Synthesis of optically pure Clausenamine-A and its demethoxylated analogs

Article abstract of DOI:10.1016/S0040-4020(00)00634-7

The first total synthesis of Clausenamine-A (3) was developed involving the Suzuki cross-coupling and oxidative coupling reaction. The synthesis of its demethoxylated analogs 1 and 2 were also reported. Resolution of (+)-1, (+)-2, (+)-3 and (-)-1, (-)-2, (-)-3 were performed via their corresponding camphorsulfonates of the racemates. The absolute configurations of (+)-1, (+)-2, (+)-3 and (-)-1, (-)-2, (-)-3 were assigned as (aR) and (aS), respectively, by X-ray analysis and their CD spectrum. The primarily cytotoxic activities of these biscarbazoles against Plasmodium falciparum were briefly described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00634-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7163–7171
Synthesis of Optically Pure Clausenamine-A and its
Demethoxylated Analogs
*
Guoqiang Lin and Aimin Zhang
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received 12 June 2000; accepted 18 July 2000
Abstract—The first total synthesis of Clausenamine-A (3) was developed involving the Suzuki cross-coupling and oxidative coupling
reaction. The synthesis of its demethoxylated analogs 1 and 2 were also reported. Resolution of (ϩ)-1, (ϩ)-2, (ϩ)-3 and (Ϫ)-1, (Ϫ)-2, (Ϫ)-3
were performed via their corresponding camphorsulfonates of the racemates. The absolute configurations of (ϩ)-1, (ϩ)-2, (ϩ)-3 and (Ϫ)-1,
(Ϫ)-2, (Ϫ)-3 were assigned as (aR) and (aS), respectively, by X-ray analysis and their CD spectrum. The primarily cytotoxic activities of
these biscarbazoles against Plasmodium falciparum were briefly described. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
A number of dimeric carbazole alkaloids have been isolated
from different natural sources during the past years, which
exhibited various biological activities including anti-tumor,
anti-inflammatory and cytotoxic activities.1,4 In 1996,
Clausenamine-A (3) was isolated from the stem and root
bark of Clausena excavata,2 which is used as the Chinese
folk medicine for detoxication treatment caused by the
poisonous snakebite. Recently, dimeric O-demethyl-
murrayafoline A (1) was found to exhibit antiplasmodial
activity against Plasmodium falciparum in vitro.3 In the
previous communications, the synthesis of these biscarba-
zoles and the evaluation of their biological activities against
cancer cells were reported.4,5
Synthesis
As shown in Scheme 1, the hydroxyl group of 4 was
protected as the benzyl ether, and the resulting product 5
was reduced by ferrum to yield 6. When compound 6 was
subjected to the Goldberg coupling reaction7a,b or the
Ullmann coupling reaction,7c the desired product 7a was
obtained in poor yields. After several attempts, amination
of 6 was achieved with satisfaction under Buchwald
condition7d,e to afford 7a in 93% yield. Cyclization of the
N-phenyl-2-benzyloxy-4-methylaniline (7a) with Pd(OAc)2
in acetic acid gave 8a in 32% yield.8 The low yield of the
cyclization is possible caused by the electron-donating
effects of the methyl and the benzyloxyl substitution in
the benzene ring. Catalytic hydrogenation of 8a afforded
the O-demethyl-murrayafoline A (9) in 73% yield. Oxida-
tive coupling of the phenolic monomer (9) was completed
by aerial treatment of 9 with (t-BuO)2 in chlorobenzene,
providing the racemic dimeric O-demethyl-murrayafoline
A (1) in 87% yield.9 Lower yield was obtained when this
oxidative coupling was performed under argon atmosphere.
In the presence of oxygen, the radicals were preferentially
provided which cause the termination of the desired
reaction. The desired coupling site was confirmed by the
disappearance of the signal of 2-H in the 1H NMR spectrum
and the analysis on X-ray spectrum.
Due to the restricted rotation around the central biaryl axis,
1, 2 and 3 are structurally atropisotopic. However, little
attention has been paid to the relationship between the
stereochemistry and the biological activity.6 Herein, we
report the first synthesis of the optically pure Clausena-
mine-A (3) and its demethoxylated analogs 1 and 2, in
which the regioselective oxidative coupling of synthetic
phenolic monomer (21) and the enantioresolution of (^)-3
were employed as the key steps. The absolute configurations
of (ϩ)-1, (ϩ)-2, (ϩ)-3 and (Ϫ)-1, (Ϫ)-2, (Ϫ)-3 were
assigned as (aR) and (aS), respectively, by X-ray analysis
and their CD spectra.
Keywords: Plasmodium falciparum; clausemine-A; Suzuki cross-coupling
reaction; resolution.
* Corresponding author. Tel.: ϩ86-21-641-63300; fax: ϩ86-21-641-
66263; e-mail: lingq@pub.sioc.ac.cn
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00634-7

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G. Lin, A. Zhang / Tetrahedron 56 (2000) 7163–7171
Scheme 1. Reagents and conditions: (i) PhCH2Br, NaOH, DMSO, 86%; (ii) Fe, H2O, NH4Cl, reflux, 83%; (iii) Pd2(dibenzylideneacetone)3, 2,20-bis(diphe-
nylphosphine)-1,10-binaphthyl, 18-C-6, t-BuONa, THF, 40ЊC, iodobenzene for 7a, 93%, 2,4-dimethoxyl-indobenzene for 7b, 77%; (iv) Pd(OAc)2, HOAc,
reflux, 32%; (v) 10% Pd/C, H2, 73%; (vi) (t-BuO)2, chlorobenzene, reflux, 87%.
After accomplishing the synthesis of racemic dimeric O-
demethyl-murrayafoline A (1), the similar manner was
employed to synthesize Clausenamine-A (3). However,
the cyclization of 7b using palladium acetate failed to afford
the desired product 8b, probably due to the electrondonating
effects exerted by the methoxyl groups in the benzene ring,
which decrease the Pd oxidative addition activity. Thus,
another approach to 2, the analog of 1, was taken as a
model study (Scheme 2). The Japp–Klingmann condensa-
tion10of p-methoxybenzenediazonium chloride with 10
resulted in hydrazone 11a, which cyclized to give 12a.11
Treatment of 12a with 10% Pd/C in a sealed tube furnished
13 in 73% yield. The next oxidative coupling of 13 provided
2 in 82% yield. The cyclization of 11b was employed to
14. Having tried the use of several protected groups, tosylate
1513 was employed as the electron-withdrawing group.
Compound 16 was gained through electrophilic aromatic
bromination14 of 15 using bromo-dimethylsulfonium bro-
mide generated in situ. The brominate position substituted
in the ortho position of the amino group was confirmed by
NOE effects (94% yield). The required biphenyl 18 was
prepared quantitatively by Suzuki cross-coupling of 3,5-
dimethoxyphenyl boronic acid (17)15 and 16 with 5%
Pd(PPh3)4 and 2N aqueous Na2CO3 in benzene.16 Conver-
sion of the amine 18a to toluene-4-sulfonic acid 2-azido-
30,50-dimethoxy-5-methyl-biphenyl-3-yl ester 18b by
diazotization followed by treatment with sodium azide17
has been tried. Unfortunately it failed to complete this
procedure; the same was met while the detosylate of 18a
was used. Analysis of the electron distributing of 18a
through the semiempirical MO calculation using the
Hyperchem programs disclosed that the phenyl ring bearing
two methoxyl groups is electron abundant, which fits for the
electrophilic bromination procedure. Bromination of 18a
using 48% HBr in DMSO afforded compound 19 in
79.5% yield.14 The five-member ring closure was success-
fully performed through a palladium(0) mediated cycliza-
tion18 of compound 19 which provided 9-H-carbazole 20 in
97% yield. Detosylation of 20 gave the monomer 21. Oxida-
tive coupling of the phenolic monomer 21 was completed by
aerial treatment of 21 with (t-BuO)2 in chlorobenzene
offering the racemic clausenamine-A (3) in 90% yield.8
The structure of 3 was characterized fully by spectroscopic
analysis.
gain the product 12b. Surprisingly, by using several reaction
12b
conditions such as TsOH/benzene,12a BF3 ·Et2O/AcOH,
0
BF3·Et2O/EtOAc,12b the cyclization of 11b was unsuccess-
ful. It is, as mentioned above, probably due to the elec-
tron-donating effects of the methoxyl groups in the
benzene ring.
