For the first time, chemists created a class of molecules previously thought too unstable to exist and used them to generate exotic compounds¹. Scientists say these notorious molecules, known as anti-Bredt olefins (ABOs), offer a new route to the synthesis of difficult drug candidates.

The work is “a historic contribution,” says Craig Williams, a chemist at the University of Queensland in Brisbane, Australia. The results are published in Science.

Organic molecules, which contain carbonusually conform to specific shapes because of the way their atoms bond together. For example, olefins, also called alkenes, hydrocarbons often used in reactions of drug development — have one or more double bonds between two carbon atoms, which means that the atoms are arranged on a single plane.

The 100-year-old Bredt rule, proposed in 1924 by organic chemist Julius Bredt — states that in small molecules consisting of two rings sharing atoms, such as certain types of alkenes, double bonds between two carbon atoms cannot occur where the rings come together, called the bridgehead position . In effect, these bonds would force the molecule into a tortured, strained 3D shape, making it very reactive and unstable, says Neil Garg, co-author of the study and a chemist at the University of California, Los Angeles. “Yet 100 years later, people would say that these types of structures are forbidden or too unstable to make,” he says.

Although the rule has made its way into chemistry textbooks, it hasn’t stopped researchers from trying to break it. Previous research has suggested that it is possible to create ABOs with a carbon-carbon double bond at the headstock.². But attempts to synthesize them in their full form failed because the reaction conditions were too harsh, says Garg.

Trapping agents

In the latest attempt, Garg and his colleagues treated a precursor compound with a fluoride source to trigger a gentler “elimination” reaction, which removes groups of atoms from molecules. This resulted in a molecule that had the telltale ABO double carbon bond. When the researchers added various trapping agents – chemicals that capture unstable molecules as they react – to this 3D ABO, they were able to produce several complex compounds that could be isolated. This suggests that reactions of ABOs with different trapping agents can be exploited to synthesize 3D molecules, useful for designing new drugs, says Garg.

Unlike typical alkenes, ABOs are chiral compounds – molecules that do not perfectly match their mirror image. Garg and his colleagues synthesized and trapped an enantio-enriched ABO, meaning they produced more of one mirror pair than the other. This finding suggests that ABOs could be used as unconventional building blocks for enantio-enriched compounds, widely used in pharmaceuticals.

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

Garg and his team are exploring other reactions involving ABOs and studying how to synthesize other molecules with seemingly impossible structures. “We can think a little more outside the box,” he says.