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for 2 h, a solution of farnesyl bromide (245 mg, 0.86 mmol) in THF
(1.0 mL) was added at –78 °C. The dry ice cooling bath was re-
moved, and the mixture was warmed to room temperature over a
period of 2 h and quenched with water (5.0 mL). The resulting
mixture was extracted with EtOAc (3 × 20 mL). The combined or-
ganic phases were washed with brine (30 mL), dried with MgSO4,
and concentrated under reduced pressure. The residue was purified
by column chromatography on aluminum oxide (EtOAc/hexane,
5:95) to yield the alkylation product (5S)-4b (C25H39ClO4, 170 mg,
in THF, 0.5 mL, 0.5 mmol) was added dropwise. The mixture was
stirred at –20 °C for 12 h and quenched with water (5.0 mL). The
resulting mixture was extracted with EtOAc (3 × 20 mL). The com-
bined extracts were washed with brine (30 mL), dried with MgSO4,
and concentrated under reduced pressure to give the crude alcohol
product as a mixture of diastereomers. Without further purification,
this sample was dissolved in CH2Cl2 (5 mL). Montmorillonite K10
(acidic clay, 200 mg, 2.2 mmol) was added, and the mixture was
stirred at room temperature for 10 min and then filtered. The filtrate
90 % yield) as a mixture of trans and cis isomers (1:1). The sample was concentrated under reduced pressure to give a residue. Purifi-
(170 mg, 0.39 mmol) that contained the trans and cis isomers (1:1) cation by column chromatography on silica gel (EtOAc/hexane,
was subjected to epimerization by treatment with NaH (2.0 mg,
0.04 mmol) in DMF (3.0 mL) at 25 °C for 24 h to give the mixture
of the trans and cis isomers (1:4) as a yellow oil; Rf = 0.53 (cis) and
10:90) gave (4R,5R,6S)-5b (C23H35ClO3, 40 mg, 44 % yield for two
steps) as a colorless oil. Rf = 0.18 (EtOAc/hexane, 10:90). [α]D25
+25.1 (c = 1.0, CHCl3). IR (neat): νmax = 3491, 2972, 2938, 2852, 1694,
=
˜
0.49 (trans, EtOAc/hexane, 10:90). IR (neat): νmax = 2966, 2936, 2855, 1683, 1380, 1223, 1010, 771 cm–1 1H NMR (500 MHz, CDCl3): δ =
.
˜
1695, 1601, 1457, 1379, 1210, 1071, 1053, 967, 808, 774 cm–1
.
1H 5.14–5.03 (m, 3 H), 4.48 (d, J = 4.3 Hz, 1 H), 3.78 (s, 3 H), 2.58 (qd,
J = 7.3, 4.3 Hz, 1 H), 2.38 (dt, J = 15.0, 7.3 Hz, 1 H), 2.30–2.22 (m, 1
H), 2.16–1.93 (m, 10 H), 1.66 (s, 3 H), 1.64 (s, 3 H), 1.58 (s, 6 H), 1.25
(d, J = 7.3 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 196.6,
148.2, 140.6, 138.0, 135.4, 131.3, 124.3, 123.8, 121.1, 72.4, 59.9, 45.2,
NMR (400 MHz, CDCl3, 1:4 mixture of isomers): δ = 5.15–4.98 (m, 6
H, olefinic protons), 4.14 (s, trans, MeO-3), 4.05 (s, cis, MeO-3), 3.32–
3.29 (s, 4 H), 3.27 (s, cis, MeO-4), 3.25 (s, trans, MeO-4), 2.95 (dt, J =
9.4, 4.0 Hz, CH, cis), 2.70 (CH, m, cis), 2.63–2.56 (CH, m, trans), 2.47
(qd, J = 7.0, 4.0 Hz, 5-H, cis), 2.43–2.30 (CH2, m, trans), 2.16–1.87 (m, 41.7, 39.8, 39.7, 26.7, 26.4, 25.8, 25.7, 17.7, 16.2, 16.0, 14.2 ppm.
