Synthesis and activity in enhancing long-term potentiation (LTP) of clausenamide stereoisomers

Article abstract of DOI:10.1016/j.bmcl.2009.03.018

Clausenamide, isolated from aqueous extract of dry leaves of Clausena lansium, a Chinese folk medicine, was found to have potent activity in enhancing LTP and show nootropic activity in animal tests. In order to discovery more potent stereoisomers and to

Full text of DOI:10.1016/j.bmcl.2009.03.018

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2112–2115
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and activity in enhancing long-term potentiation (LTP)
of clausenamide stereoisomers
*
*
Zhiqiang Feng , Xingzhou Li, Guojun Zheng, Liang Huang
Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Clausenamide, isolated from aqueous extract of dry leaves of Clausena lansium, a Chinese folk medicine,
was found to have potent activity in enhancing LTP and show nootropic activity in animal tests. In order
to discovery more potent stereoisomers and to analyze the relationship of structure–activity, the synthe-
sis of 16 (8 pairs) optically pure stereoisomers of clausenamide with four chiral centers was achieved. The
results of LTP assay showed that the nootropic activity of the stereoisomers of clausenamide is closely
related to the configuration of stereoisomers.
Received 5 January 2009
Revised 2 March 2009
Accepted 5 March 2009
Available online 10 March 2009
Keywords:
Clausenamide
Ó 2009 Elsevier Ltd. All rights reserved.
Stereoisomers
Long-term potentiation
Nootropic activity
Synaptic plasticity in mammalian brain is one of the most
widely studied topics in neuroscience over the last decade. One
of the clinical symptoms of Alzheimer’s disease (AD) is disorder
of memory that has been suggested to be related with synaptic
plasticity.1 LTP is an important form of synaptic plasticity that in-
creases the strength of synapses, and it is a physiologic correlate of
memory and a cellular model for study of learning and memory.2
The naturally occurring clausenamide is in racemic form and
was found to have potent activity in enhancing LTP and show noo-
tropic activity in animal tests.3 The synthetic single enantiomer
(ꢀ)-(3S,4R,5R,6S)-clausenamide (1) (Fig. 1) could improve Ab in-
duced impairment of spatial discrimination, potentiate basic syn-
aptic transmission and HFS-induced LTP on either anesthetized
or freely moving rats, and increase cortical ChAT activity, hippo-
campal synapses and Mossy fiber sprouting.4 In addition, 1 was
50–100 times more active than the known nootropic drug, pirace-
tam, and 5–10 times more active than the racemic clausenamide5,
which indicated that the nootropic activity may be related with the
configuration of clausenamide.
evaluated, and the primary relationships of structure–activity were
analyzed.
A number of synthetic routes are available to build into the lac-
tam core structure in clausenamide.6 Four optically pure interme-
diate compounds, (3S,4R,5R)-clausenamidone (17), (3R,4S,5S)-
clausenamidone (18), (3S,4R,5S)-neo-clausenamidone (19) and
(3R,4S,5R)-neo-clausenamidone (20), were obtained through chiral
resolution of racemic clausenamidone and neo-clausenamidone
from a biomimetic synthetic route,7 using menthoxylacetic acid
as chiral derivatizing reagent.8 Reduction of 17 with NaBH4 affor-
ded single product 1, but its C6 isomer, (3S,4R,5R,6R) epi-clausena-
mide was not found under various reduction conditions (Scheme
1) due to the steric hindrance of the C4 phenyl group.
Reduction of 20 with sodium boronhydride gave two C6 iso-
mers, (3R,4S,5R,6S)-neo-clausenamide (3) and (3R,4S,5R,6R)-epi-
neo-clausenamide (5) in almost equal yields after column chroma-
tography. However, reduction with Al(i-OPr)3/i-PrOH afforded pre-
dominantly isomer 5 (mol ratio3:5 = 1:20). Protection of C3–OH
with dihydropyran and reduction with L-selectride mainly pro-
duced 3 (mol ratio 3:5 = 10:1) (Scheme 2).9
There are four chiral centers (C3, C4, C5, C6) in clausenamide,
which means that 16 (8 pairs) stereoisomers are possible (Fig. 2).
