Preparation of Sialyl Donors Carrying Functionalized Ester Substituents: Effects on the Selectivity of Glycosylation

Abstract

Methylthio sialyl donors having various ester substituents were prepared systematically. Nucleophilic displacement of methyl ester with Ph₃SiSH and Cs₂CO₃ followed by in situ alkylation with RX or esterification with R-OH/DCC afforded these compounds in good yields. Glycosylations promoted by NIS-TfOH were examined in order to examine the effect of substituent of the ester portion. When conducted in CH₃CN, enhanced α-selectivities were observed for cyanomethyl, 2-cyanoethyl, 2-cyanobenzyl, and 2-nitrobenzyl esters, implying that these substituents are effective enhancing the solvent effect of acetonitrile, possibly by stabilizing the β-oriented nitrilium ion.

Key words

sialic acid - glycosylation - stereoselective - substituent effect - selective deprotection

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14

Typical procedure (compound 1h): To the solution of compound 1a (209 mg, 0.401 mmol), 2,6-di-t-butyl-4-cresol (18 mg, 0.08 mmol) and Ph₃SiSH (352 mg, 1.20 mmol) in dry DMF (5 mL) was added Cs₂CO₃ (352 mg, 1.08 mmol) and the mixture was stirred at 80 °C for 8 h. After cooling down to ice-water temperature, 2-nitrobenzyl bromide (261 mg, 1.21 mmol) was added and stirring continued for 4 h at 0 °C. The reaction was saturated aq KHSO₄ and extracted with EtOAc. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by flash chromatography (hexane-EtOAc, 10:1-1:2) to give compound 1h (212 mg, 82%).

18

Stabilization of anomeric cation by multiple molecules of acetonitrile was proposed. See refs. [3c] [d]

22

NMR (CD₃OD, 400 MHz) δ 1.72 (1 H, t, J = 12.0 Hz, H-3_Neu5Ac), 1.85, 1,86, 1.97, 1.98, 1.99, and 2.10 (each 3 H, s, 6Ac), 2.71 (1 H, dd, J = 12.0 Hz, 4.0 Hz, H-3_Neu5Ac), 3.37-3.42 (1 H, m, H-6_Gal), 3.52-3.60 (3 H, m, H-5_Gal, H-6_Glc, H-2_Gal), 3.83-3.88 (3 H, m, H-6_Glc, H-6′_Glc, H-5_Gal), 3.97-4.09 (3 H, m, H-4_Glc, CH ₂=CHCH₂, H-5_Neu5Ac), 4.09 (1 H, dd, J = 11.2 Hz, 8.4 Hz, H-2_Gal), 4.14 (1 H, dd, J = 12.4 Hz, 5.2 Hz, H-9_Neu5Ac), 4.14 (1 H, dd, J = 12.4 Hz, 5.2 Hz, H-9_Neu5Ac), 4.17-4.25 (2 H, m, H-9_Neu5Ac, CH ₂CH=CH₂), 4.28 (1 H, dd, J = 11.2 Hz, 8.4 Hz), 4.39 (1 H, d, J = 12.0 Hz, Bn), 4.41 (1 H, dd, J = 12.4 Hz, 3.2 Hz, H-9_Neu5Ac), 4.49 (1 H, d, J = 12.4 Hz, Bn), 4.54 (1 H, d, J = 12.0 Hz, Bn), 4.59 (1 H, d, J = 12.0 Hz, Bn), 4.69 (1 H, dd, J = 9.6 Hz, 2.4 Hz, H-3_Gal), 4.76 (1 H, d, J = 12. 0 Hz, Bn), 4.81 (1 H, d, J = 7.2 Hz, H-1_Gal), 4.88-4.96 (2 H, m, Bn), 4.98-5.03 (1 H, m, CH₂CH=CH ₂), 5.03-5.23 (2 H, m, CH₂CH=CH ₂, H-4_Neu5Ac), 5.16 (1 H, d, J = 8.4 Hz, H-1_Gal), 5.18 (1 H, d, J = 12.4 Hz, Bn), 5.38 (1 H, d, J = 2.4 Hz, H-4_Gal), 5.39 (1 H, dd, J = 8.0, 2.4 Hz, H-7_Neu5Ac), 5.66-5.77 (2 H, m, H-8_Neu5Ac, CH₂CH=CH₂), 6.82-7.90 (24 H, m, Ar).