Rapid Assembly of Oligosaccharides by Using a Hydrophobic Tag-Assisted Liquid-Phase Method

Abstract

A 3,5-didocosyloxybenzyl alcohol tag that was introduced at the anomeric position of the carbohydrate acceptor was applied in the assembly of a pentasaccharide. The intrinsic high solubility in nonpolar solvent and precipitation properties in polar solvent are crucial features of this tag. Thus, rapid and simple precipitation-centrifugation can be conducted throughout the synthetic route at each step to ease work-up and purification processes, and reduce the amount of solvent required. This method provides an efficient, environmental-friendly, and economical approach to synthesize complex oligosaccharides.

Key words

oligosaccharides - glycosylation - precipitation-centrifugation - liquid-phase - tags

• References and Notes

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• 12 General Procedure for Precipitation-Centrifugation Separation (0.08 mmol scale): After addition of MeCN (0.5 mL) to the concentrated reaction mixture, the product was precipitated, which was centrifuged for 2 min to remove the supernatant liquor. This precipitation-centrifugation process was repeated four to five times.
• 13 General Procedure of Glycosylation for 3a–e: A mixture of donor 2 (2.0 equiv), acceptor (1.0 equiv) and flame-dried 4Å powdered molecular sieves (MS, 36 mg per 30 mg donor) was stirred in anhydrous DCM (1.0 mL per 30 mg donor) for 30 min at 25 °C under Ar. TMSOTf (0.3 equiv) was added dropwise at 0 °C, and the reaction was stirred for 2 h at 25 °C. Once the reaction was completed (monitored by TLC), it was neutralized with triethylamine, followed by filtration to remove MS. The filtrate was concentrated in an Eppendorf tube, and then precipitation-centrifugation separation was performed. Compound 3a: White solid; 88% yield through precipitation-centrifugation isolation. ¹H NMR (400 MHz, CDCl₃): δ = 7.91 (d, J = 7.7 Hz, 2 H), 7.83 (t, J = 8.8 Hz, 4 H), 7.71 (d, J = 6.8 Hz, 2 H), 7.61 (d, J = 6.4 Hz, 2 H), 7.50 (q, J = 7.6 Hz, 2 H), 7.45–7.28 (m, 10 H), 7.25–7.19 (m, 3 H), 6.34 (s, 3 H), 5.79 (t, J = 9.5 Hz, 1 H), 5.62 (t, J = 9.5 Hz, 1 H), 5.56 (dd, J = 9.5, 7.6 Hz, 1 H), 4.86, 4.62 (2d, J_gem = 12.0 Hz, 2 H), 4.83 (d, J = 7.6 Hz, 1 H), 3.91–3.79 (m, 3 H), 3.73 (dt, J = 8.9, 6.5 Hz, 2 H), 3.64 (dt, J = 8.9, 6.4 Hz, 2 H), 1.68–1.60 (m, 4 H), 1.37–1.25 (m, 76 H), 1.06 (s, 9 H), 0.88 (t, J = 6.6 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 166.02, 165.28, 165.14, 160.51, 138.94, 135.80, 135.65, 133.32, 133.20, 129.97, 129.90, 129.81, 129.52, 129.33, 129.12, 128.44, 128.37, 127.79, 106.01, 101.12, 98.97, 75.36, 73.49, 72.17, 70.11, 69.50, 67.98, 62.96, 32.08, 29.86, 29.60, 29.51, 29.41, 26.82, 26.20, 19.35, 14.27. HRMS (ESI): m/z [M + Na]⁺ calcd for C₉₄H₁₃₆O₁₁Si: 1491.9852; found: 1491.9811.
