BF3-Et2O mediated biogenetic type synthesis of chromanochalcones from prenylated chalcones via a regioselective cyclization reaction

Article abstract of DOI:10.1016/j.tetlet.2007.08.124

In continuation of our program on synthetic chalcones, we have developed a simple and convenient method for the synthesis of chromanochalcones from prenylated chalcones in high yields by regioselective cyclization using BF₃-Et₂O.

Full text of DOI:10.1016/j.tetlet.2007.08.124

Tetrahedron Letters 48 (2007) 7628–7632
BF3–Et2O mediated biogenetic type synthesis
of chromanochalcones from prenylated chalcones
via a regioselective cyclization reactionI
T. Narender* and K. Papi Reddy
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, UP, India
Received 10 July 2007; revised 19 August 2007; accepted 30 August 2007
Available online 4 September 2007
Abstract—In continuation of our program on synthetic chalcones, we have developed a simple and convenient method for the syn-
thesis of chromanochalcones from prenylated chalcones in high yields by regioselective cyclization using BF3–Et2O.
ꢀ 2007 Elsevier Ltd. All rights reserved.
OH
The benzopyran system is frequently encountered in
many natural products and exhibits significant biologi-
cal activity such as anti-HIV,1a,b antihypertensive1c,d
and antifeedant.1e Several pharmaceutical compounds
(Fig. 1) such as vitamin E (antioxidant),2 clusifoliol
(antitumour)3 and troglitazone (diabetes)4 also possess
the benzopyran moiety. The relatively high incidence
of the benzopyran unit in natural products is partially
attributable to the numerous prenylation and cyclization
reactions in many polyketide biosynthetic pathways.5
Methods to prepare such chromans include the use of
HCOOH,6 H2SO4,7 Montmorillonite KSF clay,8 Zeolite
HSZ-3609 and AlCl3/HCl.10
OH
OH
O
O
O
OH
O
Dorsmanin A
Crotamadine
R1
O
OH
O
R2
HO
Vitamin E
(Antioxidant)
O
Crotaramosmin: R1=OH; R2=H
Crotaramin: R1=OCH3; R2=H
Crotin: R1, R2=OH
O
O
NH
S
O
O
OH
O
Clusifoliol
(Antitumor agent)
Troglitazone
(Antidiabetic agent)
HO
As a part of our ongoing interest in developing new
antiparasitic agents, we have recently reported on the
antimalarial activity of a few naturally occurring prenyl-
ated chalcones11a and the antileishmanial activity of
chromenodihydrochalcones, that is, crotaramosmin,
crotaramin and crotin11b–d (Fig. 1). To improve the anti-
parasitic activity, and we synthesized several prenylated
chalcones and chromenochalcones, evaluated their
antiparasitic activity and further utilized them for the
synthesis of chromanochalcones in order to study the
structure activity relationships.
Figure 1. Crotamadine from Crotalaria madurensis; Dorsmanin A
from Dorstenia mannii, crotaramosmin, crotaramin and crotin from
Crotalaria ramosissima and biologically active compounds (vitamin E,
Troglitazone and Clusifoliol) possessing a chroman ring.
Initial attempts to synthesize chromanochalcones
(Scheme 1) from readily available chalcones by the fol-
lowing methods failed: (i) cyclization of the prenyl group
of chalcone using routinely used acids such as HCOOH/
H2SO4 led to the formation of chromanoflavanone; (ii)
synthesis from chromenochalcones using several reduc-
ing agents such as Pd/C and NaBH4/NiCl2 failed to re-
duce the chromene double bond selectively and formed
the fully saturated chromanodihydrochalcones; (iii)
Keywords: Chromanochalcones; Regioselective cyclization; BF3–Et2O;
Biogenetic type synthesis.
q CDRI Communication No. 7290.
*
Corresponding author. Tel.: +91 522 2612411–17; fax: +91 522
2623405; e-mail: tnarender@rediffmail.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.124

