They achieved the impossible: chemists have managed to bypass a century-old, undeniable rule established by Bredt.

Chemists have successfully synthesized a rare class of molecules known as anti-Brett oligomers (ABO), which were long deemed too unstable to exist. Renowned for their unique structure, ABO violate the Brett rule — a principle of organic chemistry formulated in 1924 by Julius Brett. According to this rule, certain carbon structures with double bonds, especially those formed at bridge positions in cyclic molecules, cause extreme deformation that theoretically renders them impossible to maintain in a stable form, notes Nature.

A chemist from the University of California, Neil Garg, and his team managed to break this century-old rule by synthesizing ABO under mild reaction conditions, which was previously considered unattainable, as stated in their research published in the journal Science.

ABO are carbon compounds with double bonds, similar to alkenes used in drug development, but they have a critical distinction: they are chiral, meaning they possess mirror-image forms, or enantiomers. This chirality is crucial in pharmaceuticals, where one enantiomer may provide a beneficial effect, while the other could be ineffective or even harmful.

Garg and his colleagues created an enantiomer-enriched form of ABO that yields more of one mirror compound than the other, marking significant progress in the development of structurally complex 3D molecules applicable in drug design. Craig Williams, a chemist at the University of Queensland, described this work as a "landmark contribution" across various fields.

To achieve stability in ABO, Garg's team utilized a precursor compound activated by fluoride, leading to a mild elimination reaction that revealed the signature carbon structure with double bonds. When interacting with various trapping agents — reactive compounds used to capture unstable molecules — the molecules formed stable, isolated compounds, demonstrating their potential as building blocks for new chemical synthesis pathways.

This discovery paves the way for the future development of complex pharmaceuticals with intricate 3D architectures, which could enhance their efficacy while reducing many side effects. Researchers find these results promising for the synthesis of other complex molecules as well. The stability of ABO may open avenues for creating new medicinal compounds that require stable 3D scaffolds, which have traditionally been difficult to achieve. The ability to create stable, structurally diverse molecules with precise chiral configurations may allow pharmaceutical chemists to explore new design spaces that were previously simply closed off by the Brett rule.

According to Garg, the results inspire him to "think much broader," as he seeks new reactions that could yield these new "impossible" molecules. These discoveries in the realm of ABO are ushering in a new chapter in organic chemistry, making the possibility of structurally diverse and functionally rich compounds in drug development a reality, the authors believe.