Non-covalent catalysis as powerful biomimetic approaches in strain-release glycosylations

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Mini symposium: Glycobiology at the LUMC and beyond

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Non-covalent catalysis as powerful biomimetic approaches in strain-release glycosylations

Charles C.J. Loh 1,2

1 Max Planck Institute For Molecular Physiology, Department of Chemical Biology, Dortmund, Germany, 2 Technische Universität Dortmund, Fakültät für Chemie und Chemische Biologie, Dortmund, Germany

The research directions in the Loh’s research group involve the usage of state-of-the art catalysis concepts to generate challenging carbohydrate based derivatives, and to unravel novel biological activity in pseudo-glycosidic scaffolds. One of the key features is the focus of our research programme on fundamental organic chemistry mechanistic understanding to power development of new glycosidic bond forming concepts, and to address selectivity challenges. Results emerging from our research revealed that non-covalent organocatalysts are extremely versatile in constructing a wide range of O-, N-, C- and S-glycosides exploiting strain-release.

Very recently, we discovered and reported that sub-molar loadings of as low as 0.05 mol% of a charge enhanced thiourea catalyst was highly efficient in accessing a variety of glycosidic derivatives in strain-release glycosylations.[1] A series of understudied strained cyclopropane-fused furanosides and pyranosides were discovered to perform excellently in this methodology, resulting in an array of glycosides generated with high anomeric selectivity. Mechanistic investigations via in-situ NMR approaches revealed deeper intricacies in the pathway, which opened insights into the divergent and the synergistic Brønsted Acid/Hydrogen Bonding nature of thiourea catalysis reminiscent of glycosyl transferases.[2]

Very recently, further exploration into alternative non-covalent catalysis modes such as XB as an enabling tool was fruitful in our endeavors. Lately, application of these pseudo-glycosidic analogues on cell-based phenotypic screens gave unprecedented results. Applying unbiased forward chemical genetics approaches in these strain-release glycosides unraveled new Hedgehog biological activity previously not known in traditional glycobiology.

An Ultra-Low Thiourea Catalyzed Strain-Release Glycosylation

C. Xu.; C. C. J. Loh. An Ultra-low Thiourea Catalyzed Strain-Release Glycosylation and a Multicatalytic Diversification Strategy. Nat. Commun. 2018, 9, 4057.

P. Peng.; R. R. Schmidt. Acid-base Catalysis in Glycosidations: A Nature Derived Alternative to The Generally Employed Methodology. Acc. Chem. Res. 2017, 50, 1171-1183.

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