A Stereocontrolled Access to α-C-(1→3)-Linked Disaccharides Containing 2-Deoxyhexopyranoses

Abstract

A protected α-d-glucopyranosylacetaldehyde was converted by Wittig reaction with (thiazol-2-yl)carbonylmethylene­triphenyl phosphorane into the corresponding substituted 1-oxa-1,3-butadiene which by hetero-Diels-Alder reaction with ethyl vinyl ether afforded a mixture of two diastereoisomeric dihydropyran derivatives. These were separated by chromatography and the thiazol ring was transformed into an aldehyde group. Subsequent hydro­boration afforded α-C-(1→3)-linked disaccharides containing 2-deoxyhexopyranoses of d- or l-configuration.

Key words

C-disaccharides - C-glycosides - hetero-Diels-Alder reaction - oxabutadienes - Wittig reaction

References

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13

Selected data of compound 4: pale yellow oil; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.02 (d, 1 H, J = 2.9 Hz, CH-thiazole); 7.70 (d, 1 H, J = 2.9 Hz, CH-thiazole); 7.41 (d, 1 H, J = 15.7 Hz, H-1a); 7.25 (ddd, 1 H, J = 15.7 Hz, J = 7.1 Hz, J = 3.0 Hz, H-2a); 5.34 (dd, 1 H, J = 9.2 Hz, J = 8.9 Hz, H-3); 5.13 (dd, 1 H, J = 8.9 Hz, J = 5.5 Hz, H-2); 4.96 (dd, 1 H, J = 8.87 Hz, J = 8.80 Hz, H-4); 4.42 (ddd, 1 H, J = 4.9 Hz, J = 4.8 Hz, J = 5.5 Hz, H-1); 4.25 (dd, 1 H, J = 12.2 Hz, J = 6.0, H-6′); 4.04 (dd, 1 H, J = 12.2 Hz, J = 2.1 Hz, H-6); 3.92 (m, H-5); 2.85 (m, 1 H, H-7), 2.63 (m, 1 H, H-7′); 2.06, 2.05, 2.04, 2.00 (s, 4 × 3H, Ac). ¹³C NMR (125 MHz, CDCl₃) δ (ppm) : 180.85 (CO-C=C); 170.55, 196.88, 169.5, 169.41, 169.37 (4 × O=C-CH₃); 167.65 (thiazole C-2); 144.68 and 126.46 (2 × CH-thiazole); 144.62 and 126.46 (2 × -CH=); 71.16 (C-1); 69.87 (C-3); 69.73 (C-2); 69.17 (C-5); 68.40 (C-4); 61.90 (C-6); 29.74(C-7); 20.49, 20.47, 20.44, 20.38 (4 × O=C-CH₃). ESI MS: 676.4 (M + H).

14

The NOE experiments with the obtained mixture of cycloadducts proved the cis relative configurations on dihydropyran ring in both componds 6 and 7. The NMR spectra did not reveal any endo-cycloadducts in the reaction mixture.

