Synthesis and structure of flavan-4-ols and 4-methoxyflavans as new potential anticancer drugs

Article abstract of DOI:10.1016/S0040-4020(00)00566-4

Reduction of a series of substituted flavanones afforded synthetic access to flavan-4-ols and was followed for some of them by an S(N)2-type acid-catalysis in methanol to provide 4-methoxyflavans. The stereochemistry of these compounds was established by ¹H and ¹³C NMR data. Flavan-4-ols and 4-methoxyflavans have been resolved into enantiomers which are being evaluated as anticancer drugs. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00566-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6047±6052
Synthesis and Structure of Flavan-4-ols and 4-Methoxy¯avans as
New Potential Anticancer Drugs
Christelle Pouget,a Catherine Fagnere,a Jean-Philippe Basly,a Hubert Levequeb
a,
*
Â
and Albert-Jose Chulia
a
 Â
UPRES EA 1085 `Biomolecules et cibles cellulaires tumorales', Faculte de Pharmacie, 2 rue du Docteur Marcland,
87025 Limoges cedex, France
b
 Á
CHIRALSEP, Parc d'Activites de la Boissiere, 76170 La Frenaye, France
Received 13 January 2000; revised 25 May 2000; accepted 26 June 2000
AbstractÐReduction of a series of substituted ¯avanones afforded synthetic access to ¯avan-4-ols and was followed for some of them by an
SN2-type acid-catalysis in methanol to provide 4-methoxy¯avans. The stereochemistry of these compounds was established by 1H and 13
NMR data. Flavan-4-ols and 4-methoxy¯avans have been resolved into enantiomers which are being evaluated as anticancer drugs. q 2000
C
Elsevier Science Ltd. All rights reserved.
Introduction
for anticancer properties, appears to be an unexplored ®eld.
The aim of the present investigation was to prepare a
number of such prototypic molecules in order to evaluate
their cytotoxic and inhibitory activities.
There is now overwhelming evidence from epidemiological
studies that a high consumption of fruits and vegetables is
consistently associated with a low incidence of many types
of cancer. This may be relevant in hormone-dependent
cancers with considerable variations in incidence in differ-
ent countries. Among compounds of known structure, ¯avo-
noids deserve special attention because they are present in
practically all dietary plants, fruits and roots and are
consumed daily in considerable amounts. Additionally,
¯avonoids have been shown to exert a wide variety of
health-protective physiological and biological properties.1,2
Support for a role of certain ¯avonoids in breast cancer
prevention is derived from several observations: ®rst, they
were found to inhibit the growth of established cancer cell
lines derived from human breast tumors;3 then, earlier
studies have shown that some ¯avones and ¯avanones
(particularly 5 and 7-substituted)4 are able to inhibit cyto-
chrome P450 aromatase4±6 and 17b-hydroxysteroid dehy-
drogenase,4,7 two enzymes responsible for the synthesis of
estrogens, resulting in a decrease in the level of estrogen in
women.
Results and Discussion
The route adopted to the synthesis of ¯avan-4-ols and 4-
methoxy¯avans is outlined in Scheme 1. Reduction of the
¯avanones 1, 2, 3 and 4 was performed with sodium boro-
hydride to give the corresponding ¯avan-4-ols 5, 6, 7, 8, 9
and 10 and, except for 7-hydroxy¯avanone 1, weak amounts
of the corresponding ¯av-3-enes 11, 12, 13. Flav-3-enes are
conveniently obtained in one step by NaBH4 reduction of 20-
hydroxychalcones whose chemical equilibrium with ¯ava-
nones is well known.10 However, in our study, the formation
of these ¯av-3-enes occurred after acidi®cation of the reac-
tion mixture and evaporation. Therefore, we interpreted this
formation as arising from an intramolecular dehydration of
the ¯avan-4-ols. This hypothesis was con®rmed since acid-
i®cation and heating of 6 in CHCl3 led to the compound 11.
We exploited the reactivity of ¯avan-4-ols to synthesize
compounds which belong to a rare class of natural
products9: thus, compounds 5 and 6 were subjected to the
action of methanol and HCl and afforded the corresponding
4-methoxy¯avans 14 and 15.
