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Ruthenium-catalysed multicomponent synthesis of the 1,3-dienyl-6-oxy polyketide motif

Nature Chemistry volume 12, pages 629–637 (2020)Cite this article

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Abstract

Polyketide natural products are an important class of biologically active compounds. Although substantial progress has been made on the synthesis of repetitive polyketide motifs through the iterative application of a single reaction type, synthetic access to more diverse motifs that require more than one type of carbon–carbon bond connection remains a challenge. Here we describe a catalytic, multicomponent method for the synthesis of the privileged polyketide 1,3-dienyl-6-oxy motif. The method allows for the formation of two new carbon–carbon bonds and two stereodefined olefins. It generates products that contain up to three contiguous sp3 stereocentres with a high stereoselectivity in a single operation and can be used to generate chiral products. The successful development of this methodology relies on the remarkable efficiency of the ruthenium-catalysed alkene–alkyne coupling reaction between readily available vinyl boronic acids and alkynes to provide unsymmetrical 3-boryl-1,4-diene reagents. In the presence of carbonyl compounds, these reagents undergo highly diastereoselective allylations to afford the desired 1,3-dienyl-6-oxy motif and enable complex polyketide synthesis in a rapid and asymmetric fashion.

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Fig. 1: Importance of 1,3-dineyl-6-oxy motif as well as general introduction to the ruthenium-catalysed multicomponent coupling reaction.
Fig. 2: The alkene–alkyne coupling of 1,2-disubstituted vinyl boronates.
Fig. 3: NMR studies of the alkene–alkyne coupling of 1,2-disubstituted vinyl boronates and boronic acids.
Fig. 4: Alkene–alkyne coupling followed by allylation with aldehydes and ketones.
Fig. 5: One-pot methodology for the synthesis of 1,3-dienyl-6-oxy motifs with general structures A1, A2, B1 or B2.
Fig. 6: Ruthenium-catalysed multicomponent coupling for the formation of polyenes, chiral products and efomycine M.
Fig. 7: Overlay of products synthesized using this method with bioactive polyketide natural products.

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Data availability

The data supporting the finding of this study are available in this article and Supplementary information.

References

  1. Nicolaou, K. C. Catalyst: synthetic organic chemistry as a force for good. Chem 1, 331–334 (2016).

    Article  CAS  Google Scholar 

  2. Dömling, A., Wang, W. & Wang, K. Chemistry and biology of multicomponent reactions. Chem. Rev. 112, 3083–3135 (2012).

    Article  Google Scholar 

  3. Ganem, B. Strategies for innovation in multicomponent reaction design. Acc. Chem. Res. 42, 463–472 (2009).

    Article  CAS  Google Scholar 

  4. Staunton, J. & Weissman, K. J. Polyketide biosynthesis: a millennium review. Nat. Prod. Rep. 18, 380–416 (2001).

    Article  CAS  Google Scholar 

  5. Cragg, G. M., Grothaus, P. G. & Newman, D. J. Impact of natural products on developing new anti-cancer agents. Chem. Rev. 109, 3012–3043 (2009).

    Article  CAS  Google Scholar 

  6. Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70, 461–477 (2007).

    Article  CAS  Google Scholar 

  7. Rohr, J. A New role for polyketides. Angew. Chem. Int. Ed. 39, 2847–2849 (2000).

    Article  CAS  Google Scholar 

  8. Paterson, I. & Lam, N. Y. S. Challenges and discoveries in the total synthesis of complex polyketide natural products. J. Antibiot. 71, 215–233 .

  9. Dechert-Schmitt, A.-M. R., Schmitt, D. C., Gao, X., Itoh, T. & Krische, M. J. Polyketide construction via hydrohydroxyalkylation and related alcohol C–H functionalizations: reinventing the chemistry of carbonyl addition. Nat. Prod. Rep. 31, 504–513 (2014).

    Article  CAS  Google Scholar 

  10. Boxer, M. B. & Yamamoto, H. ‘Super silyl’ group for diastereoselective sequential reactions: access to complex chiral architecture in one pot. J. Am. Chem. Soc. 129, 2762–2763 (2007).

    Article  CAS  Google Scholar 

  11. Bootwicha, T., Feilner, J. M., Myers, E. L. & Aggarwal, V. K. Iterative assembly line synthesis of polypropionates with full stereocontrol. Nat. Chem. 9, 896–902 (2017).

    Article  CAS  Google Scholar 

  12. Li, J. et al. Synthesis of many different types of organic small molecules using one automated process. Science 347, 1221–1226 (2015).

    Article  CAS  Google Scholar 

  13. Chen, M. & Roush, W. R. Enantioselective synthesis of (Z)- and (E)-2-methyl-1,5-anti-pentenediols via an allene hydroboration–double-allylboration reaction sequence. J. Am. Chem. Soc. 135, 9512–9517 (2013).

