First Total Synthesis of Original Chalcone–Flavone Dimers as Cissampeloflavone Analogues

Article abstract of DOI:10.1002/ejoc.201800338

The total synthesis of furoflavones closely related to the natural product cissampeloflavone was explored following different pathways. The involvement of a flavone as a key intermediate proved to be the most efficient way to form the 7-phenyl-5H-furo[3,2-g]chromen-5-one scaffold, and the first example of furoflavone formation was achieved in this way. For the synthesis of chalcone–flavone dimers, two different strategies were examined: either acylation at the very end of the synthesis, or introduction of the 3-acyl group during furan-ring formation. The final acylation was hardly achievable with hindered benzoyl chlorides, but a simpler 4-methoxybenzoyl group was added to the furoflavone in modest yield. The alternative direct introduction of this acyl group during furan formation proved to be more efficient. Conjugate addition of an iodoflavone to an ynone followed by intramolecular Heck cyclization gave the best results, leading to the first synthetic chalcone–flavone dimer ever described.

Full text of DOI:10.1002/ejoc.201800338

A Journal of
Accepted Article
Title: First total synthesis of original chalcone-flavone dimers as
cissampeloflavone analogues
Authors: Joelle Dubois, Marion Thévenin, and Sylviane Thoret
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800338
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10.1002/ejoc.201800338
European Journal of Organic Chemistry
FULL PAPER
First total synthesis of original chalcone-flavone dimers as
cissampeloflavone analogues.
Marion Thévenin,[a] Sylviane Thoret,[a] and Joëlle Dubois*[a]
Abstract: Total synthesis of furoflavones closely related to natural
product cissampeloflavone was explored according to different
pathways. The involvement of a flavone as key intermediate proved
to be the most efficient way to form the 7-phenyl-5H-furo[3,2-
g]chromen-5-one scaffold and consisted in the first example of
furoflavone formation. To go further on chalcone-flavone dimer
synthesis two different strategies have been examined, either
acylation at the very end of the synthesis or introduction of the 3-acyl
group during furan ring formation. Ultimate acylation was hardly
total synthesis of cissampeloflavone has never been carried out
to date, we initiated a research program dedicated to the
building
of
such
7-phenyl-5H-furo[3,2-g]chromen-5-one
compounds. Many methodologies have been described to
synthesize flavones. The most classical synthetic pathways
involve either diaryl ß-diketones or chalcones as key
intermediates, such as in Baker-Venkataraman and Claisen-
Schmidt rearrangements, respectively.[3] However no synthetic
methodology has been developed to access to chalcone-flavone
dimer. Moreover no biosynthetic mechanism has really been
achievable with hindered benzoyl chlorides but
a simpler 4-
methoxybenzoyl group has been added on the furoflavone in modest
yield. The alternative direct introduction of this acyl group during
furan formation proved to be more efficient. Conjugate addition of an
iodoflavone to an ynone followed by intramolecular Heck cyclization
gave the best results affording the first synthetic chalcone-flavone
dimer ever described.
proposed, only a possible oxidative coupling between 6-
hydroxyflavone and chalcone derivatives that could further
rearranged into benzofurane.[2a]
O
O
OH
OH
O
O
O
O
O
O
O
O
HO
HO
HO
OH
OH
O
O
O
O
Introduction
O
Ridiculuflavonylchalcone B
Cissampeloflavone (1)
R1O
OH
Flavonoids and their naturally occurring precursor chalconoids
are polyphenolic compounds mainly extracted as secondary
metabolites from plants and fungi. They often display biological
activities because of their antioxidant properties. They have
shown to be active as antimicrobial or anticancer agents.
Complex molecules such as biflavonoids or chalcone-flavone
dimers are also found in plants but less frequently. In the course
of our search for new antiparasitic agents we were interested in
R2
R3
HO
O
O
OR4
OH
O
O
O
O
O
O
HO
O
O
O
O
OH
OH
O
R1 = OH, R2 = OMe, R3 = H, R4 = OMe
R1 = OMe, R2 = OH, R3 = H, R4 = OMe
R1 = OMe, R2 = H, R3 = OMe, R4 = OH
OH
HO
O
O
original polyphenolic scaffolds. Cissampeloflavone
1
has
O
OH
O
O
naturally caught our attention because of its original chalcone-
flavone dimer structure and of its activity on Trypanosoma cruzi
(IC50 = 3.4 µM) and T. brucei (IC50 = 1 µM).[1] The 7-phenyl-5H-
furo[3,2-g]chromen-5-one and more generally the chalcone-
flavone dimer scaffold have seldom been observed in natural
products. Besides cissampeloflavone 1 that was isolated from a
Venezuelan plant (Cissampelos pereira), this motif has only
been found in Ridiculuflavonylchalcone B isolated from the
Brazilian plant Aristolochia ridicula. In those species, 6 other
chalcone-flavone dimers have been isolated displaying the very
similar 6-phenyl-8H-furo[2,3-g]chromen-8-one scaffold (Figure
1).[2] Among all these bi- and tetraflavonoids, antiparasitic
activity was only evaluated for cissampeloflavone. Since the
O
O
O
O
O
O
O
O
O
OH
OH
HO
O
O
O
OH
HO
O
O
O
O
O
O
O
O
O
OH
HO
HO
OH
O
O
O
O
Figure 1. Natural bi- and tetraflavonoids
[a]
Institut de Chimie des Substances Naturelles, CNRS UPR2301
Université Paris Sud, Université Paris Saclay
1 avenue de la Terrasse 91198 Gif sur Yvette cedex, France
E-mail: joelle.dubois@cnrs.fr
http://www.icsn.cnrs-gif.fr/spip.php?article1232&lang=en
To achieve the total synthesis of cissampeloflavone 1 different
synthetic pathways have been designed. The acylation of the C-
3 position of the furan ring could be envisioned at the very end
of the synthesis after construction of the 7-phenyl-5H-furo[3,2-
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800338
European Journal of Organic Chemistry
FULL PAPER
g]chromen-5-one 2 (path a) which can be obtained either from 5-
acetylbenzofurane 3 (path b) or from the appropriate flavone 4
(path c). An alternative pathway (d) would consist in reacting the
corresponding flavone with a chalcone analogue (Scheme 1).
from 4-ethynyl anisol.[9] According to Wang et al. it was possible
to close the furan ring without intermediate purification of the
bromovinyl ether, but in our case isolation of bromovinyl
derivative 8 prior to cyclization proved to be more efficient.
Cyclization through a palladium-catalyzed intramolecular C-H
functionalization afforded benzofuranone 2 in a reasonable yield.
To avoid long reaction times at high temperature, we have
carried out these reactions under microwave irradiation heating.
