Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis.

Common anionic nucleophiles such as those derived from inorganic salts have not been used for enantioselective catalysis because of their insolubility. Here, we report that merging hydrogen bonding and phase-transfer catalysis provides an effective mode of activation for nucleophiles that are insoluble in organic solvents. This catalytic manifold relies on hydrogen bonding complexation to render nucleophiles soluble and reactive, while simultaneously inducing asymmetry in the ensuing transformation. We demonstrate the concept using a chiral bis-urea catalyst to form a tridentate hydrogen bonding complex with fluoride from its cesium salt, thereby enabling highly efficient enantioselective ring opening of episulfonium ion. This fluorination method is synthetically valuable considering the scarcity of alternative protocols and points the way to wider application of the catalytic approach with diverse anionic nucleophiles.

The dual role of thiourea in the thiotrifluoromethylation of alkenes.

Alkenes substituted with a thiourea undergo C-CF3 followed by intramolecular C-S bond formation with the Togni reagent and trifluoroacetic acid (TFA) at room temperature; thiols and thioamides are not suitable S-sources for this reaction. This anti-addition process involves a CF3 radical, and affords CF3-substituted thiazolines and thiazines for medicinal applications. A metal or photoredox catalyst is not required as the thiourea acts as a reductant, as well as serving as an S-source capable of adding to a C-centered radical. Mechanistic work comparing the reactivity of thiourea, urea, thioamide and thiol in the context of alkene trifluoromethylation demonstrates that in this series, the thiourea is unique for its ability to release CF3 radical from the Togni reagent, and to orchestrate trifluoromethylation followed by S-cyclization with both activated and unactivated alkenes.

ChEMBLSpace--a graphical explorer of the chemogenomic space covered by the ChEMBL database.

MOTIVATION: The ChEMBLSpace graphical explorer enables the identification of compounds from the ChEMBL database, which exhibit a desirable polypharmacology profile. This profile can be predefined or created iteratively, and the tool can be extended to other data sources.