Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA.
Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, IN, USA.
Nat Chem. 2020 Aug;12(8):747-754. doi: 10.1038/s41557-020-0469-5. Epub 2020 Jun 29.
Chiral nitriles and their derivatives are prevalent in pharmaceuticals and bioactive compounds. Enantioselective alkene hydrocyanation represents a convenient and efficient approach for synthesizing these molecules. However, a generally applicable method featuring a broad substrate scope and high functional group tolerance remains elusive. Here, we address this long-standing synthetic problem using dual electrocatalysis. Using this strategy, we leverage electrochemistry to seamlessly combine two canonical radical reactions-cobalt-mediated hydrogen-atom transfer and copper-promoted radical cyanation-to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidants. We also harness electrochemistry's unique feature of precise potential control to optimize the chemoselectivity of challenging substrates. Computational analysis uncovers the origin of enantio-induction, for which the chiral catalyst imparts a combination of attractive and repulsive non-covalent interactions to direct the enantio-determining C-CN bond formation. This work demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent challenges in synthetic chemistry.
手性腈及其衍生物在药物和生物活性化合物中很常见。对映选择性烯烃氰化氢加成是合成这些分子的一种方便、有效的方法。然而，具有广泛底物范围和高官能团容忍度的通用方法仍然难以实现。在这里，我们使用双电催化来解决这个长期存在的合成问题。使用这种策略，我们利用电化学将两个典型的自由基反应——钴介导的氢原子转移和铜促进的自由基氰化——无缝结合起来，在不需要化学计量氧化剂的情况下完成高度对映选择性的氰化氢加成。我们还利用电化学精确控制电位的独特特性来优化具有挑战性的底物的化学选择性。计算分析揭示了手性催化剂赋予对映诱导的起源，其赋予对映确定的 C-CN 键形成的吸引力和排斥力的非共价相互作用的组合。这项工作展示了电化学在进入新的化学空间和解决合成化学中相关挑战方面的强大功能。
