The ortho-substituted phenyl ring is a basic structural element in chemistry. It is found in more than three hundred drugs and agrochemicals. During the past decade, scientists have tried to replace the phenyl ring in bioactive compounds with saturated bioisosteres to obtain novel patentable structures. However, most of the research in this area has been devoted to the replacement of the para-substituted phenyl ring. Here we have developed saturated bioisosteres of the ortho-substituted phenyl ring with improved physicochemical properties: 2-oxabicyclo[2.1.1]hexanes. Crystallographic analysis revealed that these structures and the ortho-substituted phenyl ring indeed have similar geometric properties. Replacement of the phenyl ring in marketed agrochemicals fluxapyroxad (BASF) and boscalid (BASF) with 2-oxabicyclo[2.1.1]hexanes dramatically improved their water solubility, reduced lipophilicity and most importantly retained bioactivity. This work suggests an opportunity for chemists to replace the ortho-substituted phenyl ring in bioactive compounds with saturated bioisosteres in medicinal chemistry and agrochemistry.

邻位取代的苯环是化学中的基本结构元素。它存在于三百多种药物和农用化学品中。在过去的十年中，科学家们尝试用饱和生物等排体取代生物活性化合物中的苯环，以获得新颖的可专利结构。然而，该领域的大部分研究都致力于对位取代苯环的取代。在这里，我们开发了具有改进的物理化学性质的邻位取代苯环的饱和生物等排体：2-氧杂双环[2.1.1]己烷。晶体学分析表明这些结构和邻位取代的苯环确实具有相似的几何性质。用 2-氧杂双环[2.1.1]己烷取代市售农用化学品 Fluxapyroxad (BASF) 和啶酰菌胺 (BASF) 中的苯环，显着提高了它们的水溶性，降低了亲脂性，最重要的是保留了生物活性。这项工作为化学家提供了在药物化学和农业化学中用饱和生物等排体取代生物活性化合物中的邻位取代苯环的机会。