Diels-Alder adducts from flavonoid

Article abstract of DOI:10.1016/j.tetlet.2007.08.137

A quinoflavonoid was synthesized from commercially available products over three steps. The quinoflavonoid turned out to be an excellent dienophile in Diels-Alder reaction. Reactions were easily performed in dichloromethane, and after evaporation of the s

Full text of DOI:10.1016/j.tetlet.2007.08.137

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Tetrahedron Letters 48 (2007) 9056–9058
Diels–Alder adducts from flavonoid
Marie-France Laroche,a,b Arnaud Marchand,a Alain Duflosa,z and Georges Massiotb,*
aCentre de Recherche en Oncologie Expe´rimentale, Division Chimie Me´dicinale, Pierre Fabre Me´dicament,
ISTMT 3 rue des Satellites BP94244, 31432 Toulouse Cedex 4, France
bCentre de Recherche des Sustances Naturelles, UMS 2597 CNRS/Pierre Fabre, ISTMT 3 rue des Satellites BP94244,
31432 Toulouse Cedex 4, France
Received 19 July 2007; revised 21 August 2007; accepted 29 August 2007
Available online 18 October 2007
Abstract—A quinoflavonoid was synthesized from commercially available products over three steps. The quinoflavonoid turned out
to be an excellent dienophile in Diels–Alder reaction. Reactions were easily performed in dichloromethane, and after evaporation of
the solvent, expected products were obtained in good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
O
As a part of an ongoing screening program to find new
proteinfarnesyltransferase (PFTAse) inhibitors, we have
discovered a new series of meroterpene derivatives, of
which compound 1 is an example (Fig. 1).
O
O
O
O
O
R3
R1
R2
O
These compounds formally are Diels–Alder adducts of
labdane-dienes with a quinone derived from a flavonoid.
The originality of the structures and the hitherto rare
observation of quinoflavonoids prompted us to investi-
gate the total synthesis of such molecules. To know if
such a compound as 1 might be obtained from a
Diels–Alder reaction between a quinoflavonoid and a
diene, we have decided to evaluate this approach by
using a model reaction drawn in Scheme 1.
2
O
O
O
+
R2
O
O
R1
R3
O
O
3
O
Scheme 1. Retrosynthetic pathway.
O
O
O
O
HO
The synthesis of the target quinoflavonoid 3 is outlined
in Scheme 2. Esterification of the commercially available
2,4,5-trimethoxybenzoic acid 4 with dimethylsulfate in
the presence of potassium carbonate in acetone gave
the desired ester 5 in good yield (80%). Compound 5
was then reacted with ketone 6 in a Claisen-type conden-
sation reaction using LiHMDS as a base.1 After simple
extractive work-up, the diketone was directly used in the
next step without any further purification. The ring-
closure reaction was performed under acidic conditions
using 0.5% sulfuric acid in acetic acid to provide penta-
methoxyflavone 7 in good yield (83% over two steps).
OH
1
Figure 1. Meroterpene derivative.
Keywords: Diels–Alder reaction; Quinoflavonoid.
*
Corresponding author. Tel.: +33 534321402; fax: +33 534321414;
e-mail: georges.massiot@pierre-fabre.com
z Deceased on March, 20th 2006 during this research.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.137

M.-F. Laroche et al. / Tetrahedron Letters 48 (2007) 9056–9058
9057
Table 1. Synthesis of Diels–Alder adducts from quinoflavonoid 3
O
O
O
O
Entry Diene
Conditions
Product (yield %)
OH
O
a
b
O
OH
O
O
O
O
O
O
O
O
O
O
O
5
4
O
6
50 °C, 17 ha
O
1
O
O
10.0 equiv
8
O
O
(99)
O
O
O
O
proportion of regioisomer
83:17
c
O
O
O
O
O
O
O
7
3
O
O
O
O
O
Scheme 2. Synthesis of the quinoflavonoid 3. Reagents and conditions:
(a) Me2SO4, K2CO3, acetone, reflux, 80%; (b) (i) 6, LiHMDS 1 M
THF, anhydrous THF, argon; (ii) AcOH, H2SO4, reflux, 83% (for the
two steps); (c) AgO, HNO3 6 N, acetone, dioxane, rt, 24%.
