Synthesis of Carbalexin B, Clausine A, Clauszoline M, and 2,8-Dihydroxy-3-methylcarbazole

Article abstract of DOI:10.1055/s-0034-1378383

Using a palladium(II)-catalyzed oxidative cyclization of an N,N-diarylamine, we have achieved the total synthesis of the 2,8-dioxygenated carbazole alkaloids carbalexin B, clausine A, clauszoline M, and 2,8-dihydroxy-3-methylcarbazole.

Full text of DOI:10.1055/s-0034-1378383

PAPER
▌2651
paper
Synthesis of Carbalexin B, Clausine A, Clauszoline M, and 2,8-Dihydroxy-3-
methylcarbazole
2,8-Dioxygenated Carbazole Alkaloids
Konstanze K. Julich-Gruner, Arndt W. Schmidt, Hans-Joachim Knölker*
Department of Chemistry, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax +49(351)46337030; E-mail: hans-joachim.knoelker@tu-dresden.de
Received: 10.06.2014; Accepted: 17.06.2014
this palladium-catalyzed approach, we have previously
Abstract: Using a palladium(II)-catalyzed oxidative cyclization of
constructed 2,8-dioxygenated carbazoles that have been
an N,N-diarylamine, we have achieved the total synthesis of the 2,8-
applied in the total synthesis of murrafoline A,9 8-oxygen-
dioxygenated carbazole alkaloids carbalexin B, clausine A, clauszo-
line M, and 2,8-dihydroxy-3-methylcarbazole.
ated pyrano[3,2-a]carbazole alkaloids,10 and 7-oxygenat-
ed pyrano[2,3-a]carbazole alkaloids.10 Herein,11 we
Key words: alkaloids, catalysis, cyclization, natural products, pal-
describe in full detail the application of our method to the
synthesis of the 2,8-dioxygenated tricyclic carbazole alka-
loids carbalexin B (1), clausine A (2), clauszoline M (3),
and 2,8-dihydroxy-3-methylcarbazole (4).
ladium
A broad structural variety has been found in carbazole
natural products.1,2 The simple tricyclic carbazole alka-
loids have been classified based on their oxygenation pat-
tern.2 A minor group are the 2,8-dioxygenated carbazole
alkaloids (Figure 1). Greger et al. observed the stress-
induced formation of the phytoalexin carbalexin B (1) in
the leaves of Glycosmis parviflora.3 Carbalexin B (1) ex-
hibits strong antifungal activity. Clausine A (2) was iso-
lated by Wu et al. from the stem bark of Clausena
excavata.4 Clauszoline M (3) was described by Ito et al.
and extracted from the leaves of Clausena excavata.5 2,8-
Dihydroxy-3-methylcarbazole (4) represents the parent
compound for this group, but so far it has not been found
in nature.6
Buchwald–Hartwig coupling of o-bromoanisole (5) and
arylamine 6 in the presence of XPhos as ligand12 afforded
the N,N-diarylamine 7 (Scheme 1). The palladium(II)-
catalyzed oxidative cyclization13 of 7 led to the orthogo-
nally diprotected 2,8-dioxygenated carbazole 8 in 60%
yield. Using stoichiometric amounts of palladium(II) ace-
tate,14 compound 8 was obtained in 68% yield (see exper-
imental section, Method A). Removal of the benzyl
protecting group by hydrogenolysis led to carbalexin B
(1).15 Cleavage of the methyl ether by treatment of 1 with
boron tribromide at low temperature provided 2,8-dihy-
droxy-3-methylcarbazole (4).6
a
CHO
+
N
H
OBn
Br
H2N
OBn
MeO
OH
OH
OMe
N
H
N
H
5
6
7
MeO
MeO
carbalexin B (1)
clausine A (2)
b
c
OBn
OH
CHO
N
N
H
MeO
MeO
H
OH
OH
N
H
N
H
8
carbalexin B (1)
HO
HO
clauszoline M (3)
2,8-dihydroxy-3-
methylcarbazole (4)
d
OH
Figure 1 2,8-Dioxygenated carbazole alkaloids
N
H
HO
The useful biological activities of carbazoles and their
pharmacological potential have induced intense research
activity.7 We have developed an efficient two-step palla-
dium-catalyzed synthetic route to carbazoles that is very
flexible with respect to the substitution pattern.8 Using
2,8-dihydroxy-3-
methylcarbazole (4)
Scheme 1 Synthesis of carbalexin B (1) and 2,8-dihydroxy-3-meth-
ylcarbazole (4). Reagents and conditions: (a) Pd(OAc)2 (10 mol%),
XPhos (20 mol%), Cs2CO3 (1.5 equiv), toluene, reflux, 24 h (98%);
(b) Pd(OAc)2 (10 mol%), K2CO3 (10 mol%), PivOH, air, 85 °C, 24 h
(60%); (c) 10% Pd/C, H2 (1 atm), MeOH–CH2Cl2 (2:1), r.t., 5 d
(64%); (d) BBr3 (2 equiv), CH2Cl2, –78 °C to 0 °C, 19 h (63%).
