For the first time, chemists They created a class of molecules previously thought to be too unstable to exist and used them to produce exotic compounds¹. These notorious molecules, known as anti-Bredt olefins (ABOs), offer a new way to synthesize challenging drug candidates, scientists say.

Chemist Craig Williams of the University of Queensland in Brisbane, Australia, says the study is a “landmark contribution”. The findings are published at: Science.

Containing organic molecules carbonIt typically conforms to certain shapes because of the way its atoms bond together. For example, olefins, also called alkenes; They are hydrocarbons frequently used in reactions. drug development — one or more double bonds exist between two carbon atoms, causing the atoms to be arranged in a single plane.

100-year Bredt rule proposed in 1924 organic chemist Julius Bredt states that in small molecules consisting of two rings of common atoms, such as some types of alkenes, double bonds between the two carbon atoms cannot form where the rings meet, and this is called the bridgehead position. This is because the bonds force the molecule into a strained, stretched 3-D shape, making it highly reactive and unstable, says study co-author Neil Garg, a chemist at the University of California, Los Angeles. “Yet in 100 years people will say that such structures are prohibited or too unstable to build,” he says.

Although the rule is in chemistry textbooks, that hasn’t stopped researchers from trying to break it. Previous research has hinted that it is possible to create ABOs with double carbon-carbon bonds at the beachhead position². But Garg says attempts to synthesize them in full form have failed because the reaction conditions were too harsh.

capture agents

In the latest experiment, Garg and colleagues treated a precursor compound with a fluoride source to initiate a milder ‘elimination’ reaction that removes groups of atoms from molecules. As a result, a molecule with an ABO double carbon bond emerged. When the researchers added various trapping agents (chemicals that trap unstable molecules as they react) to this 3D ABO, they were able to produce many complex compounds that could be isolated. Garg says this suggests that reactions of ASGs with different trapping agents could be used to synthesize 3D molecules useful in the design of new drugs.

Unlike typical alkenes, ABOs are chiral compounds; molecules that do not match their mirror images perfectly. Garg and colleagues synthesized and trapped an enantioenriched ABO; This means they produce more from one pair of mirrors than from the other. This finding suggests that ABOs can be used as unusual building blocks for enantioenriched compounds commonly used in pharmaceuticals.

The approach could be used to investigate innovative synthesis routes for other challenging molecules, such as the chemotherapy drug paclitexal (sold as Taxol), says chemist Chuang-Chuang Li of the Southern University of Science and Technology in Shenzhen, China. a complex, multi-ring molecule that is difficult to create in the laboratory. “This is a valuable and reliable method,” says Li.

Garg and his team are investigating other reactions involving ASGs and exploring how to synthesize other molecules with seemingly impossible structures. “We may be thinking a little outside the box,” he says.