The experiment duration was thus reduced from several hours to
10 min (Scheme 3). Based on our previous results [10], the free
hydroxyl group of the furoflavone 2 had to be protected as a
benzyl ether before Friedel-Crafts acylation. After benzylation
using classical conditions, the Friedel-Crafts acylation of the
furan ring was performed. Unfortunately, with the appropriate
trisubstituted benzoyl chloride, it was impossible to get the
desired product in detectable amounts possibly due to the steric
hindrance coming from the phenyl substituents. Acylation with 4-
methoxybenzoyl chloride was thus carried out on compound 10
leading to acylated derivative 11 in low yield that could not be
further purified due to its low solubility. The main product of this
acylation was furoflavone 2 resulting from the debenzylation of
compound 10 in the presence of Lewis acid as previously
observed.[10]
OH
OR
O
MeO
O
OMe
a
O
O
MeO
O
OMe
MeO
O
OH
O
OH
2
OH
1
c
d
b
MeO
OR
OMe
O
OH
OH
O
MeO
O
O
O
HO
+
MeO
MeO
R’
OMe
OH
5
4
3
Scheme 1. Retrosynthetic scheme for total synthesis of cissampeloflavone
Results and Discussion
Widely used methods such as Claisen-Schmidt or Baker-
Venkatamaran rearrangements were ineffective in the case of
the furoflavone 2 synthesis from compound 3 when R = H
(unpublished results).[4] Therefore we did not go further on path
b. We thus focused on the synthesis of flavone 4, the key
OBn
MeO
O
O
(a)
O
OMe
+
4
MeO
Br
intermediate in both
c and d pathways. Many synthetic
Br
methodologies have been assayed. We observed that the
flavone formation was greatly dependent on hydroxyl protecting
groups in the privileged methods going through diaryl ß-diketone
or chalcone. Finally, the shortest and most efficient way to get
OH
9
8
(b)
OBn
OMe
OBn
OMe
unprotected flavone
4
has been proved to be the direct
O
O
O
MeO
O
MeO
O
(c)
condensation of phloroglucinol with β-ketoester 6 (Scheme 2).
This method affording flavone 4 in excellent yield has been
greatly and successfully improved when the reaction was carried
out on 1 mmol scale. Ethyl benzoylacetate 6 was obtained from
commercially available acetovanillone 7 by benzylation under
phase transfer catalysis[5] followed by condensation with
diethylcarbonate under basic conditions.[6] At last microwave
irradiation of the neat mixture of phloroglucinol and compound 6
successfully afforded the desired flavone 4 in 85 % overall
yield.[7]
O
OBn
10
OH
2
O
Cl
(d)
MeO
OBn
OMe
OBn
OMe
O
O
O
O
MeO
MeO
O
O
+
OH
11
OH
O
MeO
2
OBn
O
OBn
OMe
O
O
HO
(a)
(b)
OMe
OH
OMe
EtO
Scheme 3. Reaction conditions: (a) Cs2CO3, DMF, microwave, 110 °C, 10 min,
52 %; (b) PdCl2, K2CO3, DMF, microwave, 130 °C, 10 min, 45 %; (c) BnCl,
TBAI, K2CO3, DMF, rt, 2 days, 57 %; (d) TiCl4, CH2Cl2, rt, 1 h, 11 21 % and 2
40 %.
O
O
OH
7
6
4
Scheme 2. Reaction conditions: (a) i - BnCl, TBAI, K2CO3, DMF, rt, 30 h,
quant.; ii - diethylcarbonate, NaH 60 %, toluene, reflux, 23 h, 95 %; (b)
phloroglucinol, microwave 240 °C, 5 min, 89 %.
In summary, c and a paths can afford the synthesis of chalcone-
flavone dimer and compound 11 was the first chalcone-flavone
derivative obtained by total synthesis in 2.2 % overall yield. The
main problem is the final acylation step that could not be carried
out with hindered benzoyl chlorides. Despite compound 2 has
been obtained in only 5 steps in 20 % overall yield this synthetic
scheme did not allow the synthesis of cissampeloflavone 1.
Among the available methods to form a furan ring from phenol,
Wang procedure appeared to be the shortest way to synthesize
furoflavone 2.[8] Flavone 4 was turned into bromovinyl ether 8 by
base-promoted addition of bromoethynyl anisol 9 easily obtained
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10.1002/ejoc.201800338
European Journal of Organic Chemistry
FULL PAPER
Therefore we turned to the final retrosynthetic pathway d that
avoided this final acylation step and that is formally the addition
of a chalcone on a flavone, similar to the proposed biosynthetic
pathway.
Recently the total syntheses of two natural products bearing 2-
phenyl-3-benzoyl benzofuran moieties have been described.
possibility to obtain regioisomers of 14 by this method we
thought it would deserve some investigation. We tried the
experimental methods described by Gaster et al. in different
solvents (DCE, TFE, HFIP) with different iron salts (Fe(ClO4)3 or
FeCl3) at room temperature or with warm heating. None of these
conditions were able to give even traces of chalcone-flavone
dimer 14 or of any of its possible isomers (Scheme 4). Moreover,
both starting materials were recovered unchanged except when
the reaction mixture was warmed up to 45 °C. In that case we
could isolate the fluorescent 4’,5,7-trimethoxyflavone formed by
dehydrative cyclization of ß-diketone 13, in a very similar way as
The synthesis of Daphnodorin
intramolecular Heck reaction of
B
was realized by an
iodoaryl vinyl ether
a
intermediate very similar to bromoaryl vinyl ether 8 that was
formed by base promoted alkylation of a iodophenol with a diaryl
ynone.[11] The crucial step of the synthesis of 2’’’-
Dehydroxycalodenin B was an iron-catalyzed oxidative cross
coupling of phloroacetophenone and 1,3-bis(4-methoxyphenyl)
propane 1,3-dione.[12] (Figure 2).
the iron-catalyzed formation of
diketones.[14]
flavones from diaryl ß-
Therefore we tried the Zhang method used for the Daphnodorin
B synthesis. Contrary to the previous method, modification of
chrysin had to be modified to obtain the appropriate iodo
derivative. Preliminary attempts on 6-iodochrysin proved to be
unsuccessful. Therefore we decided to protect the 5-hydroxy
group before cyclization. Though benzyl or tosyl group could
easily be introduced on position 5, further synthetic steps were
not conclusive. Suspecting these groups to hinder the cyclization
reaction we decided to methylate the 5-hydroxy group leading to
the choice of the 6-iodo-5-methoxy-chrysin 18 as the key
intermediate. It was easily obtained in 4 steps from chrysin. The
7-hydroxyl group was protected as methoxymethyl ether before
selective introduction of iodine in position 6 according to the
Lewin’s efficient method.[15] Methylation of 6-hydroxyl group by
dimethyl sulfate followed by removal of the MOM protecting
group afforded compound 18 in 68% overall yield (scheme 5). It
is to note that this final step was tricky because of concomitant
iodide removal when higher HCl concentrations were used, as
experienced by Zhang’s group during Daphnodorin A total
synthesis.[16]
HO
OMe
OH
MeO
O
OH
I
MeO
HO
O
OH
HO
+
O
OMe
O
O
BnO
OMe
HO
OMe
OH
Daphnodorin B
HO
O
OMe
OH
HO
OH
+
O
OH
O
HO
OH
O
O
OMe
OH
O
2’’’-Dehydroxycalodenin B
Figure 2. Natural products with 2-phenyl-3-benzoyl benzofuran structure
Though flavone 4 has been synthesized in good overall yield in
only 3 steps, this method could not be scaled up to afford rapidly
suitable amount, i.e. tens of grams, to perform methodological
studies. Therefore, we decided to examine the feasibility of both
syntheses on chrysin 12, a flavone structurally close to flavone 4
and commercially available.
