Sulfonimidamides have become popular in the past decade or so as chemists explore novel motifs for drug candidates. They feature a central sulfur atom with a double bond to oxygen, a double bond to nitrogen, a single bond to another nitrogen, and a single bond to carbon. Cyclic sulfonimidamides, which have distinct properties from standard heterocycles, are particularly intriguing, but there aren’t many ways to make them.

Now chemists at the University of California, Davis, led by Jared T. Shaw and Dean J. Tantillo report a new way to cyclize sulfonimidamides to make rare five-membered heterocycles that are both aromatic and chiral (J. Am. Chem. Soc. 2026, DOI: 10.1021/jacs.6c04114).

Shaw tells C&EN that chemists in his lab were initially trying to do a different reaction to make six-membered ring sulfonimidamides. Instead, they found that they were making an N–O or an N–S bond to create aromatic five-membered rings that contain one carbon atom, one oxygen atom, and a sulfonimidamide.

“At the time we made the discovery, there was no example of this molecule anywhere in the literature,” Shaw says. Six months later, and before the UC Davis team published the results, RWTH Aachen University’s Carsten Bolm and colleagues reported a similar structure made using mechanochemistry (Angew. Chem., Int. Ed. 2024, DOI: 10.1002/anie.202413181).

Because the heterocycles that the researchers made have a stereogenic sulfur, they offer an opportunity to orient substituents in a way that’s not possible with common five-membered ring aromatic heterocycles, which are flat. This could make the cyclic sulfonimidamides particularly useful as components of drug candidates, Shaw says, where they might make key contacts within an active site.

To demonstrate this, Shaw and Tantillo’s team made an analog of the prostate cancer drug enzalutamide, which is sold under the brand name Xtandi. Computational docking studies show that one isomer of the analog can make additional contacts within enzalutamide’s protein target that the drug does not.

Michael Willis, a chemist at the University of Oxford who explores ways to make novel sulfur-based motifs, says in an email that “the power of the chemistry comes from the simplicity of the approach.” He notes that the novel heterocycles from this transformation make it possible to explore new regions of chemical space.

Shaw says the team is interested in doing that work next. “Anywhere you have a five-membered ring heterocycle, we might swap this in and see if it can do something different,” he says.

Bethany Halford is a Senior Correspondent for C&EN based in Boston.