As mentioned above, owing to the electro-donating effects
of the two methoxyl groups in the benzene ring, the desired
product can not be obtained through Pd(OAc)2 catalyzed
cyclization of N-(2,4-dimethoxy)-phenyl-2-benzyloxy-4-
methylaniline (7b) and cyclization of 4-methyl-cyclohex-
ane-1,2-dione-1-(3,5-dimethoxy)-phenylhydrone
(11b).5
Therefore, another synthetic route starting from the
commercially available 2-amino-5-methylphenol 14 was
employed, as depicted in Scheme 3. Firstly, in order to
introduce a bromine atom ortho-positioned to the amine
group, it is needed to protect the free hydroxyl group in
After accomplishing the synthesis of racemic Clausenamine-
Scheme 2. Reagents and conditions: (i) HCl, NaNO2, CH3COONa, 54%; (ii) HOAc, HCl, reflux, 44%; (iii) 10% Pd/C, 220–240ЊC, 73%; (iv) (t-BuO)2,
chlorobenzene, reflux, 82%.

G. Lin, A. Zhang / Tetrahedron 56 (2000) 7163–7171
7165
Scheme 3. Reagents and conditions: (i) TsCl, Et3N, CH2Cl2, rt, 84%; (ii) 48% HBr, DMSO, rt, 94%; (iii) 5% Pd(PPh3)4, 2N Na2CO3, benzene, 3,5-
dimethoxyphenyl boronic acid, ethanol, reflux, 99%; (iv) 48% HBr, DMSO, rt, 79.5%; (v) 1.2 equiv. Pd(PPh3)4, Na2CO3, toluene, reflux, 97%; (vi) KOH,
H2O, EtOH, reflux, 88%; (vii) (t-BuO)2, chlorobenzene, reflux, 90%.
Scheme 4. Reagents and conditions: (i) Et3N, (S)-camphorsulfonylchloride, CH2Cl2, reflux, 94%, then chromatographic separation of 3a and 3b (silica gel,
eluent; CH2Cl2/CHCl3/etherˆ50:1:2); (ii) KOH, EtOH, rt, (ϩ)-3, 84%, (Ϫ)-3, 87%.
A (3) and its demethoxylated analogs 1 and 2, it is turned to
get the optically pure ones through resolution of these race-
mic biscarbazoles. Resolution of these racemates was
accomplished by silica gel column chromatography of
their corresponding (ϩ)-camphorsulfonates19 using
CH2Cl2/CHCl3/Et2O (50:1:2) as the eluant (Scheme 4).
Some physical properties of these corresponding (ϩ)-
camphorsulfonates were listed in Table 1. Recrystallization
of 1a from ethanol provided a colorless prism, which is
good for X-ray diffraction.5 The absolute stereochemistry
of the diester 1a was determined as (aR) by correlation
with the known absolute configuration of (S)-camphor-
sulfonate moiety within the molecular.
Treatment of 1a, 1b, 2a, 2b, 3a and 3b with KOH in EtOH
and water afforded their corresponding optically pure
Table 1. Some physical properties of 1a, 1b, 2a, 2b, 3a and 3b
Entry
Resolution yield (%)
Mp (ЊC)
[a]2D1
AB signals (–CH2SO2-) in 1H NMR (300 Hz)
1a
1b
2a
2b
3a
3b
48
46
41
47
47
47
177–179
132–134
235–237
203–204
167–168
148–150
ϩ3.75Њ (c 0.1, CHCl3)
ϩ15.2Њ (c 0.48, CHCl3)
ϩ38.1Њ (c 1.08, CHCl3)
Ϫ34.9Њ (c 1.14, CHCl3)
ϩ7.7Њ (c 0.65, CHCl3)
Ϫ5.9Њ (c 0.55, CHCl3)
3.48 (2H, d, Jˆ14.8 Hz), 2.23 (2H, d, Jˆ14.8 Hz) ppm
3.13 (2H, d, Jˆ14.9 Hz), 2.53 (2H, d, Jˆ14.8 Hz) ppm
3.47 (2H, d, Jˆ14.9 Hz), 2.25 (2H, d, Jˆ14.9 Hz) ppm
3.13 (2H, d, Jˆ14.8 Hz), 2.53 (2H, d, Jˆ14.9 Hz) ppm
3.43 (2H, d, Jˆ14.8 Hz), 2.17 (2H, d, Jˆ14.8 Hz) ppm
3.08 (2H, d, Jˆ14.8 Hz), 2.48 (2H, d, Jˆ14.9 Hz) ppm

7166
G. Lin, A. Zhang / Tetrahedron 56 (2000) 7163–7171
As shown in Table 3, Clauseamine-A (3) and its demethoxyl-
ated analogs 1 and 2 exhibited moderate cytotoxic activities.
From the table it was also concluded that as the number of
methoxyl group increases, the activities are decreasing. To
our disappointment, the chiral biscarbazoles did not show
any increase activities compared with the racemic one.
In summary, we have accomplished the first synthesis of the
optically pure (R)- and (S)-Clauseamine-A (3) and its
demethoxylated analogs 1 and 2. The absolute configura-
tions of (ϩ)-1, (ϩ)-2, (ϩ)-3 were established as aR, and the
ones of (Ϫ)-1, (Ϫ), (Ϫ)-3 should be aS based on X-ray
analysis and CD spectrum. We also found these bis-
carbazoles exhibited moderate antimalarial activities.
Experimental
Figure 1. The CD spectrum of (ϩ)-3 and (Ϫ)-3 (solid line stands for (ϩ)-3
and dashed lines represents (Ϫ)-3.
Distillation of the products was performed using Kugelrohr
(Buchi); the boiling points are indicated by air-bath
temperature values without any correction. The NMR
Table 2. Some physical data of (ϩ)-1, (ϩ)-2, (ϩ)-3 and (Ϫ)-1, (Ϫ)-2, (Ϫ)-3
Entry
[a]2D1 (Solvent: CHCl3)
Yield (%)
(ϩ)-Cotton effect (nm)
(ϩ)-Cotton effect (nm)
(ϩ)-1
(Ϫ)-1
(ϩ)-2
(Ϫ)-2
(ϩ)-3
(Ϫ)-3
ϩ29.9Њ (c 0.67)
Ϫ39Њ (c 0.1)
ϩ44.3Њ (c 0.09)
Ϫ44.7Њ (c 0.13)
ϩ142.2Њ (c 0.75)
Ϫ147.6Њ (c 0.65)
73.2
94
57
90
84
256.6
227.6
256.4
229
256
227
227.4
257.4
228.6
258.4
225
87
225
spectra (1H) was recorded on a Varian GEMINI 300
spectrometer in CDCl3; tetramethylsilane (TMS) was
used as the internal standard. The IR spectra was
determined on a JASCO IR-810 spectrometer. Unless
mentioned elsewhere, the reactions were performed in
argon atmosphere.
