Recently, the research team led by Professor Liu Qinghe from the School of Engineering at our university published a groundbreaking study titled “Stereoselective Nucleophilic Di- and Monofluoro(sulfoximidoyl)methylation of C=C Bonds: Remote Neighboring Group Participation Enables Facile Access to Chiral γ-Fluorinated Amines” (Hot Paper) in the prestigious journal Angew Chem Int Ed. Ph.D. candidate Wang Bo and postdoctoral researcher Zheng Mengmeng served as co-first authors. Professor Liu Qinghe from our university, along with researchers Hu Jinbo and Xue Xiaosong from the Shanghai Institute of Organic Chemistry, acted as co-corresponding authors. China Pharmaceutical University is listed as the first corresponding institution.
The selective introduction of fluorine atoms or fluoroalkyl groups can significantly alter the physical and biological properties of organic molecules. γ-Fluoroamines have been demonstrated to play crucial roles in treating various diseases as TRPC6 channel inhibitors, CDK11 inhibitors, plant pathogenic fungal inhibitors, and cysteine protease inhibitors. However, existing methods are highly limited in applicability and typically require multi-step synthesis. Furthermore, low enantiomeric excess (ee) values persist, and efficient, highly stereoselective, and convenient approaches remain elusive. Consequently, there is an urgent need to develop a novel, efficient, and straightforward strategy for synthesizing optically pure beta-difluoromethylamine derivatives.
To address these challenges, this study employs a self-developed difluoromethylsulfonyl imine reagent to achieve highly stereoselective nucleophilic difluoromethylation with nitroalkenes, enabling the convenient construction of chiral beta-difluoromethylamines (Figure 1). The significant value and application potential of this method were validated through post-modification of bioactive complex molecules and automated scenario synthesis (Figure 2). Mechanistic experiments and theoretical calculations revealed that the remote ortho-participation effect of the nitro group plays a crucial role in controlling stereoselectivity.
Synthesis Strategy of Chiral Gamma-Fluoroamines and Construction of Fluorinated Drugs
Computer-Controlled Microreactor Strategy for Chiral Gamma-Fluoroamines
This work was supported by the National Natural Science Foundation of China, the National Key Laboratory of Multi-target Natural Medicines, the Strategic Priority Research Program of the Chinese Academy of Sciences, the Young Research Team in Basic Research of the Chinese Academy of Sciences, the National High-level Talent Program, and the High-level Talent Program of our university.
Paper link: https://onlinelibrary.wiley.com/doi/10.1002/anie.202511400
