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Reaction Mechanisms

Easy access to boronate esters and boronic acids

Methodology swaps out carboxylic acids for boron functional groups at late stages of syntheses

by Bethany Halford
April 13, 2017 | A version of this story appeared in Volume 95, Issue 16

A scheme showing a synthesis of bortezomib (Velcade)
A carboxylic acid can be converted to a boronate ester in one pot. Subsequent hydrolysis produces a boronic acid—bortezomib (Velcade), in this example.

Boron—the beloved oddball of the periodic table—can do some unique chemistry, thanks to its empty p-orbital. This has made boronic acids and boronate esters indispensable components in many compounds, such as in partners for Suzuki cross-coupling reactions, in polymers, and even in a few drugs, such as the cancer therapies bortezomib (Velcade) and ixazomib (Ninlaro). But, while there are a few ways to make boronic acids and boronate esters, none are trivial.

Phil S. Baran’s group at Scripps Research Institute, California, has now come up with a simple and practical method for converting carboxylic acids into a boronate esters and boronic acids (Science 2017, DOI: 10.1126/science.aam7355).

The method works on primary, secondary, and tertiary carboxylic acids, as well as peptidic and even natural product-derived substrates. It also tolerates a broad range of functional groups, so it can be used in the final steps of the synthesis of a densely functionalized molecule. For example, Baran’s group prepared a boronic acid analog of the antibiotic vancomycin, a compound that is packed with stereocenters and functional groups. The reaction conditions modified only vancomycin’s carboxylic acid.

To convert a carboxylic acid to a boron compound, Baran’s team first transforms it into a redox-active N-hydroxyphthalimide ester. This compound then undergoes decarboxylative borylation in the presence of a nickel catalyst, a bipyridine ligand, and bis(pinacolato)diboron to make the boronate ester. These two reactions can be carried out in a single pot. The boronate esters can then be hydrolyzed to the corresponding boronic acids.

The new method “will see immediate application in laboratories throughout academia and the pharmaceutical industry,” comments Stephen L. Buchwald, a synthetic organic chemist at MIT. “The demonstrated substrate scope and the complexity of the applications that are described are spectacular.”

“I particularly like the opportunity for late-stage transformation of more complex molecules,” adds Derek Lowe, a medicinal chemist who writes the popular “In the Pipeline” blog. “Sticking in a boronic acid at that point, though desirable, isn’t what you’d normally consider doing because of the synthetic difficulties.”

In another demonstration of the method’s power, Baran’s group teamed up with scientists at Calibr to make boronic acid analogs of human neutrophil elastase inhibitors. Neutrophil elastase is an important target in lung diseases, such as cystic fibrosis and chronic obstructive pulmonary disease. Calibr had been working with inhibitors that had failed Phase II clinical trials because of potency issues. Baran group’s chemistry added a boronic acid to these molecules and the resulting compounds proved to be far more potent than the parent compounds in tests, including enzyme assays. Calibr is currently studying the in vivo activity of the compounds.

“I always tell people that I barely know what DNA stands for and it’s hard for me to imagine making real contributions to biology or medicine,” Baran says. “But we do know organic chemistry. So this is an example of a very fundamental organic chemistry problem that has immediate ramifications in many areas—materials, medicine, fine chemicals. There are tons of practical applications.”


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