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

Abstract

ABSTRACT 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.