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铱催化的手性γ-氨基醇以及(S)-度洛西汀、(R)-氟西汀和(R)-阿托西汀中间体的对映选择性合成。

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

作者信息

Liu Chengyu, Zhang Lei, Cao Liming, Xiong Yan, Ma Yueyue, Cheng Ruihua, Ye Jinxing

机构信息

Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.

School of Chemical Engineering, East China University of Science and Technology, Shanghai, China.

出版信息

Commun Chem. 2022 May 19;5(1):63. doi: 10.1038/s42004-022-00678-4.

Abstract

Chiral γ-amino alcohols are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules. Enantioselective hydrogenation of β-amino ketones provides a straightforward and powerful tool for the synthesis of chiral γ-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 β-amino ketones. The system was greatly effective to substrates with flexible structure and functionality, and diverse β-tertiary-amino ketones and β-secondary-amino ketones were hydrogenated smoothly. The excellent reactivities and enantioselectivities were achieved in the asymmetric delivery of various chiral γ-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.

摘要

手性γ-氨基醇是药物和生物活性分子中普遍存在的结构基序和构建单元。β-氨基酮的对映选择性氢化反应为手性γ-氨基醇的合成提供了一种直接且强大的工具,但这种不对称转化在合成上具有挑战性。在此,设计、合成了一系列带有模块化且可调节的不对称邻二胺骨架的三齿二茂铁基膦配体,并在铱催化的β-氨基酮不对称氢化反应中对其进行了评估。该体系对具有灵活结构和官能团的底物具有显著效果,多种β-叔氨基酮和β-仲氨基酮均能顺利氢化。在各种手性γ-氨基醇的不对称合成中,实现了优异的反应活性和对映选择性,产率高达99%,对映体过量值(ee值)>99%,周转数(TON)为48,500。低催化剂负载量的克级反应显示出其在(S)-度洛西汀、(R)-氟西汀和(R)-托莫西汀等手性药物工业合成中的潜在应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43a7/9814375/8549b391bcc6/42004_2022_678_Fig1_HTML.jpg

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