Chen Su, Ding Decai, Yin Lingfeng, Wang Xiao, Krause Jeanette A, Liu Wei
Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, United States.
J Am Chem Soc. 2024 Nov 20;146(46):31982-31991. doi: 10.1021/jacs.4c11888. Epub 2024 Nov 6.
Cu-catalyzed enantioconvergent cross-coupling of alkyl halides has emerged as a powerful strategy for synthesizing enantioenriched molecules. However, this approach is intrinsically limited by the weak reducing power of copper(I) species, which restricts the scope of compatible nucleophiles and necessitates extensive ligand optimization or the use of complex chiral scaffolds. To overcome these challenges, we introduce an aryl-radical-enabled strategy that decouples the alkyl halide activation step from the chiral Cu center. We demonstrate that merging aryl-radical-enabled iodine abstraction with Cu-catalyzed asymmetric radical functionalization enables the conversion of racemic α-iodoamides to enantioenriched alkyl nitrile products with good yield and enantioselectivity. The rational design of chiral ligands identified a new class of carboxamide-containing BOX ligands. Mechanistic studies support an aryl-radical-enabled pathway and the unique hydrogen-bonding ability in the newly designed BOX ligands. This aryl-radical-enabled asymmetric substitution reaction has the potential to significantly expand the scope of Cu-catalyzed enantioconvergent cross-coupling reactions.
铜催化的卤代烷对映汇聚交叉偶联反应已成为合成对映体富集分子的一种强大策略。然而，这种方法本质上受到铜（I）物种还原能力较弱的限制，这限制了兼容亲核试剂的范围，并且需要进行广泛的配体优化或使用复杂的手性支架。为了克服这些挑战，我们引入了一种基于芳基自由基的策略，该策略将卤代烷活化步骤与手性铜中心解耦。我们证明，将基于芳基自由基的碘原子抽取与铜催化的不对称自由基官能化相结合，能够将外消旋α-碘代酰胺转化为具有良好产率和对映选择性的对映体富集的烷基腈产物。手性配体的合理设计确定了一类新型的含羧酰胺的BOX配体。机理研究支持基于芳基自由基的途径以及新设计的BOX配体中独特的氢键能力。这种基于芳基自由基的不对称取代反应有可能显著扩大铜催化的对映汇聚交叉偶联反应的范围。
