A study of the DIBAL-promoted selective debenzylation of α-cyclodextrin protected with two different benzyl groups

General information: In a manner similar to [15] dry solvents were tapped from a PureSolv solvent purification system. Reactants were purchased from commercial sources and used without further purification. HRMS were recorded on a Bruker Solarix XR mass spectrometer analyzing TOF. Generally, NMR spectra were recorded on a 500 MHz Bruker instrument with a cryoprobe. The 800 MHz spectra were recorded at 25 °C on a Bruker Avance Neo spectrometer with 5 mm CPTXO Cryoprobe C/N-H-D optimized for direct 13C detection. Chemical shifts (δ) are reported in ppm relative to the residue solvent signals or other solvent present. Flash chromatography was carried out on a Büchi Pure Chromatography Instrument C-805 using silica gel columns.

6A–F-Hexa-O-(2,4-dichlorobenzyl)-2A–F,3A–F-dodeca-O-benzyl-α-cyclodextrin (7): NaH (60% dispersion in mineral oil, 162 mg, 4.05 mmol) was added to a solution of hexol 6 (694 mg, 0.338 mmol) in anhydrous DMSO (20 mL) under a nitrogen atmosphere at room temperature. After bubbling had subsided, 2,4-dichlorobenzyl chloride (0.563 mL, 4.05 mmol) was added over four hours with a syringe pump. The mixture was left to stir overnight, and the reaction was quenched by addition of MeOH (10 mL). The mixture was diluted with toluene, and the organic phase washed with H2SO4 (1 M, 20 mL), then brine (3 × 20 mL), dried (MgSO4), filtered, and concentrated. Column chromatography in a solvent gradient of heptane/EtOAc 1:0 to 0:1 gave product 7 (693 mg, 0.230 mmol, 68%). 1H NMR (CDCl3, 500 MHz) δ 7.21–7.07 (m, 78H, Ar), 5.17 (d, J = 10.9 Hz, 1H, ArCH, 6H), 5.08 (d, J1,2 = 3.4 Hz, 1H, 6H, H-1) , 4.86 (d, J = 10.9 Hz, 6H, ArCH), 4.52–4.41 (m, 18H, 3 × ArCH), 4.37 (d, J = 13.4 Hz, 6H, ArCH), 4.16–4.08 (m, 12H, H-3, H-6a), 4.02–3.94 (m, 12H, H-4, H-5), 3.59 (d, J = 10.6 Hz, 6H, H-6b), 3.47 (dd, J2,3 = 9.8 Hz, 6H, H-2) ppm; 13C NMR (126 MHz, CDCl3) δ 139.17, 138.23, 134.35, 133.79, 132.95, 129.46, 128.98, 128.20, 128.06, 127.73, 127.51, 127.29, 127.07 (Ar), 98.75 (C-1), 80.90 (C-3), 79.37 (C-4), 78.97 (C-2), 75.66 (ArCH2), 72.93 (ArCH2), 71.62 (C-5), 69.94 (ArCH2) 69.91 (C-6) ppm; HRMS–MALDI+ (m/z): [M + Na]+ calcd for C162H156Cl12O30Na+, 3030.6782; found, 3030.67364.

General procedure for the reactions of 7 with DIBAL: A sample of compound 7 (65 mg, 22 μmol) was dissolved in 0 to 6 mL anhydrous toluene in a dry round-bottomed flask fitted with a septum and a stirring bar under nitrogen. Then, 1.5 mL DIBAL as a 1.5 M solution in toluene were added with a syringe. The reaction mixture was stirred at fixed temperature (50–70 °C) controlled by an oil bath. At the end of the reaction, the flasks’ contents were diluted with 20 mL toluene and was washed with 20 mL 1 M H2SO4 and water in a separating funnel. The organic layer was dried with sodium sulfate, filtered, concentrated, and analyzed by 1H NMR in CDCl3. The relative content of 7, monool, 8, 9, and 10 in the sample was determined by comparing the integrals of peaks at δ 5.70 (d, 2H, H-1BE, 8), 5.58 (d, 1H, H-1E, 9), 5.50 (d, 1H, monool), 5.42 (d, 2H, Bn, 10) and 5.08 (d, 6H, 7) ppm.

6B,C,E,F-Tetra-O-(2,4-dichlorobenzyl)-2A–F,3A–F-dodeca-O-benzyl-α-cyclodextrin (8) and 6B,C,E,F-tetra-O-(2,4-dichlorobenzyl)-2A–F,3B–F-undeca-O-benzyl-α-cyclodextrin (9): Compound 7 (200 mg, 66.5 μmol) was dissolved in DIBAL-H (1.5 M in toluene, 5 mL, 7.5 mmol) in a flask under nitrogen and stirred at 60 °C for 24 hours. Methanol (1 mL) was slowly added and the solution was poured into 20 mL H2SO4 (1 M) and toluene (20 mL). The layers were partitioned, and the organic layer washed with saturated aqueous NaHCO3 (20 mL), dried with Na2SO4, filtered, and concentrated. Column chromatography in a solvent gradient of heptane/EtOAc 1:0 to 0:1 gave consecutively 8 (56 mg, 21 μmol, 32 %) and 9 (47 mg, 18 μmol, 27%). NMR data and assignments see Table 2 (8) and Table 3 (9). HRMS–MALDI (m/z): for 8 [M + Na]+ calcd for C141H142Cl8O30Na+, 2712.7431; found: 2712.74127. for 9 [M + K]+ calcd for C162H156Cl12O30K+, 2638.6701; found, 2638.71363.

6B,C,E,F-Tetra-O-(2,4-dichlorobenzyl)-2A–F,3B,C,E,F-dodeca-O-benzyl-α-cyclodextrin (10): Compound 7 (59 mg, 20 μmol) was dissolved in anhydrous toluene (14 mL) and DIBAL (1.5 M in toluene, 1 mL, 1.5 mmol) was added. The reaction mixture was stirred at 70 °C under nitrogen atmosphere. After 6 days the reaction mixture was diluted with toluene (25 mL) and quenched by addition of H2SO4 (1 M, 25 mL), then the organic layer was washed with water (25 mL), dried (Na2SO4), and concentrated to a crude product (35 mg) that according to NMR contained 4% 8, 32% 9, and 64% 10. Flash chromatography in a EtOAc/heptane going from 1:3 to 1:1 gave 10 (8 mg, 3 μmol, 16%). NMR data and assignment see Table 4. HRMS–MALDI+ (m/z): [M + H]+ calcd for C134H137Cl8O30+, 2511.6706 (71.9%); found, 2511.69097.

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