Revolutionary Breakthrough: New Technique Unlocks CH Activation in Saturated Carbocycles!

The researchers described their new method in an article that appeared on May 31, 2023, in Nature. The method uses a designer molecule called a ligand that helps a palladium atom catalyst reach from one side of a carbon atom ring to break a carbon-hydrogen bond on the other side, allowing a new set of molecules bind at that site. This molecule-building feat was previously impossible for so-called “saturated” rings of carbon atoms, which are common features in drug molecules.

“Previously, to achieve the same result, one would have to undertake a de novo approach, what we call a cyclization reaction, which involves the formation of a new ring structure from an acyclic chain. Using this new method, we can modify directly an existing ring to avoid a cyclization process that can often be challenging,” says lead study author Jin-Quan Yu, PhD, holder of the Bristol Myers Squibb Chair of Chemistry and Frank and Bertha Hupp Professor at the Scripps Research Department of Chemistry. “In addition to saving steps, this unprecedented synthetic approach may introduce a new chemical space for drug discovery as structurally distinct substrates are incorporated into the ring.”

Yu and his lab are already known for their innovations in CH functionalization, which is a powerful way to build complex organic molecules to make new pharmaceuticals and other valuable commercial compounds. In this approach, chemists use ligands and catalysts to disconnect a hydrogen atom (H) from a carbon atom (C) at a desired position in an organic molecule. This disconnection allows a new group of molecules, known as a functional group, to join where the hydrogen atom had been.

Most of the molecules used to build new drugs include rings of carbon atoms, also called carbocycles. Thanks in part to Yu’s group, CH functionalizations of the carbon atoms in these rings have become relatively easy in many cases. However, this approach is often not applicable in cases where the existing functional group needed to anchor the ligand and catalyst is directly across the ring from the desired CH functionalization site.

“We call this scenario ‘crossing the river,’ and it has been extremely challenging because the palladium catalyst must form a tense ‘bridge’ connecting the existing functional group and the desired carbon site on the other side of the ring,” says Yu. .

The most challenging cases are those in which the carbon ring structures are “saturated”, meaning that their carbons are connected only by single carbon-carbon bonds. Saturated carbon rings are common in pharmaceutical chemistry, but are more difficult targets for CH functionalization, in part because CH bonds have less affinity for metal catalysts, compared to the CC double bonds of unsaturated carbon rings. . Yu’s lab has succeeded in functionalizing CH in unsaturated rings, but there has been no way to do it in a saturated ring, until now.

In the study, Yu and his team—including co-authors Guowei Kang, PhD, Daniel Strassfeld, PhD, and Tao Sheng, PhD, all postdoctoral research associates in Yu’s lab—were able, after months of trial and error, to develop quinuclidine-pyridone and sulfonamide-pyridone ligands that allow functionalization of crossed rings with saturated carbon rings. They showed that the approach can work for rings containing four to eight carbon atoms, within a wide variety of molecules.

The researchers demonstrated the new technique by easily functionalizing molecules that are being used to develop future drugs, including compounds called histone deacetylase inhibitors, which are being investigated as potential cancer treatments.

“We anticipate that this new tool will greatly simplify the synthesis of a large class of carbocyclic molecules used in pharmaceutical chemistry, expanding the chemical space for the discovery of new and better drugs,” says Yu.

The research was supported by grants from the National Institute of General Medical Sciences (2R01GM084019 and F32GM143921).