C-glycoside synthesis via radical cross-coupling of glycohydrazides.

Authors

Yinliang Guo, Yiheng Li, Benedikt Buchberger, Yixin Liu, Carla Capone, Tapas Adak, Shubham Ojha, Jasper L Tyler, Philipp Neigenfind, Molhm Nassir, Yu Kawamata, Varinder K Aggarwal, Phil S Baran

Published in

Nature. Jun 22, 2026. Epub Jun 22, 2026.

Abstract

Carbohydrates 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-glycosides^1-3, 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 hydrolysis^2,4. Of particular importance are C-aryl glycosides, exemplified by the SGLT2 inhibitors dapagliflozin, canagliflozin, and empagliflozin, which are frontline therapies for type 2 diabetes^5-7. 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 C-C 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.

PMID:
42332110
Bibliographic data and abstract were imported from PubMed on 23 Jun 2026.

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