A convenient and biogenetic type synthesis of few naturally occurring chromeno dihydrochalcones and their in vitro antileishmanial activity

Article abstract of DOI:10.1016/j.bmcl.2004.05.071

2′,2′-Dimethyl chromeno dihydrochalcones are very rare in nature as plant secondary metabolites. Recently we have reported three such compounds from the plant Crotalaria ramosissima. Chromeno dihydrochalcones contain a 2′,2′-dimethyl benzopyran system, which are frequently encountered in many natural products and exhibit a variety of biological activities. We here report the strategy to conveniently synthesize naturally occurring chromeno dihydrochalcones by biogenetic type pyridine or Amberlyst-15 catalyzed chromenylation of dihydrochalcones and in vitro antileishmanial activity of chromeno dihydrochalcones and their intermediates.

Full text of DOI:10.1016/j.bmcl.2004.05.071

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3913–3916
A convenient and biogenetic type synthesis of few naturally
occurring chromeno dihydrochalcones and their
in vitro antileishmanial activityq
Tadigoppula Narender,a,* Shwetaa and Suman Guptab
aDivision of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
bDivision of Parasitology, Central Drug Research Institute, Lucknow 226 001, India
Received 13 April 2004;accepted 24 May 2004
Available online 19 June 2004
Abstract—20,20-Dimethyl chromeno dihydrochalcones are very rare in nature as plant secondary metabolites. Recently we have
reported three such compounds from the plant Crotalaria ramosissima. Chromeno dihydrochalcones contain a 20,20-dimeth-
yl benzopyran system, which are frequently encountered in many natural products and exhibit a variety of biological activities. We
here report the strategy to conveniently synthesize naturally occurring chromeno dihydrochalcones by biogenetic type pyridine or
Amberlyst-15 catalyzed chromenylation of dihydrochalcones and in vitro antileishmanial activity of chromeno dihydrochalcones
and their intermediates.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
5
R1
R2
6
4
2''
3'
8'
1
In continuation of our programme on the isolation of
bioactive compounds from the Crotalaria genus,1
Leguminosae family, we have isolated several chalcones,
chromeno chalcones and chromeno dihydrochalcones.
Recently we have reported three such 20,20-dimethyl
chromeno dihydrochalcones 1–3 (Fig. 1) from Crota-
laria ramosissima, which are very rare as plant second-
ary metabolites. So far no such natural products exist
except our compounds. Few synthetic dihydrochalcones
possessing chromenyl moiety has been prepared by solid
state method.2 Chromeno dihydrochalcones, contain
20,20-dimethyl benzopyran system, frequently encoun-
tered in many natural products and some of them
exhibit significant bioactivities3 that is anti HIV, insec-
ticidal, antiinflammatory and antifeedant activity. We
therefore, wanted to get sufficient material for testing
the biological activity of these compounds.
2'
9'
O
7'
6'
3
β
1''
2
α
10'
5'
OH
4'
O
1: R1= OCH3; R2= H
2: R1= OH; R2=H
3: R1= OH; R2=OH
Figure 1. Naturally occurring chromeno dihydro chalcones isolated
from C. ramosissima.
2. Synthesis
The general synthesis of dihydrochalcones involves the
Claisen–Schmidt condensation of acetophenone with
appropriate aldehyde and subsequent Pd/C reduction of
chalcone double bond. In case of chromeno dihydro-
chalcones that contain a sensitive functionality that is
olefinic site in chromene, reduction of the corresponding
chalcone double bond cannot be used. Initially we have
attempted to synthesize these compounds from respec-
tive chromeno chalcones (9/10) by reducing a–b unsat-
urated double bond selectively.
Keywords: Chromeno dihydrochalcones;Synthesis;Antileishmanial
activity.
q CDRI Communication No.: 6525.
* Corresponding author. Tel.: +91-0522-2212411;fax: +91-0522-222-
3405/2223938;e-mail: tnarender@rediffmail.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.05.071

3914
T. Narender et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3913–3916
O
R
HO
i
+
+
(58%)
OHC
7/8
OH
O
O
OH
O
O
4
6
5
(50-70%)
ii
R
R
O
(89%)
iii
iv
(68%)
OH
O
OH
O
9/10
11/12
7/9/11: R=OH; 8/10/12: R=OCH3
Scheme 1. Reagents and conditions: (i) pyridine, reflux at 150 °C;(ii) KOH/EtOH rt;(iii) Pd/C, H 2;(iv) DDQ/benzene.
Table 1. Pyridine catalyzed chromenylation of dihydrochalcones
Several reducing agents such as Pd/C in aprotic solvents,
4
NaBH4/NiCl2 and enzymatic reaction with Saccaro-
Entry
Substrate
Product
Isolated yield (%)
mices cerevisiae5 have failed to reduce the a–b unsatu-
rated double bond selectively without affecting the
chromene double bond in 9/106;7 and ultimately we have
ended up with fully saturated product 11/12. When we
tried to selectively dehydrogenate the fully saturated
product 11/12 using DDQ, dehydrogenation took both
the places to give starting diene 9/10 (Scheme 1).
1
2
3
4
19
20
21
22
1
2
59
55
48
50
3
23
chromenylation using 3-methyl-2-butenal in presence of
pyridine11 (Table 1) or 3-hydroxy-3-methyl but-1-yn in
presence of Amberlyst-15 cation exchange resin,12 to
give 20,20-dimethyl chromeno dihydrochalcones 1–3 and
23 (Scheme 3).
Recently Krohn et al.8 synthesized these compounds by
a different method (Scheme 2). In their attempt to
alkylate the acylchromene enolate 6 with the corre-
sponding benzyl halide 14 in presence of LDA at )80 °C
also failed except the benzyl iodide 13, which was very
unstable.
The yield, however, was very poor (ꢀ10%) when we
used Amberlyst-15.
In view of the failure to reduce the chalcone double
bond selectively and to avoid the preparation of unsta-
ble benzyl iodide and also reaction conditions to con-
dense the acylchromene enolate with the benzyl iodide,
we have changed our strategy. In our approach, we have
prepared the chalcones (16–18)9 by condensation of
resacetophenone (5) with respective substituted alde-
hydes (7,8,15) using Claisen–Schmidt method. The
resultant chalcones were converted into dihydrochal-
cones (19–22)10 using Pd/C in methanol and thus the
readily available dihydrochalcones were used for
2.1. In-vitro antileishmanial activity
Licochalcone-A13 isolated from Chinese licorice roots
and subsequently a large number of synthetic chalcones
have been reported for their antileishmanial activity and
prompted us to screen our compounds activity. Chro-
meno dihydrochalcones and their intermediates were
tested against extracellular promastigotes of Leishmania
donovani14 and intracellular amastigotes15 residing
within murine macrophages (Table 2). Our compounds
OCH3
O
LDA
+
No product
-80 oC
Br
OH
O
14
OCH3
6
OCH3
O
O
LDA
+
-80 oC
(77%)
OH
O
I
OH
6
O
13
1
Scheme 2. Preparation of chromeno dihydrochalcones by alklyating the acylenolates.

