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

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.

carbohydrates - esterifications - hyaluronic acid

References

1 Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   3rd ed.:  John Wiley and Sons, Inc.; New York: 1999. 

2 Kim S. Chang H. Kim WJ. J. Org. Chem.  1985,  50:  1751 

3 Grindley TB. Adv. Carbohydr. Chem. Biochem.  1998,  53:  17 

4 Schelhaas M. Waldmann H. Angew. Chem., Int. Ed. Engl.  1996,  35:  2056 

5

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.

6 Szeja W. Carbohydr. Res.  1983,  115:  240 

7a Dasgupta F. Hay GW. Szarek WA. Shilling WL. Carbohydr. Res.  1983,  114:  153 

7b Eby R. Webster KT. Schuerch C. Carbohydr. Res.  1984,  129:  111 

7c Horton D. Priebe W. Varela O. Carbohydr. Res.  1985,  144:  317 

7d Hanessian S. Kagotani M. Carbohydr. Res.  1990,  202:  67 

8 Li Z.-J. Huang H.-Q. Cai M.-S. Carbohydr. Res.  1994,  265:  227 

9 Zhang S.-Q. Li Z.-J. Wang A.-B. Cai M.-S. Feng R. Carbohydr. Res.  1998,  308:  281 

10 Hung S.-C. Thopate SR. Wang C.-C. Carbohydr. Res.  2001,  330:  177 

11

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) ų, Z = 4, ρ_calcd = 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.

12 Schmidt RR. Kinzy W. Adv. Carbohydr. Chem. Biochem.  1994,  50:  21 

13 The Chemistry, Biology and Medical Applications of Hyaluronan and its Derivatives   Laurent TC. Portland Press; London: 1998. 

14 De Luca C. Lansing M. Martini I. Crescenzi F. Shen G.-J. O’Regan M. Wong C.-H. J. Am. Chem. Soc.  1995,  117:  5869 

15a Slaghek TM. Nakahara Y. Ogawa T. Tetrahedron Lett.  1992,  33:  4971 

15b Slaghek TM. Nakahara Y. Ogawa T. Kamerling JP. Vliegenthart JFG. Carbohydr. Res.  1994,  255:  61 

15c Halkes KM. Slaghek TM. Hyppönen TK. Kruiskamp PH. Ogawa T. Kamerling JP. Vliegenthart JFG. Carbohydr. Res.  1998,  309:  161 

15d Yeung BKS. Hill DC. Janicka M. Petillo PA. Org. Lett.  2000,  2:  1279 

16a Slaghek TM. Hyppönen TK. Ogawa T. Kamerling JP. Vliegenthart JFG. Tetrahedron Lett.  1993,  34:  7939 

16b Slaghek TM. Hyppönen TK. Ogawa T. Kamerling JP. Vliegenthart JFG. Tetrahedron: Asymmetry  1994,  5:  2291 

16c Carter MB. Petillo PA. Anderson L. Lerner LE. Carbohydr. Res.  1994,  258:  299 

16d Coutant C. Jacquinet J.-C. J. Chem. Soc., Perkin Trans. 1  1995,  1573 

16e Blatter G. Jacquinet J.-C. Carbohydr. Res.  1996,  288:  109 

17 Fischer B. Nudelman A. Ruse M. Herzig J. Gottlieb HE. Keinan E. J. Org. Chem.  1984,  49:  4988 

18

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.