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June 5, 2008
Also appeared in print Jun. 9, 2008, p. 12


Ligands Key To Chirality

Amino acids transmit information to selectively transform C–H bonds

Carmen Drahl

By relaying chiral information from an amino acid ligand to a palladium catalyst and onward to a substrate, Jin-Quan Yu and colleagues at Scripps Research Institute have selectively functionalized carbon-hydrogen bonds to form optically pure products (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200801030). This finding could reduce the number of steps needed to make molecules, one of the most coveted goals for synthetic chemists.

Activating the relatively inert C–H bond enantioselectively and catalytically can already be achieved through several approaches, but none of these techniques involve formation of a chiral carbon-metal bond during the reaction. Yu's team is the first to demonstrate this type of transformation by using a chiral palladium catalyst. Yu's proof-of-concept experiment is significant, says synthetic chemist Phil S. Baran of Scripps Research Institute, because "the ability to form a chiral center covalently attached to Pd is potentially applicable to [formation of] a wide range of C–C and carbon-heteroatom bonds using established Pd chemistry."

In their study, Yu and coworkers sought ligands that would coordinate to Pd and influence the enantioselectivity of the catalyst insertion into C–H bonds. "You need to have a chiral environment as close as possible to the Pd metal center so Pd can transmit chiral information to the C–H bond," Yu explains.

But because established chiral ligands such as phosphines are known to hinder C–H activation, designing the proper catalyst has been "a significant problem," says Melanie S. Sanford at the University of Michigan, Ann Arbor, who also develops C–H activation chemistry.

The amino acid ligands that Yu's team eventually found do not adversely affect the reaction and help form new C–C bonds with high enantioselectivity. They work like a set of gears, transferring chirality information from the amino acid's chiral α-carbon to its nitrogen atom and from the nitrogen atom to the Pd metal, which then conveys it to the target C–H bond.

So far, the technique has been applied only to a small number of substrates. However, "the diversity of available amino acid derivatives" that can potentially be used as ligands "means that there is ample opportunity for further exploration and expansion of this method," Sanford says.

GEARS In enantioselective C???H bond functionalization, an amino acid transmits chiral information via its nitrogen atom to the palladium catalyst.

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ISSN 0009-2347
Copyright © 2009 American Chemical Society


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