CATALYSIS
Radical pathway to four-way carbons FOOD
SHUTTERSTOCK
Exposure to pharmaceutical contaminants via vegetables With freshwater resources dwindling worldwide, the practice of using treated wastewater to irrigate crops is growing. But that practice might have a downside: In a new study, people who ate vegetables grown using such reclaimed water had increased urine levels of carbamazepine, an antiepileptic drug commonly detected in wastewater (Environ. Sci. Technol. 2016, DOI: 10.1021/acs. est.5b06256). The randomized, controlled study is the first to directly address human exposure to such pharmaceutical contaminants via produce, says Ora Paltiel of the Hadassah-Hebrew University of Jerusalem. Paltiel and her colleagues gave 34 healthy volunteers batches of produce to eat for a week—either vegetables grown with reclaimed water or organic vegetables grown with only freshwater. Before the study began, some volunteers had quantifiable concentrations of carbamazepine in their urine while others didn’t. This remained true for participants after a week of eating the organic produce. But after a week of eating produce grown with reclaimed water, every subject excreted detectable levels of the drug. “This fits what we’ve all suspected but have not shown experimentally,” says Alistair Boxall of the University of York. Although the urine levels were very low—four orders of magnitude lower than those from patients actually taking the drug—people who eat a lot of produce will be exposed to such contaminants throughout their lifetimes, he adds.—ALLA
KATSNELSON, special to C&EN
Chemists deal with unstable intermediate to develop first radical route to chiral quaternary carbons Many natural products, pharmaceuticals, and other biologically active molecules feature chiral carbon atoms attached to four other carbons. Chemists can synthesize these quaternary stereocenters using organometallic reagents that add carbon groups to conjugated carbonyl compounds. These reagents, however, are expensive and hard to generate, can cause problematic side reactions, and don’t always work well at crowded carbon centers. Now researchers report the first radical route to quaternary carbon stereocenters, offering a possibly easier way to form the important chiral groups. Chemists previously have tried using radical-based conjugate addition reactions to form chiral quaternary centers because, compared with organometallic reagents, radicals are cheaper and easier to produce, readily add carbons to sterically congested carbon sites, and cause less-problematic side reactions. But these radical reactions
breakdown. The result is the first enantioselective, catalytic, radical conjugate addition to generate quaternary carbon stereocenters (Nature 2016, DOI: 10.1038/nature17438). In the reaction, an organocatalyst’s amine group reacts with an enone starting material to produce a chiral iminium cation. A nucleophilic radical carbon group then adds to the molecule’s carbon-carbon double bond, forming an unstable radical intermediate. A redox-active carbazole group on the organocatalyst immediately reduces the unstable intermediate, preventing it from breaking down. The reduced intermediate then tautomerizes, changing how its atoms are connected, to form a species that is further reduced and hydrolyzed, yielding the quaternary product and releasing the original organocatalyst. A separate photocatalyst both creates the nucleophilic radical and catalyzes the final reduction. “Since this method provides a convenient route to quaternary stereocenters R–H
Enone starting material
H + N
O
R
X–
PCred
PC*
PC
Light
H + N
R Unstable iminium radical cation
Radical addition Imine formation
Chiral iminium cation
Chiral amine organocatalyst O
Electron transfer
X–
+•
NH2 PC
N
Intramolecular reduction
X–
PCred
X– Tautomerization
N
HN
+•
Reduction
R
Hydrolysis
R
R
R
H2O
Quaternary product
Imineorganocatalyst conjugate
Imine radical cation
Enamine radical cation
R is a carbon-based group, X– is an anion, PC is a photocatalyst, PC* is a light-activated version, and PCred is a reduced form.
have not worked. For example, amine-catalyzed radical conjugate additions have been hampered by the formation of an unstable radical cation intermediate. Paolo Melchiorre of the Institute of Chemical Research of Catalonia and coworkers have now found a way around that problem. In their amine-catalyzed reaction, they trap the unstable radical and prevent its
with the potential of excellent functional group tolerance, I envision a wide range of applications,” comments radical-conjugate-addition expert Steven L. Castle of Brigham Young University. Although the study demonstrated its use on a limited range of substrates, “it should be possible to extend the scope to encompass a broader range.”—STU BORMAN APRIL 18, 2016 | CEN.ACS.ORG | C&EN
9
