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Cobalt-catalysed desymmetrization of malononitriles via enantioselective borohydride reduction

Nature Chemistry (2024)Cite this article

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Abstract

The high nitrogen content and diverse reactivity of malononitrile are widely harnessed to access nitrogen-rich fine chemicals. Although the facile substitutions of malononitrile can give structurally diverse quaternary carbons, their access to enantioenriched molecules, particularly chiral amines that are prevalent in bioactive compounds, remains rare. Here we report a cobalt-catalysed desymmetric reduction of disubstituted malononitriles to give highly functionalized β-quaternary amines. The pair of cobalt salt and sodium borohydride is proposed to generate a cobalt-hydride intermediate and initiate the reduction. Meanwhile, the enantiocontrol of the dinitrile is achieved through a tailored bisoxazoline ligand with two large flanks that create a narrow gap to host the bystanding nitrile and thus restrict the C(ipso)−C(α) bond rotation of the complexed one. Combined with the extensive derivatization possibilities of all substituents on the quaternary carbon, this asymmetric reduction unlocks pathways from malononitrile as a bulk chemical feedstock to intricate, chiral nitrogen-containing molecules.

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Fig. 1: Catalytic reductive desymmetrization of malononitriles.
Fig. 2: Cobalt-catalysed desymmetric borohydride reduction of malononitriles.
Fig. 3: Access to enantioenriched and polyfunctionalized nitrogen-containing molecules.
Fig. 4: Theoretical investigations of the cobalt-catalysed desymmetrization.
Fig. 5: Catalyst–substrate interactions in intermediate 3III.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for the (−)-11, (+)-49, L1 and L4 have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers CCDC 2219267, 2219268, 2330897 and 2330898, respectively. These data can be obtained free of charge from the CCDC (http://www.ccdc.cam.ac.uk/data_request/cif). Source data are provided with this paper.

References

  1. Strittmatter, H., Hildbrand, S. & Pollak, P. in Ullmann’s Encyclopedia of Industrial Chemistry 22, 157–171 (Wiley-VCH, 2012).

  2. Freeman, F. Chemistry of malononitrile. Chem. Rev. 69, 591–624 (1969).

    Article  CAS  PubMed  Google Scholar 

  3. Fatiadi, A. J. New applications of malononitrile in organic chemistry—part I. Synthesis https://doi.org/10.1055/s-1978-24703 (1978).

  4. Fatiadi, A. J. New applications of malononitrile in organic chemistry—part II. Synthesis https://doi.org/10.1055/s-1978-24720 (1978).

  5. Feng, J., Holmes, M. & Krische, M. J. Acyclic quaternary carbon stereocenters via enantioselective transition metal catalysis. Chem. Rev. 117, 12564–12580 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zeng, X.-P., Cao, Z.-Y., Wang, Y.-H., Zhou, F. & Zhou, J. Catalytic enantioselective desymmetrization reactions to all-carbon quaternary stereocenters. Chem. Rev. 116, 7330–7396 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Wada, A., Noguchi, K., Hirano, M. & Tanaka, K. Enantioselective synthesis of C2-symmetric spirobipyridine ligands through cationic Rh(I)/modified-binap-catalyzed double [2+2+2] cycloaddition. Org. Lett. 9, 1295–1298 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Lu, Z. et al. Enantioselective assembly of cycloenones with a nitrile-containing all-carbon quaternary center from malononitriles enabled by Ni catalysis. J. Am. Chem. Soc. 142, 7328–7333 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. Cai, J. et al. Ni-catalyzed enantioselective [2+2+2] cycloaddition of malononitriles with alkyne. Chem 7, 799–811 (2021).

    Article  CAS  Google Scholar 

  10. Li, K. et al. Enantioselective synthesis of pyridines with all-carbon quaternary carbon centers via cobalt-catalyzed desymmetric [2+2+2] cycloaddition. Angew. Chem. Int. Ed. 60, 20204–20209 (2021).

    Article  CAS  Google Scholar 

  11. Hu, X.-D. et al. Enantioselective synthesis of α-all-carbon quaternary center-containing carbazolones via amino-palladation/desymmetrizing nitrile addition cascade. J. Am. Chem. Soc. 143, 3734–3740 (2021).

    Article  CAS  PubMed  Google Scholar 

  12. Chen, Z.-H. et al. Enantioselective nickel-catalyzed reductive aryl/alkenyl-cyano cyclization coupling to all-carbon quaternary stereocenters. J. Am. Chem. Soc. 144, 4776–4782 (2022).

    Article  CAS  PubMed  Google Scholar 

  13. Wang, M.-X. Enantioselective biotransformations of nitriles in organic synthesis. Acc. Chem. Res. 48, 602–611 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Ao, Y., Wang, Q. & Wang, D. Biocatalytic desymmetrization of dinitriles in organic synthesis. Chin. J. Org. Chem. 36, 2333–2343 (2016).

