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Cascade CuH-catalysed conversion of alkynes into enantioenriched 1,1-disubstituted products

Nature Catalysis volume 3, pages 23–29 (2020)Cite this article

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Abstract

Enantioenriched α-aminoboronic acids play a unique role in medicinal chemistry and have emerged as privileged pharmacophores in proteasome inhibitors. Additionally, they represent synthetically useful chiral building blocks in organic synthesis. Recently, CuH-catalysed asymmetric alkene hydrofunctionalization has become a powerful tool to construct stereogenic carbon centres. By contrast, applying CuH cascade catalysis to achieve the reductive 1,1-difunctionalization of alkynes remains an important, but largely unaddressed, synthetic challenge. Herein, we report an efficient strategy to synthesize α-aminoboron compounds by a CuH-catalysed hydroboration/hydroamination cascade of readily available alkynes. Notably, this transformation selectively delivers the desired 1,1-heterodifunctionalized product rather than the alternative homodifunctionalized, 1,2-heterodifunctionalized or reductively monofunctionalized by-products, thereby offering rapid access to these privileged scaffolds with high chemo-, regio- and enantioselectivity.

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Fig. 1: Overview of the proposed approach to CuH-catalysed cascade reductive difunctionalization of alkynes.
Fig. 2: Discovery and evaluation of the CuH cascade process.
Fig. 3: Synthetic applications of the enantioselective 1,1-aminoboration method.
Fig. 4: Mechanistic overview.

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Data availability

Most of the data that support the findings of this study are available within the article and its Supplementary Information. Additional data are available from the corresponding author upon reasonable request.

References

  1. Kolb, H. C., VanNieuwenhze, M. S. & Sharpless, K. B. Catalytic asymmetric dihydroxylation. Chem. Rev. 94, 2483–2547 (1994).

    CAS  Google Scholar 

  2. McDonald, R. I., Liu, G. & Stahl, S. S. Palladium(II)-catalyzed alkene functionalization via nucleopalladation: stereochemical pathways and enantioselective catalytic applications. Chem. Rev. 111, 2981–3019 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Derosa, J., Tran, V. T., van der Puyl, V. A. & Engle, K. M. Carbon–carbon π-bonds as conjunctive reagents in cross-coupling. Aldrichimica Acta 51, 21–32 (2018).

    CAS  Google Scholar 

  4. Sauer, G. S. & Lin, S. An electrocatalytic approach to the radical difunctionalization of alkenes. ACS Catal. 8, 5175–5187 (2018).

    CAS  Google Scholar 

  5. Nelson, H. M., Williams, B. D., Miró, J. & Toste, F. D. Enantioselective 1,1-arylborylation of alkenes: merging chiral anion phase transfer with Pd catalysis. J. Am. Chem. Soc. 137, 3213–3216 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Bergmann, A. M., Dorn, S. K., Smith, K. B., Logan, K. M. & Brown, M. K. Catalyst-controlled 1,2- and 1,1-arylboration of α-alkyl alkenyl arenes. Angew. Chem. Int. Ed. 58, 1719–1723 (2019).

    CAS  Google Scholar 

  7. Pirnot, M. T., Wang, Y.-M. & Buchwald, S. L. Copper hydride catalyzed hydroamination of alkenes and alkynes. Angew. Chem. Int. Ed. 55, 48–57 (2016).

    CAS  Google Scholar 

  8. Jordan, A. J., Lalic, G. & Sadighi, J. P. Coinage metal hydrides: synthesis, characterization, and reactivity. Chem. Rev. 116, 8318–8372 (2016).

    CAS  PubMed  Google Scholar 

  9. Lin, S. et al. A modular and concise approach to MIDA acylboronates via chemoselective oxidation of unsymmetrical geminal diborylalkanes: unlocking access to a novel class of acylborons. Chem. Sci. 10, 4684–4691 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shi, S.-L. & Buchwald, S. L. Copper-catalysed selective hydroamination reactions of alkynes. Nat. Chem. 7, 38–44 (2015).

    CAS  PubMed  Google Scholar 

  11. Cheng, L.-J. & Mankad, N. P. Cu-catalyzed hydrocarbonylative C–C coupling of terminal alkynes with alkyl iodides. J. Am. Chem. Soc. 139, 10200–10203 (2017).

    CAS  PubMed  Google Scholar 

  12. Yang, Y., Shi, S.-L., Niu, D., Liu, P. & Buchwald, S. L. Catalytic asymmetric hydroamination of unactivated internal olefins to aliphatic amines. Science 349, 62–66 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Armstrong, M. K. & Lalic, G. Differential dihydrofunctionalization of terminal alkynes: synthesis of benzylic alkyl boronates through reductive three-component coupling. J. Am. Chem. Soc. 141, 6173–6179 (2019).

    CAS  PubMed  Google Scholar 

  14. Lee, J. C. H., McDonald, R. & Hall, D. G. Enantioselective preparation and chemoselective cross-coupling of 1,1-diboron compounds. Nat. Chem. 3, 894–899 (2011).

