Mechanistic insight into benzylidene-directed glycosylation reactions using cryogenic infrared spectroscopy

Chun-Wei Chang; Kim Greis; Gurpur Rakesh D Prabhu; Dana Wehner; Carla Kirschbaum; Katja Ober; América Y Torres-Boy; Sabrina Leichnitz; Gerard Meijer; Gert von Helden; Peter H Seeberger; Kevin Pagel

doi:10.1038/s44160-024-00619-0

Mechanistic insight into benzylidene-directed glycosylation reactions using cryogenic infrared spectroscopy

Nat Synth. 2024;3(11):1377-1384. doi: 10.1038/s44160-024-00619-0. Epub 2024 Jul 26.

Authors

Chun-Wei Chang^{1

2}, Kim Greis^{1

2

3}, Gurpur Rakesh D Prabhu^{1

2}, Dana Wehner^{1

2}, Carla Kirschbaum^{1

2

4}, Katja Ober², América Y Torres-Boy², Sabrina Leichnitz^{1

5}, Gerard Meijer², Gert von Helden², Peter H Seeberger^{1

5}, Kevin Pagel^{1

2}

Affiliations

¹ Freie Universität Berlin, Institute of Chemistry and Biochemistry, Berlin, Germany.
² Fritz Haber Institute of the Max Planck Society, Berlin, Germany.
³ Present Address: Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
⁴ Present Address: Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.
⁵ Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.

Abstract

The stereoselective formation of 1,2-cis glycosidic linkages is challenging. The currently most widely used strategy for their installation uses 4,6-O-benzylidene-protected building blocks. The stereoselectivity of this reaction is thought to be driven by a covalent intermediate, which reacts via an S_N2 mechanism. However, the role of cationic S_N1-type intermediates in this reaction is unclear. Here we elucidate the structure of glycosyl cations carrying 4,6-O-benzylidene groups using cryogenic infrared ion spectroscopy and computational methods. The data reveal that the intermediates form anhydro cations, which correlates well with the stereoselective outcome of S_N1-type glycosylations. The study highlights how cryogenic infrared spectroscopy can elucidate the role of intermediates in sugar chemistry and how these structural data can be linked to reactions in solution.

Keywords: Carbohydrate chemistry; Infrared spectroscopy; Mass spectrometry; Reaction mechanisms.