Comparative Analysis of Fluorine‐Directed Glycosylation Selectivity: Interrogating C2 [OH → F] Substitution in d‐­Glucose and d‐Galactose

Abstract

The influence of C2 [OH → F] substitution on the stereochemical course of chemical glycosylation was interrogated in both D‐glucose and its C4 epimer D‐galactose. Molecular editing at C2 and configurational inversion at C4 were simultaneously investigated by variable‐temperature glycosylation studies of both systems. Extrapolation of the differences in enthalpic (ΔΔHβα‡) and entropic (ΔΔSβα‡) contributions that discriminate these closely similar systems revealed that deoxofluorination at the C2 position induces an enthalpic bias that augments β‐stereoselection. Intriguingly, the enhanced stereoselectivity of the C4 epimer D‐galactose was found to be entropic in nature. Given the prominence of these scaffolds in chemical biology, delineating the factors that underpin selectivity will be critical in developing novel glycosylation methods and in rationalizing differences with the natural systems post facto.

Stereospecific Furanosylations Catalyzed by Bis-thiourea Hydrogen-Bond Donors

“…Closely related fucofuranosyl , and galactofuranosyl , phosphate derivatives 5a and 5b underwent reaction to the desired disaccharides ( 6a and 6b ) in excellent yield and with good β-selectivity, demonstrating tolerance for variation of the C5-substituent. A C2-fluoro analog of arabinose 5c displayed lower reactivity, although glycosylation could be accomplished in good yield and only slightly diminished anomeric selectivity by increasing reaction time and temperature ( 6c ). − …”

Phenanthroline-Catalyzed Stereoselective Formation of α-1,2-cis 2-Deoxy-2-Fluoro Glycosides

“…Currently, about 20% of the market pharmaceuticals contain at least one fluorine atom . Even though both carbohydrates and fluorine play a significant role to the field of medicinal chemistry, there is a lack of methods for the stereoselective formation of fluorinated glycosides. , Recently, Gilmour and co-workers have established an effective methodology for selectively forming β-linked-fluorinated glycosides (Figure a). − The Gilmour approach is highly stereoselective toward β-1,2- trans glycosides. On the other hand, methodologies to selectively produce α-linked-fluorinated glycosides remain largely underdeveloped.…”

Stereoselectivity in Glycosylation with Deoxofluorinated Glucosazide and Galactosazide Thiodonors

“…Replacement of a protected hydroxyl group by fluorine in a glycosyl donor can influence anomeric stereoselectivity through multiple effects like destabilization of cationic transition states by the inductive effect of fluorine, stabilization of transient oxocarbenium ion conformers by electrostatic interaction with the C–F bond dipole, or attenuation of the hydrogen-bond acceptor capacity with respect to the parent oxygen substituent . However, except for an in-depth study of 2-deoxy-2-fluoro-hexopyranosyl trichloroacetimidate donors by Bucher and Gilmour, − there have been no systematic studies investigating anomeric diastereoselectivity of fluorinated donors.…”