Synthesis and anti-tubulin evaluation of chromone-based analogues of combretastatins

Article abstract of DOI:10.1016/j.tet.2006.02.024

Twenty new hybrid compounds with both combretastatin and flavone moieties were synthesized. These derivatives are classified according to the position of the trimethoxyphenyl ring at C-2 or C-3 of the chromone and presence or absence of a carbonyl as a linker between C-3 and the aryl ring. Most of these compounds were prepared from hesperidin or naringin, two natural and abundant Citrus flavonoids. Seven of these combretastatin analogues revealed anti-tubulin activity but in a medium range.

Full text of DOI:10.1016/j.tet.2006.02.024

Tetrahedron 62 (2006) 4038–4051
Synthesis and anti-tubulin evaluation of chromone-based
analogues of combretastatins
a
Jerome Quintin, Catherine Roullier, Sylviane Thoret and Guy Lewin
a
b
a,
*
´ ˆ
a
´ ´
Laboratoire de Pharmacognosie, (BIOCIS, UMR-8076 CNRS), Faculte de Pharmacie, av. J.B. Clement,
ˆ
92296 Chatenay-Malabry Cedex, France
bCNRS-ICSN, UPR 2301, 91190 Gif-sur-Yvette, France
Received 3 January 2006; revised 6 February 2006; accepted 9 February 2006
Available online 9 March 2006
Abstract—Twenty new hybrid compounds with both combretastatin and flavone moieties were synthesized. These derivatives are classified
according to the position of the trimethoxyphenyl ring at C-2 or C-3 of the chromone and presence or absence of a carbonyl as a linker
between C-3 and the aryl ring. Most of these compounds were prepared from hesperidin or naringin, two natural and abundant Citrus
flavonoids. Seven of these combretastatin analogues revealed anti-tubulin activity but in a medium range.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
cis-restricted analogues with an ethene bridge as part of a
heterocycle.7 Although the most fruitful results were found
among the substituted monocycle-bridged analogues,8 com-
pounds with a bicyclic system on the bridge, such as the indole
4, displayed a strong bioactivity.9 Furthermore, addition of a
one-carbon linker (C]O) between the bicyclic system
(indole, benzo[b]thiophene, benzo[b]furane) and the tri-
methoxyphenyl ring seemed to be favorable and sometimes
essential for cytotoxicity and ITP (6 active vs 5 inactive).9,10
Tubulin is a heterodimeric protein, which can exist as
a,b-dimers and microtubules in a dynamic equilibrium.
Polymerization into microtubules provides the main constitu-
ents of the mitotic spindle, which explains the crucial role of
this protein in cellular division. Compounds that interfere with
this equilibrium, either by stabilizing the microtubules or
inhibiting their formation, are interesting as potential anti-
cancer drugs.1 So tubulin appears as a major target in this field
ofdrugs discovery. CombretastatinA-4(CA-4)1isa powerful
inhibitor of tubulin polymerization (ITP) displaying cytotoxic
and antivascular activities by binding at the colchicine site.2
This natural stilbene, which was isolated from the bark of
Combretum caffrumKuntze, aSouthAfricanbushwillow tree,
proved to be the most promising compound of the new class of
combretastatins and was chosen as the model for the synthesis
of hundreds of analogues.3 Clear structure–activity relation-
ships could be drawn from these synthesis, which display the
importance for the bioactivity of: (a) the 3,4,5-trimethoxy-
phenylring(however, replacement bya 3,4,5-trimethylphenyl
ring is not prejudicial);4 (b) a 40-methoxy substituted phenyl
ring with or without a second substituent at C-30 (removal of
the 30-OH or its substitution by an amino group result in
compounds 25 and 36 with similar bioactivities as CA-4); (c) a
cis-ethene bridge (isomerization of CA-4 and cis combretas-
tatin analogues during storage and administration cause a
reduction in both cytotoxicity and anti-tubulin activity).7 This
last point of the SAR studies led to the synthesis of many
Keywords: Flavones; Citrus flavonoids; Combretastatins; Tubulin.
*
Corresponding author. Tel.: C33 146835593; fax: C33 146835399;
e-mail: guy.lewin@cep.u-psud.fr
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.024

J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
4039
In order to enlarge the SAR studies of these bicyclic-bridged
compounds, we have synthesized new analogues of
combretastatins with the ethene bridge as part of a
chromone. These new derivatives can be regarded as hybrid
structures with both combretastatin and flavone moieties.
This last point seemed of interest owing to the previously
described cytotoxicity and antitubulin activity of some
flavones.11 All the chromone-based analogues related in this
paper possess a substructure of combretastatins 1, 2 or 3 and
can be classified into four groups (A, B, C, D with RZH,
OH or NH2) according to the position of the trimethox-
yphenyl ring at C-2 or C-3 of the chromone and presence or
not of a C]O linker at C-3. They can also differ in the
substitution pattern (unsubstituted or 5,7-disubstituted) of
the chromone moiety. Unsubstituted flavones were prepared
by total synthesis, while most of the 5,7-disubstituted ones
were obtained by semisynthesis. By starting from some
natural abundant flavonoids (vide infra), the second aim of
this study was also to display the importance of such raw
materials for an easy access to novel possibly interesting
2,3-diaryl chromones.
2.1.1. Analogues of combretastatin 1. The synthesis of
24–29, analogues of CA-4 1 is shown in Scheme 1.
Hesperidin
7 provided by a well-known process
(I2–pyridine)13 the corresponding flavone, diosmin 9,
which led in three steps to 3-bromodiosmetin 12 via
peracetyldiosmin 10 and its 3-bromo derivative 11. It is
worth noting that the prior peracetylation step is
necessary for it allows regiospecific bromination at C-3
by deactivation of C-6 and C-8 (as previously reported,
5-deacetylated analogue of 10 underwent bromination at
C-6 and C-8 only).14 A direct Suzuki coupling with 12
was attempted [with an excess K2CO3 (6.2 equiv)
because of 5, 7, 30 free phenol groups], which provided
the expected compound 26 under tedious conditions of
isolation because of the polar character of 7-hydroxy-
flavones. Therefore, we thought that 26 would be more
conveniently obtained by carrying out the Suzuki
coupling from a lipophilic 3-bromodiosmetin protected
at the 7-OH group, such as the 7-isopropyl or 7-benzyl
ethers 13 and 14. As expected, 13 and 14 led easily and
in good yields (69 and 73%) to the corresponding
coupling compounds 27 and 25. However, we observed
that the removal of the isopropyl group of 27 by BCl3 in
CH2Cl2 always competed, more or less according to
temperature, with demethylation of the 400-methoxy group
(at 0 8C, the 400-O-demethyl 29 was even the sole reaction
compound starting from 25 or 27). In contrast, removal
of the benzyl group by hydrogenolysis over Pd–C
afforded quantitatively 26 from 25. In order to study
the influence of the substitution at C-5 on bioactivity, the
two methyl ethers 24 and 28 were also synthesized.
Access to 24 and 28 made use of the known weaker
reactivity of the 5-OH towards alkylation (by involve-
ment into chelation with the carbonyl) and the observed
slower hydrogenolysis of the 30benzyl ether group
(probably by steric hindrance).
2. Results and discussion
2.1. Synthesis of analogues of the group A (24–32, 47
and 48)
We began our study by the group A because of the easy
availability of two Citrus flavonoids, hesperidin 7 and
naringin 8, which have been used as starting materials for
semisynthesis. 7 and 8 we0re chosen because of their
adequate substitutions at C-3 and C-40 allowing access to
analogues of combretastatins 1, 2 and 3. Compounds 24–31,
47 and 48 substituted at C-5 and C-7 were prepared from 7
or 8, while total synthesis provided the last one, 32,
unsubstituted on the chromone ring. For all the compounds,
the trimethoxyphenyl ring was fixed at the C-3 carbon of the
chromone by a Suzuki reaction between a 3-bromoflavone
and 3,4,5-trimethoxybenzeneboronic acid.12
2.1.2. Analogues of combretastatin 2. Three analogs of
deoxy CA-4 2 were prepared, semisynthetically (30 and 31)
and by total synthesis (32). Access to 30 and 31 was
performed from linarin 16, a natural flavonoid previously
obtained in our laboratory by deoxygenation of diosmin.15
Synthesis of 30 and 31 from 16 via 3-bromoacacetin 17 and
7-benzyl-3-bromoacacetin 18 was similar to the sequence
9/12/14/25/26 depicted in Scheme 1. Compound
32, unsubstituted at C-5 and C-7, was obtained from the
commercial (2-hydroxybenzoyl)methylenetriphenylphos-
phorane 35 by a four-step sequence via the flavones 19

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J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
Scheme 1. Reagents and conditions: (a) I2, pyridine, 90 8C, 16 h, 90%; (b) Ac2O, pyridine, rt, 72 h, 95%; (c) NBS, CH2Cl2/pyridine 4:1, rt, 20 h, 90%; (d) HCl
11 N, 50 8C, 2 h, 75%; (e) 2-bromopropane, K2CO3, DMF, 75 8C, 6 h, 54%; (f) benzyl chloride, KHCO3, DMF, 120 8C, 2.5 h, 34% (14), 34% (15); (g) 3,4,5-
trimethoxybenzeneboronic acid, Pd(PPh3)4, K2CO3 2 N, dioxane, reflux, reaction time-yield: 3 h-95% (21), 3 h-73% (25), 4 h-69% (27); (h) BCl3, CH2Cl2,
K78 8C 30 min, then 0 8C 15 h, 43% (from 25); (i) (CH3)2SO4, tetrabutylammonium hydrogen sulfate, CH2Cl2–NaOH 0.5 N, rt, 22 h 65%; (j) H2, Pd–C 10%,
DMF, rt, reaction time-yield: 72 h-45% (23) and 10% (24), 3 h-96% (26), 5 days after; (k) 39% (28 from 23); (l) iodomethane, K2CO3, DMF, rt, 20 h.
and 20 according to Le Corre16 for synthesis of 19 and
OH
Brown17 for bromination to 20 (Scheme 2).
C6H5
35
P
C6H5
C6H5
O
2.1.3. Analogues of combretastatin 3. An easy semisyn-
thetic entry to 47 and 48, two analogues of aminocom-
bretastatin 3, requires a regiospecific nitration at C-30. First
attempts were undertaken with acacetin 36, easily available
from linarin 16. Prior deactivation of C-6 and C-8 positions
towards nitration seemed necessary and was accomplished
by esterification of the 7-OH phenol group as benzylsulfo-
nate. This group, recently described as a valuable protecting
and deactivating group in phenol chemistry, is stable under
many drastic conditions and easily removed by catalytic
hydrogenolysis.18 Unfortunately, nitration of 7-O-benzyl-
sulfonate 37 (HNO3 1 equiv in TFA, 0 8C, 2 h) provided the
mixture (4/3) of 6 and 8-nitro compounds 38 and 39 (68%).
Under the same conditions, the more deactivated 5,7-
disulfonate led to a mixture with the starting compound still
major after 24 h.
a
19
b,c
20
d
32
Scheme 2. Reagents and conditions: (a) 4-methoxybenzoyle chloride,
pyridine, toluene, reflux, 5 h (65%); (b) NBS, CH2Cl2/MeOH 2:1, rt, 3 h;
(c) THF/NaOH N 1:3, rt, 3 h, 42% (20 from 19); (d) 3,4,5-trimethoxy-
benzeneboronic acid, Pd(PPh3)4, K2CO3 2 N, dioxane, reflux, 4 h-42%.

