Kdo（3-脱氧-D-甘露-辛-2-酮糖酸）是一种存在于细菌脂多糖和荚膜多糖中的八碳糖，与脂质A通过共价键连接构成Lipid A-Kdo₂，是诱发宿主产生免疫应答的最小单元，对维持细菌的生理活性具有重要意义。对于开发理想的Lipid A-Kdo₂疫苗，最重要的是Kdo核心区域的构建。Kdo糖苷在细菌内的合成需要多种酶的共同参与，从细菌中大规模获得Kdo存在分离困难、价格高昂等问题。通过化学合成方法构建Kdo糖苷键则需要考虑其自身结构导致的低反应性和选择性。因此，发展一种简洁方便的新策略合成单一构型的Kdo糖苷化合物依然十分有必要。

本论文首先参照文献方法制备了4,5:7,8-O-异亚丙基-Kdo，而后分别合成了异亚丙基和乙酰基保护基的Kdo对甲基苯硫苷作为糖苷化反应的供体，发展了基于Tf₂O/(p-Tol)₂SO制备α-Kdo糖苷的新策略。

一、开展了以4,5:7,8-O-异亚丙基-Kdo硫苷作为糖苷化供体，2-O-苄基-4,6-O-苄叉-α-D-甘露糖甲苷作为受体进行模型反应研究，对预活化温度（-80 ^oC ~ -50 ^oC）和反应温度（-60 ^oC ~ -30 ^oC）、(p-Tol)₂SO当量数（2 ~ 7当量）、溶剂种类（DCM、DCM/MeCN）以及外源添加剂（TTBPm和DMF）进行最优条件筛选，以71%的产率获得预期的糖苷化产物（α/β: 7.6/1）。通过对9种糖基受体化合物进行底物拓展研究，发现产物的构型和产率与醇羟基的级数有关。以一级醇作为糖苷化受体时，具有高产率（73% ~ 96%）以及低选择性（α/β: 1.3 ~ 3.3/1）；而以二级醇作为糖苷化受体（惰性受体除外），反应产率适中（45% ~ 71%）选择性良好（α/β: 6.3/1 ~ α only）。

二、开展了以4,5,7,8-O-四乙酰基-Kdo硫苷作为糖苷化供体，2,3,4-三苄基-α-D-吡喃葡萄糖甲苷作为受体进行模型反应研究。通过对预活化温度（-70 ^oC~-60 ^oC）和反应温度（-50 ^oC~-40 ^oC）、(p-Tol)₂SO当量数（5 ~ 10当量）进行最优条件筛选，以91%的产率得到α糖苷化产物。对11种底物进行拓展性研究发现，可以高产率（54% ~ 97%）获得α-Kdo糖苷化产物。

总的来说，使用异亚丙基和乙酰基保护基的Kdo对甲基苯硫苷作为糖基供体，Tf₂O/(p-Tol)₂SO为促进剂，与20种糖基受体进行糖苷化反应，完成了对α-(2→1)-、α-(2→2)-、α-(2→3)-、α-(2→4)-、α-(2→6)- Kdo糖苷键的构建。

Kdo (3-deoxy-D-manno-oct-2-ulosonic acid) is an octasaccharide existing in bacterial lipopolysaccharide and capsular polysaccharide. Kdo is linked with lipid A by covalent bonds, and lipid A-Kdo₂ provides the smallest unit to induce the host to produce immune response, which is significant in maintaining the physiological activity of bacteria. For the development of ideal lipid A-Kdo₂ vaccine, the primary goal is to complete the construction of Kdo core region. The synthesis of Kdo glycosides in bacteria requires the joint participation of a variety of enzymes. The large-scale acquisition of Kdo from bacteria has some problems, such as difficult separation and high price. In addition, the construction of Kdo glycosidic bond by chemical synthesis has the problems of low reactivity and selectivity caused by its unique structure. Therefore, it is still necessary to develop simple and convenient strategy to synthesize single configuration of Kdo glycosides.

In this work, 4,5:7,8-O-isopropylidene-Kdo was prepared according to the literature method, and then two kinds of thioglycoside donors with isopropylidene and acetyl as protective groups were synthesized. A new strategy to synthesize α-Kdo based on Tf₂O/(p-Tol)₂SO was successfully developed.

The model glycosylation reactions of 4,5:7,8-O-isopropylidene-Kdo thioglycoside was carried with 2-O-benzyl-4,6-O-benzylidene-α-D-mannoside to investigate the effects of pre-activation temperature (-80 ^oC to -50 ^oC), reaction temperature (-60 ^oC to -30 ^oC), the amount of (p-Tol)₂SO (2.0 - 7.0 equiv.), solvent (DCM, DCM/MeCN) and additive TTBPm/DMF on the reaction. Under the optimum conditions, the expected glycoside product was obtained in 71% yield (α/β: 7.6/1). Among 9 different acceptors, the glycosylation of the 4,5:7,8-O-isopropylidene-Kdo thioglycoside donors with primary alcohol acceptors shows high yield (73% to 96%) and low selectivity（α/β: 1.3 to 3.3/1). However, secondary alcohol acceptors shows moderate yield (45% to 71%) except for disarmed glycosyl acceptor) and good selectivity (α/β: 6.3/1 to α only).

The model glycosylation reactions of 4,5,7,8-tetra-O-acetyl-Kdo thioglycoside was carried with methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside to explore the effects of pre-activation temperature (-70 ^oC to -60 ^oC), reaction temperature (-50 ^oC to -40 ^oC) and the amount of (p-Tol)₂SO (5.0 - 10.0 equiv.) on the reaction. Under the optimum conditions, the desired glycosylation product was obtained in 91% yield and only α-selectivity. Among 11 different glycosyl donors, a high yield (54% to 97%) and high α-selectivity were observed to provide Kdo glycoside products.

In conclusion, with isopropylidene or acetyl protected Kdo p-methylphenyl thioglycoside as glycosyl donors, Tf₂O/ (p-Tol)₂SO as promoter, the glycosylation reactions were successfully carried out with 20 kinds of glycosyl acceptors, and the α-(2→1)-、α-(2→2)-、α-(2→3)-、α-(2→4)-、α-(2→6)- Kdo glycosidic bond were constructed.