Table 3. The cytotoxic activities against Plasmodium falciparum in vitro
Sample
D6a IC50 (mg/ml)
W2a IC50 (mg/ml)
(^)-1
(^)-2
(^)-3
(ϩ)-3
(Ϫ)-3
1.357
3.196
3.219
4.387
3.382
1.215
3.395
3.375
4.256
3.337
1-Nitro-2-benzyloxy-4-methyl-benzene (5). To a suspen-
sion of 2-nitro-cresol (3.06 g, 20 mmol) in DMSO (30 ml),
NaOH (1.6 g, 40 mmol) was added with stirring. 15 min
later, benzyl bromide (6 ml, 50 mmol) was added. The stir-
ring was kept until the disappearance of the starting material
monitored by TLC, the products were quenched with water
(20 ml) and the aqueous layer was extracted with CH2Cl2
(2×30 ml). The combined organic layers were washed with
brine, dried over Na2SO4 and the solvent was removed in
vacuo. The residue was purified by recrystallization from
ether to give 5 as a yellow solid (4.20 g, 86%). Mp 54–55ЊC.
FT-IR(KBr): 1613, 1591, 1507, 1454, 1336, 1267, 1178,
a D6 is the chloroquine-sensitive clone, and W2 is the chloroquine-resis-
tant clone.
biscarbazoles, respectively. The CD spectrum of (ϩ)-3 and
(Ϫ)-3 were illustrated in Fig. 1. The structure of (ϩ)-3 was
confirmed by the CD spectrum which showed the first (posi-
tive) cotton effect at 256 nm and the second (negative) one
at 225 nm, while its isomer (Ϫ)-3 showed the first (negative)
cotton effect at 255 nm and the second (positive) one at
227 nm. Some physical data of these optically pure bis-
carbazoles were listed in Table 2. From the X-ray analysis
and CD spectrum, the absolute configurations of (ϩ)-1, (ϩ)-
2, (ϩ)-3 were established as aR, and those of (Ϫ)-1, (Ϫ)-2,
(Ϫ)-3 should be aS.20
1
1035, 1013, 817, 731 cmϪ1. H NMR (300 MHz, CDCl3):
d 7.82 (d, 1H, Jˆ8.3 Hz, 6-H), 7.26–7.49 (m, 5H, Bn-H),
6.93 (s, 1H, 3-H), 6.83 (d, 1H, Jˆ8.1 Hz, 5-H), 5.22 (s, 2H,
–OCH2), 2.39 (s, 3H, –CH3) ppm. MS m/z (EI, 70 eV): 288,
271, 228, 181, 137, 91 (100), 77, 65, 51. EA: Calcd for
C14H13NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.10;
H, 5.28; N, 5.83.
Cytotoxicity Activities
2-Benzyloxy-4-methyl-aniline (6). A flask charged with
ferrum (280 mg, 5 mmol), NH4Cl (35 mg, 0.65 mmol),
water (8 ml), was warmed to reflux for 15 min, followed
by addition of 5 (243 mg, 1 mmol). The mixture was
In the previous report, the racemic biscarbazoles (1, 2 and 3)
showed moderate activities against cancer cells.4 Here their
cytotoxic activities against P. falciparum were reported.

G. Lin, A. Zhang / Tetrahedron 56 (2000) 7163–7171
7167
refluxed for 1.5 h under vigorous stirring. After the
completion of the reaction, the solution was cooled to
room temperature, 5% NaHCO3 was added to adjust the
pH to between 7 and 8. Then filtrated and the filtrate was
extracted with ethyl acetate (2×30 ml). The combined
organic layers were washed with brine and then washed
with 5% aqueous HCl. The water layer was neutralized by
addition of 20% NaOH, extracted with ethyl acetate
(3×30 ml), finally dried over Na2SO4. Removal of the
solvent provided the product 6 (177 mg, 83%). Mp 75–
76ЊC. FT-IR(KBr): 3464, 3374, 3033, 920, 1620, 1596,
CDCl3): d 7.99 (d, 1H, Jˆ7.9 Hz, 8-H), 7.46 (s, 1H, 2-H),
7.40 (d, 1H, Jˆ10.0 Hz, 5-H), 7.36 (td, 1H, Jˆ2.1 Hz,
7.8 Hz, 7-H), 7.19 (td, 1H, Jˆ7.1 Hz, 1.7 Hz, 6-H), 6.64
(s, 1H, 4-H), 2.47 (s, 3H, –CH3) ppm. MS m/z (EI,
70 eV): 197 (Mϩ, 100), 180, 168, 167, 154, 139, 128, 115,
99, 89, 76, 71, 63, 51, 43. EA: Calcd for C13H11NO: C,
79.17; H, 5.62; N, 7.10. Found: C, 78.72; H, 5.39; N, 7.46.
1,10-Dihydroxy-3,30-dimethyl-2,20-biscarbazole (1).
A
solution of 9 (100 mg, 0.51 mmol) in chlorobenzene
(10 ml) and di-tert-butyl peroxide (140 ml, 0.76 mmol)
was refluxed for 2 h under air atmosphere. After cooling,
the solvent was evaporated in vacuo and the remaining solid
was purified by chromatography on silica gel with Ethyl
acetate:Petroleum ether (3:1) as the eluant to give 1 as a
yellow solid (92 mg, 95%). Mp Ͼ260ЊC. FT-IR (KBr):
3511, 3412, 2952, 2854, 1611, 1562, 1447, 1253, 1224,
1239, 1156, 1018, 809, 759, 699 cmϪ1
.
1H NMR
(300 MHz, CDCl3): d 7.31–7.46 (m, Bn-H), 6.70 (s, 1H,
3-H), 6.66 (d, 1H, Jˆ7.8 Hz, 6-H), 6.62 (d, 1H, Jˆ8.0 Hz,
5-H), 5.05 (s, 2H, –OCH2), 2.25 (s, 3H, –CH3) ppm. MS m/
z (EI, 70 eV): 213 (Mϩ), 167, 122 (100), 104, 94, 91, 77, 65,
51. EA: Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57.
Found: C, 78.78; H, 7.14; N, 6.58.
1
745 cmϪ1. H NMR (300 MHz, CDCl3): d 8.09 (d, 1H,
Jˆ7.7 Hz), 7.61 (s, 2H), 7.59 (m, 2H), 7.39 (m, 2H), 7.18
(td, 2H, Jˆ7.4, 1.0 Hz), 3.31 (b, 4H, N–H, O-H), 2.12 (s,
6H) ppm. MS m/z (EI, 70 eV): 392 (Mϩ), 386, 359, 330,
291, 262, 234, 196, 165, 130, 110, 91, 55, 44. HRMS
Calcd for C26H20N2O2 (Mϩ): 392.1256, Found 392.1514.
UV(Ethanol): 295.2, 253.6, 224.8 nm.
N-Benzyl-2-benzyloxy-4-methyl-aniline (7a). A 10 ml-
flask was charged with iodobenzene (0.055 ml, 0.49
mmol), 6 (114 g, 0.535 mmol), sodium tert-butoxide
(60 mg, 0.625 mmol), Pd2(DBA)3 (8 mg, Pd, 4% equiv.),
BINAP (8 mg, 0.026 mmol), 18-C-6 (116 mg, 0.63 mmol),
THF (1 ml). The mixture was warmed at 40ЊC for 48 h
under vigorous stirring. After the reaction was completed,
the solution was cooled to room temperature. The residue
after evaporation of the solvent was purified by flash chro-
matography (Ethyl acetate:Petroleum etherˆ5:1) to give 7a
(132 mg, 93%). FT-IR (KBr): 3418, 3034, 2919, 2863,
Resolution of (^)-1. To a mixture of 1 (60 mg,
0.153 mmol) and triethylamine (0.6 ml) in CH2Cl2 (10 ml)
was added (ϩ)-camphorsulfonyl (115 mg, 0.459 mmol),
and the mixture was refluxed for 2 h. Then the mixture
was treated with water (20 ml), extracted with CH2Cl2
(2×20 ml). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromato-
graphy (silica gel, CH2Cl2:CHCl3:Et2Oˆ50:1:2) provided
1b (58 mg, 46%) and 1a, respectively both as a white
solid (60 mg, 48%). 1a: mp 177–179ЊC. FT-IR (KBr):
3418, 2952, 2858, 1749, 1615, 1496, 1453, 1359, 1245,
1
1600, 1525, 1455, 1258, 1127, 746, 695 cmϪ1. H NMR
(300 MHz, CDCl3): d 7.34–7.45 (m, 5H, Bn-H), 7.25 (m,
3H), 7.12 (m, 2H), 6.91 (dd, 1H, Jˆ7.3, 1.0 Hz, 5-H), 6.81
(d, 1H, Jˆ1.3 Hz, 6-H), 6.06 (s, 1H, N–H), 5.10 (s, 2H,
–CH2), 2.31 (s, 3H,–CH3) ppm. MS m/z (EI, 70 eV): 289
(Mϩ), 271, 198 (100), 183, 170, 154, 143, 128, 115, 91, 77,
65, 51. HRMS Calcd for C20H19NO(Mϩ): 289.1468, Found
289.1478.
