Efficient Preparation of Alkaloids Polycarpine and Polycarpaurines A and C

Article abstract of DOI:10.1002/jhet.2549

An efficient method for the preparation of alkaloids polycarpine and polycarpaurines A and C via microwave-assisted three-step one-pot reaction as the key step has been developed. This is the first report about the synthesis of polycarpaurines A and C. Starting from commercially available p-methoxybenzaldehyde, polycarpine and polycarpaurine A were obtained over seven steps with 40 and 24 % overall yield, respectively. Polycarpine could convert to polycarpaurine C in 72% yield in the presence of NaHSO₃. The structure of polycarpine and polycarpaurines A and C was confirmed by¹H NMR,¹³C NMR, and HRMS.

Full text of DOI:10.1002/jhet.2549

Month 2015 Efficient Preparation of Alkaloids Polycarpine and Polycarpaurines A and C
a,b†
Shuang Yan, Zeliang Hu, Weihui Zhuang, bYan Xiong, Lanya Zhang, Ziwen Wang,a,b*
a†
a†
a†
a†
a†
Pengbin Guo,
and Qingmin Wang *
a
Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Key Laboratory of Inorganic-Organic
Hybrid Functional Material Chemistry, Ministry of Education, College of Chemistry, Tianjin Normal University,
Tianjin 300387, China
b
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
*
E-mail: wangziwen2725@163.com; wangqm@nankai.edu.cn
†
These authors contributed equally to this paper
Additional Supporting Information may be found in the online version of this article.
Received July 8, 2015
DOI 10.1002/jhet.2549
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
An efficient method for the preparation of alkaloids polycarpine and polycarpaurines A and C via
microwave-assisted three-step one-pot reaction as the key step has been developed. This is the first report
about the synthesis of polycarpaurines A and C. Starting from commercially available p-methoxy
benzaldehyde, polycarpine and polycarpaurine A were obtained over seven steps with 40 and 24 % overall
yield, respectively. Polycarpine could convert to polycarpaurine C in 72% yield in the presence of NaHSO .
3
1
13
The structure of polycarpine and polycarpaurines A and C was confirmed by H NMR, C NMR, and HRMS.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
an Indonesian ascidian P. aurata, are another two interest-
ing sulfur-containing 2-aminoimidazole alkaloids [15].
Polycarpine (1) is attracting considerable interest, not
only because of its high biological activity but also as the
first representative of a new structural type of alkaloid from
an ascidian. In spite of a wide variety of metabolites
isolated earlier from different ascidians, compounds con-
taining 2-aminoimidazole cycles linked by a disulfide
bridge were not among the sulfur-containing metabolites.
As a continuation of the previous work for discovery of
bioactive compounds from nature product, polycarpine (1)
and polycarpaurines A (2) and C (3) were selected as
interesting lead compounds. Only one route for the synthe-
sis of polycarpine (1) has been reported till now [14].
However, the given report had no experiment details.
Although a high yield was given, it is difficult to repeat.
There is no report about the synthesis of polycarpaurines
A (2) and C (3) as far as we know.
Marine natural products are important lead compounds
for the development of novel drugs. The natural product-
based drugs can sometimes be specific to a target species
and have unique mode of action with low toxicity in mam-
malian [1–3]. Many interesting sulfur-containing marine
alkaloids have been isolated from ascidians [4]. These
compounds displayed various biological activities, such
as cytotoxicity [5,6], anti-HIV activity [7], immunosup-
pressive activity [8], antibacterial activity [9], antifungal
activity [10], and enzyme inhibitory activity [11,12]. One
of such promising alkaloids is polycarpine (1, Fig. 1),
isolated from the ascidian Polycarpa aurata collected at
Flinders Reef (Coral Sea) [13]. This compound was
previously found to be active in vitro and in vivo against
a wide range of human and murine tumors [14,15].
Polycarpaurines A and C (2 and 3, Fig. 1), isolated from
©
2015 HeteroCorporation

