School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
Angew Chem Int Ed Engl. 2022 Jan 17;61(3):e202114235. doi: 10.1002/anie.202114235. Epub 2021 Dec 3.
The identification of spiro N-heterocycles as scaffolds that display structural novelty, three-dimensionality, beneficial physicochemical properties, and enable the controlled spatial disposition of substituents has led to a surge of interest in utilizing these compounds in drug discovery programs. Herein, we report the strain-release-driven Friedel-Crafts spirocyclization of azabicyclo[1.1.0]butane-tethered (hetero)aryls for the synthesis of a unique library of azetidine spiro-tetralins. The reaction was discovered to proceed through an unexpected interrupted Friedel-Crafts mechanism, generating a highly complex azabicyclo[2.1.1]hexane scaffold. This dearomatized intermediate, formed exclusively as a single diastereomer, can be subsequently converted to the Friedel-Crafts product upon electrophilic activation of the tertiary amine, or trapped as a Diels-Alder adduct in one-pot. The rapid assembly of molecular complexity demonstrated in these reactions highlights the potential of the strain-release-driven spirocyclization strategy to be utilized in the synthesis of medicinally relevant scaffolds.
螺环 N-杂环作为具有结构新颖性、三维性、有益的物理化学性质的支架被识别，并且能够控制取代基的空间排布，这导致了在药物发现计划中利用这些化合物的兴趣激增。在此，我们报告了氮杂双环[1.1.0]丁烷键合（杂）芳基的应变释放驱动的 Friedel-Crafts 螺环化，用于合成独特的氮杂环丁烷螺四氢萘文库。该反应被发现通过一种意想不到的中断 Friedel-Crafts 机制进行，生成了高度复杂的氮杂双环[2.1.1]己烷支架。这种去芳构化的中间体仅作为单一非对映异构体形成，可以在三级胺的亲电活化后转化为 Friedel-Crafts 产物，或者在一锅法中作为 Diels-Alder 加合物捕获。这些反应中展示的分子复杂性的快速组装突出了应变释放驱动的螺环化策略在合成具有药用相关性的支架中的潜在应用。
