Diastereoselective Glycosylation with Different Electrophiles

Many natural products with interesting biological activity are glycosides. In Dr. Bakstad`s research group connected to the Biolink Group and the University of Stavanger, we have for several years worked with anthocyanins, which belongs to the flavonoid class of natural products. They contain glycoside moieties like glucose, galactose and arabinose, as well as disaccharides e.g. rutinose. A significant challenge in the synthesis of anthocyanins is the glycosylation which requires the coupling of the glycosides with the right stereochemistry identical to that of natural anthocyanins. In our laboratory, we have recently developed a novel glycosylation which maintain the stereochemistry identical to that of natural anthocyanins. That means the synthetic anthocyanins and the natural ones have identical biological activities. In the Ph.D. project, we have investigated the full potential of our novel glycosylation. We have investigated the stereochemical outcome of the glycosylation. Steric and stereoelectronic factors as well as solvent effects and leaving group properties on the electrophiles have been studied. In addition, different bases, with variation in counter ions have been explored. Some of our findings are: A wide range of electrophiles, e.g. alpha-haloketones, alpha-haloesters, alpha-halonitriles and triarylhalides undergo anomeric O-alkylation. Semi-polar solvents favor the formation of beta-diastereomers. Polar solvents favor the formation of alpha-diastereomers. The novel glycosylation method described in this Ph.D. project has a significant contribution to carbohydrate chemistry and might be used in preparation of pharmacutical drugs. Target molecules with both ekvatorial or axial coupled glycosides could be prepared with our anomeric O-alkylation method.

Anomeric O-Alkylation of haloacetophenones and other electrophiles We have developed a novel highly diastereoselective glycosylation using a-halo ketones in anomeric O-alkylation. The glycosylation was recently a key step in the total synthesis of cyanidin 3-O-b-D-glucopyranoside chloride. A patent has been filed. In the project we have developed a novel glycosylation which could be used in preparation of front-line drugs derived from glycosylated natural products as well as designed targets containing a- or b-coupled glycosides. Efficient glycosylation methods are therefore of great importance both in academic laboratories as well as in industrial applications.

Glycosides are contained in various species of natural products. Many biological significant glycosides exist as glycopeptides, glycolipides and other glycoconjugates in nature. Several front-line drugs are derived from glycosylated natural products. Carbohydrates play a pivotal role in many biological processes such as bacterial and viral infection, cancer metastasis, and inflammatory reactions. Despite of this, carbohydrate-based therapeutics has developed rather slowly. One reason has been the lack of practical synthetic methods available for carbohydrate research. The bioactive properties of glycosides are often closely related to the stereochemical configuration. Efficient glycosylation methods are therefore of great importance both in academic laboratories as well as in industrial applications. In particular, glycosylation reactions have a unique issue, namely that each glycosylation can give two stereoisomers, the ?- and ?-anomers. How to achieve the desired glycosidic linkage in a stereoselective manner is one of the most important challenges in glycosylation reactions. There are several glycosylation reactions and methods established for stereoselective formation of the desired glycosides. In my research group, a novel highly diastereoselective glycosylation developed in our laboratory has been under investigation for some time. We have so far successfully prepared four natural anthocyanins by use of this glycosylation. However, more research is required in order to establish the full potential of this interesting reaction. We want to explore, steric and stereoelectronic factors as well as solvent effects and leaving group properties on the ?-substituted ketones that might affect the stereochemical outcome of the glycosylation. In addition, we are constantly looking for application of this glycosylation on bioactive target molecules exhibiting challenging architecture.