β-Carboline Alkaloids 9 [1]. Total Synthesis of the β-Carboline Alkaloids Arenarine A and (±)Arenarine B

Article abstract of DOI:10.1002/jhet.5570410206

The first total synthesis of the β-carboline alkaloids arenarine A (1) and arenarine B (2) is described. Methanolysis of the α-bromoketone 9 gives 1 in good yield. Alternatively 1 can be obtained from the diazoketone 11 with boron trifluoride/methanol in poor yield. Reduction of 1 with sodium borohydride gives racemic arenarine B (2). Regioselective homolytic methylation of norharmane (4) with tert-butyl hydroperoxide/ferrous sulfate gives the alkaloid harmane (6).

Full text of DOI:10.1002/jhet.5570410206

Mar-Apr 2004
173
β-Carboline Alkaloids 9 [1]. Total Synthesis of the β-Carboline
Alkaloids Arenarine A and (±)Arenarine B
Franz Bracher* and Andreas Puzik
Department Pharmazie – Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München,
Butenandtstr. 5-13, 81377 München, Germany
Received November 12, 2003
The first total synthesis of the β-carboline alkaloids arenarine A (1) and arenarine B (2) is described.
Methanolysis of the α-bromoketone 9 gives 1 in good yield. Alternatively 1 can be obtained from the dia-
zoketone 11 with boron trifluoride/methanol in poor yield. Reduction of 1 with sodium borohydride gives
racemic arenarine B (2). Regioselective homolytic methylation of norharmane (4) with tert-butyl hydroper-
oxide/ferrous sulfate gives the alkaloid harmane (6).
J. Heterocyclic Chem., 41, 173 (2004).
aliphatic aldehydes [6], so we planned to use chloroac-
etaldehyde as a source of the acyl radical. The resulting
chloroketone 5 should then be converted to the methyl
ether 1 under standard Williamson conditions.
1-Substituted β-carbolines represent a large group of
biologically active natural products. Consequently, the
total synthesis of these alkaloids has found widespread
interest in the past. Numerous approaches have been pub-
lished for the synthesis of 1-alkyl-, 1-aryl- and 1-het-
eroaryl-β-carbolines, either by building up the heterocyclic
ring system starting from tryptamine derivatives or by sub-
stitution reactions of 1-substituted β-carbolines [2]. In con-
trast, 1-acyl-β-carbolines cannot be readily prepared by the
classical methods. Some time ago we published new
strategies for the synthesis of 1-acyl-β-carbolines starting
from 1-bromo-β-carboline (7) [3] or from norharmane (4)
[1] following the Minisci reaction [4].
Here we present the extension of these methods to the
synthesis of the alkaloids arenarine A (1) and arenarine B
(2). These alkaloids (Scheme 1) were isolated, together with
1 - a c e t y l -β-ca rboline (3) and 1-methoxycarbonyl-β-carbo-
line, from the Chinese medical plant Arenaria kansuensis
(Caryophyllaceae). This plant (Chinese name: Xue ling zhi)
is used in Chinese folk medicine for the treatment of
influenza, lung inflammation, jaundice, and rheumatism [5].
The absolute configuration of arenarine B, a formal
reduction product of arenarine A, has not yet been deter-
mined, nor has the optical rotation of the natural product
been published.
In fact, 4 reacted with chloroacetaldehyde under Minisci
conditions (ferrous sulfate heptahydrate, t e rt- b u t y l
hydroperoxide in dilute sulfuric acid) to give a new prod-
uct. But surprisingly the spectral data clearly indicated that
the product was harmane (6). Careful investigation of the
reaction conditions showed that 6 was also formed in the
absence of chloroacetaldehyde. The methyl group intro-
duced into the β-carboline ring obviously originates from
tert-butyl hydroperoxide. A few similar ring methylations
of heteroaromatic compounds with the ferrous sulfate/tert-
butyl hydroperoxide system have been reported in the lit-
erature [7,8]. This unexpected reaction represents a new
total synthesis of the alkaloid harmane (6) (Scheme 2).
