Discovering chemistry

Visiting Nobel Laureate, Professor K. Barry Sharpless, discusses the risks and rewards of venturing into the scientific unknown

By Dr Giselle Roberts

It is not often that you meet a scientific explorer. Nobel Laureate, Professor K. Barry Sharpless, is precisely that. A Philadelphia native, he spent vacations at his family’s cottage on the New Jersey Shore, navigating its popular waters in his small motor boat. It inspired Sharpless’ lifelong love of the ocean, fishing and venturing fearlessly into “amazing places.”

Professor Sharpless thought he might become a surgeon like his father, but ended up in science instead. He received his BA from Dartmouth College in 1963 and his PhD in Chemistry from Stanford University in 1968. Before joining The Scripps Research Institute in 1990 as W. M. Keck Professor of Chemistry, Professor Sharpless was a member of the chemistry faculty at Massachusetts Institute of Technology and Stanford University.

Professor Sharpless’ career has been buoyed by the deep waters of the scientific unknown. He’s conquered chemistry’s complexity by identifying fast, easy and cost-effective ways to make molecules. In 2001, he was awarded the Nobel Prize for Chemistry for his work on catalytic asymmetric oxidation reactions, revolutionising chemical synthesis for science and industry alike.

I sat down with Professor Sharpless and his key collaborator, Professor John Moses, to find out more about their innovative brand of clever chemistry.

Making molecules… quick

GISELLE ROBERTS: Let’s start with the basics. What is click chemistry?

JOHN MOSES: Click chemistry is a philosophy about how to execute chemistry. Chemistry is an instrument for creation, but the way we do it is defined by a particular set of rules. Click chemistry looks for the easy way to make bonds. We identify molecules with function, that are simple to make, and can be made in around three or four steps. There are a vast range of potential drug-like molecules out there, so why make the ones that are difficult to make? Barry has pioneered a very good set of rules that are game-changing for the discipline.

BARRY SHARPLESS: It’s a departure from traditional chemistry. I learned the more traditional methods in a scientific culture where molecules were not impressive unless they were hard to make. It was extremely time-consuming. At any one time, you could have twenty-five scientists working on thirty different experiments, just to discover one small thing. This type of chemistry is like tunnelling through Mount Everest rather than finding a sensible trail up and over – and the costs associated with working this way are significant. So I started searching for molecules that had function, could be made in three or four steps, had a guaranteed reaction and a high yield.

Things that click

GR: So where did the term ‘click chemistry’ come from?

BS: My wife, Jan, named it click chemistry. I wanted to call it ‘neat chemistry,’ like whisky; you drink it neat. That is what we were doing, pure chemical reactions with no restraints, that were guaranteed to react. But in the United States ‘neat’ means ‘cute.’ So we decided on ‘click’ and it took off. People often say, “Our chemistry just clicked.” It is nature’s way. You can’t talk yourself out of it and you can’t stop the reaction. Biochemists loved the methods too. They didn’t know anything about the chemistry, or the click, but they knew that it worked.

GR: Your landmark example of this was with a copper catalysed click reaction, but you continue to search for new reactions, new clicks.

JM: We have developed a new kind of reaction using sulphur fluorides called ‘sleeping beauty.’ They are silent, like sleeping beauty, until they are awoken by a protein target or ‘prince.’ We want to use smart chemistry to reengineer drugs, change their properties, activity and potency. Once it goes click, the bond is forever.

BS: Sleeping beauty is not dead but she is not alive. She doesn’t do anything unless she finds her prince, and that is one particular protein in the human body. Once they get close, they click.

Unchartered territory

GR: Professor Sharpless, your career has been shaped by your incredible ability to be scientifically brave.

BS: As scientists, we all end up in places we don’t understand. When we get there, we often retreat to the places we know. It’s easier to add known things to the flask, for example, and stay where it’s safe. Throughout my career, I have enjoyed the thrill that comes with being scared, and the discoveries that come along with that leap into the unknown. The opportunity to discover something new is like finding diamonds laying on the ground. By the time other people come along with their shovels and dynamite, the person who has the ability to look for something new should be somewhere else. That is what I do.

GR: And surrendering what you know and what you might find is part of that journey.

JM: Yes, as scientists we have to take risks.

BS: You have to come to terms with the unknown in order to find something new. Every discipline has the ability to reject what it knows and does, and discover what else might be true. There is incredible freedom in that. It is not what you miss that is important, it is what you find. It is so enriching because finding usually involves jumping into new territory. And if the first idea on that scientific journey is not absurd, there is no hope for it.

Click Chemistry Symposium
Monday 12 February 2018, 4-7pm, LIMS Lecture Theatre
Professor John Moses, Professor K. Barry Sharpless and Professor Sir David Laine
Register here.

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