UCLA is challenging the old chemistry rule and blazing new trails in drug research

A recent discovery by UCLA scientists has challenged an age-old principle in organic chemistry, reshaping fundamental knowledge and expanding the possibilities for pharmaceutical research. Researchers led by Professor Neil Garg have found a way to synthesize and stabilize anti-Bredt olefins (ABOs), molecular structures. These structures were long considered too unstable to exist. This achievement dismantles Bredt’s rule – a 1924 limitation that has influenced molecular design for decades – allowing chemists to explore new chemical reactions in drug development.

Bredt’s rule and its historical significance

Bredt’s rule, established almost a hundred years ago by chemist Julius Bredt, states that in certain molecules double bonds cannot exist at the bridgehead position because this structure would disrupt molecular stability. Bredt’s rule has lasted for decades, banning chemists from designing certain types of synthetic compounds. Given that double bonds or olefins are widely used in pharmaceuticals, this limitation has affected the drug design landscape by limiting the diversity of possible molecular structures.

How UCLA Researchers Achieved the Impossible

In a paper published in Science, Garg and his team unveil a method to create ABOs by treating molecules known as silyl (pseudo)halides with a fluoride source, which triggers an elimination reaction, leading to ABO formation. To cope with the instability of ABOs, the team introduced a trapping agent to stabilize the molecules, allowing them to isolate practical reaction products. This approach provides chemists with a controlled way to work with ABOs, opening avenues for designing unique compounds with real-world applications.

Implications for the future of drug discovery

According to Garg, the pharmaceutical industry has a great interest in generating 3D structures such as are now achievable with ABOs. It could be crucial for discovering new drugs. “For more than a century, chemists have avoided anti-Bredt olefins, thinking they were impossible to work with,” Garg said, highlighting the potential of these newly accessible compounds for drug innovation. The collaboration of co-author and computational chemistry expert Professor Ken Houk also helped elucidate the potential of these compounds in practical applications.

This finding invites chemists to rethink molecular rules as flexible guidelines rather than fixed laws, which could catalyze a wave of innovation in synthetic chemistry and pharmaceutical development.