Making carbohydrate-derived drugs from naturally occurring sugars often requires chemists to temporarily shield the sugar’s many nearly identical hydroxyl groups so they do not all react with the reagents used to build the drug. Those protecting groups must later be removed, adding multiple steps that complicate and slow the synthesis.
A strategy published in 2024 showed that natural sugars could be converted directly into reactive intermediates for further chemical modification, avoiding the protecting-group steps. Those intermediates, however, could not directly produce C-aryl glycosides, in which a sugar is joined by a carbon-carbon bond to an aromatic ring. That type of linkage is found in sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are used in treatments for type 2 diabetes and in many antivirals and antibiotics.
Now two research teams, working independently, have overcome that limitation by adapting related chemistry from the laboratory of Scripps Research’s Phil Baran to produce glycosyl sulfonyl hydrazides, a class of sugar-derived compounds. Under nickel catalysis, these compounds react directly with simple aromatic building blocks to forge the elusive carbon-carbon bond.
One team, co-led by Baran, developed a platform that attaches aromatic rings not only at the sugar’s usual reactive C1 position but also at positions across the sugar ring (Nature 2026, DOI: 10.1038/s41586-026-10807-x).
A challenge was ensuring the aromatic ring adopted the desired 3D arrangement—the β-anomer—rather than the alternative α form. Optimization of the nickel-catalyzed reaction revealed that conditions employing tetramethylguanidine (TMG) as the organic base substantially improved both yield and β-selectivity.
The researchers used the method to synthesize all five SGLT2 inhibitors approved by the US Food and Drug Administration. Their work included a decagram-scale synthesis of dapagliflozin prepared directly from inexpensive, unprotected dextrose.
The Baran team’s work is “an impressively general platform,” says Zhoulong Fan, an organic chemist at the School of Pharmaceutical Sciences at Shanghai Jiao Tong University and coauthor of the second, complementary paper in the Journal of the American Chemical Society (2026, DOI: 10.1021/jacs.6c06488), in an email. “It will be the better choice when aromatic groups need to be installed at C2 through C6 or when challenging stereochemical outcomes are required.”
Fan’s group instead focused on making the most common transformation—C1 arylation—as highly stereoselective and practical as possible. To prevent the sugars’ many hydroxyl groups from interfering with nickel catalysis, the researchers designed a family of ligands that grip the nickel catalyst on three sides, shielding the metal center while directing the reaction toward the β-anomer. One ligand enables the gram-scale synthesis of empagliflozin, another SGLT2 inhibitor, directly from unprotected sugars.
The reaction also works with a wide variety of medicinally relevant aromatic compounds and could be driven by either heat or visible light.
A new C-aryl glycoside chemistry enables sugar attachment to the chemotherapy drug paclitaxel, which could improve its water solubility and tumor selectivity.
To demonstrate the method’s medicinal potential, Fan’s team used the same aryl C-glycoside chemistry to attach sugars to an aryl handle on the chemotherapy drug paclitaxel, also known as Taxol—an attractive strategy for improving water solubility and tumor selectivity. One resulting conjugate preferentially inhibited glucose-dependent cancer cells and was more than 10,000-fold more water soluble than Taxol itself.
For Varinder Aggarwal, a chemist at Bristol University and a co-leader of the Nature paper, the Taxol experiment is “a very nice demonstration” because it shows the chemistry works even on a complex drug packed with chemically reactive groups that might otherwise interfere with the reaction.
“[The Fan team’s work] is another beautiful example of how broadly applicable this technology is,” Aggarwal says. “Using different catalysts, ligands, and reagents to reach similar results suggests there’s plenty of room to fine-tune the chemistry for particular substrates.”
“These two studies will exert a profound, paradigm-shifting influence on how we synthesize C-aryl glycosides,” says Srinivas Hotha, a synthetic chemist at the Indian Institute of Science Education and Research Pune who was not involved in the work. “Achieving two-step, gram-scale syntheses [of SGLT2 inhibitors], which traditionally require five or more steps, is going to easily outweigh the cost of these specialized ligands.”
Hotha says the next challenge will be demonstrating that the same stereochemical control can be maintained with other classes of sugars, which often behave very differently in chemical reactions, and during scale-up for manufacturing, where controlling impurities becomes increasingly difficult.
