Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis

Abstract

Catalytic cross-metathesis is a central transformation in chemistry, yet corresponding methods for the stereoselective generation of acyclic trisubstituted alkenes in either the E or the Z isomeric forms are not known. The key problems are a lack of chemoselectivity—namely, the preponderance of side reactions involving only the less hindered starting alkene, resulting in homo-metathesis by-products—and the formation of short-lived methylidene complexes. By contrast, in catalytic cross-coupling, substrates are more distinct and homocoupling is less of a problem. Here we show that through cross-metathesis reactions involving E- or Z-trisubstituted alkenes, which are easily prepared from commercially available starting materials by cross-coupling reactions, many desirable and otherwise difficult-to-access linear E- or Z-trisubstituted alkenes can be synthesized efficiently and in exceptional stereoisomeric purity (up to 98 per cent E or 95 per cent Z). The utility of the strategy is demonstrated by the concise stereoselective syntheses of biologically active compounds, such as the antifungal indiacen B and the anti-inflammatory coibacin D.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The challenge of developing stereoselective trisubstituted alkene cross-metathesis.
Figure 2: Synthesis of Z- and E-trisubstituted alkenyl chlorides.
Figure 3: Synthesis of Z- and E-trisubstituted alkenyl bromides.
Figure 4: Synthesis of E- or Z-trisubstituted non-halogenated alkenes.
Figure 5: Synthesis of biologically active compounds.

References

  1. 1

    Negishi, E. et al. Recent advances in efficient and selective synthesis of di-, tri-, and tetrasubstituted alkenes via Pd-catalyzed alkenylation–carbonyl olefination synergy. Acc. Chem. Res. 41, 1474–1485 (2008)

    CAS  PubMed  Google Scholar 

  2. 2

    Siau, W.-Y., Zhang, Y. & Zhao, Y. Stereoselective synthesis of Z-alkenes. Top. Curr. Chem. 327, 33–58 (2012)

    CAS  PubMed  Google Scholar 

  3. 3

    Shang, G., Li, W. & Zhang, X. in Catalytic Asymmetric Synthesis (ed. Ojima, I. ) 344–436 (Wiley, 2010)

  4. 4

    Baslé, O., Denicourt-Nowicki, A., Crévisy, C. & Mauduit, M. in Copper-Catalyzed Asymmetric Synthesis (eds Alexakis, A., Krause, N. & Woodward, S. ) 85–119 (VCH–Wiley, 2014)

  5. 5

    Alexakis, A., Krause, N. & Woodward, S. in Copper-Catalyzed Asymmetric Synthesis (eds Alexakis, A., Krause, N. & Woodward, S. ) 33–68 (VCH–Wiley, 2014)

  6. 6

    Sreekumar, C., Darst, K. P. & Still, W. C. A direct synthesis of Z-trisubstituted allylic alcohols via the Wittig reaction. J. Org. Chem. 45, 4260–4262 (1980)

    CAS  Google Scholar 

  7. 7

    Maryanoff, B. E. & Reitz, A. B. The Wittig olefination reaction and modifications involving phosphoryl-stabilized carbanions. Stereochemistry, mechanism, and selected synthetic aspects. Chem. Rev. 89, 863–927 (1989)

    CAS  Google Scholar 

  8. 8

    Taber, D. F., Meagley, R. P. & Doren, D. J. Cyclohexenone construction by intramolecular alkylidene C–H insertion: Synthesis of (+)-cassiol. J. Org. Chem. 61, 5723–5728 (1996)

    CAS  Google Scholar 

  9. 9

    Trost, B. M. & Ball, Z. T. Addition of metalloid hydrides to alkynes: hydrometallation with boron, silicon, and tin. Synthesis 2005, 853–887 (2005)

    Google Scholar 

  10. 10

    Wang, C., Tobrman, T., Xu, Z. & Negishi, E. Highly regio- and stereoselective synthesis of (Z)-trisubstituted alkenes via propyne bromoboration and tandem Pd-catalyzed cross-coupling. Org. Lett. 11, 4092–4095 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Minato, A. & Suzuki, K. A remarkable steric effect in palladium-catalyzed Grignard coupling: regio- and stereoselective monoalkylation and -arylation of 1,1-dichloro-1-alkenes. J. Am. Chem. Soc. 109, 1257–1258 (1987)

