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Enantioselective synthesis of multifunctional alkylboronates via N-heterocyclic carbene–nickel-catalysed carboboration of alkenes

Nature Synthesis (2024)Cite this article

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Abstract

Enantioenriched boronic esters are widely used multipurpose building blocks in organic synthesis. Multicomponent processes that deliver these organoboron compounds using non-precious single-catalyst systems are highly sought-after but remain rare. This owes to the lack of an appropriate chiral ligand that is capable of inducing high efficiency and selectivity. Here we report the use of an Ni-based catalyst containing a chiral N-heterocyclic carbene for the enantioselective 1,2-carboboration of unactivated and activated alkenes without the need for directing groups. Various aryl and alkenyl motifs can be successfully installed to afford functionalized alkylboronates bearing tertiary or quaternary β-stereocentres with good to excellent regio- and enantioselectivity. Contrary to previously reported carboboration reactions, mechanistic studies suggest that the reported Ni-catalysed transformation proceeds through a regio- and stereo-determining carbonickelation and subsequent borylation. The utility of the approach is demonstrated by the concise synthesis of key biologically active molecules.

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Fig. 1: Multicomponent catalytic approaches for alkene 1,2-carboboration to access enantioenriched alkylboron compounds.
Fig. 2: Access to chiral alkylboron compounds with quaternary or heteroatom-substituted stereocentres.
Fig. 3: Catalytic 1,2-carboboration of other alkenes, 1,3-dienes and organotriflate electrophiles.
Fig. 4: Enantioselective construction of bioactive molecules.
Fig. 5: Mechanistic studies.

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Data availability

All data supporting the findings of this study are available within the article and its Supplementary Information.

References

  1. Hall, D. G. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials 2nd ed. 1–109 (Wiley-VCH, 2011).

  2. Yeung, K., Mykura, R. C. & Aggarwal, V. K. Lithiation–borylation methodology in the total synthesis of natural products. Nat. Synth. 1, 117–126 (2022).

    Article  Google Scholar 

  3. Matteson, D. S. Boronic esters in asymmetric synthesis. J. Org. Chem. 78, 10009–10023 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Andrés, P., Ballano, G., Calaza, M. I. & Cativiela, C. Synthesis of α-aminoboronic acids. Chem. Soc. Rev. 45, 2291–2307 (2016).

    Article  PubMed  Google Scholar 

  5. Jäkle, F. Recent advances in the synthesis and applications of organoborane polymers. in Synthesis and Application of Organoboron Compounds (eds Fernández, E. & Whiting, A.) 297–325 (Springer International Publishing, 2015).

  6. Sandford, C. & Aggarwal, V. K. Stereospecific functionalizations and transformations of secondary and tertiary boronic esters. Chem. Commun. 53, 5481–5494 (2017).

    Article  CAS  Google Scholar 

  7. Aiken, S. G., Bateman, J. M. & Aggarwal, V. K. Boron “ate” complexes for asymmetric synthesis. in Science of Synthesis: Advances in Organoboron Chemistry towards Organic Synthesis Ch. 13, 393–458 (Thieme, 2019).

  8. Zhang, C., Hu, W. & Morken, J. P. α-Boryl organometallic reagents in catalytic asymmetric synthesis. ACS Catal. 11, 10660–10680 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Xu, N., Liang, H. & Morken, J. P. Copper-catalyzed stereospecific transformations of alkylboronic esters. J. Am. Chem. Soc. 144, 11546–11552 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang, M. & Shi, Z. Methodologies and strategies for selective borylation of C–Het and C–C bonds. Chem. Rev. 120, 7348–7398 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Collins, B. S. L., Wilson, C. M., Myers, E. L. & Aggarwal, V. K. Asymmetric synthesis of secondary and tertiary boronic esters. Angew. Chem. Int. Ed. 56, 11700–11733 (2017).

    Article  CAS  Google Scholar 

  12. Whyte, A., Torelli, A., Mirabi, B., Zhang, A. & Lautens, M. Copper-catalyzed borylative difunctionalization of π-systems. ACS Catal. 10, 11578–11622 (2020).

    Article  CAS  Google Scholar 

  13. Hu, J., Ferger, M., Shi, Z. & Marder, T. B. Recent advances in asymmetric borylation by transition metal catalysis. Chem. Soc. Rev. 50, 13129–13188 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Ye, Y. et al. Nickel-catalyzed enantioselective 1,2-vinylboration of styrenes. Chem. Sci. 12, 13209–13215 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  Google Scholar 

  16. Jia, T., Cao, P., Wang, B., Lou, Y. & Liao, J. A Cu/Pd cooperative catalysis for enantioselective allylboration of alkenes. J. Am. Chem. Soc. 137, 13760–13763 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Dorn, S. K. & Brown, M. K. Cooperative Pd/Cu catalysis for alkene arylboration: opportunities for divergent reactivity. ACS Catal. 12, 2058–2063 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lee, H., Lee, S. & Yun, J. Pd-catalyzed stereospecific cross-coupling of chiral α-borylalkylcopper species with aryl bromides. ACS Catal. 10, 2069–2073 (2020).

    Article  CAS  Google Scholar 

  19. Chen, B. et al. Modular synthesis of enantioenriched 1,1,2-triarylethanes by an enantioselective arylboration and cross-coupling sequence. ACS Catal. 7, 2425–2429 (2017).

    Article  CAS  Google Scholar 

  20. Chen, B., Cao, P., Liao, Y., Wang, M. & Liao, J. Enantioselective copper-catalyzed methylboration of alkenes. Org. Lett. 20, 1346–1349 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Green, J. C., Joannou, M. V., Murray, S. A., Joseph, M. Z. & Meek, S. J. Enantio- and diastereoselective synthesis of hydroxy bis(boronates) via Cu-catalyzed tandem borylation/1,2-addition. ACS Catal. 7, 4441–4445 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Huang, Y., Smith, K. B. & Brown, M. K. Copper-catalyzed borylacylation of activated alkenes with acid chlorides. Angew. Chem. Int. Ed. 56, 13314–13318 (2017).

    Article  CAS  Google Scholar 

  23. Lee, J. et al. Mechanism-based enhancement of scope and enantioselectivity for reactions involving a copper-substituted stereogenic carbon centre. Nat. Chem. 10, 99–108 (2018).

    Article  CAS  PubMed  Google Scholar 

  24. Kim, N., Han, J. T., Ryu, D. H. & Yun, J. Copper-catalyzed asymmetric borylallylation of vinyl arenes. Org. Lett. 19, 6144–6147 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Itoh, T., Kanzaki, Y., Shimizu, Y. & Kanai, M. Copper(I)-catalyzed enantio- and diastereodivergent borylative coupling of styrenes and imines. Angew. Chem. Int. Ed. 57, 8265–8269 (2018).

    Article  CAS  Google Scholar 

  26. Li, Z. et al. Nickel-catalyzed regio- and enantioselective borylative coupling of terminal alkenes with alkyl halides enabled by an anionic bisoxazoline ligand. J. Am. Chem. Soc. 145, 13603–13614 (2023).

    Article  CAS  PubMed  Google Scholar 

  27. Wang, H., Liu, C.-F., Martin, R. T., Gutierrez, O. & Koh, M. J. Directing group-free catalytic dicarbofunctionalization of unactivated alkenes. Nat. Chem. 14, 188–195 (2022).

    Article  PubMed  Google Scholar 

  28. Liu, Z., Li, X., Zeng, T. & Engle, K. M. Directed, palladium (II)-catalyzed enantioselective anti-carboboration of alkenyl carbonyl compounds. ACS Catal. 9, 3260–3265 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu, C.-F. et al. Synthesis of tri- and tetrasubstituted stereocentres by nickel-catalysed enantioselective olefin cross-couplings. Nat. Catal. 5, 934–942 (2022).

    Article  CAS  Google Scholar 

  30. Jang, W. J., Song, S. M., Moon, J. H., Lee, J. Y. & Yun, J. Copper-catalyzed enantioselective hydroboration of unactivated 1,1-disubstituted alkenes. J. Am. Chem. Soc. 139, 13660–13663 (2017).

    Article  CAS  PubMed  Google Scholar 

  31. Hong, X. & Shi, S.-L. et al. Copper-catalyzed enantioselective Markovnikov protoboration of α-olefins enabled by a buttressed N-heterocyclic carbene ligand. Angew. Chem. Int. Ed. 57, 1376–1380 (2018).

    Article  Google Scholar 

  32. Wen, Y., Deng, C., Xie, J. & Kang, X. Recent synthesis developments of organoboron compounds via metal-free catalytic borylation of alkynes and alkenes. Molecules 24, 101 (2019).

