Iron-mediated total synthesis of 2,7-dioxygenated carbazole alkaloids

Article abstract of DOI:10.1002/ejoc.201201251

We describe the efficient iron-mediated total synthesis of clausine O, clausine H (clauszoline-C) and anti-HIV active 7-methoxy-O-methylmukonal and clausine K (clauszoline-J). Consecutive C-C and C-N bond formations between 3-methoxy-4-methylaniline and a cyclohexadienyliumiron complex salt afforded 2,7-dimethoxy-3-methylcarbazole, which served as common intermediate en route to the four alkaloids. Four 2,7-dioxygenated carbazole alkaloids, clausine O, clausine H (clauszoline-C), and the anti-HIV active 7-methoxy-O-methylmukonal and clausine K (clauszoline-J), have been synthesized by using an iron-mediated approach for the construction of the carbazole framework. Copyright

Full text of DOI:10.1002/ejoc.201201251

FULL PAPER
DOI: 10.1002/ejoc.201201251
Iron-Mediated Total Synthesis of 2,7-Dioxygenated Carbazole Alkaloids[‡]
Micha P. Krahl,[a] Olga Kataeva,[a] Arndt W. Schmidt,[a] and Hans-Joachim Knölker*[a]
Keywords: Total synthesis / Nitrogen heterocycles / Alkaloids / Iron / Diene ligands / Oxidation
We describe the efficient iron-mediated total synthesis of
clausine O, clausine H (clauszoline-C) and anti-HIV active 7-
methoxy-O-methylmukonal and clausine K (clauszoline-J).
Consecutive C–C and C–N bond formations between 3-
methoxy-4-methylaniline and
a
cyclohexadienyliumiron
complex salt afforded 2,7-dimethoxy-3-methylcarbazole,
which served as common intermediate en route to the four
alkaloids.
M. tuberculosis H37Rv strain, but clausine O (2) exhibited
some activity (MIC = 89 μg/mL).[6] At the same time, these
compounds were shown to be cytotoxic against African
green monkey kidney epithelial (Vero) cells. Recently, Ye
and Shen et al. tested compounds 1–4 for the inhibition in
the growth of HepG2 liver carcinoma cells and reported an
IC50 of approximately 30 μg/mL for compounds 2 and 4.[7]
Introduction
The promising biological activities of carbazole alkaloids
have prompted strong interest in these natural products and
have led to the development of numerous methods for their
synthesis.[1] Carbazoles have been isolated from various nat-
ural sources, including fungi, bacteria, algae, molds, and
higher plants of the genera Murraya, Clausena, and Gly-
cosmis (family Rutaceae). Although plants of the genera
Murraya, Clausena, and Glycosmis are often used in folk
medicine for the treatment of various ailments, the bioactive
components are often unknown. Nevertheless, in a number
of studies, the 2,7-dioxygenated carbazole alkaloids 7-meth-
oxy-O-methylmukonal (1), clausine O (2), clausine H
(clauszoline-C, 3), and clausine K (clauszoline-J, 4) have
shown biological activity (see Figure 1). In 1996, Wu et al.
reported the potent inhibitory activity of 7-methoxy-O-
methylmukonal (1), clausine H (clauszoline-C, 3), and
clausine K (clauszoline-J, 4) on platelet aggregation.[2] The
antiplasmodial activity of clausine H (3, IC50 = 5.5–10.7 μg/
mL) was reported by Yenjai and co-workers in 2000.[3]
Kongkathip et al. described the anti-HIV-1 activity of 7-
methoxy-O-methylmukonal (1) and clausine K (clauszoline-
J, 4).[4] Interestingly, these compounds showed only weak
activity in a reverse transcriptase assay. Thus, the HIV repli-
cation was influenced by a different mode of action. Kong-
kathip and co-workers also reported the activity of
clausine K (4) against Mycobacterium tuberculosis H37Ra
strain [MIC (minimum inhibitory concentration) = 100 μg/
mL].[5] However, Franzblau and Knölker et al. showed that
the carbazoles 1 and 4 were essentially inactive against the
Figure 1. Naturally occurring 2,7-dioxygenated carbazole alkaloids.
