Novel Benzyl-Free Glycosyl Donors for Highly Stereoselective 1,2-cis-Fucosylation

Dedicated to the memory of Professor Nikolay K. Kochetkov (1915–2005)

Abstract

Novel glycosyl donors with a triisopropylsilyl (TIPS) nonparticipating group at O-2 were introduced for use in 1,2-cis-fucosylation. Coupling of 2-O-TIPS-substituted thiofucosyl donors with N-trifluoroacetyl-β-d-glucosamine mono- and disaccharide derivatives was found to lead exclusively to α-linked oligosaccharides. No remote participation in 2-O-TIPS thiofucosyl donors seems to be required to favor α-selective fucosylation.

Key words

glycosylation - stereoselectivity - protecting groups - neighboring-group effects - substituent effects

• References and Notes

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• 17 General Procedure for Glycosylation: Preparation of Oligosaccharides 8–10, 12, 14, 16 A mixture of a thioglycoside 2, 4–6 (0.042 mmol, 1.5 equiv; 3 equiv were used for the synthesis of 16) and glycosyl acceptor 7, 11, 13, 15 (0.028 mmol, 1 equiv) was dried in vacuo for 2 h, then anhydrous CH₂Cl₂ (1 mL) was added under argon. Freshly activated (220 °C, 6 h, in vacuo) powdered 4 Å MS (100 mg) were added under argon to the resulting solution, and the reaction flask was flushed with argon. The suspension was stirred under argon at ca. 22 °C for 1 h, and then cooled to –40 °C (acetone–dry ice bath). Solid NIS (0.042 mmol, 1.5 equiv; 3 equiv were used for the synthesis of 16) was added, followed by AgOTf (1 mg, 0.0039 mmol, 0.14 equiv). Then the temperature was allowed to rise slowly until the appearance of a persistent characteristic iodine color at –21 °C (–24 °C for 2 + 15). The reaction was held a this temperature for 60 min, and then the reaction mixture was allowed to warm to 0 °C during 30 min. The reaction was quenched by the addition of sat. aq NaHCO₃ (50 μL), diluted with CHCl₃ (15 mL), and filtered through a Celite pad. The solids were thoroughly washed with CHCl₃ (50 mL), and the filtrate was successively washed with a mixture of sat. aq Na₂S₂O₃ (50 mL) and sat. aq NaHCO₃ (50 mL). The aqueous layer was extracted with CHCl₃ (2 × 5 mL), and combined organic extracts were filtered through a cotton wool plug, concentrated, and dried in vacuo. In those cases where the glycosyl donor 4 or 6 contained TFA groups the residue was additionally dissolved in MeOH (1.0 mL) and CH₂Cl₂ (1.0 mL), and then Et₃N (40 μL) was added to the solution. The reaction mixture was stirred for 40 min at ca. 20 °C and then diluted with CHCl₃ (15 mL) and washed with sat. aq NaHCO₃ (10 mL). The aqueous layer was extracted with CHCl₃ (2 × 5 mL), and the combined organic extracts were filtered through a cotton wool plug, concentrated, and dried in vacuo. The residue was applied to a column (50 × 2.5 cm) packed with with Bio-Beads S×3 (200–400 mesh, Bio-Rad), and the column was then eluted with toluene using a differential refractometer (Knauer) as the detector. The first eluted fraction contained the desired disaccharides (trisaccharide in the case of 16) and was concentrated, dried in vacuo, and analyzed by NMR spectroscopy to give anomeric ratio values.
