Department of Chemistry , State University of New York at Buffalo , Buffalo , New York 14260-3000 , United States.
Department of Chemistry , University of Pittsburgh , Pittsburgh , Pennsylvania 15260 , United States.
J Am Chem Soc. 2018 Apr 11;140(14):4860-4868. doi: 10.1021/jacs.8b00126. Epub 2018 Apr 2.
In pursuit of fast bioorthogonal reactions, reactive moieties have been increasingly employed for selective labeling of biomolecules in living systems, posing a challenge in attaining reactivity without sacrificing selectivity. To address this challenge, here we report a bioinspired strategy in which molecular shape controls the selectivity of a transient, highly reactive nitrile imine dipole. By tuning the shape of structural pendants attached to the ortho position of the N-aryl ring of diaryltetrazoles-precursors of nitrile imines, we discovered a sterically shielded nitrile imine that favors the 1,3-dipolar cycloaddition over the competing nucleophilic addition. The photogenerated nitrile imine exhibits an extraordinarily long half-life of 102 s in aqueous medium, owing to its unique molecular shape that hinders the approach of a nucleophile as shown by DFT calculations. The utility of this sterically shielded nitrile imine in rapid (∼1 min) bioorthogonal labeling of glucagon receptor in live mammalian cells was demonstrated.
为了追求快速的生物正交反应，反应性基团越来越多地被用于在活细胞体系中选择性标记生物分子，这对反应性和选择性提出了挑战。为了解决这一挑战，我们在这里报告了一种受生物启发的策略，其中分子形状控制瞬态、高反应性的腈亚胺偶极子的选择性。通过调节二芳基四唑的 N-芳基环邻位上连接的结构侧链的形状——腈亚胺的前体，我们发现了一种空间位阻的腈亚胺，它有利于 1,3-偶极环加成反应而不是竞争的亲核加成反应。光生成的腈亚胺在水介质中具有非常长的半衰期（102 秒），这归因于其独特的分子形状，DFT 计算表明，这种形状阻碍了亲核试剂的接近。这种空间位阻的腈亚胺在快速（约 1 分钟）对活哺乳动物细胞中的胰高血糖素受体进行生物正交标记方面得到了验证。
