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Synthesis of N-Glycopeptides by Convergent Assembly

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Abstract

Electron-donating O-benzylated glycosylamine mono-, di- and trisaccharide representing the reducing terminal of the core structure of N-glycans were incorporated, in anomerically pure from into Leu–Lys–Asn–Gly-Gly–Pro hexapeptide that is a partial structure of the Trp-cage mini-protein by convergent assembly. According to our results acylation of electron-donating O-benzylated glycosylamine with peptide acid under the proposed new reaction conditions led to the formation of glycopeptide in good yield and in anomerically pure form for the first time. This convergent approach allows the synthesis of a series of glycopeptides containing different oligosaccharides without the need to resynthesize the peptide for each individual case.

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Scheme 1
Scheme 2
Scheme 3

Notes

  1. Typical experimental procedure for the key coupling reaction: To a solution of the glycosylazide (112 μmol) in dry DMF (1 ml), PtO2 (5 mg) was added and the mixture was stirred under hydrogen for 90 min. Then, selectively protected hexapeptide (112 μmol) in dry DMF (1 ml) was added under argon followed by the addition of the mixture of HBTU (112 μmol) and iPr2NEt (224 μmol) in DMF (1 ml) at -20°C. After stirring for 2 h at -20°C the mixture was concentrated. Column chromatography of the residue afforded the glycopeptide.

  2. Selected spectroscopic and physical data: compound 4: δH (d 6-DMSO) 4.99 (1 H, H-1); δC (d 6-DMSO) 79.0 (C-1, JC1-H1 155 Hz); MALDI-TOF: C84H96O16N10 (1500.70): m/z 1523.66 [M+Na]+, 1539.67 [M+K]+. Compound 5: δH (d 6-DMSO) 4.97 (1 H, H-1), 4.66 (1 H, H-1′); δC (d 6-DMSO) 100.4 (C-1′, JC1′-H1’ 166 Hz), 79.25 (C-1, JC1-H1 156 Hz); MALDI-TOF: C106H121O21N11 (1883.87): m/z 1906.81 [M+Na]+, 1922.75 [M+K]+. Compound 6: δH (d 6-DMSO) 4.96 (1 H, H-1), 4.67 (1 H, H-1′), 4.59 (1 H, H-1′′), δC (d 6-DMSO) 101.2 (C-1′′, JC1′′-H1′′ 157 Hz), 100.70 (C-1′, JC1’-H1’ 161 Hz), 79.36 (C-1, JC1-H1 155 Hz); MALDI-TOF: C133H149O26N11 (2316.07): m/z 2339.40 [M+Na]+. Compound 7: [α]D +14.3 (c 0.2, H2O); δH (d 6-DMSO) 4.81 (1 H, H-1); δC (d 6-DMSO) 79.4 (C-1, JC1-H1 156 Hz); MALDI-TOF: C33H58O12N10 (786.42): m/z 787.49 [M+H]+, 809.49 [M+Na]+, 825.45 [M+K]+. Compound 8: [α]D -8.7 (c 0.1, H2O); δH (d 6-DMSO) 4.84 (1 H, H-1), 4.38 (1 H, H-1′); δC (d 6-DMSO) 102.6 (C-1′, JC1’-H1’ 160 Hz), 79.2 (C-1, JC1-H1 153 Hz); MALDI-TOF: C41H71O17N11 (989.50): m/z 990.53 [M+H]+, 1012.51 [M+Na]+, 1028.47 [M+K]+. Compound 9: [α]D -17.5 (c 0.08, H2O); δH (d 6-DMSO) 4.85 (1 H, H-1), 4.50 (1 H, H-1′′), 4.43 (1 H, H-1′); δC (d 6-DMSO) 102.4 (C-1′, JC1’-H1’ 160 Hz), 101.3 (C-1′′, JC1′′-H1′′ 158 Hz), 79.1 (C-1, JC1-H1 156 Hz); MALDI-TOF: C47H81O22N11 (1151.56): m/z 1174.55 [M+Na]+, 1190.49 [M+K].

  3. See footnote 2.

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Acknowledgments

We are grateful for the grant from the Hungarian National Science Foundation (OTKA-71753). We thank Dr Anikó Fekete for performing the MALDI-TOF spectra and Dr Zoltán Kele for performing the ESI MS measurements.

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Authors and Affiliations

  1. Department of Botany, Bio-organic Laboratory, Faculty of Sciences and Technology, University of Debrecen, Debrecen, Hungary

    János Kerékgyártó & László Kalmár

  2. Department of Applied Ecology, Bio-organic Laboratory, Faculty of Sciences and Technology, University of Debrecen, Debrecen, Hungary

    Zoltán Szurmai

  3. Department of Medical Chemistry, Faculty of General Medicine, University of Szeged, Szeged, Hungary

    László Kalmár, Orsolya Hegyi & Gábor K. Tóth

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  1. János Kerékgyártó
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  2. László Kalmár
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  4. Orsolya Hegyi
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  5. Gábor K. Tóth
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Correspondence to Gábor K. Tóth.

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Kerékgyártó, J., Kalmár, L., Szurmai, Z. et al. Synthesis of N-Glycopeptides by Convergent Assembly. Int J Pept Res Ther 18, 1–5 (2012). https://doi.org/10.1007/s10989-011-9271-y

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