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Enantioselective remote meta-C–H arylation and alkylation via a chiral transient mediator

Abstract

Enantioselective carbon–hydrogen (C–H) activation reactions by asymmetric metallation could provide new routes for the construction of chiral molecules1,2. However, current methods are typically limited to the formation of five- or six-membered metallacycles, thereby preventing the asymmetric functionalization of C–H bonds at positions remote to existing functional groups. Here we report enantioselective remote C–H activation using a catalytic amount of a chiral norbornene as a transient mediator, which relays initial ortho-C–H activation to the meta position. This was used in the enantioselective meta-C–H arylation of benzylamines, as well as the arylation and alkylation of homobenzylamines. The enantioselectivities obtained using the chiral transient mediator are comparable across different classes of substrates containing either neutral σ-donor or anionic coordinating groups. This relay strategy could provide an alternative means to remote chiral induction, one of the most challenging problems in asymmetric catalysis3,4.

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Fig. 1: Enantioselective C(sp2)–H activation.
Fig. 2: Enantioselective meta-C–H arylation of diarylmethylamines.
Fig. 3: Enantioselective meta-C–H activation of homobenzylamines.

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References

  1. Giri, R., Shi, B.-F., Engle, K. M., Maugel, N. & Yu, J.-Q. Transition metal-catalyzed C–H activation reactions: diastereoselectivity and enantioselectivity. Chem. Soc. Rev. 38, 3242–3272 (2009).

    Article  PubMed  CAS  Google Scholar 

  2. Newton, C. G., Wang, S.-G., Oliveira, C. C. & Cramer, N. Catalytic enantioselective transformations involving C–H bond cleavage by transition-metal complexes. Chem. Rev. 117, 8908–8976 (2017).

    Article  PubMed  CAS  Google Scholar 

  3. Clayden, J., Lund, A., Vallverdú, L. & Helliwell, M. Ultra-remote stereocontrol by conformational communication of information along a carbon chain. Nature 431, 966–971 (2004).

    Article  PubMed  ADS  CAS  Google Scholar 

  4. Hurtley, A. E., Stone, E. A., Metrano, A. J. & Miller, S. J. Desymmetrization of diarylmethylamido bis(phenols) through peptide-catalyzed bromination: enantiodivergence as a consequence of a 2 amu alteration at an achiral residue within the catalyst. J. Org. Chem. 82, 11326–11336 (2017).

    Article  PubMed  CAS  Google Scholar 

  5. Kakiuchi, F., Gendre, P. L., Yamada, A., Ohtaki, H. & Murai, S. Atropselective alkylation of biaryl compounds by means of transition metal-catalyzed C–H/olefin coupling. Tetrahedron: Asymmetry 11, 2647–2651 (2000).

    Article  CAS  Google Scholar 

  6. Shi, B.-F., Maugel, N., Zhang, Y.-H. & Yu, J.-Q. PdII-catalyzed enantioselective activation of C(sp2)–H and C(sp3)–H bonds using monoprotected amino acids as chiral ligands. Angew. Chem. Int. Ed. 47, 4882–4886 (2008).

    Article  CAS  Google Scholar 

  7. Shi, B.-F., Zhang, Y. H., Lam, J. K., Wang, D. H. & Yu, J.-Q. Pd(II)-catalyzed enantioselective C–H olefination of diphenylacetic acids. J. Am. Chem. Soc. 132, 460–461 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Du, Z. J. et al. Pd(II)-catalyzed enantioselective synthesis of P-stereogenic phosphinamides via desymmetric C–H arylation. J. Am. Chem. Soc. 137, 632–635 (2015).

    Article  PubMed  CAS  Google Scholar 

  9. Gao, D.-W., Shi, Y.-C., Gu, Q., Zhao, Z.-L. & You, S.-L. Enantioselective synthesis of planar chiral ferrocenes via palladium-catalyzed direct coupling with arylboronic acids. J. Am. Chem. Soc. 135, 86–89 (2013).

