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Dynamic radical recombination enabling stereodivergent construction of spirocycles with nonadjacent stereocenters

Author

Listed:
  • Zheng Sun

    (Yunnan University)

  • Jichao Huang

    (Central China Normal University)

  • Jiangtao Ren

    (Yunnan University
    Southwest United Graduate School)

  • Kaixin Zhao

    (Yunnan University)

  • Xixiang Chen

    (Shanghai University of Traditional Chinese Medicine)

  • Jing Liang

    (Yunnan University)

  • Yifan Li

    (Yunnan University)

  • Fangzhi Peng

    (Yunnan University)

  • Yi Jin

    (Yunnan University)

  • Yingqing Ou

    (National University of Singapore)

  • Jianrong Xu

    (Shanghai University of Traditional Chinese Medicine)

  • Zhihan Zhang

    (Central China Normal University)

  • Zhihui Shao

    (Yunnan University
    Southwest United Graduate School)

Abstract

Chiral spirocyclic scaffolds have garnered significant attention in drug discovery and chiral ligand development due to their rigid structures and potential bioactive properties, yet stereodivergent synthesis of such systems, particularly those bearing non-adjacent stereocenters, remains a formidable challenge. Herein, we report a dynamic radical recombination (DRR) strategy that enables cobalt-hydride-catalyzed ligand-controlled stereodivergent olefin hydroalkylation, delivering a series of spirocyclic compounds bearing 1,3-non-adjacent stereocenters with up to >99:1 er and >20:1 dr. Density functional theory (DFT) calculations reveal that different ligands induce distinct reaction mechanism, resulting in diastereoselectivity reversal through dynamic radical recombination pathway. Biological evaluations demonstrate that selected newly synthesized spirocyclic products markedly suppress lipopolysaccharide (LPS)-induced neuroinflammation in microglial cells, effectively reducing pro-inflammatory cytokine levels (TNF-α, IL-6, IL-1β) and restoring cells to pre-inflammatory states.

Suggested Citation

  • Zheng Sun & Jichao Huang & Jiangtao Ren & Kaixin Zhao & Xixiang Chen & Jing Liang & Yifan Li & Fangzhi Peng & Yi Jin & Yingqing Ou & Jianrong Xu & Zhihan Zhang & Zhihui Shao, 2025. "Dynamic radical recombination enabling stereodivergent construction of spirocycles with nonadjacent stereocenters," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64491-y
    DOI: 10.1038/s41467-025-64491-y
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    References listed on IDEAS

    as
    1. Yu-Hua Wen & Zi-Jing Zhang & Shuai Li & Jin Song & Liu-Zhu Gong, 2022. "Stereodivergent propargylic alkylation of enals via cooperative NHC and copper catalysis," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Mao-Mao Zhang & Ya-Ni Wang & Bao-Cheng Wang & Xiao-Wang Chen & Liang-Qiu Lu & Wen-Jing Xiao, 2019. "Synergetic iridium and amine catalysis enables asymmetric [4+2] cycloadditions of vinyl aminoalcohols with carbonyls," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
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