5326 J . Org. Chem., Vol. 66, No. 16, 2001
Kuehne et al.
16a ′-h om o-Leu r osid in e (8a ) a n d Its Vin d olin yl (C-16)
Dea cyla tion P r od u ct 37. A solution of 0.090 g (0.08 mmol)
of tosylate 33 in 10 mL of dry methanol was heated at reflux
under argon for 23 h, during which time the tosylate 33
gradually changed to the quaternary salt 35 and its deacyla-
tion product 36: TLC Rf 0 (ethyl acetate) or 0.25 (1:2
methanol-dichloromethane). The reaction mixture was cooled
to 0 °C and stirred with 20 mg of 10% palladium on carbon
under a hydrogen atmosphere for 10 min. The reaction mixture
was filtered through a pad of Celite 545 and concentrated.
Chromatography (10:2 ethyl acetate-methanol) gave 0.045 g
(68.2%) of compound 8a and 0.015 g (24.0%) of the correspond-
ing deacylated compound 37. For 8a : TLC Rf 0.44 (silica gel,
10:2 ethyl acetate-methanol, CAS, blue); [R]25D +6.52 (c 0.27,
CH2Cl2).
d ]ca r ba zole-5,6-d ica r boxyla te (42) a n d (3a R,4S,5S,11bS)-
Dim eth yl 3-Ben zyl-2,3,3a ,4,5,7-h exa h yd r o-4-[(2S)-2-eth yl-
2,3-(isop r op ylid e n e d ioxy)p r op yl]-1H -p yr r olo[2,3-d ]-
ca r ba zole-5,6-d ica r boxyla te (43). (a ) For the following
procedure, concentrated sulfuric acid was employed directly:
To a stirred solution of epoxide 41 (0.334 g, 0.67 mmol) in 67
mL of dry dioxane containing 60 µL of water (3.33 mmol) was
added concentrated sulfuric acid (0.782 g, 7.98 mmol). The
mixture was stirred for 10 min and neutralized with triethyl-
amine (4.030 g, 39.90 mmol). Concentration and flash chro-
matography (ethyl acetate) gave 0.145 g (41.6%) of a mixture
1
of diols 39 and 42 in a 1:13 ratio (85.7% de), analyzed by H
NMR with integration of the singlet at δ 3.17 (39) and 3.12
(42).
(b) For the following procedure, 3 wt % of the concentrated
sulfuric acid on silica gel was employed: To a vigorously stirred
suspension of silica gel (78.4 g) in acetone was added 3 wt %
of concentrated sulfuric acid (24 mmol). The solvent was
evaporated, and the silica gel was dried at aspirator vacuum
at 40 °C for 2 h. To this silica gel was added 200 mL of dry
dioxane containing 180 µL of water (10 mmol). With vigorous
stirring, a solution of epoxide 41 (1.004 g, 2.00 mmol) in 5 mL
of dioxane was added. The mixture was stirred for 10 min and
neutralized with triethylamine (12.120 g, 120 mmol). The silica
gel was removed by filtration and was washed with methanol
and dichloromethane. Concentration and flash chromatogra-
phy (first eluting with 1:3 ethyl acetate-hexanes, then eluting
with 4:1 ethyl acetate-hexanes) gave 0.670 g (64.4%) of a
mixture of diols 39 and 42 in a 1:31 ratio (93.7% de) and 0.152
g (13.6%) of acetonide 43. Diols 39 and 42 could be separated
by preparative thin-layer chromatography.
For 37: TLC Rf 0.32 (silica gel, 10:2 ethyl acetate-methanol,
CAS, brown); [R]25 +46.3 (c 0.27, CH2Cl2).
D
(2S,5R)-Met h yl
7,17-Dia za -5-(2(R)-et h yl-2,3-ep oxy-
p r op yl)-7-b en zylt r icyclo[8.7.0.011,16]h ep t a d eca -1(10),6,-
11(16),12,14-pen taen e-2-(10-vin dolin yl)-2-car boxylate (38)
a n d Its Cycliza tion . A solution of tosylate 33 (8.2 mg, 0.0075
mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (2.2 uL, 0.015
mmol) in 0.5 mL of dry tetrahydrofuran was stirred overnight.