Scheme 2
Scheme 1
The failure of the direct acylation of 4 prompted us to
work out an alternative approach to a α-haloacetyl-β-car-
boline. Enol ether 8 is an intermediate in the synthesis of
1-acetyl-β-carboline (3). In our previous work we prepared
8 by palladium-catalyzed cross-coupling of 1-chloro-β-
carboline with tributyl(1-ethoxyvinyl)stannane and we
directly hydrolyzed the enol ether to the methyl ketone 3
[3]. For our present purpose 8 was prepared from the even
more reactive 2-bromo-β-carboline (7) [9] and further
treated with N-bromosuccinimide in tetrahydrofuran/water
[10] to give the bromoketone 9 in 77% yield. Surprisingly,
Since arenarine A (1) is simply a α-methoxy derivative
of the readily available 1-acetyl-β-carboline (3) [1,3], we
envisaged to prepare this alkaloid by regioselective
homolytic acylation of norharmane (4) with an appropriate
aldehyde in close analogy to the synthesis of 3 [1]. This
radical reaction worked well with various aromatic and

174
F. Bracher and A. Puzik
Vol. 41
with tetramethylsilane as internal standard on Joel JNM-GX 400,
JNM-ECP 400 (400 MHz) and Joel JNM-ECP 500 (500 MHz)
spectrometers. Chemical shifts are given as δ values (ppm)
downfield from internal tetramethylsilane. Mass spectra were
recorded on a Hewlett Packard 59827A spectrometer. Flash col-
umn chromatography was carried out on Merck Kieselgel 60
(230-400 mesh). Norharmane (4) was supplied from Aldrich Co.
any attempts to convert 9 to arenarine A (1) with sodium
methoxide [11] resulted in extremely poor yields, as the
alkaloid could only be detected in traces in the reaction
mixture. Finally, we found that alcoholysis of the
bromoketone 9 with methanol at 54 °C over several days
gives 1 in 64% yield while in refluxing methanol we
obtained significantly lower yields of 1. The spectroscopic
data of the synthetic product are in accordance with those
published for the natural product [5].
Since the conversion of 9 to 1 gave disappointing results
for quite a long time, we worked out another, completely
d i fferent approach to alkaloid 1. Carboxylic acid 10 is
readily available from harmane (6) by condensation with
benzaldehyde and subsequent oxidative cleavage of the
resulting benzylidene derivative with potassium perman-
ganate [12]. Carboxylic acid 10 was converted to the cor-
responding acid chloride with oxalyl chloride in toluene,
and further to the diazoketone 11 with diazomethane [13].
Finally, 11 could be converted to arenarine A (1) with
boron trifluoride/methanol [14] in 15% yield.
Harmane (1-Methyl-9H-pyrido[3,4-b]indole; 6).
Norharmane (4) (200 mg, 1.19 mmoles) was suspended in an
ice-cooled mixture of water (3 ml), glacial acetic acid (3 ml) and
conc. sulfuric acid (0.6 ml) by means of ultrasound irradiation.
Then a solution of ferrous sulfate heptahydrate (1.0 g, 3.6
mmoles) in water (3.6 ml) and t e rt-butyl hydroperoxide (70%
solution in water) (0.5 ml, 3.6 mmoles) was added simultane-
ously with stirring. After stirring at 0° for 1 hour the same
amounts of ferrous sulfate heptahydrate and tert-butyl hydroper-
oxide were added again in the way described above and stirring
was continued for one more hour at 0°. The mixture was poured
into water (100 ml), neutralized with solid potassium carbonate
and extracted with ethyl acetate (3 x 100 ml). The combined
organic layers were dried (sodium sulfate) and evaporated. The
residue was purified by flash column chromatography
(ethanol/dichloromethane = 1/14) to give 162 mg (75%) 6 as
white needles. The product was identified by comparison with an
authentic sample [15] (tlc, nmr, ir).
Conversion of arenarine A (1) to racemic arenarine B
(2) was accomplished in high yield by reduction with
sodium borohydride in methanol [3].
Scheme 3
In conclusion, we have worked out efficient total syn-
theses of the alkaloids 1 and 2. Moreover, the reactive
intermediates 9 and 11 should offer the possibility to pre-
pare numerous further substituted β-carbolines. Work is in
progress to evaluate the synthetic potential of these build-
ing blocks for alkaloid total synthesis.
