Diastereoisomeric ratios were calculated from the integration
of suitable peaks in the proton NMR spectrum.
aqueous ammonium chloride solution (50 mL), extracted with
dichloromethane (3 × 50 mL), and dried over anhydrous
magnesium sulfate. The solvent was removed by rotary evapora-
tion, and the diastereoselectivity of the reaction was determined
by 1H NMR spectroscopy on the crude reaction mixture. The
yellow oil was purified by flash column chromatography using
100% ethyl acetate as eluent, yielding the target compound as
a white solid (1.18 g, 98%), a portion of which was recrystallized
from ethyl acetate to give colorless crystals: mp 191-192 °C;
2-(2-Oxocycloh exyl)eth a n oic Acid (1). Ethyl-2-cyclohex-
anone acetate (0.50 g, 2.71 mmol) was dissolved in a mixture of
THF (18 mL) and water (8 mL). Lithium hydroxide (0.17 g, 4.07
mmol) was added, and the mixture was stirred at room tem-
perature for 20 h. The reaction mixture was concentrated,
resuspended in water (30 mL), and acidified with 1 M HCl. The
aqueous layer was then extracted into ethyl acetate, dried over
anhydrous magnesium sulfate, and evaporated to dryness, giving
a colorless oil (0.42 g, 100%) that required no further purifica-
tion: FTIR (thin film, v, cm-1) 3200, 1702; 1H NMR (CDCl3, 250
MHz, δ, ppm) 1.30-3.00 (m, 11H), 9.10-9.90 (br. s, 1H); 13C
NMR (100 MHz, δ, ppm) 25.2, 27.8, 33.8, 34.3, 41.8, 46.9, 178.2,
211.4; MS (EI) m/z 156 [M+, 37.33%]; HRMS calcd for C8H12O3
156.0786, found M+ 156.0786.
[R]D ) -79.1 (c 0.53, CHCl3); FTIR (thin film, DCM, v, cm-1
)
1
3383, 1655; H NMR (CDCl3, 400 MHz, δ, ppm) 1.35-1.45 (m,
1H), 1.46-1.55 (m, 1H), 1.60-1.70 (m, 2H), 1.74-1.83 (m, 1H),
1.85-1.95 (m, 2H), 2.00-2.09 (m, 1H), 2.31-2.44 (m, 2H), 2.61-
2.67 (m, 1H), 2.82 (dd, J ) 16.0, 5.2, 1H), 3.13 (dd, J ) 16.0,
7.6, 1H), 3.70-3.76 (m, 1H), 3.80-3.85 (m, 1H), 3.86 (s, 3H),
3.89 (s, 3H), 3.88-3.94 (m, 1H), 4.63 (dd, J ) 7.2, 6.0, 1H), 6.65
(s, 1H), 6.88 (s, 1H); 13C NMR (100 MHz, δ, ppm) 20.8, 21.1,
27.5, 29.9, 36.2, 36.8, 38.1, 52.6, 55.9, 56.3, 64.0, 65.2, 108.4,
112.3, 126.0, 134.0, 147.4, 148.0, 176.0; MS (EI) m/z 331 [M+,
(2S)-2-Am in o-3-[3,4-d i(m eth oxy)p h en yl]p r op a n -1-ol (2).
A solution of chlorotrimethylsilane (4.50 mL, 35.52 mmol) in
THF (10 mL) was added under nitrogen to a solution of lithium
borohydride (8.88 mL of a 2.0 M solution in THF, 17.76 mmol)
over the course of 2 min. 3-(3,4-Dimethoxyphenyl)-L-alanine
(2.00 g, 8.88 mmol) was added portion-wise to the mixture over
5 min, and this mixture was then left to stir at room temperature
for 24 h. Methanol (20 mL) was slowly added to the resulting
blue solution, and the solvents were removed by rotary evapora-
tion. The residue was treated with excess 20% aqueous potas-
sium hydroxide solution and extracted with dichloromethane (3
× 20 mL). The organic phases were combined and dried over
anhydrous sodium sulfate, and the solvent was removed by
evaporation to yield white crystals in quantitative yield (1.87 g,
100%) that required no further purification: mp 82-83 °C (lit.8
mp 79-80 °C); [R]D ) -21.6 (c 0.45, EtOH), lit.8 [R]D ) -21.5 (c
8, EtOH). Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63.
29.89%]; HRMS calcd for
331.1779.
C
19H25NO4 331.1783, found M+
(9b S,13a S)-7,8-Di(m et h oxy)-2-oxo-1,4,5,10,11,12,13,13a -
octah ydr o-2H-in dolo[7a,1-a ]isoqu in olin -4-car baldeh yde (5).
