Solid-Phase Synthesis of Aryl O-Glycoside Using Aqueous Base and Phase-Transfer Catalyst

Abstract

We describe an efficient solid-phase synthesis of aryl O-glycosides using aqueous base and phase-transfer catalyst. This methodology can provide aryl O-glycosides selectively in excellent yield and purity without the production of C-glycoside. Application of this methodology to the synthesis of Phlorizin type aryl O-glycosides is reported.

Key Words

solid-phase synthesis - aryl O-glycoside - phase-transfer catalyst - glycosylation - phlorizin

References and Notes

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7

ArgoGel^{Τ Μ} (Wang chloride resin) was purchased from Argonaut Technologies, San Carlos, CA.

10

Column: Mightysil RP-18 GP (ODS) 3 µm, 4.6 mmI. D. × 50 mm; mobile phase: 20 mM NH₄OAc: MeOH = 70: 30 (0 min) Æ 10:90 (4 - 8 min); UV: 254 nm.

11

General Procedure for Glycosylation of Phenol Exemplified with the Synthesis of m -10: The resin m -6 (4 × 30 mg, 0.17 mmol/g) was loaded into IRORI^{Τ Μ} MicroKans. To a solution of Cs₂CO₃ in THF-MeOH (1:1, 4 mL) was added the MicroKans at ambient temperature. After being shaked for 17 h at the same temperature, the reaction mixture was drained to isolate the Kans. The Kans were sequentially washed with DMF (4 × 5 mL), THF-water (2:1, 4 × 5 mL), 5% HOAc-THF (4 × 5 mL), THF (4 × 5 mL), MeOH (4 × 5 mL), and dichloromethane (DCM) (4 × 5 mL) and dried in vacuo to give immobilized phenol m -7 in four Kans. Three MicroKans among them were exposed to a solution of glucosyl bromide 8a (463 mg) in 1,2-dichloroethane (4.2 mL). To the mixture were successively added 5% NaOH aq (2.1 mL), benzyl tri-n-butylammonium chloride (21.9 mg). After being shaked at ambient temperature for 15 h, the mixture was drained. Remaining three Kans were washed sequentially with DCM (5 mL), DMF (4 × 5 mL), THF-MeOH (1:1, 2 × 5 mL), 5% HOAc-THF (2 × 5 mL), THF (4 × 5 mL), MeOH (4 × 5 mL), and DCM (4 × 5 mL) and dried to give glycoside m -9. The resin in the three MicroKans was cleaved with 10% TFA-DCM (5 mL) for 30 min. The resulting solution was diluted with DCM (5 mL) and toluene (2 mL). The MicroKans were removal from the solution by means of tweezers. The acidic solution was concentrated to afford m -10 (9.8 mg, 0.014 mmol, 93%). Spectrum data of m -10: ¹H NMR (300 MHz, CDCl₃): δ = 8.03 (2 H, dd, J = 1.2, 8.4 Hz), 7.99-7.90 (4 H, m), 7.86 (2 H, dd, J = 1.5, 8.4 Hz), 7.58-7.25 (13 H, m), 7.04-6.97 (1 H, m), 6.60-6.47 (3 H, m), 5.98 (1 H, dd, J = 9.4, 9.6 Hz), 5.79 (1 H, dd, J = 7.8, 9.4 Hz), 5.70 (1 H, dd, J = 9.4, 9.6 Hz), 5.37(1 H, d, J = 7.8 Hz), 4.68 (1 H, dd, J = 3.3, 12.3 Hz), 4.53 (1 H, dd, J = 6.3, 12.3Hz), 4.37-4.28 (1 H, m); MS (ESI): 706 [M + NH₄ ⁺].

12

Spectrum data, p -10: ¹H NMR (300 MHz, CDCl₃): δ = 8.05-7.82 (8 H, m), 7.58-7.24 (13 H, m), 6.89 (2 H, d, J = 9.0 Hz), 6.61 (2 H, d, J = 9.0 Hz), 5.97 (1 H, dd, J = 9.6, 9.9 Hz), 5.76 (1 H, dd, J = 8.1, 9.9 Hz), 5.70 (1 H, dd, J = 9.6, 9.9 Hz), 5.26 (1 H, d, J = 8.1 Hz), 4.66 (1 H, dd, J = 3.0, 12.3 Hz), 4.53 (1 H, dd, J = 6.3, 12.3 Hz), 4.30-4.23 (1 H, m); MS (ESI): 706 [M + NH₄ ⁺].