7-Methoxy-O-methylmukonal (1) was first isolated in
1990 by Lange et al. from the ethanol extract of the roots
of Murraya siamensis collected in Sukhothai Province,
Thailand.[8] Locally, these small trees are known as “Prong
faa”, and the powdered roots are used for the treatment of
snakebites, eye sores, and tuberculosis. The corresponding
free diol, clausine O (2), was first described by Wu et al. in
1999.[9] This compound was obtained from the root bark of
Clausena excavata collected in Taiwan. Clausine H (3) and
clausine K (4) were first isolated in 1996 from the methanol
extract of the stem bark of the same plant, which was also
collected in Taiwan.[2] In Taiwanese folk medicine, C. exca-
vata is used for the treatment of abdominal pain, snakebites,
[‡] Transition Metal Complexes in Organic Synthesis, 106. Part
105: S. Agarwal, U. Pässler, H.-J. Knölker, ARKIVOC 2013,
(ii), 6.
[a] Department Chemie, Technische Universität Dresden,
Bergstraße 66, 01069 Dresden, Germany
Fax: +49-351-463-37030
E-mail: hans-joachim.knoelker@tu-dresden.de
Homepage: http://www.chm.tu-dresden.de/oc2/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201251.
Eur. J. Org. Chem. 2013, 59–64
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
59

M. P. Krahl, O. Kataeva, A. W. Schmidt, H.-J. Knölker
FULL PAPER
and as a detoxification agent. In the same year, Ito and co-
workers isolated the same carboxylic ester 3 from the root
bark of C. excavata Burm. f., which was collected in Singa-
pore, and named it clauszoline-C (3).[10] In 1997, the corre-
sponding carboxylic acid 4 was also obtained by Ito et al.
from the acetone extract of the roots of C. excavata Burm.
f., which were collected in a green house in Shizuoka, Ja-
pan, and named clauszoline-J (4).[11] Subsequently, carb-
azole alkaloids 1–4 have also been isolated from other
Southeast Asian Clausena species (see Table 1).
Table 1. Occurrence of the carbazole alkaloids 1–4.
Plant name
Part
Collected in
Ref.
[8]
[2]
1
M. siamensis
C. excavata
C. excavata
C. excavata
C. excavata
roots
Thailand
Taiwan
Singapore
Japan[a]
Taiwan
Thailand
Thailand
1, 3, 4
3
4
2, 4
4
stem bark
stem bark
roots
[10]
[11]
[9]
root bark
[3]
Clausena harmandiana roots
C. excavata
[5]
4
roots
Scheme 1. Retrosynthetic analysis of 2,7-dioxygenated carbazole
alkaloids.
[4a]
[12]
[13]
[14]
[12b]
[15]
[16]
1, 4
4
4
1–4
1
1, 2, 4
1, 3
C. excavata
C. excavata
C. excavata
Clausena vestita
C. excavata
roots and rhizomes Thailand
stem bark
stem and leaves
whole plant
leaves
Malaysia
China
China
Malaysia
Thailand
Thailand
cyclization of an analogous 2,7-dioxygenated carbazole has
also been applied in our total synthesis of the furo[3,2-a]-
carbazole alkaloid furoclausine A.[20g,22]
C. harmandiana
Clausena wallichii
roots
roots
[a] Plant material was collected in a green house.
Results and Discussion
We have developed an iron-mediated[17] and a palladi-
um(II)-catalyzed[18] approach for the synthesis of carbazole
alkaloids. Herein, we describe the iron-mediated total syn-
thesis of the 2,7-dioxygenated carbazole alkaloids 7-meth-
oxy-O-methylmukonal (1), clausine O (2), clausine H
(clauszoline-C, 3), and clausine K (clauszoline-J, 4) using
2,7-dimethoxy-3-methylcarbazole as a relay compound.[17h]
Key step of the iron-mediated carbazole synthesis is the
coupling of a substituted aniline with a cyclohexadienyl-
iumiron complex salt. Retrosynthetic analysis of the 2,7-
dioxygenated carbazole alkaloids 5 led to iron complex salt
6[19] and 3-methoxy-4-methylaniline (ortho-cresidine, 7) as
the starting materials for our approach (see Scheme 1). Iron
Scheme 2. Iron-mediated synthesis of carbazole 11. Reagents and
conditions: (a) 7 (2.2 equiv.), 6 (1.0 equiv.), MeCN, room temp.,
4.5 h, 76%; (b) I2 (2.6 equiv.), pyridine, 90 °C, 5.5 h, 68%.