1-(1-Ethoxyvinyl)-9H-pyrido[3,4-b]indole (8).
1-Bromo-ß-carboline (7) [3] (368 mg, 1.49 mmoles), dichloro-
bis(triphenylphosphine)-palladium(II) (52 mg, 0.074 mmoles)
and tributyl(1-ethoxyvinyl)stannane (704 mg, 1.95 mmoles) in
anhydrous toluene (4 ml) were refluxed under a nitrogen atmos-
phere for 17 hours. After cooling to room temperature the mix-
ture was poured into water (30 ml) and extracted with ethyl
acetate (2 x 120 ml). Evaporation of the organic solvents in
vacuo gave a residue, which was separated by flash column chro-
matography (ethyl acetate/hexane = 1/4) to give 298 mg (84%) 8
as an unstable, partially crystallizing viscous oil; ir (potassium
EXPERIMENTAL
Melting points were determined with a Büchi Melting Point B-
540 apparatus. Elemental analyses were performed on a CHN
Elemental Analyser (Heraeus). FTIR spectra were recorded on a
Perkin Elmer FT-IR Spectrometer PARAGON. NMR spectra
bromide): 3469, 2973, 1623, 1606, 1560, 1490, 1421, 1366,
1
1316, 1246, 1190, 1065, 968; H nmr (dimethylsulfoxide-d ): δ
8.33 (dd, 1H, 3-H, J = 4.9, 0.6 Hz), 8.22 (d, 1H, 5-H, J = 7.9 Hz),
8.10 (d, 1H, 4-H, J = 4.9 Hz), 7.73 (d, 1H, 8-H, 8.2 Hz), 7.55
6
were recorded in deuteriochloroform or dimethylsulfoxide-d
6

Mar-Apr 2004
β-Carboline Alkaloids 9
175
(ddd, 1H, 7-H, J = 8.2, 7.1, 1.2 Hz), 7.24 (ddd, 1H, 6-H, J = 7.9,
7.1, 0.7 Hz), 5.34 (d, 1H, 2'-H, J = 1.7 Hz), 4.55 (d, 1H, 2'-H, J =
1.7 Hz), 4.18 (q, 2H, OCH , J = 6.9 Hz), 1.50 (t, 3H, CH , J = 6.9
Arenarine A (1-Methoxymethylcarbonyl-9H-pyrido[3, 4- b]-
indole; 1).
2
3
13
Method A.
Hz); C nmr (dimethylsulfoxide-d ): δ 159.60 (C1'), 141.14
6
(C8a), 138.06 (C3), 138.03 (C9a), 132.65 (C1), 130.20 (C4a),
128.79 (C7), 121.99 (C5), 120.75 (C4b), 119.89 (C6), 115.28
(C4), 113.00 (C8), 86.06 (C2'), 63.96 (OCH ), 14.61 (CH ); ms
Bromoketone 9 (200 mg, 0.69 mmoles) was dissolved in anhy-
drous methanol (40 ml) under a nitrogen atmosphere and the
solution was stirred at 54° for 9 days. Then the solvent was evap-
orated and the residue was purified by flash column chromatog-
raphy (ethanol/dichloromethane = 1/14) to give 107 mg (64%) 1
as pale yellow crystals, mp 181° (lit. [5] mp 182-183°); ir (potas-
sium bromide): 3309, 1691, 1452, 1323, 1205, 1121, 1066, 1025
2
3
+
(EI): m/z 238 (M , 52), 223 (58), 209 (16), 193 (100), 168 (40),
H N O m/z: 238.1106. Found
15 14 2
140 (30). HRMS Calcd. for C
m/z: 238.1111.
2-Bromo-1-(9H-pyrido[3,4-b]indol-1-yl)ethanone (9).
