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CF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines.

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Titel: CF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines.
Autoren: Liu, Peng, He, Yan, Jiang, Chen-Hui, Ren, Wei-Ran, Jin, Ruo-Xing, Zhang, Ting, Chen, Wang-Xuan, Nie, Xuan, Wang, Xi-Sheng
Quelle: Nature Communications; 1/11/2025, Vol. 16 Issue 1, p1-8, 8p
Schlagwörter: PHYSICAL organic chemistry, DIFLUOROMETHYL compounds, DERACEMIZATION, PHYSICAL & theoretical chemistry, DRUG design
Abstract: The difluoromethyl group is a crucial fluorinated moiety with distinctive biological properties, and the synthesis of chiral CF₂H-containing analogs has been recognized as a powerful strategy in drug design. To date, the most established method for accessing enantioenriched difluoromethyl compounds involves the enantioselective functionalization of nucleophilic and electrophilic CF₂H synthons. However, this approach is limited by lower reactivity and reduced enantioselectivity. Leveraging the unique fluorine effect, we design and synthesize a radical CF₂H synthon by incorporating isoindolinone into alkyl halides for asymmetric radical transformation. Here, we report an efficient strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling. This approach demonstrates mild reaction conditions and excellent enantioselectivity. Given that optically pure difluoromethylated amines and isoindolinones are key structural motifs in bioactive compounds, this strategy offers a practical solution for the efficient synthesis of CF₂H-containing chiral drug-like molecules. The difluoromethyl group is a crucial fluorinated moiety, and the synthesis of chiral CF₂H-containing analogs is a powerful strategy in drug design and screening. Here, the authors report a strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling. [ABSTRACT FROM AUTHOR]
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Datenbank: Complementary Index
Beschreibung
Abstract:The difluoromethyl group is a crucial fluorinated moiety with distinctive biological properties, and the synthesis of chiral CF₂H-containing analogs has been recognized as a powerful strategy in drug design. To date, the most established method for accessing enantioenriched difluoromethyl compounds involves the enantioselective functionalization of nucleophilic and electrophilic CF₂H synthons. However, this approach is limited by lower reactivity and reduced enantioselectivity. Leveraging the unique fluorine effect, we design and synthesize a radical CF₂H synthon by incorporating isoindolinone into alkyl halides for asymmetric radical transformation. Here, we report an efficient strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling. This approach demonstrates mild reaction conditions and excellent enantioselectivity. Given that optically pure difluoromethylated amines and isoindolinones are key structural motifs in bioactive compounds, this strategy offers a practical solution for the efficient synthesis of CF₂H-containing chiral drug-like molecules. The difluoromethyl group is a crucial fluorinated moiety, and the synthesis of chiral CF₂H-containing analogs is a powerful strategy in drug design and screening. Here, the authors report a strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling. [ABSTRACT FROM AUTHOR]
ISSN:20411723
DOI:10.1038/s41467-025-55912-z