J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
4041
sugar moiety at C-7 makes the nitration of the flavone at
C-30 very clean: under the same conditions applied to
apigenin (5,7,40-trihydroxyflavone), significant nitration
was also observed at the other benzene ring.19 A direct
hydrolysis of crude 41 gave 30-nitroapigenin 42 while a
prior methylation then acid hydrolysis furnished 30-
nitroacacetin 43. This compound led by a similar
sequence (acetylation, bromination, hydrolysis, alkylation,
Suzuki coupling) as described in the 30 hydroxy series to
the nitro products 33 and 34. A last step of catalytic
hydrogenation (Pd–C, rt) gave, respectively, the expected
analogues 47 and 48 by reduction of the nitro group and,
in the case of 34, concomitant debenzylation of the ether
group.
These negative results led us to sele0ct, as starting
material, a 40-hydroxyflavone with a C-3 position more
activated towards nitration than in acacetin derivatives
(Scheme 3). The Citrus flavanone naringin 8 provided this
40-hydroxyflavone, rhoifolin 40, by the same dehydro-
genation procedure (I2–pyridine) previously described to
obtain diosmin. The key nitration step of rhoifolin 40 into
30-nitrorhoifolin 41 was accomplished very easily by
1 equiv HNO3 in TFA at 0 8C. The choice of TFA as
solvent on the one hand, a strict stoichiometry of HNO3
on the other hand, prevented 40 from any hydrolysis of
glycosidic bonds. It is noteworthy that presence of the
2.2. Synthesis of analogues of the group B
(54, 58 and 59)
In order to study a possible influence on the bioactivity,
we then synthesized compounds displaying a reverse
relative position of the two phenyl rings of the
combretastatin moiety on the chromone. Lack of easily
available natural flavones with a trimethoxyphenyl ring at
C-2 made total synthesis necessary. Three compounds,
54, 58 and 59, isomers, respectively, of 32, 31 and 26
were prepared.
Scheme 3. Reagents and conditions: (a) I2, pyridine, 90 8C, 16 h, 95%; (b) HNO3 53%, TFA, 0 8C, 2 h, quantitative yield (crude 41); (c) iodomethane, K2CO3,
DMF, rt, 48 h; (d) HCl 11 N, 60 8C, 1 h, 73% (43 from 41), 83% (42); (e) Ac2O, pyridine, rt, 72 h, 95%; (f) NBS, CH2Cl2/MeOH 2:1, rt, 3 h, 86%; (g) THF/
NaOH N 1:1, rt, 4 h, 80%; (h) iodomethane, K2CO3, DMF, rt, 20 h, quantitative yield; (i) benzyl chloride, KHCO3, DMF, 120 8C, 2 h, 86%; (j) 3,4,5-
trimethoxybenzeneboronic acid, Pd(PPh3)4, K2CO3 2 N, dioxane, reflux, reaction time-yield: 3 h-77% (33), 2.5 h-84% (34); (k) H2, Pd–C 10%, DMF, rt, 3 h,
quantitative yield (47 and 48).

4042
J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
2.3. Synthesis of analogues of the groups C (65, 66) and D
(67)
Taking into account the positive effect observed in some
bicyclic analogues of combretastatins by addition of a C]O
linker,9,10 we synthesized three 3-aroylflavones bearing at
C-3 either a 3,4,5-trimethoxyphenyl ring (65, 66) or a
4-methoxyphenyl ring (67). First attempts to prepare such
compounds from 3-bromoflavones by use of BuLi and the
adequate aroyl chloride were unsuccessful so that we turned
to classical synthesis of 3-aroylflavones.23 Starting from 20-
hydroxyacetophenone and 3,4,5-trimethoxy or 4-methoxy-
benzoyl chlorides, access to 65–67 (Scheme 4) proceeded in
three steps: (a) one-pot esterification of the phenol group
followed by a Baker–Vankataraman rearrangement into 60
Synthesis of 54 via 30,40,50-trimethoxyflavone 49 and its
3-bromoderivative 50 followed the procedure described
for 32. However, the Suzuki coupling step between 50
and 4-methoxyphenylboronic acid led to 54 with a poor
yield (13%) because of a major debromination of 50 into
49. This unwanted reaction was proved to be related to
the boronic acid, since the same result was observed by
coupling 7-benzyl-3-bromodiosmetin 14 with 4-methoxy-
phenylboronic acid (vs 73% yield between 14 and
trimethoxyphenylboronic acid, vide supra). Therefore we
turned to another method for this last step by using a iron-
catalysed Grignard coupling developed in the laboratory.20
The cross-coupling reaction of 4-methoxyphenylmag-
nesium bromide with 50 [THF, K25 8C, Fe(acac)3]
again provided a mixture 54/49 but 54 was isolated with
a slightly more favourable yield (18%). Preparation of the
5,7-dihydroxylated analogues 58 and 59 started with
synthesis of the 5,7-dihydroxy-30,40,50-trimethoxyflavone
(Ztricetin trimethyl ether) 51 from (2,4,6-trihydroxyben-
zoyl)methylenetriphenylphosphorane,21 and proceeded
through the 3-bromo derivative 52 and its 7-benzyl ether
53 as already described in the A group. The coupling step
of 53 at C-3 was then carried out by both methods: Suzuki
reaction with commercial 4-methoxyphenylboronic acid
produced the expected 55 (21%), while iron-catalysed
Grignard coupling with 3-benzyloxy-4-methoxyphenyl-
magnesium bromide22 led to 56 (12%). A major
debromination reaction into 57 again accounts for low
yields of both couplings. Lastly, catalytic hydrogenolysis
(Pd–C, rt) of 55 and 56 gave the expected analogues 58
and 59 quantitatively.
Scheme 4. (a) 3,4,5-Trimethoxybenzoyle chloride or 4-methoxybenzoyle
chloride, pyridine, 0 8C, 5 min, then rt, 2.5 h; addition of anhydrous KOH,
100 8C, 3 h, 37% (60) and 34% (61); (b) p-anisaldehyde or isovanillin or
3,4,5-trimethoxybenzaldehyde, piperidine, EtOH, reflux, reaction time: 5 h;
(c) SeO2, dioxane, reflux, 6 h, 36% (65 from 60), 40% (66 from 60), 54%
(67 from 61).

J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
4043
1
and 61 [according to H NMR spectra, 61 was the pure
insertion of a C]O linker between C3 and the phenyl ring
seemed favourable to ITP (65 vs 32 and, to a lower extent,
67 vs 54) with, once again, a better activity with the
analogue of 2 (65 vs 66).
keto-enol, while 60 was a mixture of b-diketone (18%) and
keto-enol (82%) forms]; (b) Knoevenagel condensation of
60 with p-anisaldehyde or isovanillin, and of 61 with 3,4,5-
trimethoxybenzaldehyde giving, respectively, crude
3-aroylflavanones 62, 63 and 64, which were used in the
next step without purification [formation of the trans
aroylflavanone form as a major compound was proved
3. Conclusion
1
in H NMR by the presence of H-2 and H-3 signals (2d,
Though failing in its initial goal of access to new
combretastatins analogues with strong ITP activity, this
study seems to us noteworthy from a chemical point of view
for the following reasons: (a) access to 3-phenyl flavones via
a cross-coupling reaction from 3-bromo-5,7-dioxygenated
flavones led us to achieve a very easy and regiospecific
3-bromination of natural 5,7-dihydroxyflavones and their
7-glycosides (3-bromination of synthetic flavones is well
documented,17,25 but has never been described to the best of
our knowledge from natural 5,7-dihydroxyflavones); (b) the
C3-aryl bond was usually formed via a Suzuki reaction, but
the coupling with a Grignard reagent, easier to prepare than
a boronic acid, seemed to be a possible alternative;
(c) synthesis of analogues of aminocombretastatin 3
allowed us to develop an original nitration process of a
flavone glycoside without prior protection nor hydrolysis of
the sugar moiety; (d) lastly, most of this study started from
two easily available Citrus flavonoids, hesperidin and
naringin, which confirms the interest of some natural
products as raw materials for organic chemistry.
JZ12.8 Hz about 5.0 and 5.8 ppm)]; (c) dehydrogenation
of 62, 63, 64 by SeO2 into the desired 3-aroylflavones 65,
66 and 67.
2.4. Biological activity
Inhibition of tubulin polymerization (ITP) was determined
according to Zavala and Guenard’s method.24 Compounds
were tested at 0.1 mg/mL (z2!10K4 M) and estimated
inactive when they decreased by less than 30%
the maximum assembly rate of tubulin without drug. The
IC50 was calculated only for the most active compounds
and expressed in relation to colchicine in terms of the IC50/
IC50 colchicine ratio. As depicted in Table 1, results were
disappointing since only seven of the twenty tested
compounds displayed an activity, usually in a medium
range. Compound 31, with a substructure of deoxycom-
bretastatin A4 2, was the most active, while all the other 5,7-
dioxygenated synthesized analogues, having combretastatin
A4 1 (24–28 and 59) or aminocombretastatin 3 (47, 48)
substructures, were devoid of activity. It is worth noting
about analogues of 2 that inversion of substituents at C2 and
C3 interfered strongly with activity in one case (31 vs 58)
but was almost ineffective (32 vs 54) in another one. Lastly,
4. Experimental
4.1. General experimental procedures
Table 1. ITP activity
Melting points were determined with a micro-Koffler and are
uncorrected. 1H NMR spectra were recorded on Bruker AC-
200 (200 MHz) or Bruker AM-400; NOESY experiments and
Compound
Activity a
the H–1H (COSY) and H–13C (HMQC and HMBC) were
performed with a Bruker AM-400. EIMS were registered on
an Automass Thermoquest with EI source (70 eV) and
ESIMS on a Navigator Aqa thermoquest with an ES source
(MeOH, flow rate: 5 mL/min) (70 eV). MHz spectrometers.
Flash chromatography (FC) was performed with silica gel 60
(9385 Merck) or aluminium oxide 90 (1097 Merck), or
alumina 90 standard II–III (1097 Merck). Preparative TLC
were performed with 60 F 254 silica gel (5715 Merck) or 60 F
254 aluminium oxide (5713 Merck).
1
1
Analogs of 1
24
25
26
27
28
59
Analogs of 2
30
31
32
54
55
58
Inactive b
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive b
2.4c
40%d
54%
35%
Inactive
4.2. Synthesis of analogues of the group A
Analogs of 3
47
48
Other 3-arylflavones
29
33
34
3-Aroylflavones
65
66
67
Reference
Colchicine
Inactive
Inactive
4.2.1. Synthesis of 3-bromoflavones, intermediates for
3-arylflavones analogues of 1 and 2.
Inactive
Inactive
Inactive
4.2.1.1. 3-Bromo-octoacetyldiosmin 11. A solution of
diosmin 9 (3.04 g, 5 mmol) in Ac2O/pyridine 1:5 (20 mL)
was left at rt for 48 h. The reaction mixture was taken up in
iced water, stirred at 0 8C for 2 h then extracted with
CH2Cl2. Standard work-up of the organic layer provided an
amorphous residue of pure octoacetyldiosmin 10 (4.5 g,
95%). A solution of 10 (4.25 g, 4.5 mmol) in CH2Cl2/
pyridine 5:1 (50 mL) was added with NBS (4.05 g,
22.5 mmol) then kept at rt for 20 h. The reaction mixture
was taken up in CH2Cl2, washed with water and evaporated
to dryness. The dried residue was left at rt for 20 h more
5.4c
39%
66%
1
a Measurement at 0.1 mg/mL.
b Decreasing !30%.
c IC50/IC50colchicine
.
d Decreasing of the maximum assembly rate of tubulin without drug.

