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Synlett 2007(4): 0649-0651  
DOI: 10.1055/s-2007-967972
LETTER
© Georg Thieme Verlag Stuttgart · New York

A New Synthetic Route to 4-Methylumbelliferyl-β-d-glucopyranosiduronic Acid (MUG)

Miguel A. López-Lópeza, Alexander Balbuzano-Deusa, Juan C. Rodríguez-Domíngueza,b, Miriam Mesa Hernándeza, Anais Fernández Villaloboa, Yulianela Ibarra Reyesa, Gilbert Kirsch*b
a Departamento de Química, Centro de Química Farmacéutica, Calle 200 y 21, Atabey, Playa, 11600 Ciudad de la Habana, Cuba
b Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique (LIMBP), Institut Jean Barriol, Université Paul Verlaine Metz, 1 Boulevard Arago, 57070 Metz, France
Fax: +33(3)87315801; e-Mail: kirsch@univ-metz.fr;
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Publikationsverlauf

Received 17 November 2006
Publikationsdatum:
21. Februar 2007 (online)

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Abstract

A synthetic route to prepare 4-methylumbelliferyl-β-d-glucopyranosiduronic acid (MUG) from 4-methylumbelliferyl-β-d-glucopyranoside (MUGluc) was developed. The primary hydroxyl group in MUGluc was protected by tritylation followed by acetylation of secondary hydroxyls. The triphenylmethyl group was selectively removed by treatment with iodine-methanol in benzene and the free hydroxyl was transformed into the carboxylic acid by phase-transfer oxidation with sodium hypochlorite and TEMPO as catalyst. Finally, the acetate groups were removed by reaction with barium methoxide in methanol to afford the MUG with an overall yield of 37% from the MUGluc.

Key words

synthesis - MUG - 4-methylumbelliferyl-β-d-gluco­pyranoside - 4-methylumbelliferyl-β-d-glucopyranosiduronic acid

