W.-D. Woggon et al.
analysis calcd (%) for C30H52O4 (446.71): C 77.97, H 11.28; found:
C 78.23, H 10.15.
analysis calcd (%) for C30H50O2 (442.72): C 81.39, H 11.38; found:
C 81.31, H 11.18.
(3R,7R,11R)-3-(4-Methoxy-2,3,5-trimethylphenoxy)-3,7,11,15-tetrameth-
yl-1-hexadecene (28): Methyltriphenylphosphonium bromide (452 mg,
1.27 mmol) was suspended in THF (10 mL) and the mixture was cooled
ACHTUNGERTN(NUNG R,R,R)-a-Tocopherol methyl ether (30): A mixture of dehydrotocopher-
ol 20 (83.4 mg, 0.19 mmol) and 10% palladium on carbon (15 mg) in
ethyl acetate (6 mL) was hydrogenated at room temperature and under
1 bar hydrogen for 30 min.[13] The mixture was filtered, the filtrate was
concentrated, and the product was purified by chromatography (silica
gel, hexane/EtOAc 40:1) to yield 30 (79.8 mg, 95%) as a colorless viscous
oil. [a]2D0 =+0.3 (c=1 in CHCl3); 94% de (2R); HPLC [Chiralcel OD-H
column (n-heptane:2-propanol 99.8:0.2), UV 220 nm, 0.8 mLminÀ1]:
major diastereomer tR =10.1 min ((R,R,R)-30), minor diastereomer tR =
8.5 min ((S,R,R)-30); 1H NMR (400 MHz, CDCl3): d=3.63 (s,3H), 2.58
(t, J=7 Hz, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H), 1.72–1.86 (m,
2H), 1.0–1.6 (m, 21H), 1.24 (s, 3H), 0.84–0.88 ppm (m, 12H); 13C NMR
(100 MHz, CDCl3): d=149.77, 148.18, 128.14, 126.12, 123.29, 117.94,
75.20, 60.82, 40.47, 39.79, 37.87, 37.83, 37.70, 33.22, 33.12, 31.69, 28.40,
25.22, 24.86, 24.31, 23.14, 23.05, 21.45, 21.05, 20.17, 20.08, 12.96, 12.18,
12.10 ppm; IR (neat): n˜ =1456, 1404, 1377, 1258 cmÀ1; EI-MS: m/z (%):
444.4 (100); elemental analysis calcd (%) for C30H52O2 (444.74): C 81.02,
H 11.78; found: C 80.82, H 11.62.
to 08C.
A 1.6m solution of n-butyllithium in hexane (0.75 mL,
1.20 mmol) was added dropwise to the mixture over 3 min, and the
yellow mixture was stirred at 08C for 15 min. Then a solution of aldehyde
27 (401 mg, 0.90 mmol) in THF (4 mL) was added over 5 min and the
yellow solution was stirred without a cooling bath for 15 min. The reac-
tion mixture was partitioned between hexane and 85% (v/v) aqueous
methanol and the aq methanol phase was re-extracted with hexane. The
combined hexane phases were concentrated in vacuo and the product
was purified by chromatography (silica gel, n-hexane/Et2O 25:1) to
afford 28 (375 mg, 94%) as a colorless viscous oil. [a]2D0 =+1.2 (c=1 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=6.70 (s,1H), 6.06 (dd, J=18,
11 Hz, 1H), 5.14 (d, J=17 Hz, 1H), 5.14 (d, J=12 Hz, 1H), 3.64 (s, 3H),
2.18 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 1.70 (t, J=8.4 Hz, 1H), 1.0–1.57
(m, 19H), 1.33 (s, 3H), 0.83–0.87 ppm (m, 12H); 13C NMR (100 MHz,
CDCl3): d=151.80, 150.39, 144.78, 130.52, 128.29, 127.35, 120.14, 114.00,
82.16, 60.43, 42.99, 39.78, 37.86, 37.83, 37.71, 33.21, 33.11, 28.39, 25.22,
24.87, 23.14, 23.04, 22.79, 21.67, 20.16, 20.11, 16.64, 13.66, 13.22 ppm;
ESI-MS: m/z: 467.9 [M+Na]+, 912.0 [2M+Na]+; elemental analysis calcd
(%) for C30H52O2 (444.74): C 81.02, H 11.78; found: C 80.99, H 11.67
2-(1,3-Dithian-2-yl)-4-methoxy-3,5,6-trimethylphenol (14): A mixture of
2-hydroxy-5-methoxy-3,4,6-trimethylbenzaldehyde (1.16 g, 6.0 mmol), 1,3-
propanedithiol (713 mg, 6.6 mmol), and tetrabutylammonium tribromide
(58 mg, 0.12 mmol) in THF (5 mL) was stirred at RT for 7 h. It was
poured into water and extracted with Et2O. The organic phase washed
with brine, dried (MgSO4), and concentrated on a rotary evaporator. The
residual oil was purified by chromatography (silica gel, n-hexane/EtOAc
6:1) to yield 14 (1.70 g, 100%) as a pale yellow solid. The analytical
sample was prepared by crystallization from Et2O/hexane. White crystals;
m.p. 93–968C; 1H NMR (400 MHz, CDCl3): d=6.95 (br s, 1H), 5.64 (s,
1H), 3.60 (s, 3H), 3.01–3.10 (m, 2H), 2.87–2.94 (m 2H), 2.32 (s, 3H),
2.18 (s, 3H), 2.14 (s, 3H), 2.15–2.23 (m, 1H), 1.85–1.98 ppm (m, 1H);
13C NMR (100 MHz, CDCl3): d=150.98, 150.17, 132.06, 125.67, 124.17,
119.17, 60.89, 45.37, 32.11, 25.23, 13.32, 12.76, 12.51 ppm; ESI-MS (neg):
283 [MÀH]; ESI-MS (pos.): 307 [M+Na]+, 591 [2M+Na]+; elemental
analysis calcd (%) for C14H20O2S2 (284.43): C 59.12, H 7.09; found:
C 59.19, H 6.98.
