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.

High-value alcohols and higher-oxidation-state compounds by catalytic Z-selective cross-metathesis

Abstract

Olefin metathesis catalysts provide access to molecules that are indispensable to physicians and researchers in the life sciences1,2. A persisting problem, however, is the dearth of chemical transformations that directly generate acyclic Z allylic alcohols, including products that contain a hindered neighbouring substituent or reactive functional units such as a phenol, an aldehyde, or a carboxylic acid. Here we present an electronically modified ruthenium–disulfide catalyst that is effective in generating such high-value compounds by cross-metathesis. The ruthenium complex is prepared from a commercially available precursor and an easily generated air-stable zinc catechothiolate. Transformations typically proceed with 5.0 mole per cent of the complex and an inexpensive reaction partner in 4–8 hours under ambient conditions; products are obtained in up to 80 per cent yield and 98:2 Z:E diastereoselectivity. The use of this catalyst is demonstrated in the synthesis of the naturally occurring anti-tumour agent neopeltolide and in a single-step stereoselective gram-scale conversion of a renewable feedstock (oleic acid) to an anti-fungal agent. In this conversion, the new catalyst promotes cross-metathesis more efficiently than the commonly used dichloro–ruthenium complexes, indicating that its utility may extend beyond Z-selective processes.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Unaddressed issues in Z-selective olefin metathesis.
Figure 2: The range of Z allylic alcohols made available through catalytic stereoselective cross-metathesis with Ru-3b.
Figure 3: Assessing the performance of different Z-selective catalysts.
Figure 4: Transformation of renewable raw materials to two different Z allylic alcohols by stereoselective cross-metathesis.

References

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

    ADS  CAS  Article  Google Scholar 

  2. Fürstner, A. Teaching metathesis “simple” stereochemistry. Science 341, 1357–1364 (2013)

    Article  Google Scholar 

  3. 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 

  4. 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)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  6. Keitz, B. K., Endo, K., Herbert, M. B. & Grubbs, R. H. Z-selective homodimerization of terminal olefins with a ruthenium metathesis catalyst. J. Am. Chem. Soc. 133, 9686–9688 (2011)

    CAS  Article  Google Scholar 

  7. Keitz, B. K., Endo, K., Patel, P. R., Herbert, M. B. & Grubbs, R. H. Improved ruthenium catalysts for Z-selective olefin metathesis. J. Am. Chem. Soc. 134, 693–699 (2012)

    CAS  Article  Google Scholar 

  8. Rosebrugh, L. E., Herbert, M. B., Marx, V. M., Keitz, B. K. & Grubbs, R. H. Highly active ruthenium metathesis catalysts exhibiting unprecedented activity and Z selectivity. J. Am. Chem. Soc. 135, 1276–1279 (2013)

    CAS  Article  Google Scholar 

  9. Occhipinti, G., Hansen, F. R., Törnroos, K. W. & Jensen, V. R. Simple and highly Z-selective ruthenium-based olefin metathesis catalyst. J. Am. Chem. Soc. 135, 3331–3334 (2013)

    CAS  Article  Google Scholar 

  10. Khan, R. K. M., Torker, S. & Hoveyda, A. H. Readily accessible and easily modifiable Ru-based catalysts for efficient and Z-selective ring-opening metathesis polymerization and ring-opening/cross-metathesis. J. Am. Chem. Soc. 135, 10258–10261 (2013)

    CAS  Article  Google Scholar 

  11. Koh, M. J., Khan, R. K. M., Torker, S. & Hoveyda, A. H. Broadly applicable Z- and diastereoselective ring-opening/cross-metathesis catalyzed by a dithiolate Ru complex. Angew. Chem. Int. Ed. 53, 1968–1972 (2014)

    CAS  Article  Google Scholar 

  12. Hoveyda, A. H. Evolution of catalytic stereoselective olefin metathesis. From ancillary transformation to purveyor of stereochemical identity. J. Org. Chem. 79, 4763–4792 (2014)

    CAS  Article  Google Scholar 

  13. Mann, T. J., Speed, A. W. H., Schrock, R. R. & Hoveyda, A. H. Catalytic Z-selective cross-metathesis with secondary silyl- and benzyl-protected allylic ethers: mechanistic aspects and applications to natural product synthesis. Angew. Chem. Int. Edn 52, 8395–8400 (2013)

    CAS  Article  Google Scholar 

  14. Buchmeiser, M. R., Sen, S., Unold, J. & Frey, W. N-Heterocyclic carbene, high oxidation state molybdenum alkylidene complexes: Functional-group-tolerant cationic metathesis catalysts. Angew. Chem. Int. Edn 53, 9384–9388 (2014)

    CAS  Article  Google Scholar 

  15. Lin, Y. A. & Davis, B. G. The allylic chalcogen effect in olefin metathesis. J. Org. Chem. 6, 1219–1228 (2010)

    CAS  Google Scholar 

  16. Torker, S., Khan, R. K. M. & Hoveyda, A. H. The influence of anionic ligands on stereoisomerism of Ru carbenes and their importance to efficiency and selectivity of catalytic olefin metathesis reactions. J. Am. Chem. Soc. 136, 3439–3455 (2014)

