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

doi:10.1055/s-2005-921889

LETTER

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;

Abstract

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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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References

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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]⁺.

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]⁺.

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.