Synthesis of methylene-bridged binary carbazole alkaloids and a related tricarbazole

Article abstract of DOI:10.1016/S0040-4020(01)00104-1

The first synthesis of the methylene-bridged binary carbazole alkaloids bismurrayafoline-A and chrestifoline-A is described. As an interesting side product, a likewise benzylically connected trimer was identified, a potential natural product.

Full text of DOI:10.1016/S0040-4020(01)00104-1

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2337±2343
Synthesis of methylene-bridged binary carbazole alkaloids and a
related tricarbazole
Gerhard Bringmannp and Stefan Tasler
È È È È
Institut fur Organische Chemie, Universitat Wurzburg, Am Hubland, D-97074 Wurzburg, Germany
Received 12 January 2001; accepted 18 January 2001
AbstractÐThe ®rst synthesis of the methylene-bridged binary carbazole alkaloids bismurrayafoline-A and chrestifoline-A is described. As
an interesting side product, a likewise benzylically connected trimer was identi®ed, a potential natural product. q 2001 Elsevier Science Ltd.
All rights reserved.
1. Introduction
only mentioned the synthesis of the related (but unnatural)
benzylic acetate 5 by NaBH4 reduction of murrayanine
(1-methoxycarbazole-3-carbaldehyde), acidi®cation with
HCl, and subsequent treatment with Ac2O, without isolating
the intermediate bismurrayafolinol (4) and without giving
yields or any further details.3 In this paper, the ®rst synthesis
of bismurrayafoline-A (3) and chrestifoline-A (6) is
described.
Among the few binary carbazole alkaloids connected
through a methylene unit,1 three are formally derived from
the 1-methoxy-3-methyl- and 1-methoxy-3-hydroxymethyl-
carbazoles murrayafoline-A (1) and koenoline (2) (Fig. 1):
bismurrayafoline-A (3),2 bismurrayafolinol (4)3 and chres-
tifoline-A (6).4 All of them have been isolated from
Murraya euchrestifolia and the latter also from M. koenigii
(Rutaceae). For bismurrayafoline-A (3) and chrestifoline-A
(6), a moderate anti-tumor activity has been found recently.5
2. Results and discussion
None of these methylene-bridged biscarbazole alkaloids,
however, have as yet been synthesized.6 Furukawa et al.
A more recent detailed investigation of the side products
in the course of an upscaling of our total synthesis of
Figure 1. Mono- and dimeric carbazoles.
Keywords: binary carbazole alkaloids; biscarbazole; tricarbazole; Murraya.
Corresponding author. Tel.: 149-931-888-5323; fax: 149-931-888-4755; e-mail: bringman@chemie.uni-wuerzburg.de
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00104-1

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G. Bringmann, S. Tasler / Tetrahedron 57 (2001) 2337±2343
Scheme 1. LiAlH4 reduction of 7 to give i.a. the binary alkaloids 3, 4 and 6.
murrayafoline-A (1),7 viz the ®nal reduction of the ester
function of 7 with LiAlH4 to give the methyl group directly,
has now revealed this reaction to yield the binary carbazole
alkaloids 3 and 4 as minor products (up to 6% each) and 6 in
even up to 40% after acidic workup in a few cases. The
product quantities obtained seemed to be dependent on
factors like the concentration of the reaction solution and
the pH value during workup.8 The standard outcome of this
reaction was the formation of murrayafoline-A (1) in 80%
yield besides 10±18% of koenoline (2) (Scheme 1). In the
case of the isolation of 40% of chrestifoline-A (6), no
koenoline (2) was found any more and the yield in murraya-
foline-A (1) decreased to 56%, indicating that almost equi-
molar quantities of these two compounds had reacted to give
6, most probably during acidic workup. These results made
it rewarding to look for more ef®cient synthetic pathways to
give the bicarbazoles in better yields.
to keep the actual amount of metalated koenoline 8 (Scheme
1) constant while decreasing the concentration of H-nucleo-
philes in the reaction mixture. This should permit other
nucleophiles (like N-deprotonated carbazole molecules;
To explore the in¯uence of a sterically more demanding
substituent at C-1, the reduction of the 3-ester functionality
was likewise performed on the O-isopropyl substrate 11
(Scheme 2). The Oi-Pr group was found to prevent side
reactions at the endocyclic nitrogen, giving rise to 92% of
the 3-methyl compound 12 without yielding any C±N-
bonded biscarbazoles. If, however, 2N HCl was used for
acidi®cation of the reaction mixture, instead of saturated
aqueous NH4Cl, the di-O-isopropyl analog 13 of chrestifo-
line-A (6) could be isolated in up to 14% yield, decreasing
the amount of 12 to 83%.
For an enhanced formation of C±N-bonded carbazoles, the
standard reduction of 7 was carried out in a highly concen-
trated solution with only 1.0 equiv. (instead of 3.0) of
LiAlH4 in the presence of AlCl3 as a Lewis acid, in order
Scheme 2. Ester reduction of the O-isopropyl compound 11: (a) 2-iodopro-
pane, Cs2CO3, acetone, D, 9 h; (b) LiAlH4, Et2O/CH2Cl2, rt, 2 h.