    CAS  Google Scholar 

  12. 12

    Mun, B., Kim, S., Yoon, H., Kim, K. H. & Lee, Y. Total synthesis of isohericerin, isohericenone, and erinacerin A: development of a copper-catalyzed methylboronation of terminal alkynes. J. Org. Chem. 82, 6349–6357 (2017)

    CAS  PubMed  Google Scholar 

  13. 13

    Negishi, E., Van Horn, D. E. & Yoshida, T. Controlled carbometallation. 20. Carbometalation reaction of alkynes with organoalane–zirconocene derivatives as a route to stereo- and regiodefined trisubstituted alkenes. J. Am. Chem. Soc. 107, 6639–6647 (1985)

    CAS  Google Scholar 

  14. 14

    Fleming, I., Newton, T. W. & Roessler, F. The silylcupration of acetylenes: A synthesis of vinylsilanes. J. Chem. Soc. Perkin Trans. I 2527–2532 (1981)

    Google Scholar 

  15. 15

    Ma, S. & Negishi, E. Anti-carbometalation of homopropargyl alcohols and their higher homologues via non-chelation-controlled syn-carbometallation and chelation-controlled isomerization. J. Org. Chem. 62, 784–785 (1997)

    CAS  Google Scholar 

  16. 16

    Lu, Z. & Ma, S. Studies on the Cu(I)-catalyzed regioselective anti-carbometallation of secondary terminal propargylic alcohols. J. Org. Chem. 71, 2655–2660 (2006)

    CAS  PubMed  Google Scholar 

  17. 17

    Gribble, G. W. Biological activity of recently discovered halogenated marine natural products. Mar. Drugs 13, 4044–4136 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Chatterjee, A. K. & Grubbs, R. H. Synthesis of trisubstituted alkenes via olefin cross-metathesis. Org. Lett. 1, 1751–1753 (1999)

    CAS  PubMed  Google Scholar 

  19. 19

    Chatterjee, A. K., Sanders, D. P. & Grubbs, R. H. Synthesis of symmetrical trisubstituted olefins by cross metathesis. Org. Lett. 4, 1939–1942 (2002)

    CAS  PubMed  Google Scholar 

  20. 20

    Morrill, C. M., Funk, T. W. & Grubbs, R. H. Synthesis of tri-substituted vinyl boronates via ruthenium-catalyzed olefin cross-metathesis. Tetrahedr. Lett. 45, 7733–7736 (2004)

    CAS  Google Scholar 

  21. 21

    Wang, Z. J., Jackson, W. R. & Robinson, A. J. An efficient protocol for the cross-metathesis of sterically demanding olefins. Org. Lett. 15, 3006–3009 (2013)

    CAS  PubMed  Google Scholar 

  22. 22

    Hoveyda, A. H., Khan, R. K. M., Torker, S. & Malcolmson, S. J. in Handbook of Metathesis (eds Grubbs, R. H., Wenzel, A. G., O’Leary, D. J. & Khosravi, E. ) 503–562 (Wiley–VCH, 2014)

  23. 23

    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  PubMed  PubMed Central  Google Scholar 

  24. 24

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

    ADS  CAS  PubMed  Google Scholar 

  25. 25

    Cuvigny, T., du Penhoat, H. & Julia, M. Isomérisation cis trans régiosélective de doubles liaison trisubstitutées. Tetrahedr. Lett. 21, 1331–1334 (1980)

    CAS  Google Scholar 

  26. 26

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

    CAS  Google Scholar 

  27. 27

    Nguyen, T. T. et al. Kinetically controlled E-selective catalytic olefin metathesis. Science 352, 569–575 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Koh, M. J., Nguyen, T. T., Zhang, H., Schrock, R. R. & Hoveyda, A. H. Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis. Nature 531, 459–465 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Lam, J. K. et al. Synthesis and evaluation of molybdenum and tungsten monoaryloxide halide alkylidene complexes for Z-selective cross-metathesis of cyclooctene and Z-1,2-dichloroethylene. J. Am. Chem. Soc. 138, 15774–15783 (2016)