SYNTHESIS 2014, 46, 2651–2655
Advanced online publication: 08.07.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1378383; Art ID: ss-2014-t0358-op
© Georg Thieme Verlag Stuttgart · New York

2652
K. K. Julich-Gruner et al.
PAPER
Oxidation of the orthogonally diprotected carbazole 8 In conclusion, we have developed an efficient route to the
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) 2,8-dioxygenated carbazole alkaloids carbalexin B (1),
afforded the corresponding carbazole-3-carbaldehyde 9 clausine A (2), clauszoline M (3), and 2,8-dihydroxy-3-
(Scheme 2). Cleavage of the benzyl ether by treatment methylcarbazole (4). A total synthesis of clauszoline M
with an excess of aluminum trichloride in 1,4-dioxane at (3) has been described for the first time [4 steps and 19%
reflux provided clausine A (2) in 71% yield.16 Using hy- overall yield, based on o-bromoanisole (5) and 68% yield
drogenolytic conditions [10% Pd/C, 1 atm H2, MeOH– for the cyclization step]. The key steps of our approach are
CH2Cl2 (2:1), r.t., 18 h], the best result for this transforma- a palladium(0)-catalyzed C–N bond formation followed
tion was a yield of 57% for clausine A (2). The moderate by a palladium(II)-catalyzed oxidative cyclization of the
yield of clausine A (2) by palladium-catalyzed hydroge- intermediate N,N-diarylamine 7. The spectroscopic data
nation of 9 is ascribed to the transformation of 2 into of the products are in full agreement with those reported
carbalexin B (1) under these reaction conditions, as previ- in the literature.3–6
ously reported.6b Cleavage of the methyl ether by treat-
ment of clausine A (2) with boron tribromide at low
temperature led largely to decomposition and afforded
All reactions were carried out in oven-dried glassware using dry
solvents under an argon atmosphere unless stated otherwise.
CH2Cl2, THF, and toluene were dried using a solvent purification
system (MBraun-SPS). Pd(OAc)2 was recrystallized from glacial
AcOH. All other chemicals were used as received from commercial
sources. Flash chromatography was performed on a Büchi Sepacore
system equipped with an UV monitor using silica gel (Acros Organ-
ics, 0.035–0.070 mm). TLC was performed with TLC plates from
Merck (60 F254) using UV light for visualization. Melting points
were measured on a Gallenkamp MPD 350 melting point apparatus.
UV spectra were recorded on a Perkin Elmer 25 UV/VIS spectro-
photometer. IR spectra were recorded on a Thermo Nicolet Avatar
360 FT-IR spectrophotometer using the ATR method. NMR spectra
were recorded on a Bruker DRX 500 spectrometer with non-deuter-
ated solvent as internal standard. Mass spectra were recorded on a
Finnigan MAT-95 spectrometer (electron impact, 70 eV) or by
GC/MS-coupling using an Agilent Technologies 6890 N GC Sys-
tem equipped with a 5973 Mass Selective Detector (electron im-
pact, 70 eV). ESI-MS spectra were recorded on an Esquire LC with
an ion trap detector from Bruker. Positive and negative ions were
detected. Elemental analyses were measured on an EuroVector
EuroEA3000 elemental analyzer.
clauszoline M (3) in only 18% yield.
CHO
a
OBn
OBn
N
H
N
H
MeO
MeO
8
9
CHO
OH
CHO
OH
b
c
N
H
N
MeO
HO
H
clausine A (2)
clauszoline M (3)
Scheme 2 Synthesis of clausine A (2). Reagents and conditions: (a)
DDQ (2.2 equiv), THF–MeOH–H2O (1:5:1), r.t., 90 min (64%); (b)
AlCl3 (5 equiv), 1,4-dioxane, reflux, 2 h (71%); (c) BBr3 (3 equiv),
CH2Cl2, –78 °C to 0 °C, 4 h (18%).
3-Benzyloxy-N-(2-methoxyphenyl)-4-methylaniline (7)
A solution of o-bromoanisole (5) (0.789 g, 4.22 mmol) in toluene
(20 mL) was added dropwise over a period of 3 h to a solution of 3-
benzyloxy-4-methylaniline8g (6) (1.08 g, 5.06 mmol), Cs2CO3 (2.08
g, 6.38 mmol), Pd(OAc)2 (95 mg, 0.42 mmol), and XPhos (402 mg,
0.84 mmol) in toluene (50 mL) at reflux. After heating at reflux for
24 h, the mixture was allowed to cool to r.t. Removal of the solvent
and flash chromatography of the crude product (silica gel, petro-
leum ether–EtOAc, 9:1) afforded 7 as a light brown solid; yield:
In an alternative route to clauszoline M (3) we have tried
to remove both protecting groups of the orthogonally di-
protected carbazole 9 in a one-pot process (Scheme 3).
Slow addition of boron tribromide to a solution of com-
pound 9 at –78 °C provided, after an increase of the tem-
perature to 0 °C, clausine A (2) in 50% yield and 1.32 g (98%); mp 74 °C.
clauszoline M (3) in 45% yield.
IR (ATR): 3414, 3058, 3031, 2934, 2849, 1596, 1507, 1481, 1460,
1435, 1409, 1381, 1339, 1296, 1242, 1215, 1173, 1124, 1024, 909,
829, 734, 695, 627 cm–1.
CHO
1H NMR (500 MHz, CDCl3): δ = 2.25 (s, 3 H), 3.88 (s, 3 H), 5.06
(s, 2 H), 6.09 (br s, 1 H), 6.67 (dd, J = 2.1, 7.9 Hz, 1 H), 6.74 (d,
J = 2.1 Hz, 1 H), 6.80–6.83 (m, 2 H), 6.85–6.88 (m, 1 H), 7.06 (d,
J = 8.0 Hz, 1 H), 7.09–7.11 (m, 1 H), 7.33 (m, 1 H), 7.39 (m, 2 H),
7.43 (m, 2 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 15.79 (CH3), 55.54
(CH3), 69.68 (CH2), 103.79 (CH), 110.32 (CH), 111.49 (CH),
113.79 (CH), 119.19 (CH), 120.16 (C), 120.85 (CH), 127.01 (2
CH), 127.67 (CH), 128.50 (2 CH), 130.96 (CH), 133.56 (C), 137.37
(C), 141.26 (C), 147.80 (C), 157.23 (C).
a
OBn
N
MeO
H
9
CHO
CHO
OH
OH
+
N
H
N
H
MS (EI): m/z (%) = 319 (100) [M+], 200 (23), 196 (19), 91 (81).
MeO
HO
Anal. Calcd for C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C,
78.98; H, 6.71; N, 4.31.
clausine A (2)
clauszoline M (3)
Scheme 3 Synthesis of clauszoline M (3). Reagents and conditions:
(a) BBr3 (3 equiv), CH2Cl2, –78 °C to 0 °C, 16 h (50% 2 and 45% 3).
Synthesis 2014, 46, 2651–2655
© Georg Thieme Verlag Stuttgart · New York

PAPER
2,8-Dioxygenated Carbazole Alkaloids
2653
2-Benzyloxy-8-methoxy-3-methyl-9H-carbazole (8)
13C NMR and DEPT (125 MHz, acetone-d6): δ = 16.72 (CH3),
55.66 (CH3), 97.30 (CH), 105.32 (CH), 112.48 (CH), 117.25 (C),
117.74 (C), 119.80 (CH), 122.12 (CH), 125.44 (C), 130.42 (C),
140.66 (C), 146.53 (C), 155.48 (C).
