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A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes

Nature Chemistry volume 13, pages 880–886 (2021)Cite this article

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Abstract

Stereodefined four-membered rings are common motifs in bioactive molecules and versatile intermediates in organic synthesis. However, the synthesis of complex, chiral cyclobutanes is a largely unsolved problem and there is a need for general and modular synthetic methods. Here we report a series of asymmetric cross-coupling reactions between cyclobutenes and arylboronic acids which are initiated by Rh-catalysed asymmetric carbometallation. After the initial carborhodation, Rh–cyclobutyl intermediates undergo chain-walking or C–H insertion so that overall a variety of additions such as reductive Heck reactions, 1,5-addition and homoallylic substitution are observed. The synthetic applicability of these highly stereoselective transformations is demonstrated in the concise syntheses of the drug candidates Belaperidone and PF-04862853. We anticipate this approach will be widely adopted by synthetic and medicinal chemists. While the carbometallation approach reported here is exemplified with Rh and arylboronic acids, it is likely to be applicable to other metals and nucleophiles.

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Fig. 1: Catalytic cross-coupling towards complex, chiral cyclobutanes.
Fig. 2: Proposed reaction mechanism for the hydroarylation of bicyclic cyclobutenes.
Fig. 3: Asymmetric 1,5-additions triggered by carbometallation.
Fig. 4: Reductive Heck reactions and remote substitution.

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All data (experimental procedures and characterization data) supporting the findings of this study are available within the article and its Supplementary Information.

References

  1. Lee-Ruff, E. & Mladenova, G. Enantiomerically pure cyclobutane derivatives and their use in organic synthesis. Chem. Rev. 103, 1449–1483 (2003).

    Article  CAS  Google Scholar 

  2. Wang, M. & Lu, P. Catalytic approaches to assemble cyclobutane motifs in natural product synthesis. Org. Chem. Front. 5, 254–259 (2018).

    Article  CAS  Google Scholar 

  3. Dembitsky, V. M. Naturally occurring bioactive cyclobutane-containing (CBC) alkaloids in fungi, fungal endophytes, and plants. Phytomedicine 21, 1559–1581 (2014).

    Article  CAS  Google Scholar 

  4. Namyslo, J. C. & Kaufmann, D. E. The application of cyclobutane derivatives in organic synthesis. Chem. Rev. 103, 1485–1537 (2003).

    Article  CAS  Google Scholar 

  5. Seiser, T., Saget, T., Tran, D. N. & Cramer, N. Cyclobutanes in catalysis. Angew. Chem. Int. Ed. 50, 7740–7752 (2011).

    Article  CAS  Google Scholar 

  6. Xu, Y., Conner, M. L. & Brown, M. K. Cyclobutane and cyclobutene synthesis: Catalytic enantioselective [2+2] cycloadditions. Angew. Chem. Int. Ed. 54, 11918–11928 (2015).

    Article  CAS  Google Scholar 

  7. Pagar, V. V. & RajanBabu, T. V. Tandem catalysis for asymmetric coupling of ethylene and enynes to functionalized cyclobutanes. Science 361, 68–72 (2018).

    Article  CAS  Google Scholar 

  8. Brimioulle, R. & Bach, T. Enantioselective lewis acid catalysis of intramolecular enone [2+2] photocycloaddition reactions. Science 342, 840–843 (2013).

    Article  CAS  Google Scholar 

  9. Du, J., Skubi, K. L., Schultz, D. M. & Yoon, T. P. A dual-catalysis approach to enantioselective [2 + 2] photocycloadditions using visible light. Science 344, 392–396 (2014).

    Article  CAS  Google Scholar 

  10. García-Morales, C. et al. Enantioselective synthesis of cyclobutenes by intermolecular [2+2] cycloaddition with non-C2 symmetric digold catalysts. J. Am. Chem. Soc. 139, 13628–13631 (2017).

    Article  Google Scholar 

  11. Wang, Y. M., Bruno, N. C., Placeres, Á. L., Zhu, S. & Buchwald, S. L. Enantioselective synthesis of carbo- and heterocycles through a CuH-catalyzed hydroalkylation approach. J. Am. Chem. Soc. 137, 10524–10527 (2015).

    Article  CAS  Google Scholar 

  12. Kim, D. K., Riedel, J., Kim, R. S. & Dong, V. M. Cobalt catalysis for enantioselective cyclobutanone construction. J. Am. Chem. Soc. 139, 10208–10211 (2017).

