Total syntheses of the chlorinated β-carboline alkaloids bauerine A, B, and C

Article abstract of DOI:10.1080/00397910701226228

The first total synthesis of the chlorinated 1-oxo-β-carboline alkaloid bauerine C based on a Japp-Klingemann reaction is reported. An intermediate of this synthesis was converted to the fully aromatic β-carboline bauerine B, and the related alkaloid baue

Full text of DOI:10.1080/00397910701226228

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Total Syntheses of the Chlorinated
β‐Carboline Alkaloids Bauerine A, B, and C
Berthold Pohl a , Thomas Luchterhandt a & Franz Bracher a
a Department of Pharmacy, Center for Drug Research,
Ludwig‐Maximilians‐Universität, Munich, Germany
Published online: 12 Apr 2007.
To cite this article: Berthold Pohl , Thomas Luchterhandt & Franz Bracher (2007): Total Syntheses of the
Chlorinated β‐Carboline Alkaloids Bauerine A, B, and C, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 37:8, 1273-1280
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Synthetic Communicationsw, 37: 1273–1280, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701226228
Total Syntheses of the Chlorinated
b-Carboline Alkaloids Bauerine A, B, and C
Berthold Pohl, Thomas Luchterhandt, and Franz Bracher
Department of Pharmacy, Center for Drug Research, Ludwig-
¨
Maximilians-Universitat, Munich, Germany
Abstract: The first total synthesis of the chlorinated 1-oxo-b-carboline alkaloid
bauerine C based on a Japp–Klingemann reaction is reported. An intermediate of
this synthesis was converted to the fully aromatic b-carboline bauerine B, and the
related alkaloid bauerine A was prepared in an analogous manner.
Keywords: alkaloids, bauerine, cyclizations, dehydrogenations, 1-oxo-b-carbolines
INTRODUCTION
b-Carboline alkaloids are widely distributed in nature (e.g., in plants, fungi,
microorganisms, and marine organisms) and have been described as exhibit-
ing significant biological activities.[1,2] In contrast to b-carbolines of terres-
trial origin, numerous alkaloids isolated from marine organisms contain
halogen substituents on the aromatic rings.[3] Prominent examples are the anti-
microbial and antiviral eudistomins isolated from the tunicate Eudistoma
olivaceum.[4] In contrast to fully aromatic b-carbolines and the corresponding
1,2,3,4-tetrahydro analogues, only very few 1-oxo-b-carbolines have been
found in nature.[5] In 1994, Larsen et al. reported on the isolation of three
chlorinated b-carbolines from the blue-green alga Dichothrix baueriana.[6]
Among these, bauerine C (1), representing a 1-oxo-b-carboline with a
N-methyl substitutent at the indole nitrogen and a unique dichlorobenzene
ring, was described as exhibiting very high cytotoxicity on tumor cell lines.
Received in the U.K. April 4, 2006
Address correspondence to Franz Bracher, Department of Pharmacy, Center for
¨
Drug Research, Ludwig-Maximilians-Universitat, Butenandtstr. 5-13, 81377 Munich,
Germany. E-mail: franz.bracher@cup.uni-muenchen.de
1273