In order to discover more potent stereoisomers and to analyze
the relationship between structure and activity of the clausena-
mide stereoisomers, herein, all optically pure stereoisomers of
clausenamide were prepared, their activity in enhancing LTP were
OH
3
4
5
H
2
O
6
HO
N
1
H
CH3
* Corresponding authors. Tel.: +86 10 63189351; fax: +86 10 83155752 (Z.F.);
tel.: +86 10 63165259 (L.H.).
(-)clausenamide
E-mail address: fengzhq@imm.ac.cn (Z. Feng).
Figure 1. The structure of (ꢀ)clausenamide (1).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.018

Z. Feng et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2112–2115
2113
clausenamide
neoclausenamide
epi-neoclausenamide
cis-clausenamide
cis-neoclausenamide
epi-cis-neoclausenamide
(3S,4R,5R,6S)
(3R,4S,5S,6R)
1
2
4
6
3 (3R,4S,5R,6S)
5 (3R,4S,5R,6R)
(3R,4R,5R,6S)
(3R,4R,5S,6R)
(3R,4R,5S,6S)
(3R,4R,5R,6R)
(3S,4R,5R,6R)
(3S,4R,5S,6R)
(3S,4R,5S,6S)
(3S,4S,5S,6R)
(3S,4S,5R,6S)
(3S,4S,5R,6R)
OH
2
4 3
7
9
11
13
15
8
5
10
12
14
16
O
6
HO
N
1
CH3
(3S,4S,5S,6S) epi-cis-clausenamide
epi-clausenamide
(3R,4S,5S,6S)
Figure 2. The configuration of 16 optically active stereoisomers of clausenamide.
OH
OH
OH
Ph
OH
Ph
OH
Ph
H
Ph
Ph
H
H
H
H
Ph
Ph
Ph
Ph
Ph
HO
O
O
O
O
O
a
N
N
N
N
N
H
H
H
H
HO
HO
HO
O
CH3
CH3
CH3
CH3
CH3
(3S,4R,5R)
17
(3R,4R,5R,6S)
7
(3S,4R,5R,6S)
1
(3S,4R,5R,6R)
(3R,4R,5R,6R)
Scheme 1. Reagents and condition: NaBH4/CH3OH (85%).
c
OH
Ph
OH
Ph
OH
Ph
H
Ph
a
H
H
Ph
b
Ph
cis-Clausenamide has three substituent groups, C3–OH, C4–Ph,
and C5-side chain on the same sides of the lactam ring. The con-
gested structure might encounter difficulty in preparation. Indeed
inversion of C3–OH in clausenamidone by Mitsunobu reaction or
CsOAc/18-Crown ether failed. An attempt of de novo synthesis
using cis epoxy cinnamate ester instead of trans epoxy in the clau-
senamide synthesis was also unsuccessful. Finally a revised syn-
thetic approach by oxidation of C3–OH of neoclausenamidone for
rebuilding the chirality of C4 into the desired configuration was de-
signed and carried out (Scheme 3).
The oxidation of C3–OH of 20 gave a product (5R)-3,4-dehydro-
clausenamidone (26). An attempt to reduce the double bond in 26
under catalytic hydrogenation in ethanol gave a complex mixture.
While treatment with NaBH4 in the presence of acetic acid in
dichloromethane, a single compound (3R,4R,5R)-cis-clausenami-
done (22) was given. Its structure was confirmed by 1H NMR and
NOESY1D, in which strong NOEs between C3–H and C4–H, C4–H
and C5–H were observed. The cis relation among C3, C4, C5 was
established.
