Acid catalyzed stereoselective rearrangement and dimerization of flavenes: synthesis of dependensin

Article abstract of DOI:10.1016/j.tet.2007.03.173

Appropriately substituted flavenes undergo stereoselective rearrangement and dimerization when treated with methanolic hydrochloric acid to give benzopyranobenzopyrans. A rationale for the rearrangement is proposed. This synthetic methodology has been used for a high yield synthesis of the natural product dependensin.

Full text of DOI:10.1016/j.tet.2007.03.173

Tetrahedron 63 (2007) 5227–5235
Acid catalyzed stereoselective rearrangement and dimerization
of flavenes: synthesis of dependensin
*
Mandar Deodhar, David StC Black and Naresh Kumar
School of Chemistry, University of New South Wales, UNSW, Sydney, NSW 2052, Australia
Received 5 January 2007; revised 13 March 2007; accepted 29 March 2007
Available online 4 April 2007
Abstract—Appropriately substituted flavenes undergo stereoselective rearrangement and dimerization when treated with methanolic hydro-
chloric acid to give benzopyranobenzopyrans. A rationale for the rearrangement is proposed. This synthetic methodology has been used for
a high yield synthesis of the natural product dependensin.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
There are no reports on the total synthesis of dependensin in
the literature. The heterocyclic ring system present in 1 is
quite unique and is not found in any other natural product.
The polycyclic structure of 1 contains a dense array of func-
tionality and stereochemistry, which includes two fused
benzopyran ring systems, four stereocentres and one trans
double bond. This unique structural complexity has promp-
ted the development of an efficient synthetic approach in an
attempt to develop new agents for the treatment of malaria.
The flavonoids are widely distributed in the plant kingdom.
Many natural flavonoids exist as ‘dimers’ in which two fla-
vonoid molecules are coupled together at various positions.
These dimeric flavonoids have been shown to possess a wide
range of physiological and biological properties including
antioxidant,1 anticancer,2 anti-inflammatory3 and antiviral4
activities. Some of the major limitations in using these com-
pounds as medicaments include their low abundance in the
plant material, tedious methods of extraction and purifica-
tion and limited availability of biological data. A possible
solution to these problems is the development of efficient
synthetic methodologies for these compounds.
As part of an ongoing investigation into the chemistry of
dimeric flavonoids, the synthesis of 40,7-dihydroxyflavene
2 was required. Attempts to synthesize this compound by al-
kaline hydrolysis of 40,7-diacetoxyflavene 3 resulted in the
formation of polymeric products. However, it was found
that when treated with methanolic hydrochloric acid, diace-
toxyflavene 3 undergoes stereoselective rearrangement and
dimerization to give the benzopyranobenzopyran 4, in ex-
cellent yield. The corresponding 5-hydroxy and 6-hydroxy
substituted flavenes were also synthesized with a view that
they might undergo similar rearrangement. However, treat-
ment with hydrochloric acid under similar conditions gave
a polymeric product and a complex mixture, respectively.
The dimeric flavonoid dependensin (1) was isolated as a ra-
cemate from the root bark of the Tanzanian medicinal plant
Uvaria dependens.5 The complex polycyclic architecture
was delineated by 1D and 2D NMR spectroscopies. Al-
though the biological activity of pure dependensin has not
been investigated due to unavailability of material, the crude
Uvaria extract shows potent anti-malarial activity.
MeO
OMe
OMe
OMe
H
Based on acid catalyzed dimerization of diacetoxyflavene 3,
it was envisaged that dependensin could be formed in nature
by dimerization of a trimethoxyflavene. In order to test this
hypothesis the synthesis of dependensin was attempted in
a similar way.
MeO
O
H
H
H
O
OMe
2. Results and discussion
2.1. Formation of flavenes
Dependensin (1)
Keywords: Dimers; Dependensin; Acid catalyzed dimerization; Benzopyra-
nobenzopyran.
Thecondensation of resacetophenone 5 with 4-hydroxybenz-
aldehyde was carried out in the presence of an excess of
* Corresponding author. Tel.: +61 2 9385 4698; fax: +61 2 9385 6141;
e-mail: n.kumar@unsw.edu.au
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.173

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M. Deodhar et al. / Tetrahedron 63 (2007) 5227–5235
potassium hydroxide to give 4,20,40-trihydroxy chalcone
6.6 The cyclization of 6 was then effected by heating it
with methanolic hydrochloric acid followed by acetylation
using excess acetic anhydride and pyridine to give flava-
none 8.
It is assumed that initially the flavene 3 undergoes acid
catalyzed hydrolysis to give dihydroxyflavene 2, which is
protonated and ring opened to give the stabilized benzylic
carbocation 11. This is attacked by another dihydroxy-
flavene molecule to generate another benzylic carbocation
12, which cyclizes stereoselectively to give compound 4
(Scheme 2).
Catalytic hydrogenation of 8 using palladium on charcoal
gave cis-flavanol 9 in 90% yield (Scheme 1). The stereo-
chemistry of 9 was established on the basis of an NOE ob-
served between H2 and H4. The dehydration of 9 was
carried out by heating it in toluene with a catalytic amount
of p-toluenesulfonic acid to give flavene 3 in 70% yield.
When 3 was treated with concd hydrochloric acid in metha-
nol, benzopyranobenzopyran 4 was isolated in 92% yield.
HO
OH
MeOH
HCl
3
HO
O
H
OH
1
The structure of 4 was established on the basis of H and
13C, and two-dimensional NMR experiments. The observed
important NOEs are as shown in Figure 1. However, at-
tempts to obtain a single crystal of 4 by crystallization
from various solvents were unsuccessful. The corresponding
tetraacetoxy derivative 10 was also synthesized, but a single
crystal of this derivative could not be obtained either.
OH
11
OH
OH
HO
OH
HO
OH
O
O
4
O
O
a
b
OH
OH
HO
HO
OH
OH
6
OH
OH
5
12
OH
O
OH
Scheme 2.
d
e
The literature procedure for the synthesis of chalcone 13
involves condensation of 4-hydroxybenzaldehyde and 20,50-
dihydroxyacetophenone in the presence of 40% potassium
hydroxide at room temperature for a period of seven days.7
Therefore, a procedure outlined for the synthesis of 6 was
used for the preparation of chalcone 13. However, in this
case in addition to the desired product 13, compound 14
formed by Michael addition of 20,50-dihydroxyacetophenone
to the chalcone 13 was also isolated. The cyclization of 13 to
flavanone 15 was effected by refluxing it with methanolic
hydrochloric acid in 92% yield. This was followed by acet-
ylation and catalytic hydrogenation using palladium on char-
coal to give flavanol 17 in 99% yield. The stereochemistry of
the flavanol 17 was found to be predominantly cis (cis:trans:
95:5) based on NOESYexperiments. Flavanol 17 was dehy-
drated by heating it with toluene in the presence of a catalytic
amount of p-toluenesulfonic acid to give flavene 18 in 95%
yield (Scheme 3).
R
c
O
AcO
O
R
7 : R = OH
8 : R = OAc
OAc
R
9
H
H
O
H
R
H
R
f
O
R
O
R
2 : R = OH
3 : R = OAc
R
4 : R = OH
10: R = OAc
g
Scheme 1. Reagents and conditions: (a) 4-hydroxybenzaldehyde, 60% aq
KOH, 100 ꢀC, 1.5 h, 65%; (b) concd HCl, MeOH, reflux, 24 h, 62%; (c)
Ac2O, pyridine, 100 ꢀC, 1 h, 76%; (d) H2, Pd/C, THF, 48 h, rt, 90%;
(e) p-TSA, toluene, reflux, 2 h, 70%; (f) concd HCl, MeOH, rt, 6 h, 92%;
(g) Ac2O, pyridine, 100 ꢀC, 6 h, 74%.
Surprisingly, treatment of 18 with methanolic hydrochloric
acid gave a complex mixture. On the contrary, when 18
was treated with aqueous potassium hydroxide solution fol-
lowed by acidification, dihydroxyflavene 19 was isolated in
47% yield.
