Construction of Divergent Enantioenriched 3D-Fluoro Scaffolds via Ni(0) π-Lewis Base-Mediated Umpolung of Fluorodienes.

Enantioenriched three-dimensional (3D) fluorinated scaffolds are pivotal in drug discovery, whereas the asymmetric synthesis directly from readily available 2D fluoroalkenes represents a desirable yet challenging synthetic objective. The α-carbon of gem-difluoroalkenes is inherently electrophilic, which typically precludes their utility in nucleophilic assemblies. Herein, we report an umpolung strategy that utilizes low-valent Ni(0) as a π-Lewis base activator for gem-difluorodienes and leverages d → π* backdonation to effectively reverse their intrinsic electrophilicity, thereby enabling the addition to aldehydes and imines stereoselectively. Two distinct transformative pathways for the resultant difluoro π-allylnickel(II) species are developed: exclusively (Z)-defined defluorination and reductive coupling, finally furnishing chiral fluoroalkenyl and gem-difluoro homoallylic derivatives, respectively. In addition, stereodivergent control over vicinal fluorine-containing stereocenters is achievable under the identical catalysis, by simply using geometric isomers of 1-fluorodienes. The current Ni(0)-based umpolung paradigm of fluorodienes establishes a powerful framework for constructing structurally diverse and enantioenriched fluorinated compounds with pharmaceutical significance.