A solution of (4S,9bS,13aS)-4-(hydroxymethyl)-7,8-di(methoxy)-
1,4,5,10,11,12,13,13a-octahydro-2H-indolo[7a,1-a]isoquinolin-2-
one (1.18 g, 3.56 mmol) in dichloromethane (25 mL) was added
to a solution of Dess-Martin periodinane (11.08 mL of a 15 wt
% solution in dichloromethane, 3.92 mmol) in dichloromethane
(25 mL) with stirring. After 20 h, excess dichloromethane was
removed, and the yellow oil was loaded directly on to silica.
Purification by flash column chromatography using a 2:1 mixture
of ethyl acetate and hexanes as eluent yielded a 1:1 mixture of
inseparable aldehyde diastereoisomers as a colorless oil (1.02
g, 87%): FTIR (thin film, v, cm-1) 1733, 1683; 1H NMR (both
isomers, CDCl3, 250 MHz, δ, ppm) 1.21-3.16 (m, 26H), 3.80-
3.85 (m, 12H), 4.20 (m, 1H), 4.50 (m, 1H), 6.60 (s, 1H), 6.68 (s,
1H), 6.84 (s, 1H), 6.92 (s, 1H), 9.53 (s, 1H), 9.66 (s, 1H); 13C NMR
(100 MHz, δ, ppm) 20.8 and 20.9, 21.2 and 21.6, 26.1 and 27.5,
27.7 and 28.1, 35.6 and 36.0, 36.8 and 37.2, 38.1 and 38.6, 55.9
and 56.0, 56.3 and 56.4, 57.1 and 57.2, 62.7 and 63.7, 108.2 and
108.4, 112.08 and 112.13, 124.0 and 124.4, 134.3 and 134.4, 147.7
and 147.8, 148.15 and 148.19, 174.4 and 176.0, 199.7 (2); MS
(EI) m/z 329 [M+, 32.07%]; HRMS calcd for C19H23NO4 329.1627,
found M+ 329.1627.
(9bS,13a S)-7,8-Di(m eth oxy)-1,10,11,12,13,13a -h exa h yd r o-
2H-in d olo[7a ,1-a ]isoqu in olin -2-on e (6). [Bis(triphenylphos-
phine)]rhodium(I) carbonyl chloride (88 mg, 0.12 mmol) was
added to anhydrous xylene (20 mL) under a nitrogen atmo-
sphere. The mixture was stirred at 80 °C for 15 min. 1,3-Bis-
(diphenyl phosphino)propane (0.12 g, 0.30 mmol) was added, and
the mixture was heated at 80 °C for 30 min until formation of
a yellow precipitate. (9bS,13aS)-7,8-Di(methoxy)-2-oxo-1,4,5,10,-
11,12,13,13a-octahydro-2H-indolo[7a,1-a]isoquinolin-4-carbalde-
hyde (0.81 g, 2.47 mmol) in anhydrous xylene (20 mL) was added,
and the mixture was heated at reflux for 192 h. The solvent was
removed by rotary evaporation giving a thick green oil. Purifica-
tion by flash column chromatography using a mixture of 1:1
ethyl acetate and hexanes as eluent gave the product as white
crystals (0.42 g, 57%), a portion of which was recrystallized from
Found: C, 62.29; H, 8.02; N, 6.53. FTIR (thin film, DCM, v, cm-1
)
3356; 1H NMR (CDCl3, 400 MHz, δ, ppm) 2.48 (dd, J ) 13.6,
8.4, 1H), 2.69-2.76 (br. s, 3H), 2.74 (dd, J ) 13.6, 5.2, 1H), 3.08-
3.13 (m, 1H), 3.42 (dd, J ) 10.6, 6.9, 1H), 3.64 (dd, J ) 10.6,
3.7, 1H), 3.86 (s, 3H), 6.71-6.74 (m, 2H), 6.78-6.80 (m, 1H);
13C NMR (100 MHz, δ, ppm) 40.2, 54.3, 55.9 (2), 66.1, 111.4,
112.4, 121.2, 131.3, 147.7, 149.2; MS (EI) m/z 211 [M+, 6.51%];
HRMS calcd for C11H17NO3 211.1208, found M+ 211.1210.