15

Ethyl vinyl ether (1.5mL, 15 mmol) and Eu(fod)₃ (460 mg, 0.4 mmol) were added to a solution of 5 (4 g, 6.2 mmol) in dichloromethane (10.7 mL) and the reaction mixture was sonicated for 6 h at room temperature. The solvent and the excess ethyl vinyl ether were evaporated. Chromatography of the residue (light petroleum-EtOAc, 8:1) afforded 2.05 g (48%) of compound 8 (R_f = 0.29) and 1.94 g (46%) of compound 9 (R_f = 0.42).
Selected data of compound 8: ¹H NMR (500 MHz, CDCl₃): δ (ppm) 7.83 (d, 1 H, J = 3.3 Hz, CH-thiazole); 7.17-7.32 (m, 21 H, 4 × C₆H₅, CH-thiazole); 6.08 (d, 1 H, J = 3.4 Hz, H-4a); 5.20 (dd, 1 H, J = 2.1 Hz, J = 6.8 Hz, H-1a); 4.96-4.48 (m, 8 H, 4 × C₆H₅-CH ₂); 4.30 (m, 1 H, H-1); 4.02 (dq, 1 H, J = 9.6 Hz, J = 7.0, -O-CH ₂-CH₃); 3.82-3.62 (m, 8 H, H-2, H-3, H-4, H-5, H-6, H-6′, -O-CH ₂ -CH₃); 2.62 (m, 1 H, H-3a); 2.17 (ddd, 1 H,, J = 2.1 Hz, J = 4.6 Hz, J = 11.5, H-2a_eq); 1.98 (m, 2 H, H-7, H-7′); 1.88 (ddd, 1 H, J = 6.8 Hz, J = 11.5 Hz, J = 11.5, H-2a_ax); 1.30 (t, 3 H, J = 7.0, -O-CH₂-CH ₃). ¹³C NMR (125 MHz, CDCl₃) δ (ppm): 164.62 (thiazole C-2); 143.73 (C-5a); 143.28 (CH-thiazole); 138.36, 138.27, 138.22, 138.12 (4 × ipso C ₆H₅-CH₂), 128.36-127.57 (20 × C ₆H₅-CH₂); 118.48 (CH-thiazole); 104.24 (C-4a); 99.61 (C-1a); 82.36, 80.13, 78.07, 72.31, 71.48 (C-1, C-2, C-3, C-4, C-5); 75.42, 74.96, 73.53, 73.14 (4 × C₆H₅-CH₂); 69.1 (C-6); 64.65 (O-CH₂-CH₃); 33.76 (C-2a); 30.22 (C-7); 27.67 (C-3a); 15.27 (O-CH₂-CH₃). ESI MS: 748.2 (M + H).
Selected data of compound 9: ¹H NMR (500 MHz, CDCl₃): δ (ppm) 7.82 (d, 1 H, J = 3.3 Hz, CH-thiazole); 7.15-7.38 (m, 21 H, 4 × C₆H₅, CH-thiazole); 5.97 (d, 1 H, J = 3.2 Hz, H-4a); 5.20 (dd, 1 H, J = 1.7 Hz, J = 6.7 Hz, H-1a); 4.97-4.50 (m, 8 H, 4 × C₆H₅-CH ₂); 4.25 (m, 1 H, H-1); 4.05 (dq, 1 H, J = 9.6 Hz, J = 7.0 Hz, O-CH ₂-CH₃); 4.08-3.59 (m, 8 H, H-2, H-3, H-4, H-5, H-6, H-6′, O-CH ₂-CH₃); 2.67 (m, 1 H, H-3a), 2.22 (ddd, 1 H, J = 1.7 Hz, J = 2.6 Hz, J = 13.3 Hz, H-2a_eq); 2.09 (m, 1 H, H-7); 1.87 (m, 1 H, H-7′); 1.75 (ddd, 1 H, J = 6.7 Hz, J = 13.3 Hz, J = 13.3 Hz, H-2a_ax); 1.30 (t, 3 H, J = 7.0 Hz, O-CH₂-CH ₃). ¹³C NMR (125 MHz, CDCl₃) δ (ppm): 164.40 (thiazole C-2); 143.86 (C-5a); 143.29 (CH-thiazole); 138.68, 138.22, 138.04 (4 × ipso C₆H₅-CH₂); 128.49-127.57 (20 × C ₆H₅-CH₂); 118.40 (CH-thiazole); 105.65 (C-4a); 99.85 (C-1a); 82.53, 79.95, 77.99, 71.45, 71.32 (C-1, C-2, C-3, C-4, C-5); 77.56, 76.36, 73.47, 72.83 (4 × C₆H₅-CH₂); 68.89 (C-6); 64.74 (O-CH₂-CH₃); 32.36 (C-2a); 30.16 (C-7); 27.15 (C-3a); 15.28 (O-CH₂-CH₃). ESI MS: 748.2 (M + H).

17

A solution of aldehyde 10 (230 mg, 0.33 mmol) in tetrahydrofuran (3.4 mL) was cooled to 0 °C and then treated with 1 M solution of (CH₃)₂S˙BH₃ in tetrahydrofuran (0.69 mL, 0.69 mmol). The reaction mixture was stirred for 20 min at 0 °C and for 18 h at room temperature. Then, 0.37 mL of 30% NaOH and 0.37 mL of 30% H₂O₂ were added at 0 °C, and the solution was stirred at room temperature for 40 min. After dilution with brine (10 mL), the solution was extracted with ethyl acetate (3 × 10 mL), and the combined organic layers were dried (Mg₂SO₄). Evaporation of the solvent under reduced pressure and chromatography of the residue (light petroleum-ethyl acetate 1:1) afforded 143 mg (60%) of 12 (R_f = 0.5) as a colorless oil.