T. Narender, K. P. Reddy / Tetrahedron Letters 48 (2007) 7628–7632
7629
3''
OR
5''
4''
2''
1''
OR
HCOOH
(i)
4
OR
OR
H2O
OR
BF3-Et2O
BF3
O
O
H
O
4'
5'
HO
OH
O
HO
β
1
α
2'
OH
O
-
O
O +
OH
O
O
B
F
F
O
Flavanone
Prenylated chalcone
Figure 2. Possible reaction mechanism.
OR
OR
Pd/C
(ii)
O
OH
O
O
OH
O
Dihydrochromanochalcone
Chromenochalcone
OMe
OR
OR
4
O
O
OMe
O
OH
O
OH
BF3-Et2O/3h
DDQ
(iii)
OH
HO
Flavanone
β
1
2'
4'
Dioxane
97%
O
OMe
α
1''
5'
2''
1'
OH
O
O
O
4''
O
Dihydrochromanochalcone
Chromenochalcone
3''
5''
1a
1b
Scheme 1. (i) Cyclization of prenylated chalcone gave chromano-
flavanone; (ii) hydrogenation of chromenochalcone provided
chromanodidhydrochalcone; and (iii) dehydrogenation led to
chromenochalcone.
O
Scheme 2. Biogenetic type synthesis of chromanochalcones from
prenylated chalcones using BF3–Et2O.
Table 1. Synthesis of chromanochalcones by regioselective cyclization of C-alkylated (prenylated and phytylated) polyhydroxychalcones using
BF3–Et2O
Entry
Substrate
Product
Yielda (%)
OMe
OMe
HO
OH
O
OH
1
97
1aO
O
1b
OH
OH
O
OH
HO
OH
2
3
94
98
2a O
2b
O
O
OH
O
HO
OH
O
3a
3b
OMe
OMe
O
OH
O
HO
OH
4
5
6
89
96
4b
4a
O
Me
Me
O
OH
O
HO
OH
O
5a
5b
OMe
OMe
OMe
OMe
O
OH
HO
OH
O
95
6a
(continued on next page)
6b
O

7630
T. Narender, K. P. Reddy / Tetrahedron Letters 48 (2007) 7628–7632
Table 1 (continued)
Entry
Substrate
Product
Yielda (%)
NO
2
NO
2
O
OH
O
HO
OH
O
7
93
7a
7b
O
OH
HO
OH
O
8
9
94
93
O
NO2
8b
NO2
8a
O
OH
HO
OH
O
9a
O
9b
Me
Me
O
OH
O
HO
OH
O
10
11
92
91
10b
10a
Me
Me
N
N
Me
Me
O
OH
HO
OH
11a
11b
O
O
OH
OH
12
13
94
92
12a
OH
O
O
O
12b
Me
Me
OH
OH
O
13a
O
OH
13b
O
OMe
OMe
14b
O
OH
87
95
HO
OH
O
14a O
14b
OMe
OMe
15b
OH
O
OH
HO
O
O
15a
15b
a Isolated yields.
b Stereochemistry was not determined.