20

General Methods TLC was performed on precoated plates of silica gel GF-254 (Merck); EtOAc-CHCl3-AcOH (8:6:1) and n-BuOH-H2O-AcOH (5:1:1) were used as mobile phases. The chromatograms were visualized in a Camag UV/Vis lamp (λ = 254 and 360 nm). Compounds were also detected by spraying the plates with 5% H2SO4-EtOH reagent followed by heating. Melting points(mp) were determined using a Büchi capillary apparatus and are uncorrected. 1H NMR and 13C NMR spectra were registered on a Bruker AC 250F spectrometer for 250 MHz and 62.5 MHz, respectively, using CDCl3, CDCl3 + MeOD4 or DMSO-d 6 as solvents and TMS as internal standard. Optical rotation of MUG was measured at 20 °C with an ADP220 Bellenghan + Stanley Ltd. apparatus. Elemental analysis was done in a Thermofinnigan FlashEA 1112 equipment.
4-Methylumbelliferyl-2,3,4-tri- O -acetyl-6- O -trityl-β- d -glucopyranoside ( 1)
Trityl chloride (4.25 g, 15.25 mmol) was added to a stirred suspension of 4-methylumbelliferyl-β-d-glucopyranoside (5.0 g, 14.78 mmol) in pyridine (11 mL). The mixture was heated at 90-100 °C for 5 h. After cooling to 0-5 °C, Ac2O (7.5 mL, 79.34 mmol) was added and the mixture was left to stand overnight at r.t., poured into cold H2O (225 mL) and stirred for 2 h. The resultant solid was filtered off, washed with cold H2O (3 × 50 mL), vacuum-dried at 40 °C and recrystallized from EtOH to afford 1. Yield 7.60 g (73%); mp 212-215 °C. 1H NMR (CDCl3): δ = 1.78 (3 H, s), 2.03 (3 H, s), 2.08 (3 H, s) 2.40 (3 H, s), 3.25 (2 H, m), 3.76 (1 H, m), 5.09-5.43 (4 H, m), 6.21 (1 H, s), 6.99-7.60 (18 H, m). 13C NMR (CDCl3): δ = 18.61, 20.31, 20.59, 20.60, 62.02, 68.40, 71.15, 72.78, 73.91, 86.89, 98.52, 104.40, 113.18, 113.74, 115.48, 125.72, 127.07 (3 C), 127.81 (6 C), 128.60 (6 C), 143.40 (3 C), 152.02, 154.83, 159.42, 160.76, 168.96, 169.28, 170.20. Anal. Calcd for C41H38O12 (722.73): C, 68.14; H, 5.30. Found: C, 68.20; H, 5.17.
4-Methylumbelliferyl-2,3,4-tri- O -acetyl-β- d -gluco-pyranoside ( 2)
A solution of iodine (0.3 g, 1.18 mmol) in MeOH was added to a solution of compound 1 (1.8 g, 2.55 mmol) in benzene (18 mL) and the mixture was stirred at 65 °C for 24 h. The solvents were evaporated under vacuum and the residue was dissolved in EtOAc (60 mL), washed with 10% aq Na2S2O3 (30 mL), followed by H2O (3 × 10 mL), and dried over anhyd Na2SO4. The organic extract was evaporated to dryness under reduced pressure and the residue was stirred 2 h with diisopropyl ether (30 mL). The resulting solid was filtered off, washed with diisopropyl ether (3 × 5 mL) and vacuum-dried at 40 °C to afford 2. Yield: 1.10 g (92%); mp 176-178 °C. 1H NMR (CDCl3): δ = 2.04 (6 H, s), 2.07 (3 H, s) 2.37 (3 H, s), 3.72 (3 H, m), 5.21 (4 H, m), 6.15 (1 H, s), 6.70-7.56 (3 H, m). 13C NMR (CDCl3): δ = 18.56, 20.52 (3 C), 60.91, 68.21, 71.04, 72.42, 74.65, 98.23, 103.95, 113.03, 113.61, 115.41, 125.75, 152.20, 154.70, 159.17, 160.81, 169.24, 170.06 (2 C). Anal. Calcd for C22H24O12 (480.42): C, 55.00; H, 5.04. Found: C, 55.33; H, 5.20.
4-Methylumbelliferyl-2,3,4-tri- O -acetyl-β- d -gluco-pyranosiduronic Acid ( 3) A sat. solution of aq NaHCO3 (15 mL) and a 5% solution of NaOCl (19 mL) were added to a solution of 2 (1.25 g, 2.7 mmol), NaBr (0.06 g, 0.583 mmol), TBAB (0.06 g, 0.186 mmol), and TEMPO (0.06 g, 0.384 mmol) in a 1:1 mixture of CH2Cl2-H2O (20 mL) at 0 °C. After 2-3 h the aqueous phase was separated and washed with CH2Cl2 (2 × 10 mL). The, CH2Cl2 (20 mL) was added; the mixture was cooled to 0-5 °C and adjusted to pH 3 with 10% HCl. The organic phase was separated, washed with H2O (10 mL) and dried over anhyd Na2SO4. The solvent was evaporated to dryness under reduced pressure and the resulting solid was vacuum-dried to afford 3. Yield 0.87 g (68%); mp 218-221 °C. 1H NMR (CDCl3 + MeOD4): δ = 2.00 (6 H, s), 2.02 (3 H, s), 2.36 (3 H, s), 4.22 (1 H, m), 5.21-5.36 (4 H, m), 6.14 (1 H, s), 6.87-7.55 (3 H, m). 13C NMR (CDCl3 + MeOD4): δ = 18.46, 20.37 (3 C), 68.86, 70.78, 71.92, 72.13, 98.11, 104.22, 112.80, 113.90, 115.50, 125.73, 152.70, 154.49, 159.09, 161.30, 167.94, 169.35, 169.69, 170.17. Anal. Calcd for C22H22O13 (494.40): C, 53.45; H, 4.49. Found: C, 53.77; H, 5.03.
4-Methylumbelliferyl-β- d -glucopyranosiduronic Acid (MUG, 4).
A suspension of 3 (2.0 g, 4.18 mmol) in MeOH (30 mL) was stirred at 0-5 °C with a solution of Ba(OMe)2 (0.503 g, 2.52 mmol) in MeOH (10 mL). After 24 h, concentrated H2SO4 (0.14 mL, 2.52 mmol) was added, the precipitated BaSO4 was filtered off, the filtrate was evaporated to dryness under reduced pressure and the residue was crystallized with Et2O (20 mL). The resultant solid was separated by filtration, washed with Et2O (3 × 5 mL) and vacuum-dried to afford 4. Yield 1.25 g (85%); mp 140-143 °C; [α]D -116 (c 0.25, H2O); {lit. [12] mp 139-145 °C; [α]D -114 (c 0.25, H2O)}. 1H NMR (DMSO-d 6): δ = 2.40 (3 H, s), 3.23 (1 H, m), 3.56 (1 H, m), 4.98-5.19 (2 H, m), 5.38 (1 H, m), 6.22 (1 H, s), 6.99-7.75 (3 H, m). 13C NMR (DMSO-d 6): δ = 17.93, 71.82, 72.96, 73.63, 76.43, 100.00, 103.29, 111.46, 113.43, 113.89, 126.14, 153.13, 154.22, 159.92, 160.23, 172.22.