Neighbouring Group Participation During Glycosylation: Do 2‐Substituted Ethyl Ethers Participate?

Abstract

The development of new protecting groups that undergo neighbouring group participation (NGP) via six‐membered ring intermediates to promote the formation of α‐1,2‐cis glycosidic linkages complements the established use of 5‐ring NGP in terms of stereochemical outcome. A selection of glycosyl donors was synthesised that possessed novel 2‐iodo‐ and 2‐(phenylseleno)ethyl ether protecting groups in an attempt to promote highly α‐selective glycosylation by 6‐ring NGP. Although the fully armed donors produced α‐glucosides as the predominant reaction products, low‐temperature NMR studies did not show NGP by the observation of cyclised reaction intermediates. The corresponding disarmed glycosyl donors were unexpectedly less stereoselective. NMR spectroscopy revealed that the 2‐iodoethyl ether did not participate in any of the glycosylation processes; however, the 2‐(phenylseleno)ethyl ether did participate, and β‐configured cyclic intermediates were observed. The fact that considerable amounts of β‐glycoside product were formed in these latter cases indicated that the predominant reaction pathway to product did not occur through the observed cyclic species. Clearly, a fine balance exists during glycosylation reactions, and the reaction pathway to product depends on a variety of factors. Notably, the formation of cyclised intermediates by 6‐ring NGP is not on its own sufficient to ensure high levels of α‐stereoselectivity.

Cation Clock Reactions for the Determination of Relative Reaction Kinetics in Glycosylation Reactions: Applications to Gluco- and Mannopyranosyl Sulfoxide and Trichloroacetimidate Type Donors

“…The excellent cis -selectivity observed in this kinetic ring closure contrasts with the thermodynamic trans -selectivity seen on ring closure of 2- O -(2-thioethyl)glucopyranosyl cations and related systems to hetero-bicyclo[4.4.0]decane-like systems, which are governed by the steric factors in the product. 129–131 The preference of the tricyclic glucose derivative 32 for the 1 S 5 conformation of the pyranose ring as opposed to the 4 C 1 chair must arise because of a combination two unfavorable steric interactions in the chair: the 1,3-diaxial interaction between the axial anomeric CC bond and the axial C3-H3 bond and the gauche butane interaction emphasized in red in Scheme 8. This is because simple 4,6- O -benzylidene protected α- C -glucopyranosides, with an axial substituent at C1 but lacking the third ring, exist predominantly as 4 C 1 conformers (vide infra).…”

Mechanism of Glycosylation of Anomeric Sulfonium Ions

“…The oxygen-containing auxiliary of 2S and 2R was expected to be a less efficient neighboring group participant compared to the thiophenyl-containing derivative. 19 Finally, glycosyl donors 3S and 3R having chiral C-2 moieties at C-2 are derived from 1S and 1R and cannot participate because of a lack of a heteroatom at the C-2′ position. It was found that the nature of the heteroatom of the auxiliary greatly influenced the anomeric outcome of the glycosylations and only the use of glycosyl donor 1S gave consistently α -anomeric products.…”

Further studies on cation clock reactions in glycosylation: observation of a configuration specific intramolecular sulfenyl transfer and isolation and characterization of a tricyclic acetal

“…15,17 Analogous six-membered selenonium ions have also been characterized by NMR at low temperature and used as glycosyl donors. 20 Differences in the composition of product mixtures arising from the activation of 5 and 6 in the presence of isopropanol, with only 6 affording any isopropyl glycosides, are best explained by the change in the protection at the 4- and 6-positions. It is widely appreciated that the 4,6- O -benzylidene acetal group is more disarming than two correspondingly located benzyl ethers owing to a combination of torsional and electronic effects.…”