HO
7
O
MOMO
O
MOMO
I
O
O
(a)
(b)
6
5
OH
O
OH
15
O
OH
16
12
(c)
O
OMe
HO
I
O
MOMO
I
(d)
O
MeO
O
OMe O
OMe O
HO
O
O
(a)
+
OMe
18
O
17
MeO
O
OH
O
O
OH
OH
MeO
OH
MeO
14
12
13
Scheme 5. Reaction conditions: (a) MOMCl, DIPEA, DMF, 0 °C to rt, 12 h,
91 %; (b) BTMA.ICl2, CaCO3, CH2Cl2/MeOH (1:1), rt, quant.; (c) Me2SO4,
acetone, 60 °C, 83 %; (d) HCl 10 % in MeOH, 70 °C, 93 %.
Scheme 4. Reaction conditions: (a) Fe(ClO4)3 hydrate or FeCl3 hydrate,
tBuOOtBu, TFE/HFIP (1:1) or TFE/DCE (1:1), rt or 45 °C overnight, 0 %.
The second reactant of the Daphnodorin-like synthesis was the
diphenyl propynone 19. It was obtained in 3 steps in 65 %
overall yield from 4,6-dimethoxysalicyladehyde: after benzylation
of the free hydroxyl group, the protected aldehyde was reacted
with the 4-ethynylanisol carbanion followed by oxidation of the
The advantage of the iron-catalyzed oxidative cross coupling
method is the use of unmodified chrysin and the easy synthesis
of ß-diketone 13, a formal analogue of chalcone 5, by following
an already reported procedure.[13] Though we were aware of the
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10.1002/ejoc.201800338
European Journal of Organic Chemistry
FULL PAPER
alcohol without intermediate purification. Compound 19 purity
appeared to be critical for the following steps leading us to
rapidly use it after its formation. In Zhang’s article, both O-
alkylation and palladium-catalyzed cyclization have been carried
out in acetonitrile. However, iodoflavone 18 was hardly soluble
in this solvent and most of our assays performed in acetonitrile
were unsuccessful. The reactants were much more soluble in
DMF that was therefore chosen as solvent for both reactions.
Another problem in this synthesis was the duration of conjugate
addition since no reaction time data were given in the article.[11]
Indeed the authors monitored the O-alkylation by TLC to carry
out palladium-catalyzed following step only when the conjugate
addition reached to completion. However in our case it proved
difficult to follow the O-alkylation of iodoflavone 18 by TLC.
Therefore we controlled the conversion of 18 to 20 by LC/MS. It
appeared that we never reached completion, even after 48h
heating at 75 °C. Nevertheless compound 20 was formed in
about 50 % yield. When heating for 96 h, both compounds 18
and 20 were degraded. Contrary to what we observed for the
formation of compounds 2 and 8 microwave heating has only led
to degradation. Then different bases were tried for the conjugate
addition and we found that tBuOK and K3PO4 gave the best
results. To shorten reaction time we increased base amount to 5
equiv and compound 20 appeared to be formed in 48 % yield in
24 h when potassium phosphate was used as a base.
in the presence of silver carbonate that afforded compound 21 in
61% LC/MS-estimated yield. Therefore we applied our best
conditions (5 equiv. K3PO4, 24 h at 75 °C then, without
intermediate purification, Pd(OAc)2, polymer-bound PPh3,
Ag2CO3, 115 °C, 15 h) to a larger amount of starting materials
and compound 21 was obtained in 9 % isolated yield. The
difference between LC/MS-estimated and isolated yields
accounted for the difficulty to purify these derivatives because of
their low solubility in many solvents. The subsequent steps were
the selective deprotection of flavone methoxy group and
debenzylation. Selective demethylation of 21 was performed
with MgBr2.OEt2 according to the reported procedure[13] in 61%
yield. This method was very efficient to selectively remove the
methyl group ortho to the flavone carbonyl though we also
observed partial ortho demethylation of the 2-(benzyloxy)-4,6-
dimethoxybenzoyl group when the reaction was carried out for
longer times. Final debenzylation was quantitatively carried out
under classical conditions with ammonium formate and Pd/C
affording the close analogue of cissampeloflavone 14. In
summary compound 14 was obtained in 7 steps from chrysin in
3.8 % overall yield.[17] Though overall yield was modest it was
reasonable to attempt to synthesize cissampeloflavone by this
method. The only modification to make in scheme 7 was related
to the flavone precursor of cissampeloflavone, 3’-benzyloxy-4’,5-
dimethoxy-6-iodoflavone 22 that was easily synthesized from
flavone 4 according to scheme 5 in 42 % overall yield. Then the
optimized conditions were applied to this iodoflavone 22 and the
reaction mixture was analyzed by LC/MS. Many products were
formed in this reaction and compound 23 was detected but, as a
minor product (5% determined from the UV profile of the
reaction mixture). Its low formation yield discouraged us to
attempt any purification.
OMe
H
O
MeO
OH
(a)
O
MeO
MeO
OBn
MeO
O
I
O
O
(b)
MeO
19
BnO
OMe OMe O
OMe
OBn
18
20
OBn
OMe
O
MeO
O
OMe
HO
I
O
(c)
BnO
19
+
O
OMe
O
OMe O
O
O
OMe
MeO
MeO
O
O
MeO
22
23
(d)
HO
BnO
O
O
OMe
OH
O
O
Scheme 7. Reaction conditions: i) K3PO4, DMF, 75 °C, 24 h; ii) Pd(OAc)2,
OMe
OMe
PPh3, Ag2CO3, DMF, 115 °C, 15 h, traces.
MeO
MeO
14
21
Scheme 6. Reaction conditions: (a) i) BnCl, K2CO3, acetone, rt, overnight,
83 %; ii) 4-ethynylanisol, nBuLi, THF, -78 °C, 2 h then 0 °C 30 min; iii) MnO2,
CH2Cl2, rt, 48h, 78 % for ii and iii; (b) K3PO4, DMF, 75 °C, 24 h; (c) Pd(OAc)2,
PPh3, Ag2CO3, DMF, 115 °C, 15 h, 9 % for b and c ; (d) i) MgBr2.OEt2, CH3CN,
80 °C, 14i 61 %; ii) ammonium formate, Pd/C (10 %), EtOH, 40 °C, quant.
