Synthesis of Hexahydroindolinone Alkaloids
J . Org. Chem., Vol. 66, No. 9, 2001 3125
(3,4-dimethoxyphenyl)-1-methyl-octahydroindole-5-ol (16) and
0.02 g (10%) of trans-3a-(3,4-dimethoxyphenyl)-1-methyl-
octahydroindole-5-ol (17). The stereochemistry of each isomer
was assigned on the basis of their characteristic NMR spectra.
3-(Ben zo[1,3]d ioxol-5-yl)bu t-3-en -1-ol (21). To a mixture
containing 1.0 mL (10 mmol) of 3-bromobut-3-en-1-ol,45 0.35 g
(0.3 mmol) of tetrakis(triphenylphosphine)palladium, 10 mL
of a 2.0 M sodium carbonate solution, and 20 mL of benzene
was added a slurry containing 1.8 g (11 mmol) of 3,4-
methylene-dioxyphenylboronic acid (19) in 10 mL of ethanol.
The mixture was heated at reflux for 12 h under an argon
atmosphere. After cooling, the mixture was treated with 1 mL
of hydrogen peroxide for 30 min. The organic phase was
separated, and the aqueous phase was extracted with ether.
The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure, and the residue was
purified by silica gel chromatography to give 1.0 g (54%) of
alcohol 21 as a yellow oil: IR (neat) 3360, 1503, 1490, and
The major cis-diastereoisomer 16 consisted of a yellow oil
that exhibited the following spectral properties: IR (neat)
3364, 1520, and 1253 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.50-
2.00 (m, 8H), 2.20-2.23 (m, 1H), 2.30-2.37 (m, 1H), 2.33 (s,
3H), 2.55 (s, 1H), 3.27 (dt, 1H, J ) 9.2 and 4.8 Hz), 3.46-3.55
(m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), and 6.79-6.89 (m, 3H); 13
C
NMR (CDCl3, 100 MHz) δ 22.1, 29.7, 40.3, 41.0, 44.6, 49.2,
54.1, 55.8, 55.9, 67.5, 67.8, 110.1, 110.6, 118.2, 139.4, 147.0,
and 148.7. Anal. Calcd for C17H25NO3: C, 70.06; H, 8.65; N,
4.81. Found: C, 69.83; H, 8.79; N, 4.68.
1
1441 cm-1; H NMR (CDCl3, 400 MHz) δ 2.03 (brs, 1H), 2.73
The minor trans-stereoisomer 17 consisted of a yellow oil
that exhibited the following spectral properties: IR (neat)
3562, 1513, and 1260 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.40-
2.28 (m, 10H), 2.39 (s, 3H), 2.95-3.03 (m, 2H), 3.85 (s, 3H),
3.87 (s, 3H), 3.96-4.02 (m, 1H), 6.81 (d, 1H, J ) 8.6 Hz), 7.38
(t, 2H, J ) 6.4 Hz), 3.71 (t, 2H, J ) 6.4 Hz), 5.07 (d, 1H, J )
0.8 Hz), 5.31 (d, 1H, J ) 0.8 Hz), 5.96 (s, 2H), 6.77 (d, 1H, J
) 8.4 Hz), and 6.88-6.92 (m, 2H); 13C NMR (CDCl3, 100 MHz)
δ 38.9, 61.1, 101.3, 106.8, 108.3, 113.8, 119.8, 134.7, 144.4,
147.4, and 148.0. Anal. Calcd for C11H12O3: C, 68.74; H, 6.29.
Found: C, 68.49; H, 6.37.
(dd, 1H, J ) 8.6 and 1.8 Hz), and 7.57 (d, 1H, J ) 1.8 Hz); 13
C
NMR (CDCl3, 100 MHz) δ 19.3, 33.4, 41.5, 41.6, 43.9, 46.5,
52.7, 55.7, 55.9, 67.8, 76.0, 110.7, 112.8, 120.8, 136.7, 146.8,
and 148.3; HRMS calcd for C17H25NO3 291.1835, found 291.1844.
