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Modular access to chiral bridged piperidine-γ-butyrolactones via catalytic asymmetric allylation/aza-Prins cyclization/lactonization sequences

Author

Listed:
  • Cong Fu

    (Wuhan University
    Nankai University)

  • Ling He

    (Wuhan University)

  • Hui Xu

    (Tianjin University)

  • Zongpeng Zhang

    (Wuhan University)

  • Xin Chang

    (Wuhan University)

  • Yanfeng Dang

    (Tianjin University)

  • Xiu-Qin Dong

    (Wuhan University)

  • Chun-Jiang Wang

    (Wuhan University
    Nankai University)

Abstract

Chiral functionalized piperidine and lactone heterocycles are widely spread in natural products and drug candidates with promising pharmacological properties. However, there remains no general asymmetric methodologies that enable rapid assemble both critical biologically important units into one three-dimensional chiral molecule. Herein, we describe a straightforward relay strategy for the construction of enantioenriched bridged piperidine-γ-butyrolactone skeletons incorporating three skipped stereocenters via asymmetric allylic alkylation and aza-Prins cyclization/lactonization sequences. The excellent enantioselectivity control in asymmetric allylation with the simplest allylic precursor is enabled by the synergistic Cu/Ir-catalyzed protocol; the success of aza-Prins cyclization/lactonization can be attributed to the pivotal role of the ester substituent, which acts as a preferential intramolecular nucleophile to terminate the aza-Prins intermediacy of piperid-4-yl cation species. The resulting chiral piperidine-γ-butyrolactone bridged-heterocyclic products show impressive preliminary biological activities against a panel of cancer cell lines.

Suggested Citation

  • Cong Fu & Ling He & Hui Xu & Zongpeng Zhang & Xin Chang & Yanfeng Dang & Xiu-Qin Dong & Chun-Jiang Wang, 2024. "Modular access to chiral bridged piperidine-γ-butyrolactones via catalytic asymmetric allylation/aza-Prins cyclization/lactonization sequences," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44336-2
    DOI: 10.1038/s41467-023-44336-2
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    References listed on IDEAS

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    1. Warren R.J.D. Galloway & Albert Isidro-Llobet & David R. Spring, 2010. "Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules," Nature Communications, Nature, vol. 1(1), pages 1-13, December.
    2. Liang Wei & Qiao Zhu & Lu Xiao & Hai-Yan Tao & Chun-Jiang Wang, 2019. "Synergistic catalysis for cascade allylation and 2-aza-cope rearrangement of azomethine ylides," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    3. Shi-Ming Xu & Liang Wei & Chong Shen & Lu Xiao & Hai-Yan Tao & Chun-Jiang Wang, 2019. "Stereodivergent assembly of tetrahydro-γ-carbolines via synergistic catalytic asymmetric cascade reaction," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    4. Thien Phuc Le & Shinji Tanaka & Masahiro Yoshimura & Kazuhiko Sato & Masato Kitamura, 2022. "Stereodivergent dehydrative allylation of β-keto esters using a Ru/Pd synergistic catalyst," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
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