腦膜炎雙球菌莢膜多醣主結構之合成研究

Abstract

摘要

血清型 W135 之腦膜炎雙球菌 (Neisseria meningitidis) 莢膜多醣體 (capsular polysaccharide) [→6)-□-D-Galp-(1→4)-□-D-Neup5Ac(9OAc)-(2→] 衍生物，四醣化合物的合成。利用 C9-OH 以 tert-butyldiphenylsilyl (TBDPS) 保護的 thiosialoside 當醣基予體 (glycosyl donor)，以常用的N-碘代丁二醯亞胺 (NIS) 和三氟甲磺酸 (TfOH) 當促進劑 (promoter)，跟 galactoside 反應可以得到高立體選擇性的雙醣產物 (□ 2→6 linkage)。將 thiosialoside 進行磷酸化反應 (phosphorylation) 所得到之 phosphosialoside 當醣基予體，以三甲基矽三氟甲基磺酸鹽 (trimethylsilyl trifluoromethanesulfonate，TMSOTf) 當促進劑 (promoter)，可與醣基受體 thiogalactoside 進行反應，得單一立體結構 (□ 2→6 linkage) 並具有 thio-group 的雙醣。將進行去乙醯基反應(deacetylation) 所得的 C-4、C-7、C-8 OH 無保護基的雙醣當醣基受體，跟上述所得之具有 thio-group 的雙醣化合物進行醣化反應，以N-碘代丁二醯亞胺和三氟甲磺酸當促進劑，在二氯甲烷中—40 oC下可得具有高位向選擇性跟高立體選擇性的四醣化合物 (□ 1→4 linkage)。

The thesis describes a novel synthetic approach for the preparation of a biological relevant tetrasaccharide [→6)-□-D-Galp-(1→4)-□- D-Neup5Ac(9OAc)-(2→], which constitutes the essential component of capsular polysaccharide in Neisseria meningitidis serotype W135. In the synthesis, 9-O-(……silyl)-N-acetyl-5-N,4-O-carbonyl-protected thiosialoside was used for glycosylation of galactosyl acceptor at C-6 hydroxyl. The desired □ 2→6 glycosidic linkage was formed with high stereoselectivity. Exclusive □-selectivity was obtained for chemoselective glycosylation of thiogalactosyl acceptor with 9-O-(…..silyl)-N-actyl-5-N,4-O-carbonyl-protected sialosyl phosphate donor. Subsequent protecting group manipulation gave the appropriate disaccharide acceptor with unprotected hydroxyls at C-4, C-7 and C-8, which was successfully glycosylated with a disaccharide thioglycoside at C-4 hydroxyl to afford the fully protected tetrasaccharide with high □-selectivity and regioselectivity. Vigorous NMR characterization for the furnished tetrasaccharide was performed. Global deprotection of protected tetrasaccharide is in progress.