Golden ticket to trifluoromethylations - C&EN Global Enterprise (ACS

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Science Concentrates SYNTHESIS

Golden ticket to trifluoromethylations Borane catalyst and gold reagent forge C–CF3 bonds, opening another route to radiotracers

tion conditions of aromatic nitration when used to synthesize the rheumatoid arthritis drug leflunomide (Arava). The Berkeley chemists discovered the trifluoromethylation serendipitously when they were trying to Aromatic do a different renitration; (C6H5)2Zn reduction action. Observing NH2 Au Cl Au Au that they’d made O a trifluoromethF3C O ylated product, Cl O N N they decided B(C6F5)3 O N O NH Au to look into the N H O mechanism of this Leflunomide (Arava) unexpected transSynthesis of the formation. They rheumatoid arthritis N figured out that the drug leflunomide IPr CF3 , IPr = Au Au Cl = trifluoromethyl N (Arava) features a new Cl F3C group loses and trifluoromethylation regains a fluoride reaction. during the course of the reaction—a so-called fluoride remention a new mechanism to help us think bound mechanism. about synthetic problems.” “The fluoride rebound made it clear that “The paper is a beautiful combination we had an opportunity to do something of novel reactivity and useful application,” new in the radiochemical arena,” says the comments Tobias Ritter, an organofluorine report’s first author Mark D. Levin. Workchemistry expert at the Max Planck Institute ing with O’Neil’s team, they determined for Kohlenforschung. It’s “a great example they could use radiolabeled potassium of how an unusual discovery can open the fluoride and a cryptand to swap the 18F into doors for valuable reaction chemistry, if their trifluoromethylated products. At the you think carefully about it.”—BETHANY moment, the radiolabeling reaction is limHALFORD :

Medicinal chemists love to add trifluoromethyl groups to drug candidates. The substituents are roughly the size of a milquetoast methyl, but the C–F bonds make the moieties resistant to metabolism, helping compounds to circulate longer in the body. Now, chemists led by F. Dean Toste at the University of California, Berkeley, report a new method for adding trifluoromethyl substituents to molecules. Working in collaboration with researchers at Lawrence Berkeley National Laboratory, led by James P. O’Neil, the chemists adapted the reaction to make molecules with one 18F in the trifluoromethyl group, creating a new method for making radiolabeled compounds for positron emission tomography (PET). The reaction uses a tris(pentafluorophenyl)borane catalyst and stoichiometric amounts of a gold complex to generate the trifluoromethylated product (Science 2017, DOI: 10.1126/science.aan1411). The gold complex tolerates a wide range of reactions, including aluminum hydride reduction, Simmons-Smith cyclopropanation, osmium-catalyzed dihydroxylation, periodate-mediated diol cleavage, and palladium-catalyzed cross-coupling—all without rupturing the Au–C bond. The complex withstands even the harsh reac-

ited to trifluoromethylating sp3 carbons, but the chemists hope to make it work for radiolabeling aromatic trifluoromethyl compounds as well. “None of us started this project with PET in mind,” Levin says. “But now, because we stopped to investigate an unexpected result, we have a platform from which we can start to develop new tracers, not to

BIOLOGICAL CHEMISTRY

What triggers organ transplant rejection? About half of all transplanted organs get rejected by the body within 10 years. To improve this acceptance rate, researchers want to figure out what triggers the rejection process. Scientists already know that the adaptive immune system, made up of specialized cells such as B cells, is responsible for recognizing and attacking foreign tissue and invaders. But this system is activated by the less-specialized innate immune system, which is less well understood. A team led by Fadi G. Lakkis of the University of Pittsburgh and Jayne S. Danska

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C&EN | CEN.ACS.ORG | JUNE 26, 2017

of the University of Toronto has now identified a key cell receptor in the innate immune response to tissue grafts (Sci. Immunol. 2017, DOI: 10.1126/sciimmunol. aam6202). To find the receptor protein, the researchers studied mice genetically engineered to lack an adaptive immune system. By using a genetic mapping method called positional cloning, the team found that the animals’ innate immune response to a tissue graft depended on signal regulatory protein α (SIRPα), a receptor found on the surface of many cells.

The researchers observed that if SIRPα in graft tissue differs from SIRPα in the animals’ own tissues, the innate immune system senses CD47, the receptor’s ligand, bind more tightly to the graft tissue version of the receptor and initiates the rejection response. “It will be interesting to see if this translates to humans and if the innate or adaptive immune response contributes more to accelerated rejection,” says Neil L. Kelleher of Northwestern University, who is using mass spectrometry to identify protein markers of transplant rejection.—CELIA

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