    CAS  PubMed  Google Scholar 

  30. 30

    Chemler, S. R., Trauner, D. & Danishefsky, S. J. The B-alkyl Suzuki–Miyaura cross-coupling reaction: Development, mechanistic study, and applications in natural product synthesis. Angew. Chem. Int. Ed. 40, 4544–4568 (2001)

    CAS  Google Scholar 

  31. 31

    Miyazawa, M., Ishibashi, N., Ohnuma, S. & Miyashita, M. Stereospecific internal alkylation of terminal γ,δ-epoxy acrylates. Tetrahedr. Lett. 38, 3419–3422 (1997)

    CAS  Google Scholar 

  32. 32

    Anantoju, K. K., Mohd, B. S. & Maringanti, T. C. An efficient and concise synthesis of indiacen A and indiacen B. Tetrahedr. Lett. 58, 1499–1500 (2017)

    CAS  Google Scholar 

  33. 33

    Ely, R. J. & Morken, J. P. Stereoselective nickel-catalyzed 1,4-hydroboration of 1,3-dienes. Org. Synth. 88, 342–352 (2011)

    CAS  Google Scholar 

  34. 34

    Mori, A., Fujiwara, J., Maruoka, K. & Yamamoto, H. Nucleophilic cleavage of acetals using organometallic reagents. J. Organomet. Chem. 285, 83–94 (1985)

    CAS  Google Scholar 

  35. 35

    Brown, H. C., Bhat, N. G. & Rajagopalan, S. Stereoselective synthesis of (E)- and (Z)-disubstituted vinyl bromides via organoboranes. Synthesis 480–482 (1986)

  36. 36

    Kirchhoff, J. H., Netherton, M. R., Hills, I. D. & Fu, G. C. Boronic acids: New coupling partners in room-temperature Suzuki reactions of alkyl bromides. Crystallographic characterization of an oxidative-addition adduct generated under remarkably mild conditions. J. Am. Chem. Soc. 124, 13662–13663 (2002)

    CAS  PubMed  Google Scholar 

  37. 37

    Zhang, H., Yu, E. C., Torker, S., Schrock, R. R. & Hoveyda, A. H. Preparation of macrocyclic Z-enoates and (E,Z)- or (Z,E)-dienoates through catalytic stereoselective ring-closing metathesis. J. Am. Chem. Soc. 136, 16493–16496 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Koh, M. J. et al. Molybdenum chloride catalysts for Z-selective olefin metathesis reactions. Nature 542, 80–85 (2017)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Edwards, J. T. et al. Decarboxylative alkenylation. Nature 545, 213–218 (2017)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Steinmetz, H. et al. Indiacens A and B: prenyl indoles from the myxobacterium Sandaracinus amylolyticus. J. Nat. Prod. 75, 1803–1805 (2012)

    CAS  PubMed  Google Scholar 

  41. 41

    Marsch, N., Jones, P. G. & Lindel, T. SmI2-mediated dimerization of indolylbutenones and synthesis of the myxobacterial natural product indiacen B. Beilstein J. Org. Chem. 11, 1700–1706 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Coombs, J. R., Zhang, L. & Morken, J. P. Synthesis of vinyl boronates from aldehydes by a practical boron–Wittig reaction. Org. Lett. 17, 1708–1711 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Balunas, M. J. et al. Coibacins A–D, antileishmanial marine cyanobacterial polyketides with intriguing biosynthetic origins. Org. Lett. 14, 3878–3881 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Tsukamoto, H., Uchiyama, T., Suzuki, T. & Kondo, Y. Palladium(0)-catalyzed direct cross-coupling reaction of allylic alcohols with aryl- and alkenylboronic acids. Org. Biomol. Chem. 6, 3005–3013 (2008)

    CAS  PubMed  Google Scholar 

  45. 45

    Koh, M. J. et al. High-value alcohols and higher-oxidation-state compounds by catalytic Z-selective cross-metathesis. Nature 517, 181–186 (2015)