    Article  CAS  Google Scholar 

  15. Kamezaki, S., Akiyama, S., Kayaki, Y., Kuwata, S. & Ikariya, T. Asymmetric nitrile-hydration with bifunctional ruthenium catalysts bearing chiral N-sulfonyldiamine ligands. Tetrahedron Asymmetry 21, 1169–1172 (2010).

    Article  CAS  Google Scholar 

  16. Tanaka, K., Suzuki, N. & Nishida, G. Cationic rhodium(I)/modified-BINAP catalyzed [2+2+2] cycloaddition of alkynes with nitriles. Eur. J. Org. Chem. https://doi.org/10.1002/ejoc.200600347 (2006).

  17. Shibasaki, M. & Kanai, M. Asymmetric synthesis of tertiary alcohols and α-tertiary amines via Cu-catalyzed C−C bond formation to ketones and ketimines. Chem. Rev. 108, 2853–2873 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Xu, P., Shen, C., Xu, A., Low, K.-H. & Huang, Z. Desymmetric cyanosilylation of acyclic 1,3-diketones. Angew. Chem. Int. Ed. 61, e20220844 (2022).

    Google Scholar 

  19. Xu, P. & Huang, Z. Catalytic reductive desymmetrization of malonic esters. Nat. Chem. 13, 634–642 (2021).

    Article  CAS  PubMed  Google Scholar 

  20. Petersen, K. S. Nonenzymatic enantioselective synthesis of all-carbon quaternary centers through desymmetrization. Tetrahedron Lett. 56, 6523–6535 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nájera, C., Foubelo, F., Sansano, J. M. & Yus, M. Enantioselective desymmetrization reactions in asymmetric catalysis. Tetrahedron 106–107, 132629 (2022).

    Article  Google Scholar 

  22. Farona, M. F. & Kraus, K. F. Coordination of organonitriles through CN π systems. Inorg. Chem. 9, 1700–1704 (1970).

    Article  CAS  Google Scholar 

  23. Storhoff, B. N. & Lewis, H. C. Jr. Organonitrile complexes of transition metals. Coord. Chem. Rev. 23, 1–29 (1977).

    Article  CAS  Google Scholar 

  24. Gill, M. S., Ahuja, H. S. & Rao, G. S. Complexes of niobium(V) and tantalum(V) halides with dinitriles. I. Malononitrile and succinonitrile. Inorg. Chim. Acta 7, 359–364 (1973).

    Article  CAS  Google Scholar 

  25. Pellissier, H. & Clavier, H. Enantioselective cobalt-catalyzed transformations. Chem. Rev. 114, 2775–2823 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Nagata, T., Yorozu, K., Yamada, T. & Mukaiyama, T. Enantioselective reduction of ketones with sodium borohydride, catalyzed by optically active (β-oxoaldiminato)cobalt(II) complexes. Angew. Chem. Int. Ed. 34, 2145–2147 (1995).

    Article  CAS  Google Scholar 

  27. Yamada, T., Ohtsuka, Y. & Ikeno, T. Enantioselective borohydride 1,4-reduction of α,β-unsaturated carboxamides using optically active cobalt(II) complex catalysts. Chem. Lett. 27, 1129–1130 (1998).

    Article  Google Scholar 

  28. Ohtsuka, Y., Koyasu, K., Ikeno, T. & Yamada, T. Reductive desymmetrization of 2-alkyl-1,3-diketones catalyzed by optically active β-ketoiminato cobalt complexes. Org. Lett. 3, 2543–2546 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Yamada, T. et al. Enantioselective borohydride reduction catalyzed by optically active cobalt complexes. Chem. Eur. J. 9, 4485–4509 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Leutenegger, U., Madin, A. & Pfaltz, A. Enantioselective reduction of α,β-unsaturated carboxylates with NaBH4 and catalytic amounts of chiral cobalt semicorrin complexes. Angew. Chem. Int. Ed. 28, 60–61 (1989).

    Article  Google Scholar 

  31. Liu, C. et al. Enantioselective synthesis of 3a-amino-pyrroloindolines by copper-catalyzed direct asymmetric dearomative amination of tryptamines. Angew. Chem. Int. Ed. 55, 751–754 (2016).

    Article  CAS  Google Scholar 

  32. Sugi, K. D., Nagata, T., Yamada, T. & Mukaiyama, T. Practical and efficient enantioselective borohydride reduction of aromatic ketones catalyzed by optically active cobalt(II) complexes using pre-modified borohydride. Chem. Lett. 25, 1081–1082 (1996).

    Article  Google Scholar 

  33. Ai, W., Zhong, R., Liu, X. & Liu, Q. Hydride transfer reactions catalyzed by cobalt complexes. Chem. Rev. 119, 2876–2953 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Semproni, S. P., Milsmann, C. & Chirik, P. J. Four-coordinate cobalt pincer complexes: electronic structure studies and ligand modification by homolytic and heterolytic pathways. J. Am. Chem. Soc. 136, 9211–9224 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Duan, Y.-N. et al. Homogeneous hydrogenation with a cobalt/tetraphosphine catalyst: a superior hydride donor for polar double bonds and N-heteroarenes. J. Am. Chem. Soc. 141, 20424–20433 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Hu, Y., Zhang, Z., Liu, Y. & Zhang, W. Cobalt-catalyzed chemo- and enantioselective hydrogenation of conjugated enynes. Angew. Chem. Int. Ed. 60, 16989–16993 (2021).

