School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
Angew Chem Int Ed Engl. 2017 Nov 13;56(46):14602-14606. doi: 10.1002/anie.201708991. Epub 2017 Oct 16.
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 for n→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.
将含有 7 元氮杂环的二苯并氮杂䓬类似物替换为 9-12 元环，通过五至八元杂环邻苯二甲酰亚胺的未活化 Smiles 重排来实现。起始原料中叔酰胺的构象偏好导致一系列芳基环的分子内迁移，即使是那些缺乏吸电子活化基团的芳基环也能进行迁移，为 n→n+4 环扩展提供了一种方法。中环产物采用具有分子内反式环状氢键的手性基态。其对映异构体构象的互变异构速率取决于溶剂极性。环大小和相邻的空间位阻调节这种隐藏的亲水性，从而使该支架成为药物开发的良好候选物。
