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

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

• 1a Packer L. Fuchs J. Vitamin E in Health and Disease   Marcel Dekker Inc.; New York: 1993. 
• 1b Isler O. Brubacher G. Vitamins I   Georg Thieme Verlag; Stuttgart: 1982.  p.126 
• 1c For a general review on chromans and tocopherols see: Parkhurst RM. Skinner WA. Chromans and Tocopherols, In Chemistry of Heterocyclic Compounds   Vol. 36:  Ellis GP. Lockhardt IM. Wiley; New York: 1981. 
• 1d Netscher T. Synthesis and Production of Vitamin E, In Lipid Synthesis and Manufacture   Gunstone FD. Sheffield Academic Press Ltd.; Sheffield, UK: 1990.  p.250-267  
• The preparation is given in:
• 2a Schudel P. Mayer H. Metzger J. Rüegg R. Isler O. Helv. Chim. Acta  1963,  46:  636 
• 2b For NMR data see: Schröder H. Netscher T. Magn. Reson. Chem.  2001,  39:  701 
• 2c Fales HM. Lloyd HA. Ferretti JA. Silverton JV. Davis DG. Kon HJ. J. Chem. Soc., Perkin Trans. 2  1990,  1005 
• 3 For a review on oQMs see: Van de Water RW. Pettus TRR. Tetrahedron  2002,  58:  5367 
• 4a Nelan DR. Robeson CD. J. Am. Chem. Soc.  1962,  84:  2963 
• 4b

  See also ref. [2a]

• 5 Hope MJ. Bally MB. Webb G. Cullis PR. Biochim. Biophys. Acta  1985,  812:  55 
• 6 Gille L. Staniek K. Nohl H. Free Radic. Biol. Med.  2001,  30:  865 
• 7 Nakamura T. Kijima S. Chem. Pharm. Bull.  1972,  20:  1681 
• 8 Rosenau T. Potthast A. Kosma P. Habicher WD. Synlett  1999,  291 
• 9a de Bruyn PJ. Lim ASC. Looney MG. Solomon DH. Tetrahedron Lett.  1994,  35:  4627 
• 9b

  This procedure provided a mixture of methano-dimer 7 and ethano-dimer 5, which was rather difficult to separate (unpublished results by T.N.).

• 10 Rosenau T. Habicher WD. Tetrahedron  1995,  51:  7919 
• 12a Pettus TRR. van De Water RW. Magdziak DJ. Chau JN. J. Am. Chem. Soc.  2000,  122:  6502 
• 12b Rodriguez R. Adlington RM. Moses JE. Cowley A. Baldwin JE. Org. Lett.  2004,  6:  3617 
• See also:
• 15a McLoughlin BJ. J. Chem. Soc., Chem. Commun.  1969,  540 
• 15b Minami N. Kijima S. Chem. Pharm. Bull.  1979,  27:  816 
• 15c Mitchell D. Doecke CW. Hay LA. Koenig TM. Wirth DD. Tetrahedron Lett.  1995,  36:  5335 

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, H_A), 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, H_B). ¹³C NMR: δ = 145.3 (C-6), 123.8 (C-5), 115.8 (C-4a), 30.8 (C_A), 22.3 (C_B). 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, H_A), 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, H_B). ¹³C NMR: δ = 145.4 (C-6), 123.2 (C-5), 115.4 (C-4a), 32.0 (C_B), 29.9 (C_A). 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, H_A), 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, H_B), 1.35 (m, 2 H, H_C). ¹³C NMR: δ = 145.6 (C-6), 122.6 (C-5), 115.6 (C-4a), 31.3 (C_B), 30.8 (C_C), 30.0 (C_A). 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, H_A), 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, H_B), 1.30 (t, 4 H, H_C). ¹³C NMR: δ = 145.4 (C-6), 122.8 (C-5), 115.7 (C-4a), 30.8 (C_B), 29.5 (C_A), 29.0 (C_C). Anal. Calcd for C₆₂H₁₀₆O₄ (915.53): C, 81.34; H, 11.67. Found: C, 81.46; H, 11.90.