Total Synthesis of (-)-Ilimaquinone
1710, 1455, 1189, 1086 cm-1 1H NMR (CDCl3) δ 3.98-3.85
(m, 4H), 2.50-2.21 (m, 3H), 1.91 (dt, 1H), 1.80-1.46 (m, 8H),
1.24 (s, 3H), 0.99 (d, 3H); 13C NMR (CDCl3) δ 208.4, 112.5,
65.0, 64.9, 48.0, 44.9, 42.3, 37.5, 30.6, 29.9, 24.9, 22.6, 14.1,
11.6. Anal. Calcd for C14H22O3: C, 70.56; H, 9.30. Found: C,
70.76; H, 9.37.
J . Org. Chem., Vol. 63, No. 17, 1998 5893
;
(CDCl3) δ 148.8, 141.1, 126.4, 100.0, 61.0, 56.4, 22.7. Anal.
Calcd for C11H15BrO4: C, 45.61; H, 5.33. Found: C, 45.36; H,
5.15.
(1R,4a S)-1,2,4a ,5,6,7,8,8a -Octa h yd r o-1r-[(2,3,5,6-tetr a -
m eth oxyben zen e)m eth yl]-1â,4aâ-dim eth yl-5-(1,3-dioxolan -
2-yl)n a p h th a len -2-on e (16). To a solution of LiHMDS (3.6
mmol, prepared from n-BuLi, 1.6 M in hexane, and hexam-
ethyldisilazane at 0 °C) in dry THF (10 mL) was added a
solution of enone 11 (708 mg, 3 mmol) in dry THF (5 mL) at
-78 °C. The mixture was allowed to warm to 0 °C over 30
min and then cooled to -78 °C, and a solution of bromobenzyl
15 (1.047 g, 3.6 mmol) in dry THF (10 mL) was added
dropwise. The mixture was allowed to warm to room temper-
ture over 30 min and heated at 50 °C for an additional 1 h.
The mixture was cooled and solvent removed in vacuo. The
residue was extracted with CH2Cl2, washed with water and
brine, dried over MgSO4, and concentrated in vacuo. Flash
chromatography (hexanes-EtOAc 1:1) gave compound 16
(1.217 g, 91%) as white crystals: mp 136 °C; Rf: 0.16 (7:3
hexane-AcOEt); [R]D -1.2 (c 1.7, CHCl3); MS m/z (EI) 446
(1S,4a S)-1,2,4a ,5,6,7,8,8a -Oct a h yd r o-1r,4a â-d im et h yl-
5-(1,3-d ioxola n -2-yl)n a p h th a len -2-on e (11). To a solution
of LDA (4.8 mmol, prepared from n-BuLi 1.6 M in hexane and
diisopropylamine at 0 °C) in dry THF (10 mL) was added a
solution of 10 (952 mg, 4 mmol) in dry THF (10 mL) at -78
°C. The mixture was stirred for 1 h at -78 °C. TMSCl (1
mL, 8 mmol) was added. The reaction was stirred for 30 min
at -78 °C and then allowed to warm at room temperature.
The THF was evaporated under reduced pressure and the
residue diluted with ether, washed with water and saturated
NaCl, dried over MgSO4, and concentrated in vacuo. The
crude silyl enol was dissolved in CH3CN (16 mL), Pd(OAc)2
(986 mg, 4.4 mmol) was added, and the mixture was heated
under reflux for 1 h. The mixture was filtered and the solvent
removed under reduced pressure. The residue was subjected
to flash column chromatography using hexanes-EtOAc (8:2)
as eluent to give compound 11 (897 mg, 95%) as colorless
needles: mp 79 °C; Rf 0.31 (4:1 hexane-AcOEt); [R]D -30.8 (c
3.0, CHCl3); MS m/z (CI) 237 (MH+); IR (KBr) 2929, 1660, 1460
cm-1; 1H NMR (CDCl3) δ 6.97 (d, 1H), 5.83 (d, 1H), 4.02-3.88
(m, 4H), 2.22 (m, 1H), 2.03 (dt, 1H), 1.69-1.41 (m, 5H), 1.22
(m, 1H), 1.13 (s, 3H), 1.06 (d, 3H); 13C NMR (CDCl3) δ 201.4,
155.3, 127.4, 111.4, 65.1, 64.6, 45.6, 45.2, 41.9, 29.0, 23.7, 22.5,
16.0, 12.2. Anal. Calcd for C14H20O3: C, 71.16; H, 8.53.
