Anomer Preferences for Glucuronic and Galacturonic Acid and Derivatives and Influence of Electron-Withdrawing Substituents

Abstract

Equilibrium anomeric ratios are reported for pyranoses (hemiacetals) of glucuronic and galacturonic acid and their derivatives. These are compared to related gluco- and galactopyranoses and to deoxyfluorogluco- and deoxyfluorogalactopyranoses. An association between axial anomer stability and the sum of H NMR downfield chemical shifts for protons H-3 and H-5 was observed in DO with gluco- and galactopyranoses as reference compounds. When compared to 2-hydroxytetrahydropyran in water, introduction of three OAc substituents and one carboxylic acid substituent leads to an increase in stability of the axial anomer by 0.89-1.05 kcal/mol. This is interpreted as the electron-withdrawing substituents causing a reduction in the steric (gauche) interaction and an increase in favourable Coulombic interaction between CH groups of the pyranose and the anomeric group through substituent deshielding effects. Anomer preferences for galacturonic acid and its derivatives were more sensitive to solvent polarity compared to other pyranoses, and this may be linked to the electrostatic potential and reduced stabilization of the equatorial anomeric OH group due to reduced hydrogen bonding. The latter is more notable in nonpolar chloroform. Analysis of crystal structures combined with molecular dynamics indicated there are conformational distinctions between galacturonic acid and glucuronic acid that could influence properties.

Fluorinated carbohydrates as chemical probes for molecular recognition studies. Current status and perspectives

“…A systematic study involving the determination of the anomeric ratios of glucose, galactose and their monodeoxyfluorinated analogues (Table 1) showed that there was no significant variation upon deoxyfluorination. 52 However, in all cases, deoxyfluorination lead to an increased preference for the axial anomer, which was explained by the larger electron withdrawing effect of fluorine compared to that of OH. This results in an increased deshielding of the nearby axial C-H bonds, resulting in a reduced 1,3-diaxial repulsion (or increased intramolecular electrostatic interaction).…”

“…Fluorinated phosphonate of general structure 6.2 and 6.3 have been also developed either as non-hydrolyzable analogues of glycosyl-1phosphates (6.2) or as transition state analogues (6.3) 142 of GTs or, more generally, enzymes processing carbohydrates phosphorylated at the anomeric position. 64,143 Nucleotide-sugars fluorinated at the 3-, 4-, 5-or 6-position of the sugars have also been synthesized as enzymatic probes, 52,56,144 and have been successfully applied as chain terminator agents of polysaccharide biosynthesis. 145 In molecules 6.1, the electron-withdrawing character of the fluorine atom is believed to destabilize the transition state of the glycosylation reaction, which likely displays a substantial cationic character.…”

“…Anomeric composition of glucose, galactose, and their monodeoxyfluorinated derivatives in D 2 O as determined by quantitative NMR52 …”

Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design

“…It is important to keep in mind that the modification of carbohydrates with functional groups that are more electron-withdrawing (e.g., OH to F, CO 2 − in uronic acids), regardless of position, has been shown to increase stability of and preference for the α-anomer [88]. Although somewhat counter-intuitive, since electron-withdrawing groups reduce electron density on the endocyclic- O -atom and thereby would reduce the strength of the endo-anomeric effect, it is suggested that these electron-withdrawing substituents can reduce steric gauche interactions and enhance favorable Coulombic interactions between the C-1 and C–H ring substituents [88].…”

Conformational Analysis of 2-halo-1,3,2-dioxaphosphinanes: A Density Functional Theory (DFT) Investigation

“…The anomeric effect isoccurred when two electronegative substituents are attached to a sp 3 -hybridized carbon atom. Many theoretical investigations have assessed the anomeric effect [19][20][21][22][23][24][25][26][27][28].…”