1274
B. Pohl, T. Luchterhandt, and F. Bracher
In addition, two chlorinated fully aromatic b-carbolines, bauerine A (2) and
bauerine B (3), were isolated from the same alga (Scheme 1). The three
alkaloids were also reported as exhibiting antiviral activity. The first total
syntheses of bauerine A[7] and bauerine B,[8] both based on transition metal-
based coupling reactions, have been described in the literature.
Here we describe the first total synthesis of bauerine C (1) and new
approaches to bauerine A and B.
RESULTS AND DISCUSSION
Because among the alkaloids from Dichothrix baueriana described previously,
bauerine C (1) shows highest cytotoxic activity and was the only one that had
not been synthesized before, we looked for a synthetic strategy that offered
an easy entry to the 1-oxo-b-carboline ring system. The approaches we used
earlier for related alkaloids[5,9] were not appropriate here, because the respective
chlorinated tryptamines are not readily available. Following the method
described by Abramovitch and Shapiro,[10] sodium 2-oxopiperidine-3-carboxy-
late (4) (freshly prepared from the corresponding ethyl ester by alkaline
hydrolysis) was reacted with diazotated 2,3-dichloroaniline 5a in a Japp–
Klingemann reaction to give the arylhydrazone 6a in 71% yield. Subsequent
Fischer cyclization with formic acid gave the tetrahydro-1-oxo-b-carboline
7a in 61% yield. Anhydrous formic acid was found to be superior to 70%
formic acid[10] for this reaction, because the substrate 6a more readily
dissolves in this solvent. Selective N-methylation at the indolic nitrogen to
give 8a was achieved in 79% yield by deprotonation with potassium tert.-
butoxide in dimethylsulphoxide (DMSO) followed by treatment with methyl
iodide. Comparable results were obtained with ethanolic KOH solution and
acetone as a solvent. The regioselectivity of this N-alkylation was unambigu-
ously verified by nuclear Overhauser (NOE)-experiments. Alternative
attempts with dimethyl sulfate, the methylating reagent originally described
to be superior for this purpose,[11] did not give substantial amounts of the
desired monomethylated product 8a. Deprotonation with sodium hydride in
toluene, followed by treatment with methyl iodide, gave mainly the N2,N9-
dimethyl derivative. To complete the total synthesis of bauerine C (1), inter-
mediate 8a had to be dehydrogenated at the C-3/C-4 position. First attempts
with palladium on charcoal in high boiling solvents[9,12] were not successful.
Finally, dehydrogenation of 8a with 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) in refluxing THF gave alkaloid 1 in 43% yield (Scheme 2).
Intermediate 8a also offered a new entry to the total synthesis of the
alkaloid bauerine B (3). Lactam 8a was easily reduced to the tetrahydro-b-
carboline 9a by diborane. In the final step, 9a had to be dehydrogenated to
the fully aromatic alkaloid 3. A literature search revealed that this reaction
might be difficult. Rinehart[4] described a dehydrogenation of 7-bromo-
1,2,3,4-tetrahydro-b-carboline with diphenylseleniumbis(trifluoroacetate) in

Chlorinated b-Carboline Alkaloids
1275
Scheme 1.
40% yield, whereas Schumacher[13] reported that this reaction failed to give
the desired product. In the latter publication, other dehydrogenation
reagents (manganese dioxide, palladium on charcoal, chloranil, and DDQ)
were also described to be ineffective, whereas sulphur in refluxing xylene
gave the desired b-carboline in 15% yield. Trichloroisocyanuric acid–
mediated dehydrogenation of tetrahydro-b-carbolines has been reported to
result in mixtures of 3,4-dihydro-b-carbolines and b-carbolines.[14] Dantale
[7]
and Soderberg used manganese dioxide for dehydrogenation in the first
¨
total synthesis of bauerine A. In our hands, reaction of 9a with DDQ in
refluxing dioxane gave the best yield (17%) of bauerine B (3). The product
was accompanied by large amounts of an insoluble, tarry mass (Scheme 3).
The related alkaloid bauerine A (2) was prepared in an analogous manner.
Thus, the Japp–Klingemann reaction of diazotated 3-chlorophenylhydrazine
(5b) with ketoacid 4 gave the hydrazone 6b in 59% yield. Subsequent cycliza-
tion with formic acid gave a poorly separable mixture of the desired 7-chloro-
derivative 7b and the isomeric 5-chloro compound 7c. N9-methylation of 7b to
8b and reduction of the lactam group gave the tetrahydro-b-carboline 9b, which
was dehydrogenated to bauerine A (2) with DDQ in 12% yield (Scheme 3).
Scheme 2.