O
O
N
O
N
CH3
(5R)
N
CH3
O
O
CH3
O
(3R,4S,5R)
(3R,4R,5R)
22
20
26
d
OH
Ph
OH
Ph
Ph
OH
H
e
Ph
H
H
Ph
Ph
+
O
O
N
O
N
H
N
HO
H
O
CH3
HO
CH3
CH3
(3R,4R,5S,6S)
11
(3R,4R,5S,6R)
9
(3R,4R,5S)
24
Scheme 3. Reagents and conditions: (a) Na2Cr2O7/H2SO4/H2O/CH2Cl2, 30–40 °C
(76%); (b) NaBH4/HOAc/CH2Cl2, 0 °C–rt (79%); (c) NaBH4/CH3OH (85%); (d) KOH/
CH3OH, rt (90%); (e) NaBH4/CH3OH, 0 °C–rt (80%).
According to the structure of 22, the reduction of C6@O should
favor the Si face to give C6(S) configuration, (3R,4R,5R,6S)-cis-clau-
senamide, as the Re face is highly hindered by C4 phenyl group. In-
deed, the reduction of 22 with NaBH4 in methanol at 0 °C gave a
product 7.
½
a 2D2
ꢁ
+19.2 (c 0.525, CH3OH), 9 with mp: 164.5–166 °C, ½a D22
ꢁ
+66.7
(c 0.46, CH3OH). Their structure was confirmed by spectra, MSFAB
showed: FW = 297, and 1H NMR data of 11 and 9 showed that
the configuration of C6 in 11 is different from that of C6 in 9, which
was inferred from the clear difference between 11 and 9,
J5,6 = 2.7 Hz in 11, J5,6 = 5.4 Hz in 9.
The treatment of (3R,4R,5R)-cis-clausenamidone (22) with
K2CO3 in methanol afforded quantitatively a single C5 isomer 24,
which was recrystallized three times in acetone until specific rota-
tion was consistent, giving white crystals with mp: 143–145 °C,
The absolute configuration of C6 in 11 could be deduced by
comprehensive analysis for the dominant conformation, the reduc-
tion mechanism of 24 and the spectra of 11 and 24. The reduction
of C6@O should favor the Si face to give C6(S) configuration,
(3R,4R,5S,6S)-epi-cis-neoclausenamide (11) as
which is identical with the result of 11:9 = 2:1 (mol ratio). The
product 9 should be (3R,4R,5S,6R)-cis-neo-clausenamide.
½
a 2D0
ꢁ
+140.5 (c 0.56, CHCl3).
Reduction of 24 with NaBH4 in methanol gave a mixture of two
a main isomer,
C6 isomer 9 and 11 in 80% combined yield, which was separated by
column chromatography, with a ratio of 11:9 being 2:1. Then they
were purified by repeated crystallization, 11 with mp: 248–250 °C,
O
OH
OH
Ph
OH
Ph
Ph
O
Ph
H
H
H
H
Ph
HO
Ph
Ph
Ph
O
b
O
O
*
a
O
N
N
N
c
N
H
H
O
HO
CH3
CH3
O
CH3
CH3
(3R,4S,5R)
20
(3R,4S,5R,6R)
5
(3R,4S,5R)
(3R,4S,5R,6S)
25
3
Scheme 2. Reagents and conditions: (a) Al(i-OPr)3/i-PrOH (90%); (b) 3,4-dihydro-2H-pyran/CH2Cl2 (85%); (c) L-selectride/THF; TsOH/EtOH, rt (two steps, 75%).

2114
Z. Feng et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2112–2115
epi-cis-Clausenamide, a C6 isomer of cis-clausenamide, could
been fully determined. (ꢀ)clausenamide(1) showed potent noo-
tropic activity in many behavioral experiments, and is developed
as a promising antidementia drug. The nootropic activity of
other stereoisomers of clausenamide were evaluated herein in
LTP assays compared with (ꢀ)clausenamide (1), as a positive
control.
