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Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides
Nature Chemistry ( IF 19.2 ) Pub Date : 2022-01-27 , DOI: 10.1038/s41557-021-00856-2
Juan J Rojas 1 , Rosemary A Croft 1 , Alistair J Sterling 2 , Edward L Briggs 1 , Daniele Antermite 1 , Daniel C Schmitt 3 , Luka Blagojevic 1 , Peter Haycock 1 , Andrew J P White 1 , Fernanda Duarte 2 , Chulho Choi 3 , James J Mousseau 3 , James A Bull 1
Affiliation  

Bioisosteres provide valuable design elements that medicinal chemists can use to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides—extremely common pharmacophores—but are rarely examined due to the lack of available synthetic methods. Here we describe a class of reactions for sulfonyl fluorides to form amino-oxetanes by an alternative pathway to the established SuFEx (sulfonyl–fluoride exchange) click reactivity. A defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared. Kinetic and computational studies support the formation of an oxetane carbocation as the rate-determining step, followed by a chemoselective nucleophile coupling step.



中文翻译:

通过磺酰氟的替代脱氟磺酰偶联作为酰胺等排体的氨基氧杂环丁烷

生物等排体提供了有价值的设计元素,药物化学家可以使用这些元素将生物活性化合物的结构和药代动力学特征调整为可行的候选药物。芳基氧杂环丁胺作为苯甲酰胺(非常常见的药效团)的生物等排体具有令人兴奋的潜力,但由于缺乏可用的合成方法而很少被检查。在这里,我们描述了磺酰氟通过已建立的 SuFEx(磺酰氟交换)点击反应性的替代途径形成氨基氧杂环丁烷的一类反应。脱氟磺酰化仅在加热时形成平面氧杂环丁烷碳正离子。这种断开与典型的酰胺化相当,将允许应用大量现有的胺库。该反应对多种极性官能团具有耐受性,适用于阵列形式。制备了十种具有生物活性的苯甲酰胺和已上市药物的氧杂环丁烷类似物。动力学和计算研究支持氧杂环丁烷碳正离子的形成作为速率决定步骤,然后是化学选择性亲核偶联步骤。

更新日期:2022-01-27
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