4044
J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
(this step allowed completion of the bromination), then
taken up in CH2Cl2, and washed with 0.1 M aqueous sodium
thiosulphate then water. Standard work-up of the reaction,
then purification of the residue by FC (silica gel, CH2Cl2/
MeOH 98.5:1.5) led to 3-bromo-octoacetyldiosmin 11
(4.15 g, 90%). Yellowish amorphous powder. 1H NMR
(CDCl3) d [aglycone moiety]: 2.33 and 2.44 (6H, 2s, OAc-5
and 30), 3.91 (3H, s, OMe-40), 6.69 (1H, d, JZ2 Hz, H-6),
6.89 (1H, d, JZ2 Hz, H-8), 7.08 (1H, d, JZ8.8 Hz, H-50),
7.58 (1H, d, JZ2.2 Hz, H-20), 7.77 (1H, dd, JZ8.8, 2.2 Hz,
H-60); [sugar moiety: inner glucose (00) and terminal
rhamnose (000)] 1.13 (3H, d, JZ6.4 Hz, H-6000), 1.92–2.06
(18H, 6s0,006 sugar acetyles)0.0 3.66 (1H, H-600), 3.80 (2H, H-600
4.2.1.4. 3-Bromodiosmetin 7-benzyl ether 14 and
3-bromodiosmetin 7,30-dibenzyl ether 15. To a mixture
of 12 (380 mg, 1 mmol) and KHCO3 (150 mg, 1.5 mmol) in
DMF (10 mL) was added benzyl chloride (0.23 mL,
2 mmol) and the mixture stirred under nitrogen for 2.5 h
at 120 8C. The reaction mixture was cooled, filtered, and
evaporated to dryness. The dried residue was purified by FC
(silica gel, CH2CH2 then CH2CH2/MeOH 99:1) to provide
3-bromodiosmetin 7,30-dibenzyl ether 15 (190 mg, 34%)
then 3-bromodiosmetin 7-benzyl ether 14 (160 mg, 54%).
Compound 14. Pale-yellow crystals: mp: 191–194 8C
1
(MeOH); H NMR (CDCl3) d 3.90 (s, 3H, OMe-40), 5.25
(s, 2H, benzyl), 6.57 (d, JZ2 Hz, 1H, H-6), 6.80 (d, JZ
2 Hz, 1H, H-8), 7.12 (d, JZ8.4 Hz, 1H, H-50), 07.3–7.5 (m,
7H, H-20, H-60 and benzyl), 9.50 (s, 1H, OH-3 ), 12.40 (s,
000
and 0H00 -5 ), 3.94 (1H, H-5 ), 4.67 (1H, s, H-1 ), 4.99 (1H,
000
H-4 ), 5.13–5.28 (5H, H-200, 300, 400, 2000 and 3 ), 5.27 (1H,
H-100). 13C NMR (CDCl3) d [aglycone moiety] 56.0 (OMe-
40), 101.4 (C-8), 109.5 and 110.7 (C-3 and C-10), 109.8 (C-
6), 111.6 (C-50), 124.1 (C-20), 124.50(C-10), 128.7 (C-60),
139.2 (C-30), 150.8 (C-5), 153.4 (C-4 ), 157.6 (C-9), 159.7
and 159.9 (C-200and C-7), C-4 not detected; [sugar moiety:
inner glucose ( ) and terminal rhamnose (000)] 17.2 (C-6000),
65.9 (C-600), 66.6 (C-5000), 68.5, 60800.8, 69.1,0070 0.6, 70.7 and
1H, OH-5). C NMR (DMSO-d6) d 56.1 (OMe-40), 70.5
13
(benzyl), 903.7 (C-8), 99.4 (C-6), 103.9 (C-10), 105.4 (C-3),
111.9 (C-5 ), 116.6 (C-20), 121.9 (C-60), 124.4 (C-10), 128.02,
128.5 and 0128.9 (benzyl), 136.3 (benzyl), 146.4 (C-3 ),
150.8 (C-4 ), 157.1 (C-9), 160.9 (C-5), 162.8 (C-2), 164.9
(C-7), 176.9 (C-4). Compound 15. Yellow crystals: mp:
165–167 8C (MeOH); 1H NMR (CDCl3) d 3.98 (s, 3H,
OMe-40), 5.11 and 5.23 (2s, 4H, benzyls), 6.45 and 6.47 (20d,
JZ2 Hz, 2H, H-6 and H-8), 7.00 (d, JZ8.4 Hz, 1H, H-5 ),
7.3–7.5 (m, 12H, H-20, H-60 and benzyls), 9.50 (s, 1H, OH-
300), 12.40 (s, 1H, OH-5). 13C NMR (CDCl3) d 56.0 (OMe-
4 ), 70.5 and 71.3 (benzyls), 93.1 (C-8), 99.2 0(C-6), 104.2
(C-10), 105.7 (C-3), 111.0 (C-50), 115.4 (C-2 ), 123.5 (C-
60), 124.3 (C-10), 127.1, 127.3, 127.4, 128.0, 128.3 and
128.7 (benzyls), 135.5 and 136.3 (benzyls), 147.4 (C-30),
152.3 (C-40), 157.0 (C-9), 161.7 (C-2 and C-5), 164.8 (C-7),
177.0 (C-4).
00
00
72.2 (C-2 , C-300, C-4 , C-2000, C-3 and C-4 ), 73.5 (C-500),
00
000
97.5 (C-1 ), 97.9 (C-1 ); 20.5–21 and 168.6–170.6 (8 sugar
acetyl groups).
4.2.1.2. 3-Bromodiosmetin 12. 3-Bromo-octoacetyl-
diosmin 11 (4 g, 3.9 mmol) in aqueous 11 N HCl (75 mL)
was stirred at 55 8C for 2 h and left for 2 h at rt. The
resulting suspension was filtered, washed several times with
water then dried with P2O5 under vacuum to yield a crude
residue of 3-bromodiosmetin 12, which was crystallized
from MeOH (1.11 g, 75%). Beige-yellowish crystals: mpO
300 8C (MeOH); 1H NMR (DMSO-d6) d 3.87 (s, 3H, OMe-
40), 6.27 (d, JZ1.8 Hz, 1H, H-6), 6.40 (d, JZ1.8 Hz, 1H, H-
8), 7.09 (d, JZ8.2 Hz, 1H, H-50), 7.31 (d, JZ2 Hz, 1H, H-
20), 7.33 (dd, JZ8.2, 2 Hz, 1H, H-60), 9.46 (s, 1H, OH-30),
11.0 (s, 1H, OH-7),012.38 (s, 1H, OH-5). 13C NMR (DMSO-
d6) d 56.1 (OMe-4 ), 94.2 (C-8), 99.6 (C-6), 102.9 (C-10),
105.1 (C-3), 111.90(C-50), 116.5 (C-20), 121.8 (C-60), 124.5
(C-10), 146.4 (C-3 ), 150.7 (C-40), 157.2 (C-9), 161.2 and
162.3 (C-2 or C-5), 165.0 (C-7), 176.7 (C-4). EIMS m/z (%)
380–378 (MC, 92–100), 379–377 (54–38).
4.2.1.5. 3-Bromoacacetin 17; 3-bromoacacetin 7-ben-
zyl ether 18. 3-Bromoacacetin 17 was prepared from
900 mg (1.5 mmol) linarin 16 as 12 from 9 (60% 17 from
16), then its benzyl ether 18 as 14 from 12 (1.1 equiv
KHCO3, 1.2 equiv BnCl, 77%). Compound 17. Beige-
yellowish crystals: mp: 297–29808C (MeOH); 1H NMR
(DMSO-d6) d 3.86 (s, 3H, OMe-4 ), 6.27 (d, JZ2 Hz, 1H,
H-6), 6.41 0(d, JZ2 Hz, 1H, H-8), 7.12 (d, JZ8.8 Hz, 2H, H-
30 and H-5 ), 7.84 (d, JZ8.8 Hz, 2H, H-20 and H-60), 11.0 (s,
1H, OH-7), 12.37 (s, 1H, OH-5). 13C NMR (DMSO-d6) d
55.9 (OMe-40), 94.3 (C-8),099.7 (C-6), 102.9 (C-10), 105.2
(C-3), 114.2 (C-30 and C-5 ), 124.4 (C-10), 131.6 (C-20 and
C-60), 157.2 (C-9), 161.2, 161.9 and 162.0 (C-2, C-5 and C-
40), 165.0 (C-7), 176.7 (C-4). ESIMS (C) m/z 387–385
[MCNa]C, 365–363 [MCH]C. Compound 18. Light-
yellow crystals: mp: 134–13608C (MeOH); 1H NMR
(CDCl3) d 3.90 (s, 3H, OMe-4 ), 5.13 (s, 2H, benzyl),
6.50 (s, 2H, H-6 and H-8), 7.02 (d, JZ8.8 Hz, 2H, H-30 and
H-50), 7.35–7.45 (m, 5H, benzyl), 7.87 (d, JZ8.8 Hz, 2H,
H-20 and H-60), 12.41 (s, 1H, OH-5). 13C NMR (CDCl3) d
55.5 (OMe-40), 70.6 (benzyl), 93.2 (C-8), 99.3 (C-6), 1040.1
(C-10), 105.6 (C-3), 113.7 (C-30 and C-50), 124.4 (C-10),
127.4, 128.4 and 128.7 (benzyl), 131.2 (C-20 and C-6 ),
135.6 (benzyl), 157.1 (C-9), 161.7, 161.8 and 162.0 (C-2, C-
5 and C-40), 164.9 (C-7), 177.0 (C-4).
4.2.1.3. 3-Bromodiosmetin 7-isopropyl ether 13. To a
mixture of 12 (152 mg, 0.4 mmol) and K2CO3 (55 mg,
0.4 mmol) in DMF (6 mL) was added isopropyl bromide
(0.4 mL, 4 mmol) and the mixture stirred under nitrogen for
6 h at 75 8C. The reaction mixture was cooled, filtered, and
evaporated to dryness. The dried residue was purified by FC
(silica gel, CH2CH2/MeOH 99.5:0.5) to provide 3-bromo-
diosmetin 7-isopropyl ether 13 (90 mg, 54%). Pale-yellow
crystals: mp: 182–185 8C (MeOH); 1H NMR (CDCl3) d 1.37
(d, JZ6 Hz, 6H, isopropyl), 4.62 (heptuplet, JZ6 Hz, 1H,
isopropyl), 3.99 (s, 3H, OMe-40), 6.38 and 6.39 (2d, JZ
2 Hz, 2H, H-6 and H-8), 6.97 (d, JZ8.4 Hz, 1H, H-50), 7.44
(d, JZ2.1 Hz, 1H, H-20), 7.46 (dd, JZ8.4, 2.1 Hz, 1H, H-
60), 12.36 (s, 1H, OH-5). 13C NMR (CDCl3) d 21.7
(isopropyl), 55.9 (OMe-40), 71.0 (isopropyl), 93.2 (C-8),
99.60(C-6), 103.8 0(C-10), 110.0 (C-50), 115.4 (C-20), 121.9
(C-6 ), 125.4 (C-1 ), 145.5 (C-30), 149.1 (C-40), 156.9 (C-9),
161.2 (C-2), 162.0 (C-5), 164.1 (C-7); C-3 and C-4 not
detected.
4.2.1.6. 40-Methoxyflavone 19. Flavone 19 (655 mg,
65% from 4 mmol phosphorane) was prepared according to
Ref.16 White-yellowish crystals: mp: 159–161 8C (MeOH),
lit.16 157–158 8C; 1H NMR (CDCl3) d 3.90 (s, 3H, OMe-40),

