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Kinetic resolution of planar chiral metallocenes using Rh-catalysed enantioselective C–H arylation

Nature Synthesis volume 2, pages 49–57 (2023)Cite this article

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Abstract

Planar chiral metallocenes have found application in the fields of asymmetric catalysis, medicinal chemistry and materials science. Asymmetric C–H functionalisation provides an efficient synthetic route to substituted chiral metallocenes. However, these methods are often limited by the metallocene substitution patterns they can access. Here, we report a Rh-catalysed asymmetric C–H arylation of 1,2-disubstituted and 1,3-disubstituted pyridyl ferrocenes. Pre-installation of substituents at either the 2- or 3-position of the pyridyl ferrocenes enables this kinetic resolution process to provide access to enantio-enriched 1,2-disubstituted and 1,3-disubstituted metallocenes, and their corresponding C–H arylated products, in excellent enantioselectivity, with selectivity factor values up to 618. This process is able to tolerate a broad range of pre-installed functional groups, such as alkyl, alkenyl, aryl, silyl, thio and fluoro, as well as substitution on the 1′-cyclopentadienyl ring. The utility of the process has been shown through synthesis and examination of chiral ferrocene ligands.

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Fig. 1: The methods for synthesizing planar chiral metallocenes.
Fig. 2: Reaction scale-up, product synthetic utility and reaction monitoring.

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Data availability

All data relating to the experimental procedures, optimisation studies and characterisation of the new compounds are included in the Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2119566 (7ca). Copies of the CCDC data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We thank the National Key R&D Program of China (2021YFA1500100), NSFC (21821002, 91856201, 22071260) and Science and Technology Commission of Shanghai Municipality (19590750400, 21520780100). S.-L.Y. acknowledges support from the Tencent Foundation through the Xplorer Prize.

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Authors and Affiliations

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

    Chen-Xu Liu, Fangnuo Zhao, Zuolijun Feng, Quannan Wang, Qing Gu & Shu-Li You

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Contributions

S.-L.Y. conceived the work and designed the experiments. C.-X.L. conducted the experiments. C.-X.L., F.Z., Z.F. and Q.W. synthesised and characterised the substrates. C.-X.L., Q.G. and S.-L.Y. wrote the manuscript.

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Correspondence to Shu-Li You.

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Nature Synthesis thanks Zhong Jin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary Information

Supplementary Discussion.

Supplementary Data 1

Crystallographic data for 7ca; CCDC reference 2119566.

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Liu, CX., Zhao, F., Feng, Z. et al. Kinetic resolution of planar chiral metallocenes using Rh-catalysed enantioselective C–H arylation. Nat. Synth 2, 49–57 (2023). https://doi.org/10.1038/s44160-022-00177-3

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