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June 4, 2010

Better connections through green catalysis

Finely tuned nickel complexes combine important biomolecular precursors with high efficiency and low environmental impact

Figure 1: Nickel complexes catalyze the addition of α-ketoesters to nitroalkenes under extremely mild, environmentally non-harmful conditions.  

© 2010 Mikiko Sodeoka

In chemistry, the nitro group (O-N=O) has a formidable reputation. The high reactivity that makes some nitro-bearing molecules potent explosives—think nitroglycerin or trinitrotoluene (TNT)—also enables NO2 to be extremely versatile in organic synthesis. Chemists can transform nitro groups into numerous other functionalities, such as biologically important amines or carbonyl compounds, providing a constant demand for new, efficient reactions involving these compounds.

Now, researchers led by Mikiko Sodeoka from the RIKEN Advanced Science Institute in Wako have developed an innovative way to connect organic molecules known as nitroalkenes and α-ketoesters together with precisely controlled geometries1. Because this synthesis uses an ‘environmentally friendly’ catalytic system, it can help create a broad range of molecules, including therapeutic natural products, under mild conditions.

Typically, reactions between nitroalkenes and α-ketoesters require hazardous liquids, generous quantities of catalysts, and very low temperatures to be successful. Instead, Sodeoka and her team were able to complete this chemical transformation at room temperature, with a non-toxic propanol solvent, by using small amounts of a nickel acetate catalyst (Fig. 1)—an advance with significant cost-saving and environmental-hazard reducing potential.

According to Yoshitaka Hamashima, a co-author of the paper, this discovery originated in the team’s previous finding that certain palladium complexes are stable and active catalysts, even in water2. After several trials, the researchers determined that nickel catalysts, which share similar properties to palladium materials, allowed the α-ketoesters to add to nitroalkenes with high yields and purity; over 90% of the final product corresponded to a specific stereoisomer, a molecule with a hard-to-achieve, geometrically distinct structure.

Hamashima explains that the nickel complexes are particularly effective because they recognize specific carbon atoms on the α-ketoesters and chemically activate them, generating products with precise frameworks. Furthermore, nickel has the right properties to maintain a delicate catalytic balance. “Nickel has a reasonable—not too strong, but not too weak—affinity towards nitro groups,” says Hamashima. “This affinity enabled the facile dissociation of the product from the catalyst, allowing high catalytic turnover.” 

The high selectivity of this process, when combined with the mild reaction conditions, allowed the researchers to perform similar reactions on a broad range of molecules—including a highly efficient synthesis of the natural product kainic acid analog, a chemical that can bind to glutamate receptors within neuronal cells.

“Such selective activations are key to the success of our reaction,” says Hamashima. “Otherwise, undesired side reactions would occur when compounds with various functional groups are used as substrates.”

References

  1. Nakamura, A., Lectard, S., Hashizume, D., Hamashima, Y. & Sodeoka, M. Diastereo- and enantioselective conjugate addition of α-ketoesters to nitroalkenes catalyzed by a chiral Ni(OAc)2 complex under mild conditions. Journal of the American Chemical Society 132, 4036–4037 (2010).  (Link)
  2. Sodeoka, M. & Hamashima, Y. Chiral Pd aqua complex-catalyzed asymmetric C–C bond-forming reactions: a Brønsted acid–base cooperative system. Chemical Communications 5787–5798 (2009). (Link)