    ADS  CAS  PubMed  Google Scholar 

  46. 46

    Xu, C., Shen, X. & Hoveyda, A. H. In situ methylene capping: A general strategy for efficient stereoretentive catalytic olefin metathesis. The concept, methodological implications, and applications to synthesis of biologically active compounds. J. Am. Chem. Soc. 139, 10919–10928 (2017)

    CAS  PubMed  Google Scholar 

  47. 47

    Kolská, K., Ghavre, M., Pour, M., Hybelbauerová, S. & Kotora, M. Total synthesis of coibacin D by using enantioselective allylation and metathesis reactions. Asian J. Org. Chem. 5, 646–651 (2016)

    Google Scholar 

  48. 48

    Nunnery, J. K. et al. Biosynthetically intriguing chlorinated lipophilic metabolites from geographically distant tropical marine cyanobacteria. J. Org. Chem. 77, 4198–4208 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Romo, D. et al. Total synthesis and immunosuppressive activity of (–)-pateamine A and related compounds: implementation of a β-lactam-based macrocyclization. J. Am. Chem. Soc. 120, 12237–12254 (1998)

    CAS  Google Scholar 

  50. 50

    Northcote, P. T., Blunt, J. W. & Munro, M. H. G. Pateamine: a potent cytotoxin from the New Zealand marine sponge, Mycale sp. Tetrahedr. Lett. 32, 6411–6414 (1991)

    CAS  Google Scholar 

  51. 51

    Ondi, L., Nagy, G. M., Czirok, J. B., Bucsai, A. & Frater, G. E. From box to bench: Air-stable molybdenum catalyst tablets for everyday use in olefin metathesis. Org. Process Res. Dev. 20, 1709–1716 (2016)

    CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the United States National Institutes of Health, Institute of General Medical Sciences (GM-59426 and, in part, CHE-1362763). M.J.K. and T.J.M. are grateful for support in the form of a Bristol Myers-Squibb Fellowship in Organic Chemistry and a John LaMattina Graduate Fellowship, respectively.

Author information

Affiliations

Authors

Contributions

T.T.N. and M.J.K. were involved in the discovery, design and development of the cross-metathesis strategies and their applications. T.J.M. carried out the initial exploratory studies with 1,1-disubstituted alkenes. A.H.H. designed and directed the investigations. A.H.H. and R.R.S. conceived the studies that led to the development of molybdenum complexes used in this study. A.H.H. wrote the manuscript with revisions provided by T.T.N., M.J.K. and T.J.M.

Corresponding author

Correspondence to Amir H. Hoveyda.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

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

Extended data figures and tables

Extended Data Figure 1 Non-productive olefin metathesis pathways.

Cross-metathesis between v and 1a via symmetrical metallacyclobutane iv′ (right, in black) is more likely than one involving complex iv″ as an intermediate (left, in red). This is as a result of greater steric pressure between the Cα substituent and the sizeable aryloxide ligand27. Cycloreversion of iv′ would then regenerate v and afford 1a (a non-productive process).

Extended Data Figure 2 Distinctive pathways for cross-metathesis of 22 and vinyl–B(pin) with Mo-1 and Mo-2.

a, Cross-metathesis between 25 and vinyl–B(pin) in the presence of Mo-1 and Mo-2 results in different product distribution and stereoselectivity profiles. b, The reactions proceed via mcbIMe because of severe steric repulsion between the larger Cβ aryl group in mcbIIMe and the Me units of the aryloxide ligand in Mo-3. By-product 33 may react with vinyl–B(pin) to furnish Z-32. c, There is less steric pressure at Cβ in mcbIt- Bu and mcbIIt- Bu; consequently, steric repulsion between the Cα metallacyclobutane substituent and an ortho fluorine substituent of the arylimido becomes more of a factor. Therefore, cross-metathesis probably proceeds via mcbIIt- Bu to afford the corresponding alkenyl–B(pin) compound (E-32). The resulting reaction of xiv with vinyl–B(pin) probably affords 34, which may then react with vinyl–B(pin) to furnish E-3n.

Supplementary information

Supplementary Information

This file contains all experimental and analytical data – see contents page for details. (PDF 13050 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nguyen, T., Koh, M., Mann, T. et al. Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis. Nature 552, 347–354 (2017). https://doi.org/10.1038/nature25002

Download citation

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.