MS (EI): m/z (%) = 227 (100) [M+], 212 (41), 184 (64).
HRMS: m/z [M+] calcd for C14H13NO2: 227.0946; found: 227.0934.
UV (MeOH): λ = 252, 262 (sh), 300, 317, 331 nm.
Method A: A mixture of 3-benzyloxy-N-(2-methoxyphenyl)-4-
methylaniline (7) (382 mg, 1.19 mmol), Pd(OAc)2 (322 mg, 1.43
mmol), and AcOH (20 mL) was heated at 85 °C for 48 h. After cool-
ing to r.t., EtOAc was added and the mixture was washed several
times with sat. aq K2CO3 solution; the organic layer was dried
(MgSO4). Removal of the solvent and flash chromatography of the
crude product (silica gel, petroleum ether–EtOAc, 7:1) afforded 8;
yield: 257 mg (68%).
Fluorescence (MeOH): λex = 300 nm, λem = 356 nm.
Method B: A mixture of 3-benzyloxy-N-(2-methoxyphenyl)-4-
methylaniline (7) (3.18 g, 9.95 mmol), Pd(OAc)2 (223.3 mg, 0.995
mmol), K2CO3 (137.5 mg, 0.995 mmol), and pivalic acid (8.95 g)
was heated at 85 °C for 24 h in the presence of air. After cooling to
r.t., EtOAc was added and the mixture was washed several times
with sat. aq K2CO3 solution; the organic layer was dried (MgSO4).
Removal of the solvent and flash chromatography of the crude
product (silica gel, petroleum ether–EtOAc, 7:1) afforded 8; yield:
1.88 g (60%).
Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C,
73.38; H, 6.51; N, 5.68.
2,8-Dihydroxy-3-methyl-9H-carbazole (4)
A 1 M solution of BBr3 in CH2Cl2 (309 μL, 0.309 mmol) was added
slowly to a solution of carbalexin B (1) (35.1 mg, 0.154 mmol) in
CH2Cl2 (5 mL) at –78 °C. The mixture was stirred for an additional
30 min at –78 °C, warmed to 0 °C, and stirred overnight. After the
addition of H2O at 0 °C, the mixture was extracted with Et2O (3 ×),
and the combined organic layers were dried (MgSO4). Removal of
the solvent and flash chromatography of the crude product (silica
gel, petroleum ether–EtOAc, 1:1) afforded 4 as a colorless solid;
yield: 20.8 mg (63%); mp 250 °C dec. (Lit.6b 272 °C dec.).
Brownish solid; mp 114–117 °C.
IR (ATR): 3420, 3367, 3009, 2919, 2849, 1632, 1579, 1509, 1450,
1428, 1390, 1333, 1302, 1264, 1251, 1222, 1174, 1152, 1093, 1040,
1027, 993, 883, 824, 779, 738, 723, 692 cm–1.
IR (ATR): 3433, 2921, 2856, 2547, 1697, 1624, 1581, 1540, 1505,
1463, 1449, 1384, 1327, 1291, 1273, 1242, 1197, 1167, 1136, 1056,
1003, 957, 883, 820, 783, 741, 631, 597, 556 cm–1.
1H NMR (500 MHz, acetone-d6): δ = 2.38 (s, 3 H), 6.79 (d, J = 7.7
Hz, 1 H), 6.94 (t, J = 7.7 Hz, 1 H), 7.05 (s, 1 H), 7.48 (d, J = 7.7 Hz,
1 H), 7.76 (s, 1 H), 8.24 (s, 1 H), 8.52 (s, 1 H), 9.81 (br s, 1 H).
13C NMR and DEPT (125 MHz, acetone-d6): δ = 16.71 (CH3),
97.27 (CH), 109.60 (CH), 111.42 (CH), 117.46 (C), 117.51 (C),
119.86 (CH), 122.12 (CH), 126.07 (C), 130.07 (C), 140.76 (C),
143.51 (C), 155.44 (C).
MS (EI): m/z (%) = 213 (100) [M+], 184 (24).
UV (MeOH): λ = 235, 254 (sh), 300, 320, 333 nm.
