From soapsuds to gold: Chemists develop powerful method for transforming simple, cheap chemicals into complex and valuable ones
New method for desaturating aliphatic acids overcomes a long-standing challenge in synthetic chemistry.
November 12, 2021
LA JOLLA, CA—Chemists at Scripps Research have solved a long-standing problem in synthetic chemistry by devising a set of reactions for transforming simple, cheap, and ubiquitous organic compounds called aliphatic acids—a very broad family that ranges from detergents to vegetable oils—into much more complex and valuable compounds.
The new reactions, described in a paper this week in Science, should have a broad utility for molecule-building, making chemists’ tasks easier—and potentially making chemical products cheaper and easier to develop—across multiple industries. This includes the pharmaceutical industry, which is already beginning to use the new reactions for discovering new drugs.
“These reactions are going to be general tools for making complex molecules, and because they use simple molecular oxygen to drive their catalytic cycles they can potentially be applied to large-scale manufacturing,” says Jin-Quan Yu, PhD, professor of chemistry at Scripps Research, who led the study.
Aliphatic acids include chain-like arrangements of carbon atoms covered with hydrogen atoms. In most simple aliphatic acids, this chain of carbon atoms is linked together by unreactive single bonds. The new reactions enable chemists essentially to convert a selected one of these single bonds to a reactive and versatile double bond—often a key step for installing polar groups in improving a compound’s pharmacological properties—and to do so much more quickly and easily than ever before. The double bond itself does not improve pharmacological properties, but this can be accomplished through further reactions to install polar groups.
“Double bonds can then be converted to diverse structures using many other well-known reactions, including those invented by my colleagues at Scripps Research,” Yu says.
The researchers also found that by tuning the structures of the catalysts that assist the dehydrogenation reaction, the newly formed double bond can further react with an alkyne partner in a cascade that yields complex bioactive compounds called lactones.
Humans and other organisms have evolved enzymes that accomplish the single-to-double bond-conversion process efficiently and effortlessly in specific contexts, for example in converting fatty acids into cellular fuel. But until now synthetic chemists haven’t had a relatively simple and broad method of doing so via laboratory chemical reactions.
The new reactions use a palladium catalyst to perform the crucial first step of removing a hydrogen atom from the targeted carbon on an aliphatic acid, thus effectively freeing up electrons to form the new double bond. The key to the reactivity of the palladium catalyst is a rationally designed helper molecule—a “ligand”—called a pyridine-pyridone, which holds the palladium in a way that promotes the hydrogen removal. Yu and his team designed the pyridine-pyridone to have the precise geometry needed to carry out this task on the starting aliphatic acid without also removing hydrogen atoms from the product compound as it is formed.
The Yu lab’s many innovations in synthetic chemistry over the past two decades have attracted the interest of the pharmaceutical industry, and the new work was partly funded by Bristol Myers Squibb—which is currently investigating how to apply this new reaction to synthesize potential new drug compounds, Yu says.
“Ligand-controlled divergent dehydrogenative reactions of carboxylic acids via C–H activation” was co-authored by first authors Zhen Wang and Liang Hu, and by Nikita Chekshin, Zhe Zhuang, Shaoqun Qian, Jennifer Qiao, and Jin-Quan Yu, all of Scripps Research.
The work was funded by the National Institutes of Health (2R01GM084019) and Bristol Myers Squibb.
For more information, contact press@scripps.edu