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<p>Bridged-ring scaffolds are prevalent in numerous natural products and pharmaceuticals. However, achieving enantioselective construction of these architectures presents a significant challenge, due to the considerable structural strain of the products and the presence of multiple stereocenters. Herein, we report a Pd/Cu co-catalyzed substrate-dependent enantiodivergent tandem Heck/Sonogashira reaction for the synthesis of alkyne-tethered (<i>R</i>,<i>S</i>,<i>S</i>)-bicyclo[3.2.1]octenes and (<i>S</i>,<i>R</i>,<i>R</i>)-benzo-bicyclo[3.2.1]octanes, each featuring one quaternary and two adjacent tertiary stereocenters. Intramolecular cyclization of the resultant bridged-ring skeletons facilitates the stereospecific synthesis of rigid chiral tricyclodecanes and tetracyclotetradecanes. The alkene, alkyne and ester motifs within bicyclo[3.2.1]octenes and benzo-bicyclo[3.2.1]octanes enables a diverse of transformations, providing access to versatile bridged-ring compounds. Preliminary activity assays demonstrate that two of chiral bridged-ring compounds display good inhibitory effects on the cGAS-STING signaling pathway. Mechanistic studies and DFT calculations indicate that reductive elimination is the rate-determining step in tandem Heck/Sonogashira reaction. Furthermore, key factors responsible for the substrate-dependent enantiodivergence are elucidated through DFT calculations.</p>

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Catalytic asymmetric tandem Heck/Sonogashira reaction enabling access to versatile chiral bridged ring scaffolds

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Jing Zhong,
  • Mengxian Li,
  • Changhui Wu,
  • Hui Li,
  • Hongyue Dong,
  • Chunchen Che,
  • Aijun Lin,
  • Hequan Yao

摘要

Bridged-ring scaffolds are prevalent in numerous natural products and pharmaceuticals. However, achieving enantioselective construction of these architectures presents a significant challenge, due to the considerable structural strain of the products and the presence of multiple stereocenters. Herein, we report a Pd/Cu co-catalyzed substrate-dependent enantiodivergent tandem Heck/Sonogashira reaction for the synthesis of alkyne-tethered (R,S,S)-bicyclo[3.2.1]octenes and (S,R,R)-benzo-bicyclo[3.2.1]octanes, each featuring one quaternary and two adjacent tertiary stereocenters. Intramolecular cyclization of the resultant bridged-ring skeletons facilitates the stereospecific synthesis of rigid chiral tricyclodecanes and tetracyclotetradecanes. The alkene, alkyne and ester motifs within bicyclo[3.2.1]octenes and benzo-bicyclo[3.2.1]octanes enables a diverse of transformations, providing access to versatile bridged-ring compounds. Preliminary activity assays demonstrate that two of chiral bridged-ring compounds display good inhibitory effects on the cGAS-STING signaling pathway. Mechanistic studies and DFT calculations indicate that reductive elimination is the rate-determining step in tandem Heck/Sonogashira reaction. Furthermore, key factors responsible for the substrate-dependent enantiodivergence are elucidated through DFT calculations.