A. Reactions of allylmagnesium reagents with carbonyl compounds and compounds with C═N double bonds: their diastereoselectivities generally cannot be analyzed using the Felkin–Anh and chelation-control models. Chem. Rev. 120, 1513–1619 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Muñoz-Bascón, J., Sancho-Sanz, I., Álvarez-Manzaneda, E., Rosales, A. & Oltra, J. E. Highly selective Barbier-type propargylations and allenylations catalyzed by titanocene(III). Chem. –Eur. J. 18, 14479–14486 (2012).

    Article  PubMed  Google Scholar 

  34. Frigerio, M. & Santagostino, M. A mild oxidizing reagent for alcohols and 1,2-diols: o-iodoxybenzoic acid (IBX) in DMSO. Tetrahedron Lett. 35, 8019–8022 (1994).

    Article  CAS  Google Scholar 

  35. Montgomery, J. Nickel-catalyzed reductive cyclizations and couplings. Angew. Chem. Int. Ed. 43, 3890–3908 (2004).

    Article  CAS  Google Scholar 

  36. Moslin, R. M., Miller-Moslin, K. & Jamison, T. F. Regioselectivity and enantioselectivity in nickel-catalysed reductive coupling reactions of alkynes. Chem. Commun. 4441–4449 (2007).

  37. Crabtree, R. H. & Davis, M. W. Directing effects in homogeneous hydrogenation with [Ir(cod)(PCy3)(py)]PF6. J. Org. Chem. 51, 2655–2661 (1986).

    Article  CAS  Google Scholar 

  38. Spartan 18 v.1.4.8 (Wavefunction, 2018).

  39. Riedl, R. H., Heilmayer, W. & Spence, L. Process for the preparation for the preparation of pleuromutilins. AT Patent WO/2011/146954 (2011).

  40. Lykkeberg, A. K., Cornett, C., Halling-Sørensen, B. & Hansen, S. H. Isolation and structural elucidation of tiamulin metabolites formed in liver microsomes of pigs. J. Pharm. Biomed. Anal. 42, 223–231 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Lykkeberg, A. K., Halling-Sørensen, B. & Jensen, L. B. Susceptibility of bacteria isolated from pigs to tiamulin and enrofloxacin metabolites. Vet. Microb. 121, 116–124 (2007).

    Article  CAS  Google Scholar 

  42. Marx, J. N. & Norman, L. R. Synthesis of (–)-acorone and related spirocyclic sesquiterpenes. J. Org. Chem. 40, 1602–1606 (1975).

    Article  CAS  Google Scholar 

  43. Ito, Y., Hirao, T. & Saegusa, T. Synthesis of α,β-unsaturated carbonyl compounds by palladium(II)-catalyzed dehydrosilylation of silyl enol ethers. J. Org. Chem. 43, 1011–1013 (1978).

    Article  CAS  Google Scholar 

  44. Shvo, Y. & Arisha, A. H. I. Regioselective catalytic dehydrogenation of aldehydes and ketones. J. Org. Chem. 63, 5640–5642 (1998).

    Article  CAS  Google Scholar 

  45. Bell, M. G. et al. Pyrazole derivatives useful as aldolsterone synthase inhibitors. US Patent WO 2012/173849 Al (2012).

  46. Nakamura, E., Matsuzawa, S., Horiguchi, Y. & Kuwajima, I. Me3SiCl accelerated conjugate addition of stoichiometric organocopper reagents. Tetrahedron Lett. 27, 4029–4032 (1986).

    Article  CAS  Google Scholar 

  47. Ito, Y., Fujii, S. & Saegusa, T. Reaction of 1-silyloxybicyclo[n.1.0]alkanes with iron(III) chlorides. A facile synthesis of 2-cycloalkenones via ring enlargement of cyclic ketones. J. Org. Chem. 41, 2073–2074 (1976).

    Article  CAS  Google Scholar 

  48. Sammakia, T. & Jacobs, J. S. Picolinic acid as a partner in the Mitsunobu reaction: subsequent hydrolysis of picolinate esters under essentially neutral conditions with copper acetate in methanol. Tetrahedron Lett. 40, 2685–2688 (1999).

    Article  CAS  Google Scholar 

  49. Richter, M. F. et al. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545, 299–304 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge financial support from the National Institutes of Health NIGMS (grant no. R35-GM131913), the Chemistry Biology Interface Training Program (grant no. T32GM067543 to M.D.) and Yale University (Wiberg Fellowship to O.G.). We acknowledge T. Smeltzer (Treehouse Biotech) and A. Heuer (Yale University) for preliminary experiments. We thank M. Espinosa (Yale University) for helpful suggestions and glovebox assistance. We acknowledge F. Menges for obtaining the high-resolution mass spectrometry data, B. Mercado for obtaining the X-ray crystallography data and E. Paulson for assistance with NMR processing.

Author information

Authors and Affiliations

  1. Department of Chemistry, Yale University, New Haven, CT, USA

    Olivia Goethe, Mikaela DiBello & Seth B. Herzon

  2. Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA

    Seth B. Herzon

Authors
  1. Olivia Goethe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mikaela DiBello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seth B. Herzon
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

O.G. and S.B.H. initiated the project. O.G., S.B.H. and M.D. designed the synthetic routes. O.G. and M.D. performed the chemical syntheses and characterizations. All of the authors wrote and edited the manuscript.

Corresponding author

Correspondence to Seth B. Herzon.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Paul Hergenrother, William Wuest and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–7, and experimental procedures and detailed characterization data for all new compounds, and methods for antimicrobial susceptibility testing.

Supplementary Data 1

Crystallographic data for compound S3; CCDC reference 2114513.

Supplementary Data 2

Crystallographic data for compound 19; CCDC reference 2114514.

Supplementary Data 3

Crystallographic data for compound 26; CCDC reference 2114515.

Supplementary Data 4

Crystallographic data for compound S20; CCDC reference 2114516.

Supplementary Data 5

Crystallographic data for compound S35; CCDC reference 2114517.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Goethe, O., DiBello, M. & Herzon, S.B. Total synthesis of structurally diverse pleuromutilin antibiotics. Nat. Chem. 14, 1270–1277 (2022). https://doi.org/10.1038/s41557-022-01027-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-022-01027-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing