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Copper-catalysed asymmetric hydroboration of alkenes with 1,2-benzazaborines to access chiral naphthalene isosteres

Nature Chemistry (2024)Cite this article

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Abstract

Bioisosteric replacement has emerged as a clear strategy for drug-structure optimization. Naphthalene is the core element of many chiral pharmaceuticals and drug candidates. However, as a promising isostere of naphthalene, the chiral version of 1,2-benzazaborine has rarely been explored due to the lack of efficient synthetic methods. Here we describe a copper-catalysed enantioselective hydroboration of alkenes with 1,2-benzazaborines. The method provides a general platform for the atom-economic and efficient construction of diverse chiral 1,2-benzazaborine compounds (more than 60 examples) that bear a 2-carbon-stereogenic centre or allene skeleton in high yields and excellent enantioselectivities. Three 1,2-benzazaborine analogues of bioactive chiral naphthalene-containing molecules have been prepared, and a series of transformations around chiral 1,2-benzazaborines have also been developed. Notably, the hydroboration process of this study reveals that the identity of 1,2-benzazaborine plays an essential role in the rate-determining step and catalyst resting state.

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Fig. 1: Asymmetric hydroboration reaction for the construction of chiral naphthalene isosteres.
Fig. 2: Functionalization of complex molecules and synthetic applications.
Fig. 3: Mechanistic investigation.

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Data availability

The data that support the findings of this study are available within the Article and its Supplementary Information files. Crystallographic data for the structure reported in this Article has been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2245401 (3b). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Patani, G. A. & LaVoie, E. J. Bioisosterism: a rational approach in drug design. Chem. Rev. 96, 3147–3176 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Brown, N. (ed.) Bioisosteres in Medicinal Chemistry (Wiley, 2012).

  3. Makar, S., Saha, T. & Singh, S. K. Naphthalene, a versatile platform in medicinal chemistry: sky-high perspective. Eur. J. Med. Chem. 161, 252–276 (2019).

    Article  CAS  PubMed  Google Scholar 

  4. Bosdet, M. J. D. & Piers, W. E. B-N as a C-C substitute in aromatic systems. Can. J. Chem. 87, 8–29 (2009).

    Article  Google Scholar 

  5. Giustra, Z. X. & Liu, S.-Y. The state of the art in azaborine chemistry: new synthetic methods and applications. J. Am. Chem. Soc. 140, 1184–1194 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Stojanović, M. & Baranac-Stojanović, M. Mono BN-substituted analogues of naphthalene: a theoretical analysis of the effect of BN position on stability, aromaticity and frontier orbital energies. New J. Chem. 42, 12968–12976 (2018).

    Article  Google Scholar 

  7. McConnell, C. R. & Liu, S.-Y. Late-stage functionalization of BN-heterocycles. Chem. Soc. Rev. 48, 3436–3453 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bhattacharjee, A., Davies, G. H. M., Saeednia, B., Wisniewski, S. R. & Molander, G. A. Selectivity in the elaboration of bicyclic borazarenes. Adv. Synth. Catal. 363, 2256–2273 (2021).

    Article  CAS  PubMed  Google Scholar 

  9. Abengózar, A., García-García, P., Fernández-Rodríguez, M. A., Sucunza, D. & Vaquero, J. J. in Advances in Heterocyclic Chemistry (eds Scriven, E. F.V. & Ramsden, C. A.) Vol. 135, 197–259 (Elsevier, 2021).

  10. Rombouts, F. J. R., Tovar, F., Austin, N., Tresadern, G. & Trabanco, A. A. Benzazaborinines as novel bioisosteric replacements of naphthalene: propranolol as an example. J. Med. Chem. 58, 9287–9295 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Vlasceanu, A., Jessing, M. & Kilburn, J. P. BN/CC isosterism in borazaronaphthalenes towards phosphodiesterase 10A (PDE10A) inhibitors. Bioorg. Med. Chem. 23, 4453–4461 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Lee, H., Fischer, M., Shoichet, B. K. & Liu, S.-Y. Hydrogen bonding of 1,2-azaborines in the binding cavity of T4 lysozyme mutants: structures and thermodynamics. J. Am. Chem. Soc. 138, 12021–12024 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lovering, F. Escape from Flatland 2: complexity and promiscuity. Med. Chem. Commun. 4, 515–519 (2013).