Found: C, 70.78; H, 8.96.
(M+); IR (KBr) 2963, 2922, 1665, 1598, 1490, 814 cm-1 1H
;
NMR (CDCl3) δ 6.86 (d, 1H), 6.47 (s, 1H), 6.01 (d, 1H), 3.95-
3.84 (m, 4H), 3.82 (s, 6H), 3.64 (s, 6H), 3.19 (d, 1H), 2.85 (d,
1H), 2.18-2.13 (dd, 1H), 1.56-1.23 (m, 6H), 1.18 (s, 3H), 1.16
(s, 3H); 13C NMR (CDCl3) δ 202.7, 152.6, 148.6, 141.9, 127.7,
126.4, 111.8, 98.8, 64.9, 64.5, 59.9, 56.5, 47.9, 45.1, 42.6, 34.5,
29.6, 22.7, 22.6, 20.9, 19.3. Anal. Calcd for C25H34O7: C, 67.24;
H, 7.67. Found: C, 67.48; H, 7.88.
(1R,4a S)-Deca h yd r o-1â,4a â-d im et h yl-1r-[(2,3,5,6-t et -
r a m eth oxyben zen e)m eth yl]-n a p h th a len -2-on e (17).
A
mixture of enone 16 (1.12 g, 2.511 mmol) and 10% Pd/C (110
mg) in EtOH (20 mL) was stirred at room temperature under
1 atm of hydrogen for 4 h. The reaction was filtered through
Celite and the filtrate concentrated in vacuo. Flash chroma-
tography (hexanes-EtOAc 1:1) gave compound 17 (1.08 g,
96%) as a white solid: mp 95 °C; Rf 0.24 (7:3 hexane-AcOEt);
[R]D +29.8 (c 1.98, CHCl3); MS m/z (EI) 448 (M+); IR (KBr)
2,3,5,6-Tetr a m eth oxyben zyl Alcoh ol (14). To a solution
of 1,2,4,5-tetramethoxybenzene (3.01 g, 15.2 mmol) in dry THF
(75 mL) was added n-BuLi (1.6 M in hexane, 10 mL, 16 mmol)
dropwise at -78 °C over 30 min. The reaction was warmed
to -10 °C over 1 h and stirred at this temperature for an
additional 1 h. The mixture was cooled to -78 °C, and dry
DMF (5.84 mL, 76 mmol) was added in one portion. The
reaction was allowed to warm to 0 °C over 1 h. THF was
removed under reduced pressure, water was added, and the
residue was extracted with ether (2×). The combined organic
layers were washed with brine, dried over MgSO4, and
concentrated in vacuo to give the crude benzaldehyde 13 (3.39
g), which was used for the next step without further purifica-
tion. To a solution of the crude benzaldhyde 13 (3.39 g) in
dry THF (70 mL) was added LiAlH4 (577 mg, 15.2 mmol) in
small portions at 0 °C. The reaction was stirred for 1 h at 0
°C. EtOAc was added to destroy the excess of LiAlH4 and the
mixture concentrated in vacuo. The residue was extracted
with CH2Cl2, washed successively with 1 N HCl, water, and
brine, dried over MgSO4, and concentrated. The residue was
subjected to flash column chromatography using hexanes-
EtOAc (1:1) as eluent to give compound 14 (3.1 g, 89%): white
solid; mp 86 °C; MS m/z (EI) 228 (M+); IR (KBr) 3400, 3000,
1
2934, 1703, 1598, 1492, 1466, 1240 cm-1; H NMR (CDCl3) δ
6.46 (s, 1H), 3.92 (m, 4H), 3.82 (s, 6H), 3.66 (s, 6H), 3.15 (d,
1H), 2.79 (d, 1H), 2.73 (m, 1H), 2.32 (m, 1H), 2.22-2.08 (m,
2H), 1.65-1.28 (m, 7H), 1.03 (s, 3H), 1.00 (s, 3H); 13C NMR
(CDCl3) δ 206.1, 148.4, 141.9, 125.7, 112.8, 98.9, 64.9, 64.6,
59.9, 56.5, 50.5, 46.0, 42.1, 34.3, 34.1, 29.9, 28.6, 22.7, 22.5,
20.5, 17.2. Anal. Calcd for C25H36O7: C, 66.94; H, 8.09. Found:
C, 66.81; H, 8.32.
