Degree
Doctor of Philosophy (PhD)
Department
Chemistry
Document Type
Dissertation
Abstract
Carbohydrates are integral to various biological processes such as cell signaling, function and regulation. Carbohydrates also play critical roles in various disease and metastatic pathways. This has garnered considerable attention to the field of glycoscience, however, the study of carbohydrate-containing compounds remains a challenge due to the difficulty in obtaining pure samples from natural sources. As a result, the biological evaluation of carbohydrates relies on synthetic chemistry to produce pure compounds in significant quantities. However, the synthesis of carbohydrates present their own challenges owing to the complexity in controlling stereochemistry and regiochemistry. The most significant of these challenges is controlling stereoselectivity of the glycosylation reaction. Glycosylation reactions can result in two possible stereoisomers at the anomeric carbon, defined as 1,2-cis or 1,2-trans. Neighboring group participation of a 2-acyl substituent is the general approach to obtaining 1,2-trans glycosidic linkages. However, 1,2-cis selectivity is far harder to obtain, and a generalized approach to the formation of stereoselective 1,2-cis linkages remains a challenge in oligosaccharide synthesis. In chapter 1, I will discuss some of the advancements and progress made in the area of 1,2-cis stereoselective O-glycosylation.
The plethora of innovative approaches to achieve 1,2-cis-selective glycosylation, underscores the complexity these linkages present. However, current methods rely on laborious, multi-step syntheses of the glycosyl donor to incorporate specialized protecting groups, leaving groups, and chiral auxiliaries, or necessitates the use of costly and/or hazardous reagents. Additionally, many of the reported strategies display a narrow scope, showing compatibility only with specific systems. In chapter 2, I will discuss my development of a novel approach to 1,2-cis-selective O-glycosylation via in-situ benzyne-mediated activation of chalcogenoglycoside donors. This method is highly stereoselective and demonstrates compatibility across a wide range of donors and acceptors. In addition, the glycosyl donors used for this approach can be synthesized with relative ease and do not require installation of protecting groups or auxiliaries to achieve high stereoselectivity.
In chapter 3, I discuss several alternative approaches to benzyne-mediated activation of chalcogenoglycosides that I investigated. Aryne-mediated activation using bromane salts was the most promising method evaluated. A limited optimization study was conducted where excellent to modest yields of the O-glycosylation product was achieved. This represents the second method of aryne-mediated activation of chalcogenoglycosides developed.
Chalcogenoglycosides such as thio- and selenoglycosides are widely utilized in oligosaccharide synthesis due to their configurational stability and amenability to multistep synthesis. However, their activation requires use of highly electrophilic reagents not suitable in the presence of sensitive functional groups. Photochemistry has proven to be an effective alternative activation approach whereby photons supply the energy needed to activate chalcogenoglycosides via a single electron transfer process. In chapter 4, I will discuss my development of a visible-light-promoted O-glycosylation method. This approach utilizes simple selenoglycoside donors, mild visible light activation, and commercially available reagents. In addition, this method results in stereoselective O-glycosidic products and is compatible across a broad range of donors and acceptors.
Selenoglycosides are common glycosyl donors in oligosaccharide synthesis, demonstrating advantages in orthogonal reactivity in the presence of alternative donors. However, selenoglycosides have recently gained considerable interest from medicinal chemists due to their promising biological activities. Changes in N- and O-linked glycans are associated with disease pathways such as auto-immune disorders, infection, and cancer. The development of small molecules that disrupt N- and O-linked glycan biosynthesis associated with pathogenic pathways can lead to novel strategies to treat various diseases and infections. Selenoglycosides have been identified as effective inhibitors of glycosylation processes due to their ability to resist intracellular hydrolysis. In chapter 5, I will discuss my synthesis of various selenoglycoside analogs that will be evaluated as potential N- and O-glycan decoys.
Date
7-23-2024
Recommended Citation
Duong, Tiffany, "Novel Approaches to the Activation of Chalcogenoglycosides for O-Glycosylation" (2024). LSU Doctoral Dissertations. 6523.
https://repository.lsu.edu/gradschool_dissertations/6523
Committee Chair
Justin Ragains