    Article  CAS  Google Scholar 

  14. Smith, A. B. et al. Multicomponent linchpin couplings. Reaction of dithiane anions with terminal epoxides, epichlorohydrin, and vinyl epoxides: efficient, rapid, and stereocontrolled assembly of advanced fragments for complex molecule synthesis. J. Am. Chem. Soc. 125, 14435–14445 (2003).

    Article  CAS  Google Scholar 

  15. Dictionary of Natural Products 28.2 (CRC Press, accessed 26 March 2020); http://dnp.chemnetbase.com/faces/chemical/ChemicalSearch.xhtml

  16. Wishart, D. S. et al. DrugBank 5.0: a major update to the Drugbank database for 2018. Nucleic Acid Res. 46, D1074–D1082 (2017).

    Article  Google Scholar 

  17. Willwacher, J., Kausch-Busies, N. & Fürstner, A. Divergent total synthesis of the antimitotic agent leiodermatolide. Angew. Chem. Int. Ed. 51, 12041–12046 (2012).

    Article  CAS  Google Scholar 

  18. Hoffmann, R. W. & Landmann, B. Stereoselective synthesis of alcohols, XXII. E/Z-selectivity on addition of α-substituted allylboronates to aldehydes. Chem. Ber. 119, 1039–1053 (1986).

    Article  CAS  Google Scholar 

  19. Trost, B. M. & Indolese, A. Ruthenium-catalyzed addition of alkenes to acetylenes. J. Am. Chem. Soc. 115, 4361–4362 (1993).

    Article  CAS  Google Scholar 

  20. Trost, B. M. & Cregg, J. J. Ruthenium-catalyzed alkene–alkyne coupling of disubstituted olefins: application to the stereoselective synthesis of trisubstituted enecarbamates. J. Am. Chem. Soc. 137, 620–623 (2015).

    Article  CAS  Google Scholar 

  21. Trost, B. M., Frederiksen, M. U. & Rudd, M. T. Ruthenium-catalyzed reactions—a treasure trove of atom-economic transformations. Angew. Chem. Int. Ed. 44, 6630–6666 (2005).

    Article  CAS  Google Scholar 

  22. Trost, B. M. & Dean Toste, F. A new Ru catalyst for alkene–alkyne coupling. Tetrahedron Lett. 40, 7739–7743 (1999).

    Article  CAS  Google Scholar 

  23. Rummelt, S. M., Cheng, G.-J., Gupta, P., Thiel, W. & Fürstner, A. Hydroxy-directed ruthenium-catalyzed alkene/alkyne coupling: increased scope, stereochemical implications, and mechanistic rationale. Angew. Chem. Int. Ed. 56, 3599–3604 (2017).

    Article  CAS  Google Scholar 

  24. Shirakawa, K., Arase, A. & Hoshi, M. Preparation of (E)-1-alkenylboronic acid pinacol esters via transfer of alkenyl group from boron to boron. Synthesis 2004, 1814–1820 (2004).

    Article  Google Scholar 

  25. Schneider, U. & Kobayashi, S. Catalytic activation of pinacolyl allylboronate with indium(i): development of a general catalytic allylboration of ketones. Angew. Chem. Int. Ed. 46, 5909–5912 (2007).

    Article  CAS  Google Scholar 

  26. Schneider, U., Ueno, M. & Kobayashi, S. Catalytic use of indium(0) for carbon−carbon bond transformations in water: general catalytic allylations of ketones with allylboronates. J. Am. Chem. Soc. 130, 13824–13825 (2008).

    Article  CAS  Google Scholar 

  27. Shi, S.-L., Xu, L.-W., Oisaki, K., Kanai, M. & Shibasaki, M. Identification of modular chiral bisphosphines effective for Cu(i)-catalyzed asymmetric allylation and propargylation of ketones. J. Am. Chem. Soc. 132, 6638–6639 (2010).

    Article  CAS  Google Scholar 

  28. Raducan, M., Alam, R. & Szabó, K. J. Palladium‐catalyzed synthesis and isolation of functionalized allylboronic acids: selective, direct allylboration of ketones. Angew. Chem. Int. Ed. 51, 13050–13053 (2012).

    Article  CAS  Google Scholar 

  29. Cui, Y., Sato, T., Yamashita, Y. & Kobayashi, S. Catalytic use of zinc amide for transmetalation with allylboronates: general and efficient catalytic allylation of carbonyl compounds, imines, and hydrazones. Adv. Synth. Catal. 355, 1193–1205 (2013).