8
Wahala and coworkers showed that the cis- and trans-4 ,7-
0
È È È
dihydroxyiso¯avan-4-ols, identi®ed as metabolites of daid-
zein, were potent inhibitors of the growth of prostate cancer
cells in culture. However, the synthesis of ¯avan-4-ols and
4-methoxy¯avans, which are of a rare occurrence in nature,9
The assignment of stereochemistry to these ¯avan-4-ols and
4-methoxy¯avans is readily made on the basis of the vicinal
coupling constants. The key signals and the associated
Keywords: ¯avonoids; reduction; NMR; stereochemistry.
* Corresponding author. Tel.: 133-555-435-834; fax: 133-555-435-910;
e-mail: jose.chulia@unilim.fr
1
coupling constants in the H NMR spectra of the ¯avan-4-
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00566-4

6048
C. Pouget et al. / Tetrahedron 56 (2000) 6047±6052
Scheme 1.
ols and 4-methoxy¯avans are given in Table 1. The hetero-
cyclic ring protons of these compounds have ABXY-type
spectra in which JXYˆ0 Hz (the 3eq, 3ax, 2 and 4 protons are
labeled A, B, X and Y).
on the sum J4,3ax1J4,3eq. The sum of the coupling constants
of C(4) H to its two neighbors at C(3) for compounds 8 and
10 is 6.0 Hz which is characteristic for a trans arrangement
while the sum for compounds 5, 6, 7 and 9 is between 16.5
and 17.3 Hz which is characteristic for a cis arrangement.9
As to the 4-methoxy¯avans 14 and 15, the sum J4,3ax1J4,3eq
which is 5.5 Hz allows to determine a trans relative con®g-
uration of these compounds.
The coupling constants are fully compatible with either the
half-chair (a) or sofa (b) conformation of the heterocyclic
ring in which the 2-aryl group is in the equatorial position
(Scheme 2).11
All 13C NMR signals could be assigned by the C±H COSY
and long-range C±H COSY techniques and are in agree-
ment with values found in the literature (see Table 2).14
The spectra of the cis and trans isomers are very similar,
the only notable difference being in the chemical shifts of C-
2. In the trans-¯avan-4-ols, this carbon (at d 73.0 ppm) is
shifted up®eld from the corresponding carbon (at d
77.0 ppm) in the cis isomers. This up®eld shift is evidently
due to the g-gauche effect of the axial hydroxyl in the trans
isomers. The C-4 resonances for compounds 7, 8, 9 and 10
are shielded for the presence of the 5-methoxy group.
Assignment of the axial proton at C-3 as the high-®eld
proton of the H-3eq, H-3ax pair agrees with results obtained
in cyclohexanes.12,13 Then, the value of J2,3ax for these
compounds is so large that it can only arise from a trans-
diaxial coupling: thus, H-2 is axial and the 2-phenyl group is
equatorial. In the case of the compounds 5, 6, 7 and 9, the
large value J4,3ax requires H-4 to be quasi-axial. Therefore,
these products have the 2,4-cis structure with both substitu-
ents occupying equatorial positions. In the case of the
compounds 8 and 10, the lower value of J4,3ax means that
H-4 is in a quasi-equatorial position. Thus, these two
products have the 2,4-trans structure with the 4-hydroxyl
group in a pseudo-axial position. Con®rmation of stereo-
chemical analysis of 4-substituted ¯avans spectra is based
NaBH4 reduction of 7-hydroxy¯avanone 1 and 7-methoxy-
¯avanone 2 is stereoselective since it leads respectively to
the 2,4-cis-7-hydroxy¯avan-4-ol 5 and the 2,4-cis-7-
Table 1. Selected 1H NMR data on ¯avan-4-ols and 4-methoxy¯avans
d H-3ax
d H-3eq
d H-4
d H-2
J3ax±3eq
J2±3ax
J2±3eq
J4±3ax
J4±3eq
J4±3ax1J4±3eq
5
6
14
15
7
8
9
10
2.10
2.13
2.02
2.04
2.27
2.06
2.24
2.04
2.51
2.52
2.34
2.36
2.54
2.30
2.51
2.27
5.04
5.05
4.25
4.27
5.32
5.05
5.26
5.00
5.16
5.17
5.25
5.28
5.04
5.15
5.03
5.16
13.1
13.2
14.4
14.3
13.2
14.4
13.4
14.5
11.2
11.4
12.1
12.2
12.1
12.0
11.9
12.4
1.9
2.0
1.9
2.2
1.7
1.7
1.8
1.6
10.3
10.2
3.2
3.2
10.1
4.1
6.2
6.3
2.3
2.3
7.2
1.9
7.2
1.9
16.5
16.5
5.5
5.5
17.3
6.0
9.8
4.1
17.0
6.0

C. Pouget et al. / Tetrahedron 56 (2000) 6047±6052
6049
Scheme 2.
methoxy¯avan-4-ol 6. The hydride attack on the opposite
side from the phenyl group is responsible for this stereo-
chemistry.
compounds exist as a (1:1) mixture of two optical isomers:
2R,4R and 2S,4S for cis-compounds, 2R,4S and 2S,4R for
trans-compounds. Once preparative separation of the
compounds 5±10 and 14±15 into enantiomers is carried
out, they will be tested for their antiproliferative and aroma-
tase inhibitory properties. Detailed biochemical results will
be reported elsewhere.
Reduction of the 4-keto group of the 5-methoxy¯avanone 3
afforded a mixture of 2,4-cis-5-methoxy¯avan-4-ol 7 and
2,4-trans-5-methoxy¯avan-4-ol 8 in a 70:30 ratio. In the
same way, reduction of 5,7-dimethoxy¯avanone 4 led to
the 2,4-cis-5,7-dimethoxy¯avan-4-ol 9 and 2,4-trans-5,7-
dimethoxy¯avan-4-ol 10 in a 75:25 ratio. We interpreted
the formation of the two isomers cis and trans as arising
from the presence of a 5-methoxy group which creates a
steric hindrance decreasing the facial discrimination due
to the phenyl group.
Experimental
NMR spectra were recorded on a Bruker 400 MHz spectro-
meter with Me4Si as internal standard. High resolution mass
spectra were obtained with a VG AUTOSPEC instrument
using EI ionization at 70 eV and ESP-MS spectra were
performed on a Waters Alliance system equipped with an
API-MS interface. IR spectra were recorded in CH2Cl2 with
a Satellite Mattson FT-IR spectrophotometer and UV with a
930 UVIKON spectrophotometer. Enantiomeric separation
of ¯avan-4-ols was carried out using CHIROSE C1w no.
9604/3202, 5 mm, 250£4.6 mm2 (CHIRALSEP) as a chiral
stationary phase. The ¯ow-rate of the mobile phase (hexane/
i-PrOH) was 1 ml/min. 7-Hydroxy¯avanone was obtained
from Indo®ne Chemical Company; 7-methoxy¯avanone
and 5-methoxy¯avanone were purchased from Sigma
Aldrich while 5,7-dimethoxy¯avanone was obtained from
Lancaster Synthesis.
The 2,4-cis-7-hydroxy¯avan-4-ol 5 and 2,4-cis-7-methoxy-
¯avan-4-ol 6, through the action of methanol and HCl led to
the 2,4-trans-7-hydroxy-4-methoxy¯avan 14 and 2,4-trans-
4,7-dimethoxy¯avan 15 respectively. Inversion of con®g-
uration involves an acidic catalyzed SN2 reaction in which
methanol acts as nucleophile.
The convenient synthesis described here uses moderately
cheap reagents and affords two series of compounds, the
¯avan-4-ols and the 4-methoxy¯avans, which are of a rare
occurrence in nature. Flav-3-enes were also identi®ed as by-
products but they were not further investigated in view of
their instability. Reduction, which was performed on race-
mic ¯avanones, was expected to afford ¯avan-4-ols as race-
mates. Direct enantiomeric separation of the ¯avan-4-ols
and 4-methoxy¯avans has been achieved by HPLC using
an analytical column (CHIROSE C1w) as a chiral stationary
phase. Chromatographic results indicate that these
2,4-cis-7-Hydroxy¯avan-4-ol 5. To a stirred solution of 7-
hydroxy¯avanone 1 (70 mg, 2.9£1024 mol) in ethanol
(30 ml) at room temperature, was added 210 mg of
NaBH4 (5.7£1023 mol). The reaction was monitored by
TLC on silica gel (hexane±ethyl acetate, 7:3) and after
three days, the reaction mixture was diluted with H2O
(30 ml), acidi®ed with aqueous HCl (pH 6) and extracted
with Et2O (3£30 ml). The combined ethereal extracts were
dried over anhydrous MgSO4, ®ltered and concentrated.
