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Synlett 2007(7): 1121-1123  
DOI: 10.1055/s-2007-973905
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of Cyclic Glycolipid Analogues

Gérald Coste, Sandrine Gerber-Lemaire*
Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), Batochime, 1015 Lausanne, Switzerland
Fax: +41(21)6939355; e-Mail: Sandrine.Gerber@epfl.ch;
Further Information

Publication History

Received 11 January 2007
Publication Date:
13 April 2007 (online)

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Abstract

A straightforward approach to macrocyclic structures containing deoxysugar subunits was developed through the functionalization of a bishemiketal. The choice of the length and the ­nature of the linkers can provide macrocycles with diverse rigidities and polarities.

Key words

cyclic glycolipid analogues - biscoupling reaction - coupling reagent - C-glycosylation - ring-closing metathesis

14

Preparation and Data for 4: A solution of 2 (176 mg, 0.305 mmol) in pyridine-Ac2O (1:1, 6 mL) was treated with DMAP (15 mg, 0.122 mmol, 0.4 equiv) at 25 °C for 3 h. After completion of the reaction, solvents were evaporated in vacuo. Purification of the residue by flash chromatog-raphy (60% EtOAc in pentane) afforded the resulting peracetylated bishemiketal as a yellow oil (205 mg, quant.). To a solution of this intermediate in MeCN (68 mL) was added 4 Å MS (1.4 g) and the mixture was stirred for 30 min. Allyltrimethylsilane (525 µL, 3.303 mmol, 12 equiv) was introduced and the solution was stirred for an additional 30 min. At 0 °C, BF3·OEt2 (210 µL, 1.651 mmol, 6 equiv) was added. After stirring for 1 h at 0 °C the reaction mixture was poured into a sat. aq NaHCO3 solution (40 mL) and filtered through a pad of celite®. The filtrate was extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (70 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (30% EtOAc in pentane) afforded 4 as a colorless oil (153 mg, 71% over two steps). IR (film): 3410, 2100, 1450, 1370, 1240, 1190, 1140, 1060, 960, 830, 780 cm-1. 1H NMR (400 MHz, MeOD): δ = 7.25-7.35 (m, 10 H), 5.74-5.80 (m, 2 H), 4.98-5.10 (m, 6 H), 4.78 (s, 4 H), 4.60 (s, 4 H), 3.95-4.02 (m, 4 H), 3.73-3.80 (m, 2 H), 2.32-2.48, 2.13-2.24 (2 × m, 2 × 2 H), 1.96-2.07, 1.53-1.72 (2 × m, 4 H), 1.83-1.96, 1.27-1.36 (2 × m, 4 H), 1.73-1.83, 1.53-1.72 (2 × m, 6 H), 1.98 (s, 6 H). 13C NMR (100 MHz, MeOD): δ = 171.5, 171.4, 142.2, 135.5, 135.4, 128.4, 128.0, 127.7, 116.4, 116.3, 92.9, 70.8, 70.7, 69.9, 69.8, 69.6, 69.5, 69.0, 66.8, 66.0, 39.9, 39.5, 38.6, 37.4, 37.3, 37.2, 37.1, 34.9, 20.4, 20.3. ESI-MS: m/z = 709.3 [M + H]. MALDI-HRMS: m/z [M + Na] calcd for C41H56O10: 731.3771; found: 731.3769.