16 H), 1.65 (s, 5 H), 1.62 (s, 4 H), 1.57 (s, 10 H), 0.96 (d, J = 6.5 Hz,
Me-5, trans), 0.79 (d, J = 7.0 Hz, Me-5, cis) ppm. 13C NMR (100 MHz,
CDCl3, 1:4 mixture of isomers): δ = 193.0, 165.9, 137.3, 135.1, 131.3,
124.3, 124.0, 121.1, 102.0, 61.2, 51.4, 48.1, 47.6, 39.9, 39.8, 39.7, 37.8,
26.8, 26.6, 25.7, 25.1, 17.7, 16.2, 16.0, 9.4 ppm. HRMS: calcd. for
HRMS: calcd. for C23H35NaClO3 [M + Na]+ 417.2167; found 417.2160.
(4R,5R,6S)-5-Farnesyl-4-hydroxy-2-methoxy-6-methylcyclohex-
2-en-1-one (5d):[8] Under nitrogen, a solution of (5S)-4d (100 mg,
0.25 mmol, mixture of trans and cis isomers, 1:4) in THF (3.0 mL)
was stirred at –20 °C for 15 min, and LS-Selectride (1.0
M in THF,
C
25H39NaClO4 [M + Na]+ 461.2435; found 461.2437.
0.5 mL, 0.5 mmol) was added dropwise. The mixture was stirred at
–20 °C for 12 h and quenched with water (5 mL). The resulting
mixture was extracted with EtOAc (3 × 20 mL), and the combined
extracts were washed with brine (30 mL), dried with MgSO4, and
concentrated under reduced pressure to give the crude alcohol (S)-
5d as a mixture of diastereomers. Without further purification, this
sample was dissolved in CH2Cl2 (5 mL). Montmorillonite K10 (acidic
clay, 200 mg, 2.17 mmol) was added, and the mixture was stirred
at room temperature for 10 min and then filtered. The filtrate was
concentrated under reduced pressure to give a residue. Purification
by column chromatography on silica gel (EtOAc/hexane, 10:90) gave
(4R,5R,6S)-5d (C23H36O3, 27 mg, 30 % yield for two steps) as a color-
less oil. Rf = 0.28 (EtOAc/hexane, 30:70). [α]2D5 = +21.7 (c = 0.525,
(5S,6RS)-6-Farnesyl-3,4,4-trimethoxy-5-methylcyclohex-2-en-1-
one (4d):[8] Under nitrogen, lithium hexamethyldisilazide (1.0
in
M
THF, 1.0 mL, 1.0 mmol) was added to a solution of (S)-3d (100 mg,
0.5 mmol) in THF (2.0 mL) at –78 °C. After the mixture was stirred
at –78 °C for 2 h, a solution of farnesyl bromide (285 mg, 1.0 mmol)
in THF (1.0 mL) was added at –78 °C. The dry ice cooling bath was
removed, and the mixture was warmed to room temperature over
a period of 2 h and quenched with water (5 mL). The resulting
mixture was extracted with EtOAc (3 × 20 mL). The combined or-
ganic phases were washed with brine (30 mL), dried with MgSO4,
and concentrated under reduced pressure. The residue was purified
by column chromatography on aluminum oxide (EtOAc/hexane,
10:90) to yield the alkylation product (5S)-4d (C25H40O4, 192 mg,
95 % yield) as a mixture of trans and cis isomers (1:1). This sample
(192 mg, 0.48 mmol) that contained trans and cis isomers (1:1) was
subjected to epimerization by treatment with NaH (2.0 mg,
0.05 mmol) in DMF (3.0 mL) at 25 °C for 24 h to give the mixture
of the trans and cis isomers (1:4) as a yellow oil. Rf = 0.50 (cis) and
CHCl3). IR (neat): νmax = 3474, 2972, 2926, 2855, 1687, 1631, 1451,
˜
1
1378, 1220, 1080, 772 cm–1. H NMR (500 MHz, CDCl3): δ = 5.68 (d,
J = 3.7 Hz, 1 H), 5.17 (br. s, 1 H.), 5.06 (d, J = 6.7 Hz, 2 H), 4.68–4.76
(m, 1 H), 3.62 (s, 3 H), 2.59 (dd, J = 7.3, 3.7 Hz, 1 H), 2.29 (d, J =
4.3 Hz, 2 H), 2.10–1.91 (m, 10 H), 1.66 (s, 3 H), 1.61 (s, 3 H), 1.58 (s,
6 H), 1.22 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
196.7, 150.6, 137.5, 135.4, 131.3, 124.3, 123.8, 122.5, 115.2, 69.5, 55.1,
45.4, 39.7, 39.6, 29.7, 26.7, 26.4, 25.7, 24.1, 17.7, 16.2, 16.0, 13.8 ppm.
