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And then there was light! Discovery of how distal acyl groups are of interest in a glycosylation reaction

Date of news: 29 May 2020

Controlling the chemical linkage of sugars (glycosylation reaction) is a great challenge in the organic chemistry. The chemical glycosylation often results in a mixture of products due to the creation of a new chiral centre. The structure of the reactive intermediates formed during the glycosylation reaction have been a mystery for a long time. Until now. A team of researchers from Leiden University, HFML-FELIX and the Institute for Molecules and Materials (IMM) have discovered how distal acyl groups can play a critical role in determining the outcome of glycosylation reactions. The results have been published in Nature Communications. “This fundamental understanding opens new routes to make carbohydrate products. It is essential for biological research”, researchers Hidde Elferink and Thomas Boltje say.

“We wanted to find out at which positions in the sugar acyl groups can participate to form dioxolenium ions and what role they play in the chemical glycosylation. In this way we should be able to control product outcome”, Elferink explains. The Organic Chemistry field has been studying this for a long time. “We understand what happens in the early stage and the end phase of the reaction. However, the big challenge was to measure what occurs in the process”, Boltje adds.

To elucidate the reaction mechanism of glycosylations, a combination of computational and experimental research was used. Researchers Jeroen Codee and Thomas Hansen of the Leiden Institute of Chemistry have calculated which intermediate sugar shapes most likely to form but could not experimentally confirm this. “It is very difficult to study cationic intermediates because of their high reactivity. That is where our collaboration started, as with the IR mass spectrometer at FELIX Laboratory, we were able to isolate and characterize the ions”, Boltje clarifies. Hidde Elferink was able to confirm the theory by doing experiments within the FELIX lab in collaboration with the group of Jos Oomens using the Infrared/Terahertz free-electron lasers. Oomens: “Our method of ion spectroscopy enables us to structurally characterize ionic species in solutions; interestingly, many intermediates in organic chemistry are ionic and this is the perfect method to verify the hypothesized structures of these elusive intermediates.”

Finally, solution phase glycosylation experiments performed in Leiden showed excellent agreement with the reaction outcome predicted for the intermediates characterized by Hidde Elferink. “Now we have provided clarity and we can design new sugar building blocks. Basically, the calculations in Leiden have been confirmed by experiments in Nijmegen. This Dutch joint research project is unique and has a large impact in our research field”, Boltje says.

Nature comm

Workflow of the characterization of glycosyl cations. Glycosyl oxocarbenium ions are first created by tandem MS and are subsequently characterized by IR-ion spectroscopy to determine the influence of participating groups. LG: Leaving group.

The fundamental knowledge that formation of dioxolenium ion intermediates and the utilization of this effect to gain stereocontrol will facilitate the assembly of glycoconjugates that fuel biological research. “With this knowledge we can better predict reactions and make complex glycosylation reactions easier and better”, Elferink and Boltje conclude.


Characterization of Glycosyl Dioxolenium Ions and Their Role in Glycosylation Reactions,Thomas Hansen, Hidde Elferink, Jacob M. A. van Hengst, Kas Houthuijs, Wouter A. Remmerswaal, Alexandra Kromm, Giel Berden, Stefan van der Vorm, Anouk M. Rijs, Herman S. Overkleeft, Dmitri V. Filippov, Floris P. J. T. Rutjes, Gijsbert A. van der Marel, Jonathan Martens, Jos Oomens, Jeroen D. C. Codée and Thomas J. Boltje, Nature Communications 11,  2664 (2020)

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Jos Oomens