Carbazole 11 then served as relay compound for the total
complex salt 6 is easily available on a large scale by the synthesis of natural products 1–4 and dihydroxycarbazole
1-azadiene-catalyzed complexation of 1-methoxycyclohexa- 12, which has been reported in the literature (see Scheme 3).
1,4-diene (8) with pentacarbonyliron.[20] Aniline 7 is com- Cleavage of the methyl ether groups in 11 by using boron
mercially available, but, alternatively, can also be prepared tribromide at low temperatures provided 2,7-dihydroxy-3-
in two steps by O-alkylation and hydrogenation from the methylcarbazole (12), which was an intermediate in Kapil’s
much cheaper nitrophenol 9.[21]
synthesis of the pyrano[3,2-a]carbazole alkaloid O-methyl-
Reaction of iron complex salt 6 and aniline 7 in mahanine.[23] Unfortunately, Kapil et al. did not provide
acetonitrile at room temperature provided iron–diene com- any spectroscopic data for 12. For the synthesis of the natu-
plex 10 in good yield on a multigram scale (9.49 g of 10, ral products 1–4, the methyl group at C-3 was first oxidized
see Scheme 2). Treatment of complex 10 with iodine in pyr- to a formyl group, using 2,3-dichloro-5,6-dicyano-1,4-
idine at 90 °C induced an oxidative cyclization with con- benzoquinone (DDQ) in a mixture of methanol and water,
comitant aromatization and demetalation to provide 2,7- to provide 7-methoxy-O-methylmukonal (1) in 73% yield.
dimethoxy-3-methylcarbazole (11) in 68% yield (64% yield Cleavage of the methyl ether groups in 1 by using boron
on a gram scale). The same procedure for the oxidative tribromide under carefully controlled conditions led to the
60
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Total Synthesis of Carbazole Alkaloids
oxygen-sensitive clausine O (2). Clausine H (clauszoline-C,
3) was obtained by oxidation of 7-methoxy-O-methylmu-
konal (1) using Corey’s cyanohydrin method.[24] The treat-
ment of 1 with an excess amount of manganese dioxide in
the presence of potassium cyanide in methanol provided 3,
quantitatively. The structure of clausine H (3) was con-
firmed by an X-ray crystal structure analysis (see Figure 2).
Finally, the cleavage of the methyl ester in clausine H (3)
under basic conditions provided clausine K (4). The spec-
troscopic data of our synthetic products are in full agree-
ment with those reported for the natural compounds 1–
4.[2,8–11]
Conclusions
Four naturally occurring 2,7-dioxygenated carbazole
alkaloids have been synthesized using our iron-mediated
approach. The key steps were carried out on a large scale,
and intermediate 11 was delivered in gram quantities. 7-
Methoxy-O-methylmukonal (1) was obtained in three steps
and 38% overall yield based on iron complex salt 6.
Clausine O (2, four steps, 26% overall yield), clausine H (3,
four steps, 38% overall yield), and clausine K (4, five steps,
20% overall yield) were synthesized from 1 by one or two
simple transformations. Thus, the iron-mediated carbazole
synthesis provides convenient access to 2,7-dioxygenated
carbazole alkaloids.
Experimental Section
General Methods: All reactions were carried out in oven-dried
glassware using dry solvents under argon, unless stated otherwise.
Dichloromethane was dried using a solvent purification system
(MBraun-SPS). Chemicals were used as received from the commer-
cial sources. Flash chromatography was performed using silica gel
from Merck (0.040–0.063 mm). Thin layer chromatography was
performed with TLC plates from Merck (60 F254) using UV light
for visualization. Melting points were measured with an Electro-
thermal IA9100 melting point apparatus. Ultraviolet spectra were
recorded with a Perkin–Elmer 25 UV/Vis spectrometer (sh, shoul-
der). Infrared spectra were recorded with a Thermo Nicolet Avatar
360 FTIR spectrometer using the ATR method (Attenuated Total
Reflectance). The NMR spectroscopic data were recorded with a
Bruker DRX 500 spectrometer. Chemical shifts δ are reported in
ppm with the nondeuterated solvent as the internal standard. The
abbreviations used are s (singlet), d (doublet), dd (doublet of dou-
blets), ddd (doublet of dd), dt (doublet of triplet), m (multiplet),
and br. (broad). Mass spectra were recorded with a Finnigan MAT-
95 spectrometer (electron impact, 70 eV) or by GC–MS coupling
with an Agilent Technologies 6890 N GC System, equipped with a
5973 Mass Selective Detector (electron impact, 70 eV). Elemental
analyses were measured with a EuroVector EuroEA3000 elemental
analyzer.
Scheme 3. Synthesis of 12 and the carbazole alkaloids 1–4. Rea-
gents and conditions: (a) BBr3 (7.2 equiv.), CH2Cl2, from –78 °C to
–30 °C to room temp., 3.5 d, 99%; (b) DDQ (4.3 equiv.), MeOH/
H2O (10:1), room temp., 80 min, 73%; (c) BBr3 (4.2 equiv.),
CH2Cl2, –30 °C, 3 d, 68%; (d) KCN (4.5 equiv.), MnO2 (30 equiv.),
MeOH, room temp., 16 h, 100%; (e) KOH (160 equiv.), EtOH/H2O
(2:1), reflux, 3 h, 53%.
3-Methoxy-4-methylaniline (7): A solution of 2-methyl-5-nitro-
anisole (20.2 g, 121 mmol) in methanol (200 mL) was added to a
suspension of palladium on activated carbon (10 wt.-% Pd, 2.15 g)
in a minimum amount of methanol, and the mixture was hydroge-
nated in a Parr shaker hydrogenation apparatus (model 3911 EF)
under hydrogen (5 bar) for 10 h. The mixture was filtered through
a short pad of Celite® 557 (diethyl ether), and the solvent was re-
moved to provide 3-methoxy-4-methylaniline (7, 16.5 g, 120 mmol,
1
99%) as a colorless solid. H NMR (500 MHz, CDCl3): δ = 2.10
(s, 3 H), 3.55 (br. s, 2 H), 3.77 (s, 3 H), 6.21 (m, 2 H), 6.89 (m, 1
H) ppm. 13C NMR and DEPT (125 MHz, CDCl3): δ = 15.31
(CH3), 55.14 (CH3), 98.49 (CH), 106.75 (CH), 116.51 (C), 130.95
(CH), 145.49 (C), 158.40 (C) ppm.
[(1–4-η)-5-(2-Amino-4-methoxy-5-methylphenyl)-2-methoxycyclo-
hexa-1,3-diene]tricarbonyliron (10): A solution of 3-methoxy-4-
methylaniline (7, 9.86 g, 71.9 mmol) and iron complex salt 6
(10.9 g, 32.4 mmol) in acetonitrile (380 mL) was stirred at room
temperature for 4.5 h. The solvent was evaporated, and the residue
was purified by flash chromatography on silica gel (hexane/ethyl
acetate, 3:1) to afford iron complex 10 (9.49 g, 24.6 mmol, 76%) as
light yellow crystals; m.p. 115–117 °C. UV (MeOH): λ = 213,
Figure 2. Molecular structure of clausine H (3) in the crystal.
ORTEP plot showing thermal ellipsoids at the 50% probability
level.
