General, catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein we describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. This asymmetric C(sp³)−C(sp³) coupling features high flexibility in introducing a diverse set of alkyl groups at the α-position of chiral N-heterocycles. The utility of this methodology has been demonstrated by late-stage functionalization of drug molecules, asymmetric synthesis of bioactive molecules, natural products and functional materials, and identification of a class of molecules exhibiting anti-apoptosis activities in UVB-irradiated HaCaT cells. Ligands play a vital role in controlling the reaction regioselectivity. Changing the ligand from bi-dentate L6 to tridentate L12 enables CoH-catalyzed Markovnikov hydroalkylation. Mechanistic studies disclose that the anti-Markovnikov hydroalkylation involves a migratory insertion process while the Markovnikov hydroalkylation involves a MHAT process.

手性α,α-二烷基吲哚的一般催化和对映选择性构建是一个重要但具有挑战性的待开发目标。在此，我们描述了通过远程立体控制的钴催化对映选择性反马尔可夫尼科夫烯烃加氢烷基化，用于合成α,α-二烷基吲哚和其他N-杂环。这种不对称的 C(sp ³ )−C(sp ³ ) 偶联具有在手性N杂环的α位引入不同烷基的高度灵活性。该方法的实用性已通过药物分子的后期功能化、生物活性分子、天然产物和功能材料的不对称合成以及在 UVB 照射的 HaCaT 细胞中表现出抗凋亡活性的一类分子的鉴定得到证明。配体在控制反应区域选择性方面起着至关重要的作用。将配体从双齿L6更改为三齿L12可以实现 CoH 催化的马尔可夫尼科夫加氢烷基化。机理研究表明，反马尔可夫尼科夫加氢烷基化涉及迁移插入过程，而马尔可夫尼科夫加氢烷基化涉及MHAT过程。