Chemists have found a new way to utilize visible light in the synthesis of a group of compounds that are highly suitable for pharmaceutical applications. These compounds, known as azetidines, have been recognized as excellent candidates for creating therapeutic drugs, but their production through chemical reactions has been challenging. However, a team has now devised a method to manufacture a specific subgroup of azetidines called monocyclic azetidines by harnessing visible light in conjunction with a photocatalyst.
University of Michigan chemists have found a method to utilize visible light for the synthesis of a group of compounds that are particularly well-suited for pharmaceutical use.
The class of compounds, known as azetidines, was previously identified as promising candidates for drug development. However, due to the complexity of chemical reactions involved, their production has posed difficulties. A team led by University of Michigan chemist Corinna Schindler has now developed a technique to produce monocyclic azetidines, a specific subclass of azetidines, using visible light and a photocatalyst. Their findings have been published in the journal Science.
About 60% of pharmaceutical drugs contain nitrogen heterocycles, which are ring-like structures containing nitrogen atoms that serve as important building blocks. The stability of these structures, especially those with five- and six-membered ring systems, is crucial for their effectiveness in pharmaceuticals.
While these building blocks are easily accessible and versatile for creating compounds, many of the commonly used ring systems are not as stable as desired, which can lead to breakdown in the body, affecting the drug’s efficacy. This instability poses a challenge in drug development, as the compound may undergo metabolic changes within the body after ingestion.
Researchers advocate for the use of more stable monocyclic azetidines, a type of four-membered ring system. However, traditional methods for producing azetidines present specific obstacles, limiting their applicability and ability to create diverse substitution patterns needed for drug synthesis and screening.
The University of Michigan researchers employed a [2+2]-cycloaddition method to generate monocyclic azetidines, a process that typically involves photoexcitation, i.e., the activation of atoms or molecules through the absorption of light energy. This light-induced reaction utilized acyclic imines and alkenes as starting materials, offering flexibility in generating various products.
Previous attempts at similar reactions using ultraviolet light posed safety concerns and used different starting materials. The team’s innovation lies in harnessing visible light to produce monocyclic azetidines, enhancing accessibility to these valuable building blocks.
Their approach leveraged visible light and a photocatalyst to enable the required excited state intermediates to undergo an aza Paternò-Büchi reaction. Collaborating with the lab of Heather Kulik, an associate professor at MIT, the team conducted computational analyses to optimize the reaction’s efficiency and yields.
This breakthrough requires demonstrating the reaction’s versatility across various substrates, crucial for pharmaceutical applications. The team showcased the method’s effectiveness on multiple imine and alkene compounds, ensuring its potential usefulness in diverse pharmaceutical contexts.
By successfully producing biologically relevant azetidine compounds, including incorporating them into estrogen derivatives and tumor cell-toxic analogues, the researchers showcased the method’s adaptability in synthesizing complex and medicinally important molecules.
Understanding the underlying principles of this innovative reaction opens doors for designing future reactions in medicinal chemistry. This pioneering work establishes a foundation for developing novel pharmaceutical compounds using azetidines previously inaccessible through conventional methods.
