ACCEPTED MANUSCRIPT
to -78 °C and 2.5 M n-butyllithium (12.16 mL, 30.4 mmol) added. The
(50 mL), the organics were washed with water (6 x 50 mL), dried over
magnesium sulfate, filtered and concentrated under reduced pressure
onto celite (2 g). Purification by flash column chromatography over silica
(25 g) eluting 40-60 petrol ether: ethyl acetate (100:0) to (70:30) gave the
title compound as a white solid (835 mg, 84%, m.p. 58-59 °C): Rf 0.24
(20% ethyl acetate / 80% 40-60 petrol ether); 1H (500 MHz, chloroform-d)
δ 12.41 (1 H, s), 10.13 (1H, s), 6.28 (1H, s), 3.89 (3H, s), 2.95 – 2.86
(2H, m), 2.57 (3H, s), 2.45 – 2.38 (2H, m), 1.44 (9H, s). 13C NMR (126
MHz, chloroform-d) δ 193.1, 172.7, 164.1, 162.9, 142.3, 114.1, 113.6,
105.2, 79.9, 55.7, 34.2, 28.13, 18.4, 17.8. HRMS (ESI): calcd. 279.1955
for C17H27O3 [M+H]+, found 279.1948 m/z.
reaction was warmed to room temperature then cooled to -78 °C and tert-
butyl 3-(2-methoxy-4-methyl-6-oxo-cyclohexen-1-yl)propanoate (14) (6.8
g, 25.3 mmol) added. The reaction was stirred for 1 hour at -78 °C
then methyl formate (2.34 mL, 38.0 mmol) was added and it was allowed
to warm to room temperature overnight. The reaction was concentrated
under reduced pressure, diluted water (50 mL) and neutralised by careful
addition of 1M aqueous hydrogen chloride solution. The organics were
dried over magnesium sulfate, filtered and concentrated under reduced
pressure onto celite (5 g). Purification by flash column chromatography
over silica (100 g) eluting 40-60 petrol ether: ethyl acetate (100:0) to
(70:30) gave the title compound as a yellow oil (4.41 g, 58.6%): Rf 0.22
(20% ethyl acetate / 80% 40-60 petrol ether); 1H NMR (500 MHz,
chloroform-d) δ 7.21 – 7.07 (1 H, m), 3.79 (3 H, s), 2.76-2.69 (1 H, m),
2.67-2.60 (1 H, m), 2.60-2.56 (2 H, m), 2.35-2.25 (3 H, m), 1.41 (9 H, s),
1.16 (3 H, d, J = 6.8 Hz); 13C NMR (126 MHz, chloroform-d) δ 191.7,
172.7, 170.0, 160.3, 116.5, 111.2, 79.7, 55.2, 34.3, 32.0, 28.3, 28.1,
20.3, 17.5. IR (neat, νmax) cm-1 2972, 1721, 1607, 1366, 1241, 1146,
1080, 998, 847; HRMS (ESI): calcd. 319.1521 for C16H24NaO5 [M+Na]+,
found 319.1521 m/z.
2-Chloro-6-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-4-formyl-5-hydroxy-
3-methylphenyl acetate (20) To a solution of 2-chloro-5-{[(2E)-3,7-
dimethylocta-2,6-dien-1-yl]oxy}-4-formyl-3-methylphenyl acetate (5) (757
mg, 2.07 mmol) in toluene (7.5 mL) was added Fluorosil (100-200 mesh,
2.3 g). The reaction mixture was heated at reflux for 3 hours before being
allowed to cool to room temperature and being filtered. The Fluorosil was
washed with ethyl acetate (3 x 15 mL) and the combined filtrate was
concentrated under reduced pressure. Purification by flash column
chromatography (25 g silica), eluting with a gradient of petrol ether : ethyl
acetate (100 : 0) to (95 : 5), gave the title compound as a colourless oil
(212 mg, 28%): Rf 0.67 (5% ethyl acetate / 95% 40-60 petrol ether) 1H
NMR (500 MHz, Chloroform-d) δ 12.53 (s, 1H), 10.31 (s, 1H), 5.21 – 4.96
(m, 2H), 3.35 – 3.25 (m, 2H), 2.66 (s, 3H), 2.38 (s, 3H), 2.09 – 2.01 (m,
2H), 2.01 – 1.93 (m, 2H), 1.75 (s, 3H), 1.66 (s, 3H), 1.59 (s, 2H). LCMS
(ESI) retention time 6.83 min, m/z 365.43 / 367.21.