G. Bringmann, S. Tasler / Tetrahedron 57 (2001) 2337±2343
2339
Scheme 4. Preparation of chrestifoline-A (6): (a) Et2O/CH2Cl2, concd HCl,
rt, 30 min.
Scheme 3. Synthesis of bismurrayafoline-A (3): (a) LiAlH4, Et2O/CH2Cl2,
rt, 30 min; (b) addition of 7 in Et2O/CH2Cl2 over 30 min, rt, further 60 min.
see Scheme 1, nucleophile b) to compete in the ®nal trap-
ping of the reactive intermediate 9. This procedure,
however, led to an isolation of 53% koenoline (2) besides
33% murrayafoline-A (1), while the benzylic bicarbazoles
were again formed only as minor products.
In another approach, 2.0 equiv. of murrayafoline-A (1) were
stirred in a small volume of Et2O/CH2Cl2 together with
3.0 equiv. of LiAlH4 for 30 min at rt prior to the slow addi-
tion of 1.0 equiv. of ester 7 dissolved in the same solvent
(Scheme 3). The ®rst step was expected to provide an excess
of carbazolic nucleophilesÐthe N-deprotonated murrayafo-
line-AÐwhich should thus more easily `win' against the
H-nucleophiles in the competition to react with 9 formed
by the reduction of 7. After 1 h stirring at rt, as much as 19%
of 7 (i.e. three times more than above) had been converted to
bismurrayafoline-A (3).9
Figure 2. Structure of the novel tricarbazole 14.
As an entirely unprecedented minor side product (up to 4%),
the twofold methylene-bridged tricarbazole 14 (Fig. 2) was
identi®ed in a few cases. The possibility of oligomer forma-
tion had already been mentioned by Furukawa et al., who,
however, did not provide any concrete structures or spectral
evidence.3
For an improved synthesis of chrestifoline-A (6), acidic
conditions seemed to be appropriate according to the obser-
vations mentioned above for the coincidental formation of 6
and 13. A concentrated solution of 1.0 equiv. of koenoline
(2) and 3.0 equiv. of murrayafoline-A (1) in Et2O/CH2Cl2
was treated with some drops of concentrated HCl and stirred
for 30 min. In this case, up to 70% of koenoline (2) and the
same absolute amount of murrayafoline-A (1) reacted to
give the desired binary carbazole 6 (Scheme 4). The reac-
tion was, however, not easy to control, so that the product
quantities could vary.
3. Conclusion
In summary, the binary carbazoles bismurrayafoline-A (3)
and chrestifoline-A (6) were prepared for the ®rst time,
giving up to 19 and 70% yields, respectively. Bismurraya-
folinol (4) was likewise attained synthetically even though
only as a minor product during the standard reduction of
ester 7. With these alkaloids now preparatively available,
further investigations on biological activities have become

2340
G. Bringmann, S. Tasler / Tetrahedron 57 (2001) 2337±2343
possible. The tricarbazole 14 with its unprecedented struc-
ture represents a potential novel type of natural products.
nine,7 542 mg (3.92 mmol) of K2CO3 and 298 ml (396 mg,
3.14 mmol) of dimethyl sulfate were added to a solution of
1.00 g (3.92 mmol) crude ester 10 in 40 ml dry acetone.
After 7 h under re¯ux, excessive dimethyl sulfate was
scavenged by treatment of the mixture with 5 ml concd
aqueous NH3 and renewed heating under re¯ux for
30 min. Removal of the solvents, puri®cation of the remain-
ing residue by column chromatography on silica gel
(petroleum ether/diethyl ether 5:1), and recrystallization
from EtOH/pentane afforded 899 mg (3.34 mmol, 85%) of
7: mp 2098C (pale yellow crystals); IR (KBr): nˆ3320 (N±
H), 3040 (Ar±H), 2980, 2960, 2910 (C±H), 1675 (CvO),
1615, 1595, 1570 (Ar), 1485 (alkyl); 1H NMR (250.1 MHz,
d6-acetone): dˆ1.41 (t, Jˆ7.0 Hz, 3H, CO2CH2CH3), 4.07
(s, 3H, OMe), 4.39 (q, Jˆ7.0 Hz, 2H, CO2CH2CH3), 4.20 (s,
3H, NMe), 7.26 (ddd, Jˆ7.9, 7.0, 1.2 Hz, 1H, 6-H), 7.46
(ddd, Jˆ8.2, 7.0, 1.2 Hz, 1H, 7H), 7.60 (d, Jˆ1.2 Hz, 1H,
2-H), 7.63 (d, Jˆ8.2 Hz, 1H, 8-H), 8.20 (d, Jˆ7.9 Hz, 1H,
5-H), 8.49 (d, Jˆ1.2 Hz, 1H, 4-H), 10.78 (s, 1H, NH); 13C
NMR (62.9 MHz, d6-acetone): dˆ14.79 (CO2CH2CH3),
56.03 (OMe), 61.07 (CO2CH2CH3), 107.1 (C-2), 112.6
(C-8), 116.5 (C-4), 120.6 (C-6), 121.3 (C-5), 122.8, 124.3
(each Cq), 127.0 (C-7), 134.0, 141.3, 146.3 (each Cq), 167.5
(CO2Et); one Cq signal overlayed; MS: m/z (%)ˆ269 (100)
[M1], 254 (24) [M12Me], 241 (31) [M12C2H4], 226 (28)
[2412Me], 224 (50) [M12OEt], 196 (20) [M12CO2Et],
182 (28) [1962CH2], 181 (21) [1822H]; Anal. calcd for
C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 71.51; H,
5.32; N, 5.08. Likewise obtained were 6% (62.2 mg, 220
mmol) of the corresponding N-methyl derivative, ethyl
4. Experimental
4.1. General
Melting points (Reichert-Jung Thermovar microscope) are
uncorrected. IR spectra were measured using Perkin±Elmer
1420 and FTIR 1600 spectrometers. 1H and 13C NMR
spectra were recorded at rt on a Bruker AM 250. Chemical
shifts d are reported in ppm and coupling constants J in Hz.
