C-glycoside synthesis through radical cross-coupling of glycohydrazides
5 affiliations
- 1Department of Chemistry, Scripps Research, La Jolla, CA, USA
- 2School of Chemistry, University of Bristol, Bristol, UK
- 3Department of Chemistry, Scripps Research, La Jolla, CA, USA. [email protected]
- 4School of Chemistry, University of Bristol, Bristol, UK. [email protected]
- 5Department of Chemistry, Scripps Research, La Jolla, CA, USA. [email protected]
Abstract
Carbohydrates are among the most abundant and structurally diverse biomolecules in nature, playing central roles in energy storage, molecular recognition and cell signalling. 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 relied traditionally on protected sugar derivatives, lengthy sequences or conventional cross-couplings that often suffer from poor selectivity, limited scope and extensive protecting-group manipulation 6 . 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 several 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.
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BibTeX
@article{guo2026cglycoside,
title = {{C-glycoside synthesis through radical cross-coupling of glycohydrazides}},
author = {Yinliang Guo and Yiheng Li and Benedikt Buchberger and Yixin Liu and Carla Capone and Tapas Adak and Shubham Ojha and Jasper L. Tyler and Philipp Neigenfind and Molhm Nassir and Yu Kawamata and Varinder Kumar Aggarwal and Phil S. Baran},
journal = {Nature},
year = {2026},
month = jun,
doi = {10.1038/s41586-026-10807-x},
url = {https://doi.org/10.1038/s41586-026-10807-x},
note = {CC BY},
}
RIS
TY - JOUR
TI - C-glycoside synthesis through radical cross-coupling of glycohydrazides
AU - Yinliang Guo
AU - Yiheng Li
AU - Benedikt Buchberger
AU - Yixin Liu
AU - Carla Capone
AU - Tapas Adak
AU - Shubham Ojha
AU - Jasper L. Tyler
AU - Philipp Neigenfind
AU - Molhm Nassir
AU - Yu Kawamata
AU - Varinder Kumar Aggarwal
AU - Phil S. Baran
PY - 2026
DA - 2026/06/22
JO - Nature
DO - 10.1038/s41586-026-10807-x
UR - https://doi.org/10.1038/s41586-026-10807-x
AB - Carbohydrates are among the most abundant and structurally diverse biomolecules in nature, playing central roles in energy storage, molecular recognition and cell signalling. 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 relied traditionally on protected sugar derivatives, lengthy sequences or conventional cross-couplings that often suffer from poor selectivity, limited scope and extensive protecting-group manipulation 6 . 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 several 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.
SN - 0028-0836
SN - 1476-4687
ER -