Zweifel olefination for C-glycosylation

• Published in: Communications chemistry 2024-12, Vol.7 (1), p.306-10, Article 306
• Main Authors: Trauner, Florian, Boutet, Bilel, Pilz, Fabian, Weber, Verena, Didier, Dorian
• Format: Article
• Language: English
• Subjects: 639/638/403/931; 639/638/403/933; Bioavailability; Boron; Carbohydrates; Carbon; Chemical synthesis; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Diabetes; Glycosides; Glycosylation; Oxidation; Stereochemistry
• ISSN: 2399-3669; 2399-3669
• DOI: 10.1038/s42004-024-01339-4

C-glycosides are significant in medicinal chemistry due to their resistance to enzymatic hydrolysis, making them more stable and bioavailable compared to O-glycosides. Their unique structure also offers potential for developing drugs with improved therapeutic properties, particularly in treating diseases like diabetes and cancer. The main challenge in synthesizing C-glycosides lies in forming the carbon-carbon bond between the sugar and aglycone efficiently, while controlling the stereochemistry and minimizing side reactions. Starting from glycal derivatives, the Zweifel olefination presents an elegant opportunity to access C -glycosides in a selective manner. α-Lithiation of D-glucal, L-rhamnal, D-xylal and L-arabinal scaffolds was employed as a starting point in the synthesis of corresponding unsaturated aryl-, heteroaryl- and alkenyl- C -glycosides. This provides a straightforward strategy towards pharmacorelevant gliflozins and other unreported rhamnal- and xylal-analogs. Carbohydrates play a pivotal role in drug discovery and the pharmaceutical industry, however, synthetic methods for C-glycosylation remain challenging. Here, the authors report Zweifel olefination to access C-glycosides selectively by starting from unsaturated glycal derivatives.