The asymmetric alkylation of aldehydes is made possible by a combination of an organocatalyst and a photoredox catalyst
Organocatalysis — the use of small organic molecules to catalyse reactions — has been shown to be immensely powerful in synthesis in recent years. However, some transformations that seem straightforward on paper have remained elusive. Of particular note is the intermolecular asymmetric α-alkylation of aldehydes, examples of which are extremely rare. Organocatalysts have been shown to be particularly successful in activating the α-position of aldehydes by forming a reactive enamine species, but so far reaction of this with simple electrophiles such as alkyl bromides has proved difficult.
Now, David MacMillan and David Nicewicz from Princeton University have combined an organocatalytic process with the photoredox properties of a simple ruthenium complex to achieve just such a reaction1. Nature often uses a series of consecutive single-electron transfer steps because they have a lower activation energy than the equivalent two-electron processes. Inspired by this, MacMillan and Nicewicz first used a photoexcited ruthenium complex to generate an alkyl radical from an alkyl bromide, then reacted it with an aldehyde in the presence of a chiral amine catalyst. Thus far, a series of electron-withdrawing alkyl bromides have been used by the researchers to produce a variety of 1,4-dicarbonyl compounds with high enantioselectivity, including structures bearing quaternary stereocentres that can be particularly difficult to access.
Importantly, the light from a standard 15-W fluorescent light bulb was sufficient to drive the photocatalytic cycle, which without the ruthenium catalyst did not provide sufficient energy to generate the desired radical.
Nicewicz, D. A. & Macmillan, D. W. C. Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes. Science 10.1126/science.1161976 (2008).
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Davey, S. Making light work of it. Nature Chem (2008). https://doi.org/10.1038/nchem.64