Acetaldehyde prevented from running amok in the Mannich reaction, opening up new avenues in drug discovery

German chemists have prevented acetaldehyde from running amok during the Mannich reaction - opening up new avenues in drug discovery. 

Acetaldehyde is potentially a useful substrate for the Mannich reaction, a carbon-carbon bond-forming process where carbonyl compounds, containing C=O, such as aldehydes, react with compounds containing the C=N bond. Controlling the stereochemistry of the reaction to produce the correct right- or left-handed product, or enantiomer, could allow a library of useful compounds to be made. In particular by reacting acetaldehyde with imines, beta-aminoaldehydes are formed and these can be simply converted into beta-amino acids - many of which could be the basis for new drugs.

However, controlling the stereoselectivity of reactions involving acetaldehyde has proved possible in only a small handful of cases, using expensive and fragile enzymes to catalyse the reactions. Without such measures, acetaldehyde can polymerise, or there can be other unwanted reactions creating by-products that are difficult to separate.

Now, Benjamin List’s lab at the Max-Planck-Institut in Muelheim an der Ruhr has shown that it can be done using the cheap and widely available organic molecule proline as catalyst1. The key is simply to add an excess of acetaldehyde to the reaction mixture.


Highly enantioselective prolinecatalysed Mannich reactions of acetaldehyde with N-Boc-imines

The chemists reacted a range of imines with a large excess of acetaldehyde in the presence of the organocatalyst and discovered to their delight that respectable yields - of around 50 per cent - of the corresponding beta-amino aldehydes were produced in only the desired chiral form.

’Normally you would expect the acetaldehyde to react with itself, and also for the aminoaldehyde to react with the imine,’ List told Chemistry World. ’But in the presence of an excess of acetaldehyde the imine tends to react with the acetaldehyde rather than with the reaction product. And because this reaction is faster than the polymerisation of the acetaldehyde, we can stop the reaction and extract the product before the polymerisation starts.’

Commenting on the work, Andrew Smith, who researches organocatalysis at the University of St Andrews in the UK, said, ’Although the product yields are reasonable to modest, the high enantioselectivity of the highly desirable beta-amino carbonyl compounds is impressive. It would be interesting to discover if these reactions can be readily scaled in order to make bulk quantities of the desired compounds.’

Smith noted that another group had recently independently shown that crossed-aldol reactions of acetaldehyde can be carried out asymmetrically with a proline derivative2 suggesting that the molecule may be able to participate in numerous organocatalytic processes.

Simon Hadlington