P. Guo, S. Yan, Z. Hu, W. Zhuang, Y. Xiong, L. Zhang, Z. Wang, and Q. Wang
Vol 000
Figure 1. Structures of alkaloids polycarpine (1), polycarpaurines A (2) and C (3).
Using microwave irradiation to carry out reactions is a
growing popularity and hence becoming an attractive
method for chemical synthesis [16–20]. It involves neat
reactants to be exposed to microwave irradiation so as to
acquire greater selectivity and achieve high yields within
a short reaction time and with ease in experimentation.
Here, we report the efficient method for the prepara-
tion of alkaloids polycarpine and polycarpaurines A and
C via microwave assisted three-step one-pot reaction as
the key step.
in higher yield when the reaction was carried out at 0°C for
1.5 h with Br as the bromination agent and 1,4-dioxane
2
and dichloromethane (v/v, 1/2) as the solvents. The addi-
tion of concentrated HCl can efficiently inhibit further bro-
mination of bromide 9. As bromide 9 is unstable at room
temperature, it was used for the next step directly with no
further separation. Condensation of 9 and pyrimidine 10
[21] under microwave condition gave intermediate 11,
which was converted to 12 rapidly. Then hydrolysis of
12 with 80% N H · H O gave 2-aminoimidazole 13 in
2
4
2
6
8% yield over three steps from aldehyde 8. Oxidative
coupling of 13 gave the alkaloid polycarpine (1) in 91%
yield. Although this step has been reported by Novikov
and co-authors [14], the experiment details were not given.
The ratio of S Cl and 2-aminoimidazole 13 is the critical
RESULTS AND DISCUSSION
As shown in Scheme 1, following Darzens reaction,
hydrolysis reaction, and decarboxylation reaction, 4-meth
oxyphenylacetaldehyde (8) was obtained with 64% yield
over three steps from p-methoxybenzaldehyde (4). The
bromination of 8 was carried out under numerous condi-
tions with GC as the detector. The bromide 9 was obtained
2
2
factor of the reaction. When the ratio of S Cl and 2-
2
2
aminoimidazole 13 is lower than 1/2, polycarpaurine A
1
(2) was detected as byproduct by H NMR and HRMS.
As the molecular polarity of polycarpine (1) and
polycarpaurine A (2) is similar, they cannot be separated
Scheme 1. Synthesis of polycarpine (1).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Polycarpine and Polycarpaurines A and C
Scheme 2. Synthesis of polycarpaurine A (2).
downfield from internal tetramethylsilane. High-resolution
mass spectra were obtained with an FT-ICR MS spectrom-
eter (Ionspec, 7.0 T). Microwave instrument: CEM Fo-
™
cused Microwave Synthesis System, Discover, S-Class.
Synthesis of 4-methoxyphenylacetaldehyde (8). To the
solution of p-methoxybenzaldehyde (4, 13.6g, 0.10 mol)
and methyl chloroacetate (5, 16.3g, 0.15 mol) in ethyl
alcohol (70 mL) was added dropwise the solution of
sodium methylate (30%, 27.0 g, 0.15 mol) in ethyl
alcohol (70 mL) at 15°C, and the mixture was stirred for
4 h. Then, the reaction mixture was added to the solution
of KOH (8.4g, 0.15 mol) in ethyl alcohol (100 mL) at 15°C,
and the mixture was stirred for further 5 h at 15°C and
stood for 3 h at 0°C. The mixture was filtered to give
potassium salt 7 as a white solid.
by column chromatography on silica gel. When the ratio of
S Cl and 2-aminoimidazole 13 is more than 1/2, the
2
2
byproduct polycarpaurine A (2) can be avoid. When the
ratio rises to 0.55, polycarpine (1) was obtained in 91%
yield. As shown in Scheme 2, replacing of S Cl with
2
2
SCl , polycarpaurine A (2) was obtained in 56% yield by
To the solution of the mentioned potassium salt 7 earlier
2
using similar procedure for the preparation of polycarpine
in H O (150 mL) and dichloromethane (150mL) was
2
(
1). The introduction of S SO H group is very difficult.
added KH PO (14.0g, 0.10mol), and the mixture was
2
3
2
4
For the preparation of polycarpaurine C (3), we found that
stirred at room temperature for 4 h and separated. The
aqueous phase was washed with dichloromethane
(3 × 80mL). The combined organic phase was washed with
