Scholarlink

<p>A highly efficient metal and catalyst-free approach for the preparation of synthetically challenged <i>tri</i>-OMe-aryl-substituted heterocyclic, <i>di</i>-/<i>tri</i>-OMe-aryl-based cyclic and acyclic 1,2,4,5-tetraoxanes (<b>5a–l</b> and <b>6a–k</b>) is presented herein. Under green-chemistry conditions, the reactions occur in two key steps. The first one involves azeotropic activation of hydrogen peroxide for <i>N</i>-sulfonylpiperidone (<b>2a–f</b>), substituted cyclic and acyclic ketones (<b>2a</b><sub><b>1</b></sub><b>–a</b><sub><b>4</b></sub>) oxidation, whereas the second one was H<sup>+</sup>[BF<sub>4</sub>]ˉ (50–55% solun; 25&#xa0;mol%)-catalyzed cyclization of the highly reactive <i>gem</i>-dihydroperoxide (<b>3a–f</b> and <b>3a</b><sub><b>1</b></sub><b>–a</b><sub><b>4</b></sub>) intermediates in an SN<sub>1</sub>-type manner with secondary keto compounds (<b>4a–d</b>). Both reactions furnished a diverse array of heterocyclic, cyclic, and open-chain 1,2,4,5-tetraoxane analogues (<b>5a–l</b> and <b>6a–k</b>; 19–83%) in attainable yields. The outcomes of the control and competition experiment strongly indicate that the electronic effects of the EWGs group and the strong steric influence of the bulky <i>tri</i>-OMe-aryl group directly impacted reaction advancement. These effects were clearly observed in the reactivity of the substituted <i>N</i>-sulfonylpiperidones (<b>2a–f</b>) and <i>gem</i>-dihydroperoxides (<b>3a–f</b> and <b>3a</b><sub><b>1</b></sub><b>–a</b><sub><b>4</b></sub>), and finally, also in the construction of the final products (<b>5a–l</b> and <b>6a–k</b>). In addition, this metal-free approach is also suitable for the ‘one pot’ synthesis of structurally complex, highly substituted, pharmaceutically privileged <i>di</i>-/<i>tri</i>-OMe-aryl-based cyclic and acyclic 1,2,4,5-tetraoxanes (<b>6a–h</b> and <b>6k</b>), offering significant potential for synthetic advancements in malaria and cancer chemotherapy. Furthermore, in preliminary biological evaluations, the in vitro antiplasmodial and cytotoxic potentials of novel <i>tri</i>-OMe-aryl-substituted <i>N</i>-sulfonylpiperidine-spiro-1,2,4,5-tetraoxanes (<b>5a–l</b>) were established against the chloroquine-resistant FcB1 strain of <i>Plasmodium falciparum</i> and human cancer cell lines, including HeLa and A2780 cells.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Efficient and metal catalyst-free approach towards highly-substituted N-sulfonylpiperidine-/mono-spiro-1,2,4,5-tetraoxanes for potential applications in chemotherapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月25日

查看全文
  • Mohit K. Tiwari,
  • Malgorzata Kucinska,
  • Agnieszka Zgoła-Grześkowiak,
  • Philippe Grellier,
  • Marek Murias,
  • Łukasz Marczak,
  • Lukasz Popenda,
  • Tomasz Goslinski

摘要

A highly efficient metal and catalyst-free approach for the preparation of synthetically challenged tri-OMe-aryl-substituted heterocyclic, di-/tri-OMe-aryl-based cyclic and acyclic 1,2,4,5-tetraoxanes (5a–l and 6a–k) is presented herein. Under green-chemistry conditions, the reactions occur in two key steps. The first one involves azeotropic activation of hydrogen peroxide for N-sulfonylpiperidone (2a–f), substituted cyclic and acyclic ketones (2a1–a4) oxidation, whereas the second one was H+[BF4]ˉ (50–55% solun; 25 mol%)-catalyzed cyclization of the highly reactive gem-dihydroperoxide (3a–f and 3a1–a4) intermediates in an SN1-type manner with secondary keto compounds (4a–d). Both reactions furnished a diverse array of heterocyclic, cyclic, and open-chain 1,2,4,5-tetraoxane analogues (5a–l and 6a–k; 19–83%) in attainable yields. The outcomes of the control and competition experiment strongly indicate that the electronic effects of the EWGs group and the strong steric influence of the bulky tri-OMe-aryl group directly impacted reaction advancement. These effects were clearly observed in the reactivity of the substituted N-sulfonylpiperidones (2a–f) and gem-dihydroperoxides (3a–f and 3a1–a4), and finally, also in the construction of the final products (5a–l and 6a–k). In addition, this metal-free approach is also suitable for the ‘one pot’ synthesis of structurally complex, highly substituted, pharmaceutically privileged di-/tri-OMe-aryl-based cyclic and acyclic 1,2,4,5-tetraoxanes (6a–h and 6k), offering significant potential for synthetic advancements in malaria and cancer chemotherapy. Furthermore, in preliminary biological evaluations, the in vitro antiplasmodial and cytotoxic potentials of novel tri-OMe-aryl-substituted N-sulfonylpiperidine-spiro-1,2,4,5-tetraoxanes (5a–l) were established against the chloroquine-resistant FcB1 strain of Plasmodium falciparum and human cancer cell lines, including HeLa and A2780 cells.