Abstract
Achieving mono-selectivity in C–H activation reactions is a considerable challenge when multiple identical C–H bonds coexist. Despite recent rapid advances in site-selective and enantioselective C–H activation, a large number of C–H activation reactions still suffer from poor mono-selectivity. Here we report the use of commercial enzymes as ligands for palladium catalysts, enabling enhanced reactivity and exceptionally high mono-selectivity (up to 99%) in both ortho- and meta-C–H activation of arenes, which originally used bifunctional mono-N-protected amino acid ligands but with poor mono-selectivity. Notably, the Pd–enzyme complex was identified as the active catalyst species. Mechanistic investigations and structural analyses of the enzymes suggest that the enzyme primary structure, the sequence length and the percentage of amino acids with hydrophobic side chains are critical for achieving mono-selectivity. By leveraging these findings, we further developed a glycine-containing oligopeptide capable of achieving similarly high mono-selectivity.
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The data supporting the findings of this study are available within the Article and its Supplementary Information or from the authors upon reasonable request.
References
Wu, K. et al. Palladium (II)-catalyzed C−H activation with bifunctional ligands: from curiosity to industrialization. Angew. Chem. Int. Ed. 63, e202400509 (2024).
Prabagar, B., Yang, Y. & Shi, Z. Site-selective C–H functionalization to access the arene backbone of indoles and quinolines. Chem. Soc. Rev. 50, 11249–11269 (2021).
Josephitis, C. M., Nguyen, H. M. H. & McNally, A. Late-stage C–H functionalization of azines. Chem. Rev. 123, 7655–7691 (2023).
Saint-Denis, T. G., Zhu, R.-Y., Chen, G., Wu, Q.-F. & Yu, J.-Q. Enantioselective C(sp3)–H bond activation by chiral transition metal catalysts. Science 359, eaao4798 (2018).
Kuninobu, Y., Ida, H., Nishi, M. & Kanai, M. A meta-selective C–H borylation directed by a secondary interaction between ligand and substrate. Nat. Chem. 7, 712–717 (2015).
Hoque, M. E., Bisht, R., Haldar, C. & Chattopadhyay, B. Noncovalent interactions in Ir-catalyzed C–H activation: L-shaped ligand for para-selective borylation of aromatic esters. J. Am. Chem. Soc. 139, 7745–7748 (2017).
Lam, N. Y. S. et al. Empirical guidelines for the development of remote directing templates through quantitative and experimental analyses. J. Am. Chem. Soc. 144, 2793–2803 (2022).
Fan, Z. et al. Molecular editing of aza-arene C–H bonds by distance, geometry and chirality. Nature 610, 87–93 (2022).
Engle, K. M., Wang, D.-H. & Yu, J.-Q. Constructing multiply substituted arenes using sequential palladium(II)-catalyzed C–H olefination. Angew. Chem. Int. Ed. 49, 6169–6173 (2010).
Wan, L., Dastbaravardeh, N., Li, G. & Yu, J.-Q. Cross-coupling of remote meta-C–H bonds directed by a U-shaped template. J. Am. Chem. Soc. 135, 18056–18059 (2013).
Davis, H. J., Mihai, M. T. & Phipps, R. J. Ion pair-directed regiocontrol in transition-metal catalysis: a meta-selective C–H borylation of aromatic quaternary ammonium salts. J. Am. Chem. Soc. 138, 12759–12762 (2016).
Patureau, F. W. & Glorius, F. Rh catalyzed olefination and vinylation of unactivated acetanilides. J. Am. Chem. Soc. 132, 9982–9983 (2010).
Chernyak, N., Dudnik, A. S., Huang, C. & Gevorgyan, V. PyDipSi: a general and easily modifiable/traceless Si-tethered directing group for C–H acyloxylation of arenes. J. Am. Chem. Soc. 132, 8270–8272 (2010).
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).
Wang, P. et al. Ligand-promoted meta-C–H arylation of anilines, phenols, and heterocycles. J. Am. Chem. Soc. 138, 9269–9276 (2016).
Hoque, M. E., Hassan, M. M. M. & Chattopadhyay, B. Remarkably efficient iridium catalysts for directed C(sp2)–H and C(sp3)–H borylation of diverse classes of substrates. J. Am. Chem. Soc. 143, 5022–5037 (2021).
Chaturvedi, J., Haldar, C., Bisht, R., Pandey, G. & Chattopadhyay, B. Meta selective C–H borylation of sterically biased and unbiased substrates directed by electrostatic interaction. J. Am. Chem. Soc. 143, 7604–7611 (2021).
Bisht, R. et al. Metal-catalysed C–H bond activation and borylation. Chem. Soc. Rev. 51, 5042–5100 (2022).
Lu, Y., Wang, D.-H., Engle, K. M. & Yu, J.-Q. Pd(II)-catalyzed hydroxyl-directed C–H olefination enabled by monoprotected amino acid ligands. J. Am. Chem. Soc. 132, 5916–5921 (2010).
Cheng, G., Li, T.-J. & Yu, J.-Q. Practical Pd(II)-catalyzed C–H alkylation with epoxides: one-step syntheses of 3,4-dihydroisocoumarins. J. Am. Chem. Soc. 137, 10950–10953 (2015).