    Article  PubMed  CAS  Google Scholar 

  10. Pi, C. et al. Redox of ferrocene controlled asymmetric dehydrogenative Heck reaction via palladium-catalyzed dual C–H bond activation. Chem. Sci. 4, 2675–2679 (2013).

    Article  CAS  Google Scholar 

  11. Chu, L., Xiao, K.-J. & Yu, J.-Q. Room-temperature enantioselective C–H iodination via kinetic resolution. Science 346, 451–455 (2014).

    Article  PubMed  PubMed Central  ADS  CAS  Google Scholar 

  12. Gao, D.-W., Gu, Q. & You, S.-L. Pd(II)-catalyzed intermolecular direct C–H bond iodination: an efficient approach toward the synthesis of axially chiral compounds via kinetic resolution. ACS Catal. 4, 2741–2745 (2014).

    Article  CAS  Google Scholar 

  13. Albicker, M. R. & Cramer, N. Enantioselective palladium-catalyzed direct arylations at ambient temperature: access to indanes with quaternary stereocenters. Angew. Chem. Int. Ed. 48, 9139–9142 (2009).

    Article  CAS  Google Scholar 

  14. Shintani, R., Otomo, H., Ota, K. & Hayashi, T. Palladium-catalyzed asymmetric synthesis of silicon-stereogenic dibenzosiloles via enantioselective C–H bond functionalization. J. Am. Chem. Soc. 134, 7305–7308 (2012).

    Article  PubMed  CAS  Google Scholar 

  15. Kuninobu, Y., Yamauchi, K., Tamura, N., Seiki, T. & Takai, K. Rhodium-catalyzed asymmetric synthesis of spirosilabifluorene derivatives. Angew. Chem. Int. Ed. 52, 1520–1522 (2013).

    Article  CAS  Google Scholar 

  16. Lee, T., Wilson, T. W., Berg, R., Ryberg, P. & Hartwig, J. F. Rhodium-catalyzed enantioselective silylation of arene C–H bonds: desymmetrization of diarylmethanols. J. Am. Chem. Soc. 137, 6742–6745 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Sun, Y. & Cramer, N. Rhodium(III)-catalyzed enantiotopic C–H activation enables access to P-chiral cyclic phosphinamides. Angew. Chem. Int. Ed. 56, 364–367 (2017).

    Article  CAS  Google Scholar 

  18. Shibata, T. & Shizuno, T. Iridium-catalyzed enantioselective C–H alkylation of ferrocenes with alkenes using chiral diene ligands. Angew. Chem. Int. Ed. 53, 5410–5413 (2014).

    Article  CAS  Google Scholar 

  19. Saidi, O. et al. Ruthenium-catalyzed meta sulfonation of 2-phenylpyridines. J. Am. Chem. Soc. 133, 19298–19301 (2011).

    Article  PubMed  CAS  Google Scholar 

  20. Hofmann, N. & Ackermann, L. meta-Selective C–H bond alkylation with secondary alkyl halides. J. Am. Chem. Soc. 135, 5877–5884 (2013).

    Article  PubMed  CAS  Google Scholar 

  21. Leow, D., Li, G., Mei, T.-S. & Yu, J.-Q. Activation of remote meta-C–H bonds assisted by an end-on template. Nature 486, 518–522 (2012).

    Article  PubMed  PubMed Central  ADS  CAS  Google Scholar 

  22. Phipps, R. J. & Gaunt, M. J. A meta-selective copper-catalyzed C–H bond arylation. Science 323, 1593–1597 (2009).

    Article  PubMed  ADS  CAS  Google Scholar 

  23. Wang, X.-C. et al. Ligand-enabled meta-C–H activation using a transient mediator. Nature 519, 334–338 (2015).

    Article  PubMed  PubMed Central  ADS  CAS  Google Scholar 

  24. Dong, Z., Wang, J. & Dong, G. Simple amine-directed meta-selective C–H arylation via Pd/norbornene catalysis. J. Am. Chem. Soc. 137, 5887–5890 (2015).