1
1175, 746 cmϪ1. H NMR (300 MHz, CDCl3): d 8.90 (2H,
N–H), 8.04 (d, 2H, Jˆ7.8 Hz), 7.96 (s, 2H), 7.46 (m, 4H),
7.25 (m, 2H), 3.48 (d, 2H, Jˆ14.8 Hz), 2.23 (d, 2H,
Jˆ14.8 Hz), 2.31 (s, 6H), 1.2–2.1 (m, 14H), 0.64 (s, 6H),
0.31 (s, 6H) ppm. MS m/z (EI, 70 eV): 823, 822, 757, 606,
542, 392 (100), 373, 330, 196, 109, 81. HRMS Calcd for
C46H48N2O8S2 (Mϩ): 820.1954, Found 820.2887. UV
(Ethanol): 300, 252.4, 220.4 nm. [a]2D0ˆϩ3.75Њ (c 0.1,
CHCl3). 1b: mp 132–134ЊC. FT-IR (KBr): 3420, 2962,
1-Benzyloxy-3-methyl-9-H-carbazole (8a). To a stirred
solution of 7a (84 mg, 0.29 mmol) in HOAc (5 ml) was
added Pd(OAc)2 (98 mg, 0.44 mmol). The mixture was
refluxed for 1 h under vigorous stirring. After the reaction
was completed, the solution was cooled to room tempera-
ture. Then the HOAc was removed in vacuo and the residue
was purified by flash chromatography (Ethyl acetate:
Petroleum etherˆ10:1) to give 8a as a yellow oil (25 mg,
32%). FT-IR (KBr): 3429, 3034, 2922, 2862, 1588, 1504,
1
1749, 1615, 1497, 1454, 1363, 1246, 1172, 748 cmϪ1. H
NMR (300 MHz, CDCl3): d 8.94 (2H, N–H), 8.05 (d, 2H,
Jˆ7.8 Hz), 7.98 (s, 2H), 7.45 (m, 4H), 7.27 (m, 2H), 3.13 (d,
2H, Jˆ14.9 Hz), 2.53 (d, 2H, Jˆ14.8 Hz), 2.34 (s, 6H),
0.88–2.27 (m, 14H), 0.50 (s, 6H), 0.41 (s, 6H) ppm. MS
m/z (EI, 70 eV): 822, 757, 606, 542, 392 (100), 373, 330,
196, 109, 81. HRMS Calcd for C46H48N2O8S2 (Mϩ):
820.1954, Found 820.2812. UV (Ethanol): 298.8, 254.6,
220.8 nm. [a]2D0ˆϩ15.2Њ (c 0.48, CHCl3).
1
1455, 1305, 1233, 1130, 1026, 748, 732 cmϪ1. H NMR
(300 MHz, CDCl3): d 8.22 (1H, N–H), 8.02 (d, 1H,
Jˆ7.7 Hz), 7.20–7.80 (m, 10H, Ar-H), 6.83 (s, 1H, Ar-H),
5.24 (s, 2H, –CH2), 2.53 (s, 3H, –CH3) ppm. MS m/z (EI,
70 eV): 287 (Mϩ), 271, 258, 196 (100), 180, 168, 154, 139,
105, 91, 77, 65, 51. HRMS Calcd for C20H17NO (Mϩ):
287.1311, Found 287.1305.
1-Hydro-3-methyl-9-H-carbazole (9). To a suspension of
8a (70 mg, 0.24 mmol) in 95% ethanol (20 ml), 10% Pd/C
(25 mg) was added. Hydrogenation of the mixture gave 9 by
routine flash chromatography (Ethyl acetate:Petroleum
etherˆ5:1) as a yellow solid (35 mg, 72.8%). FT-IR (KBr):
3464, 3412, 2922, 1615, 1587, 1500, 1454, 1298, 1227,
(ϩ)-1,10-Dihydroxy-3,30-dimethyl-2,20-biscarbazole (aR-
1). To a mixture of 1a (20 mg, 0.024 mmol) in EtOH–H2O
(1:1, 30 ml) was added KOH (80 mg, 1.43 mmol) at room
temperature. When TLC showed no starting material left,
the mixture was extracted with CH2Cl2 (3×20 ml). The
combined organic layers were dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification of the
1118, 1091, 975, 766, 730 cmϪ1. 1H NMR (300 MHz,
.

7168
G. Lin, A. Zhang / Tetrahedron 56 (2000) 7163–7171
residue by flash chromatography (silica gel, Ethyl acetate:
C, 73.33; H, 6.60; N, 6.11. Found: C, 72.83; H, 6.29; N,
6.10.
Petroleum etherˆ2:1) provided (ϩ)-1 as a white solid
1
(7 mg, 73.2%). MpϾ260ЊC. H NMR (300 MHz, CDCl3)
d 8.28 (b, 2H, N–H), 8.09 (d, 2H, Jˆ8.0 Hz), 7.70 (s,
2H), 7.43 (m, 4H), 7.26 (m, 2H), 2.17 (s, 6H) ppm. FT-IR
(KBr): 3508, 3409, 2922, 1614, 1564, 1251 nm. MS m/z (EI,
70 eV): 392, 391 (100), 197, 196. HRMS Calcd for
C26H20N2O2 (Mϩ): 392.1526, found 392.1513. UV
(Ethanol): 296.4, 252.4, 224.4 nm. [a]2D0ˆϩ29.9Њ (c 0.67,
CHCl3).
1-Hydroxy-3-methyl-6-methoxy-carbazole (13). A 25 ml-
flask was charged with 12 (700 mg, 3.06 mmol), 10% Pd/C
(450 mg), biphenyl ether (30 ml), 1,2,4-trimethylbenzene
(3.5 ml), and the mixture was warmed at 200ϳ220ЊC for
12 h in vacuo. Then the mixture was cooled to room
temperature, and the product was purified by flash chroma-
tography (Ethyl acetate:Petroleum etherˆ20:1, then
CH2Cl2/HCOOHˆ100:0.1) provided 13 as a yellow solid
(504 mg, 73%). FT-IR (KBr): 3429, 3282, 2911, 1622,
1591, 1506, 1482, 1288, 1206, 1178, 1143, 832,
(Ϫ)-1,10-Dihydroxy-3,30-dimethyl-2,20-biscarbazole (aS-
1). To a mixture of 1b (20 mg, 0.024 mmol) in EtOH/H2O
(1:1, 30 ml) was added KOH (100 mg) at room temperature.
