A. van der Klei, R. L. P. de Jong, J. Lugtenburg, A. G. M. Tielens
FULL PAPER
[1Ј-14C]-3-Acetoxy-6-geranyl-2-methoxy-5-methyl-1,4-benzoquinone
CH3), 25.4 (1Ј-CH2), 17.7 (10Ј-CH3), 16.3 (9Ј-CH3), 11.6 (3-CH3).
and
3-Acetoxy-6-geranyl-2-methoxy-5-methyl-1,4-benzoquinone: HRMS (DIP): calcd. for C16H24O4 304.1675; found
Freshly distilled BF3·OEt2 (2.8 g, 20 mmol) in dichloromethane (10
304.166Ϯ0.003. IR: ν˜ ϭ 3366 (OH), 1639 (CϭO), 1617 (CϭO)
mL) was added over 3 min under nitrogen at Ϫ70 °C to a solution cmϪ1
of 3-acetoxy-2-methoxy-5-methyl-1,4-benzoquinone (5, 1.1 g,
.
5.2 mmol) in dichloromethane (30 mL). This was followed by the
addition over 20 min and at Ϫ70 °C of distilled tri-n-butyl(geranyl)-
tin (12, 2.6 g, 6.0 mmol) in dichloromethane (15 mL). After stirring
for 3 h at Ϫ70 °C, the reaction mixture was poured into an ice-cold
HCl solution (10%, 60 mL), directly followed by addition of brine
(30 mL). After stirring for 10 min, this mixture was extracted with
dichloromethane (2 ϫ 25 mL). The organic phase was concentrated
in vacuo and dissolved in ether (40 mL), and FeCl3 (5 g) in water
(25 mL) was added. After the mixture had been stirred overnight,
the layers were separated, the water phase was extracted with ether
(1 ϫ 30 mL), and the combined organic layers were concentrated
in vacuo. The residue was dissolved in ether (25 mL), and KF (5 g)
in water (25 mL) was added. After stirring for 90 min, the mixture
was filtered through Hyflo, the water phase was extracted with
ether (4 ϫ 15 mL), the combined organic phases were dried with
MgSO4 and filtered, and the solvents were evaporated in vacuo.
The product was purified by silica gel chromatography (100% pet-
roleum ether Ǟ 40% ether in petroleum ether), which gave 1.05 g
of a yellow oil (75%, 3.8 mmol). 1H NMR (CDCl3, 300 MHz): δ ϭ
Synthesis of 5-Demethoxyubiquinone-2 (3)
rac-1,4,4a,8aα-Tetrahydro-7-methoxy-4aα-methyl-1aα,4α-methano-
naphthaline-5,8-dione (8): Freshly distilled cyclopentadiene (3.4 mL,
51 mmol) was added under nitrogen to a solution of 30 (1.3 g,
8.6 mmol) in THF (30 mL). The nitrogen flow was stopped and
the reaction mixture was stirred for 20 h, after which it was concen-
trated in vacuo. The DielsϪAlder product was purified by silica gel
chromatography (40% ether in petroleum ether). A cream-coloured
solid 8 was obtained, with a yield of 1.6 g (87%, 7.5 mmol); m.p.
102 °C. 1H NMR (CDCl3, 300 MHz): δ ϭ 6.16 (dd, JHϪH
ϭ
3
3
2.9 Hz, 5.6, 1 H, CH), 6.00 (dd, JHϪH ϭ 2.9 Hz, 5.6, 1 H, CH),
5.85 (s, 1 H, CH), 3.74 (s, 3 H, OCH3), 3.45 (m, 1 H, CH), 3.08
(m, 1 H, CH), 2.89 (d, 3JHϪH ϭ 3.9 Hz, 1 H, CH), 1.68 ϩ 1.53 (br.
