Installation of Minimal Tetrazines through Silver-Mediated Liebeskind-Srogl Coupling with Arylboronic Acids
Installation of Minimal Tetrazines through Silver-Mediated Liebeskind-Srogl Coupling with Arylboronic Acids
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DOI：
10.1021/jacs.9b08677
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发表时间：
2019-10-30
影响因子：
15
通讯作者：
Fox, Joseph M.
中科院分区：
文献类型：
--
作者：
Lambert, William D.;Fang, Yinzhi;Fox, Joseph M.
描述了通过Ag介导的Liebeskind-Srogl交叉偶联的第一个实例安装最小的6-甲基四嗪-3-基的一般方法。生物正交四嗪在复杂分子上的附接通常依赖于可负面影响缀合物的生理化学性质的接头。与芳基硼酸和新试剂3-（（对联苯-4-基甲基）硫基）-6-甲基四嗪（b-Tz）的交叉偶联在温和的PdCl 2（dppf）催化条件下进行，以引入最小的无接头的四嗪官能团。安全考虑指导了我们的b-Tz的设计，其可以在十克规模上制备而不处理肼并且不形成挥发性的高氮四嗪副产物。用Ag 2 O介体代替Liebeskind-Srogl交叉偶联中使用的常规Cu（I）盐导致了在广泛的芳基和杂芳基硼酸文库中的更高的产率，并提供了对荧光四嗪-BODIPY缀合物的改进的获得。以高产率合成了结合6-甲基四嗪基官能团的MAGL的共价探针，并在活细胞中标记内源性MAGL。这种新的银介导的交叉偶联方法，使用b-Tz的预期找到其他应用直接引入四嗪亚基复杂的基板。
Described is a general method for the installation of a minimal 6-methyltetrazin-3-yl group via the first example of a Ag-mediated Liebeskind-Srogl cross-coupling. The attachment of bioorthogonal tetrazines on complex molecules typically relies on linkers that can negatively impact the physiochemical properties of conjugates. Cross-coupling with arylboronic acids and a new reagent, 3-((p-biphenyl-4-ylmethyl)thio)-6-methyltetrazine (b-Tz), proceeds under mild, PdCl2(dppf)-catalyzed conditions to introduce minimal, linker-free tetrazine functionality. Safety considerations guided our design of b-Tz which can be prepared on decagram scale without handling hydrazine and without forming volatile, high-nitrogen tetrazine byproducts. Replacing conventional Cu(I) salts used in Liebeskind-Srogl cross-coupling with a Ag2O mediator resulted in higher yields across a broad library of aryl and heteroaryl boronic acids and provides improved access to a fluorogenic tetrazine-BODIPY conjugate. A covalent probe for MAGL incorporating 6-methyltetrazinyl functionality was synthesized in high yield and labeled endogenous MAGL in live cells. This new Ag-mediated cross-coupling method using b-Tz is anticipated to find additional applications for directly introducing the tetrazine subunit to complex substrates.