Synthesis of arcyriarubin a and arcyriaflavin a via cross-coupling of indolylboronic acid with dibromomaleimides

Article abstract of DOI:10.1080/00397910902962878

Arcyriarubin A was first isolated by Steglich in 1980; it is also the key intermediate in the synthesis of indolocarbazole compounds. A new synthetic approach to the natural products arcyriaflavin A and arcyriarubin A is described. The key step is a Suzuk

Full text of DOI:10.1080/00397910902962878

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Synthesis of Arcyriarubin A and
Arcyriaflavin A via Cross-Coupling
of Indolylboronic Acid with
Dibromomaleimides
Ke Wang a b & Zhanzhu Liu a b
a Key Laboratory of Bioactive Substances and Resources Utilization
of Chinese Herbal Medicine, Ministry of Education, Beijing, China
b Institute of Materia Medica, Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing, China
Published online: 09 Dec 2009.
To cite this article: Ke Wang & Zhanzhu Liu (2009) Synthesis of Arcyriarubin A and Arcyriaflavin A
via Cross-Coupling of Indolylboronic Acid with Dibromomaleimides, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:1, 144-150, DOI:
10.1080/00397910902962878
To link to this article: http://dx.doi.org/10.1080/00397910902962878
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Synthetic Communications1, 40: 144–150, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902962878
SYNTHESIS OF ARCYRIARUBIN A AND ARCYRIAFLAVIN
A VIA CROSS-COUPLING OF INDOLYLBORONIC ACID
WITH DIBROMOMALEIMIDES
Ke Wang and Zhanzhu Liu
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese
Herbal Medicine, Ministry of Education and Institute of Materia Medica,
Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing, China
Arcyriarubin A was first isolated by Steglich in 1980; it is also the key intermediate in the
synthesis of indolocarbazole compounds. A new synthetic approach to the natural products
arcyriaflavin A and arcyriarubin A is described. The key step is a Suzuki cross-coupling
reaction using indolylboronic acid as the starting material. The preparation of arcyriaflavin
A was accomplished in eight steps from indole for a total yield of 21%.
Keywords: Arcyriaflavin A; arcyriarubin A; indolocarbazoles; Suzuki coupling
INTRODUCTION
Since the isolation of staurosporine in 1977,[1] many indolocarbazoles have
been isolated from different organisms, including bacteria, fungi, and inverte-
brates.[2] This family of compounds has attracted the attention of chemists, bio-
logists, and physicians because of the wide range of biological activities that the
compounds possess, including antimicrobial, hypotensive, and cell cytotoxic activi-
ties as well as inhibition of protein kinase C and platelet aggregation.[3] Several
indolocarbazole analogs are currently being tested in the clinic against cancer or
other diseases.[4]
Arcyriarubin A[5] is the simplest bisindolylmaleimide, which is also the key
intermediate in the synthesis of indolocarbazole compounds. Arcyriaflavin A was
isolated by Steglich et al.[5] (Figure 1) in 1980. It exhibits micromolar and submicro-
molar inhibition against seven protein kinase C isoenzymes, and it inhibits the pro-
liferation of the human lung cancer A549 and P388 murine leukemia cell lines.[6]
Various approaches to the synthesis of this family of natural products have
been reported[7]: reaction of indole Grignard reagents with dibromomaleimides,
reaction of 3-indolyl lithium with dibromomaleimides, reaction of indolyl-3-glyoxlyl
Received December 22, 2008.
Address correspondence to Zhanzhu Liu, Institute of Materia Medica, Chinese Academy of
Medical Sciences and Peking Union Medical College, Beijing, 100050, China. E-mail: liuzhanzhu@
imm.ac.cn
144

