Photoreleasable Ubiquinol-2
J. Am. Chem. Soc., Vol. 120, No. 8, 1998 1663
of 8 (1.68 g) dissolved in 20 mL of toluene was refluxed for 60 min;
during this time the solution turned from a pale yellow to a reddish
orange. Solvent was removed in vacuo and the resultant oil purified
by flash column chromatography using 4/1 hexane/EtOAc. Yield 1.4
g (>99%). 1H NMR (CDCl3, TMS) δ 5.03 (t,1H), 4.93 (t, 1H), 4.00
(s, 3H), 3.98 (s, 3H), 3.18 (d, 2H), 2.01 (s, 3H), 1.99 (m, 4H), 1.73 (s,
3H), 1.65 (s, 3H), 1.58 (s, 3H); HRMS (FAB) m/z (MH+) calcd
319.19876, obsd 319.199838.
Synthesis of 4-(Triethylsiloxy)-2-[3,7-dimethyl-(2E)-2,6-octadi-
enyl]-5,6-dimethoxy-3-methylphenol and 4-(Triethylsiloxy)-3-[3,7-
dimethyl-(2E)-2,6-octadienyl]-5,6-dimethoxy-2-methylphenol (9a and
9b). A round-bottom flask equipped with stir bar is charged with 2
(0.63 g, 2.0 mmol) and 10 mL of 10/1 methanol/water. With vigorous
stirring, sodium dithionite (0.38 g, 2.2 mmol) was added. The reddish
orange color of the ubiquinone-2 quickly dissipates, signaling the
formation of the ubiquinol. The resultant slurry is extracted with 100
mL of hexane and filtered into a dry round-bottom flask through a
small plug of MgSO4. Solvent is removed in vacuo, and the nearly
colorless oil is redissolved in dry acetonitrile and the flask purged with
dry nitrogen. The flask is charged with a stirring bar and dry pyridine
(0.16 g, 2.2 mmol). Chlorotriethylsilane (0.33 g, 2.2 mmol) was added
dropwise using a syringe pump over a 6 h period. The reaction was
monitored by GC/MS. Solvent and excess TESCl were removed in
vacuo when the disilyl product began to accumulate. The resultant oil
is purified by flash chromatography using 9/1 hexane/EtOAc to give a
clear colorless oil. Yield 0.4 g (61%). 1H NMR (CDCl3, TMS) for
9a δ 5.43 (s, 1H), 5.19 (m, 2H), 3.89 (s, 3H), 3.76 (s, 3H), 3.28 (d,
2H), 2.09 (s, 3H), 2.00 (m, 4H), 1.72 (s, 3H), 1.65 (s, 3H), 1.56 (s,
3H), 0.95 (t, 9H), 0.73 (q, 6H). 1H NMR (CDCl3, TMS) for 9b δ 5.41
(s, 1H), 5.06 (m, 2H), 3.89 (s, 3H), 3.76 (s, 3H), 3.31 (d, 2H), 2.09 (s,
3H), 2.00 (m, 4H), 1.75 (s, 3H), 1.65 (s, 3H), 1.56 (s, 3H), 0.96 (t,
9H), 0.73 (q, 6H); HRMS (FAB) m/z (MH+) calcd 435.29304, obsd
435.29323 for a mixture of 9a and 9b.
Synthesis of (()-3,5-Dimethoxyphenyl-2-phenyl-1,3-dithi-2-yl-
methanol (3). A flame dried flask was charged with a stir bar, 100
mL of dry THF, and 2-phenyl-1,3-dithiane (3.9 g, 20 mmol). This
solution is cooled to 0 °C, and 22 mmol of n-butyllithium was added
dropwise via syringe (11 mL of a 2.0 M solution in hexane). Formation
of the dithiane anion is indicated by the presence of a pale olive green
color. Upon completion of the addition the reaction is allowed to stir
for 30 min, and then 3,5-dimethoxy benzaldehyde dissolved in dry THF
is added via syringe (3.3 g, 20 mmol, 2 × 10 mL THF). The reaction
is allowed to stir for 1 h at 0 °C and then poured into 100 mL of 0.1
M HCl and extracted with diethyl ether. The organic phase was filtered
through a plug of MgSO4, and solvent removed in vacuo to yield a
colorless oil which was further purified by flash chromatography using
4/1 hexane/EtOAc. Yield: 7.1 g (98.6%). 1H NMR (300 MHz, CDCl3)
δ 7.73 (dd, 2H), 7.31 (m, 3H), 6.30 (t, 1H), 5.99 (d, 2H), 4.94 (d, 1H),
3.00 (d, 1H), 3.57 (s, 6H), 2.74-2.65 (bm, 4H), 1.94-1.90 (bm, 2H);
HRMS (FAB) m/z (MH+) calcd 363.1122, obsd 363.1513.
Figure 4. HPLC analysis of the photoproducts formed in Figure 2,
following air oxidation.
with an Oriel 66011 Hg vapor lamp operating at 450 W and filtered
through a 355 nm band-pass filter. The sample was removed, and the
optical absorbance recorded at 5 min time intervals using an HP 8452
diode array spectrophotometer. HPLC analysis was performed using
a Waters 625LC system equipped with a Delta-Pak C18 reverse phase.
Transient Photolysis of 1. A 10 µM solution of 1 in methanol
was prepared in a 1 cm path length quartz cuvette equipped with a
septum. The sample was purged with oxygen free argon and irradiated
at 355 nm using a 10 ns pulse from a Nd:YAG laser. Absorbance
spectra were then recorded after successive laser shots.