Chrysin derivative 18 and flavone 22 were very similar
compounds bearing only a different substitution pattern of the
phenyl ring. Contrary to what we expected this slight
modification, far away from the reactive centers implied in the
conjugate addition and intramolecular Heck cyclization, was
significant for their reactivity. Therefore to achieve the total
synthesis of cissampeloflavone both attempted methods using
chrysin should be reexamined starting from flavone 4.
Compounds 4, 21, and 14 were evaluated for their inhibitory
activity against parasitic growth. They were assayed on the
bloodstream form of Trypanosoma brucei and on the
intraerythrocytic stages of Plasmodium falciparum. Compounds
4, 21 and 14 exhibited micromolar inhibitory activities against T.
brucei (IC50 = 28 ± 6.9 µM, 3.8 ± 0.5 µM and 1.6 ± 0.1 µM
The palladium-catalyzed Heck reaction was also monitored by
LC/MS. Some variations of the conditions described in reference
11 have been tried such as the palladium source (Pd(OAc)2 and
tetrakis triphenylphosphine palladium), the absence or the
presence of silver carbonate, and the phosphine ligand (o-
tolylphosphine,
triphenylphosphine
and
polymer-bound
triphenylphosphine). The best conditions for Heck-cyclization
were palladium acetate with polymer-bound triphenylphosphine
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10.1002/ejoc.201800338
European Journal of Organic Chemistry
FULL PAPER
General: All commercial reagents were used without any further
purification. Where necessary, organic solvents were routinely dried
and/or distilled prior to use and stored over molecular sieves under
argon. All reactions were conducted in oven-dried glassware under an
argon atmosphere, unless stated otherwise. Microwave heatings were
performed with Anton Paar Microwave 300 or CEM Discover. Analytical
thin-layer chromatography was carried out on precoated silica gel
aluminium plates (SDS TLC plates, silica gel 60F254). Column
chromatography was performed on prepacked Redisep columns.
Preparative TLC (PLC) was performed on Merck TLC with silica gel
60F254. NMR spectra, including 1H, 13C (HMQC and HMBC) experiments,
were recorded on a Brucker Avance 300 (300 MHz) and Avance 500
(500 MHz) spectrometers. Chemical shifts (δ) are given in ppm relative to
CDCl3 (7.26 ppm; 77.2 ppm) or DMSO- d6 (2.50 ppm; 39.5 ppm).
Splitting patterns are designed as: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet and combinations thereof. Coupling constants J are
reported in hertz (Hz). IR spectra were recorded on a Perkin-Elmer
Spectrum BX. Mass spectra were recorded on Thermoquest AQA
Navigator with a TOF detection (ESI-HRMS) or on Waters LCT premier
XE using electrospray ionization with a TOF detection (ESI-HRMS)
coupled with Waters Acquity UPLC. Melting points were measured on
Büchi b-450.
respectively). It is to note that trypanocidal activities are very
similar if we compare flavone 4 with chrysin (IC50 = 14.4 ± 2.0
µM)[18] and compound 14 with cissampeloflavone (IC50 = 1
µM).[1] Both flavones (4 and chrysin) were found to be inactive
against P. falciparum (IC50 >50 µM) whereas compounds 21 and
14 displayed moderate anti-plasmodium activity (IC50 = 3.1 ± 0.1
µM and 24.9 ± 1.9 µM, respectively). When comparing the
inhibitory activities of chrysin with flavone 4 and of compound 14
with cissampeloflavone (IC50 >50 µM)[1] the same order of
potency also prevails against P. falciparum.
Conclusions
The first synthesis of chalcone-flavone dimer has been designed
according to two different pathways. Our original pathways went
through the building of the furoflavone scaffold from flavone. We
have met many difficulties to synthesize flavone-chalcone
dimers since there was no method to form these dimers and we
have had to adapt those described with simple phenolic
compounds to flavone as starting material. The successful
synthesis of furoflavone 2 was easily achieved in only 5 steps
and 20 % overall yield. It should be noted that this is the first
synthesis of such a furoflavone derivative and more generally of
this scaffold, since, to the best of our knowledge, no similar
compound has been described so far. To go to chalcone-flavone
dimer the last acylation step has proved to be difficult and only a
simple benzoyl group has been introduced. The second pathway
was more promising with direct formation of the dimer between
an iodochalcone and an ynone. Considering the ynone as a
chalcone analogue, this synthetic scheme appeared to be the
most closely related to the hypothesized biosynthesis. We
successfully synthesized the first chalcone-flavone dimer by this
method, thus proving that the total synthesis of chalcone-flavone
dimer was actually possible from commercially available
chemicals in few steps. However the low solubility of flavonoids
was detrimental to efficient synthesis that has nevertheless been
overcome by carrying out reactions without solvent or in DMF,
when possible. It should also be mentioned that the crucial
formation of the benzoyl benzofurane described by Zhang’s
group in Daphnodorin A and B syntheses occurred in only 44 to
55 % optimized yield.
Ethyl 3-(4-(benzyloxy)-3-methoxyphenyl)-3-oxopropanoate (6): (i) 4-
benzyloxy-3-methoxy-acetophenone: K3PO4 (6.25 g, 45.1 mmol, 1.5
equiv.) and tetra-nbutylammonium iodide (1.11 g, 3.01 mmol, 0.1 equiv.)
were added to a solution of acetovanillone (5 g, 30.1 mmol, 1equiv.) in
dry DMF (45 mL). Benzyl chloride (4.22 mL, 36.1 mmol, 1.2 equiv.) was
added dropwise and the reaction mixture was stirred for 30 h at room
temperature. Ethyl acetate was added to the reaction mixture and the
organic layer was washed twice with brine, dried over MgSO4 and
concentrated under vacuum. The crude product was recrystallized in
ethanol/heptane 1:4 (v/v) to afford 4-benzyloxy-3-methoxy acetophenone
(7.71 g, quant.) as white needles. The 1H and 13C NMR chemical shifts of
the product are in accordance with literature.[19] MS (ESI+, MeOH +
+
CH2Cl2): m/z 257.1 [M+H]+; HRMS calcd for C16H17O3 [M+H]+ 257.1177,
found 257.1176 (ii) ethyl 3-(4-(benzyloxy)-3-methoxyphenyl)-3-
oxopropanoate (6): Diethyl carbonate (11.9 mL, 98.4 mmol, 2 equiv.) was
added to NaH (60 % in oil) (5.93 g) in anhydrous toluene (63 mL) then a
solution of 4-benzyloxy-3-methoxy-acetophenone in anhydrous toluene
(63 mL) was added dropwise while refluxing. The solution was kept
under reflux for 23 h. After cooling, acetic acid was added carefully until
neutral pH was reached. A saturated solution of ammonium chloride was
added and the solution was extracted 3 times by ethyl acetate. The
combined organic layers were washed twice with saturated NH4Cl, once
with brine, dried over MgSO4 and concentrated under vacuum. The crude
product was then purified by flash chromatography on silica gel (gradient
toluene to toluene/EtOAc 95:5 (v/v) in 40 min) to afford compound 6
(15.3 g, 95%) as yellow oil. The 1H and 13C NMR chemical shifts of the
product are in accordance with literature.[20] MS (ESI+, MeCN + CH2Cl2):
It is to note that the absence of substituents on the phenyl group
of 7-phenyl-5H-furo[3,2-g]chromen-5-one has little influence on
biological activity, especially against Trypanosoma brucei where
both cissampeloflavone and its analogue 14 exhibited the same
inhibitory potency.
Therefore the synthesis of new analogues could be envisioned
through this scheme though many improvements remain to be
done in this synthesis like using uncommon and innovative
solvents. Indeed, this first synthesis of a complex furoflavone
scaffold opens the way to the design and synthesis of more
original structures.
+
m/z 329.1 [M+H]+; HRMS calcd for C19H21O5 [M+H]+ 329.1389, found
329.1393.
2-(4-(Benzyloxy)-3-methoxyphenyl)-5,7-dihydroxy-4H-chromen-4-
one (4): Phloroglucinol (126 mg, 1 mmol) and compound 6 (1 g, 3 mmol,
3 equiv) were introduced in a pressure tube and heated at 240 °C for 5
min by microwave irradiation (Anton Paar, P = 900 W). After cooling,
MTBE and aqueous 10% NaOH were added to the reaction mixture. The
aqueous layer was extracted 6-times with MTBE to remove remaining
compound 6 and acidified with concentrated HCl until a precipitate was
formed. The solid was filtered, washed twice with water and dried to
afford flavone 4 (347 mg, 89 %) as a brown amorphous solid. Mp: 265
1
°C; H NMR (DMSO-d6) δ 12.2 (s, 1H), 10.8 (s, 1H), 7.65 (d, 1H, J = 8.0
Hz), 7.59 (s, 1H), 7.47-7.35 (m, 5H), 7.21 (d, 1H, J = 8.0 Hz), 6.97 (s,
Experimental Section
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800338
European Journal of Organic Chemistry
FULL PAPER
1H), 6.53 (s, 1H), 6.20 (s, 1H), 5.20 (s, 2H), 3.89 (s, 3H).; 13C NMR
(DMSO-d6) δ 181.8, 164.2, 163.2, 161.4, 157.3, 151.1, 149.3, 136.5,
128.5 (2C), 128.0, 127.9 (2C), 123.2, 119.9, 113.2, 109.7, 103.9, 103.7,
98.9, 94.1, 69.9, 55.9; MS (ESI+, MeCN + CH2Cl2): m/z 391.1 [M+H]+;
(m, 4H), 6.65 (s, 1H), 5.27 (s, 2H), 5.24 (s, 2H), 3.99 (s, 3H), 3.84 (s,
3H); 13C NMR (CDCl3) δ 177.9, 160.3, 160.2, 157.3, 156.4, 156.0, 151.4,
151.1, 149.8, 136.7, 136.5, 128.8 (2C), 128.7 (2C), 128.2, 127.7, 127.3
(2C), 126.8 (2C), 126.2 (2C), 124.3, 122.6, 119.5, 114.4 (2C), 113.4,
112.7, 111.7, 109.1, 108.5, 96.6, 94.0, 71.4, 71.0, 56.3, 55.5; MS (ESI+,
+
HRMS calcd for C23H19O6 [M+H]+ 391.1181, found 391.1227; IR (neat,
cm-1) 1737, 1637, 1582, 1503, 1456, 1423, 1333, 1254, 1210, 1165,
1143, 1026.
MeCN + CH2Cl2): m/z 611.2 [M+H]+; HRMS calcd for C39H31O7 [M+H]+
+
611.2070, found 611.2047; IR (neat, cm-1) 1737, 1642, 1603, 1249,
1175, 1141, 1021.
(Z)-2-(4-(benzyloxy)-3-methoxyphenyl)-7-((2-bromo-1-(4-methoxy-
phenyl)vinyl)oxy)-5-hydroxy-4H-chromen-4-one (8):
A
solution of
7-(4-(benzyloxy)-3-methoxyphenyl)-4-hydroxy-3-(4-
flavone 4 (77 mg, 0.2 mmol), bromoethynyl-4-anisol 9 (125 mg, 0.59
mmol, 3 equiv) and Cs2CO3 (77 mg, 0.24 mmol, 1.2 equiv) in DMF (1 mL)
were heated at 110 °C for 10 min by microwave irradiation (Discover
CEM). The cooled reaction mixture was filtered over a Celite® pad that
was washed with ethyl acetate. After concentration of the organic filtrate,
the crude product was purified by flash chromatography on silica gel
(gradient heptane to heptane/EtOAc 7:3 (v/v) in 25 min) to afford
compound 8 (61.7 mg, 52%) as a yellow amorphous solid. Mp: 124 °C;
1H NMR (CDCl3) δ 12.8 (s, 1H), 7.46-7.32 (m, 9H), 6.96 (d, 1H, J = 8.4
Hz), 6.85 (d, 2H, J = 9.0 Hz), 6.56 (m, 2H), 6.49 (s, 1H), 6.46 (d, 1H, J =
2.1 Hz), 5.22 (s, 2H), 3.96 (s, 3H), 3.78 (s, 3H); 13C NMR (CDCl3) δ
182.5, 164.3, 162.5, 161.8, 160.8, 157.7, 152.2, 151.6, 149.9, 136.3,
128.8 (2C), 128.3, 127.3 (2C), 127.0 (2C), 125.3, 124.0, 120.2, 114.5
(2C), 114.0, 109.5, 106.7, 104.9, 100.0, 94.6, 94.4, 71.0, 56.4, 55.4; MS
methoxybenzoyl)-2-(4-methoxyphenyl)-5H-furo[3,2-g]chromen-5-one
(11): p-Anisoyl chloride (13,2 mg, 0.077 mmol, 1.2 equiv) and TiCl4
(0.077 mL, 0.077 mmol, 1.2 equiv) were added to a solution of compound
10 (39 mg, 0.064 mmol) in dichloromethane (1.5 mL) cooled at 0°C. The
reaction mixture was stirred for 1 h at room temperature and ice was
added to stop the reaction. The aqueous layer was extracted twice with
dichloromethane and the combined organic layers were washed twice
with brine, dried over MgSO4 and concentrated under vacuum. The crude
product was purified by TLC (dichloromethane/ MeOH 9:1 (v/v)) to afford
compound 11 (8.9 mg, 21 %) and compound 2 (13.2 mg, 40 %) as yellow
amorphous solids. Compound 11: 1H NMR (CDCl3) δ 12.8 (s, 1H), 8.04
(d, 2H, J = 8.7 Hz), 7.76 (d, 2H, J = 8.8 Hz), 7.60-7.27 (m, 10H), 7.09-
6.88 (m, 7H), 6.69 (s, 1H), 5.25 (s, 2H), 4.01 (s, 3H), 3.86 (s, 6H); MS
(ESI+, MeOH + CH2Cl2): m/z 655.2 [M+H]+;
+
(ESI+, MeCN + CH2Cl2): m/z 601.1 [M+H]+; HRMS calcd for C32H26BrO7
[M+H]+ 601.0862, found 601.0861; IR (neat, cm-1) 1737, 1656, 1596,
1511, 1492, 1350, 1276, 1254, 1146, 1026.
