Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
Angew Chem Int Ed Engl. 2021 Jul 26;60(31):16928-16931. doi: 10.1002/anie.202104780. Epub 2021 Jun 26.
The selective N-arylation of p-aminophenylalanine in polypeptides with pre-formed palladium oxidative addition complexes is described. The depressed pKa of the aniline NH group enables chemoselective C-N bond formation on peptides containing multiple other aliphatic amino groups at lysines or the N-terminus via Curtin-Hammett control under mild conditions. Using palladium complexes derived from electron-poor aryl halides, p-aminophenylalanine is fully arylated in aqueous buffer in as little as one hour at micromolar concentrations. A complementary protocol using the non-nucleophilic, organic base 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), expands the substrate scope to tolerate electron-rich functional groups provides up to 97 % conversion. These procedures enable the chemoselective conjugation of functionally diverse small molecule pharmaceuticals to p-aminophenylalanine containing derivatives of cell-penetrating peptides.
本文描述了在预先形成的钯氧化加成复合物存在下，多肽中对-氨基苯丙氨酸的选择性 N-芳基化反应。由于苯胺 NH 基团的 pKa 降低，因此在温和条件下通过 Curtin-Hammett 控制，可以在含有赖氨酸或 N-末端的多个其他脂肪族氨基酸的肽中选择性地形成 C-N 键。使用衍生自缺电子芳基卤化物的钯配合物，在微摩尔浓度下，在水性缓冲液中仅需 1 小时即可完全芳基化 p-氨基苯丙氨酸。使用非亲核性有机碱 1,5-二氮杂双环[4.3.0]壬-5-烯（DBN）的补充方案扩展了底物范围，可以耐受富电子官能团，最高转化率可达 97%。这些方法可用于将功能多样的小分子药物化学选择性地连接到含有穿透细胞肽的 p-氨基苯丙氨酸衍生物上。