Preparation and Data for 5: O3 was passed through a solution of 4 (200 mg, 0.282 mmol) in CH2Cl2 (9 mL) during 5 min at -78 °C. After persistence of a blue coloration, O2 was passed through the solution to eliminate the excess of O3. Dimethyl sulfide (83 µL, 1.128 mmol, 4 equiv) was added and the mixture was stirred for an additional 10 min. The solvent was evaporated in vacuo at 0 °C. The residual oil was dissolved in t-BuOH-H2O (1:1, 4 mL) and treated with KH2PO4 (461 mg, 3.385 mmol, 12 equiv), NaClO2 (383 mg, 231 mmol, 15 equiv) and 2-methylbut-2-ene (200 µL, 231 mmol, 15 equiv) at 25 °C for 12 h. The mixture was poured into brine (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (5-20% of MeOH in CH2Cl2) afforded 5 as a yellow oil (74 mg, 35% over three steps). IR (film): 3440, 2940, 1740, 1715, 1680, 1375, 1245, 1100, 1140, 740, 700 cm-1. 1H NMR (400 MHz, MeOD): δ = 7.24-7.34 (m, 10 H), 5.10-5.16 (m, 2 H), 4.78 (d, 4 H), 4.61 (s, 4 H), 4.49-4.57 (m, 2 H), 3.93-4.04 (m, 2 H), 3.83-3.91, 3.67-3.78 (2 × m, 2 × 1 H), 2.54-2.65, 2.27-2.35 (2 × m, 2 × 2 H), 2.05, 2.03 (2 × s, 6 H), 1.87-1.98, 1.61-1.86 (3 × m, 14 H). 13C NMR (100 MHz, MeOD): δ = 181.7, 181.6, 174.2, 173.3, 139.4, 129.4, 128.9, 128.7, 93.8, 71.3, 70.9, 70.9, 70.6, 70.6, 70.3, 69.8, 68.2, 67.6, 42.2, 41.7, 41.6, 39.8, 39.3, 38.5, 37.8, 36.7, 36.6, 21.6, 21.5. ESI-HRMS: m/z [M + K] calcd for C39H52O14: 783.2994; found: 783.3040.
Preparation and Data for 6: To a solution of 5 (25 mg, 0.033 mmol) in DMF (1.4 mL) were added (i-Pr)2NEt (15 µL, 0.081 mmol, 2.4 equiv), and PyBOP (40 mg, 0.081 mmol, 2.4 equiv). Pentane-1,5-diamine (3 µL, 0.033 mmol, 1 equiv) solution in DMF (1 mL) was added dropwise, at 0 °C, over 6 h. The mixture was stirred at 25 °C for 6 h. After completion of the reaction, the solvent was evaporated in vacuo. The crude oil was taken up in MeOH (1.5 mL) and treated with K2CO3 (20 mg, 0.145 mmol, 4 equiv) at 25 °C for 4 h. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (2-4% MeOH in CH2Cl2) afforded 6 (7 mg, 37% over two steps). IR (film): 3440, 2930, 1740, 1715, 1410, 1355, 1245, 1180, 1100, 1140, 740, 700 cm-1. 1H NMR (400 MHz, MeOD): δ = 7.25-7.50 (m, 10 H), 4.86 (br s, 4 H), 4.60 (br s, 4 H), 4.53-4.59, 4.44-4.49 (2 × m, 2 H), 3.92-4.07 (m, 6 H), 2.97-3.12, 2.78-2.87 (2 × m, 2 × 2 H), 1.94-2.20 (m, 4 H), 1.66-1.78 (m, 4 H), 1.52-1.65 (m, 6 H), 1.20-1.50 (m, 10 H). 13C NMR (100 MHz, MeOD): δ = 176.4, 175.7, 142.0, 131.9, 131.5, 131.2, 96.2, 75.7, 73.3, 73.2, 72.7, 71.7, 68.9, 73.1, 73.7, 73.5, 47.8, 47.1, 46.9, 42.7, 42.5, 42.2, 42.1, 42.0, 39.8, 39.1, 32.5, 32.2, 27.2. ESI-HRMS: m/z [M + Na] calcd for C40H58N2O10: 749.3989; found: 749.3995.