    Article  PubMed  CAS  Google Scholar 

  25. Shen, P.-X., Wang, X.-C., Wang, P., Zhu, R.-Y. & Yu, J.-Q. Ligand-enabled meta-C–H alkylation and arylation using a modified norbornene. J. Am. Chem. Soc. 137, 11574–11577 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Ye, J. & Lautens, M. Palladium-catalysed norbornene-mediated C–H functionalization of arenes. Nat. Chem. 7, 863–870 (2015).

    Article  PubMed  CAS  Google Scholar 

  27. Della Ca’, N., Fontana, M., Motti, E. & Catellani, M. Pd/norbornene: a winning combination for selective aromatic functionalization via C−H bond activation. Acc. Chem. Res. 49, 1389–1400 (2016).

    Article  PubMed  CAS  Google Scholar 

  28. Wang, P., Farmer, M. E. & Yu, J.-Q. Ligand-promoted meta-C-H functionalization of benzylamines. Angew. Chem. Int. Ed. 56, 5125–5129 (2017).

    Article  CAS  Google Scholar 

  29. Ding, Q. et al. Ligand-enabled meta-selective C–H arylation of nosyl-protected phenethylamines, benzylamines, and 2-aryl anilines. J. Am. Chem. Soc. 139, 417–425 (2017).

    Article  PubMed  CAS  Google Scholar 

  30. Albrecht, B. K. & Williams, R. M. A concise, total synthesis of the TMC-95A/B proteasome inhibitors. Proc. Natl Acad. Sci. U.S.A. 101, 11949–11954 (2004).

    Article  PubMed  PubMed Central  ADS  CAS  Google Scholar 

  31. Musaev, D. G., Kaledin, A., Shi, B.-F. & Yu, J.-Q. Key mechanistic features of enantioselective C–H bond activation reactions catalyzed by [(chiral mono-N-protected amino acid)-Pd(II)] complexes. J. Am. Chem. Soc. 134, 1690–1698 (2012).

    Article  PubMed  CAS  Google Scholar 

  32. Plata, R. E. et al. A role for Pd(IV) in catalytic enantioselective C–H functionalization with monoprotected amino acid ligands under mild conditions. J. Am. Chem. Soc. 139, 9238–9245 (2017).

    Article  PubMed  CAS  Google Scholar 

  33. Jiao, L., Herdtweck, E. & Bach, T. Pd(II)-catalyzed regioselective 2-alkylation of indoles via a norbornene-mediated C–H activation: mechanism and applications. J. Am. Chem. Soc. 134, 14563–14572 (2012).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We acknowledge The Scripps Research Institute, the National Institutes of Health (National Institute of General Medical Sciences grant 5R01GM102265) and Shanghai RAAS Blood Products Co. Ltd for their financial support. Y.S. thanks Jiangsu Overseas Research & Training Program for University Prominent Young & Middle-aged Teachers and Presidents.

Reviewer information

Nature thanks M. Catellani, G. Chen and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

Authors

Contributions

J.-Q.Y. and H.S. conceived the concept. H.S. developed the enantioselective remote C−H activation. H.S. and A.N.H. performed the mechanistic study. H.S., A.N.H., Y.S. and Q.S. prepared reaction substrates. J.-Q.Y. directed the project.

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Correspondence to Jin-Quan Yu.

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The authors declare no competing interests.

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Supplementary Information

This file contains General Information, Experimental Section, X-Ray Crystallographic Data, NMR Spectra, SFC Traces and References

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Shi, H., Herron, A.N., Shao, Y. et al. Enantioselective remote meta-C–H arylation and alkylation via a chiral transient mediator. Nature 558, 581–585 (2018). https://doi.org/10.1038/s41586-018-0220-1

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