The solvent signal was used as the internal standard [1H: d
(CDCl3)ˆ7.26, d (d6-acetone)ˆ2.05; 13C: d (CDCl3)ˆ
77.01, d (d6-acetone)ˆ29.82]. The mass (MS) and high
resolution mass (HRMS) spectra were measured on a
Finnigan MAT 90 and MAT 8200 mass spectrometer by
using electron impact ionization (EI). The spectra are
reported in wave numbers (cm21), the relative intensities
are given in brackets. Microanalyses were performed by
the microanalytical laboratory of the Institute of Inorganic
Chemistry of the University of WuÈrzburg. All reactions,
except those involving H2O, were done under nitrogen
and with dried solvents and glassware.
4.1.1. Ethyl 1-hydroxy-9H-carbazole-3-carboxylate (10).
Compound 10 was prepared in analogy to the ®nal step in
the synthesis of clausine E,7 but here using ethanol as
the solvent. A mixture of the cyclization products ethyl
1-acetoxy-9-acetyl-9H-carbazole-3-carboxylate and ethyl
1-methoxy-9-methyl-9H-carbazole-3-carboxylate:10
mp
1088C (EtOH/pentane, colorless needles); IR (KBr):
nˆ3030 (Ar±H), 2985, 2950, 2935, 2910, 2875, 2810
1-acetoxy-9H-carbazole-3-carboxylate
(together
37.8
mmol) were dissolved in 150 ml EtOH and treated with
15.7 g (113 mmol) of K2CO3 for 4.5 h under re¯ux. The
reaction was quenched by acidi®cation to pH 4±5 using
2N HCl. The solvents were removed in vacuo and by
lyophilization and the residue was separated between H2O
and diethyl ether. After drying of the combined organic
layers over MgSO4, and removal of the solvent gave 10 in
95% yield (9.19 g, 36.0 mmol) as crude, orange colored
product, which was directly used for the following O-alkyl-
ation reaction. For a complete characterization, a sample
was recrystallized from EtOH/pentane to provide beige
crystals: mp 1848C; IR (KBr): nˆ3310 (N±H, O±H),
3020 (Ar±H), 2950, 2900, 2820 (C±H), 1630 (CvO),
1610, 1580 (Ar), 1470 (alkyl); 1H NMR (250.1 MHz,
d6-acetone): dˆ1.39 (t, Jˆ7.0 Hz, 3H, CO2CH2CH3), 4.37
(q, Jˆ7.0 Hz, 2H, CO2CH2CH3), 7.25 (ddd, Jˆ7.9, 7.0,
0.9 Hz, 1H, 6-H), 7.45 (ddd, Jˆ8.2, 7.0, 1.2 Hz, 1H, 7-H),
7.64 (d, Jˆ1.2 Hz, 1H, 2-H), 7.65 (dt, Jˆ8.2, 0.9 Hz, 1H,
8-H), 8.19 (d, Jˆ7.9 Hz, 1H, 5-H), 8.44 (d, Jˆ1.2 Hz, 1H,
4-H), 9.09 (s, 1H, OH), 10.66 (s, 1H, NH); 13C NMR
(62.9 MHz, d6-acetone): dˆ14.74 (CO2CH2CH3), 60.97
(CO2CH2CH3), 111.5 (C-2), 112.5 (C-8), 115.4 (C-4),
120.4 (C-6), 121.2 (C-5), 122.8, 124.4, 124.9 (each Cq),
127.0 (C-7), 133.6, 141.3, 143.4 (each Cq), 167.6 (CO2Et);
MS: m/z (%)ˆ255 (100) [M1], 240 (11) [M12Me], 227
(45) [M12C2H4], 210 (89) [M12OEt], 182 (37)
[2102CO]; Anal. calcd for C15H13NO3: C, 70.58; H, 5.13;
N, 5.49. Found: C, 70.31; H, 5.21; N, 5.43.
