Sulfones at Scripps

A new cross-coupling simplifies the synthesis of drug-like molecules

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LA JOLLA, Calif.—Researchers at The Scripps Research Institute (TSRI) have designed a new molecule-building method that uses sulfones as partners for cross-coupling reactions, the joining of two distinct chemical entities in a programmed fashion aided by a catalyst. The technique, published in February in the journal Science, opens the way toward other new chemical reactions and facilitates the synthesis of pharmaceutically-relevant molecules.
“It’s already clear that this method opens the door to creating new types of compounds and new types of bonds,” said Dr. Phil S. Baran, senior author of the study—“Modular radical cross-coupling with sulfones enables access to sp3-rich (fluoro)alkyl-containing scaffolds”—and Darlene Shiley, a professor of chemistry at TSRI.
This work was inspired by previous cross-coupling chemistry developed in the Baran lab, and catalyzed by discussions with pharmaceutical industry partners who view this as an area of unmet need. Baran and his colleagues have previously studied decarboxylative cross-coupling reactions, where commonly found carboxylic acids are transformed into many different molecules using inexpensive metal catalysts and techniques commonly used for amide-bond synthesis.
According to study co-authors Jacob Edwards and Rohan Merchant—both TSRI graduate students—and Tian Qin, a TSRI senior research associate, “Our molecule-building method uses sulfones in a cross-coupling reaction where the sulfone is removed and a new bond between two carbon atoms is formed. This cross-coupling uses an inexpensive nickel catalyst and a bipyridine ligand. Sulfones are highly desirable starting materials for organic chemistry because they are very stable, require little purification and are easy to prepare.
“We have recently been working on decarboxylative cross-coupling reactions using nickel catalysts. In these cases, we take a carboxylic acid that has been activated in a manner analogous to that for peptide coupling chemistry and react the activated carboxylic acid, or redox-active ester, with an organometallic coupling partner and a nickel catalyst. We found that in some cases, certain sulfones behave similarly to carboxylic acids in these cross-coupling reactions and can be used to form new bonds between carbon atoms. Sulfones have some advantages over redox-active esters, due to a high degree of stability.”
Throughout these studies, Baran and colleagues showed that decarboxylative cross-coupling can have broad applicability and facilitate the synthesis of pharmaceuticals and natural products. These reactions hinge on the transfer of one electron from the metal catalyst to an activated carboxylic acid, which allows for the cross-coupling to occur.
“One unique aspect of this work is that fluorine atoms can be incorporated without significantly changing the way the molecule was made,” Edwards, Merchant and Qin tell DDNews. “Typically, new synthetic routes or strategies are needed to put fluorine atoms into drug-like molecules. With our method, this process is much simpler. In fact, we tried using fluorinated carboxylic acids in decarboxylative cross-couplings, but for a variety of reasons this was largely unsuccessful.”
In this work, the authors demonstrate the new desulfonylative cross-coupling reaction by synthesizing over 60 representative molecules, including alkyl-fluorinated compounds inaccessible with earlier generation methodologies developed in the Baran group. Access to such compounds are critical for drug discovery campaigns, since fluorine atoms enhance drug-like molecular properties. Representative molecules described in the Science paper include some reported by Merck and Novartis in published patents.
“We synthesized a variety of molecules that can be found in the patent literature from a number of companies, such as Schering-Plough, Merck and the Genomics Institute of the Novartis Research Foundation,” note Qin, Merchant and Edwards. “We compared the synthesis of these molecules using our desulfonylative cross-coupling method to those reported in the initial patents or publications.”
Baran’s group has already made their sulfone reagents and methods used in this study available to other chemists who would like to use the technique, via Twitter in December.
The new method is already having an impact on drug discovery programs at pharmaceutical companies with whom TSRI collaborates. “This work was conceptualized and carried out in collaboration with medicinal chemists at Pfizer, who found an immediate use for it in their drug discovery programs,” say Edwards, Qin and Merchant.
“This project was very exciting for us to work on because we were helping scientists at Pfizer solve problems in real-time that they were facing in their drug discovery programs; it was edifying to see our work being used to make compounds that may have important biological properties,” the trio concludes.
“I think the job of chemists in academia is to make things simpler. If we can have a small positive influence in making medicinal chemists' lives easier, that will be a success for us,” said Baran. “This chemistry is another step in that direction.”

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