Asymmetric benzylic C(sp3)−H acylation via dual nickel and photoredox catalysis

This work is dedicated to 100th anniversary of Xiamen University and its Chemistry.手性α-芳基酮，是一个非常重要的药效官能团，广泛存在于药物分子中，虽然含有α-季碳手性中心的芳基酮的不对称合成已经有较多报道，但是相应的具有α-叔碳手性中心的芳基酮的高效不对称合成依然极具挑战性，因为相对活泼的叔碳手性中心很容易发生外消旋化。霍浩华教授课题组在前期工作的基础上（JACS, 2020, 142, 19058.），经过一系列探索，成功将“溴自由基介导的C-H活化策略”由α-氨基sp3 C-H键拓展至苄位sp3 C-H键，在镍和光的协同催化下，实现了首例不对称苄位C(sp3)-H的酰基化反应。该研究工作在霍浩华教授指导下完成，博士研究生环磊桃和束晓敏为该论文的共同第一作者，博士研究生祖维赛和硕士研究生钟德参与了部分研究工作。Asymmetric C(sp3)−H functionalization is a persistent challenge in organic synthesis. Here, we report an asymmetric benzylic C−H acylation of alkylarenes employing carboxylic acids as acyl surrogates for the synthesis of α-aryl ketones via nickel and photoredox dual catalysis. This mild yet straightforward protocol transforms a diverse array of feedstock carboxylic acids and simple alkyl benzenes into highly valuable α-aryl ketones with high enantioselectivities. The utility of this method is showcased in the gram-scale synthesis and late-stage modification of medicinally relevant molecules. Mechanistic studies suggest a photocatalytically generated bromine radical can perform benzylic C−H cleavage to activate alkylarenes as nucleophilic coupling partners which can then engage in a nickel-catalyzed asymmetric acyl cross-coupling reaction. This bromine-radical-mediated C−H activation strategy can be also applied to the enantioselective coupling of alkylarenes with chloroformate for the synthesis of chiral α-aryl esters.We are grateful for financial support from the NSFC (22071203) and the Xiamen University. We thank professor Hai-Chao Xu (Xiamen University) for assistance and helpful discussions. We acknowledge Wesley Harrison (UIUC) for manuscript revision.研究工作得到了国家高层次青年人才项目、厦门大学南强A计划、国家自然科学基金委项目（No. 22071203）的资助