2
rt, 22 h
O
4.4 equiv
9
(92)
Oxidative demethylation of 7 was carried out in a mix-
ture of acetone–1,4-dioxane 1:1 in the presence of AgO
and 6 N HNO3 at room temperature.2 The desired quino-
flavonoid 3 was finally obtained after silica gel column
chromatography in 24% yield.3,6
O
O
O
O
O
OSiMe3
3
rt, 92 h
O
O
OSiMe3
Quinoflavonoid 3 was then engaged in Diels–Alder reac-
tions with different dienes (Table 1). All the reactions
were performed in CH2Cl2. The progress of the reac-
tions was monitored by HPLC (disappearance of quino-
flavonoid 3). After completion of the reactions, the
volatiles were removed by evaporation under reduced
pressure to yield practically pure Diels–Alder adducts.
1.0 equiv
10
(93)
O
O
O
OSiMe3
O
O
The reaction with isoprene (entry 1) was initially per-
formed at room temperature with only 1 equiv of diene.
The reaction was not complete, even when further
amounts of isoprene were added during the reaction.
By using an ace pressure tube and heating at 50 °C, an
essentially quantitative yield of the expected product
was achieved. Thus, the reaction was repeated using
the conditions described in entry 1. This approach led
to compound 8 in an excellent yield.6 The NMR
spectrum indicated the presence of two regioisomers
differing in the position of the methyl group on the
carbon–carbon double bond. Structure of the major
product is represented in Table 1. In entry 2, the
Diels–Alder reaction was performed at room tempera-
ture with also an excess of 2,3-dimethylbutadiene and
in a very good yield. Indeed, the reaction was initially
started with 1 equiv of diene and 3.4 additional equiva-
lents were added over 22 h to complete the reaction.
Entries 3 and 4, with only 1 equiv of diene introduced,
showed that the mesomeric (+M) effect of the methoxy
group greatly increased the kinetics of the reaction. In
both cases, the NMR spectra indicated the presence of
only one regioisomer with good yields. However, with
the commercially available Danishefsky’s diene (entry
4),5 the NMR spectrum was contaminated by a small
amount of the ketone derivative that was initially
4
rt, 15 min
MeO
OMe
O
O
OSiMe3
1.0 equiv
11
(87)
O
O
O
O
O
5b
rt, 41 h
O
O
1.0 equiv
12
(88)
MeO2C
6
rt, eight
No reaction
days then
50 °C, 70 ha
1.0 equiv
a The reaction was conducted in an ace pressure tube.
b For synthesis of the diene, see Ref. 4

9058
M.-F. Laroche et al. / Tetrahedron Letters 48 (2007) 9056–9058
Compound 8: 1H NMR:
d 6.36 and 6.35 (d, 1H,
present in the starting material (10%). Even with 1 equiv
of a sterically hindered diene as used in entry 5, the
Diels–Alder reaction worked well and gave only one
regioisomer in a good yield. Finally, in entry 6 there
was no reaction with 1 equiv of the desactivated diene
methylsorbate. Even when the reaction was performed
in an ace tube pressure for three days, the HPLC indi-
cated that the two starting materials were still present.