5-Hydroxy-7-(methoxymethoxy)-2-phenyl-4H-chromen-4-one (15): A
solution of chrysin (2.0 g, 7.8 mmol) and N,N-diisopropylethylamine (3.14
mL, 9.4 mmol, 1.1 equiv) in dry DMF (46 mL) was cooled to 0°C before
dropwise addition of methoxymethyl chloride (0.72 mL, 9.4 mmol, 1.2
equiv). The reaction mixture was stirred at room temperature for 6 h
before adding water and saturated aqueous NH4Cl. The aqueous layer
was extracted 6 times with ethyl acetate, the combined organic layers
were washed 3 times with brine, dried over MgSO4 and concentrated
under vacuum. The crude product was purified by flash chromatography
on silica gel (Heptane/EtOAc 7:3, (v/v)) to afford compound 15 (2.13 g,
91%) as a yellow amorphous solid. 1H NMR (CDCl3) δ 12.6 (s, 1H), 7.81
(m, 2H), 7.45 (m, 3H), 6.60 (d, 1H, J = 2.2 Hz), 6,59 (s, 1H), 6.41 (d, 1H,
J = 2.2 Hz), 5.17 (s, 2H), 3.43 (s, 3H); 13C NMR (CDCl3) δ 182.6, 164.1,
163.1, 162.1, 157.7, 131.9, 131.3, 129.1, 126.3, 106.4, 105.9, 100.2,
94.4, 94.3, 56.4; MS (ESI+, MeOH + CH2Cl2): m/z 299.1 [M+H]+; HRMS
calcd for C17H15O5+ [M+H]+ 299.0919, found 299.0925.
7-(4-(benzyloxy)-3-methoxyphenyl)-4-hydroxy-2-(4-methoxyphenyl)-
5H-furo[3,2-g]chromen-5-one (2): A solution of compound 8 (142 mg,
0.24 mmol), PdCl2 (8 mg, 0.012 mmol, 0.05 equiv) and K2CO3 (65 mg,
0.47 mmol, 2 equiv) in DMF (0.4 mL) was heated at 130°C for 10 min by
microwave irradiation (Discover CEM). Ethyl acetate and aqueous 1N
HCl were added to the cooled reaction mixture and the aqueous layer
was extracted 3 times with ethyl acetate. The combined organic layers
were washed twice with brine, dried over MgSO4 and concentrated under
vacuum. The crude product was purified by flash chromatography on
silica gel (gradient heptane to heptane/EtOAc 7:3 (v/v) in 25 min) to
afford compound 2 (67.0 mg, 45%) as a yellow amorphous solid. Mp: 206
°C; 1H NMR (CDCl3) δ 12.8 (s, 1H), 7.75 (d, 2H, J = 8.7 Hz), 7.52 (dd,
1H, J = 8.4 Hz, J’ = 2.1 Hz), 7.48-7.34 (m, 6H), 7.01 (d, 1H, J = 8.4 Hz),
7.01 (s, 1H), 6.97 (d, 2H, J = 8.7 Hz), 6.92 (s, 1H), 6.66 (s, 1H), 5.26 (s,
2H), 4.01 (s, 3H), 3.86 (s, 3H); 13C NMR (CDCl3) δ 183.2, 163.7, 160.3,
159.1, 158.4, 155.9, 151.8, 150.1, 149.4, 136.4, 128.9 (2C), 128.3, 127.4
(2C), 126.3 (2C), 124.0, 122.6, 120.2, 114.5 (2C), 113.6, 110.7, 109.6,
107.6, 105.5, 96.1, 95.4, 71.1, 56.4, 55.5; MS (ESI+, MeCN + CH2Cl2):
6-Iodo-5-hydroxy-7-(methoxymethoxy)-2-phenyl-4H-chromen-4-one
(16): CaCO3 (7 g, 70 mmol, 10 equiv) and benzyltrimethylammonium
dichloroiodide (3.3 g, 7 mmol, 1 equiv) were added to a solution of
compound 15 (2.1 g, 7.0 mmol) in CH2Cl2/MeOH (1:1 (v/v), 120 mL). The
reaction mixture was stirred at room temperature for 15 h before adding
water and aqueous 1 N HCl. The aqueous layer was extracted 3 times
with CH2Cl2/MeOH (5:2 (v/v), the combined organic layers were washed
twice with water, dried over MgSO4 and concentrated under vacuum to
afford compound 16 (3 g, quant) as a beige amorphous solid. 1H
NMR (DMSO- d6) δ 13.8 (s, 1H), 8.11 (m, 2H), 7.59 (m, 3H), 7.14 (s, 1H),
7.06 (s, 1H), 5.42 (s, 2H), 3.45 (s, 3H); 13C NMR (DMSO- d6) δ 181.5,
163.8, 160.7; 160.5, 157.2, 132.3, 130.3, 129.1, 126.5, 105.4, 105.2,
94.8, 93.8, 71.6, 56.3; MS (ESI+, MeOH + CH2Cl2): m/z 425.0 [M+H]+;
HRMS calcd for C17H14IO5+ [M+H]+ 424.9886, found 424.9901.
+
m/z 521.2 [M+H]+; HRMS calcd for C32H25O7 [M+H]+ 521.1600, found
521.1610; IR (neat, cm-1) 1738, 1660, 1593, 1505, 1251, 1234, 1142,
1022.
4-benzyloxy-7-(4-(benzyloxy)-3-methoxyphenyl)-2-(4-
methoxyphenyl)-5H-furo[3,2-g]chromen-5-one (10): K2CO3 (59 mg,
0.43 mmol, 2 equiv) and tetrabutylammonium iodide (8 mg, 0.022 mmol,
0.1 equiv) were added to a solution of compound 2 (112 mg, 0.22 mmol,
1equiv) in dry DMF ( 0.75 mL). Benzyl chloride (0.05 mL, 0.43 mmol, 2
equiv) was added and the reaction mixture was stirred for 48 h. Water
was added to the reaction mixture and neutralized with aqueous 1N HCl.
