816
F. Mazzini et al. / Tetrahedron 61 (2005) 813–817
D) were purchased from C/D/N Isotopes (Canada), whilst
NaBD4 (98 at.% D) and D2O (99.8 at.% D) from Aldrich.
2R,40R,80R-a-Tocopherol (Covitol F1490) was purchased
from Henkel. All other commercial reagents were used
without further purification. Column chromatography was
performed on silica gel 60 (70–230 mesh). TLC was
performed on silica gel Macherey–Nagel Alugram Sil
G/UV254 (0.20 mm). All yields given refer to isolated yields.
chromatography (Hex/EtOAc 15:1), affording 8 (1.17 g,
92% yield) as yellow dense oil.
1H NMR, (CDCl3/TMS): d 0.95–1.6 (m, 36H, C(2a)H3 and
C16H33 chain), 1.7 (m, 2H, ArCH2CH2), 2.1 (s, 3H, ArCH3),
2.3 (s, 3H, CH3CO), 3.05 (t, JZ6.2 Hz, 2H, ArCH2CH2). 2H
NMR (CHCl3): d 2.01 (s, 3D, ArCD3), 10.25 (s, 1D,
ArCDO). 13C NMR (CDCl3): d 12.9, 13.01 (m), 19.6, 19.7,
20.4, 20.9, 22.5, 22.6, 23.8, 24.7, 27.9, 30.5, 30.7, 32.6,
32.7, 37.2, 37.3, 37.4, 39.3, 39.9, 75.8, 120.5, 122.8, 128.2,
136.6, 145.0, 149.8, 169.6, 189.9 (t, JZ105 Hz). APCI-MS
(in MeOH), m/z (amu): positive ion mode, 491.4 [MCH]C,
508.6 [MCNH4]C. C31H46D4O4 (490.7): calcd C 75.87, H
11.09, found C 75.41, H 11.27.
4.1.1. (5-2H3,7-2H3)-(2R,40R,80R)-a-tocopherol (5).16 To a
solution of natural d-tocopherol (1.95 g, 4.72 mmol) in
anhydrous i-Pr2O (50 mL) were added anhydrous SnCl2
(13.9 g, 73.3 mmol, 15.5 equiv), DCl in D2O (50 g, 35%,
99.9% D) and (CD2O)n (1.1 g, 34.3 mmol, 7.28 equiv). The
mixture was heated at 65 8C for 4 h, and then water was
added. The aqueous phase was extracted with Et2O (3!
100 mL). The combined organic extracts were subsequently
washed to neutrality with water, dried over Na2SO4 and
concentrated to dryness. Purification by column chroma-
tography (Hex/EtOAc 12:1) afforded 5 (1.52 g, 74% yield)
as pale yellow oil.
4.1.4. 6-O-Acetyl-(7-2H3)-(2R,40R,80R)-g-tocopherol-5-
carboxylic acid (9). To a solution of 8 (490 mg, 1 mmol)
in 1,4-dioxane (20 mL), NH2SO3H (160 mg, 1.6 mmol,
1.6 equiv) and water (7 mL) were added. After stirring for
20 min, NaClO2 (180 mg, 1.4 mmol, 1.4 equiv) and water
(5 mL) were added. After stirring for further 30 min,
Na2SO3 (150 mg) was added to destroy excess of NaClO2
and HOCl formed during the reaction. Water was then
added and the aqueous phase was extracted with Et2O (3!
50 mL). The combined organic extracts were subsequently
washed to neutrality with water, dried over Na2SO4 and
concentrated to dryness, giving pure 9 (485 mg, 96% yield)
without further purification, as yellow oil.
1H NMR, (CDCl3/TMS): d 0.7–1.6 (m, 36H, C(2a)H3 and
C16H33 chain), 1.8 (m, 2H, ArCH2CH2), 2.1 (s, 3H, ArCH3),
2
2.6 (t, JZ6.2 Hz, 2H, ArCH2CH2). H NMR (CHCl3): d
2.09 (s, 3D, ArCD3), 2.13 (s, 3D, ArCD3). 13C NMR
(CDCl3): d 10–11.1 (m), 11.7, 19.6, 19.7, 20.7, 21.03, 22.6,
22.7, 23.8, 24.4, 24.8, 27.9, 30.8, 31.6, 32.7, 32.8, 37.3,
37.4, 37.5, 39.4, 39.8, 74.5, 117.4, 118.4, 120.9, 122.6,
144.6, 145.6. APCI-MS (in MeOH), m/z (amu): positive ion
mode, 437.6 [M]C.
