Total synthesis and biological activity of marine alkaloid eudistomins Y1-Y7 and their analogues

Article abstract of DOI:10.3390/md11051427

Eudistomin Y class compounds are a series of β-carbolines which was originally isolated from a marine turnicate or ascidian near the South Korea Sea. These compounds contain bromo-substituted groups, which is one of the typical characters of marine natural products. We report herein the chemical synthesis and biological evaluation of seven new β-carboline-based metabolites, Eudistomins Y₁-Y₇, and their hydroxyl-methylated phenyl derivatives. Using bromo-substituted tryptamines and bromo-substituted phenylglyoxals as the key intermediates, Eudistomins Y ₁-Y₇ and their derivatives were synthesized via the acid-catalyzed Pictet-Spengler reaction and fully characterized by ¹H- and ¹³C-NMR and mass spectroscopy. Biological studies revealed that all of the compounds showed moderate growth inhibitory activity against breast carcinoma cell line MDA-231 with IC₅₀ of 15-63 μM and the inhibitory activities of hydroxyl-methylated phenyl products were higher than that of the corresponding natural products Eudistomins Y ₁-Y₇.

Full text of DOI:10.3390/md11051427

Mar. Drugs 2013, 11, 1427-1439; doi:10.3390/md11051427
OPEN ACCESS
Marine Drugs
ISSN 1660-3397
www.mdpi.com/journal/marinedrugs
Article
Total Synthesis and Biological Activity of Marine Alkaloid
Eudistomins Y1–Y7 and Their Analogues
Huijuan Jin 1,†, Puyong Zhang 1,†, Krikor Bijian 2, Sumei Ren 1, Shengbiao Wan 1,
Moulay A. Alaoui-Jamali 2,* and Tao Jiang 1,*
1
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy,
Ocean University of China, Qingdao 266003, China; E-Mails: jinhuijuan@126.com (H.J.);
zhangpy819@163.com (P.Z.); rensumei@ouc.edu.cn (S.R.); biaowan@ouc.edu.cn (S.W.)
2
Departments of Medicine, Oncology, and Pharmacology and Therapeutics, Lady Davis Institute for
Medical Research, Segal Cancer Center of the Sir Mortimer B. Davis Jewish General Hospital,
McGill University, Montreal, QC H3T 1E2, Canada; E-Mail: krikor.bijian@mail.mcgill.ca
†
These authors contributed equally to this work.
* Authors to whom correspondence should be addressed;
E-Mails: moulay.alaoui-jamali@mcgill.ca (M.A.A.-J.); jiangtao@ouc.edu.cn (T.J.);
Tel.: +1-514-340-8260/8222 (ext. 3438/3432) (M.A.A.-J.); +86-532-82032712 (T.J.);
Fax: +1-514-340-7576 (M.A.A.-J.); +86-532-82033054 (T.J.).
Received: 25 February 2013; in revised form: 25 March 2013 / Accepted: 7 April 2013 /
Published: 29 April 2013
Abstract: Eudistomin Y class compounds are a series of β-carbolines which was originally
isolated from a marine turnicate or ascidian near the South Korea Sea. These compounds
contain bromo-substituted groups, which is one of the typical characters of marine natural
products. We report herein the chemical synthesis and biological evaluation of seven new
β-carboline-based metabolites, Eudistomins Y1–Y7, and their hydroxyl-methylated phenyl
derivatives. Using bromo-substituted tryptamines and bromo-substituted phenylglyoxals as
the key intermediates, Eudistomins Y1–Y7 and their derivatives were synthesized via the
1
13
acid-catalyzed Pictet-Spengler reaction and fully characterized by H- and C-NMR and
mass spectroscopy. Biological studies revealed that all of the compounds showed moderate
growth inhibitory activity against breast carcinoma cell line MDA-231 with IC50 of
15–63 μM and the inhibitory activities of hydroxyl-methylated phenyl products were higher
than that of the corresponding natural products Eudistomins Y1–Y7.

Mar. Drugs 2013, 11
Keywords: marine alkaloid; Eudistomins Y1–Y7; β-carboline; Pictet-Spengler reaction
1428
1. Introduction
The diversity of marine compounds offers a great advantage for being developed into new drugs
because of their unique and complex structures, developed through old and underexplored species
evolution. However, most marine alkaloids were usually isolated in very small quantities, hindering
further studies to establish their biological activities as well as structure modifications [1]. Therefore,
chemical synthesis of marine alkaloids in larger quantities and by sufficient means is necessary to
investigate their mode of action and their biological implications. β-carbolines are a large group of natural
and synthetic indole alkaloids with different substitutions at the C-1, C-6 and C-7 position, some of
which are widely distributed in many plants and mammals and exhibit a wide spectrum of biological
activities [2–4].
Eudistomin Y class β-carboline compounds are different from previously isolated marine metabolites
due to the presence of a benzoyl group attached to the β-carboline nucleus at C-1. These compounds
contain bromo-substituted groups, which is one of the typical characters of the marine natural products.
Seven eudistomins compounds, Eudistomins Y1–Y7, were isolated from a tunicate of the genus Eudistoma
collected near Tong-Yeong City, South Sea, Korea in 2008 [5], and another six Eudistomins Y8–Y13
were isolated from Korean ascidian Synoicum sp. in 2012 [6]. From bioactivity evaluation results,
several of these natural compounds exhibited moderate to significant antibacterial, antimicrobial activity
and weak cytotoxic activity [5,6].
Kennedy et al. have reported the synthetic methods of Eudistomins Y1–Y7 with 3 steps in a two-pot
process; overall yields ranged from 6% to 25% [7]. In the present paper, we report the total chemical
syntheses of the marine alkaloid Eudistomins Y1–Y7 23–29 and their hydroxyl-methylated phenyl
derivatives (16–22) with modified one-pot oxidation via the acid-catalyzed Pictet-Spengler reaction, as
well as their biological activities against breast carcinoma cell line MDA-231. All structures of target
1
compounds were confirmed by H NMR, 13C NMR and HRMS. The spectra data of synthetic
compounds 23–29 were consistent with those of natural β-carboline alkaloids Eudistomins Y1–Y7 in the
literature [5].
2. Results and Discussion
2.1. Chemistry
The particularity of the marine environment leads to the rich bromine in the marine natural products,
so the syntheses of bromo-substituted indole compounds are the key step in the preparations of marine
alkaloid Eudistomins Y1–Y7 23–29. The target compounds were started from the commercially available
indole. Substituted indole-3-carboxaldehyde 2a–c was synthesized from 1a–c by Vilsmeier-Hacck
reaction with phosphorus oxychloride (POCl3) and N,N-dimethylformamide (DMF) according to the
reference [8]. Intermediates 2a–c was condensed with nitromethane (CH3NO2) based on the classical
Henry reaction to form the corresponding vinyl nitro compounds 3a–c [9], reduction of which by NaBH4
at room temperature gave compounds 4a–c in high yields. Subsequently, 4a was reduced by Pd/C in