J = 2.2 Hz), 6.16 (s, 1H), 5.93 (s, 1H), 5.40 (m, 1H), 3.93
and 3.82 (s, 3H, ArOMe), 3.86 (s, 3H, OMe of the quinone
part), 3.73 (dd, 1H, H at ring junction, J = 5.6 Hz), 2.74
and 2.45 (d, 1H, J = 18 Hz), 2.54 and 1.99 (dd, 1H, J = 18;
3.9 Hz), 1.67 (s, 3H); 13C NMR: d 195.4, 192.4, 176.9,
164.1, 163.1, 161.1, 160.9, 159.9, 132.0, 116.8, 112.8, 109.3,
108.9, 96.4, 92.4, 56.6, 56.4, 55.8, 55.7, 48.1, 30.0, 27.7, 23.1;
ESITOFMS (positive mode) m/z 843. 3056 [2M+Na]+,
433.1262 [M+Na]+ (calcd for C23H22NaO7 433.1258); IR
(diamond point): 2943, 1716, 1647, 1600, 1457, 1337, 1221,
In conclusion, we report a three step entry into a so far
little-known family of products, the quinoflavonoids
with 16% overall yield. Their Diels–Alder reaction with
a variety of dienophiles was performed in a very simple
procedure (CH2Cl2 as solvent, monitoring with HPLC,
evaporation of volatiles) and under mild conditions
(room temperature or 50 °C at maximum, neutral envi-
ronment, no catalyst). Expected products were obtained
in very good yields and with an excellent regioselectivity.
1
1202, 1159, 1098, 823. Compound 9: H NMR: d 6.36 and
6.34 (d, 1H, ArH, J = 2.25 Hz), 6.04 (s, 1H), 5.93 (s, 1H),
3.93 and 3.81 (s, 3H, ArOMe), 3.86 (s, 3H, OMe of the
quinone part), 3.66 (dd, 1H, H at ring junction, J = 5.9 Hz),
2.71 and 2.32 (d, 1H, J = 18.05 Hz), 2.52 and 2.03 (dd, 1H,
J = 18; 4.3 Hz), 1.67 and 1.62 (s, 3H); 13C NMR: d 195.2,
192.6, 176.9, 164.1, 163.4, 161.0, 160.9, 159.8, 123.6, 121.9,
112.4, 109.3, 108.9, 96.4, 92.4, 56.5, 56.4, 55.8, 55.7, 48.2,
35.7, 29.5, 18.7; ESITOFMS (positive mode) m/z 871.2944
[2M+Na]+, 447.1399 [M+Na]+ (calcd for C24H24NaO7
447.1414); IR (diamond point): 3087, 2844, 1713, 1655,
1601, 1457, 1421, 1334,1221, 1202, 1099, 845. Compound
Acknowledgment
1
10: H NMR: d 6.36 and 6.35 (d, 1H, J = 2.2 Hz), 6.21 (s,
1H), 5.94 (s, 1H), 4.82 (m, 1H), 3.93, 3.86 and 3.84 (s, 3H),
3.81 (m, 1H), 2.76–2.64 (dt, 2H, J = 17.8; 2 Hz), 2.54 (dd,
1H, J = 17.6; 3.2 Hz), 2.04 (dd, 1H, J = 18.5; 4.1 Hz), 0.18
(s, 9H); 13C NMR: d 195.4, 191.6, 176.8, 164.4, 164.1, 162.4,
161.2, 159.9, 129.0, 113.2, 109.9, 109.3, 99.3, 96.4, 92.5,
56.6, 56.5, 55.8, 55.7, 48.5, 28.9, 26.8, 0.3; ESITOFMS
(positive mode) m/z 507.1424 [M+Na]+ (calcd for
C25H28NaO8Si 507.1446); IR (diamond point): 2953,
1718, 1647, 1605, 1458, 1338, 1204, 1160, 1101, 843.
We wish to thank Pierre Fabre Medicament and the
CNRS for their support of this research.
References and notes
1. Nagarathnam, D.; Cushman, M. J. Org. Chem. 1991, 56,
4884–4887.
2. Parker, K. A.; Spero, D. M.; Koziski, K. A. J. Org. Chem.
1987, 52, 183–188.