Puri®cation via preparative TLC on silica gel (hexane±
ethyl acetate, 7:3) afforded 5 (26.6 mg, 38%). Rf 0.13 (hex-
ane±ethyl acetate, 7:3); lmax (MeOH)/nm 219, 282; nmax
(CH2Cl2) cm21: 3221, 1619, 1596; dH (400 MHz; CDCl3)
2.10 (1H, ddd, J3ax,3eqˆ13.1 Hz, J3ax,2ˆ11.2 Hz,
Table 2. Selected 13C NMR data on ¯avan-4-ols
5
6
7
9
cisa
transa
8
10
C-2
C-3
C-4
77.1
40.2
65.6
77.1
40.2
65.5
77.0
37.8
63.7
77.3
37.9
63.4
76.9
40.2
65.9
73.0
38.2
63.8
73.3
37.6
59.5
73.7
37.6
59.3
a From Ref. 13.

6050
C. Pouget et al. / Tetrahedron 56 (2000) 6047±6052
J3ax,4ˆ10.3 Hz, 3ax-H), 2.51 (1H, ddd, J3eq,3axˆ13.2 Hz,
J3eq,4ˆ6.2 Hz, J3eq,2ˆ1.9 Hz, 3eq-H), 5.04 (1H, dd,
J4,3axˆ10.0 Hz, J4,3eqˆ6.2 Hz, 4-H), 5.16 (1H, dd,
J2,3axˆ11.2 Hz, J2,3eqˆ1.7 Hz, 2-H), 6.38 (1H, d,
J8,6ˆ2.4 Hz, 8-H), 6.49 (1H, dd, J6,5ˆ8.4 Hz, J6,8ˆ2.4 Hz,
6-H), 7.37 (1H, d, J5,6ˆ8.6 Hz, 5-H), 7.34±7.45 (5H, m,
Ph); dC (100 MHz; CDCl3) 40.2 (CH2, C-3), 65.6 (CH, C-
4), 77.1 (CH, C-2), 103.2 (CH, C-8), 108.7 (CH, C-6), 118.5
(Cq, C-4a), 126.0 (2£CH, C-20 and C-60), 128.3 (2£CH, C-
40 and C-5), 128.6 (2£CH, C-30 and C-50), 140.4 (Cq, C-10),
155.6 (Cq, C-8a), 156.3 (Cq, C-7); m/z (EI), M1 242,
(Found: M1, 242.0938. C15H14O3 requires M, 242.0943).
20and C-60), 127.7 (CH, C-40), 128.2 (CH, C-5), 128.6
(2£CH, C-30 and C-50), 140.4 (Cq, C-10), 155.5 (Cq, C-
8a), 160.5 (Cq, C-7); m/z (EI), M1 256, (Found: M1,
256.1104. C16H16O3 requires M, 256.1099).
7-Methoxy¯av-3-ene 11. Rf 0.88 (toluene±Et2O, 8:2); lmax
(MeOH)/nm 280, 305; dH (400 MHz; CDCl3) 3.75 (3H, s, 7-
OCH3), 5.66 (1H, dd, J3,4ˆ9.8 Hz, J3,2ˆ3.4 Hz, 3-H), 5.88
(1H, dd, J2,3ˆ3.1 Hz, J2,4ˆ2.0 Hz, 2-H), 6.38 (1H, d,
J8,6ˆ2.4 Hz, 8-H), 6.43 (1H, dd, J6,5ˆ8.2 Hz, J6,8ˆ2.5 Hz,
6-H), 6.49 (1H, dd, J4,3ˆ9.8 Hz, J4,2ˆ1.9 Hz, 4-H), 6.92
(1H, d, J5,6ˆ8.2 Hz, 5-H), 7.34±7.45 (5H, m, Ph); dC
(100 MHz; CDCl3) 55.3 (OCH3), 77.1 (CH, C-2), 101.8
(CH, C-8), 107.0 (CH, C-6), 114.7 (Cq, C-4a), 121,9 (CH,
C-3), 123.7 (CH, C-4), 127.1 (2£CH, C-20 and C-60), 127.3
(CH, C-5), 128.4 (CH, C-40), 128.6 (2£CH, C-30 and C-50),
140.9 (Cq, C-10), 154.4 (Cq, C-8a), 160.9 (Cq, C-7).
2,4-trans-7-Hydroxy-4-methoxy¯avan 14. To a stirred
solution of 2,4-cis-7-hydroxy¯avan-4-ol
5
(15 mg,
6.2£1025 mol) in methanol (15 ml), was added 2 M HCl.
