Scripps Research scientists demonstrate a faster, cheaper route to making critical drugs using common table sugar

LA JOLLA, CA-Some of the world's best-selling diabetes drugs depend on a chemical bond that has long been notoriously difficult, slow and expensive to manufacture. Now, scientists at Scripps Research and the University of Bristol have developed a new, simple method to build that same chemical bond, starting with common table sugar and vinegar.

Carbohydrates are everywhere in biology and medicine, yet they have long been among the most frustrating molecules to work with in the lab for a variety of reasons, making traditional synthesis a slog of multiple steps and often disappointing results. This is especially true for C-glycosides-molecules in which a carbon atom replaces the oxygen that normally links a sugar to another fragment. These structures are prized because they resist enzymatic breakdown, giving them better metabolic stability than alternatives.

In the new work, the researchers showed that C-glycosides can be created with a much more straightforward protocol than had historically been used. The research, published in Nature on June 22, 2026, centers on dapagliflozin, canagliflozin, empagliflozin and similar medicines, known as SGLT2 inhibitors, all of which contain C-glycosides. Together, these drugs bring in more than $20 billion a year treating type 2 diabetes.

The point of this is to show that anyone in a garage can make an SGLT2 inhibitor with reagents that are widely available, says co-senior author Phil Baran, a professor and the Dr. Richard A. Lerner Endowed Chair at Scripps Research. We have not patented this method, so we welcome any generic drug company-or anyone else-who wants to use it to help bring costs down for patients.

To effectively treat diabetes, SGLT2 inhibitors must resemble glucose enough to bind to a protein in the kidneys that normally pulls glucose out of the blood, but not so closely that the body breaks them down for fuel. Creating the drugs requires modifying a section of a sugar molecule so it contains a C-glycoside, making the sugar resistant to breakdown. However, swapping a sugar's oxygen for a carbon has long been a manufacturing challenge.

A sugar molecule is covered in reactive sites called hydroxyl groups, and conventional methods for making a C-glycoside require temporarily shielding nearly all of the hydroxyls before the key bond is formed, and then removing those shields afterward. It involves many steps and requires hazardous, highly reactive reagents.

Baran's lab has pioneered sulfonyl hydrazide reactions, which can forge new carbon-carbon bonds without these reagents. In one of these sulfonyl hydrazide reactions, a small nitrogen-containing chemical group is attached to a molecule at a specific site. When the hydrazide is heated in the presence of a particular type of metal, it breaks apart and releases nitrogen gas, generating a reactive fragment called a radical at that exact spot. Because it is so reactive, that radical immediately seeks out and bonds with a second molecule, forming a new carbon-carbon bond without requiring any other added chemicals.

In the new study, the team showed that a sugar molecule can be directly converted into a sulfonyl hydrazide by mixing it with a common reagent in mild acid (like acetic acid or vinegar) and letting the product crystallize. That single step installs the hydrazide group at the exact carbon where the sugar's C-glycoside bond needs to form, setting up the sugar to react as a radical precursor in the same way Baran's lab had previously shown for simpler organic molecules.

This removes the engineering barrier to activating the radical precursor, says Baran. You don't need more complicated techniques like photochemistry, electrochemistry or stoichiometric metal salts-none of which are as easy to scale up.

To demonstrate how far this could be pushed, the team showed that the chemistry works at a much larger scale using dextrose powder bought at Walmart for about $5 a pound, dissolved in ordinary household vinegar, and documented the entire process in a video posted online.

A boring reaction is a useful one, says Baran. It's simple to run and can be performed in labs across the world.

Using this approach, the team made all of the currently approved SGLT2 inhibitors, several related compounds still in clinical trials, and complex natural products that previously required up to 20 separate synthetic steps to produce. They also showed that the same chemistry could attach new chemical groups to other positions on a sugar molecule, not just the one site relevant to these particular diabetes drugs-a capability the team says could be useful for building entirely different classes of sugar-based compounds.

Making complex molecules directly from unprotected sugars has long been a major challenge in chemistry, yet solving it could accelerate the discovery of new medicines and create shorter routes in their manufacture, says Varinder Aggarwal of the University of Bristol, co-senior author of the new work. After several unsuccessful attempts, we found that the Baran hydrazide coupling method worked exceptionally well with these sugars and so we joined forces with the team at Scripps to further develop the chemistry. Due to its operational simplicity and ready availability of the starting materials, I have no doubt it will be the method of choice to make these important molecules.

The new reaction will likely have multiple impacts on the processes of drug discovery, development and manufacturing, Baran adds, since the rate at which you can discover new drugs is tied to the rate of advancement in the field of organic chemistry.

Baran has often spoken of wanting radical cross-coupling to become unremarkable. With glycohydrazides, that vision has taken another concrete step forward-turning one of the most structurally ornate and biologically important

LINK:	https://www.scripps.edu/news-events/news/20260629-baran-nature/...
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