Fluorescence (MeOH): λex = 333 nm, λem = 363 nm.
1H NMR (500 MHz, CDCl3): δ = 2.41 (s, 3 H), 3.98 (s, 3 H), 5.15
(s, 2 H), 6.80 (d, J = 7.8 Hz, 1 H), 6.92 (s, 1 H), 7.10 (t, J = 7.8 Hz,
1 H), 7.32 (m, 1 H), 7.39 (m, 2 H), 7.48 (m, 2 H), 7.54 (d, J = 7.8
Hz, 1 H), 7.78 (s, 1 H), 8.07 (br s, 1 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 16.92 (CH3), 55.46
(CH3), 70.07 (CH2), 94.11 (CH), 104.66 (CH), 112.10 (CH), 116.85
(C), 119.60 (CH), 119.68 (C), 121.72 (CH), 124.45 (C), 127.08 (2
CH), 127.73 (CH), 128.52 (2 CH), 129.35 (C), 137.45 (C), 138.66
(C), 145.44 (C), 156.33 (C).
MS (EI): m/z (%) = 317 (100) [M+], 302 (15).
HRMS: m/z [M+] calcd for C21H19NO2: 317.1416; found: 317.1410.
UV (MeOH): λ = 253 (sh), 263 (sh), 298, 317, 330 nm.
Fluorescence (MeOH): λex = 330 nm, λem = 373 nm.
Anal. Calcd for C21H19NO2: C, 79.47; H, 6.03; N, 4.41. Found: C,
78.99; H, 6.69; N, 4.01.
2-Benzyloxy-3-formyl-8-methoxy-9H-carbazole (9)
DDQ (233 mg, 1.028 mmol) was added portionwise to a solution of
2-benzyloxy-8-methoxy-3-methyl-9H-carbazole (8) (148 mg,
0.467 mmol) in THF–MeOH–H2O (1:5:1, 105 mL). The mixture
was stirred at r.t. for 90 min, then diluted with Et2O, washed with 2
M NaOH (3 ×) and with sat. aq NaCl solution; the organic layer was
dried (MgSO4). Removal of the solvent and flash chromatography
of the crude product (silica gel, petroleum ether–EtOAc, 2:1) af-
forded 9 as an orange powder; yield: 100 mg (64%); mp 236 °C.
Carbalexin B (1)
A mixture of 2-benzyloxy-8-methoxy-3-methyl-9H-carbazole (8)
(145 mg, 0.457 mmol) and 10% Pd on activated carbon (29 mg) in
MeOH–CH2Cl2 (2:1, 15 mL) was stirred at r.t. for 5 d under a H2 at-
mosphere at normal pressure. The mixture was filtered over Celite
and the Celite was subsequently washed with Et2O. Removal of the
solvent from the combined filtrates and flash chromatography of the
crude product (silica gel, petroleum ether–EtOAc, 2:1) afforded 1 as
a colorless solid; yield: 67.6 mg (64%); mp 193–195 °C (Lit.3 196–
198 °C, Lit.6b 195–196 °C).
IR (ATR): 3151, 2923, 2849, 1656, 1626, 1604, 1574, 1507, 1456,
1437, 1392, 1316, 1244, 1213, 1172, 1155, 1091, 1019, 995, 911,
863, 817, 780, 731, 696 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 3.97 (s, 3 H), 5.33 (s, 2 H),
6.99 (d, J = 7.8 Hz, 1 H), 7.126 (s, 1 H), 7.130 (t, J = 7.8 Hz, 1 H),
7.36 (m, 1 H), 7.43 (m, 2 H), 7.56 (m, 2 H), 7.72 ( d, J = 7.8 Hz, 1
H), 8.48 (s, 1 H), 10.43 (s, 1 H), 11.76 (s, 1 H).
13C NMR and DEPT (125 MHz, DMSO-d6): δ = 55.44 (CH3), 69.94
(CH2), 94.58 (CH), 106.73 (CH), 112.62 (CH), 117.06 (C), 118.19
(C), 120.61 (CH), 121.27 (CH), 124.06 (C), 127.53 (2 CH), 127.93
(CH), 128.53 (2 CH), 130.07 (C), 136.66 (C), 144.96 (C), 145.52
(C), 159.67 (C), 188.17 (CHO).