Activity data in enhancing LTP for the all stereoisomers of clau-
senamide are reported in Table 1. Results showed that 60 min after
compounds administration, 7 increased PS amplitude by 105.4%,
16 increased PS amplitude by 107.8%, 9 increased PS amplitude
by 92.3% in comparison with before compounds treatment. The in-
creased PS amplitude is over 30% and can maintained for more
than 40 min, indicating that the three stereoisomers could increase
basal synaptic transmission and induce LTP formation. Moreover,
the increased PS amplitude (%) of the three isomers are greater
than that of (ꢀ)clausenamide (1) (58.1%), suggesting that 7, 9
and 16 had more potent nootropic activity than 1.
not be produced by reduction of cis-clausenamidone. The prepara-
tion of (3R,4R,5R,6R)-epi-cis-clausenamide 13 required a Re reduc-
tion of C6@O of (3R,4R,5R) cis-clausenamidone 22. Since the Re
reduction of C6@O in the C4/C5 cis series (4R,5R) is very unfavor-
able, for the preparation of compound 13, Scheme 4 was modified
by using compound (+)(3R,4S,5R,6R)epi-neoclausenamide 5, a com-
pound carrying C6(R) configuration as starting material instead of
C6@O (Scheme 4).
The C3–OH in 5 was first transferred into the acid labile pyranyl
ether 27. The C6–OH was acetylated to form the acid stable ester
29. By acid treatment to set free the C3–OH yielded compound
31, which was ready to build the cis part by the method used for
compound 7. The epi-cis-clausenamidyl acetate 35 obtained was
then hydrolyzed in basic medium to give compound 13,
(3R,4R,5R,6R)epi-cis-clausenamide, in 19.5% total yield from start-
ing material 5 through six steps.
epi-Clausenamide, a C6-isomer of clausenamide, could not be
obtained from the reduction of clausenamidone above. For its
preparation, we also selected a compound carrying C6(R) configu-
ration, (3R,4R,5R,6R)epi-cis-clausenamidyl acetate 35 as starting
material. Through inversion of C3–OH and hydrolysis of acetate,
(ꢀ)(3S,4R,5R,6R)epi-clausenamide (15) was produced.
In addition, 7, 9 and 16 exhibited much more potent nootropic
activity than their enantiomers, 8, 10 and 15. Stereoisomer 7 was 5
times more active than its enantiomer 8 (with increased PS ampli-
tude by 22.5%), 16 was 6 times more active than its enantiomer 15
(with increased PS amplitude by 17.3%), and 9 was even more
times than its enantiomer 10 (with increased PS amplitude by
ꢀ5.1%).
The preparation of eight optically pure isomers, 1, 3, 5, 7, 9,
11, 13 and 15 were described above. Their enantiomers, 2, 4,
6, 8, 10, 12, 14 and 16 were obtained from the corresponding
starting material by the similar corresponding process described
above. The physical data of 16 stereoisomers were given as fol-
low (Table 1).
Results in Table 1 also showed that 60 min after compounds
administration, the increased PS amplitudes (%) of 1, 7, 9 and 16
are between 58.1 and 107.8, but other stereoisomers are between
ꢀ15.4 and 22.5. The configuration range patterns for four chiral
carbons in the four stereoisomers that could clearly increase basal
synaptic transmission and induce LTP formation are
LTP was discovered in the mammalian hippocampus by Terje
Lømo in 1966 and has remained a popular subject of neuroscien-
tific research since. LTP is believed to play a critical role in
behavioral learning, but its biological mechanisms have not yet
(3S,4R,5R,6S)(1),
(3R,4R,5R,6S)(7),
(3R,4R,5S,6R)(9)
and
(3R,4S,5S,6S)(16), respectively. These results indicated that induc-
tion of LTP has the high selectivity for the configuration of clausen-
amide stereoisomers, and the nootropic activity of stereoisomers of
clausenamide is closely related to the configuration of
stereoisomers.
We should expect to elucidate the mechanisms of compounds
(1, 7, 9, 16) enhancing LTP, such as the activation of N-methyl-D-
aspartate(NMDA) receptor and the production of brain derived
neurotrophic factor, to draw a causal link between LTP and behav-
ioral learning, and to find out the effect of compounds (1, 7, 9, 16)
on Alzheimer’s disease and vascular dementia.
