technology for recycling Ph3PO back to Ph3P,27 but it would
obviously be desirable to avoid this add-on process. We
searched for a more economical oxygen acceptor but were
not successful. Dimethyl sulfide in place of Ph3P gave no
deoxygenation. The use of hypophosphorus acid was also
studied. This gave acid-catalyzed epoxide ring-opening in
aqueous systems and the use of sodium hypophosphite in
water/alcohol mixtures afforded low yields of olefinic
product accompanied by triols arising from epoxide reaction
with water. Attempted phase-transfer reactions did not work.
Although the need to recycle triphenylphospine oxide
remains an obvious place for improvement, the chemistry
reported herein offers a promising new approach to vitamin
E synthesis. Our conversion of bio-based geranylgeraniol to
a tocopherol side-chain synthon in three steps is a radical
departure from the conventional petrochemical-based mul-
tistep approach to isophytol yet allows a drop-in replacement
in the final trimethylhydroquinone condensation. The valu-
able rhenium catalyst is quantitatively recoverable by extrac-
tion into dilute aqueous bases, where it forms the stable
yellow perrhenate ion.24 The use of the epoxide functionality
to protect an olefin during reduction may prove to be a useful
addition to synthetic methodology.
40 °C for 4 h. The reaction mixture was vented, purged,
filtered (Celite), and stripped of solvent to give 5.03 g (95%)
of 9 as a colorless oil. NMR: 3.9-3.8, m, 1H; 3.75-3.65,
m, 1H; 2.97, m, 4 lines, 1H; 1.7-1.0, br m, 21H; 1.30, s,
3H; 0.9-0.8, m, 12H. Mass spectrum: m/z 312 (calcd, 312).
Epoxyphytol 9 from Phytol 5.28 A 3-L flask was charged
with 100 g (0.337 mol) of phytol, 800 mL of n-hexane, and
0.9 g of V(acac)3. The mixture was refluxed under nitrogen
during the dropwise addition of 61.2 mL of 5.5 M (0.337
mol) tert-butylhydroperoxide in n-decane. The reaction
mixture was cooled to room temperature and stirred overnight
with 200 mL of 5% aqueous sodium bisulfite, and the organic
phase then washed with water and brine, dried (MgSO4),
and stripped of hexane on the rotovap. Decane was then
removed under gentle warming on the high-vacuum line to
leave 97.2 g (92%) of 9 as a light yellow oil. NMR and
mass spectra were identical to those of material prepared
from geranylgeraniol.
Phytan-1,3-diol 10.17 A 300-mL flask was charged with
11.3 g (0.036 mol) of epoxyphytol 9 and 100 mL of dry
toluene. The mixture was stirred under argon at 0 °C during
the addition of 17.4 mL of Aldrich Red-Al (65% Na bis(2-
methoxyethoxy)aluminum hydride in toluene; 0.038 mol).
The reaction was allowed to warm to 22 °C over 4 h, at
which time TLC analysis of an acidified sample disclosed
the formation of a single polar product. The reaction was
cooled to 5-10 °C and quenched by addition of 50 mL of
2-propanol. Acidification with 5% aqueous HCl was followed
by phase separation and washing of the organic layer with
water (3 × 100 mL) and brine (1 × 100 mL) and drying
over MgSO4. Removal of solvent under vacuum left 10.6 g
(93%) of 10 as a pale yellow viscous syrup. (Other runs gave
yields as high as 97%; the average was 95%). NMR: 3.87,
d of t, 2H; 1.8-1.0, br m, 23H; 1.24, s, 3H; 0.9-0.8, m,
12H. Mass spectrum: m/z 314 (calcd, 314). Acetylation of
a sample of 10 (excess acetic anhydride, pyridine, 0-20 °C,
4 h) gave a 91% yield of a single monoacetate: NMR: 4.23,
t, 2H; 2.07, s, 3H; 1.72-1.00, complex m, 23H; 1.22, s, 3H;
0.9-0.8, m, 12 H. Mass spectrum: m/z 356 (calcd,
356).
Experimental Section
General Methods. 1H NMR spectra were recorded at 300
MHz on a Varian Gemini 300 instrument in CDCl3 solvent
with TMS internal standard. Spectra were re-recorded after
a drop of D2O was added to all samples containing alcohols
or phenols. Mass spectra were collected in field desorption
mode on a Micromass Autospec magnetic double focusing
instrument. Solvents and reagents were purchased from
Sigma-Aldrich and were used as received.
Geranylgeraniol-2,3-epoxide 8. A solution of 5.0 g of
all trans-geranylgeraniol 7 (0.0172 mol) in 20 mL of toluene
was treated with 50 mg of vanadium tris(acetylacetonate)
(0.8 mol %) and stirred under reflux in a nitrogen atmo-
sphere. There was added dropwise 5.76 mL of 3.3 M tert-
butylhydroperoxide in toluene (0.0190 mol). At the end of
the addition, heating was discontinued, and the mixture
allowed to cool to 23 °C. TLC analysis indicated complete
conversion of the starting material to a single product. The
mixture was treated with about 20 mL of 5% aqueous sodium
bisulfite solution, stirred 10 min, and decanted, and the
organic layer was washed (20 mL each) with water, 5%
sodium bicarbonate solution, and brine, and dried over
MgSO4. Removal of solvent under vacuum afforded 5.28 g
(98%) of pale yellow oily epoxide 7. NMR: 5.2-5.05, m,
3H; 3.9-3.75, m, 1H; 3.65-3.75, m, 1H; 2.96, m, 1H; 2.2-
1.95, m, 10H; 1.75-1.6, m, 12H; 1.6-1.4, m, 2H; 1.4-1.2,
m, 3H. Mass spectrum: m/z 306 (calcd, 306). Anal: Calcd
for C20H34O2: C, 78.38; H, 11.18. Found: C, 78.11; H, 11.22.
Epoxyphytol 9 from 8. The crude product from an
epoxidation performed as described above was dissolved in
50 mL of ethanol, treated with 0.20 g of 5% Pd/C catalyst,
and hydrogenated (Parr apparatus) at 40 psi hydrogen and
r-Tocopherol 2 from Diol 10. A solution of 1.20 g
(0.0079 mol) of trimethylhydroquinone and 0.80 g (0.0059
mol) of anhydrous zinc chloride in 9 mL of glacial acetic
acid was stirred under argon at reflux. To this was added
dropwise a solution of 2.70 g (0.0086 mol) of phytandiol 10
in 5 mL of acetic acid and the solution refluxed 16 h. There
was then added 5 mL of acetic anhydride and the mix
refluxed a further 3 h. Workup by aqueous drownout,
extraction with ethyl acetate, washing with 5% aqueous
NaHCO3, water, and brine, and drying (MgSO4) followed
by removal of solvent left 3.92 g of a dark oil which assayed
54 wt % R-tocopheryl acetate by internal standard VPC
analysis. Yield of tocopherol, 60%.
Various modifications of this reaction using different stoi-
chiometry, addition of cocatalysts and use of different Lewis
acids, different solvents, and so forth gave yields of toco-
pherol in the 55-65% assay range. TLC analyses indicate
(27) (a) Wunsch, G.; Wintersberger, K.; Geierhaas, H. Z. Anorg. Allg. Chem.
1969, 369, 33. (b) Broger, E. U.S. Patent 4,249,023 1979.
(28) Bhati, A. Perfum. J. 1966, 57, 563.
786
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Vol. 6, No. 6, 2002 / Organic Process Research & Development