In a groundbreaking development, chemists at UCLA have achieved the impossible. They’ve synthesized a type of molecule that experts once believed could never exist.
These molecules, known as anti-Bredt olefins (ABOs), have defied a 100-year-old rule in organic chemistry and opened new doors in drug development.
For a century, a principle called Bredt’s rule kept scientists from pursuing these compounds. German chemist Julius Bredt introduced the rule in 1924, arguing that some structures were too unstable.
The rule states that certain double bonds, specifically those at bridgehead positions in bridged ring systems, would force a molecule into an overly strained shape. This strain makes it impossible for these molecules to exist.
In double-bonded molecular structures, atoms must align in a single plane for stability. However, placing a double bond at a bridgehead — where two rings join — forces the molecule to strain and break out of this plane. This configuration creates extreme instability, and chemists have long considered such compounds “forbidden” or unachievable.
However, some researchers never stopped dreaming of a way to create these elusive molecules. Anti-Bredt olefins contain a double bond at the bridgehead position and could open pathways to new chemistry, especially in drug design.
While previous research hinted at their possibility under controlled conditions, attempts to synthesize and isolate ABOs had failed.
Neil Garg, a chemistry professor at UCLA, led a team to tackle this problem using a fresh approach. Rather than traditional synthesis methods, which proved too harsh, they tried a more controlled, mild elimination reaction. They began with a specially designed precursor compound and introduced a fluoride source to initiate the reaction. This approach allowed them to produce the ABO structure without breaking it down.
But even with this initial success, they faced the challenge of stabilizing the ABO. Garg’s team turned to “trapping agents” to accomplish this. Trapping agents are chemicals that react with unstable molecules, allowing researchers to “capture” fleeting intermediates. When the team introduced these agents to the 3D ABO structure, they triggered reactions that produced stable, complex compounds.
Using different trapping agents, Garg’s team successfully created a range of complex compounds from ABOs. This success marked the first time researchers had synthesized and stabilized ABOs, showing that these elusive molecules could indeed serve as building blocks for complex, three-dimensional compounds.
With this approach, Garg and his team had defied one of the oldest rules in organic chemistry.
Craig Williams, a chemist at the University of Queensland, called the work a “landmark contribution.” Williams said it could lead to synthetic chemistry breakthroughs once thought impossible. This achievement opened up a new toolkit for creating challenging molecules for researchers worldwide.
One fascinating aspect of this discovery is the chirality of ABOs. Chirality means that a molecule has a non-superimposable mirror image, much like how a left hand and a right hand are mirror images but not identical.
In pharmaceuticals, chirality is essential, as a molecule’s two “mirror images,” or enantiomers, can have drastically different effects on the body.
Garg and his team managed to produce an “enantioenriched” ABO. This means that they created more of one mirror-image form than the other. This ability to control chirality could transform how scientists design certain drugs.
Compounds derived from ABOs could be precious for creating enantioenriched compounds, which are in high demand in drug development because of their specific biological effects.
In drug discovery, precision matters, and the unique three-dimensional structures of ABOs offer new possibilities. For instance, the chemotherapy drug paclitaxel, marketed as Taxol, relies on a complex, multi-ring structure that poses challenges in synthesis.
Chuang-Chuang Li, a chemist at the Southern University of Science and Technology in China, sees potential here. He believes Garg’s approach could be valuable for creating similarly complex molecules that were previously challenging to synthesize. “It’s a valuable and reliable method,” Li says.
Garg’s work does more than break a long-standing rule in organic chemistry; it changes how chemists approach synthesis. Researchers worldwide now have a new pathway to creating molecular structures that were once impossible.
The unique configurations of ABOs could impact fields such as materials science, agrochemicals, and any industry requiring complex organic synthesis.
Neil Garg sees this moment as a turning point. “We’re at a point where we can start thinking a little bit more outside of the box,” he explained. His team’s work shows that with the right approach, chemists don’t have to follow every textbook rule.
With this discovery, Garg and his team aren’t stopping. They’re exploring additional reactions involving ABOs, looking for ways to synthesize other “impossible” molecules. They’re optimistic that their approach could lead to new types of drugs, especially those that need precise three-dimensional structures to interact effectively with biological systems.
The team’s work, recently published in Science, has already created a stir among chemists and researchers. Many see this achievement as a new standard in organic chemistry that could inspire further discoveries.
Researchers worldwide are eager to apply these findings, exploring the potential of ABOs in everything from drug synthesis to the creation of advanced materials.
Craig Williams reflects on the significance of Garg’s work, emphasizing that sometimes, rules are made to be broken in Science. The synthesis of ABOs demonstrates the power of persistence, creativity, and the willingness to question established norms. For Garg and his team, this is just the beginning.
As they continue their research on ABOs and similar molecules, the scientific community is watching closely, ready to see how this discovery will reshape synthetic chemistry.
For those working on the cutting edge of molecular Science, Garg’s breakthrough offers a new sense of possibility. His work reminds scientists that innovation sometimes means breaking down barriers and rewriting the rules in chemistry.