Guan Jing, Luo Yicong, Wang Qiyuan, Chen Jianzhong, Zhang Wanbin
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontier Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, 200240, Shanghai, P. R. China.
Angew Chem Int Ed Engl. 2025 Jan 21;64(4):e202416313. doi: 10.1002/anie.202416313. Epub 2024 Oct 30.
The asymmetric hydrogenation of benzophenones, catalyzed by low-activity earth-abundant metal copper, has hitherto remained a challenge due to the substrates equipped with two indistinguishably similar aryl groups. In this study, we demonstrated that the prochiral carbon of the ortho-bromine substrate exhibits the highest electrophilicity and high reactivity among the ortho-halogen substituted benzophenones, as determined by the Fukui function (f) analysis and hydrogenation reaction. Considering that the enantiodirecting functional bromine group can be easily derivatized and removed in the products, we successfully achieved a green copper-catalyzed asymmetric hydrogenation of ortho-bromine substituted benzophenones. This method yielded a series of chiral benzhydrols with excellent results. The utility of this protocol has been validated through a gram-scale reaction and subsequent product transformations. Independent gradient model based on Hirshfeld partition (IGMH) and energy decomposition analysis (EDA) indicate that the CH⋅⋅⋅HC multiple attractive dispersion interactions (MADI) effect between the catalyst and substrate enhances the catalyst's activity.
由低活性且储量丰富的金属铜催化的二苯甲酮不对称氢化反应，由于底物带有两个难以区分的相似芳基，至今仍是一项挑战。在本研究中，通过福井函数（f）分析和氢化反应确定，邻溴底物的前手性碳在邻卤代二苯甲酮中表现出最高的亲电性和高反应活性。考虑到对映体导向官能溴基团在产物中可易于衍生化并去除，我们成功实现了铜催化的邻溴取代二苯甲酮的绿色不对称氢化反应。该方法得到了一系列手性二苯甲醇，结果优异。此方案的实用性已通过克级反应及后续产物转化得到验证。基于赫希菲尔德划分的独立梯度模型（IGMH）和能量分解分析（EDA）表明，催化剂与底物之间的CH⋅⋅⋅HC多重吸引色散相互作用（MADI）效应增强了催化剂的活性。
