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Use of α-trifluoromethyl carbanions for palladium-catalysed asymmetric cycloadditions

Nature Chemistry volume 12, pages 294–301 (2020)Cite this article

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Abstract

The development of new methodologies that enable chemo- and stereoselective construction of fluorinated substituents, such as the trifluoromethyl (CF3) group, plays an essential role in the synthesis of new pharmaceutical agents. The exceptional ability of the CF3 moiety to prevent in vivo metabolism as well as improve other pharmacological properties has led to numerous innovative strategies for installing this unique functional group. One potential yet underdeveloped approach to access these trifluoromethylated products is direct substitution of α-trifluoromethyl carbanions. Although the electron-withdrawing nature of the CF3 group should facilitate deprotonation of adjacent hydrogens, the propensity of the resulting carbanions to undergo α-elimination of fluoride renders this process highly challenging. Herein, we describe a new strategy for stabilizing and utilizing transient α-trifluoromethyl carbanions that relies on a neighbouring cationic π-allyl palladium complex. These palladium-stabilized zwitterions participate in asymmetric [3 + 2] cycloadditions with a broad range of acceptors, generating valuable di- and trifluoromethylated cyclopentanes, pyrrolidines and tetrahydrofurans.

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Fig. 1: Existing asymmetric catalytic strategies for the construction of chiral trifluoromethylated carbons.
Fig. 2: Proposed strategy to stabilize and utilize α-CF3 carbanions for asymmetric cycloadditions and reaction development.
Fig. 3: Reaction scope and synthetic applications.
Fig. 4: Millimole-scale reaction and proposed transition states.

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Data availability

All of the characterization data and experimental protocols are provided in this Article and its Supplementary Information. Data are also available from the corresponding author upon request. Crystallographic data for compound 7k have been deposited at the Cambridge Crystallographic Data Centre under deposition number 1909105 and can be obtained free of charge (http://www.ccdc.cam.ac.uk/data_request/cif).

References

  1. Muller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007).

    PubMed  Google Scholar 

  2. Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem. 54, 2529–2591 (2011).

    CAS  PubMed  Google Scholar 

  3. Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).

    CAS  PubMed  Google Scholar 

  4. Le, C., Chen, T. Q., Liang, T., Zhang, P. & MacMillan, D. W. C. A radical approach to the copper oxidative addition problem: trifluoromethylation of bromoarenes. Science 360, 1010–1014 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Yang, X., Wu, T., Phipps, R. J. & Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 115, 826–870 (2015).

    CAS  PubMed  Google Scholar 

  6. Ma, J.-A. & Cahard, D. Asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions. Chem. Rev. 104, 6119–6146 (2004).

    CAS  PubMed  Google Scholar 

  7. Deng, Q.-H., Wadepohl, H. & Gade, L. H. Highly enantioselective copper-catalyzed electrophilic trifluoromethylation of β-ketoesters. J. Am. Chem. Soc. 134, 10769–10772 (2012).

    CAS  PubMed  Google Scholar 

  8. Iseki, K., Nagai, T. & Kobayashi, Y. Asymmetric trifluoromethylation of aldehydes and ketones with trifluoromethyltrimethylsilane catalyzed by chiral quaternary ammonium fluorides. Tetrahedron Lett. 35, 3137–3138 (1994).

    CAS  Google Scholar 

  9. Nagib, D. A., Scott, M. E. & MacMillan, D. W. C. Enantioselective α-trifluoromethylation of aldehydes via photoredox organocatalysis. J. Am. Chem. Soc. 131, 10875–10877 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Kornfilt, D. J. P. & MacMillan, D. W. C. Copper-catalyzed trifluoromethylation of alkyl bromides. J. Am. Chem. Soc. 141, 6853–6858 (2019).

    CAS  PubMed  Google Scholar 

  11. Kautzky, J. A., Wang, T., Evans, R. W. & MacMillan, D. W. C. Decarboxylative trifluoromethylation of aliphatic carboxylic acids. J. Am. Chem. Soc. 140, 6522–6526 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Nie, J., Guo, H.-C., Cahard, D. & Ma, J.-A. Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates. Chem. Rev. 111, 455–529 (2011).

    CAS  PubMed  Google Scholar 

  13. Morandi, B., Mariampillai, B. & Carreira, E. M. Enantioselective cobalt-catalyzed preparation of trifluoromethyl-substituted cyclopropanes. Angew. Chem. Int. Ed. 50, 1101–1104 (2011).

    CAS  Google Scholar 

  14. He, X.-H., Ji, Y.-L., Peng, C. & Han, B. Organocatalytic asymmetric synthesis of cyclic compounds bearing a trifluoromethylated stereogenic center: recent developments. Adv. Synth. Catal. 361, 1923–1957 (2019).

    CAS  Google Scholar 

  15. Pitterna, T., Böger, M. & Maienfisch, P. gem-Difluorovinyl derivatives as insecticides and acaricides. Chimia 58, 108–116 (2004).