1
(C±H), 1675 (CvO), 1605, 1575, 1560 (Ar); H NMR
(250.1 MHz, d6-acetone): dˆ1.41 (t, Jˆ7.0 Hz, 3H,
CO2CH2CH3), 4.07 (s, 3H, OMe), 4.21 (s, 3H, NMe), 4.39
(q, Jˆ7.0 Hz, 2H, CO2CH2CH3), 7.28 (ddd, Jˆ7.6, 6.7,
1.2 Hz, 1H, 6-H), 7.52 (ddd, Jˆ8.2, 6.7, 1.2 Hz, 1H, 7-H),
7.57 (dd, Jˆ8.2, 1.2 Hz, 1H, 8-H), 7.61 (d, Jˆ1.2 Hz, 1H,
2-H), 8.20 (dt, Jˆ7.6, 1.2 Hz, 1H, 5-H), 8.46 (d, Jˆ1.2 Hz,
1H, 4-H); 13C NMR (62.9 MHz, CDCl3): dˆ14.48
(CO2CH2CH3), 31.96 (NMe), 55.62 (OMe), 60.64
(CO2CH2CH3), 107.5 (C-2), 108.9 (C-8), 115.9 (C-4),
119.6 (C-6), 120.2 (C-5), 121.3, 123.0, 123.8 (each Cq),
126.0 (C-7), 132.9, 141.7, 146.3 (each Cq), 167.3 (CO2Et);
MS: m/z (%)ˆ283 (100) [M1], 268 (42) [M12Me], 255
(19) [M12C2H4], 240 (61) [2552Me], 210 (10)
[M12CO2Et], 195 (10) [2102Me], 180 (4) [1952Me];
Anal. calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94.
Found: C, 71.74; H, 6.03; N, 4.91.
4.2. Spectral data for binary carbazole alkaloids
A detailed analysis of the product mixture obtained from
LiAlH4 reductions of up to 500 mg (up to 1.86 mmol) of
ester 7 to give murrayafoline-A (1) as the main product
following a literature procedure7 revealed varying quantities
of bismurrayafoline-A (3), bismurrayafolinol (4) and
chrestifoline-A (6) as side products.
4.2.1. Bismurrayafoline-A (3). Mp 1748C (EtOH/pentane,
colorless powder) {Ref.2 176±1778C (diethyl ether)}; IR
(®lm): nˆ3380 (N±H), 3020 (Ar±H), 2940, 2920, 2840
4.1.2. Ethyl 1-methoxy-9H-carbazole-3-carboxylate (7).
Following a literature procedure for the synthesis of muko-

G. Bringmann, S. Tasler / Tetrahedron 57 (2001) 2337±2343
2341
1
(C±H), 1710 (C±N), 1570 (Ar), 1445 (alkyl); H NMR
(250.1 MHz, d6-acetone): dˆ2.49 (s, 3H, Me), 3.84 (s,
3H, 1-OMe), 4.04 (s, 3H, 10-OMe), 6.03 (s, 2H, NCH2),
6.92 (s, 1H, 2-H), 7.00 (s, 1H, 20-H), 7.09, 7.14 (each
ddd, Jˆ7.9, 7.0, 0.9 Hz, 1H, 6-H, 60-H), 7.32, 7.36
(each ddd, Jˆ7.9, 7.0, 0.9 Hz, 1H, 7-H, 70-H), 7.51 (d,
Jˆ7.9 Hz, 1H, 80-H), 7.56 (s, 1H, 40-H), 7.61 (s, 1H,
4-H), 7.64 (d, Jˆ7.9 Hz, 1H, 8-H), 7.90 (d, Jˆ7.9 Hz, 1H,
50-H), 8.05 (d, Jˆ7.9 Hz, 1H, 5-H), 10.29 (s, 1H, NH);
13C NMR (62.9 MHz, d6-acetone): dˆ21.67 (Me), 49.77
(NCH2), 55.70, 56.09 (1-OMe, 10-OMe), 106.3, 110.0,
110.9, 111.8, 112.1, 113.5 (C-2, C-20, C-4, C-40, C-8,
C-80), 119.6 (C-6, C-60), 120.8 (C-5, C-50), 124.1, 124.7,
125.8 (each Cq), 126.2 (C-7, C-70, Cq), 129.6, 129.9,
131.9, 132.0, 141.0, 142.2, 146.7, 147.7 (each Cq);
MS: m/z (%)ˆ420 (16) [M1], 210 (100) [C14H12NO],
195 (10) [2102Me], 180 (6) [1952Me], 167 (36)
[C12H9N].