-1
1
cm ; H nmr (deuteriochloroform): δ 8.48 (d, 1H, 3-H, J = 4.9
Hz), 8.15 (d, 1H, 4-H, J = 4.9 Hz), 8.14 (dd, 1H, 5-H, J = 7.8, 0.8
Hz), 7.61 (m, 2H, 7-H, 8-H), 7.34 (ddd, 1H, 6-H, J = 7.9, 5.3, 2.8
A solution of 8 (100 mg, 0.42 mmoles) in tetrahydrofuran (7.5
ml) and water (3 ml) was cooled to 0°. Then N-bromosuccinimide
(75 mg, 0.42 mmoles) was added in one portion under stirring.
The solution was allowed to warm up to room temperature over a
period of 30 minutes. Water (50 ml) was added and the mixture
was extracted with dichloromethane (2 x 50 ml). The combined
o rganic layers were dried (sodium sulfate) and evaporated. The
yellow residue was purified by flash column chromatography
(ethyl acetate/hexane = 1/4) to give 93 mg (77%) 9 as yellow nee-
dles, mp 175-176°; ir (potassium bromide): 3394, 3309, 1654,
13
Hz), 5.24 (s, 2H, 2'-H), 3.61 (s, 3H, OCH ); C nmr (deuterio-
3
chloroform): δ 199.45 (C=O), 141.21 (C8a), 138.00 (C3), 135.13
(C9a), 134.17 (C1), 131.71 (C4a), 129.46 (C7), 121.81 (C5),
120.89 (C6), 120.45 (C4b), 119.38 (C4), 112.09 (C8), 74.96
+
(C2'), 59.53 (OCH ) [16]; ms (EI): m/z 240 (M , 29), 225 (100),
3
197 (10), 167 (55), 140 (27).
Anal. Calcd. for C
H N O : C, 69.99; H, 5.03; N, 11.66.
14 12 2 2
Found: C, 69.77; H, 4.96; N, 11.54.
-1
1
1622, 1492, 1462, 1432, 1316, 1253, 1215, 1120, 1055 cm ; H
nmr (deuteriochloroform): δ 8.52 (d, 1H, 3-H, J = 4.9 Hz), 8.18
(dd, 1H, 4-H, J = 4.9, 0.6 Hz), 8.16 (d, 1H, 5-H, J = 7.9 Hz), 7.60
(m, 2H, 8-H, 7-H), 7.35 (ddd, 1H, 6-H, J = 7.9, 7.0, 1.3 Hz), 5.04
Method B.
Diazoketone 11 (340 mg, 1.44 mmoles) was suspended in
anhydrous methanol (40 ml) under a nitrogen atmosphere. Then
boron trifluoride diethyl etherate (0.50 ml, 4.0 mmoles) was
added dropwise and the mixture was stirred at room temperature
for 10 minutes. After evaporation the residue was separated by
flash column chromatography (hexane/ethyl acetate = 4/1) to
give 52 mg (15%) 1 as pale yellow crystals, mp 181°.
13
(s, 2H, 2'-H); C nmr (deuteriochloroform): δ 194.91 (C=O),
141.13 (C1), 138.30 (C3), 135.89 (C8a), 133.01 (C9a), 131.94
(C4a), 129.65 (C7), 121.93 (C5), 121.12 (C6), 120.49 (C4b),
+
119.81 (C4), 112.08 (C8), 32.08 (C2'); ms (EI): m/z 290 (M , 13),
+
288 (M , 13), 210 (100), 182 (43), 168 (68), 140 (39).
Anal. Calcd. for C H BrN O: C, 54.00; H, 3.14; N, 9.69.
13
Found: C, 54.11; H, 3.22; N, 9.67.
9
2
(±)-Arenarine B (1-(2-Methoxy-1-hydroxyethyl-9H-pyrido[3, 4-
b]indole; 2).
2-Diazo-1-(9H-2-Diazo-1-(9H-pyrido[3, 4-b]indol-1-yl)ethanone
(11).