NaHSO can efficiently disrupt the SS bond of polycarpine
3
(
1) to give polycarpaurine C (3) in 72% yield (Scheme 3).
In summary, the efficient preparation of alkaloids
H O (3 ×100 mL) and brine (3× 100mL), dried over
2
polycarpine and polycarpaurines A and C has been accom-
plished. This is the first report about the synthesis of
polycarpaurines A and C. Polycarpine can convert to
polycarpaurine C in 72% yield in the presence of NaHSO3.
The structure of polycarpine and polycarpaurines A and C
were confirmed by H NMR, C NMR, and HRMS.
Present study provides fundamental support for the further
SAR studies of these alkaloids.
MgSO , and concentrated to afford 4-methoxyphenylace
4
taldehyde (8, 9.6 g, 64% yield over three steps from 4) as
1
a yellow oil. H NMR (400 MHz, CDCl ): δ 9.72 (s, 1H,
3
CHO), 7.13 (d, J= 8.7 Hz, 2H, Ar-H), 6.90 (d, J =8.7 Hz,
2H, Ar-H), 3.80 (s, 3H, OMe), 3.62 (d, J= 2.3Hz, 2H,
1
13
Ar-CH ) ppm.
2
Synthesis of 4-(4-methoxyphenyl)-1-methyl-1H-imidazol-2-
amine (13).
To the solution of aldehyde (8, 2.0 g,
3.3 mmol), concentrated HCl (1 d) in 1,4-dioxane
15 mL) and dichloromethane (15 mL) was added the
solution of Br (2.13g, 13.3mmol) in dichloromethane
1
(
EXPERIMENTAL
2
(15 mL) at 0°C (about 1 h complete the addition), and the
Reagents were purchased from commercial sources and
were used as received. Reaction progress was monitored
by GC or thin-layer chromatography on silica gel GF-254
with detection by UV. Melting points were determined
on an X-4 binocular microscope melting point apparatus
mixture was stirred at 0°C for further 0.5h.
Dichloromethane (80 mL) was added, and the mixture
was washed with saturated NaHCO solution (100mL),
3
saturated Na S O
2 3
solution (100mL), and brine
2
(100 mL); then dried with anhydrous MgSO ; and
4
(
Beijing Tech Instruments Co., Beijing, China) and were
concentrated in vacuo to give bromide 9.
1
uncorrected. H NMR spectra were obtained by using
Bruker AV 400 spectrometer. Chemical shifts (δ) were
given in parts per million (ppm) and were measured
To a 35-mL vessel was added the aforementioned bro-
mide 7, 2-methylaminopyrimidine (9, 1.45g, 13.3 mmol)
and acetonitrile (15 mL). The reaction vessel was sealed
Scheme 3. Synthesis of polycarpaurine C (3).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. Guo, S. Yan, Z. Hu, W. Zhuang, Y. Xiong, L. Zhang, Z. Wang, and Q. Wang
Vol 000
and placed into microwave instrument and stirred under the
conditions of 150W and 150°C for 30min and then cooled
to room temperature and added 80% hydrazine hydrate
129.2, 119.8, 114.7, 113.8, 55.2, 29.6. HRMS (ESI)
+
1 14 3 4 2
+
Calcd. for C H N O S [M + H] : 316.0420. Found:
1
316.0410.
(4.17g, 66.7mmol). The mixture was stirred under the
conditions of 100W and 100°C for further 10min and con-
centrated in vacuo. The residue was purified by column
chromatography on silica gel (CH Cl /CH OH 20/1 as el-
Acknowledgments. We gratefully acknowledge assistance from
National Natural Science Foundation of China (21132003,
2
2
3
uent) to give compound 13 (1.8 g, 68% yield over three
2
1421062, 21372131, 21402142), Tianjin Natural Science
1
steps from 8) as a slight yellow solid, mp 148–150°C; H
Foundation (15JCQNJC05600), the college students’ innovative
project of Tianjin Normal University (201414), Scientific
Research Foundation of Tianjin Normal University (5RL125),
and Specialized Research Fund for the Doctoral Program of
Higher Education (20130031110017).
NMR (400 MHz, CDCl ): δ 7.57 (d, J = 8.4 Hz, 2H,
3
Ar-H), 6.88 (d, J= 8.4Hz, 2H, Ar-H), 6.71 (s, 1H, Ar-H),
4
.00 (br, 2H, NH ), 3.81 (s, 3H, OMe), 3.44 (s, 3H,
2
+
NMe) ppm. HRMS (ESI) Calcd. for C H N O (M+H) :
11 14 3
2
04.1131. Found: 204.1135.
Synthesis of polycarpine (1). The solution of compound
3 (1 g, 4.93mmol) and S Cl (0.37 g, 2.71 mmol) in acetic
1
2
2
REFERENCES AND NOTES
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3
3
6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet