An enzymatic alternative to the chemical synthesis of chiral gem-difluorinated alcohols has been developed. The method is highly effective and stereoselective, feasible at laboratory temperature, avoiding the use of toxic heavy metal catalysts which is an important benefit in medicinal chemistry including the synthesis of drugs and drug precursors. Candida antarctica lipases A and B were applied for the enantioselective resolution of side-chain modified gem-difluorinated alcohols, (R)- and (S)-3-benzyloxy-1,1-difluoropropan-2-ols (1a and 1b), compounds serving as chiral building blocks in the synthesis of various bioactive molecules bearing a gem-difluorinated grouping. The catalytic activity of these lipases was investigated for the chiral acetylation of 1a and 1b in non-polar solvents using vinyl acetate as an acetyl donor. The dependence of the reaction course on various substrate and enzyme concentrations, reaction time, and temperature was monitored by chiral capillary electrophoresis (CE) using sulfobutyl ether β-cyclodextrin as a stereoselective additive of the aqueous background electrolyte. The application of CE, NMR, and MS methods has proved that the complex enzyme effect of Candida antarctica lipase B leads to the thermodynamically stable (S)-enantiomer 1b instead of the expected acetylated derivatives. In contrast, the enantioselective acetylation of racemic alcohol 1 was observed as a kinetically controlled process, where (R)-enantiomer 1a was formed as the main product. This process was followed by enzymatic hydrolysis and chiral isomerisation. Finally, single pure enantiomers 1a and 1b were isolated and their absolute configurations were assigned from NMR analysis after esterification with Mosher's acids.
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http://dx.doi.org/10.1016/j.bmc.2019.02.022 | DOI Listing |
Org 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.
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June 2024
Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006 Guangzhou, China.
We herein disclose the Pd/amine dual-catalyzed ring-opening cross-coupling reaction between -difluorinated cyclopropanes (-FCPs) with aldehydes, which enables the diversity-oriented synthesis (DOS) of 2-fluoroallylic aldehydes bearing all-carbon quaternary centers with features of broad scope and excellent functional group tolerance. The synthetic value of this Tsuji-Trost system was further demonstrated by late-stage functionalization of natural product-derived -FCPs and the diverse synthesis of various fluoroallylic aldehyde derivatives, including alcohol, alkyne, alkene, and amine.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
September 2023
Institute of Molecular Sciences and Engineering, Institute of Frontier and Interdisciplinary Science, Shandong University, Qingdao, Shandong 266237, China.
The incorporation of fluorine atoms in organics improves their bioactivity and lipophilicity. Catalytic functionalization of gem-difluorodienes represents one of the most straightforward approaches to access fluorinated alkenes. In contrast to the regular 1,3-dienes that undergo diverse asymmetric di/hydrofunctionalizations, the regio- and enantioselective oxyamination of gem-difluorodienes remains untouched.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
June 2023
School of Natural and Environmental Sciences, Newcastle University Bedson Building, Newcastle upon Tyne, NE1 7RU, UK.
C-F Insertion reactions represent an attractive approach to prepare valuable fluorinated compounds. The high strength of C-F bonds and the low reactivity of the fluoride released upon C-F bond cleavage, however, mean that examples of such processes are extremely scarce in the literature. Here we report a reaction system that overcomes these challenges using hydrogen bond donors that both activate C-F bonds and allow for downstream reactions with fluoride.
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September 2023
Department of Chemistry and Biotechnology, Center for Research on Green Sustainable Chemistry, Tottori University, 4-101 Koyama-minami, 680-8552, Tottori, Japan.
The incorporation of fluorine atoms into an organic compound can alter the chemical reactivity or biological activity of the resulting compound due to the strong electron withdrawing nature of the fluorine atom. We have synthesized many original gem-difluorinated compounds and described the results in four sections. The first section describes the synthesis of optically active-gem-difluorocyclopropanes via the chemo-enzymatic reaction; we applied these compounds to liquid crystalline molecules, then further discovered a potent DNA cleavage activity for the gem-difluorocyclopropane derivatives.
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