Mar. Drugs 2013, 11
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methanol at room temperature to give 5a. 4b–c were reduced by LiAlH4 and refluxed in THF to give
bromo-substituted tryptamines 5b–c [10]. The reaction routes were outlined in Scheme 1.
Scheme 1. Reagents and conditions: (a) POCl3/DMF/NaOH; (b) CH3NO2/CH3COONH4/
benzene, reflux; (c) NaBH4/THF/CH3OH, rt.; (d) Pd/C, H2, rt., for 5a; LiAlH4/THF, refulx,
for 5b and 5c.
Methylation of bromophenol by dimethyl sulfate in acetone, 7 and 12 was converted to substituted
methoxybenzene 8 and 13. Intermediate 14 was prepared by 1-bromo-2-methoxybenzene 13 using
acetyl chloride by Friedel–Craft acylation. The substituted acetophenones 8, 10 and 14 were converted
to substituted phenylglyoxals 9, 11 and 15 by oxidation with SeO2 in dioxane–water mixture [11]. The
reaction routes were outlined in Scheme 2.
Scheme 2. Reagents and conditions: (a) NBS/H2SO4/H2O, 92%; (b) (CH3)2SO4/K2CO3/
acetone, 95%; (c) SeO2/dioxane, 80 °C, 71%; (d) SeO2/dioxane, 80 °C, 75%; (e) (CH3)2SO4/
K2CO3/acetone; (f) acetyl chloride, AlCl3/CS2, 76%; (g) SeO2/dioxane, 80 °C, 74%.
O
O
O
O
Br
Br
H
Br
c
H3C
H3C
b
a
H3C
O
OCH3
OH
OCH3
OH
Br
Br
Br
9
8
6
7
O
O
H
d
H3C
O
OCH3
OCH3
11
10
O
O
Br
OH
Br
OCH3
Br
OCH3
H
Br
OCH3
e
f
g
H3C
O
12
13
14
15
The classical method to prepare β-carboline alkaloids through Pictet-Spengler reaction was a
two-step method, and involved the acid-catalyzed condensation of an aliphatic amine attached to a
sufficiently reactive aromatic nucleus with aldehydes. Specifically, in the first step, an imine was

Mar. Drugs 2013, 11
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formed, which can be activated by acids, while in the second step, the endo cyclization occurred between
a carbon nucleophile of a sufficiently reactive aromatic moiety and the activated iminium ion, resulting
in tetrahydro-β-carboline by the formation of N-heterocyclic ring through a new C–C bond. After
dehydrogenation, tetrahydro-β-carboline was converted to β-carboline [12–15]. In our experiments, the
treatment of substituted tryptamines with substituted phenylglyoxal [16,17] under the acidic conditions
did not produce the expected tetrahydro-β-carboline but rather directly generated a dehydrogenated
β-carboline product 16–22 as reported by Zhang et al. [18]. It is possible that the acidity and polarity of
glacial acetic acid promote the reaction of cyclization and dehydrogenation aromatizing to completion
continuously. The reaction routes were outlined in Scheme 3. Pictet-Spengler cyclization of substituted
tryptamine 5a–d with substituted phenylglyoxal 9, 11 or 15 in acetic acid afforded compounds 16–22,
which was transformed into the target compounds Eudistomins Y1–Y7 23–29 in the presence of BBr3 in
CH2Cl2 at −1278 °C with the yields of 62%–68%. The reaction routes were outlined in Scheme 3.
The modified one-pot oxidation reaction shown as the Scheme 3 was more efficient and convenient in
preparing 1-substituted β-carbolines without the need of aromatization step or decarboxylation. Using
this modified Pictet-Spengler reaction, the target compounds Eudistomins Y1–Y7 23–29 were synthesized.
Scheme 3. The synthesis routes of Eudistomins Y1–Y7.
2.2. Biological Results and Discussion
The in vitro anti-proliferative activity of select compounds 16–29 was evaluated against the breast
carcinoma cell line MDA-231 using the 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) metabolic assay. Briefly, exponentially growing cells (1 × 103 cells) were seeded in 96-well
plates. After 18 h, cells were continuously treated with compounds 16–29. Following this, after 96 h, cell
survival was evaluated. The inhibitory activity (IC50) of the various compounds on cell proliferation was
determined (Table 1). Moderate anti-proliferative activity was observed with all the compounds tested.
Surprisingly, Eudistomins Y1–Y3 and Y5–Y7 with a hydroxyl group were found to have a poor cytotoxic
activity compared with their precursors 16–18 and 20–22. In summary, in vitro inhibitory activities of
methylated products were preferable to the demethylated products except for compounds 19 and 26.

