Xu M, Galindo-Murillo R, Cheatham T E, Franzini R M
Department of Medicinal Chemistry, College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT-84112, USA.
Org Biomol Chem. 2017 Nov 29;15(46):9855-9865. doi: 10.1039/c7ob02191g.
Bioorthogonal dissociative reactions boast diverse potential applications in chemical biology and drug delivery. The reaction of benzonorbornadienes with tetrazines to release amines from carbamate leaving groups was recently introduced as a bioorthogonal bond-cleavage reaction. The present study aimed at investigating the scope of leaving groups that are compatible with benzonorbornadienes. Synthesis of several benzonorbornadienes with different releasable groups is reported, and the reaction of these molecules with tetrazine was found to be rapid and afforded high release yields. The tetrazine-induced release of molecules proceeds in a cascade of steps including inverse-electron demand cycloaddition and cycloreversion reactions that form unstable isoindoles/isobenzofuran intermediates and spontaneously eliminate a leaving group of interest. In the case of oxygen-bridged BNBDs at room temperature, we observed the formation of an unproductive byproduct.
生物正交解离反应在化学生物学和药物递送领域具有多种潜在应用。最近，苯并降冰片二烯与四嗪反应从氨基甲酸酯离去基团释放胺的反应被引入作为一种生物正交键裂解反应。本研究旨在探究与苯并降冰片二烯兼容的离去基团的范围。报道了几种具有不同可释放基团的苯并降冰片二烯的合成，并且发现这些分子与四嗪的反应迅速且释放产率高。四嗪诱导的分子释放过程包括一系列步骤，包括逆电子需求环加成和环化逆转反应，形成不稳定的异吲哚/异苯并呋喃中间体，并自发消除目标离去基团。在室温下的氧桥联苯并降冰片二烯的情况下，我们观察到了非生产性副产物的形成。