1276
B. Pohl, T. Luchterhandt, and F. Bracher
Scheme 3.
CONCLUSION
A convenient first total synthesis (four steps, 14% overall yield) of the 1-oxo-
b-carboline alkaloid bauerine C (1) has been developed starting from com-
mercially available materials using the Japp–Klingemann reaction as the
key step. New approaches to the fully aromatic analogues bauerine A (2)
and bauerine B (3), albeit in poor yields, were worked out using the same
approach, followed by reduction of the corresponding 1-oxo-tetrahydro-b-car-
bolines and subsequent dehydrogenation.
EXPERIMENTAL
General Data
Elemental analyses: Analysator CHN-O Rapid (Heraeus). Mass spectra: CH 7
(Varian MAT). IR spectra: Perkin-Elmer 881 IR-1600 FT-IR and FT-IR-
Paragon 1000. Melting points (uncorrected): Bu¨chi B 50 apparatus. NMR:
Jeol GSX 400 (400 MHz for 1H, 100 MHz for 13C); TMS as internal
standard. Solvents were dried using standard methods and freshly destilled
prior to use. Flash-column chromatography (FCC) was performed on
Kieselgel 60 (0.040–0.063 mm; Merck).
3-(2,3-Piperidinedione)-(2,3-dichlorophenyl)hydrazone (6a)
2,3-Dichloroaniline (6.6 g, 41 mmol) was suspended in 60 ml of water con-
taining 11 ml of conc. hydrochloric acid and cooled to 0–58C. After
addition of 3.6 g (52 mmol) of sodium nitrite in water (10 ml), the solution
was kept at this temperature for 10 min. Then 2.0 g of urea were added; the
mixture was neutralized with satd. NaHCO3 solution and stirred until the
evolution of gas ceased. This mixture was added to an ice-cooled solution
of 6.8 g (40 mmol) of 3-ethoxycarbonyl-2-oxopiperidine, which had been
kept at 308C for 2.5 h with 2.4 g (43 mmol) of potassium hydroxide in
80 ml of water. The mixture was adjusted to pH 4 by addition of acetic acid
and then stirred for an additional 8 h at room temperature. The precipitate

Chlorinated b-Carboline Alkaloids
1277
was separated, washed with water and toluene, and recrystallized from
methanol to give 7.8 g (71%) of 6a as a red solid, mp 2268C. IR (KBr):
3221, 2960, 1689, 1662, 1589, 1451, 1327, 1302, 1196, 1142, 1106, 1042,
1
767 cm21. H NMR (DMSO-d6) d 8.55 (s, 1H, NH), 8.08 (s, 1H, NH), 7.54
(d, J ¼ 8.1 Hz, 1H, CH), 7.33 (dd, J ¼ 8.1 Hz, 8.1 Hz, 1H, CH), 7.15
(d, J ¼ 8.1 Hz, 1H, CH), 3.22 (m, 2H, CH2), 2.70 (t, J ¼ 6.5 Hz, 2H, CH2),
1.86 (m, 2H, CH2). MS (70 eV) m/z (%): 275 (12) [Mþ], 273 (60) [Mþ],
271 (90) [Mþ], 236 (100). Anal. calcd. for C11H11Cl2N3O (272.13): C,
48.55; H, 4.07; N, 15.44. Found C, 48.45; H, 4.02; N, 15.24.
3-(2,3-Piperidinedione)-(3-chlorophenyl)hydrazone (6b)
Prepared in the same manner as described previously from 3-chloroaniline in
59% yield. Red crystals, mp 2408C. IR (KBr): 3217, 3168, 3036, 2952, 1661,
1597, 1566, 1474, 1463, 1433, 1329, 1299, 1193 cm21. 1H NMR (DMSO-d6)
d 9.75 (s, 1H, NH), 7.91 (s, 1H, NH), 7.30 (d, J ¼ 2.1 Hz, 1H, CH), 7.25 (dd,
J ¼ 8.0 Hz, 8.0 Hz, 1H, CH), 7.17 (m, 1H, CH), 6.85 (m, 1H, CH), 3.20
(m, 2H, CH2), 2.67 (t, J ¼ 6.6 Hz, 2H, CH2), 1.86 (m, 2H, CH2). Anal.
calcd. for C11H12ClN3O (237.69): C, 55.59; H, 5.05; N, 17.68. Found C,
55.32; H, 5.14; N, 17.41.
7,8-Dichloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (7a)
A solution of 7.7 g (28 mmol) of 6a in 200 ml of formic acid was stirred at 808C
for 24 h, and then the formic acid was removed by distillation. The residue was
dissolved in ethyl acetate, and the mixture was washed with satd. NaHCO3
solution and water. After evaporation, the residue was crystallized from acetone
to give 4.4 g (61%) of 7a as a pale yellow powder, mp 2128C. IR (KBr): 3234,
1
1651, 1503, 1318, 767 cm21. H NMR (DMSO-d6) d 11.21 (s, 1H, NH), 7.75
(s, 1H, NH), 7.60 (d, J ¼ 8.5 Hz, 1H, CH), 7.26 (d, J ¼ 8.5 Hz, 1H, CH), 3.53
(m, 2H, CH2), 2.94 (t, J ¼ 6.9 Hz, 2H, CH2). MS (70 eV) m/z (%): 258 (12)
[Mþ], 256 (61) [Mþ], 254 (95) [Mþ], 197 (100). Anal. calcd. for C11H8Cl2N2O
(255.10): C, 51.79; H, 3.16; N, 10.98. Found C, 52.18; H, 3.46, N; 10.92.
7-Chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (7b) and
5-Chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (7c)
Prepared in the same manner as described previously from 6b as a poorly
separable mixture in 59% overall yield. FCC separation (eluent: ethyl
acetate) gave, in the order of elution, 13% of 7c, 28% of a mixture of both
compounds, and 12% of 7b.

