Science Concentrates FLUORINATION
Deoxyfluorinations evolve, again Latest approach offers a very mild and general strategy for converting phenols to aryl fluorides It’s no secret that adding fluorine to bioactive molecules such as pharmaceuticals and agrochemicals can enhance their effectiveness. The trick for chemists has been to fluorinate molecules using inexpensive reagents that operate under mild conditions and to do so on a useful scale. A research team including Sydonie D. Schimler, Megan A. Cismesia, and Melanie S. Sanford at the R University of Michigan, working in collaboration with process chemists at Dow Chemical, is reporting success in meeting all those goals for the deoxyfluorination of phenols, an important reaction for making aryl fluorides (J. Am. Chem. Soc. 2017, DOI: 10.1021/ jacs.6b12911). Other methods chemists use for preparing aryl fluorides are aromatic substitution of aryl chlorides with metal fluorides,
palladium-catalyzed fluorination of aryl triflates, and treatment of phenols with deoxyfluorinating reagents such as phenylsulfur fluorides or fluoroimidazoles. But those methods have limitations, including high cost, low stability, poor functional group selectivity, O O
R
O
OH + F
S F O
S F O Intermediate
R
(CH3)4NF
and the need for an auxiliary reagent such as a base. The Michigan-Dow team members continued looking for a better way, which it found via aryl fluorosulfonate intermediates. The team first discovered that treating aryl fluorosulfonates bearing either electron-withdrawing or electron-donating
substituents with tetramethylammonium fluoride, (CH3)4NF, is a straightforward way to prepare a broad array of fluoride derivatives, often at room temperature. Taking a step back, the researchers then found that the aryl fluorosulfonates could be generated and fluorinated in the same reaction vessel by treating phenols with sulfuryl fluoride, SO2F2, and then (CH3)4NF. The end result is a one-pot, catalyst-free deoxyfluorination process to convert phenols to aryl and heteroaryl fluorides, including analogs of commerF cial drugs and herbicides. “Plenty of interesting and useful arene fluorination reactions have recently been developed,” says Tobias Ritter of Harvard University and the Max Planck Institute for Kohlenforschung. Ritter’s group, for instance, has developed the PhenoFluor family of fluoroimidazole deoxyfluorinating reagents. “But this new one stands out by its simplicity and also the low cost of the fluorinating reagents, which will make it very useful,” he says.—STEVE RITTER
NEUROSCIENCE
Reducing tau by targeting RNA Efforts to treat people with Alzheimer’s disease by targeting the peptide amyloid-β have largely failed so far, but researchers are also pursuing another target: tau protein. Like amyloid-β, tau aggregates in the brains of people with Alzheimer’s. Until now, strategies against tau have mainly involved the use of antibodies and small-molecule drugs. But Timothy M. Miller and colleagues at Washington University in St. Louis are taking a different approach. “We are turning down the production of the tau gene,” Miller says. As Alzheimer’s progresses, tau forms fibrous tangles inside neurons. To decrease tau levels in mice, Miller’s group uses antisense oligonucleotides, which are synthetic, chemically modified, single-stranded DNA molecules that bind complementarily to mRNA that codes for tau, shutting down tau protein production. The team’s candidate therapy, supplied
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C&EN | CEN.ACS.ORG | JANUARY 30, 2017
by Ionis Pharmaceuticals, is made of a strand of 20 nucleotides. Five nucleotides on either end are chemically modified with 2'-O-methoxyethyl groups to make it bind tau mRNA more tightly. To test the potential therapy, Miller used mice engineered to express high levels of human tau protein and thus typically experience neuron death and brain shrinkage. The researchers installed pumps on the animals’ backs to slowly infuse the antisense oligonucleotide into their spines. The researchers found that it significantly lowered tau mRNA and tau protein throughout the brain. The oligonucleotide also prevented brain volume loss, neuron death, and even reversed preexisting tau clustering in the mice (Sci. Transl. Med. 2017, DOI: 10.1126/scitranslmed.aah7029). “The ability of these antisense oligonucleotides to reverse pathology is exciting,” says Matthew D. Disney of Scripps Re-
Neurons (cell bodies about 10 µm in diameter) containing the new antisense agent (red) are deplete of tau tangles (green). search Institute Florida. “Although these drugs are experimental and not without risks, they appear ready to be assessed for efficacy in humans.” This approach “has a clear path toward a human clinical trial,” Miller contends. Just one month ago, FDA approved the antisense oligonucleotide therapy Spinraza (see page 28), also developed by Ionis.—RYAN CROSS
CREDIT: SARAH DEVOS/WASHINGTON UNIVERSITY SCHOOL OF MEDICINE
Antisense oligonucleotide therapy halts buildup of Alzheimer’s protein in mice
