Total synthesis of munchiwarin, a triprenylated chalcone from Crotalaria medicagenia

Article abstract of DOI:10.1021/ol702187m

An efficient method is developed for the synthesis of the modified triprenylated chalcone, munchiwarin (1), isolated from the roots of Crotalaria medicagenia. The synthesis of 1 utilizes a Claisen-Schmidt condensation between 2,4-dihydroxy-3,5-C-diprenyl

Full text of DOI:10.1021/ol702187m

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5369-5372
Total Synthesis of Munchiwarin, a
Triprenylated Chalcone from Crotalaria
medicagenia#
T. Narender,*,§ K. Papi Reddy,§,† Shweta,§,‡ Kumkum Srivastava,
|
D. K. Mishra, and S. K. Puri
DiVision of Medicinal and Process Chemistry, DiVision of Parasitology, and DiVision
of Botany, Central Drug Research Institute, Lucknow-226 001 (U.P), India
tnarender@rediffmail.com
Received September 11, 2007
ABSTRACT
An efficient method is developed for the synthesis of the modified triprenylated chalcone, munchiwarin (1), isolated from the roots of Crotalaria
medicagenia. The synthesis of 1 utilizes a Claisen Schmidt condensation between 2,4-dihydroxy-3,5-C-diprenyl acetophenone and 4-methoxy
−
benzaldehyde in the presence of Ba(OH)2 to yield the unusual chalcone 5 that contains a nine-membered ether ring. Further prenylation of 5
with 1-bromo-3-methylbut-2-ene and its subsequent demethylation with BBr3 gave munchiwarin (1).
Chalcones are main precursors for the biosynthesis of a large
number of ubiquitous flavonoids, which are frequent com-
ponents of the human diet. In vitro and in vivo antimalarial1
and antileishmanial activity2 has been reported for licochal-
cone A (Figure 1) isolated from Glycyrrhiza inflata Batalin
(licorice). Medicagenin 2 isolated from the roots of Crota-
laria medicagenia DC, exhibits antimalarial activity3 (Figure
1). 3-Methoxy-4-hydroxy lonchocarpin isolated from the
Lonchocarpus utilis A.C. Sm. inhibits NADH:ubiquinone
oxidoreductase activity (Figure 1).4
* Address correspondence to this author. Phone: +91 522 2612411.
Fax: +91 522 2623405.
# CDRI Comunication No.7328.
§ Division of Medicinal and Process Chemistry.
Division of Parasitology.
| Division of Botany.
† Total synthesis of the munchiwarin (1) and its analogues.
Figure 1. Naturally occurring chalcones: licochalcone A from
‡ Isolation of the munchiwarin (1) from C. medicagenia.
Glycyrrhiza inflata (licorice), 3-methoxy-4-hydroxy lonchocarpin
from Lonchocarpus utilis, and munchiwarin (1) and medicagenin
(2) from Crotalaria medicagenia.
(1) Chen, M.; Theander, T. G.; Christensen, S. B.; Hviid, L.; Zhai, L.;
Kharazmi, A. Antimicrob. Agents Chemother. 1994, 38, 1470.
(2) Chen, M.; Christensen, S. B.; Blom, J.; Lemmich, E.; Nadelmann,
L.; Fich, K.; Theander, T. G.; Kharazmi, A. Antimicrob. Agents Chemother.
1993, 37, 2550. Chen, M.; Christensen, S. B.; Theander, T. G.; Kharazmi.
A. Antimicrob. Agents Chemother. 1994, 38, 1339.
(3) Narender, T.; Shweta; Tanvir, K.; Rao, M. S.; Srivastava, K.; Puri,
S. K. Bioorg. Med. Chem. Lett. 2005, 15, 2453.
Recent biological evaluation of various chalcones has also
revealed anticancer,5 anti-inflammatory,6 antimitotic,7 anti-
10.1021/ol702187m CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/22/2007

