Science Concentrates SYNTHESIS
Simplification of hallucinogen pays off Researchers disclose total synthesis of salvinorin A analog in ChemRxiv paper The report is one of the first manuSalvinorin A, a hallucinogen produced by scripts posted on the ChemRxiv Beta site, the Mexican plant Salvia divinorum, holds a preprint server operated by ACS in partpromise for treating itch and pain because it activates the kappa opioid receptor while nership with the Royal Chemical Society, the German Chemical Society, and other avoiding the mu opioid receptor, a sister organizations. The authors dereceptor that’s been associated with opioid O clined to discuss the work with abuse. Chemists have tried to synthesize C&EN for this story except to salvinorin A so that they could alter the H confirm its factual accuracy, in structure to sidestep the compound’s psyO H H O compliance with the embargo choactive effects while preservO ing its analgesic properties. But O policies of the journal in which O the paper has been submitted. salvinorin A’s scaffold has been R A long-standing problem challenging to recreate. for the total synthesis of salvinorin A Now, a team of scientists at the CH O O 3 and its analogs is the molCalifornia and Florida branches Salvinorin A, R = CH3 ecules’ propensity to epiof Scripps Research Institute, 20-Norsalvinorin A, R = H merize, or switch chirality at as well as at the University of a particular stereogenic center, according Southern California, report a 10-step total synthesis of 20-norsalvinorin A (ChemRxiv to synthetic chemist Mark Rizzacasa 2017, DOI: 10.26434/chemrxiv.5318188). The of the University of Melbourne. When salvinorin A epimerizes, it twists itself into compound differs from salvinorin A by a single methyl group and binds to the kappa the more stable, less active 8-epi isomer. On the basis of calculations and exopioid receptor with an affinity similar to perimental data, the researchers, led by that of the natural product. When given to Scripps’s Ryan Shenvi, proposed that this mice, it also relieves itch.
epimerization is driven by an unfavorable interaction between a hydrogen atom and the C20 methyl group within the molecule. They hypothesized that deleting the C20 methyl group to make 20-norsalvinorin A would stabilize the structure. This analog’s ability to bind to the target kappa opioid receptor was unknown, but the researchers performed computational studies that suggested the molecule would indeed bind with an affinity similar to that of salvinorin A. “Careful attention to modeling gave a measure of confidence to the venture, although to some extent, it was still a leap of faith,” says Jonathan Scheerer, an organic chemist at William & Mary. Salvinorin A had previously been made in 20–29 steps. The team’s route reaches 20-norsalvinorin A in 10 steps and includes a six-step sequence to an intermediate in 13% yield that can then be diversified to make similar analogs. Along with 20-norsalvinorin A, the research team prepared other derivatives that also demonstrated binding preference for the kappa opioid receptor over the mu and delta opioid receptors.—TIEN NGUYEN
RESEARCH INTEGRITY
Chemists carry out a structural do over Orvig and the journal’s editors agreed a dimeric structure. But the team had a In what is being called an honest mistake, a the best solution would be to retract the hard time growing crystals of the ligand research group has reported that the strucpaper (Inorg. Chem. 2017, DOI: 10.1021/ and couldn’t confirm its structure by ture of the headline compound from a paacs.inorgchem.7b01932). But they also X-ray analysis. When the group recently per it published in 2002 is incorrect. To set agreed that Orvig’s group could publish revisited the ligand for a new project, the the record straight, the team has retracted a new paper reporting the correct strucresearchers were able to get the paper and at the same time published a O ture (Inorg. Chem. 2017, DOI: 10.1021/acs. a crystal structure and new paper reporting the actual structure. OH O inorgchem.7b01117). The original paper published by Chris HO O Inorganic Chemistry Editor-in-chief Orvig and his group at the University O N N OH P William B. Tolman of the University of British Columbia reported the OH OH P OH of Minnesota applauds Orvig for synthesis of a new tetraazamacrocy- HO P N N O coming forward to self-correct the O HO N N cle ligand (Inorg. Chem. 2002, DOI: O mistake. “This is precisely why the 10.1021/ic010716a). The researchers O HO Correct: retraction mechanism exists—to cormade the compound to see how reMonomeric ligand rect the published record,” Tolman says. O placing two methylene groups in a mac“Orvig realized the error, did a bunch rocyclic ring with phosphinate groups Incorrect: affected the stability of complexes Dimeric ligand found the molecule is half of work to reexamine it, and then pushed to have it corrected despite it being years the size expected—it is formed with lanthanide ions. Such comlater.” Tolman adds that he would hope monomeric, not dimeric—and forms a 2:1 plexes are of interest as contrast agents researchers view this case as one of many complex with lanthanides instead of a 1:1 for magnetic resonance imaging. complex as originally thought, which nulli- data points in the larger story of how sciOrvig says all the characterization data ence corrects itself.—STEVE RITTER fied the paper’s conclusions. were consistent with the ligand having