The reaction mixture was heated at 408C for 5 min, then
diluted with H2O (30 ml) and extracted with Et2O
(3£30 ml). The combined ethereal extracts were dried
over anhydrous MgSO4, ®ltered and concentrated. Puri®ca-
tion via preparative TLC on silica gel (hexane±ethyl ace-
tate, 7:3) afforded 14 (12 mg, 76%). Rf 0.39 (hexane±ethyl
acetate, 7:3); lmax (MeOH)/nm 227, 280, 286; nmax
(CH2Cl2) cm21: 3324, 1619; dH (400 MHz; CDCl3) 2.02
(1H, ddd, J3ax,3eqˆ14.4 Hz, J3ax,2ˆ12.3 Hz, J3ax,4ˆ3.2 Hz,
3ax-H), 2.34 (1H, br dt, J3eq,3axˆ14.3 Hz, Jˆ2.3 Hz, 3eq-
H), 3.45 (3H, s, 4-OCH3), 4.25 (1H, br t, Jˆ2.8 Hz, 4-H),
5.25 (1H, dd, J2,3axˆ12.1 Hz, J2,3eqˆ1.9 Hz, 2-H), 6.41 (1H,
d, J8,6ˆ2.5 Hz, 8-H), 6.44 (1H, dd, J6,5ˆ8.2 Hz,
J6,8ˆ2.5 Hz, 6-H), 7.13 (1H, d, J5,6ˆ8.2 Hz, 5-H), 7.34
(1H, m, 40-H), 7.40 (2H, m, 30-H and 50-H), 7.46 (2H, m,
20-H and 60-H); dC (100 MHz; CDCl3) 35.2 (CH2, C-3), 55.8
(OCH3), 72.3 (CH, C-4), 73.4 (CH, C-2), 103.5 (CH, C-8),
108.0 (CH, C-6), 113.5 (Cq, C-4a), 126.3 (2£CH, C-20 and
C-60), 128.1 (CH, C-40), 128.6 (2£CH, C-30 and C-50),
132.0 (CH, C-5), 141.1 (Cq, C-10), 156.2 (Cq, C-8a),
157.1 (Cq, C-7); m/z (EI), M1 256, (Found: M1,
256.1103. C16H16O3 requires M, 256.1099).
2,4-trans-4,7-Dimethoxy¯avan 15. To a stirred solution of
2,4-cis-7-methoxy¯avan-4-ol 6 (20 mg, 7.9£1025 mol) in
methanol (10 ml), was added 2 M HCl. The reaction
mixture was heated at 408C for 5 min, then diluted with
H2O (30 ml) and extracted with Et2O (3£30 ml). The
combined ethereal extracts were dried over anhydrous
MgSO4, ®ltered and concentrated. Puri®cation via prepara-
tive TLC on silica gel (upper phase of toluene±Et2O±H2O
10% AcOH, 50:50:50) afforded 15 (17 mg, 80%). Rf 0.75
(upper phase of toluene±Et2O±H2O 10% AcOH, 50:50:50);
lmax (MeOH)/nm 233, 279; nmax (CH2Cl2) cm21: 1617,
1581; dH (400 MHz; CDCl3) 2.04 (1H, ddd,
J3ax,3eqˆ14.3 Hz, J3ax,2ˆ12.1 Hz, J3ax,4ˆ3.2 Hz, 3ax-H),
2.36 (1H, br dt, J3eq,3axˆ14.2 Hz, Jˆ2.3 Hz, 3eq-H), 3.47
(3H, s, 4-OCH3), 3.78 (3H, s, 7-OCH3), 4.27 (1H, br t,
Jˆ2.8 Hz, 4-H), 5.28 (1H, dd, J2,3axˆ12.2 Hz,
J2,3eqˆ2.2 Hz, 2-H), 6.52 (1H, d, J8,6ˆ2.5 Hz, 8-H), 6.54
(1H, dd, J6,5ˆ8.0 Hz, J6,8ˆ2.5 Hz, 6-H), 7.19 (1H, d,
J5,6ˆ8.0 Hz, 5-H), 7.34±7,50 (5H, m, Ph); dC (100 MHz;
CDCl3) 35.2 (CH2, C-3), 55.3 (OCH3), 55.7 (OCH3), 72.3
(CH, C-4), 73.5 (CH, C-2), 101.4 (CH, C-8), 107.5 (CH, C-
6), 113.3 (Cq, C-4a), 126.3 (2£CH, C-20 and C-60), 128.0
(CH, C-40), 128.5 (2£CH, C-30 and C-50), 131.6 (CH, C-5),
141.2 (Cq, C-10), 156.1 (Cq, C-8a), 161.0 (Cq, C-7); m/z
(EI), M1 270, (Found: M1, 270.1256. C17H18O3 requires M,
270.1256).
