Anhui Province Engineering Laboratory for Green Pesticide Development and Application, College of Plant Protection, Anhui Agricultural University, Hefei, Anhui, 230036, China.
Institute of Physical Science and Information Technology, Anhui University, Hefei, 230601, China.
Nat Commun. 2022 May 26;13(1):2953. doi: 10.1038/s41467-022-30693-x.
Nonpolar alkyl moieties, especially methyl group, are frequently used to modify bioactive molecules during lead optimization in medicinal chemistry. Thus transition-metal catalyzed alkylative cross-coupling reactions by using readily available and environmentally benign C-O electrophiles have been established as powerful tools to install alkyl groups, however, the C(sp)-C(sp) cross-coupling via asymmetric activation of aromatic C-O bond for the synthesis of alkylated chiral compounds remains elusive. Here, we unlock a C(sp)-C(sp) cross-coupling via enantioselective activation of aromatic C-O bond for the efficient synthesis of versatile axially chiral 2-alkyl-2'-hydroxyl-biaryl compounds. By employing a unique chiral N-heterocyclic carbene ligand, this transformation is accomplished via nickel catalysis with good enantiocontrol. Mechanistic studies indicate that bis-ligated nickel complexes might be formed as catalytically active species in the enantioselective alkylative cross-coupling. Moreover, further derivation experiments suggest this developed methodology holds great promise for complex molecule synthesis and asymmetric catalysis.
在药物化学的先导优化过程中，非极性烷基部分，特别是甲基，常用于修饰生物活性分子。因此，利用易得且环境友好的 C-O 亲电试剂，过渡金属催化的烷基交叉偶联反应已成为引入烷基的有效工具，然而，通过不对称活化芳基 C-O 键实现 C(sp)-C(sp) 交叉偶联以合成烷基化手性化合物仍然难以实现。在这里，我们通过对芳基 C-O 键的对映选择性活化解锁了 C(sp)-C(sp) 交叉偶联，从而高效合成了多功能轴手性 2-烷基-2'-羟基联苯化合物。通过使用独特的手性 N-杂环卡宾配体，该转化通过镍催化实现，并具有良好的对映选择性控制。机理研究表明，双配体镍配合物可能作为催化活性物种形成于对映选择性烷基交叉偶联中。此外，进一步的衍生实验表明，该发展的方法学在手性催化和复杂分子合成方面具有很大的应用潜力。
