A General Organophotoredox Strategy to Difluoroalkyl Bicycloalkane (CF2-BCA) Hybrid Bioisosteres** |
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| Authors: | Dr Sara Cuadros Dr Giulio Goti Giorgia Barison Alfredo Raulli Tommaso Bortolato Prof Giorgio Pelosi Dr Paolo Costa Prof Luca Dell'Amico |
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| Institution: | 1. Department of Chemical Sciences, University of Padova, Via Francesco Marzolo 1, 35131 Padova, Italy;2. Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Science 17, 43124 Parma, Italy |
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| Abstract: | Here, we report a general approach to the synthesis of the difluoroalkyl bicycloalkanes (CF2-BCAs), as structural surrogates of aryl ketones and ethers. The chemistry is driven by a dihydrobenzoacridine photocatalyst, that engages in a catalytic electron-donor acceptor (EDA) complex, or directly reduces the fluorinated substrate. These two convergent manifolds lead to the generation of the R-CF2 radical, that reacts with the 1.1.1]- or 3.1.1.]-propellane. The method is extremely general, and extendable to complex bioactive molecules (30 examples, up to 87 % yield). The structural features of the CF2-BCP hybrid bioisostere were investigated by single crystal X-ray. Finally, we synthesised a CF2-BCP analogue of a Leukotriene A4 hydrolase inhibitor, replacing the original aryl ether motif. In silico docking studies indicated that this new analogue maintains the same arrangement within the enzyme pocket, profiling the use of the CF2-BCA hybrid bioisostere in medicinal chemistry settings. |
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| Keywords: | Fluorine Chemistry Hybrid Bioisostere Photoredox Catalysis Propellanes Sustainable Synthesis |
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