Organic molecules, which contain carbon (pictured), form certain shapes because of the way their atoms bond.Credit: Dennis Kunkel Microscopy/Science Photo Library
For the first time, chemists created a class of molecules previously thought to be too unstable to exist, and used them to generate exotic compounds1. Scientists say these infamous molecules, known as anti-Bredt olefins (ABOs), offer a new route to synthesizing challenging drug candidates.
The work is “a milestone,” says Craig Williams, a chemist at the University of Queensland in Brisbane, Australia. The findings were published in Science.
Organic molecules, which contain carbontypically conform to specific shapes because of the way their atoms bond together. For example, olefins, also called alkenes, are hydrocarbons that are often used in reactions drug development — have one or more double bonds between two carbon atoms, causing the atoms to be arranged in one plane.
Bredt’s 100 year old rule, proposed in 1924 by organic chemist Julius Bredt – states that in small molecules consisting of two rings sharing atoms, such as some types of alkene, double bonds cannot occur between two carbon atoms where the rings come together, the so-called bridgehead position. This is because the bonds force the molecule into a tortured, tense 3D shape, making it highly reactive and unstable, says study co-author Neil Garg, a chemist at the University of California, Los Angeles. “Still, a hundred 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 breaking it. Previous research has hinted that it is possible to create ABOs that have a carbon-carbon double bond at the bridgehead position2. But attempts to synthesize them in their complete form were unsuccessful because the reaction conditions were too harsh, Garg says.
Catches
In the latest attempt, Garg and his colleagues treated a precursor compound with a fluoride source to trigger a milder ‘elimination’ reaction, in which groups of atoms are removed from molecules. This resulted in a molecule with the telltale ABO double carbon bond. When the researchers added various capture 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 the reactions of ABOs with different capture agents can be used to synthesize 3D molecules, which are useful for designing new drugs, says Garg.
Unlike typical alkenes, ABOs are chiral compounds: molecules that do not perfectly match their mirror images. Garg and his colleagues synthesized and captured an ABO that was enantioverenriched, meaning they produced more of one mirror pair than the other. This finding suggests that ABOs can be used as unconventional building blocks for enantioenriched compounds, which are widely used in pharmaceuticals.
Chuang-Chuang Li, a chemist at the Southern University of Science and Technology in Shenzhen, China, says the approach could be used to explore innovative synthesis routes for other challenging molecules, such as the chemotherapy drug paclitexal (sold as Taxol) – a complex , multi-ringed molecule that is difficult to make in the laboratory. “It is a valuable and reliable method,” says Li.
Garg and his team are investigating other reactions involving ABOs, and exploring how other molecules with seemingly impossible structures can be synthesized. “We can think a little more outside the box,” he says.