The stirring was kept until the disappearance of the starting
material on TLC. The products were extracted with CH2Cl2
(3×20 ml). The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica
gel, Ethyl acetate:Petroleum etherˆ2:1) provided (Ϫ)-1 as a
white solid (9 mg, 94%). MpϾ260ЊC. 1H NMR (300 MHz,
CDCl3) d 8.28 (b, 2H, N–H), 8.09 (d, 2H, Jˆ8.0 Hz), 7.71
(s, 2H), 7.47 (m, 4H), 7.26 (m, 2H), 2.18 (s, 6H) ppm. FT-IR
(KBr): 3510, 3422, 2925, 1615, 1564, 1253 nm. MS m/z (EI,
70 eV): 392, 391 (100), 197, 196. HRMS Calcd for
C26H20N2O2 (Mϩ): 392.1526, found 392.1531. UV
(Ethanol): 295.2, 253.6, 224.8 nm. [a]2D0ˆϪ39Њ (c 0.1,
CHCl3).
1
761 cmϪ1. H NMR (300 MHz, CDCl3): d 7.47 (d, 1H,
Jˆ2.4 Hz, 5-H), 7.40 (s, 1H, 4-H), 7.27 (d, 1H, Jˆ8.7 Hz,
8-H), 7.06 (dd, 1H, Jˆ8.8, 2.4 Hz, 7-H), 6.60 (s, 1H, 2-H),
5.00 (b, 2H, N–H, O–H), 3.91 (s, 3H, –OCH3), 2.46 (s, 3H,
–CH3) ppm. MS m/z (EI, 70 eV): 227 (Mϩ, 100), 212, 198,
184, 166, 155, 140, 128, 113, 91, 77, 63. HRMS Calcd for
C14H13NO2(Mϩ): 227.0947, found 227.0947.
1,10-Dihydroxy-3,30-dimethyl-6,60-methoxy-2,20-biscar-
bazole (2). A solution of 13 (100 mg, 0.44 mmol) in chloro-
benzene (10 ml) and di-tert-butyl peroxide (122 ml,
0.66 mmol) was refluxed for 2 h under air atmosphere.
After cooling, the solvent was evaporated in vacuo and
the remaining solid was purified by chromatography on
silica gel with Ethyl acetate:Petroleum ether (3:1) as the
eluant to give 2 as a yellow solid (75 mg, 79.3%). Mp
Ͼ260ЊC. FT-IR (KBr): 3518, 3406, 2924, 1621, 1564,
4-Methyl-cyclohexane-1,2-dione-1-(40-methoxy)-phenyl-
hydrazone (11a). To a stirred solution of sodium acetate
(22 g, 27 mmol) in H2O (15 ml) was added 10 (1.4 g,
10 mmol) in methanol (29 ml). The solution was kept for
the next step. Another 50 ml-flask charged with 4-methoxy-
aniline (1.42 g, 11.5 mmol), ice (5 g), water (5 g), 12N HCl
(4.8 ml) was cooled to 0ЊC, and then sodium nitrite (0.8 g,
11.5 mmol) in water (10 ml) was added. The mixture was
stirred for 25 min at this temperature, then stirred under
room temperature for another 15 min. The solution above
was added slowly, and the mixture was stirred for 30 min,
filtrated, washed by water. The red solid was dried and
recrystallized from ethanol to give 11a as red solid
(1.33 g, 54%). Mp 203–204ЊC. FT-IR (KBr): 3243, 2926,
1658, 1600, 1488, 1420, 1219, 1038, 831, 724 cmϪ1. MS
m/z (EI, 70 eV): 246 (Mϩ), 229, 175, 135, 122, 108, 95, 77,
69, 55, 42. EA: Calcd for C14H18N2O2: C, 68.27; H, 7.37; N,
11.37, Found: C, 68.06; H, 7.35; N, 11.35.
1496, 1300, 1211, 1154, 1031, 779 cmϪ1 1H NMR
.
(400 MHz, D-acetone): d 7.64 (d, 2H, Jˆ2.4 Hz, 5-H),
7.57 (d, 2H, Jˆ0.8 Hz, 4-H), 7.48 (dd, 2H, Jˆ8.8 Hz,
0.3 Hz, 8-H), 7.04 (dd, 2H, Jˆ8.7, 2.5 Hz, 7-H), 3.91 (s,
6H, –OCH3), 3.02 (s, 4H, N–H, O-H), 2.10 (s, 3H,
–CH3) ppm. MS m/z (EI, 70 eV): 452 (Mϩ), 437, 419,
376, 333, 292, 250, 226, 211, 197, 160, 139. HRMS Calcd
for C28H24N2O4: 452.1737, Found: 452.1738.
Resolution of (^)-2. To a mixture of 2 (50 mg, 0.11 mmol)
and triethylamine (0.5 ml) in CH2Cl2 (10 ml) was added
(ϩ)-camphorsulfonyl (84 mg, 0.33 mmol), and the mixture
was refluxed for 2 h. Then the mixture was treated with
water (20 ml), extracted with CH2Cl2 (2×15 ml). The
combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica
gel, CH2Cl2:CHCl3:Et2Oˆ50:1:2) provided 2b (47 mg,
48.3%) and 2a, respectively, both as a white solid (40 mg,
41%). 2a: mp 235–237ЊC. FT-IR (KBr): 3413, 2956, 2925,
1-Oxo-3-methyl-6-methoxy-1,2,3,4-tetrahydrocarbazole
(12). A 25 ml-flask was charged with 11a (1.23 g,
5.37 mmol), HOAc (9 ml), 12N HCl (3 ml), and the
mixture was refluxed for 10 min. Water (60 ml) was
added slowly while cooling the mixture. The yellow solid
was gained after filtrating, then washed with water and dried
over infrared lamp. The yellow solid was recrystallized
from benzene to give yellow solid 12 (560 mg, 44.2%).
Mp 200–203ЊC. FT-IR (KBr): 3251, 2953, 1653, 1537,
1
1748, 1585, 1496, 1466, 1360, 1291, 1212, 800 cmϪ1. H
NMR (300 MHz, CDCl3): d 8.76 (2H, N–H), 7.91 (s, 2H,
4-H), 7.50 (d, 2H, Jˆ2.4 Hz, 5-H), 7.38 (d, 2H, Jˆ8.8 Hz,
8-H), 7.09 (dd, 2H, Jˆ8.8, 2.6 Hz, 7-H), 3.93 (s, 6H,
–OCH3), 3.47 (d, 2H, Jˆ14.9 Hz), 2.25 (d, 2H,
Jˆ14.9 Hz), 2.29 (s, 6H), 1.2–2.1 (m, 14H), 0.64 (s, 6H),
0.33 (s, 6H) ppm. MS m/z (EI, 70 eV): 882, 881, 817, 753,
667, 602, 452 (100), 397, 333, 226, 152, 109, 81. HRMS
Calcd for C48H52N2O8S2 (Mϩ): 880.3065, Found 880.3068.
[a]2D0ˆϩ38.1Њ (c 1.08, CHCl3). 2b: mp 203–204ЊC. FT-
IR(KBr): 3412, 2956, 2925, 1748, 1585, 1496, 1466,
1484, 1447, 1216, 1139, 1029, 808 cmϪ1 1H NMR
.
(300 MHz, CDCl3): d 9.05 (s, 1H), 7.34 (m, 1H), 7.04 (m,
2H), 3.87 (s, 3H, –OCH3), 3.11 (dd, 1H, Jˆ5.3, 3.0 Hz),
2.53 (m, 4H), 1.23 (d, 3H, Jˆ5.9 Hz, –CH3) ppm. MS m/z
(EI, 70 eV): 229 (Mϩ), 214, 201, 186, 170, 159, 144, 129,
116, 103, 89, 77, 69, 51, 42. EA: Calcd for C14H13NO3:
.
