Photodeprotection of up to Eight Photolabile Protecting Groups from a Single Glycan

Abstract

Permanent protecting groups are essential for oligosaccharide synthesis. However, the removal of the traditionally used protecting groups is not trivial and demands considerable expertise. Using photolabile protecting groups as permanent protection for glycan can overcome many limitations associated with the traditional oligosaccharide synthesis approach. It is demonstrated here that up to eight photolabile protecting groups can be readily removed from a single glycan using a benchtop LED setup that is very easy to operate. This report suggests that further development of the strategy will offer an attractive alternative for oligosaccharide synthesis.

Key words

photolabile protecting groups - carbohydrates - glycosylation - photochemistry - oligosaccharides

• References and Notes

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• 11 oNBC Removal and Workup Procedure for Compound 6: A oNBC-protected maltose 6 (10 mg) derivative was dissolved in a MeCN–TDW (1.5 mL, 70:30) mixture. The solution was transferred into a quartz cuvette equipped with a small magnetic stirrer. The LED lamp was set to pass the beam directly into the solution of the cuvette. The sample was irradiated at 365 nm in a dark room with uniform magnetic stirring. The solution slowly starts to turn brown indicating the removal of the oNBC groups. The complete removal of the protecting groups was monitored by either TLC, or RP-HPLC or ¹H NMR. It took around 9 h of the irradiation time to completely remove all the eight oNBC groups. Workup Procedure: After complete removal of all the eight oNBC groups, the reaction mixture was transferred into a 15-mL conical centrifuge tube and lyophilized. The lyophilized crude maltose was triturated with Et₂O (2 mL), CH₂Cl₂ (1.5 mL) and dried under vacuum. Maltose with natural anomeric ratio (NMR confirmation) was obtained with a yield of 58%. The pure unprotected maltose was obtained without any chromatographic purification.
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• 13 Synthesis of Phenyl 3,4,6-Tri-O-oNBC-2-deoxy-2-azido-1-seleno-β-d-galactopyranoside 9: To a solution of phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-azido-1-seleno-β-d-galactopyranoside (500 mg, 1.1 mmol) dissolved in MeOH (5 mL) was added NaOMe (20 mg, 0.37 mmol) dissolved in MeOH (5 mL) at rt. After the reaction went to completion [monitored by TLC (EtOAc–hexane, 1:1)] the reaction was quenched with Amberlite-120-H⁺, filtered and washed with MeOH. The solvent was evaporated to obtain the phenyl 3,4,6-trihydroxy-2-deoxy-2-azido-1-seleno-β-d-galactopyranoside. The crude phenyl 3,4,6-trihydroxy-2-deoxy-2-azido-1-seleno-β-d-galactopyranoside was protected with oNBC-Cl without any further purification. Briefly, oNBC-Cl (10.32 mmol) was added dropwise to a stirred solution of phenyl 3,4,6-trihydroxy-2-deoxy-2-azido-1-seleno-β-d-galactopyranoside and DMAP (12.9 mmol) was dissolved in anhyd DMF (10 mL) at 0 °C. The reaction was allowed to stir at