(3R,7R,11R)-3-(4-Methoxy-2,3,5-trimethylphenoxy)-3,7,11,15-tetrameth-
yl-1-hexadecanol (29):
A mixture of vinyl compound 28 (371 mg,
0.83 mmol) and tris(triphenylphosphine)rhodium(I) chloride (32.0 mg, 35
mmol) in THF (2.5 mL) was stirred at room temperature for 30 min. A
1m solution of catecholborane in THF (1.8 mL, 1.8 mmol) was added to
the orange solution. After stirring at room temperature for 4 h, the mix-
ture was diluted with THF (6 mL) and treated with 2n aq NaOH
(4.0 mL) and 30% H2O2 (3.0 mL). The biphasic mixture was stirred for
1 h while the temperature was maintained at 25–358C. The mixture was
extracted with TBME, and the organic phase was washed with brine,
dried (MgSO4), and concentrated on a rotary evaporator. The residual
brown oil was purified by chromatography (silica gel, n-hexane/EtOAc
6:1) to afford 29 (353 mg, 91%) as a colorless viscous oil. [a]2D0 =À18.2
(c=1 in CHCl3); 1H NMR (400 MHz, CDCl3): d=6.71 (s, 1H), 3.93 (q,
J=5.5 Hz, 2H), 3.65 (s, 3H), 2.81 (t, J=5.5 Hz, 1H, O-H), 2.23 (s, 3H),
2.17 (s, 3H), 2.12 (s, 3H), 1.99 (t, J=6 Hz, 2H), 1.47–1.82 (m, 3H), 1.0–
1.42 (m, 18H), 1.24 (s, 3H), 0.82–0.88 ppm (m, 12H); 13C NMR
(100 MHz, CDCl3): d=152.94, 149.02, 130.92, 130.03, 127.97, 122.81,
85.01, 60.42, 60.18, 41.66, 40.31, 39.77, 37.99, 37.83, 37.81, 37.69, 33.20,
33.16, 28.39, 25.21, 24.87, 24.62, 23.13, 23.04, 22.52, 20.15, 20.08, 16.62,
14.41, 13.32 ppm; IR (neat): n˜ =3390 cmÀ1; ESI-MS: m/z: 485.7 [M+Na]+
; elemental analysis calcd (%) for C30H54O3 (462.75): C 77.87, H 11.76;
found: C 77.99, H 11.61.
(2R,6R,10R)-2-[2-(1,3-Dithian-2-yl)-4-methoxy-3,5,6-trimethylphenoxy]-
2,6,10,14-tetramethylpentadecanoic acid methyl ester (17): Diisopropyl
azodicarboxylate (DIAD, 290 mg, 1.43 mmol) was added to a solution of
2 (344 mg, 1.04 mmol), 14 (356 mg, 1.25 mmol), and triphenylphosphine
(330 mg, 1.26 mmol) in toluene (8 mL). The yellow solution was stirred
at 258C for 20 h. Additional amounts of triphenylphosphine (165 mg and
105 mg) and DIAD (145 mg and 91 mg) were added after 4 h and 8 h of
stirring. The reaction mixture was partitioned between hexane and 85%
(v/v) aqueous methanol. The methanol phase was re-extracted with
hexane and the combined hexane phases were concentrated in vacuo.
