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

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.

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

References and Notes

1 Manafi M. Kneifel W. Bascomb S. Microbiol. Rev.  1991,  55:  335 

2 Dealler SF. Rev. Med. Microbiol.  1993,  4:  198 

3 Shadix LC. Rice EW. Can. J. Microbiol.  1991,  37:  908 

4 Berg JD. Fiksdal L. Appl. Environ. Microbiol.  1988,  54:  2118 

5 Brenner KP. Rankin CC. Roybal YR. Stelma GN. Scarpino PV. Dufour AP. Appl. Environ. Microbiol.  1993,  59:  3534 

6 Feng PCS. Hartman PA. Appl. Environ. Microbiol.  1982,  43:  1320 

7 Kilian M. Bulow P. Acta Pathol. Microbiol. Scand., Sect. B  1976,  84:  245 

8 Rippey SR. Chandler LC. Watkins WD. J. Food Prot.  1987,  50:  685 

9 Walsh JS. Patanella JE. Halm KA. Facchine KL. Drug Metab. Dispos.  1995,  23:  869 

10 Bollemback J. Long JW. Bejamin DG. Lindquist JA. J. Am. Chem. Soc.  1955,  77:  3310 

11 Berrang B. Twine CE. Hennessee GL. Carroll FI. Synth. Commun.  1975,  5:  231 

12 Courtin-Duchateau MC. Veyrières A. Carbohydr. Res.  1978,  65:  23 

13 Baggett N. Samra AK. Smithson A. Carbohydr. Res.  1983,  124:  63 

14 Randazzo G. Capasso R. Cicala MR. Evidente A. Carbohydr. Res.  1980,  85:  298 

15 Lehrfeld J. J. Org. Chem.  1967,  32:  2544 

16 Wahlstrom JL. Ronald RC. J. Org. Chem.  1998,  63:  6021 

17 Yeung BKS. Hill DC. Janicka M. Petillo PA. Org. Lett.  2000,  2:  1279 

18 Brown RT. Scheinmann F. Stachulski AV. J. Chem. Res., Synop.  1997,  370 

19 Stachulski AV. Jenkins GN. Nat. Prod. Rep.  1998,  173 

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.