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C&EN | CEN.ACS.ORG | SEPTEMBER 11, 2017
MICROSCOPY
Technique pinpoints active sites on surfaces University of California, Berkeley. Bandarenka and coworkers used the technique to identify reactive sites on electrodes while the surfaces catalyzed hydrogen-evolution and oxygen-reduction is about an order of magnitude better than Many industrial processes use solid catreactions in solution. They found that catSECM’s. alysts to accelerate chemical reactions in alytic activity is stronger at step edges than The ultimate goal is atomic resolution— gases or liquids. The activity of these heton plateaus of a terraced Pt surface. still about two orders of magnitude away. erogeneous catalysts often varies considerWhat makes the technique work is that But the new technique goes well beyond ably from site to site across their surfaces. electron-tunneling current between an STM earlier approaches in its ability to identify If scientists were able to identify highly tip and a nearby surface spot varies considsite activity precisely, comments heterogereactive sites precisely, they could improve erably with reaction activity. As a reaction the catalysts by redesigning them to include neous catalysis expert Alexis T. Bell of the occurs, localized surface variations, such more of those sites. as molecular adsorption and desorption, Aliaksandr S. Bandarenka and cocause noise changes in the electron-tunworkers at the Technical University neling current. The researchers identify of Munich have now devised a scanand measure activity differences by ning tunneling microscopy (STM) monitoring these changes. technique that identifies surface Hans Niemantsverdriet, director of activity variations during reactions the catalysis and surface science firm at higher spatial precision than has Syngaschem, says the work “is truly been possible before (Nature 2017, remarkable and a significant step forDOI: 10.1038/nature23661). Scanning ward in making catalytic sites visible” electrochemical microscopy (SECM), and wonders if it can also be extended which Allen J. Bard and coworkers at An STM instrument measures high electronto gas-phase reactions, in which noise the University of Texas developed, can tunneling signal noise at step edges (yellow) than on terraced Pt surface (blue) as it catalyzes water variations would be smaller.—STU also map surface activity, but the new STM technique’s 1- to 2-nm resolution splitting (red = oxygen, white = hydrogen). BORMAN
Scanning microscopy detects activity with unprecedented resolution while reactions occur
POLLUTION
Probiotic-treated trees clean up a carcinogen C R E D I T: NAT UR E ( ST M) ; JO H N FR E EM A N / IN TR I N SYX TEC H N O LO GI ES ( TR E ES)
Symbiotic bacteria help poplars strip trichloroethylene from groundwater Poplar trees inoculated with bacteria could help remediate sites contaminated with the carcinogen trichloroethylene (TCE), a new study shows (Environ. Sci. Technol. 2017, DOI: 10.1021/acs.est.7b01504). TCE contaminates the soil or water of more than 1,000 Superfund sites around the U.S., posing an expensive cleanup problem, says Sharon L. Doty of the University of Washington. Plants can be used to soak up a variety of pollutants—a method called phytoremediation—and introducing symbiotic, pollutant-destroying bacteria to the plants has shown even more promise in lab tests. Several years ago, Doty and her colleagues discovered a strain of Enterobacter in a hybrid poplar (Populus deltoides crossed with Populus nigra) that completely degrades TCE into chloride ions and carbon dioxide. The researchers found that they could successfully inoculate
other poplar trees by soaking tree cuttings in a solution containing the microbe. In collaboration with several environmental engineering firms, the researchers decided to test the fast-growing trees and the microbes at a Superfund study area in California contaminated with TCE. The team planted about 400 tree cuttings, half treated with the microbe and half with a control solution. Over three years, the researchers tracked the trees’ growth, and then tested groundwater at the end of the experiment. TCE concentrations upstream of the trees were about 300 µg/L, whereas downstream they were below EPA’s drinking water limit of 5 µg/L. The poplars treated with the microbe grew faster and visibly larger than the control trees. “It’s a really simple way to get rid of an important carcinogen,” Doty says. Om Parkash Dhankher, a phytoremediation expert at the University of Massa-
Poplar trees grow at a test site contaminated with trichloroethylene. The rows of larger trees have been given microbes and are growing faster than the poplars with no microbes. chusetts, Amherst, says it’s exciting that Doty’s team has shown that the method works in the real world. “This is a very cheap and green, clean technology,” he says.—DEIRDRE LOCKWOOD, special to
