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Synlett 2004(2): 0275-0278  
DOI: 10.1055/s-2004-815415
LETTER
© Georg Thieme Verlag Stuttgart · New York

Moisture Stable Promoters for Selective α-Fucosylation Reactions: Synthesis of Antigen Fragments

Matteo Adinolfi, Alfonso Iadonisi*, Alessandra Ravidà, Marialuisa Schiattarella
Dipartimento di Chimica Organica e Biochimica, Università degli Studi di Napoli Federico II, Via Cynthia 4, I-80126 Napoli, Italy
Fax: +39(81)674330; e-Mail: iadonisi@unina.it;
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Publication History

Received 14 October 2003
Publication Date:
12 January 2004 (online)

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Abstract

Moisture stable reagents Yb(OTf)3 and acid washed molecular sieves (AW 300 MS) can act as mild promoters for selective α-fucosylation reactions. Using a combination of Yb(OTf)3 and AW 300 MS a good stereocontrol is achieved with a perbenzylated fucosyl N-phenyl trifluoroacetimidate donor by exploiting the ­directing effect of ether solvents. With the AW 300 MS alone the selectivity can be obtained with partially acetylated donors by ­exploiting a long-range participation effect. Both systems proved suitable for the synthesis of fragments contained in important antigen sequences, included the Lewis X trisaccharide.

Key words

carbohydrates - synthesis of oligosaccharides - stereo­selectivity in fucosylation reactions - acid-washed molecular sieves - ytterbium triflate

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Procedure A: A mixture of acceptor (0.2 mmol) and donor 1 (see Table 1 for relative amounts) were coevaporated three times in anhyd toluene and the residue was kept under vacuum for 1 h. Acid washed molecular sieves (4 Å AW 300 MS, pellets, 200 mg) were then added and the mixture was dissolved at 0 °C with CH2Cl2 (2.8 mL), and Et2O (700 µL). After cooling at -30 °C, a solution of Yb(OTf)3 (12.5 mg, 0.02 mmol) in dioxane (700 µL) was added drop-wise. The mixture was kept under stirring at this temperature until complete consumption of the fucosyl donor (1-3 h, TLC) and then few drops of Et3N were added. The mixture was filtered on a short pad of silica gel, concentrated, and the residue purified by silica gel chromatography (eluent: hexane/EtOAc mixtures).

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Procedure B: A mixture of acceptor (0.2 mmol) and donor 2 (see Table [1] for relative amounts) were coevaporated three times in anhyd toluene and the residue was kept under vacuum for 1 h. Acid washed molecular sieves (4 Å AW 300 MS, pellets, 1.5-2 g) were then added and the solvent (dichloroethane or toluene, 2-4 mL) was added at 0 °C. The mixture was kept at 0 °C under stirring for 30 min and then temperature was left to rise spontaneously. After complete consumption of the donor (24-36 h), the mixture was filtered through a cotton pad and concentrated. The residue was purified by silica gel chromatography (eluent: hexane/EtOAc mixtures).

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All compounds were identified by 1H NMR and 13C NMR analyses. Spectroscopic selected data of representative compounds are reported. Compound 15: 1H NMR (300 MHz, CDCl3): δ = 7.50-7.20 (aromatic protons), 5.10 (1 H, d, J 1,2 = 3.9 Hz, H-1 Fuc), 5.07 (1 H, d, J 1,2 = 8.2 Hz, H-1 GlcN), 5.03 (1 H, dd, J 1,2 = 7.4 Hz, J 2,3 = 10.2 Hz, H-2 Gal), 4.62 (1 H, d, H-1 Gal), 4.90-4.34 (17 H, Troc CH2, 7 × benzyl CH2 and H-5 Fuc), 4.18 (1 H, t, J 2,3 = J 3,4 = 9.6 Hz, H-3 GlcN), 4.04-3.26 (12 H, H-3 Gal, H-4 Gal, H-5 Gal, H2-6 Gal, H-4 GlcN, H-5 GlcN, H2-6 GlcN, H-2 Fuc, H-3 Fuc, and H-4 Fuc), 3.81 (3 H, s, -OCH3), 3.03 (1 H, m, H-2 GlcN), 1.13 (3 H, d, J 5,6 = 6.2 Hz, H3-6 Fuc), 0.86 [9 H, s, -SiC(CH3)3], 0.08 and 0.03 [6 H, 2 × s, -Si(CH3)2]. 13C NMR (50 MHz, CDCl3): δ = 155.0 and 153.4 (-NH-CO-OCH2CCl3, -O-CO-OMe), 139.3, 139.2, 138.8, 138.6, 138.4, 137.9, and 137.8 (aromatic C), 128.8-127.0 (aromatic CH), 99.5, 97.3, and 94.4 (C-1 Gal, GlcN, Fuc), 95.1 (-NH-CO-OCH2CCl3), 55.0 (-OCH3), 25.6 [-SiC(CH3)3], 17.9 [-SiC(CH3)3], 16.2 (C-6 Fuc), -4.2 and -5.3 [-Si(CH3)2]; other signals at δ = 80.9, 79.6, 78.8, 76.6, 76.0, 75.4, 75.0, 74.7, 73.8, 73.4, 73.2, 72.8, 72.4, 72.3, 68.2, 67.6, 66.4, 61.8. Compound 16: 1H NMR (400 MHz, CDCl3): δ = 7.40-7.15 (aromatic protons), 5.27 (1 H, dd, J 2,3 = 10.4 Hz, J 3,4 = 3.2 Hz, H-3 Fuc), 5.21 (1 H, bd, H-4 Fuc), 5.15 (1 H, d, J 1,2 = 3.6 Hz, H-1 Fuc), 5.11 (1 H, d, J 1,2 = 7.8 Hz, H-1 GlcN), 5.00-4.96 (2 H, m, H-2 Gal and H-5 Fuc), 4.59 (1 H, d, J 1,2 = 8.0 Hz, H-1 Gal), 4.72-4.40 (12 H, Troc CH2, 5 × benzyl CH2), 4.20 (1 H, t, J 2,3 = J 3,4 = 9.4 Hz, H-3 GlcN), 3.98-3.28 (10 H, H-3 Gal, H-4 Gal, H-5 Gal, H2-6 Gal, H-4 GlcN, H-5 GlcN, H2-6 GlcN, and H-2 Fuc), 3.78 (3 H, s, -OCH3), 2.91 (1 H, m, H-2 GlcN), 2.09 and 1.98 (6 H, 2 × s, 2 × acetyl CH3), 0.93 (3 H, d, J 5,6 = 6.2 Hz, H3-6 Fuc), 0.84 [9 H, s, -SiC(CH3)3], 0.06 and 0.01 [6 H, 2 × s, -Si(CH3)2]. 13C NMR (50 MHz, CDCl3): δ = 170.4 and 169.4 (2 × -COCH3), 155.1 and 154.0 (-NH-CO-CH2CCl3, -O-CO-OMe), 138.6, 138.3, 138.3, 138.1, and 138.1 (aromatic C), 129.0-127.2 (aromatic CH), 99.4, 97.5, 93.9 (C-1 Gal, GlcN, and Fuc), 55.0 (-OCH3), 25.6 [-SiC(CH3)3], 20.9 and 20.7 (2 × -COCH3), 17.9 [-SiC(CH3)3], 15.2 (C-6 Fuc), -4.2 and -5.3 [-Si(CH3)2]; other signals at δ = 80.5, 74.8, 74.6, 74.4, 73.6, 73.2, 73.1, 72.3, 72.0, 71.8, 70.3, 67.9, 67.8, 64.5, 61.8.