H
OH
H
H
H
O
H
HO
H
H
Attempts to synthesize chalcone 20 by condensation of
4-hydroxybenzaldehyde with 20,60-dihydroxyacetophenone
21 in the presence of excess potassium hydroxide at
100 ꢀC gave a polymeric compound. Furthermore, literature
methods for the synthesis of chalcone 20 by condensation
of 20,60-dihydroxyacetophenone 21 and 4-hydroxybenzal-
dehyde in the presence of sodium hydroxide8 or potassium
hydroxide9 at room temperature gave very poor yields.
O
H
H
H
H
H
H
H
H
OH
OH
Figure 1. Key NOE correlations for 4.

M. Deodhar et al. / Tetrahedron 63 (2007) 5227–5235
5229
O
O
O
O
OH
THPO
OH
O
HO
HO
b,c
a
a
OH
OH
OH
OH
OH
20
22
21
13
OH
OH
OH
O
O
OH
O
O
OAc O
AcO
R
d
e
d
b
O
O
R
OAc
OH
g
25
OAc
17
24
15 : R = OH
16 : R = OAc
c
OH
OAc OH
OH
f
O
O
OH
HO
O
O
R
e
OAc
OAc
HO
OH
27
26
14
O
Scheme 4. Reagents and conditions: (a) 3,4-dihydro-2H-pyran, p-TSA,
THF, overnight, rt, 55%; (b) 4-(tetrahydro-2-pyranoxy)benzaldehyde 23,
KOH, EtOH, rt, overnight; (c) 2 M HCl, MeOH, 70 ꢀC, 30 min, 56%
(over two steps); (d) NaOAc, EtOH, reflux, 1 h, 92%; (e) Ac2O, pyridine,
100 ꢀC, 2 h, 94%; (f) NaBH4, MeOH, ꢁ15 ꢀC, 2 h, 95%; (g) p-TSA, tolu-
ene, reflux, 1.5 h, 15%.
R
18 : R = OAc
19 : R = OH
f
Scheme 3. Reagents and conditions: (a) 4-hydroxybenzaldehyde, 60%
aq KOH, 100 ꢀC, 2 h, 48%; (b) concd HCl, MeOH, reflux, 48 h,
92%; (c) Ac2O, pyridine, 100 ꢀC, 1 h, 65%; (d) H2, Pd/C, THF, 48 h, rt,
99%; (e) p-TSA, toluene, reflux, 1.5 h, 95%; (f) 1 M KOH, MeOH, rt,
1 h, 47%.
out under standard conditions, using p-toluenesulfonic
acid, but was also accompanied by hydrolysis of one of
the acetoxy groups. This results in poor yields of the fla-
vene 27 and formation of substantial amounts of polymeric
material. The deprotection of the O-acetyl group at the
5-position can be explained on the basis of neighbouring
group participation.
This observation has been confirmed by Takahashi
et al.10 who have reported similar problems with the
reported methods. This problem can be overcome by pro-
tecting one of the OH groups prior to condensation.11
Hence, 21 was reacted with 3,4-dihydro-2H-pyran in the
presence of p-toluenesulfonic acid to give 20-hydroxy-60-
tetrahydropyran-2-yloxyacetophenone 22 in 55% yield.
The hydroxyl group of 4-hydroxybenzaldehyde was also
protected as the THP ether 23. The condensation of 22
with 23 was then carried out under standard conditions
in the presence of excess potassium hydroxide followed
by deprotection to give 20,60,4-trihydroxychalcone 20 in
56% overall yield. Attempts to cyclize 20 under acidic
conditions (similar to the ones used for cyclization of 6
and 13) were unsuccessful resulting in the isolation of
unreacted starting materials. An alternative method9 of
cyclization using aqueous sodium hydroxide and hydrogen
peroxide also gave very poor yields. Surprisingly this cycli-
zation was achieved very effectively when sodium acetate
was used as a base to give flavanone 24 in 92% yield
(Scheme 4). The high yield and ease of formation of 24
under these mildly alkaline conditions are probably due
to the presence of the 60-hydroxyl group, which stabilizes
the intermediate anion by hydrogen bonding. The two
hydroxyl groups in the flavanone 24 were then protected
by acetylation to give diacetoxyflavanone 25 in 94% yield.
Attempts to reduce the flavanone 25 by catalytic hydro-
genation using palladium charcoal as catalyst at ambient
temperature and at 60 ꢀC were unsuccessful and the
starting material was recovered. Attempted reduction by
transfer hydrogenation using palladium charcoal and am-
monium formate gave multiple products, whereas catalytic
hydrogenation using Raney nickel gave only starting mate-
rial. However, the reduction was successfully effected
using sodium borohydride12 to give the desired trans-
flavanol 26 in 93% yield. The dehydration of 26 was carried
2.2. Synthesis of dependensin 1
Reaction of 3,4,5-trimethoxyphenol 28 with methyl iodide
and potassium carbonate in acetone gave 1,3,4,5-tetra-
methoxybenzene 29 in 96% yield. Acetylation following
the literature procedure13 involving aluminium chloride
and acetyl chloride gave acetophenone 30 in 56% yield,
which was converted to chalcone 31 in 95% yield by reaction
with benzaldehyde and potassium hydroxide in aqueous
ethanol.
The cyclization of the chalcone 31 to flavanone 32 was
achieved in 63% yield by refluxing with methanolic
hydrochloric acid. Attempts to reduce flavanone 32 by
hydrogenation with palladium on charcoal were not suc-
cessful. The reaction was sluggish (ca. 5–7 days) and
the product was a complex mixture. However, reduction
using sodium borohydride in (1:1) THF and methanol
gave cis-flavanol 33 as a sticky solid in 95% yield. The
stereochemistry was established on the basis of the
NOE between H2 and H4. Compound 33 was found to
be unstable, and was quickly converted by dehydration
with p-toluenesulfonic acid in refluxing toluene into the
related flavene 34, which on treatment with methanolic
hydrochloric acid gave dependensin 1 in 72% yield
(Scheme 5).
The structure and stereochemistry of dependensin were
established on the basis of 1D and 2D NMR spectroscopies
and reported spectroscopic data.

5230
M. Deodhar et al. / Tetrahedron 63 (2007) 5227–5235
OH
acid. The precipitated yellow solid was filtered, washed
O
OMe
OMe
with water (200 mL) and air dried to give 6 as a yellow solid
(7.5 g, 65%). Mp: 200 ꢀC (from methanol/water) lit.14 200–
201 ꢀC; IR (KBr) 3383, 1627, 1605, 1513, 1225, 1211,
a
b
MeO
OMe
OMe
MeO
MeO
OMe
OH
OMe
1
1143 cmꢁ1; H NMR (acetone-d6, 300 MHz): d 6.35 (d,
OMe
OMe
J¼2.3 Hz, 1H), 6.45 (dd, J¼2.3, 9.0 Hz, 1H), 6.91 (d,
J¼8.7 Hz, 2H), 7.72 (d, J¼8.7 Hz, 2H), 7.74 (d, J¼
16.2 Hz, 1H), 7.83 (d, J¼16.2 Hz, 1H), 8.1 (d, J¼9.0 Hz,
1H), 9.1 (br, 2H), 13.59 (s, 1H); 13C NMR (acetone-d6,
75.6 MHz): d 102.5, 107.7, 113.6, 115.8, 117.4, 126.6,
130.8, 132.3, 144.1, 160.0, 164.6, 166.6, 191.9.
30
28
29
O
OMe O
c
d
MeO
MeO
O
OH
OMe
OMe
32
31
4.1.2. 40,7-Dihydroxyflavanone (7). A suspension of 6 (3 g,
11.7 mmol) in methanol (50 mL) and concd hydrochloric
acid (25 mL) was refluxed for 24 h. Methanol was removed
under vacuum and the resulting dark solution was diluted
with water (150 mL). The product was extracted with ethyl
acetate (100 mLꢂ3), dried over anhydrous sodium sulfate
and the solvent evaporated under vacuum. The crude product
was chromatographed using light petroleum/ethyl acetate
(50:50) as eluent to yield the title compound as a pale yellow
solid (1.86 g, 62%). Mp: 195–197 ꢀC (from benzene/light
petroleum) lit.14 195–196 ꢀC; Rf (50% ethyl acetate/light
petroleum) 0.35; IR (KBr) 3377, 1656, 1601, 1516, 1465,
OH
OMe
OMe
OMe
e
g
f
1
MeO
MeO
O
O
OMe
33
34
Scheme 5. Reagents and conditions: (a) MeI, K2CO3, acetone, 24 h, 96%;
(b) AlCl3, AcCl, Et2O, 0 ꢀC to rt, overnight, 56%; (c) benzaldehyde,
KOH, EtOH, overnight, 95%; (d) concd HCl, MeOH, 40 h, reflux, 63%;
(e) NaBH4, THF/MeOH, 0 ꢀC, 1 h, 95%; (f) p-TSA, toluene, reflux,
15 min, 80%; (g) concd HCl, MeOH, rt, overnight, 72%.
