SCIENCE & TECHNOLOGY CONCENTRATES
Nitrogen-rich heterocyclic groups are often key components of drugs and other biologically active molecules. But because of their free N–H groups, appending these substituents usually requires tedious protection and deprotection steps. Now, researchers at MIT have gotten around those extra steps by developing a Suzuki-Miyaura cross-coupling of aryl boronic acids with unprotected, nitrogen-rich heterocyclic halides (J. Am. Chem. Soc. 2013, DOI: 10.1021/ja4064469). Stephen L. Buchwald, M. Alexander Düfert, and Kelvin L. Billingsley came up with the transformation, which makes use of a palladium precatalyst to Cl N + F
B(OH)2 Pd precatalyst
N H
coax the hetereocyclic halide to react. The reaction (example shown) provides easy access to compounds containing indazole, benzimidazole, pyrazole, indole, oxindole, and azaindole groups. The MIT team used the cross-coupling in a two-step synthesis
O
O O
O
H2, immobilized Rh catalyst Flow system, no solvent
O
O
Similar hydrogenations require supercritical carbon dioxide solvent. Solventless reactions, however, can reduce costs and waste. Rubén Duque, Peter J. Pogorzelec, and David J. Cole-Hamilton anchored a chiral rhodium catalyst to alumina using phosphotungstic acid. They packed the alumina into a 10-mL steel column and pumped substrate and hydrogen gas through it. At ambient temperature and roughly 5-atm pressure, they collected (S)-(–)-dibutyl 2-methylsuccinate directly from the reactor in 98% enantiomeric excess. The product elutes with 45-ppb rhodium, which leaches from the reactor. The reaction’s enantioselectivity decreases after 23 hours. The team is working on making the catalyst more stable.—CD
of a kinase inhibitor containing an indazole group. The researchers also investigated the mechanism of the reaction, concluding that transmetalation is the rate-determining step. Knowing this, the researchers note, should help chemists pick optimal conditions and reagent combinations.—BH
INFRARED IMAGING IN THREE DIMENSIONS A new infrared spectroscopy method allows for nondestructive, three-dimensional imaging without labels, contrast agents, or sectioning (Nat. Methods 2013, DOI: 10.1038/nmeth.2596). The technique, synchrotron Fourier transF form infrared (FTIR) spectro FTIR spectromicrotomography reveals microtomography, was develthe composition of a strand of human oped by a group led by Michael hair, with protein (red) filling the cortex N C. Martin of Lawrence Berkeley and phospholipids packing the central National Laboratory and Carol N medulla (blue-green). Top left image is a H visible micrograph. J. Hirschmugl of the University of Wisconsin, Milwaukee. It reveals the chemically rich combines computed tomograVIDEO ONLINE information available from phy—the same technique that IR spectroscopy. The researchers used the produces 3-D medical X-ray images—with method to show the structures of cell walls 2-D synchrotron-based FTIR spectrosin zinnia plants and eastern cottonwood copy. The end result is a 3-D image that CEN.ACS.ORG
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HOOKING UP WITH HETEROCYCLES
The ideal reaction for an industrial chemist, Nobel Laureate Sir John W. Cornforth said humorously in 1975, “is something to be carried out in a disused bathtub by a one-armed man who cannot read, the product being collected continuously through the drain hole in 100% purity and yield.” Rare is the reaction that clears that bar, but a team at the University of St. Andrews, in Scotland, is giving it their best shot. They’ve developed a continuous hydrogenation that requires no solvent and yields a nearly enantiomerically pure product (Angew. Chem. Int. Ed. 2013, DOI: 10.1002/anie.201302718).
O
HIV is certainly a sly pathogen. But now researchers have discovered it is less wily than previously believed. For many years, scientists thought that one reason HIV infections are so successful is that the pathogen avoids immediate immune system detection. Recently, researchers found that HIV does indeed trigger some alarm signals in host cells, but the precise nature of the sensor remained elusive. Now, a team led by Zhijian J. Chen of the University of Texas Southwestern Medical Center has reported that cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase is an HIV sensor (Science 2013, DOI: 10.1126/science/1240933). The team showed that cGAMP synthase detects HIV’s reverse-transcribed DNA, the hallmark of retroviruses. Production of cGAMP in turn triggers signal transduction pathways that activate innate immunity. The authors propose that cGAMP might one day be used in the development of an HIV vaccine as an adjuvant, an ingredient in vaccines used to enhance the response of the immune system to an antigen.—SE
SOLVENT-FREE HYDROGENATION FLOWS ON
O
AN IMMUNE SYSTEM SENSOR FOR HIV
SCIENCE & TECHNOLOGY CONCENTRATES
ADDING UNNATURAL COVALENT BOND TO PROTEINS Covalent bonds between amino acid side chains help stabilize protein structures and interactions. The ability to form types of covalent bonds other than disulfide bonds between cysteines could make it possible to design proteins with a wider variety of properties and functions. Lei Wang and coworkers at the Salk Institute for Biological Studies, in La Jolla, Calif., use well-established methods to incorporate into proteins unnatural amino acids that form covalent bonds not normally seen in proteins (Nat. Methods 2013, DOI: 10.1038/nmeth.2595). Researchers have previously avoided unnatural amino acids that react with other side chains, opting instead for so-called bioorthogonal side chains. Wang and coworkers designed p2´-fluoroacetylphenylalanine to react with cysteine (reaction shown). The reaction occurs only when the two amino acids are close to one another in the same protein
Researchers have been tinkering with various properties of ionic liquids, in particular their stability at high temperatures, to make them useful as heattransfer fluids. James H. New cations Davis Jr. of the University help heated of South Alabama and ionic liquid keep its white colleagues have now color (right), developed what may be ionic the most thermally stable while liquids with ionic liquids yet. The other cations group synthesized a suite evaporate and of new tetraarylphosleave ash.
