Total synthesis of aristogin C in aqueous systems

Article abstract of DOI:10.1080/00397910600941125

Aristogin C (4), a new diaryl either isolated from the leaves of Aristolochia elegans, was synthesized through a three-step procedure with readily available materials. All of the three reactions were carried out in aqueous systems. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600941125

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Total Synthesis of Aristogin C in Aqueous
Systems
Hong‐Yun Gao a b & Cheng‐Yong Ha a
a Key Laboratory of Cellulose and Lignocellulosics Chemistry , Guangzhou
Institute of Chemistry, Chinese Academy of Sciences , Guangzhou, China
b Graduate School of the Chinese Academy of Sciences , Beijing, China
Published online: 23 Nov 2006.
To cite this article: Hong‐Yun Gao & Cheng‐Yong Ha (2006) Total Synthesis of Aristogin C in Aqueous Systems,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
36:22, 3283-3286, DOI: 10.1080/00397910600941125
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Synthetic Communicationsw, 36: 3283–3286, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600941125
Total Synthesis of Aristogin C
in Aqueous Systems
Hong-Yun Gao
Key Laboratory of Cellulose and Lignocellulosics Chemistry, Guangzhou
Institute of Chemistry, Chinese Academy of Sciences, Guangzhou, China
and Graduate School of the Chinese Academy of Sciences, Beijing, China
Cheng-Yong Ha
Key Laboratory of Cellulose and Lignocellulosics Chemistry, Guangzhou
Institute of Chemistry, Chinese Academy of Sciences, Guangzhou, China
Abstract: Aristogin C (4), a new diaryl either isolated from the leaves of Aristolochia
elegans, was synthesized through a three-step procedure with readily available
materials. All of the three reactions were carried out in aqueous systems.
Keywords: Aqueous system, aristogin C, total synthesis
INTRODUCTION
In a continuing search for novel bioactive compounds from the genus
Aristolochia, aristogin C (4), a new biphenyl ether, was isolated from the
leaves of Aristolochia elegans.[1] The structure of 4, elucidated by spectro-
scopic (NMR and MS) analyses, has a diaryl ether structural unit. This struc-
tural unit is presented in numerous naturally occurring products and is also
prevalent in numerous weed-killing chemicals. A number of compounds con-
taining this structural unit had been reported to have significant biological
activity.[2] We are interested in the bioactivity of compound 4; however, its
Received in R.O.C. February 9, 2006
Address correspondence to Cheng-Yong Ha, Key Laboratory of Cellulose and
Lignocellulosics Chemistry, Guangzhou Institute of Chemistry, Chinese Academy of
Sciences, Guangzhou 510650, China. E-mail: cyha@gic.ac.cn
3283

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H.-Y. Gao and C.-Y. Ha
bioactivity was not reported. Thus, to obtain a larger quantity of 4, a synthetic
way needed to be established.
An important area of green chemistry investigations has centered around
the selection of a medium in which to carry out a synthetic transformation.
Aqueous systems have been investigated for reasons of efficacy and selectivity
over the years, and that work has provided an excellent basis for the use of
these systems as environmentally benign solvents.[3] Herein we describe the
first total synthesis of 4 in aqueous systems through a three-step procedure
with readily available materials.
RESULTS AND DISCUSSION
Our retrosynthetic analysis of the target molecule 4 relied upon the creation of
the diaryl ether bond by means of Ullmann[4] condensation. In the context of
bromination[5] regioselective control, this bromination process relied on the
use and proper choice of the reagents and conditions to deliver the anticipated
mono-bromine substitute product, methyl 3-bromoanisate 3. Methyl p-anisate
2 was generated from readily available methyl p-hydroxybenzoate 1 by
methyl etheration.[6]
The synthetic sequence starting from 1 is depicted in Scheme 1. Firstly,
methyl etheration of phenol 1 with 0.95 eq. of dimethyl sulfate in the presence
of KOH aqueous solution furnished methyl p-anisate 2 in 90% yield. Then
methyl 3-bromoanisate 3 was achieved in 88% yield by treatment 2 with Br2/
KBrO3 (3: 1) at room temperature in H2O, and no dibrominated product 5 was
detected. The system of bromination with Br2/KBrO3 was designed to prevent
HBr gas from emitting. Finally, aristogin C (4) was obtained by the Ullmann
Scheme 1. Reagents and conditions: a) Me2SO4 (0.95 mol eq.), KOH (1 mol eq.), H2O,
MeOH, rt, 1 h : b) Br2 (0.5 mol eq.), KBrO3 (0.17 mol eq.), H2O, rt, 2.5 h; c) phenol 1
(2 mol eq.), NaOEt (1 mol eq.), H2O, Cu2Cl2, Cu, pyridine, reflux, 14 h.

