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Reports Make Progress In Transforming C–H Bonds Into Druglike Motifs

Organic Chemistry: Palladium-catalyzed routes build unnatural amino acids and meta-substituted aromatic rings

by Carmen Drahl
March 14, 2014 | A version of this story appeared in Volume 92, Issue 11

Reaction scheme shows a route to aromatic rings with meta-substitution.

Carbon-hydrogen bonds are ubiquitous, and chemists would love to transform them at will into entry points to materials or drugs.

Despite great strides, that goal is far from a reality.

A pair of reports now furthers the C–H bond transformation field by taking advantage of weak coordination to palladium catalysts. The chemistry comes from Jin-Quan Yu and coworkers at Scripps Research Institute, La Jolla, Calif.

They describe a tactic for making electron-rich aromatic rings with meta-substitution (Nature 2014, DOI: 10.1038/nature12963). They also control reactivity to make chiral amino acids not found in nature (Science 2014, DOI:10.1126/science.1249198).

Credit: Science
This X-ray crystal structure depicts a C–H activation intermediate involving Yu’s quinoline ligand. Pd = purple, C = gray, O = red, H = white, N = blue, F = green.
X-ray crystal structure shows a C-H activation intermediate that involves Yu’s quinolone ligand.
Credit: Science
This X-ray crystal structure depicts a C–H activation intermediate involving Yu’s quinoline ligand. Pd = purple, C = gray, O = red, H = white, N = blue, F = green.

Coordinating ligands help transition metals such as palladium cleave C–H bonds with surgical precision. Many useful reactions involve ligands that bind palladium tightly. But weakly coordinating groups offer additional options because of how they affect catalyst reactivity, Yu explains.

Ligands may be directing groups, which are attached to a substrate and guide the metal to the correct spot, or they may be free-floating components of a reaction mixture. Directing groups are important, says Emory University’s Huw M. L. Davies, the director of the National Science Foundation Center for Selective C–H Functionalization, where Yu has an affiliation. “But what Jin realized years ago,” he says, “is that you can subtly control a lot of reactivity with the other ligands, too.”

This proved to be the case for Yu’s meta-substitution advance, a continuation of prior work. His team had a route to aromatic rings with meta-substitution, but it didn’t work on electron-rich rings such as tetrahydroquinolines and anilines.

To remedy that, Yu’s team made modifications to their directing group. But despite the team’s efforts to coax the directing group into place, it would stay put only briefly. So they also added a free-floating N-acetylglycine ligand to help palladium do its work quickly.

Organometallic chemist Milton R. Smith III of Michigan State University praised the work but said he’d love to see the chemistry without a directing group, even though Yu’s is reusable.

Carefully chosen ligands also helped Yu’s lab build unnatural chiral amino acids. They began with a derivative of the amino acid alanine. But they had to find a way to add two different aromatic groups to alanine’s methyl side chain, one at a time. Usually, that reaction would go overboard and add two of the same group. Yu’s group managed to control the process with ligands derived from pyridine and quinoline.

“Yu takes advantage of the fact that his 2-methyl pyridine ligand is a weak binder,” notes organometallic chemist William D. Jones of the University of Rochester. “It activates the catalyst to monoarylate the C–H bond” and stop there, he explains. The quinoline ligand facilitates the second arylation.

“The point of doing C–H activation is that you don’t want your chemistry to be limited to a particular bond,” Yu says. He thinks the work will prove adaptable to many scenarios. Bristol-Myers Squibb is already using the alanine derivatives for peptide drug discovery. Both processes are patent pending, and select reagents from both reports will soon be available from Sigma-Aldrich.


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