MS (ESI, +10 V): m/z = 332 [(M + H)+].
UV (MeOH): λ = 241, 272, 294, 356 nm.
Fluorescence (MeOH): λex = 350 nm, λem = 363 nm.
IR (ATR): 3448, 3049, 2918, 2847, 1718, 1638, 1621, 1578, 1504,
1468, 1446, 1426, 1387, 1303, 1263, 1244, 1218, 1164, 1134, 1085,
1057, 991, 887, 858, 835, 780, 737, 727 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.40 (s, 3 H), 3.99 (s, 3 H), 4.79
(br s, 1 H), 6.82 (d, J = 7.8 Hz, 1 H), 6.85 (s, 1 H), 7.10 (t, J = 7.8
Hz, 1 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.75 (s, 1 H), 8.04 (br s, 1 H).
1H NMR (500 MHz, acetone-d6): δ = 2.38 (s, 3 H), 3.99 (s, 3 H),
6.87 (d, J = 7.8 Hz, 1 H), 7.06 (t, J = 7.8 Hz, 1 H), 7.07 (s, 1 H), 7.57
(d, J = 7.8 Hz, 1 H), 7.78 (s, 1 H), 8.32 (s, 1 H), 9.98 (br s, 1 H).
13C NMR and DEPT (125 MHz, CDCl3): δ = 16.17 (CH3), 55.46
(CH3), 96.66 (CH), 104.89 (CH), 112.07 (CH), 116.32 (C), 117.68
(C), 119.65 (CH), 121.93 (CH), 124.40 (C), 129.51 (C), 138.95 (C),
145.43 (C), 153.01 (C).
Anal. Calcd for C21H17NO3: C, 76.12; H, 5.12; N, 4.23. Found: C,
76.22; H, 5.31; N, 4.25.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2651–2655

2654
K. K. Julich-Gruner et al.
PAPER
Clausine A (2)
References
AlCl3 (85.7 mg, 0.643 mmol) was added to a solution of 2-benzyl-
oxy-3-formyl-8-methoxy-9H-carbazole (9) (42.6 mg, 0.129 mmol)
in 1,4-dioxane (4 mL) and the mixture was heated at reflux for 2 h.
After addition of H2O, the mixture was extracted with Et2O (3 ×),
and the combined organic layers were dried (Na2SO4). Removal of
the solvent and flash chromatography of the crude product (silica
gel, petroleum ether–EtOAc, 2:1) afforded clausine A (2) as light
yellow crystals; yield: 22.0 mg (71%); mp 179–181 °C (Lit.4 184–
186 °C).
(1) (a) Chakraborty, D. P.; Roy, S. In Progress in the Chemistry
of Organic Natural Products; Vol. 57; Herz, W.; Grisebach,
H.; Kirby, G. W.; Steglich, W.; Tamm, C., Eds.; Springer:
Wien, 1991, 71. (b) Chakraborty, D. P. In The Alkaloids;
Vol. 44; Cordell, G. A., Ed.; Academic Press: New York,
1993, 257.
(2) (a) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102,
4303. (b) Knölker, H.-J.; Reddy, K. R. In The Alkaloids;
Vol. 65; Cordell, G. A., Ed.; Academic Press: Amsterdam,
2008, 1. (c) Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J.
Chem. Rev. 2012, 112, 3193.
(3) Pacher, T.; Bacher, M.; Hofer, O.; Greger, H.
Phytochemistry 2001, 58, 129.
(4) Wu, T.-S.; Huang, S.-C.; Wu, P.-L. Phytochemistry 1996,
43, 1427.
(5) Ito, C.; Katsuno, S.; Ohta, H.; Omura, M.; Kajiura, I.;
Furukawa, H. Chem. Pharm. Bull. 1997, 45, 48.
(6) (a) Mester, I.; Bergenthal, D.; Reisch, J. Z. Naturforsch. B
1979, 34, 650. (b) Sharma, R. B.; Seth, R.; Anwer, F.; Kapil,
R. S. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
1981, 20, 701.
