Methodological studies of chiral auxiliary assisted galactosylation and the development of glycoconjugate vaccines for C.difficile
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The rapid assembly of the complex carbohydrates is the one of the major challenges in the development of glycoscience. Herein, we established a set of strategies which combined the selected orthogonal protecting groups, glycosyl donors modified by a (S)-phenylthiomethylbenzyl ether at C-2 and fluorous tag-assisted solution phase synthesis into one synthetic procedure. Through this strategy, the rapid preparation of the complex branched carbohydrates with biological importance is possible. The C-2 auxiliaries controlling the 1,2-cis galactosylation were investigated and the technique guaranteed the desired glycosylic linkages in the complex molecule. 2-Naphthylmethyl ether (Nap) and levulinic ester (Lev) were installed as the orthogonal protecting groups to generate glycosyl acceptors and served as the branch spots. Once the glycosylation is completed, the C-2 auxiliary can be selectively removed under acidic condition, but the conditions kept the Lev and Nap orthogonal protecting groups, which made the immediate installation of the 1,2-cis linkage possible. The light fluorous tag simplified the purification process into a simple filtration procedure by using fluorocarbons modified silica gel. The synthesis of the hexasaccharide moiety of GPI anchor of Trypanosoma brucei was accomplished, and it could be a potential target for the development of carbohydrate conjugate vaccine against sleeping sickness in humans and similar diseases in domestic animals. Clostridium difficile can cause severe nosocomial infections which further cause high mortality worldwide. The traditional antibiotics failed to stop such infection, and the patients suffer from the reoccurrence of the C.difficile. Thus, there is an urgent need to development a vaccine which could stop the infection. The C. difficile surface glycan PS-II now is one of the high potential targets for the vaccine development. Herein, we investigated five possible synthetic routes for the assembly of the hexasaccharide from PS-II. By using phenyldiselenide as the anomeric protection group, the aglycon transfer was prevented. A new method to remove the trichloroacetyl amine protecting group by using cesium carbonate was established in the synthesis. Moreover, a reliable route to synthesize the hexasaccharide was confirmed.