Total Synthesis of Aristogin C in Aqueous Systems
3285
condensation of 3 with sodium salt of 1 in water in the presence of Cu2Cl2,
copper power, and pyridine under reflux. The structure of compound 4 was
characterized by its spectra of MS, IR, and NMR, which are in accord with
those in the literature.[1]
In summary, we have achieved a first total synthesis of the natural product
4 in aqueous systems from readily available materials.
EXPERIMENTAL
Melting points were determined on a X-4 melting-point apparatus with micro-
scope (Shanghai) and are uncorrected. The IR spectra were recorded using an
Analect RFX-65A infrared spectrometer. The NMR spectra were recorded on
a Bruker DRX-400 NMR spectrometer (1H NMR at 400 MHz and 13C NMR at
100 MHz) in CDCl3. The chemical shifts (d ppm) and coupling constants (Hz)
were reported in the standard fashion with reference to the central line
1
(7.24 ppm) of CDCl3 (for H) and (77.0 ppm) of CDCl3 (for 13C). The mass
spectra (EI, 70ev) were measured on a Shimadzu’s GCMS-QP5050A mass
spectrometer using direct inlet.
Methyl p-Anisate (2)
To a solution of phenol 1 (15.2 g, 0.1 mol) in MeOH (10 mL), KOH (5.6 g,
0.1 mol, in 40 mL of H2O) and Me2SO4 (9 mL, 0.095 mol, in 10 mL of
MeOH) were added simultaneously. After stirring at room temperature for
1 h, the reaction mixture was poured into a 4% aqueous solution of Na2CO3
(50 mL) and left overnight. The solid was filtered; washed with cold 10%
Na2CO3 aq., cold water, and brine, and dried (K2CO3). Compound 2 was
given in 90% (15.0 g) yield. White solid, mp 41–428C. IR (KBr) : 1710,
1606, 1512, 1466, 1322, 1286, 1257 cm21; 1H NMR (CDCl3): d 3.83 (s, 3H),
3.85 (s, 3H), 6.89 (d, J ¼ 7.2 Hz, 2H), 7.97 (d, J ¼ 7.2 Hz, 2H); 13C NMR
(CDCl3): d 166.7, 163.2, 131.4, 122.5, 55.2, 51.6; MS m/z: 166(Mþ), 135 (100).
Methyl 3-Bromoanisate (3)
To a solution of methyl p-anisate 2 (15 g, 0.09 mol) and KBrO3 (2.52 g,
0.015 mol) in H2O (100 mL), Br2 (2.4 mL, 0.045 mol) was added, and the
mixture was stirred at room temperature for 2.5 h. The reaction mixture was
extracted with diethyl ether (60 mL ꢀ 3). The combined organic extracts
were washed with H2O and with brine, dried (MgSO4), filtered, and evapor-
ated to yield the crude product as a white solid (19.4 g) in 88% yield.
Mp 96–978C (hexane). IR (KBr) : 1709, 1601, 1500, 1463, 1431, 1275,
1
1119 cm21; H NMR (CDCl3): d 3.87 (s, 3H), 3.93 (s, 3H), 6.89 (d, 1H,

3286
H.-Y. Gao and C.-Y. Ha
J ¼ 8.8 Hz), 7.96 (dd, 1H, J ¼ 8.8, 2.0 Hz), 8.21 (d, 1H, J ¼ 2.0 Hz);
13C NMR (CDCl3): d 165.3, 159.1, 134.4, 130.3, 123.4, 111.1, 110.8, 56.1,
51.8; MS m/z: 246 and 244 (1 : 1, Mþ), 169 (100).
Aristogin C (4)
To a solution of phenol 1 (6.08 g, 0.04 mol) and NaOEt (1.36 g, 0.02 mmol) in
water (40 mL) were added 3 (4.90 g, 0.02 mmol), Cu2Cl2 (0.1 g), copper
(0.1 g), and pyridine (0.79 g, 0.01 mol) at ambient temperature. After
heating under reflux for 14 h, the mixture was acidified with HCI aq. and
extracted with EtOAc (40 mL ꢀ 3). The combined organic extracts were
washed with Na2CO3 twice and with brine, dried (MgSO4), filtered, and evap-
orated. The concentrated mixture was washed with hexane and then purified
by flash column chromatogrphy (first, hexane/benzene, 2 : 3; second,
benzene) to afford 1.58 g of aristogin C 4. White solid; yield: 25%. Mp 93–
1
948C (95% EtOH). IR (film): 1645, 1610, 1510 cm21; H NMR (CDCl3) d
3.83 (s, 3H), 3.86 (s, 3H), 3.93 (s, 3H), 6.89 (d, 2H, J ¼ 8.8 Hz), 6.92
(d, 1H, J ¼ 8.8 Hz), 7.90 (d, 1H, J ¼ 2.0 Hz), 7.92 (dd, 1H, J ¼ 8.8,
2.0 Hz), 8.04 (d, 2H, J ¼ 8.8 Hz); 13C NMR (CDCl3) d 51.5, 51.6, 55.7,
111.6, 115.4, 122.8, 123.0, 123.8, 127.6, 131.1, 142.6, 155.0, 161.2, 165.6,
166.1; MS m/z 316 (Mþ, 100).
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