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

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

References and Notes

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1

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

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

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.