2,4-cis-7-Methoxy¯avan-4-ol 6 and 7-methoxy¯av-3-ene
11. To a stirred solution of 7-methoxy¯avanone 2 (100 mg,
4£1024 mol) in ethanol (30 ml) at room temperature, was
added 76 mg of NaBH4 (2£1023 mol). The reaction was
monitored by TLC on silica gel (toluene±Et2O, 8:2) and
after 4 h, the reaction mixture was diluted with H2O
(50 ml), acidi®ed with aqueous HCl (pH 4) and extracted
with Et2O (3£30 ml). The combined ethereal extracts were
dried over anhydrous MgSO4, ®ltered and concentrated.
Puri®cation via preparative TLC on silica gel (toluene±
Et2O, 8:2) afforded 6 (60 mg, 59%) and 11 (6 mg, 6%).
2,4-cis and 2,4-trans-5-Methoxy¯avan-4-ols 7 and 8, 5-
methoxy¯av-3-ene 12. To a stirred solution of 5-methoxy-
¯avanone 3 (50 mg, 2£1024 mol) in ethanol (30 ml) at room
temperature, was added 38 mg of NaBH4 (1023 mol). The
reaction was monitored by TLC on silica gel (toluene±Et2O,
9:1) and after 2 h, the reaction mixture was diluted with H2O
(30 ml), acidi®ed with aqueous AcOH (pH 5) and extracted
with Et2O (3£30 ml). The combined ethereal extracts were
dried over anhydrous MgSO4, ®ltered and concentrated.
Puri®cation via preparative TLC on silica gel (toluene±
Et2O, 9:1) afforded 7 (20 mg, 39%), 8 (8.2 mg, 16%) and
12 (1.5 mg, 3%).
2,4-cis-7-Methoxy¯avan-4-ol 6. Rf 0.37 (toluene±Et2O,
:
8:2); lmax (MeOH)/nm 229, 282; nmax (CH2Cl2) cm21
3226, 1619, 1580; dH (400 MHz; CDCl3) 2.13 (1H, ddd,
J3ax,3eqˆ13.2 Hz, J3ax,2ˆ11.4 Hz, J3ax,4ˆ10.2 Hz, 3ax-H),
2.52
(1H,
ddd,
J3ax,3eqˆ13.2 Hz,
J3eq,4ˆ6.3 Hz,
J3eq,2ˆ2.0 Hz, 3eq-H), 3.78 (3H, s, 7-OCH3), 5.05 (1H, br
s, 4-H), 5.17 (1H, dd, J2,3axˆ11.4 Hz, J2,3eqˆ2.0 Hz, 2-H),
6.46 (1H, d, J8,6ˆ2.5 Hz, 8-H), 6.59 (1H, dd, J6,5ˆ8.6 Hz,
J6,8ˆ2.5 Hz, 6-H), 7.36 (1H, d, J5,6ˆ8.6 Hz, 5-H), 7.34±
7.45 (5H, m, Ph); dC (100 MHz; CDCl3) 40.2 (CH2, C-3),
55.3 (OCH3), 65.5 (CH, C-4), 77.1 (CH, C-2), 101.1 (CH, C-
8), 108.1 (CH, C-6), 118.1 (Cq, C-4a), 126.0 (2£CH, C-
2,4-cis-5-Methoxy¯avan-4-ol 7. Rf 0.41 (toluene±Et2O,
:
9:1); lmax (MeOH)/nm 232, 277; nmax (CH2Cl2) cm21
3552, 1590, 1470; dH (400 MHz; CDCl3) 2.27 (1H, ddd,
J3ax,3eqˆ13.2 Hz, J3ax,2ˆ12.1 Hz, J3ax,4ˆ10.1 Hz, 3ax-H),
2.54
(1H,
ddd,
J3eq,3axˆ13.5 Hz,
J3eq,4ˆ7.2 Hz,

C. Pouget et al. / Tetrahedron 56 (2000) 6047±6052
6051
J3eq,2ˆ1.7 Hz, 3eq-H), 3.91 (3H, s, 5-OCH3), 4.07 (1H, br s,
4-OH), 5.04 (1H, dd, J2,3axˆ11.9 Hz, J2,3eqˆ1.1 Hz, 2-H),
5.32 (1H, br t, Jˆ8.6 Hz, 4-H), 6.51 (1H, d, J6,7ˆ8.2 Hz,
6-H), 6.59 (1H, d, J8,7ˆ8.3 Hz, 8-H), 7.14 (1H, t, J7,6 and
J7,8ˆ8.3 Hz, 7-H), 7.34 (1H, m, 40-H), 7.40 (2H, m, 30-H
and 50-H), 7.46 (2H, m, 20-H and 60-H); dC (100 MHz;
CDCl3) 37.8 (CH2, C-3), 55.7 (OCH3), 63.7 (CH, C-4),
77.0 (CH, C-2), 102.8 (CH, C-6), 110.6 (CH, C-8), 114.4
(Cq, C-4a), 126.3 (2£CH, C-20 and C-60), 128.2 (CH, C-40),
128.6 (2£CH, C-30 and C-50), 129.0 (CH, C-7), 140.4 (Cq,
C-10), 156.0 (Cq, C-8a), 158.6 (Cq, C-5); m/z (EI), M1 256,
(Found: M1, 256.1095. C16H16O3 requires M, 256.1099).