HRMS: calcd. for C23H36NaO3 [M + Na]+ 383.2557; found 383.2556.
0.51 (trans, EtOAc/hexane, 20:80). IR (neat): νmax = 2966, 2925, 2854,
˜
1
1663, 1616, 1457, 1364, 1210, 1069, 1052 cm–1. H NMR (400 MHz,
CDCl3, 1:4 mixture of isomers): δ = 5.36 (s, trans, 2-H), 5.32 (s, cis, 2-
H), 5.12–5.02 (m, 6 H, olefinic protons), 3.73 (s, trans, MeO-3), 3.71
(s, cis, MeO-3), 3.28 (s, 4 H), 3.25 (s, cis, MeO-4), 3.21 (s, trans, MeO-
4), 2.94–2.83 (CH, m, cis), 2.71–2.61 (CH, m, cis), 2.59–2.54 (CH, m,
trans), 2.53–2.45 (m, cis, 5-H), 2.45–2.35 (CH, m, trans), 2.35–2.23 (CH,
m, trans), 2.12–1.89 (m, 12 H), 1.65 (s, 4 H), 1.62 (s, 3 H), 1.57 (s, 7
H), 0.96 (d, J = 7.0 Hz, Me-5, trans), 0.79 (d, J = 7.0 Hz, Me-5, cis) ppm.
13C NMR (100 MHz, CDCl3, 1:4 mixture of isomers): δ = 199.6, 170.1,
136.8, 135.0, 131.2, 124.3, 124.1, 121.6, 103.3, 100.6, 55.9, 51.1, 47.7,
47.6, 39.9, 39.8, 38.2, 26.8, 26.6, 25.6, 24.5, 17.6, 16.2, 16.0, 9.4 ppm.
HRMS: calcd. for C25H41O4 [M + H]+ 405.3005; found 405.3004.
(4R,5R,6R)-5-Farnesyl-4-hydroxy-2,3-dimethoxy-6-methylcyclo-
hex-2-en-1-one [1a, (+)-Antroquinonol]:[1] A mixture of (4R,5R,6S)-
5b (40 mg, 0.1 mmol) and K2CO3 (41 mg, 0.3 mmol) in MeOH
(2.0 mL) was stirred at room temperature for 12 h for the inversion
of the configuration at C-6 and substitution of the chloro group
with a methoxy group. The mixture was quenched with saturated
aqueous NH4Cl (5 mL) and then extracted with CH2Cl2 (3 × 20 mL).
The combined organic phases were washed with brine (30 mL),
dried with MgSO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
(EtOAc/CH2Cl2, 2:98) to give (+)-antroquinonol (C24H38O4, 31 mg,
(4R,5R,6S)-3-Chloro-5-farnesyl-4-hydroxy-2-methoxy-6-methyl-
cyclohex-2-en-1-one (5b): Under nitrogen, a solution of (5S)-4b
(100 mg, 0.23 mmol, mixture of trans and cis isomers, 1:4) in THF
80 % yield) as a yellow oil. Rf = 0.56 (EtOAc/hexane, 25:75). [α]D25
=
+45.0 (c = 0.48, CHCl3); ref.[1] [α]D18 = +72.7 (c = 0.28, CHCl3); ref.[4]
[α]D20 = +52.0 (c = 0.364, MeOH); ref.[6] [α]2D5 = +44.6 (c = 1.2, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 5.14 (t, J = 7.3 Hz, 1 H), 5.07 (t, J =
(3.0 mL) was stirred at –20 °C for 15 min, and LS-Selectride (1.0
M
Eur. J. Org. Chem. 0000, 0–0
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