The Disarming Effect of the 4,6-Acetal Group on Glycoside Reactivity: Torsional or Electronic?

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Abstract
An evaluation of whether the well-known deactivating effect of a 4,6-acetal protection group on glycosyl transfer is caused by torsional or an electronic effect from fixation of the 6-OH in the tg conformation was made. Two conformationally locked probe molecules, 2,4-dinitrophenyl 4,8-anhydro-7-deoxy-2,3,6-tri-O-methyl-β-d-glycero-d-gluco-octopyranoside (18 R) and the l-glycero-d-gluco isomer (18 S), were prepared, and their rate of hydrolysis was compared to that of the flexible 2,4-dinitrophenyl 2,3,4,6-tetra-O-methyl-β-d-glucopyranoside (21) and the locked 2,4-dinitrophenyl 4,6-O-methylidene-2,3-di-O-methyl-β-d-glucopyranoside (26). The rate of hydrolysis at pH 6.5 was 21 > 18 R > 18 S > 26, which showed that the deactivating effect of the 4,6-methylene group is partially torsional and partially electronic. A comparison of the rate of acidic hydrolysis of the corresponding methyl α-glycosides likewise showed that the probe molecules 17 S and 17 R hydrolyzed significantly slower than methyl tetra-O-methyl-glucoside 19, confirming a deactivating effect of locking the saccharide in the 4C1 conformation. The experiments showed that the hydroxymethyl rotamers deactivate the rate of glycoside hydrolysis in the order tg ≫ gt > gg.

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