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Cobalt coaxes enamides into asymmetric hydrogenation

Chemists use the reaction to develop a greener route to epilepsy drug

by Bethany Halford
May 28, 2018 | A version of this story appeared in Volume 96, Issue 22

Scheme shows asymmetric hydrogenation to form levetiracetam (Keppra) from an enamide precursor.

Asymmetric hydrogenation—adding H2 across a double bond in a manner that produces a single alkane enantiomer—has helped chemists make medicines, fragrances, and fine chemicals. But the transformation requires expensive precious metal catalysts or catalysts that are air- and moisture-sensitive. Seeking to make asymmetric hydrogenation easier, cheaper, and more environmentally friendly, chemists led by Princeton’s Paul J. Chirik and Merck & Co.’s Michael Shevlin have been crafting cobalt catalysts for the reaction. The researchers discovered they can use zinc in a single-electron process that reduces earth-abundant Co(II) to Co(I). The reduced cobalt is better at coordinating with chiral phosphine ligands, producing complexes that asymmetrically hydrogenate enamides (Science 2018, DOI: 10.1126/science.aar6117). The reaction takes place in methanol, a green solvent that solubilizes H2 as well as drug intermediates with polar groups. The chemists used the transformation to create the epilepsy drug levetiracetam (Keppra) from its enamide precursor (shown). When they did the reaction on 200-gram scale with only 0.08 mole % catalyst loading, they got 97% yield and 98.2% enantiomeric excess of the desired isomer.


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