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Synlett 2005(19): 2958-2962  
DOI: 10.1055/s-2005-921889
LETTER
© Georg Thieme Verlag Stuttgart · New York

Highly Efficient Sialylation towards α(2-3)- and α(2-6)-Neu5Ac-Gal Synthesis: Significant ‘Fixed Dipole Effect’ of N-Phthalyl Group on α-Selectivity

Katsunori Tanaka, Takashi Goi, Koichi Fukase*
Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama 1-1, Toyonaka, Osaka 560-0043, Japan
Fax: +81(6)68505419; e-Mail: koichi@chem.sci.osaka-u.ac.jp;
Further Information

Publication History

Received 24 June 2005
Publication Date:
27 October 2005 (online)

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Abstract

Highly α-selective sialylation of sialic acid N-phenyltrifluoroacetimidate with galactose acceptors, up to 100:0 and 92% for α(2-6)-sialoglycoside, while 97:3 and 77% for α(2-3)-sialoglycoside linkage formations, has been realized by introducing the C-5 N-phthalyl group on the donor. The ‘fixed dipole effect’ of N-phthalyl group was proposed in order to explain the high reactivity and α-selectivity. The N-phthalyl group was removed by treatment with ­methylhydrazine acetate, of which Neuα-Gal units can be readily applicable to the synthesis of a variety of N-linked oligosaccharides.

Key words

stereoselective sialylation - α-glycoside - oligosaccharides - N-phthalyl group - fixed dipole effect

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Experimental Procedure of 4d.
To a solution of the donor 2d (50 mg, 66.6 µmol), acceptor 3 (45 mg, 99.9 µmol), and MS 4 Å in propionitrile (1 mL) was added TMSOTf (2.5 µL, 13.3 µmol) at -78 °C under Ar atmosphere. After the mixture was stirred for 30 min at this temperature, the reaction was quenched by a sat. NaHCO3 solution. After MS 4 Å was removed by filtration, the filtrate was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The residue was purified by column chromato-graphy on silica gel (CHCl3) to afford the α-sialoside 4d
(61 mg, 92%).
1H NMR (500 MHz, CDCl3): δ = 8.01 (4 H, m, PhCO-), 7.83 (2 H, m, Pht), 7.73 (2 H, m, Pht), 7.50 (4 H, m, PhCO-), 7.37 (2 H, m, PhCO-), 5.87 (1 H, ddd, J = 5.5, 10.7, 22.3 Hz,
-OCH2CH=CH2), 5.71 (2 H, m, H-2, H-3), 5.51 (1 H, td, J = 6.3, 16.5 Hz, H-4′), 5.45 (1 H, td, J = 2.7, 5.5 Hz, H-8′), 5.34 (1 H, H-4), 5.31 (1 H, dd, J = 1.7, 17.2 Hz,
-OCH2CH=CH2), 5.18 (1 H, dd, J = 2.4, 8.3 Hz, H-7′), 5.15 (1 H, dd, J = 1.4, 10.4 Hz, -OCH2CH=CH2), 5.10 (1 H, dd, J = 2.3, 10.6 Hz, H-6′), 4.43 (1 H, s, H-1), 4.29 (1 H, dd, H-9′a), 4.28 (1 H, dd, OCH2CH=CH2), 4.23 (1 H, t, J = 10.6 Hz, H-5′), 4.19 (1 H, H-5), 4.08 (1 H, dd, -OCH2CH=CH2), 4.05 (1 H, dd, H-9′), 4.03 (1 H, H-6a), 3.91 (3 H, s,
-COOCH3) 3.87 (1 H, dd, J = 6.5, 10.0 Hz, H-6b), 3.03 (1 H, -OH), 2.80 (1 H, dd, J = 5.1, 12.9 Hz, H-3′eq), 2.15, 2.13, 1.88, 1.84 (3 H, s, CH3CO-), 2.01 (1 H, H-3′ax). ESI-MS (+): m/z = 1012.24 [M + Na]+.

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Data for α-anomer of 6: 1H NMR (500 MHz, CDCl3): δ = 8.13 (4 H, m, PhCO-), 7.83 (2 H, m, Pht), 7.73 (2 H, m, Pht), 7.58 (4 H, m, PhCO-), 7.47 (2 H, m, PhCO-), 7.35 (5 H, m, PhCH2-), 5.90 (1 H, ddd, J = 4.5, 9.7, 22.1 Hz,
-OCH2CH=CH2), 5.52 (1 H, td, J = 5.0, 15.9 Hz, H-4′), 5.43-5.39 (2 H, m, H-8′, H-2), 5.31 (1 H, -OCH2CH=CH2), 5.24 (1 H, d, J = 2.6 Hz, H-1), 5.14 (1 H, dd, H-7′), 5.14 (1 H, dd, J = 1.7, 10.9 Hz, -OCH2CH=CH2), 5.02 (1 H, dd, J = 1.7, 10.9 Hz, H-6′), 4.76 (1 H, dd, J = 3.6, 10.3 Hz, H-9′a), 4.64 (1 H, d, J = 8.5 Hz, PhCH2-), 4.62 (1 H, d, J = 8.5 Hz, PhCH2-), 4.21 (1 H, dd, OCH2CH=CH2), 4.21 (1 H, H-3), 4.17 (1 H, H-5′), 4.19 (1 H, H-5), 4.06 (1 H, dd, J = 6.0, 13.3 Hz, -OCH2CH=CH2), 4.00 (1 H, dd, J = 5.4, 12.4 Hz, H-9′b), 3.89-3.78 (2 H, H-6), 3.82 (3 H, s, -COOCH3), 2.95 (1 H, -OH), 2.62 (1 H, dd, J = 4.9, 13.3 Hz, H-3′eq), 2.12, 2.00, 1.91, 1.80 (3 H, s,CH3CO-), 2.07 (1 H, H-3′ax). ESI-MS (+): m/z = 998.34 [M + Na]+.

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The C2-α-configuration in (2-3)- and (2-4)-sialoglycosides 8 and 9 were assigned from the NOEs between methyl protons of the ester and H-4 and/or H-6 in the neuramic acid moiety.