    CAS  Article  Google Scholar 

  17. Werner, H., Grünwald, C., Stüer, W. & Wolf, J. Deactivation of the Grubbs carbene complex [RuCl2( = CHPh)(PCy3)2] by allylic alcohols. Organometallics 22, 1558–1560 (2003)

    CAS  Article  Google Scholar 

  18. Hoveyda, A. H., Lombardi, P. J., O’Brien, R. V. & Zhugralin, A. R. H-bonding as a control element in stereoselective Ru-catalyzed olefin metathesis. J. Am. Chem. Soc. 131, 8378–8379 (2009)

    CAS  Article  Google Scholar 

  19. Cannon, J. S. & Grubbs, R. H. Alkene chemoselectivity in ruthenium-catalyzed Z-selective olefin metathesis. Angew. Chem. Int. Edn 52, 9001–9004 (2013)

    CAS  Article  Google Scholar 

  20. Hartung, J. & Grubbs, R. H. Catalytic, enantioselective synthesis of 1,2-anti-diols by asymmetric ring-opening/cross-metathesis. Angew. Chem. Int. Ed. 53, 3885–3888 (2014)

    CAS  Article  Google Scholar 

  21. Rossiter, B. E., Katsuki, T. & Sharpless, K. B. Asymmetric epoxidation provides shortest routes to four chiral epoxy alcohols which are key intermediates in syntheses of methymycin, erythromycin, leukotriene C-1, and disparlure. J. Am. Chem. Soc. 103, 464–465 (1981)

    CAS  Article  Google Scholar 

  22. Kiesewetter, E. T. et al. Synthesis of Z-(pinacolato)allylboron and Z-(pinacolato)alkenylboron compounds through stereoselective catalytic cross-metathesis. J. Am. Chem. Soc. 135, 6026–6029 (2013)

    CAS  Article  Google Scholar 

  23. Wright, A. E. et al. Neopeltolide, a macrolide from Lithistid sponge of the family Neopeltidae. J. Nat. Prod. 70, 412–416 (2007)

    CAS  Article  Google Scholar 

  24. D’Ambrosio, M., Guerriero, A., Debitus, C. & Pietra, F. 6. Leucascandrolide A, a new type of macrolide: the first powerfully bioactive metabolite of calcareous sponges (Leucascandra caveolata, a new genus from the coral sea). Helv. Chim. Acta 79, 51–60 (1996)

    Article  Google Scholar 

  25. Miao. Yu. Schrock, R. R. & Hoveyda, A. H. Catalyst-controlled stereoselective olefin metathesis as a principal strategy in multi-step synthesis design. A concise route to (+)-neopeltolide. Angew. Chem. Int. Ed. http://dx.doi.org/ 10.1002/anie.201409120 (2014)

  26. Biermann, U., Bornscheuer, U., Meier, M. A. R., Metzger, J. & Schäfer, H. Oils and fats as renewable raw materials in chemistry. Angew. Chem. Int. Ed. 50, 3854–3871 (2011)

    CAS  Article  Google Scholar 

  27. Gunstone, F. D. in Oleochemical Manufacture and Applications (eds Gunstone, F. D. & Hamilton, R. J. ) Vol. 1 (Academic Press, 2001)

    Google Scholar 

  28. Behr, A. & Gomes, J. P. The cross-metathesis of methyl oleate with cis-2-butene-1,4-diyl acetate and the influence of protecting groups. J. Org. Chem. 7, 1–8 (2011)

    CAS  Google Scholar 

  29. Suzuki, Y., Kurita, O., Kono, Y., Hyakutake, H. & Sakurai, A. Structure of a new antifungal C11-hydroxyfatty acid isolated from leaves of wild rice (Oryza officinalis). Biosci. Biotechnol. Biochem. 59, 2049–2051 (1995)

    CAS  Article  Google Scholar 

  30. Kajetanowicz, A., Sytniczuk, A. & Grela, K. Metathesis of renewable raw materials—influence of ligands in the indenylidene type catalysts on self-metathesis of methyl oleate and cross-metathesis of methyl oleate with (Z)-2-butene-1,4-diol diacetate. Green Chem. 16, 1579–1585 (2014)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This research was supported by a grant from the National Science Foundation (CHE-1362763). R.K.M.K. and M.Y. were partially supported as AstraZeneca Graduate Fellows. We thank Boston College for access to computational facilities.

Author information

Authors and Affiliations

Authors

Contributions

M.J.K. and R.K.M.K. carried out the catalyst synthesis, method development studies and applications related to renewable feedstock, S.T. performed the computational investigations, M.Y. carried out the experiments in connection with neopeltolide, and M.S.M. studied modes of catalyst decomposition. A.H.H. conceived and directed the investigations and composed the manuscript with revisions provided by the other authors.

Corresponding author

Correspondence to Amir H. Hoveyda.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data – see contents pages for details. (PDF 11364 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Koh, M., Khan, R., Torker, S. et al. High-value alcohols and higher-oxidation-state compounds by catalytic Z-selective cross-metathesis. Nature 517, 181–186 (2015). https://doi.org/10.1038/nature14061

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature14061

Further reading

Comments

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.

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