Synthesis of [2.2.2] L-Iduronate Lactone Thioglycoside and D-Galactosamine Derivatives Relevant to Glycosaminoglycan Fragments

Abstract

Glycosaminoglycans are complicated structures, covalently binding to core proteins, to form a basic unit of proteoglycans. This thesis presents the synthesis of L-iduronic acid (IdoA) and D-N-galactosamine (GalN) derivatives, which are key building blocks for the assembly of glycosaminoglycan (GAG) disaccharides units. A disarmed [2.2.2] L-iduronic lactone thioglycoside and its ring opened form, have been demonstrated to switch the reactivity to be either a glycosyl donor (open ring) or acceptor only (lactone) to enable chemoselective glycosidation, and thus, this type of building block can not only be exploited in accessing the desired disaccharides with fewer steps, but also avoids the tedious manipulation in subsequent glycosylation reactions. The above advantages make this type of building block more attractive. Synthesis of iduronic lactone has been completed in 11 steps, via the C-5 epimerization to convert the furanose ring into pyranose ring, then finally oxidation to generate the L-iduronic lactone. Furthermore, this synthesis route also allows for large scale reaction. Synthesis of a GalN monosaccharide unit was achieved using D-Galactosamine hydrochloride as a starting material, followed by 8 steps to generate the GalN derivative. The key step is installing the 3-O-TBDMS protecting group, which has been reported to survive under lactone ring-opening reaction. This thesis presents IdoA thioglycoside and new GalN monosaccharide building block syntheses to afford fragments suitable for the synthesis of dermatan sulfate (DS) disaccharide, providing for further access to exploring DS binding-protein activity.

Date of Award	31 Dec 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Gardiner (Supervisor) & Simon Webb (Supervisor)