15

Spectrum data, 18a: ¹H NMR (300 MHz, CDCl₃): δ = 12.99 (1 H, s), 7.99 (2 H, d, J = 8.0 Hz), 7.96-7.89 (4 H, m), 7.84 (2 H, d, J = 8.0 Hz), 7.60-7.24 (12 H, m), 7.10 (1 H, dd, J = 8.1, 8.4 Hz), 6.61 (1 H, d, J = 8.4 Hz), 6.56 (1 H, d, J = 8.1 Hz), 6.03 (1 H, dd, J = 9.6, 10.0 Hz), 5.92 (1 H, dd, J = 7.5, 9.6 Hz), 5.74 (1 H, dd, J = 9.6, 10.0 Hz), 5.63 (1 H, d, J = 7.5 Hz), 4.68 (1 H, dd, J = 2.7, 13.2 Hz), 4.52 (1 H, dd, J = 7.8, 13.2 Hz), 4.42-4.33 (1 H, m), 2.61 (3 H, s); MS (ESI): 748 [M + NH₄ ⁺]. 18b: ¹H NMR (300 MHz, CDCl₃): δ = 13.00 (1 H, s), 8.09 (2 H, dd, J = 1.5, 8.4 Hz), 8.03 (2 H, dd, J = 1.5, 8.4 Hz), 7.91 (2 H, dd, J = 1.5, 8.7 Hz), 7.81 (2 H, dd, J = 1.5, 8.7 Hz), 7.68-7.23 (12 H, m), 7.10 (1 H, dd, J = 7.5, 8.4 Hz), 6.63 (1 H, d, J = 7.5 Hz), 6.60 (1 H, d, J = 8.4 Hz), 6.17 (1 H, dd, J = 8.1, 10.2 Hz), 6.07 (1 H, d, J = 3.3 Hz), 5.71 (1 H, dd, J = 3.3, 10.2 Hz), 5.62 (1 H, d, J = 8.1 Hz), 4.67-4.50 (3 H, m), 2.65 (3 H, s); MS (ESI): 748 [M + NH₄ ⁺]. 18c: ¹H NMR (300 MHz, CDCl₃): δ = 12.97 (1 H, s), 8.03 (2 H, d, J = 6.9 Hz), 7.99-7.88 (4 H, m), 7.61-7.30 (10 H, m), 6.68 (2 H, dd, J = 2.0, 8.4 Hz), 5.92 (1 H, dd, J = 7.5, 7.8 Hz), 5.77 (1 H, dd, J = 5.7, 7.8 Hz), 5.64 (1 H, d, J = 5.7 Hz), 5.49-5.40 (1 H, m), 4.53 (1 H, dd, J = 3.5, 13.2 Hz), 3.89 (1 H, dd, J = 8.0, 13.2 Hz), 2.62 (3 H, s); MS (ESI): 614 [M + NH₄ ⁺]. 18d: ¹H NMR (300 MHz, CDCl₃): δ = 12.97 (1 H, s), 8.06 (2 H, dd, J = 1.5, 8.4 Hz), 7.98 (2 H, dd, J = 1.5, 8.7 Hz), 7.91 (2 H, dd, J = 1.2, 8.4 Hz), 7.65-7.25 (10 H, m), 6.69 (1 H, d, J = 8.4 Hz), 6.67 (1 H, d, J = 8.4 Hz), 6.09 (1 H, dd, J = 6.6, 9.0 Hz), 5.81-5.75 (1 H, m), 5.71 (1 H, dd, J = 3.3, 9.0 Hz), 5.58 (1 H, d, J = 6.6 Hz), 4.43 (1 H, dd, J = 3.9, 13.2 Hz), 4.08 (1 H, dd, J = 2.0, 13.2 Hz), 2.66 (3 H, s); MS (ESI): 614 [M + NH₄ ⁺].