Fig. 1, taken from Hindustantimes.com
The 2021 Nobel Prize in Chemistry was awarded to chemists Benjamin List and David W.C. MacMillan of Frankfurt, Germany, and Bellshill, Scotland, respectively. List and MacMillan had developed a new way to construct molecules through a process known as asymmetric organocatalysis, a novel form of catalysis. This revolutionary finding has since left an indelible mark on pharmaceutical research and has allowed chemistry to become a more environmentally-friendly practice.
Chemistry can be used for a variety of purposes within the real world; amongst many of its applications, research areas and industries are reliant on the use of chemistry to construct elastic yet durable structures, store energy inside of batteries, and inhibit the progression of diseases. Such tasks share a common relation: the need for catalysts. A catalyst is a substance that speeds up a chemical reaction without being consumed or altered by the very reaction itself. Though it was long believed that catalysts only existed in two forms, metals and enzymes, List and MacMillan independently developed a third type of catalysis in 2000 that builds upon small organic molecules – a form of catalysis they termed asymmetric organocatalysis.
To the surprise of many, the 2021 Nobel Prize for Chemistry was awarded to two scientists who had developed a seemingly simple yet elegant way of catalyzing reactions over two decades ago: List and MacMillan showed the world just how small organic molecules could not only be used to match, but beat metals and enzymes to the catalysis of reactions to create chiral molecules, molecules which cannot be superimposed on its own mirror image.
The process of symmetric organocatalysis, in short, is the production of chemicals that exist in two versions, with one being a mirror image of the other. This has allowed for the creation of enantiomers, molecules that are mirror images of one another that are non-superimposable. Such molecules are very much like our left and right hands which are mirror images of one another that cannot appear identical via reorientation.
Fig. 2, taken from The Royal Swedish Academy of Sciences
Organocatalysts bind to reacting molecules to form intermediates that are more reactive than the substrate molecules on their own. Being a chiral molecule, the catalyst would then transpose its handedness to the substrate itself, in turn controlling which side of the intermediate can react further. Using MacMillan’s work as an illustration of the process, the phenylalanine derivative reacts with the unsaturated aldehyde to form an iminium ion, whose lowest unoccupied molecular orbital energy is lower than that of aldehyde itself, making it more reactive. Further, the catalyst attaches to the substrate with a reversible covalent bond, allowing it to transfer its chirality onto the reagents.
So just what distinguishes asymmetric organocatalysis from the use of metals and enzymes in catalysis? Transition metals, despite being excellent catalysts, can be very toxic to the environment. Thus, they often have to be removed from the products that have been made with them. Further, such metals are so reactive to the point that they need to be kept away from moisture or air to work, making the use of them in catalysis on the large-scale to be both painstaking and costly. On the other hand, enzymes cannot usually be made in a laboratory, and while they tend to work well within the body, such is not the case in synthetic chemistry. Thus, organocatalysts, which are often cheap and easy to produce, have not only the potential to make the process of catalysis more environmentally-friendly, but may even catalyse complex reactions better than metals or enzymes would.
The impact of asymmetric organocatalysis on the field of organic synthesis and medicinal chemistry has also been immense. If the human body is able to distinguish between two enantiomers, this may also be the case for the use of drugs to treat illnesses. Applying the biological concept of “structure determines function,” the use of asymmetrical organocatalysis may create two molecules of varying structures and thus, varying functions. As such, a molecule that has a harmful effect or no impact on the human body can actually become indirectly beneficial to the field of medicine; different versions of the same molecule may have different effects on the body when ingested. A tragic example of this principle would be the drug thalidomide, which had been improved for treating morning sickness back in the 1950s. However, its medication contained two mirror versions of the same chemical compound that had been mixed together, with the function of one version being the damaging of a developing fetus. As such, the drug was later withdrawn when it was found to cause disabilities in babies. Despite its harsh past history, the use of asymmetric organocatalysis can now be used to reap its benefits in the development of new and effective drugs.
Finally, according to an estimate made in 2015, the process of catalysis contributes to over 35% of the world’s GDP; its impact on the world and field of chemistry has been encapsulated by the seven Chemistry nobel prizes that have gone to discoveries within the field itself.
Though the use of asymmetric organocatalysis has come a long way from its humble beginnings back in 2000 in the context of research and discovery, it has yet to find its way into large-scale production. However, the explosion into this area of study is still ongoing, and through the use of asymmetric organocatalysis to produce antiviral, anticancer, neuroprotective, cardiovascular, antibacterial, and antiparasitic agents, the future prospect and applications of asymmetric organocatalysis screams findings of valuable, environmentally-friendly, and economically-viable medicinal compounds in the near future.
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