The Influence of Neighboring Group Participation on the Hydrolysis of 2-O-Substituted Methyl Glucopyranosides

Abstract

Does neighboring group participation actually enhance the reactivity of the anomeric center when the participating group is inherently disarming? To investigate the influence of the neighboring group effect from a 2-O protective group on acidic glycoside hydrolysis, 10 methyl glucosides having different protective groups on O2 have been synthesized and a clear trend between anomeric configuration, participation of the protective group, and the rate of hydrolysis could be observed.

Influence of Alkoxy Groups on Rates of Acetal Hydrolysis and Tosylate Solvolysis: Electrostatic Stabilization of Developing Oxocarbenium Ion Intermediates and Neighboring-Group Participation To Form Oxonium Ions

“…Whatever substrate is chosen and whichever comparison is made, it is evident that the influence of an alkoxy group on acetal hydrolysis is larger than the effect determined for acyloxy groups in similar systems, which exert a seven-to thirteen-fold rate acceleration after compensation for inductive destabilization. 50 The hydrolysis rates reported here indicate that it is not appropriate to make the generalization that an alkoxy group (or likely a hydroxyl group, which is electronically similar) cannot participate in acetal hydrolysis. Instead, in carbohydrate-derived systems, it does not engage in participation because to do so would impart ring strain.…”

“…9,10 A similar electrostatic stabilization has also been invoked to explain the small acceleration observed in the hydrolysis of carbohydrate derivatives bearing acyloxy groups at C-2. 50 Alternatively, a new covalent bond could form between the alkoxy group and the acetal carbon atom during hydrolysis. The resulting intermediate oxonium ion 38, however, would develop a significant fraction of the ring strain inherent in the trans-bicyclo[3.3.0]-octane system (>15 kcal/mol).…”

“…The acceleration in the rate of ionization exerted by the acyloxy group of acetal 59 ( Figure 11) through neighboring-group participation was determined to be 13-fold after correction for inductive effects. 50 In the related acetal trans-6, which positions an oxygen atom at the same distance (Figure 11), the alkoxy group accelerated the rate of ionization by 33-to 67-fold after correction for inductive effects. These results suggest that appropriate caveats should be taken when it is assumed that an alkoxy group cannot participate in the reactions of acetals.…”

Additive Tendency of Substituent Effects onto Rate Constant of Acidic Hydrolysis of Methyl 4‐O‐Methyl‐β‐d‐Glucopyranoside

“…Hydrolyses of 1 – 8 at 0.05 mol⋅L −1 concentrations of the respective compound in DCl/D 2 O (3 mol⋅L −1 ) at 70 °C. The reaction was monitored by 1 H NMR . During the hydrolysis reaction, three types of H ‐1 signals were discernible, one from the starting methyl β‐glucoside derivative I and two from the derived α‐ and β‐glucose derivatives IVα and IVβ (see Scheme ).…”

Superarming of Glycosyl Donors by Combined Neighboring and Conformational Effects

“…41 On the other hand, reactivity difference between 1c and 1e could also be partly due to the anomeric effect lowering the ground state energy of the α-anomer. 42,43 In the absense of the anchimeric assistance, axial thioglycosides have been found to be more reactive than their equatorial counterparts. This has been explained with the importance of an anti-periplanar arranggement between the leaving group and one of the ring-oxygens lone-pairs.…”