Skip to main content

Thank you for visiting 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.

Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis


Many natural products contain a C = C double bond through which various other derivatives can be prepared; the stereochemical identity of the alkene can be critical to the biological activities of such molecules. Catalytic ring-closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings1,2; however, cyclizations often proceed without control of alkene stereochemistry2. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations2. Here we outline a reliable, practical and general approach for the efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% of the Z isomer owing to control induced by a tungsten-based alkylidene. Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3–5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM7,8,9,10,11,12. The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Two cases in natural product total synthesis where catalytic RCM with commonly used complexes (1, 2b–d) delivers the macrocyclic alkene with minimal stereoselectivity.
Figure 2: Total synthesis of nakadomarin A realized through late-stage tungsten-catalysed RCM of pentacyclic 13, and comparison with results delivered by Ru catalysts.


  1. Hoveyda, A. H. & Zhugralin, A. R. The remarkable metal-catalyzed olefin metathesis reaction. Nature 450, 243–251 (2007)

    CAS  ADS  Article  Google Scholar 

  2. Gradillas, A. & Perez-Castells, J. Macrocyclization by ring-closing metathesis in the total synthesis of natural products: reaction conditions and limitations. Angew. Chem. Int. Edn 45, 6086–6101 (2006)

    CAS  Article  Google Scholar 

  3. Höfle, G. et al. Epothilone A and B — novel 16-membered macrolides with cytotoxic activity: isolation, crystal structure, and conformation in solution. Angew. Chem. Int. Edn 35, 1567–1569 (1996)

    Article  Google Scholar 

  4. Kowalski, R. J., Giannakakou, P. & Hamel, E. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (taxol). J. Biol. Chem. 272, 2534–2541 (1997)

    CAS  Article  Google Scholar 

  5. Bollag, D. M. et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res. 55, 2325–2333 (1995)

    CAS  PubMed  Google Scholar 

  6. Kobayashi, J., Watanabe, D., Kawasaki, N. & Tsuda, M. Nakadomarin A, a novel hexacyclic manzamine-related alkaloid from Amphimedon sponge. J. Org. Chem. 62, 9236–9239 (1997)

    CAS  Article  Google Scholar 

  7. Nicolaou, K. C. et al. The olefin metathesis approach to epothilone A and its analogues. J. Am. Chem. Soc. 119, 7960–7973 (1997)

    Article  Google Scholar 

  8. Meng, D. et al. Total synthesis of epothilones A and B. J. Am. Chem. Soc. 119, 10073–10092 (1997)

    CAS  Article  Google Scholar 

  9. Nagata, T., Nakagawa, M. & Nishida, A. The first total synthesis of nakadomarin A. J. Am. Chem. Soc. 125, 7484–7485 (2003)

    CAS  Article  Google Scholar 

  10. Ono, K., Nakagawa, M. & Nishida, A. Asymmetric total synthesis of (–)-nakadomarin A. Angew. Chem. Int. Edn 43, 2020–2023 (2004)

    CAS  Article  Google Scholar 

  11. Young, I. S. & Kerr, M. A. Total synthesis of (+)-nakadomarin A. J. Am. Chem. Soc. 129, 1465–1469 (2007)

    CAS  Article  Google Scholar 

  12. Jakubec, P., Cockfield, D. M. & Dixon, D. J. Total synthesis of (–)-nakadomarin A. J. Am. Chem. Soc. 131, 16632–16633 (2009)

    CAS  Article  Google Scholar 

  13. Schrock, R. R. & Hoveyda, A. H. Molybdenum and tungsten imido alkylidene complexes as efficient olefin metathesis catalysts. Angew. Chem. Int. Edn 42, 4592–4633 (2003)

    CAS  Article  Google Scholar 

  14. Scholl, M., Ding, S., Lee, C. W. & Grubbs, R. H. Synthesis and activity of a new generation of ruthenium-based olefin metathesis catalysts coordinated with 1,3-dimesityl-4,5-dihydroimidazol-2-ylidine ligands. Org. Lett. 1, 953–956 (1999)

    CAS  Article  Google Scholar 

  15. Garber, S. B., Kingsbury, J. S., Gray, B. L. & Hoveyda, A. H. Efficient and recyclable monomeric and dendritic Ru-based metathesis catalysts. J. Am. Chem. Soc. 122, 8168–8179 (2000)

    CAS  Article  Google Scholar 

  16. Altmann, K. H. et al. The total synthesis and biological assessment of trans-epothilone A. Helv. Chim. Acta 85, 4086–4110 (2002)

    CAS  Article  Google Scholar 

  17. Starks, C. M., Zhou, Y., Liu, F. & Licari, P. J. Isolation and characterization of new epothilone analogues from recombinant Myxococcus xanthus fermentation. J. Nat. Prod. 66, 1313–1317 (2003)