With use of the retrosynthetic strategy outlined in Scheme
1, 2,4-dihydroxy-3,5-C-diprenyl acetophenone 3a was pre-
pared from 2,4-dihydroxy acetophenone 4 and 2-methyl-but-
3-en-2-ol with BF3-Et2O.16 It was originally planned to carry
out a Claisen-Schmidt condensation between 2,4-dihydroxy-
3,5-C-diprenyl acetophenone 3a and 4-methoxy benzalde-
hyde to obtain the diprenylated chalcone 6 (Scheme 2).
Scheme 1
Scheme 2
tuberculosis,8 cardiovascular,9 cell differentiation inducing,10
nitric oxide regulation modulatory,11 and antihyperglycemic
activities.12
As a part of our ongoing interest in developing new
antiparasitic agents, we have recently reported the antima-
larial activity of a few naturally occurring prenylated
chalcones3 and the antileishmanial activity of chromenodi-
hydrochalcones.13
In continuation of our search for an efficient antimalarial
agent, munchiwarin (1) was isolated from the roots of
Crotalaria medicagenia DC (yield: 0.0025% from 1 kg of
roots).14 Munchiwarin (1) was the first naturally occurring
chalcone with a 2,2,6-triisoprenylcyclohex-5-ene-1,3-dione
skeleton previously isolated from another Crotalaria species
(C. trifoliastrum) and characterized by 2D NMR spectros-
copy and X-ray crystallography; however, the antimalarial
activity was not studied.15 The goal of the present investiga-
tion was to devise and execute a practical synthesis of
munchiwarin (1) and its analogues and to study their
antimalarial activity.
Further prenylation on the diprenylated chalcone 6 might
then provide the triprenylated chalcone 11 and subsequent
demethylation of 11 would give desired munchiwarin (1).
However, the Claisen-Schmidt condensation17 instead pro-
vided the unusual chalcone 5 in 92% isolated yield (Scheme
2), which possesses a nine-membered ether ring. The
structure of 5 was confirmed by 2D NMR experiments
including HMBC, HSQC, and COSY (Figure 2). Compound
(4) Fang, N.; Casida, J. E. J. Nat. Prod. 1999, 62, 205.
(5) Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.; Nakanishi, Y.; Lee,
K.-H. Bioorg. Med. Chem. Lett. 2000, 10, 699. Bois, F.; Beney, C.;
Boumendjel, A.; Mariotte, A.-M.; Conseil, G.; Di Pietro, A. J. Med. Chem.
1998, 41, 4161.
(6) Hsieh, H.-K.; Tsao, L.-T.; Wang, J.-P. J.Pharmacol. 2000, 52, 163.
Hsieh, H.-K.; Lee, T.-H.; Wang, J.-P.; Wang, J.-J.; Lin, Ch.-N. Pharma.
Res. 1998, 15, 39. Herencia, F.; Ferra´ndiz, M. L.; Ubeda, A.; Dom´ınguez,
J. N.; Charris, J. E.; Lobo, G. M.; Alcaraz, M. J. Bioorg. Med. Chem. Lett.
1998, 8, 1169.
(7) Ducki, S.; Forrest, R.; Hadfield, J. A.; Kendall, A.; Lawrence, N. J.;
McGown, A. T.; Rennison, D. Bioorg. Med. Chem. Lett. 1998, 8, 1051.
(8) Lin, y.-M.; Zhou, Y.; Flavin, M. T.; Zhou, L.-M.; Nie, W.; Chen,
F.-C. Bioorg. Med. Chem. 2002, 10, 2795.
(9) Furman, C.; Lebeau, J.; Fruchart, J.-C.; Bernier, J.-L.; Duriez, P.;
Cotelle, N.; Teissier, E. J. Biochem. Mol. Toxicol. 2001, 15, 270.
(10) Park, E. J.; Park, H. R.; Lee, J. S.; Kim, J. W. Planta Med. 1998,
64, 464.
Figure 2. 1H (in parentheses) and 13C NMR chemical shifts and
selected HMBC (1Hf13C) correlations of 5.
(11) Rojas, J.; Paya, M.; Dom´ınguez, J. N.; Luisa Ferrandiz, M. Bioorg.
Med. Chem. Lett. 2002, 12, 1951. Herencia, F.; Ferrandiz, M. L.; Ubeda,
A.; Guillen, I.; Dom´ınguez, J. N.; Charris, J. E.; Lobo, G. M.; Alcaraz, M.
J. Free Radical Biol. Med. 2001, 30, 43.
(12) Satyanarayana, M.; Tiwari, P.; Tripathi, B. K.; Srivastava, A. K.;
Pratap, R. Bioorg. Med. Chem. 2004, 12, 883.
(13) Kumar, J. K.; Narender, T.; Rao, M. S.; Rao, P. S.; Toth, G.; Balazs,
B.; Duddeck, H. J. Braz. Chem. Soc. 1999, 10, 278. Narender, T.; Shweta;
Gupta, S. Bioorg. Med. Chem. Lett. 2004, 14, 3913. Narender, T.; Tanvir,
K.; Shweta; Nishi; Goyal, N.; Gupta, S. Bioorg. Med. Chem. 2005, 13,
6543.
5 might be forming by migration of chalcone 6’s C-3′ prenyl
group to the C-4′ hydroxy group via a retro-Claisen rear-
rangement followed by cyclization of the migrated C-3′
prenyl group and C-5′ prenyl group to give the nine-
membered ether ring (Figure 3).
(14) Please see the Supporting Information for the isolation procedure.
(15) Yang, S. W.; Cordell, G. A.; Lotter, H.; Wagner, H.; Mouly, B. C.;
Appa Rao, A. V. N.; Rao, P. S. J. Nat. Prod. 1998, 61, 1274.
(16) Jain, A. C.; Lal, P.; Seshadri, T. R. Tetrahedron 1970, 26, 2631
(17) Barrios, J.; Marinas, J. M.; Sinisterra, J. V. Bull. Soc. Chim. Belg.
1986, 95, 107.
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Org. Lett., Vol. 9, No. 26, 2007

