2.1.1. General Information
All moisture and air-sensitive reactions were carried out under argon using oven-dried glassware. Starting materials and reagents were obtained from commercial sources and used without further purification. Solvents were dried by distillation over appropriate drying agents under argon atmosphere. Thin-layer chromatography (TLC) was performed on silica gel aluminum sheets (0.25 mm, silica gel 60 F254, Merck, Darmstadt, Germany), by spraying with ammonium molybdate/cerium(IV) sulfate solution, followed by heating. Flash chromatography (FC) was performed using 230–400 mesh silica gel (J. T. Baker, Center Valley, PA, USA). Melting points were determined by the capillary method using the MP70 Melting Point System (Mettler Toledo). 1H NMR (400 MHz) and 13C NMR (100 MHz) were recorded on a Bruker Avance II 400 MHz NMR spectrometer (Bruker GmbH, Mannheim, Germany). The chemical shifts (δ) are given in parts per million (ppm) relative to tetramethylsilane (TMS) using residual solvent protons as an internal standard. IR spectra were recorded using the Nicolet 6700 (KBr) or Nicolet Magna-IR 550 series II (ATR) FT-IR spectrometers (Thermo Fisher Scientific, Waltham, MA, USA). EI spectra were measured with the AMD-604 mass spectrometer (AMD Intectra GmbH, Harpstedt, Germany). ESI-HRMS spectra were obtained on the Agilent 6530 Accurate-Mass Q-TOF LC/MS system.
All-
rac-α-tocopherol (α-T) was obtained from all-
rac-α-tocopheryl acetate via acid hydrolysis (methanol, conc. H
2SO
4), and was purified by FC (hexane/EtOAc, 12:1,
v/
v). All-
rac-α-tocopheryl acetate (≥95%), farnesol (≥95%), and
R,
S-Trolox (
1a, 97%) were purchased from Sigma-Aldrich Co. (Steinheim, Germany). The syntheses of compounds
1b [
22],
1c [
23],
4,
5, and
10 [
21] were carried out according to the literature. Synthesis of phosphonium salt
9 is described in the
Supplementary File S1.
2.1.2. Synthesis of all-rac-1-carba-α-tocopherol (6)
(6-Methoxy-2,5,7,8-tetramethyl-1,2,3,4-tetrahydronaphthalen-2-yl)methanol (11)
LiAlH4 (0.124 g, 3.27 mmol) was added to a stirred solution of compound 10 (0.9 g, 3.26 mmol) in dry THF (30 mL) under argon atmosphere at 0 °C. After stirring for 18 h at room temperature (TLC control), the reaction mixture was poured into saturated NH4Cl solution (30 mL) and extracted with Et2O (3 × 30 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The crude product was purified using FC (hexane/ethyl acetate, 7:2, v/v) to give compound 11 as a white powder (0.712 g, 88%). Mp 103.8–105.1 °C; Rf = 0.20 (hexane/ethyl acetate, 7:1, v/v); 1H NMR (400 MHz, CDCl3): δ 3.69 (s, 3H), 3.52–3.44 (m, 2H), 2.68–2.64 (m, 2H), 2.53 (d, J = 16.6 Hz, 1H), 2.39 (d, J = 16.6 Hz, 1H), 2.26, 2.20, 2.16 (3s, 9H), 1.79 (bs, 1H), 1.74–1.67 (m, 1H), 1.63–1.57 (m, 1H), 1.01 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 154.29, 133.71, 132.84, 129.30, 126.51, 125.78, 71.37, 60.22, 36.47, 33.89, 30.17, 24.17, 22.31, 15.18, 12.72, 11.78 ppm; IR (KBr): 3315, 2915, 1456, 1247, 1108, 1042, 1012 cm−1; HRMS (ESI) m/z: [M+Na]+ calcd for C16H24O2Na 271.1674; found 271.1679.
6-Methoxy-2,5,7,8-tetramethyl-1,2,3,4-tetrahydronaphthalene-2-carbaldehyde (12)
Dess-Martin periodinane (DMP, 1.336 g, 3.15 mmol) was added to a stirred solution of compound 11 (0.6 g, 2.42 mmol) in dry CH2Cl2 (15 mL) under argon at room temperature. After completion of the reaction (TLC control, 2 h), the mixture was quenched with water (20 mL) and extracted with CH2Cl2 (3 × 15 mL). The organic layers were combined, washed with saturated solution of NaHCO3 and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by FC (hexane/ethyl acetate, 9:1, v/v) to give compound 12 (0.494 g, 83%) as a white solid. Mp 65.1–67.6 °C; Rf = 0.54 (hexane/ethyl acetate, 7:1, v/v); 1H NMR (400 MHz, CDCl3): δ 9.59 (s, 1H), 3.68 (s, 3H), 2.99 (d, J = 16.7 Hz, 1H), 2.69 (t, J = 6.7 Hz, 2H), 2.46 (d, J = 16.7 Hz, 1H), 2.26, 2.20, 2.17 (3s, 9H), 2.08–2.00 (m, 1H), 1.76–1.69 (m, 1H), 1.17 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 205.74, 154.68, 133.60, 132.16, 127.78, 126.89, 125.88, 60.17, 44.87, 33.80, 28.64 23.90, 20.60, 15.20, 12.71, 11.74 ppm; IR (KBr): 2925, 2720, 1723, 1463, 1245, 1099, 1008 cm−1; HRMS (ESI) m/z: [M+Na]+ calcd for C16H22O2Na 269.1517; found 269.1526.
