scale (Org. Process Res. Dev. 2017, DOI: 10.1021/acs.oprd.7b00206). The new— and simpler—synthesis is based on a cross-coupling reaction between a dienol phosphate and a Grignard reagent that uses an iron-based catalyst instead of a more expensive palladium catalyst. The route starts with a cheaper six-carbon alcohol, proceeds in one reactor, and has an 85% yield, compared with an 11% yield for the original process. The researchers are working on a microencapsulated formulation that gradually releases the pheromone when sprayed on grapevines and should cost the same as conventional pesticides, Guerret says.—LOUISA DAL-
TON, special to C&EN
SYNTHESIS
C R E D I T: YA N G S H I /WAS H I NGTO N U N I V E RS I T Y S C H O O L O F M E D I CI NE ( S LI C ES )
▸ A new route to fastacting antidepressants Ketamine is a drug that has been administered as an anesthetic for more than 50 years. A decade ago, scientists found that a small dose of ketamine can also serve as a fast-acting antidepressant. Then last year, researchers discovered that ketamine’s antidepressant activity comes from a metabolite, (2R,6R)-hydroxynorketamine (HNK), which lacks ketamine’s psychological side effects that Cl O increase its risk OH of being abused. In yet anothHCl·H2N er ketamine Hydroxynorketamine development, a team led by E. J. Corey of Harvard University has now developed an enantioselective synthesis of HNK and related analogs that could help scientists determine the compound’s specific biological target and lead to new antidepressants (Org. Lett. 2017, DOI: 10.1021/acs.orglett.7b02498). The ninestep HNK synthesis contains two novel features. In one step, the team used a mechanistic model of the classic Jacobsen epoxidation reaction to design a modified manganese salen catalyst that enables the epoxidation of an intermediate. In another step, the researchers used aluminum- or titanium-based azide reagents to open the benzylic oxygen position of the epoxide with retention of stereochemical configuration instead of the typical inversion. HNK could be a promising drug candidate, Corey says, because as a ketamine metabolite it has already been encountered by thousands of people.—TIEN NGUYEN
NEUROSCIENCE
New insight into Alzheimer’s genetic risk factor The greatest genetic risk factor for Alzheimer’s disease is carrying the E4 version of the gene ApoE, which codes for apolipoprotein E. People with two copies of ApoE4 have a Mice carrying the ApoE4 gene (left) 12-fold increased risk of developing had greater loss of brain tissue caused by aggregating tau protein compared the neurodegenerative disease, says with animals without ApoE (right). David M. Holtzman of Washington University School of Medicine in St. Each brain slice is about 5 mm wide. Louis. Most research into the mechanism connecting ApoE and Alzheimer’s has focused on how the protein increases deposition of amyloid-β, the main protein that aggregates and forms clumps in the brains of people with the disease. Holtzman and colleagues now report that, in mice, ApoE also enhances the damage caused by tau, the other aggregating protein linked to Alzheimer’s (Nature 2017, DOI: 10.1038/ nature24016). The findings suggest that knocking down expression of ApoE could slow the progression of neurodegeneration. The scientists studied mice engineered to produce a mutated version of tau that is prone to aggregate. They then bred those mice with other mice that express one or none of the three versions of the human ApoE gene. Of the resulting offspring, the mice carrying ApoE4 had the highest tau levels throughout the brain, as well as the greatest loss of brain tissue. Mice without ApoE still had tau accumulation but almost no tissue loss. The scientists think ApoE enhances a damaging inflammatory response triggered by the tau tangles.—MICHAEL TORRICE
SYNTHESIS
▸ Amines built using cobalt nanoparticles Amine-containing compounds bear a nitrogen atom that’s ready to interact with proteins thanks to its lone pair of electrons; these molecules often have desirable biological properties. One of the most popular methods for making primary amines involves coupling ammonia O and an aldehyde or ketone + in a reductive amination reaction. The downside of this transformation is that it usually requires a precious-metal catalyst. Chemists led by Matthias Beller of the Leibniz Institute for Catalysis have now created a non-precious-metal catalyst that can make primary, secondary, tertiary, and N-methylamines via reduc-
tive amination. The catalyst consists of cobalt nanoparticles encased in a carbon shell (Science 2017, DOI: 10.1126/science. aan6245). Beller and colleagues make the nanoparticles by assembling a cobalt-diamine-dicarboxylic acid metal-organic framework on a carbon template and then heating this assembly to 800 °C. The chemists used the catalyst nanoparticles to make more than 140 amines, including several pharmaceutical compounds such
NH3
Carbon shell cobalt nanoparticle catalyst
NH2 Amphetamine
as the stimulant amphetamine. Furthermore, they show that reactions with the catalyst can be scaled to 50 g without loss of yield and that the catalyst nanoparticles can be recycled up to six times.—BETHA-
NY HALFORD SEPTEMBER 25, 2017 | CEN.ACS.ORG | C&EN
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