852
LANKHORST ET AL.
composition was determined by using the acetal method (after oxidation
of the primary alcohol to the corresponding aldehyde) as described in the
literature.22,23
to room temperature and the supernatant filtered through a syringe filter
(0.45 μm) into an oven-dried two-necked round-bottomed flask. The re-
maining Mg turnings were washed with THF (5 mL) and the supernatant
was filtered through a syringe filter (0.45 μm) and added to the solution
obtained above. The combined solutions of the Grignard reagent
(14.51 g yellowish liquid) were stored at room temperature in a flask
sealed by rubber septa. Titration of the solution (sec. butanol, o-
phenanthroline method25) gave a 73% yield (0.35 M solution).
3,4-Dihydro-6-benzyloxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-
yl]methanol. To a suspension of NaH (7.42 g, 97%, dry, Aldrich, Mil-
waukee, WI, 300.0 mmol, 3.0 equiv.) in THF (200 mL) the solution of
Trolox (25.06 g, 99.9%, 100.0 mmol) was added dropwise at 26 °C under
stirring. Additional THF (150 mL) was added to facilitate stirring. The
beige suspension was heated to reflux (oil bath 90 °C) under stirring
for 2 h. Benzyl bromide (26.18 g, 98%, 300.0 mmol, 3.0 equiv.) was added,
and the mixture further stirred at reflux temperature for 2.5 h. The mix-
ture was cooled to 0 °C, and LiAlH4 (15.65 g, 97%, 400.0 mmol, 4 mol
equiv.) was added carefully in portions. After heating for 30 min at reflux
temperature (oil bath 95 °C), the mixture was stirred at 23 °C for 16 h. At
0 °C small portions of ice were added slowly and carefully until foaming
ceased, and 2 N HCl (750 mL) was added to the gray suspension. The or-
ganic phase was separated, and the aqueous phase extracted with diethyl
ether (250 mL, twice). The organic phases were washed separately with
1 N HCl and sat. NaCl solution (100 mL each), combined, dried over so-
dium sulfate, filtered, evaporated (20 mbar, 40 °C), and dried (30 min,
0.022 mbar, 24 °C). The 36.34 g red-yellow oil was dissolved in n-pentane/
diethyl ether (85 mL/ 15 mL). After crystallization (À20 °C, 16 h) and
washing with cold n-pentane/ diethyl ether (9:1, 75 ml) the crystals were
dried (0.022 mbar, 24 °C): 28.76 g (88%) off-white crystals. From the
mother liquor, additional 4.79 g yellow oil was obtained. An analytically
pure sample (colorless crystals, 98.1%) was obtained from the crystals
by recrystallization from the same solvent mixture.
6-Benzyloxy-α-tocopherol26–28
. The triflate (3.52 g, 97.7%, 7.5 mmol)
and a magnetic stirrer bar were placed in an oven-dried 100 mL two-
necked round-bottomed flask. After threefold evacuation followed by
purging with argon, THF (4 mL) was added, and the flask placed in a
cooling bath of À20 °C. The Grignard solution in THF (0.35 M, 32.1 mL,
11.25 mmol, 1.5 equiv.) was dropped in, followed by the solution of
Li2CuCl4 in THF29 (3 mL, 0.1 M, 0.3 mmol, 4 mol%). After stirring for
48 h at À20 to 24 °C additional Li2CuCl4 in THF (3 mL, 0.1 M, 0.3 mmol,
4 mol%) was added. After overall 95 h (TLC control; SiO2, n-hexane/
toluene 7:3, benzyl-tocopherol Rf 0.38, triflate Rf 0.14) the reaction mix-
ture was poured onto ice (25 g). The organic phase was separated and
washed subsequently with 2 N H2SO4, sat. NaHCO3 and NaCl solutions
(50 mL each). The water phases were extracted with diethyl ether
(100 mL, three times), and the combined organic extracts dried over so-
dium sulfate, filtered, evaporated (20 mbar, 40 °C), and dried (2 h, high
vacuum, room temperature): 6.39 g black solid. Column chromatography
(SiO2, n-hexane/toluene 7:3) delivered, after evaporation and drying
(20 mbar, 50 °C/0.021 mbar, 23 °C), 2.42 g (purity 97.3% by NMR, yield
60%) benzyl-tocopherol as a yellowish oil, and in a second fraction 0.53 g
(yield 15%) triflate as a purple-colored solid.
3,4-Dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]
methyl trifluoromethane-sulfonate. Triflic anhydride (19.75 g,
11.5 mL, 70.0 mmol, 1.4 equiv.) was added dropwise during 20 min to
the stirred solution of the alcohol (16.93 g, 96.4%, 50.0 mmol) and 2,6-
lutidine (8.20 g, 8.90 mL, 98%, 75.0 mmol, 1.5 equiv.) in dichloromethane
(240 mL) at À30 °C.24 After stirring for 1 h at this temperature, the mix-
ture was poured onto 2 N H2SO4 of 0 °C (100 mL). The organic phase
was separated and washed with sat. NaHCO3 and NaCl solutions
(100 mL each). The water phases were extracted with dichloromethane
(100 mL), and the combined organic extracts dried over sodium sulfate,
filtered, evaporated (20 mbar, 40 °C), and dried (1 h, 0.022 mbar, 24 °C).