Data for 7: IR (film): 3365, 2960, 1610, 1570, 1410, 1335, 1070, 740, 700 cm-1. 1H NMR (400 MHz, MeOD): δ = 7.28-7.37 (m, 10 H), 4.84 (br s, 4 H), 4.64 (s, 4 H), 4.40-4.59 (m, 2 H), 3.85-4.07 (m, 6 H), 2.97-3.15, 2.75-2.85 (2 × m, 2 × 2 H), 1.97-2.21 (m, 4 H), 1.66-1.82 (m, 4 H), 1.46-1.64 (m, 10 H), 1.23-1.43 (m, 14 H). 13C NMR (100 MHz, MeOD): δ = 176.3, 176.0, 142.0, 131.9, 131.5, 131.2, 96.4, 73.8, 73.2, 72.0, 71.7, 70.1, 69.6, 73.4, 73.1, 48.0, 46.8, 46.7, 42.9, 42.5, 42.4, 41.9, 41.4, 39.6, 39.4, 32.8, 32.7, 32.6, 30.2, 29.9. ESI-HRMS: m/z [M + Na] calcd for C44H66N2O10: 805.4615; found: 805.4620.
Preparation and Data for 9: To a solution of 8 (70 mg, 0.097 mmol) dissolved in CH2Cl2 (1 mL) were added Et3N (122 µL, 0.879 mmol, 9 equiv) and methanesulfonyl chloride (28 µL, 0.293 mmol, 3 equiv) at 0 °C. After stirring for 2 h at 0 °C, the reaction mixture was poured into a sat. aq NaHCO3 solution (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. The residual oil was dissolved in a mixture of DMF-allylamine (3:1, 4 mL) and treated, at 40 °C, with K2CO3 (120 mg, 0.879 mmol, 9 equiv) for 12 h. The solvents were evaporated in vacuo. The residual oil was taken up in MeOH (3 mL) and the solution was stirred for 3 h. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (4% NH4OH in MeCN) afforded 9 (28 mg, 42% over three steps) as a colorless oil. IR (film): 3440, 2950, 1740, 1715, 1455, 1370, 1240, 1165, 1100, 1040, 740, 700 cm-1. 1H NMR (400 MHz, MeOD): δ = 7.26-7.34 (m, 10 H), 5.85-5.99 (m, 2 H), 4.31, 5.28 (2 × d, 4 H), 4.82 (s, 4 H), 4.61 (s, 4 H), 3.87-4.15 (m, 8 H), 3.37, 3.35 (2 × d, 4 H), 2.74-2.92 (m, 4 H), 2.13-2.50 (3 × m, 14 H), 1.22-1.50 (m, 4 H). 13C NMR (100 MHz, MeOD): δ = 139.4, 134.3, 134.2, 129.4, 128.9, 128.7, 119.9, 119.8, 93.9, 93.8, 71.4, 70.9, 70.8, 70.7, 70.0, 69.4, 67.7, 66.6, 70.6, 52.4, 52.3, 47.0, 46.8, 45.7, 44.3, 43.8, 39.3, 38.3, 37.1, 37.0, 31.8, 31.3. ESI-HRMS: m/z [M + H] calcd for C41H62N2O8: 711.4584; found: 711.4588.
Preparation and Data for 10: To a solution of 9 (25 mg, 0.035 mmol) dissolved in CH2Cl2 (15 mL) was added Grubbs’ II catalyst (6 mg, 0.007 mmol, 0.2 equiv) and the mixture was stirred at 50 °C for 9 h. The solvent was evaporated in vacuo. The crude oil was dissolved in MeOH-EtOAc (1:3, 3 mL) and was treated at 25 °C for 4 h with a catalytic amount of Pd(OH)2 on activated charcoal under 1 atm of H2. The reaction mixture was filtered through a pad of celite®. The filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (5% NH4OH in MeCN) afforded 10 as a pale yellow oil (18 mg, 48%). IR (film): 3405, 2955, 1730, 1605, 1510, 1450, 1370, 1250, 1170, 1110, 1030, 850, 775 cm-1. 1H NMR (400 MHz, MeOD): δ = 7.27-7.35 (m, 10 H), 4.82 (s, 4 H), 4.62 (s, 4 H), 3.85-4.15 (m, 8 H), 3.21-3.83 (2 × m, 8 H), 1.91-2.12, 1.50-1.90 (2 × m, 18 H), 1.23-1.52 (m, 4 H). 13C NMR (100 MHz, MeOD): δ = 130.0, 128.4, 127.9, 126.9, 93.0, 92.9, 69.7, 69.6, 70.0, 69.9, 69.6, 69.5, 69.2, 68.5, 66.3, 65.6, 49.8, 49.7, 46.3, 45.8, 45.3, 42.9, 42.2, 38.0, 36.3, 35.9, 26.6, 26.5, 26.3. ESI-HRMS: m/z [M + Na] calcd for C39H60N2O8: 707.4247; found: 707.4234.