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61

M. P. Krahl, O. Kataeva, A. W. Schmidt, H.-J. Knölker
FULL PAPER
298 nm. IR (ATR): ν = 3420, 3343, 2969, 2930, 2841, 2041, 1963,
was added, and the mixture was poured into water. The resulting
solution was extracted with dichloromethane. The organic layers
were dried with magnesium sulfate, and the solvent was evaporated
to provide 2,7-dihydroxy-3-methylcarbazole (12, 43.7 mg,
205 μmol, 99%) as a colorless solid; m.p. 225 °C. UV (MeOH): λ
˜
1950, 1613, 1583, 1507, 1483, 1461, 1443, 1422, 1409, 1317, 1297,
1266, 1247, 1229, 1201, 1170, 1149, 1118, 1092, 1021, 1000, 928,
897, 881, 824, 756, 735, 686, 648 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 1.68 (ddd, J = 14.8, 3.4, 2.3 Hz, 1 H), 2.10 (s, 3 H),
2.37 (ddd, J = 14.8, 11.0, 3.8 Hz, 1 H), 2.74 (dd, J = 6.5, 3.4 Hz,
1 H), 3.14 (dt, J = 11.0, 3.4 Hz, 1 H), 3.43 (dt, J = 3.8, 2.3 Hz, 1
H), 3.46 (br. s, 2 H), 3.69 (s, 3 H), 3.74 (s, 3 H), 5.25 (dd, J = 6.5,
2.3 Hz, 1 H), 6.14 (s, 1 H); 6.79 (s, 1 H) ppm. 13C NMR and DEPT
= 238, 265, 315, 322 nm. IR (ATR): ν = 3395, 3207, 2919, 1615,
˜
1499, 1452, 1345, 1316, 1257, 1218, 1186, 1129, 1011, 952, 879,
1
827, 802, 746, 725, 626 cm–1. H NMR (500 MHz, [D6]acetone): δ
= 2.36 (s, 3 H), 6.70 (dd, J = 8.3, 2.1 Hz, 1 H), 6.88 (d, J = 2.1 Hz,
(125 MHz, CDCl3): δ = 15.55 (CH3), 32.66 (CH2), 37.55 (CH), 1 H), 6.93 (s, 1 H), 7.67 (s, 1 H), 7.75 (d, J = 8.3 Hz, 1 H), 8.07 (s,
53.13 (CH), 54.09 (CH), 54.39 (CH3), 55.29 (CH3), 66.99 (CH),
1 H), 8.14 (s, 1 H), 9.73 (br. s, 1 H) ppm. 13C NMR and DEPT
98.99 (CH), 116.65 (C), 122.25 (C), 128.48 (CH), 139.95 (C), 142.15 (125 MHz, [D6]acetone): δ = 16.65 (CH3), 97.11 (CH), 97.35 (CH),
(C), 156.55 (C), 211.27 (3 CO) ppm. MS (EI): m/z (%) = 385 (5)
108.55 (CH), 117.03 (C), 117.40 (C), 117.60 (C), 120.18 (CH),
[M]+, 357 (5), 329 (68), 301 (40), 299 (100), 269 (11), 245 (6), 243 121.14 (CH), 140.68 (C), 142.32 (C), 154.23 (C), 156.05 (C) ppm.
(15), 193 (40), 137 (16). HRMS: calcd. for C18H19FeNO5 [M]+ MS (EI): m/z (%) = 213 (100) [M]+, 212 (36), 196 (5), 184 (10).
385.0613; found 385.0626. C18H19FeNO5 (385.19): calcd. C 56.13,
H 4.97, N 3.64; found C 56.11, H 5.01, N 3.66.
HRMS: calcd. for C13H11NO2 [M]+ 213.0790; found 213.0796.
C13H11NO2 (213.23): calcd. C 73.23, H 5.20, N 6.57; found C
72.52, H 5.50, N 6.55.