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Science Concentrates CHEMICAL SENSING TOXICOLOGY
Detecting food allergens on the go
▸ How poison dart frogs avoid poisoning themselves
A single amino acid swap keeps golden poison dart frogs safe from their own toxin. 2 mg in adults—to kill more than 20,000 mice, yet their voltage-gated sodium channel membrane protein is immune to its paralytic effects. Sho-Ya Wang and Ging Kuo Wang of the University at Albany now report that a single amino acid swap can render sodium channels almost completely resistant to batrachotoxin. The researchers built off a study published last year by another research team that identified five amino acid substitutions differentiating poison dart frog and rat sodium channels. In the new study, scientists tested whether creating the five frog substitutions in the rat sodium channel, individually and in combination, conferred batrachotoxin resistance. Monitoring cells engineered to produce either normal or modified sodium channels revealed that replacing just one amino acid—asparagine with threonine at HO3SO
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position 1,584—conferred “exceptional” batrachotoxin resistance (Proc. Natl. Acad. Sci. USA 2017, DOI: 10.1073/pnas.1707873114). Sodium channels with substitutions at the other four locations remained sensitive to the toxin. Sho-Ya Wang says gaining a better understanding of how batrachotoxin interacts with sodium channels may help improve the design of therapeutic drugs that target the same region of the protein.—EMMA HIOLSKI
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C&EN | CEN.ACS.ORG | SEPTEMBER 11, 2017
killed people. A synthetic heparin called fondaparinux is safer and homogeneous. But people taking heparin sometimes experience uncontrolled bleeding, and although a drug called protamine can reverse the anticoagulant activity of unfractionated heparin, it does so incompletely with low-molecular-weight heparin and doesn’t reverse fondaparinux activity at all. Robert J. Linhardt of Rensselaer Polytechnic Institute, Jian Liu of the University of North Carolina, Chapel Hill, and coworkers re-
▸ Synthetic heparin could improve bloodthinning treatments A new synthetic version of the sulfated polysaccharide heparin that could be safer or have more-reversible activity than currently approved versions of the
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DRUG DEVELOPMENT
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anticoagulant has been produced in quantities that begin to approach those needed for commercialization. Three types of heparins are currently approved as blood thinners to treat clotting disorders and prevent clotting in people undergoing kidney dialysis and surgery. Unfractionated heparin and low-molecular-weight heparin, derived from pig intestines, are mixtures with batch-to-batch inconsistencies, and contaminated batches have at times
cently used chemoenzymatic synthesis to make a synthetic heparin that is less prone to contamination, more consistent, and more amenable to protamine reversal than other heparins are. But they could produce only milligram amounts. Now, a group led by Linhardt, Liu, and UNC’s Rafal Pawlinski has added a sulfate that makes the heparin easier to synthesize, boosted the activity of two key enzymes, and found a way to produce cofactors in higher yield. The
C R E D I T: ACS N A NO ( D E T ECTO R ) ; M IC H A L . R I ES E R / WI KI MED I A CO MMO N S (F RO GS )
Doctors estimate that each year more than 200,000 people in the U.S. visit hospital iEAT consists of a portable antigen extraction kit and a emergency rooms because of food allergies. key-chain detector. This number includes an estimated 90,000 cases of life-threatening anaphylaxis. The main approach doctors recommend when it comes to food allergies is simply to avoid those foods. But that can be difficult when eating at restaurants or when traveling to countries that have less-stringent food allergen labeling laws. Researchers led by Massachusetts General Hospital’s Hakho Lee and Ralph Weissleder have now developed a prototype point-of-use allergen detection system that picks up traces of peanuts, hazelnuts, wheat, milk, and egg whites in less than 10 minutes (ACS Nano 2017, DOI: 10.1021/acsnano.7b04318). The system, dubbed iEAT, requires two steps: antigen extraction followed by detection. Antigens in the food are captured with antibody-containing magnetic beads, which are subsequently labeled with other antibodies conjugated to the oxidizing agent horseradish peroxidase. A sheathed magnet collects the magnetic beads, which are then placed on the detector, where they undergo an electrochemical reaction. The major innovation, Lee notes, is the detector that fits on a key chain, which can differentiate up to eight allergens, connect to smartphones via Bluetooth, and charge wirelessly. Each disposable antigen extraction system costs about $4.00, and the detector costs $40.—BETHANY HALFORD
Scientists have wondered how golden poison dart frogs resist succumbing to the high doses of toxin they store in their skin. Certain species of Phyllobates frogs are loaded with enough batrachotoxin—up to
