Going big with δ-cyclodextrin

Chemists have a sweet spot for cyclodextrin (CD) rings, cyclic molecules made of glucose sugars linked together like dancers in a Henri Matisse painting. Cyclodextrins have found use as drug delivery agents that encapsulate active pharmaceutical ingredients, as air fresheners that soak up stinky compounds, and as water purification systems that capture and destroy pollutants. Each year, chemical makers churn out thousands of metric tons of the most common ones: six-, seven-, and eight-sugar rings, known as α-, β-, and γ-CD, respectively.

But little is known about the nine-sugar ring δ-CD because scientists have been able to prepare only scant quantities of it—until now. Technical University of Denmark chemists led by Sophie R. Beeren have developed a multigram-scale synthesis of δ-CD (J. Am. Chem. Soc. 2025, DOI: 10.1021/jacs.5c02055).

The scale-up will help scientists explore how to use δ-CD, Beeren says. “The fact that α-, β-, and γ-cyclodextrin are produced on a 10,000-ton scale annually and have found so many applications in formulation of drugs and other products suggests to me that δ-cyclodextrin would also be useful in those sorts of applications,” she says. “It's just no one has ever been able to really test it because no one ever had any in significant quantities.”

Yong Wu, a chemist at Sichuan University who studies cyclodextrins and was not involved in the work, says in an email that because δ-CD has a large cavity, being able to make it on a large scale “could inevitably unlock its unexplored potential in materials science, chiral sensing, catalysis, and separation, not to mention in drug delivery systems where δ-CD may serve as a superior host for supramolecular complexation with macromolecular pharmaceuticals such as proteins and nucleic acids.”

When chemists make α-, β-, and γ-CD, they also make a small amount of δ-CD. But it is less stable, so it appears only transiently. Members of Beeren’s group reasoned they could make δ-CD in large quantities if they used the dodecaborate B₁₂Cl₁₂^2- as a template for the ring to build around. “We thought if this template could bind strongly to δ-cyclodextrin, we could push the equilibrium towards that product. And it's kind of surprising just how well it works,” Beeren says.

The chemists start with α-CD, the template molecule B₁₂Cl₁₂^2- and use the food-grade enzyme cyclodextrin glucanotransferase to make grams of δ-CD in roughly 40% yield. What’s more, Beeren says, the researchers get greater than 95% purity of the compound without having to do any chromatography. “That's why I think you could industrialize it as a process,” she says.

After delving into the details of the reaction, Beeren says, it turns out the specificity of the synthesis is not just driven by how strongly the template binds δ-CD. “It's the competition with the other cyclodextrins; it's the relative stability of the other cyclodextrins; it's the stoichiometry of the binding. And you put all that together, and then this comes out as being the best template.”

Although B₁₂Cl₁₂^2- is commercially available, it costs about $3,000 for 5 grams. It’s possible to make the template, but the synthesis isn’t trivial. On the plus side, Beeren says, “the template isn't consumed in the reaction, so once you've made some then you can use it over and over again for subsequent reaction cycles.”

The group has patented the method and hopes to find an industrial partner to scale it up further.