1
1234, 1163 cmꢁ1; H NMR (acetone-d6, 300 MHz): d 2.66
3. Conclusion
(dd, J¼3, 16.8 Hz, 1H), 3.03 (dd, J¼13.0, 16.8 Hz, 1H),
5.44 (dd, J¼3, 13.0 Hz, 1H), 6.41 (d, J¼2.3 Hz, 1H), 6.56
(dd, J¼2.3, 8.7 Hz, 1H), 6.88 (d, J¼8.7 Hz, 2H), 7.38 (d,
J¼8.7 Hz, 2H), 7.71 (d, J¼8.7 Hz, 1H), 8.45 (br, 1H), 9.3
(br, 1H); 13C NMR (acetone-d6, 75.6 MHz): d 43.7, 79.5,
102.7, 110.2, 114.3, 115.2, 128.0, 128.5, 130.3, 157.5,
163.5, 164.2, 189.6.
40,7-Dihydroxyflav-3-ene 2 undergoes stereoselective rear-
rangement and dimerization on treatment with methanolic
hydrochloric acid to give benzopyranobenzopyran. How-
ever, the corresponding 40,5- or 40,6-dihydroxy substituted
flavenes do not rearrange and dimerize under similar condi-
tions. This synthetic methodology has been used for an
efficient synthesis of the natural product dependensin.
4.1.3. 40,7-Diacetoxyflavanone (8). A mixture of 7 (500 mg,
1.95 mmol), pyridine (0.6 mL) and acetic anhydride (3 mL)
was heated with stirring at 100 ꢀC for 1 h. The reaction
mixture was cooled to room temperature. After 2 h the pre-
cipitated white solid was filtered and washed with methanol–
water (10 mL, 50:50) and air dried (510 mg, 76%). Mp:
192–194 ꢀC, lit.15 195–198 ꢀC; IR (KBr) 1763, 1742,
1693, 1609, 1511, 1441, 1425, 1370, 1282, 1246, 1196,
4. Experimental
4.1. General
All reagents and solvents were obtained from commercial
sources and appropriately purified, if necessary. Melting
points were measured using a Mel-Temp melting point appa-
ratus and are uncorrected. Microanalyses were performed on
a Carlo Erba Elemental Analyser EA 1108 at the Campbell
Microanalytical Laboratory, University of Otago, New Zea-
1142, 1118, 1063, 1013, 914 cmꢁ1 1H NMR (CDCl3,
;
300 MHz): d 2.30 (s, 3H), 2.31 (s, 3H), 2.88 (dd, J¼3.0,
16.8 Hz, 1H), 3.05 (dd, J¼13.0, 16.8 Hz, 1H), 5.49 (dd,
J¼3.0, 13 Hz, 1H), 6.81 (dd, J¼2.3, 8.3 Hz, 1H), 6.82 (d,
J¼2.3 Hz, 1H), 7.16 (d, J¼8.3 Hz, 2H), 7.48 (d, J¼8.3 Hz,
2H), 7.95 (d, J¼8.3 Hz, 1H); 13C NMR (CDCl3,
75.6 MHz,): d 19.9, 20.0, 43.7, 79.4, 111.0, 115.6, 118.7,
121.9, 127.5, 127.7, 136.5, 151.1, 156.7, 162.2, 168.1,
168.6, 189.7.
land. H and 13C NMR spectra were obtained on Bruker
1
DPX300 (300 MHz) and Bruker DPX600 (600 MHz) spec-
trometers. Mass spectra were recorded on either a Bruker
FT-ICR MS (EI) or a Micromass ZQ2000 (ESI). Infrared
spectra were recorded with a Thermo Nicolet 370 FTIR
Spectrometer using KBr discs. Column chromatography
was carried out using Merck 230–400 mesh ASTM silica
gel, whilst preparative thin layer chromatography was per-
4.1.4. cis-40,7-Diacetoxyflavan-4-ol (9). To a solution of 8
(700 mg, 2.05 mmol) in THF (28 mL) was added 10% palla-
dium on charcoal (200 mg). The mixture was hydrogenated
at room temperature and atmospheric pressure for 48 h and
filtered through a pad of CeliteÒ. Evaporation of the solvent
under vacuum afforded 7 (630 mg, 90%) as a white solid.
Mp: 156–158 ꢀC (from methanol); IR (KBr) 3471, 1756,
1738, 1613, 1588, 1494, 1425, 1371, 1219, 1196, 1142,
formed using Merck silica gel 7730 60GF254
.
4.1.1. 4,20,40-Trihydroxychalcone (6). To a mixture of
5
(6.8 g, 44.7 mmol), 4-hydroxybenzaldehyde (5.6 g,
45.9 mmol) and ethanol (5.6 mL) was added aqueous potas-
sium hydroxide (41.6 mL, 60% w/w). The resulting suspen-
sion was heated at 100 ꢀC for 1.5 h and then kept overnight
at room temperature. The reaction mixture was poured onto
ice (100 g) and acidified to pH 4 using concd hydrochloric
1117, 1017, 968, 914, 832 cmꢁ1
;
1H NMR (CDCl3,
300 MHz): d 2.10 (ddd, J¼10.4, 11.7, 13.2 Hz, 1H), 2.28
(s, 3H), 2.30 (s, 3H), 2.51 (ddd, J¼1.9, 6.4, 13.2 Hz, 1H),
5.07 (dd, J¼6.4, 10.4 Hz, 1H), 5.18 (dd, J¼1.9, 11.7 Hz,

M. Deodhar et al. / Tetrahedron 63 (2007) 5227–5235
5231
1H), 6.62 (d, J¼2.3 Hz, 1H), 6.72 (dd, J¼2.3, 8.7 Hz, 1H),
7.12 (d, J¼8.7 Hz, 2H), 7.44 (d, J¼8.7 Hz, 2H), 7.52 (d,
J¼8.7 Hz, 1H); 13C NMR (CDCl3, 75.6 MHz): d 20.9,
21.0, 39.7, 65.3, 109.8, 114.3, 121.7, 123.5, 127.1, 127.7,
137.7, 150.4, 150.9, 155.0, 169.4; Anal. Calcd for
C19H18O6: C, 66.65; H, 5.29. Found: C, 66.35; H, 5.35;
HRMS (ESI) m/z 365.0995 (MNa+, C19H18O6Na, requires
365.0996).
4.1.7. 6a,12a-Dihydro-3,10-diacetoxy-6-(40-acetoxy-
phenyl)-7-[(1E)-2-(400-acetoxyphenylethenyl)]-6H,7H-
[1]benzopyrano[4,3-b][1]benzopyran (10). A mixture of
compound 4 (50 mg, 0.104 mmol), acetic anhydride
(1 mL) and pyridine (0.5 mL) was heated at 100 ꢀC for
6 h. The reaction mixture was cooled to room temperature
and poured over cold water (50 mL). The white solid was
filtered, washed with water (10 mL) and dried (50 mg,
74%). Mp: 140–142 ꢀC (ethyl acetate/light petroleum); IR
(KBr) 2923, 1762, 1616, 1498, 1369, 1209, 1144, 1115,
4.1.5. 40,7-Diacetoxyflav-3-ene (3). A mixture of p-toluene-
sulfonic acid (120 mg) and toluene (750 mL) was heated to
reflux for 45 min with Dean–Stark apparatus to remove
traces of water. Diacetoxyflavan-4-ol 9 (1.8 g, 5.26 mmol)
was added and the heating was continued for a further 2 h.
