Chemists develop a bioinspired strategy for controlled polyene synthesis

They occur in nature, are reactive, and play a role in many biological processes: polyenes. Not surprisingly, chemists have long been interested in the efficient construction of these compounds, especially in order to use them in future biomedical applications. However, these designs are currently neither simple nor inexpensive and present highly challenging organic chemicals. Scientists at the University of Münster (Germany) led by Professor Ryan Gilmour have found a bioinspired solution to the problem: They managed to build complex polyenes like retinoic acid from simple and geometrically well defined alkene building blocks. To do this, the scientists used small molecules as “antennas” that excited them with light, thus allowing difficult chemical reactions to take place through a process known as “Energy Transfer Catalysis”.

“The process provides us with an operationally light and simple solution to a puzzle that has long plagued us,” says Dr. John J. Molloy, the study’s first author. The new possibility of forming complex polyenes could facilitate the exploration of these bioactive materials for drug discovery. The study has been published in the journal. Science.

Background and method:

The alkenes used by scientists are structural units that can exist in two non-equivalent geometric shapes. These so-called stereoisomers, that is, compounds in which the binding pattern is the same but differ in the spatial arrangement of atoms, are a valuable source of chemical information in biology and are common structural features in larger complex molecules such as retina, a vitamin A derivative. Although alkene geometry plays a critical role in the function, for example, by regulating the mammalian visual cycle, strategies for accessing the geometrically defined alkene building blocks for Iterative synthesis are notably underdeveloped. Although there are many methods to access each isomer independently, they are often riddled with poor selectivity or require laborious independent synthesis campaigns.

Just as plants convert light into energy, the researchers used inexpensive small organic molecules under irradiation to “flip” the building blocks of common alkenes in the most challenging way. This process is called “energy transfer catalysis”.

Since these materials are functionalized at both sites, they could be iteratively extended to build complex bioactive polyenes like retinoic acid, which can exist in multiple forms under alkene stereoisomerism. Münster’s team demonstrated the power of their method in short, stereocontrolled syntheses of two retinoic acid-based medications, Isotretinoin and Alitretinoin.

The new method combines the importance of carbonyl chemistry in biosynthesis with the versatility of organoboronic motifs in contemporary organic chemistry. “This article is dedicated to Prof. Duilio Arigoni, who passed away recently. He was a pioneer in bioorganic chemistry with whom I had the pleasure of working in Zürich years ago and often highlighted the urgency of this problem. This innovative Solution is testimony to the work hard, innovation and dedication from a very talented group of highly motivated coworkers, “says Ryan Gilmour.