The residual oil was purified by chromatography (silica gel, n-hexane/
EtOAc 25:1) to yield 17 (424.5 mg, 68%) as a colorless viscous oil.
[a]2D0 =+8.6 (c=1 in CHCl3); 1H NMR (400 MHz, CDCl3): d=6.06 (s,
1H), 3.83 (s, 3H), 3.64 (s, 3H), 2.95–3.05 (m, 2H), 2.77–2.87 (m, 2H),
2.65 (s, 3H), 2.1–2.3 (m, 2H), 2.13 (s, 3H), 2.02 (s, 3H), 1.84–1.97 (m,
2H), 1.0–1.57 (m, 19H), 1.16 (s, 3H), 0.83–0.88 ppm (m, 12H); 13C NMR
(100 MHz, CDCl3): d=174.59, 154.47, 147.59, 130.96, 130.73, 130.32,
85.05, 60.21, 52.58, 46.93, 42.37, 39.77, 37.84, 37.77, 37.72, 37.70, 33.23,
33.15, 32.93, 32.76, 28.39, 26.08, 25.21, 24.94, 23.13, 23.03, 22.49, 20.66,
20.15, 14.94, 14.51, 13.53 ppm; IR (neat): n˜ =1739 cmÀ1; ESI-MS: m/z:
617.3 [M+Na]+, 1211.2 [2M+Na]+; elemental analysis calcd (%) for
C34H58O4S2 (594.95): C 68.64, H 9.83; found: C 68.63, H 9.68.
ACHTUNGTRENNUNG(R,R,R)-a-3,4-Dehydrotocopherol methyl ether (20): Alcohol 29
(112.2 mg, 0.24 mmol) was dissolved in dichloromethane (4 mL). The
Dess–Martin periodinane reagent (123 mg, 0.29 mmol) was added and
the solution was stirred at room temperature for 90 min. Trifluoroacetic
acid (50 mL, 65 mmol) was added and the reaction mixture was stirred at
room temperature for 2 h. It was diluted with Et2O (15 mL); saturated
aq NaHCO3 (3 mL) and Na2S2O3 (400 mg) were added and the mixture
was stirred for 10 min. The organic phase was washed with brine, dried
(MgSO4), and concentrated. The pale yellow oil was purified by chroma-
tography (silica gel, n-hexane/EtOAc 40:1) to yield 20 (87.7 mg, 82%) as
a colorless viscous oil. [a]2D0 =À38.2 (c=1 in CHCl3); 94% de (2R);
HPLC [Chiralcel OD-H column (n-heptane/2-propanol 99.8:0.2), UV
220 nm; 0.8 mLminÀ1]: major diastereomer tR =6.0 min ((R,R,R)-20),
minor diastereomer tR =7.2 min ((S,R,R)-20); 1H NMR (400 MHz,
CDCl3): d= 6.50 (d, J=10 Hz, 1H), 5.59 (d, J=10 Hz, 1H), 3.62 (s, 3H),
2.21 (s, 3H), 2.18 (s, 3H), 2.09 (s, 3H), 1.0–1.7 (m, 21H), 1.33 (s, 3H),
0.82–0.89 ppm (m, 12H); 13C NMR (100 MHz, CDCl3): d=150.52, 147.27,
130.41, 129.89, 123.52, 123.02, 120.54, 118.27, 77.49, 60.75, 41.31, 39.78,
37.85, 37.75, 37.69, 33.21, 33.12, 28.39, 26.04, 25.22, 24.88, 23.14, 23.04,
21.79, 20.16, 20.06, 13.20, 11.97, 11.55 ppm; IR (neat): n˜ =1460, 1406,
1377, 1263 cmÀ1; EI-MS: m/z (%): 442.4 (4), 427 (5), 217 (100); elemental
(2R,6R,10R)-2-[2-(1,3-Dithian-2-yl)-4-methoxy-3,5,6-trimethylphenoxy]-
2,6,10,14-tetramethyl-1-pentadecanol (31): LiAlH4 (76 mg, 2.0 mmol) was
added to a solution of a-phenoxy ester 17 (424 mg, 0.71 mmol) in THF
(12 mL) at 08C and the mixture was stirred at room temperature for
40 min. Excess hydride was quenched with sodium sulfate decahydrate;
after stirring for 20 min, the mixture was filtered and the filtrate was con-
centrated in vacuo to give 31 (409 mg, 101%) as a colorless gum.
1H NMR (400 MHz, CDCl3): d=5.96 (s, 1H), 3.81 (dd, J=11, 5 Hz, 1H),
3.74 (dd, J=11, 7 Hz, 1H), 3.64 (s, 3H), 2.98–3.10 (m, 2H), 2.82–2.90 (m,
1310
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1306 – 1311