    CAS  Google Scholar 

  16. Shimizu, R., Egami, H., Hamashima, Y. & Sodeoka, M. Copper-catalyzed trifluoromethylation of allylsilanes. Angew. Chem. Int. Ed. 51, 4577–4580 (2012).

    CAS  Google Scholar 

  17. Seebach, D., Beck, A. K. & Renaud, P. Di- and trifluoro-substituted dilithium compounds for organic syntheses. Angew. Chem. Int. Ed. Engl. 25, 98–99 (1986).

    Google Scholar 

  18. Komatsu, Y., Sakamoto, T. & Kitazume, T. Synthetic applications of the carbanion with a fluoroalkyl group generated by palladium(0) catalyst under neutral conditions. J. Org. Chem. 64, 8369–8374 (1999).

    CAS  PubMed  Google Scholar 

  19. Itoh, Y., Yamanaka, M. & Mikami, K. Direct generation of Ti-enolate of α-CF3 ketone: theoretical study and high-yielding and diastereoselective aldol reaction. J. Am. Chem. Soc. 126, 13174–13175 (2004).

    CAS  PubMed  Google Scholar 

  20. Yin, L., Brewitz, L., Kumagai, N. & Shibasaki, M. Catalytic generation of α-CF3 enolate: direct catalytic asymmetric Mannich-type reaction of α-CF3 amide. J. Am. Chem. Soc. 136, 17958–17961 (2014).

    CAS  PubMed  Google Scholar 

  21. Wu, Y., Hu, L., Li, Z. & Deng, L. Catalytic asymmetric umpolung reactions of imines. Nature 523, 445–450 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Sun, Q. et al. The squaramide-catalyzed 1,3-dipolar cycloaddition of nitroalkenes with N-2,2,2-trifluoroethylisatin ketimines: an approach for the synthesis of 5′-trifluoromethyl-spiro[pyrrolidin-3,2′-oxindoles]. Adv. Synth. Catal. 357, 3187–3196 (2015).

    CAS  Google Scholar 

  23. Trost, B. M. [3+2] Cycloaddition approaches to five-membered rings via trimethylenemethane and its equivalents. Angew. Chem. Int. Ed. 25, 1–20 (1986).

    Google Scholar 

  24. Nakamura, E. [3+2] Cycloaddition of trimethylenemethane and its synthetic equivalents. Org. React. 61, 1–217 (2003).

    Google Scholar 

  25. Trost, B. M., Stambuli, J. P., Silverman, S. M. & Schwörer, U. Palladium-catalyzed asymmetric [3+2] trimethylenemethane cycloaddition reactions. J. Am. Chem. Soc. 128, 13328–13329 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Trost, B. M., Silverman, S. M. & Stambuli, J. P. Palladium-catalyzed asymmetric [3+2] cycloaddition of trimethylenemethane with imines. J. Am. Chem. Soc. 129, 12398–12399 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Trost, B. M., Bringley, D. A. & Silverman, S. M. Asymmetric synthesis of methylenetetrahydrofurans by palladium-catalyzed [3+2] cycloaddition of trimethylenemethane with aldehydes—a novel ligand design. J. Am. Chem. Soc. 133, 7664–7667 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Trost, B. M. & Bringley, D. A. Enantioselective synthesis of 2,2-disubstituted tetrahydrofurans: palladium-catalyzed [3+2] cycloadditions of trimethylenemethane with ketones. Angew. Chem. Int. Ed. 52, 4466–4469 (2013).

    CAS  Google Scholar 

  29. Allen, B. D. W., Lakeland, C. P. & Harrity, J. P. A. Utilizing palladium-stabilized zwitterions for the construction of N-heterocycles. Chem. Eur. J. 23, 13830–13857 (2017).

    CAS  PubMed  Google Scholar 

  30. Rivinoja, D. J., Gee, Y. S., Gardiner, M. G., Ryan, J. H. & Hyland, C. J. T. The diastereoselective synthesis of pyrroloindolines by Pd-catalyzed dearomative cycloaddition of 1-tosyl-2-vinylaziridine to 3-nitroindoles. ACS Catal. 7, 1053–1056 (2017).

    CAS  Google Scholar 

  31. Laugeois, M. et al. Palladium(0)-catalyzed dearomative [3+2] cycloaddition of 3-nitroindoles with vinylcyclopropanes: an entry to stereodefined 2,3-fused cyclopentannulated indoline derivatives. Org. Lett. 19, 2266–2269 (2017).

    CAS  PubMed  Google Scholar 

  32. Li, W.-K., Liu, Z.-S., He, L., Kang, T.-R. & Liu, Q.-Z. Enantioselective cycloadditions of vinyl cyclopropanes and nitroolefins for functionally and optically enriched nitrocyclopentanes. Asian J. Org. Chem. 4, 28–32 (2015).