Arenarine A (1) (50 mg, 0.21 mmoles) was suspended in anhy-
drous methanol (6 ml) under a nitrogen atmosphere. After addi-
tion of sodium borohydride (8 mg, 0.2 mmoles) the mixture was
stirred at room temperature for two hours. The solution was
poured into water (50 ml) and the mixture was extracted with
ethyl acetate (3 x 20 ml). The combined organic layers were dried
(sodium sulfate) and evaporated. The residue was purified by
flash column chromatography (ethanol/dichloromethane = 1/14)
to give 44 mg (87%) 2 as white crystals, mp 168° (lit. [5] mp 157-
158°); ir (potassium bromide): 3266, 3090, 2891, 1626, 1498,
A solution of carboxylic acid 10 [12] (500 mg, 2.35 mmoles)
in anhydrous toluene (7 ml) was cooled to 0° under a nitrogen
atmosphere. Then oxalyl chloride (0.81 ml, 9.4 mmoles) in anhy-
drous toluene (5 ml) was added slowly and the solution was
stirred at 55° for 4 hours. Evaporation of the volatile components
in vacuo gave a white crystalline residue. This was suspended in
anhydrous diethyl ether (50 ml) and cooled to 0°. To the stirred
suspension a solution of diazomethane in diethyl ether was added
dropwise until no further nitrogen evolved. Then the mixture was
stirred at 0° for additional 3 hours. The solvent was evaporated
and the residue was separated by flash column chromatography
(ethanol/dichloromethane = 1/14) to give 340 mg (60%) of 11 as
pale yellow needles, mp 167°; ir (potassium bromide): 3354,
-1
1
1433, 1322, 1237, 1128, 1075 cm ; H nmr (deuteriochloro-
form): δ 8.34 (d, 1H, 3-H, J = 5.3 Hz), 8.11 (d, 1H, 5-H, J = 7.9
Hz), 7.89 (d, 1H, 4-H, J = 5.3 Hz), 7.53 (m, 2H, 8-H, 7-H), 7.28
(ddd, 1H, 6-H, J = 7.9 Hz, 6.8, 1.6 Hz), 5.38 (t, 1H, 1'-H, J = 6.2
Hz), 3.88 (dd, 1H, 2'-H, J = 9.5, 6.2 Hz), 3.84 (dd, 1H, 2'-H, J =
13
9.5, 6.2 Hz), 3.48 (s, 3H, OCH ); C nmr (deuteriochloroform):
-1
1
3135, 2095, 1601, 1389, 1351, 1317, 1288 cm ; H nmr (deu-
teriochloroform): δ 8.40 (d, 1H, 3-H, J = 4.9 Hz), 8.16 (d, 1H,
5-H, J = 8.1 Hz), 8.12 (d, 1H, 4-H, J = 4.9 Hz), 7.60 (ddd, 1H, 7-
H, J = 8.0, 7.0, 1.2 Hz), 7.56 (dd, 1H, 8-H, J = 8.1, 0.7 Hz), 7.32
3
δ 143.23 (C1) [17], 140.74 (C8a), 137.19 (C3), 133.88 (C9a),
130.11 (C4a), 128.83 (C7), 121.94 (C5), 121.49 (C4b), 120.20
(C6), 114.35 (C4), 112.04 (C8), 77.00 (C2'), 72.43 (C1'), 59.46
13
+
(ddd, 1H, 6-H, J = 8.1, 7.0, 1.2 Hz), 6.92 (s, 1H, 2'-H); C nmr
(OCH ); ms (EI): m/z 242 (M , 16), 225 (10), 197 (100), 168
3
(14).
(deuteriochloroform): δ 188.28 (C=O), 141.15 (C8a), 137.72
(C3), 134.79 (C9a), 134.64 (C1), 131.56 (C4a), 129.31 (C7),
121.80 (C5), 120.62 (C6), 120.43 (C4b), 118.78 (C4), 111.98
HRMS Calcd. for C
H N O m/z: 242.1055. Found m / z:
14 14 2 2
242.1055.
+
(C8), 53.58 (C2'); ms (EI): m/z 236 (M , 56), 208 (63), 179
(100), 168 (40), 153 (29), 140 (26), 126 (20).
Anal. Calcd. for C H N O: C, 66.10; H, 3.41; N, 23.72.
Acknowlegement.
Financial support of this work by the Fonds der Chemischen
Industrie, Frankfurt, Germany is greatly acknowledged.
13
Found: C, 65.76; H, 2.97; N, 23.59.
8 4

176
F. Bracher and A. Puzik
Vol. 41
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