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Cyclopentadienyl Ligands Go Chiral

Catalysis: Chemists tune workhorse ligands for stereoselective reactions

by Stephen K. Ritter
October 26, 2012 | A version of this story appeared in Volume 90, Issue 44

Chemical modifications that introduce chiral features to cyclopentadienyl (Cp) ligands have allowed two research teams to carry out rhodium-catalyzed C–H functionalization reactions to prepare single-enantiomer products. The work provides new pathways for chemists to use one of the most popular organic-synthesis ligands with one of the most synthetically useful transition-metal cations to selectively make bioactive enantiomers, which hasn’t been practical before.

Chiral Cp ligands have previously been used for asymmetric catalysis involving early transition metals such as zirconium, which have ample open coordination sites for ligand and reactant binding. But introducing chiral Cp ligands to late transition metals, such as rhodium, has been problematic. The difficulty arises from the inability to design ligands with substituents that don’t compete with reactants for limited metal coordination sites but still effectively control the orientation of reactants to produce a single-enantiomer product.

Baihua Ye and Nicolai Cramer of the Swiss Federal Institute of Technology, Lausanne, overcame those problems by preparing a rhodium catalyst coordinated by a chiral Cp ligand bearing a symmetrical benzophenone-cyclohexenyl substituent (Science, DOI: 10.1126/science.1226938). The enantioselectivity arises from the ability of the bulky Cp ligand to direct the approach of reactants so they bind rhodium on only one side.

A team led by Thomas R. Ward of the University of Basel, in Switzerland, and Tomislav Rovis of Colorado State University solved the problem in a different way. The researchers created an artificial enzyme by tethering biotin to a Cp ring and then anchoring the biotinylated rhodium Cp assembly inside the protein streptavidin. The team also engineered a glutamate residue into the streptavidin active site, which acts in concert with the rhodium catalyst to optimize the catalytic efficiency (Science, DOI: 10.1126/science.1226132). Like a natural enzyme, the artificial version selectively aligns and binds reactants to produce only one enantiomer.

Both research teams tested their new catalysts by coupling benzamides with alkenes to form R enantiomers of dihydroisoquinolones.

The Ward-Rovis artificial enzyme approach “is extremely novel,” says Michael E. Kopach, a chemist at pharmaceutical firm Eli Lilly & Co. and cochair of the ACS Green Chemistry Institute’s Pharmaceutical Roundtable. But the scope of substrates used and the enantiomeric excesses would likely need to be improved for industrial utility, he says. The chiral catalyst designed by Cramer’s group “has significant industrial potential as the enantioselectivity is high, catalyst loads are low, and there should be relatively broad utility,” Kopach notes.

“Both these approaches to achieving enantioselective transformations are complementary and should be useful in preparing new scaffolds for medicinal chemistry,” adds Robert A. Singer, a chemist at Pfizer. The methods are particularly attractive because they operate under mild conditions, he notes, which will aid the use of reactants sporting sensitive functional groups. In addition, future refinements could adapt the strategies to work with metals that are more abundant and less expensive than rhodium, Singer says.


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