Diastereoselective Glycosylation with Different Electrophiles

En rekke naturprodukter med interessant biologisk aktivitet er glykosider. I Dr. Bakstad`s forskningsgruppe tilknyttet Biolink Group og Universitetet i Stavanger har vi i flere år arbeidet med anthocyaniner som hører til den store gruppen av naturprodukter som kalles flavonoider. Anthocyaninene inneholder glukose, galaktose og arabinose, men også disakkarider som rutinose. En stor utfordring med syntetisk fremstilling av anthocyaniner er å få koblet på glykosidet med rett stereokjemi, identisk med det vi finner i naturlige anthocyaniner. I dette prosjektet har vi utviklet en ny glykosyleringsreaksjon som gir rett stereokjemi og dermed er de syntetisk fremstilte anthocyaninene identiske med de naturlige. Det betyr også at de har identisk biologisk aktivitet. I dette doktorgradsprosjektet har vi kartlagt glykosyleringsreaksjonens fulle potensiale. Vi har undersøkt hvordan diastereoselektivitet påvirkes av reaksjonsbetingelsene, valg av løsningsmidler, elektrofil og base er studert. Følgende resultater er oppnådd: Et bredt utvalg av elektrofiler som alfa-haloketoner, alfa-haloestere, alfa-halonitriler og trihalogenerte elektrofiler undergår anomeric O-alkylering. Semi-polare løsningsmidler favoriserer dannelsen av of beta-diastereomere glykosider. Polare løsningsmidler favoriserer dannelsen av of alfa-diastereomere glykosider. Glykosyleringsmetoden beskrevet i dette Ph.D. prosjektet har høy diastereoselektivitet og kan således ha et betydelig bidrag til karbohydrat kjemi.

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.