    Article  Google Scholar 

  33. Qi, X. & Diao, T. Nickel-catalyzed dicarbofunctionalization of alkenes. ACS Catal. 10, 8542–8556 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lin, C. & Shen, L. Recent progress in transition metal-catalyzed regioselective functionalization of unactivated alkenes/alkynes assisted by bidentate directing groups. ChemCatChem 11, 961–968 (2019).

    Article  CAS  Google Scholar 

  35. Nattmann, L. & Cornella, J. Ni(4‑tBustb)3: a robust 16-electron Ni(0) olefin complex for catalysis. Organometallics 39, 3295–3300 (2020).

    Article  CAS  Google Scholar 

  36. Ma, X., Kuang, Z. & Song, Q. Recent advances in the construction of fluorinated organoboron compounds. J. Am. Chem. Soc. Au 2, 261–279 (2022).

    CAS  Google Scholar 

  37. Hupe, E., Marek, I. & Knochel, P. Diastereoselective reduction of alkenylboronic esters as a new method for controlling the stereochemistry of up to three adjacent centers in cyclic and acyclic molecules. Org. Lett. 4, 2861–2863 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Denmark, S. E. & Fu, J. Catalytic enantioselective addition of allylic organometallic reagents to aldehydes and ketones. Chem. Rev. 103, 2763–2794 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Yus, M., González-Gómez, J. C. & Foubelo, F. Diastereoselective allylation of carbonyl compounds and imines: application to the synthesis of natural products. Chem. Rev. 113, 5595–5698 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Sardini, S. R. & Brown, M. K. Catalyst controlled regiodivergent arylboration of dienes. J. Am. Chem. Soc. 139, 9823–9826 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Franz, A. K. & Wilson, S. O. Organosilicon molecules with medicinal applications. J. Med. Chem. 56, 388–405 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Logan, K. M. & Brown, M. K. Catalytic enantioselective arylboration of alkenylarenes. Angew. Chem. Int. Ed. 129, 869–873 (2017).

    Article  Google Scholar 

  44. Chen, L.-A., Lear, A. R., Gao, P. & Brown, M. K. Nickel-catalyzed arylboration of alkenylarenes: synthesis of boron-substituted quaternary carbons and regiodivergent reactions. Angew. Chem. Int. Ed. 58, 10956–10960 (2019).

    Article  CAS  Google Scholar 

  45. Simlandy, A. K., Sardini, S. & Brown, M. K. Construction of congested Csp3–Csp3 bonds by a formal Ni-catalyzed alkylboration. Chem. Sci. 12, 5517–5521 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sardini, S. R. & Brown, M. K. Nickel-catalyzed arylboration of cyclopentene. Org. Synth. 97, 355–367 (2020).

    Article  CAS  PubMed  Google Scholar 

  47. Xu, J. et al. Selective oxidation of alkenes to carbonyls under mild conditions. Green Chem. 23, 5549–5555 (2021).

    Article  CAS  Google Scholar 

  48. Sonawane, R. P. et al. Enantioselective construction of quaternary stereogenic centers from tertiary boronic esters: methodology and applications. Angew. Chem. Int. Ed. 50, 3760–3763 (2011).

    Article  CAS  Google Scholar 

  49. Turnbull, B. W. H. & Evans, P. A. Enantioselective rhodium-catalyzed allylic substitution with a nitrile anion: construction of acyclic quaternary carbon stereogenic centers. J. Am. Chem. Soc. 137, 6156–6159 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Ishibashi, H. et al. A convenient synthesis of 1,3,4,5-tetrahydro-2H-3-benzazepin-2-ones by acid-catalyzed cylization of N-(2-arylethyl)-N-methyl-2-sulfinylacetamides. Chem. Pharm. Bull. 37, 939–943 (1989).

    Article  CAS  Google Scholar 

  51. Coote, S. J., Davies, S. G., Middlemiss, D. & Naylor, A. Enantiospecific synthesis of (+)-(R)-1-phenyl-3-methyl-1,2,4,5-tetrahydrobenz[d]azepine from (+)-(S)-N-methyl-1-phenyl ethanolamine (halostachine) via arene chromium tricarbonyl methodology. Tetrahedron Lett. 30, 3581–3588 (1989).