(1R,4aS)-Decah ydr o-1r-[(2,3,5,6-tetr am eth oxyben zen e)-
m eth yl]-1â,4aâ-dim eth yl-2-m eth ylen e-5-(1,3-dioxolan -2-yl)-
n a p h th a len e (18). NaH (60% oil dispersion; 0.456 g, 11.4
mmol) was washed with several portions of hexane. Dry
DMSO (10 mL) was introduced and the mixture heated at 80
°C for 45 min. The resulting solution of methylsulfinyl
carbanion was cooled to 0 °C (ice-water bath), and a solution
of methyltriphenylphosphonium iodide (5.9 g, 14.6 mmol) in
warm DMSO (15 mL) was added dropwise over 30 min. The
reaction mixture was stirred at room temperature for an
additional 30 min, and a solution of ketone (725 mg, 1.62
mmol) in dry DMSO (5 mL) was added dropwise over 1 min.
The reaction mixture was heated at 75-80 °C for 24 h, cooled
to 0 °C, diluted with water (20 mL), and extracted with ether
(3×). The combined organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo. Flash chroma-
tography (hexanes-EtOAc 8:2) gave compound 18 (658 mg,
91%) as a white solid: mp 56 °C; Rf 0.35 (4:1 hexane-AcOEt);
[R]D +63.8 (c 0.83, CHCl3); MS m/z (EI) 446 (M+); IR (KBr)
1
2942, 2840, 1600, 1499, 1350, 1250, 813, 640 cm-1; H NMR
(CDCl3) δ 6.52 (s, 1H), 4.73 (d, 2H), 3.85 (s, 3H), 3.81 (s, 3H),
2.81 (t, 1H); 13C NMR (CDCl3) δ 148.7, 140.8, 128.3, 98.8, 61.3,
56.2, 55.6. Anal. Calcd for C11H16O5: C, 57.97; H, 7.08.
Found: C, 57.89; H, 7.01.
2,3,5,6-Tetr a m eth oxyben zyl Br om id e (15). To a solution
of alcohol 14 (2.97 g, 13 mmol) in dry CH2Cl2 (60 mL) was
added CBr4 (5.173 g, 15.6 mmol) at -7 °C (salt ice bath),
followed by addition of Ph3P (4.427 g, 16.9 mmol, 1.3 equiv)
in small portion. The mixture was stirred at this temperature
for an additional 15 min. The CH2Cl2 was removed under
reduced pressure, ether was added, and the mixture was
filtered. The filter cake was washed with ether (3×). The
filtrate was washed with water and brine, dried over MgSO4,
and concentrated. The residue was purified over silica gel
(hexanes-EtOAc 7:3) to give 15 (3.3 g, 87%) as a white solid:
mp 127 °C; MS m/z (EI) 290-292 (M+); IR (KBr) 3000, 2942,
2840, 1595, 1502, 1340, 1255, 813, 590 cm-1; 1H NMR (CDCl3)
δ 6.54 (s, 1H), 4.65 (s, 2H), 3.92 (s, 3H), 3.85 (s, 3H); 13C NMR
1
1640, 1598, 1480, 890, 813 cm-1; H NMR (CDCl3) δ 6.39 (s,
1H), 4.59 (s, 1H), 4.09 (d, 1H), 4.00-3.85 (m, 4H), 3.79 (s, 6H),
3.64 (s, 6H), 2.77 (d, 1H), 2.60 (d, 1H), 2.43 (m, 1H), 2.17-
1.93 (m, 3H), 1.69-1.06 (m, 7H), 1.00 (s, 3H), 0.88 (s, 3H); 13
C
NMR (CDCl3) δ 153.7, 148.1, 142.1, 126.5, 113.8, 106.9, 97.3,
64.9, 64.4, 60.3, 56.2, 47.7, 44.2, 42.9, 35.4, 32.1, 29.4, 23.4,
23.0, 21.0, 19.2. Anal. Calcd for C26H38O6: C, 69.93; H, 8.58.
Found: C, 69.84; H, 8.81.
(1R,2S,4a S)-Decah ydr o-1â,2â,4a â-tr im eth yl-1r-[(2,3,5,6-
tetr am eth oxyben zen e)m eth yl]-5-(1,3-dioxolan -2-yl)n aph -
th a len e (19) a n d (1R,2R,4a S)-Deca h yd r o-1â,2r,4a â-tr i-