In summary, an efficient and economical synthesis of the 16
(8 pairs) optically pure stereoisomers of clausenamide with four
chiral carbons was described. Based on a biomimetic synthetic
route used for the preparation of clausenamide, two racemic
intermediates clausenamidone and neoclausenamidone were
produced; through the resolution with natural Menthol, four
optically pure intermediates, 17, 18, 19 and 20 were obtained
as starting chiral material used for the synthesis of all stereoiso-
mers of clausenamide; by the strategy of elimination and regen-
eration of chiral centers and the invertion of C5 substituent
group, four other optically pure intermediates, 22, 24 and their
enantiomers 23, 25 were prepared; through a variety of reducing
agents, 12 stereoisomers of clausenamide (1–12) were prepared;
in the protecting of C6 configuration, the final 4 stereoisomers of
clausenamide (13–16) were obtained. Their nootropic activities
were evaluated by LTP assay, the result indicated that the in-
creased PS amplitude of clausenamide stereoisomers is strongly
related to the configuration of stereoisomers, and three isomers
(7, 9, 16) exhibited more potent nootropic activity than 1, how-
ever their corresponding enantiomers (8, 10, 15) displayed less
potency than 1. The discovery of three highly active compounds
(7, 9, 16) may afforded more candidates for the developing of
new nootropic drugs or antidementia drug. The high stereoselec-
tivity of inducing LTP for the configuration of clausenamide
OTHP
Ph
H
OH
OTHP
Ph
Ph
H
H
Ph
Ph
Ph
a
O
b
O
O
N
N
N
H
H
H
HO
HO
AcO
CH3
CH3
CH3
(3R,4S,5R,6R)
5
(3R,4S,5R,6R)
27
(3R,4S,5R,6R)
29
c
OH
Ph
OH
Ph
OH
Ph
H
Ph
e
H
H
Ph
Ph
d
O
N
O
O
H
N
N
AcO
H
H
CH3
AcO
AcO
CH3
CH3
(5R6R)
33
(3R,4R,5R,6R)
(3R,4S,5R,6R)
31
35
f
g
OH
Ph
H
OH
Ph
H
Ph
Ph
O
O
N
N
H
H
HO
HO
CH3
CH3
(3S,4R,5R,6R)
15
(3R,4R,5R,6R)
13
Scheme 4. Reagents and conditions: (a) 3,4-dihydro-2H-pyran/CH2Cl2, rt (84%); (b)
acetic anhydride/pyridine (80%); (c) TsOH/EtOH, rt (78%); (d) Na2Cr2O7/H2SO4/H2O/
CH2Cl2, 30–40 °C (68%); (e) NaBH4/HOAc/CH2Cl2, 0 °C–rt (73%); (f) K2CO3/CH3OH
(75%); (g) DEAD/PPh3/ClCH2COOH/toluene, rt; TsOH/CH3OH, rt (two steps, 18%).

Z. Feng et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2112–2115
2115
Table 1
The physical properties and their activity data in enhancing LTP of 16 optically active stereoisomers of clausenamide
No.