• 14 General Procedure for Deprotection of 6-O-TBDPS: The substrate (1.0 equiv) was dissolved in anhydrous THF (1.0 mL per 0.034 mmol) in an Eppendorf tube. The solution was treated with 70% HF-pyridine (20.0 equiv) at 0 °C, and it was stirred at 25 °C for 4 h. Once the reaction was completed (monitored by TLC), it was concentrated and then precipitation-centrifugation separation was performed. Compound 4a: White solid; quant. yield through precipitation-centrifugation isolation. ¹H NMR (400 MHz, CDCl₃): δ = 7.97–7.87 (m, 4 H), 7.86–7.78 (m, 2 H), 7.55–7.47 (m, 2 H), 7.45–7.32 (m, 5 H), 7.31–7.25 (m, 2 H), 6.40–6.29 (m, 3 H), 5.88 (t, J = 9.5 Hz, 1 H), 5.57 (dd, J = 9.5, 8.0 Hz, 1 H), 5.50 (t, J = 9.5 Hz, 1 H), 4.87 (d, J = 8.0 Hz, 1 H), 4.84, 4.64 (d, J_gem = 12.5 Hz, 1 H), 3.92–3.71 (m, 3 H), 3.80–3.71 (m, 2 H), 3.70–3.61 (m, 2 H), 1.70–1.58 (m, 4 H,), 1.38–1.27 (m, 76 H), 0.88 (t, J = 6.7 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 166.20, 165.93, 165.21, 160.50, 138.73, 133.80, 133.36, 133.27, 130.06, 129.95, 129.86, 129.35, 128.98, 128.63, 128.45, 106.15, 101.15, 99.36, 74.77, 72.93, 71.93, 70.88, 69.73, 68.02, 61.46, 32.07, 29.85, 29.59, 29.51, 29.39, 26.18, 22.84, 14.27. HRMS (ESI): m/z [M + Na]⁺ calcd for C₇₈H₁₁₈O₁₁: 1253.8674; found: 1253.8545.
• 15 Experimental Data of Compound 3e: White solid; 95% yield through precipitation-centrifugation isolation. ¹H NMR (500 MHz, CDCl₃): δ = 8.0–7.71 (m, 29 H), 7.68–7.64 (m, 2 H), 7.60–7.56 (m, 2 H), 7.54–7.44 (m, 7 H), 6.98 (t, J = 7.7 Hz, 2 H), 6.31 (s, 3 H), 6.12, 5.98, 5.95 (3t, J = 9.5 Hz, 3 H), 5.90–5.84 (m, 2 H), 5.83 (s, 1 H), 5.71, 5.62 (2t, J = 9.5 Hz, 2 H), 5.57–5.48 (m, 3 H), 5.48–5.38 (m, 4 H), 5.35 (t, J = 9.5 Hz, 1 H), 5.04, 4.94, 4.90, 4.82, 4.75 (5d, J = 8.0 Hz, 5 H), 4.74, 4.42 (2d, J_gem = 12.5 Hz, 2 H), 4.20 (m, 1 H), 4.06–3.57 (m, 18 H), 1.64–1.56 (m, 4 H), 1.35–1.21 (m, 76 H), 1.01 (s, 9 H), 0.88 (t, J = 7.0 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 165.91, 165.83, 165.79, 165.78, 165.73, 165.60, 165.40, 165.31, 165.28, 165.27, 165.22, 165.19, 165.13, 165.07, 160.37, 138.89, 135.69, 135.48, 133.64, 133.57, 133.37, 133.35, 133.28, 133.25, 133.17, 133.08, 132.98, 132.79, 130.07, 130.04, 129.98, 129.94, 129.91, 129.85, 129.79, 129.77, 129.74, 129.67, 129.63, 129.51, 129.47, 129.30, 129.23, 129.16, 129.16, 129.03, 128.97, 128.92, 128.86, 128.84, 128.74, 128.72, 128.69, 128.64, 128.50, 128.42, 128.37, 128.33, 128.27, 128.18, 128.09, 127.70, 127.67, 105.85, 101.98, 101.43, 101.32, 101.26, 101.19, 99.70, 75.44, 74.43, 74.26, 73.80, 73.64, 73.17, 73.01, 72.87, 72.67, 72.36, 72.20, 72.07, 71.94, 70.84, 70.54, 70.51, 70.10, 69.85, 69.35, 69.19, 68.28, 68.14, 67.91, 63.00, 32.06, 29.87, 29.85, 29.82, 29.80, 29.77, 29.64, 29.51, 29.43, 26.72, 26.19, 22.84, 19.19, 14.28. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀₂H₂₂₄O₄₃Si: 3388.5111; found: 3388.4900.