Stereoselective synthesis of glycosides through novel catalytic method development

Abstract

Carbohydrates are one of the most prevalent natural product class with a wide range of structural and functional properties. Further, glycoside bond formation is one of the most important process in carbohydrate chemistry, particularly the production of O(S)-glycosides, which are abundant in bioactive compounds. To achieve this, glycosyl donors are synthesized and converted into reactive glycosylating species using catalysis. In this thesis, various activation strategies have been established to activate different glycosyl donors to synthesize a range of O(S)-glycosides, some of which are bioactive compounds. A phosphonochalcogenide (PCH) catalyzed strategy was developed to catalyze a stereoselective α-iminoglycosylation of iminoglycals with a wide range of glycosyl acceptors with remarkable protecting group tolerance in chapter 3. Mechanistic research revealed the catalyst's unexpected role in serially activating both the glycosyl donor and acceptor in the upstream and downstream stages of the reaction via chalcogen bonding (ChB). The dynamic interaction of chalcogens with substrates brings up new mechanistic possibilities based on repetitive ChB catalyst engagements and disengagements in multiple elementary steps. This research addressed the overall shortage of robust catalytic iminoglycosylations and provided a feasible approach for biologically relevant sp2-iminoglycosidic scaffolds. This methodology will demonstrate the enormously underexploited potential of sigma hole-based activation in broadening the frontiers of stereoselective carbohydrate and glycomimetic synthesis in the future. A synergistic chiral Rh(I) and organoboron-catalyzed protocol was introduced to catalyze site selective carbohydrate functionalization to synthesize biologically relevant anomeric aryl naphthalene glycosides with excellent enantioselectivity, diastereoselectivity and regioselectivity in chapter 4. The proper choice of an organoboron catalyst and ligands are critical to the success of this protocol. Following further investigation of this approach, my study revealed that structurally related allylic carbonate substrates were also well tolerated to furnish functionalized carbohydratesl with outstanding regio- and diastereoselectivity. This successful methodology would stimulate more effort in the development of chiral transition catalytic systems for demanding site-selective functionalizations of carbohydrates with prochiral electrophiles.