Interplay of Protecting Groups and Side Chain Conformation in Glycopyranosides. Modulation of the Influence of Remote Substituents on Glycosylation?

Abstract

The synthesis and conformational analysis of a series of phenyl 2,3,6-tri-O-benzyl-β-d-thio galacto- and glucopyranosides and their 6S-deuterio isotopomers, with systematic variation of the protecting group at the 4-position, are described. For the galactopyranosides, replacement of a 4-O-benzyl ether by a 4-O-alkanoyl or aroyl ester results in a small but measurable shift in side chain population away from the trans,gauche conformation and in favor of the gauche,trans conformer. In the glucopyranoside series on the other hand, replacement of a 4-O-benzyl ether by a 4-O-alkanoyl or aroyl ester results in a small but measurable increase in the population of the trans,gauche conformer at the expense of the gauche,gauche conformer. The possible modulating effect of these conformational changes on the well-known changes in the anomeric reactivity of glycosyl donors as a function of protecting group is discussed, raising the possibility that larger changes may be observed at the transition state for glycosylation. A comparable study with a series of ethyl 2,3,4-tri-O-benzyl-β-d-thioglucopyranosides reveals that no significant influence in side chain population is observed on changing the O6 protecting group.

Direct Experimental Characterization of a Bridged Bicyclic Glycosyl Dioxacarbenium Ion by 1H and 13C NMR Spectroscopy: Importance of Conformation on Participation by Distal Esters

“…Chemie increased population of the gauche,trans (gt)r otamer at the expense of the trans,gauche (tg)one. [20,21] Secure in the knowledge that methylation changes the average conformation of at least the benzoate ester group,we turned to its influence on reactivity.A ctivation of the methylated Boc ester 4 with diphenyl sulfoxide and triflic anhydride [22] in dichloromethane solution at À78 8 8Cfollowed by stirring for 3hand then quenching with aqueous sodium bicarbonate before warming to room temperature and chromatographic isolation afforded the 1,4-bridged bicyclic carbonate 12 in 56 %yield, indicative of the formation of the bridged ion 11 on activation, with subsequent loss of the tertbutyl group (Scheme 1). Thec yclic carbonate 12 was characterized inter alia by an IR carbonyl stretch at g 1748 cm À1 ,and the HMBC correlation of H1 and the carbonyl carbon.…”

Automated Quantification of Hydroxyl Reactivities: Prediction of Glycosylation Reactions

“…Neighboring group effect [15d, 24] and long‐range participation [10c, 21b, 25] are known to significantly influence the stereoselectivity in glycosylation, although the real mechanism and participating level of carbonyl group are at present still unclear. To precisely analyze the correlation between the stereoselectivity and reactivity differences of donor/acceptor counterparts, we studied the trends mathematically on donors A ‐ M functionalized with only non‐participating groups, and the RRV and Aka were introduced and emphasized as the main parameters.…”

“…The remote participation effect [10c, 21b, 25] related to stereoselective glycosylation can be preliminarily analyzed in a statistical manner (Figure S24, Table S3), although more data are necessary to elucidate a detailed trend. The results of a series of acetylated 2‐azido‐2‐deoxy‐thioglucoside (GlcN 3 ) [25a] and 2‐azido‐2‐deoxygalactosyl (GalN 3 ) [25b] donors were obtained from literature.…”

“…The building blocks for oligosaccharide synthesis can be more accurately selected using the RRV‐Aka database in the GlycoComputer program. Since neighboring group effects, [15d, 24] long‐range participation [10c, 21b, 25] and temperature effects [5, 29] are all important factors to control the stereoselectivity of glycosylation reactions, the numeric analysis of stereoselectivity change on acylated donors is now underway at various temperatures. We are also trying to connect the relationship of stereoselectivity and intermediate change using linear free energy relationships (LFER) [31]…”

Direct Experimental Characterization of a Bridged Bicyclic Glycosyl Dioxacarbenium Ion by 1H and 13C NMR Spectroscopy: Importance of Conformation on Participation by Distal Esters

“…Chemie Forschungsartikel 25602 www.angewandte.de increased population of the gauche,trans (gt)r otamer at the expense of the trans,gauche (tg)one. [20,21] Secure in the knowledge that methylation changes the average conformation of at least the benzoate ester group,we turned to its influence on reactivity.A ctivation of the methylated Boc ester 4 with diphenyl sulfoxide and triflic anhydride [22] in dichloromethane solution at À78 8 8Cfollowed by stirring for 3hand then quenching with aqueous sodium bicarbonate before warming to room temperature and chromatographic isolation afforded the 1,4-bridged bicyclic carbonate 12 in 56 %yield, indicative of the formation of the bridged ion 11 on activation, with subsequent loss of the tertbutyl group (Scheme 1). Thec yclic carbonate 12 was characterized inter alia by an IR carbonyl stretch at g 1748 cm À1 ,and the HMBC correlation of H1 and the carbonyl carbon.…”