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Copper catalysts team up for chiral amide synthesis

Blue light powers a radical route to ubiquitous functional group

by Mark Peplow, special to C&EN
July 12, 2021

Reaction scheme shows how copper catalyzes the formation of a chiral secondary amide from a primary amide and a secondary alkyl bromide.

A pair of copper catalysts can create chiral amides in a new, light-driven process, offering a useful alternative to the standard method for making these staples of medicinal chemistry (Nature 2021, DOI: 10.1038/s41586-021-03730-w).

“Amides are ubiquitous functional groups in bioactive molecules, such as peptides,” says Gregory C. Fu at the California Institute of Technology, who coled the work.

The conventional route to amides involves reacting an amine with a carboxylic acid derivative. So if chemists want to selectively create just one of the mirror-image enantiomers of a chiral amide, they generally start with a single enantiomer of the amine. That sequence typically involves at least two steps—one to control the stereochemistry of the amine precursor and a second to form the amide.

In contrast, the Caltech team’s method achieves this in a single step without using single-enantiomer precursors by controlling the stereochemistry of the amide as it forms. “We’re hoping this leads to a more efficient process,” Fu says.

The reaction relies on two different copper catalysts and combines an amide with an alkyl bromide to form a chiral secondary amide—where the nitrogen atom is bonded to a hydrogen and two carbons, one of which is chiral.

The first catalyst is a copper (I) bisphosphine phenoxide complex. Once activated by blue light, it removes bromine from the alkyl bromide to release an alkyl radical. Meanwhile, the second catalyst, a chiral copper (II) diamine complex, binds to the primary amide and unites it with the alkyl radical. This stereoselectively forms a C–N bond, replacing one of the amide’s hydrogen atoms with the alkyl group to produce a secondary amide. As these two catalytic cycles keep turning, the copper complexes alternate between +1 and +2 oxidation states.

The reaction is tolerant to air or moisture and works for a diverse array of primary amides. It is also compatible with various functional groups in the alkyl bromide precursor. Amide yields range from 53%–95%, with a single enantiomer making up at least 95% of the product. “I find it quite remarkable that Caiyou Chen, the postdoc who’s done this work, has been able to showcase efficacy over such a broad range of directing groups, with such high yields and enantioselectivity,” says Caltech’s Jonas C. Peters, who coled the work with Fu.

“I think this paper is really amazing,” says Nicolas Blanchard, a French National Center for Scientific Research research director at the University of Strasbourg, who was not involved in the research. “With three simple ligands, they’ve been able to solve something that was really unattainable, in my view.”

Blanchard’s own research involves copper-catalyzed reactions for organic synthesis, and he says the new amide-forming reaction highlights growing interest in the metal. “Copper is used more and more, especially in photocatalyzed reactions,” he says. “These authors were pioneers in that regard.”


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