Cyclodextrins, reflected

Chemists love to tinker with cyclodextrins (CDs)—macrocyclic daisy chains of glucose molecules that feature a hydrophobic core surrounded by a hydrophilic exterior. They’ve been used to encapsulate drugs, in air fresheners to sop up smelly molecules, and in water purification systems to capture and destroy micropollutants.

Now, more than 130 years after their discovery, CDs are finally getting a glimpse of their mirror image. For the first time, chemists have synthesized L-CDs using the unnatural sugar L-glucose.

University of Hong Kong’s J. Fraser Stoddart led the work. His team created 500 mg quantities of α-, β-, and γ-L-cyclodextrins, which have 6, 7, and 8 sugar units, respectively, via synthetic routes of 8 steps or fewer (Nat. Synth. 2024, DOI: 10.1038/s44160-024-00495-8).

“We think it’s a fundamental addition to the cyclodextrin toolbox. It may take time for us to see some really unique applications,” says Yong Wu, a postdoctoral scholar in Stoddart’s lab and the paper’s first author.

Because the mirror-image CDs have unnatural stereochemistry, they might be more challenging for enzymes to break down, making them useful in some drug-delivery applications. The L-CDs could also be a boon for enantioselective catalysis, says Matthieu Sollogoub, who studies supramolecular chemistry at the Sorbonne University and was not involved in the research. “We will finally be able to address the perennial question: ‘What if I want to synthesize the other enantiomer?’ Our answer now is simple: use the mirror-image cyclodextrin!” he says in an email.

Sophie R. Beeren, an expert in supramolecular chemistry at the Technical University of Denmark, who was also not involved in the work, calls the mirror-image CDs an important development. But she notes that the starting materials for the synthesis are expensive, and the synthesis is more complicated than that of the D-CDs. “The reason D-CDs are so widely applied in a range of industries is that they are cheap and readily available because they are produced enzymatically directly from starch,” she says in an email. “It remains to be seen,” she says, if L-CDs can “reach beyond the confines of academic research.”