Bioisosterism is a valuable principle exploited in drug discovery to fine-tune physicochemical properties of bioactive compounds. Functionalized 3-aryl oxetanes, as an important class of bioisosteres for benzoyl groups (highly prevalent structures in approved drugs), have been rarely utilized in agrochemicals and pharmaceuticals due to significant synthetic challenges. Here, we present a modular synthetic strategy based on the unexplored yet readily available reagents, oxetanyl trichloroacetimidates, inspired by Schmidt glycosylation, enabling easy access to a library of functionalized oxetanes. This operationally simple protocol leverages the vast existing libraries of aryl halides and various nucleophiles. The power and generality of this approach is demonstrated by late-stage functionalization of complex molecules, as well as the rapid synthesis of oxetane analogues of bioactive molecules and marketed drugs. Preliminary mechanistic study suggests that the oxygen atom in the oxetane ring plays a crucial role in stabilizing the carbocation intermediates.

中文翻译：

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模块化获得功能化氧杂环丁烷作为苯甲酰生物等排体


生物等排现象是药物发现中用于微调生物活性化合物的理化性质的重要原理。官能化 3-芳基氧杂环丁烷作为苯甲酰基（已批准药物中高度普遍的结构）的一类重要的生物电子等排体，由于重大的合成挑战，很少在农用化学品和药品中使用。在这里，我们提出了一种基于未探索但容易获得的试剂氧杂环丁烷基三氯乙酰亚胺酯的模块化合成策略，受施密特糖基化的启发，可以轻松访问功能化氧杂环丁烷库。这种操作简单的方案利用了现有的大量芳基卤化物和各种亲核试剂库。复杂分子的后期功能化以及生物活性分子和市售药物的氧杂环丁烷类似物的快速合成证明了这种方法的强大功能和通用性。初步机理研究表明氧杂环丁烷环中的氧原子在稳定碳阳离子中间体中起着至关重要的作用。