Total synthesis of a unique tetrasaccharide present in the human clotting factor IX and mammalian Notch 1 receptor

The synthesis of a unique tetrasaccharide linked to the serine 61 of human clotting factor IX through an α-l-fucose residue has been achieved for the first time in excellent yield. All glycosylation and protecting group manipulation steps are high yielding and reproducible for a scale-up preparation. A sequential glycosylation strategy has been used to assemble suitably protected monosaccharide synthons for the preparation of the target tetrasaccharide.

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2-(Trimethylsilyl) ethyl 2-O-benzyl-3,4-O-isopropylidine-α-l-fucopyranosideC21H34O5Si[α]D25=-78 (c 1.0, CHCl3)Source of chirality: l-fucoseAbsolute configuration: (1S,2S,3S,4S,5S)

2-(Trimethylsilyl) ethyl 3,4-di-O-acetyl-6-O-benzyl-2-deoxy-2-N-phthalimido-β-d-glucopyranosyl-(1→3)-4-O-acetyl-2-O-benzyl-α-l-fucopyranosideC45H55NO14Si[α]D25=-37 (c 1.0, CHCl3)Source of chirality: d-glucosamine, l-fucoseAbsolute configuration: (1R,2S,3R,4S,5S); (1S,2S,3S,4S,5S)

2-(Trimethylsilyl)ethyl 2,3,4-tri-O-acetyl-6-O-benzyl-β-d-galactopyranosyl-(1→4)-6-O-benzyl-2-deoxy-2-N-phthalimido-β-d-glucopyranosyl-(1→3)-4-O-acetyl-2-O-benzyl-α-l-fucopyranosideC60H73NO20Si[α]D25=-37 (c 1.0, CHCl3)Source of chirality: d-galactose, d-glucosamine, l-fucoseAbsolute configuration: (1S,2R,3R,4S,5S); (1R,2S,3R,4S,5S); (1S,2S,3S,4S,5S)

2-(Trimethylsilyl) ethyl (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-d-glycero-α-d-galacto-2-nonulopyranosylonate)-(2→3)-2,4-di-O-acetyl-6-O-benzyl-β-d-galactopyranosyl-(1→4)-2-acetamido-3-O-acetyl-6-O-benzyl-2-deoxy-β-d-glucopyranosyl-(1→3)-4-O-acetyl-2-O-benzyl-α-l-fucopyranosideC74H100N2O31Si[α]D25=-64 (c 1.0, CHCl3)Source of chirality: N-acetylneuraminic acid, d-galactose, d-glucosamine, l-fucoseAbsolute configuration: (2R,4R,5R,6S,7S,8R); (1S,2R,3R,4S,5S); (1R,2S,3R,4S,5S); (1S,2S,3S,4S,5S)

2-(Trimethylsilyl) ethyl (sodium 5-acetamido-3,5-dideoxy-d-glycero-α-d-galacto-2-nonulopyranosylonate)-(2→3)-β-d-galactopyranosyl-(1→4)-2-acetamido-2-deoxy-β-d-glucopyranosyl-(1→3)-α-l-fucopyranosideC36H63N2NaO23Si[α]D25=-49 (c 1.0, H2O)Source of chirality: N-acetylneuraminic acid, d-galactose, d-glucosamine, l-fucoseAbsolute configuration: (2R,4R,5R,6S,7S,8R); (1S,2R,3R,4S,5S); (1R,2S,3R,4S,5S); (1S,2S,3S,4S,5S)