On the Stereoselectivity of Fluorine and Acetylhypofluorite Additions to Glycals: The Synthesis of 2-Deoxy-2-Fldorohexoses

Abstract

Electrophilic syn additions of fluorine and acetylhypofluorite across double bonds in 3,4,6-tri-0-acetyl-D-glucal (1a) and D-glucal (1b) followed by acid hydrolysis gave mixtures of 2-deoxy-2-fluoro-D-glucose (8) and 2-deoxy-2-fluoro-D-mannose (9). These addition reactions were conducted in various solvents with a view to investigating the reaction mechanism based on the product distribution analysis by ¹⁹F NMR. Tight ion pair intermediates (4 and 5) have been invoked to explain the stereospecific characteristics of the addition of fluorine or acetylhypofluorite to glycals. The relative stabilities of these intermediates control the product distributions and are governed by a) the anomeric effect (axial vs equatorial preference of C(1) electronegative substituents in pyranose rings), b) dipole-dipole interactions of the lone pairs of electrons on the ring oxygen and the electronegative substituents on C(2), and c) the gauche relationship that exists between the C(2) fluorine and polar groups in the molecule. The overall contribution of these three factors largely depends upon the polarity of the solvent. A rationale for the ¹⁹F NMR chemical shifts as well as the anomeric distributions of the α and β anomers of 2-FDG (8) and 2-FDM (9) has been proposed.