Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated δ C–H Cyanation
Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated δ C–H Cyanation
复制标题
通过对映选择性、自由基介导的 δ C–H 氰化从无环胺制备手性哌啶
DOI：
10.1016/j.chempr.2019.09.010
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发表时间：
2019
期刊：
影响因子：
23.5
通讯作者：
Nagib, David A.
中科院分区：
文献类型：
--
作者：
Zhang, Zuxiao;Zhang, Xin;Nagib, David A.
二甲双胍是药物中最常见的杂环。然而，尽管它们通常是手性的，但仍然没有稳健的方法用于它们的不对称合成。为了解决这一挑战，我们中断了已有百年历史的Hofmann-Löffler-Freytag（HLF）反应，以提供这种特权杂环。本文所述的无环胺的催化、区域选择性和对映选择性的δ C-H氰化反应在δ位置选择性地引入羰基等价物。这种δ C-H氰化反应是通过手性Cu催化剂实现的，该催化剂通过N中心自由基中继机制引发和终止分子内氢原子转移（HAT）。介绍了这种高度对映选择性的δ C-C形成方法的广泛范围和实用性，以及将所得对映体富集的δ-氨基腈转化为一类手性哌啶。还包括探索这种HAT机制的化学选择性、区域选择性和对映选择性的实验，以使其能够扩展到其他立体选择性δ C-H官能化。
Piperidines are the most prevalent heterocycle found in medicines. Yet, although they are often chiral, there remain no robust methods for their asymmetric syntheses. To solve this challenge, we have interrupted the century-old Hofmann-Löffler-Freytag (HLF) reaction to afford this privileged heterocycle. The catalytic, regio-, and enantioselective δ C–H cyanation of acyclic amines described here, incorporates a carbonyl equivalent selectively at the δ position. This δ C–H cyanation is enabled by a chiral Cu catalyst, which both initiates and terminates intramolecular hydrogen atom transfer (HAT) by an N-centered radical relay mechanism. The broad scope and utility of this highly enantioselective method for δ C–C formation is presented, as well as conversion of the resulting enantioenriched δ-amino nitriles to a family of chiral piperidines. Experiments probing the chemo-, regio-, and enantio-selectivity of this HAT mechanism are also included to enable extension to other stereoselective δ C–H functionalizations.