    Article  CAS  Google Scholar 

  13. Xiao, K. J. et al. Palladium(ii)-catalyzed enantioselective C(sp3)-H activation using a chiral hydroxamic acid ligand. J. Am. Chem. Soc. 136, 8138–8142 (2014).

    Article  CAS  Google Scholar 

  14. Zhong, C. et al. Enantioselective synthesis of 3‐substituted cyclobutenes by catalytic conjugate addition/trapping strategies. Angew. Chem. Int. Ed. 59, 2750–2754 (2020).

    Article  CAS  Google Scholar 

  15. Chen, Y. J., Hu, T. J., Feng, C. G. & Lin, G. Q. Synthesis of chiral cyclobutanes via rhodium/diene-catalyzed asymmetric 1,4-addition: a dramatic ligand effect on the diastereoselectivity. Chem. Commun. 51, 8773–8776 (2015).

    Article  CAS  Google Scholar 

  16. Audisio, D. et al. Palladium-catalyzed allylic substitution at four-membered-ring systems: formation of η1-allyl complexes and electrocyclic ring opening. Angew. Chem. Int. Ed. 52, 6313–6316 (2013).

    Article  CAS  Google Scholar 

  17. Guisán-Ceinos, M., Parra, A., Martín-Heras, V. & Tortosa, M. Enantioselective synthesis of cyclobutylboronates via a copper-catalyzed desymmetrization approach. Angew. Chem. Int. Ed. 55, 6969–6972 (2016).

    Article  Google Scholar 

  18. Feng, S., Hao, H., Liu, P. & Buchwald, S. L. Diastereo- and enantioselective CuH-catalyzed hydroamination of strained trisubstituted alkenes. ACS Catal. 10, 282–291 (2020).

    Article  CAS  Google Scholar 

  19. Roy, S. R., Eijsberg, H., Bruffaerts, J. & Marek, I. Zirconocene catalyzed diastereoselective carbometalation of cyclobutenes. Chem. Sci. 8, 334–339 (2016).

    Article  Google Scholar 

  20. Didier, D. et al. Modulable and highly diastereoselective carbometalations of cyclopropenes. Chem. Eur. J. 20, 1038–1048 (2014).

    Article  CAS  Google Scholar 

  21. Takaya, Y., Ogasawara, M., Hayashi, T., Sakai, M. & Miyaura, N. Rhodium-catalyzed asymmetric 1,4-addition of aryl- and alkenylboronic acids to enones. J. Am. Chem. Soc. 120, 5579–5580 (1998).

    Article  CAS  Google Scholar 

  22. Tian, P., Dong, H.-Q. & Lin, G.-Q. Rhodium-catalyzed asymmetric arylation. ACS Catal. 2, 95–119 (2012).

    Article  CAS  Google Scholar 

  23. Sidera, M. & Fletcher, S. P. Rhodium-catalysed asymmetric allylic arylation of racemic halides with arylboronic acids. Nat. Chem. 7, 935–939 (2015).

    Article  CAS  Google Scholar 

  24. Goetzke, F. W., Mortimore, M. & Fletcher, S. P. Enantio- and diastereoselective Suzuki–Miyaura coupling with racemic bicycles. Angew. Chem. Int. Ed. 58, 12128–12132 (2019).

    Article  CAS  Google Scholar 

  25. Hall, D. G. Boronic Acids: Preparation, Applications in Organic Synthesis and Medicine (John Wiley & Sons, 2006).

  26. Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).

    Article  CAS  Google Scholar 

  27. Dian, L. & Marek, I. Rhodium-catalyzed arylation of cyclopropenes based on asymmetric direct functionalization of three-membered carbocycles. Angew. Chem. Int. Ed. 57, 3682–3686 (2018).

    Article  CAS  Google Scholar 

  28. Wiberg, K. B. The concept of strain in organic chemistry. Angew. Chem. Int. Ed. 25, 312–322 (1986).

    Article  Google Scholar 

  29. Menard, F. & Lautens, M. Chemodivergence in enantioselective desymmetrization of diazabicycles: ring-opening versus reductive arylation. Angew. Chem. Int. Ed. 47, 2085–2088 (2008).

    Article  CAS  Google Scholar 

  30. Bexrud, J. & Lautens, M. A rhodium IBiox[(-)-menthyl] complex as a highly selective catalyst for the asymmetric hydroarylation of azabicyles: an alternative route to epibatidine. Org. Lett. 12, 3160–3163 (2010).

    Article  CAS  Google Scholar 

  31. So, C. M., Kume, S. & Hayashi, T. Rhodium-catalyzed asymmetric hydroarylation of 3-pyrrolines giving 3-arylpyrrolidines: protonation as a key step. J. Am. Chem. Soc. 135, 10990–10993 (2013).

