藉由競爭型與交錯型方法合成第一型四醣體

Abstract

第一型醣體(Gal-β1,3-GlcNAc)是許多結構複雜碳水化合物的主要骨架結構， 包含路易士抗原(Lewis antigens) (路易士a 與路易士b)和ABO血型。細胞表面的醣類以低濃度並且微異均質(microheterogeneous)形式存在，藉由化學合成方式製備高純度的醣體是不可或缺的方法，藉由化學合成法能於醣體特定位置進行後修飾(例如:引入岩藻醣或硫酸根團)。本實驗室已經開發高效率合成方法，合成具有交錯型保護基(orthogonal protecting group)的Gal-β1,3/4-GlcNAc雙醣分子。本篇碩士論文研究目標是延續開發好的合成方法進行第一型醣體的延伸，並且具有高產率。首先，調查[1+1]醣化反應中，半乳醣醣予體(galactoside donors) 3號位的保護 基是影響立體選擇性(stereoselectivity)和反應活性的重要因素；在3號位引入萘醚基能得到最佳的醣化反應結果。在[2+2]四醣體的合成中，當醣予體與醣受體同時為硫代醣苷(thioglycosides)時，會發生配醣基轉移(aglycon transfer)和形成副產物 噁唑崊(oxazoline)，導致無法獲得四醣體產物。在醣受體引入第三丁基二甲基矽醚基(tert-butyldimethylsilyl)作為暫時性保護基能解決配醣基轉移的問題，並能得到 四醣體產物。此外，經由逐步合成法調整反應條件後，我們成功地運用[1+1+2]一 鍋化合成法製備四醣體。

Gal-β1,3-GlcNAc-containing oligosaccharides, also called Type I glycans, serve as the backbone of complex carbohydrates, such as Lewis antigens (e.g., Lea and Leb) and ABO-blood groups. Since these glycan molecules usually exist in low concentrations and highly heterogeneous, synthesis becomes indispensable for preparing a sufficient quantity and introducing desirable modifications (e.g., to attach a L-fucose residue or a sulfate group). We previously developed an efficient method to prepare Gal-β1,3/4-GlcNAc disaccharides with orthogonally protecting groups. To continue this effort, this thesis research aims at applying the developed method for making Gal-β1,3-GlcNAc-containing saccharides of a longer chain in satisfying yields. First of all, the protecting group at O3 of galactosyl donors was found to be critical to the resulting stereoselectivity and reactivity on galactosylation. The optimal result was obtained when O3 was masked with 2-naphthlylmethyl ether. To carry out the [2+2] tetrasaccharide synthesis, the usage of Stolyl group of both donor and acceptor for reactivity-based glycosylation did not afford satisfying yield due to the occurrence of aglycone transfer and the formation of oxazoline side product. The problem was solved by the substitution with tert-butyldimethylsilyl ether in the acceptor as the temporary protecting group. In addition, the one-pot synthesis [1+1+2] was accomplished to give the same tetrasaccharide.