J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
4045
6.75 (s, 1H, H-3), 7.03 (d, JZ9 Hz, 2H, H-30 and H-50), 7.41
(t, JZ8.1 Hz, 1H, H-6), 7.55 (dd, JZ7.8, 1.4 Hz, 1H, H-8),
7.69 (m, 1H, H-7), 7.90 (d, JZ9 Hz, 2H, H-20 and H-60),
8.23 (dd, JZ8.1, 1.7 Hz, 1H, H-5).
benzyl-7), 6.45 (s, 2H, H-200 and H-600), 6.46 (d, JZ1.8 Hz,
1H, H-6), 6.56 (d, JZ1.8 Hz, 1H, H-8),06.80 (d, JZ8.5 Hz,
1H, H-50), 6.90 (d, JZ2.1 Hz, 1H, H-2 ), 7.12 (dd, JZ8.5,
2.1 Hz, 1H, H-60), 7.2–7.5 (m, 10H, benzyls). 13C NMR
(CDCl3) d 55.8 (CH3, OMe-40), 55.9 (2CH3, OMe-300 and
500), 56.1 0(OMe-5), 60.8 (OMe-400), 70.2 (benzyl-7), 70.4
(benzyl-3 ), 93.0 (C-8), 96.2 (C-6), 108.1 (C-200 and C-600),
108.7 (C-10), 110.7 (C-50), 114.1 (C-20), 122.1 (C-3), 122.5
(C-60), 124.9 (C-10), 126–130 (benzyls), 128.3 (C-100), 1350.5
(C, benzyl-7), 136.1 (benzyl-30), 137.0 (C-400), 147.0 (C-3 ),
151.0 (C-40), 152.7 (C-300 and C-500), 157.8 (C-2), 158.9 (C-
9), 161.1 (C-5), 162.9 (C-7); C-4 not detected. EIMS m/z
(%) 660 (MC, 11), 570 (43), 569 (100), 541 (28).
4.2.1.7. 3-Bromo-40-methoxyflavone 20. Bromination
of the flavone 19 was performed from Ref. 17: a solution of
19 (504 mg, 2 mmol) in CH2Cl2/MeOH 2:1 (60 mL) was
added with NBS (712 mg, 4 mmol) then kept at rt for 3 h.
The reaction mixture was taken up in CH2Cl2, and washed
with 0.1 M aqueous sodium thiosulphate then water.
Standard work-up furnished a dried residue, which was
dissolved then stirred in the mixture THF/NaOH 0.5 M 1:3
(60 mL) for 3 h at rt. The reaction mixture was adjusted to
pH 6 with HCl 11 N then extracted with CH2Cl2. Standard
work-up of the reaction, then purification 0of the residue by
FC (alumina, CH2Cl2) led to 3-bromo-4 -methoxyflavone
20 (276 mg, 42%). 20. Light-yellow crystals: mp: 137–
4.2.2.3. 3-(300,400,500-Trimethoxyphenyl)diosmetin 30-
benzyl-5-methyl ether 23 and 3-(300,400,500-trimethoxy-
phenyl)diosmetin 5-methyl ether 24. A solution of 22
(86 mg, 0.13 mmol) in DMF (3 mL) was hydrogenated
under 1 atm pressure hydrogen with 10% Pd–C (8.5 mg) at
rt for 72 h. The catalyst was separated and the filtrate
concentrated to dryness. Crystallization of the dried residue
from CH2Cl2–MeOH afforded pure 23 (26 mg, 35%), while
TLC (silica gel, CH2Cl2/MeOH 94:6) of the mother liquor
provided 23 (8 mg, 10%) and 24 (6 mg, 10%). Compound
23. Pale-yellow crystals: mp: 206–210 8C (MeO0H0 ); 1H
NMR (DMSO-d6) d 3.62 (s, 9H, OMe-300, 400 and 5 ), 3.74
(s, 3H, OMe-400), 3.78 (s, 3H, OMe-40), 3.92 (s, 3H, OMe-5),
4.70 (s, 2H, benzyl), 6.38 (d, JZ1.8 Hz, 1H, H-6), 6.43 (s,
2H, H-200 and H-600), 6.46 (d, JZ1.8 Hz, 1H, H-8), 6.93 (d,
JZ8.5 Hz, 1H, H-50), 6.97 (d,0 JZ1.7 Hz, 1H, H-20), 7.13
(dd, JZ8.5, 1.7 Hz, 1H, H-6 ), 7.3–7.4 (m, 5H, benzyl
groups). HRESIMS m/z 593.1818 (calcd for C33H30O9Na,
593.1788). Compound 24. Pale-yellow crystals: mp: 267–
270 8C (MeOH); 1H NMR (DMSO-d6) d 3.62 (s, 6H, OMe-
300 and 500), 3.67 (s, 3H, OMe-400), 3.75 (s, 3H, OMe-40), 3.78
(s, 3H, OM0e0 -5), 6.38 (d, JZ2 Hz, 1H, H-6), 6.40 (s, 2H, H-
200 and H-6 ), 6.43 (d, JZ2 Hz, 1H, H-8), 6.78 (dd, JZ8.2,
1.9 Hz, 1H, H-60), 6.85 (d, JZ8.2 Hz, 1H, H-50), 6.86 (d,
JZ1.9 Hz, 1H, 0H0 -20). 13C NMR (DMSO-d6) d 55.6 (OMe-
7, 40, 300 and 5 ), 59.8 (OMe-400), 94.4 (C-8), 96.6 (C-6),
109.0 (C-200 and C-600), 111.1 (C-50), 115.070 (C-20), 1210.1
(C-60), 121.8 (C-3), 124.4 (C-10), 1030 6.4 (C-4 ), 145.5 (C-3 ),
148.8 (C-40), 151.8 (C-300 and C-5 ), 160.8 (C-5); C-2, C-4,
C-7, C-9, C-10 and C-100 not detected. HRESIMS m/z
503.1345 (calcd for C26H24O9Na, 503.1318), 481.1543
(calcd for C26H25O9, 481.1499).
1
139 8C (MeOH), lit.25d 140–141 8C; H NMR (CDCl3) d
3.91 (s, 3H, OMe-40), 7.04 (d, JZ8.9 Hz, 2H, H-30 and H-
50), 7.40–7.55 (m, 2H, H-6 and H-8), 7.65–7.75 (m, 1H, H-
7), 7.88 (d, JZ8.9 Hz, 2H, H-20 and H-60), 8.29 (dd, JZ7.9,
1.5 Hz, 1H, H-5).
4.2.2. Synthesis of 3-arylflavones analogues of 1 and 2.
Typical procedure of the Suzuki cross-coupling reaction: a
3-bromoflavone (0.1 mmol), 3,4,5-trimethoxybenzeneboro-
nic acid (35 mg, 0.16 mmol) and tetrakis(triphenylpho-
sphine)palladium (5 mg, 0.005 mmol) were added in a flask
fitted with a reflux condenser. The flask was evacuated and
back-filled with nitrogen and then 3 mL of dioxane and
0.16 mL of a 2 M solution of K2CO3 were added (with
3-bromo-hydroxyflavones, 0.05 mL 2 M K2CO3 more were
added per each phenol group). The reaction mixture was
stirred at 110 8C until completion of the reaction. After
cooling, the mixture was taken up in water, adjusted to pH 6
with 1 N HCl and extracted with CH2Cl2. Standard work-up
then purification by FC led to the expected 3-arylflavone.
4.2.2.1. 3-(300,400,500-Trimethoxyphenyl)diosmetin 7,30-
dibenzyl ether 21. Prepared by Suzuki cross-coupling from
224 mg (0.4 mmol) 15; yield 95% (245 mg). Light-yellow
crystals: mp: 182–185 8C (MeOH); 1H NMR (CDCl3) d 3.73
(s, 6H, 0OMe-300 and 500), 3.84 (s,03H, OMe-400), 3.87 (s, 3H,
OMe-4 ), 4.86 (s, 2H, ben0z0 yl-3 ), 5.17 (s, 2H, benzyl-7),
6.46 (s, 2H, H-200 and H-6 ), 6.46 and 6.49 (2d, JZ2 Hz,
2H, H-6 and H-8), 6.79 (d, JZ8.5 Hz, 1H, H-50), 6.89 (d,
JZ2.1 Hz, 1H, H-20), 7.11 (dd, JZ8.5, 2.1 Hz, 1H, H-60),
7.2–7.5 (m, 10H, benzyls), 12.87 (s, 1H, OH-5). EIMS m/z
(%) 646 (MC, 73), 556 (76), 555 (100), 540 (47).
4.2.2.4. 3-(300,400,500-Trimethoxyphenyl)diosmetin
7-benzyl ether 25. Prepared by Suzuki cross-coupling
from 282 mg (0.6 mmol) 14; yield 73% (244 mg). Light-
yellow crystals: mp: 235–238 080C (MeOH); 1H NMR
(CDCl3) d 3.74 (s, 6H, OMe-3 and 500), 3.86 (s, 3H,
OMe-400), 30.088 (s, 3H, OMe-40), 5.15 (s, 2H, benzyl-7), 6.45
(s, 2H, H-2 and H-600), 6.46 (d, JZ2.2 Hz, 1H, H-6), 6.53
(d, JZ2.2 Hz, 1H, H-8), 6.670(d, JZ8.5 Hz, 1H, H-50), 6.79
(dd, JZ8.5, 2.1 Hz, 1H, H-6 ), 7.14 (d, JZ2.1 Hz, 1H, H-
20), 7.3–7.5 (m, 5H, benzyl), 12.90 (s, 1H, OH-5). 13C NMR
(CDCl3) d 55.8 (OMe-40), 55.9 (OMe-300 and 500), 60.7
(OMe-400), 70.1 (benzyl), 92.7 (C-8), 98.3 0(C-6), 105.4 (C-
10), 107.8 (C-200 and C-600), 109.50 (C-5 ), 115.0 (C-20),
120.8 (C-3), 122.7 (C-60), 125.3 (C-1 ), 127–128.5 (benzyl),
127.2 (C-1000), 135.5 (benzyl), 137.1 (C-400), 145.0 (C-30),
147.5 (C-4 ), 152.9 (C-300 and C-500), 157.0 (C-9), 161.8
4.2.2.2. 3-(300,400,500-Trimethoxyphenyl)diosmetin 7,30-
dibenzyl-5-methyl ether 22. A solution of 21 (183 mg,
0.28 mmol) in CH2Cl2 (30 mL) was stirred for 22 h at rt in
the presence of 0.5 M aqueous NaOH (30 mL), dimethyl
sulfate (3 mL) and tetrabutylammonium hydrogen sulfate
(50 mg) as phase-transfer catalyst. Standard work-up of the
organic layer, then purification of the dry residue by FC
(silica gel, CH2Cl2/MeOH 99:1; alumina, CH2Cl2/MeOH
99.5:0.5) provided 22 (121 mg, 65%). Pale-yellow crystals:
mp: 163–166 8C (MeOH); 1H NMR (CDCl3) d 3.71 (s, 6H,
OMe-300 and 500), 3.84 (s, 3H, OMe-400), 3.880(s, 3H, OMe-
40), 3.92 (s, 3H, OMe-5), 4.85 (s, 2H, benzyl-3 ), 5.18 (s, 2H,

