Researchers unlock rare chemical transformation that can produce desired chemicals at higher yields with less waste

“Thalidomide is an extreme example of potential negative health impacts of an enantiomer with off-target effects, but it really highlights why we need to be able to make these molecules in an enantiopure fashion so we can evaluate on a case-by-case basis whether the mirror images will interact with biological systems differently,” explains Casey Roos, Ph.D., a former postdoctoral researcher in the Narayan lab and a lead author of the Nature study. “These can range from the really tragic effects of the 'incorrect' enantiomer of thalidomide to an inactive enantiomer that would just dilute the effectiveness of the active compound. 

Narayan’s lab at the U-M Life Sciences Institute uses enzymes — proteins that have evolved naturally to perform highly selective and specific reactions — as the foundation to develop tools that can perform more powerful reactions in the lab.

Recently, her team was engineering an enzyme to produce one enantiomer of a commonly used molecule called a BINOL. This compound is used to control the selectivity of other chemical reactions, so ensuring the right three-dimensional structure is essential for determining results of subsequent reactions. 

The BINOL that the team was working with produces two enantiomers that are related through the rotation of one bond. Due to the structure of the molecule, that bond is too hindered to rotate again once it has formed, so it becomes locked in place. 

While testing a version of the enzyme, they discovered a surprising result. They measured the product of the reaction after about five minutes and found a mixture of the two enantiomers. An hour later, though, the product was composed almost entirely of the single version they were aiming for.

“That's not how a well-behaved reaction presents,” Narayan explains. In general, when both enantiomers are produced during a reaction, their ratio remains the same as a reaction proceeds. To adjust the ratio and isolate one enantiomer, chemists use methods to physically remove the unwanted enantiomer, reducing the total amount of their end product they are left with. 

“But that’s not what we found,” Narayan recalls. “In this case, as time progressed, it appeared that one enantiomer was actually converting to the other. That type of process is very, very rare.” 

The enzyme the team had engineered was in fact performing a two-step reaction to convert one enantiomer of BINOL to the other enantiomer. One step altered the BINOL structure just enough to enable a rotation that converted the unwanted enantiomer into its mirror image, the desired product.

The results offer a proof-of-concept for the use of enzymes to enrich for a single enantiomer of a compound where the two enantiomers are related through bond rotation. Such a mechanism could dramatically reduce chemical waste by removing the need to separate and discard unwanted enantiomers; instead, the unwanted enantiomer could be converted to the desired product in one reaction. Narayan believes this approach can be fine-tuned to work on a broad range of molecules.

“It’s an example of really careful observation leading down paths that are even more fascinating than what we could have planned out on paper,” she says. “We were engineering just for this property of having as much of one enantiomer as possible, and we actually engineered a new mechanism.”