N-[3-(Ben zo[1,3]d ioxol-5-yl)bu t-3-en yl]-N-(fu r a n -2-yl)-
ca r ba m ic Acid Meth yl Ester (24). To a solution containing
1.0 g (5.4 mmol) of alcohol 21 and 0.9 mL (6.4 mmol) of
triethylamine in 20 mL of dry CH2Cl2 was added 0.5 mL (5.9
mmol) of methanesulfonyl chloride at 0 °C. The mixture was
stirred at room temperature overnight, diluted with water, and
extracted with CH2Cl2. The combined organic layers were
washed with water, dried over MgSO4, and concentrated under
reduced pressure to give 1.4 g (95%) of crude mesylate 22,
which was used in next step reaction without further purifica-
tion.
3a -(3,4-Dim eth oxyp h en yl)-1-m eth yl-octa h yd r oin d ole-
5-on e. A mixture containing 0.02 g (0.06 mmol) of the cis
hydroindole 16, 0.02 g (0.1 mmol) of PCC, and 0.02 g of silica
gel in 10 mL of CH2Cl2 was stirred at room temperature
overnight. Removal of the solvent under reduced pressure
followed by flash silica gel chromatography gave 0.015 g (99%)
of the title compound as a pale yellow oil: IR (neat) 2941, 1712,
1525, and 1465 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.68-1.79
(m, 1H), 1.87-2.03 (m, 2H), 2.06-2.21 (m, 2H), 2.39 (s, 3H),
2.50-2.61 (m, 3H), 2.79 (d, 2H, J ) 3.6 Hz), 3.29 (dt, 1H, J )
8.8 and 3.6 Hz), 3.86 (s, 3H), 3.88 (s, 3H), and 6.79-6.89 (m,
3H); 13C NMR (CDCl3, 100 MHz) δ 22.9, 35.1, 40.0, 40.1, 50.2,
52.3, 54.5, 55.8, 55.9, 70.8, 110.0, 110.9, 118.5, 138.9, 147.4,
148.7, and 212.5. Anal. Calcd for C17H23NO3: C, 70.55; H, 8.02;
N, 4.84. Found: C, 70.48; H, 7.92; N, 4.77.
To a stirred suspension containing 0.76 g (5.4 mmol) of
furan-2-ylcarbamic acid methyl ester (23)26 and 2.6 g (8.0
mmol) of cesium carbonate in 4 mL of dry DMF at 60 °C was
added dropwise a solution containing the above mesylate in 1
mL of dry THF. The resulting mixture was stirred at 60 °C
for 12 h. The mixture was diluted with water, extracted with
ether, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel chromatogra-
phy to give 1.02 g (64%) of carbamate 24 as a pale yellow oil:
(()-Mesem br a n e (18). A mixture containing 0.02 g (0.06
mmol) of the above ketone, 13 µL (0.1 mmol) of BF3‚OEt2, and
8 µL (0.1 mmol) of 1,2-ethylene dithiol in 10 mL of CH2Cl2
was stirred at room temperature for 16 h. The solution was
quenched with a 5% NaOH solution and extracted with ether.
The combined organic layers was dried over Na2SO4 and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 0.02 g (99%)
of the dithiolane derivative of 3a-(3,4-dimethoxyphenyl)-1-
methyl-octahydroindole-5-one as a white solid: mp 115-116
IR (neat) 1719, 1609, 1503, 1442, and 1300 cm-1 1H NMR
;