4046
J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
(C-2), 162.1 (C-5), 164.3 (C-7); C-4 not detected. EIMS m/z
(%) 556 (MC, 45), 91 (100).
anhydrous CH2CH2 (5 mL) stirred at K78 8C under
nitrogen was added dropwise 1 M boron trichloride in
CH2CH2 (1 mL). The reaction was stirred for 0.5 h at
K78 8C then 16 h at 0 8C. The reaction mixture was taken
up in iced water, adjusted at pH 6 with NaHCO3 then
extracted with AcOEt. Standard work-up of the organic
layer afforded a dry residue (29 mg), which was purified by
TLC (silica gel, CH2CH2/MeOH 96:4) to give 29 (14 mg,
4.2.2.5. 3-(300,400,500-Trimethoxyphenyl)diosmetin 26.
Catalytic hydrogenation of 25 (110 mg, 0.2 mmol) in DMF
(Pd–C, rt, 3 h) provided after filtration of the catalyst a dry
residue of pure 26 (87 mg, 96%). Pale-beige yellowish
crystals: mp: 262–264 8C (MeOH); 1H NMR (DMSO-d6) d
3.62 (s, 6H,0OMe-300 and 500), 3.67 (s, 3H, OMe-400), 3.75 (s,
3H, OMe-4 ), 6.21 (d, JZ2 Hz, 1H, H-6), 6.40 (d, JZ2 Hz,
1H, H-8), 6.49 (s, 2H, H-200 and H-600), 6.803 (dd, JZ8.5,
2 Hz, 1H, H-60), 6.87 (d, JZ8.5 Hz, 1H, H-5 ), 6.90 (d, JZ
2 Hz, 1H, H-20), 12.97 (s, 1H, OH-5). 13C NMR (DMSO-d6)
1
43%). Light-yellow crystals: mp: 280–283 8C (MeOH); H
NMR (DMSO-d6) d 3.61 (s, 6H, OMe-300 and 500), 3.76 (s,
3H, OMe-40), 6.20 (d, JZ2 Hz, 1H, H-6), 6.38 (d, JZ2 Hz,
1H, H-8), 6.42 (s, 2H, H-200 and H-600), 6.709 (dd, JZ8.5,
2 Hz, 1H, H-60), 6.86 (d, JZ8.5 Hz, 1H, H-5 ), 6.92 (d, JZ
2 Hz, 1H, H-20), 13.04 (s, 1H, OH-5). 13C NMR (DMSO-d6)
d 55.9 (OMe-40), 56.4 (OMe-300 and 500), 93.8 (C-8), 990.1
(C-6), 103.7 (C-10), 109.4 (C-200 and C-600), 111.7 (C-5 ),
116.5 (C-20), 120.1 (C-3), 121.8 (C-60), 122.1 (0C0 -100), 125.3
(C-10), 1350.7 (C-400), 146.2 (C-30), 148.2 (C-3 and C-500),
149.8 (C-4 ), 157.5 (C-9), 162.0 and 162.1 (C-2 and C-5),
164.7 (C-7), 181.3 (C-4). EIMS m/z (%) 452 (MC, 100),
451 (10).
00
d 55.9 (OMe-40), 56.0 (OMe-300 and 500), 60.5 (OMe-4 ),
00
93.3 (C-8),099.0 (C-6), 103.2 (C-10), 108.5 (C-200 and C-6 ),
111.4 (C-5 ), 116.1 0(0C-20), 119.8 (C-3), 121.6 (C-60), 124.9
(C-100), 127.8 (C-1 ), 137.1 00(C-400), 146.0 (C-30), 149.8
(C-4 ), 152.5 (C-300 and C-5 ), 157.2 (C-9), 161.9 (C-2),
162.0 (C-5), 164.2 (C-7); C-4 not detected. EIMS m/z (%)
466 (MC, 100), 451 (48).
4.2.2.6. 3-(300,400,500-Trimethoxyphenyl)diosmetin
7-isopropyl ether 27. Prepared by Suzuki cross-coupling
from 42 mg (0.1 mmol) 13; purification by FC (silica gel,
CH2Cl2/MeOH 98:2); yield 69% (35 mg). Light-yellow
crystals: mp: 219–219 8C (MeOH); 1H NMR (CDCl3) d 1.39
(d, JZ6 Hz, 6H, isopropyl), 4.64 (heptuplet, JZ6 Hz, 1H,
isopropyl), 3.74 (s, 6H, 0OMe-300 and 500), 3.86 (s, 3H, OMe-
400), 3.89 (s, 3H, OMe-4 ), 6.35 and 6.43 (2d, JZ2.2 Hz, 2H,
H-6 and H-8), 6.44 (s, 2H, H-200 and H-600), 6.68 (d, JZ
8.5 Hz, 1H, H-50), 6.79 (dd, JZ8.5, 2.1 Hz, 1H, H-60), 7.15
(d, JZ2.1 Hz, 1H, H-20), 12.86 (s, 1H, OH-5). 13C NMR
(CDCl3) d 21.6 (isopropyl), 55.8 (OMe-40), 56.0 (OMe-300
and 500), 60.6 (OMe-400), 70.7 (isopropyl), 090 3.0 (C-8), 980.8
(C-6), 104.1 (C-10), 107.8 (C-200 and C-6 ), 110.0 (C-5 ),
115.1 (C-20), 120.8 (C-3), 122.7 (C-60), 125.5 (C-10), 137.0
(C-400), 145.0 (C-30), 147.9 (C-40), 152.9 (C-300 and C-500),
157.1 (C-9), 162.2 (C-5); C-2, C-4, C-7 and C-100 not
detected. EIMS m/z (%) 508 (MC, 100), 451 (33), 151 (27).
4.2.2.9. 3-(300,400,500-Trimethoxyphenyl)acacetin 7-ben-
zyl ether 30. Prepared by Suzuki cross-coupling from
136 mg (0.3 mmol) 18; reaction time 1 h; purification by FC
(silica gel, CH2Cl2/MeOH 95:5); yield 90% (146 mg).
1
Light-yellow crystals: mp: 184–185 8C (MeOH); H NMR
(CDCl3) d 3.74 (s, 6H, OMe-300 and 500), 3.80 and 3.85 (2s,
6H, OMe-40 and 400), 5.14 (s, 2H, benzyl), 6.45 (s, 2H, H-200
and H-600), 6.45 and 6.53 (2d, JZ2 Hz, 2H, H-6 and H-8),
6.78 (d, JZ8.8 Hz, 2H, H-30 and H-50), 7.3–7.45 (m, 7H,
H-20, H-60 and benzyl), 12.94 (s, 1H, OH-5). 13C NMR
(CDCl3) d 55.2 (OMe-40), 56.0 (OMe-300 and 500), 60.8
(OMe-400), 70.3 (benzyl), 93.0 (C-8), 98.7 (C-6), 105.2
(C-10), 108.3 (C-200 and C-600), 113.5 (C-30 and C-50), 120.1
(C-3), 124.6 (C-10), 127.3, 128.2 and 128.6 (benzyl), 130.9
(C-20 an0d0 C-60), 135.7 (benzyl), 137.7 (C-400), 153.3 (C-300
and C-5 0), 157.3 (C-9), 161.1, 161.7 and 162.4 (C-2, C-5
and C-4 ), 164.6 (C-7), 181.3 (C-4); C-100 not detected.
HRESIMS m/z 541.1883 (calcd for C32H29O8, 541.1862).
4.2.2.7. 3-(300,400,500-Trimethoxyphenyl)diosmetin 5,7-
dimethyl ether 28. Methylation of 23 (27 mg, 0.047 mmol)
in DMF by the system K2CO3/MeI, then catalytic
hydrogenation (DMF, rt, 5 days), and final purification by
TLC (silica gel, CH2Cl2/MeOH 95:5) led to 28 (9 mg, 39%
from 23). Light-yellow crystals: mp: 178–180 8C (MeOH);
1H NMR (CDCl3) d 3.72 (s, 6H, OMe-300 and 500), 3.85 (s,
3H, OMe-400), 3.88 (s, 3H, OMe-40), 3.91 (s, 3H, OMe-7),
3.93 (s, 3H, OMe-050 ), 6.38 (d, JZ2.2 Hz, 1H, H-6), 6.46 (s,
2H, H-200 and H-6 ), 6.53 (d, JZ2.2 Hz, 1H, H-8), 6.66 (0d,
JZ8.5 Hz, 1H, H-50), 6.77 (dd, JZ8.5, 2.1 Hz, 1H, H-6 ),
7.19 (d, JZ2.1 Hz, 1H, H-20). 13C NMR (CDCl3) d 55.7 and
56.3 (OMe-7 and 40), 55.9 (2OMe-300 and 500), 60.9 (OMe-
400),0092.4 (C-8), 906.1 (C-6), 108.7 (C-10), 108.7 (C-200 and
C-6 ), 109.8 (C-5 ), 1140.09 (C-20), 122.5 (C-3), 122.8 (C-60),
125.6 (C-10), 128.10(0C-1 ), 137.3 (C-400), 144.8 (C-30), 148.3
(C-40), 153.5 (C-3 and C-500), 158.7 (C-2), 159.1 (C-9),
161.1 (C-5), 164.0 (C-7); C-4 not detected. HRESIMS m/z
517.1481 (calcd for C27H26O9Na, 517.1475), 495.1635
(calcd for C27H27O9, 495.1635).
4.2.2.10. 3-(300,400,500-Trimethoxyphenyl)acacetin 31.
Catalytic hydrogenation of 30 (81 mg, 0.15 mmol) in
DMF (Pd–C, rt, 3 h) provided after filtration of the catalyst
a dry residue of pure 31 (63 mg, 93%). Pale-yellow crystals:
1
mp: 284–288 8C (MeOH); H NMR (DMSO-d6) d 3.61 (s,
6H, OMe-300 and 500), 3.67 (s, 3H, OMe-400), 3.76 (s, 3H,
OMe-40), 6.23 (d, JZ1.8 Hz, 1H, H-6), 6.44 (d, JZ1.8 Hz,
1H, H-8), 6.50 (s, 2H, H-200 and H-600), 6.91 (d,0JZ8.8 Hz,
2H, H-30 and H-50), 7.38 (d, JZ8.8 Hz, 2H, H-2 and H-60),
12.97 (s, 1H, OH-5). 13C NMR (DMSO-d6) d 55.8 (OMe-
40), 56.0 (OMe-300 and 500), 60.5 (OMe-400), 93.8 (C-8),098.8
(C-6), 102.8 (C-10), 108.6 (C-200 and C-600), 113.8 (C-3 and
C-50), 119.1 (C-3), 1240.05 (C-10), 131.0 (C-20 and C-60),
137.0 (C-400), 152.8 (C-3 and C-500), 157.0 (C-9), 160.9 (C-
2), 161.0 (C-40), 161.9 (C-5); C-4, C-7 and C-100 not
detected. HRESIMS m/z 473.1243 (calcd for C25H22O8Na,
473.1212), 451.1406 (calcd for C25H23O8, 451.1393).
4.2.2.11. 40-Methoxy-3-(300,400,500-trimethoxyphenyl)-
flavone 32. Prepared by Suzuki cross-coupling from
100 mg (0.3 mmol) 20; reaction time 4 h; yield 42%
(52 mg). White crystals: mp: 170–172 8C (MeOH); 1H
4.2.2.8.
diosmetin 29. To a solution of 25 (40 mg, 0.072 mmol) in
3-(300,500-Dimethoxy-400-hydroxyphenyl)-

J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
4047
NMR (CDCl3) d 3.71 (s, 6H, OMe-300 and 500), 3.81 (s, 3H,
OMe-40), 3.86 (s, 3H, OMe-400), 6.47 (s, 2H, H-200 and H-
600), 6.80 (d, JZ8.7 Hz, 20H, H-30 and H-50), 7.39 (d, JZ
8.7 Hz, 2H, H-20 and H-6 ), 7.42 (t, JZ7.8 Hz, 1H, H-6),
7.53 (d, JZ7.8 Hz, 1H, H-8), 7.70 (t, JZ7.8 Hz, 1H, H-7),
8.28 (d,0 JZ7.8 Hz, 1H,00H-5). 13C NMR (CDCl3) d 54.6
(OM0e0 -4 ), 55.9 (OMe-3 and 500), 61.0 (OMe-400), 108.9
(C-2 and C-600), 114.0 (C-30 and C-50), 117.9 (C-8), 121.4
(C-3), 123.1 (C-10), 124.80(C-10), 1205.7 (C-6), 126.3 (C-5),
128.3 (C-100), 132.020 (C-2 and C-6 ), 133.5 (C-7), 1370.0
(C-400), 152.6 (C-3 and C-500), 156.0 (C-9), 161.2 (C-4 ),
176.8 (C-4); C-2 not detected. ESIMS (C) m/z 441 [MC
Na]C, 419 [MCH]C.
H-100), 6.39 (d, JZ1.6 Hz, 1H, H-6), 6.83 (d, JZ1.6 Hz, 1H,
H-8), 7.03 (s, 1H, H-3), 7.26 (d, JZ8.8 Hz, 1H, H-50), 8.18
(dd, JZ8.8, 2.2 Hz, 1H, H-60), 8.50 (d, JZ2.2 Hz, 1H, H-
20). 13C NMR (DMSO-d6) d [aglycone moiety] 94.5 (C-8),
99.50(C-6), 104.9 (C-3), 105.5 (C-10), 119.6 (C-50), 121.4
(C-1 ), 123.4 (C-20), 132.3 (C-60), 137.6 (C-30), 154.4 (C-
40), 156.9 (C-9), 161.0 (C-5), 161.7 (C-2), 162.6 (C-7),
181.8 (C-4); [sugar moiety]: inner glucose 60.4 (C-600),
69.5a (C-400), 76.4b (C-200), 76.9b (C-300), 77.0b (C-500), 97.6
(C-100); terminal rhamnose 17.9 (C-6000), 68.3 (C-5000), 70.0a
(C-2000), 70.2a (C-3000), 72.0 (C-4000), 100.4 (C-1000)a,b
interchangeable. ESIMS (K) m/z 622 [MKH]K.
4.2.3.3. 30-Nitroapigenin 42; 30-nitroacacetin 43.
Hydrolysis of crude 41 (311 mg, 0.5 mmol) by 11 N HCl
(see above 11/12) provided a dry residue of pure 30-
nitroapigenin 42 (131 mg, 83%). Methylation of crude 41
(1.38 g, 2.25 mmol) was performed in DMF (20 mL, stirring
at rt) by successive additions of the couple K2CO3/MeI until
completion of the reaction (1.1 equiv K2CO3/0.45 mL MeI
for 10 h, 0.55 equiv/0.2 mL for 16 h, 0.22 equiv/0.1 mL for
20 h). The reaction mixture was then filtered and evaporated
to dryness. Dry residue was hydrolyzed in 11 N HCl (see
above) and furnished after a final crystallization in MeOH
30-nitroacacetin 43 (541 mg, 73% from 41). Compound 42.
Lemon-yellow crystals: mpO300 8C (MeOH); 1H NMR
(DMSO-d6) d 6.19 (d, JZ1.4 Hz, 1H, H-6), 6.50 (d, JZ
1.4 Hz, 1H, H-8), 6.93 (s, 1H, H-3), 7.25 (d, JZ8.8 Hz, 1H,
H-50), 8.19 (dd, JZ8.8, 1.9 Hz, 1H, H-60), 8.51 (d, JZ
1.9 Hz, 1H, H-20), 12.78 (s, 1H, OH-5). 13C NMR (DMSO-
d6) d 93.4 (C-8), 98.6 (C-6), 103.5 (C-10), 104.1 (C-3),
119.4 (C-50), 121.5 (C-10), 122.8 (C-20), 131.8 (C-60), 137.5
(C-30), 153.9 (C-40), 157.5 (C-9), 161.3 (C-5), 161.6 (C-2),
164.0 (C-7), 181.9 (C-4). ESIMS (K) m/z 314 [MKH]K.
Compound 43. Dark-yellow crystals: mp: 299–300 8C
4.2.3. Synthesis of 3-bromoflavones, intermediates for
3-arylflavones analogues of 3. (a) From acacetin 36.
4.2.3.1. 7-Benzylsulfonylacacetin 37; 7-benzylsul-
fonyl-6-nitroacacetin 38 and 7-benzylsulfonyl-8-nitro-
acacetin 39. A solution of acacetin 36 (85 mg, 0.3 mmol) in
anhydrous THF (10 mL) was added with triethylamine
(0.1 mL) and a-toluenesulfonyl chloride (57 mg,
0.3 mmol), then left at rt for 0.5 h. Standard work-up of
the reaction provided the sulfonate 37 (123 mg, 94%). To a
solution of 37 (44 mg, 0.1 mmol) in TFA (4 mL) at 0 8C was
added 1 equiv HNO3 53%. The reaction was stirred for 2 h
at 0 8C, then taken up in iced water and carefully adjusted at
pH 6 with 30% aqueous NaOH. Standard work-up of the
reaction then purification of the dried residue by FC (silica
gel, CH2Cl2/MeOH 99.5:0.5) afforded pure isomers 38
(19 mg, 39%) and 39 (14 mg, 29%).
Compound 37. Beige-yellowish crystals: mp: 170–173 8C
(MeOH); 1H NMR (CDCl3) d 3.92 (s, 3H, OMe-40), 4.58 (s,
2H, benzyl), 6.50 (d, JZ1.8 Hz, 1H, H-6), 6.62 (s, 1H, H-3),
6.85 (d, 0JZ1.8 Hz, 1H, H-8), 7.02 (d, JZ8.8 Hz, 2H, H-30
and H-5 ), 7.48 (m, 5H, benzyl), 7.82 (d, JZ8.8 Hz, 2H, H-
20 and H-60), 12.89 (s, 1H, OH-5). ESIMS (C) m/z 899
[2MCNa]C. Compound 38. Orange-yellow crystals: mp:
198–202 8C (MeOH); 1H NMR (CDCl3) d 3.92 (s, 3H,
OMe-40), 4.69 (s, 2H, benzyl), 6.72 (s, 1H, H-3), 7.05 (d,
JZ8.8 Hz, 2H, H-30 and H-50), 7.07 (s, 1H, H-8), 7.47 (m,
5H, benzyl), 7.85 (d, JZ8.8 Hz, 2H, H-20 and H-60), 14.05
(s, 1H, OH-5). Compound 39. Orange-yellow crystals: mp:
193–196 8C (MeOH); 1H NMR (CDCl3) d 3.93 (s, 3H,
OMe-40), 4.69 (s, 2H, benzyl), 6.72 (s, 1H, H0-3), 6.78 (s, 1H,
H-6), 7.05 (d, JZ8.8 Hz, 2H, H-30 an0d H-5 ), 7.48 (m, 5H,
benzyl), 7.85 (d, JZ8.8 Hz, 2H, H-2 and H-60), 13.48 (s,
1H, OH-5). ESIMS (K) m/z 482 [MKH]K.
1
(MeOH); H NMR (DMSO-d6) d 4.01 (s, 3H, OMe-40),
6.20 (d, JZ1.4 Hz, 1H, H-6), 6.53 (d, JZ1.4 Hz, 1H, H-8),
7.02 (s, 1H, H-3),07.51 (d, JZ9 Hz, 1H, H-50), 8.33 (dd, JZ
9, 2 Hz, 1H, H-6 ), 8.54 (d, JZ2 Hz, 1H, H-20), 10.90 (s,
1H, OH-7), 12.75 (s, 1H, OH-5). 13C NMR (DMSO-d6) d
57.0 (OMe-40), 93.9 (C-8), 98.08 (C-6), 103.3 (C-10), 1040.8
(C-3), 114.5 (C-50), 122.2 (C-1 ), 122.5 (C-20), 131.8 (C-6 ),
139.5 (C-30), 153.8 (C-40), 156.9 (C-9), 160.9 (C-2), 161.5
(C-5), 164.1 (C-7), 181.5 (C-4). ESIMS (C) m/z 352 [MC
Na]C, 330 [MCH]C.
4.2.3.4. 3-Bromo-30-nitroacacetin 44; 3-bromo-30-
nitroacacetin 7-methyl ether 45; 3-bromo-30-nitroacace-
tin 7-benzyl ether 46. Acetylation of 43 (165 mg,
0.5 mmol) then bromination of the dry residue by the two-
step sequence (see above 19/20) afforded 3-bromo-30-
nitroacacetin 44 (133 mg, 65% from 43). Methylation
(DMF, 1 equiv K2CO3, 10 MeI, rt, 20 h) and benzylation
(DMF, 1.05 equiv KHCO3, 3 equiv BnCl, 120 8C, 2 h) of 44
(61 mg, 0.15 mmol for each reaction) provided, respect-
ively, 45 (quantitative yield) and 46 (86%). Compound 44.
(b) From naringin 8
4.2.3.2. 30-Nitrorhoifolin 41. Rhoifolin 40 was prepared
from naringin by the classical procedure (I2, pyridine, 90 8C,
16 h, 95%).13 To a solution of rhoifolin 40 (6.87 g,
11.2 mmol) in TFA (50 mL) at 0 8C was added dropwise
1 equiv HNO3 53%. The reaction was stirred for 2 h at 0 8C,
then carefully evaporated at rt with a vacuum system
equipped with a KOH trap, and finally dried in a dessicator
to provide crude 30-nitrorhoifolin 41 (quantitative yield)
used as it is in the following steps. Lemon-yellow crystals:
mp: 220–230 8C; 1H NMR (DMSO-d6) d 1.22 (d, JZ6 Hz,
3H, Me-6000), 5.14 (s, 1H, H-1000), 5.26 (d, JZ7 Hz, 1H,
1
Light-yellow crystals: mp: 291–294 8C (MeOH); H NMR
(DMSO-d6) d 4.03 (s, 3H, OMe-40), 6.30 (d, JZ1.8 Hz, 1H,
H-6), 6.44 (d, JZ1.8 Hz, 1H, H-8), 7.57 (d, JZ9 Hz, 1H, H-
50), 8.16 (dd, JZ9, 2.1 Hz, 1H, H-60), 8.42 (d, JZ2.1 Hz,
1H, H-20), 11.07 (s, 1H, OH-7), 12.27 (s, 1H, OH-5). 13C
NMR (DMSO-d6) d 56.8 (OMe-40), 93.8 (C-8), 99.0 (C-6),
102.3 (C-10), 114.1 (C-50), 123.6 (C-10), 126.1 (C-20), 135.1

