A general organophotoredox strategy to difluoroalkyl bicycloalkane (CF2-BCA) hybrid bioisosteres


Here, we report a mild approach to the construction of the difluoroalkyl bicyclopentane and bicycloheptane (CF2-BCP and CF2-BCHep) units, as the structural surrogates of para- and meta-substituted aryl ketones and aryl ethers. The chemistry is orchestrated by the key activity of a dihydrobenzoacridine photocatalyst (PC). Depending by the nature of the substrate, the PC engages in catalytic electron-donor acceptor (EDA) complex or promotes the direct reduction of the substrate (Ered up to -1.9 V vs SCE) through a single-electron transfer (SET) mechanism. These two convergent manifolds leads to the generation of the reactive R-CF2 radical that reacts trough a strain-release atom-transfer-radical addition (ATRA) process with the [1.1.1]- or [3.1.1]-propellane. The method is general and tolerant of a variety of functional groups, such as sulfones, amines, amides or alkynes (30 examples, yields up to 90%), and extendable to complex bioactive molecules, including aminoacids, dipeptides or carbohydrates. The structural features of the CF2-BCP hybrid bioisostere were investigated in the solid state by single crystal X-ray analysis. Finally, we synthesised a CF2-BCP analogue of a Leukotriene A4 (LTA4) hydrolase inhibitor, replacing the original aryl ether motif. Interestingly, in-silico docking studies indicated that this new molecule maintains the same arrangement and key interactions within the enzyme pocket.


Supplementary material

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Supporting information. Spectra, mechanistic investigations, synthetic procedures etc.