Aliphatic acids—hydrocarbon chains with a carboxylic acid on one end—are everywhere. But unfortunately, they’re not much use to synthetic chemists. The saturated chain has only two carbon atoms that can react—the one in the carboxyl group and the one adjacent to it. Jin-Quan Yu and coworkers at Scripps Research and Bristol Myers Squibb have designed a reaction that doubles the number of reactive carbons in these molecules to four, transforming the molecules into versatile synthetic building blocks. With a palladium catalyst and one of two pyridine-pyridone ligands, the team reported that they can do a one-step dehydrogenation that selectively attacks the C–H bond two carbons away from the carboxyl group instead of the traditionally more reactive adjacent carbon (Science, 2021, DOI: 10.1126/science.abl3939).
This creates compounds with reactive double bonds which chemists can use to construct a plethora of cyclic and acyclic structures, including drugs and other bioactive compounds. Yu says this reaction can essentially make drugs out of soap. Chemists have long dreamed of using aliphatic acids, the essential backbone of many soaps, as a chemical reagent, he says. The group synthesized over 80 compounds in two variations of the reaction, each using a different ligand. The first, with a simpler pyridine-pyridone ligand, selectively produces α,β-unsaturated carboxylic acids (shown). The other ligand, with a bridging isomethyl group between the pyridine and pyridone rings, gives γ-alkylidene butenolides. The group also incorporated the butenolide motifs into more complex compounds, such as a precursor to the asthma drug Seratrodast.
Double bonds, which are more reactive than single bonds, are the starting point for many bread-and-butter organic synthetic reactions. “Once you create a double bond, now you are connected to all these reactions,” Yu says. Researchers can then add functional groups across this new double bond, allowing access to four carbons on the molecule: the carboxyl plus the next three carbons on the chain.
This research represents a tremendous step in reactivity of free carboxylic acids, says Manuel van Gemmeren, an organic chemist at the University of Münster. The design of the two ligands was clever, and the ability to select between carboxylic acids and other carbonyls in the molecule is unusual and very useful, says Nuno Maulide, an organic chemist at the University of Vienna. Butenolides are effective building blocks for bioactive molecule synthesis, “and this rapid and selective means of assembling them could be a game-changer for many synthetic campaigns,” says Julian G. West, an organic chemist at Rice University.
Yu had been working on this reaction for 20 years, he says. “Now I can say this is not science fiction,” he says. “It’s real.”