(3S,6a S,10a R)-3-{[3,4-Di(m et h oxy)p h en yl]m et h yl}p er -
h yd r o[1,3]oxa zolo[2,3-1]in d ol-5-on e (3). (2S)-2-Amino-3-[3,4-
di(methoxy)phenyl]propan-1-ol (1.60 g, 7.58 mmol) and ethyl-
2-cyclohexanoneacetate (1.18 g, 7.58 mmol) were dissolved in
toluene (100 mL) and refluxed under Dean-Stark conditions for
144 h. After this time the solution was allowed to cool, and the
solvent was removed by rotary evaporation. The resulting yellow
oil was purified by flash column chromatography using a 1:1
mixture of ethyl acetate and hexanes as eluent. Evaporation of
the desired fractions under reduced pressure afforded the target
compound as a yellow oil (1.45 g, 58%): [R]D ) +26.9 (c 0.34,
CHCl3); FTIR (thin film, v, cm-1) 1702; 1H NMR (CDCl3, 400
MHz, δ, ppm) 1.37-1.90 (m, 8H), 2.30-2.41 (m, 2H), 2.57-2.65
(m, 1H), 2.69 (dd, J ) 13.8, 9.2, 1H), 3.04 (dd, J ) 13.8, 5.2,
1H), 3.85 (s, 3H), 3.87 (s, 3H), 3.93 (dd, J ) 8.8, 5.6, 1H), 4.02
(dd, J ) 8.8, 6.8, 1H), 4.23-4.27 (m, 1H), 6.72-6.81 (m, 3H);
13C NMR (100 MHz, δ, ppm) 19.8, 20.9, 25.1, 32.8, 39.2, 39.6,
40.8, 55.3, 55.9, 56.0, 71.7, 99.6, 111.3, 112.5, 121.3, 129.7, 147.9,
149.0, 176.2; MS (EI) m/z 331 [M+, 41.22%]; HRMS calcd for
C19H25NO4 331.1783, found M+ 331.1786.
ethyl acetate to give colorless crystals: mp 175-177 °C; [R]D
)
-238.7 (c 0.45, CHCl3); FTIR (thin film, DCM, v, cm-1) 1696,
730; 1H NMR (CDCl3, 250 MHz, δ, ppm) 1.14-1.61 (m, 4H),
1.72-1.89 (m, 1H); 1.96-2.24 (m, 3H), 2.48 (dd, J ) 17.1, 9.3,
1H), 2.60 (dd, J ) 17.1, 11.7, 1H), 2.80-2.97 (m, 1H), 3.89 (s,
3H), 3.92 (s, 3H), 5.94 (d, J ) 7.4, 1H), 6.67 (s, 1H), 6.85 (d, J )
7.6, 1H), 6.97 (s, 1H); 13C NMR (100 MHz, δ, ppm) 20.0, 20.8,
27.0, 35.1, 35.3, 37.9, 56.0, 56.4, 61.9, 108.9, 109.2, 111.2, 119.5,
124.1, 130.2, 147.9, 148.2, 170.7; MS (EI) m/z 299 [M+, 30.63%];
HRMS calcd for C18H21NO3 299.1521, found M+ 299.1526.
(9bS,13a S)-7,8-Di(m eth oxy)-1,4,5,10,11,12,13,13a -octa h y-
d r o-2H-in d olo[7a ,1-a ]isoqu in olin -2-on e (7). (9bS,13aS)-7,8-
Di(methoxy)-1,10,11,12,13,13a-hexahydro-2H indolo[7a,1-a] iso-
quinolin-2-one (0.14 g, 0.47 mmol) was dissolved in absolute
ethanol (15 mL) in a Schlenk tube. The reaction mixture was
(4S,9bS,13a S)-4-(Hyd r oxym eth yl)-7,8-d i(m eth oxy)-1,4,5,-
10,11,12,13,13a -octa h yd r o-2H-in d olo[7a ,1-a ]isoqu in olin -2-
on e (4). (3S,6aS,10aR)-3-{[3,4-Di(methoxy)phenyl]methyl}-
perhydro[1,3]oxazolo[2,3-1]indol-5-one (1.20 g, 3.63 mmol) was
dissolved in dry dichloromethane (50 mL) under a nitrogen
atmosphere. The mixture was cooled to -78 °C, and 3 equiv of
TiCl4 (1.19 mL, 10.88 mmol) was added dropwise via syringe.
After stirring at this temperature for 10 min, the mixture was
allowed to reach room temperature and left to stir for a further
20 h. The reaction mixture was quenched with saturated
(8) Schrecker, A. W.; Hartwell, J . L. J . Am. Chem. Soc., 1957, 79,
3827-3831.
9466 J . Org. Chem., Vol. 67, No. 26, 2002