6-(Hydroxymethylene)-3-methoxy-5-methyl-2-octylcyclohex-2-enone
(17)
Diisopropylamine (2.67 mL, 19.0 mmol) was dissolved in
dry tetrahydrofuran (150 mL) and cooled to -78 °C and n-butyllithium
(6.18 mL, 15.5 mmol) added. The mixture was allowed to warm to room
temperature and stirred for 30 minutes. This was cooled to -78 °C and a
solution of 3-methoxy-5-methyl-2-octyl-cyclohex-2-en-1-one (15) (3.00 g,
11.9 mmol) in dry tetrahydrofuran (5 mL) was added via syringe. This
was stirred for 1 hour and dry methyl formate (1.47 mL, 23.77 mmol) was
added, the reaction was allowed to warm to room temperature overnight
slowly in the dry ice acetone bath. The reaction mixture was
concentrated under reduced pressure and diluted with ethyl acetate (30
mL) and water (30 mL). This was neutralised with 1M aqueous hydrogen
chloride, the ethyl acetate separated and washed with water (30 mL).
The organics were dried over magnesium sulfate, filtered and
concentrated under reduced pressure onto celite (2 g). Purification by
flash column chromatography over silica (25 g) eluting 40-60 petrol ether:
ethyl acetate (100:0) to (90:10) gave the title compound as a clear yellow
oil (2.25 g, 68%): Rf 0.46 (20% ethyl acetate / 80% 40-60 petrol ether)
1H (500 MHz, chloroform-d) δ 7.19 (1 H, d, J = 1.2 Hz), 3.79 (3 H, s),
2.75 (1 H, q, J = 6.7 Hz), 2.65 (1 H, dd, J = 16.6, 6.1 Hz), 2.37 – 2.27 (3
H, m), 1.34 (2 H, m), 1.27 (10 H, m), 1.18 (3 H, d, J = 6.8 Hz), 0.88 (3 H,
t, J = 6.8 Hz); 13C NMR (126 MHz, chloroform-d) δ 191.9, 169.3, 160.5,
111.3, 55.0, 31.9, 31.8, 29.6, 29.4, 29.2, 28.6, 28.3, 22.6, 21.6, 20.4,
14.0. IR (neat, νmax) cm-1 2923, 1608, 1378, 1238, 1159, 1130, 1006,
953; HRMS (ESI): calcd. 281.2117 for C17H29O3 [M+H]+, found 281.2113
m/z.
5-Chloro-3-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-2,4-
dihydroxybenzaldehyde (21) To a solution of 6-chloro-2-[(2E)-3,7-
dimethylocta-2,6-dien-1-yl]-4-formyl-3-hydroxyphenyl acetate (22) (70.0
mg, 0.200 mmol) in tetrahydrofuran (4 mL) and methanol (1 mL) was
added 1 M aqueous sodium hydroxide (1.0 mL, 1.00 mmol). The reaction
mixture was stirred at room temperature for 6 hours before being
quenched with 1 M aqueous hydrochloric acid (5 mL) and extracted with
ethyl acetate (3 x 10 mL). The combined organic fractions dried over
magnesium sulfate, filtered and concentrated under reduced pressure.
Purification by flash column chromatography (10 g silica), eluting with a
gradient of petrol ether : ethyl acetate (100 : 0) to (90 : 10), gave the title
compound as an off-white solid (55 mg, 89%): Rf 0.40 (5% ethyl acetate /
95% 40-60 petrol ether) 1H NMR (500 MHz, Chloroform-d) δ 11.53 (s,
1H), 9.67 (s, 1H), 7.39 (s, 1H), 6.38 (s, 1H), 5.29 – 5.19 (m, 1H), 5.10 –
5.02 (m, 1H), 3.44 (d, J = 7.2 Hz, 2H), 2.13 – 2.04 (m, 2H), 2.04 – 1.97
(m, 2H), 1.81 (d, J = 1.5 Hz, 3H), 1.66 (d, J = 1.7 Hz, 3H), 1.58 (s, 3H).
