Study of the intramolecular cyclization of N-methyl-3-phenyl-N-(2-(E)-phenylethenyl)-trans(cis)-oxiranecarboxamide - Syntheses of Homoclausenamide and Dehydroclausenamide

Article abstract of DOI:10.1016/j.ejmech.2007.11.022

Homoclausenamide was synthesized for the first time, and the intramolecular cyclization study of N-methyl-3-phenyl-N-(2-(E)-phenylethenyl)-trans(cis)-oxiranecarboxamide well demonstrated how the stereochemistry affects the cyclization paths.

Full text of DOI:10.1016/j.ejmech.2007.11.022

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European Journal of Medicinal Chemistry 43 (2008) 1781e1784
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Laboratory note
Study of the intramolecular cyclization of N-methyl-3-phenyl-N-(2-(E )-
phenylethenyl)-trans(cis)-oxiranecarboxamide e Syntheses of
Homoclausenamide and Dehydroclausenamide
*
Nianchun Ma , Kemei Wu, Liang Huang
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Received 27 September 2007; received in revised form 22 November 2007; accepted 27 November 2007
Available online 11 January 2008
Abstract
Homoclausenamide was synthesized for the first time, and the intramolecular cyclization study of N-methyl-3-phenyl-N-(2-(E )-phenyle-
thenyl)-trans(cis)-oxiranecarboxamide well demonstrated how the stereochemistry affects the cyclization paths.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Homoclausenamide; Dehydroclausenamide; Amides; Bicyclic compound; Biomimetic syntheses
1. Introduction
2. Results and discussion
Clausena lansium has attracted increasing attention for its
leaves can be used as Chinese Traditional Medicine for hepa-
toprotection [1,2]. The components of the leaves were studied
and five cyclic amides, among which 1e4 are racemic mix-
tures and 5 is optically active, were isolated (Fig. 1) [1,3e
5]. The initial pharmacological study showed that all of the
cyclic amides 1e5 have hepatoprotective activity against
chemical toxins, such as carbon tetrachloride and thioaceta-
mide, and have inducing effect on cytochrome P450 [1,3e
5]. The total syntheses of Clausenamide 3, Neoclausenamide
4, and Dehydroclausenamide 5 have been fulfilled via differ-
ent routes [6e11]. However, no other work has been reported
on the synthesis of Homoclausenamide 1, except for our ear-
lier report as a summary [12]. Its poor content (16.2 ppm) [4]
in the leaves stimulated us to study its synthesis by the cycli-
zation of N-methyl-3-phenyl-N-(2-(E )-phenylethenyl)-trans-
oxiranecarboxamide 8 under Lewis acid condition.
The Darzen’s condensation [13] of benzaldehyde with
2-chloro-N-methyl-N-(2-(E )-phenylethenyl)-acetamide 7 was
conducted in anhydrous MeOH with NaOMe as the base to
give trans and cis epoxides: N-methyl-3-phenyl-N-(2-(E )-
phenylethenyl)-trans-oxiranecarboxamide 8 (JHa,b ¼ 2.2 Hz)
and N-methyl-3-phenyl-N-(2-(E )-phenylethenyl)-cis-oxirane-
carboxamide 9 (JHa,b ¼ 4 Hz), along with a base replaced
by-product 10. The reaction was slow and more (15%) of
kinetically controlled 9 was produced (Eq. (1)).
* Corresponding author. Present address: NDT Corporation, 501 Via Del
Monte, Oceanside, CA 92054, USA. Tel.: þ1 760 435 7024; fax: þ1 760
435 7050.
(1)
E-mail address: manianch@yahoo.com (N. Ma).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.11.022

1782
N. Ma et al. / European Journal of Medicinal Chemistry 43 (2008) 1781e1784
O
affects the cyclization to give absolutely different products.
O
O
CH3
N
In addition, the cyclization of 8 not only gave the desired
Homoclausenamide 1, but also afforded Dehydroclausenamide
5 and the dehydro-derivative 11 of Neoclausenamide 4, which
would provide important information for the biomimetic syn-
theses of the cyclic amides.
HO
CH3
HO
CH3
OH
N
N
HO
1
2
3
4. Experimental
O
N
HO
CH3
OH
4.1. General
H
O
O
N
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. UV
spectra were recorded on a Shimadzu UV240 spectrometer.
Analyses indicated by the symbols of the elements were
within ꢁ0.4% of the theoretical values. Column chromatogra-
phy was performed using silica gel H (10e40 mm, Qingdao
Haiyang Chemical Factory, China). TLC plate was prepared
by coating silica gel G254 (Qingdao Haiyang Chemical Fac-
tory, China) on a sheet of glass, and the sample to be analyzed
ran two times on the plate unless otherwise mentioned. Anhy-
drous CH2Cl2 was dried and distilled from P2O5; MeOH was
treated with Mg, and related anhydrous reactions were con-
ducted under N2.
CH3
H
4
5 (optically active)
Fig. 1.
The cyclization of compound 8 was conducted in anhy-
drous CH2Cl2 under the presence of BF3$OEt2. The reaction
was progressed slowly, and it took 12 h to complete even at
room temperature under the presence of excess (4 eq)
BF3$OEt2. Four compounds were isolated in which the desired
compound 1 with m.p. 199e201 ꢀC and identical spectra with
those of the authentic sample (m.p. 201.5e202.5 ꢀC) [4] were
obtained but only in yield of 13%. Compound 5 with m.p.
1
164e166 ꢀC gave identical H NMR and MS with those of
the natural Dehydroclausenamide 5 (m.p. 164e166 ꢀC) [1],
except it is a racemic compound while the natural product is
optically active with optical purity of 50% ee [5]. The struc-
ture of compound 11 with m.p. 188e191 ꢀC was identified
as a bicyclic compound which (m.p. 188e190 ꢀC) has been
obtained previously while treating Neoclausenamide 4 with
acid on heating [1]. In addition, a dehydrated product 12
was also obtained. Apparently C1eCb (exo) and C2eCb
(endo) cyclizations of compound 8 have taken place giving
the corresponding five and six member rings (Scheme 1).
The cyclization of compound 9 was also conducted under the
presence of BF3$OEt2. But the reaction was progressed very
quickly (30 min), and the result was very different, giving
mainly six-membered ring products. Opening the epoxide and
the cyclization was taking place at the same time, so the cycliza-
tions of 8 and 9 afforded only compounds 1 and 13, respectively.
For the cyclization of 9, anti-elimination is greatly favored to
give predominantly dehydrated product 12 (Eq. (2)).
4.1.1. Synthesis of compounds 8 and 9
To the solution of benzaldehyde (1.70 g, 99%, 16.0 mmol)
and compound 7 [14] (2.10 g, 10.0 mmol) in anhydrous
MeOH (100 ml) was added dropwise a solution of sodium
methoxide (prepared from Na and MeOH) in MeOH
(15.46 g, 5.59% g/g, 16.0 mmol) at 15e20 ꢀC. After the addi-
tion, it was stirred at the same temperature till the starting ma-
terial 7 was disappeared (4 days, settled during night). It was
cooled to 0e5 ꢀC, and AcOH (0.36 g, 6.0 mmol) was added to
neutralise the base. It was concentrated, and the residue was
dissolved in CH2Cl2 (100 ml). It was washed with water,
and the aqueous phase was extracted with Et2O. The combined
organic phase was washed with water and brine, dried
(Na2SO4) and concentrated for column chromatography using
petroleum ether (30e60 ꢀC) and EtOAc (2:1) as the eluent to
afford 8 [14] (1.11 g, 40%) and 9 (0.42 g, 15%); m.p.: 152e
1
154 ꢀC. H NMR (90 MHz, CDCl3) d ppm: 3.00 and 3.16 (s,
3H, NCH3), 4.01 and 4.05 (d, J ¼ 4 Hz, 1H, PheCH), 4.32
and 4.37 (d, J ¼ 4 Hz, 1H, CHeCO), 5.82 and 5.90 (d,
J ¼ 14.4 Hz, 1H, ]CHePh), 7.00e7.60 (m, 11H, HeAr and
NeCH]). MS m/z (%): 280 (Mþ þ 1, 9), 279 (Mþ, 40),
193 (24), 173 (22), 144 (90), 133 (41), 132 (19), 117 (23),
91 (100). Anal. C18H17NO2 (C, H, N). In addition, by-product
(2).
1
10 (370 mg, 18%) was obtained; m.p.: 37e39 ꢀC. H NMR
3. Conclusion
(90 MHz, CDCl3) d ppm: 3.21 (s, 3H, NCH3), 3.44 (s, 3H,
OCH3), 4.26 (s, 2H, CHeCO), 5.98 (d, J ¼ 14.4 Hz, 1H,
]CHePh), 7.00e7.50 (m, 6H, HeAr and NeCH]). Anal.
C12H15NO2 (C, H, N).
The cyclization study of compounds 8 and 9 well demon-
strated how the stereochemistry of the starting materials

N. Ma et al. / European Journal of Medicinal Chemistry 43 (2008) 1781e1784
1783
O
CH3
N
O
8
BF3·OEt2
Cβ-C1
exo-cyclization
Cβ-C2
endo-cyclization
O
O
_
CH3 F3BO
_
O
O
_
_
CH3
F3BO
F3BO
CH3 F3BO
CH3
N
N
N
N
+
+
+
+
O
O
O
HO
CH3
CH3
HO
CH3
N
N
H
N
O
N
O
CH3
H
5
11
1
12
6%
19%
39%
13%
Scheme 1.
4.1.2. The intramolecular cyclization of compound 8
d ppm: 3.68 (s, 3 H, NCH3), 7.20e7.80 (m, 12 H, HeAr
and CHeCO, NeCH]). MS m/z (%): 262 (Mþ þ 1, 18),
261 (Mþ, 100), 233 (16), 192 (2), 191 (7), 91 (20), 41 (27).
13C NMR (125 Hz, CDCl3) d ppm: 38.5, 120.0, 125.8,
127.3, 127.8, 128.1, 128.7, 129.1, 131.4, 134.7, 136.6,
136.7, 137.5, 161.2. IR (KBr, cmꢂ1): 3445, 3063, 1648,
1595, 1555, 1500, 755, 697. UV/vis (CHCl3) lmax (log 3)
(nm): 255 (4.34), 340 (3.98). Anal. (recrystallized from
MeOH) C18H15NO2$1/5CH3OH (C, H, N).
To the solution of 8 (419 mg, 1.5 mmol) in anhydrous
CH2Cl2 (40 ml) was added dropwise a solution of BF3$OEt2
(859 mg, 6 mmol) in anhydrous CH2Cl2 (4 ml) at 20e25 ꢀC.
After being stirred for 12 h, it was diluted with Et2O (80 ml)
and washed with water. The aqueous phase was extracted
with Et2O. The combined organic phase was washed with
water and brine, dried (Na2SO4) and concentrated for column
chromatography using petroleum ether (30e60 ꢀC) and EtOAc
(2:1) as the eluent to afford following products.
Product 11 [1] (165 mg, 39%); m.p.: 188e191 ꢀC; Rf: 0.20
1
(petroleum ethereEtOAc, 2:1). H NMR (90 MHz, CDCl3)
Dehydroclausenamide 5 [1] (81 mg, 19%); m.p.: 164e
166 ꢀC; Rf: 0.64 (petroleum ethereEtOAc, 2:1). 1H NMR
(90 MHz, CDCl3) d ppm: 2.94 (s, 3H, NCH3), 3.59 (br s, 1H,
CHeCO), 4.07 (br s, 1H, CHeN), 4.81 (br s, 1H, PheCH),
4.99 (br s, 1H, PheCHeO), 7.11e7.51 (m, 10H, HeAr). MS
m/z (%): 280 (Mþ þ 1, 1), 279 (Mþ, 2), 173 (100), 144 (61),
91 (19), 77 (13), 65 (4), 42 (22).
d ppm: 2.71 (br s, 1H, exchangeable with D2O, OH), 2.92
(s, 3H), 3.96 (m, 1H), 4.32 (m, 3H), 6.80e7.48 (m, 9H). MS
m/z (%): 280 (Mþ þ 1, 25), 279 (Mþ, 100), 262 (17), 204
(33), 192 (72), 178 (25), 165 (30), 144 (17), 115 (30), 91
(19), 77 (12), 42 (56).
Homoclausenamide 1 [4] (54 mg, 13%); m.p.: 199e201 ꢀC;
4.1.3. The intramolecular cyclization of compound 9
1
Rf: 0.47 (petroleum ethereEtOAc, 2:1). H NMR (90 MHz,
To the solution of 9 (279 mg, 1.0 mmol) in anhydrous
CH2Cl2 (20 ml) was added dropwise the solution of BF3$OEt2
(170 mg, 1.2 mmol) in anhydrous CH2Cl2 (2 ml) at 10e
15 ꢀC. After being stirred for 30 min (TLC showed that reac-
tion was finished), it was diluted with Et2O (50 ml) and
washed with water. The aqueous phase was extracted with
Et2O. The combined organic phase was washed with brine,
dried (Na2SO4) and concentrated for column chromatography
using petroleum ether (30e60 ꢀC) and EtOAc (2:1) as the el-
uent to afford 13 (25 mg, 9%); m.p.: 153e155 ꢀC; Rf: 0.71
CDCl3) d ppm: 2.96e3.16 (br s, 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, CHeCO), 6.38 (s, 1H, NeCH]),
6.90e7.30 (m, 10H, HeAr). MS m/z (%): 280 (Mþ þ 1, 18),
279 (Mþ, 84), 262 (2), 251 (18), 250 (100), 222 (15), 91
(18), 77 (10), 42 (26). IR (KBr, cmꢂ1): 3263, 1663, 1648,
1394, 1219, 1058.
Product 12 (25 mg, 6%); m.p.: 177e179 ꢀC; Rf: 0.42 (pe-
troleum ethereEtOA, 2: 1). 1H NMR (90 MHz, CDCl3)

1784
N. Ma et al. / European Journal of Medicinal Chemistry 43 (2008) 1781e1784
(petroleum ethereEtOAc, 3:1, ran three times). 1H NMR
(90 MHz, CDCl3) d ppm: 3.24 (s, 3H, NCH3), 3.22e3.32 (br
s, 1H, exchangeable with D2O, OH), 4.18 (d, J ¼ 7.6 Hz,
1H, PheCH), 4.74 (d, J ¼ 7.6 Hz, 1H, CHeCO), 6.61 (s,
1H, NeCH]), 7.04e7.60 (m, 10H, HeAr). MS m/z (%):
280 (Mþ þ 1, 15), 279 (Mþ, 82), 262 (2), 251 (16), 250
(100), 222 (15), 91 (14). Anal. C18H17NO2 (C, H, N). In addi-
tion, compound 12 (136 mg, 52%) was isolated.
[2] V. Lakshmi, R. Kumar, S.K. Agarwal, Nat. Prod. Res. 19 (4) (2005)
355e357 and references cited therein.
[3] M.H. Yang, Y.Y. Chen, L. Huang, Phytochemistry 27 (2) (1988)
445e450.
[4] M.H. Yang, Y.Y. Chen, L. Huang, Chin. Chem. Lett. 2 (4) (1991)
291e292.
[5] M.H. Yang, L. Huang, Chin. Chem. Lett. 2 (6) (1991) 775e776.
[6] W. Hartwig, L. Born, J. Org. Chem. 52 (19) (1987) 4352e4358.
[7] G.Z. Yang, L.H. Wang, L. Huang, Chin. Chem. Lett. 4 (12) (1993)
1035e1036.
[8] E.C. Rao, H. Hong, G.Z. Yang, H. Lin, L. Huang, Chin. Chem. Lett. 5 (4)
(1994) 267e268.
Acknowledgment
[9] M.W. Cappi, R.W. Flood, S.M. Roberts, J. Skidmore, N.M. Williamson,
W.P. Chen, Y.W. Liao, J.A. Smith, Chem. Commun 10 (1998) 1159e1160.
[10] T. Yakura, Y. Matsumura, M. Ikeda, Synlett 1991 (5) (1991) 343e344.
[11] D.F. Huang, L. Huang, Tetrahedron 46 (9) (1990) 3135e3142.
[12] N.C. Ma, K.M. Wu, L. Huang, Chin. Chem. Lett. 7 (8) (1996)
706e708.
We are grateful to National Science Foundation of China
for financial support.
References
[13] C.C. Tung, A.J. Speziale, H.W. Franzier, J. Org. Chem. 28 (6) (1963)
1514e1521.
[14] For the preparation of compounds 7 and 8 see: N. Ma, K. Wu, L. Huang
Eur. J. Med. Chem. (2007) Available online 3 June.
[1] M.H. Yang, Y.H. Cao, Y.Q. Yang, Y.Y. Chen, L. Huang, Yaoxue Xuebao
22 (1) (1987) 33e40.