研發alpha-立體選擇性醣基化反應於非活性三疊氮去氧醣硫?予體

Abstract

在這三年期計劃的申請書裡，我們將研究兩個重要合成化學議題：（i)將應用小分子調 控的概念，研發立體選擇性醣基化反應，應用於非活性三疊氮去氧醣硫苷予體；（ii)利 用以上的方法合成大腸桿菌O86:B7細胞壁中具有一種寡糖抗原的重複單元。

(i)這計劃書的第一階段，我們將利用本實驗室已開發的小分子調控的基本原理，來 篩選一系列小形親核試劑如二曱基亞風，氧化三苯磷酸，四曱基尿素等等。含孤電子對 的分子，有助於截留醣基化反應中產生的陽離子中間體。上述研究的結果，讓我們評 估親核試劑的預活化能力及立體化學定向性，最佳的將被選擇在醣基化反應中作為調 控分子，用於解除三疊氮去氧硫代葡醣苷及三疊氮去氧半乳醣苷。

(ii)這計劃書的第二階段，我們將利用調控醣基化反應方法的迭代性（iterative)，合 成天然pentasaccharide寡醣目標物。合成的策略是從研製四醣的合成開始，引入的 岩藻糖(L-fucose)的分支，利用上述的調控醣酣化反應方法，製備具有立體選擇性的 1,2-順式-alpha醣苷鍵。而beta-醣苷鍵的合成，就利用鄰基參與方法。由於完成的 目標被苯醚功能基和疊氮功能基保護，須進行脫保護，從而得到我們需要的目標產品。

In the proposed three-year project, we would apply the concept of modulation to development of stereoselective glycosylation method for 2-azido-2-deoxy-thioglycoside donors. This new iterative glycosylation method would be used for the total synthesis of a pentasaccharide O-antigen repeating unit found in cell wall of Escherichia coli O86:B7.

(i) In this proposal, we apply the established modulation protocol as a blueprint to screen a panel of small nucleophiles such as dimethyl sulfoxide (DMSO), triphenylphosphine oxide (Ph3〇), ^,^-dialkyl acetamide [CH3(C=O)N(CH3)2], tetra-methyl urea CO[N(CH3)2], etc. The oxo-bearing molecules may be useful for entrapment of cationic intermediates generated in glycosylation. The results of the aforementioned study allow us to assess the pre-activation ability and stereo-chemical directing property of the nucleophiles. The best candidate will be selected as the modulator for disarming 2-azido-2-deoxy-thioglucoside and 2-azido-2-deoxythiogalactoside donors in glycosylation reaction. Furthermore, we would elaborate the method to iterative glycosylation, which should find useful in oligosaccharide synthesis.

(ii) The second part of the proposed project is to demonstrate the utility of the iterative glycosylation procedure developed in the first stage of the proposal for the total synthesis of a pentasaccharide O-antigen repeating unit of Escherichia coli O86:B72. Such pentasaccharide unit was first discovered by Peng et al. in 2008 and it contains three 1,2-cis a-glycosidic bonds deriving from L-fucosyl, D-galactosyl, and 2-acetamido-2-deoxy-D-galactosyl units. The proposed synthetic scheme commenced with the preparation of orthogonally protected tetrasaccharide a-D-Gal-(1，3)-P-D-Gal-(1，3)-a-D-GalNAc-(1，3)-D-GalNAc, followed by introduction of the fucosyl branching unit. Construction of the stereoselectivity of 1,2-cis a-glycosidic bond formation were taken care by the aforementioned modulated glycosylation methods; while synthesis of the (3-glycosidic linkage was achieved by the neighboring group participation method. As the furnished target was protected with solely benzyl ether function and azido function, global deprotection will be carried out to give the deprotected carbohydrate product.