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H2020Individual fellowship2020–2021

SWEET-PI · Aromatic stacking in Glycochemistry: can glycosidations be tamed?

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2020-01-01 → 2021-12-31
EU contribution
€172,932
Participants
1
Scheme
MSCA-IF-EF-RI

Lines connect the coordinator with its partners.

Results in brief

Aromatic stacking in Glycochemistry: can glycosidations be tamed?

The biological relevance of the human glycome, together with the increasing importance of carbohydrates in medicinal chemistry, provides significant opportunities and challenges for chemists in the field of synthetic oligosaccharide and glycoconjugate research. Regarding oligosaccharide synthesis, the formation of glycosidic bonds usually represents the key step. In this context, supra-molecular interactions can offer significant opportunities to modulate the properties of glycosidic donors and acceptors, and in fact, this bio-mimetic strategy presents the potential to ultimately dictate the yield and stereochemical course of the reaction. In particular, carbohydrate/aromatic stacking represents a frequent structural motif for the molecular recognition of glycosides, either by protein binding domains, enzymes, or synthetic receptors. Interestingly, it has also been proposed that aromatic residues can assist in the formation/cleavage of glycosidic bonds by stabilizing positively charged intermediates through cation/π interactions. Despite the potential benefits derived from understanding aromatic catalysis in glycosylations, this had not been explored yet. In this project, we tackled the first experimental study on this relevant topic, based on the design, synthesis, and reactivity evaluation of a large number of carbohydrate systems, some of them equipped with varying aromatic platforms. Different geometries and dynamic features, anomeric leaving groups, sugar configurations, and reaction conditions have been explicitly considered. The use of variable temperature NMR techniques has been of crucial importance not only for the monitorization of reaction progress, but also for the identification of highly unstable reaction intermediates.

Data: CORDIS, © European Union

Project objective

Progress in chemical synthesis has provided access to a large variety of complex glycostructures, having a major impact in the expansion of Glycoscience. Central to carbohydrate chemistry is the glycosidation reaction, which involves the formation of a glycosidic bond between donor and acceptor molecules. It is commonly accepted that this process requires the formation of transient ionic species, whose stability, conformational properties and interactions determine to a large extend the reaction outcome. In principle, these elusive species are stabilized by means of inter- and intramolecular interactions, and in fact, this is a key feature for the activity of glycosidases and glycosyltransferases, typically requiring the participation of electron-rich functional groups, such as carboxylates. Interestingly, aromatic/carbohydrate interactions have too been detected and evaluated as supramolecular recognition motifs but, to the best of our knowledge, never at the reaction intermediate level, despite being frequently invoked to play a major role during enzymatic catalysis. Our hypothesis in this project revolves around the idea that stacking interactions involving electron-rich aromatic systems can be employed to stabilize the glycosyl oxocarbenium ion and to enhance the glycosyl acceptor reactivity; in the first case, these contacts might increase the life-time of the cationic intermediates, facilitating their detection and potentially allowing the modulation of the glycosidic donor in order to better control the stereochemical course of the reaction. Alternatively, CH/pi complexes involving the glycosyl acceptor could enhance the electron density of the reactive functional group, thus its nucleophilicity. This project aims to test both aspects of the carbohydrate/aromatic interaction employing a bioorganic approach based on the design, synthesis and systematic analysis of appropriate molecular models.

Original text from CORDIS.

Participants

  • AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS · MadridCoordinatorSpain

Links

Data: CORDIS, © European Union