An example of the 1,2 transposition transformation developed by Sarpong and team. Illustration courtesy of Richmond Sarpong.
A team of UC Berkeley chemists has figured out a clever way to shuffle peripheral pieces of a molecule around by changing its core, interior structure. Their new method, described this week in Science, could make it faster and easier to tweak promising drug compounds in the lab, potentially speeding up the discovery of new medicines.
“This method moves the chemical groups on the outside of the molecule by twisting around the interior structure – kind of like how you play with a Rubik’s cube,” said Richmond Sarpong, the senior author of the new paper. “Rather than peeling all the colored stickers off a Rubik’s cube to move them, you change their location by rearranging the inside of the cube.”
The new work, led by graduate student Ryan Steele and visiting research scientist Motohiro Fujiu from Shionogi Company in Japan, focused on a class of ring-shaped molecules called dihydrobenzofurans. These structures are common in natural products and drugs, and chemists often want to rearrange certain chemical groups on them to study whether those changes improve their desired function.
Normally, moving a group like an acyl (a part of a molecule related to acids) from one spot on the ring to another would require building the whole molecule again from scratch — a time-consuming process. But Steele and Fujiu, while studying how to make one particular chemical, found a shortcut.
They discovered that if they shine blue or ultraviolet light on dihydrobenzofurans, the ring temporarily twists into a new shape. As the interior of the ring morphs, the attached acyl groups also move into new positions on the ring.
“In many ways, this could accelerate the pace of drug discovery because it reduces the need to start from the beginning to build each of your compounds,” said Sarpong.
What makes this “skeletal rearrangement” especially useful is that it doesn’t just work for one type of acyl group. The team showed that the strategy can be used to reposition a variety of important chemical groups—carboxylic acids, esters, and amides among them—that commonly appear in drug candidates.
The method could be a game-changer in medicinal chemistry, particularly in the early phases of drug discovery. Pharmaceutical chemists often work with “matched pairs” of molecules—nearly identical structures that differ by the position of a single group—to test which arrangement works best in the body. Generating these pairs typically requires separate syntheses from scratch.
“What we’re offering is a way to take one version of a molecule and directly convert it into its matched pair,” said Sarpong. “That saves a lot of time and investment.”
The idea for the method originated while the team was working on a completely different problem: modifying the internal ring structure of morphine to reduce its addictive potential. That project led them to an old paper that hinted at a strange light-driven rearrangement in a morphine-like molecule. Curious, Sarpong’s team dug into the mechanism—and realized it could be generalized into a broader tool.
Detailed analyses of what was happening at the atomic level revealed that the new approach leads to short-lived chemical intermediates that have unpaired electrons – making them highly reactive and explaining why the method is so powerful and unique.
While this study focused on dihydrobenzofurans, the team sees this as a proof-of-concept for a broader class of skeletal editing strategies that could be extended to other ring systems. Looking ahead, they hope to study its applicability to rings containing nitrogen atoms—a common feature in pharmaceuticals. They also aim to develop variations of the reaction that can be driven by visible light, which is safer and more practical than the blue light emitting diodes and ultraviolet lamps currently required.
“There’s a broader concept here,” Sarpong said. “For a long time, chemists have focused on modifying the periphery of molecules. But sometimes, the best way to change the outside is to tweak the inside. This opens up a new dimension in molecular editing.”