1364, 1291, 1212, 802 cmϪ1 1H NMR (300 MHz,
CDCl3): d 8.78 (2H, N–H), 7.94 (s, 2H, 4-H), 7.51 (d,

G. Lin, A. Zhang / Tetrahedron 56 (2000) 7163–7171
7169
2H, Jˆ2.4 Hz, 5-H), 7.37 (d, 2H, Jˆ8.8 Hz, 8-H), 7.09 (dd,
2H, Jˆ8.8, 2.5 Hz, 7-H), 3.93 (s, 6H, –OCH3), 3.13 (d, 2H,
Jˆ14.8 Hz), 2.53 (d, 2H, Jˆ14.9 Hz), 2.32 (s, 6H), 1.2–2.1
(m, 14H), 0.51 (s, 6H), 0.42 (s, 6H) ppm. MS m/z (EI,
70 eV): 882, 881, 817, 753, 667, 602, 452 (100), 392, 301,
226, 152, 109, 95. HRMS Calcd for C48H52N2O8S2 (Mϩ):
880.3065, Found 880.3065. [a]2D0ˆϪ34.9Њ (c 1.14, CHCl3).
CH3) ppm. MS m/z (EI, 70 eV): 350, 349 (Mϩ, 100),
291, 258, 243, 227, 212, 184, 144, 110, 91, 77, 65, 52.
HRMS Calcd for C22H23NO3 (Mϩ): 349.1679, Found
349.1668.
4-Methyl-cyclohexane-1,2-dione-1-(30,50-dimethoxy)-
phenylhydrazone (11b). To a stirred solution of sodium
acetate (4.4 g, 54 mmol) in H2O (15 ml) was added 10
(2.8 g, 20 mmol) in methanol (29 ml). The solution was
kept for the next step. Another 50 ml-flask charged with
3,5-dimethoxylaniline (3.52 g, 25 mmol), ice (5 g), water
(5 g), 12N HCl (9.5 ml) was cooled to 0ЊC, and then sodium
nitrite (1.6 g, 23 mmol) in water (10 ml) was added. The
mixture was stirred for 25 min at this temperature, then
stirred under room temperature for another 15 min. The
solution above was added slowly, and the mixture was stir-
red for 30 min, filtrated, washed by water. The red solid was
dried and recrystallized from ethanol to give 11b as red
solid (4.02 g, 72.5%). Mp 91–93ЊC. FT-IR (KBr): 2929,
(ϩ)-1,10-Dihydroxy-3,30-dimethyl-6,60dimethoxy-2,20-
biscarbazole (aR-2). To a mixture of 2a (21 mg,
0.024 mmol) in 95% EtOH (30 ml) was added KOH
(100 mg) at room temperature. The accomplishment of the
hydrolysis was monitored by TLC, then the products were
extracted with CH2Cl2 (3×20 ml). The combined organic
layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash
chromatography (silica gel, Ethyl acetate:Petroleum
etherˆ2:1) provided (ϩ)-2 as a white solid (6 mg, 57%).
1
MpϾ260ЊC. H NMR(300 MHz, CDCl3) 8.13 (b, 2H, N–
H), 7.66 (s, 2H), 7.55 (d, 2H, Jˆ2.4 Hz), 7.40 (d, 2H,
Jˆ8.8 Hz), 7.11 (dd, 2H, Jˆ8.8, 2.4 Hz), 5.12 (s, 2H, O-
H), 3.96 (s, 6H, –OCH3), 2.17 (s, 3H, –CH3). FT-IR (KBr):
3529, 3414, 2924, 1622, 1564, 1212. UV (Ethanol): 302.0,
254.0, 226.0, 203.2 nm. MS m/z (EI, 70 eV): 453, 452 (Mϩ),
227, 226. HRMS Calcd for C28H24N2O4 (Mϩ): 452.1737,
found 4520.1738. [a]2D0ˆϩ44.3Њ (c 0.09, CHCl3).
1620, 1517, 1497, 1208, 1164, 1026 cmϪ1 1H NMR
.
(300 MHz, CDCl3): d 14.0(1H, N–H), 7.53 (d, 1H,
Jˆ8.2 Hz), 6.49 (m, 2H), 3.89 (s, 3H, –OCH3), 3.79 (s,
3H, –OCH3), 2.69 (m, 3H), 2.04 (m, 3H), 1.46 (m, 1H),
1.04 (d, 3H, Jˆ6.6 Hz, –CH3) ppm. MS m/z (EI, 70 eV):
276 (Mϩ), 261, 165, 152 (100), 138, 124, 109, 93, 79, 69, 55,
42. EA: Calcd for C15H20N2O3: C, 65.22; H, 7.25; N, 10.14.
Found: C, 65.26; H, 7.47; N, 10.11.
(Ϫ)-1,10-Dihydroxy-3,30-dimethyl-6,60dimethoxy-2,20-
biscarbazole (aS-2). To
a
mixture of 2b (28 mg,
Toluene-4-sulfonic acid 2-amino-5-methyl-phenyl ester
(15). To a suspension of 2-amino-5-methylphenol (2.66 g,
20 mmol) in CH2Cl2 (40 ml) cooled to 0ЊC, triethylamine
(2.78 ml, 20 mmol) and p-tosyl chloride (3.81 g, 20 mmol)
were added with stirring. When TLC showed no starting
material left, the products were quenched with water
(30 ml) and the aqueous layer was extracted with CH2Cl2
(3×20 ml). The combined organic layers were dried over
Na2SO4, filtered, and the solvent was removed in vacuo.
The residue was purified by recrystallization from ether to
give 15 as a yellow solid (4.27 g, 77%). Mp 81–82ЊC. FT-IR
(KBr): 3482, 3389, 3035, 2919, 1740, 1630, 1597, 1521,
0.032 mmol) in EtOH–H2O (1:1, 30 ml) was added KOH
(500 mg) at room temperature. When TLC showed no start-
ing material was left, the products were extracted with
CH2Cl2 (3×20 ml). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromato-
graphy (silica gel, Ethyl acetate:Petroleum etherˆ2:1)
provided (Ϫ)-2 as
a
white solid (13 mg, 90%).
MpϾ260ЊC. 1H NMR (400 MHz, CDCl3) 8.10 (b, 2H,
N–H), 7.65 (s, 2H), 7.55 (d, 2H, Jˆ2.4 Hz), 7.39 (d, 2H,
Jˆ8.7 Hz), 7.10 (dd, 2H, Jˆ8.8, 2.5 Hz), 3.95 (s, 6H,
–OCH3), 2.17 (s, 3H, –CH3). FT-IR(KBr): 3520, 3412,
2924, 1561, 1465, 1213. UV (Ethanol): 302.0, 253.6,
226.8, 203.6 nm. MS m/z (EI, 70 eV): 453, 452 (Mϩ),
227, 226. HRMS Calcd for C28H24N2O4 (Mϩ): 452.1737,
found 4520.1738. [a]2D0ˆϪ44.7Њ (c 0.13, CHCl3).
1
1198, 1089 cmϪ1. H NMR (90 MHz, CDCl3): d 7.85 (d,
2H, Jˆ9.0 Hz), 7.32 (d, Jˆ9.0 Hz, 2H), 6.62–6.91 (m, 3H),
3.96 (2H, –NH2), 2.50 (s, 3H, CH3), 2.22 (s, 3H, –
CH3) ppm. MS m/z (EI, 70 eV): 278, 277 (Mϩ), 213, 198,
185, 170, 155, 122 (100), 107, 94, 77, 65, 51, 42. EA: Calcd
for C14H15NSO3: C, 60.63; H, 5.46; N, 5.05. Found: C,
60.51; H, 5.39; N, 5.24.
N-(30,50-Dimethoxy)-benzyl-2-benzyloxy-4-methyl-aniline
(7b). A 10 ml-flask was charged with 2,4-dimethoxy-iodo-
benzene (132 mg, 0.5 mmol), 6 (128 g, 0.6 mmol), sodium
tert-butoxide (67 mg, 0.7 mmol), Pd2(DBA)3 (10 mg, Pd,
4% equiv.), BINAP (9 mg, 0.026 mmol), 18-C-6 (116 mg,
0.63 mmol), THF (1 ml). The mixture was warmed at 40ЊC
for 48 h under vigorous stirring. After the reaction was
completed, the solution was cooled to room temperature.
