文献类型：期刊文献

英文题名：Iridium-catalyzed enantioselective synthesis of chiral γ-amino alcohols and intermediates of (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine

作者：Liu, Chengyu[1];Zhang, Lei[1];Cao, Liming[1];Xiong, Yan[2];Ma, Yueyue[3];Cheng, Ruihua[2,3];Ye, Jinxing[1,3]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Minist Educ,Engn Res Ctr Pharmaceut Proc Chem, Shanghai, Peoples R China;[2]East China Univ Sci & Technol, Sch Chem Engn, Shanghai, Peoples R China;[3]Guangdong Univ Technol, Sch Biomed & Pharmaceut Sci, Guangzhou, Peoples R China

年份：2022

卷号：5

期号：1

外文期刊名：COMMUNICATIONS CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000798043300001)】；

基金：This work was supported by the National Natural Science Foundation of China (22071056).

语种：英文

摘要：Enantioselective hydrogenation of beta-amino ketones is a powerful tool to produce bioactive molecules, but their asymmetric transformation is synthetically challenging. Here, an iridium-catalysed system with tridentate ferrocene-based phosphine ligands bearing unsymmetrical vicinal diamine scaffolds is developed for the efficient asymmetric synthesis of diverse gamma tertiary-amino and gamma-secondary-amino alcohols, including intermediates of (S)-duloxetine, (R)-fluoxetine and (R)-atomoxetine. Chiral gamma-amino alcohols are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules. Enantioselective hydrogenation of beta-amino ketones provides a straightforward and powerful tool for the synthesis of chiral gamma-amino alcohols, but the asymmetric transformation is synthetically challenging. Here, a series of tridentate ferrocene-based phosphine ligands bearing modular and tunable unsymmetrical vicinal diamine scaffolds were designed, synthesized, and evaluated in the iridium-catalyzed asymmetric hydrogenation of beta-amino ketones. The system was greatly effective to substrates with flexible structure and functionality, and diverse beta-tertiary-amino ketones and beta-secondary-amino ketones were hydrogenated smoothly. The excellent reactivities and enantioselectivities were achieved in the asymmetric delivery of various chiral gamma-amino alcohols with up to 99% yields, >99% ee values, and turnover number (TON) of 48,500. The gram-scale reactions with low catalyst loading showed the potential application in industrial synthesis of chiral drugs, such as (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine.