An elegant synthesis of Zetaclausenamide

Article abstract of DOI:10.1016/j.ejmech.2007.05.010

Zetaclausenamide, which was isolated as a hepatoprotective agent from the leaves of medicinal plant Clausena lansium, was synthesized for the first time in six steps including Darzen's condensation, photoisomerization, and the final cyclization reactions.

Full text of DOI:10.1016/j.ejmech.2007.05.010

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European Journal of Medicinal Chemistry 43 (2008) 893e896
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Laboratory note
An elegant synthesis of Zetaclausenamide
,1
Nianchun Ma , Kemei Wu, Liang Huang
*
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Received 25 March 2007; received in revised form 10 May 2007; accepted 24 May 2007
Available online 3 June 2007
Abstract
Zetaclausenamide, which was isolated as a hepatoprotective agent from the leaves of medicinal plant Clausena lansium, was synthesized for
the first time in six steps including Darzen’s condensation, photoisomerization, and the final cyclization reactions.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Zetaclausenamide; Clausena lansium; Darzen’s condensation; Photoisomerization; Cyclization
1. Introduction
Zetaclausenamide 1, except for our earlier report [11] as
a summary. It is usually much more difficult to construct
eight-membered ring than to construct five- or six-membered
ring. The study of the synthesis of Zetaclausenamide 1 would
be helpful in designing and synthesizing different eight-
membered ring products.
The medicinal plant Clausena lansium is locally produced
in the south-west Yunnan province in China [1]. The aqueous
extract of it’s leaves has often been used in Chinese folk medi-
cine as an effective means for protecting the liver and been
administered against acute and chronic viral hepatitis [1,2].
These attracted chemical researchers to study it’s chemical
components in detail. As a result, Zetaclausenamide 1 and
Clausenamide 2, along with other five amides, were isolated
[1e5]. The initial pharmacological study showed that both 1
and 2 have hepatoprotective activity against chemical toxins,
such as carbon tetrachloride and thioacetamide, and have
inducing effect on cytochrome P450, which is essential for
the metabolisation of xenobiotics [2,4].
Further pharmacological studies required larger amounts of
Zetaclausenamide 1 than can be obtained by the complicated
extraction process. It is therefore necessary to provide a
chemical process which facilitates the preparation of 1. The
total synthesis of Clausenamide 2 has attracted much attention,
and several synthetic routes were reported [6e10]. We have
not found any other literature regarding the synthesis of
2. Results and discussion
Zetaclausenamide 1 is a z-lactam. It has similar molecular
formula as that of Clausenamide 2, but different skeleton.
From compound 6, our lab has successfully fulfilled the total
syntheses of 2 and dehydroclausamide, another product of
the seven amides, by an elegant base induced cyclization
(Fig. 1) [8,12]. Opening the a,b-epoxide of compound 6 to
construct the a-hydroxy and b-phenyl of 2 indeed gave a useful
clue in designing the synthesis of 1. Based upon it and the
retro-analysis of 1 (Fig. 1), compound 5 was designed as the
key intermediate to prepare 1. To convert the trans-double
bond of 5 to cis is necessarily important. Photochemical con-
dition needs to be carefully controlled in case of destroying the
epoxide group.
As shown in Scheme 1, the key intermediate 5 can be
obtained by straightforward reactions. 2-Phenylethanol 7 was
oxidized with potassium dichromate using phase transfer
reaction [13] to afford aldehyde 8 [14]. The reaction of phe-
nylacetaldehyde 8 with methylamine proved troublesome.
* Corresponding author. Tel.: þ1 760 435 7024; fax: þ1 760 435 7050.
E-mail address: manianch@yahoo.com (N. Ma).
1
Present address: NDT Corporation, Bio Grop, 501 Via Del Monte, Ocean-
side, CA 92054, USA.
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.05.010