Compound
Absolute configuration
Mp (°C)
½
a 2D0
ꢁ
(c, solvent)
Increased PSA%:means SD
15 min
30 min
60 min
58.1 4.2*
6.4 4.1
ꢀ2.5 18.9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
(ꢀ)Clausenamide
3S,4R,5R,6S
3R,4S,5S,6R
3R,4S,5R,6S
3S,4R,5S,6R
3R,4S,5R,6R
3S,4R,5S,6S
3R,4R,5R,6S
3S,4S,5S,6R
3R,4R,5S,6R
3S,4S,5R,6S
3R,4R,5S,6S
3S,4S,5R,6R
3R,4R,5R,6R
3S,4S,5S,6S
3S,4R,5R,6R
3R,4S,5S,6S
161–162
161–162
186–187
186–187
220–222
221–222
196–198
197–199
164–166
168–170
248–250
250–252
199–202
198–199
107–109
108–110
ꢀ146 (0.21, MeOH)
+147 (0.19, MeOH)
+89.5 (0.2, MeOH)
ꢀ88.6 (0.18, MeOH)
+36.5 (0.15, MeOH)
ꢀ37.7 (0.16, MeOH)
ꢀ6.07 (0.675, CHCl3)
+6.30 (0.46, CHCl3)
+66.7 (0.46, MeOH)
ꢀ65.3 (0.32, MeOH)
+19.2 (0.53, MeOH)
ꢀ20.7 (0.265, MeOH)
ꢀ38.37 (0.66, CHCl3)
+39.7 (0.78, CHCl3)
ꢀ203 (0.242, MeOH)
+201 (0.345, MeOH)
31.8 0. 4
ꢀ9.4 0.3
ꢀ0.7 29.6
ꢀ18.2 14.0
4.7 8.0
38.5 8.9
10.1 13.1
ꢀ29.1 7.9
ꢀ34.5 4.3
ꢀ5.3 10.3
ꢀ8.1 15.2
41.2 8.6
2.9 5.9
50.9 19.9
ꢀ1.8 6.6
10.1 25.7
ꢀ11.9 9.4
0.3 12.3
9.7 11.7
ꢀ8.8 22.5
47.5 15.0
(+)Clausenamide
(+)Neoclausenamide
(ꢀ)Neoclausenamide
(+)epi-Neoclausenamide
(ꢀ)epi-Neoclausenamide
(ꢀ)cis-Clausenamide
(+)cis-Clausenamide
(+)cis-Neoclausenamide
(ꢀ)cis-Neoclausenamide
(+)epi-cis-Neoclausenamide
(ꢀ)epi-cis-Neoclausenamide
(ꢀ)epi-cis-Clausenamide
(+)epi-cis-Clausenamide
(ꢀ)epi-Clausenamide
(+)epi-Clausenamide
1.1 28.5
ꢀ9.4 11.9
18.2 15.4
105.4 24.7*
22.5 14.5
92.3 22.4*
ꢀ5.1 17.5
21.7 37.1
ꢀ15.4 16.8
5.4 24.2
26.2 2.3
ꢀ12.7 4.4
35.0 12.9
ꢀ5.9 6.7
ꢀ3.0 18.9
ꢀ11.5 10.2
7.2 15.8
1.7 5.2
9.6 12.6
ꢀ2.2 21.7
17.3 22.5
36.0 22.8
107.8 12.8*
The average amplitude of the population spikes recorded 30 min before drug administration was defined as 100%. The average amplitude of the population spikes recorded
after drug administration was defined as PSA%. The increased PSA% values in table 1 were calculated by the formula: PSA% ꢀ 100%. All data are represented as mean SD of 5
observations.
*
p < 0.05.
3. (a) Liu, Y.; Shi, C. Z. Acta Pharm. Sin. 1991, 26, 166; (b) Chen, Y.R.; Yang, M.H.;
stereoisomers may contribute to the study on biological mecha-
nisms of LTP.
Hang, L. U.S. Patent 4879390, 1989.; (c) Chen, Y.R.; Yang, M.H.; Hang, L.; Liu, G.T.
E.P. Patent 0172514, 1985.; (d) Duan, W. Z.; Zhang, J. T. Chin. Med. J. 1998, 111,
1035.
4. (a) Liu, S. L.; Zhang, J. T. Acta Pharm. Sin. 1998, 33, 254; (b) Liu, S. L.; Zhao, M. R.;
Acknowledgements
Zhang, J. T. Acta Pharm. Sin. 1999, 325; (c) Tang, K.; Zhang, J. T. Neurol. Res. 2002,
24, 473.
We are grateful to the Chinese Post-doctor Foundation and Na-
tional Natural Science Foundation of China for their financial sup-
port, and to professor Jun-Tian Zhang and the group of the
neouropharmacological study laboratory for affording LTP assay
data of 16 stereoisomers of clausenamide.
5. (a) Zhang, J.T.; Huang, L. U.S. Patent 20030207935, 2003.; (b) Tang, K.; Zhang, J.
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