Spacer-Mediated Synthesis of Bis-spiroketal Disaccharides: Nonsymmetrical Furanose-Pyranose Difructose Dianhydrides

Farida Louis; M. Isabel García-Moreno; Patricia Balbuena; Carmen Ortiz Mellet; José M. García Fernández

doi:10.1055/s-2007-991055

LETTER

Spacer-Mediated Synthesis of Bis-spiroketal Disaccharides: Nonsymmetrical Furanose-Pyranose Difructose Dianhydrides

Farida Louis^a,, M. Isabel García-Moreno^a, Patricia Balbuena^a, Carmen Ortiz Mellet*^a, José M. García Fernández*^b
^a Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Profesor García González 1, 41012 Sevilla, Spain
Fax: +34(954)624960; e-Mail: mellet@us.es;
^b Instituto de Investigaciones Químicas, CSIC, Universidad de Sevilla, Américo Vespucio 49, Isla de la Cartuja, 41092 Sevilla, Spain
Fax: +34(954)460565; e-Mail: jogarcia@iiq.csic.es;

Abstract

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Abstract

The stereochemical outcome of the dimerization reaction of d-fructose, leading to tricyclic bis-spiroketal systems, can be tuned by inserting a xylylene template between the reacting moieties. Spirocyclization becomes then an intramolecular process, the available conformational space depending on the nature of the tether. The methodology is here illustrated by the stereoselective synthesis of two nonsymmetrical di-d-fructose dianhydrides present in commercial caramel.

Key words

acetals - difructose dianhydrides - spiroacetals - oligosaccharides - spiro compounds

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References

References and Notes

1

Permanent address: Department of Chemistry, Faculty of Sciences, University of Alexandria, P.O. Box 426 Ibrahimia, 21321 Alexandria, Egypt.

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13

4,5-Di- O -benzyl-3- O -(3-bromomethylbenzyl)-1,2- O -isopropylidene-β-d-fructopyranose (13)
To a solution of 1,3-bis(bromomethyl)benzene (1.99 g, 7.56 mmol, 2 equiv) in anhyd DMF (50 mL), NaH (60% in mineral oil, 378 mg, 9.45 mmol) was added and the suspension was stirred at r.t. for 15 min. Compound 10 ¹² (1.0 g, 3.78 mmol) was then added and the reaction mixture was further stirred for 24 h. Afterwards, Et₂O (15 mL) and H₂O (15 mL) were added, the organic layer was separated, washed with H₂O (5 × 10 mL), dried (MgSO₄), filtered, and concentrated. The resulting residue was purified by column chromatography (EtOAc-PE, 1:10) to yield 11 (955 mg, 57%). Compound 11 (400 mg, 0.9 mmol) was dissolved in 60% aq AcOH (2.4 mL) and stirred at 45 °C for 2 h. The reaction mixture was then diluted with H₂O (5 mL) and extracted with EtOAc (4 × 4 mL). The combined organic phase was washed with sat. aq NaHCO₃ (6 mL), dried (MgSO₄), filtered, and concentrated. The resulting residue was purified by column chromatography (EtOAc-PE, 2:1) to give 12 (254 mg, 70%). Conventional benzylation of 12 (323 mg, 0.80 mmol) with NaH/BnBr afforded 13 (303 mg, 65%).

14

General Procedure for the Preparation of ( O -6→ O -3′)-Xylylene-Tethered Fructofuranose-Fructopyranose Derivatives (15 and 18)
To a solution of 2,3-di-O-benzyl-1,2-O-isopropylidene-β-d-fructofuranose 14 ^9a (188 mg, 0.47 mmol) in dry DMF (3 mL), NaH (60% in mineral oil, 46 mg, 0.98 mmol) was added and the reaction mixture was stirred at r.t. for 1 h. A solution of 13 or 17 ¹³ (225 mg, 0.39 mmol) in anhyd DMF (4 mL) was then added, the reaction mixture was further stirred at r. t. for 3 h, quenched by addition of H₂O (2 mL), concentrated and the resulting residue was purified by column chromatography using EtOAc-toluene (1:6) as eluent to give 15 (190 mg, 54%) or 18 (220 mg, 62%).

15

General Procedure for Xylylene-Mediated Synthesis of Type II DFA Derivatives (16, 19, and 20)
To a solution of the corresponding m- or o-xylylene-tethered precursor 15 or 18 (280 mg, 0.31 mmol) in CH₂Cl₂ (20 mL) at -78 °C under Ar, TfOH (41 µL) was added. The reaction mixture was allowed to reach r.t. and stirred for 1 h, then quenched by addition of Et₃N (0.1 mL) and concentrated. Column chromatography of the resulting residue (1:3 → 1:1 EtOAc-PE for 15; 1:5 → 1:2 EtOAc-PE for 18) afforded 16 (142 mg, 59%) or 19 (48.7 mg, 20.8%) and 20 (72.8 mg, 31.2%), respectively, as the only intramolecular reaction products.