    Article  CAS  Google Scholar 

  14. Ishikawa, M. & Hashimoto, Y. Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. J. Med. Chem. 54, 1539–1554 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Mazzanti, A., Mercanti, E. & Mancinelli, M. Axial chirality about boron-carbon bond: atropisomeric azaborines. Org. Lett. 18, 2692–2695 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Yang, J. et al. Chiral phosphoric acid-catalyzed remote control of axial chirality at boron-carbon bond. J. Am. Chem. Soc. 143, 12924–12929 (2021).

    Article  CAS  PubMed  Google Scholar 

  17. Zhang, X. et al. Stepwise asymmetric allylic substitution-isomerization enabled mimetic synthesis of axially chiral B,N‐heterocycles. Angew. Chem. Int. Ed. 61, e202210456 (2022).

    Article  CAS  Google Scholar 

  18. Morita, T., Murakami, H., Asawa, Y. & Nakamura, H. Enantioselective synthesis of oxazaborolidines by palladium-catalyzed N-H/B-H double activation of 1,2-azaborines. Angew. Chem. Int. Ed. 61, e202113558 (2022).

    Article  CAS  Google Scholar 

  19. Wisniewski, S. R., Guenther, C. L., Argintaru, O. A. & Molander, G. A. A convergent, modular approach to functionalized 2,1-borazaronaphthalenes from 2-aminostyrenes and potassium organotrifluoroborates. J. Org. Chem. 79, 365–378 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Bagutski, V., Ros, A. & Aggarwal, V. K. Improved method for the conversion of pinacolboronic esters into trifluoroborate salts: facile synthesis of chiral secondary and tertiary trifluoroborates. Tetrahedron 65, 9956–9960 (2009).

    Article  CAS  Google Scholar 

  21. Noh, D., Yoon, S. K., Won, J., Lee, J. Y. & Yun, J. An efficient copper(I)-catalyst system for the asymmetric hydroboration of β-substituted vinylarenes with pinacolborane. Chem. Asian J. 6, 1967–1969 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Jang, W. J., Song, S. M., Park, Y. & Yun, J. Asymmetric synthesis of γ-hydroxy pinacolboronates through copper-catalyzed enantioselective hydroboration of α,β-unsaturated aldehydes. J. Org. Chem. 84, 4429–4434 (2019).

    Article  CAS  PubMed  Google Scholar 

  23. Sang, H. L., Yu, S. & Ge, S. Copper-catalyzed asymmetric hydroboration of 1,3-enynes with pinacolborane to access chiral allenylboronates. Org. Chem. Front. 5, 1284–1287 (2018).

    Article  CAS  Google Scholar 

  24. 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 

  25. Xi, Y. & Hartwig, J. F. Diverse asymmetric hydrofunctionalization of aliphatic internal alkenes through catalytic regioselective hydroboration. J. Am. Chem. Soc. 138, 6703–6706 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Huang, Y., del Pozo, J., Torker, S. & Hoveyda, A. H. Enantioselective synthesis of trisubstituted allenyl-B(pin) compounds by phosphine-Cu-catalyzed 1,3-enyne hydroboration. insights regarding stereochemical integrity of Cu-allenyl intermediates. J. Am. Chem. Soc. 140, 2643–2655 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Noh, D., Chea, H., Ju, J. & Yun, J. Highly regio- and enantioselective copper-catalyzed hydroboration of styrenes. Angew. Chem. Int. Ed. 48, 6062–6064 (2009).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. Chen, X., Cheng, Z., Guo, J. & Lu, Z. Asymmetric remote C-H borylation of internal alkenes via alkene isomerization. Nat. Commun. 9, 3939 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gao, D.-W. et al. Cascade CuH-catalysed conversion of alkynes into enantioenriched 1,1-disubstituted products. Nat. Catal. 3, 23–29 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Rubina, M., Rubin, M. & Gevorgyan, V. Catalytic enantioselective hydroboration of cyclopropenes. J. Am. Chem. Soc. 125, 7198–7199 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Yu, S., Wu, C. & Ge, S. Cobalt-catalyzed asymmetric hydroboration/cyclization of 1,6-enynes with pinacolborane. J. Am. Chem. Soc. 139, 6526–6529 (2017).

