Chemists create ‘impossible’ molecules that break 100-year-old bonding rule

For the first time, chemists have created a class of molecules previously thought too unstable to exist and used them to create exotic compounds.¹. Scientists say these notorious molecules, known as anti-Bredt olefins (ABOs), offer a new route to the synthesis of promising drug candidates.

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

Organic molecules containing carbon usually have a specific shape because of the way their atoms bond with each other. For example, olefins, also called alkenes—hydrocarbons often used in reactions in drug development—have one or more double bonds between two carbon atoms, causing the atoms to lie in the same plane.

Bredt’s 100-year-old rule, proposed in 1924 by organic chemist Julius Bredt, states that in small molecules consisting of two rings that share atoms, such as some types of alkenes, double bonds between two carbon atoms cannot occur. the place where the rings join together is called the bridgehead position. That’s because the bonds force the molecule into a tortured, tense three-dimensional shape, making it highly reactive and unstable, says study co-author Neil Garg, a chemist at the University of California, Los Angeles. “Yet 100 years from now people will say that such structures are prohibited or too unstable to build,” he says.

Although this rule was included in chemistry textbooks, this did not stop researchers from trying to break it. Previous studies have hinted that it is possible to create ABOs that have a carbon-carbon double bond at the bridgehead position.². But attempts to synthesize them in their complete form failed because the reaction conditions were too harsh, Garg says.

Traps

In the latest attempt, Garg and his colleagues treated the precursor compound with a source of fluoride to trigger a milder “elimination” reaction that removes groups of atoms from molecules. The result was a molecule with the characteristic ABO double carbon bond. When the researchers added various trapping agents to this 3D ABO—chemicals that trap unstable molecules as they react—they were able to produce several complex compounds that could be isolated. “This suggests that ABO reactions with different decoys can be used to synthesize three-dimensional molecules that will be useful for the development of new drugs,” says Garg.

Unlike typical alkenes, ABOs are chiral compounds—molecules that do not exactly match their mirror image. Garg and his colleagues synthesized and captured an ABO that was enantioenriched, meaning they produced more of one mirror image pair than the other. This discovery suggests that ABOs can be used as unconventional building blocks for enantioenriched compounds that are widely used in pharmaceuticals.

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

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