    Article  CAS  Google Scholar 

  30. Andersen, M. C., Hildebrandt, B., Köster, G. & Hoddmann, R. W. Stereoselective synthesis of alcohols, XXX: E‐ and Z‐pentenylboronates, reagents for simple diastereoselection on addition to aldehydes. Chem. Ber. 122, 1777–1782 (1989).

    Article  CAS  Google Scholar 

  31. Althaus, M., Mahmood, A., Suárez, J. R., Thomas, S. P. & Aggarwal, V. K. Application of the lithiation−borylation reaction to the preparation of enantioenriched allylic boron reagents and subsequent in situ conversion into 1,2,4-trisubstituted homoallylic alcohols with complete control over all elements of stereochemistry. J. Am. Chem. Soc. 132, 4025–4028 (2010).

    Article  CAS  Google Scholar 

  32. Chen, J. L.-Y., Scott, H. K., Hesse, M. J., Willis, C. L. & Aggarwal, V. K. Highly diastereo- and enantioselective allylboration of aldehydes using α-substituted allyl/crotyl pinacol boronic esters via in situ generated borinic esters. J. Am. Chem. Soc. 135, 5316–5319 (2013).

    Article  CAS  Google Scholar 

  33. Li, Y. & Houk, K. N. Transition structures for the allylboration of formaldehyde by allyborane and allylboronic acids. J. Am. Chem. Soc. 111, 1236–1240 (1989).

    Article  CAS  Google Scholar 

  34. Trost, B. M., Koester, D. C. & Sharif, E. U. Ruthenium-catalyzed multicomponent reactions: access to α-silyl-β-hydroxy vinylsilanes, stereodefined 1,3-dienes, and cyclohexenes. Chem. Eur. J. 22, 2634–2638 (2016).

    Article  CAS  Google Scholar 

  35. Chen, M. & Roush, W. R. Highly stereoselective synthesis of anti,anti-dipropionate stereotriads: a solution to the long-standing problem of challenging mismatched double asymmetric crotylboration reactions. J. Am. Chem. Soc. 134, 3925–3931 (2012).

    Article  CAS  Google Scholar 

  36. Brinkmann, H. & Hoffmann, R. W. Stereoselective synthesis of alcohols, XXXV. Addition of E- and Z-crotylboronates to chiral α-substituted aldehydes. Chem. Ber. 123, 2395–2401 (1990).

    Article  CAS  Google Scholar 

  37. Barth, R. & Mulzer, J. Total synthesis of efomycine M. Angew. Chem. Int. Ed. 46, 5791–5794 (2007).

    Article  CAS  Google Scholar 

  38. Diner, C. & Szabó, K. J. Recent advances in the preparation and application of allylboron species in organic synthesis. J. Am. Chem. Soc. 139, 2–14 (2017).

    Article  CAS  Google Scholar 

  39. WHO Model List of Essential Medicine, 21st List (World Health Organization, 2019)

  40. Bew, S. P., Barks, J. M., Knight, D. W. & Middleton, R. J. Stereochemical features of iodocyclisations of 3-alkene-1,2-diols to β-hydroxytetrahydrofurans. Tetrahedron Lett. 41, 4447–4451 (2000).

    Article  CAS  Google Scholar 

  41. Anslyn, E. V. & Dougherty, D. A. Modern Physical Organic Chemistry (University Science Books, 2006).

  42. Hildebrandt, B., Brinkmann, H. & Hoffmann, R. W. syn/anti-Configurational assignment of sec-butalcarbinols based on 13C-NMR spectra. Chem. Ber. 123, 869–873 (1990).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the Tamaki Foundation and Chugai Pharmaceuticals for their generous, partial funding of our programme.

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Authors and Affiliations

  1. Department of Chemistry, Stanford University, Stanford, CA, USA

    Barry M. Trost, James J. Cregg, Christoph Hohn, Wen-Ju Bai, Guoting Zhang & Jacob S. Tracy

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  1. Barry M. Trost
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Contributions

J.J.C. and B.M.T. conceived the work. J.J.C., C.H., W.-J.B., J.S.T. and B.M.T. designed the experiments and analysed the data. J.J.C., C.H., W.-J.B., G.Z. and J.S.T. performed the experiments. J.J.C., W.-J.B., J.S.T. and B.M.T. wrote the manuscript.

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Correspondence to Barry M. Trost.

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Supplementary Information

Supplementary Figs. 1–5, materials, methods, text, experiments, references and NMR spectra.

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Trost, B.M., Cregg, J.J., Hohn, C. et al. Ruthenium-catalysed multicomponent synthesis of the 1,3-dienyl-6-oxy polyketide motif. Nat. Chem. 12, 629–637 (2020). https://doi.org/10.1038/s41557-020-0464-x

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