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Nickel-catalysed asymmetric heteroarylative cyclotelomerization of isoprene

Nature Catalysis volume 5, pages 708–715 (2022)Cite this article

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Abstract

Monoterpenoids are a class of isoprenoids produced from geranyl diphosphate by various monoterpene synthases. Nature has evolved over millions of years to produce various cyclic monoterpenoids. Herein, we present a serendipitous creation of an unnatural monoterpene skeleton through heteroarylative telomerization of isoprene with heterocycles. Under nickel catalysis, a series of cyclic monoterpene derivatives bearing quaternary carbon stereocentre are constructed with up to 98% yield and 97% enantiomeric excess. Preliminary mechanistic studies suggest this atom-economic reaction proceeds through an enantioselective dimerization of isoprene and a sequential C–H alkylation of heterocycles pathway. This work not only contributes an efficient enantioselective transformation of bulk chemical isoprene, but also provides a guide to create an unnatural monoterpene framework that may exhibit different biological activities.

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Fig. 1: Catalytic synthesis of monoterpenoids.
Fig. 2: Substrate scope of purines, adenines and imidazoles.
Fig. 3: Substrate scope of other conjugated dienes and transformation of chiral telomers.
Fig. 4: Proposed mechanism and calculated transition states.
Fig. 5: Mechanistic studies.

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Data availability

Data relating to the characterization data of materials and products, general methods, optimization studies, experimental procedures, mechanistic studies, mass spectrometry, high-performance liquid chromatography, NMR spectra and computational studies are available in the Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2127531 (3a). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We thank Y.-G. Zhou (Dalian Institute of Chemical Physics) and Z.-S. Ye (Dalian University of Technology) for helpful discussions and manuscript revisions. Financial support from Dalian Institute of Chemical Physics (grant no. DICPI201902), Dalian Outstanding Young Scientific Talent (grant no. 2020RJ05) and the National Natural Science Foundation of China (grant no. 22071239) is acknowledged.

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Authors and Affiliations

  1. Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China

    Gong Zhang, Chao-Yang Zhao, Xiang-Ting Min, Ying Li, Xiang-Xin Zhang, Heng Liu, Ding-Wei Ji, Yan-Cheng Hu & Qing-An Chen

  2. University of Chinese Academy of Sciences, Beijing, China

    Gong Zhang, Chao-Yang Zhao, Ying Li, Xiang-Xin Zhang, Heng Liu & Qing-An Chen

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Contributions

Q.-A.C. conceived and supervised the project. Q.-A.C. and G.Z. designed the experiments. G.Z., C.-Y.Z., X.-T.M., Y.L., X.-X.Z., H.L., D.-W.J. and Y.-C.H. performed the experiments and analysed the data. All authors discussed the results and commented on the manuscript.

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Correspondence to Qing-An Chen.

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Nature Catalysis thanks Mengchun Ye, Wei Guan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–7, Tables 1–10, Methods, Discussions, References and Copies of NMR and HPLC for products.

Supplementary Data 1

Compound 3a.

Supplementary Data 2

Structure factor of 3a.

Supplementary Data 3

Computational data.

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Zhang, G., Zhao, CY., Min, XT. et al. Nickel-catalysed asymmetric heteroarylative cyclotelomerization of isoprene. Nat Catal 5, 708–715 (2022). https://doi.org/10.1038/s41929-022-00825-z

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