Catching elusive glycosyl cations in a condensed phase with HF/SbF5 superacid

Journal name:
Nature Chemistry
Volume:
8,
Pages:
186–191
Year published:
DOI:
doi:10.1038/nchem.2399
Received
Accepted
Published online

Abstract

Glycosyl cations are universally accepted key ionic intermediates in the mechanism of glycosylation, the reaction that covalently links carbohydrates to other molecules. These ions have remained hypothetical species so far because of their extremely short life in organic media as a consequence of their very high reactivity. Here, we report the use of liquid hydrofluoric acid–antimony pentafluoride (HF/SbF5) superacid to generate and stabilize the glycosyl cations derived from peracetylated 2-deoxy and 2-bromoglucopyranose in a condensed phase. Their persistence in this superacid medium allows their three-dimensional structure to be studied by NMR, aided by complementary computations. Their deuteration further confirms the impact of the structure of the glycosyl cation on the stereochemical outcome of its trapping.

At a glance

Figures

  1. Prototype of the glycosylation mechanism and ionic species observed by NMR.
    Figure 1: Prototype of the glycosylation mechanism and ionic species observed by NMR.

    a, Generally accepted mechanism for glycosylation starting from glycosyl donor A and involving associated species B, glycosyl oxocarbenium ion C, covalent intermediate D, contact ion pair E or solvent separated ion pair F, depending on the glycosylation conditions and the structure of the glycosyl donor. P, protecting group; LG, leaving group; E+, electrophile; X, electrophile counterion. b, Key NMR signals recorded for tetrahydropyranosyl cation 1 (obtained by treatment of 2-acetoxytetrahydropyran with HF/SbF5) and methyl acylium ion in superacid. c, Structure and major conformation adopted by sugar-derived ions 25 (obtained by treatment of peracetylated α-D-glucopyranose, α-D-glucosamine, β-D-glucopyranose and β-D-glucosamine, respectively, with HF/SbF5), as deduced from the analysis of the experimental vicinal JH,H coupling constants and by comparison between the experimental and GIAO-DFT calculated 13C chemical shifts and coupling constants for their optimized structure.

  2. Generation and NMR spectra of 2-deoxyglucosyl oxocarbenium ion 6 in HF/SbF5 at −40 °C.
    Figure 2: Generation and NMR spectra of 2-deoxyglucosyl oxocarbenium ion 6 in HF/SbF5 at −40 °C.

    The high-quality NMR spectra including the signals at 8.89 ppm for the anomeric proton and at 229.1 ppm for the anomeric carbon unambiguously confirm the generation of the 2-deoxyglucosyl oxocarbenium ion 6 and allow its structural analysis. a, Generation of ion 6 in HF/SbF5. b, 1H NMR spectrum of ion 6. c, 1H–1H COSY (homonuclear correlated spectroscopy) NMR spectrum of ion 6. d, 13C NMR spectrum of ion 6. e, 1H–13C HSQC (heteronuclear single quantum correlation) NMR spectrum of ion 6.

  3. Conformational preferences of 2-deoxy- and 2-bromo-glucosyl oxocarbenium ions 6 and 7 in HF/SbF5 superacid.
    Figure 3: Conformational preferences of 2-deoxy- and 2-bromo-glucosyl oxocarbenium ions 6 and 7 in HF/SbF5 superacid.

    Glycosyl cations 6 and 7 respectively adopt a 4E and a 4H5 conformation according to the perfect matching between the experimental and calculated 1H and 13C chemical shifts and JHH coupling constants. a, Comparison of experimental and simulated 1H NMR spectra and 13C NMR shifts for 2-deoxyglucosyl oxocarbenium ion 6. b, Comparison of experimental and simulated 1H NMR and 13C NMR shifts for 2-bromoglucosyl oxocarbenium ion 7.

  4. Monitoring of the chemical stability of 2-deoxyglucosyl oxocarbenium ion 6 in HF/SbF5 by 1H-NMR.
    Figure 4: Monitoring of the chemical stability of 2-deoxyglucosyl oxocarbenium ion 6 in HF/SbF5 by 1H-NMR.

    Glycosyl cation 6 proved to be stable in HF/SbF5 superacid between −50 °C and 0 °C and for at least 4 h at −40 °C. a, Monitoring by 1H-NMR of the chemical stability of 2-deoxyglucosyl oxocarbenium ion 6 in HF/SbF5 over a range of temperatures (the NMR tube was left for 15 min at each temperature starting at −50 °C). b, Monitoring by 1H-NMR of the chemical stability of 2-deoxyglucosyl oxocarbenium ion 6 in HF/SbF5 over a period of time at −40 °C.

  5. Generation of 2-deoxy- and 2-bromo-glucosyl oxocarbenium ions 6 and 7 in HF/SbF5 followed by their trapping with methanol (40 equiv.) or cyclohexane-d12 (2 equiv.).
    Figure 5: Generation of 2-deoxy- and 2-bromo-glucosyl oxocarbenium ions 6 and 7 in HF/SbF5 followed by their trapping with methanol (40 equiv.) or cyclohexane-d12 (2 equiv.).

    Generated ions 6 and 7 treated with a large excess of methanol give the anticipated α- and β-methyl glycosides 8 and 9, respectively. In parallel, glucosyl cations 6 and 7 are also efficiently deuterated in HF/SbF5 using 2 equiv. of cyclohexane-d12 to respectively afford the α- and β-anomers 10 and 11. The formation of the deuterated monosaccharides 10 and 11 is under kinetic control and can be directly rationalized exploiting the three-dimensional structure of ions 6 and 7. In the case of glucosyl cation 6, the nucleophile preferentially attacks from the bottom face of the pyranose ring. This face is sterically hindered by the bromine atom in the case of the glucosyl cation 7, thus favouring the observed β-selectivity. a, Results obtained with 2-deoxy-glucosyl oxocarbenium ion 6. b, Results obtained with 2-bromo-glucosyl ion 7. Yields are determined after flash chromatography purification and anomeric ratios are determined by 1H-NMR analysis on the crude reaction mixture.

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Affiliations

  1. Université de Poitiers, UMR-CNRS 7285, IC2MP, Equipe ‘Synthèse organique’, 4 rue Michel Brunet, TSA 51106, Poitiers Cedex 9 86073, France

    • A. Martin,
    • J. Désiré,
    • A. Martin-Mingot,
    • N. Probst,
    • S. Thibaudeau &
    • Y. Blériot
  2. CIC bioGUNE, Parque Tecnológico de Bizkaia, Edif. 801A-1°, Derio-Bizkaia 48160, and Ikerbasque, Basque Foundation for Science, Maria López de Haro 3, 48013 Bilbao, Spain

    • A. Arda &
    • J. Jiménez-Barbero
  3. Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 8232, IPCM, LabEx MiChem, F-75005 Paris, France

    • P. Sinaÿ

Contributions

Y.B. and P.S. initiated the study. Y.B. and S.T. designed the study. A.M., N.P. and J.D. synthesized the sugar precursors. A.M., A.M.M. and N.P. performed the superacid experiments. A.M., A.M.M., J.D., S.T., Y.B., J.J.-B. and A.A. analysed the NMR spectra. J.J.-B. and A.A. performed the computation. Y.B., J.J.B. and S.T. wrote the paper. All authors discussed the results and commented on the manuscript.

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