The reaction mixture was cooled to room temperature and
washed with water (200 mLꢂ2). The organic layer was
dried over anhydrous sodium sulfate and the solvent was re-
moved under vacuum. Column chromatography using ethyl
acetate/light petroleum (25:75) afforded 3 (1.2 g, 70%) as
colourless crystals. Mp: 110–112 ꢀC (methanol); Rf (25%
ethyl acetate/light petroleum) 0.48; IR (KBr) 1756, 1497,
1
1015 cmꢁ1; H NMR (CDCl3, 300 MHz): d 2.26 (s, 3H),
2.28 (s, 6H), 2.31 (s, 3H), 2.49 (ddd, J¼2.3, 3.0, 9.8 Hz,
1H), 3.24 (dd, J¼2.3 6.4 Hz, 1H), 5.08 (d, J¼3.0 Hz, 1H),
5.08 (d, J¼9.8 Hz, 1H), 6.07 (d, J¼15.8 Hz, 1H), 6.16 (dd,
J¼6.4, 15.8 Hz, 1H), 6.67 (dd, J¼2.3, 8.3 Hz, 1H), 6.69
(d, J¼2.3 Hz, 1H), 6.69 (d, J¼2.3 Hz, 1H), 6.73 (dd,
J¼2.3, 8.3 Hz, 1H), 6.96 (d, J¼8.3 Hz, 1H), 6.99 (d,
J¼8.6 Hz, 2H), 7.14 (d, J¼8.3 Hz, 2H), 7.28 (d, J¼8.6 Hz,
2H), 7.31 (d, J¼8.3 Hz, 2H), 7.39 (d, J¼8.3 Hz, 1H). 13C
NMR (CDCl3, 75.6 MHz): d 21.0, 37.9, 40.9, 66.9, 76.2,
110.2, 110.2, 114.3, 114.5, 117.6, 118.4, 121.6, 121.8,
127.2, 128.2, 130.8, 131.0, 131.5, 132.3, 134.2, 135.8,
150.0, 150.6, 150.9, 152.2, 153.0, 155.1, 169.1, 169.1,
169.1, 169.2; Anal. Calcd for C38H32O10: C, 70.36; H,
4.97. Found: C, 70.41; H, 5.27.
1
1372, 1218, 1202, 1191, 1139, 1115, 910 cmꢁ1; H NMR
(CDCl3, 300 MHz): d 2.25 (s, 3H), 2.29 (s, 3H), 5.75 (dd,
J¼3.4, 9.8 Hz, 1H), 5.91 (dd, J¼1.1, 3.4 Hz, 1H), 6.51
(dd, J¼1.1, 9.8 Hz, 1H), 6.53 (d, J¼2.3 Hz, 1H), 6.61 (dd,
J¼2.3, 7.9 Hz, 1H), 6.98 (d, J¼7.9 Hz, 1H), 7.09 (d,
J¼8.7 Hz, 2H), 7.44 (d, J¼8.7 Hz, 2H); 13C NMR (CDCl3,
75.6 MHz): d 21.0, 76.6, 109.6, 114.2, 118.9, 121.7, 123.4,
123.9, 126.9, 128.2, 138.0, 150.6, 151.3, 153.7, 169.0,
169.3; Anal. Calcd for C19H16O5: C, 70.36; H, 4.97. Found:
C, 70.55; H, 4.97; HRMS (ESI) m/z 347.0893 (MNa+,
C19H16O5Na, requires 347.0890).
4.1.8. 4,20,50-Trihydroxychalcone (13). To a mixture of 2,5-
dihydroxyacetophenone (1.36 g, 8.94 mmol), 4-hydroxy-
benzaldehyde (1.12 g, 9.1 mmol) and ethanol (1.12 mL)
was added potassium hydroxide solution (8 mL, 60% w/w).
The dark mixture was heated at 100 ꢀC for 2 h. TLC analysis
showed formation of two products. The reaction mixture was
cooled to room temperature and poured over ice cold water
(30 mL). The mixture was acidified to pH 5 with concd
hydrochloric acid (ca. 13 mL). The solid was filtered,
washed with water (50 mL) and dried at 80 ꢀC. The crude
product was chromatographed over silica gel using ethyl
acetate/light petroleum (40:60) as eluent to yield title com-
pound 13 (1.1 g, 48%) as yellow solid. Mp: 228–230 ꢀC,
lit.7 223–235 ꢀC; Rf (40% ethyl acetate/light petroleum)
0.4; IR (KBr) 3358, 3174, 1705, 1636, 1599, 1583, 1541,
1516, 1437, 1369, 1321, 1289, 1268, 1186, 1168,
4.1.6. 6a,12a-Dihydro-3,10-dihydroxy-6-(40-hydroxy-
phenyl)-7-[(1E)-2-(400-hydroxyphenylethenyl)]-6H,7H-
[1]benzopyrano[4,3-b][1]benzopyran (4). To a suspension
of 3 (350 mg, 1.08 mmol) in methanol (35 mL) was added
10 M HCl (2.7 mL). The mixture was stirred under an
argon atmosphere for 6 h. Methanol was evaporated off at
30 ꢀC under vacuum and the residue was taken up in ethyl
acetate (50 mL). The organic layer was washed with water
(25 mLꢂ2), dried over anhydrous sodium sulfate and con-
centrated under vacuum. The crude product was chromato-
graphed over silica gel using ethyl acetate/light petroleum
(70:30) as eluent to yield 4 (240 mg, 92%) as a light red
solid. Mp: 190–192 ꢀC (ethyl acetate/light petroleum);
Rf (70% ethyl acetate/light petroleum) 0.45; IR (KBr)
3407, 2958, 1616, 1511, 1458, 1230, 1159, 1119, 1017,
821 cmꢁ1
;
1H NMR (acetone-d6, 300 MHz): d 6.79
(d, J¼8.6 Hz, 1H), 6.91 (d, J¼8.6 Hz, 2H), 7.05 (dd,
J¼3.0, 8.6 Hz, 1H), 7.52 (d, J¼3.0 Hz, 1H), 7.68 (d,
J¼15.1 Hz, 1H), 7.72 (d, J¼8.6 Hz, 2H), 7.84 (d, J¼
15.1 Hz, 1H), 8.03 (s, 1H), 8.98 (s, 1H), 12.40 (s, 1H).
Further elution gave compound 14 as pale yellow solid
(350 mg, 20%).
1
696, 836 cmꢁ1. H NMR (acetone-d6, 600 MHz): d 2.51
(ddd, J¼2.1, 2.4, 10.9 Hz, 1H), 3.11 (dd, J¼2.1, 6.7 Hz,
1H), 4.89 (d, J¼10.9 Hz, 1H), 5.08 (d, J¼2.4 Hz, 1H),
6.02 (d, J¼15.7 Hz, 1H), 6.24 (dd, J¼6.7, 15.7 Hz, 1H),
6.33 (d, J¼2.3 Hz, 1H), 6.33 (d, J¼2.4 Hz, 1H), 6.41
(dd, J¼2.4, 8.3 Hz, 1H), 6.48 (dd, J¼2.3, 8.3 Hz, 1H),
6.74 (d, J¼8.6 Hz, 2H), 6.77 (d, J¼8.3 Hz, 1H), 6.89 (d,
J¼8.5 Hz, 2H), 7.19 (d, J¼8.6 Hz, 2H), 7.2 (d, J¼8.5 Hz,
2H), 7.25 (d, J¼8.3 Hz, 1H), 8.31 (br s, 2H), 8.52 (br
s, 2H); 13C NMR (acetone-d6, 150 MHz): d 38.7, 41.6,
67.6, 77.0, 102.9, 103.2, 108.6, 109.1, 112.2, 113.7
(2ꢂ115.7), 127.9, 129.2, 129.4, 130.3, 130.9, 131.3,
131.5, 132.0, 154.1, 156.5, 157.3, 157.9, 158.1, 159.7;
HRMS (ESI) m/z 503.1478 (MNa+, C30H24O6Na, requires
503.1465).