100 ml dry acetone, 2.55 g (7.84 mmol) of Cs2CO3 and
510 ml (867 mg, 5.10 mmol) of 2-iodopropane were added
and the mixture was stirred for 9 h under re¯ux. The reac-
tion was quenched by addition of 10 ml concd aqueous NH3
solution and stirring for another 30 min under re¯ux. The
product 11 was attained as colorless needles after removal
of the solvents in vacuo, subsequent puri®cation by column
chromatography on silica gel (petroleum ether/diethyl ether
4:1), and recrystallization from EtOH/pentane in 79% yield
(877 mg, 3.10 mmol): mp 1208C; IR (KBr): nˆ3350 (N±
H), 3090, 3030 (Ar±H), 2970, 2930, 2890, 2850 (C±H),
1
1670 (CvO), 1615, 1595, 1570 (Ar), 1485 (alkyl); H
NMR (250.1 MHz, d6-acetone): dˆ1.39 (d, Jˆ6.1 Hz, 6H,
OCH(CH3)2), 1.45 (t, Jˆ7.0 Hz, 3H, CO2CH2CH3), 4.46 (q,
Jˆ7.0 Hz, 2H, CO2CH2CH3), 4.85 (sept, Jˆ6.1 Hz, 1H,
OCH(CH3)2), 7.27 (ddd, Jˆ7.9, 7.0, 1.2 Hz, 1H, 6-H),
7.47 (ddd, Jˆ8.2, 7.0, 1.2 Hz, 1H, 7-H), 7.67 (d,
Jˆ8.2 Hz, 1H, 8-H), 7.72 (d, Jˆ0.9 Hz, 1H, 2-H), 8.21 (d,
Jˆ7.9 Hz, 1H, 5-H), 8.59 (d, Jˆ0.9 Hz, 1H, 4-H), 10.73 (s,
1H, NH); 13C NMR (62.9 MHz, d6-acetone): dˆ14.77
(CO2CH2CH3), 22.34 (OCH(CH3)2), 61.04 (CO2CH2CH3),
71.60 (OCH(CH3)2), 109.8 (C-2), 112.5 (C-8), 116.3 (C-4),
120.6 (C-6), 121.2 (C-5), 122.8, 124.4, 124.5 (each Cq),
127.0 (C-7), 135.2, 141.2, 144.3 (each Cq), 167.5 (CO2Et);
MS: m/z (%)ˆ297 (44) [M1], 255 (100) [M12C3H6], 240
(12) [2552Me], 227 (40) [2552C2H4], 210 (54)
[2552OEt], 182 (34) [2102CO]; Anal. calcd for
C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C, 72.89;
H, 6.25; N, 4.64.
4.2.2. Bismurrayafolinol (4). Mp 1178C (EtOH/pentane,
colorless powder) (Ref.3 colorless oil); IR (KBr): nˆ3380
(N±H), 3280 (O±H), 3040 (Ar±H), 2970, 2920, 2820
1
(C±H), 1575 (Ar), 1445 (alkyl); H NMR (250.1 MHz,
d6-acetone): dˆ3.84 (s, 3H, 1-OMe), 4.06 (s, 3H, 10-
OMe), 4.16 (t, Jˆ5.8 Hz, 1H, CH2OH), 4.78 (d,
Jˆ5.8 Hz, 2H, CH2OH), 6.06 (s, 2H, NCH2), 7.01 (d,
Jˆ1.2 Hz, 1H, 2-H), 7.12 (d, Jˆ1.2 Hz, 1H, 20-H), 7.09,
7.16 (each ddd, Jˆ7.9, 7.3, 0.9 Hz, 1H, 6-H, 60-H), 7.33,
7.38 (each ddd, Jˆ8.2, 7.3, 1.2 Hz, 1H, 7-H, 70-H), 7.51 (d,
Jˆ8.2 Hz, 1H, 80-H), 7.61 (s, 1H, 40-H), 7.67 (d, Jˆ8.2 Hz,
1H, 8-H), 7.74 (d, Jˆ1.2 Hz, 1H, 4-H), 7.90 (d, Jˆ7.9 Hz,
1H, 50-H), 8.09 (d, Jˆ7.9 Hz, 1H, 5-H), 10.30 (s, 1H, NH);
13C NMR (62.9 MHz, d6-acetone): dˆ49.80 (NCH2), 55.71,
56.12 (1-OMe, 10-OMe), 65.43 (CH2OH), 106.3, 107.9
(C-2, C-20), 111.0, 111.8, 112.2 (C-4, C-40, C-8, C-80),
119.6, 119.8 (C-6, C-60), 120.8 (C-5, C-50), 124.0, 124.2,
124.7, 125.4 (each Cq), 126.2, 126.3 (C-7, C-70), 130.0,
130.1, 131.8, 135.3, 141.0, 142.2, 146.7, 147.8 (each Cq);
MS: m/z (%)ˆ436 (7) [M1], 227 (6) [C14H13NO2], 210
(100) [C14H12NO], 195 (11) [2102Me], 180 (4)
[1952Me], 167 (32) [C12H9N].