The residue after evaporation of the solvent was purified
by flash chromatography (Ethyl acetate:Petroleum
etherˆ5:1) to give 7b (96 mg, 77%). FT-IR (KBr): 3421,
2938, 2834, 1618, 1528, 1509, 1465, 1280, 1258,
Toluene-4-sulfonic acid 2-amino-3-bromo-5-methyl-
phenyl ester (16). To a stirred solution of 15 (1.369 g,
4.94 mmol), in DMSO (15 ml) was added 15 ml 48%
aqueous HBr. Heat was applied after stirring for 24 h at
room temperature. The reaction progress was monitored
by TLC analysis. Then the reaction mixture was diluted
with water and made basic (pHˆ10) by slow addition of
solid NaOH. The aqueous layer was extracted with ether
(3×30 ml) and the combined organic layers were washed
by brine, dried over Na2SO4. The solvent was removed in
vacuo and the residue purified by flash chromatography
(silica gel, Ethyl acetate:Petroleum etherˆ5:1) to give 16
as a white solid (1.41 g, 80%). Mp 134–135ЊC. FT-
IR(KBr): 3475, 3389, 2928, 1629, 1596, 1495, 1365,
1
1208 cmϪ1. H NMR (300 MHz, CDCl3): d 7.32–7.47 (m,
5H, Bn-H), 7.22 (d, 1H, Jˆ8.3 Hz, 4-H), 7.06 (d, 1H,
Jˆ7.7 Hz, 3-H), 6.76 (s, 1H, 1-H), 6.68 (d, 1H, Jˆ8.0 Hz,
2-H), 6.51 (d, 1H, Jˆ2.3 Hz, 6-H), 5.11 (s, 2H, –CH2), 3.80
(s, 3H, –OCH3), 3.79 (s, 3H, –OCH3), 2.28 (s, 3H,
1
1177, 1091 cmϪ1. H NMR (300 MHz, CDCl3): d 7.79 (d,

7170
G. Lin, A. Zhang / Tetrahedron 56 (2000) 7163–7171
2H, Jˆ8.3 Hz), 7.32 (d, 2H, Jˆ8.1 Hz), 7.13 (d, 1H,
Jˆ1.0 Hz), 6.67 (d, 1H, Jˆ1.1 Hz), 3.79 (b, 2H, –NH2),
2.47 (s, 3H, –CH3), 2.14 (s, 3H, –CH3) ppm. MS m/z (EI,
70 eV): 358, 357, 356 (Mϩ), 355, 241, 214, 202 (100), 184,
174, 172, 155, 134, 120, 93, 65. HRMS Calcd for
C24H25NO5 (Mϩ): 407.1734, Found 407.1729.
3H, –CH3), 2.38 (s, 3H, –CH3) ppm. MS m/z (EI, 70 eV):
412, 256, 232, 226, 213, 198. HRMS Calcd for C22H21NSO5
(Mϩ): 411.1141, Found 411.1137.
6,8-Dimethoxy-3-methyl-9H-carbazole-1-OH (21).
A
mixture of 20 (36 mg, 0.09 mmol) and NaOH (98 mg) in
water (5 ml) and ethanol (5 ml) was stirred under reflux for
1 h. The mixture was quenched with water (10 ml). After
extractive work up (CH2Cl2, 3×30 ml), the combined
organic layers were washed by brine and dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica
gel, Ethyl acetate:Petroleum etherˆ5:1) provided 21 as a
yellow solid (20 mg, 88%). Mp 181–182ЊC. FT-IR (KBr):
3518, 3380, 1588, 1512 cmϪ1. 1H NMR (300 MHz, CDCl3):
d 8.27 (s, 1H, –NH), 7.40 (s, 1H), 7.06 (d, 1H, Jˆ1.9 Hz),
6.64 (s, 1H), 6.57 (d, 1H, Jˆ2.0 Hz), 5.36 (s, 1H, –OH),
3.97 (s, 3H, –OCH3), 3.92 (s, 3H), 2.46 (s, 3H, –CH3) ppm.
MS m/z (EI, 70 eV): 257, 242, 226, 214, 199. EA: Calcd for
C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.32; H,
6.03; N, 5.29.
Toluene-4-sulfonic acid 2-amino-30,50-dimethoxy-5-
methyl-biphenyl-3-yl ester (18a). A 25 ml-flask was
charged Pd(PPh3)4 (20 mg, 0.017 mmol), benzene (15 ml),
16 (180 mg, (0.5 mmol) and aqueous solution of Na2CO3
(2 ml of 2 M, 4 mmol), then 3,5-dimethoxy-phenylboronic
acid (110 mg, 0.6 mmol) in ethanol (4 ml) was added. The
mixture was refluxed for 8 h under vigorous stirring. After
the reaction was completed, the solution was cooled to room
temperature. The product was extracted with ether, washed
by brine, and finally dried over Na2SO4. The residue after
evaporation of the solvent was purified by flash chromato-
graphy (Ethyl acetate:Petroleum etherˆ5:1) to give 18a
(204 mg, 99%). Mp 122–123ЊC. FT-IR (KBr): 3498,
3406, 2941, 1629, 1588, 1366, 1205, 1154, 1089, 1062,
1
775 cmϪ1. H NMR (300 MHz, CDCl3): d 7.82 (d, 2H,
Jˆ8.3 Hz), 7.35 (d, 2H, Jˆ8.1 Hz), 6.84 (s, 1H), 6.75 (s,
1H), 6.47 (d, Jˆ2.0 Hz, 1H), 6.44 (d, Jˆ2.1 Hz, 1H), 6.04
(dd, Jˆ8.0, 2.0 Hz, 1H), 3.79 (s, 6H, –OCH3), 3.74 (s, 2H, –
NH2), 2.47 (s, 3H, –CH3), 2.20 (s, 3H, –CH3) ppm. MS m/z
(EI, 70 eV): 414, 413 (Mϩ), 374, 277, 258(100), 243, 227,
212, 184, 154, 122, 111, 91, 77, 42. HRMS Calcd for
C22H23NSO5 (Mϩ): 413.1298, Found 413.1295.
Clausenamine-A (3). A solution of 21 (80 mg, 0.31 mmol)
in chlorobenzene (10 ml) and di-tert-butyl peroxide (86 ml,
0.45 mmol) was refluxed for 2 h under air atmosphere. After
cooling, the solvent was evaporated in vacuo and the
remaining solid was purified by chromatography on silica
gel with Ethyl acetate:Petroleum ether (3:1) as the eluant to
give 3 as a yellow solid (72 mg, 90%). FT-IR (KBr): 3493,
1
3404, 1596 cmϪ1. H NMR (300 MHz, CDCl3): d 8.76 (s,
Toluene-4-sulfonic acid 2-amino-20-bromo-30,50-di-
methoxy-5-methyl-biphenyl-3-yl ester (19). To a stirred
solution of 18a (150 mg, 0.36 mmol), in DMSO (5 ml)
was added 2 ml 48% aqueous HBr at room temperature
for 4 days. Then the reaction mixture was diluted with
water and made basic (pHˆ10) by slow addition of solid
NaOH. The aqueous layer was extracted with ether
(3×30 ml) and the combined organic layers were washed
by brine, dried over Na2SO4. The solvent was removed in
vacuo and the residue purified by flash chromatography
(silica gel, Ethyl acetate:Petroleum etherˆ5:1) to give 19
as a white solid (142 mg, 79.5%). Mp 140–141ЊC. FT-IR
2H, –NH), 7.59 (s, 2H), 7.02 (s, 2H), 6.43 (s, 2H), 5.83 (s,
2H, –OH), 3.90 (s, 6H, –OCH3), 3.56 (s, 6H), 2.14 (s, 6H,
–CH3) ppm. MS m/z (EI, 70 eV): 512, 497, 482, 449, 255.
