Building next-gen molecules with Organocatalysis

In order to build compounds that facilitate and improve daily life, people have long attempted to copy natural strategies. However, chemists’ earlier methods usually generated mixture of compounds as products in test tubes than desired.  However, a chemist look for as pure product as possible at the end of the reaction. Both List and MacMillan, Nobel Laureates in Chemistry, 2021, conducted experiments to demonstrate that just one molecule can function as a catalyst. The complete enzyme, comprising of millions of unique molecules, are not necessary.

“Simple ideas are often the hardest to imagine,” says Professor Peter Somfai, member of the Nobel Committee.

Chiral
The term chiral is derived from the Greek word cheir, which means “hand.” Our hands, like most molecules in life, are chiral (our right hand is a reflection of our left hand). When we look at the common amino acid alanine, it has one stereogenic center and hence exists in two forms: (S)-alanine and (R)-alanine, which are mirror images of each other.

When alanine is synthesized in a laboratory under normal (achiral) conditions, a racemic mixture is formed, an equimolecular mixture of S-alanine and R-alanine. The synthesis is symmetrical in the sense that it offers 50:50 mixture of both the enantiomers.

Asymmetric synthesis, enantioselective synthesis a more appropriate vocabulary, on the other hand, is concerned with the production of an excess of one of the forms. Why is this so important? Let us look at nature to find the answer.

Nature is chiral
One might assume that both types of chiral molecules are equally common in nature and that the reactions are symmetrical. However, when we examine the molecules of the cells closely, we find that nature basically uses one of the enantiomeric pair. Only the D-sugars goes into the building up of nucleic acids and proteins are made up of L-amino acids. Unichirality is hall mark of nature!!!

Thus, enzymes and other receptors that play important roles in cell machinery are chiral. This means that they prefer to bind to one of the enantiomers. In other words, the receptors are extremely selective; only one of the enantiomers fits the receptor’s site like a key fits a lock. (This analogy comes from Nobel Laureate in Chemistry, Emil Fischer, who received the Prize in 1902).

Chiral drugs and the smell of lemons
Major proportion of the drugs in the market is chiral. It is often only one of the enantiomeric pair is able to fit with the biological target in the cell and is of interest. In certain cases the other form may even be harmful as in the case of thalidomide. Limonene is another example to illustrate how a simple chiral molecule exhibit wildly differing biological property through their differential interaction with the biological target in the cell. Limonene is chiral, but the two enantiomers can be difficult to distinguish at first glance (figure 2). The olfactory receptors in our nose can differentiate. One form certainly smells of lemons but the other of oranges.

Since enantiomeric pair of a chiral molecule exhibit wildly differing pharmacodynamic behavior on cells, it is critical to be able to produce both forms in pure form.

Pre 2000s
Catalysts are thus essential tools for chemists, but up until the year 2000, researchers believed that chemical reactions could only be catalyzed by metal compounds or enzymes.

Catalytic asymmetric synthesis: What is it?
It is important for industry to be able to produce as pure products as possible. It is also necessary to be able to produce large quantities of a product. As a consequence, the use of catalysts is critical. A catalyst is a substance that accelerates a reaction without being consumed in the process.

Exhaustive research has been conducted in recent decades to develop methods for the synthesis of enantiopure molecules. The Nobel Prize in Chemistry 2001 was awarded, for the discovery and development chiral catalysts to accelerate and control important chemical reactions, to William S. Knowles and Ryoji Noyori and K. Barry Sharpless.  The Laureates developed chiral catalysts for hydrogenations and oxidations, two important types of organic chemistry reactions.

Post  2000s
It had long been assumed that only metals or enzymes could catalyze chemical reactions, so it took two scientists who could look beyond rigid notions, reduce science to its most basic form, and solve a problem.

David MacMillan leaves sensitive metals behind...
MacMillan had been working on improving asymmetric catalysis using metals at Harvard; however, he realized that many metal catalysts developed in the lab were rarely translated for use in industrial applications. He recognized this to metal catalysts being too difficult, sensitive, and expensive to use due to their frequent need for oxygen- and moisture-free conditions. When he moved to UC Berkeley, he realized he would need to take a different path if the catalysts he developed were to be used as intended by industry. He decided to quit the metals and started working with organic compounds, which he established worked very well as asymmetric catalysts.

David MacMillan began to create simple organic molecules that, like metals, could provide or accommodate electrons temporarily. He chose several organic molecules with the right properties and tested their ability to drive a Diels-Alder reaction, which is used by chemists to build rings of carbon atoms. It worked perfectly, just as he had hoped and expected. Some organic molecules were also very good at asymmetric catalysis, was able to achieve enantiomeric excess or more than 90% of the product

Benjamin List
On the other hand, List began to consider whether an entire enzyme was required to catalyze a reaction, or if a single amino acid could accomplish the same feat.

A study conducted in the early 1970s revealed that proline could be used as a catalyst; however, this research was never pursued further. Assuming that there must be a reason why this had never been pursued, List attempted to catalyze an aldol reaction and to his surprise, it was extremely effective, and he also discovered that proline functioned as an asymmetric catalyst.

List’s experiments established not only that proline is an effective catalyst, but also that this amino acid can force asymmetric catalysis. One of the two possible enantiomeric pair formed far more frequently than the other. List acknowledged its enormous potential of proline and believed it as a chemist’s dream tool when compared to metals and enzymes. It is a simple, inexpensive, and environmentally friendly molecule. List described asymmetric catalysis with organic molecules as a new concept with many opportunities when he published his discovery in February 2000: “The design and screening of these catalysts is one of our future aims.”

Benjamin List and David MacMillan were awarded the Nobel Prize in Chemistry 2021 for their work in developing a third type of catalysis independently in 2000. Asymmetric organocatalysis is a new and precise tool for molecular construction. This has had a significant impact on pharmaceutical research and has made chemistry greener. “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,” says Johan Åqvist, who is chair of the Nobel Committee for Chemistry.

Since the year 2000, organocatalysis has sophisticated at an amazing rate. Benjamin List and David MacMillan continue to be field leaders, demonstrating that organic catalysts can be used to drive a wide range of chemical reactions. Researchers can now more efficiently build anything from new pharmaceuticals to molecules that can capture light in solar cells using these reactions. Organocatalysts provide the greatest benefit to humanity in this way.

Organocatalysis crucial  in pharmaceutical production
Asymmetric catalysis is often required in pharmaceutical research, so organocatalysis has had a considerable impact. The method is also used in pharmaceutical companies to rationalize the production of existing pharmaceuticals. Examples include paroxetine, which is used to treat anxiety and depression, and oseltamivir, an antiviral medication used to treat respiratory infections. Researchers can now synthesize large quantities of various chiral molecules relatively easily using organocatalysis. They can, for example, produce substances that may be useful for healing but are only found in trace amounts in rare plants or deep-sea organisms.

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