Research For Synthesis Of Carbohydrate Drugs Topiramate, MDP And The Intermediate Of GMDP And Glycosylation Reaction

Carbohydrate compounds are a class of organic compounds with the most widely existence and the most species in nature. They are not only the important material composed of organisms, but also almost involved in the whole process of life. With the progress of separation and analysis techniques, the understanding of the carbohydrate compounds is gradually expanded from the main energy source to the important part of biology, medicine, immunology and pharmacy.The development of carbohydrate chemistry, especially carbohydrate synthetic chemistry, greatly facilitates the discovery and development of carbohydrate drugs. Because of carbohydrate drugs having characteristics of carbohydrate compounds, such as strong hydrophilicity, the specific effect with protein, and low toxicity and side effects by acting on the cell surface, they become the focus of attention by medicinal chemistry and synthetic chemistry.Topiramate, which is the antiepileptic drugs with a certain market share, is one typical simple carbohydrate drug. It is a monosaccharide drug having diacetonide fructopyranose sulfonamide structure. Immunostimulant is a large class of agents which can adjust, enhance and restore the immune function, and mainly used for infectious diseases, some autoimmune diseases and cancer adjuvant therapy in clinical. Peptidoglycan, the main component of bacterial cell wall, is an effective immunostimulant and immune adjuvant. The minimum structure required for the immunostimulation muramyl dipeptide (MDP) and the repeating unit glucosaminylmuramyl dipeptide (GMDP) also have immunomodulatory activity. In this dissertation, we designed and synthesized the carbohydrate intermediate of the above three molecules.Chapter1is the short introduction of carbohydrate compounds, the characteristics, classification and examples of carbohydrate drugs. In this chapter, the most crucial reactions in the synthesis of carbohydrate drugs——glycosylation reaction was also presented, including its development and several methods of glycosylation.In chapter2monosaccharide drug, including Topiramate and MDP were designed and synthesized. The routine of Topiramate aimed to using simple and commercial materials and convenient operations to synthesize the final product. We started from D-fructopyranose through three-step reaction to obtain the product with high purity. MDP can be divided into two parts, which are muramyl acid and dipeptide. We designed the routine from2-acteyl glucosamine to muramyl acid derivative, in which we focus on the selection of appropriate protective groups. In another hand, we synthesized the D-Isoglutamines from D-Glutamic acid with several conversions. Under the optimized condensation conditions, D-Isoglutamines reacted with L-Alanine to produce the dipeptide offering the peptide part of MDP.In chapter3, we designed a routine for the disaccharide intermediate of GMDP by2-acetyl glucosamine and muramyl acid. We synthesized several glycosyl donors including halogen glycosides, trichloroacetimidate ester and glucosinolate, and muramyl acid derivatives with various protective group as glycosyl acceptors. We tried the glycosylation reactions with different activators. Although the glycosylation products were not successfully obtained, we summarized the factors affecting the reactivity, and predicted the structure of glycosyl acceptors and donors with higher reactivity.In chapter4, according to the experience of failure, the new type of glycosyl acceptors and donors with high reactivity were designed. We started from2-Glucosamine to synthesize both phthaloyl glucosamine derivatives as glycosyl acceptors instead of muramyl acid and benzyl glucosamine as glycosyl donors. We tried different combination of glycosyl acceptors and donors, and eventually found the pair to obtain the glycosyl product with high selectivity and high yield. At last we also made some alternations of protective group to get the precursor compounds linked to the peptide chain.In chapter5, we designed several kinds of carbohydrate sulfoxide compounds with diazo group, which were expected to be the new glycosyl donor in glycosylation reaction. In addition, we did the research about scale-up reaction of three components reactions giving α-hydroxy-β-amino acid ester and the scale-up reaction of synthesis the BINOL-phosphate acid.