    Article  CAS  PubMed  Google Scholar 

  33. Chen, X., Cheng, Z. & Lu, Z. Cobalt-catalyzed asymmetric Markovnikov hydroboration of styrenes. ACS Catal. 9, 4025–4029 (2019).

    Article  CAS  Google Scholar 

  34. Jin, S. et al. Enantioselective Cu-catalyzed double hydroboration of alkynes to access chiral gem-diborylalkanes. Nat. Commun. 13, 3524 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dong, W. et al. Enantioselective Rh-catalyzed hydroboration of silyl enol ethers. J. Am. Chem. Soc. 143, 10902–10909 (2021).

    Article  CAS  PubMed  Google Scholar 

  36. Mazet, C. & Gérard, D. Highly regio- and enantioselective catalytic asymmetric hydroboration of α-substituted styrenyl derivatives. Chem. Commun. 47, 298–300 (2011).

    Article  CAS  Google Scholar 

  37. Bochat, A. J., Shoba, V. M. & Takacs, J. M. Ligand-controlled regiodivergent enantioselective rhodium-catalyzed alkene hydroboration. Angew. Chem. Int. Ed. 58, 9434–9438 (2019).

    Article  CAS  Google Scholar 

  38. Bai, X.-Y., Zhao, W., Sun, X. & Li, B.-J. Rhodium-catalyzed regiodivergent and enantioselective hydroboration of enamides. J. Am. Chem. Soc. 141, 19870–19878 (2019).

    Article  CAS  PubMed  Google Scholar 

  39. Gao, T.-T., Zhang, W.-W., Sun, X., Lu, H.-X. & Li, B.-J. Stereodivergent synthesis through catalytic asymmetric reversed hydroboration. J. Am. Chem. Soc. 141, 4670–4677 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Shoba, V. M., Thacker, N. C., Bochat, A. J. & Takacs, J. M. Synthesis of chiral tertiary boronic esters by oxime-directed catalytic asymmetric hydroboration. Angew. Chem. Int. Ed. 55, 1465–1469 (2016).

    Article  CAS  Google Scholar 

  41. Chakrabarty, S. & Takacs, J. M. Synthesis of chiral tertiary boronic esters: phosphonate-directed catalytic asymmetric hydroboration of trisubstituted alkenes. J. Am. Chem. Soc. 139, 6066–6069 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Brown, A. N., Zakharov, L. N., Mikulas, T., Dixon, D. A. & Liu, S.-Y. Rhodium-catalyzed B-H activation of 1,2-azaborines: synthesis and characterization of BN isosteres of stilbenes. Org. Lett. 16, 3340–3343 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. DeFrancesco, H., Dudley, J. & Coca, A. in Boron Reagents in Synthesis (ed. Coca, A.) Ch. 1 (American Chemical Society, 2016).

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

    Article  CAS  PubMed  Google Scholar 

  45. Sun, C., Potter, B. & Morken, J. P. A catalytic enantiotopic-group-selective Suzuki reaction for the construction of chiral organoboronates. J. Am. Chem. Soc. 136, 6534–6537 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hong, K., Liu, X. & Morken, J. P. Simple access to elusive α-boryl carbanions and their alkylation: an umpolung construction for organic synthesis. J. Am. Chem. Soc. 136, 10581–10584 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Potter, B., Szymaniak, A. A., Edelstein, E. K. & Morken, J. P. Nonracemic allylic boronates through enantiotopic-group-selective cross-coupling of geminal bis(boronates) and vinyl halides. J. Am. Chem. Soc. 136, 17918–17921 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ma, S. Some typical advances in the synthetic applications of allenes. Chem. Rev. 105, 2829–2872 (2005).