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Table 1. Cytotoxicity of eudistomins Y1–Y7 23–29 and derivatives 16–22 (Scheme 3)
in vitro a (μM).
IC50 (μM) b
MDA-231 c
31.1
IC50 (μM) b
MDA-231 c
56.3
Compound
Compound
16
17
18
19
20
21
22
23
24
25
26
27
28
29
15.8
51.1
30.2
63.6
31.2
15.6
28.1
32.1
20.1
28.1
25.9
37.2
a Data represent the mean values of three independent determinations; b Cytotoxicity as IC50 for each cell line,
is the concentration of compound that causes a 50% growth inhibition to untreated cells using the MTT assay;
c Breast carcinoma cell lines MDA-231.
In order to determine the intracellular target of these compounds, the inhibitory activity of compound 26
was tested against various kinases in vitro. Briefly, human recombinant full-length kinases were
incubated in kinase buffer containing ATP and substrate (Poly Glu:Tyr) for 4 h at room temperature with
or without the presence of compounds 26 at 10 μM final concentration. Remaining ATP in solution was
then quantified utilizing the Kinase-Glo-luminescence kit (Promega). The ability of compound 26 to
inhibit the kinase activity of these kinases was evaluated (Table 2). As such, the anti-proliferative
activity of compound 26 does not seem to be significantly modulated by any of the kinases tested.
Table 2. Inhibitory kinase activity of compound 26 (10 μM) against various kinases.
Kinase
Aurora B
EGFR
MEK1
FAK
Src
Inhibition (%)
10
0
3
9
2
3. Experimental Section
3.1. Materials and Methods
The starting materials and reagents, purchased from commercial suppliers, were used without further
purification. All reactions were monitored by thin-layer chromatography (TLC), on aluminium sheets
(Silica gel 60-F254, E. Merck). Compounds were visualized by UV light. Column chromatography was
carried out using silica gel (200–300 mesh). All reaction solvents were dried prior to use according to
standard procedures. All primary reagents were commercially available. Silica gel chromatography
solvents were of analytical grade. Melting points were recorded on a micro melting point apparatus
MP-500D and were uncorrected. NMR spectra were recorded on a Jeol JNM-ECP spectrometer at
600 MHz for 1H NMR and 150 MHz for 13C NMR with TMS as the internal standard. Chemical shifts
are expressed in δ (ppm) and coupling constants (J) in Hz. Multiplicity is indicated as follows:
s (singlet), d (doublet), t (triplet), dd (doublet of doublets), brs (broad singlet), etc. Mass spectra were
recorded using a Q-TOF Ultima™ Global by chemical ionization.

Mar. Drugs 2013, 11
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3.2. General Procedure for Compounds 2a–c
In a separate tear-shaped flask under a nitrogen atmosphere, 40 mL of DMF was cooled to 0 °C ,
and then POCl3 (150 mmol) was added dropwise within 0.5 h under nitrogen. After the addition, stirring
was continued for 1.5 h at 0 °C. It was followed by addition of a solution of indole 1a–c (100 mmol) in
DMF (20 mL) below 0 °C within 1.5 h. Then the reaction solution was heated to 40 °C for another 2 h
and cooled to 0 °C. Subsequently, crushed ice (50 g) was added, and then the pH was adjusted to 8–9 by
adding NaOH solution (20%, w/w). The resulting reaction mixture was then heated at reflux for 12 h.
And then, the resulting suspension solution was cooled naturally to the room temperature and filtered
through celite to afford a white crude product. The crude product was purified by flash column
chromatography using silica gel as the stationary phase and using ethyl acetate/hexane (1:3) as the
mobile phase to provide the compounds 2a–c [8].
1H-Indole-3-carbaldehyde (2a): White solid; yield 96%; 1H NMR (600 MHz, CDCl3) δ 11.21 (brs,
1H), 10.04 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.21 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.30–7.23 (m, 2H); 13C
NMR (151 MHz, CDCl3) δ 184.6, 137.3, 124.7, 123.7, 122.2, 121.4, 119.2, 112.2.
1
6-Bromo-1H-indole-3-carbaldehyde (2b): White solid; yield 95%; H NMR (600 MHz, CDCl3) δ
11.33 (brs, 1H), 10.03 (s, 1H), 8.24 (s, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.39
13
(dd, J = 8.3, 1.8 Hz, 1H); C NMR (151 MHz, CDCl3) δ 184.7, 137.9, 125.3, 123.6, 122.9, 119.0,
116.5, 115.2.
1
5-Bromo-1H-indole-3-carbaldehyde (2c): White solid; yield 95%; H NMR (600 MHz, CDCl3) δ
11.36 (brs, 1H), 10.02 (s, 1H), 8.39 (d, J = 1.8 Hz, 1H), 8.26 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.40 (dd,
J = 8.7 Hz, 1.8 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 184.6, 138.2, 136.1, 126.5, 126.4, 123.8, 118.5,
115.3, 114.2.
3.3. General Procedure for Compounds 3a–c
To a solution of 1H-indole-3-carbaldehyde 2a–c (80 mmol) in CH3NO2 (80 mL), was added
ammonium acetate (40 mmol) and benzene (1.1 mL, 12.4 mmol). The reaction mixture was heated at
reflux for 12 h. After cooling to room temperature, some solvent was removed under reduced pressure
and filtered through Celite to afford a yellow crude product. The crude product was purified by flash
column chromatography using silica gel as the stationary phase and using ethyl acetate/hexane (1:2) as
the mobile phase to provide the compounds 3a–c [9].
1
(E)-3-(2-Nitrovinyl)-1H-indole (3a): Deep yellow solid; yield 92%; H NMR (600 MHz, CDCl3) δ
11.33 (brs, 1H), 8.39 (d, J = 13.3 Hz, 1H), 8.16 (d, J = 3.2 Hz, 1H), 7.97 (dd, J = 5.9, 2.3 Hz, 1H), 7.92 (d,
13
J = 13.3 Hz, 1H), 7.59 (dd, J = 5.9, 2.3 Hz, 1H), 7.32–7.29 (m, 2H); C NMR (151 MHz, CDCl3) δ
138.2, 135.1, 133.9, 131.9, 125.1, 123.6, 122.1, 120.5, 112.8, 108.8.
1
(E)-6-Bromo-3-(2-nitrovinyl)-1H-indole (3b): Deep yellow solid; yield 91%; H NMR (600 MHz,
CDCl3) δ 11.39 (brs, 1H), 8.36 (d, J = 13.3 Hz, 1H), 8.18 (s, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.91 (d,
J = 13.3 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H); 13C NMR (151 MHz,
CDCl3) δ 138.9, 135.4, 133.2, 132.7, 124.9, 124.1, 122.0, 116.5, 115.7, 108.8.

