Enabling Technology to Facilitate the Stereo-controlled Synthesis of Complex, Fluorinated Carbohydrates

Chemists at the WWU Münster have developed an automated method to generate well-defined, site-selectively modified glycomimetics for applications in biomedicine and chemical biology.

Carbohydrates are amongst the most abundant biopolymers on the planet, and are essential mediators in cell structure, metabolism and molecular recognition across the five biological kingdoms. In human health, complex glycans are crucial in developing diagnostic and therapeutic regimes and so strategies to enable their synthesis is a core endeavour in contemporary organic chemistry. The biomedical potential of complex glycans is therefore expansive, but stereocontrolled synthesis remains a persistent challenge. Automated glycan assembly has revolutionised the field by enabling complex, biologically important scaffolds to be constructed using validated algorithms. Although this has been convincingly demonstrated in natural sugars, controlling selectivity with modified carbohydrates (glycomimetics) is in its infancy.

About the method:
Given the importance of fluorinated sugars in drug discovery and enzyme probe design, and their enhanced hydrolytic stability, fluorine-directed automated glycan assembly has been developed. This strategy leverages the fluorine atom for stereocontrolled glycosylation on solid support, thereby eliminating the reliance on O-based directing groups and expanding automated synthesis to the synthesis of site-selectively fluorinated glycomimetics. The logical design of C2-fluorinated mannose building blocks, and their application in the fully (α-)stereocontrolled assembly is validated in solution and then translated to an automated paradigm. Reactions are characterized by extremely high levels of efficiency and selectivity, and the synthesis of both linear and branched fluorinated oligomannosides is disclosed on a Glyconeer 2.1® instrument. Prof. Ryan Gilmour notes that “The project was made possible by the vision and dedication of a very talented colleague, Dr. Charlotte Teschers, who merged her expertise in fluorine chemistry, analytics, automation and stereocontrolled synthesis. Watch out for this rising star!”

Original Publication:
Fluorine-Directed Automated Mannoside Assembly
C. Teschers and R. Gilmour, Angew. Chem. Int. Ed. 2022, e202213304.
DOI numbers 10.1002/anie.202213304 and 10.1002/ange.202213304.
https://onlinelibrary.wiley.com/doi/10.1002/anie.202213304

Funding
We gratefully acknowledge generous support from the WWU Münster, the European Research Council (Grant number 757913), the Verband der Chemischen Industrie (Kekulé scholarship to CST), and the Studienstiftung des Deutschen Volkes (scholarship to CST).

Research Group Link:
https://www.uni-muenster.de/Chemie.oc/gilmour/