4.1.9. 1,5-Bis(2,5-dihydroxyphenyl)-3-(4-hydroxyphenyl)
pentane-1,5-dione (14). Mp: 179–181 ꢀC; Rf (40% ethyl
acetate/light petroleum) 0.22; IR (KBr) 3404, 1642, 1629,
1
1609, 1485, 1232, 1198, 1176, 999, 792 cmꢁ1; H NMR
(acetone-d6, 300 MHz): d 3.42 (dd, J¼7.5, 16.6 Hz, 2H),
3.52 (dd, J¼6.4, 16.6 Hz, 2H), 3.99 (dt, J¼6.4, 7.5 Hz,
1H), 6.71 (d, J¼8.6 Hz, 2H), 6.76 (d, J¼9.0 Hz, 2H), 7.06
(dd, J¼3.0, 9.0 Hz, 2H), 7.21 (d, J¼8.6 Hz, 2H), 7.40 (d,
J¼3.0 Hz, 2H), 8.07 (s, 2H), 8.08 (s, 1H), 11.65 (s, 2H);
13C NMR (acetone-d6, 75.6 MHz): d 36.2, 44.6, 114.7,
115.0, 118.3, 119.3, 124.7, 128.5, 134.1, 149.3, 154.9,
155.8, 205.1; HRMS (ESI) m/z 431.1099 (MNa+,
C23H20O7Na, requires 431.1101).

5232
M. Deodhar et al. / Tetrahedron 63 (2007) 5227–5235
4.1.10. 40,6-Dihydroxyflavanone (15). A mixture of 13
(2.5 g, 9.76 mmol), methanol (125 mL) and concd hydro-
chloric acid (10 mL) was refluxed for 48 h. The reaction
mixture concentrated under vacuum to 20 mL and diluted
with water (100 mL). The product was filtered, washed
with water and dried. The title compound was obtained as
a pale yellow solid (2.33 g, 92%). Mp: 235–237 ꢀC, lit.7
230 ꢀC; IR (KBr) 3500–2500, 3331, 1669, 1617, 1476,
reaction mixture was cooled to room temperature and
washed with satd sodium bicarbonate solution (100 mL).
The organic layer was dried over anhydrous sodium sulfate
and the solvent was evaporated off under vacuum. The crude
product was chromatographed over silica gel using ethyl
acetate/light petroleum (25:75) as eluent to yield title com-
pound (900 mg, 95%) as white solid. Mp: 97–99 ꢀC; Rf
(25% ethyl acetate/light petroleum) 0.4; IR (KBr) 3064,
1
1
1374, 1318, 1214, 1135, 837, 777 cmꢁ1; H NMR (ace-
1752, 1743, 1483, 1370, 1207, 1193, 1165, 909 cmꢁ1; H
tone-d6, 300 MHz): d 2.71 (dd, J¼2.6, 17.0 Hz, 1H), 3.07
(dd, J¼13.2, 17.0 Hz, 1H), 5.4 (dd, J¼2.6, 13.2 Hz, 1H),
6.88 (d, J¼6.8 Hz, 2H), 6.89 (d, J¼8.6, 1H), 7.07 (dd,
J¼3.4, 8.6 Hz, 1H), 7.23 (d, J¼3.4 Hz, 1H), 7.38
(d, J¼6.8 Hz, 2H), 8.34 (s, 1H), 8.51 (s, 1H); 13C NMR
(acetone-d6, 75.6 MHz): d 44.0, 79.3, 110.2, 115.1, 118.9,
121.1, 124.1, 127.9, 130.4, 151.5, 155.3, 157.6, 191.4.
NMR (CDCl3, 300 MHz): d 2.26 (s, 3H), 2.28 (s, 3H), 5.8
(dd, J¼3.4, 10.1 Hz, 1H), 5.90 (dd, J¼1.9, 3.4 Hz, 1H),
6.48 (dd, J¼1.9, 10.1 Hz, 1H), 6.75 (d, J¼8.7 Hz, 1H),
6.76 (d, J¼3.0 Hz, 1H), 6.81 (dd, J¼3.0, 8.7 Hz, 1H), 7.09
(d, J¼8.7 Hz, 2H), 7.45 (d, J¼8.7 Hz, 2H); 13C NMR
(CDCl3, 75.6 MHz): d 20.9, 21.0, 76.6, 116.5, 119.3,
121.7, 121.7, 122.0, 123.6, 125.4, 128.2, 137.9, 144.4,
150.4, 150.6, 169.2, 169.6; Anal. Calcd for C19H16O5: C,
70.36; H, 4.97. Found: C, 70.11; H, 5.10; HRMS (ESI) m/z
347.0893 (M+Na+, C19H16O5Na, requires 347.0890).
4.1.11. 40,6-Diacetoxyflavanone (16). A mixture of 15
(2.3 g, 9.0 mmol), acetic anhydride (14 mL) and pyridine
(2.3 mL) was heated at 100 ꢀC for 1 h. The reaction mixture
was cooled to room temperature and maintained there for
2 h. The precipitated white solid was filtered and washed
with methanol–water (50 mL, 1:1) and dried to give the title
compound as a white solid (2 g, 65%). Mp: 181–183 ꢀC
(methanol); IR (KBr) 1768, 1748, 1683, 1613, 1485, 1365,
4.1.14. 40,6-Dihydroxyflav-3-ene (19). To a suspension of
18 (100 mg, 0.3 mmol) in methanol (5 mL) was added 1 M
potassium hydroxide solution (25 drops). The mixture was
stirred under an argon atmosphere for 1 h. The reaction mix-
ture was neutralized by adding 1 M acetic acid solution (25
drops). Water (25 mL) was added and the mixture was ex-
tracted with ethyl acetate (25 mLꢂ3). The combined organic
extract was washed with satd sodium bicarbonate solution
(25 mL), dried over anhydrous sodium sulfate and evapo-
rated under vacuum. The crude product was purified by pre-
parative thin layer chromatography using ethyl acetate/light
petroleum (1:1) as mobile phase. The title compound was
obtained as a pink solid (35 mg, 47%). Mp: 140–142 ꢀC;
Rf (50% ethyl acetate/light petroleum) 0.35; IR (KBr)
3656–3002, 1517, 1486, 1278, 1250, 1213, 1033, 836,
1
1280, 1226, 1197, 1181, 1013, 920, 907 cmꢁ1; H NMR
(CDCl3, 300 MHz): d 2.29 (s, 3H), 2.31 (s, 3H), 2.88 (dd,
J¼3.0, 16.9 Hz, 1H), 3.05 (dd, J¼13.2, 16.9 Hz, 1H), 5.47
(dd, J¼3.0, 13.2 Hz, 1H), 7.06 (d, J¼8.7 Hz, 1H), 7.16 (d,
J¼8.7 Hz, 2H), 7.23 (dd, J¼2.6, 8.7 Hz, 1H), 7.49 (d,
J¼8.7 Hz, 2H), 7.61 (d, J¼2.6 Hz, 1H); 13C NMR (CDCl3,
75.6 MHz): d 20.8, 21.0, 44.3, 79.2, 119.1, 119.2, 121.1,
121.1, 127.2, 129.8, 135.9, 144.8, 150.8, 158.9, 169.2,
169.4, 190.8; Anal. Calcd for C19H16O6: C, 67.05; H, 4.73.
Found: C, 67.25; H, 4.78; HRMS (ESI) m/z 363.0834
(M+Na+, C19H16O6Na, requires 363.0839).
1
775 cmꢁ1; H NMR (acetone-d6, 300 MHz): d 5.71 (dd,
J¼1.5, 3.4 Hz, 1H), 5.85 (dd, J¼3.4, 9.8 Hz, 1H), 6.55 (m,
4H), 6.79 (d, J¼8.6 Hz, 2H), 7.26 (d, J¼8.6 Hz, 2H), 8.15
(br, 2H); 13C NMR (acetone-d6, 75.6 MHz): d 76.1, 112.7,
115.0, 115.4, 116.1, 123.7, 126.0, 128.5, 131.8, 146.0,
151.4, 157.4; HRMS (ESI) m/z 263.0681 (M+Na+,
C15H12O3Na, requires 263.0681).