4048
J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
(C-60), 138.5 (C-30), 153.9 (C-40), 157.1 (C-9), 159.1 (C-2),
160.9 (C-5), 164.2 (C-7); C-3 and C-4 not detected. ESIMS
(K) m/z 408–406 [MKH]K. Compound 45. Light-yellow
crystals: mp: 256–259 8C (MeOH); 1H NMR (CDCl3) d 3.86
(s, 3H, OMe-7), 4.05 (s, 3H, OMe-40), 6.43 (s, 2H, H-6 and
H-8), 7.23 (d, JZ9 Hz, 1H, H-50), 8.13 (dd, JZ9, 2.1 Hz,
1H, H-60), 8.37 (d, JZ2.1 Hz, 1H, H-20), 12.24 (s, 1H, OH-
5). Compound 46. Amorphous; 1H NMR (CDCl3) d 4.05 (s,
3H, OMe-40), 5.10 (s, 2H, benzyl), 6.51 (s, 2H, H-6 and H-
8), 7.22 (d, JZ9 Hz, 1H, H-50),07.3–7.45 (m, 5H, benzyl),
8.11 (dd, JZ9, 2.1 Hz, 1H, H-6 ), 8.37 (d, JZ2.1 Hz, 1H,
H-20), 12.24 (s, 1H, OH-5).
(dd, JZ8.5, 2.1 Hz, 1H, H-60), 6.82 (d, JZ2.1 Hz, 1H, H-
20), 12.93 (s, 1H, OH-5). 13C NMR (CDCl3) d 55.4, 55.6 and
56.0 (OMe-7, 40, 300 and 500), 60.8 (OMe-400), 92.0 (C-8),
97.9 (C-6), 105.0 (C-10), 108.3 (C-200 and C-600), 109.4 (C-
50), 114.9 (C-20), 120.0 (C-3), 120.7 (C-600)0, 124.9 (C-100),
00
127.7 (C-1 ), 135.8 and 137.7 (C-30 and C-4 ), 148.8 (C-4 ),
00
153.2 (C-3 and C-500), 157.4 (C-9), 162.2 and 162.3 (C-2
and C-5), 165.5 (C-7), 181.3 (C-4). HRESIMS m/z 502.1491
(calcd for C26H25NO8Na, 502.1478), 480.1655 (calcd for
C26H26NO8, 480.1658). Compound 48. Dark-yellow crys-
tals: mp: 133–135 8C (MeOH); 1H NMR (DMSO-d6) d 3.63
(s, 6H, 0OMe-300 and 500), 3.68 (s, 3H, OMe-400), 3.75 (s, 3H,
OMe-4 ), 6.22 (d, JZ1.8 Hz, 1H, H-6), 6.40 (d, JZ1.8 Hz,
1H, H-8), 6.51 (s, 2H, H-200 and H-600), 6.502 (dd, JZ8.2,
2 Hz, 1H, H-60), 6.71 (d, JZ8.2 Hz, 1H, H-5 ), 6.88 (d, JZ
2 Hz, 1H, H-20), 13.01 (s, 1H, OH-5). 13C NMR (DMSO-d6)
4.2.4. Synthesis of 3-arylflavones analogues of 3.
4.2.4.1. 30-Nitro-3-(300,400,500-trimethoxyphenyl)acace-
tin 7-methyl ether 33. Prepared by Suzuki cross-coupling
from 55 mg (0.13 mmol) 45; reaction time 3 h; yield 77%
(51 mg). Light-yellow crystals: mp: 245–247 8C (MeOH);
1H NMR (CDCl3) d 3.76 (s, 6H, OMe-300 and 500), 3.88 (s,
3H, OMe-400), 3.91 (s, 3H, OMe-7), 3.97 (s, 3H, OMe-40),
6.40 (d, JZ2 Hz, 1H, H-6), 6.45 (s, 2H, H-200 and H-6000),
6.51 (d, JZ2 Hz, 1H, H-8), 6.92 (d, JZ9 Hz, 1H, H-5 ),
7.39 (dd, JZ9, 2.1 Hz, 1H, H-60), 8.17 (d, JZ2.1 Hz, 1H,
H-20), 12.70 (s, 1H, OH-5). 13C NMR (CDCl3) d 56.2 (OMe-
00
d 55.2 (OMe-40), 55.8 (OMe-300 and 500), 60.0 (OMe-4 ),
00
93.3 (C-8),098.7 (C-6), 103.2 (C-10), 108.7 (C-200 and C-6 ),
109.5 (C-5 ), 113.5 (C-20), 118.4 (C-60), 119.3 (C-3), 124.5
(C-100), 127.7 (C-100), 136.9 and 137.2 (C-30 and C-400), 147.8
(C-4 ), 152.4 (C-300 and C-500), 157.0 (C-9), 161.6 and 162.3
(C-2 and C-5), 164.2 (C-7), 180.5 (C-4). HRESIMS m/z
488.1309 (calcd for C25H23NO8Na, 488.1321), 466.1548
(calcd for C25H24NO8, 466.1502).
00
7), 56.7 (OMe-300 and 500), 57.1 (OMe-40), 60.6 (OMe-4 ),
00
92.9 (C-8),098.8 (C-6), 105.5 (C-10), 107.8 (C-200 and C-6 ),
4.3. Synthesis of analogues of the group B
112.3 (C-5 ), 121.1 (C-3), 124.9 (C-10), 126.2 (C-100), 127.0
(C-20), 135.7 (C-60), 138.3 (C-400), 139.1 (C-30), 153.8 (C-300
and C-500), 154.2 (C-40), 157.1 (C-9), 158.4 (C-2), 162.7
(C-5), 166.0 (C-7); C-4 not detected. HRESIMS m/z
532.1218 (calcd for C26H23NO10Na, 532.1220), 510.1406
(calcd for C26H24NO10, 510.1400).
4.3.1. Synthesis of 3-bromoflavones, intermediates for
3-arylflavones analogues of 1 and 2.
4.3.1.1. 30,40,50-Trimethoxyflavone 49; 3-bromo-
30,40,50-trimethoxyflavone 50. For the preparation, see
compounds 19 and 20. Compound 49. (735 mg, 79% from
3 mmol phosphorane). White crystals: mp: 172–174 8C
1
4.2.4.2. 30-Nitro-3-(300,400,500-trimethoxyphenyl)acace-
tin 7-benzyl ether 34. Prepared by Suzuki cross-coupling
from 60 mg (0.3 mmol) 46; reaction time 2.5 h; yield 84%
(59 mg). Pale-yellow crystals: mp: 16800 –171 8C (MeOH); 1H
NMR (CDCl3) d 3.76 (s, 6H, OMe-3 and 500), 3.88 (s, 3H,
OMe-400), 3.96 (s, 3H, OMe-40), 5.17 (s, 2H, benzyl), 6.45
(s, 2H, H-200 and H-600), 6.49 (d, JZ2 Hz, 1H, H-6), 6.58 (d,
JZ2 Hz, 1H, H-8), 6.92 0(d, JZ9 Hz, 1H, H-50), 7.35–7.45
(m, 6H, benzyl and H-6 ), 8.16 (d, JZ2.1 Hz, 1H, H-20),
12.70 (s, 1H, OH-50). 13C NMR (CDCl3) d 56.2 (OMe-300 and
500), 56.8 (OMe-4 ), 60.9 (OMe-400), 70.5 (benzyl), 93.1
(C-8), 99.2 (C-6), 105.2 (C-10), 1008.0 (C-200 and C-600),
113.0 (C-50), 121.4 (C-3), 124.6 (C-1 ), 126.5 (C-100), 1270.4
(C-20), 128.4, 128.7 and 128.900(5CH, benzyl), 135.2 (C-6 ),
135.6 (C, benzyl), 138.3 (C-4 ), 139.2 (C-30), 153.8 (C-300
and C-500), 154.1 (C-40), 157.3 (C-9), 158.4 (C-2), 162.4 (C-
5), 165.0 (C-7), 181.2 (C-4). HRESIMS m/z 586.1741 (calcd
for C32H28NO10, 586.1713).
(MeOH), lit.26 175 8C; H NMR (CDCl3) d 3.94 (s, 3H,
OMe-40), 3.96 (s, 6H, OMe-30 and 50), 6.77 (s, 1H, H-3),
7.14 (s, 2H, H-30 and H-50), 7.43 (t, JZ7.9 Hz, 1H, H-6),
7.58 (d, JZ8 Hz, 1H, H-8), 7.71 (m, 1H, H-7), 8.24 (d, JZ
7.9 Hz, 1H, H-5). Compound 50. (348 mg, 44% from
2 mmol 49). White crystals: mp: 158–159 8C (MeOH),
1
li0t.25b 155–156 8C; H NMR (CDCl3) d 3.94 (s, 3H, OMe-
4 ), 3.96 (s, 6H, OMe-30 and 50), 7.10 (s, 2H, H-30 and H-50),
7.49 (m, 2H, H-6 and H-8), 7.73 (t, JZ8.5 Hz, 1H, H-7),
8.30 (d, JZ7.8 Hz, 1H, H-5).
4.3.1.2. Tricetin 30,40,50-trimethyl ether 51; 3-bromo-
tricetin 30,40,50-trimethyl ether 52; 3-bromotricetin
7-benzyl-30,40,50-trimethyl ether 53. Flavone 51 was
prepared according Ref. 21 for bromination then benzyla-
tion to 52 and 53, see above 43/44/46. Compound 51.
(463 mg, 34% from 4 mmol phosphorane). Lemon-yellow
1
crystals: mp: 270–273 8C (MeOH), lit.27 277–278 8C; H
NMR (DMSO-d6) d 3.75 (s, 3H, OMe-40), 3.90 (s, 6H,
OMe-30 and 50), 6.22 (d, JZ2 Hz, 1H, H-6), 6.560 (d, JZ
20Hz, 1H, H-8), 7.04 (s, 1H, H-3), 7.32 (s, 2H, H-3 and H-
5 ), 10.81 (s, 1H, OH-7), 12.84 (s, 1H, OH-5). Compound
52. (296 mg, 59% from 1.2 mmol 51). Lemon-yellow
4.2.4.3. 30-Amino-3-(300,400,500-trimethoxyphenyl)aca-
cetin 7-methyl ether 47; 30-amino-3-(300,400,500-trimethoxy
phenyl)acacetin 48. Catalytic hydrogenation of 33 (31 mg,
0.06 mmol) and 34 (38 mg, 0.065 mmol) in DMF (Pd–C, rt,
3 h) provided, respectively, after filtration of the catalyst dry
residues of pure 47 (29 mg) and 48 (29 mg) in quantitative
yields. Compound 47. Dark-yellow crystals: mp: 225–
1
crystals: mp: 244–247 8C (MeOH); H NMR (DMSO-d6)
d 3.77 (s, 3H, OMe-40), 3.84 (s, 6H, OMe-30 and 50), 6.30 (d,
JZ2 Hz, 1H, 0H-6), 6.46 (d, JZ2 Hz, 1H, H-8), 7.17 (s, 2H,
H-30 and H-5 ), 11.01 (s, 1H, OH-7), 12.32 (s, 1H, OH-5).
Compound 53. (237 mg, 69% from 0.67 mmol 52). Pale-
yellow crystals: mp: 123–126 8C (MeOH); 1H NMR
(CDCl3) d 3.92 (s, 3H, OMe-40), 3.95 (s, 6H, OMe-30 and
1
227 8C (MeOH); H NMR (CDCl3) d 3.73 (s, 6H, OMe-300
00
and 500), 3.83, 3.85 and 3.86 (3s, 9H, OMe-7, 40 and 4 ), 6.36
00
(d, JZ2.2 Hz, 1H, H-6), 6.45 (s, 2H, H-200 and H-6 ), 6.45
0
(d, JZ2.2 Hz, 1H, H-8), 6.60 (d, JZ8.5 Hz, 1H, H-5 ), 6.70

