Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation

Abstract

The replacement of a functional group with its corresponding bioisostere is a widely employed tactic during drug discovery campaigns that allows medicinal chemists to improve the ADME properties of candidates while maintaining potency. However, the incorporation of bioisosteres typically requires lengthy de novo resynthesis of potential candidates, which represents a bottleneck in their broader evaluation. An alternative would be to directly convert a functional group into its corresponding bioisostere at a late stage. Herein, we report the realization of this approach through the conversion of aliphatic alcohols into the corresponding difluoromethylated analogues via the merger of benzoxazolium-mediated deoxygenation and copper-mediated C(sp3)–CF2H bond formation. The utility of this method is showcased in a variety of complex alcohols and drug compounds.

Direct Synthesis of 2-Hydroxytrifluoroethylacetophenones via Organophotoredox-Mediated Net-Neutral Radical/Polar Crossover

“…Within the field of drug design, the difluoromethyl (−CF 2 H) group is recently earning considerable attention because it has been proved to be a more metabolically stable bioisostere of thiol and alcohol groups and a good lipophilic hydrogen bond donor . Despite the significance of this chemical space, the availability of bifunctional CF 2 H sources as effective reagents is limited . The bench-stable N -difluoroethoxyphthalimide 1b was prepared and tested in the difunctionalization process (Table ).…”

Cross-Double Deoxygenative Carbon–Carbon Bond Formation between Benzyl Benzoates and Allylic Alcohols

“…On the bias of the reported precedents on alcohol C–O bond activation using NHC salts ,− and the aforementioned experiments and DFT calculations, a preliminary mechanism is proposed in Scheme . The reaction of N1 and allylic alcohols first takes place to afford the NHC-allyl alcohol adduct ( Int 1 ) under basic conditions.…”

“…Recently, the Macmillan group developed a general strategy for deoxygenative cross-coupling reactions of alcohols with several coupling partners to construct C­(sp 3 )-C bonds. − Particularly, during the preparation of the manuscript, they reported a double deoxygenative cross-coupling of two alcohols to construct C­(sp 3 )-C­(sp 3 ) bonds . The key to these reactions is the use of innovative N -heterocyclic carbene (NHC) salts to activate the C–O bond in alcohols.…”