rt for 12 h. The reaction was quenched with ice and the crude oNBC-protected phenyl 3,4,6-tri-O-oNBC-2-deoxy-2-azido-1-seleno-β-d-galactopyranoside was isolated into EtOAc (2 × 15 mL). The combined organic layer was washed with H₂O (15 mL) and brine (10 mL) and the solvent was evaporated. The crude product was purified using silica column chromatography (15% EtOAc in hexane) to afford the pure compound 9 (white solid, overall yield: 38%). ¹H NMR (CDCl₃): δ = 8.09–8.15 (m, 3 H), 7.57–7.67 (m, 8 H), 7.42–7.53 (m, 3 H), 7.27–7.30 (m, 3 H), 6.01–6.02 (d, J = 5.4 Hz, 1 H, H1), 5.57–5.67 (m, 4 H), 5.54–5.55 (d, J = 6.8 Hz, 2 H), 5.46–5.47 (m, 1 H, H4), 4.98–5.01 (dd, J = 3.2, 10.8 Hz, 1 H, H3), 4.76–4.78 (t, J = 6.5 Hz, 1 H, H5), 4.36–4.39 (dd, J = 5.5, 10.8 Hz, 1 H, H2), 4.28–4.32 (m, 1 H, H6′), 4.20–4.23 (m, 1 H, H6). ¹³C NMR (125 MHz, CDCl₃): δ = 154.3, 154.2, 153.3, 147.1, 146.9, 146.8, 135.0, 134.1, 134.0, 134.0, 131.1, 129.3, 129.0, 128.9, 128.8, 128.7, 128.4, 128.1, 126.9, 125.1, 83.8, 75.0, 70.9, 68.4, 66.8, 66.8, 66.3, 64.8, 58.5. MS (ESI): m/z [M + Na]⁺ calcd for C₃₆H₃₀N₆O₁₆SeNa: 905.08; found: 904.11.
• 14 Synthesis of Azido-1-O-allyl-2-deoxy-3,4,6-tri-O-oNBC-d-galactopyranoside 7: To a stirred solution of 9 (50 mg, 0.056 mmol) in anhyd CH₂Cl₂ (1.5 mL) 4 Å powdered molecular sieves were added and the mixture was stirred for 1 h at rt under an argon atmosphere. Allyl alcohol (0.680 mmol, 46 μL) and N-iodosuccinimide (19.1 mg, 0.085 mmol) were added sub­sequently under argon and the reaction mixture was cooled to 0 °C. Then the reaction mixture was treated with trifluoro­methanesulfonic acid (0.030 mmol, 3 μL) and stirred at 0 °C for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with TEA (30 μL) and treated with sat. sodium thiosulfate. Then the mixture was diluted with CH₂Cl₂ (10 mL) and filtered. The filtrate was washed with H₂O (2 × 10 mL), brine (10 mL). The organic layer was dried over Na₂SO₄. After evaporation of the solvent, the crude solid material was purified by column chromatography (15% EtOAc–hexane) to afford 7 (28 mg, 64%) as a white solid. Compound 7: isolated as a mixture of isomers and was used as such for the removal of oNBC protecting groups; 28 mg (64% yield); white solid. ¹H NMR (CDCl₃): δ = 8.10–8.15 (m, 3 H), 7.63–7.68 (m, 4 H), 7.56–7.60 (m, 2 H), 7.43–7.53 (m, 3 H), 5.88–5.99 (m, 1 H), 5.56–5.69 (m, 6 H), 5.44–5.45 (d, J = 4.3 Hz, 1 H), 5.383–5.389 (m, 1 H), 5.33–5.35 (m, 1 H), 5.26–5.29 (m, 2 H), 5.10–5.11 (d, J = 3.8 Hz, 0.5 H, H1α), 4.65–4.69 (dd, J = 7.6, 14.2 Hz, 1 H), 4.47–4.49 (d, J = 5.8 Hz, 0.5 H, H1β), 4.42–4.46 (m, 1 H), 4.36–4.40 (m, 1 H), 4.17–4.26 (m, 1 H), 4.08–4.12 (m, 1 H), 3.92–3.95 (m, 1 H), 3.81–3.86 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 154.4, 154.3, 153.5, 153.4, 147.4, 134.3, 134.3, 134.27, 134.1, 134.1, 133.5, 133.3, 130.7, 129.6, 129.5, 129.5, 129.5, 129.3, 129.2, 128.6, 128.5, 128.5, 125.0, 100.5, 96.7, 74.9, 72.5, 71.9, 70.9, 70.1, 69.8, 68.6, 66.6, 66.3, 66.1, 65.4, 65.2, 60.6, 57.4. MS (ESI): m/z [M + Na]⁺ calcd for C₃₃H₃₀N₆O₁₇Na: 805.16; found: 805.17.