Shi, B.-F., Maugel, N., Zhang, Y.-H. & Yu, J.-Q. Pd(II)-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).
Shao, Q., Wu, K., Zhuang, Z., Qian, S. & Yu, J.-Q. From Pd(OAc)2 to chiral catalysts: the discovery and development of bifunctional mono-n-protected amino acid ligands for diverse C–H functionalization reactions. Acc. Chem. Res. 53, 833–851 (2020).
Sambasivan, R. & Ball, Z. T. Metallopeptides for asymmetric dirhodium catalysis. J. Am. Chem. Soc. 132, 9289–9291 (2010).
van den Heuvel, N., Mason, S. M., Mercado, B. Q. & Miller, S. J. Aspartyl β-turn-based dirhodium(II) metallopeptides for benzylic C(sp3)–H amination: enantioselectivity and X-ray structural analysis. J. Am. Chem. Soc. 145, 12377–12385 (2023).
Bowles, M. O., Willis, E. L., Trombley, M. D., Chen, C.-H. & Proulx, C. Metallo-azapeptides: controlled metal chelation to peptide backbone nitrogen. J. Am. Chem. Soc. 147, 1404–1410 (2025).
Craven, E. J. et al. Programmable late-stage C–H bond functionalization enabled by integration of enzymes with chemocatalysis. Nat. Catal. 4, 385–394 (2021).
Miller, D. C., Athavale, S. V. & Arnold, F. H. Combining chemistry and protein engineering for new-to-nature biocatalysis. Nat. Synth. 1, 18–23 (2022).
Mondal, D., Snodgrass, H. M., Gomez, C. A. & Lewis, J. C. Non-native site-selective enzyme catalysis. Chem. Rev. 123, 10381–10431 (2023).
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).
Chen, G. et al. Ligand-accelerated enantioselective methylene C(sp3)–H bond activation. Science 353, 1023–1027 (2016).
Wu, Q.-F. et al. Formation of α-chiral centers by asymmetric β-C(sp3)–H arylation, alkenylation, and alkynylation. Science 355, 499–503 (2017).
Shen, P.-X., Hu, L., Shao, Q., Hong, K. & Yu, J.-Q. Pd(II)-catalyzed enantioselective C(sp3)–H arylation of free carboxylic acids. J. Am. Chem. Soc. 140, 6545–6549 (2018).
Zhuang, Z. et al. Ligand-enabled β-C(sp3)–H olefination of free carboxylic acids. J. Am. Chem. Soc. 140, 10363–10367 (2018).
Ortiz, C. et al. Novozym 435: the “perfect” lipase immobilized biocatalyst? Catal. Sci. Technol. 9, 2380–2420 (2019).
Deng, Y. & Yu, J.-Q. Remote meta-C–H olefination of phenylacetic acids directed by a versatile U-shaped template. Angew. Chem. Int. Ed. 54, 888–891 (2015).
Li, S., Cai, L., Ji, H., Yang, L. & Li, G. Pd(II)-catalysed meta-C–H functionalizations of benzoic acid derivatives. Nat. Commun. 7, 10443 (2016).
Li, G. et al. Pd(II)-catalyzed C–H functionalizations directed by distal weakly coordinating functional groups. J. Am. Chem. Soc. 137, 4391–4397 (2015).
Wang, D.-H., Engle, K. M., Shi, B.-F. & Yu, J.-Q. Ligand-enabled reactivity and selectivity in a synthetically versatile aryl C–H olefination. Science 327, 315–319 (2010).
Li, X. et al. Highly active enzyme–metal nanohybrids synthesized in protein–polymer conjugates. Nat. Catal. 2, 718–725 (2019).
Shugrue, C. R. & Miller, S. J. Applications of nonenzymatic catalysts to the alteration of natural products. Chem. Rev. 117, 11894–11951 (2017).
Acknowledgements
H.-J.X. and Y.H. acknowledge the National Natural Science Foundation of China (grant nos. 22001123 and 22178174), the Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture (grant no. XTC2206), the State Key Laboratory of Materials-Oriented Chemical Engineering (grant no. SKL-MCE-24B015) and Basic Research Program of Jiangsu (grant no. BK20233003). Z.F. acknowledges the Natural Science Foundation of Shanghai (grant no. 24ZR1430800) and start-up funding from Shanghai Jiao Tong University. We thank K. Wu for proofreading and providing helpful suggestions in preparing the manuscript.
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H.-J.X., B.-B.N., C.-H.G., S.-J.S. and W.Z. carried out the experimental investigations and data analyses. Z.F. conducted structural analysis of enzymes, proposed the mechanism and designed the oligopeptides. H.-J.X., Y.H. and Z.F. wrote the manuscript. J.-Q.Y. provided suggestions on the proposed mechanism. Y.H. directed the project.
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Xu, HJ., Fan, Z., Nian, BB. et al. Achieving mono-selective palladium(II)-catalysed C–H activation of arenes with protein ligands. Nat Catal 8, 948–956 (2025). https://doi.org/10.1038/s41929-025-01407-5
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DOI: https://doi.org/10.1038/s41929-025-01407-5