HRMS Calcd for C30H28N2O6 (Mϩ): 512.1948, Found
512.1974.
Resolution of (^)-3. To a mixture of 3 (14 mg,
0.027 mmol) and triethylamine (0.25 ml) in CH2Cl2
(10 ml) was added (ϩ)-camphorsulfonyl (13 mg,
0.052 mmol), and the mixture was refluxed for 2 h. Then
the mixture was treated with water (20 ml), extracted with
CH2Cl2 (2×15 ml). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash
chromatography (silica gel, CH2Cl2:CHCl3:Et2Oˆ50:1:2)
provided 3b (12 mg, 47%) and 3a respectively both as a
white solid (12 mg, 47%). 3a: mp 167–168ЊC. FT-IR
1
(KBr): 3452, 3368, 2939, 1584 cmϪ1. H NMR (300 MHz,
CDCl3): d 7.79 (d, 2H, Jˆ8.4 Hz), 7.31 (d, 2H, Jˆ7.3 Hz),
6.94 (d, 1H, Jˆ2.32 Hz), 6.72 (d, 1H, Jˆ2.01 Hz), 6.48 (d,
1H, Jˆ2.73 Hz), 6.37 (d, 1H, Jˆ2.85 Hz), 3.89 (s, 6H, –
OCH3), 3.78 (s, 2H, –NH2), 2.44 (s, 3H, –CH3), 2.23 (s, 3H,
–CH3) ppm. MS m/z (EI, 70 eV): 494, 492, 412, 337,
257(100), 242. HRMS Calcd for C22H22NBrSO5 (Mϩ):
491.0402, Found 491.0403.
(KBr): 3434, 2924, 1749 cmϪ1 1H NMR (300 MHz,
.
CDCl3): d 8.75 (s, 2H, –NH), 7.88 (s, 2H), 7.06 (d, 2H,
Jˆ1.8 Hz), 6.60 (d, 2H, Jˆ1.9 Hz), 3.95 (s, 6H, –OCH3),
3.93 (s, 6H, –OCH3), 3.43 (d, 2H, Jˆ14.8 Hz), 2.17 (d, 2H,
Jˆ14.8 Hz), 2.36 (s, 6H), 0.8–1.9 (M, 14H), 0.61 (s, 6H),
0.30 (s, 6H) ppm. MS m/z (EI, 70 eV): 942, 940, 878, 876,
727, 663, 512. HRMS Calcd for C50H56N2S2O12 (Mϩ):
940.3271, Found 940.3151. 3b: mp 148–150ЊC. FT-IR
Toluene-4-sulfonic acid 6,8-dimethoxy-3-methyl-9H-
carbazole-1-yl ester (20). A solution of Pd(PPh3)4
(704 mg, 0.6 mmol), toluene (10 ml), 19 (250 mg,
0.5 mmol), Na2CO3 (65 mg) were refluxed for 6 h. The
mixture was cooled and the solvent was removed in
vacuo. The residue was purified by flash chromatography
to give the product 20 as a white solid (188 mg, 90%). Mp
152–154ЊC. FT-IR (KBr): 3384, 2920, 1596 cmϪ1. 1H NMR
(300 MHz, CDCl3): d 7.82 (s, 1H, –NH), 7.77 (d, 2H,
Jˆ8.4 Hz), 7.65 (s, 1H), 7.29 (d, 1H, Jˆ8.8 Hz), 7.01 (d,
1H, Jˆ2.0 Hz), 6.70 (d, 1H, Jˆ0.8 Hz), 6.57 (d, 1H,
Jˆ2.1 Hz), 3.96 (s, 3H, –OCH3), 3.90 (s, 3H), 2.42 (s,
(KBr): 3431, 2924, 1749 cmϪ1 1H NMR (300 MHz,
.
CDCl3): d 8.75 (s, 2H, –NH), 7.90 (s, 2H), 7.07 (d, 2H,
Jˆ1.9 Hz), 6.60 (d, 2H, Jˆ2.0 Hz), 3.96 (s, 6H, –OCH3),
3.93 (s, 6H, –OCH3), 3.08 (d, 2H, Jˆ14.8 Hz), 2.48 (d, 2H,
Jˆ14.9 Hz), 2.32 (s, 6H), 0.8–2.2 (M, 14H), 0.49 (s, 6H),
0.40 (s, 6H) ppm. MS m/z (EI, 70 eV): 942, 878, 813, 727,
663, 512. HRMS Calcd for C50H56N2S2O12 (Mϩ): 940.3271,
Found 940.3344.

G. Lin, A. Zhang / Tetrahedron 56 (2000) 7163–7171
7171
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(ϩ)-Clausenamine-A (3). The mixture of 3a (35 mg,
0.037 mmol) in EtOH–H2O (1:1, 30 ml) and KOH
(100 mg) was kept stirring at room temperature until no
starting material was left, the products were extracted with
CH2Cl2 (3×20 ml). The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromato-
graphy (silica gel, Ethyl acetate:Petroleum etherˆ2:1)
provided (ϩ)-3 as a white solid (16 mg, 84%). FT-IR
(KBr): 3398, 2932, 1595 cmϪ1 1H NMR (300 MHz,
.
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CDCl3): d 8.69 (s, 2H, –NH), 7.60 (s, 2H, -4H), 7.04 (d,
2H, Jˆ1.7 Hz, -5H), 6.45 (d, 2H, Jˆ1.6 Hz, -7H), 5.73 (s,
2H, –OH), 3.91 (s, 6H, –OCH3), 3.63 (s, 6H), 2.15 (s, 6H, –
CH3) ppm. MS m/z (EI, 70 eV): 512, 497, 482, 449, 256.
HRMS Calcd for C30H28N2O6 (Mϩ): 512.1948, Found
512.1970. [a]2D1ˆϩ142.2Њ (c 0.75, CHCl3).
(Ϫ)-Clausenamine-A (3). To a mixture of 3b (37 mg,
0.037 mmol) in EtOH–H2O (1:1, 30 ml) was added KOH
(100 mg) at room temperature. The accomplishment of the
hydrolysis was monitored by TLC, then the products were
extracted with CH2Cl2 (3×20 ml). The combined organic
layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash
chromatography (silica gel, Ethyl acetate:Petroleum
etherˆ2:1) provided (Ϫ)-3 as a white solid (17 mg, 87%).
FT-IR (KBr): 3400, 2935, 1595 cmϪ1. 1H NMR (300 MHz,
CDCl3): d 9.12 (s, 2H, –NH), 7.59 (s, 2H, -4H), 6.95 (d, 2H,
Jˆ1.4 Hz, -5H), 6.38 (s, 2H, –OH), 6.30 (d, 2H, Jˆ1.0 Hz,
-7H), 3.87 (s, 6H, –OCH3), 3.26 (s, 6H), 2.15 (s, 6H,
–CH3) ppm. MS m/z (EI, 70 eV): 512, 497, 482, 449, 256.
HRMS Calcd for C30H28N2O6 (Mϩ): 512.1948, Found
512.1923. [a]2D1ˆϪ147.6Њ (c 0.65, CHCl3).
12. (a) Murakami, Y.; Watanabe, T.; Takahashi, H.; Yokoo, H.;
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Acknowledgements
We are grateful to the National Science Foundation of China
(29772052) and the Chinese Academy of Science (KT951-
A1-506-05) for financial support. We also thank Prof. John
Pezzuto and Pamela Tamez at UIC in USA for the
antimalarial bioassays.
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