(7) For selected recent examples, see: (a) Roy, J.; Jana, A. K.;
Mal, D. Tetrahedron 2012, 68, 6099. (b) Alcaide, B.;
Almendros, P.; Alonso, J. M.; Fernández, I. J. Org. Chem.
2013, 78, 6688. (c) Jaiswal, P. K.; Biswas, S.; Singh, S.;
Samanta, S. Org. Biomol. Chem. 2013, 11, 8410.
(d) Trosien, S.; Böttger, P.; Waldvogel, S. R. Org. Lett.
2014, 16, 402. (e) Fujii, M.; Nishiyama, T.; Choshi, T.;
Satsuki, N.; Fujiwaki, T.; Abe, T.; Ishikura, M.; Hibino, S.
Tetrahedron 2014, 70, 1805. (f) Gao, H.; Xu, Q.-L.;
Yousufuddin, M.; Ess, D. H.; Kürti, L. Angew. Chem. Int.
Ed. 2014, 53, 2701. (g) Goetz, A. E.; Silberstein, A. L.;
Corsello, M. A.; Garg, N. K. J. Am. Chem. Soc. 2014, 136,
3036. (h) Jella, R. R.; Nagarajan, R. Synthesis 2014, 46,
1211. (i) An, Y.; Wang, Y.; Hu, X. Eur. J. Org. Chem. 2014,
3715.
(8) Reviews: (a) Knölker, H.-J. Curr. Org. Synth. 2004, 1, 309.
(b) Knölker, H.-J. Chem. Lett. 2009, 38, 8. (c) Bauer, I.;
Knölker, H.-J. Top. Curr. Chem. 2012, 309, 203. Recent
applications: (d) Gensch, T.; Rönnefahrt, M.; Czerwonka,
R.; Jäger, A.; Kataeva, O.; Bauer, I.; Knölker, H.-J. Chem.
Eur. J. 2012, 18, 770. (e) Huet, L.; Forke, R.; Jäger, A.;
Knölker, H.-J. Synlett 2012, 23, 1230. (f) Börger, C.; Krahl,
M. P.; Gruner, M.; Kataeva, O.; Knölker, H.-J. Org. Biomol.
Chem. 2012, 10, 5189. (g) Hesse, R.; Gruner, K. K.;
Kataeva, O.; Schmidt, A. W.; Knölker, H.-J. Chem. Eur. J.
2013, 19, 14098. (h) Hesse, R.; Jäger, A.; Schmidt, A. W.;
Knölker, H.-J. Org. Biomol. Chem. 2014, 12, 3866.
(9) Kumar, V. P.; Gruner, K. K.; Kataeva, O.; Knölker, H.-J.
Angew. Chem. Int. Ed. 2013, 52, 11073.
IR (ATR): 3367, 2921, 2849, 1727, 1631, 1580, 1508, 1462, 1436,
1392, 1367, 1315, 1272, 1227, 1198, 1161, 1090, 1008, 895, 842,
832, 783, 744, 717 cm–1.
1H NMR (500 MHz, acetone-d6): δ = 4.03 (s, 3 H), 6.98 (s, 1 H),
7.03 (d, J = 7.9 Hz, 1 H), 7.20 (t, J = 7.9 Hz, 1 H), 7.70 (d, J = 7.9
Hz, 1 H), 8.45 (s, 1 H), 10.02 (s, 1 H), 10.80 (br s, 1 H), 11.46 (s, 1
H).
13C NMR and DEPT (125 MHz, acetone-d6): δ = 55.92 (CH3),
97.57 (CH), 107.60 (CH), 113.06 (CH), 116.33 (C), 118.80 (C),
121.98 (CH), 125.24 (C), 128.83 (CH), 131.47 (C), 146.65 (C),
146.74 (C), 161.61 (C), 196.66 (CHO).
MS (EI): m/z (%) = 241 (100) [M+], 226 (32), 198 (52).
HRMS: m/z [M+] calcd for C14H11NO3: 241.0739; found: 241.0740.
UV (MeOH): λ = 216, 241, 274, 289, 351.
Fluorescence (MeOH): λex = 351 nm, λem = 422 nm.
Anal. Calcd for C14H11NO3: C, 69.70; H, 4.60; N, 5.81. Found: C,
69.71; H, 5.45; N, 5.27.