2
3
dd, JHϪH ϭ 45, JHϪH ϭ 1.3 Hz, 2 H, CH2), 1.49 (s, 3 H, CH3)
ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 202.8 (CϭO), 194.9 Cϭ
O), 163.2 (CO), 139.3 (CC), 134.7 (CH), 114.7 (2XCH), 57.8
(OCH3), 57.0 (CH), 54.1 (CH), 50.2 (CH), 47.1 (CH2), 27.2 (CH3)
ppm. MS (ESI): m/z ϭ 218.
3
3
5.03 (t, JHϪH ϭ 6.6 Hz, 1 H, CH), 4.93 (t, JHϪH ϭ 6.2 Hz, 1 H,
3
[1Ј-14C]5-Demethoxyubiquinone-2 (3a) and 5-Demethoxyubiquinone-
2 (3): Commercially available tBuOK (0.67 g, 6.0 mmol) was dis-
solved in a 4:1 mixture of tert-butyl alcohol and toluene (10 mL)
and cooled to 0 °C. A mixture of the DielsϪAlder adduct 8 (0.66 g,
3.0 mmol) and geranyl bromide (14), dissolved in tert-butyl alcohol/
toluene (4:1 mixture, 5 mL), was added dropwise. The reaction mix-
ture was stirred for 80 min with ice cooling (0Ϫ5 °C), after which
it was poured into an aqueous saturated ammonium chloride solu-
tion. The water layer was extracted with ether (3 ϫ 10 mL), the
combined organic fractions were washed with brine and dried with
MgSO4, and the solvents were evaporated in vacuo. The product
was purified by silica gel chromatography (50% ether in petroleum
ether) and yielded 56% of the product (0.40 g, 1.13 mmol). The
cyclopentadiene group was removed by heating under reflux in
toluene (30 mL). According to TLC, cleavage was complete after
60 min. After evaporation of toluene, the pure product was ob-
tained as a yellow oil in quantitative yield (0.34 g, 1.1 mmol). 1H
NMR (CDCl3, 600 MHz): δ ϭ 5.88 (s, 1 H, 5-CH), 5.03 (t,
CH), 4.06 (s, 3 H, OCH3), 3.20 (d, JHϪH ϭ 6.6 Hz, 2 H, CH2),
2.32 (s, 3 H, CH3), 2.03 (m, 2 H, CH2), 2.00 (s, 3 H, CH3), 1.99
(m, 2 H, CH2), 1.73 (s, 3 H, CH3), 1.65 (s, 3 H, CH3), 1.58 (s, 3 H,
CH3) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 182.5 (CϭO), 181.3
(CϭO), 178.1 (CϭO), 168.0 (CO), 147.1 (CO), 141.7 (C), 139.2
(C), 137.5 (C), 131.3 (C), 123.8 (CH), 118.4 (CH), 60.1 (OCH3),
39.4 (CH2), 26.3 (CH2), 25.4 (CH2), 25.2 (CH2), 20.1 (CH3), 17.4
(CH3), 16.1 (CH3), 11.7 (CH3) ppm. MS (ESI): m/z ϭ 346 [M].