1278
B. Pohl, T. Luchterhandt, and F. Bracher
7b: White solid, mp 2118C. IR (KBr): 3228, 1659, 1616, 1543, 1322, 1264,
1
1195, 1061, 850, 778 cm21. H NMR (DMSO-d6) d 11.75 (s, 1H, NH,),
7.63 (s, 1H, NH), 7.62 (d, J ¼ 8.2 Hz, 1H, CH), 7.38 (d, J ¼ 1.5 Hz, 1H,
CH), 7.07 (dd, J ¼ 8.2 Hz, 1.5 Hz, 1H, CH), 3.51 (m, 2H, CH2), 2.92
(t, J ¼ 7.0 Hz, 2H, CH2). Anal. calcd. for C11H9ClN2O (220.66): C, 59.88;
H, 4.11; N, 12.70. Found C, 60.02; H, 4.03; N, 12.17.
7c: White solid, mp 2088C. IR (KBr): 3215, 1660, 1615, 1544, 1510, 1490,
1415, 1331, 1307, 948, 776. H NMR (DMSO-d6) d 11.97 (s, 1H, NH),
1
7.72 (s, 1H, NH), 7.35 (d, J ¼ 8.2 Hz, 1H, CH), 7.17 (dd, J ¼ 7.5 Hz,
8.2 Hz, 1H, CH), 7.09 (d, J ¼ 7.5 Hz, 1H, CH), 3.51 (m, 2H, CH2), 3.19
(t, J ¼ 7.0 Hz, 2H, CH2).
7,8-Dichloro-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-
one (8a)
Compound 7a (2.29 g, 8.98 mmol) was dissolved in 10 ml of DMSO, treated
with 1.05 g (9.38 mmol) of potassium tert.-butylate, and stirred at 808C for
30 min. After cooling to 208C, 2 ml of methyl iodide were added; the mixture
was stirred at 808C for 30 min and then poured into ice-cooled 2M ammonia.
Extraction with ethyl acetate, evaporation, and crystallization from acetone
gave 1.9 g (79%) of 8a as a off-white powder, mp 2138C. IR (KBr): 3208,
2919, 1671, 1489, 1300, 1158, 1042, 901, 797 cm21. 1H NMR (CDCl3) d 7.38
(d, J ¼ 8.4 Hz, 1H, 5-H), 7.20 (d, J ¼ 8.6 Hz, 1H, 6-H), 5.70 (br. s, NH), 4.53
(s, 3H, N-CH3), 3.64 (dt, J ¼ 6.8 Hz, 2.8 Hz, 2H, CH2), 2.99 (t, J ¼ 6.8 Hz,
2H, CH2). NOE experiment: saturation at 3.64 ppm (3-H) led to an effect at
5.70 ppm (N2-H). MS (70 eV) m/z (%): 272 (12) [Mþ], 270 (67) [Mþ], 268
(100) [Mþ], 239 (39), 211 (96). Anal. calcd. for C12H10Cl2N2O (269.13): C,
53.55; H, 3.75; N, 10.41. Found C, 53.59; H, 3.89; N, 10.43.
7-Chloro-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (8b)
Prepared in the same manner as described previously from 7b in 81% yield.
White crystals, mp 1688C (from methanol). IR (KBr): 3228, 1659, 1616,
1
1543, 1322, 1264, 1195, 1061, 850, 778 cm21. H NMR (DMSO-d6) d 7.71
(s, 1H, NH), 7.66 (m, 2H, 2 CH), 7.12 (dd, 1H, J ¼ 8.6 Hz, 1.7 Hz, 1H,
CH), 4.02 (s, 3H, CH3), 3.46 (m, 2H, CH2), 2.92 (t, 2H, J ¼ 7.0 Hz, 2H,
CH2). Anal. calcd. for C12H11ClN2O ꢀ CH3OH (266.73): C, 58.54; H, 5.67;
N, 10.50. Found: C, 58.03; H, 5.09; N: 10.44.
Bauerine C (1)
Compound 8a (0.27 g, 1.0 mmol) and 0.45 g (2.0 mmol) of DDQ were
refluxed in 20 ml of anhydrous THF for 12 h. After cooling to room