The 24.73 g slightly beige crystals were dissolved in diethyl ether
(200 mL), treated with active carbon (1.0 g), filtered through Dicalite,
and the solution evaporated under reduced pressure to ~40 g. n-Pentane
(30 mL) was added, and crystallization (room temperature, then À20 °C,
16 h) gave, after filtration, washing (cold n-pentane / diethyl ether 1:1,
100 mL) and drying (2 h, 0.021 mbar, 24 °C) 17.33 g (97.7% by NMR,
yield 73.8%). The colorless crystals should be stored at À20 °C in order
to avoid decomposition. From the mother liquor, additional 4.84 g yel-
lowish crystals (yield 21%) were obtained.
α-Tocopherol. α-Tocopheryl benzyl ether (2.36 g, 97.3%, 4.4 mmol),
EtOAc (30 mL) and 5% Pd/C (1.17 g, 50 wt%) were placed in an autoclave
(50 mL, glass, gassing stirrer). After threefold evacuation followed by
purging with argon, and 3-fold purging with hydrogen gas (5 bar) and
subsequent pressure release, the autoclave was pressurized with hydro-
gen gas (10 bar), and the stirrer (1000 rpm) was started. After 9 min, hy-
drogen uptake was completed. After pressure release the reaction
mixture was filtered, and the catalyst residue washed with additional
EtOAc (~4 g). Evaporation of the filtrate (20 mbar, 40 °C) and drying
(0.1 mbar, 23 °C, 2 h) gave 1.89 g slightly yellowish oil, which was puri-
fied by column chromatography (SiO2, n-hexane/EtOAc 9:1), evaporated
(20 mbar, 40 °C) and dried (0.021 mbar, 23 °C, 2 h): 1.80 g almost color-
less oil, purity 97.6% by quant. GC, yield 92.6%.
Three samples of the following stereoisomeric composition were pre-
pared. Reference sample 1 (“RRR”): 2R,4’R,8’R 93.40%, 2R,4’R,8’S 5.81%,
2R,4’S,8’R 0.75%, 2R,4’S,8’S 0%; reference sample 2 (“SRR”): 2S,4’R,8’R
93.40%, 2S,4’R,8’S 5.81%, 2S,4’S,8’R 0.75%, 2S,4’S,8’S 0%; reference sample
3 (“SSS”): 2S,4’R,8’R 0.12%, 2S,4’R,8’S 6.21%, 2S,4’S,8’R 1.36%, 2S,4’S,8’S
92.21%.
Hexahydrofarnesylmagnesium bromide. The mixture of hexahy-
drofarnesol (11.67 g, 97.9%, 50.0 mmol) and HBr (63% in water, 41.7 g,
325 mmol, 6.5 equiv.) was heated under stirring to 120 °C (oil bath 130 °C)
for 5 h. Completion of the conversion was checked by TLC control (SiO2, n-
hexane/EtOAc 9:1): alcohol Rf 0.07, bromide Rf 0.65. After cooling to room
temperature the mixture was poured onto ice-water (50 mL) and extracted
with n-hexane (75 mL, twice). The combined organic phases were washed
with sat. NaHCO3 and NaCl solutions (50 mL each), dried over sodium sulfate,
filtered, evaporated (20 mbar, 40 °C), and dried (1 h, 0.022 mbar, 24 °C):
13.93 g yellowish oil which was filtered through SiO2 (100 g). The fractions
containing the bromide were evaporated (20 mbar, 40 °C) and dried
(0.021 mbar, 24 °C). The colorless oil (13.24 g) was distilled (0.27 mbar,
140 °C, Kugelrohr oven): 12.96 g colorless liquid (98.9% by NMR, yield 88%).
Grignard magnesium turnings (469 mg, Alfa Aesar 99.8%, 19.25 mmol,
2.75 equiv.) were placed in an oven-dried 25 mL two-necked round-
bottomed flask and heated in an oil bath to 90 °C. THF (4 mL) was added,
and the solution of bromide (2.06 g, 98.9%, 7.0 mmol) in THF (8 mL) was
added dropwise under magnetic stirring for 30 min. After 6 h heating un-
der reflux (TLC control: no bromide detectable) the mixture was cooled
RESULTS AND DISCUSSION
Method Development
1H NMR spectra are shown in the Supporting Information
(S1). It is clear that spectra are too crowded to extract informa-
tion on the stereochemical composition. Therefore, the dis-
crimination of all eight stereoisomers was attempted with a
13C NMR measurement, which is outlined below. The full
13C NMR spectrum is shown and its assignment according
to previous results17,18 is shown in Supporting Information S2.
In the abovementioned previous NMR work17,18 separate
13C NMR signals for each of the four pairs of enantiomers
for C3’ and C2’ were detected. NMR spectra were recorded
in acetone as solvent, but, unfortunately, acetone is not suit-
able for separation of signals of enantiomers with the aid of
the chiral solvating agent TFAE, because acetone is too polar.
Enantiodiscrimination requires the use of an apolar solvent
such as chloroform or benzene. In deuterated chloroform
Chirality DOI 10.1002/chir