(DMSO-d6, 70 °C, 400 MHz) δ 2.68 (t, 2H, J ) 7.6 Hz), 3.61 (t,
2H, J ) 7.6 Hz), 3.63 (s, 3H), 5.00 (s, 1H), 5.29 (s, 1H), 6.00 (s,
2H), 6.15 (d, 1H, J ) 3.2 Hz), 6.43-6.47 (m, 1H), 6.84 (d, 1H,
J ) 8.0 Hz), 6.90 (dd, 1H, J ) 8.0 and 1.6 Hz), 6.97 (d, 1H, J
) 1.6 Hz), and 7.42 (d, 1H, J ) 1.6 Hz); 13C NMR (DMSO-d6,
70 °C, 100 MHz) δ 33.6, 48.0, 52.7, 100.7, 101.9, 105.8, 105.9,
107.7, 110.8, 112.6, 119.0, 133.8, 138.9, 143.6, 146.6, 147.2,
and 154.4. Anal. Calcd for C17H17NO5: C, 64.75; H, 5.43; N,
4.44. Found: C, 65.03; H, 5.39; N, 4.47.
°C; IR (neat) 2931, 1520, 1470, and 1258 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 1.67-1.82 (m, 2H), 1.92-2.03 (m, 2H),
2.16-2.28 (m, 3H), 2.31 (s, 3H), 2.51 (dd, 1H, J ) 13.8 and
1.4 Hz), 2.67 (s, 1H), 2.75 (d, 1H, J ) 13.8 Hz), 2.95-3.22 (m,
5H), 3.88 (s, 3H), 3.89 (s, 3H), and 6.80-6.89 (m, 3H); 13C NMR
(CDCl3, 100 MHz) δ 23.6, 37.1, 37.2, 39.2, 40.2, 41.3, 49.0, 49.9,
53.4, 55.7, 55.9, 64.6, 67.4 110.3, 110.9, 118.9, 139.0, 147.2,
and 148.3. Anal. Calcd for C19H27NO2S2: C, 62.44; H, 7.45; N,
3.83. Found: C, 62.41; H, 7.32; N, 3.66.
3a -(Ben zo[1,3]d ioxol-5-yl)-5-oxo-2,3,3a ,4,5,6-h exa h y-
d r oin d ole-1-ca r b-oxylic Acid Meth yl Ester (25). A 0.6 g
(1.9 mmol) sample of carbamate 24 in 10 mL of dry toluene
was heated in a sealed tube under an argon atmosphere at
180 °C for 15 h. After cooling to room temperature, the mixture
was concentrated under reduced pressure, and the residue was
purified by flash silica gel chromatography to give 0.5 g (85%)
of ketoenamide 25 as a pale yellow solid: mp 114-115 °C; IR
(KBr) 1716, 1671, 1502, and 1386 cm-1; 1H NMR (CDCl3, 400
MHz) δ 2.07-2.15 (m, 1H), 2.25-2.30 (m, 1H), 2.70-3.03 (m,
5H), 3.24 (m, 1H), 3.78 (brs, 3H), 5.92 (s, 2H), 6.38 (brs, 1H),
and 6.69-6.75 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 14.3,
37.7, 38.9, 46.3, 52.7, 53.7, 60.5, 101.3, 106.9, 108.4, 119.7,
134.5, 146.9, 148.3, and 208.6. Anal. Calcd. for C17H17NO5: C,
64.74; H, 5.43; N, 4.44. Found: C, 64.46; H, 5.39; N, 4.29.
A suspension containing 0.02 g (0.05 mmol) of the above
dithiolane and excess Raney nickel in 8 mL of ethanol was
heated at reflux for 6 h. The mixture was filtered through a
pad of Celite, and the filtrate was concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 0.15 g (87%) of (()-mesembrane (18)20 as
a colorless oil: IR (neat) 2936, 1525, and 1268 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.08-1.65 (m, 5H), 1.74-1.98 (m, 5H),
2.26-2.32 (m, 1H), 2.33 (s, 3H), 2.58 (brs, 1H), 3.25 (dt, 1H, J
) 9.2 and 4.4 Hz), 3.87 (s, 3H), 3.89 (s, 3H), 6.81 (d, 1H, J )
8.4 Hz), and 6.89-6.94 (m, 2H); 13C NMR (CDCl3, 100 MHz)
δ 20.4, 22.9, 23.7, 36.1, 40.6, 41.1, 47.5, 54.4, 55.8, 55.9, 68.7,
110.5, 110.7, 118.8, 140.3, 146.7, and 148.5. Anal. Calcd for
cis-3a ,7a -(Be n zo[1,3]d ioxol-5-yl)-5-(2,2,2-t r iflu or o-
eth a n oyloxy)-2,3,3a ,4,5,6,7,7a -octa h yd r oin d ole-1-ca r box-
ylic Acid Meth yl Ester (26). A mixture containing 0.63 g
(2.0 mmol) of keto-enamide 25 and 0.63 g (4.0 mmol) of bis-
(tert-butyl)methylsilane28 in 6 mL of trifluoroacetic acid was
C
17H25NO2: C, 74.13; H, 9.16; N, 5.09. Found: C, 74.08; H,
(45) Barton, T. J .; Lin, J .; Ijadi-Maghsoodi, S.; Power, M. D.; Zhang,
9.11; N, 4.93.
X. J . Am. Chem. Soc. 1995, 117, 11695.