GoKawiilCarbohydrates are among the most abundant and structurally diverse biomolecules in nature, playing central roles in energy storage, molecular recognition, and cell signaling. Within this domain, C-glycosides1-3, in which the oxygen atom of the glycosidic bond in O-glycosides is replaced by carbon, have emerged as valuable motifs in medicinal chemistry due to their resistance to enzymatic hydrolysis2,4. Of particular importance are C-aryl glycosides, exemplified by the SGLT2 inhibitors dapagliflozin, canagliflozin, and empagliflozin, which are frontline therapies for type 2 diabetes5-7. However, scalable syntheses of C-aryl glycosides have traditionally relied on protected sugar derivatives, lengthy sequences, or conventional cross-couplings that often suffer from poor selectivity, limited scope, and extensive protecting-group manipulation6. Herein, we report a practical approach to C-aryl glycosides using glycosyl sulfonyl hydrazides as redox-neutral radical precursors for cross-coupling. Prepared directly from unprotected native sugars, these reagents generate glycosyl radicals under mild conditions and enable efficient access to diverse C-aryl glycosides, including all approved SGLT2 inhibitors, natural products such as salmochelins and neopetrosins, and medicinally relevant probes. Beyond anomeric functionalization, this platform enables CāC bond formation at multiple positions on carbohydrate scaffolds and supports stereoretentive radical coupling that can override inherent stereochemical biases, expanding practical access to carbohydrate-derived therapeutics and chemical tools.
C-glycoside synthesis via radical cross-coupling of glycohydrazides
Why This Matters
This breakthrough in C-glycoside synthesis offers a more efficient, scalable, and selective method for producing complex carbohydrate derivatives, including important medicinal compounds like SGLT2 inhibitors. It simplifies the process by using unprotected sugars and mild conditions, potentially accelerating drug development and expanding therapeutic options. This advancement could significantly impact the pharmaceutical industry and improve access to carbohydrate-based medicines.
Key Takeaways
- Enables efficient synthesis of C-aryl glycosides from unprotected sugars.
- Supports stereoretentive radical coupling, overcoming stereochemical biases.
- Facilitates production of medicinally relevant compounds, including approved SGLT2 inhibitors.
Explore topics:
c-glycoside
glycosyl sulfonyl hydrazides
sglt2 inhibitors
dapagliflozin
radical cross-coupling
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