    CAS  Article  Google Scholar 

  18. Schinzer, D. et al. Total synthesis of (–)-epothilone A. Chem. Eur. J. 5, 2483–2491 (1999)

    CAS  Article  Google Scholar 

  19. Fürstner, A., Mathes, C. & Lehmann, C. W. Alkyne metathesis: development of a novel molybdenum-based catalyst system and its application to the total synthesis of epothilone A and C. Chem. Eur. J. 7, 5299–5317 (2001)

    Article  Google Scholar 

  20. Nilson, M. G. & Funk, R. L. Total synthesis of (–)-nakadomarin A. Org. Lett. 12, 4912–4915 (2010)

    CAS  Article  Google Scholar 

  21. Coutelier, O. & Mortreux, A. Terminal alkyne metathesis: a further step towards selectivity. Adv. Synth. Catal. 348, 2038–2042 (2006)

    CAS  Article  Google Scholar 

  22. Smith, B. J. & Sulikowski, G. A. Total synthesis of (±)-haliclonacyclamine C. Angew. Chem. Int. Edn 49, 1599–1602 (2010)

    CAS  Article  Google Scholar 

  23. Zhang, W. & Moore, J. S. Alkyne metathesis: catalysts and synthetic applications. Adv. Synth. Catal. 349, 93–120 (2007)

    CAS  Article  Google Scholar 

  24. Wang, Y. et al. Control of olefin geometry in macrocyclic ring-closing metathesis using a removable silyl group. J. Am. Chem. Soc. 133, 9196–9199 (2011)

    CAS  Article  Google Scholar 

  25. Malcolmson, S. J., Meek, S. J., Sattely, E. S., Schrock, R. R. & Hoveyda, A. H. Highly efficient molybdenum-based catalysts for alkene metathesis. Nature 456, 933–937 (2008)

    CAS  ADS  Article  Google Scholar 

  26. Ibrahem, I., Yu, M., Schrock, R. R. & Hoveyda, A. H. Highly Z- and enantioselective ring-opening/cross-metathesis reactions catalyzed by stereogenic-at-Mo adamantylimido complexes. J. Am. Chem. Soc. 131, 3844–3845 (2009)

    CAS  Article  Google Scholar 

  27. Jiang, A. J., Zhao, Y., Schrock, R. R. & Hoveyda, A. H. Highly Z-selective metathesis homocoupling of terminal olefins. J. Am. Chem. Soc. 131, 16630–16631 (2009)

    CAS  Article  Google Scholar 

  28. Meek, S. J., O’Brien, R. V., Llaveria, J., Schrock, R. R. & Hoveyda, A. H. Catalytic Z-selective olefin cross-metathesis for natural product synthesis. Nature 471, 461–466 (2011)

    CAS  ADS  Article  Google Scholar 

  29. Fürstner, A. & Langemann, K. Macrocycles by ring-closing metathesis. Synthesis 792–803 (1997)

  30. Fürstner, A., Stelzer, F., Rumbo, A. & Krause, H. Total synthesis of the turrianes and evaluation of their DNA-cleaving properties. Chem. Eur. J. 8, 1856–1871 (2002)

    Article  Google Scholar 

Download references


This work was supported by the United States National Institutes of Health, Institute of General Medical Sciences (grant GM-59426 to A.H.H. and R.R.S.). M. Y. is a John LaMattina graduate fellow, A.F.K. the recipient of an EPSRC-GlaxoSmithKline synthesis studentship, and P.J. an EPSRC postdoctoral fellow. D.J.D. is grateful for an EPSRC leadership fellowship. We thank S. J. Meek, S. J. Malcolmson, R. V. O’Brien, T. J. Mann and E. T. Kiesewetter for discussions; A. R. Zhugralin, S. Torker and D. L. Silverio for DFT calculations; K. Wu for experimental assistance; and Boston College for providing access to computational facilities. The X-ray facilities at Boston College are supported by the United States National Science Foundation (CHE-0923264).

Author information

Authors and Affiliations



M.Y. and C.W. were involved in the discovery, design and development of the Z-selective macrocyclic ring-closing metathesis strategies and applications to the natural product syntheses. A.F.K., P.J. and D.J.D. devised routes for and performed enantioselective syntheses of precursors 5 and 13. R.R.S. and A.H.H. were involved in the discovery and development of the catalysts used in the study; A.H.H. conceived and directed the investigations and composed the manuscript with revisions provided by M.Y. and C.W.

Corresponding author

Correspondence to Amir H. Hoveyda.

Ethics declarations

Competing interests

A.H.H. and R.R.S. are founders of a company that utilizes the catalysts and the resulting technology used in the submitted manuscript.

Supplementary information

Supplementary Information

The file contains Supplementary Text and Data (see contents list for more details) and Supplementary Tables 1-7. (PDF 8584 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yu, M., Wang, C., Kyle, A. et al. Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis. Nature 479, 88–93 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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