Nobel Prize in Chemistry 2021

Posted on 2021-11-08

Asymmetric Organocatalysis

The Nobel Prize in Chemistry 2021 was presented to Benjamin List and David MacMillan for their work on asymmetric organocatalysis. Asymmetric organocatalysts are organic compounds which catalyse reactions, with the ability to encourage the production of one enantiomer of compounds with chiral carbons. They also have the added benefits of being air and moisture-stable and are easy to handle on a large scale as well as being relatively less-toxic than traditional catalysts. Traditional catalysts typically require vacuum lines or glove boxes as well as large amounts of solvents; no longer needing to use these significantly reduces the waste of solvents and energy during production.

Before the year 2000, it was thought that the only types of catalysts that existed were enzymes and metals. List and MacMillan independently made these breakthrough discoveries in the year 2000 and since then the research in this field has greatly expanded. List began by looking at enzymes. Whilst enzymes consist of hundreds of amino acids, only a few of these are required for the reaction. List made the discovery that proline, the simplest the amino acid, was all that was needed to catalyse reactions between aldehydes and alcohols (aldol reactions). This is because proline contains a nitrogen atom which is able to give and receive electrons. MacMillan was working with metal catalysts and started to work on finding a more stable catalyst. He discovered that iminium ions, which can be produced from the reaction of amines with aldehydes and ketones, are able to catalyse Diels-Alder reactions between conjugated diene bonds and alkenes, resulting in cyclohexene molecules.

Since these discoveries, further work has been done to find more asymmetric organocatalysts and to refine them.

There are now 4 subtypes of organocatalysts which are:

Subtypes of Organocatalysts
This includes proline, phenylalanine and secondary amines such as diethylamine.
Synthetic Catalysts
These are derived from biomolecules.
Hydrogen-bonding Catalysts
This includes TADDOLS, NOBIN and organocatalysts based on thioureas.
Triazolium Salts
These catalyse Stetter reactions.

Organocatalysts catalyse using either covalent or non-covalent interactions (see figure 1). Non-covalent interactions work by first forming ionic pairs by either phase transfer catalysis or Bronsted base catalysis, then hydrogen bonds are formed. Covalent interactions involve catalysis with N-heterocyclic carbenes followed by catalysis with amines via either iminium ions, enamines, dienamines, radical cations or ammonium ions. 

Fig. 1 – Steps of several types of organocatalysis

Merging the original organocatalysis with photoredox reactions has enabled asymmetric organocatalysis to become recyclable, allowing near-perfect enantioselectivity to be preserved after more than 250 cycles. This development has major impacts on the pharmaceutical industry as it allows for medicinal drugs containing only one enantiomer to be produced. The addition of photocatalysis makes organocatalysts easier to remove from reaction mixtures because it enables them to be immobilised whilst still being active. Their photo and chemical stability are also increased, making them more durable. These properties make these organocatalysts reusable and, due to them being made of entirely organic material, this allows for medicinal drugs to be produced in a more sustainable way than when using traditional metal or enzymatic catalysts.

Different enantiomers of a drug can have significantly different effects on a patient, with one being beneficial and the other potentially causing possibly life-threatening problems.

Many common drugs with enantiomers are produced using organocatalysis including:

Drugs with Enantiomers using Organocatalysts
This drug is considered to be active against types of influenza viruses, and uses enamine catalysis.
This is used in the treatment of AIDS by acting against HIV and uses a (S)-proline-derived catalyst.
This is used for the treatment of anxiety and depressive disorders. A combined thiourea-chinchona organocatalyst is used in its production.