ARCYRIARUBIN A AND ARCYRIAFLAVIN A
145
Figure 1. The structures of some bisindole alkaloids.
chlorides with indole-3-acetimidates, and iodine-promoted oxidative coupling of the
indole-3-acetic acid trianion and the methylindole-3-acetate dianion. Despite the
available synthetic routes to the indolo[2,3-a]pyrrolo[3,4-c]carbazole ring system, a
simpler and more efficient one is still needed. We report a novel method for the syn-
thesis of bisindolymaleimide via palladium-catalyzed cross-coupling of indolyl-3-
boronic acid with dibromomaleimides.
DISCUSSION
Preparation of the indole boronic acid 3 from indole 1 was accomplished
through the following steps: protection of the indole NH with p-toluenesulfonyl
chloride (TsCl) and then treatment with Hg(OAc)2 to yield compound 2. Reaction
of 2 with BH3-tetrahydrofuran (THF) followed by hydrolytic workup gave 3 in a
total yield of 82%[8] (Scheme 1).
Bisindolylmaleimide 5 was synthesized by the Suzuki cross-coupling of indole
boronic acid 3 and dibromomaleimide 4. Several coupling conditions were tested[9]
(Table 1), and the best one was Pd(PPH3)4-Na2CO3-dioxane=CH3OH, under which
compound 5 was obtained in 52% yield (Scheme 2).
With compound 5 in hand, cleavage of both indole nitrogen protective groups
was readily accomplished.[10] Basic treatment of 6 led to anhydride 7. The dimethyl-
formamide (DMF) solution of maleic anhydrides 7 were treated with 1,1,1,3,3,3-
hexamethyldisilazane (HMDS)=methanol at room temperature for 16 h to give imide
8 in an excellent yield.[11] Treatment of 8 with 1 equivalent of palladium acetate in
acetic acid at reflux for 18 h gave the desired product 9 in 72% yield[12] (Scheme 3).
In conclusion, we have developed a new, efficient approach for the synthesis
of bisindolylmaleimides via the Suzuki cross-coupling reaction. The preparation of
Scheme 1. The synthesis of N-tosyl-3-indolylboronic acid.

146
K. WANG AND Z. LIU
Table 1. Conditions and yields for Suzuki cross-coupling reaction between 3 and 4a
Solvent A
Solvent B
Base
Yield (%)b
Benzene
DMF
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
2 M Na2CO3
2 M Na2CO3
2 M Na2CO3
2 M Cs2CO3
2 M K3PO4
2 M Na2CO3
27
15
52
46
29
45
Dioxane
Toluene
Toluene
Toluene
aReaction conditions: solvent A, 15 ml: solvent B, 3 ml; base 2 ml; catalyst,
10 mol%; refluxing; 10 h.
bIsolated yields.
Scheme 2. The synthesis of bisindolylmaleimide skeleton via Suzuki reaction.
Scheme 3. The synthesis of arcyriarubin A and arcyriaflavin A.

