Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Oct 20;9(42):eadk0531.
doi: 10.1126/sciadv.adk0531. Epub 2023 Oct 18.

Unraveling the promoter effect and the roles of counterion exchange in glycosylation reaction

Chun-Wei Chang  1 , Mei-Huei Lin  1 , Tsun-Yi Chiang  1 , Chia-Hui Wu  1 , Tzu-Chun Lin  1 , Cheng-Chung Wang  1   2
Affiliations

Unraveling the promoter effect and the roles of counterion exchange in glycosylation reaction

Chun-Wei Chang et al. Sci Adv. .

Abstract

The stereoselectivity of glycosidic bond formation continues to pose a noteworthy hurdle in synthesizing carbohydrates, primarily due to the simultaneous occurrence of SN1 and SN2 processes during the glycosylation reaction. Here, we applied an in-depth analysis of the glycosylation mechanism by using low-temperature nuclear magnetic resonance and statistical approaches. A pathway driven by counterion exchanges and reaction byproducts was first discovered to outline the stereocontributions of intermediates. Moreover, the relative reactivity values, acceptor nucleophilic constants, and Hammett substituent constants (σ values) provided a general index to indicate the mechanistic pathways. These results could allow building block tailoring and reaction condition optimization in carbohydrate synthesis to be greatly facilitated and simplified.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.. The scope of the byproduct participation and intermediate exchanges in the glycosylation reaction.
#RRV quantifies the reactivity of the thioglycoside; &Aka quantifies the reactivity of the acceptor.
Fig. 2.
Fig. 2.. Intermediate transformation via the participation of reaction byproducts.
Fig. 3.
Fig. 3.. Glycosylations of donor 1 with three types of acceptors using 1.0 equiv of promotor (AgOTf/TolSCl, AgOTf/PhSeCl, and AgOTf/p-NO2PhCl) in DCM at −70°C at standard conditions (c = 0.077 mM).
(A) Preactivation of donor. (B) Premixed donor and acceptor. Orange-colored cells represent the α-selectivity, while blue-colored cells represent the β-selectivity.
Fig. 4.
Fig. 4.. Schematic overview of NMR studies on glycosyl triflate (orange) and sulfonium ion (blue).
The effect of preactivation time on the influences of stereoselective glycosylation.
Fig. 5.
Fig. 5.. Mechanistic investigations for validating intermediate transformation from glycosyl triflate and glycosyl halide.
(A) Plausible mechanism on the formation of glycosyl halides in NXS/TfOH. %Supported by computational calculation (23). (B) Mechanistic studies to validate the involvement of TolSX byproduct. (C) Detection of intermediate conversion in low-temperature NMR experiments.
Fig. 6.
Fig. 6.. Schematic overview to study the transformation of the glycosyl intermediate.
#The recording of the intermediate transformations was halted because of the complete decomposition of the glycosyl triflate, resulting in messy NMR spectra that impeded detection. (A) Donor 3, RRV = 2656. (B) Donor 4, RRV = 5.4. (C) Donor 5, RRV = 5.0.
Fig. 7.
Fig. 7.. Effect of change in reagent stoichiometry on the stereoselectivity glycosylation of donor 3 with three types of model acceptors at standard conditions (c = 0.077 mM).
(A) Effect of iodonium reagents. (B) Effect of triflic acid (TfOH) amount. The orange-colored cells represent the α-selectivity, while the blue-colored cells represent the β-selectivity.
Fig. 8.
Fig. 8.. Modulate intermediate formation in glycosylation through reagent dosage.
(A) Reagent dosage effect on the changes in intermediates. (B) Intermediate-controlled stereoselective glycosylation using different reagent dosages.
See this image and copyright information in PMC

References

    1. T. J. Boltje, T. Buskas, G.-J. Boons, Opportunities and challenges in synthetic oligosaccharide and clycoconjugate research. Nat. Chem. 1, 611–622 (2009). - PMC - PubMed
    1. T. J. Wadzinski, A. Steinauer, L. Hie, G. Pelletier, A. Schepartz, S. J. Miller, Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent. Nat. Chem. 10, 644–652 (2018). - PMC - PubMed
    1. Y. Maki, R. Okamoto, M. Izumi, Y. Kajihara, Chemical synthesis of an erythropoietin glycoform having a triantennary N-glycan: Significant change of biological activity of glycoprotein by addition of a small molecular weight trisaccharide. J. Am. Chem. Soc. 142, 20671–20679 (2020). - PubMed
    1. D. Crich, En route to the transformation of glycoscience: A chemist's perspective on internal and external crossroads in glycochemistry. J. Am. Chem. Soc. 143, 17–34 (2020). - PMC - PubMed
    1. A. A. Hettikankanamalage, R. Lassfolk, F. S. Ekholm, R. Leino, D. Crich, Mechanisms of stereodirecting participation and ester migration from near and far in glycosylation and related reactions. Chem. Rev. 120, 7104–7151 (2020). - PMC - PubMed