Mar. Drugs 2013, 11
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1
(E)-5-Bromo-3-(2-nitrovinyl)-1H-indole (3c): Deep yellow solid; yield 91%; H NMR (600 MHz,
CDCl3) δ 11.41 (brs, 1H), 8.35 (d, J = 13.7 Hz, 1H), 8.19 (s, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.97 (d,
J = 13.7 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.42 (dd, J = 8.7, 1.8 Hz, 1H); 13C NMR (151 MHz,
CDCl3) δ 136.7, 135.5, 133.0, 132.7, 126.8, 126.3, 122.9, 115.0, 114.5, 108.3.
3.4. General Procedure for Compounds 4a–c
To a solution of (E)-3-(2-nitrovinyl)-1H-indole 3a–c (20mmol) in THF (60 mL) and CH3OH
(9 mL), was added NaBH4 (40 mmol) in batch over 0.5 h. The above reaction solution was stirred at
room temperature for about 1 h and the completion of the reaction was monitored by TLC. Then water
(100 mL) and hydrochloric acid (100 mL, 10%, v/v) was added slowly. The resulting reaction mixture
was extracted with CH2Cl2 (30 mL × 3). The combined organic phase was washed with H2O (20 mL × 3)
and brine (20 mL × 3), dried over anhydrous MgSO4 and the solvent was removed under reduced
pressure. The residue was purified by flash column chromatography using silica gel as the stationary
phase and using ethyl acetate/hexane (1:3) as the mobile phase to provide the compounds 4a–c [10].
3-(2-Nitroethyl)-1H-indole (4a): Brown solid; yield 96%; 1H NMR (600 MHz, CDCl3) δ 8.09 (brs,
1H), 7.59 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.25 (t, J = 7.8, 7.3 Hz, 1H), 7.18 (t, J = 8.3,
13
7.3 Hz, 1H), 7.04 (s, 1H), 4.67 (t, J = 6.9 Hz, 2H), 3.49 (t, J = 6.9 Hz, 2H); C NMR (151 MHz,
CDCl3) δ 136.3, 126.7, 122.7, 122.6, 119.9, 118.2, 111.6, 110.0, 75.8, 23.7.
1
6-Bromo-3-(2-nitroethyl)-1H-indole (4b): Brown solid; yield 98%; H NMR (600 MHz, CDCl3) δ
8.13 (brs, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.24 (dd, J = 8.2, 1.8 Hz, 1H), 7.00 (d,
J = 1.8 Hz, 1H), 4.64 (t, J = 6.9 Hz, 2H), 3.49 (t, J = 6.9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 137.1,
125.7, 123.3, 123.2, 119.5, 116.1, 114.5, 110.3, 75.8, 23.5.
1
5-Bromo-3-(2-nitroethyl)-1H-indole (4c): Brown solid; yield 95%; H NMR (600 MHz, CDCl3) δ
8.18 (brs, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 8.7, 1.8 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.03 (d,
J = 1.8 Hz, 1H), 4.64 (t, J = 7.3 Hz, 2H), 3.41 (t, J = 7.3 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 134.9,
128.5, 125.4, 124.0, 120.8, 113.2, 113.1, 109.7, 75.7, 23.4.
2-(1H-indol-3-yl)ethanamine (5a): To a solution of 3-(2-nitroethyl)-1H-indole 4a (1.9 g, 10 mmol) in
methanol (30 mL), was added 10% Pd/C (0.08 g). H2 was passed in at room temperature, then
hydrogenated under normal pressure for 24 h. The completion of the reaction was monitored by TLC.
The reaction mixture was then filtered and evaporated under reduced pressure. The residue was
purified by flash column chromatography using silica gel as the stationary phase and using ethyl
acetate/methanol (10:1) as the mobile phase to provide 2-(1H-indol-3-yl)ethanamine 5a as an white
solid in a yield of 98%. 1H NMR (600 MHz, CDCl3) δ 11.04 (brs, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.42
(d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 7.11 (t, J = 7.8 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 2.89 (t, J = 6.8 Hz,
2H), 2.83 (t, J = 6.8 Hz, 2H), 2.70 (s, 2H); 13C NMR (151 MHz, CDCl3) δ 136.9, 127.9, 123.2, 121.4,
118.9, 113.0, 111.9, 43.1, 29.8.

