Medium-Sized-Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion
Medium-Sized-Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion
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通过构象诱导微笑环扩展得到二苯二氮卓类药物的中型环类似物
DOI：
10.1002/ange.201708991
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发表时间：
2017
影响因子：
--
通讯作者：
Costil R
中科院分区：
文献类型：
--
作者：
Costil R
二苯并二氮杂卓的类似物，其中七元氮杂环被9-12元环取代，通过五至八元杂环邻氨基苯甲酰胺的未活化的Smiles重排制备。起始材料中叔酰胺的构象偏好导致一系列芳环的分子内迁移，即使是那些缺乏吸电子活化基团的芳环，并提供了n →n+4扩环的方法。中环产物采用具有分子内跨环氢键的手性基态。它们的对映体构象的相互转化率取决于溶剂的极性。环的大小和相邻的空间位阻调节这种隐藏的亲水性，从而使这种支架成为药物开发的良好候选者。
Analogues of dibenzodiazepines, in which the seven‐membered nitrogen heterocycle is replaced by a 9–12‐membered ring, were made by an unactivated Smiles rearrangement of five‐ to eight‐membered heterocyclic anthranilamides. The conformational preference of the tertiary amide in the starting material leads to intramolecular migration of a range of aryl rings, even those lacking electron‐withdrawing activating groups, and provides a method forn→n+4 ring expansion. The medium‐ring products adopt a chiral ground state with an intramolecular, transannular hydrogen bond. The rate of interconversion of their enantiomeric conformers depends on solvent polarity. Ring size and adjacent steric hindrance modulate this hidden hydrophilicity, thus making this scaffold a good candidate for drug development.