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Synlett 2005(2): 243-246  
DOI: 10.1055/s-2004-837193
LETTER
© Georg Thieme Verlag Stuttgart · New York

Facile Synthesis of α,ω-Bis(5-γ-tocopheryl)alkanes

Thomas Rosenau*a, Thomas Netscherb, Gerald Ebnera, Paul Kosmaa
a University of Natural Resources and Applied Life Sciences Vienna (BOKU), Department of Chemistry, Muthgasse 18, 1190 Vienna, Austria
b DSM Nutritional Products, Research and Development, P.O. Box 3255, 4002 Basel, Switzerland
Fax: +43(1)360066059; e-Mail: thomas.rosenau@boku.ac.at;
Further Information

Publication History

Received 18 October 2004
Publication Date:
17 December 2004 (online)

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Abstract

α,ω-Bis(5-γ-tocopheryl)alkanes were prepared in a high yield, one-pot procedure starting from γ-tocopherol. The reaction involves acylation by carboxylic acid anhydrides to intermediate bis(phenones), which are subsequently reduced directly to the target alkylphenols by borohydride via ortho-quinone methide intermediates. Ethyl chloroformate acts as an auxiliary in both steps.

Key words

tocopherol - vitamin E - acylation - reduction - ortho-quinone methide - antioxidants

    References

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11

The reaction time can be shortened to 24 h at r.t., followed by 1 h at 60 °C, albeit at the expense of partial epimerization (16%, tested by capillary electrophoresis) at C-2, which makes the product mixture more complex.
The NMR assignment for 7 in ref. [7] was incomplete. (all-R)-7: 1H NMR (300.13 MHz, CDCl3): δ = 4.12 (s, 2 H, H-5a), 2.74 (t, 4 H, 3 J = 6.8 Hz, H-4), 2.13 (s, 6 H, H-7a), 2.05 (s, 6 H, H-8b), 1.80 (m, 6 H, H-3). 13C NMR (75.47 MHz, CDCl3): δ = 145.5 (C-8b), 144.9 (C-6), 122.6 (C-8), 121.8 (C.7), 119.3 (C-5), 115.7 (C-4a), 75.7 (C-2), 33.1 (C-3), 23.4 (C-5a), 26.7 (C-2a), 20.5 (C-4), 13.1 (C-8b), 12.3 (C-7a). Anal. Calcd for C57H96O4 (845.40): C, 80.98; H, 11.45. Found: C, 81.13; H, 11.56.

13

Unpublished results (T.N.).

14

A solution of acylating agent (0.5 mmol), ClCO2Et (1 mmol, 0.11 g, M = 108.53), and BF3·OEt2 (7.1 mg, M = 141.93) in dioxane (10 mL) was added during 15 min to a solution of (all-R)-γ-tocopherol (1 mmol, 0.417 g) in the same solvent (50 mL). The mixture was stirred for about 1 h at r.t., and heated to reflux. ClCO2Et (0.2 mmol, 22 mg, M = 108.53) in 10 mL of dioxane was added dropwise during about 10 min, refluxing was continued for 1 h, and the mixture was cooled to 0 °C in an ice bath. ClCO2Et (2 mmol, 0.22 g, M = 108.53), H2O (30 mL) and fresh NaBH4 (4 mmol, 0.15 g) were added, and the mixture was stirred for 30 min in an inert atmosphere. 2 M HCl (aq) was slowly added until effervescence ceased. After addition of H2O (approx. 50 mL), the mixture was extracted three times with n-hexane (20 mL). The combined organic phases were washed with concd aq NaHCO3 solution and H2O. Drying, evaporation of the solvent under reduced pressure and column chromatography on silica gel in toluene-EtOAc (v/v = 1:1) afforded the pure products (for yields see Scheme [2] ).
The stereochemistry of the products was not further studied; even though (2R,4′R,8′R)-2 was used as starting material, a (partial) erosion of the stereochemistry cannot be excluded at this point. In the 13C NMR spectra only the data of the alkane bridges as well as C-4a, C-5 and C-6 are given, since the influence of the bridge length on the other tocopheryl resonances is very small (δ < 0.2 ppm). 1H resonances of the alkane bridges below δ = 1.8 ppm are superimposed by the strong signals of the isoprenoid side chain; their chemical shift was thus assigned by means of correlated spectra.
Propane derivative 8, light yellow, scaly wax, mp 42-45 °C. 1H NMR: δ = 2.76 (s, 4 H, HA), 2.74 (‘t’, 4 H, 3 J = 7.0 Hz, H-4), 2.12 (s, 6 H, H-7a), 2.04 (s, 6 H, H-8b), 1.80 (m, 4 H, H-3), 1.60 (pent, 2 H, HB). 13C NMR: δ = 145.3 (C-6), 123.8 (C-5), 115.8 (C-4a), 30.8 (CA), 22.3 (CB). Anal. Calcd for C59H100O4 (873.45): C, 81.13; H, 11.54. Found: C, 81.22; H, 11.72.
Butane derivative 9, colorless, waxy flakes, mp 38-40 °C. 1H NMR: δ = 2.72 (‘t’, 4 H, 3 J = 7.0 Hz, H-4), 2.70 (t, 4 H, HA), 2.13 (s, 6 H, H-7a), 2.05 (s, 6 H, H-8b), 1.81 (m, 4 H, H-3), 1.47 (m, 4 H, HB). 13C NMR: δ = 145.4 (C-6), 123.2 (C-5), 115.4 (C-4a), 32.0 (CB), 29.9 (CA). Anal. Calcd for C60H102O4 (887.48): C, 81.20; H, 11.58. Found: C, 81.29; H, 11.68.
Pentane derivative 10, light yellow oil/wax, mp approx. 20 °C. 1H NMR: δ = 2.73 (‘t’, 4 H, 3 J = 7.1 Hz, H-4), 2.66 (t, 4 H, HA), 2.13 (s, 6 H, H-7a), 2.06 (s, 6 H, H-8b), 1.83 (m, 4 H, H-3), 1.42 (m, 4 H, HB), 1.35 (m, 2 H, HC). 13C NMR: δ = 145.6 (C-6), 122.6 (C-5), 115.6 (C-4a), 31.3 (CB), 30.8 (CC), 30.0 (CA). Anal. Calcd for C61H104O4 (901.51): C, 81.27; H, 11.63. Found: C, 81.44; H, 11.81.
Hexane derivative 11, yellow, viscous oil. 1H NMR: δ = 2.72 (‘t’, 4 H, 3 J = 6.9 Hz, H-4), 2.66 (t, 4 H, HA), 2.12 (s, 6 H, H-7a), 2.05 (s, 6 H, H-8b), 1.80 (m, 4 H, H-3), 1.46 (m, 4 H, HB), 1.30 (t, 4 H, HC). 13C NMR: δ = 145.4 (C-6), 122.8 (C-5), 115.7 (C-4a), 30.8 (CB), 29.5 (CA), 29.0 (CC). Anal. Calcd for C62H106O4 (915.53): C, 81.34; H, 11.67. Found: C, 81.46; H, 11.90.