Mechanism of C-3 Acyl Neighboring Group Participation in Mannuronic Acid Glycosyl Donors

Frank F. J. de Kleijne; Peter H. Moons; Floor ter Braak; Hero R. Almizori; Luuk J. H. Jakobs; Kas J. Houthuijs; Giel Berden; Jonathan Martens; Jos Oomens; Floris Rutjes; Paul B. White; Thomas Boltje

doi:10.1021/jacs.4c13910

Mechanism of C-3 Acyl Neighboring Group Participation in Mannuronic Acid Glycosyl Donors

Frank F. J. de Kleijne
, Peter H. Moons
, Floor ter Braak
, Hero R. Almizori
, Luuk J. H. Jakobs
, Kas J. Houthuijs
, Giel Berden
, Jonathan Martens
, Jos Oomens
, Floris Rutjes
, Paul B. White
, Thomas Boltje^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

One of the main challenges in oligosaccharide synthesis is the stereoselective introduction of the glycosidic bond. In order to understand and control glycosylation reactions, thorough mechanistic studies are required. Reaction intermediates found by NMR spectroscopy often cannot explain the glycosylation’s stereochemical outcome. Hence, reactions may proceed through low-abundance reaction intermediates that are difficult to detect, according to a Curtin–Hammett scenario. We have previously observed that manno-type sugars can engage in C-3 acyl neighboring group participation. Herein, we report the detection of glycosyl dioxanium ions that result from C-3 neighboring group participation in mannuronic acid donors. Using a suite of exchange NMR techniques, we were able to dissect the kinetics of the conformational ring-flip that precedes C-3 acyl participation and the participation event itself in various manno-type sugars. Hence, this study provides a complete picture of mannosyl dioxanium ion formation.

Original language	English
Pages (from-to)	932-944
Number of pages	13
Journal	Journal of the American Chemical Society
Volume	147
Issue number	1
Early online date	18 Dec 2024
DOIs	https://doi.org/10.1021/jacs.4c13910
Publication status	Published - 8 Jan 2025
Externally published	Yes

Funding

We thank Pepijn Geutjes, dr. Tom Bloemberg, and Luuk van Summeren from the Radboud University Faculty of Science teaching laboratories for allowing us to use their Bruker 300 MHz Avance III HD nanobay NMR spectrometer for conducting this research. We kindly thank Lara van Tetering for her help in acquiring the HRMS spectra of the glycosyl cations. This work was supported by a Dutch Research Council NWO-VIDI grant (VI.Vidi.192.070) awarded to T.J.B. We also acknowledge NWO for the support of the FELIX Laboratory (\u201CNationale Roadmap Grootschalige Wetenschappelijke Infrastructuur\u201D grant 184.034.022).

Funders	Funder number
Radboud Universiteit
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	VI.Vidi.192.070
NWO	184.034.022

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Kleijne, F. F. J. D., Moons, P. H., Braak, F. T., Almizori, H. R., Jakobs, L. J. H., Houthuijs, K. J., Berden, G., Martens, J., Oomens, J., Rutjes, F., White, P. B., & Boltje, T. (2025). Mechanism of C-3 Acyl Neighboring Group Participation in Mannuronic Acid Glycosyl Donors. Journal of the American Chemical Society, 147(1), 932-944. https://doi.org/10.1021/jacs.4c13910

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title = "Mechanism of C-3 Acyl Neighboring Group Participation in Mannuronic Acid Glycosyl Donors",

abstract = "One of the main challenges in oligosaccharide synthesis is the stereoselective introduction of the glycosidic bond. In order to understand and control glycosylation reactions, thorough mechanistic studies are required. Reaction intermediates found by NMR spectroscopy often cannot explain the glycosylation{\textquoteright}s stereochemical outcome. Hence, reactions may proceed through low-abundance reaction intermediates that are difficult to detect, according to a Curtin–Hammett scenario. We have previously observed that manno-type sugars can engage in C-3 acyl neighboring group participation. Herein, we report the detection of glycosyl dioxanium ions that result from C-3 neighboring group participation in mannuronic acid donors. Using a suite of exchange NMR techniques, we were able to dissect the kinetics of the conformational ring-flip that precedes C-3 acyl participation and the participation event itself in various manno-type sugars. Hence, this study provides a complete picture of mannosyl dioxanium ion formation.",

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AU - Jakobs, Luuk J. H.

AU - Houthuijs, Kas J.

AU - Berden, Giel

AU - Martens, Jonathan

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AU - Rutjes, Floris

AU - White, Paul B.

AU - Boltje, Thomas

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AB - One of the main challenges in oligosaccharide synthesis is the stereoselective introduction of the glycosidic bond. In order to understand and control glycosylation reactions, thorough mechanistic studies are required. Reaction intermediates found by NMR spectroscopy often cannot explain the glycosylation’s stereochemical outcome. Hence, reactions may proceed through low-abundance reaction intermediates that are difficult to detect, according to a Curtin–Hammett scenario. We have previously observed that manno-type sugars can engage in C-3 acyl neighboring group participation. Herein, we report the detection of glycosyl dioxanium ions that result from C-3 neighboring group participation in mannuronic acid donors. Using a suite of exchange NMR techniques, we were able to dissect the kinetics of the conformational ring-flip that precedes C-3 acyl participation and the participation event itself in various manno-type sugars. Hence, this study provides a complete picture of mannosyl dioxanium ion formation.

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Mechanism of C-3 Acyl Neighboring Group Participation in Mannuronic Acid Glycosyl Donors

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