    Article  CAS  Google Scholar 

  37. Chirik, P. J. Iron- and cobalt-catalyzed alkene hydrogenation: catalysis with both redox-active and strong field ligands. Acc. Chem. Res. 48, 1687–1695 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Nakao, Y. Metal-mediated C–CN bond activation in organic synthesis. Chem. Rev. 121, 327–344 (2021).

    Article  CAS  PubMed  Google Scholar 

  39. Mills, L. R., Graham, J. M., Patel, P. & Rousseaux, S. A. L. Ni-catalyzed reductive cyanation of aryl halides and phenol derivatives via transnitrilation. J. Am. Chem. Soc. 141, 19257–19262 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Miyazaki, D. et al. Enantioselective borodeuteride reduction of aldimines catalyzed by cobalt complexes: preparation of optically active deuterated primary amines. Org. Lett. 5, 3555–3558 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Wang, G. & Hollingsworth, R. I. Direct conversion of (S)-3-hydroxy-γ-butyrolactone to chiral three-carbon building blocks. J. Org. Chem. 64, 1036–1038 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Xu, Z. & Lin, Z. Transition metal tetrahydroborato complexes: an orbital interaction analysis of their structure and bonding. Coord. Chem. Rev. 156, 136–162 (1996).

    Article  Google Scholar 

  43. Dapporto, P., Midollini, S., Orlandini, A. & Sacconi, L. Complexes of cobalt, nickel and copper with the tripod ligand 1,1,1-tris(diphenylphosphinomethyl)ethane (p3). Crystal structures of the [Co(p3)(BH4)] and [Ni(p3)(SO2)] complexes. Inorg. Chem. 15, 2768–2774 (1976).

  44. Corey, E. J., Cooper, N. J., Canning, W. M., Lipscomb, W. N. & Koetzle, T. F. Preparation, unusual spectral properties and structural characterization of (terpyridine)(tetrahydroborato-H,H’)cobalt. Inorg. Chem. 21, 192–199 (1982).

  45. Prasanth, C. P. et al. Stabilization of NaBH4 in methanol using a catalytic amount of NaOMe. Reduction of esters and lactones at room temperature without solvent-induced loss of hydride. J. Org. Chem. 83, 1431–1440 (2018).

    Article  CAS  Google Scholar 

  46. Lam, K. C., Lam, W. H., Lin, Z., Marder, T. B. & Norman, N. C. Structural analysis of five-coordinate transition metal boryl complexes with different d-electron configurations. Inorg. Chem. 43, 2541–2547 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Yang, T., Sheong, F. K. & Lin, Z. Understanding of Co(I)-catalyzed hydrogenation of C=C and C=O substrates. Top. Catal. 65, 472–480 (2022).

    Article  CAS  Google Scholar 

  48. Van der Sluys, L. S. et al. An attractive cis-effect of hydride on neighbor ligands: experimental and theoretical studies on the structure and intramolecular rearrangements of Fe(H)2(η2-H2)(PEtPh2)3. J. Am. Chem. Soc. 112, 4831–4841 (1990).

    Article  Google Scholar 

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Acknowledgements

We thank the National Natural Science Foundation of China (22322113, Z.H.) and the Research Grants Council of Hong Kong (16302222, Z.L., and C7001-23Y, Z.H.). We acknowledge funding support from the Laboratory for Synthetic Chemistry and Chemical Biology under the Health@InnoHK Program launched by the Innovation and Technology Commission, the Government of HKSAR. J. Yip and B. Yan are acknowledged for mass spectroscopy and NMR spectroscopy, respectively.

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Author notes

  1. These authors contributed equally: Yin Zheng, Tilong Yang.

Authors and Affiliations

  1. State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China

    Yin Zheng, Ka Fai Chan & Zhongxing Huang

  2. Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, China

    Tilong Yang & Zhenyang Lin

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Contributions

Z.H. conceived and designed the project. Y.Z. and K.F.C. carried out the experiments. Z.L. supervised the computational study. T.Y. carried out the DFT calculation. All authors analysed the data and wrote the paper.

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Correspondence to Zhenyang Lin or Zhongxing Huang.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–22, experimental procedures, product characterization data and mechanistic studies.

Supplementary Data 1

Crystallographic data for compound 11; CCDC reference 2219267.

Supplementary Data 2

Crystallographic data for compound 49; CCDC reference 2219268.

Supplementary Data 3

Crystallographic data for compound L1; CCDC reference 2330897.

Supplementary Data 4

Crystallographic data for compound L4; CCDC reference 2330898.

Supplementary Data 5

Cartesian coordinates of DFT-optimized structures.

Source data

Source Data Fig. 2

Statistical source data.

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Zheng, Y., Yang, T., Chan, K.F. et al. Cobalt-catalysed desymmetrization of malononitriles via enantioselective borohydride reduction. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01592-z

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