Mar. Drugs 2013, 11
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3.5. General Procedure for Compounds 5b–c
To a solution of substituted 3-(2-nitroethyl)-1H-indole 4b–c (10 mmol) in THF (30 mL), was added
LiAlH4 (20 mmol) slowly. After the addition, it was heated at reflux for about 5 h. The completion of
the reaction was monitored by TLC. The mixture was allowed to cool to room temperature and
quenched by dropwise addition of saturated Na2SO4 solution. The resulting suspension mixture was
filtered through Celite, and the filtrate was extracted with EtOAc (30 mL × 3). The combined organic
phase was washed with H2O (20 mL × 3) and brine (20 mL × 3), dried over anhydrous MgSO4 and the
solvent was removed under reduced pressure. The residue was purified by flash column
chromatography using silica gel as the stationary phase and using ethyl acetate/methanol (10:1) as the
mobile phase to provide the compounds 5b–c as a gray solid [10].
2-(6-Bromo-1H-indol-3-yl)ethanamine (5b): White solid; yield 92%; 1H NMR (600 MHz, CDCl3) δ
11.08 (brs, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.18 (s, 1H), 7.09 (dd, J = 8.7,
1.8 Hz, 1H), 3.53 (s, 2H), 2.83 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H); 13C NMR (151 MHz, CDCl3)
δ 137.7, 126.9, 124.4, 121.5, 120.7, 114.5, 114.2, 113.1, 42.6, 28.7.
2-(5-Bromo-1H-indol-3-yl)ethanamine (5c): White solid; yield 88%; 1H NMR (600 MHz, CDCl3) δ
11.17 (brs, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.31–7.21 (m, 2H), 7.16 (s, 1H), 3.51 (s, 2H), 2.83 (t,
13
J = 6.4 Hz, 2H), 2.74 (t, J = 6.4 Hz, 2H); C NMR (151 MHz, CDCl3) δ 135.4, 129.7, 124.9, 124.0,
123.7, 121.1, 113.9, 111.2, 42.4, 28.5.
1-(3,5-Dibromo-4-hydroxyphenyl)ethanone (7): To a suspended mixture of 1-(4-hydroxyphenyl)
ethanone (4.08 g, 30 mmol) and deionized water (200 mL), was added N-Bromosuccinimide (8.01 g,
45 mmol). The reaction mixture was heated to 60 °C, then 40% (v/v) H2SO4 (20 mL) was added. After
stirred for about 10 h and the completion of the reaction was monitored by TLC, the reaction mixture
was filtered through Celite to afford a white crude product. The crude product was purified by flash
column chromatography using silica gel as the stationary phase and using ethyl acetate/hexane (1:3) as
the mobile phase to provide a compound 1-(3,5-dibromo-4-hydroxyphenyl)ethanone (7) as a white
solid in the yield of 92%.
1-(3,5-Dibromo-4-methoxyphenyl)ethanone (8): To a solution of 7 (20 mmol) in anhydrous acetone
(50 mL) were added potassium carbonate (30.0 mmol) and dimethyl sulfate (2.84 mL, 30.0 mmol), and
refluxed for 2 h. After cooled to room temperature, the reaction mixture was filtered through Celite,
and the filtrate was concentrated under vacuum. The residue was purified by flash column
chromatography using silica gel as the stationary phase and using ethyl acetate/hexane (1:2) as the
1
mobile phase to provide the desired compound 8 as a white solid in the yield of 95%. H NMR
13
(600 MHz, CDCl3) δ 8.08 (s, 2H), 3.93 (s, 3H), 2.56 (s, 3H); C NMR (151 MHz, CDCl3) δ 194.5,
158.1, 135.1, 133.0, 118.7, 60.9, 26.6.
3.6. General Procedure for Compounds 9, 11, 15
To a solution of dioxane/deionized water (20:1) (30 mL) was added SeO2 (12 mmol). The mixture
was heated to 80 °C and stirred until the solid dissolved. It was followed by addition of substituted
phenylethanone 8, 10, 14 (10 mmol), and was refluxed for about 12 h and the completion of the

