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Synlett 2003(9): 1364-1366
DOI: 10.1055/s-2003-40338
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Regioselective Esterification of Various d-Glucopyranosides: Synthesis of a Fully Protected Disaccharide Unit of Hyaluronic Acid

Xin-An Lu, Chien-Hung Chou, Cheng-Chung Wang, Shang-Cheng Hung*
Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan
Fax: +886(2)27831237; e-Mail: schung@chem.sinica.edu.tw.;
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Publication History

Received 28 May 2003
Publication Date:
30 June 2003 (online)

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Abstract

A highly regioselective esterification of various d-glucopyranosides with triethylamine and acid anhydrides in excellent yields is described here. Its application toward the synthesis of a fully protected disaccharide unit of hyaluronic acid is also highlighted.

Key words

carbohydrates - esterifications - hyaluronic acid

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Following is the general procedure for the regioselective esterification of various d-glucopyranosyl diols. To a solution of the diol in CH2Cl2 (10 mL/g) was added acid anhydride (1.4 equiv) at r.t. under nitrogen. After stirring for 10 min, Et3N (9 equiv) was added to the mixture, and the whole solution was kept stirring overnight. MeOH (5 equiv) was added to quench the reaction, and the resulting solution was evaporated under reduced pressure. The syrup was dissolved in EtOAc, and the mixture was sequentially washed by water, aq sat. NaHCO3(twice), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by either recrystallization in ethanol or flash column chromatography on silica gel to give the desired product.

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Colorless crystals from chloroform/hexane, C20H19N3O6, fw = 397.14, crystal dimensions: 0.43 × 0.31 × 0.19 mm3, crystal system: orthorhombic, space group: P212121, unit-cell dimensions: a = 8.7073(7), b = 11.0684(21), c = 19.784(6) Å, V = 1906.7(7) Å3, Z = 4, ρcalcd = 1.384 gcm-3, wavelength = 0.7107 Å, F(000) = 831.85, mu = 0.10 mm-1, 2θ(max) = 50.0. The deposition number at the Cambridge Crystallographic Data Centre is CCDC 162431.

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The selected physical data of key compounds is listed. Compound 22: [α]D 25 -103.1 (c 1.0, CHCl3). Mp 209-210 °C. IR (CHCl3): ν = 2956 (w), 2115 (s), 1751 (s), 1635 (m), 1374 (m), 1219 (s), 912 (w)cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 7.2 Hz, 2 H, ArH), 7.63 (t, J = 7.2 Hz, 1 H, ArH), 7.49 (t, J = 7.6 Hz, 2 H, ArH), 7.44-7.37 (m, 5 H, ArH), 5.81 (d, J = 8.3 Hz, 1 H, H-1), 5.53 (s, 1 H, benzylidene), 5.25-5.14 (m, 2 H, H-3′, H-4′), 5.05 (t, J = 8.3 Hz, 1 H, H-2′), 4.84 (d, J = 8.0 Hz, 1 H, H-1′), 4.35 (dd, J = 10.3, 4.8 Hz, 1 H, H-5), 3.84-3.73 (m, 5 H, H-2, H-3, H-4, H-6, H-5′), 3.64-3.60 (m, 1 H, H-6′), 3.61 (s, 3 H, OMe), 2.08 (s, 3 H, OAc), 2.01 (s, 3 H, OAc), 1.99 (s, 3 H, OAc). 13C NMR (100 MHz, CDCl3): δ = 170.08 (C), 169.34 (C), 169.30 (C), 166.77 (C), 164.37 (C), 136.76 (C), 134.09 (CH), 130.08 (CH), 129.17 (CH), 128.65 (CH), 128.31 (CH), 125.90 (CH), 101.54 (CH), 100.84 (CH), 93.68 (CH), 80.01 (CH), 79.39 (CH), 72.42 (CH), 72.08 (CH), 71.55 (CH), 69.25 (CH), 68.21 (CH2), 67.06 (CH), 65.02 (CH), 52.69 (CH3), 20.55 (CH3), 20.42 (CH3). HRMS (FAB, MH+) calcd for C33H36N3O15: 714.2146. Found: 714.2111. Anal. Calcd for C33H35N3O15: C, 55.54; H, 4.94; N, 5.89. Found: C, 55.41; H, 4.64; N, 5.55. Compound 23: [α]D 25 -66.2 (c 0.9, CHCl3). Mp 188-189 °C. IR (CHCl3): ν = 3417 (w), 2955 (m), 1756 (s), 1751 (s), 1735 (s), 1654 (m), 1249 (s), 1084 (s), 753 (m)cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 7.5 Hz, 2 H, ArH), 7.60 (t, J = 7.5 Hz 1 H, ArH), 7.48-7.44 (m, 4 H, ArH), 7.41-7.37 (m, 3 H, ArH), 6.29 (d, J = 7.9 Hz, 1 H, H-1), 5.87 (d, J = 7.9 Hz, 1 H, NH), 5.52 (s, 1 H, benzylidene), 5.23-5.15 (m, 2 H, H-3′, H-4′), 5.00 (t, J = 7.7 Hz, 1 H, H-2′), 4.90 (d, J = 7.7 Hz, 1 H, H-1′), 4.45 (t, J = 8.7 Hz, 1 H, H-3), 4.36 (dd, J = 8.9, 3.3 Hz, 1 H, H-6), 3.95-3.89 (m, 2 H, H-2, H-4), 3.82-3.72 (m, 3 H, H-5, H-5′, H-6), 3.62 (s, 3 H, OMe), 1.99 (s, 3 H, OAc), 1.98 (s, 3 H, OAc), 1.96 (s, 3 H, OAc), 1.94 (s, 3 H, OAc). 13C NMR (100 MHz, CDCl3): δ = 170.42 (C), 170.05 (C), 169.43 (C), 169.39 (C), 167.08 (C), 164.81 (C), 136.97 (C), 133.82 (CH), 130.09 (CH), 129.12 (CH), 128.65 (CH), 128.60 (CH), 128.29 (CH), 126.07 (CH), 101.51 (CH), 99.67 (CH), 92.38 (CH), 79.76 (CH), 77.32 (CH), 72.09 (CH), 71.56 (CH), 69.24 (CH), 68.57 (CH2), 66.63 (CH), 55.43 (CH), 52.68 (CH3), 23.29 (CH3), 20.53 (CH3), 20.43 (CH3). HRMS (FAB, MH+) calcd for C35H40NO16: 730.2347. Found: 730.2360. Anal. Calcd for C35H39NO16: C, 57.61; H, 5.39; N, 1.92. Found: C, 57.58; H, 5.33; N, 1.85.