A Solvation-Assisted Model for Estimating Anomeric Reactivity. Predicted versus Observed Trends in Hydrolysis of n-Pentenyl Glycosides¹

Abstract

An attempt has been made to predict qualitative trends in reactivity at the anomeric center, using N-bromosuccinimide-induced hydrolysis of n-pentenyl glycosides (NPGs) as the experimental model. Calculated relative activation energies based on internal energy differences between a reactant and the associated intermediate are not always in agreement with experimental observations. However, solvation energies obtained by the generalized Born surface area model in MacroModel developed by Still et al. give modified activation energies that are in excellent agreement with the experimentally observed trends. It is shown that the solvation model does not disturb the normally observed reactivity trends that can be rationalized on the basis of internal energies alone. The value of the methodology has been demonstrated for several substrates by first calculating their relative activation energies, then testing them experimentally, and finding excellent agreement with predictions. 5280

A propos of glycosyl cations and the mechanism of chemical glycosylation; the current state of the art

“…The well-known disarming effect of a trans -fused benzylidene ring, attributed by Fraser-Reid to torsional effects, 45–46 was rationalized by Bols as a combination of torsional effects and electronic disarming effects with the latter predominating and arising from the imposition of the tg conformation. 47 Crich and coworkers, adapting the Bols method to the galactopyranose series, revealed the cis -fused alkylidene ring system also to be disarming pointing to the importance of a torsional component.…”

Determination of the Influence of Side‐Chain Conformation on Glycosylation Selectivity using Conformationally Restricted Donors

“…[2] In the context of glycosylation, following the seminal work of Bols, [3] the conformation of the side chain is also recognized to be an important factor in the reactivity of glycosyl donors. [4] Thus, the disarming effect of the 4,6- O -benzylidene acetal-type protecting group recognized by Fraser-Reid [5] and a part of the Wong relative reactivity value index, [6] was established to be the result of locking the C5-C6 bond in the tg conformation thereby maximizing the electron-withdrawing effect of the C6-O6 and its destabilizing effect the nascent glycosyl oxocarbenium ion. [3, 4g] NMR and computational studies with conformationally unrestricted 1-ethoxy-5-alkoxylmethyl tetrahydropyrylium ions reveal that the pendant alkoxymethyl group prefers the gg conformation when it is pseudoequatorial to the half-chair of the oxocarbenium ion, and a gauche conformation projecting the C6-O6 bond toward the center of positive charge when it is pseudoaxial to an oxocarbenium ion half-chair conformation.…”

Influence of Side Chain Conformation and Configuration on Glycosyl Donor Reactivity and Selectivity as Illustrated by Sialic Acid Donors Epimeric at the 7-Position

“…3-9 In this respect the influence of side chain protecting groups and conformation on the reactivity and selectivity of glycosyl donors is an area of considerable current interest. 10 Interest in the role of side chain conformation stems from the discovery of Fraser-Reid and co-workers of the retarding effect of cyclic protecting groups on the reactivity of glycosyl donors, which they termed the torsionally disarming effect, 11-12 and from the critical role played by 4,6- O -benzylidene acetals in β-mannopyranosylation. 3,13-15 Bols and co-workers dissected the benzylidene effect into torsional and electronic components based on the relative rates of hydrolysis of a series of cyclic 6-methoxy-7-carba-glucopyranoside probes (Fig 1a), 16 reaching the conclusion that the major part of the effect is electronic and arises from the locking of the C5-C6 bond in the tg conformation 17-18 (Fig 2a).…”