A general organophotoredox strategy to difluoroalkyl bicyclo-alkane (CF2-BCA) hybrid bioisosteres.

Abstract

Here, we report a general approach to the synthesis of the difluoroalkyl bicycloalcanes (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 single-electron reduce 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.