• 18 4-(2-Chloroethoxy)phenyl 6-O-tert-butyldiphenylsilyl-3-O-chloroacetyl-2-deoxy-4-O-(3,4-di-O-benzoyl-2-O-triisopropylsilyl-α-l-fucopyranosyl)-2-trifluoroacetamido-β-d-glucopyranoside (8) The title compound 8 was obtained according to general procedure for glycosylation in 95% yield. R_f = 0.41 (light PE–EtOAc, 3:1). [α]_D ²⁰ –53.3 (c 1.0, CHCl₃). ESI-HRMS: m/z calcd for C₆₃H₇₆Cl₂F₃NNaO₁₄Si₂ [M + Na]: 1276.4026; found: 1276.4014; m/z calcd for C₆₃H₇₆Cl₂F₃KNO₁₄Si₂ [M + K]: 1292.3765; found: 1292.3754. ¹H NMR (500 MHz, CDCl₃): δ = 0.67–1.02 [m, 21 H, (CH₃)₂CH)], 1.05 [s, 9 H, (CH₃)₃C)], 1.13 (d, J ₅,₆ = 5.8 Hz, 3 H, H-6^II), 3.71–3.81 (m, 3 H, CH₂Cl, H-4^I), 3.82–3.95 (m, 2 H, H-6^Ia, H-5^I), 4.07–4.19 (m, 4 H, ClCH₂COO, CH₂O), 4.29–4.39 (m, 2 H, H-2^I, H-5^II), 4.39–4.48 (m, 2 H, H-2^II, H-6^Ib), 5.02 (s, 1 H, H-1^II), 5.08 (d, J = 7.9 Hz, 1 H, H-1^I), 5.27 (app t, J = 9.2 Hz, 1 H, H-3^I), 5.47 (app d, J = 10.6 Hz, 1 H, H-3^II), 5.65 (s, 1 H, H-4^II), 6.69–6.75 (m, 3 H, OC₆H₄O, NH), 6.98–7.05 (m, 2 H, OC₆H₄O), 7.24–7.42 (m, 8 H, Ph), 7.44–7.52 (m, 3 H, Ph), 7.59–7.65 (m, 1 H, Ph), 7.65–7.73 (m, 4 H, Ph), 7.73–7.79 (m, 2 H, Ph), 7.99–8.04 (m, 2 H, Ph). ¹³C NMR (126 MHz, CDCl₃): δ = 12.2 [(CH₃)₂ CH], 15.4 (С-6^II), 17.8 [(CH₃)₂CH], 17.9 [(CH₃)₂CH], 19.3 [(CH₃)₃ C], 26.8 [(CH₃)₃C], 40.7 (ClCH₂CO₂), 41.8 (CH₂ CH₂Cl), 54.3 (C-2^I), 63.8 (C-6^I), 66.7 (C-5^II), 68.4 (C-2^II), 68.7 (CH₂O), 70.9 (C-3^II), 72.1 (C-4^II), 75.8 (C-3^I), 76.30 (C-4^I or C-5^I), 76.34 (C-5^I or C-4^I), 99.5 (C-1^I), 100.9 (C-1^II), 115.6 (q, J = 288.2 Hz, CF)₃, 115.9 (OC₆H₄O), 118.1 (OC₆H₄O), 127.6 (Ph), 127.8 (Ph), 128.0 (Ph), 128.4 (Ph), 129.4 (Ph), 129.59 (Ph), 129.61 (Ph), 129.8 (Ph), 129.9 (Ph), 132.86 (Ph), 132.94 (Ph), 133.1 (Ph), 133.4 (Ph), 135.4 (Ph), 135.6 (Ph), 151.6 (OC₆H₄O), 154.1 (OC₆H₄O), 157.6 (q, J = 37.7 Hz, CF₃CO), 165.6 (PhCO), 165.7 (PhCO), 168.0 (ClCH₂ CO)
• 19 No β-anomer was detected although the whole oligosaccharide fraction was isolated by size-exclusion chromatography and analyzed by NMR spectroscopy.
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• 30 Comparison of NMR data of 17 with NMR data of the known ethyl 2,3-di-O-acetyl-1-thio-β-l-fucopyranoside³¹ suggests that some conformational change has occurred in 17 due to the steric bulk of the protecting groups. Analyical Data for 17 ¹H NMR (300 MHz, C₆D₆): δ = 1.10–1.22 [m, 24 H, SCH₂CH ₃, CH(CH₃)₂], 1.23–1.30 [m, 18 H, CH(CH₃)₂], 1.32 (d, 3 H, H-6, J = 6.5 Hz), 1.36–1.53 [m, 3 H, CH(CH₃)₂], 2.22 (d, 1 H, OH, J = 6.0 Hz), 2.53 (dq, 1 H, SCH ₂CH₃, J = 12.7, 7.5 Hz), 2.68 (dq, 1 H, SCH ₂CH₃, J = 12.7, 7.4 Hz), 3.41 (qd, 1 H, H-5, J = 6.4, 1.3 Hz), 3.71 (app t, 1 H, H-4, J = 4.2 Hz), 3.88 (dd, 1 H, H-3, J = 7.1, 3.8 Hz), 4.10 (app t, 1 H, H-2, J = 7.3 Hz), 4.47 (d, 1 H, H-1, J = 7.6 Hz). ¹H–²⁹Si HMBC correlations: δ_H = 4.10/δ_Si = 13.5 [H-2/(i-Pr)₃Si], δ_H = 3.88/δ_Si = 14.5 [H-3/(i-Pr)₃Si].
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