T. Narender, K. P. Reddy / Tetrahedron Letters 48 (2007) 7628–7632
7631
DDQ catalyzed dehydrogenation of fully saturated
Acknowledgements
chromanodihydrochalcone also failed to dehydrogenate
the required saturated double bond selectively and pro-
vided chromenochalcone.
The authors are thankful to the Director and SAIF
Division of CDRI. K.P.R. thanks the CSIR, New Delhi,
for financial support.
A few natural chromanochalcones, which contain an
a,b-unsaturated double bond and a saturated chroman
ring (dihydrobenzopyran) in the same molecule, have
appeared in the literature (Fig. 1: Crotamadine and
Dorsmanin A).12,13 In continuation of our efforts to syn-
thesize chromanochalcones, we herein report the bioge-
netic type synthesis of chromanochalcones by
regioselective cyclization of prenyl group of the preny-
lated chalcones using BF3–Et2O.
Supplementary data
Spectral data of all the compounds associated with this
article are available as supplementary data. It can be
downloaded from the internet. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2007.08.124.
Recently, we developed a new and simple methodology
for the synthesis of chalcones in high yields using BF3–
Et2O.14 We wanted to utilize BF3–Et2O for regioselec-
tive cyclization and anticipated that BF3–Et2O might
form a complex with the chelated hydroxyl group (C-
20) and the a,b-unsaturated carbonyl group of the
prenylated chalcone. This complexation prevents the
formation of a flavanone. The second mole of the re-
agent might provide cyclization of the prenyl group to
give the chromanochalcone (Fig. 2).
References and notes
1. (a) Kashman, Y.; Gustafson, K. R.; Fuller, R. W.;
Cardellina, J. H.; McMahon, J. B., II; Currens, M. J.;
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5497.
To investigate this possibility we carried out a cycliza-
tion reaction with the prenylated chalcone 20,40,-dihy-
droxy-4-methoxy-50-C-prenylchalcone
1a
in
the
presence of BF3–Et2O. Gratifyingly, regioselective
cyclization of the prenyl group occurred to give exclu-
sively chromanochalcone 1b, but we did not observe
formation of the corresponding flavanone (Scheme
2).15 To demonstrate the generality of the reaction we
have used several prenylated chalcones 2a–13a and syn-
thesized chromanochalcones 2b–13b in excellent yields
(Table 1).
3. (a) Seeram, N. P.; Jacobs, H.; McLean, S.; Reynolds, W.
F. Phytochemistry 1998, 49, 1389–1391; (b) Tanaka, T.;
Asai, F.; Iinuma, M. Phytochemistry 1998, 49, 229–232.
4. Matsumoto, K.; Miyake, S.; Yano, M.; Ueki, Y.; Tom-
inaga, Y. Lancet 1997, 350, 1748.
Several natural chalcones exist with long chain alkyl
groups such as geranyl, farnesyl and phytyl. We also
prepared such chalcones and succeeded to cyclize the
long chain alkyl group selectively to give chromano-
chalcones 14b and 15b without the formation of the
corresponding flavanones (Table 1). Recently, we
demonstrated the tolerability of BF3–Et2O towards acid
or base sensitive functional groups such as O-acyl and
N-acyl groups, therefore BF3–Et2O can be used as a
regioselective cyclizing agent in the presence of such
functional groups.14 In the case of acid or base catalyzed
cyclizations, these sensitive groups undergo hydrolysis
leading to deacylated compounds along with the forma-
tion of flavanone.
5. Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao,
G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc.
2000, 122, 9939–9953.
6. Pushpa, B.; Rameshwar, D. Indian J. Chem. 2002, 41B,
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7. Charles, D. H.; William, A. H. J. Org. Chem. 1940, 5, 212–
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8. William, G. D.; Jeffrey, M. C.; Victor, B. Tetrahedron
Lett. 1990, 31, 3241–3244.
9. Bigi, F.; Carloni, S.; Maggi, R.; Muchetti, C.; Rastelli, M.;
Sartori, G. Synthesis 1998, 301–304.
10. Wang, Y.; Wu, J.; Xia, P. Synth. Commun. 2006, 36, 2685–
2698.
11. (a) Narender, T.; Shweta; Tanvir, K.; Rao, M. S.;
Srivastava, K.; Puri, S. K. Bioorg. Med. Chem. Lett. 2005,
15, 2453–2455; (b) Kumar, J. K.; Narender, T.; Rao, M.
S.; Rao, P. S.; Toth, G.; Balazs, B.; Duddeck, H. J. Braz.
Chem. Soc. 1999, 10, 278–280; (c) Narender, T.; Shweta;
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(d) Narender, T.; Tanvir, K.; Shweta; Nishi; Goyal, N.;
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In summary, we have demonstrated the use of BF3–
Et2O as a regioselective cyclizing agent for the synthesis
of chromanochalcones from prenylated chalcones and
long chain phytylated chalcones. Our method has sev-
eral advantages over existing methods such as no side
reactions (flavanone formation), high yields, simple
workup, short reaction times and tolerates base or acid
sensitive functional groups. This methodology can be
used for the synthesis of several natural products and
their analogues.
14. Narender, T.; Reddy, K. P. Tetrahedron Lett. 2007, 48,
3177–3180.

7632
T. Narender, K. P. Reddy / Tetrahedron Letters 48 (2007) 7628–7632
15. Representative procedure for the preparation of chroman-
ochalcones from prenylated chalcones: To a stirred solution
of 20,40,-dihydroxy-4-methoxy-50-C-prenyl chalcone 1a
(500 mg, 1.4 mmol) in dry 1,4-dioxane (5 mL), was added
gradually BF3–Et2O (0.23 mL, 1.7 mmol) at room tem-
perature. The solution was stirred for 3 h at room
temperature. After dilution with ethyl acetate (100 mL),
the mixture was washed with water (3 · 30 mL) to
discharge the colour and the BF3–Et2O complex. The
organic solution obtained after extraction was dried over
anhyd Na2SO4 and evaporated under reduced pressure.
The crude mixture was purified by silica gel column
chromatography to afford chromanochalcone 1b (485 mg,
97%).