Ann Arbor Times

University of Michigan chemists have discovered a method to use visible light in synthesizing azetidines, compounds suitable for pharmaceuticals. The team, led by chemist Corinna Schindler, developed a process to produce monocyclic azetidines using visible light and a photocatalyst. Their findings are published in the journal Science.

Approximately 60% of pharmaceutical drugs contain nitrogen heterocycles, which are ring structures with at least one nitrogen atom. These five- and six-membered rings are commonly used as building blocks in pharmaceuticals but often lack stability within the human body.

“These building blocks are very accessible and you can put them together like Legos to build compounds that we can then use for chemical or medicinal testing. But the problem is that a lot of these five or six membered ring systems are not as stable as you’d want them to be,” Schindler said.

“The ring systems can break down in the body after a patient has ingested a therapeutic drug. Because the compound can be metabolized by the human body, what you give initially to a patient may not necessarily be what you would find in the body after the patient has taken it, and that is a problem.”

Researchers suggest using monocyclic azetidines, which have more stable four-membered ring systems. However, producing azetidines presents specific challenges. According to Emily Wearing, lead author of the study who recently earned her doctorate from Schindler’s lab, key reactions used by chemists either cannot be widely applied or only produce azetidines with specific substitution patterns.

The U-M researchers employed a [2+2]-cycloaddition method requiring photoexcitation—exciting atoms or molecules through energy absorption—to create monocyclic azetidines. This reaction typically needs light.

In their reaction, they used acyclic imines and alkenes as starting materials because they can easily vary to produce different products. However, when excited by light, acyclic imine decays before undergoing cycloaddition.

Previously successful examples of this reaction utilized ultraviolet light but presented safety challenges and different imines and alkenes.

“This also means access to these highly desirable monocyclic azetidine building blocks is much more limited using this approach,” Wearing said. “The use of visible light versus UV light is an important benefit, but our key discovery was being able to use a visible light approach to produce monocyclic azetidines.”

Their method uses visible light and a photocatalyst in an aza Paternò-Büchi reaction. To understand why this worked, Schindler’s lab collaborated with Heather Kulik's lab at MIT for computational analysis. They found that specific classes of imine and alkene starting materials facilitated better energy matching between them, lowering the reaction barrier and yielding high amounts of azetidines.

Seren Parikh and Yu-Cheng Yeh demonstrated that their reaction could work on multiple versions of imine and alkene compounds.

“Someone might show that a new reaction works, but if it only works on a single compound, it is not useful to anyone because pharmaceutical companies are likely wanting to use the reaction on their unique compound,” Parikh said. “What we can do is show that the reaction works on a diverse range of substrates to essentially prove that the reaction is worth the pharmaceutical company’s time to try.”

Parikh and Yeh produced six biologically relevant azetidine compounds using this method. Yeh synthesized analogues of penaresidin B toxic to tumor cells—the first total synthesis using [2+2]-cycloaddition.

“The synthesis of these azetidine compounds are examples to demonstrate that this synthetic methodology can be applied to make complicated molecules and medicine-like molecules,” Yeh said.

Understanding this chemical reaction will enable further development in medicinal chemistry for related reactions in future pharmaceuticals.

“Now we can access these types of building blocks that people have wanted for a long time but couldn’t directly access,” Schindler said. “The process we have developed can now be used in the future as basically a blueprint for future reaction development.”