    Article  CAS  Google Scholar 

  32. Celanire, S. & Poli, S. (eds) Small Molecule Therapeutics for Schizophrenia Vol. 13 (Springer, 2015).

  33. Buter, J., Moezelaar, R. & Minnaard, A. J. Enantioselective palladium catalyzed conjugate additions of ortho-substituted arylboronic acids to β,β-disubstituted cyclic enones: total synthesis of herbertenediol, enokipodin A and enokipodin B. Org. Biomol. Chem. 12, 5883–5890 (2014).

    Article  CAS  Google Scholar 

  34. Hayashi, T., Takahashi, M., Takaya, Y. & Ogasawara, M. Catalytic cycle of rhodium-catalyzed asymmetric 1,4-addition of organoboronic acids. Arylrhodium, oxa-π-allylrhodium, and hydroxorhodium intermediates. J. Am. Chem. Soc. 124, 5052–5058 (2002).

    Article  CAS  Google Scholar 

  35. Sommer, H., Juliá-Hernández, F., Martin, R. & Marek, I. Walking metals for remote functionalization. ACS Cent. Sci. 4, 153–165 (2018).

    Article  CAS  Google Scholar 

  36. Oguma, K., Miura, M., Satoh, T. & Nomura, M. Merry-go-round multiple alkylation on aromatic rings via rhodium catalysis. J. Am. Chem. Soc. 122, 10464–10465 (2000).

    Article  CAS  Google Scholar 

  37. Miller, L. C. & Sarpong, R. Divergent reactions on racemic mixtures. Chem. Soc. Rev. 40, 4550–4562 (2011).

    Article  CAS  Google Scholar 

  38. Steiner, G., Unger, L., Behl, B., Teschendorf, H.-J. & Munschauer, R. N-substituted 3-azabicyclo[3.2.0]heptane derivates useful as neuroleptic agents, etc. WIPO patent WO1994000458A1 (1994).

  39. Steiner, G., Munschauer, R., Klebe, G. & Siggel, L. Diastereoselective synthesis of exo-6-aryl-3-azabicyclo[3.2.0]heptane derivatives by intramolecular [2+2] photocycloadditions of diallylic amines. Heterocycles 40, 319–330 (1995).

    Article  CAS  Google Scholar 

  40. Denisenko, A. V. et al. Photochemical synthesis of 3-azabicyclo[3.2.0]heptanes: advanced building blocks for drug discovery. J. Org. Chem. 82, 9627–9636 (2017).

    Article  CAS  Google Scholar 

  41. Meyers, M. J. et al. Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain. Bioorg. Med. Chem. Lett. 21, 6545–6553 (2011).

    Article  CAS  Google Scholar 

  42. Panteleev, J., Menard, F. & Lautens, M. Ligand control in enantioselective desymmetrization of bicyclic hydrazines: rhodium(i)-catalyzed ring-opening versus hydroarylation. Adv. Synth. Catal. 350, 2893–2902 (2008).

    Article  CAS  Google Scholar 

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Acknowledgements

F.W.G. and S.P.F. thank M. Mortimore (Vertex Pharmaceuticals) for discussion. F.W.G. is grateful to the National Research Fund, Luxembourg, for an AFR PhD Grant (11588566), the EPSRC Doctoral Training Partnership (DTP) for a studentship (EP/N509711/1) and Vertex Pharmaceuticals for financial support. L.v.D. is grateful for a studentship from the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1). F.W.G. thanks N. Amin for his help with NMR spectroscopy and S. Karabiyikoglu and S. Mishra for discussion.

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  1. Department of Chemistry, University of Oxford, Oxford, UK

    F. Wieland Goetzke, Alexander M. L. Hell, Lucy van Dijk & Stephen P. Fletcher

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  1. F. Wieland Goetzke
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  2. Alexander M. L. Hell
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Contributions

F.W.G. conceived the project and S.P.F. guided the research. F.W.G., A.M.L.H. and L.v.D. performed the experimental work. All authors analysed the data and planned experiments. F.W.G. and S.P.F. wrote the manuscript with contributions from all other authors.

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Correspondence to Stephen P. Fletcher.

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Peer review information Nature Chemistry thanks Ilan Marek and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Goetzke, F.W., Hell, A.M.L., van Dijk, L. et al. A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes. Nat. Chem. 13, 880–886 (2021). https://doi.org/10.1038/s41557-021-00725-y

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