Synthesis and Strategic Application of Difluorinated-C-Glycoside Derivatives in Medicinal Chemisitry
Date of Award
1-1-2025
Document Type
Dissertation
Degree Name
Ph.D. in Chemistry
First Advisor
David A. Colby
Second Advisor
John M. Rimoldi
Third Advisor
Jonah W. Jurss
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
Bioactive natural carbohydrates are vital in medicinal chemistry, addressing diseases such as bacterial infections, cancer, diabetes, and cardiovascular conditions. However, their therapeutic potential is hindered by poor metabolic stability and clinical trial failures, primarily due to the fragile C-O bond. Our research focuses on replacing the cleavable C-O bond with a robust C-CF2 bond to enhance stability, a promising yet challenging strategy in medicinal chemistry. Additionally, the inherent pharmacokinetic and pharmacodynamic limitations of natural carbohydrates have led to the exploration of glycomimetic as an alternative, offering improved hydrolytic and metabolic stability. We investigated two synthetic strategies to achieve the precursors for the synthesis of difluorinated C-glycosyl compounds. The first strategy targeted the synthesis of difluoromethylated benzopyrans, incorporating carbohydrate moieties to mimic natural glycosyl features. Despite the relevance of benzopyrans in bioactive compounds, this approach faced challenges, including low yields and complex product mixtures. The second strategy involved the synthesis of difluoro olefins of exo-cyclic enol ethers derived from gluconolactone. This approach tackled significant synthetic hurdles, as only a few methods— Wittig, modified-Julia olefination, and a three-step route—have been developed for the synthesis of such precursors in the past 60 years. In our work, we synthesized acetate-protected difluoro olefins, which balance stability and sensitivity, alongside benzyl- and silyl-protected counterparts. From these precursors, we synthesized the difluoro-C-glycosides. Using radical coupling chemistry, we proceeded to synthesize difluoro-C-glycosides. Employing the Barton-McCombie radical reaction, we successfully synthesized difluoro-C-glycosides by forming C-S bonds through radical coupling, achieving bio-isosteric replacement of the C-O bond with a C-SCF2 bond at the anomeric position. A series of difluoro-C-glycosides of glucose and galactose derivatives were synthesized for further studies. Preliminary stability evaluations revealed that difluoro-C-glycosides demonstrate hydrolytic stability, unlike O-glycosides. This research represents a strategic advancement in developing metabolically stable compounds, offering promising prospects for future drug development.
Recommended Citation
Begum, Amena, "Synthesis and Strategic Application of Difluorinated-C-Glycoside Derivatives in Medicinal Chemisitry" (2025). Electronic Theses and Dissertations. 3244.
https://egrove.olemiss.edu/etd/3244