Synthesis of a Glycosylphosphatidylinositol (GPI) Fragment as a Potential Substrate for Mannoprotein Transglycosidases

Abstract

A glycophosphatidylinositol tetrasaccharide fragment was synthesized to mimic the core features of primary model, that of Saccharomyces cerevisiae. The salient feature of this approach is centered on the quick access to various α-1,2- and α-1,6-mannosyl and α-1,4-glycosyl linkages by using simple glycosylation and protective-group techniques. 1D and 2D-J-resolved NMR spectroscopy was used to verify the α-configuration of the new linkages. The tetrasaccharides obtained in this work are useful for examining fungal cell-wall glycoprotein cross-linking by transglycosidase enzymes for antifungal drug development.

Key words

oligosaccharides - glycosylation - medicinal chemistry

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• 32 GPI Tetrasaccharide Fragment 25 ²⁹ Tetrasaccharide polyol 24 (4 mg, 5.54 μmol) was heated with hydrazine hydrate (0.5 mL) at 120 °C with stirring overnight. The solution was co-evaporated in vacuo with toluene (2 × 0.5 mL) and the residue was purified by flash chromatography [silica gel, 0.5% Et₃N in EtOAc–MeOH–H₂O (7:2:1 to 1:9:0)], followed by reverse-phase chromatography [silica gel, H₂O–MeCN (1:0 to 19:1 to 9:1), 200 μL fractions] to give a white solid; yield: 2.8 mg, (68%); mp 163 °C. ¹H NMR (400 MHz, D₂O): δ = 5.09 (s, 1 H, H1^D), 5.01 (s, 1 H, H1^B), 4.90 (s, 1 H, H1^C peak suppressed), 4.75 (s, 1 H, H1^A peak suppressed), 3.95–4.42 [m, 23 H, H(3,4,5,6,6′)^A, H(2,3,4,5,6,6′)^B,^C,^D], 3.28 (s, 3 H, OMe), 2.65 (dd, J ₁,₂ = 3.7, J ₂,₃ = 10.3 Hz, 1 H, H2^A). ¹³C NMR (100 MHz, CDCl₃): δ = 102.3 (C1^D), 101.8 (C1^B), 99.2 (C1^A), 98.3 (C1^C), 78.7, 77.3, 73.7, 73.2, 72.7, 72.2, 70.7, 70.4, 70.3, 70.2, 69.9, 66.9, 66.9, 66.5, 66.3, 61.1, 60.9, 60.8, 55.2, 54.8 [C(2,3,4,5,6)^A,^B,^C,^D]. HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₅H₄₆NO₂₀: 680.25970; found: 680.26077.