Research Projects

Glycobiology is a rapidly advancing field emphasizing designing and chemical synthesis to generate carbohydrate-based libraries of small molecules. Glycoconjugates play vital roles in biological systems, including cell signaling, immune recognition, and disease progression. The structural diversity of carbohydrates, especially when functional groups are introduced at non-natural positions, allows for the development of glycomimetics with improved biological profiles. Many natural products with medicinal value, such as antibiotics, anticancer, antiviral, and cardiotonic agents, contain rare or deoxy sugars as essential components. However, making these sugars and their glycosides selectively and practically remains a significant challenge in synthetic organic chemistry. The β-glycosidic linkage is especially prevalent in many bioactive compounds, the development of β-stereoselective glycosylation strategies a high priority for carbohydrate chemists. However, achieving β-selectivity, particularly in 2-deoxy and 2,6-dideoxy sugars, remains a significant challenge because of the intrinsic α-anomeric effect and the lack of NGP at the C-2 position. Traditional strategies often rely on complex protecting group manipulations or multistep de novo synthesis, which limits their practicality and scalability. This project focuses on developing new, stereoselective methods to synthesize β-glycosidic linkages using glycal-based donors. In particular, the work addresses the difficulty in making β-2-deoxy and β-2,6-dideoxy glycosides, which are commonly found in bioactive molecules. Traditional methods struggle with selectivity because these sugar units lack directing groups at the C-2 position and often favor the undesired α-anomer due to the natural anomeric effect. The approach involves using remote group participation (RGP or LRP); a strategy where stereodirecting protecting groups at C-3, C-4, or C-6 positions influence the stereochemical outcome of the glycosylation. This will be combined with eco-friendly metal catalysts such as bismuth and ruthenium to activate glycal donors under mild conditions. These conditions promote β-selective glycosylation via either Ferrier rearrangement or direct 1,2-addition pathways to access a wide variety of 2-deoxy, 2,6-dideoxy, and rare sugar glycosides. Additionally, the project will explore complexity-generating reactions, such as dihydroxylation and hydrogenation, to access 2,3-dideoxy glycosides, C-2 functionalized β-2-deoxy glycomimetics, and relevant bioactive natural products. Scientific Motivation and Advantages of Sugar-Based Molecules: Carbohydrate templates are highly attractive due to their multiple stereocenters, oxygen-rich frameworks, and compatibility with orthogonal protection strategies. Their enantiomeric purity makes them ideal starting materials for synthesizing natural products and small-molecule therapeutics. Finally, this research aims to develop efficient, stereodivergent protocols to expand the chemical space for sugar-based drug candidates and provide valuable chemical tools for glycobiology. Despite the significant advances in anomeric glycosylation, the β-stereoselective synthesis of rare/unnatural sugars remains a significant challenge, particularly, the synthesis of β-2-deoxy-glycosidic linkages, due to the lack of substituents at C-2 and the electron-rich nature of the donors; this intrinsic bias poses a significant challenge for the stereoselective synthesis of β-glycosidic linkages. To address this, the present proposal builds upon a “state-of-the-art” approach that employs glycal donors and utilizes β-stereoselective glycosylation strategies: Ferrier Rearrangement or 1,2-Addition, guided by stereo-directing remote group participation (RGP or LRP) at the C-3/C-4, and/or C-6 positions. The proposed research focuses on stereodirecting remote group participation (RGP/LRP), solvent-controlled reactivity, and direct access to rare sugars and β-2-deoxyglycosides.