4.3.2. 1-Isopropoxy-3-methyl-9H-carbazole (12). Accord-
ing to the procedure presented in Ref. 7 for the synthesis of
murrayafoline-A (1), 200 mg (673 mmol) of ester 11 were
dissolved in 40 ml of CH2Cl2/diethyl ether (1:1) and
reduced with 76.6 mg (2.02 mmol) LiAlH4 for 3 h at rt.
The reaction mixture was neutralized with saturated
aqueous NH4Cl solution and the pH value was adjusted to
5±6 using 0.5N HCl. After extraction with diethyl ether,
drying of the combined organic layers over MgSO4, and
removal of the solvent, the residue was puri®ed by column
chromatography on silica gel (petroleum ether/diethyl ether
3:1) to yield 148 mg (618 mmol, 92%) of 12 as a pale yellow
oil, which failed to crystallize from a solvent, but solidi®ed
upon standing: mp 728C; IR (KBr): nˆ3320 (N±H), 3030
(Ar±H), 2955, 2930, 2890 (C±H), 1570 (Ar), 1440 (alkyl);
1H NMR (250.1 MHz, CDCl3): dˆ1.48 (d, Jˆ6.1 Hz, 6H,
OCH(CH3)2), 2.57 (s, 3H, 3-Me), 4.79 (sept, Jˆ6.1 Hz, 1H,
OCH(CH3)2), 6.79 (s, 1H, 2-H), 7.23 (ddd, Jˆ7.9, 6.1,
2.0 Hz, 1H, 6-H), 7.38±7.47 (m, 2H, 7-H, 8-H), 7.51 (s,
1H, 4-H), 8.05 (d, Jˆ7.9 Hz, 1H, 5-H), 8.21 (s, 1H, NH);
13C NMR (62.9 MHz, d6-acetone): dˆ21.93 (3-Me), 22.38
(OCH(CH3)2), 70.60 (OCH(CH3)2), 110.2 (C-2), 110.8
(C-8), 112.4 (C-4), 119.0 (C-6), 120.4 (C-5), 123.6, 124.5
(each Cq), 125.4 (C-7), 129.1, 129.3, 139.4, 143.4 (each Cq);
MS: m/z (%)ˆ239 (34) [M1], 197 (100) [M12C3H6], 196
(46) [M12C3H7], 167 (25) [C12H9N]; Anal. calcd for
C16H17NO: C, 80.30; H, 7.16; N, 5.82. Found: C, 80.23;
H, 7.14; N, 5.82.
4.2.3. Chrestifoline-A (6). Mp 1508C (EtOH/pentane, pale
beige powder) (Ref.4 colorless oil); IR (®lm): nˆ3380
(N±H), 3020 (Ar±H), 2960, 2920, 2900, 2820 (C±H),
1
1565 (Ar), 1480, 1435 (alkyl); the H NMR spectrum is
identical with that reported in Ref. 4; 13C NMR
(62.9 MHz, d6-acetone): dˆ19.64 (3-Me), 36.15 (30-CH2),
55.70 (10-OMe), 55.83 (1-OMe), 107.8 (C-20), 109.7 (C-2),
112.0 (C-8), 112.1 (C-40, C-80), 119.4 (C-6, C60), 120.8
(C-50), 123.3 (C-5), 124.1 (C-4b0), 124.2 (C-4b), 124.5
(4a0), 125.0 (C-30), 125.5 (C-7), 125.9 (C-70), 126.1
(C-4a), 128.3 (C-4), 129.5 (C-9a0), 129.9 (C-9a), 132.4
(C-3), 141.0 (C-8a0), 141.2 (C-8a), 144.9 (C-1), 146.8
(C-10); MS: m/z (%)ˆ420 (100) [M1], 405 (24)
[M12Me], 390 (9) [4052Me], 375 (9) [3902Me], 224
(19) [C15H14NO], 223 (59) [2242H], 210 (100)
[C14H12NO].