6-Chloro-2-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-4-formyl-3-
hydroxyphenyl acetate (22) To a solution of 2-chloro-5-{[(2E)-3,7-
dimethylocta-2,6-dien-1-yl]oxy}-4-formylphenyl
acetate
(synthesised
using the same method to make 5) (430 mg, 1.22 mmol) in toluene (6.5
mL) was added Fluorosil (100-200 mesh, 2.2 g). The reaction mixture
was heated at reflux for 3 hours before being allowed to cool to room
temperature and being filtered. The Fluorosil was washed with ethyl
acetate (3 x 15 mL) and the combined filtrate was concentrated under
reduced pressure. Purification 3 times by flash column chromatography
(10 g silica), eluting with a gradient of petrol ether : ethyl acetate (100 : 0)
to (95 : 5), gave the title compound as a pale yellow oil (78 mg, 18%): Rf
0.59 (5% ethyl acetate / 95% 40-60 petrol ether) 1H NMR (500 MHz,
Chloroform-d) δ 11.41 (s, 1H), 9.82 (s, 1H), 7.51 (s, 1H), 5.13 – 5.08 (m,
1H), 5.08 – 5.04 (m, 1H), 3.34 (d, J = 7.0 Hz, 2H), 2.38 (s, 3H), 2.13 –
2.01 (m, 2H), 2.01 – 1.91 (m, 2H), 1.76 (s, 3H), 1.66 (s, 3H), 1.59 (s, 3H).
LCMS (ESI) retention time 6.64 min, m/z 351.59 / 353.19.
Tert-butyl-3-(3-formyl-2-hydroxy-6-methoxy-4-
methylphenyl)propanoate (18) (Z)-tButyl 3-(5-(hydroxymethylene)-2-
methoxy-4-methyl-6-oxocyclohex-1-en-1-yl)propanoate (16) (1.00 g, 3.4
mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.92 g, 4.1
mmol) were dissolved in toluene (100 mL) and stirred for 16 hours at
room temperature. The reaction was diluted with diethyl ether (200 mL),
the organics were washed with water (6
x 100 mL), dried over
magnesium sulfate, filtered and concentrated under reduced pressure
onto celite (2 g). Purification by flash column chromatography over silica
(25 g) eluting 40-60 petrol ether: ethyl acetate (100:0) to (70:30) gave the
title compound as a white solid (835 mg, 84%, m.p. 58-59 °C): Rf 0.36
(20% ethyl acetate / 80% 40-60 petrol ether); 1H (500 MHz, chloroform-d)
δ 12.41 (1 H, s), 10.13 (1 H, s), 6.28 (1 H, s), 3.89 (3 H, s), 2.95-2.86 (2
H, m), 2.57 (3 H, s), 2.45-2.38 (2 H, m), 1.44 (9 H, s). 13C NMR (126
MHz, chloroform-d) δ 193.1, 172.7, 164.1, 162.9, 142.3, 114.1, 113.6,
105.2, 79.9, 55.7, 34.2, 28.1, 18.4, 17.8. IR (neat, νmax) cm-1 2967, 1722,
1637, 1366, 1248, 1125, 1004, 816, 644; HRMS (ESI): calcd. 317.1365
for C16H22NaO5 [M+Na]+, found 317.1363 m/z.
3-[(2E)-3,7-Dimethylocta-2,6-dien-1-yl]-2,4-dihydroxy-6-
methylbenzaldehyde (23) To a solution of 2-[(2E)-3,7-dimethylocta-2,6-
dien-1-yl]-4-formyl-3-hydroxy-5-methylphenyl acetate (24) (6.0 mg, 0.018
mmol) in tetrahydrofuran (0.5 mL) and methanol (0.12 mL) was added 4
M aqueous sodium hydroxide (9 µL, 1.00 mmol). The reaction mixture
was stirred at room temperature for 3 hours before being acidified to pH
2 with 1 M aqueous hydrochloric acid and extracted with ethyl acetate (3
x 3 mL). The combined organic fractions dried over magnesium sulfate,
filtered and concentrated under reduced pressure. Purification by flash
column chromatography (1 g silica), eluting with a gradient of petrol ether
: ethyl acetate (100 : 0) to (90 : 10), gave the title compound as a white
solid (2.7 mg, 51%): Rf 0.15 (10% ethyl acetate / 90% 40-60 petrol ether)
1H NMR (500 MHz, Chloroform-d) δ 12.78 (s, 1H), 10.09 (s, 1H), 6.22 (s,
1H), 6.15 (s, 1H), 5.31 – 5.22 (m, 1H), 5.12 – 5.00 (m, 1H), 3.42 (d, J =
7.2 Hz, 2H), 2.51 (s, 3H), 2.19 – 2.01 (m, 4H), 1.82 (d, J = 1.5 Hz, 3H),
2-Hydroxy-4-methoxy-6-methyl-3-octylbenzaldehyde
(19)
6-
(Hydroxymethylene)-3-methoxy-5-methyl-2-octylcyclohex-2-enone (17)
(77 mg, 0.3 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (73
mg, 4.1 mmol) were dissolved in toluene (20 mL) and stirred for 16
hours at room temperature. The reaction was diluted with diethyl ether