Chlorinated b-Carboline Alkaloids
1279
temperature, the solution was diluted with ethyl acetate and washed with 1 N
sodium hydroxide solution until the aqueous layer was only slightly yellow.
Evaporation of the organic layer and crystallization from ethyl acetate gave
0.115 g (43%) of 1 as a pale yellow solid, mp 254–2588C (decomp.; lit.:[6]
mp . 2208C). 1H NMR (DMSO-d6) d 11.58 (br. s, 1H, NH), 8.08
(d, J ¼ 8.5 Hz, 1H, 5-H), 7.41 (d, J ¼ 8.5 Hz, 1H, 6-H), 7.16 (m, 1H, 3-H),
7.02 (d, J ¼ 6.8 Hz, 1H, 4-H), 4.63 (s, 3H, N-CH3). 13C NMR (DMSO-d6)
d 156.0 (C55O), 136.3 (aromat., quart.), 130.6 (aromat., quart.), 128.0
(aromat., quart.), 126.3 (aromat., CH), 124.9 (aromat., quart.), 122.9
(aromat., quart.), 121.8 (aromat., CH), 121.3 (aromat., CH), 115.1 (aromat.,
quart.), 99.0 (aromat., CH), 34.1 (CH3).
7,8-Dichloro-9-methyl-1,2,3,4-tetrahydro-1H-pyrido-[3,4-b]indole (9a)
Compound 8a (0.22 g, 0.82 mmol) was dissolved in 15 ml of THF, 10 ml of
1 M borane–THF were added under nitrogen, and the mixture was refluxed
for 14 h. After cooling, conc. hydrochloric acid was added carefully until
gas evolution ceased, then 100 ml water was added, and the mixture was
refluxed for 2 h. After cooling, the mixture was brought to pH 9 with
potassium hydroxide and extracted with ethyl acetate (3 ꢀ 50 ml). The
extract was dried, evaporated, and purified by FCC (eluent: ethyl acetate) to
give 134 mg (65%) of 9a as a white solid, mp 1418C. IR (KBr): 3304,
2931, 1558, 1448, 1410, 798 cm21
.
1H NMR (DMSO-d6) d 7.33
(d, J ¼ 8.4 Hz, 1H, CH), 7.14 (d, J ¼ 8.4 Hz, 1H, CH), 3.88 (s, 3H, CH3),
3.87 (s, 2H, CH2), 2.94 (t, J ¼ 7.0 Hz, 2H, CH2), 2.56 (m, 2H, CH2), 1.88
(s, 1H, NH). Anal. calcd. for C12H12Cl2N2 (255.15): C, 56.49; H, 4.74; N,
10.98. Found: C, 56.20; H, 4.83; N, 9.79.
7-Chloro-9-methyl-1,2,3,4-tetrahydro-9H-pyrido-[3,4-b]indole (9b)
Prepared in the same manner as described previously from 8b in 63% yield.
1
White solid, mp 598C. H NMR (CDCl3) d 7.37 (d, J ¼ 8.4 Hz, 1H, CH),
7.25 (d, J ¼ 1.6 Hz, 1H, CH), 7.04 (dd, J ¼ 8.4 Hz, 1.6 Hz, 1H, CH), 4.03
(s, 2H, CH2), 3.54 (s, 3H, CH3), 3.17 (t, J ¼ 5.6 Hz, 2H, CH2), 2.74
(t, J ¼ 5.6 Hz, 2H, CH2).
Bauerine A (2)
Compound 9b (90 mg, 0.4 mmol) and 180 mg (0.79 mmol) of DDQ in 15 ml
of dioxane were refluxed for 24 h. The mixture was concentrated; the residue
was treated with 100 ml of 0.5 M sodium hydroxide and extracted with ethyl
acetate (3 ꢀ 50 ml). The extract was concentrated and purified by FCC

