Kinetically Stereocontrolled <i>Gem</i> ‐Fluoro(chloro)‐Olefination of Carbonyls by an Unprecedented Sulfoximine: Programmable Construction of Challenging Persubstituted Alkenyl Fluorides

Persubstituted alkenyl fluorides represent pivotal motifs in drug discovery, agrochemical development, and biological science. The (E)-isomeric persubstituted alkenyl fluoride, widely recognized as a conformationally stable mimic of the amide bond, frequently exhibits significantly higher bioactivity than the (Z)-counterpart. Despite their potential, the synthesis of this scaffold remains challenging, due to the severe steric encumbrance. Herein, we reported a highly stereoselective carbonyl gem-fluoro(chloro)olefination with an unprecedented sulfoximine reagent, affording an array of (Z)-persubstituted gem-fluoro(chloro)alkenes. Subsequent cross-couplings enabled them rapidly into a wide array of challenging stereodefined (E)- or (Z)-alkenyl fluorides. The experimental and computational data demonstrated that the key mechanistic feature involved a predominant 1,5-attack pathway, which operated as the rate-determining step with kinetic stereocontrol and prevailed over both the 1,3- and 1,4-attack pathways. The synthetic utility was demonstrated through microfluid synthesis, late-stage modifications, and a streamlined stereoselective synthesis of factor Xa inhibitor and RXR regulator.