Regio- and Enantioselective C–H Cyclization of Pyridines with Alkenes Enabled by a Nickel/N-Heterocyclic Carbene Catalysis

Annulated pyridines are ubiquitous scaffolds in many bioactive molecules. A highly regio- and enantioselective Ni(0)-catalyzed endo-selective C–H cyclization of pyridines with alkenes has been developed. An unprecedented enantioselective C–H activation at pyridyl 3- or 4-positions was enabled by bulky chiral N-heterocyclic carbene ligands. This protocol provides expedient access to a series of optically active 5,6,7,8-tetrahydroquinolines and 5,6,7,8-tetrahydroisoquinolines, compounds otherwise accessed with difficulty, in moderate to high yields (up to 99% yield) and enantioselectivities (up to 99% ee). To our knowledge, this is the first example of enantioselective C–H cyclization of pyridines to chiral annulated products.

稠合吡啶（annulated pyridines）骨架广泛分布于各类生物活性分子之中。本研究开发了一种兼具高区域选择性与对映选择性的零价镍（Ni(0)）催化吡啶与烯烃发生内型选择性（endo-selective）C-H环化的反应体系。该体系借助位阻型手性氮杂环卡宾配体（bulky chiral N-heterocyclic carbene ligands），实现了吡啶环3位或4位上前所未有的对映选择性C-H活化过程。该合成策略可便捷地获取一系列光学活性的5,6,7,8-四氢喹啉与5,6,7,8-四氢异喹啉；此类化合物此前往往难以合成，本反应可取得中等至优异的收率（最高可达99%）以及优异的对映选择性（最高可达99% ee，对映体过量值，enantiomeric excess）。据我们所知，这是首例以吡啶为底物，通过对映选择性C-H环化反应制备手性稠合吡啶产物的案例。