phonium cations that pair with the anion Tf2N– [bis(trifluoromethylsulfonyl)imide] to form ionic liquids that are stable at temperatures of up to 350 °C. The researchers found that even after heating at that temperature for 96 hours, the material remained colorless and less than 10% had evaporated (Chem. Commun. 2013, DOI: 10.1039/c3cc44118k). In contrast, other popular ionic liquids with cations such as imidazolium, quaternary ammonium, or tetraalkylphosphonium thoroughly decomposed when subjected to those conditions and left dark solids at the bottom of the dish. The researchers are now working to expand the ionic liquids’ capabilities by decreasing their melting points yet maintaining their thermal stability.—EKW
O +NH 3 –OOC
COO–
O F
HS +
+
H 3N
S
+NH 3
COO–
or interacting proteins. The researchers show that when the unnatural amino acid is incorporated in an antibody mimetic, it enables irreversible binding between the mimetic and its protein substrate. They suspect the approach will also work with unnatural amino acids designed to react with amino acids other than cysteine.—CHA
IONIC LIQUIDS STABLE AT HIGH TEMPS Ionic liquids—essentially liquid salts—can be used in all sorts of ways, including as solvents and electrically conducting fluids.
+
NH3
–OOC
CHEMISTS GIVE PEPTIDOMIMETICS AN F Organofluorine chemists have long appreciated that fluorinated alkene groups can serve as stand-ins for amide groups in modified natural peptides or synthetic peptides being explored as drugs. Fluorine provides distinct properties, such as decreased hydrogen-bonding abilities, which can improve the stability and bioactivity of the peptidomimetics. Ming-Hsiu Yang, Siddharth S. Matikonda, and Ryan A. Altman of the University of Kansas, Lawrence, have now come up with CEN.ACS.ORG
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JAMES H. DAVIS JR.
trees on the basis of hydroxyl and hydrocarbon signals. In human hair samples, the team imaged protein filling the cortex and phospholipids in the central medulla. They probed a mouse embryoid body and found heterogeneous lipid distribution, which they hypothesize corresponds to differentiating cells. They also studied a volcanic glass fragment and imaged the water distribution, which could hold clues to how and why the volcano erupted.—JK
a convenient strategy for introducing fluoroalkene groups into peptide building blocks, steroids, and other bioactive molecules at a late stage in the synthesis (Org. Lett. 2013, DOI: 10.1021/ol401637n). The team went after the fluoroalkenes by altering the Shapiro reaction, which is widely used in natural product synthesis. This reaction typically involves condensing an N-sulfonyl hydrazide with a ketone, creating a vinyllithium intermediate, and then trapping the vinyl anion with H+ to obtain the alkene product. In the Altman group’s fluorination scheme, the researchers used N-fluorobenzenesulfonimide as a source of F+ to trap the fluoroalkene product. Given the number of ketone functional groups in natural products and pharmaceutically important building blocks, the researchers believe there’s a rich variety of substrates awaiting the new transformation.—SR
PHENOLS ADD TO ALKYNES VIA COOPERATIVE GOLD A new reaction uses cooperative gold catalysts to achieve an organic synthetic goal infrequently explored: adding tertiary alcohols and phenols to alkynes. Steven P. Nolan of the University of St. Andrews, in Scotland, and colleagues had previously developed a dinuclear gold hydroxide catalyst, [Au(NHC)]2(µ-OH)][BF4], where NHC is an N-heterocyclic carbene. They reasoned that this compound could behave as two catalysts and applied it to the hydrophenoxylation of alkynes. They predicted that the BF4 segment would react with an alkyne to form a gold-alkyne complex and that the OH segment would react with phenols to form a gold-phenoxide complex. The researchers tested this idea with numerous alkynes and phenols and found that the dinuclear gold catalyst indeed behaved like two cooperative gold catalysts (Angew. Chem. Int. Ed. 2013, DOI: 10.1002/ anie.201304182). The reactions produced various aryl vinyl ethers with moderate to good yields, the authors say. They add that “these findings provide new insights into the chemistry of gold catalysis and open the door to the development of new catalytic transformations.”—EKW
