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Synthesis of planar chiral ferrocenes via enantioselective remote C–H activation

Nature Chemistry volume 15, pages 815–823 (2023)Cite this article

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Abstract

Planar chiral ferrocenes are widely studied structures in asymmetric catalysis, materials science and medicinal chemistry. Although synthetic methods for 1,2-disubstituted planar chiral ferrocenes are well known, methods for the direct construction of 1,3-disubstituted planar chiral ferrocenes remain elusive. Here we report a modular platform for the construction of planar chirality in 1,3-disubstituted ferrocenes/ruthenocenes via an enantioselective relay remote C–H activation strategy. This method demonstrates a mechanism for remote enantiocontrol via enantiodetermining initial C‒H activation at the C2 position, enabled by a chiral mono-N-protected natural amino-acid ligand, and subsequent relay to the remote C3 position by a bridgehead-substituted norbornene mediator. A wide variety of 1,3-disubstituted planar chiral metallocenes are prepared with high enantioselectivity (96‒99% e.e.). The reaction shows good functional-group tolerance and high step-economy, and aryl iodides/bromides are compatible as coupling partners. The resulting metallocenes can be readily derivatized to yield planar chiral ligands and catalysts for asymmetric catalysis as well as building blocks for other applications.

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Fig. 1: Strategies to access planar chiral ferrocenes.
Fig. 2: Proposed reaction mechanism and initial investigation.
Fig. 3: Transformations of products and applications.
Fig. 4: Preliminary mechanistic studies.

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Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. CCDC 2116139 (3a-2), 2117209 (3b) and 2116140 (8). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other characterization data and detailed experimental procedures are available in the Supplementary Information.

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Acknowledgements

This paper is dedicated to the 130th anniversary of Wuhan University. We thank H. Cong (WHU), X.-G. Meng (CCNU) and Y.-Q. Zhou (SCU) for X-ray crystallographic analysis assistance. We gratefully acknowledge D. Ma (SIOC), L.-Q. Lu (CCNU), W.-B. Liu, G. Yin and Q. Lu (WHU) for helpful discussions, X. Qi (WHU) for calculation studies, W. Reid (J-STAR Research Inc.) for assistance with the preparation of the manuscript and H. Li (ZMU) for technical assistance. This work was supported by the National Key Research and Development Program of China (no. 2022YFA1503703), National Natural Science Foundation of China (nos. 21801193, 21871213 and 22071189), Natural Science Foundation of Jiangsu Province (grant no. BK20210119, H.-G.C.), the Fundamental Research Funds for the Central Universities (2042021kf0214 and 2042020kf0039) and start-up funding from Wuhan University.

Author information

Author notes

  1. These authors contributed equally: Lan Zhou, Hong-Gang Cheng.

Authors and Affiliations

  1. Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education), Hubei Key Lab on Organic and Polymeric OptoElectronic Materials, College of Chemistry and Molecular Sciences, The Institute for Advanced Studies, and TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, P. R. China

    Lan Zhou, Hong-Gang Cheng, Lisha Li, Jing Hou, Chengkang Jiao, Shuang Deng, Zirui Liu & Qianghui Zhou

  2. Suzhou Institute of Wuhan University, Suzhou, Jiangsu, P. R. China

    Hong-Gang Cheng

  3. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA

    Kevin Wu & Jin-Quan Yu

  4. State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, P. R. China

    Qianghui Zhou

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Contributions

L.Z., L.L., J.H., C.J. and Z.L. prepared the substrates and NBE mediators, performed the reaction optimization, substrate scope exploration and synthetic applications under the supervision of H.-G.C., J.-Q.Y. and Q.Z. S.D. performed the density functional theory calculations. H.-G.C., K.W., J.-Q.Y. and Q.Z. co-wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Hong-Gang Cheng, Jin-Quan Yu or Qianghui Zhou.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–9 and Tables 1–11.

Supplementary Data 1

Crystallographic data for compound 3a-2. CCDC reference 2116139.

Supplementary Data 2

Crystallographic data for compound 3b. CCDC reference 2117209.

Supplementary Data 3

Crystallographic data for compound 8. CCDC reference 2116140.

Supplementary Data 4

Cartesian coordinates (Å) and energies of optimized structures.

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Zhou, L., Cheng, HG., Li, L. et al. Synthesis of planar chiral ferrocenes via enantioselective remote C–H activation. Nat. Chem. 15, 815–823 (2023). https://doi.org/10.1038/s41557-023-01176-3

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