Catalytic Ring Expanding Difluorination: An Enantioselective Platform to Access β,β‐Difluorinated Carbocycles

Abstract Cyclic β,β‐difluoro‐carbonyl compounds have a venerable history as drug discovery leads, but limitations in the synthesis arsenal continue to impede chemical space exploration. This challenge is particularly acute in the arena of fluorinated medium rings where installing the difluoromethylene unit subtly alters the ring conformation by expanding the internal angle (∠C−CF 2 −C>∠C−CH 2 −C): this provides a handle to modulate physicochemistry (e.g. p K a ). To reconcile this disparity, a highly modular ring expansion has been devised that leverages simple α,β‐unsaturated esters and amides, and processes them to one‐carbon homologated rings with concomitant geminal difluorination (6 to 10 membered rings, up to 95 % yield). This process is a rare example of the formal difluorination of an internal alkene and is enabled by sequential I(III)‐enabled O ‐activation. Validation of enantioselective catalysis in the generation of unprecedented medium ring scaffolds is reported (up to 93 : 7 e.r .) together with X‐ray structural analyses and product derivatization.