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New Coupling Technique May Have Immediate Applications in Pharmaceuticals, Materials, Agricultural, and Fragrance Chemistry

Chemists at The Scripps Research Institute (TSRI) in La Jolla, California, have invented a powerful method for joining complex organic molecules. This method is extraordinarily robust and can be used to make pharmaceuticals, fabrics, dyes, plastics, and other materials previously inaccessible to chemists. “We are rewriting the rules for how one thinks about the reactivity of basic organic building blocks, and in doing so we’re allowing chemists to venture where none has gone before,” said Dr. Phil S. Baran, the Darlene Shiley Chair in Chemistry at TSRI, whose laboratory reported the finding on functionalized olefin cross-coupling in an online article in Nature published on December 17, 2014. With the new technique, scientists can join two compounds known as olefins to create a new bond between their carbon-atom backbones. Carbon-to-carbon coupling methods are central to chemistry, but until now have been plagued by certain limitations: they often fail if either of the starting compounds contains small, reactive regions known as “functional groups” attached to their main structure. They also frequently don’t work well in the presence of “heteroatoms”—non-carbon atoms such as nitrogen, oxygen and iodine—despite the importance of these types of atoms in chemical synthesis. The new method is what chemists call “mild,” meaning that it doesn’t require the use of extreme temperatures or pressures, nor harsh chemicals. As a result, portions of the building blocks used that are particularly fragile remain unaltered by the reaction. “Functional groups that would be destroyed by other cross-coupling methods are totally unscathed when using our method,” said Julian C. Lo, a graduate student who was a co-lead author of the report with Research Associate Dr. Jinghan Gui.

The innovation arose from a Baran laboratory project to synthesize natural compounds found in traditional Chinese medicines. As they developed a technique for constructing the desired molecules in the lab, the researchers recognized that they could adapt the technique to join two relatively simple olefins together, as they first reported in January 2014 in the Journal of the American Chemical Society.

The next step was to adapt the technique in order to combine more complex olefins attached to heteroatoms, which is reported in the new Nature paper.

“The reaction setup is easy,” said Dr. Gui. “We use a simple iron catalyst, a commercially available silane, and ethanol [i.e., grain alcohol] as the solvent, and we can do the reaction in an open flask, meaning that we don’t need to exclude air or moisture.”

Mr. Lo, Dr. Gui, and their colleagues demonstrated the robustness of their reaction by taking an unconventional approach and running it in vodka, gin, whiskey, tequila, beer, and wine instead of pure alcohol.

“Think of wine—it has this incredibly complex flavor because of the hundreds of compounds in it besides alcohol. And yet our reaction is still able to proceed in that mess, whereas traditional coupling techniques can’t even handle water that well,” said Mr. Lo.

Importantly, the chemists showed that their reaction can be used to make compounds that were previously either impractical to synthesize or couldn’t have been made at all. In their report, they described making more than 60 compounds with the new method. “Around 90 percent of these are new chemical entities,” said Dr. Baran. “We expect that this method will have immediate application to pharmaceuticals, materials, and even agricultural and fragrance chemistry.”

Indeed, Dr. Baran has already used the method to help one company solve a difficult chemical synthesis problem and has disseminated the method’s details to other researchers at scientific meetings. Beyond the immediate practical applications, the new method removes some significant constraints on chemists’ thinking, essentially opening up new worlds of possibilities.

“This new chemistry allows for bond constructions that have previously been simply unimaginable,” said Dr. Baran.

Images shows the TSRI team (left to right) of Dr. Jinghan Gui, Dr. Chung-Mao (Eddie) Pan, Dr. Phil Baran, Dr. Yuki Yabe, and Mr. Julian Lo; here, Dr. Gui and Mr. Lo are holding molecular models, and Dr. Baran holds the actual iron catalysts.

[Press release] [Nature abstract]