Skeletal editing through direct nitrogen deletion of secondary amines
Skeletal editing through direct nitrogen deletion of secondary amines
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DOI：
10.1038/s41586-021-03448-9
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发表时间：
2021-05-13
期刊：
影响因子：
64.8
通讯作者：
Levin, Mark D.
中科院分区：
文献类型：
--
作者：
Kennedy, Sean H.;Dherange, Balu D.;Levin, Mark D.
使用端基酰胺试剂从仲胺中“删除”氮，该试剂与胺反应形成异二氮烯，然后释放氮气，所得碳自由基结合形成碳-碳键。合成化学旨在从简单原料构建分子复杂性(1)。然而，尽管具有扩展可及化学空间的巨大潜力，但施加精确改变来操纵分子骨架本身的连接性的能力仍然有限(2,3)。在这里，我们报告了一种从有机分子中“删除”氮的反应。我们发现，N-新戊酰氧基-N-烷氧基酰胺（异头酰胺的一个亚类）可促进脂肪族仲胺的分子间活化，产生分子内碳-碳偶联产物。机理实验表明，反应通过异二氮烯中间体进行，异二氮烯中间体将氮原子挤出为二氮，产生短寿命的双自由基，迅速偶联形成新的碳-碳键。该反应表现出广泛的官能团耐受性，这使得常规胺合成方案能够转化为碳-碳键构建和环合成策略。在生物活性化合物的合成和骨架编辑中使用该反应突出了这一点。
Nitrogen is 'deleted' from secondary amines using anomeric amide reagents, which react with the amine to form an isodiazene, after which nitrogen gas is released and the resulting carbon radicals combine to form a carbon-carbon bond.Synthetic chemistry aims to build up molecular complexity from simple feedstocks(1). However, the ability to exert precise changes that manipulate the connectivity of the molecular skeleton itself remains limited, despite possessing substantial potential to expand the accessible chemical space(2,3). Here we report a reaction that 'deletes' nitrogen from organic molecules. We show that N-pivaloyloxy-N-alkoxyamides, a subclass of anomeric amides, promote the intermolecular activation of secondary aliphatic amines to yield intramolecular carbon-carbon coupling products. Mechanistic experiments indicate that the reactions proceed via isodiazene intermediates that extrude the nitrogen atom as dinitrogen, producing short-lived diradicals that rapidly couple to form the new carbon-carbon bond. The reaction shows broad functional-group tolerance, which enables the translation of routine amine synthesis protocols into a strategy for carbon-carbon bond constructions and ring syntheses. This is highlighted by the use of this reaction in the syntheses and skeletal editing of bioactive compounds.