Glycosylation under Thermodynamic Control: Synthesis of the Di‐ and the Hexasaccharide Fragments of the O‐SP of Vibrio Cholerae O:1 Serotype Ogawa from Fully Functionalized Building Blocks

Abstract

The known 5-(methoxycarbonyl)pentyl α-glycoside of the hexasaccharide of the O-SP of Vibrio cholerae O:1, serotype Ogawa 31 was newly prepared from side-chain-equipped disaccharide building blocks. The intermediate tetrasaccharide 25 was prepared from the disaccharide glycosyl acceptor 11 and the (1Ǟ2)-linked disaccharide thioglycoside glycosyl donor 8, having a (non-participating) saccharide moiety at C-2 in the downstream end. When performed conventionally (at room or at sub 0°C temperatures), glycosylations with 11, carried out without anchimeric assistance, showed poor stereoselectivity but the formation of the 1,2-trans-glycosidic linkage could be markedly improved through thermodynamic control. This synthetic strategy towards 31 was more efficient than the step-wise approach, which was based

Enhanced stereoselectivity of α-mannosylation under thermodynamic control using trichloroacetimidates

“…Encouraged by the high stereoselectivity of formation of the α-mannopyranosyl linkage in the absence of anchimeric assistance,7,16,17 and by the precedence21 for highly stereoselective formation of α-mannosyl linkage from the fully assembled donor 2 , we used11 donors 3–5 for glycosylation in the assembly of the Ogawa hexasaccharide 27 . It turned out11 that, unlike with glycosyl donors 1 and 2 , the presence of the side chain in the oligosaccharide donors 3–5 resulted in loss of the ability of these donors to form α-mannosyl linkage with high stereoselectivity.…”

“…It turned out11 that, unlike with glycosyl donors 1 and 2 , the presence of the side chain in the oligosaccharide donors 3–5 resulted in loss of the ability of these donors to form α-mannosyl linkage with high stereoselectivity. For example,11 the reaction of thioglycoside 4 with methyl 6-hydroxyhexanoate in DCM at −20°C gave mainly the unwanted β glycoside. Thus, paradoxically, although the synthesis of the β-mannosyl linkage is one of the most difficult glycosidic linkages to synthesize, we faced the uncommon task to minimize formation of that linkage.…”

“…Thus, paradoxically, although the synthesis of the β-mannosyl linkage is one of the most difficult glycosidic linkages to synthesize, we faced the uncommon task to minimize formation of that linkage. Conducting the glycosidation of methyl 6-hydroxyhexanoate at higher temperatures changed the situation considerably, as it resulted in increased relative amount of the desired α product formed, with the later slightly predominating when the reaction was conducted at the temperature of refluxing toluene 11. With oligosaccharide glycosyl acceptors 6 and 7 and donor 4 , the α:β ratio of products could be increased from 2:1 (DCM as solvent, room temp) to 5:1 (refluxing toluene) 11.…”

“…Our recent blockwise synthesis11 of the Ogawa hexasaccharide from disaccharide glycosyl donors bearing the 4-(3-deoxy-L- glycero -tetronamido) group in place (fully assembled glycosyl donors, as opposed to donors bearing 4-azido groups) has definite advantages over previous approaches, despite less than optimum stereoselectivity in the formation of the α-(1→2)-interglycosidic linkages. There,11 we were able to improve the yield of the desired, α-linked product by reacting a disaccharide thioglycoside donor under thermodynamic control.…”

“…There,11 we were able to improve the yield of the desired, α-linked product by reacting a disaccharide thioglycoside donor under thermodynamic control. Here we report on further improvement of the synthesis of the hexasaccharide sequence, which was accomplished by the use of relevant mono- and disaccharide trichloroacetimidates as glycosyl donors.…”