16

Selected data for 16: [α]_D ²² +10.1 (c 0.9, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 4.16 (d, 1 H, J _1a _′,1b _′ = 11.6 Hz, H-1′a), 4.14 (m, 1 H, H-5), 4.00 (d, 1 H, J _3,4 = 2.5 Hz, H-3), 3.99 (m, 1 H, H-6a), 3.96 (d, 1 H, J _1a,1b = 11.8 Hz, H-1a), 3.94 (dd, 1 H, J ₃ _′,4 _′ = 9.5 Hz, J ₄ _′,5 _′ = 3.2 Hz, H-4′), 3.83 (d, 2 H, J _6a _′,6b _′ = 12.0 Hz, H-6′a, H-1b), 3.74 (m, 1 H, H-6b), 3.72 (m, 1 H, H-5′), 3.61 (d, 1 H, H-3′), 3.60 (d, 1 H, H-6′b), 3.54 (dd, 1 H, J _4,5 = 7.5 Hz, H-4), 3.39 (d, 1 H, H-1′b). ¹³C NMR (125.7 MHz, CDCl₃): δ = 102.3 (C-2), 95.9 (C-2′), 89.0 (C-3), 85.1 (C-4), 80.1 (C-5), 78.9 (C-3′), 78.6 (C-4′), 73.5 (C-5′), 75.8 (CH₂Ph), 74.8 (C-6), 74.3, 72.5, 72.3, 71.2 (CH₂Ph), 62.5 (C-1′), 62.0 (C-1), 60.3 (C-6′). MS-FAB: m/z (%) = 809 (60) [M + Na]⁺. Anal. Calcd for C₄₈H₅₀O₁₀: C, 73.26; H, 6.40. Found: C, 73.07; H, 6.07.

17

General Procedure for the Synthesis of Fully Unprotected DFAs (4 and 5) Catalytic hydrogenation of 16 and 19 or 20 (0.038 mmol) with 10% Pd/C in EtOAc-MeOH (1:1) containing 10% HCOOH (1 mL) at 1 atm overnight, afforded the fully unprotected bis-spiro fructodisaccharide 4 or 5 in quantitative yield having physicochemical properties identical to those reported.^2,4d

18 Rubio EM. García-Moreno MI. Balbuena P. Ortiz Mellet C. García Fernández JM. Org. Lett. 2005, 7: 729

19

Selected data for 19: [α]_D ²² +4.9 (c 0.8, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 4.06 (d, 1 H, J _6a,6b = 12.6 Hz, H-6a), 4.01 (br d, 1 H, J _4,5 = 8.7 Hz, H-5), 3.98 (dd, 1 H, J ₃ _′,4 _′ = 9.7 Hz, J ₄ _′,5 _′ = 3.1 Hz, H-4′), 3.88 (d, 1 H, J _3,4 = 3.7 Hz, H-3), 3.86 (d, 1 H, J _1a,1b = 13.7 Hz, H-1a), 3.84 (m, 1 H, H-6b), 3.72 (dd, H, J _6a _′,6b _′ = 11.5 Hz, J ₅ _′,6a _′ = 3.0 Hz, H-6′a), 3.71 (m, 1 H, H-5′), 3.70 (d, 1 H, H-1b), 3.65 (d, 1 H, H-6′b), 3.61 (dd, 1 H, H-4), 3.55 (d, 1 H, H-3′), 3.39 (d, 1 H, J _1a _′,1b _′ = 12.0 Hz, H-1′a), 3.05 (d, 1 H, H-1′b). ¹³C NMR (125.7 MHz, CDCl₃): δ = 102.0 (C-2), 95.2 (C-2′), 88.8 (C-3), 86.2 (C-4), 79.6 (C-5), 78.9 (C-4′), 74.5 (C-3′), 73.4 (C-5′), 72.9, 72.5, 72.4, 72.0, 71.4 (CH₂Ph), 71.2 (C-6), 68.5 (CH₂Ph), 62.6 (C-1′), 62.4 (C-1), 60.6 (C-6′). ESI-MS: m/z = 809 [M + Na]⁺. Anal. Calcd for C₄₈H₅₀O₁₀: C, 73.26; H, 6.40. Found: C, 73.13; H, 6.48.

20

Selected data for 20: [α]_D ²² +18.1 (c 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 4.59 (d, 1 H, J _1a,1b = 12.5 Hz, H-1a), 4.24 (dt, 1 H, J _5,6b = 10.5 Hz, J _5,6a = J _4,5 = 4.5 Hz, H-5), 4.19 (d, 1 H, J _1a _′,1b _′ = 11.4 Hz, H-1′a), 4.15 (d, 1 H, J ₃ _′,4 _′ = 7.9 Hz, H-3′), 4.13 (dd, 1 H, J _3,4 = 6.3 Hz, H-4), 4.05 (dd, 1 H, J _6a _′,6b _′ = 12.2 Hz, J ₅ _′,6a _′ = 5.8 Hz, H-6′a), 3.87 (d, 1 H, H-3), 3.74 (dt, 1 H, J ₄ _′,5 _′ = J ₅ _′,6b _′ = 3.0 Hz, H-5′), 3.70 (d, 1 H, H-1b), 3.65 (dd, 1 H, J _6a,6b = 10.5 Hz, H-6a), 3.60 (t, 1 H, H-6b), 3.52 (d, 1 H, H-1′b), 3.45 (dd, 1 H, H-6′b), 3.41 (dd, 1 H, H-4′). ¹³C NMR (125.7 MHz, CDCl₃): δ = 101.4 (C-2), 97.7 (C-2′), 85.1 (C-4), 84.7 (C-3), 79.0 (C-5), 78.0 (C-3′), 76.3 (C-4′), 72.9, 72.7, 72.0 (CH₂Ph), 71.9 (C-6), 71.6 (C-5′), 71.2, 70.9, 70.2 (CH₂Ph), 63.8 (C-1′), 61.0 (C-6′), 59.8 (C-1). ESI-MS: m/z = 809 [M + Na]⁺. Anal. Calcd for C₄₈H₅₀O₁₀: C, 73.26; H, 6.40. Found: C, 73.13; H, 6.06.