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Iodine Catalysis Goes Green

Synthetic Chemistry: Oxidative cyclization route to chiral drug scaffolds is metal-free

by Sarah Everts
June 14, 2010 | A version of this story appeared in Volume 88, Issue 24

With just a pinch of salt, a team of researchers in Japan have come up with an environmentally friendly catalyst to build 2,3-dihydrobenzofuran motifs via asymmetric oxidative cyclization of ketophenols. The team, led by Muhammet Uyanik and Kazuaki Ishihara of Nagoya University, employs iodine as a way to sidestep the toxic heavy metals normally required to build these pharmaceutically useful motifs (Science 2010, 328, 1376). The enantioselective reaction also uses reagents that are greener than those used in previous iodine-based catalytic strategies.

To create the catalyst, the team uses hydrogen peroxide or tert-butyl hydroperoxide to convert iodide into hypoiodite (IO) or iodite (IO2 ), with water as a waste product. These two anionic catalysts can’t perform asymmetric reactions without help, which comes in the form of a chiral ammonium cation, Ishihara notes. Using a variety of aromatically substituted ammonium molecules, the team was able to do the cycloetherification with enantiomeric excesses of 85% and higher—sometimes up to 96%. This reaction is “competitive with metal-catalyzed reactions in both yield and selectivity,” Andrew N. French, a chemist at Albion College, comments in an associated perspective.

In addition to being metal-free, this reaction is green thanks to its atom economy, says Wei Zhang, a green chemist at the University of Massachusetts, Boston, who is currently editing a book on pharmaceutical green chemistry. There have been several examples of enantioselective oxidative reactions catalyzed by chiral hypervalent iodine compounds, which are usually generated by oxidation of aryliodides with m-chloroperbenzoic acid and benzoic acid as waste products. Because it relies on a chiral ammonium iodide salt and hydrogen peroxide instead of m-chloroperbenzoic acid, the new reaction has better atom economy and avoids benzoic acid as waste, Zhang adds.

Ishihara points out that the reaction’s 2,3-dihydro­benzofuran product is the base for a wide variety of biologically active products, including tremetone, a PPAR-α agonist that Merck & Co. has investigated for its cholesterol-lowering abilities. Other molecules with the same benzofuran base include those that are active against cancer cell lines and those that act as opioid receptor agonists, which might be developed into pain relievers, Ishihara notes.

Now, the team is working on using chiral ammonium hypoiodites in place of transition-metal catalysts in other oxidative coupling reactions, particularly intermolecular ones, Ishihara says.

“Iodine chemistry, with its versatile reactivity, is an excellent area to discover new, more environmentally friendly, greener organocatalysts. The chemistry described is but a taste of what is to come,” French notes.



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