A synthetic route to polyenes inspired by nature could open up new applications for these compounds in biomedical research and drug discovery. Given that these compounds have a role in various biological processes, the work might represent a turning point.
Ryan Gilmour of the University of Münster, Germany, and colleagues demonstrated a method for the synthesis of complex polyenes, such as retinoic acid, from simple alkene building blocks. The key to their success was the use of light-activated antenna molecules that facilitate energy transfer catalysis. [Molloy, J. J., Schäfer, M. et al. Science (2020) DOI: 10.1126/science.abb7235]
"The process provides us with a light-driven, operationally simple solution to a conundrum that has occupied us for a long time," explains team member John Molloy.
The team hoped to start with stereoisomers of their alkene building blocks, a critical move in terms of synthesizing the biological form of retinal, the vitamin A derivative, for instance. Historically, however, alkene geometry although it plays a pivotal role in biological function is underdeveloped as an area within synthesis, particularly when it comes to concatenating different building blocks to form more complex structures with numerous carbon-carbon double bonds along the length of a molecule. There are many approaches available to chemists hoping to make each isomer individually, but these often have poor selectivity and take too many separate reaction steps to be tenable in creating physiologically interesting polyenes.
The team has now shown that by attaching a light-activated unit, they can use light energy to flip the alkene to the appropriate isomer. They describe in detail their strategy for a photocatalytic isomerization of beta-borylacrylate derivatives that "enables access to both geometric isomers of ambiphilic C3 linchpins". Moreover, given that now both ends of the alkene are functionalized they can be extended iteratively to build more sophisticated structures all guided towards the biological form of a molecule like retinal rather than the various non-natural isomers that are possible. The Münster team demonstrated the power of their method in a short, stereocontrolled syntheses of two pharmaceuticals, isotretinoin (an acne treatment) and alitretinoin (an anticancer drug), both based on retinoic acid.
"This platform for the stereocontrolled generation of complex polyenes might prove to be expansive and may facilitate the exploration of these bioactive materials in drug discovery," the team concludes.
David Bradley