T. Narender et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3913–3916
3915
R1
R2
R1
HO
HO
i
+
OHC
R2
(30-70%)
OH
O
OH
O
16, 17, 18
7,8,15
5
(70-80%)
ii
R1
R2
R1
R2
HO
O
iii
iv
OH
O
OH
O
19, 20, 21, 22
1, 2, 3, 23
1/7/16/19: R1=OCH3; R2=H; 2/8/17/20: R1=OH; R2=H
3/22: R1=OH; R2=OH; 15/18/21/23: R1=OCH3; R2=OCH3
Scheme 3. Reagents and conditions: (i) KOH/EtOH, rt;(ii) Pd/C, H 2;(iii) 3-methyl-2-butenal/pyridine reflux at 150 °C;(iv) 3-hydroxy-3-methyl-1-
butyne/Amberlyte-15 resin in benzene at 100 °C.
Table 2. In-vitro antileishmanial activity of naturally occurring chal-
cones at 50 lg/mL dose (inhibition in percentage)
the compound has low promastigotes inhibition (15%).
The chromeno chalcone 10 and its dimethylated com-
pound 9 have good antileishmanial activity than chro-
meno dihydrochalcone 1 and its dimethylated derivative
2 indicating that the a–b unsaturated double bond also
contributing towards more antileishmanial activity. In
compounds 9/10 and 1/2 the 40-hydroxyl group is
involved in the chromene formation and these are
more potent than 40-hydroxy,4-methoxy chalcone 16,
which support the substitution at 40 position by a
large group also important for their antileishmanial
activity. Orthodihydric or orthodimethoxy substitution
pattern in ring-A (3,21) decreased the antileishmanial
activity.
Compound
Motility of
promastigotes
Promastigotes MQ amastigotes
(% inhibition) (% inhibition)
1
Nonmotile
Nonmotile
Active
78
89
47
2
Toxic
Inactive
74
3
30
84
9
Nonmotile
Nonmotile
Nonmotile
Nonmotile
Active
10
16
21
23
85
60
53
15
79
Inactive
97
Toxic
22
50
Pentamidine Nonmotile and
5 lg/mL
Stibanate
50 lg/mL
vacuolated
Active
Inactive
85
3. Conclusion
have shown 30–89% inhibition in viability of prom-
astigotes and 22–74% inhibition in amastigotes multi-
plication at 50 lg/mL dose. The most potent compound
that is chromeno chalcone 9, which has hydroxyl group
on 4-position in ring A, shown 84% inhibition against
promastigotes and 74% inhibition against amastigotes,
where as its methylated compound 10, has good prom-
astigotes inhibition (85%) but comparatively less am-
astigotes inhibition (53%). The compound 9 also has
better antileishmanial activity than the 20,40-hydroxy,4-
methoxy chalcone 16. Comparisons of the above in vitro
activity results (Table 2) disclose that hydroxyl group at
4-position in ring-A is essential for the antileishmanial
activity in chromeno chalcones. Chromeno dihydroch-
alcone 1, which has methoxy substitution similar to
compound 10 shown 78 and 47% inhibition against
promastigotes and amastigotes, respectively. The 20,20-
dimethyl chromeno dihydrochalcone 2 has 89% prom-
astigotes inhibition and toxic to amastigotes at 50 and
25 lg/mL doses and at a further low dose of 12.5 lg/mL
In summary we developed operationally simplified
method for the synthesis of chromeno dihydrochal-
cones, which contain a sensitive functional group. We
have also obtained few naturally occurring chalcones,
dihydrochalcones and chromeno chalcones as interme-
diates in the process of synthesis of chromeno dihydro-
chalcones and investigated their antileishmanial activity
to provide a scientific rational for the antiprotozoal
potency of plants used in ethnomedicine in the search of
new antiprotozoal drugs. Our results shows that the
chalcones, which contain 20,20-dimethyl benzopyran
system are potent antileishmanial agents than the simple
chalcones.
Acknowledgements
We are grateful to the Director, CDRI, Lucknow for his
constant encouragement for this programme. Shweta is

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T. Narender et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3913–3916
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