The phenyl ring is a basic structural element in chemistry. Here, we show the design, synthesis, and validation of its new saturated bioisostere with improved physicochemical properties − 2-oxabicyclo[2.2.2]octane. The design of the structure is based on the analysis of the advantages and disadvantages of the previously used bioisosteres: bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, and cubane. The key synthesis step is the iodocyclization of cyclohexane-containing alkenyl alcohols with molecular iodine in acetonitrile. 2-Oxabicyclo[2.2.2]octane core is incorporated into the structure of Imatinib and Vorinostat (SAHA) drugs instead of the phenyl ring. In Imatinib, such replacement leads to improvement of physicochemical properties: increased water solubility, enhanced metabolic stability, and reduced lipophilicity. In Vorinostat, such replacement results in a new bioactive analog of the drug. This study enhances the repertoire of available saturated bioisosteres of (hetero)aromatic rings for the use in drug discovery projects.

苯环是化学中的基本结构元素。在这里，我们展示了具有改进的物理化学性质的新型饱和生物等排体——2-氧杂双环[2.2.2]辛烷的设计、合成和验证。结构的设计基于对先前使用的生物等排体的优缺点的分析：双环[1.1.1]戊烷、双环[2.2.2]辛烷和立方烷。关键的合成步骤是含环己烷的烯醇与分子碘在乙腈中的碘环化。2-氧杂双环[2.2.2]辛烷核心取代苯环被纳入伊马替尼和伏立诺他（SAHA）药物的结构中。在伊马替尼中，这种替代导致理化性质的改善：增加水溶性、增强代谢稳定性和降低亲脂性。在伏立诺他中，这种替代产生了该药物的新生物活性类似物。这项研究增强了（杂）芳香环的可用饱和生物电子等排体的库，用于药物发现项目。