Total synthesis of a novel tetracyclic alkaloid, cassiarin F from the flowers of Cassia siamea

Article abstract of DOI:10.1021/ol201674a

A novel alkaloid, cassiarin F (1), which showed potent antiplasmodial activity against Plasmodium falciparum in vitro, was isolated from the flowers of Cassia siamea, and its structure was elucidated on the basis of 2D NMR analyses. A total synthesis of 1

Full text of DOI:10.1021/ol201674a

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4344–4347
Total Synthesis of A Novel Tetracyclic
Alkaloid, Cassiarin F from the Flowers of
Cassia siamea
Jun Deguchi,† Tomoe Hirahara,† Shiori Oshimi,† Yusuke Hirasawa,† Wiwied Ekasari,‡
Osamu Shirota,§ Toshio Honda,† and Hiroshi Morita*,†
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41 Shinagawa-ku,
Tokyo 142-8501, Japan, Faculty of Pharmacy, Airlangga University, Jalan
Dharmawangsa Dalam, Surabaya 60286, Indonesia, and Faculty of Pharmaceutical
Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki City,
Kagawa 769-2193, Japan
moritah@hoshi.ac.jp
Received June 22, 2011
ABSTRACT
A novel alkaloid, cassiarin F (1), which showed potent antiplasmodial activity against Plasmodium falciparum in vitro, was isolated from the
flowers of Cassia siamea, and its structure was elucidated on the basis of 2D NMR analyses. A total synthesis of 1 was also achieved by employing
the Suzuki coupling constructing biaryl unit, nucleophilic aromatic substitution, and HoubenꢀHoesch type ring construction as key steps.
CassiasiameaLam. (Leguminosae) hasbeenusedwidely
in traditional medicine, particularly for treatment of periodic
fever and malaria in Indonesia.1 Recently we isolated cassiar-
in A (2),2 an alkaloid with an unprecedented tricyclic skeleton
exhibiting potent antiplasmodial activity, and chrobisiamone
A,3 a bischromone, from the leaves of C. siamea.
Owingtotheattractivebiological activityand theunique
structural feature of cassiarin A, which showed in vivo
antimalarial4 and vasorelaxant activities,5 we investigated
its total synthesis and succeeded in establishing an efficient
synthetic strategy.6 In 2009 we reported the isolation of
new types of dimeric alkaloids, cassiarins D and E from the
flowers of C. siamea.7
† Hoshi University.
‡ Airlangga University.
§ Tokushima Bunri University.
(1) (a) Mbatchi, S. F.; Mbatchi, B.; Banzouzi, J. T.; Bansimba, T.;
Nsonde Ntandou, G. F.; Ouamba, J. M.; Berry, A.; Benoit-Vical, F. J.
Ethnopharmacol. 2006, 104, 168–174. (b) Sanon, S.; Ollivier, E.; Azas,
N.; Mahiou, V.; Gasquet, M.; Ouattara, C. T.; Nebie, I.; Traore, A. S.;
Esposito, F.; Balansard, G.; Timon-David, P.; Fumoux, F. J. Ethno-
pharmacol. 2003, 86, 143–147.
(2) Morita, H.; Oshimi, S.; Hirasawa, Y.; Koyama, K.; Honda, T.;
Ekasari, W.; Indrayanto, G.; Zaini, N. C. Org. Lett. 2007, 9, 3691–3693.
(3) Oshimi,S.;Tomizawa,Y.;Hirasawa, Y.; Honda, T.; Widyawaruyanti,
A.; Rudyanto, M.; Ekasari, W.; Indrayanto, G.; Zaini, C. N.; Morita, H.
Bioorg. Med. Chem. Lett. 2008, 18, 3761–3763.
(4) Ekasari, W.; Widyawaruyanti, A.; Zaini, N. C.; Syafruddin, D.;
Honda, T.; Morita, H. Heterocycles 2009, 78, 1831–1836.
(5) Morita, H.; Tomizawa, Y.; Deguchi, J.; Ishikawa, T.; Arai, H.;
Zaima, K.; Hosoya, T.; Hirasawa, Y.; Matsumoto, T.; Kamata, K.;
Ekasari, W.; Widyawaruyanti, A.; Wahyuni, T. S.; Zaini, N. C.; Honda,
T. Bioorg. Med. Chem. 2009, 17, 8234–8240.
Further investigation on extracts from the flowers of C.
siamea resulted in the isolation of a novel tetracyclic
alkaloid, cassiarin F (1). In this paper, we would like to
(6) Rudyanto, M.; Tomizawa, Y.; Morita, H.; Honda, T. Org. Lett.
2008, 10, 1921–1922.
r
10.1021/ol201674a
Published on Web 07/14/2011
2011 American Chemical Society

report the structure elucidation based on spectroscopic
analyses and a total synthesis of 1.
Cassarin F (1)8 was obtained as a yellow amorphous
solid, and its molecular formula was established to be
C26H21NO5 by HRESITOFMS analysis. In addition to
1H and 13C NMR data (Table 1), 2D NMR correlations
indicated that 1 had a cassiarin A type skeleton with a
biaryl moiety, which is the first example of Cassia alkaloid
(Figure 1). The biaryl moiety of 1 was considered to be
racemic from its small optical rotation value and CD
spectrum, in which no Cotton effect was observed. Cas-
siarin F (1) showed potent antiplasmodial activity against
the chloroquine-sensitive P. falciparum strain 3D7 (IC50
3.3 μM), while showing no cytotoxicity against human
blood premyelocytic leukemia (HL-60, >50 μM).
Figure 1. Selected 2D NMR correlations for cassiarin F (1) in
pyridine-d5.
Making the two disconnections shown to 1 led to 3 as the
key intermediate for the HoubenꢀHoesch type ring clo-
sure. Two further disconnections generated the three
building blocks (phenol 4, benzonitrile 5, and boronic acid
6) needed for the assembly of 3 (Figure 2). It was envisaged
that a Suzuki coupling of 5 with 6 would lead to formation
of the desired biphenyl unit.9 Then selective nucleophilic
aromatic substitution of the resulting halogenated biaryl
derivative with 4 would give the key intermediate 3.
Table 1. 1H [δH (J, Hz)] and 13C NMR Data [δC] of Cassiarin F
(1) in Pyridine-d5 at 300 K
Position
2
155.7
119.1
148.3
139.9
101.2
161.8
100.1
154.1
111.6
114.2
153.1
24.6
3
4
5
6
6.91 (1H, d, 2.2)
6.98 (1H, d, 2.2)
7
8
9
10
11
12
13
14
20
30
40
50
60
70
80
90
100
110a
110b
120
130
140
6.89 (1H, s)
2.26 (3H, s)
7.01 (1H, d, 1.0)
117.0
141.2
130.5
138.0
134.0
108.6
158.7
102.6
157.2
120.0
49.8
7.09 (1H, d, 1.0)
6.99 (1H, d, 2.4)
7.08 (1H, d, 2.4)
Figure 2. Retrosynthetic analysis for cassiarin F (1).
3.60 (1H, d, 13.3)
3.65 (1H, d, 13.3)
Our synthesis began with preparation of the boronic
acid 6, which was readily accessible from known propa-
none 7.10
206.0
29.2
21.0
1.97 (3H, s)
2.20 (3H, s)
Ketalization of 7 with ethylene glycol and subsequent
bromination with N-bromosuccinimide (NBS) gave bro-
mide 8 in good yield. The boronic ester was obtained by
halogenꢀmetal interchange with n-butyllithium and trap-
ping the generated compound with triisopropyl borate.
The desired boronic acid 6 was obtained by hydrolysis of
the ester with hydrochloric acid. Suzuki coupling of 6 with
511 was carried out in the usual manner to provide the
biaryl 9 in 84% yield (Scheme 1).
In order to confirm its unique tetracyclic structure, a
total synthesis of cassiarin F (1) was undertaken. Our
retrosynthetic analysis of 1 is outlined in Figure 2. In this
approach, the two heterocyclic rings would be constructed
at a late stage in the synthesis, because of their suscept-
ibility to acidic and basic reaction conditions.
(7) Oshimi, S.; Deguchi, J.; Hirasawa, Y.; Ekasari, W.; Widyawaruyanti,
A.; Wahyuni, T. S.; Zaini, N. C.; Shirota, O.; Morita, H. J . Nat. Prod. 2009,
72, 1899–1901.
(8) Cassiarin F (1): yellow amorphous solid; IR (KBr) νmax 3430,
3270, 1710, and 1600 cmꢀ1; UV (MeOH) λmax 202 (ε 13000), 245 (ε 3200)
and 290 (ε 1400) nm; 1H and 13C NMR (Table 1); ESIMS (þpos.) m/z 428
(M þ H)þ; HRESITOFMS m/z 428.1473 (M þ H) , calcd for
C26H22NO5 428.1498.
(9) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(10) Bringmann, G.; Gulder, T.; Reichert, M.; Meyer, F. Org. Lett.
2006, 8, 1037–1040.
(11) Kristensen, J. L. Tetrahedron Lett. 2008, 49, 2351–2354.
Org. Lett., Vol. 13, No. 16, 2011
4345

Our first trial, starting from 3 in concentrated sulfuric
acid, expectedly only led to extensive decomposition. For-
tunately, treatment of 3 with sulfuric acid in acetic acid
produced the tetracyclic core 12. Trials with different
combinations of acids or solvents are summarized
(Scheme 3). The best result was obtained with the reaction
conditions of entry 5. Thus a 30% yield of the tetracyclic
core 12 with a side product 1314 was obtained using sulfuric
acid and acetic acid in a ratio of 1:1.
Scheme 1. Synthesis of Key Biaryl Intermediate 9
Scheme 3. Construction of the Tetracyclic Core of Cassiarin F
(1) via a HoubenꢀHoesch Type Ring Closurea
The phenol 4 was readily accessed in a five-step process
from the known carboxylic acid 10.12 Treatment of 10 with
oxalyl chloride provided the corresponding acyl chloride,
which was directly reacted with N,O-dimethylhydroxyla-
mine in the presence of triethylamine to give the Weinreb
amide. The resulting Weinreb amide was treated with
MeMgBr to generate the desired methyl ketone 11 in
80% yield from 10. Debenzylation of 11 via Pd-catalyzed
hydrogenation, followed by ketalization ofcarbonyl group
with ethylene glycol, gave the desired phenol 4. Selective
nucleophilic aromatic substitution of 9 with 4 in the
presence of cesium carbonate in DMSO gave 3 in excellent
yield (Scheme 2).
a Concentration; 1 mL for 10 mg of 3. bIsolated yields.
Scheme 2. Synthesis of Key Intermediate 3 for HoubenꢀHoesch
Type Ring Closure
The tris-O-demethylation of aryl methyl ether 12 was
achieved by treatment of iodocyclohexane in DMF.15
Spectroscopic data (1H and 13C NMR, MS, and IR)
and TLC behavior of the synthesized compound were
identical to those of the authentic sample of isolated
compound.
In summary, we have isolated a novel alkaloid, cas-
siarin F (1), a hybrid compound consisting of cassiarin A
and a biphenyl unit with an acetonyl moiety. The
occurrence of a tetracyclic polysubstituted skeleton with
a biaryl unit is very rare. Cassiarin F (1) might be bio-
synthetically produced by a transformation of a
(13) (a) Cameron, D. W.; Deutscher, K. R.; Feutrill, G. I.; Hunt,
D. E. Aust. J. Chem. 1982, 35, 1451–1468. (b) Auricchio, S.; Antonella,
B.; Pastormerlo, E.; Ricca, A.; Truscello, A. M. Tetrahedron 1994, 50,
7589–7596. (c) Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J.
Am. Chem. Soc. 1995, 117, 3037–3043. (d) Yato, M.; Ohwada, T.;
Shudo, K. J. Am. Chem. Soc. 1991, 113, 691–692. (e) Amer, M. I.;
Booth, B. L.; Noori, G. F. M.; Proenca, M. F. J. R. P. J. Chem. Soc.,
Perkin Trans. 1 1983, 1075–1081.
(14) 13 should be produced by the FriedelꢀCrafts type reaction with
acetic acid. 13 was obtained in the way we predicted by the treatment of
12 with sulfuric acid in acetic acid. The position of methyl ketone of 13
was determined by NOESY correlations.
(15) (a) Zuo, L.; Yao, S.; Wang, W.; Duan, W. Tetrahedron Lett.
2008, 49, 4054–4056. (b) Since 12 has a labile functionality, methyl
ketone, acidic conditions utilizing Lewis acids such as BBr3 cannnot be
applied for this purpose. The use of Lewis acids led to significant
decomposition of the material.
Having the desired cyano compound in hand, our
attention was focused on construction of the two hetero-
cyclic rings as follows. It has been recognized that both a
Brønsted acid and Lewis acid generate ketimine species
from the corresponding nitriles in a HoubenꢀHoesch type
cyclization.13 Therefore, treatment of 3 with acid could lead
to the formation of two heterocyclic rings, simultaneously.
(12) Pearson, A. J.; Belmont, P. O. Tetrahedron Lett. 2000, 41, 1671–
1675.
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Org. Lett., Vol. 13, No. 16, 2011

bischromone, chrobisiamone A. We have also achieved
the total synthesis of cassiarin F (1) (8 steps, 10% overall
yield) by combination of the Suzuki coupling reaction,
Education, Culture, Sports, Science, and Technology of
Japan, and by grants from the Research Foundation for
Pharmaceutical Sciences and The Open Research Center
Project.
nucleophilic aromatic substitution, and
a Hou-
benꢀHoesch type ring construction as key reactions.
As such we have confirmed its structure; the strategy
with a HoubenꢀHoesch type ring construction seems to
be an innovative approach to the synthesis of the tetra-
cyclic core of 1.
Supporting Information Available. Experimental pro-
cedures for isolation of cassiarin F; preparation of com-
1
pounds 1, 3, 4, 6, 8, 9, 11, 12, and S1; copies of H, 13C
NMR, and 2D spectral data for natural cassiarin F; and
1H and 13C NMR spectral data for compounds 1, 3, 4, 8,
9, 11, 12, 13, and S1. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research from the Ministry of
Org. Lett., Vol. 13, No. 16, 2011
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