    Google Scholar 

  33. Kobayashi, S. & Jørgensen, K. A. Cycloaddition Reactions in Organic Synthesis (Wiley, 2001).

  34. Gordon, D. J., Fenske, R. F., Nanninga, T. N. & Trost, B. M. Molecular orbital study of substituted trimethylenemethane-bis(phosphine)palladium complexes. J. Am. Chem. Soc. 103, 5974–5976 (1981).

    CAS  Google Scholar 

  35. Trost, B. M. & Chan, D. M. T. New conjunctive reagents. 2-acetoxymethyl-3-allyltrimethylsilane for methylenecyclopentane annulations catalyzed by palladium(0). J. Am. Chem. Soc. 101, 6429–6432 (1979).

    CAS  Google Scholar 

  36. Shimuzu, I., Ohashi, Y. & Tsuji, J. Palladium-catalyzed [3+2] cycloaddition reaction using 2-(sulfonylmethyl)- or 2-(cyanomethyl)allyl carbonate. Tetrahedron Lett. 25, 5183–5186 (1984).

    Google Scholar 

  37. Trost, B. M. & Wang, Y. A deprotonation approach to the unprecedented amino-trimethylenemethane chemistry: regio, diastereo, and enantioselective synthesis of complex amino cycles. Angew. Chem. Int. Ed. 57, 11025–11029 (2018).

    CAS  Google Scholar 

  38. Bunten, K. A., Chen, L., Fernandez, A. L. & Poë, A. J. Cone angles: Tolman’s and Plato’s. Coord. Chem. Rev. 233–234, 41–51 (2002).

    Google Scholar 

  39. Trost, B. M. & Lam, T. M. Development of diamidophosphite ligands and their application to the palladium-catalyzed vinyl-substituted trimethylenemethane asymmetric [3+2] cycloaddition. J. Am. Chem. Soc. 134, 11319–11321 (2012).

    CAS  PubMed  Google Scholar 

  40. Adams, G. L. et al. Il-8 receptor antagonists. International patent WO2008070707A1 (2008).

  41. Butora, G. et al. Heterocyclic cyclopentyl tetrahydroisoquinoline and tetrahydropyridopyridine modulators of chemokine receptor activity. International patent WO2004094371A2 (2004).

  42. Swann, S. L. & Vasudevan, A. Compounds useful as inhibitors of ROCK kinases. US patent 20090258907A1 (2009).

  43. Zafrani, Y. et al. Difluoromethyl bioisostere: examining the ‘lipophilic hydrogen bond donor’ concept. J. Med. Chem. 60, 797–804 (2017).

    CAS  PubMed  Google Scholar 

  44. Kim, K. H., Lin, N.-H. & Anderson, D. J. Quantitative structure–activity relationships of nicotine analogues as neuronal nicotinic acetylcholine receptor ligands. Bioorg. Med. Chem. 4, 2211–2217 (1996).

    CAS  PubMed  Google Scholar 

  45. Trost, B. M. & Silverman, S. M. Enantioselective construction of pyrrolidines by palladium-catalyzed asymmetric [3+2] cycloaddition of trimethylenemethane with imines. J. Am. Chem. Soc. 134, 4941–4954 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Trost, B. M., Bringley, D. A. & O’Keefe, B. M. Highly substituted enantioenriched cyclopentane derivatives by palladium-catalyzed [3+2] trimethylenemethane cycloadditions with disubstituted nitroalkenes. Org. Lett. 15, 5630–5633 (2013).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to the Tamaki Foundation and Chugai Pharmaceutical for financial support. C. Kalnmals is acknowledged for proofreading the manuscript. We also thank Z. Jiao for technical assistance and S. Lynch for conducting some nuclear Overhauser effect and 19F-decoupled experiments. Finally, we acknowledge J. Maclaren (Stanford University) for X-ray crystallographic analysis.

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  1. These authors contributed equally: Youliang Wang, Chao-I (Joey) Hung.

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

    Barry M. Trost, Youliang Wang & Chao-I (Joey) Hung

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Contributions

B.M.T. conceived and designed the project. Y.W. and C.-I.H. carried out the experiments. B.M.T., Y.W. and C.-I.H. wrote the manuscript. All authors analysed the data and discussed the results.

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Correspondence to Barry M. Trost.

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Supplementary information

Supplementary Information

Experimental protocols and characterization data (NMR, infrared, optical rotation, high-performance liquid chromatography and so on) for every new product mentioned in this work.

Crystallographic data

Crystallographic data for compound 7k (CCDC reference 1909105).

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Trost, B.M., Wang, Y. & Hung, CI.(. Use of α-trifluoromethyl carbanions for palladium-catalysed asymmetric cycloadditions. Nat. Chem. 12, 294–301 (2020). https://doi.org/10.1038/s41557-019-0412-9

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