α-Haloketones are valuable intermediates in the synthesis of pharmaceuticals and natural products because they display two electrophiles. Although chemoselective additions to each of these functional groups are known, the use of fluorinated nucleophiles has not been characterized, except for the dimerization of fluorohalomethyl ketones. Our studies demonstrate the use of difluoroenolates to create difluorinated bromohydrins and chlorohydrins from α-haloketones without any cyclization or rearrangement due to the mild conditions.
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http://dx.doi.org/10.1021/acs.orglett.1c01636 | DOI Listing |
Org Lett
January 2025
Arcus Biosciences, Inc, 3928 Point Eden Way, Hayward, California 94545, United States.
We disclose a stereodivergent strategy to prepare difluorinated tetralins from γ-substituted tetralones via a combination of catalyst-controlled transfer hydrogenation and substrate-controlled fluorinations. This process is easily scalable and amenable to highly functionalized substrates, as demonstrated here in the late-stage synthesis of casdatifan, a clinical-stage inhibitor of hypoxia-inducible factor-2α. Analysis of the physicochemical properties of casdatifan, which features a difluoride, revealed a higher level of facial polarization compared to its difluoride isomers.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
January 2025
Department of Chemistry, University of Missouri, 601 S College Ave, Columbia, MO 65211, USA.
Toxic organic solvents and electrolytes, traditionally indispensable for electro-organic synthesis, are now being reconsidered. In developing more sustainable electro-organic synthesis, we've harnessed the aqueous micelles as solvents and electrolyte-like structures when deformed under an electric field. The technology is showcased in synthetically highly valued hydrodefluorination reactions of difluorinated indoles.
View Article and Find Full Text PDFInt J Mol Sci
December 2024
Faculty of Chemistry, Jagiellonian University, 30-387 Kraków, Poland.
Difluorinated sulfonamide porphyrin (FPGly) and bacteriochlorin (FBGly), modified by glycine residues, were synthesized and evaluated for photodynamic therapy (PDT). F₂PGly exhibits superior stability and singlet oxygen generation efficiency but features a low-intensity band in the red range (λ = 639 nm). In contrast, FBGly shows a favorable, red-shifted absorption spectrum (λ = 746 nm) that aligns well with phototherapeutic window, facilitating deeper tissue penetration.
View Article and Find Full Text PDFOrg Lett
December 2024
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, State Key Laboratory of Antiviral Drugs, School of Chemistry and Chemical Engineering Henan Normal University, Xinxiang, Henan 453007, China.
Difluoromethylene and pyridine cores are very important structural units in medicinal chemistry. Herein, we report the development of photoredox-catalyzed ring-opening and 1,3-alkoxypyridylation of -difluorinated cyclopropanes using 4-cyanopyrines and alcohols, employing cyclopropane radical cations as the key intermediate. The reaction exhibits high regioselectivity under mild conditions and can also be practiced on gram-scale synthesis, telescoped reaction, and late-stage functionalization of biological molecules.
View Article and Find Full Text PDFOrg Lett
December 2024
West China School of Public Health and West China Fourth Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China.
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