    CAS  PubMed  Google Scholar 

  15. Feng, X., Jeon, H. & Yun, J. Regio- and enantioselective copper(I)-catalyzed hydroboration of borylalkenes: asymmetric synthesis of 1,1-diborylalkanes. Angew. Chem. Int. Ed. 52, 3989–3992 (2013).

    CAS  Google Scholar 

  16. Niljianskul, N., Zhu, S. & Buchwald, S. L. Enantioselective synthesis of α-aminosilanes by copper-catalyzed hydroamination of vinylsilanes. Angew. Chem. Int. Ed. 54, 1638–1641 (2015).

    CAS  Google Scholar 

  17. Nishikawa, D., Hirano, K. & Miura, M. Asymmetric synthesis of α-aminoboronic acid derivatives by copper-catalyzed enantioselective hydroamination. J. Am. Chem. Soc. 137, 15620–15623 (2015).

    CAS  PubMed  Google Scholar 

  18. Kato, K., Hirano, K. & Miura, M. Synthesis of β-boryl-α-aminosilanes by copper-catalyzed aminoboration of vinylsilanes. Angew. Chem. Int. Ed. 55, 14400–14404 (2016).

    CAS  Google Scholar 

  19. Han, J. T., Jang, W. J., Kim, N. & Yun, J. Asymmetric synthesis of borylalkanes via copper-catalyzed enantioselective hydroallylation. J. Am. Chem. Soc. 138, 15146–15149 (2016).

    CAS  PubMed  Google Scholar 

  20. Lee, J., Torker, S. & Hoveyda, A. H. Versatile homoallylic boronates by chemo-, SN2′-, diastereo- and enantioselective catalytic sequence of Cu−H addition to vinyl-B(pin)/allylic substitution. Angew. Chem. Int. Ed. 56, 821–826 (2017).

    CAS  Google Scholar 

  21. Bross, P. F. et al. Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin. Cancer Res. 10, 3954–3964 (2004).

    CAS  PubMed  Google Scholar 

  22. Matteson, D. S. α-Amido boronic acids: a synthetic challenge and their properties as serine protease inhibitors. Med. Res. Rev. 28, 233–246 (2008).

    CAS  PubMed  Google Scholar 

  23. Touchet, S., Carreaux, F., Carboni, B., Bouillon, A. & Boucher, J.-L. Aminoboronic acids and esters: from synthetic challenges to the discovery of unique classes of enzyme inhibitors. Chem. Soc. Rev. 40, 3895–3914 (2011).

    CAS  PubMed  Google Scholar 

  24. Rentsch, A. et al. Synthesis and pharmacology of proteasome inhibitors. Angew. Chem. Int. Ed. 52, 5450–5488 (2013).

    CAS  Google Scholar 

  25. Ohmura, T., Awano, T. & Suginome, M. Stereospecific Suzuki–Miyaura coupling of chiral α-(acylamino)benzylboronic esters with inversion of configuration. J. Am. Chem. Soc. 132, 13191–13193 (2010).

    CAS  PubMed  Google Scholar 

  26. Shiro, T., Schuhmacher, A., Jackl, M. K. & Bode, J. W. Facile synthesis of α-aminoboronic acids from amines and potassium acyltrifluoroborates (KATs) via trifluoroborate-iminiums (TIMs). Chem. Sci. 9, 5191–5196 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Matteson, D. S., Sadhu, K. M. & Lienhard, G. E. R-l-Acetamido-2-phenylethaneboronic acid. A specific transition-state analog for chymotrypsin. J. Am. Chem. Soc. 103, 5241–5242 (1981).

    CAS  Google Scholar 

  28. He, Z., Zajdlik, A., St. Denis, J. D., Assem, N. & Yudin, A. K. Boroalkyl group migration provides a versatile entry into α-aminoboronic acid derivatives. J. Am. Chem. Soc. 134, 9926–9929 (2012).

    CAS  PubMed  Google Scholar 

  29. Zajdlik, A. et al. α-Boryl isocyanides enable facile preparation of bioactive boropeptides. Angew. Chem. Int. Ed. 52, 8411–8415 (2013).

    CAS  Google Scholar 

  30. Beenen, M. A., An, C. & Ellman, J. A. Asymmetric copper-catalyzed synthesis of α-amino boronate esters from N-tert-butanesulfinyl aldimines. J. Am. Chem. Soc. 130, 6910–6911 (2008).

    CAS  PubMed  Google Scholar 

  31. Li, C. et al. Decarboxylative borylation. Science 356, eaam7355 (2017).

    PubMed  PubMed Central  Google Scholar 

  32. Hong, K. & Morken, J. P. Catalytic enantioselective one-pot aminoborylation of aldehydes: a strategy for construction of nonracemic α-amino boronates. J. Am. Chem. Soc. 135, 9252–9254 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, D. et al. Copper(I)-catalyzed asymmetric pinacolboryl addition of N-Boc-imines using a chiral sulfoxide–phosphine ligand. Org. Lett. 17, 2420–2423 (2015).

