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Interview - A new mechanism to control the synthesis of sugar chains

During stepwise synthesis of sugar chains, two stereometric variants are formed at each step unless the steps are steered. Through an extensive investigation, Daan Hoogers investigated a new steering mechanism, for which he was nominated for the Young Star Award 2021.

Daan Hoogers

When going to university, Daan Hoogers, who liked chemistry at school, hesitated between either a technological or a theoretical study in chemistry. To keep both options open, he chose Molecular Science and Technology. And when, in the second year, students were expected to choose one of three programmes, synthesis, materials or technology, he could not decide either. So, he finished all three programmes. But finally, for his Bachelor’s research project, he had to make a choice. He opted for synthesis and did a project in glycochemistry: the synthesis of sugar chains (polysaccharides).

Researchers want to have sugar chains purely

Sugar chains occur on the membranes of cell surfaces, surrounded by millions of other compounds. They are of interest for research, for instance in medicine or biology, and to study them, researchers want to have them purely. ‘It is unfeasible to isolate them from cell surfaces’, Hoogers tells. ‘But their structure is known, and they can be synthesized in the lab by linking building blocks, monosaccharides, to each other one by one.’

There is one problem, though. When linking a monosaccharide to a growing sugar chain, the new compound will occur in two stereometric forms: the added component is either coplanar with or perpendicular to the chain, influencing how the chain behaves in biological processes. On cells, in contrast, sugars occur in one form only. ‘So, it is important to steer the synthesis in one direction at each step’, Hoogers says.

What happens when adding a picoloyl-group?

There are solutions to this problem, one of which Hoogers has elaborated. ‘A Russian scientist had discovered that adding a picoloyl-group to the monosaccharide seemed to steer the linking reaction, but how this effect precisely works was still subjected to significant debate. We unravelled this process.’

‘I liked this research because it combines several chemical subdisciplines’

When a monosaccharide binds to a growing sugar chain, A functional group leaves from the sugar chain, which is replaced by the monosaccharide. Picoloyl, Hoogers explains, is a cyclic organic compound that can be added to one of the hydroxyl-groups of the monosaccharide to protect it during the reaction. After the reaction, picoloyl detaches. ‘We can easily add it to the upper or lower side of the monosaccharide. Dependent on this choice, either a coplanar or a perpendicular bond will then form during synthesis. So, as a side effect of protection, picoloyl steers the reaction.’

Hydrogen bond

The hypothesis for the mechanism was that the picoloyl group on the monosaccharide forms a hydrogen bond with the growing sugar chain, forcing the monosaccharide to approach the chain in only one of the two orientations that are possible. Hoogers confirmed this hypothesis and discovered that picoloyl steers best when the monosaccharide is an acidic compound.

‘I liked this research because it combines several chemical subdisciplines’, he says. ‘We unravelled the mechanism by systematically varying the compounds, analysing the mechanism using computational chemistry, and assessing in what proportion the two stereometric forms of sugar chains were formed. We now have a proof of concept of the steering function of the picoloyl moiety. When optimized, this could provide a new tool in glycochemistry.’

His choice is now definite: he is doing his Master in fundamental chemistry in Leiden. ‘We are preparing a paper on our picoloyl research, and I hope to touch the topic again in the future.’

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