Concentration and chromatography (ethyl acetate) gave 6.4
mg (92%) of epoxide 38: TLC Rf 0.39 (silica gel, ethyl acetate,
CAS, brown).
Under argon, a solution of epoxide 38 (6.4 mg, 0.007 mmol)
in 5 mL of dry MeOH was heated at reflux for 15 h. The
epoxide gradually changed to the quaternary salt 35: TLC Rf
0 (ethyl acetate), 0.25 (1:2 methanol-dichloromethane); CD
data (7.0 × 10-4M in methanol) λ (ellipticity) 224 (+45), 252
(+31), 275 (-14), 311 (-2). The reaction mixture was cooled
to 0 °C and hydrogenated with 2 mg of 10% palladium on
carbon under a hydrogen atmosphere for 20 min. Filtration
through Celite 545 and chromatography (10:2 ethyl acetate-
methanol) gave 4.5 mg (78%) of 16a′-homoleurosidine 8a and
trace of deacylated 16a′-homoleurosidine 37.
By employing 6 wt % of concentrated sulfuric acid on silica
gel, hydrolysis of epoxide 41 gave 61.7% of a mixture of diols
39 and 42 in a 1:22 ratio (91.3% de) and 12.2% of acetonide
43.
For the diol 42: TLC Rf 0.47 (silica gel, ethyl acetate, CAS,
blue); [R]25 +199.1 (c 0.22, CH2Cl2).
D
(3aR,4S,5S,11bS)-Dim eth yl 3-Ben zyl-2,3,3a,4,5,7-h exah y-
d r o-4-[(2R)-2-et h yl-2,3-(d ih yd r oxy)p r op yl]-1H -p yr r olo-
[2,3-d ]ca r ba zole-5,6-d ica r boxyla te (39). A solution of ace-
tonide 11a (3.300 g, 5.89 mmol) in 90 mL of methanol and 40
mL of 10% hydrochloric acid was heated at reflux for 15 min.
After removal of most of the methanol, the mixture was
basified to pH 9 with ammonium hydroxide and extracted with
dichloromethane (3 × 70 mL). The combined organic layers
were washed with brine (40 mL) and dried over magnesium
sulfate. Concentration gave 3.065 g (99%) of diol 39, which
was pure enough (TLC) for spectroscopic characterization and
for the next step: TLC Rf 0.50 (silica gel, ethyl acetate, CAS,
P r ep a r a tion of Aceton id e 43 fr om Diol 42. A solution
of diol 42 (1.200 g, 2.31 mmol) and 2 mL of 2,2-dimethoxypro-
pane in 20 mL of dry benzene was heated at reflux with a
catalytic amount of p-toluenesulfonic acid for 2 h. The mixture
was basified with 0.5 mL of ammonium hydroxide. The solvent
was removed under reduced pressure, and the crude product
was purified by chromatography (ethyl acetate-hexanes, 1:3)
to give 1.244 g (96.1%) of acetonide 43.
For acetonide 43: TLC Rf 0.55 (silica gel, ethyl acetate-
hexane 1:3, CAS, blue); [R]25 +150.7 (c 1.52, CH2Cl2).
D
(3a R,4S,5S,11bS)-Meth yl 3-Ben zyl-2,3,3a ,4,5,7-h exa h y-
d r o-4-[(2S)-2-eth yl-2,3-(isop r op ylid en ed ioxy)p r op yl]-1H-
p yr r olo[2,3-d ]ca r b a zole -5-h yd r oxym e t h yl-6-ca r b oxy-
la te (44). To a solution of 11.200 g (20.00 mmol) of acetonide
43 in 200 mL of dry THF, under argon, was added dropwise
120 mL of 1 M diisobutylaluminum hydride in hexanes, at 0
°C, over 1 h. The reaction mixture was allowed to warm to
room temperature and stirred for another 3 h. After quenching
with methanol at 0 °C, the reaction mixture was added to 150
mL of a 1 M NaOH solution, and shaken. The organic layer
was separated, and the aqueous layer was extracted with ethyl
ether (3 × 100 mL). The combined organic extracts were
washed with brine (2 × 50 mL), dried with powdered anhy-
drous MgSO4 overnight, and then filtered through Celite 545.