The aqueous layer was extracted twice with ethyl acetate. The combined
organic layers were washed 4 times with brine, dried over MgSO4 and
concentrated under vacuum. The crude product was purified by flash
chromatography on silica gel (gradient toluene to toluene/EtOAc 8:2 (v/v)
in 25 min) to afford compound 10 (75.0 mg, 57 %) as a yellow
amorphous solid. Mp: 185 °C; 1H NMR (CDCl3) δ 7.72 (d, 2H, J = 8.4
Hz), 7.66 (d, 1H, J = 7.5 Hz), 7.48-7.30 (m, 10H), 7.02 (s, 1H), 6.99-6.94
5-Methoxy-6-iodo-7-(methoxymethoxy)-2-phenyl-4H-chromen-4-one
(17): K2CO3 (1.94 g, 14.1 mmol, 6 equiv) was added to a solution of
compound 16 (1g, 2.35 mmol) in acetone (42 mL). Dimethyl sulfate (1.32
mL, 14.1 mmol, 6 equiv) was added dropwise to the reaction mixture that
was stirred at 60 °C for 6 h. After cooling, the reaction mixture was
filtered and the precipitate was washed with water and dried to afford
1
compound 17 (0.85 g, 83 %) as pale yellow needles. H NMR (CDCl3) δ
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800338
European Journal of Organic Chemistry
FULL PAPER
8.06 (m, 2H), 7.56 (m, 3H), 7.31 (s, 1H), 6.90 (s, 1H), 5.45 (s, 2H), 3.78
(s, 3H), 3.46 (s, 3H); 13C NMR (CDCl3) δ 174.7, 160.4, 159.4, 159.2,
158.8, 131.6, 130.6, 129.0, 126.1, 113.0, 107.9, 99.4, 94.8, 84.5, 61.2,
56.4; MS (ESI+, MeOH + CH2Cl2): m/z 439.0 [M+H]+; HRMS calcd for
C18H16IO5+ [M+H]+ 439.0043, found 439.0065.
for 15 h. The solution was cooled to room temperature, filtered over a
Celite® pad and concentrated under vacuum. The crude product was
purified by preparative TLC (heptane/EtOAc 3:7 (v/v)) to afford
compound 21 (15 mg, 9 %) as a light brown amorphous solid. 1H
NMR (CDCl3) δ 7.95 (m, 2H), 7.64 (d, 2H, J = 8.5 Hz), 7.56 (m, 3H), 7.28
(s, 1H), 7.12 (m, 3H), 6.96 (m, 2H), 6.81 (d, 2H, J = 8.5 Hz), 6.70 (s, 1H),
6.06 (dd, 2H, J = 15 Hz, J’ = 2Hz), 4.75 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H),
3.81 (s, 3H), 3.79 (s, 3H); 13C NMR (CDCl3) δ 188.5, 178.0, 163.6, 161.2,
160.5, 160.5, 156.2, 155.7, 154.9, 153.7, 135.6, 131.7, 131.3, 129.3,
129.0, 128.2, 127.6, 127.4, 126.1, 122.0, 121.0, 119.6, 114.5, 113.6,
113.1, 107.9, 96.0, 91.5, 91.2, 70.6, 62.9, 56.1, 55.3, 55.3; MS (ESI+,
MeOH + CH2Cl2): m/z 669.2 [M+H]+; HRMS calcd for C41H32O9Na+
[M+Na]+ 691.1944, found 691.1940.
7-Hydroxy-6-iodo-5-methoxy-2-phenyl-4H-chromen-4-one
(18):
Compound 17 (0.85 g, 1.94 mmol) was solubilized in a solution of HCl
10% in MeOH (52 mL). The reaction mixture was stirred under reflux for
5h. After addition of water to the cooled reaction mixture, precipitates
were formed and filtered, washed with water and dried to afford
compound 18 (0.711 g, 93 %) as
a
brown amorphous solid. 1H
NMR (DMSO- d6) δ 11.78 (s, 1H), 8.04 (m, 2H), 7.58 (m, 3H), 6.97 (s,
1H), 6.84 (s, 1H), 3.78 (s, 3H); 13C NMR (DMSO- d6) δ 174.7, 161.4,
160.2, 159.8, 158.7, 131.5, 130.8, 129.1, 126.1, 111.4, 107.8, 98.2, 83.2,
61.1; MS (ESI+, MeOH + CH2Cl2): m/z 395.0 [M+H]+; HRMS calcd for
C16H12IO4+ [M+H]+ 394.9798, found 394.9780.
4-Hydroxy-3-(2-hydroxy-4,6-dimethoxybenzoyl)-2-(4-
methoxyphenyl)-7-phenyl-5H-furo[3,2-g]chromen-5-one (14) : (i) 4-
Hydroxy-3-(2-(benzyloxy)-4,6-dimethoxybenzoyl)-2-(4-methoxyphenyl)-7-
phenyl-5H-furo[3,2-g]chromen-5-one 14i. A solution of compound 21 (25
mg, 0.037 mmol) and MgBr2.OEt2 (24 mg, 0.093 mmol, 2.5 equiv) in
acetonitrile (0.78 mL) was stirred in a pressure tube at 80 °C for 2 h. After
concentration under vacuum, the crude product was purified by
preparative TLC (heptane/EtOAc 3:7 (v/v)) to afford 14i (14.7 mg, 61%)
1-(2-(Benzyloxy)-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-
yn-1-one (19 ): (i) 2-(benzyloxy)-4,6-dimethoxybenzaldehyde. K2CO3
(3.1 g, 22.4 mmol, 2 equiv) and benzyl chloride (2.7 mL, 22.4 mmol, 2
equiv) were successively added to
a
solution of 4,6-
1
as a light orange amorphous solid. H NMR (CDCl3) δ 13.2 (s, 1H), 7.87
dimethoxybenzaldehyde (2 g, 11.3 mmol) in acetone (79 mL). The
reaction mixture was stirred at room temperature overnight. The reaction
mixture was concentrated and diluted with dichloromethane. The organic
layer was washed twice with water, dried over MgSO4 and concentrated
under vacuum. The crude product was purified by flash chromatography
on silica gel (Heptane/EtOAc 7:3, (v/v)) to afford 2-benzyloxy-4,6-
dimethoxybenzaldehyde (2.6 g, 83 %) as a white amorphous solid. The
1H and 13C NMR chemical shifts of the product are in accordance with
literature.[19] MS (ESI+, MeOH + CH2Cl2): m/z 273.1 [M+H]+; (ii) 1-(2-
(benzyloxy)-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-yn-1-one.
