Fachbeirat 2022

Mechanistic Insights into Benzylidene-Directed Glycosylations by Cryogenic Infrared Spectroscopy

Not scheduled

20m

Speakers

Dr Chun-Wei Chang (Freie Universität Berlin)Prof. Kevin Pagel (Freie Iniversität Berlin)

Description

The chemical synthesis of glycoconjugates is very cumbersome, due to the unpredictable stereoselectivity in glycosylation reactions. As a result, today only few structures are accessible for functional studies in biology. Despite years of significant progress in method development, no gold standard technique to construct glycosidic bonds with well-defined stereochemistry has been reported. Recently, numerous reports highlighted how a better understanding of the reaction mechanism can help to optimize the reaction conditions significantly. However, the impact of the underlying reaction intermediate – the glycosyl cation – is still sparse due to its instability and extremely short lifetime that makes it difficult to analyze.

In previous studies we have shown that glycosyl cations can be trapped in a mass spectrometer and probed using cryogenic IR spectroscopy.¹ From the resulting spectra, high resolution structures can be deduced in combination with first-principles theory. First data provided direct structural information of glycosyl cation intermediates bearing prominent features such as neighboring group participation², remote participation³ and Ferrier-type structures⁴, revealing the origins of stereoselectivity.

In the European Research Council (ERC) Consolidator Project GlycoSpec (2020-2025) we built on these promising initial results and aim to unravel the mechanistic details of glycosylation reactions. Currently in focus are for example 4,6-O-benzylidene directed glycosylations⁵, which are promising tools to install highly challenging 1,2-cis glycosidic linkages. Our data reveal an unexpected rearrangement on the 4,6-O-benzylidene acetal group that leads to an energetically more stable anhydro cation. The potential influences of the rearrangement are followed using chemical test reactions. First data indicate that the 1,6-anhydro ring on the intermediate shields the beta-face of the anomeric carbon and therefore induces a nucleophilic addition from the opposite alpha-side. In the future, this brand-new pathway will enable the reliable stereoselective formation of 1,2-cis glycosides.

References
1 Grabarics, M. et al. Mass Spectrometry-Based Techniques to Elucidate the Sugar Code. Chem. Rev. 122, 7840-7908 (2022).
2 Mucha, E. et al. Unravelling the Structure of Glycosyl Cations via Cold-ion Infrared Spectroscopy. Nat. Commun. 9, 4174 (2018).
3 Marianski, M. et al. Remote Participation during Glycosylation Reactions of Galactose Building Blocks: Direct Evidence from Cryogenic Vibrational Spectroscopy. Angew. Chem. Int. Ed. 59, 6166-6171 (2020).
4 Greis, K. et al. Direct Experimental Characterization of the Ferrier Glycosyl Cation in the Gas Phase. Org. Lett. 22, 8916-8919 (2020).
5 Huang, M. et al. Dissecting the Mechanisms of a Class of Chemical Glycosylation using Primary 13C Kinetic Isotope Effects. Nat. Chem. 4, 663-667 (2012).