4.1.12. cis-40,6-Diacetoxyflavan-4-ol (17). To a solution of
16 (2 g, 5.88 mmol) in THF (80 mL) was added 10% palla-
dium on charcoal (200 mg). The mixture was hydrogenated
at room temperature and atmospheric pressure for 48 h. The
catalyst was filtered off through CeliteÒ and the bed was
washed with dichloromethane (25 mLꢂ2). Evaporation of
the filtrate under vacuum afforded 17 (2 g, 99%) as a white
solid. Mp: 142–143 ꢀC (methanol); IR (KBr) 3464, 1755,
4.1.15. 20-Hydroxy-60-tetrahydropyranyl-2-oxyaceto
phenone (22). p-Toluenesulfonic acid (30 mg, 0.15 mmol)
was added to a mixture of 21 (3.02 g, 19.86 mmol), 3,4-
dihydro-2H-pyran (10 mL) and dry THF (15 mL). The mix-
ture was stirred under an argon atmosphere overnight. The
reaction mixture was poured into satd sodium bicarbonate
solution (50 mL) and stirred for 5 min. Light petroleum
(100 mL) was added and the layers were separated. The
organic layer was washed with 2 M sodium hydroxide
(50 mLꢂ2). The pH of the aqueous layer was adjusted to 8
using 1 M hydrochloric acid and again the product was
extracted with light petroleum (50 mLꢂ3), dried with
anhydrous sodium sulfate and the solvent was partially
removed under vacuum. The solution was kept in the refrig-
erator overnight and filtered. The title compound was
obtained as pale yellow crystals11 (unstable) (2.6 g, 55%).
1H NMR (acetone-d6, 300 MHz): d 1.7–1.9 (m, 6H), 2.71
(s, 3H), 3.72 (m, 2H), 5.5 (m, 1H), 6.51 (d, J¼8.2 Hz, 1H),
6.60 (d, J¼8.2 Hz, 1H), 7.32 (t, J¼8.2 Hz, 1H), 13.14 (s,
1H). 13C NMR (acetone-d6, 75.6 MHz): d 19.0, 24.9, 30.2,
1
1483, 1367, 1223, 1395, 1018, 898, 836 cmꢁ1; H NMR
(CDCl3, 300 MHz): d 2.04 (ddd, J¼4.5, 11.7, 13.2 Hz,
1H), 2.27 (s, 3H), 2.30 (s, 3H), 2.44 (ddd, J¼1.9, 6.0,
13.2 Hz, 1H), 5.01 (dd, J¼4.5, 6.0 Hz, 1H), 5.13 (dd,
J¼1.9, 11.7 Hz, 1H), 6.84 (d, J¼8.3 Hz, 1H), 6.89 (dd,
J¼2.3, 8.3 Hz, 1H), 7.11 (d, J¼8.7 Hz, 2H), 7.22 (d, J¼2.3 Hz,
1H), 7.41 (d, J¼8.7 Hz, 2H); 13C NMR (CDCl3,
75.6 MHz): d 20.9, 21.0, 39.6, 65.5, 76.5, 117.3, 119.7,
121.7, 122.2, 126.5, 127.2, 137.8, 144.3, 150.4, 151.9,
169.3, 170.0; Anal. Calcd for C19H18O6: C, 66.65; H, 5.29.
Found: C, 67.14; H, 5.37; HRMS (ESI) m/z 365.0999
(M+Na+, C19H18O6Na, requires 365.0996).
4.1.13. 40,6-Diacetoxyflav-3-ene (18). A mixture of p-tolu-
enesulfonic acid monohydrate (66 mg, 0.35 mmol) and
toluene (425 mL) was heated to reflux for 45 min with a
Dean–Stark apparatus to remove traces of water. Compound
17 was added and the heating was continued for 1.5 h. The

M. Deodhar et al. / Tetrahedron 63 (2007) 5227–5235
5233
33.6, 62.2, 97.3, 104.6, 111.2, 111.7, 136.0, 159.0, 164.3,
204.9.
(acetone-d6, 75.6 MHz): d 43.0, 78.9, 107.3, 107.9, 108.7,
115.2, 128.0, 129.6, 138.1, 157.8, 161.9, 162.0, 199.0.
4.1.16. 4-(Tetrahydro-2-pyranoxy)benzaldehyde (23).
p-Toluenesulfonic acid (30 mg, 0.15 mmol) was added to a
solution of 4-hydroxybenzaldehyde (2.4 g, 19.67 mmol) in
3,4-dihydro-2H-pyran (10 mL) and dry THF (15 mL). The
mixture was stirred under an argon atmosphere overnight.
The reaction was quenched by pouring into satd sodium
bicarbonate solution (25 mL) followed by stirring for 5 min.
The organic layer was separated, dried over anhydrous
sodium sulfate and concentrated under vacuum at room
temperature. The crude product was chromatographed using
dichloromethane/light petroleum (33:66) as eluent to yield
23 as yellowish oil16 (3.2 g, 80%). Rf (33% dichloro-
methane/light petroleum) 0.33; 1H NMR (CDCl3, 300 MHz):
d 1.37 (m, 3H), 1.66 (m, 3H), 3.36 (m, 1H), 3.57 (m, 1H),
5.27 (t, J¼2.8, 1H), 6.90 (d, J¼8.8 Hz, 2H), 7.56 (d,
J¼8.8 Hz, 2H), 9.60 (s, 1H); 13C NMR (CDCl3,
75.6 MHz): d 17.7, 24.3, 29.3, 61.2, 95.4, 116.0, 129.7,
131.0, 161.5, 190.1.
4.1.19. 40,5-Diacetoxyflavanone (25). A mixture of 24
(1.2 g, 4.68 mmol), acetic anhydride (7.2 mL, 76.2 mmol)
and pyridine (1.2 mL, 14.9 mmol) was heated with stirring
at 100 ꢀC for 2 h. The reaction mixture was cooled to
room temperature and poured over a mixture of hydrochloric
acid (2 M, 50 mL) and ice (100 g). The mixture was stirred
for 10 min and filtered. The solid was washed with water
(50 mL) and air dried to give the title compound as white
solid (1.5 g, 94%). Mp: 134–135 ꢀC, lit.9 114 ꢀC (methanol);
IR (KBr) 1764, 1745, 1682, 1616, 1467, 1370, 1222, 1190,
1
1046, 911 cmꢁ1; H NMR (CDCl3, 300 MHz): d 2.31 (s,
3H) and 2.39 (s, 3H), 2.78 (dd, J¼2.3, 16.6 Hz, 1H), 3.04
(dd, J¼13.2, 16. 6 Hz, 1H), 5.48 (dd, J¼2.3, 13.2 Hz, 1H),
6.7 (d, J¼7.9 Hz, 1H), 6.96 (d, J¼8.3 Hz, 1H), 7.15 (d,
J¼8.67, 2H), 7.48 (m, 3H); 13C NMR (CDCl3, 75.6 MHz):
d 21.0, 45.3, 78.7, 106.7, 113.8, 116.2, 122.0, 127.3,
135.8, 150.1, 150.9, 162.4, 169.2, 169.6, 172.7, 189.8;
Anal. Calcd for C19H16O6: C, 67.05; H, 4.73. Found: C,
67.18; H, 4.66.
4.1.17. 20,4,60-Trihydroxy chalcone (20). To a solution
of 22 (0.77 g, 3.26 mmol) and 23 (0.73 g, 3.58 mmol) in
absolute ethanol (3 mL) was added solution of potassium
hydroxide (3 g) in water (2 mL). The mixture was stirred
at ambient temperature overnight, poured into water
(150 mL) and acidified to pH 5. The product was extracted
with ethyl acetate (25 mLꢂ3), dried over sodium sulfate
and evaporated under vacuum. The crude product (1.5 g)
was dissolved in methanol (30 mL), hydrochloric acid
(10 mL, 2 M) was added and the mixture was heated at
70 ꢀC for 30 min. The reaction was poured into water
(150 mL) and extracted with ethyl acetate (25 mLꢂ4). The
combined organic extract was dried over anhydrous sodium
sulfate and concentrated under vacuum. The crude product
was chromatographed over silica gel using ethyl acetate/
light petroleum (50:50) as eluent to yield the title compound
(470 mg, 56%) as orange needles. Mp: 214–216 ꢀC, lit.10
215–216 ꢀC; Rf (50% ethyl acetate/light petroleum) 0.39;
IR (KBr) 3363, 3235, 1632, 1581, 1511, 1499, 1453, 1205,
4.1.20. trans-40,5-Diacetoxyflavanol (26). A suspension of
25 (900 mg, 2.64 mmol) and methanol (40 mL) was stirred
at room temperature for 10 min. The mixture was cooled
to ꢁ15 ꢀC using salt and ice bath under an argon atmosphere
and powdered sodium borohydride (580 mg, 15.33 mmol)
was added in portions over 15 min. The mixture was stirred
at ꢁ15 to ꢁ10 ꢀC for 1.5 h, then quenched by dropwise ad-
dition of acetic acid (65 drops) over 15 min and poured into
ice–water (200 mL). The solid was filtered and washed with
water (50 mL). The title compound was obtained as a white
solid (850 mg, 93%). Mp: >320 ꢀC (acetone); IR (KBr)
3230, 1757, 1697, 1593, 1466, 1371, 1268, 1199, 1176,
1
1051, 1035, 916, 786 cmꢁ1; H NMR (CDCl3, 300 MHz):
d 2.15 and 2.3 (m, 2H), 2.18 and 2.31 (2ꢂs, 6H), 3.34
(dd, J¼2.3, 12.4 Hz, 1H), 5.98 (t, J¼2.8 Hz, 1H), 6.52 and
6.53 (2ꢂd, J¼7.9 Hz, 2H), 7.14 (d, J¼8.6, 2H), 7.19 (t,
J¼7.9 Hz, 1H), 7.49 (d, J¼8.6 Hz, 2H), 8.32 (br s, 1H);
13C NMR (CDCl3, 75.6 MHz): d 21.0, 21.3, 35.3, 63.8,
72.0, 106.9, 108.8, 109.1, 121.7, 127.3, 131.7, 137.8, 150.5,
156.0, 156.1, 169.3, 173.9; Anal. Calcd for C19H18O6: C,
66.65; H, 5.29. Found: C, 66.44; H, 5.45.