Scheme 3
ring and subsequent Claisen rearrangement of the O-modified
prenyl group (Figure 3) to generate the diketo system in ring
B with the activated C-3′ as in 12. Further prenylation with
prenylbromide gave the triprenylated chalcone O-methyl-
munchiwarin 11. Finally O-methylmunchiwarin 11 was
demethylated with borontribromide (BBr3) in anhydrous CH2-
Cl2 at -78 °C to rt to provide the desired munchiwarin (1)
in 53% isolated yield.
Prenylation of chalcone 9 under similar conditions also
provided the triprenylated chalcone 10 with the munchiwarin
skeleton (Scheme 3). These results support our proposal that
the O-methylmuchiwarin 11 and its analogue 10 might have
formed through intermediates 12 and 14 (Figure 3), respec-
tively. However, further studies are required to confirm the
reaction mechanism.
Figure 3. Possible reaction pathway in the formation of chalcones
5, 10, and 11.
Condensation of 2,4-dihydroxy-3,5-C-diprenyl acetophe-
none 3a with 4-hydroxy benzaldehyde instead of 4-methoxy
benzaldehyde led to formation of chalcone 7, in which
migration of the C-5′ prenyl group to the C-4′ hydroxy group
(retro-Claisen rearrangement) and subsequent cyclization of
the migrated C-5′ prenyl group and C-3′ prenyl group led to
a nine-membered ether ring (Scheme 2). To confirm the
sequence of reactions (Claisen-Schmidt condensation, retro-
Claisen rearragement, and subsequent cyclization) in the
formation of 5 and 7, a reaction was carried out in the
absence of benzaldehyde. There was no retro-Claisen rear-
rangement and subsequent cyclization supports that the
Claisen-Schmidt condensation is the first step to give the
diprenylated chalcone 2/6 (Figure 3). The extended conjuga-
tion in the diprenylated chalcone 2/6 permits further rear-
rangements to give chalcones 5 and 7 (Scheme 2).
Munchiwarin (1) was evaluated for antimalarial activity18
against the chloroquine (CQ) sensitive 3D7 strain of P.
falciparum by SYBR Green based assay19 and ID50 for
antimalarial response was determined as 2 µM while the ID50
Scheme 4
To determine the role of the substituent effect in ring-A a
reaction was carried out with aldehydes with deactivating
groups instead of ring-A activating groups. Condensation of
2,4-dihydroxy-3,5-C-diprenyl acetophenone 3a with 3-py-
ridinecarboxaldehyde and 2,4-dichlorobenzaldehyde surpris-
ingly gave chalcones 8 and 9, respectively (Scheme 3). In
the presence of activating groups on ring-A (OMe and OH),
prenyl group migration occurs to give 5 and 7, whereas in
the presence of deactivating groups on ring-A reaction occurs
without migration to give 8 and 9.
Further prenylation of 5 by using 1-bromo-3-methylbut-
2-ene (prenyl bromide) and NaH in DMF at -50 °C provided
O-methylmunchiwarin 11 in 95% isolated yield, which
possesses three prenyl groups in ring-B (Scheme 4). This
might be occurring via opening of the nine-membered ether
Org. Lett., Vol. 9, No. 26, 2007
5371

