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<p>The incorporation of three-dimensional small-ring scaffolds into bioactive molecules can enhance metabolic stability and solubility. Over the last decade, 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) have emerged as valuable bioisosteres for <i>para</i>-substituted benzene rings in drug discovery. However, BCP synthesis typically requires de novo synthesis from volatile [1.1.1]propellane, whereas more stable BCP reagents, such as alkyl BCP iodides, allow modification at only one end, limiting their application to end groups. Here we describe a stable, bifunctional iodobicyclo[1.1.1]pentylmethyl thianthrenium (IBM-TT<sup>+</sup>) reagent for modular BCP bioisostere production. The cationic thianthrenium group at the neopentyl site of IBM-TT<sup>+</sup> facilitates chemoselective substitutions through electrostatic interactions, overcoming the high energy barriers of bimolecular nucleophilic substitution (S<sub>N</sub>2) at neopentyl sites. The retained BCP iodide functionality serves as a second versatile handle for metal–halogen exchange, photoredox chemistry or transition-metal catalysis. The dual reactivity of IBM-TT<sup>+</sup> allows synthesis of a multitude of BCP bioisosteres for benzyl amines, ethers, esters, thioethers and diarylmethanes.</p><p></p>

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Thianthrenium-enabled modular synthesis of bicyclo[1.1.1]pentanes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月4日

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  • Zibo Bai,
  • Zikuan Wang,
  • Thomas Hin-Fung Wong,
  • Tobias Ritter

摘要

The incorporation of three-dimensional small-ring scaffolds into bioactive molecules can enhance metabolic stability and solubility. Over the last decade, 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) have emerged as valuable bioisosteres for para-substituted benzene rings in drug discovery. However, BCP synthesis typically requires de novo synthesis from volatile [1.1.1]propellane, whereas more stable BCP reagents, such as alkyl BCP iodides, allow modification at only one end, limiting their application to end groups. Here we describe a stable, bifunctional iodobicyclo[1.1.1]pentylmethyl thianthrenium (IBM-TT+) reagent for modular BCP bioisostere production. The cationic thianthrenium group at the neopentyl site of IBM-TT+ facilitates chemoselective substitutions through electrostatic interactions, overcoming the high energy barriers of bimolecular nucleophilic substitution (SN2) at neopentyl sites. The retained BCP iodide functionality serves as a second versatile handle for metal–halogen exchange, photoredox chemistry or transition-metal catalysis. The dual reactivity of IBM-TT+ allows synthesis of a multitude of BCP bioisosteres for benzyl amines, ethers, esters, thioethers and diarylmethanes.