1169, 1009, 822, 746 cmꢁ1
;
1H NMR (acetone-d6,
300 MHz): d 6.44 (d, J¼8.3 Hz, 2H), 6.90 (d, J¼8.7 Hz,
2H), 7.25 (t, J¼8.3 Hz, 1H), 7.59 (d, J¼8.7 Hz, 2H),
7.80 (d, J¼15.5 Hz, 1H), 8.08 (d, J¼15.5 Hz, 1H), 8.99 (s,
1H), 11.55 (s, 2H); 13C NMR (acetone-d6, 75.6 MHz):
d 107.6, 115.9, 124.2, 126.9, 130.5, 135.7, 143.4, 160.0,
162.1, 194.3.
4.1.21. 40-Acetoxy-5-hydroxyflav-3-ene (27). This was pre-
pared by the procedure used for preparation of 18 (80 mg,
15%) as off-white solid. IR (KBr) 3437, 1756, 1736, 1613,
1
1463, 1369, 1196, 1067, 1015, 913, 776 cmꢁ1; H NMR
4.1.18. 40,5-Dihydroxyflavanone (24). A mixture of 20
(1.3 g, 5.07 mmol), sodium acetate (1.3 g, 15.8 mmol) and
ethanol (26 mL) was refluxed for 1 h. The reaction mixture
was cooled to room temperature, poured into water
(100 mL) and acidified to pH 5 using 1 M hydrochloric
acid. The white solid was filtered, washed with water and
air dried to give 24 (1.2 g, 92%) as colourless needles.
Mp: 205–207 ꢀC (methanol) lit.17 206–207 ꢀC; IR (KBr)
3415, 3257, 1632, 1618, 1460, 1371, 1218, 1209, 1057,
(300 MHz, CDCl3): d 2.29 (s, 3H), 5.47 (br s, 1H), 5.75
(dd, J¼3.4, 9.8 Hz, 1H), 5.84 (dd, J¼1.7, 3.4 Hz, 1H),
6.27 (d, J¼7.9 Hz, 1H), 6.39 (d, J¼8.3 Hz, 1H), 6.85 (dd,
J¼1.7, 9.8 Hz, 1H), 6.92 (dd J¼7.9, 8.3 Hz, 1H), 7.08 (d,
J¼8.7 Hz, 2H), 7.46 (d, J¼8.7 Hz, 2H); 13C NMR (CDCl3,
75.6 MHz): d 21.0, 76.0, 108.2, 108.7, 109.6, 118.6, 121.6,
122.7, 128.2, 129.3, 138.3, 150.4, 151.6, 153.9, 169.6.
Anal. Calcd for C17H14O4: C, 72.33; H, 5.00. Found: C,
72.26; H, 5.10.
1
837, 714 cmꢁ1; H NMR (acetone-d6, 300 MHz): d 2.83
(dd, J¼3.0, 17.0 Hz, 1H), 3.29 (dd, J¼12.8, 17.0 Hz, 1H),
5.52 (dd, J¼3.0, 12.8 Hz, 1H), 6.47 (2ꢂd, J¼8.3 Hz, 2H),
6.89 (d, J¼8.6 Hz, 2H), 7.41 (d, J¼8.6 Hz, 2H), 7.43 (t,
J¼8.3 Hz, 1H), 8.50 (s, 1H), 11.79 (s, 1H); 13C NMR
4.1.22. 1,2,3,5-Tetramethoxybenzene (29). To a suspension
of 3,4,5-trimethoxyphenol (3 g, 16.3 mmol), potassium
carbonate (3 g, 21.7 mmol) in acetone (75 mL) was added
methyl iodide (2 mL, 32.1 mmol). The mixture was heated

5234
M. Deodhar et al. / Tetrahedron 63 (2007) 5227–5235
to reflux for 24 h with addition of methyl iodide (2 mL,
32.1 mmol) after every 6 h. Acetone was distilled off under
vacuum and the residue was dissolved in water (40 mL) and
extracted with dichloromethane (25 mLꢂ3). The combined
organic extracts were dried over sodium sulfate and solvent
concentrated under vacuum to give 1,3,4,5-tetramethoxy-
benzene 29 (3.1 g, 96%). Mp: 46 ꢀC, lit.18 47 ꢀC; 1H NMR
(CDCl3, 300 MHz): d 3.78 (s, 3H), 3.784 (s, 3H), 3.84 (s,
6H), 6.15 (s, 2H); 13C NMR (CDCl3, 75.6 MHz): d 55.4,
56.0, 60.9, 91.7, 132.3, 153.6, 156.2.
3.0 (dd, J¼12.0, 16.6 Hz, 1H), 3.80 (s, 3H), 3.91 (s, 3H),
3.93 (s, 3H), 5.46 (dd, J¼3.4, 12.0 Hz, 1H), 6.13 (s, 1H),
7.4 (m, 5H); 13C NMR (CDCl3, 75.6 MHz): d 45.5, 56.0,
56.1, 61.1, 78.9, 89.4, 106.3, 125.9, 128.4, 128.6, 131.0,
138.8, 156.2, 157.8, 158.7, 189.2.
4.1.26. cis-5,7,8-Trimethoxyflavan-4-ol (33). A solution of
32 (250 mg, 7.96 mmol) in a mixture of methanol–THF
(20 mL, 50:50) was cooled to 10 ꢀC. Sodium borohydride
(200 mg) was added in portions and the mixture was stirred
at the same temperature for a further 1 h. The reaction was
quenched by dropwise addition of acetic acid solution
(10%, 4 mL), followed by stirring for 5 min. The reaction
mixture was diluted with sodium chloride solution (10%,
100 mL) and the product extracted with ethyl acetate
(25 mLꢂ4). The solvent was distilled off and the residue
was redissolved in ethyl acetate (25 mL), the extract dried
over anhydrous sodium sulfate and concentrated to give
the title compound as sticky solid (240 mg, 95%). Attempts
to solidify the product by trituration with various solvents
and cooling failed. The product was found to be unstable
and hence was quickly used in the next reaction. IR (chloro-
form) 3500–2800, 3017, 1610, 1502, 1466, 1137, 1118,
4.1.23. 2-Hydroxy-3,4,6-trimethoxyacetophenone (30). A
solution of 29 (3 g, 15.1 mmol) in dry ether (15 mL) was
cooled to 0 ꢀC under an argon atmosphere. Aluminium chlo-
ride (3 g, 22.5 mmol) was added in portions followed by
addition of acetyl chloride (3 mL, 42.2 mmol) over 5 min.