1H NMR, (CDCl3/TMS): d 0.95–1.6 (m, 36H, C(2a)H3 and
C16H33 chain), 1.7 (m, 2H, ArCH2CH2), 2.1 (s, 3H, ArCH3),
2.28 (s, 3H, CH3CO), 2.9 (t, JZ6.2 Hz, 2H, ArCH2CH2),
2
4.1.2. 6-O-Acetyl-5-(5-2H2)-bromomethyl-(7-2H3)-(2R,
40R,80R)-g-tocopherol (7). To a solution of 5 (1.38 g,
3.16 mmol) in dry hexane (25 mL) was added dropwise a
solution of Br2 (0.17 mL, 3.32 mmol, 1.05 equiv) in dry
hexane (10 mL). The solution was stirred for 3 h. The
solvent and the remaining Br2 were removed in vacuo at rt,
9.2 (bs, 1H, CO2H). H NMR (CHCl3): d 2.01 (s, ArCD3).
13C NMR (CDCl3): d 12.8, 12.9 (m), 19.6, 19.7, 20.6, 21.1,
22.5, 22.7, 24, 24.4, 24.7, 27.9, 30.6, 32.7, 37.2, 37.3, 39.3,
40.1, 76, 118.3, 121.5, 128.9, 130.3, 140.5, 150, 170.1,
171.9. APCI-MS (in MeOH), m/z (amu): negative ion mode,
504.5 [MKH]K. C31H47D3O5 (505.7): calcd C 73.62, H
10.56, found C 73.25, H 10.85.
1
affording 6 without further purification. H NMR of 6 was
consistent with reported data.17 In the same flask was then
carried out the acetylation reaction to prepare 7. To 6,
obtained as described above, were added CH2Cl2 (12 mL),
AcOH (12 mL), Ac2O (2.2 mL) and H2SO4 (0.2 mL). The
dark mixture was stirred overnight at rt. Then water was
added and CH2Cl2 evaporated. The aqueous phase was
extracted with hexane (3!100 mL). The combined organic
extracts were subsequently washed to neutrality with water,
dried over Na2SO4 and concentrated to dryness. Purification
by column chromatography (Hex/EtOAc 10:1) afforded 7
(1.45 g, 82% yield from 5) as yellow dense oil.
4.1.5. (7-2H3)-(2R,40R,80R)-g-tocopherol-5-carboxylic
acid (10). To 9 (490 mg, 0.97 mmol) was added a solution
of KOH in MeOH (10 mL, 2 M). The solution was heated at
50 8C for 2 h, then MeOH was evaporated and water added.
The aqueous phase was extracted with Et2O (3!50 mL).
The combined organic extracts were subsequently washed
to neutrality with water, dried over Na2SO4 and concen-
trated to dryness, giving pure 10 (420 mg, 93% yield)
without further purification, as yellow semi-solid.
1H NMR, (CDCl3/TMS): d 0.95–1.6 (m, 36H, C(2a)H3 and
C16H33 chain), 1.7 (m, 2H, ArCH2CH2), 2.1 (s, 3H, ArCH3),
3.05 (t, JZ6.2 Hz, 2H, ArCH2CH2), 9.8 (bs, 1H, ArOH),
11.1 (bs, 1H, CO2H). 2H NMR (CHCl3): d 2.01 (s, ArCD3).
13C NMR (CDCl3): d 11.8, 13.0 (m), 19.6, 19.7, 20.9, 22.6,
22.7, 23.6, 24, 24.4, 24.8, 27.9, 30.9, 31.4, 32.6, 32.8, 37.2,
37.3, 37.4, 39.3, 39.6, 74.6, 106.7, 119, 124, 136.1, 144.8,
155.9, 176.8. APCI-MS (in MeOH), m/z (amu): negative ion
mode, 462.6 [MKH]K. C29H45D3O4 (463.7): calcd C
75.11, H 11.08, found C 75.01, H 11.21.
1H NMR, (CDCl3/TMS): d 0.95–1.8 (m, 36H, C(2a)H3 and
C16H33 chain), 1.8 (m, 2H, ArCH2CH2), 2.1 (s, 3H, ArCH3),
2.37 (s, 3H, CH3CO2), 2.75 (t, JZ6.6 Hz, 2H, ArCH2CH2).
2H NMR (CHCl3): d 1.94 (s, 3D, ArCD3), 4.36 (s, 2D,
ArCD2Br). C31H46D5BrO3 (490.7): calcd C 66.89, H 10.14,
Br 14.35, found C 66.65, H 10.35, Br 14.48.
4.1.3. 6-O-Acetyl-5-(5-2H1)-formyl-(7-2H3)-(2R,40R,80R)-
g-tocopherol (8). To a solution of 7 (1.34 g, 2.41 mmol) in
dry acetonitrile (20 mL), NMMO (1.14 g, 9.7 mmol,
4 equiv) was added. After stirring for 5 h at rt, the solvent
was evaporated and the crude residue purified by column
4.1.6. (7-2H3)-(2R,40R,80R)-g-tocopherol (11). Compound
10 (300 mg, 0.65 mmol) was heated at 170 8C for 3 h. After