2,7-Dimethoxy-3-methylcarbazole (11): (A) Milligram scale: Iodine
(309 mg, 1.22 mmol) was added to a solution of iron complex 10
(180 mg, 0.468 mmol) in pyridine (5.5 mL) at 90 °C. After stirring
at 90 °C under air for 5.5 h, the reaction mixture was cooled to
room temperature. A solution of sodium thiosulfate (670 mg) and
citric acid (350 mg) in H2O (5 mL) was added, and the mixture was
extracted with diethyl ether. The combined organic layers were
dried with MgSO4. Evaporation of the solvent and purification of
the residue by flash chromatography on silica gel (hexane/ethyl
acetate, 3:1) provided 2,7-dimethoxy-3-methylcarbazole (11,
76.4 mg, 0.317 mmol, 68%). (B) Gram scale: Iodine (5.68 g,
22.4 mmol) was added to a solution of iron complex 10 (3.18 g,
8.26 mmol) in pyridine (100 mL) at 90 °C. After stirring at 90 °C
under air for 6.5 h, the reaction mixture was cooled to room tem-
perature. A solution of sodium thiosulfate (10.6 g) and citric acid
(4.26 g) in H2O (20 mL) was added, and the mixture was extracted
with diethyl ether. The combined organic layers were dried with
magnesium sulfate. Evaporation of the solvent and purification of
the residue by flash chromatography on silica gel (hexane/ethyl
acetate, 3:1) provided 2,7-dimethoxy-3-methylcarbazole (11, 1.28 g,
5.30 mmol, 64%) as colorless crystals; m.p. 243–244 °C. UV
7-Methoxy-O-methylmukonal (1): DDQ (5.65 g, 18.8 mmol) was
added to a solution of 2,7-dimethoxy-3-methylcarbazole (11,
1.05 g, 4.35 mmol) in a mixture of methanol (300 mL) and water
(30 mL), and the solution was stirred at room temperature for
80 min. Diethyl ether (150 mL) was added, and the mixture was
washed with sodium hydroxide (2 n aqueous solution). The aque-
ous layer was extracted with diethyl ether, and the combined or-
ganic layers were dried with magnesium sulfate. The solvent was
evaporated, and purification of the residue by flash chromatog-
raphy on silica gel (petroleum ether/acetone, 2:1) provided 7-meth-
oxy-O-methylmukonal (1, 815 mg, 3.19 mmol, 73%) as a light yel-
low solid; m.p. 225 °C. UV (EtOH): λ = 240, 300, 347 nm. IR
(ATR): ν = 3234, 3009, 2856, 1665, 1595, 1509, 1469, 1427, 1354,
˜
1323, 1272, 1249, 1205, 1152, 1033, 899, 860, 818, 812, 784, 730,
614 cm–1. 1H NMR (500 MHz, [D6]acetone): δ = 3.90 (s, 3 H), 4.04
(s, 3 H), 6.89 (dd, J = 8.5, 2.2 Hz, 1 H), 7.07 (d, J = 2.2 Hz, 1 H),
7.16 (s, 1 H), 8.04 (d, J = 8.5 Hz, 1 H), 8.42 (s, 1 H), 10.49 (s, 1
H), 10.55 (br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]-
acetone): δ = 55.76 (CH3), 56.30 (CH3), 93.77 (CH), 96.18 (CH),
109.47 (CH), 117.87 (C), 118.24 (C), 119.46 (C), 120.12 (CH),
121.48 (CH), 143.01 (C), 146.58 (C), 160.00 (C), 161.71 (C), 188.55
(CHO) ppm. MS (EI): m/z (%) = 255 (100) [M]+, 254 (10), 240 (45),
226 (6), 212 (14), 209 (13), 198 (8), 184 (11), 169 (21), 141 (11).
HRMS: calcd. for C15H13NO3 [M]+ 255.0895; found 255.0903.
C15H13NO3 (255.27): calcd. C 70.58, H 5.13, N 5.49; found C
70.64, H 5.32, N 5.38.
(MeOH): λ = 236, 263, 312, 320 nm. IR (ATR): ν = 3377, 3003,
˜
2947, 2839, 1612, 1578, 1498, 1452, 1342, 1327, 1308, 1267, 1231,
1
1192, 1161, 1141, 1020, 946, 881, 822, 811, 792, 726, 673 cm–1. H
NMR (500 MHz, [D5]pyridine): δ = 2.48 (s, 3 H), 3.73 (s, 3 H),
3.74 (s, 3 H), 7.06 (dd, J = 8.5, 2.2 Hz, 1 H), 7.14 (s, 1 H), 7.21 (d,
J = 2.2 Hz, 1 H), 7.93 (s, 1 H), 8.12 (d, J = 8.5 Hz, 1 H), 11.83 (br.
s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D5]pyridine): δ =
17.09 (CH3), 55.38 (CH3), 55.50 (CH3), 93.47 (CH), 95.73 (CH),
107.93 (CH), 117.05 (C), 118.15 (C), 118.48 (C), 120.41 (CH),
121.35 (CH), 140.88 (C), 142.25 (C), 156.95 (C), 158.59 (C) ppm.