The reaction mixture was stirred at 0 ꢀC for 3 h and then
kept overnight at room temperature. The reaction was
quenched by addition of a mixture of concd hydrochloric
acid (5 mL) and ice (50 g). The precipitated solid was fil-
tered and washed with water (50 mL) and dried. The crude
product was chromatographed over silica gel using ethyl
acetate/light petroleum (30:70) as eluent to yield the title
compound 30 (1.9 g, 56%). Mp: 114–115 ꢀC, lit.13 112–
113 ꢀC; Rf (30% ethyl acetate/light petroleum) 0.39; IR
(KBr) 3500 br, 2933, 1625, 1588, 1471, 1421, 1360, 1295,
1
1042 cmꢁ1; H NMR (acetone-d6, 300 MHz): d 2.21 (ddd,
J¼9.4, 11.7, 13.5 Hz, 1H), 2.53 (ddd, J¼1.8, 7.1, 13.5 Hz,
1H), 3.79 (s, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 5.07 (dd,
J¼1.8, 11.7 Hz, 1H), 5.26 (dd, J¼7.1, 9.4 Hz, 1H), 6.16 (s,
1H), 7.4 (m, 5H); 13C NMR (CDCl3, 75.6 MHz): d 38.5,
55.1, 55.7, 59.8, 62.7, 76.9, 90.1, 125.9, 127.7, 128.3,
131.9, 141.2, 149.5, 152.9, 154.3; HRMS (ESI) m/z
339.1205 (M+Na+, C18H20O5Na, requires 339.1203).
1
1278, 1233, 1212, 1126, 1025, 991, 791 cmꢁ1; H NMR
(CDCl3, 300 MHz): d 2.61 (s, 3H), 3.81 (s, 3H), 3.89 (s,
3H), 3.93 (s, 3H), 5.96 (s, 1H), 13.76 (s, 1H); 13C NMR
(CDCl3, 75.6 MHz): d 33.0, 55.5, 55.9, 60.6, 86.4, 106.3,
130.5, 158.3, 158.7, 158.9, 203.6.
4.1.24. 20-Hydroxy-30,40,60-trimethoxychalcone (31). To
a stirred mixture of 30 (1.8 g, 7.96 mmol), benzaldehyde
(1.2 g, 11.3 mmol) and ethanol (60 mL) was added a solution
of potassium hydroxide (15 g) in water (15 mL). The reac-
tion mixture was stirred overnight under an argon atmo-
sphere. Crushed ice (100 g) was added and the mixture
was acidified to pH 3 with concd hydrochloric acid. The
precipitated solid was filtered, washed with water and dried
to give chalcone 31 (2.37 g, 95%). Mp: 141–142 ꢀC, lit.19
138 ꢀC; IR (KBr) 3447, 1625, 1558, 1420, 1330, 1245,
4.1.27. 5,7,8-Trimethoxyflav-3-ene (34). A mixture of
p-toluenesulfonic acid (16 mg) in toluene (120 mL) was
heated to reflux for 1 h with azeotropic removal of water.
A solution of 33 (240 mg, 0.75 mmol) in dichloromethane
(2 mL) was added over 2 min and heating was continued
for 15 min. The reaction mixture was cooled to room tem-
perature and washed with satd sodium bicarbonate solution
(25 mLꢂ2). The toluene layer was dried over anhydrous
sodium sulfate and the solvent evaporated under vacuum.
The crude product was chromatographed over silica gel
using ethyl acetate/light petroleum (20:80) as eluent to yield
the title compound 34 (180 mg, 80%) as an oil. The product
was found to be unstable,5 and hence was quickly analyzed
and used in the next step. Rf (20% ethyl acetate/light petro-
leum) 0.3; IR (neat) 2933, 1606, 1503, 1464, 1455, 1136,
1206, 1124, 1009, 793 cmꢁ1
;
1H NMR (CDCl3,
300 MHz): d 3.84 (s, 3H), 3.95 (s, 6H), 6.02 (s, 1H), 7.4
(m, 3H), 7.61 (m, 2H), 7.88 (d, J¼15.3 Hz, 1H), 7.87 (d,
J¼15.3 Hz, 1H); 13C NMR (CDCl3, 75.6 MHz): d 55.9,
56.0, 60.6, 87.1, 106.9, 127.4, 128.3, 128.8, 130.0, 130.9,
135.4, 142.5, 158.4, 158.5, 159.3, 193.2.
1
1116 cmꢁ1; H NMR (CDCl3, 300 MHz): d 3.65 (s, 3H),
3.81 (s, 3H), 3.84 (s, 3H), 5.69 (dd, J¼3.8, 10.1 Hz, 1H),
5.88 (dd, J¼1.5, 3.8 Hz, 1H), 6.05 (s, 1H), 6.83 (dd,
J¼1.5, 10.1 Hz, 1H), 7.34 and 7.48 (m, 5H); 13C NMR
(CDCl3, 75.6 MHz): d 55.8, 56.1, 61.0, 89.4, 105.3,
118.6, 120.3, 126.9, 128.1, 128.4, 131.8, 140.4, 146.8,
151.1, 153.6.
4.1.25. 5,7,8-Trimethoxyflavanone (32). A mixture of chal-
cone 31 (2.4 g, 7.6 mmol), methanol (120 mL) and concd
hydrochloric acid (60 mL) was refluxed for 40 h. Methanol
was distilled off under vacuum and the residue was diluted
with ice water (200 mL). The solid was filtered, washed
with water (100 mL) and dried. The crude product was chro-
matographed over silica gel using ethyl acetate/light petro-
leum (50:50) as eluent to yield starting material 31 (0.5 g,
21%). Rf (50% ethyl acetate/light petroleum) 0.65; further
elution with pure ethyl acetate gave the title compound 32
(1.52 g, 63%). Mp: 163–165 ꢀC, lit.20 167–168 ꢀC; Rf
(50% ethyl acetate/light petroleum) 0.5; IR (KBr) 3007,
4.1.28. 6a,12a-Dihydro-1,3,4,8,10,11-hexamethoxy-6-
phenyl-7-[(1E)-2-phenylethenyl]-6H,7H-[1]benzopyr-
ano[4,3-b][1]benzopyran (dependensin) (1). To a solution
of 34 (500 mg, 1.67 mmol) in methanol (50 mL) was added
concd hydrochloric acid (10 M, 4 mL). The mixture
was stirred overnight at room temperature. Methanol was
removed under vacuum and the product was dissolved in
ethyl acetate, dried over anhydrous sodium sulfate and
1
2937, 1682, 1598, 1569, 1346, 1276, 1124, 703 cmꢁ1; H
NMR (CDCl3, 300 MHz): d 2.86 (dd, J¼3.4, 16.6 Hz, 1H),

M. Deodhar et al. / Tetrahedron 63 (2007) 5227–5235
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concentrated. The crude product was chromatographed over
silica gel using ethyl acetate/light petroleum (50:50) as elu-
ent to yield title compound 1 (360 mg, 72%) as a white solid.
The analytical sample was prepared by crystallization from
methanol. Mp: 197–199 ꢀC; Rf (50% ethyl acetate/light
petroleum) 0.58; IR (KBr) 2933, 1609, 1501, 1455, 1204,
1140, 1116 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 2.31
;
(ddd, J¼1.9, 2.6, 11.3 Hz, 1H), 3.35 (ddd, J¼1.5, 1.9,
5.7 Hz, 1H), 3.67 (s, 3H), 3.74 (s, 3H), 3.82 (s, 3H), 3.86
(s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 4.96 (d, J¼11.3 Hz,
1H), 5.40 (d, J¼2.6 Hz, 1H), 5.99 (dd, J¼1.5, 15.8 Hz,
1H), 6.15 (s, 1H), 6.17 (s, 1H), 6.17 (dd, J¼5.7, 15.8 Hz,
1H), 7.1–7.4 (m, 10H); 13C NMR (CDCl3, 75.6 MHz):
d 33.4, 41.5, 56.3, 56.4, 56.8, 56.9, 61.3, 61.5, 63.0, 77.2,
89.6, 89.9, 103.4, 104.9, 126.6, 127.5, 127.8, 128.8ꢂ2,
128.9, 131.0, 131.9, 132.9, 137.7, 139.3, 147.6, 149.9,
152.5, 153.9, 154.5, 155.2; Anal. Calcd for C36H36O8: C,
72.46; H, 6.10. Found: C, 72.26; H, 6.10; MS (ESI) m/z
619.21 (M+Na+, C36H36O8Na, requires 619.23).
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