A solution of 4-ethynylanisol (0.39 mL, 3.2 mmol, 2 equiv) in dry THF (3.2
mL) was cooled to -78 °C before dropwise addition of nBuLi (1.6 M in
hexanes, 2.2 mL, 3.52 mmol, 2.2 equiv). The solution was stirred at -78
°C for 1 h, then 2-benzyloxy-4,6-dimethoxybenzaldehyde (0.43 g, 1.6
mmol) in dry THF (2.65 mL) was added dropwise. After stirring for 1 h at -
78 °C then 30 min at 0 °C, a saturated aqueous solution of ammonium
chloride was added to the reaction mixture. The solution was extracted
with EtOAc, the combined organic layers were washed twice with brine,
dried over MgSO4 and concentrated under vacuum. The crude product
was diluted with dichloromethane (1.6 mL) and after addition of activated
MnO2 (0.695 g, 8.0 mmol, 5 equiv) the reaction mixture was stirred at
room temperature for 48 h. The solution was filtered over a Celite® pad
and concentrated under vacuum. The crude product was purified by flash
chromatography on silica gel (Heptane/EtOAc 8:2, (v/v)) to afford
compound 19 (0.5 g, 78 %) as a white amorphous solid. 1H NMR (CDCl3)
δ 7.44 (m, 4H), 7.26 (m, 3H), 6.84 (d, 2H, J = 8 Hz), 6.17 (dd, 2H, J =
10.3 Hz, J’ = 2.2 Hz), 5.15 (s, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H);
13C NMR (CDCl3) δ 177.0, 163.3, 161.2, 159.9, 159.1, 136.5, 134.8,
128.5, 127.7, 127.0, 114.1, 113.1, 112.8, 92.2, 91.2, 90.7, 70.7, 56.1,
55.5, 55.4; MS (ESI+, MeOH + CH2Cl2): m/z 403.15 [M+H]+; HRMS calcd
for C25H23O5+ [M+H]+ 403.1545, found 403.1531.
(m, 2H), 7.59 (m, 2H), 7.50 (m, 3H), 7.06 (m, 3H), 6.94 (m, 3H), 6.73 (d,
2H, J = 2.3 Hz), 6.62 (s, 1H), 5.98 (d, 2H, J = 2.3 Hz), 4.70 (s, 2H), 3.71
(s, 3H), 3.74 (s, 3H), 3.71 (s, 3H); 13C NMR (CDCl3) δ 183.8, 163.4,
161.2, 160.5, 156.0, 155.4, 155.7, 135.9, 131.9, 131.4, 129.6, 129.1,
128.2, 127.6, 127.3, 126.4, 122.0, 113.9, 113.5, 113.3, 105.1, 91.6, 91.3,
90.0, 70.7, 56.3, 55.3; MS (ESI+, MeOH + CH2Cl2): m/z 655.2 [M+H]+;
+
HRMS calcd for C40H31O9 [M+H]+ 655.1968, found 655.1964. (ii) 4-
Hydroxy-3-(2-hydroxy-4,6-dimethoxybenzoyl)-2-(4-methoxyphenyl)-7-
phenyl-5H-furo[3,2-g]chromen-5-one 14. A solution of 14i (20 mg, 0.031
mmol), ammonium formate (17.4 mg, 0.27 mmol, 9 equiv) and Pd/C 10
% (5.6 mg) in ethanol (0.5 mL) was stirred at 40 °C for 2 h. The reaction
mixture was filtered over a Celite® pad and concentrated under vacuum.
The crude product was purified by preparative TLC (heptane/EtOAc 3:6
(v/v)) to afford final compound 14 (17 mg, quant) as a brown amorphous
solid. NMR (CDCl3) δ 13.7 (s, 1H), 13.3 (s, 1H), 7.95 (m, 2H), 7.67 (m,
2H), 7.57 (m, 3H), 7.18 (s, 1H), 6.92 (m, 2H), 6.62 (bs, 1H), 6.19 (d, 1H,
J = 2.2 Hz), 5.82 (d, 1H, J = 2.2 Hz), 3.87 (s, 3H), 3.84 (s, 3H), 3.29 (s,
3H); 13C NMR (CDCl3) δ 193.3, 184.0, 168.0, 167.5, 164.4, 163.3, 160.5,
157.2, 154.1, 152.2, 132.0, 131.4, 129.1, 128.2, 126.4, 121.9, 117.7,
114.3, 113.98, 107.7, 106.2, 105.2, 93.6, 91.2, 90.4, 55.7, 55.5, 55.4; MS
+
(ESI+, MeOH + CH2Cl2): m/z 564.15 [M+H]+; HRMS calcd for C33H25O9
[M+H]+ 565.1499, found 565.1513.
Acknowledgements
This work was supported by ICSN and Centre National de la
Recherche Scientifique (CNRS). The authors thank Pr G. Lewin,
Drs Y.S. Wang and B. Darses for helpful discussions and O.
Thoison and her co-workers for LC/MS analyses. They gratefully
acknowledge Pr P. Grellier and E. Mouray for biological
evaluations on P. falciparum and T. brucei.
3-(2-(Benzyloxy)-4,6-dimethoxybenzoyl)-4-methoxy-2-(4-
methoxyphenyl)-7-phenyl-5H-furo[3,2-g]chromen-5-one (21) : To a
solution of iodoflavone 18 (98.7 mg, 0.25 mmol) and ynone 19 (100 mg,
0.25 mmol, 1 equiv) in dry DMF (2.0 mL) was added K3PO4 (266 mg,
1.25 mmol, 5 equiv), and then the reaction mixture was stirred at 75 °C
for 24 h. After cooling, the reaction mixture was concentrated under
vacuum and immediately diluted with dry DMF (2.5 mL). Pd(OAc)2 (3.0
mg, 0.025 mmol, 0.05 equiv), polymer-bound triphenylphosphine (83 mg,
3 mmol/g, 1 equiv) and Ag2CO3 (69 mg, 0.25 mmol) were added to this
solution and the reaction mixture was stirred in a pressure tube at 115 °C
Keywords: Natural products • total synthesis • oxygen
heterocycles • flavonoids • 7-phenyl-5H-furo[3,2-g]chromen-5-
ones
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10.1002/ejoc.201800338
European Journal of Organic Chemistry
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10.1002/ejoc.201800338
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Natural product synthesis*
OMe
MeO
O
O
O
Marion Thévenin, Sylviane Thoret and
Joëlle Dubois*
HO
I
O
O
OMe
OMe
+
MeO
OH
O
Page No. – Page No.
OR’
O
OH
OR
MeO
First total synthesis of original
chalcone-flavone dimers as
cissampeloflavone analogues
Total synthesis of furoflavones closely related to natural product cissampeloflavone
was achieved according to different pathways. Conjugate addition of an iodoflavone
to an ynone followed by intramolecular Heck cyclization gave the best results
affording the first synthetic chalcone-flavone dimer ever described.
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