4.3.3. 1-Isopropoxy-4-[10-isopropoxy-30-methylene-90H-
carbazole]-3-methyl-9H-carbazole (13). If 2N HCl was
used for quenching the reduction described above, up to
22.8 mg (47.9 mmol, 14%) of dimer 13 could be isolated
4.3. O-Isopropyl compounds
4.3.1. Ethyl 1-isopropoxy-9H-carbazole-3-carboxylate
(11). To a solution of 1.00 g (3.92 mmol) of crude 10 in

2342
G. Bringmann, S. Tasler / Tetrahedron 57 (2001) 2337±2343
along with 134 mg (560 mmol, 83%) 12. Product 13
crystallized as a yellow solid from EtOH/pentane: mp
1278C; IR (®lm): nˆ3400 (N±H), 3020 (Ar±H), 2995,
2920, 2880, 2820 (C±H), 1555 (Ar), 1470, 1425 (alkyl);
1H NMR (250.1 MHz, d6-acetone): dˆ1.26 (d, Jˆ6.1 Hz,
6H, 10-OCH(CH3)2), 1.42 (d, Jˆ6.1 Hz, 6H, 1-OCH(CH3)2),
2.47 (s, 3H, 3-Me), 4.55 (sept, Jˆ6.1 Hz, 3H, 10-
OCH(CH3)2), 4.78 (s, 2H, NCH2), 4.83 (sept, Jˆ6.1 Hz,
3H, 1-OCH(CH3)2), 6.96±7.02 (m, 3H, 2-H, 20-H, 6-H),
7.04 (ddd, Jˆ7.9, 7.0, 1.2 Hz, 1H, 60-H), 7.28 (ddd,
Jˆ8.2, 7.0, 1.2 Hz, 1H, 7-H), 7.29 (ddd, Jˆ8.2, 7.0,
1.2 Hz, 1H, 70-H), 7.46 (s, 1H, 40-H), 7.49 (d, Jˆ8.2 Hz,
1H, 80-H), 7.55 (d, Jˆ8.2 Hz, 1H, 8-H), 7.83 (d, Jˆ7.9 Hz,
1H, 50-H), 8.11 (d, Jˆ7.9 Hz, 1H, 5-H), 10.13 (s, 1H, 90-H),
10.25 (s, 1H, 9-H); 13C NMR (62.9 MHz, d6-acetone):
dˆ19.64 (3-Me), 22.34 (10-OCH(CH3)2), 22.60 (1-
OCH(CH3)2), 36.09 (30-CH2), 71.01 (10-OCH(CH3)2),
71.32 (1-OCH(CH3)2), 110.8 (C-20), 111.9 (C-2), 112.0
(C-8), 112.2 (C-40), 112.8 (C-80), 119.3 (C-6, C-60), 120.7
(C-50), 123.2 (C-5), 124.1 (C-4b0), 124.3 (C-4b), 124.6
(4a0), 125.2 (C-30), 125.5 (C-7), 125.9 (C-70), 126.4
(C-4a), 128.1 (C-4), 130.6 (C-9a0), 131.3 (C-9a), 132.3
(C-3), 140.9 (C-8a0), 141.2 (C-8a), 142.8 (C-1), 144.6
(C-10); MS: m/z (%)ˆ476 (100) [M1], 434 (33)
[M12C3H7], 392 (71) [M122C3H6], 377 (11) [3922Me],
210 (22) [C14H12NO], 209 (49) [C14H11NO], 196 (67) [392,
zˆ2], 188.5 (19) [377, zˆ2]; HRMS calcd for C32H32N2O2
476.246, found 476.246.
4.5. Synthesis of chrestifoline-A (6)
To a solution of 11.0 mg (48.4 mmol) of koenoline (2) and
30.7 mg (145 mmol) of murrayafoline-A (1) in 3 ml CH2Cl2/
diethyl ether (1:1), 5 drops of concd aqueous HCl were
added at rt and the solution was stirred for 30 min. The
mixture was diluted with 5 ml of H2O and extracted with
diethyl ether. Further workup in accordance to the one
described for the synthesis of 3, gave, besides 22.8 mg
(108 mmol) murrayafoline-A (1), 14.2 mg (33.8 mmol,
70% referring to the incorporation of one molecule of 2
into one molecule of 6) of chrestifoline-A (6).
4.5.1. 1-Methoxy-9-[10-methoxy-90-(100-methoxy-300-methyl-
ene-900H-carbazole)-30-methylene-90H-carbazole]-3-
methyl-9H-carbazole (14). In a few cases, compound 14
could be isolated as a minor product (up to 4%, yellow oil)
from the reaction mixture of the chrestifoline-A synthesis.
IR (KBr): nˆ3370 (N±H), 3020 (Ar±H), 2930, 2900, 2830
(C±H), 1570, 1490 (Ar), 1440 (alkyl); 1H NMR
(250.1 MHz, d6-acetone): dˆ2.49 (s, 3H, 3-Me), 3.78,
3.89, 4.04 (each s, 3H, 1OMe, 10-OMe, 100-OMe), 5.99,
6.04 (each s, 2H, 30-CH2, 300-CH2), 6.92, 6.94 (each d,
Jˆ1.2 Hz, 1H, 2-H, 200-H), 7.10 (d, Jˆ1.2 Hz, 1H, 20-H),
7.08, 7.11, 7.14 (each ddd, Jˆ7.9, 7.0, 0.9 Hz, 1H, 6-H,
60-H, 600-H), 7.31, 7.34, 7.37 (each ddd, Jˆ8.2, 7.0,
1.2 Hz, 1H, 7-H, 70-H, 700-H), 7.49 (d, Jˆ8.2 Hz, 1H, 800-
H), 7.55, 7.56 (each s, 1H, 40-H, 400-H), 7.65 (s, 1H, 4-H),
7.62, 7.67 (each d, Jˆ8.2 Hz, 1H, 8-H, 80-H), 7.86, 7.91
(each d, Jˆ7.9 Hz, 1H, 50-H, 500-H), 8.05 (d, Jˆ7.9 Hz,
1H, 5-H), 10.26 (s, 1H, NH); MS: m/z (%)ˆ629 (6)
[M1], 419 (11) [M12C14H12NO], 405 (1) [4192CH2],
224 (2) [C15H14NO], 210 (100) [C14H12NO], 196 (8)
[C13H10NO], 195 (7) [C13H9NO], 180 (7) [1952Me], 167
(23) [C12H9N]; HRMS calcd for C42H35N3O3 629.268, found
629.269.