    Article  PubMed  Google Scholar 

  49. Rivera-Fuentes, P. & Diederich, F. Allenes in molecular materials. Angew. Chem. Int. Ed. 51, 2818–2828 (2012).

    Article  CAS  Google Scholar 

  50. Neff, R. K. & Frantz, D. E. Recent advances in the catalytic syntheses of allenes: a critical assessment. ACS Catal. 4, 519–528 (2014).

    Article  CAS  Google Scholar 

  51. Huang, X. & Ma, S. Allenation of terminal alkynes with aldehydes and ketones. Acc. Chem. Res. 52, 1301–1312 (2019).

    Article  CAS  PubMed  Google Scholar 

  52. Yu, K.-L. et al. Retinoic acid receptor β,γ-selective ligands: synthesis and biological activity of 6-substituted 2-naphthoic acid retinoids. J. Med. Chem. 39, 2411–2421 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Yonova, I. M. et al. Stereospecific nickel-catalyzed cross-coupling reactions of alkyl Grignard reagents and identification of selective anti-breast-cancer agents. Angew. Chem. Int. Ed. 53, 2422–2427 (2014).

    Article  CAS  Google Scholar 

  54. Taylor, B. L. H., Swift, E. C., Waetzig, J. D. & Jarvo, E. R. Stereospecific nickel-catalyzed cross-coupling reactions of alkyl ethers: enantioselective synthesis of diarylethanes. J. Am. Chem. Soc. 133, 389–391 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Larouche-Gauthier, R., Elford, T. G. & Aggarwal, V. K. Ate complexes of secondary boronic esters as chiral organometallic-type nucleophiles for asymmetric synthesis. J. Am. Chem. Soc. 133, 16794–16797 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Financial support from the National Natural Science Foundation of China (22271048 and 22001038 to K.Y.; 21931013 and 22271105 to Q.S.), the Natural Science Foundation of Fujian Province (2022J05016 to K.Y.; 2022J02009 to Q.S.), Fuzhou University (510578 to Q.S.), Guangdong Provincial Key Laboratory of Catalysis (2020B121201002 to P.Y.) and Shenzhen Science and Technology Program (KQTD20210811090112004 to P.Y.) is gratefully acknowledged. Computational work was supported by the Center for Computational Science and Engineering and the CHEM High-Performance Supercomputer Cluster (CHEM-HPC) of the Department of Chemistry, Southern University of Science and Technology.

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Authors and Affiliations

  1. Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian, China

    Wanlan Su, Jide Zhu, Xu Zhang, Weihua Qiu, Kai Yang & Qiuling Song

  2. Department of Chemistry and Shenzhen Grubbs Institute, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, China

    Yu Chen & Peiyuan Yu

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  1. Wanlan Su
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Contributions

Q.S. and K.Y. conceived and directed the project. W.S., J.Z., X.Z. and W.Q. performed experiments. W.S. prepared the Supplementary Information. P.Y. and Y.C. performed the DFT calculations and drafted the DFT parts. Q.S., P.Y. and K.Y. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Kai Yang, Peiyuan Yu or Qiuling Song.

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Nature Chemistry thanks Bi-Jie Li, Ying He and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Tables 1–13, Figs. 1–12 and starting material preparation, experimental procedures, synthetic transformations, mechanistic studies and product characterization.

Supplementary Data 1

Crystallographic data of compound 3b, CCDC reference 2245401.

Supplementary Data 2

Contains the many computational structures used in this study to generate potential energy surfaces. The ‘Opt_Freq’ folder includes the key sections in the output files of structure optimizations and frequency calculations. The ‘Quasiharmonic’ folder includes the output files formed by Truhlar’s quasiharmonic correction. The ‘Solvation_SPE’ folder includes output files obtained by performing single point energy calculations using the solvation model. All these files are included in the zipped file.

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Su, W., Zhu, J., Chen, Y. et al. Copper-catalysed asymmetric hydroboration of alkenes with 1,2-benzazaborines to access chiral naphthalene isosteres. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01505-0

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