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 A(4) 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.

A General Organophotoredox Strategy to Difluoroalkyl Bicycloalkane (CF2-BCA) Hybrid Bioisosteres / Cuadros, Sara; Goti, Giulio; Barison, Giorgia; Raulli, Alfredo; Bortolato, Tommaso; Pelosi, Giorgio; Costa, Paolo; Dell'Amico, Luca. - In: ANGEWANDTE CHEMIE. INTERNATIONAL EDITION. - ISSN 1433-7851. - (2023). [10.1002/anie.202303585]

A General Organophotoredox Strategy to Difluoroalkyl Bicycloalkane (CF2-BCA) Hybrid Bioisosteres

Pelosi, Giorgio;Dell'Amico, Luca
2023-01-01

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 A(4) 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.
2023
A General Organophotoredox Strategy to Difluoroalkyl Bicycloalkane (CF2-BCA) Hybrid Bioisosteres / Cuadros, Sara; Goti, Giulio; Barison, Giorgia; Raulli, Alfredo; Bortolato, Tommaso; Pelosi, Giorgio; Costa, Paolo; Dell'Amico, Luca. - In: ANGEWANDTE CHEMIE. INTERNATIONAL EDITION. - ISSN 1433-7851. - (2023). [10.1002/anie.202303585]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2968633
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