6-Methoxy-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridec-1-enyl)-1,2,3,4-tetrahydronaphthalene (13)
LHMDS (solution in THF, 1.0 M, 1.5 mL, 1.5 mmol) was added dropwise to a suspension of compound 9 (0.714 g, 1.3 mmol) in dry THF (8 mL) under argon at −20 °C. After stirring for 30 min, a solution of compound 12 (0.25 g, 1.0 mmol) in dry THF (4 mL) was added and stirred for 30 min at −20 °C and at room temperature overnight. The reaction mixture was poured into saturated ammonium chloride solution and extracted with Et2O (3 × 15 mL). The crude product was purified by FC (hexane/ethyl acetate, 9:1, v/v) to give compound 13 as a colorless oil (0.399 g, 89%). Rf = 0.72 (hexane/CH2Cl2, 2:1, v/v); 1H NMR (400 MHz, CDCl3): δ 5.32–5.25 (m, 2H), 3.68 (s, 3H), 2.78 (d, J = 16.4 Hz, 1H), 2.64–2.62 (m, 2H), 2.78 (d, J = 16.4 Hz, 1H), 2.24, 2.17, 2.16 (3s, 9H), 2.03–1.98 (m, 2H), 1.65–1.09 (m, 17H), 1.24 (s, 3H), 0.91–0.87 (m, 12H) ppm; MS (EI) m/z: 440.2 (M+, 100%).
6-Hydroxy-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-1,2,3,4-tetrahydronaphthalene (6)
Hydrogenation. A mixture of compound 13 (0.269 g, 0.61 mmol) and 5% Pd/C (0.06 g) in ethyl acetate (15 mL) was stirred and hydrogenated under atmospheric pressure at room temperature. After total conversion (24 h), the reaction mixture was filtered through a pad of Celite and silica gel with hexane/CH2Cl2 (8:2, v/v) and the filtrate was evaporated under reduced pressure to give compound 14 as a colorless oil (0.243 g, 90%). Rf = 0.70 (hexane/CH2Cl2, 2:1, v/v); 1H NMR (400 MHz, CDCl3): δ 3.69 (s, 3H), 2.62 (t, J = 6.6 Hz, 2H), 2.46 (d, J = 16.5 Hz), 2.38 (d, J = 16.5 Hz, 1H), 2.26, 2.20, 2.16 (3s, 9H), 1.61–1.03 (m, 23H), 0.96 (s, 3H), 0.91–0.88 (m, 12H) ppm.
Demethylation. Boron trifluoride–dimethylsulfide complex (0.58 mL, 5.5 mmol, 10 eq) and anhydrous AlCl3 (0.366 g, 2.75 mmol) were added to a solution of compound 14 (0.243 g, 0.55 mmol) in dry CH2Cl2 (5 mL) and acetonitrile (3 mL) under argon at 0 °C. After stirring for 18 h at room temperature, the reaction mixture was concentrated under reduced pressure. Saturated NaHCO3 aqueous solution (20 mL) was added to the obtained residue, which was extracted with diethyl ether (3 × 30 mL). Combined organic phases were washed with brine and water and, dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by FC (hexane/ethyl acetate 10:1, v/v) to give compound 6 as a colorless oil (0.202 g, 86%). Rf = 0.46 (hexane/ethyl acetate, 9:1, v/v); 1H NMR (400 MHz, CDCl3): δ 4.56 (brs, 1H, OH), 2.65 (t, J = 6.5 Hz, 2H), 2.45 (d, J = 16.4 Hz, 1H), 2.37 (d, J = 16.4 Hz, 1H), 2.24 (s, 3H), 2.17 (s, 6H), 1.64–1.04 (m, 23H), 0.96 (s, 3H), 0.92–0.89 (m, 12H) ppm; 13C NMR (100 MHz, CDCl3): δ 149.29, 133.14, 132.51, 126.71, 119.40, 118.10, 41.57, 40.65, 40.62, 39.37, 38.08, 38.06, 37.99, 37.97, 37.50, 37.46, 37.41, 37.39, 37.28, 33.42, 33.40, 32.79, 32.77, 31.43, 27.97, 24.91, 24.80, 24.47, 24.46, 22.72, 22.63, 21.03, 19.75, 19.72, 19.69, 15.18, 12.31, 11.24 ppm; IR (ATR): 3479, 2922, 2866, 1458, 1375, 1209, 1099 cm−1; HRMS (ESI) m/z: [M-H]- calcd for C30H51O 427.3940, found 427.3947.