ARCYRIARUBIN A AND ARCYRIAFLAVIN A
147
arcyriaflavin A was realized in eight steps from indole in a total yield of 21%.
This method is operationally simple, obviating the necessity for anhydrous reaction
conditions. Synthesis of indolocarbazole alkaloids and analogs with this method is
ongoing in our laboratory.
EXPERIMENTAL
All reagents and solvents were pure analytical-grade materials purchased from
commercial sources and were used without further purification, if not stated other-
1
wise. H NMR (300 or 400 MHz) spectra were recorded at 24ꢀC unless otherwise
stated. The data are reported as chemical shift (ppm), and the interpretation of peak
with relevant coupling constants is reported in hertz. Mass spectra (MS) were
obtained using an ion trap mass spectrometer equipped with electrospray ionization
(ESI) ion source.
3-Acetoxymercurio-N-tosylindole (2)
Tetrabutylammonium hydrogensulfate (1.6 g, 4.8 mmol), potassium hydroxide
(KOH; 50% aqueous solution, 88 ml), and a solution of p-toluenesulfonyl chloride
(15.6 g, 82 mmol) in toluene (120 ml) were added to a solution of indole (8.0 g,
68.2 mmol) in toluene (60 ml). After stirring for 4 h, H2O (120 ml) was added and
the layers were separated. The organic layer was washed with H2O (2 ꢁ 50 ml) and
brine (1 ꢁ 50 ml),dried over magnesium sulfate, and concentrated under reduced
1
pressure to afford N-tosylindole (18.2 g, 98%) as an off-white powder. H NMR
(DMSO-d6): 300 MHz d 7.94 (m, 1H), 7.87 (m, 2H), 7.79 (d, J ¼ 3.6 Hz, 1H), 7.60
(m, 1H), 7.39 (d, J ¼ 8.1 Hz, 2H), 7.33 (m, 1H), 7.24 (m, 1H), 6.83 (m, 1H), 2.31
(s, 3H).
Mercuric acetate (4.8 g, 15.0 mmol) was added to a solution of N-tosylindole
(4.0 g, 14.8 mmol) in acetic acid (100 ml). After stirring at 23ꢀC for 10 min, perchloric
acid (five drops) was added. The mixture was stirred for 24 h, poured into H2O
(150 ml), and then filtered. The resulting white solid was washed with copious
amounts of water and dried under vacuum for 12 h to afford organomercurial deriva-
tive 2 (7.7 g, 99%) as an unstable white powder that was used immediately without
1
further purification: H NMR (DMSO-d6): 300 MHz d 8.00 (d, J ¼ 8.4 Hz, 1H),
7.84 (d, J ¼ 8.4 Hz, 2H), 7.73 (d, J ¼ 7.8 Hz, 1H), 7.49 (s, 1H), 7.39(d, J ¼ 7.8 Hz,
2H), 7.32–7.19 (m, 2H), 2.31 (s, 3H), 1.97 (s, 3H).
N-Tosyl-3-indolyboronic Acids (3)
Borane solution (1 M in THF, 32 mL, 32 mmol) was added to a solution of 2
(3.4 g, 6.4 mmol) in THF (100 ml) at 23ꢀC. The resulting solution was stirred for
1 h, and then H2O (38 ml) was added very slowly. After filtration, the organic solvent
was evaporated under reduced pressure and the residue was extracted with EtOAc
(2 ꢁ 60 ml). The combined organic layers were washed with brine (1 ꢁ 30 ml) and
concentrated under reduced pressure. Trituration of the crude product with hexanes
(four times) afforded boronic acid 3 (1.72 g, 85%) as an unstable off-white solid
which was used immediately without further purification.