for the reference drug, chloroquine, was 0.015 µM in the
same assay. The ID50 of 1 for cytotoxicity assay20 against
the Vero cell line (C-1008: monkey kidney fibroblast)21 was
determined as 15.1 µM, thus 1 showed a poor therapeutic
index (TI) of 7.55.
Acknowledgment. The authors are grateful to the Direc-
tor of the CDRI in Lucknow, India, for his constant en-
couragement and support to our program on the isolation of
bioactive compounds from the Indian medicinal plants and
synthesis of antiparasitic agents. We also thank Dr. Katherine
Maloney, UCSD, USA, for editing the manuscript, the SAIF
Division for spectral data, J. P. Chaturvedi for technical
support, and the CSIR in New Delhi for financial support.
In summary, we isolated the triprenylated chalcone
munchiwarin 1 from the roots of C. medicagenia and
evaluated its antimalarial activity. We also achieved the first
total synthesis of munchiwarin 1 and its analogues 10 and
11 from commercially available 2,4-dihydroxy acetophenone
4, discovering an unexpected route to the nine-membered
ether ring containing chalcones 5 and 7 in the process.
Further studies are underway to examine the reaction
mechanism, to adjust the conditions to synthesize larger
cyclic ether compounds, and to synthesize munchiwarin (1)
analogues for further biological activity studies.
Note Added after ASAP Publication. There was an error
in Scheme 4 in the version published ASAP on November
22, 2007; the corrected version was published November 26,
2007.
Supporting Information Available: One- and two-
dimensional NMR, mass, and IR spectral data of compounds
1, 5, and 11, and one-dimentional NMR, mass, and IR
spectral data of 3a and 7-10. This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) Evalution of ID50 of munchiwarin (1): SYBR Green I-based
fluorescence (MSF) assay was used. A 200 µL sample of Asynchronous P.
falciparum parasites at 0.5% parasitemia, 1.5% hematocrit, and varying
concentration of munchiwarin (1) was incubated at 37 °C for 72 h. After
the incubation, 100 µL of lysis buffer [20 mM Tris (pH 7.5), 5 mM EDTA,
0.008% (w/v) saponin, and 0.08% (v/v) Triton X-100] containing SYBR
Green I (1 × final concentration) was added to each well and plates were
reincubated for another hour at room temperature. The plates were examined
for the relative fluorescence units (RFUs) per well using the FLUOstar,
BMG labtechnologies. The 50% inhibitory dose (ID50) was determined with
GraphPad Prism software by nonlinear regression analysis of log dose-
response curves. For both assays, micro titer plate wells containing non-
infected erythrocytes in the absence of drugs served as negative control,
while parasitized erythrocytes in the presence of chloroquine (CQ) served
as positive control.
OL702187M
(19) Smilkstein, M.; Srivilaijaoren, N.; Kelly, J. X.; Wilairat, P.; Risocoe,
M. Antimicrob. Agents Chemother. 2004, 48, 1803.
(20) The cytotoxic activity of munchiwarin (1) was determined against
the Vero cell line (C-1008; monkey kidney fibroblast) by MTT assay. The
cells (1 × 104/well) were incubated with varying concentrations of
munchiwarin (1) for 72 h and inhibitory dose (ID50) values represent the
concentration of compound required to kill 50% of the fibroblast cells.
(21) Mosmann, T. J. Immunol. Methods 1983, 65, 55.
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Org. Lett., Vol. 9, No. 26, 2007