Carbohydrates are ubiquitous in all living systems and play a vital role in many important biological events. Oligosaccharides containing 1,2-cis-alpha-glycosidic linkages, such as alpha-glucosides, alpha-galactosides, and alpha-fucosides are very common in human and bacterial glycans. To date, they are still considered to be challenging glycosidic linkages in carbohydrate synthesis. Stereoselective methods for their synthesis are highly desirable. In this proposal, we will develop an efficient and general strategy for the stereoselective synthesis of oligosaccharides containing 1,2-cis-alpha-glycosidic linkages. The strategy involves a very minimal number of steps and is compatible with the current platform for the synthesis of 1,2-trans-beta- glycosidic linkages.
In Aim 1, we propose to develop a novel transition metal-catalyzed method to attach a wide range of directing groups to the C2-position of monosaccharides.
In Aim 2, we propose to form 1,2-cis- alpha-glycosidic linkages stereoselectively, which is controlled by the directing group on the C2-position. We will also explore different conditions for the removal of the directing group. The above proposed aims are significant because they will yield readily available chemical tools for carbohydrate chemists and glycobiologists to study the structures and functions of biomedically relevant carbohydrates in many living systems. The above sequence of attachment, glycosylation, and cleavage for the synthesis of 1,2-cis-alpha- glycosides is compatible with and also comparable to the current platform for the synthesis of 1,2-trans-beta- glycosides, which involves attachment of an acyl group to the C2-OH, stereoselective glycosylation, and cleavage of the C2-acyl group. A unified platform for both types of glycosides will transform the synthesis of oligosaccharides by changing the current case-by-case approach to a more systematic and general strategy.
Synthetic methods and strategies developed in this proposal can be applied to the preparation of many bioactive carbohydrates, which may facilitate our understanding for human diseases and the development of therapeutics.