894
N. Ma et al. / European Journal of Medicinal Chemistry 43 (2008) 893e896
O
the protons (CH-2) of 10 and (CH-a, CH-b, CH-2) of 5 show
1
two doublets in the H NMR spectrum.
CH3
OH
HO
N
The photoisomerization [17] of compound 5 was conducted
in degassed anhydrous benzene. The solution of 5 in benzene
was irradiated with 450 W medium-pressure mercury lamp
through a 0.1 M SnCl2/concentrated hydrochloride filter
(l > 300 nm). There is equilibrium established in this reaction,
and product 3 (JH1,2 ¼ 8.7 Hz) was obtained in 50% yield based
on 67% conversion. Conducting the reaction at l > 300 nm is
very important. Without the filter, the TLC of the reaction
was complex, and no desired 3 was obtained.
OH
N
O
CH3
1
2
.
[H]
N
BF3 Et2O
O
O
Ph
HO
CH3
O
O
CH3
The cyclization of 3 was conducted in anhydrous dichloro-
methane under the presence of boron trifluoride-diethyl etherate
at room temperature to afford the desired Zetaclausenamide 1 in
N
Ph
3
4
1
30% yield. It’s melting point (186e189 ꢀC), IR, MS and H
[B]
hυ
NMR are identical with those of the naturally isolated Zetaclau-
senamide [4]. In addition, Homoclausenamide 11 was also iso-
lated in 7% yield, which is another product of the seven natural
amides. The cyclization condition was not optimized. Except
for the above two products, several traces of different com-
pounds were obtained, and their structures were not identified.
O
Ph
O
Ph
CH3
N
CH3
N
O
O
O
Ph
Fig. 1. Retro-analysis.
Ph
5
6
3. Conclusion
It’s product 9 is unstable and is readily polymerized at room
temperature [15]. So the reaction was conducted at low tem-
perature (0e5 ꢀC) and 9 was not isolated and treated directly
with chloroacetyl chloride with pyridine as the base to
afford desired 2-chloro-N-methyl-N-(2-(E )-phenylethenyl)-
acetamide 10 in a poor 29% yield. After the reaction of alde-
hyde 8 with methylamine, it was dried with KOH at 0e5 ꢀC.
Possibly, the drying time is too long (w8 h), leaving more of 9
polymerized. The trans-ene conformation of 10 was deter-
mined by the JH1,2 ¼ 14.4 Hz. The Darzen’s condensation
[16] of benzaldehyde with 10 occurred smoothly in toluene
at 0e5 ꢀC with potassium tert-butoxide as the base to afford
trans-epoxide, N-methyl-3-phenyl-N-(2-(E )-phenylethenyl)-
trans-oxiranecarboxamide 5 (JHa,b ¼ 2.2 Hz) in 87% yield.
Owing to the rotation hindrance of the molecules, the protons
(NCH3, CH-a) of 10 and (NCH3) of 5 show two singlets, and
Zetaclausenamide was prepared in a very short way in 2.8%
overall yield. The Darzen’s condensation of N,N-disubstituted
chloroacetamide with benzaldehyde and the olefin photoiso-
merization reactions play crucial roles during this process.
4. Experimental
4.1. General
Melting points were measured with a YANACO MP-500
apparatus and were not corrected. IR spectra were recorded
on a PerkineElmer 399B spectrometer (KBr disk). Mass spec-
tra (electron impact) were obtained on a ZAB-2F, MAT711 in-
strument. 1H NMR spectra were recorded on a JEOL FX-90Q
(90 MHz) spectrometer using TMS as internal standard. Anal-
yses indicated by the symbols of the elements were within
ꢁ0.4% of the theoretical values. Column chromatography
was performed using silica gel H. 450 W Hamonia medium-
pressure mercury lamp was used for the photoisomerization.
Anhydrous solvents (dichloromethane, benzene and toluene)
were dried and distilled from P2O5; BF3$Et2O was distilled
from CaH2 and related anhydrous reactions were conducted
under dried N2/CaCl2.
K2Cr2O7
CH3NH2
PhCH2CH2OH
PhCH2CH
PhCH2CHO
NCH3
7
9
8
Ph
O
O
C
CH3
N
CH3
N
ClCH2COCl
hυ
PhCHO
ClH2C
t
BuOK
Py
O
Ph
Ph
10
5
O
4.1.1. Synthesis of compound 10
HO
CH3
O
N
Into a separatory funnel (3000 ml) containing a solution of
potassium dichromate (36.2 g, 0.123 mol) in 9 M sulfuric acid
(750 ml) was added the solution of 7 (36.7 ml, 0.30 mol) and
tetra-n-butylammonium bisulfate (9.0 g, 0.27 mol) in dichloro-
methane (750 ml). It was shaken vigorously until no more heat
was exited. The organic phase was separated and the aqueous
layer was extracted with diethyl ether. The combined
organic phase was washed with brine, dried (Na2SO4) and
Ph
.
OH
BF3 Et2O
O
+
O
N
CH3
N
CH3
3
1
11
7%
30%
Scheme 1.

