25 October 2021
The Royal Swedish Academy of Sciences awarded the 2021 Nobel Prize in the field of Chemistry to both Benjamin List of the Max-Planck Institute and David W.C. MacMillan of Princeton University, who independently developed asymmetric organic catalysts (organocatalysis) in 2000.
Prior to this discovery, it was believed that just two types of catalysts were available: namely metal complexes and enzymes. Organic catalysts provide a precise, more cost-effective, and environmentally friendly alternative and are formed from a stable framework of carbon atoms, to which one or more active chemical groups, typically comprising oxygen, nitrogen, sulphur, or phosphorus, can be attached.
List and MacMillan both followed different pathways in the discovery of this new field of chemistry.
After completing his postgraduate doctorate, David MacMillan set his sights on finding a simple, cost-effective, and more stable alternative to the moisture- and air-sensitive transition metal catalysts he had previously used in his research. As discussed in J. Am. Chem. Soc. 200, 122, 4243-4244, MacMillan’s research focused on the use of iminium ions from α,β-unsaturated aldehydes and amines to mimic the equilibrium dynamics and π-orbital electronics inherent in Lewis acid catalysts. To support this hypothesis, MacMillan demonstrated the use of chiral amines as enantioselective catalysts in Diels-Alder reactions between α,β-unsaturated aldehydes and various dienes.
In contrast, Benjamin List worked with X-ray diffraction scientists during this postdoctoral research, to determine how aldolase antibodies function. It was discovered that an amino group and an acid group were essential to the reactivity of the enzyme. As part of his research, List looked into the possibility of a simplified catalyst based on the identified essential functional groups rather than the use of a large and complex enzyme structure. The Hajos–Parrish–Eder–Sauer–Wiechert reaction (discovered in the 1970s), which uses the amino acid proline as a catalyst for asymmetric adol reactions, formed the basis of his research. Benjamin List’s paper, J. Am. Chem. Soc. 2000, 122,2395-2395, successfully demonstrates the use of proline as an effective asymmetric catalyst for a direct adol reaction between unmodified acetone and a variety of different aldehydes.
The discoveries by List and MacMillan offer an alternative method of producing organic compounds which does not rely on the traditional transition metal catalysts and enzymes.
Of this research, Johan Åqvist, chair of the Nobel Committee for Chemistry, explained: “This concept for catalysis is as simple as it is ingenious, and the fact is that many people have wondered why we didn’t think of it earlier.”
The discovery seems to be of particular importance to the field of pharmaceuticals. Many pharmaceutical compounds are produced as enantiomers – i.e. compounds formed having structures that are mirror images of one another. The individual enantiomeric structures can produce very different, and sometimes harmful, pharmacological effects within the body, and so only one of these mirror image structures is generally required for a specific drug. The organic catalysts developed by List and MacMillan can selectively produce one desired structure of a drug molecule.
Since the publication of this significant research, organic catalysts have already shown promising effects in methods of drug discovery and fine chemicals production.
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