X-ray Crystallograpy of (()-2,6-Dimethoxyphenoxy-3,5-dimethoxy-
phenyl(2-phenyl-1,3-dithi-2-yl)methoxymethanone (6). A total of
10 078 reflections were collected at room temperature using a CAD-4
diffractometer and the ω-scan method. The data were reduced and
merged in CRYM (Duchamp, D. J. Amer. Crystallogr. Assoc. Meet.
1964, 29) to give a total of 10 078 unique reflections with an Rcryst
0.042. Structure solution was performed with SHELXS-86 direct
methods (Sheldrick, G. M. Acta. Crystallogr. 1990, A46, 467). The
model was refined against F2 using 1/σ2 weights with SHELXL-93
(Sheldrick, G. M., University of Gottingen), and the positions of
hydrogen atoms were revealed in difference Fourier maps.
Synthesis of 4,5-Dimethoxy-2-methyltricyclo[6.2.1.02,7]undeca-4,9-
diene-3,6-dione (7). A 25 mL flask was charged with a stir bar, 5 mL
of dry methanol, and 500 mg (3 mM) of 2,3-dimethoxy-5-methyl-1,4-
benzoquinone. To this solution is added 3 mL of freshly distilled
cyclopentadiene. The reaction is allowed to stir overnight during which
time the dark reddish orange color of the 2,3-dimethoxy-5-methyl-1,4-
benzoquinone fades to the pale yellow color of the product. Solvent
and excess cyclopentadiene are removed in vacuo to give a pale yellow
oil. Yield 0.75 g, (>99%). 1H NMR (CDCl3, TMS) δ 6.15 (m, 1H),
6.00 (m, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.41 (bs, 1H), 3.07 (bs, 1H),
2.82 (d, 1H) 1.66 (d, 1H), 1.53 (d, 1H), 1.47 (s, 3H); HRMS (FAB)
m/z (MH+) calcd 249.11267, obsd 249.11283.
Synthesis of 2-[3,7-Dimethyl-(2E)-2,6-octadienyl]-4,5-dimethoxy-
7-methyltricyclo[6.2.1.02,7]undeca-4,9-diene-3,6-dione (8). A flame
dried flask is charged with geranyl bromide (1.44 g, 6.6 mmol), 7 (1.5
g, 6 mmol), a stir bar, and 40 mL of dry 1/3 toluene/tert-butyl alcohol.
This solution is cooled to 0 °C using an ice bath, and 10 mL of 1 M
potassium tert-butoxide in tert-butyl alcohol is added via cannula with
rapid stirring. The solution immediately turns a dark brown color, and
the reaction is allowed to stir for 1 h at 0 °C. The reaction mixture is
then poured into 50 mL of saturated NH4Cl and extracted with 2 ×
100 mL of dry diethyl ether. The organic layers are combined, filtered
through a plug of MgSO4, and solvent removed in vacuo. The resultant
dark brown oil is purified by flash column chromatography using 4/1
hexane ethyl acetate to yield 1.68 g (73%) of 8. 1H NMR (CDCl3,
TMS) δ 6.05 (bs, 2H), 5.07 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.05
(d, 2H), 3.75 (dd, 1H), 2.42 (dd, 1H), 2.00 (m, 4H), 1.65 (s, 3H), 1.57
(s, 3H), 1.58 (s, 3H), 1.49 (s, 3H), 1.78 (d, 1H), 1.45 (d, 1H); HRMS
(FAB) (MH+) m/z calcd 384.230060, obsd 384.228649.
Synthesis of (()-2-Nitrophenoxy-3,5-dimethoxyphenyl(2-phenyl-
1,3-dithi-2-yl)methoxymethanone (5). A flame dried flask equipped
with stirring bar and septum was charged with 3 (8.16 g, 24.4 mmol),
150 mL of dry methylene chloride, and 2-nitrophenyl chloroformate
at room temperature under dry nitrogen. To this solution was added
2.2 equiv of dry pyridine via syringe. The solution was allowed to
stir for 1 h at room temperature, and then solvent was removed in vacuo.
The resultant residue was washed with dry ether, and the ether extract
was filtered through a plug of MgSO4. Solvent was removed in vacuo
to yield a thick oil which when dried under high vacuum produced a
pale yellow solid. Yield 9.96 g (77%). 1H NMR (300 MHz, CDCl3)
δ 8.11 (dd, 1H), 7.74 (m, 2H), 7.66 (t, 1H), 7.42 (t, 1H), 7.32 (m, 4H),
6.36 (t, 1H), 6.03 (s, 1H), 6.01 (d, 2H), 3.59 (s, 6H), 2.75 (m, 4H),
1.96 (m, 2H); HRMS (FAB) m/z (MH+) cacld 527.107246, obsd
527.106851.
Synthesis of (()-2,6-Dimethoxyphenoxy-3,5-dimethoxyphenyl(2-
phenyl-1,3-dithi-2-yl)methoxymethanone (6). A flame dried flask
equipped with stir bar and septum was charged with 5 (0.53 g, 1 mmol),
2,6-dimethoxyphenol (0.15 g, 1 mmol), DMAP (0.13 g, 1 mmol), and
10 mL of methylene chloride under dry nitrogen. The reaction was
allowed to stir at room temperature for 72 h, then poured into 10 mL
Synthesis of 2-[3,7-Dimethyl-(2E)-2,6-octadienyl]-5,6-dimethoxy-
3-methylbenzo-1,4-quinone (Ubiquinone-2) (2). A stirred solution