18

Selected data of compound 14: ¹H NMR (CDCl₃) : δ (ppm) 5.25 (dd, 1 H, J = 9.4 Hz, J = 9.4 Hz, H-3); 4.98 (dd, 1 H,
J = 9.4 Hz, J = 5.7 Hz, H-2); 4.93 (dd, 1 H, J = 9.4 Hz, J = 9.2 Hz, H-4); 4.75 (dd, 1 H, J = 9.0 Hz, J = 10.0 Hz, H-4a); 4.52 (dd, 1 H, J = 1.0 Hz, J = 9.4 Hz, H-1a); 4.31-4.20 (m, 4 H, H-1, H-6a, H-6, H-6′); 4.12 (dd, 1 H J = 2.2 Hz, J = 12.1 Hz, H-6a′); 3.95 (m, 1 H, O-CH₂-CH ₃); 3.85 (m, 1 H, H-5); 3.59-3.51 (m, 2 H, H-5a, -O-CH₂-CH ₃); 2.20 (m, 1 H, H-2a_eq.); 2.14-2.04 (m, 19 H, 6 × Ac, H-7); 1.65 (m, 2 H, H-3a, H-7′); 1.54 (m, 1 H, H-2a_ax.); 1.23 (t, 1 H, J = 7.0 Hz, O-CH₂-CH ₃). ¹³C NMR (125 MHz CDCl₃) δ (ppm): 100.74 (C-1a); 74.50 (C-5a); 72.58 (C-1); 71.70 (C-4a); 70.05 (C-2); 69.56 (C-3); 68.77 (C-5); 68.66 (C-4); 64.67 (O-CH₂-CH₃); 62.63 (C-6); 62.38 (C-6a); 37.16 (C-2a); 36.00 (C-7); 27.50 (C-3a); 20.50 (Ac); 15.00 (O-CH₂-CH₃). ESI MS: 627.3 (M + Na).
Selected data of compound 17: ¹H NMR (CDCl₃) : δ (ppm) 5.25 (dd, 1 H, J = 8.9 Hz, J = 8.9 Hz, H-3); 5.09 (dd, 1 H,
J = 9.2 Hz, J = 5.7 Hz, H-2); 4.94 (dd, 1 H, J = 8.9 Hz, J = 8.9 Hz, H-4); 4.74 (dd, 1 H, J = 9.9 Hz, J = 9.9 Hz H-4a); 4.53 (d, 1 H, J = 8.1 Hz, H-1a); 4.33-4.18 (m, 4 H, H-1, H-6a, H-6, H-6′); 4.08 (dd, 1 H, J = 2.3 Hz, J = 12.1 Hz, H-6a′); 3.96 (dq, 1 H, J = 9.2 Hz, J = 7.1 Hz, O-CH ₂-CH₃); 3.82 (m, 1 H, H-5); 3.59-3.51 (m, 2 H, H-5a, O-CH ₂-CH₃); 2.17-2.02 (m, 19 H, 6 × Ac, H-2a_eq.); 1.99-1.87 (m, 2 H, H-7, H-3a); 1.41 (ddd, 1 H,, J = 8.1 Hz, J = 9.7 Hz, J = 12.7 Hz, H-2a_ax.); 1.3-1.18 (m, 1 H, H-7′); 1.24 (t, 3 H, J = 7.1 Hz, -O-CH₂-CH ₃). ¹³C NMR (125 MHz CDCl₃) δ (ppm) : 101.22 (C-1a); 74.51 (C-5a); 70.44 (C-4a); 69.99 (C-3); 69.90 (C-2); 69.11 (C-4); 68.60 (C-5); 68.45 (C-1); 64.66 (O-CH₂-CH₃); 62.80 (C-6a); 62.1(C-6); 35.04 (C-2a); 34.41 (C-3a); 26.57 (C-7); 20.62 (Ac), 14.94 (O-CH₂-CH₃). ESI MS: 627.3 (M + Na).

19

Crystallographic data for the structure 17 have been deposited with the Cambridge Crystallographic Data Centre; reference number CCDC 203383. Copies of the data can be obtained on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (E-mail: [e-mail].u).