Mar. Drugs 2013, 11
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reaction was monitored by TLC. The hot solution was filtered through Celite, and the filtrate was
concentrated under vacuum. The residue was purified by flash column chromatography using silica gel
as the stationary phase and using ethyl acetate/hexane (1:3) as the mobile phase to provide the desired
compound 9, 11, 15 [11].
2-(3,5-Dibromo-4-methoxyphenyl)-2-oxoacetaldehyde (9): Light brown solid; yield 71%; 1H NMR
(600 MHz, CDCl3) δ 9.42 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 3.85 (s, 3H); 13C NMR (151 MHz,
CDCl3) δ 193.6, 191.9, 157.9, 134.5, 132.3, 118.3, 61.2.
1
2-(4-Methoxyphenyl)-2-oxoacetaldehyde (11): Light brown solid; yield 75%; H NMR (600 MHz,
CDCl3) δ 9.53 (s, 1H), 8.06 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H); 13C NMR
(151 MHz, CDCl3) δ 195.2, 192.5, 164.0, 132.4, 126.7, 114.4, 56.1.
1
2-(3-Bromo-4-methoxyphenyl)-2-oxoacetaldehyde (15): Light brown solid; yield 74%; H NMR
(600 MHz, CDCl3) δ 9.43 (s, 1H), 8.28 (s, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 3.93
(s, 3H); 13C NMR (151 MHz, CDCl3) δ 194.4, 192.6, 159.9, 134.8, 131.7, 127.8, 112.7, 110.9, 57.2.
1-(3-Bromo-4-methoxyphenyl)ethanone (14): To a suspension mixture of anhydrous AlCl3 (3.0 g,
22.5 mmol) in CS2 (50 mL) , was added 1-bromo-2-methoxybenzene (2.79 g, 15 mmol). The above
mixture was maintained at room temperature and stirred for 0.5 h, and then acetyl chloride (1.6 mL,
22.5 mol) was added dropwise. After the addition, stirring was continued for another 0.5 h. And then,
the reaction mixture was refluxed for 2 h. After cooled to room temperature, it was poured into 80 mL
of ice-water containing 20 mL of concentrated hydrochloric acid and stirred to reach room
temperature. The mixture was extracted with CH2Cl2 (20 mL × 3). The combined organic phase was
washed with H2O (20 mL × 3), 10% aqueous NaOH (10 mL × 2), H2O (20 mL × 3) and brine (20 mL × 3),
dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The residue was
purified by recrystallization from petroleum ether (20 mL) to afford 1-(3-bromo-4-methoxyphenyl)
ethanone (14) as a brown solid in the yield of 76%.
3.7. General Procedure for Compounds 16–22
To a solution of substituted phenylglyoxal 9, 11, 15 (3 mmol) in AcOH (30 mL), was added
substituted tryptamine 5a–d (3 mmol). The above mixture was heated at 90 °C for 10 h, then cooled and
adjusted pH to 5 by adding concentrated ammonium hydroxide. The resulting mixture was diluted with
100 mL of water and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with
H2O (20 mL × 3) and brine (20 mL × 3), dried over anhydrous MgSO4 and the solvent was removed
under reduced pressure. The residue was purified by flash column chromatography using silica gel as
the stationary phase and using ethyl acetate/hexane (1:3) as the mobile phase to provide the desired
compounds 16–22.
(4-Methoxyphenyl)(9H-pyrido[3,4-b]indol-1-yl)methanone (16): Yellow solid; yield 35%; mp
182–183 °C; 1H NMR (600 MHz, CDCl3) δ 10.46 (brs, 1H), 8.60 (d, J = 5.0 Hz, 1H), 8.45 (d, J = 8.7 Hz,
2H), 8.17 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 5.0 Hz, 1H), 7.62–7.58 (m, 2H), 7.34 (t, J = 7.8 Hz, 1H), 7.03 (d,
J = 8.7 Hz, 2H), 3.91 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 193.7, 163.4, 141.1, 138.0, 137.4, 137.1,