[1Ј-14C]-5-Demethoxy-5-hydroxyubiquinone-2 (2a) and 5-Deme-
thoxy-5-hydroxyubiquinone-2 (2): Nitrogen gas was passed through
a solution of 3-acetoxy-6-geranyl-2-methoxy-5-methyl-1,4-benzo-
quinone (1.05 g, 3.8 mmol) in THF (40 mL). A solution of K2CO3
(1.7 g, 15 mmol) in water (15 mL) was added dropwise at 0 °C over
10 min, during which the solution turned dark purple. According
to TLC analysis, deacetylation was complete after stirring for 1 h
at 5Ϫ10 °C. The mixture was acidified with concentrated HCl until
the mixture turned yellow. After separation, the water layer was
extracted with ether (4 ϫ 10 mL), the combined ether fractions
were dried with MgSO4 and filtered, and the solvents were evapor-
ated in vacuo. According to NMR spectroscopic data, this com-
pound had a purity of about 97%, but it was further purified by
the following method, continuously under the exclusion of air. The
product was dissolved in ether (50 mL) and this was extracted with
a nitrogen-flushed NaOH solution (0.02 , 4 ϫ 15 mL). The purple
water layer was washed with ether (3 ϫ 10 mL), and the water layer
was acidified with concentrated HCl until the colour changed from
orange to red. This was extracted with ether (5 ϫ 10 mL), dried
with MgSO4, filtered, and concentrated in vacuo. This resulted in
an 84% yield of an orange oil of 2, with a purity over 99% (0.75 g,
3
3JHϪH ϭ 7.0 Hz, 1 H, 2Ј-CH), 4.94 (t, JHϪH ϭ 7.0 Hz, 1 H, 6Ј-
3
CH), 3.80 (s, 3 H, 6-OCH3), 3.22 (d, JHϪH ϭ 7.0 Hz, 2 H, 1Ј-
CH2), 2.04 (m, 2 H, 5Ј-CH2), 2.04 (s, 3 H, 3-CH3), 1.95 (m, 2 H,
4Ј-CH2), 1.74 (s, 3 H, 9Ј-CH3), 1.65 (s, 3 H, 8Ј-CH3), 1.57 (s, 3 H,
10Ј-CH3) ppm. 13C NMR (CDCl3, 150 MHz): δ ϭ 187.7 (4-CO),
181.8 (1-CO), 158.3 (6-CO), 141.8 (3-C), 141.3 (2-C), 137.6 (3Ј-C),
131.5 (7Ј-C), 124.0 (6Ј-CH), 118.8 (2Ј-CH), 107.0 (5-CH), 56.1 (6-
OCH3), 39.6 (4Ј-CH2), 26.5 (5Ј-CH2), 25.7 (8Ј-CH3), 25.2 (1Ј-CH2),
17.6 (10Ј-CH3), 16.3 (9Ј-CH3), 12.1 (3-CH3). HRMS (DIP): calcd.
for C18H24O3 288.1725; found 288.1707. IR: ν˜ ϭ 1648 (CϭO), 1608
(CϭO) cmϪ1
.
1
2.46 mmol). H NMR (CDCl3, 600 MHz): δ ϭ 6.50 (br. s, 1 H, 5-
3
3
OH), 5.03 (t, JHϪH ϭ 7.0 Hz, 1 H, 2Ј-CH), 4.92 (t, JHϪH
ϭ
3
6.6 Hz, 1 H, 6Ј-CH), 4.07 (s, 3 H, 6-OCH3), 3.20 (d, JHϪH
ϭ
Acknowledgments
7.0 Hz, 2 H, 1Ј-CH2), 2.06 (m, 2 H, 5Ј-CH2), 2.04 (s, 3 H, 3-CH3),
1.97 (m, 2 H, 4Ј-CH2), 1.74 (s, 3 H, 9Ј-CH3), 1.65 (s, 3 H, 8Ј-CH3), We want to thank Richard van der Haas and Rutger Boers for
1.58 (s, 3 H, 10Ј-CH3) ppm. 13C NMR (CDCl3, 150 MHz): δ ϭ
their help in the early phase of the organic synthesis. The authors
185.2 (4-CO), 183.2 (1-CO), 143.4 (6-CO), 139.3 (5-COH), 137.8 are also grateful to Fons Lefeber and Cees Erkelens for their help
(3Ј-C), 137.1 (2-C), 136.2 (3-C), 131.6 (7Ј-C), 124.0 (6Ј-CH), 118.7 in acquiring the NMR spectra, and to Bertil Hofte, Barry Karaba-
(2Ј-CH), 60.3 (6-OCH3), 39.7 (4Ј-CH2), 26.5 (5Ј-CH2), 25.7 (8Ј-
tak, and Cees Versluis for recording the mass spectra.
Eur. J. Org. Chem. 2002, 3015Ϫ3023
3022