Chemists’ technique to turn cheap dicarboxylic acids into complex lactones could boost industries from pharmaceuticals to plastics

Scripps Research chemists have unveiled a method to turn cheap and widely available chemicals known as dicarboxylic acids into potentially very valuable molecules called lactones.

Lactone structures are common in biologically active natural molecules; they are found, for example, in vitamin C and in erythromycin, an antibiotic of bacterial origin. Techniques for synthesizing lactones have long been available to chemists, but these techniques are quite limited in what they can produce. The achievement, reported on May 26, 2022, in Sciencemakes building diverse and complex lactones easier than ever.

“This method should be very widely useful for developing new pharmaceuticals, polymeric materials, fragrances and many other chemicals – we are already receiving inquiries from interested manufacturers,” says Jin-Quan Yu, PhD, Professor Frank and Bertha Hupp of Chemistry at Scripps Research.

Yu and his lab are known for their innovations in building molecules, particularly with regard to “CH activation”. It involves the use of specially designed catalyst molecules to remove a hydrogen (H) atom from a carbon (C) atom on an organic molecule and to replace the hydrogen atom with a group of atoms more complex.

The overall goal is to develop a set of methods to perform CH activation selectively on any chosen carbon atom on a starting molecule – and the dream is to use these methods to transform cheap molecules and relatively simple ones into complex and valuable drugs, plastics and other molecules.

In this case, Yu and his team aimed to perform particularly difficult and selective CH activations to convert cheap and readily available dicarboxylic acids into high-value lactones. Dicarboxylic acids, despite their seemingly complicated name, are relatively simple molecules and are ideal starting materials for many types of chemical synthesis. But chemists attempting CH activation of dicarboxylic acids have always faced considerable obstacles.

“CH activations at sites of a dicarboxylic acid away from one of its carboxyl groups have been very difficult to date,” says Yu. “Being able to target distant carbons and/or closer carbons, selectively through catalyst control, seemed like an impossible dream.”

The feat achieved by Yu and his team, including first author Sam Chan, PhD, a Croucher Foundation postdoctoral fellow in the Yu lab, was a set of methods using palladium-based catalysts to freely obtain CH activations on of reaching carbons on a dicarboxylic acid.

“Over the past two decades, we have succeeded in developing good methods for activating the two-carbon CH of a carboxyl, but now, with our new methods, we can also achieve one more carbon, and with the freedom to choose between the two sites, we can easily access a new chemical space in drug discovery,” Yu says. essentially with this approach, one can construct a very wide range of complex lactone compounds.”

Yu and his team demonstrated the ease and utility of their new methods by synthesizing – from cheap dicarboxylic acids – two complex natural lactones, a fungal molecule called myrotheciumone A, which has been studied for anti-cancer properties, and the pedicellosin vegetable lactone.

Chemists are now using the new methods to generate hundreds of diverse lactone structures, whose properties – and potential to develop into future pharmaceuticals – they are exploring in collaboration with the lab of Ben Cravatt, PhD, Gilula Chair of Biology chemical at Scripps Research.

“We are also using our methods to develop improved one-ton scale production processes of lactones used by chemical manufacturers,” says Yu.

“Catalyst-controlled site-selective CH methylene lactonization of dicarboxylic acids” was co-authored by Hau Sun Sam Chan, Ji-Min Yang, and Jin-Quan Yu of Scripps Research.

Funding was provided by the National Institute of General Medical Sciences (2R01GM084019) and the Croucher Foundation.

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