Mar. Drugs 2013, 11
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134.0, 131.7, 130.4, 129.4, 122.0, 121.0, 120.8, 118.4, 113.6, 112.1, 55.7; HRMS: m/z calcd. for
+
C19H15N2O2 , 303.1133; found: 303.1130.
(6-Bromo-9H-pyrido[3,4-b]indol-1-yl)(4-methoxyphenyl)methanone (17): Yellow solid; yield 36%;
1
mp 194–195 °C; H NMR (600 MHz, CDCl3) δ 10.48 (brs, 1H), 8.62 (d, J = 5.0 Hz, 1H), 8.45 (d,
J = 8.7 Hz, 2H), 8.29 (d, J = 1.8 Hz, 1H), 8.10 (d, J = 5.0 Hz, 1H), 7.68 (dd, J = 8.7, 1.8 Hz, 1H), 7.48 (d,
J = 8.7 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 3.92 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 193.4, 163.5,
139.7, 138.3, 137.6, 137.4, 134.0, 132.1, 130.5, 130.1, 124.7, 122.8, 120.8, 118.5, 113.6, 113.5, 55.7;
HRMS: m/z calcd. for C19H14N2O2Br+, 381.0239; found: 381.0237.
(3-Bromo-4-methoxyphenyl)(9H-pyrido[3,4-b]indol-1-yl)methanone (18): Yellow solid; yield 36%;
1
mp 192–193 °C; H NMR (600 MHz, CDCl3) δ 10.40 (brs, 1H), 8.69 (d, J = 1.8 Hz, 1H), 8.59 (d,
J = 5.0 Hz, 1H), 8.49 (dd, J = 8.7, 2.2 Hz, 1H), 8.15 (m, 2H), 7.60 (m, 2H), 7.35–7.33 (m, 1H), 7.01 (d,
13
J = 8.7 Hz, 1H), 3.99 (s, 3H); C NMR (151 MHz, CDCl3) δ 192.2, 159.4, 141.1, 138.1, 137.5, 136.9,
136.5, 133.1, 131.8, 131.4, 129.5, 122.0, 120.9, 118.7, 112.2, 111.5, 110.9, 56.6; HRMS: m/z calcd. for
C19H14N2O2Br+, 381.0239; found: 381.0220.
(3-Bromo-4-methoxyphenyl)(6-bromo-9H-pyrido[3,4-b]indol-1-yl)methanone (19): Yellow solid;
1
yield 31%; mp 195–196 °C; H NMR (600 MHz, CDCl3) δ 10.50 (brs, 1H), 8.68 (d, J = 1.8 Hz, 1H),
8.59 (d, J = 5.0 Hz, 1H), 8.47 (dd, J = 8.7, 2.2 Hz, 1H), 8.26 (s, 1H), 8.08 (d, J = 5.0 Hz, 1H), 7.66 (dd,
J = 8.7, 2.2 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H); 13C NMR (151 MHz,
CDCl3) δ 191.9, 159.5, 139.6, 138.3, 137.5, 136.8, 133.2, 132.2, 131.1, 130.7, 124.7, 122.7, 118.7,
+
113.6, 111.5, 110.9, 56.6; HRMS: m/z calcd. for C19H13N2O2Br2 , 458.9344; found: 458.9327.
(3,5-Dibromo-4-methoxyphenyl)(9H-pyrido[3,4-b]indol-1-yl)methanone (20): Yellow solid; yield
1
38%; mp 197–198 °C; H NMR (600 MHz, CDCl3) δ 10.38 (brs, 1H), 8.62 (d, J = 5.0 Hz, 1H), 8.59 (s,
1H), 8.20–8.18 (m, 1H), 7.65–7.62 (m, 2H), 7.38–7.36 (m, 1H), 3.98 (s, 3H); 13C NMR (151 MHz, CDCl3)
δ 191.5, 157.5, 141.2, 138.4, 137.5, 136.0, 135.6, 132.1, 129.7, 122.1, 121.2, 120.9, 119.2, 118.1,
+
112.2, 60.9; HRMS: m/z calcd. for C19H13N2O2Br2 , 458.9344; found: 458.9333.
(6-Bromo-9H-pyrido[3,4-b]indol-1-yl)(3,5-dibromo-4-methoxyphenyl)methanone (21): Yellow solid;
1
yield 35%; mp 234–235 °C; H NMR (600 MHz, CDCl3) δ 10.41 (brs, 1H), 8.64 (d, J = 5.0 Hz, 1H),
8.60 (s, 2H), 8.32 (d, J = 1.8 Hz, 1H), 8,16 (d, J = 5.0 Hz, 1H), 7.72 (dd, J = 8.7, 1.8 Hz, 1H), 7.52 (d,
13
J = 8.7 Hz, 1H), 3.99 (s, 3H); C NMR (151 MHz, CDCl3) δ 191.3, 157.6, 139.7, 138.7, 137.6, 136.1,
135.4, 134.1, 132.5, 131.0, 124.9, 122.7, 119.3, 118.1, 114.0, 113.8, 60.9; HRMS: m/z calcd. for
+
C19H12N2O2Br3 , 536.8449; found: 536.8442.
(7-Bromo-9H-pyrido[3,4-b]indol-1-yl)(3,5-dibromo-4-methoxyphenyl)methanone (22): Yellow solid;
1
yield 36%; mp 216–217 °C; H NMR (600 MHz, CDCl3) δ 10.38 (brs, 1H), 8.63 (d, J = 5.0 Hz, 1H),
8.59 (s, 2H), 8,16 (d, J = 5.0 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.48 (dd, J = 8.7,
1.8 Hz, 1H), 3.98 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 191.3, 157.7, 141.9, 138.9, 137.5, 136.1,
135.4, 131.5, 124.7, 123.5, 123.2, 119.9, 119.1, 118.1 115.4, 60.9; HRMS: m/z calcd. for
+
C19H12N2O2Br3 , 536.8449; found: 536.8464.