(OCH3), 63.4 (CH, C-4), 77.3 (CH, C-2), 92.4 (CH, C-6),
93.9 (CH, C-8), 107.2 (Cq, C-4a), 126.3 (2£CH, C-20 and C-
60), 128.2 (CH, C-40), 128.6 (2£CH, C-30 and C-50), 140.3
(Cq, C-10), 156.6 (Cq, C-8a), 159.3 (Cq, C-5), 160.7 (Cq, C-
7); ESP-(40V) m/z, [M2H]2 285 (Found [M2H]2,
284.8227, C17H18O4 requires [M2H]2, 285.1132).
2,4-trans-5,7-Dimethoxy¯avan-4-ol 10. Rf 0.20 (toluene±
:
Et2O, 9:1); lmax (MeOH)/nm 234, 277; nmax (CH2Cl2) cm21
3575, 1615, 1591; dH (400 MHz; CDCl3) 2.04 (1H, ddd,
J3ax,3eqˆ14.6 Hz, J3ax,2ˆ12.4 Hz, J3ax,4ˆ4.1 Hz, 3ax-H),
2.27 (1H, br dt, J3eq,3axˆ14.4 Hz, Jˆ1.9 Hz, 3eq-H), 2.50
(1H, br s, 4-OH), 3.77 (3H, s, OCH3), 3.87 (3H, s, OCH3),
5.00 (1H, m, 4-H), 5.16 (1H, dd, J2,3axˆ12.2 Hz,
J2,3eqˆ1.6 Hz, 2-H), 6.12 (1H, d, J6,8ˆ2.2 Hz, 6-H), 6.16
(1H, d, J8,6ˆ2.2 Hz, 8-H), 7.34 (1H, m, 40-H), 7.40 (2H,
m, 30-H and 50-H), 7.48 (2H, m, 20-H and 60-H); dC
(100 MHz; CDCl3) 37.6 (CH2, C-3), 55.4 (OCH3), 55.6
(OCH3), 59.3 (CH, C-4), 73.7 (CH, C-2), 91.8 (CH, C-6),
93.4 (CH, C-8), 106.1 (Cq, C-4a), 126.3 (2£CH, C-20 and C-
60), 128.0 (CH, C-40), 128.6 (2£CH, C-30 and C-50), 140.9
(Cq, C-10), 156.4 (Cq, C-8a), 159.3 (Cq, C-5), 161.2 (Cq, C-
7); m/z (EI), M1 286, (Found: M1, 286.1203. C17H18O4
requires M, 286.1205).
2,4-trans-5-Methoxy¯avan-4-ol 8. Rf 0.32 (toluene±Et2O,
9:1); lmax (MeOH)/nm 229, 277; nmax (CH2Cl2) cm21: 3575,
1597, 1470; dH (400 MHz; CDCl3) 2.06 (1H, ddd,
J3ax,3eqˆ14.4 Hz, J3ax,2ˆ12.0 Hz, J3ax,4ˆ4.1 Hz, 3ax-H),
2.30 (1H, br dt, J3eq,3axˆ14.4 Hz, Jˆ1.9 Hz, 3eq-H), 2.66
(1H, br s, 4-OH), 3.91 (3H, s, 5-OCH3), 5.05 (1H, m, 4-
H), 5.15 (1H, dd, J2,3ax 12.0, J2,3eqˆ1.7 Hz, 2-H), 6.51 (1H,
d, J6,7ˆ8.2 Hz, 6-H), 6.63 (1H, d, J8,7ˆ8.4 Hz, 8-H), 7.20
(1H, t, J7,6 and J7,8ˆ8.2 Hz, 7-H), 7.34 (1H, m, 40-H), 7.40
(2H, m, 30-H and 50-H), 7.46 (2H, m, 20-H and 60-H); dC
(100 MHz; CDCl3) 37.6 (CH2, C-3), 55.6 (OCH3), 59.5
(CH, C-4), 73.3 (CH, C-2), 102.1 (CH, C-6), 110.4 (CH,
C-8), 113.2 (Cq, C-4a), 126.3 (2£CH, C-20 and C-60), 128.0
(CH, C-40), 128.5 (2£CH, C-30 and C-50), 129.6 (CH, C-7),
141.0 (Cq, C-10), 155.7 (Cq, C-8a), 158.5 (Cq, C-5); m/z
(EI), M1 256, (Found: M1, 256.1091. C16H16O3 requires M,
256.1099).
