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Regio- and enantioselective remote dioxygenation of internal alkenes

Nature Chemistry volume 15, pages 862–871 (2023)Cite this article

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Abstract

Methods for the enantioselective direct oxygenation of internal alkenes have provided chemists with versatile and powerful toolboxes for the synthesis of optically pure alcohols, one of the most privileged structural motifs. Regioselectivity, however, remains a formidable challenge in the functionalization of internal alkenes. Here we report a palladium-catalysed highly regio- and enantioselective remote 1,n-dioxygenation (n ≥ 4) of internal alkenes with engineered pyridine-oxazoline (Pyox) ligands. The reactions proceed efficiently and exhibit a broad substrate scope with excellent regio- and enantioselectivity, affording optically pure 1,n-diol acetates as the key synthons for important bioactive molecules. Experimental studies and density functional theory calculations provide evidence that the regioselectivity is governed by the reactivity disparity of two allylic C–H bonds, where the oxypalladation is reversible and the first palladium migration step proves to be the regioselectivity-determining step, enabled by the modified phenyl-substituted Pyox ligands.

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Fig. 1: Selective functionalization of internal alkenes (using 2-pentene as a representative substrate).
Fig. 2: Regio- and enantioselective 1,n-dioxygenation of internal alkenes.
Fig. 3: Mechanistic investigation.
Fig. 4: Key results from the DFT calculations.
Fig. 5: Synthetic applications.

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Data availability

The experiments and DFT calculation data supporting the findings of this study are available in this article and its Supplementary Information. Crystallographic data for structures 23a and 70a have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. CCDC 2201049 and 2127361. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. The DFT calculations on the regioselective and enantioselective remote dioxygenation of internal alkenes are available at https://doi.org/10.6084/m9.figshare.21655823.

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Acknowledgements

Financial support was provided by the National Key R&D Program of China (2021YFA1500100), the National Natural Science Foundation of China (grants nos. 91956202, 22171279, 92256301 and 21821002), the Science and Technology Commission of Shanghai Municipality (grants 20JC1417000, 21520780100 and 19590750400), the International Partnership Program (121731KYSB20190016) and the Youth Innovation Promotion Association of Chinese Academy of Sciences (no. Y2022074) of the Chinese Academy of Sciences, and the Research Grants Council of Hong Kong (HKUST 16300620 and 16300021 to Z.L.). Xiaonan Li thanks Q. Yue for his assistance regarding the preparation of some alkene substrates. G.L. thanks H. Guan at the University of Cincinnati and F. Wang at Nankai University for helpful and insightful discussions. G.L. dedicates this work to the memory of Prof. Xiyan Lu.

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Author notes

  1. These authors contributed equally: Xiaonan Li, Tilong Yang.

Authors and Affiliations

  1. State Key Laboratory of Organometallic Chemistry and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Xiaonan Li, Jiayuan Li, Xiang Li, Pinhong Chen & Guosheng Liu

  2. Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

    Tilong Yang & Zhenyang Lin

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Contributions

Xiaonan Li, J.L. and G.L. conceived the work and designed the experiments. Xiaonan Li performed most laboratory experiments. J.L. and Xiang Li contributed to the experiments. T.Y. and Z.L. conducted DFT calculations. Xiaonan Li, P.C., Z.L. and G.L. analysed the data and wrote the manuscript.

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Correspondence to Zhenyang Lin or Guosheng Liu.

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Extended data

Extended Data Fig. 1 Stereochemistry of oxypalladation.

a, The ARD reactions of Z-1au-d2 with no observation of deuterium migration. Reaction conditions: (a) K2CO3 (2 equiv.), MeOH, 25 °C; (b) Cu(CH3CN)4OTf, bpy, TEMPO, NMI, MeCN, 25 °C. b, The X-ray of 70a.

Supplementary information

Supplementary Information

Supplementary Tables 1–3, Figs. 1–21, methods, mechanism experiments, data and references.

Supplementary Data 1

Crystallographic data for compound (1R,2S,4R)-23a; CCDC reference 2201049.

Supplementary Data 2

Crystallographic data for compound 70a; CCDC reference 2127361.

Supplementary Data 3

Cartesian coordinates of DFT-optimized structures.

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Li, X., Yang, T., Li, J. et al. Regio- and enantioselective remote dioxygenation of internal alkenes. Nat. Chem. 15, 862–871 (2023). https://doi.org/10.1038/s41557-023-01192-3

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