Clauszoline M (3)
A 1 M solution of BBr3 in CH2Cl2 (337 μL, 0.337 mmol) was added
slowly to a solution of 2-benzyloxy-3-formyl-8-methoxy-9H-car-
bazole (9) (37.2 mg, 0.112 mmol) in CH2Cl2 (7 mL) at –78 °C. The
mixture was stirred for 3 h at –78 °C, warmed to 0 °C, and stirred
overnight. After the addition of H2O at 0 °C, the mixture was ex-
tracted with Et2O (3 ×), and the combined organic layers were dried
(MgSO4). Evaporation of the solvent and flash chromatography of
the crude product (silica gel, petroleum ether–EtOAc, 2:1) afforded
clausine A (2) (13.4 mg, 50%), and clauszoline M (3) as a light yel-
low solid; yield: 11.4 mg (45%); mp >240 °C.
IR (ATR): 3325, 2923, 2851, 2472, 1698, 1624, 1581, 1501, 1472,
1456, 1399, 1356, 1317, 1286, 1225, 1193, 1162, 1092, 1061, 921,
870, 837, 776, 721, 702, 684 cm–1.
1H NMR (500 MHz, acetone-d6): δ = 6.95 (d, J = 7.8 Hz, 1 H), 6.98
(s, 1 H), 7.10 (t, J = 7.8 Hz, 1 H), 7.63 (d, J = 7.8 Hz, 1 H), 8.46 (s,
1 H), 8.95 (s, 1 H), 10.03 (s, 1 H), 10.72 (br s, 1 H), 11.48 (s, 1 H).
13C NMR and DEPT (125 MHz, acetone-d6): δ = 97.34 (CH),
111.76 (CH), 112.07 (CH), 116.14 (C), 118.97 (C), 121.99 (CH),
125.80 (C), 128.77 (CH), 130.84 (C), 143.77 (C), 146.63 (C),
161.43 (C), 196.56 (CHO).
(10) Julich-Gruner, K. K.; Kataeva, O.; Schmidt, A. W.; Knölker,
H.-J. Chem. Eur. J. 2014, 20, 8536.
(11) Part 122 of Transition Metals in Organic Synthesis; for Part
121, see: Gassner, C.; Hesse, R.; Schmidt, A. W.; Knölker,
H.-J. Org. Biomol. Chem. 2014, 12, in press.
(12) (a) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(b) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131. (c) Charles, M. D.; Schultz, P.; Buchwald, S. L.
Org. Lett. 2005, 7, 3965. (d) Surry, D. S.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2008, 47, 6338.
(13) (a) Knölker, H.-J.; O’Sullivan, N. Tetrahedron 1994, 50,
10893. (b) Knölker, H.-J.; Fröhner, W.; Reddy, K. R.
Synthesis 2002, 557. (c) Krahl, M. P.; Jäger, A.; Krause, T.;
Knölker, H.-J. Org. Biomol. Chem. 2006, 4, 3215. (d) Forke,
MS (EI): m/z (%) = 227 (100) [M+].
HRMS: m/z [M+] calcd for C13H9NO3: 227.0582; found: 227.0568.
UV (MeOH): λ = 242, 267 (sh), 275, 295, 356 nm.
Fluorescence (MeOH): λex = 356 nm, λem = 400 nm.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunpfgIpi
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Synthesis 2014, 46, 2651–2655
© Georg Thieme Verlag Stuttgart · New York

PAPER
R.; Krahl, M. P.; Däbritz, F.; Jäger, A.; Knölker, H.-J. Synlett
2008, 1870. (e) Liégault, B.; Lee, D.; Huestis, M. P.; Stuart,
D. R.; Fagnou, K. J. Org. Chem. 2008, 73, 5022.
(14) Åkermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E.
J. Org. Chem. 1975, 40, 1365.
2,8-Dioxygenated Carbazole Alkaloids
2655
(15) For previous syntheses of carbalexin B (1), see ref. 6b and:
Mester, I.; Choudhury, M. K.; Reisch, J. Liebigs Ann. Chem.
1980, 241.
(16) For a previous synthesis of clausine A (2), see: Sharma, R.
B.; Kapil, R. S. Chem. Ind. 1982, 268.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2651–2655