Synthesis of 2-acetamido-2-deoxy-β-D-glucopyranose o-glycopeptides from N-dithiasuccinoyl-protected derivatives

Knud J. Jensen, Paul R. Hansen, D. Venugopal, George Barany

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67 Scopus citations

Abstract

2-Acetamido-2-deoxy-β-D-glucopyranose (β-D-GlcpNAc), in O-glycosidic linkage to the side chain hydroxyls of serine (Ser) and threonine (Thr) residues, is often found in nuclear and cytoplasmic proteins. The 'active ester' approach for solid phase glycopeptide synthesis calls for the direct glycosylation of N(α)-(9-fluorenylmethyloxycarbonyl)amino acid pentafluorophenyl esters (N(α)-Fmoc-AA-OPfp's). The synthesis of the required Ser(β-D-GlcpNAc) and Thr(β-D-GlcpNAc) building blocks poses special problems arising from the 2-amino substituent in the corresponding glycosyl donors. Activation of donors with a 2-N-acyl group provides relatively unreactive oxazoline intermediates, whereas the otherwise promising phthaloyl (Phth) group requires prolonged base treatment at elevated temperatures for its removal, and incomplete deprotection is often encountered. The dithiasuccinoyl (Dts) group provides bivalent protection in the same way as the Phth group, but has the advantage of being removed rapidly under mild conditions by thiolysis or other reductive procedures. The novel donor 3,4,6-tri-O-acetyl-2-deoxy-2-(dithiasuccinoylamino)-D-glucopyranosyl bromide (8) was prepared from D-glucosamine in four steps and overall 58% yield; this compound served for the fast and efficient glycosylation of N(α)-Fmoc-Ser-OPfp and N(α)-Fmoc-Thr-OPfp. The resultant glycosylated building blocks N(α)-Fmoc-Ser(Ac3-β-D-GlcpNDts)-OPfp (9) and N(α)-Fmoc-Thr(Ac3-β-D-GlcpNDts)-OPfp (10) were applied in the solid phase synthesis of several glycopeptides. Following incorporation of the glycosylated residue, the Dts function was removed quantitatively by thiolysis, the resultant free 2-amino group was acetylated, and stepwise chain elongation by Fmoc chemistry continued. Alternatively, it was possible to achieve selective Dts removal from 9 and 10 (without affecting the Pfp ester) by reduction with zinc under acidic conditions; in situ acetylation of the exposed amine provided the alternative building blocks N(α)-Fmoc-Ser(Ac3-β-D-GlcpNAc)-OPfp (11) and N(α)-Fmoc-Thr(Ac3-β-D-GlcpNAc)-OPfp (12).

Original languageEnglish (US)
Pages (from-to)3148-3155
Number of pages8
JournalJournal of the American Chemical Society
Volume118
Issue number13
DOIs
StatePublished - Apr 3 1996

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