MS (EI): m/z (%) = 241 (100) [M]+, 226 (85), 211 (8), 198 (5), 183
(8), 167 (6). HRMS: calcd. for C15H15NO2 [M]+ 241.1103; found
241.1121. C15H15NO2 (241.29): calcd. C 74.67, H 6.27, N 5.81;
found C 74.73, H 6.30, N 5.88.
Clausine O (2): Boron tribromide (1 m solution in dichloromethane,
9.20 mL, 9.20 mmol) was added at –78 °C to a solution of 7-meth-
oxy-O-methylmukonal (1, 559 mg, 2.19 mmol) in dichloromethane
(300 mL), and the mixture was stirred at –30 °C for 3 d. Methanol
(40 mL) and water (80 mL) were added, and the mixture was ex-
tracted several times with diethyl ether. The combined organic lay-
ers were dried with magnesium sulfate, and the solvent was evapo-
rated. Purification of the residue by flash chromatography on de-
gassed silica gel (hexane/acetone, 10:7) provided clausine O (2,
337 mg, 1.48 mmol, 68%) as a light yellow solid; m.p. Ͼ 300 °C
(decomp). UV (MeOH): λ = 222, 238, 253 (sh), 290 (sh), 301, 322
2,7-Dihydroxy-3-methylcarbazole (12): Boron tribromide (1 m solu-
tion in dichloromethane, 500 μL, 500 μmol) was added at –78 °C
to a solution of 2,7-dimethoxy-3-methylcarbazole (11, 50.3 mg,
208 μmol) in dichloromethane (10 mL), and the mixture was stirred
at that temperature for 2 h. The mixture was warmed to –30 °C
and stirred for 19 h at that temperature. Boron tribromide (1 m
solution in dichloromethane, 500 μL, 500 μmol) was added, and
the mixture was stirred at –30 °C for 24 h. Then, an additional
portion of boron tribromide (1 m solution in dichloromethane,
500 μL, 500 μmol) was added. The solution was stirred at –30 °C
for 25 h and then at room temperature for 17 h. Methanol (3 mL)
(sh), 340 nm. IR (ATR): ν = 3363, 3216, 2923, 1608, 1576, 1463,
˜
1
1441, 1372, 1325, 1252, 1216, 1171, 1146, 815, 691 cm–1. H NMR
(500 MHz, [D6]acetone): δ = 6.83 (dd, J = 8.4, 2.1 Hz, 1 H), 6.87
(s, 1 H), 6.98 (d, J = 2.1 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 8.31
(s, 1 H), 8.54 (s, 1 H), 10.00 (s, 1 H), 10.55 (br. s, 1 H), 11.48 (s, 1
H) ppm. 13C NMR and DEPT (125 MHz, [D6]acetone): δ = 97.16
(CH), 98.21 (CH), 110.30 (CH), 115.91 (C), 116.82 (C), 118.99 (C),
121.35 (CH), 126.68 (CH), 143.53 (C), 147.20 (C), 157.68 (C),
62
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Eur. J. Org. Chem. 2013, 59–64

Total Synthesis of Carbazole Alkaloids
161.14 (C), 196.53 (CHO) ppm. MS (EI): m/z (%) = 227 (100) Supporting Information (see footnote on the first page of this arti-
[M]+, 226 (39), 198 (9), 170 (12). HRMS: calcd. for C13H9NO3
[M]+ 227.0582; found 227.0576.
cle): Copies of the 1H and 13C NMR spectra for all key intermedi-
ates and final products.
