The Nobel Prize in Chemistry 2022 will be awarded to three researchers who have developed and applied techniques that make chemical reactions faster and more efficient. Their work has revolutionised synthetic chemistry and is allowing unprecedented insights into living cells.
Modern life as we know it would be unimaginable without sophisticated chemical synthesis, which is a testament to the remarkable ingenuity of generations of chemists. We are now at a point where chemists can produce a huge diversity of highly complex structures with remarkable fidelity. However, while so much is now possible, synthesis of the most complex compounds has often required years of painstaking work by huge numbers of dedicated scientists. Could there be a way of making synthesis of important chemicals faster and easier?
A Double Success
This was the question posed by US chemist K. Barry Sharpless and his collaborators. Sharpless who had already won one half of the Nobel Prize in Chemistry in 2001 “for his work on chirally catalysed oxidation reactions”, reasoned, with particular reference to the production of pharmaceutical drugs, that faster, easier chemical reactions would not only drive down costs but would also allow synthetic chemists to transfer easily between different types of compounds. Essentially, they were looking for a way to efficiently synthesise complex and functional molecules using a modular approach that was based on a small set of reactions which were known to function well, or a “a few good reactions”, as Sharpless and colleagues termed them in 2001.
What were these reactions and where were they to be found? In proposing their new functional form of chemistry, Sharpless and his colleagues were inspired by nature, which has evolved methods for creating biomolecules comprised of linked carbon atoms. While nature does this efficiently, recreating these bonds in the lab and “convincing” carbon atoms to react with each other to form complex structures has proven more difficult. Sharpless’ big idea was to propose that chemists start with simple reactions where there is a strong preference for molecules to bind one another and use these as building blocks for the more complex structures.
An Unusual Reaction
At this point in the story, we welcome Danish chemist Morten Meldal. Meldal’s research, which he carried out at the University of Copenhagen, was aimed at the discovery of novel pharmaceutical compounds, a goal which he pursued by synthesising large numbers of molecules that he could screen against potential therapeutic targets. One day, Meldal and his colleagues noticed something peculiar in one of their synthesis reactions. Specifically, an unusual reaction had taken place between two chemical groups, an azide and an alkyne, resulting in the formation of a ring-shaped chemical building block known as a triazole. Excitingly, the copper that had been present in the reaction vessel had induced the molecules to snap together such that no undesirable side-products were formed, a problem which had long bedevilled triazole synthesis.
In parallel and independently, Barry Sharpless also successfully established a chemical reaction between azides and alkynes that is catalysed by copper: the prototypical click chemistry reaction, which came to be known as CuACC, was born. CuACC has already found application in a huge number of chemical synthesis reactions, perhaps most notably in the production of medical and pharmaceutical compounds. Sharpless and Meldal have each received 1/3 of the Chemistry Prize 2022.
One huge area where the CuAAC reaction was limited, however, was in biological systems, where the potential of using click reaction to label and study biomolecules is huge. The issue was the toxicity of copper ions for cells and organisms. Was there a way to perform these reactions without the harmful copper?
Click Chemistry in Living Systems
Carolyn R. Bertozzi, who receives the remaining 1/3 of the Nobel Prize in Chemistry 2022, and whose specific innovation was to develop and refine click chemistry for use in living systems, came at the topic from a very different angle. Bertozzi had been studying glycans, complex carbohydrates often found on the surface of cells. Glycans are intrinsically interesting, and owing to their roles in immunity and metabolism, these molecules are also undeniably important. However, in contrast to proteins, the tools that scientists had at their disposal to study glycans were very limited. Bertozzi and her team set out to rectify this by applying the principles of click chemistry to induce glycans to produce an azide as a chemical handle that could bind fluorescent tags, allowing researchers to follow these molecules inside cells.
Bertozzi was by this time aware of the findings of Sharpless and Meldal that her handle – the azide – can rapidly click into place with an alkyne as long in the presence of copper ions. However, the toxicity of these ions remained a problem. Around 2004, Bertozzi and colleagues, with reference to work from the 1960s, found that in living cells azides and alkynes can in fact react very well with each other without any copper – if the alkyne is forced into a ring-shaped chemical structure. These reactions have since then been further developed and refined to allow researchers to track – and fight – cancer cells.
A Powerful Tool
The work of Sharpless, Meldal and Bertozzi has provided chemists and biologists with an incredibly powerful toolkit to synthesise new chemical compounds and study biomolecules in their natural settings, a prime example of excellent science with huge real-world applications.