Concentration and chromatography (ethyl acetate-hexanes
1:2) gave 8.692 g (81.7%) of the title alcohol: TLC Rf 0.40 (silica
blue); [R]25 +181.0 (c 0.68, CH2Cl2).
D
(3aR,4S,5S,11bS)-Dim eth yl 3-Ben zyl-2,3,3a,4,5,7-h exah y-
d r o-4-[(2R)-2-eth yl-2-h yd r oxy-3-tosyloxyp r op yl]-1H-p yr -
r olo[2,3-d ]ca r ba zole-5,6-d ica r boxyla te (40). To a stirred
solution of diol 39 (2.510 g, 4.82 mmol), triethylamine (0.869
g, 8.69 mmol), and 4-(dimethylamino)pyridine (0.058 g, 0.48
mmol) in 20 mL of dichloromethane was added p-toluensul-
fonic anhydride (0.944 g, 2.90 mmol) in one portion. Two hours
later, another portion of p-toluenesulfonic anhydride (0.944 g,
2.90 mmol) was added again and the reaction was continued
for another 3 h. Concentration and flash chromatography
(ethyl acetate-hexane 1:1) gave 3.206 g (98.7%) of the tosylate
40: TLC Rf 0.47 (silica gel, ethyl acetate-hexane 1:1, CAS,
blue); [R]25 +155.2 (c 0.52, CH2Cl2).
D
(3aR,4S,5S,11bS)-Dim eth yl 3-Ben zyl-2,3,3a,4,5,7-h exah y-
d r o-4-[(2R)-2-et h yl-2,3-ep oxyp r op yl]-1H -p yr r olo[2,3-d ]-
ca r ba zole-5,6-d ica r boxyla te (41). A solution of tosylate 40
(0.750 g, 1.13 mmol) in 15 mL of dry tetrahydrofuran was
stirred with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.257 g, 1.69
mmol) for 8 h. The solvent was evaporated under reduced
pressure, and the residue was purified by flash chromatogra-
phy (ethyl acetate-hexanes 1:2) to afford 0.546 g (96.3%) of
epoxide 41: TLC Rf 0.55 (silica gel, ethyl acetate-hexanes 1:2,
gel, ethyl acetate-hexanes 1:2, CAS, blue); [R]25 +195.4 (c
D
0.49, CH2Cl2).
(3aR,4S,5S,11bS)-Meth yl 2,3,3a,4,5,7-Hexah ydr o-4-[(2S)-
2-eth yl-2,3-(isop r op ylid en ed ioxy)p r op yl]-1H-p yr r olo[2,3-
d ]ca r b a zole-5-h yd r oxym et h yl-6-ca r b oxyla t e (45) a n d
(3a R,4S,5S,11bS)-Meth yl 3-(Ben zyloxyca r bon yl)-2,3,3a ,4,-
5,7-h exa h yd r o-4-[(2S)-2-eth yl-2,3-(isop r op ylid en ed ioxy)-
p r op yl]-1H-p yr r olo[2,3-d ]ca r ba zole-5-h yd r oxym eth yl-6-
ca r boxyla te (46). A solution of alcohol 44 (7.586 g, 14.26
mmol), 1.520 g of 10% palladium on carbon, and 4.947 g (78.43
mmol) of ammonium formate in 120 mL of methanol and 60
mL of ethyl acetate was heated at reflux for 2 h. The reaction
CAS blue); [R]25 +183.9 (c 0.27, CH2Cl2).
D
(3aR,4S,5S,11bS)-Dim eth yl 3-Ben zyl-2,3,3a,4,5,7-h exah y-
d r o-4-[(2S)-2-eth yl-2,3-d ih yd r oxyp r op yl]-1H-p yr r olo[2,3-