Stratingh Institute for Chemistry, 9747 AG Groningen, Netherlands.
Science. 2016 Apr 22;352(6284):433-7. doi: 10.1126/science.aaf1983.
Catalytic asymmetric conjugate addition reactions represent a powerful strategy to access chiral molecules in contemporary organic synthesis. However, their applicability to conjugated alkenyl-N-heteroaromatic compounds, of particular interest in medicinal chemistry, has lagged behind applications to other substrates. We report a highly enantioselective and chemoselective catalytic transformation of a wide range of β-substituted conjugated alkenyl-N-heteroaromatics to their corresponding chiral alkylated products. This operationally simple methodology can introduce linear, branched, and cyclic alkyl chains, as well as a phenyl group, at the β-carbon position. The key to this success was enhancement of the reactivity of alkenyl-heteroaromatic substrates via Lewis acid activation, in combination with the use of readily available and highly reactive Grignard reagents and a copper catalyst coordinated by a chiral chelating diphosphine ligand.
催化不对称共轭加成反应是当代有机合成中获取手性分子的一种强大策略。然而，它们在手性药物化学中特别感兴趣的共轭烯基-N-杂芳烃化合物中的应用落后于其他底物的应用。我们报道了一种广泛的β-取代共轭烯基-N-杂芳烃的高对映选择性和化学选择性的催化转化，得到相应的手性烷基化产物。这种操作简单的方法可以在β-碳位置引入线性、支链和环状烷基链，以及一个苯基。成功的关键是通过路易斯酸活化增强烯基-杂芳烃底物的反应性，同时使用易得且高反应性的格氏试剂和手性螯合双膦配体配位的铜催化剂。