    CAS  PubMed  Google Scholar 

  34. Schwamb, C. B. et al. Enantioselective synthesis of α-amidoboronates catalyzed by planar-chiral NHC-Cu(I) complexes. J. Am. Chem. Soc. 140, 10644–10648 (2018).

    CAS  PubMed  Google Scholar 

  35. Jang, H., Zhugralin, A. R., Lee, Y. & Hoveyda, A. H. Highly selective methods for synthesis of internal (α-) vinylboronates through efficient NHC−Cu-catalyzed hydroboration of terminal alkynes. Utility in chemical synthesis and mechanistic basis for selectivity. J. Am. Chem. Soc. 133, 7859–7871 (2011).

    CAS  PubMed  Google Scholar 

  36. Jang, W. J., Lee, W. L., Moon, J. H., Lee, J. Y. & Yun, J. Copper-catalyzed trans-hydroboration of terminal aryl alkynes: stereodivergent synthesis of alkenylboron compounds. Org. Lett. 18, 1390–1393 (2016).

    CAS  PubMed  Google Scholar 

  37. Bai, T., Yang, Y. & Han, C. Isolation and characterization of hydrocarbon soluble NHC copper(I) phosphoranimide complex and catalytic application for alkyne hydroboration reaction. Tetrahedron Lett. 58, 1523–1527 (2017).

    CAS  Google Scholar 

  38. Wang, H., Yang, J. C. & Buchwald, S. L. CuH-catalyzed regioselective intramolecular hydroamination for the synthesis of alkyl-substituted chiral aziridines. J. Am. Chem. Soc. 139, 8428–8431 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bandar, J. S., Pirnot, M. T. & Buchwald, S. L. Mechanistic studies lead to dramatically improved reaction conditions for the Cu-catalyzed asymmetric hydroamination of olefins. J. Am. Chem. Soc. 137, 14812–14818 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Xia, Y. & Hartwig, J. F. Mechanistic studies of copper-catalyzed asymmetric hydroboration of alkenes. J. Am. Chem. Soc. 139, 12758–12772 (2017).

    Google Scholar 

  41. Lee, J., Radomkit, S., Torker, S., del Pozo, J. & Hoveyda, A. H. Mechanism-based enhancement of scope and enantioselectivity for reactions involving a copper-substituted stereogenic carbon centre. Nat. Chem. 10, 99–108 (2018).

    CAS  PubMed  Google Scholar 

  42. Revunova, K. & Nikonov, G. I. Base-catalyzed hydrosilylation of ketones and esters and insight into the mechanism. Chem. Eur. J. 20, 839–845 (2014).

    CAS  PubMed  Google Scholar 

  43. Laitar, D. S., Tsui, E. Y. & Sadighi, J. P. Copper(I) β-boroalkyls from alkene insertion: isolation and rearrangement. Organometallics 25, 2405–2408 (2006).

    CAS  Google Scholar 

  44. Jang, W. J., Han, J. T. & Yun, J. NHC-copper-catalyzed tandem hydrocupration and allylation of alkenyl boronates. Synthesis 49, 4753–4758 (2017).

    CAS  Google Scholar 

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Acknowledgements

D. G. Blackmond, D. E. Hill and J. S. Bandar are acknowledged for helpful discussions regarding the reaction mechanism. This work was financially supported by The Scripps Research Institute, Pfizer, Bristol-Myers Squibb (unrestricted grant) and the National Institutes of Health (5R35GM125052-02, R35GM128779). We gratefully acknowledge the Nankai University College of Chemistry for a Summer Project Scholarship (T.-Z.Q.) and the China Scholarship Council for supporting a visiting studentship (X.W.). Calculations were performed at the Center for Research Computing at the University of Pittsburgh and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the NSF.

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Author notes

  1. These authors contributed equally: De-Wei Gao, Yang Gao.

Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA

    De-Wei Gao, Yang Gao, Tian-Zhang Qiao, Xin Wang & Keary M. Engle

  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    Huiling Shao & Peng Liu

  3. Automated Synthesis Facility, The Scripps Research Institute, La Jolla, CA, USA

    Brittany B. Sanchez & Jason S. Chen

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  1. De-Wei Gao
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Contributions

D.-W.G. and K.M.E. conceived the project. D.-W.G. optimized the reaction conditions. D.-W.G., Y.G., T.-Z.Q. and X.W. prepared substrates and examined the substrate scope. D.-W.G. and Y.G. studied the mechanism and explored the synthetic applications. H.S. and P.L. carried out DFT studies. B.B.S. and J.S.C. assisted with analytical aspects of the project. P.L. and K.M.E. directed the project. D.-W.G., Y.G., H.S., P.L. and K.M.E. wrote the manuscript with input from all authors.

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Correspondence to Peng Liu or Keary M. Engle.

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Supplementary information

Supplementary Information

Supplementary Methods, Figures 1–13 and references.

Supplementary Data 1

Coordinates of optimized structures.

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Gao, DW., Gao, Y., Shao, H. et al. Cascade CuH-catalysed conversion of alkynes into enantioenriched 1,1-disubstituted products. Nat Catal 3, 23–29 (2020). https://doi.org/10.1038/s41929-019-0384-6

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