J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
4049
50), 5.13 (s, 2H, benzyl), 6.51 (s, 2H, H-6 and H-8), 7.07 (s,
2H, H-30 and H-50), 7.35–7.45 (m, 5H, benzyl), 12.35 (s, 1H,
OH-5).
and H-60), 6.7–7.0 (m, 3H, H-200, H-500 and H-600), 7.2–7.5
(m, 10H, benzyls), 12.90 (s, 1H, OH-5).
4.3.2.4. Tricetin 7-benzyl-30,40,50-trimethyl ether 57.
1
4.3.2. Synthesis of 3-arylflavones analogues of 1 and 2.
Method (a) by Suzuki cross-coupling between a 3-bromo-
flavone and 4-methoxybenzeneboronic acid according
typical procedure.
Pale-yellow crystals: mp: 203–205 8C (MeOH); H NMR
(CDCl3) d 3.94 (s, 3H, OMe-40), 3.95 (s, 6H, OMe-30 and
50), 5.15 (s, 2H, benzyl), 6.48 (d, JZ2 Hz, 1H, H-6), 6.59 (d,
JZ2 Hz, 1H, H-8), 6.78 (s, 1H, H-3), 7.09 (s, 2H, H-30 and
H-50), 7.35–7.45 (m, 5H, benzyl), 12.72 (s, 1H, OH-5).
Method (b) by iron-catalysed Grignard coupling: to a
mixture of 3-bromoflavone (0.1 mmol) and Fe(acac)3
(6 mg, 0.015 mmol) in THF (4 mL) between K20 and
K30 8C under nitrogen was added arylmagnesium bromide
(0.2 mmol). The reaction mixture was stirred at the same
temperature for 3 h, then taken up in water and extracted
with CH2Cl2. Standard work-up then purification by FC
and/or TLC led to the expected 3-arylflavone.
4.3.2.5. 3-(400-Methoxyphenyl)tricetin 30,40,50-tri-
methyl ether 58; 3-(300-hydroxy-400-methoxyphenyl)tri-
cetin 30,40,50-trimethyl ether 59. Catalytic hydrogenation
of 55 (15 mg, 0.028 mmol) and 56 (15 mg, 0.023 mmol) in
THF (Pd–C, rt, 3 h) provided, respectively, after filtration of
the catalyst dry residues of pure 58 (12 mg) and 59 (10 mg)
in quantitative yields. Compound 58. Amorphous; 1H NMR
(DMSO-d6) d 3.56 (s, 6H, OMe-30 and 50), 3.66 (s, 3H,
OMe-40), 3.75 (s, 3H, OMe-400), 6.24 (d, JZ2.1 0Hz, 1H, H-
6), 6.49 (d, JZ2.1 Hz, 1H, H-8), 6.69 (s, 2H, H-2 and H-60),
6.93 (d, JZ8.6 Hz, 2H, H-300 and H-500), 7.13 (d, JZ8.6 Hz,
2H, H-200 and H-600), 10.89 (s, 1H, OH-7), 12.92 (s, 1H, OH-
4.3.2.1. 3-(400-Methoxyphenyl)-30,40,50-trimethoxyfla-
vone 54. Preparation by: method (a) (5.5 mg, 13% from
0.1 mmol 50); method (b) (7.5 mg, 18% from 0.1 mmol 50);
purification by FC (silica gel CH2Cl2/MeOH 98.5:1.5) and
1
13
TLC (alumina CH2Cl2/cyclohexane 1:1). Amorphous; H
5). C NMR (DMSO-d6) d 55.1 (OMe-400), 55.6 (OMe-30
NMR (CDCl3) d 3.65 (s, 6H, OMe-30 and 50), 3.80 (s, 3H,
OMe-400), 3.86 (s, 3H, OMe-40), 6.67 (s, 2H, H-20 and H-60),
6.89 (d, JZ8.6 Hz, 2H, H-300 and H-500), 7.18 (d, JZ8.6 Hz,
2H, H-200 and H-600), 7.43 (t, JZ7.9 Hz, 1H, H-6), 7.55 (d,
JZ8.4 Hz, 1H, H-8), 7.71 (m, 1H, H-7), 8.29 (d, JZ7.9 Hz,
1H, H-5). 13C NMR (CDCl3) d 55.3 (OMe-400), 56.0 (OMe-
3000 and 50), 60.9 (OMe-40), 107.3 (C-20 and C-60), 114.1 (C-
3 and C-500), 1170.09 (C-8), 122.2 (C-3), 123.5 (C-10), 125.0
(C-6), 125.5 (C-1 ), 126.4 (C-5), 128.2 (C-10), 132.1 (C-200
and C-600), 133.6 (C-7), 010 39.6 (C-40), 152.7 (C-30 and C-50),
155.9 (C-9), 159.1 (C-4 ), 160.7 (C-2), 177.6 (C-4). ESIMS
(C) m/z 441 [MCNa]C, 419 [MCH]C.
and 50), 60.00 (OMe-40), 93.8 (C-8),0098.8 (C-6), 103.3 (C-10),
107.2 (C-200 and C-60), 113.6 (C-3 and C-500), 119.8 (C-3),
124.1 (C-1 ), 127.2 (C-10), 132.1 (C-200 and C-600), 138.9 (C-
40), 152.1 (C-30 and C-50), 157.1 (C-9), 158.7 (C-400),
160.8 (C-2), 161.5 (C-5), 164.4 (C-7), 180.8 (C-4). ESIMS
(C) m/z 473 [MCNa]C, 451 [MCH]C. Compound 59.
1
Amorphous; H NMR (DMSO-d6) d 3.58 (s, 6H, OMe-30
and 50), 3.66 (s, 3H, OMe-40), 3.75 (s, 3H, OMe-400), 6.21 (d,
JZ2.1 Hz, 1H, H-6), 60.046 (d, JZ2.1 Hz, 1H, H-8), 6.58 (dd,
JZ8.2, 2 Hz, 1H, H-6 ), 6.64 (d, JZ2 Hz, 1H, H-200), 6.73
(s, 2H, H-20 and H-60), 6.90 (d, JZ8.2 Hz, 1H, H-500), 12.94
(s, 1H, OH-5). 13C NMR (DMSO-d6) d 55.5 (OMe-30, 50 and
400),060.0 (OMe-400)0 , 93.5 (C-8), 98.3 (C-6), 107.1 (C-20 and
C-6 ), 112.3 (C0-5 ), 118.5 (C-200), 121.9 (C-600), 124.8 (C-
100), 127.4 (C-1 ), 139.2 (C-40), 146.4 (C-300), 147.7 (C-400),
152.4 (C-30 and C-50), 161.0 (C-2); C-3, C-4, C-5, C-7, C-9
and C-10 not detected. ESIMS (C) m/z 489 [MCNa]C, 467
[MCH]C.
4.3.2.2. 3-(400-Methoxyphenyl)tricetin 7-benzyl-
30,40,50-trimethyl ether 55. Preparation by method (a);
purification by TLC (alumina CH2Cl2/MeOH 99:1); (23 mg,
21% from 0.2 mmol 53). White crystals: mp: 145–148 8C
(MeOH); 1H NMR (CDCl3) d 3.64 (s, 6H, OMe-30 and 50),
3.80 (s, 3H, OMe-400), 3.86 (s, 3H, OMe-40), 5.16 (s, 2H,
benzyl), 6.47 (d, JZ2.2 Hz, 1H, H-6), 6.56 (d, JZ2.2 Hz,
1H, H-8), 6.64 (s, 020 H, H-20 and H-60), 6.91 (d, JZ8.6 Hz,
2H, H-300 and H-5 ), 7.16 (d, JZ8.6 Hz, 2H, H-200 and H-
600), 7.3–7.45 (m, 5H, benzyl), 12.90 (s, 1H, OH-5). 13C
NMR (CDCl3) d 55.4 (OMe-400), 56.0 (OMe-30 and 50), 60.9
(OMe-40), 70.40 (benzyl)0, 93.2 (C-8), 090 8.8 (C-6), 105.3 (C-
10), 107.2 (C-2 and C-6 ), 114.3 (C-3 and C-500), 120.6 (C-
3), 124.3 (C-100), 127.5, 128.4 and 128.7 (benzyl), 132.1 (C-
200 and C-600), 135.8 (benzyl), 139.8 (C-40), 152.6 (C-30 and
C-50), 157.4 (C-9), 159.3 (C-400), 161.1 (C-5), 162.5 (C-2),
164.7 (C-7), 181.7 (C-4); C-10 not detected. ESIMS (C) m/z
563 [MCNa]C, 541 [MCH]C.
4.4. Synthesis of analogues of the groups C and D
4.4.1. One-pot access to keto-enols 60 and 61 by
esterification then Baker–Vankataraman rearrange-
ment.
4.4.1.1. 30,40,50-Trimethoxy-2-hydroxy-dibenzoyl-
methane 60 (mixture of keto-enol and b-diketone
tautomers 82/18); 40-methoxy-2-hydroxy-dibenzoyl-
methane 61. A solution of 20-hydroxyacetophenone
(1.36 g, 10 mmol) in dry pyridine (10 mL) at 0 8C under
nitrogen was added with the adequate aroyl chloride
(15 mmol), and the reaction mixture stirred for 2.5 h at rt.
Powdered dry KOH (1.68 g, 30 mmol) was added and the
reaction heated at 100 8C for 2 h, then same quantity of
KOH was added again and the mixture heated for a further
1 h. After cooling, the mixture was poured into water,
adjusted to pH 6 with 1 N HCl and extracted by CH2Cl2.
Standard work-up of the organic layer and crystallization in
MeOH provided the intermediates 60 (1.23 g, 37%) and 61
(925 mg, 34%). Compound 60. Lemon-yellow crystals: mp:
134–136 8C (MeOH), lit.26 136 8C; 1H NMR (CDCl3)
4.3.2.3. 3-(300-Benzyloxy-400-methoxyphenyl)tricetin
7-benzyl-30,40,50-trimethyl ether 56. Preparation by
method (b); purification by FC (silica gel CH2Cl2/MeOH
99:1) and TLC (silica gel cyclohexane/acetone 1:1); (15 mg,
1
12% from 0.2 mmol 53). Amorphous; H NMR (CDCl3) d
3.60 (s, 6H, OMe-30 and 50), 3.85 and 3.88 (2s, 6H, OMe-40
and 400), 5.03 and 5.16 (2s, 4H, benzyls), 6.48 (d, JZ2.2 Hz,
1H, H-6), 6.53 (d, JZ2.2 Hz, 1H, H-8), 6.57 (s, 2H, H-20

4050
J. Quintin et al. / Tetrahedron 62 (2006) 4038–4051
characteristic signals at d 4.70 (s, CH2) and 12.12 (s, phenol)
for the b-diketone form; at 6.84 (s, CH–C]O), 12.20 (s,
phenol) and 15.84 (s, enol) for the enol tautomer.
Compound 61. Lemon-yellow crystals: mp: 110–111 8C
114.1 (C-300 and C-500), 118.0 (C-8), 122.6 0(C-3), 123.3 (C-
10), 125.6 00(C-6), 126.1 (C-5), 126.7 (C-1 ), 130.4 (C-100),
131.8 (C-20 and C-600), 134.2 (C-7), 140.5 (C-40), 153.2 (C-
30 and C-5 ), 156.0 (C-9), 161.5 (C-2), 164.2 (C-400), 176.4
(C-4), 192.0 (C]O). ESIMS (C) m/z 915 [2MCNa]C, 469
[MCNa]C.
1
(MeOH), lit.26 114 8C; H NMR (CDCl3) d 3.90 (s, OMe-
40), 06.89 (d, H-3), 6.97 and 7.45 (m, H-4 and H-5), 6.98 (d,
H-3 and 50), 7.76 (d, H-6), 7.92 (d, H-20 and 60), 6.77 (s,
CH–C]O), 12.17 (s, phenol), 15.80 (s, enol).
Acknowledgements
4.4.2. Knoevenagel condensation to crude 3-aroylflava-
nones then dehydrogenation by SeO2 to 65, 66 and 67.
General procedure: compounds 60 or 61 (0.5 mmol) and
adequate aromatic aldehyde (0.55 mmol) were dissolved in
EtOH (5 mL) by heating under reflux. Piperidine (12 mg,
0.14 mmol) was then added, and the reaction stirred under
reflux for 5 h. The reaction mixture was evaporated to
dryness and used as it is in the following step. Fifth of the
dried residue and SeO2 (in equal weight) were stirred in
dioxane at reflux for 6 h under nitrogen. Reaction mixture
was filtered, and evaporated to dryness. Dry residue was
then purified by FC and crystallization.
´
We thank Dr. Daniel Guenard (ICSN-CNRS) for accurate
tubulin tests, Jean-Christophe Jullian for NMR measure-
ments and Andrew Pearson for proof reading.
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1
(MeOH); H NMR (CDCl3) d 3.81 (s, 9H, OMe-40, 300 and
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13
H-5).00 C NMR (CDCl3) d 55.4 (OMe-40), 56.3 (OMe-300
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30-Hydroxy-40-methoxy-3-(300,400,500-tri-
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1
98.5:1.5); (18 mg, 40% from 60). 00Amorphous; H NMR
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OMe-40 and 400), 6.78 (d, JZ8.5 Hz, 1H,00H-50), 7.16 (dd,
JZ8.5, 2.2 Hz, 1H, H-600), 7.19 (s, 2H, H-2 and H-600), 7.33
(d, JZ2.2 Hz, 1H, H-2 ), 7.45 (m, 1H, H-6), 7.58 (d, JZ
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