    Article  CAS  Google Scholar 

  52. Goode-Romero, G. et al. New information of dopaminergic agents based on quantum chemistry calculations. Sci. Rep. 10, 21581 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang, D. et al. Asymmetric copper-catalyzed intermolecular aminoarylation of styrenes: efficient access to optical 2,2-diarylethylamines. J. Am. Chem. Soc. 139, 6811–6814 (2017).

    Article  CAS  PubMed  Google Scholar 

  54. Belloni, P. N., Jolidon, S., Klaus, M. & Lapierre, J.-M. New gamma selective retinoids. WO patent 2001/083438 A2 (2001).

  55. González-Rodríguez, J., Soengas, R. G. & Rodríguez-Solla, H. A cooperative zinc/catalytic indium system for the stereoselective sequential synthesis of (E)-1,3-dienes from carbonyl compounds. Org. Chem. Front. 8, 591–598 (2021).

    Article  Google Scholar 

  56. Gilmore, J. L. et al. Synthesis and structure–activity relationships of novel indazolyl glucocorticoid receptor partial agonists. Bioorg. Med. Chem. Lett. 23, 5448–5451 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Sheppeck, J. E. Modulators of glucocorticoid receptor, AP-1, and/or NF-κΒ activity and use thereof. WO patent 2008/057857 Al (2008).

  58. Liu, C.-F. et al. Olefin functionalization/isomerization enables stereoselective alkene synthesis. Nat. Catal. 4, 674–683 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tasker, S. Z., Gutierrez, A. C. & Jamison, T. F. Nickel-catalysed Mizoroki–Heck reaction of aryl sulfonates and chlorides with electronically unbiased terminal olefins: high selectivity for branched products. Angew. Chem. Int. Ed. 53, 1858–1861 (2014).

    Article  CAS  Google Scholar 

  60. Liu, C.-F., Luo, X., Wang, H. & Koh, M. J. Catalytic regioselective olefin hydroarylation (alkenylation) by sequential carbonickelation-hydride transfer. J. Am. Chem. Soc. 143, 9498–9506 (2021).

    Article  CAS  PubMed  Google Scholar 

  61. Guo, L. et al. General method for enantioselective three-component carboarylation of alkenes enabled by visible-light dual photoredox/nickel catalysis. J. Am. Chem. Soc. 142, 20390–20399 (2020).

    Article  CAS  Google Scholar 

  62. Huang, M. et al. Ni-catalyzed borylation of aryl sulfoxides. Chem. Eur. J. 27, 8149–8158 (2021).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by the Ministry of Education of Singapore Academic Research Fund Tier 2: A-8000941-00-00 (M.J.K.), the National Key Research & Development Program of China: 2019YFA0905100 and the National Natural Science Foundation of China: 92156025 (J.-A.M.), the National Natural Science Foundation of China: 22325110, 92256303, 22171280 (S.-L.S.) and the National Key Research & Development Program of China: 2021YFF0701700 (J.N.).

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Author notes

  1. These authors contributed equally: Xiaohua Luo, Wei Mao.

  2. These authors jointly supervised this work: Jing Nie, Shi-Liang Shi, Jun-An Ma, Ming Joo Koh.

Authors and Affiliations

  1. Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University, Binhai New City, China

    Xiaohua Luo, Wei Mao, Jun-An Ma & Ming Joo Koh

  2. Department of Chemistry, National University of Singapore, Singapore, Singapore

    Xiaohua Luo, Wei Mao, Chen-Fei Liu, Yu-Qi Wang & Ming Joo Koh

  3. College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China

    Yu-Qi Wang

  4. Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for Synthetic Biology (Ministry of Education), and Tianjin Collaborative Innovation Centre of Chemical Science & Engineering, Tianjin University, Tianjin, China

    Jing Nie & Jun-An Ma

  5. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Shi-Liang Shi

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Contributions

M.J.K., X.L. and C.-F.L. conceived the work. X.L., W.M. and Y.-Q.W. developed the method. M.J.K., J.-A.M., S.-L.S. and J.N. directed the investigations. M.J.K. wrote the manuscript with revisions provided by the other authors.

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Correspondence to Jing Nie, Shi-Liang Shi, Jun-An Ma or Ming Joo Koh.

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Supplementary Tables 1–8, Figs. 1 and 2, experimental data, synthesis and characterization data, NMR spectra, HPLC traces and references.

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Luo, X., Mao, W., Liu, CF. et al. Enantioselective synthesis of multifunctional alkylboronates via N-heterocyclic carbene–nickel-catalysed carboboration of alkenes. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00492-x

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