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Acetaldehyde In Action

Troublesome reagent coaxed into organocatalyzed, enantioselective reactions

by Bethany Halford
February 25, 2008 | APPEARED IN VOLUME 86, ISSUE 8

Acetaldehyde can act as a nucleophile in organocatalyzed, enantioselective Mannich (top) and crossed-aldol (bottom) reactions with good yields and high enantiomeric excess (ee).

Activity boost
Acetaldehyde can act as a nucleophile in organocatalyzed, enantioselective Mannich (top) and crossed-aldol (bottom) reactions with good yields and high enantiomeric excess (ee).

DESPITE ITS VALUE as a nucleophile, the simple molecule acetaldehyde has long been considered too problematic to use in enantioselective reactions catalyzed by small molecules. Now, thanks to tweaking of reaction conditions, two groups have managed to get this finicky aldehyde to work well in organocatalyzed carbon-carbon bond-forming reactions. The finding offers synthetic chemists a new tool for constructing all manner of molecules.

"These two reports are the first instances where acetaldehyde has been successfully engaged" in organocatalyzed, enantioselective Mannich and aldol reactions, comments David A. Evans, a chemistry professor at Harvard University. The two-carbon aldehyde tends to be troublesome because it reacts with itself to form oligomers and polymers, and its reaction products, which are also unbranched aldehydes, will compete with acetaldehyde to give unwanted by-products.

Benjamin List and colleagues at the Max Planck Institute in Mülheim, Germany, found they could get acetaldehyde to work as a nucleophile in a proline-catalyzed Mannich reaction-wherein an aldehyde is coupled with an imine-by adding a five- to 10-fold excess of the reagent (Nature, DOI: 10.1038/nature06740). "With a higher acetaldehyde concentration, the competition between the initial reaction product and acetaldehyde for the imine electrophile should be in favor of acetaldehyde, simply because there is more of it," List explains.

The reaction works with both aromatic and aliphatic imines to produce β-aminoaldehydes in reasonable yields and with high enantioselectivities. "We have shown these compounds to be extremely valuable in the synthesis of biologically active molecules and also new drug entities," List notes.

Similarly, by using a fivefold excess of acetaldehyde and a bulky trifluoromethyl-substituted diarylprolinol catalyst, Yujiro Hayashi and coworkers at Japan's Tokyo University of Science report the first direct, enantioselective crossed-aldol reaction of acetaldehyde (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200704870). The crossed-aldol reaction works with both aromatic and olefinic aldehydes, Hayashi's group reports.

Because the resulting aldol products are unstable, Hayashi's group reduced the compounds to the corresponding diols before calculating yields and enantioselectivities, which were, respectively, good and excellent. The researchers believe the stereoselectivity is dictated by hydrogen bonding between the electrophilic aldehyde and the enamine nucleophile formed by the acetaldehyde and the diarylprolinol catalyst.

Both List and Hayashi believe the newfound usefulness of acetaldehyde in organocatalyzed, enantioselective reactions will have numerous applications in organic synthesis.



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