Getting acetaldehyde to behave as a substrate for organic synthesis.
Organic chemists had all but given up on acetaldehyde when it came to certain types of reactions because this deceptively simple molecule has a tendency to go through many side reactions. Benjamin List's group at the Max Planck Institute for Coal Research in Mülheim an der Ruhr, Germany, have managed to tame the highly reactive molecule and use it in the Mannich reaction (a process for forming carbon–carbon bonds), opening the door to a broad range of applications in drug design.
Many small biological molecules come in two mirror-image forms, or enantiomers, that can have dramatically different biological effects. Chemical reactions that produce one enantiomer only were thought to be catalysed by either enzymes or heavy metals. But simple organic molecules such as amino acids recently burst on the scene as a third class of inexpensive catalysts for reactions with enantiomer selectivity, which are required for drug synthesis.
In 2000, List used the amino acid proline to catalyse a Mannich reaction — which combines a carbonyl, an aldehyde, and an amine compound to produce β-amino carbonyl compounds, and is used widely in the synthesis of biologically active molecules, including medicinal drugs. The new proline-catalysed Mannich reaction yielded high amounts of only one enantiomer.
But the simplest of all substrates, acetaldehyde, still wouldn't work. Acetaldehyde has many desirable qualities for chemistry: it's a small, plentiful and inexpensive molecule. But it also likes to react with itself. “The general feeling was that it would not work because it was considered a really troublesome reagent,” says List.
His view changed in 2006, when his group discovered that the substrate N-tert-butoxycarbonyl (N-Boc)-imine gave very high amounts of essentially a single enantiomer in proline-catalyzed Mannich reactions. “Because these reactions were so extremely efficient, we decided to give acetaldehyde another try,” says List.
The first time List's group tried combining acetaldehyde with N-Boc-imines in a proline-catalysed Mannich reaction they obtained only about 1% of product. “The yields were tiny, but the product was formed as essentially a single enantiomer, so in a sense this was encouraging,” he explains.
Over the next few months, colleagues tried to improve the yield without much success. Then, during a Monday morning jog, inspiration struck and List realized how to tackle the problem. Back in the lab he put together a four-person team that sketched out the different conditions to test and what kind of products they should synthesize to demonstrate the reaction's applications. Four weeks later they had accomplished their goal (see page 453). They had optimized the reaction and were able to synthesize a newly approved anti-AIDS drug and several other biologically active substances.
List says pharmaceutical companies have already expressed an interest in this work and a number of researchers, including himself, are trying to use acetaldehyde in other types of chemical reactions. “The biggest challenge was not really a technical or chemical one but rather having to give up the notion that it was impossible to use acetaldehyde in these types of reactions,” he says. “It was not easy to convince ourselves that this would work, given the initial ridiculous yields.”
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Benjamin List. Nature 452, xiii (2008). https://doi.org/10.1038/7186xiiia