Selective N-Arylation of p-Aminophenylalanine in Unprotected Peptides with Organometallic Palladium Reagents.
Selective N-Arylation of p-Aminophenylalanine in Unprotected Peptides with Organometallic Palladium Reagents.
复制标题
使用有机金属钯试剂对未受保护的肽中的对氨基苯丙氨酸进行选择性 N-芳基化。
DOI：
10.1002/anie.202104780
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Buchwald,StephenL
中科院分区：
文献类型：
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作者：
Mallek,AaronJ;Pentelute,BradleyL;Buchwald,StephenL
描述了用预先形成的钯氧化加成复合物对多肽中的对氨基苯丙氨酸进行选择性N-芳基化。苯胺NH 2基团的pKa降低，使得在温和条件下，通过Curtin-Hammett控制，在赖氨酸或N-末端含有多个其他脂肪族氨基的肽上形成化学选择性C-N键。使用衍生自贫电子芳基卤化物的钯络合物，在微摩尔浓度下，对氨基苯丙氨酸在水性缓冲液中在短短1小时内完全芳基化。使用非亲核有机碱1，5-二氮杂双环（4.3.0）壬-5-烯（DBN）的补充方案扩大了底物范围以耐受富电子官能团，提供高达97%的转化率。这些程序使得功能多样的小分子药物能够化学选择性地缀合至含有细胞穿透肽的衍生物的对氨基苯丙氨酸。
The selective N‐arylation of p‐aminophenylalanine in polypeptides with pre‐formed palladium oxidative addition complexes is described. The depressed pKa of the aniline NH2group 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.