5,7-Dimethoxy¯av-3-ene 13. Rf 0.80 (toluene±Et2O, 9:1);
lmax (MeOH)/nm 277; dH (400 MHz; CDCl3) 3.74 (3H, s,
OCH3), 3.80 (3H, s, OCH3), 5.61 (1H, dd, J3,4ˆ9.9 Hz,
J3,2ˆ3.4 Hz, 3-H), 5.83 (1H, dd, J2,3ˆ3.3 Hz, J2,4ˆ1.9 Hz,
2-H), 6.03 (1H, d, J6,8ˆ2.2 Hz, 6-H), 6.05 (1H, d,
J8,6ˆ2.2 Hz, 8-H), 6.80 (1H, dd, J4,3ˆ9.9 Hz, J4,2ˆ1.8 Hz,
4-H), 7.34±7.47 (5H, m, Ph); dC (100 MHz; CDCl3) 55.4
(OCH3), 55.6 (OCH3), 77.2 (CH, C-2), 91.9 (CH, C-6), 93.8
(CH, C-8), 104.4 (Cq, C-4a), 118,8 (CH, C-4), 119.8 (CH,
C-3), 127.1 (2£CH, C-20 and C-60), 128.3 (CH, C-40), 128.6
(2£CH, C-30 and C-50), 140.9 (Cq, C-10), 154.9 (Cq, C-5),
156.3 (Cq, C-8a), 163.1 (Cq, C-7).
5-Methoxy¯av-3-ene 12. Rf 0.78 (toluene±Et2O, 91); dH
(400 MHz; CDCl3) 3.83 (3H, s, 5-OCH3), 5.76 (1H, dd,
J3,4ˆ10.0 Hz, J3,2ˆ3.5 Hz, 3-H), 5.85 (1H, dd,
J2,3ˆ3.2 Hz, J2,4ˆ2.0 Hz, 2-H), 6.43 (1H, d, J6,7ˆ8.8 Hz,
6-H), 6.46 (1H, d, J8,7ˆ9.1 Hz, 8-H), 6.89 (1H, dd,
J4,3ˆ10.0 Hz, J4,2ˆ1.4 Hz, 4-H), 7.05 (1H, t, J7,6 and
J7,8ˆ8.2 Hz, 7-H), 7.30±7.50 (5H, m, Ph).
2,4-cis and 2,4-trans-5,7-Dimethoxy¯avan-4-ols 9 and 10,
5,7-dimethoxy¯av-3-ene 13. To a stirred solution of 5,7-
dimethoxy¯avanone 4 (50 mg, 1.7£1024 mol) in ethanol
(20 ml) at room temperature, was added 20 mg of NaBH4
(5£1024 mol). The reaction was monitored by TLC on silica
gel (toluene±Et2O, 9:1) and after 8 h, the reaction mixture
was diluted with H2O (20 ml), acidi®ed with aqueous AcOH
(pH 6) and extracted with Et2O (3£30 ml). The combined
ethereal extracts were dried over anhydrous MgSO4, ®ltered
and concentrated. Puri®cation via preparative TLC on silica
gel (toluene±Et2O, 9:1) afforded 9 (20 mg, 41%), 10
(6.5 mg, 13%) and 13 (2.5 mg, 5%).
Acknowledgements
The authors are grateful to the Region Limousin as to the
Â
Comite Haute-Vienne of the `Ligue Nationale contre le
cancer' for their ®nancial support and to P. Sigaud and C.
Hemmerlin for running the MS and the NMR spectra
respectively.
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