Mar. Drugs 2013, 11
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3.8. General Procedure for Compounds 23–29
To a solution of the compounds 16–22 (0.5 mmol) in CH2Cl2 (10mL) at −78 °C under argon
atmosphere, was slowly added dropwise BBr3 (5 mmol). The reaction mixture was stirred and warmed
to r.t. and stirred for 24 h. NaOH solution (5 mL, 2 mol/L) was then slowly added dropwise. After
addition, a short period of stirring was continued, and then the solution was acidified with hydrochloric
acid (20 mL, 2 mol/L), followed by extraction with CH2Cl2 (30 mL × 3). The combined organic phase
was washed with H2O (20 mL × 3) and brine (20 mL × 3), dried over anhydrous MgSO4 and the solvent
was removed under reduced pressure. The residue was purified by flash column chromatography using
silica gel as the stationary phase and using ethyl acetate/hexane (1:3) as the mobile phase to provide
the desired compounds eudistomins Y1–Y7 23–29.
(4-Hydroxyphenyl)(9H-pyrido[3,4-b]indol-1-yl)methanone (Eudistomins Y1 23): Yellow solid;
1
yield 65%; mp 217–218 °C; H NMR (600 MHz, acetone-d6) δ 11.30(s, 1H), 9.26 (s, 1H), 8.56 (d,
J = 5.0 Hz, 1H), 8.47 (d, J = 8.8 Hz, 2H), 8.38 (d, J = 5.0 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 7.88 (d,
J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7. 34 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H); 13C NMR
(151 MHz, acetone-d6) δ 192.0, 163.1, 142.5, 139.0, 138.4, 137.6, 135.0, 131.0, 130.2, 129.4, 122.7,
−
122.1, 121.3, 119.7, 115.6, 113.5; HRMS: m/z calcd. for C18H11N2O2 , 287.0821; found: 287.0830.
(6-Bromo-9H-pyrido[3,4-b]indol-1-yl)(4-hydroxyphenyl)methanone (Eudistomins Y2 24): Yellow
1
solid; yield 68%; mp 247–248 °C; H NMR (600 MHz, acetone-d6) δ 11.46 (s, 1H), 9.30 (s, 1H), 8.60
(d, J = 5.0 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.47 (d, J =8.8 Hz, 2H), 8.43 (d, J = 5.0 Hz, 1H),
13
7.88 (d, J = 8.8 Hz, 1H), 7.76 (dd, J = 8.8, 1.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H); C NMR (151 MHz,
acetone-d6) δ 192.2, 162.8, 141.1, 139.0, 138.5, 137.5, 135.1, 132.3, 131.1, 130.0, 125.4, 123.5, 119.1,
115.5, 113.5, 112.0; HRMS: m/z calcd. for C18H10N2O2Br−, 364.9926; found: 364.9925.
(3-Bromo-4-hydroxyphenyl)(9H-pyrido[3,4-b]indol-1-yl)methanone (Eudistomins Y3 25): Yellow
1
solid; yield 63%; mp 231–232 °C; H NMR (600 MHz, DMSO-d6) δ 11.99 (s, 1H), 11.28 (s, 1H), 8.57
(d, J = 2.2 Hz, 1H), 8.54 (d, J = 4.4 Hz, 1H), 8.43 (d, J = 4.4 Hz, 1H), 8.32 (d, J = 7.7 Hz, 1H), 8.24 (dd,
J = 8.8, 2.2 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.13 (d,
J = 7.7 Hz, 1H); 13C NMR (151 MHz, DMSO-d6) δ 190.1, 158.2, 141.6, 137.0, 136.7, 136.4, 135.8,
132.5, 131.0, 129.6, 128.9, 121.8, 120.1, 120.0, 118.7, 115.6, 112.9, 108.8; HRMS: m/z calcd. for
C18H10N2O2Br−, 364.9926; found: 364.9932.
(3-Bromo-4-hydroxyphenyl)(6-bromo-9H-pyrido[3,4-b]indol-1-yl)methanone (Eudistomins Y4 26):
1
Yellow solid; yield 66%; mp 265–266 °C; H NMR (600 MHz, DMSO-d6) δ 12.13 (s, 1H), 11.30 (s,
1H), 8.61 (s, 1H), 8.57 (d, J = 5.5 Hz, 1H), 8.56 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.23 (dd, J = 8.8,
2.2 Hz, 1H), 7.75–7.72 (m, 1H), 7.13 (d, J = 8.8 Hz, 1H); 13C NMR (151 MHz, DMSO-d6) δ 189.9,
158.3, 140.3, 137.3, 137.1, 136.4, 135.9, 132.5, 131.4, 129.9, 129.4, 124.5, 122.0, 119.1, 115.6, 114.9,
−
112.2, 108.8; HRMS: m/z calcd. for C18H9N2O2Br2 , 442.9031; found: 442.9012.
(3,5-Dibromo-4-hydroxyphenyl)(9H-pyrido[3,4-b]indol-1-yl)methanone (Eudistomins Y5 27): Yellow
solid; yield 66%; mp 267–268 °C; 1H NMR (600 MHz, DMSO-d6) δ 12.04 (s, 1H), 10.96 (s, 1H), 8.57
(d, J = 5.5 Hz, 1H), 8.54 (s, 2H), 8.47 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 7.3 Hz, 1H), 7.81 (d,
J = 8.2 Hz, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H); 13C NMR (151 MHz, DMSO-d6) δ

Mar. Drugs 2013, 11
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188.9, 154.5, 141.7, 137.1, 136.0, 135.9, 135.4, 131.2, 131.0, 129.0, 121.9, 120.3, 120.0, 119.1, 113.0,
−
110.9; HRMS: m/z calcd. for C18H9N2O2Br2 , 442.9031; found: 442.9030.
(6-Bromo-9H-pyrido[3,4-b]indol-1-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (Eudistomins Y6 28):
Yellow solid; yield 62%; mp 277–278 °C; 1H NMR (600 MHz, DMSO-d6) δ 12.16 (s, 1H), 10.97 (brs,
1H), 8.61 (s, 1H), 8.59 (d, J = 4.4 Hz, 1H), 8.52 (s, 2H), 8.51 (d, J = 4.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H),
7.73 (dd, J = 8.8, 2.2 Hz, 1H); 13C NMR (151 MHz, DMSO-d6) δ 188.8, 154.6, 140.4, 137.4, 136.4,
136.0, 135.4, 131.5, 130.8, 130.1, 124.5, 122.0, 119.6, 115.0, 112.3, 110.9; HRMS: m/z calcd. for
−
C18H8N2O2Br3 , 520.8136; found: 520.8134.
(7-Bromo-9H-pyrido[3,4-b]indol-1-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (Eudistomins Y7 29):
Yellow solid; yield 62%; mp 297–298 °C; 1H NMR (600 MHz, DMSO-d6) δ 12.11 (s, 1H), 10.96 (brs,
1H), 8.58 (d, J = 4.6 Hz, 1H), 8.53 (s, 2H), 8.46 (d, J = 4.6 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.97 (d,
13
J = 1.8 Hz, 1H), 7.45 (dd, J = 8.2, 1.8 Hz, 1H); C NMR (151 MHz, DMSO-d6) δ 188.8, 154.6, 142.5,
137.7, 136.3, 136.0, 135.4, 130.8, 130.6, 123.7, 123.2, 121.8, 119.2, 115.6, 110.8; HRMS: m/z calcd. for
−
C18H8N2O2Br3 , 520.8136; found: 520.8141.
4. Conclusion
In summary, we reported the synthesis of the natural β-carboline alkaloid Eudistomins Y1–Y7 using
the modified Pictet-Spengler reaction in a one-pot process. The preliminary biological activities of the
target marine alkaloids and their methylated productions 16–22 were studied.
Acknowledgments
This work was supported by Natural Science Foundation of China (Grant No. 21171154) and Special
Fund for Marine Scientific Research in the Public Interest (01005024).
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