Clausine H (Clauszoline-C, 3): Potassium cyanide (124 mg,
1.90 mmol) and manganese(IV) oxide (Merck Schuchardt, precipi-
tated active, 1.10 g, 12.7 mmol) were sequentially added at room
Acknowledgments
temperature to
a
solution of 7-methoxy-O-methylmukonal
(1,107 mg, 0.419 mmol) in methanol (30 mL), and the mixture was
stirred at room temperature for 16 h under argon. The mixture was
filtered through Celite® 557 (ethyl acetate), and the solvent was
evaporated to give clausine H (clauszoline-C, 3, 119 mg,
0.417 mmol, 100%) as colorless crystals; m.p. 191–192 °C. UV
(MeOH): λ = 223, 245, 279, 282, 309, 320, 332 (sh) nm. IR (ATR):
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) (grant number KN 240/16-1).
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ν = 3286, 2943, 2837, 1696, 1615, 1575, 1435, 1226, 1185, 1152,
˜
1086, 1039, 1025, 797, 780, 727, 618 cm–1. 1H NMR (500 MHz,
[D6]acetone): δ = 3.88 (s, 3 H), 3.89 (s, 3 H), 3.93 (s, 3 H), 6.86 (dd,
J = 8.5, 2.2 Hz, 1 H), 7.07 (d, J = 2.2 Hz, 1 H), 7.15 (s, 1 H), 7.99
(d, J = 8.5 Hz, 1 H), 8.46 (s, 1 H), 10.46 (br. s, 1 H) ppm. 13C
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(CH3), 56.37 (CH3), 94.91 (CH), 95.94 (CH), 109.18 (CH), 113.44
(C), 117.17 (C), 117.71 (C), 121.08 (CH), 123.85 (CH), 142.80 (C),
144.66 (C), 158.92 (C), 159.68 (C), 167.41 (C=O) ppm. MS (EI):
m/z (%) = 285 (100) [M]+, 270 (32), 254 (17), 240 (7). HRMS:
calcd. for C16H15NO4 [M]+ 285.1001; found 285.1020. C16H15NO4
(285.29): calcd. C 67.36, H 5.30, N 4.91; found C 66.82, H 5.31, N
4.94. Crystal data for 3: C16H15NO4, M = 285.29, orthorhombic,
space group Pca21, a = 23.051(1) Å, b = 7.509(1) Å, c = 7.739(1) Å,
V = 1339.5(3) Å3, Z = 4, ρ calcd. = 1.415 gcm–3, μ = 0.102 mm–1,
T = 198(2) K, λ = 0.71073 Å, θ range was 3.17–25.40°, 15467 reflec-
tions measured, 2198 independent reflections (Rint = 0.0463), 193
parameters. The structure was solved by direct methods and refined
by full-matrix least-squares on F2; final R indices for 1835 observed
reflections [I Ͼ 2σ(I)]: R1 = 0.0324, wR2 = 0.0693; maximal resid-
ual electron density: 0.137 eÅ–3. CCDC-273763 (for 3) contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Clausine K (Clauszoline-J, 4): Clausine H (clauszoline-C, 3,
95.3 mg, 0.334 mmol) was added at room temperature to a solution
of potassium hydroxide (3.00 g, 53.5 mmol) in ethanol (8 mL) and
water (4 mL), and the mixture was heated at reflux for 3 h. The
mixture was cooled to room temperature, and the major part of
the solvent was evaporated. The residue was acidified with hydro-
chloric acid (2 n solution), and the mixture was extracted several
times with diethyl ether. The combined organic extracts were dried
with magnesium sulfate, and the solvent was evaporated. Purifica-
tion of the residue by flash chromatography on silica gel (hexane/
ethyl acetate, 2:1) provided clausine K (clauszoline-J, 4, 47.8 mg,
0.176 mmol, 53%) as a light yellow solid; m.p. 239–240 °C. UV
(MeOH): λ = 225, 238 (sh), 244, 279, 284, 309, 319, 337 (sh) nm.
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1232, 1199, 1161, 1114, 1082, 1037, 1022, 902, 817, 802 cm–1. 1H
NMR (500 MHz, [D6]DMSO): δ = 3.83 (s, 3 H), 3.89 (s, 3 H), 6.77
(dd, J = 8.5, 2.2 Hz, 1 H), 6.97 (d, J = 2.2 Hz, 1 H), 7.03 (s, 1 H),
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66.53, H 4.93, N 4.82.
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Received: September 20, 2012
Published Online: November 21, 2012
64
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