1280
B. Pohl, T. Luchterhandt, and F. Bracher
(eluent: ethyl acetate) to give 13 mg (12%) of 2 as a pale yellow solid, mp
1078C (decomp.; lit.:[6] mp 109–1108C). 1H NMR (acetone-d6) d 9.02
(d, J ¼ 0.5 Hz, 1H, 1-H), 8.44 (d, J ¼ 5.1 Hz, 1H, 3-H), 8.25 (dd,
J ¼ 8.4 Hz, 0.5 Hz, 1H, 5-H), 8.08 (dd, J ¼ 5.1 Hz, 1.1 Hz, 1H, 4-H), 7.73
(d, J ¼ 1.7 Hz, 1H, 8-H), 7.29 (dd, J ¼ 8.4 Hz, 1.7 Hz, 1H, 6-H), 4.04
(s, 3H, CH3). 13C NMR (acetone-d6): d 143.3 (aromat., quart.), 140.2
(aromat., CH), 138.3 (aromat., quart.), 134.4 (aromat., quart.), 133.6
(aromat., CH), 128.0 (aromat., quart.), 123.8 (aromat., CH), 120.7 (aromat.,
CH), 120.6 (aromat., quart.), 115.0 (aromat., CH), 110.6 (aromat., CH),
29.6 (CH3).
Bauerine B (3)
Prepared in the same manner as described previously from 9a in 17% yield.
Pale yellow solid, mp 1488C (decomp.; lit.:[6] mp 164–1648C, lit.:[8] 147–
1488C). 1H NMR (acetone-d6): d (ppm) 9.08 (s, 1H, 1-H), 8.48
(d, J ¼ 5.3 Hz, 1H, 3-H), 8.23 (d, J ¼ 8.4 Hz, 1H, 5-H), 8.10 (dd,
J ¼ 5.3 Hz, 1.1 Hz, 1H, 4-H), 7.46 (d, J ¼ 8.4 Hz, 1H, 6-H), 4.41 (s, 3H,
CH3). 13C NMR (acetone-d6): d 140.8 (aromat., CH), 139.2 (aromat.,
quart.), 138.8 (aromat., quart.), 134.2 (aromat., CH), 133.5 (aromat., quart.),
127.8 (aromat., quart.), 123.7 (aromat., quart.), 122.5 (aromat., CH), 121.9
(aromat., CH), 116.2 (aromat., quart.), 114.8 (aromat., CH), 33.2 (CH3).
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