148
K. WANG AND Z. LIU
2,3-Bis(1-tosyl-indol-3-yl)-N-methylmaleimide (5)
Aqueous sodium carbonate (2 M, 2 ml) was added to the solution containing
dibromo-maleimide 4 (159 mg, 0.6 mmol) and boronic acid 3 (400 mg, 1.3 mmol) in
dioxane (15 ml)–methanol (3 ml). The mixture was deoxygenated by bubbling a
steam of argon through the reaction mixture for 10 min. Then tetra(triphenylpho-
sphine)palladium (231 mg, 0.2 mmol) was added. The reaction mixture was stirred
at refluxing for 10 h and quenched by addition of sodium sulfate (500 mg). Filtration
and concentration to dryness under reduced pressure, followed by further purifi-
cation through flash chromatography (hexane=EtOAc 10:2), afforded compound
1
5 (200 mg, 52% yield) as a yellow solid: H NMR (CDCl3): 300 MHz d 8.09 (s,
2H), 7.90 (d, J ¼ 8.4 Hz, 2H), 7.75 (d, J ¼ 8.4 Hz, 4H), 7.23 (d, J ¼ 8.0 Hz, 4H),
7.11 (t, J ¼ 7.6 Hz, 2H), 6.65 (d, J ¼ 8.0 Hz, 2H), 6.55 (t, J ¼ 7.6 Hz, 2H), 3.20 (s,
3H), 2.36 (s, 6H). HRMS: calcd. 650.1420 for C35H28N3O6S2 [MþH]þ; found
650.1443.
2,3-Bis(1H-indol-3-yl)-N-methylmaleimide (6)
A mixture of 5 (119 mg, 0.18 mol), K2CO3 (276 mg, 2 mmol), H2O (5 ml), and
MeOH (15 ml) was refluxed under N2 with magnetic stirring for 5 h. The mixture was
allowed to cool to room temperature, and the solvent was removed in vacuo to give a
red solid. This was dissolved in EtOAc (20 ml), washed with H2O (2 ꢁ 20 ml) and
brine (20 ml), and dried (Na2SO4). The solvent was removed in vacuo to give 6
1
(52.6 mg, 84%) as a red solid. H NMR (DMSO-d6) 300 MHz d 11.67 (s, 2H), 7.74
(d, J ¼ 2.7 Hz, 2H), 7.36 (d, 2H, J ¼ 7.8 Hz), 6.97 (t, J ¼ 16.2 Hz, 2H), 6.79 (d,
J ¼ 8.1 Hz, 2H), 6.62 (t, J ¼ 16.2 Hz, 2H), 3.04 (s, 3H). HRMS (ESI): calcd.
342.1237 for C21H16N3O2 [MþH]þ; found 342.1224.
2,3-Bis(1H-indol-3-yl)-maleic Anhydride (7)
Compound 6 (300 mg, 0.88 mmol) was refluxed for 1 h in 10% aqueous potass-
ium hydroxide (120 ml), cooled, and acidified with 2 M HCl. The red precipitate was
1
collected to afford 7 as a red solid (236 mg, 82%). H NMR (DMSO-d6) 300 MHz d
11.89 (d, J ¼ 1.8 Hz, 2H), 7.83 (d, J ¼ 3.0 Hz, 2H), 7.41 (d, J ¼ 8.1 Hz, 2H), 7.00–7.05
(m, 2H), 6.85 (d, J ¼ 8.1 Hz, 2H), 6.67–6.72 (m, 2H). HRMS (ESI): calcd. 329.0921
for C21H16N3O2 [MþH]þ; found 329.0926.
2,3-Bis(1H-indol-3-yl)-maleimide (8) (Arcyriarubin A)
A solution of 7 (110 mg, 0.34 mmol) in DMF (4 ml) was treated with a mixture
of 1,1,1,3,3,3-hexamethyldisilazane (542 mg, 3.36 mmol) and methanol (60 mg,
1.87 mmol). After stirring at room temperature for 16 h, the mixture was poured into
water and extracted with ethyl acetate. The combined extracts were washed well with
water and dried (MgSO4). Removal of solvent under reduced pressure gave
2,3-bis-(1H-indolyl)-maleimide 8 (Arcyriarubin A) as a red solid (106.4 mg, 97%).
1H NMR (CD3OD) 300 MHz d 7.61 (d, J ¼ 1.8 Hz, 2H), 7.22 (d, J ¼ 8.1 Hz, 2H),

ARCYRIARUBIN A AND ARCYRIAFLAVIN A
149
6.84–6.89 (m, 2H), 6.74 (d, J ¼ 8.4 Hz, 2H), 6.50 (t, J ¼ 14.7 Hz, 2H). HRMS (ESI):
calcd. 328.1086 for C20H14N3O2 [MþH]þ; found 328.1080.
Arcyriaflavin A (9)
Palladium acetate (27 mg, 0.12 mmol) was added to a solution of 8 (80 mg,
0.24 mmol) in acetic acid (15 ml), and the reaction mixture was stirred at refluxing
for 18 h, then the mixture was filtered, and the filtrate was concentrated under reduced
pressure. Chromatography of the residue on silica gel using THF=petroleum ether
(PE) (1=2) as eluant afforded 9 (arcyriaflavin A) as a greenish yellow solid (57 mg,
72%). 1H NMR (CD3COCD3) 300 MHz d 11.12 (s, 2H), 9.79 (s, 1H), 9.14 (d,
J ¼ 8.1 Hz, 2H), 7.70 (d, J ¼ 8.1 Hz, 2H), 7.53 (t, J ¼ 15.3 Hz, 2H), 7.36 (t, J ¼ 14.7 Hz,
Hz, 2H). HRMS (ESI): calcd. 326.0924 for C20H12N3O2 [MþH]þ; found 326.0917.
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