N. Ma et al. / European Journal of Medicinal Chemistry 43 (2008) 893e896
895
concentrated to the volume of w60 ml. Gaseous-mass spec-
trometer analysis shows 73% of 8 formed.
degassed and irradiated with 450 W Hamonia medium-
pressure mercury lamp from outside under nitrogen while stir-
ring. The reaction vessel was cooled with strong air gun and
the irradiation was stopped after 30 min to let the reaction so-
lution to cool. It was then irradiated for another 30 min. This
process was repeated and the reaction was monitored by TLC
till no more starting material was obviously reacted (4 h). It
was cooled and concentrated for column chromatography
using petroleum ether (bp: 30e60 ꢀC) and EtOAc (3:1) as
the eluent to afford unreacted 5 (350 mg, 33% recovered)
and 3 (350 mg, 50% based on 67% conversion); m.p.: 115e
118 ꢀC. 1H NMR (90 MHz, CDCl3) d ppm: 3.12 (s, 3H,
NCH3), 3.75 (d, J ¼ 1.4 Hz, 1H, PheCH), 3.81 (d,
J ¼ 1.4 Hz, 1H, CHeCO), 6.19 (d, J ¼ 8.6 Hz, 1H, ]CHePh),
6.35 (d, J ¼ 8.6 Hz, 1H, NeCH]), 6.90e7.40 (m, 10H, H-Ar).
MS m/z (%): 280 (Mþ þ 1, 25), 279 (Mþ, 8), 193 (14), 173 (22),
144 (41), 133 (38), 132 (21), 117 (23), 103 (24), 91 (100). Anal.
C18H17NO2 (C, H, N).
To the solution of methanamine in dichloromethane
(175 ml, 7.1% g/ml, 0.40 mol) was added dropwise the above
aldehyde solution at 0e5 ꢀC. After the addition, it was stirred
for 20 min, followed by addition of potassium hydroxide
(12.0 g, 0.21 mol) and saturated aqueous sodium chloride
(50 ml). After being vigorously stirred at 0e5 ꢀC for 20 min,
the organic layer was separated, dried with potassium hydrox-
ide at 0 ꢀC (8 h) and decanted for the following reaction.
The above solution was diluted with anhydrous dichloro-
methane (100 ml) and pyridine (42.2 ml, 0.30 mol) was added.
It was cooled to 0e5 ꢀC, and a solution of 2-chloroacetyl chlo-
ride (36.6 ml, 0.45 mol) in anhydrous dichloromethane
(50 ml) was added dropwise under stirring. After the addition,
it was allowed to warm to room temperature and stirred for
10 h. It was washed with water and the aqueous phase was ex-
tracted with diethyl ether. The combined organic phase was
washed with water, brine, dried (Na2SO4) and concentrated
for chromatography using petroleum ether (bp: 30e60 ꢀC)
and diethyl ether (2:1) as the eluent to afford 10 (17.1 g,
4.1.4. Synthesis of Zetaclausenamide 1
To the solution of compound 3 (250 mg, 0.9 mmol) in an-
hydrous dichloromethane (25 ml) was added dropwise the so-
lution of boron trifluoride-diethyl etherate (136 ml, 1.1 mmol)
in anhydrous dichloromethane (2 ml) at room temperature
while stirring. After the addition, the reaction was continued
for 30 min. Then it was diluted with diethyl ether (100 ml),
washed with water, and the aqueous phase was extracted
with diethyl ether. The combined organic phase was washed
with water and brine, dried (Na2SO4) and concentrated for
chromatography using petroleum ether (bp: 30e60 ꢀC) and
EtOAc (1:1) as the eluent, the so obtained main products
were concentrated for chromatography again using dichloro-
methane and methanol (100:1.25) as the eluent to afford Zeta-
1
29% from 8); m.p.: 77e79 ꢀC. H NMR (90 MHz, CDCl3):