Compound 11: 1H NMR:
d 6.36 and 6.35 (d,1H,
J = 2.0 Hz), 6.17 (s, 1H), 6.04 (s, 1H), 5.21 (d, 1H,
J = 5.5 Hz), 4.25 (d, 1H, J = 5.6 Hz), 3.93 (s, 3H), 3.86 (s,
6H), 3.74 (m, 1H), 3.14 (s, 3H), 3.03 (d, 1H, J = 18.3 Hz),
1.94 (dd, 1H, J = 18.7; 7.3 Hz), 0.21 (s, 9H); 13C NMR: d
195.1, 190.1, 176.5, 164.6, 164.1, 161.3, 160.9, 159.8, 153.6,
114.2, 111.8, 108.9, 100.4, 96.3, 92.5, 75.2, 59.7, 56.5, 55.8,
55.6, 46.2, 25.0, 0.2; ESITOFMS (positive mode) m/z
537.1551 [M+Na]+ (calcd for C26H30NaO9Si 537.1551); IR
(diamond point): 2963, 1719, 1653, 1604, 1458, 1334, 1204,
3. Compound 3 has already been synthesized and described
(mass, elemental analysis, and UV) in Ho¨rhammer, L.;
Wagner, H.; Ro¨sler, H.; Keckeisen, M.; Farkas, L. Tetra-
hedron 1965, 21, 969–975.
4. Desai, S. R.; Gore, V. K.; Mayelvaganan, T.; Padma-
kumar, R.; Bhat, S. V. Tetrahedron 1992, 48, 481–490.
5. Danishefsky’s diene was introduced in the following sem-
inal paper: Danishefsky, S. J.; Kitahara, T. J. Am. Chem.
Soc. 1974, 96, 7807–7808; The further development of this
diene motif is chartered in the following reviews: (a)
Danishefsky, S. Acc. Chem. Res. 1981, 14, 400–406; (b)
Danishefsky, S. Aldrichim. Acta 1986, 56–69.
1
1159, 1106, 844. Compound 12: H NMR: d 7.31–7.16 (m,
3H), 7.07 (d, 2H, J = 7.2 Hz), 6.36 and 6.34 (d, 1H,
J = 2.1 Hz), 6.16 (s, 1H), 6.01 (s, 1H), 5.29 (m, 1H), 3.92,
3.87 and 3.86 (s, 3H), 3.78 (m, 1H), 3.19–3.11 (m, 2H), 2.80
(dd, 1H, J = 13.5; 4.6 Hz), 2.45 (dd, 1H, J = 13.5; 9.5 Hz),
2.08 (m, 1H), 1.31 (s, 3H); 13C NMR: d 196.1, 192.7, 176.9,
164.1, 163.7, 163.0, 160.9, 159.8, 139.8, 135.3, 128.8, 128.4,
126.6, 119.8, 113.4, 112.6, 111.3, 96.3, 92.5, 60.7, 56.6, 56.4,
55.7, 46.5, 45.9, 38.6, 24.0, 20.7; ESITOFMS (positive
mode) m/z 523.1724 [M+Na]+ (calcd for C30H28NaO7
523.1727); IR (diamond point): 2943, 1713, 1648, 1601,
1455, 1331, 1219, 1157, 1101, 824, 700.
6. Physical and spectral data of compounds (3, 8–12): NMR
1
spectra were all run in CDCl3 at 500 MHz for H and at
1
125 MHz for 13C. Compound 3: H NMR: d 7.38 (s, 1H),
7.30 (s, 1H), 6.47 and 6.38 (d, 1H, J = 2.3 Hz), 6.05 (s, 1H),
3.96, 3.91 and 3.89 (s, 3H); 13C NMR: d 183.9, 181.5, 176.6,
164.6, 161.0, 159.6, 158.3, 152.0, 136.1, 131.9, 119.1, 109.3,
109.1, 96.4, 92.5, 56.3, 55.8; ESITOFMS (positive mode)
m/z 365.0625 [M+Na]+ (calcd for C18H14NaO7 365.0632).