4.4. Attempts for a directed synthesis of bismurray-
afoline-A (3)
Method A. The reduction of 60.0 mg (223 mmol) of ethyl 1-
methoxy-9H-carbazole-3-carboxylate (7) was performed in
1 ml CH2Cl2/diethyl ether (1:1) using 8.46 mg (223 mmol)
LiAlH4 in the presence of 29.7 mg (223 mmol) of AlCl3, ®rst
for 4 h at 08C, then for further 20 h at rt. The reaction
mixture was neutralized with saturated aqueous NH4Cl
solution and the pH value was adjusted to 5±6 using 0.5N
HCl. After extraction with diethyl ether, drying of the
combined organic layers over MgSO4, and removal of the
solvent, the residue was puri®ed by column chromatography
on silica gel (petroleum ether/diethyl ether 5:1) to yield
15.5 mg (73.6 mmol, 33%) murrayafoline-A (1), 26.8 mg
(118 mmol, 53%) koenoline (2) and 23.5 mg (5.60 mmol,
5%) bismurrayafoline-A (3), along with 4.74 mg
(17.6 mmol, 8%) of starting material 7. Spectral data of 1
and 2 were identical to those given in Ref. 7.
Acknowledgements
We thank H. Endress for excellent experimental assistance.
Financial support by the Deutsche Forschungsgemeinschaft
(SFB 347 `Selektive Reaktionen Metall-aktivierter
Moleku
Èle') and by the Fonds der Chemischen Industrie is
gratefully acknowledged.
References
1. (a) Chakraborty, D. P. In The Alkaloids, Brossi, A., Ed.;
Academic Press: New York, 1993; Vol. 44, pp 257±364.
(b) Furukawa, H. Trends Heterocycl. Chem. 1993, 3, 185±
197.
Method B. A solution of 47.0 mg (222 mmol) of murrayafo-
line-A (1) in 3 ml CH2Cl2/diethyl ether (1:1) was treated
with 12.7 mg (334 mmol) of LiAlH4 and stirred for 30 min
at rt. Over a period of 30 min, 30.0 mg (111 mmol) of ester 7
dissolved in 2 ml of the same solvent mixture were added
and the suspension was stirred for another 60 min before it
was treated with further 4.22 mg (111 mmol) of LiAlH4.
After additional 60 min of stirring, workup was done
according to method A. Besides the 47.0 mg (222 mmol)
murrayafoline-A (1) used as starting material, further
16.4 mg (77.6 mmol, 70% referring to the reduction of 7)
1 and 4.46 mg (10.6 mmol, 19%)9 bismurrayafoline-A (3)
were isolated.
2. Furukawa, H.; Wu, T.-S.; Ohta, T. Chem. Pharm. Bull. 1983,
31, 4202±4205.
3. Ito, C.; Wu, T.-S.; Furukawa, H. Chem. Pharm. Bull. 1987, 35,
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G. Bringmann, S. Tasler / Tetrahedron 57 (2001) 2337±2343
2343
6. For the synthesis of axially chiral aryl±aryl- and aryl±
heteroaryl-coupled biscarbazole alkaloids, see: (a) Bring-
mann, G.; Ledermann, A.; Stahl, M.; Gulden, K.-P.
7. Bringmann, G.; Tasler, S.; Endress, H.; Peters, K.; Peters,
E.-M. Synthesis 1998, 1501±1505.
8. The reaction mixture should be quenched using saturated
aqueous NH4Cl solution and the pH value should be adjusted
to 5±6 with 0.5N HCl rather than only using 2N HCl as stated
in Ref. 7.
È
Tetrahedron 1995, 51, 9353±9360. (b) Knolker, H.-J.;
Goesmann, H.; Hofmann, C. Synlett 1996, 737±739.
(c) Murphy, W. S.; Bertrand, M. J. Chem. Soc., Perkin
Trans. 1 1998, 4115±4119. (d) Lin, G.; Zhang, A. Tetrahedron
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H.; Kraus, J.; Messer, K.; Wohlfarth, M.; Lobin, W.; J. Am.
Chem. Soc. 2001, in press.
9. This yield refers to the reduction of 7 as the only source for
both molecular halves of 3.
10. Peters, K.; Peters, E.-M.; Tasler, S.; Endress, H.; Bringmann,
G. Z. Kristallogr. NCS 2001, 216, 119±120.