d ppm: 3.26 and 3.30 (s, 3H, NCH3), 4.20 and 4.26 (s, 2H,
CH2CO), 6.04 and 6.08 (d, J ¼ 14.4 Hz, 1H, ]CHePh),
7.10e7.60 (m, 6H, H-Ar and NeCH]). MS m/z (%): 211
(33) and 209 (Mþ, 100), 174 (24), 133 (83), 132 (46), 117
(61), 91 (72), 90 (80), 77 (17), 42 (33). Anal. C11H12ClNO
(C, H, N).
4.1.2. Synthesis of compound 5
To the solution of benzaldehyde (1.07 g, 99%, 10.0 mmol)
and compound 10 (2.10 g, 10.0 mmol) in anhydrous toluene
(150 ml) was added dropwise the solution of potassium tert-
butoxide (prepared from potassium and tert-butyl alcohol) in
tert-butyl alcohol (11.20 g, 3.8% g/g, 11.0 mmol) at 5e
10 ꢀC. After the addition, it was stirred for 1 h at the same
temperature, then it was diluted with diethyl ether (200 ml)
and washed with water. The aqueous phase was extracted
with diethyl ether. The combined organic phase was washed
with water and brine, dried (Na2SO4) and concentrated for re-
crystallization (dichloromethane/diethyl ether) to afford 5
(2.26 g). The mother solution was concentrated for column
chromatography using petroleum ether (bp: 30e60 ꢀC) and
EtOAc (5:1) as the eluent to afford more of 5 (160 mg, overall
1
clausenamide 1 (74 mg, 30%); m.p.: 187e189 ꢀC. H NMR
(90 MHz, CDCl3) d ppm: 2.92 (s, 3H, NCH3), 2.96e3.16
(brs, 1H, exchangeable with D2O, OH), 4.10 (d, J ¼ 9 Hz,
1H, PheCH), 5.06 (d, J ¼ 9 Hz, 1H, HOeCH), 6.14 (d,
J ¼ 8 Hz, 1H, PheCH]), 6.80 (d, J ¼ 8 Hz, 1H, NeCH]),
6.98e7.38 (m, 9H, H-Ar). MS m/z (%): 280 (Mþ þ 1, 3.4),
279 (Mþ, 11), 262 (0.2), 250 (100), 222 (43), 192 (77), 178
(37), 144 (73), 91 (31), 77 (28), 42 (60). IR (KBr, cmꢂ1):
3337, 1641, 1394, 1259, 1071. In addition, compound 11
1
was also obtained (17 mg, 7%); m.p.: 196e200 ꢀC. H NMR
(90 MHz, CDCl3) d ppm: 2.96e3.16 (brs, 1H, exchangeable
with D2O, OH), 3.22 (s, 3H, NCH3), 4.17 (d, J ¼ 10 Hz, 1H,
PheCH), 4.37 (d, J ¼ 10 Hz, 1H, HOeCH), 6.38 (s, 1H,
CH]), 6.90e7.30 (m, 10H, H-Ar). MS m/z (%): 280
(Mþ þ 1, 18), 279 (Mþ, 84), 262 (2), 251 (18), 250 (100),
222 (15), 91 (18), 77 (10). IR (KBr, cmꢂ1): 3263, 1663,
1
yield 87%); m.p.: 103e105 ꢀC. H NMR (90 MHz, CDCl3)
d ppm: 3.29 and 3.32 (s, 3H, NCH3), 3.75 and 3.77 (d,
J ¼ 2.2 Hz, 1H, PheCH), 4.09 and 4.13 (d, J ¼ 2.2 Hz, 1H,
CHeCO), 6.02 and 6.08 (d, J ¼ 14.4 Hz, 1H, ]CHePh),
7.00e7.60 (m, 11H, H-Ar and NeCH]). MS m/z (%): 280
(Mþ þ 1, 6), 279 (Mþ, 30), 193 (18), 173 (20), 144 (65), 133
(52), 132 (28), 117 (30), 91 (100). Anal. C18H17NO2 (C, H, N).
1
1648, 1394, 1219, 1058. It’s melting point, IR, MS and H
NMR are identical with those of the naturally isolated Homo-
clausenamide [4].
4.1.3. Synthesis of compound 3
Into a cylindrical and jacketed quart reaction vessel
(500 ml) with a solution of SnCl2 in concentrated hydrochlo-
ride (0.1 M) in it’s jacket was added the solution of compound
5 (1.05 g, 3.76 mmol) in anhydrous benzene (250 ml). It was
Acknowledgments
We are grateful to National Science Foundation of China
for financial support.

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N. Ma et al. / European Journal of Medicinal Chemistry 43 (2008) 893e896
[9] M.W. Cappi, R.W. Flood, S.M. Roberts, J. Skidmore, N.M. Williamson,
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