Studies on flavans. III. The total synthesis of (±)-7,4′ -dihydroxy-3′-methoxyflavan, (±)-7,3′-dihydroxy-4′ -methoxyflavan, and (±)-7,4′-dihdroxyflavan

Article abstract of DOI:10.1081/SCC-120024733

The first total synthesis of (±)-7,3′-dihydroxy-4′ -methoxyflavan (1) and (±)-7,4′-dihydroxy-3′-methoxyflavan (2), along with the synthesis of (±)-7,4′-dihydroxyflavan (3), three naturally occurring flavans, were described. The key step is the cyclization of 1,3-diaryl-1-propanol by BF₃·Et₂O.

Full text of DOI:10.1081/SCC-120024733

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Studies on Flavans. III. The Total Synthesis of (±)-7,4′-
Dihydroxy-3′-methoxyflavan, (±)-7,3′-Dihydroxy-4′-
methoxyflavan, and (±)-7,4′-Dihydroxyflavan
Jijun Xue a , Xianshu Zhang a , Xuesong Chen a , Yingpeng Zhang a & Ying Li a
a National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry,
Lanzhou University, Lanzhou, Gansu, People's Republic of China
Version of record first published: 15 Aug 2006.
To cite this article: Jijun Xue, Xianshu Zhang, Xuesong Chen, Yingpeng Zhang & Ying Li (2003): Studies on Flavans. III. The
Total Synthesis of (±)-7,4′-Dihydroxy-3′-methoxyflavan, (±)-7,3′-Dihydroxy-4′-methoxyflavan, and (±)-7,4′-Dihydroxyflavan,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:20,
3527-3536
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 20, pp. 3527–3536, 2003
Studies on Flavans. III. The Total Synthesis
of (1)-7,40-Dihydroxy-30-methoxyflavan,
2
(1)-7,30-Dihydroxy-40-methoxyflavan, and
2
(1)-7,40-Dihydroxyflavan
2
Jijun Xue, Xianshu Zhang, Xuesong Chen,
*
Yingpeng Zhang, and Ying Li
National Laboratory of Applied Organic Chemistry and
Institute of Organic Chemistry, Lanzhou University,
Lanzhou, Gansu, People’s Republic of China
ABSTRACT
The first total synthesis of (ꢀ)-7,30-dihydroxy-40-methoxyflavan (1)
and (ꢀ)-7,40-dihydroxy-30-methoxyflavan (2), along with the synthesis
of (ꢀ)-7,40-dihydroxyflavan (3), three naturally occurring flavans,
were described. The key step is the cyclization of 1,3-diaryl-1-
propanol by BF3ꢁEt2O.
Key Words: Synthesis; Flavans.
*Correspondence: Ying Li, National Laboratory of Applied Organic Chemistry
and Institute of Organic Chemistry, Lanzhou University, 298 Tianshui Road,
Lanzhou, Gansu, 730000, People’s Republic of China; E-mail: liying@lzu.
edu.cn.
3527
DOI: 10.1081/SCC-120024733
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3528
Xue et al.
Naturally occurring flavans, a branch of flavanoids, exist widely in
the plant kingdom and exhibit many important biological and
pharmacological activities.[1–3] There are many approaches to the synthe-
sis of flavans, but they are commonly in poor yield and in intense
conditions.[4–7] The lack of a general and efficient method for the for-
mation of benzopyran presents a major challenge for the total synthesis
of this class of natural products. In previous work,[8,9] we have reported a
convenient and efficient synthetic method[8] based on the Lewis acid
(BF3ꢁEt2O)-mediated benzopyran formation in an aprotic polar solvent
and two naturally occurring flavans has been synthesized.[9] In order to
support the practicability of this method and develop it, in continuation
of our studies, this method was used for synthesizing other flavans.
Herein we report its development and three naturally occurring products
were synthesized by this method, they are (ꢀ)-7,30-dihydroxy-40-
methoxyflavan (1), (ꢀ)-7,40-dihydroxy-30-methoxyflavan (2) and (ꢀ)-
7,40-dihydroxyflavan (3) (Sch. 1). As well as we know, the total synthesis
of 1 and 2 have not been reported yet.
R1
HO
O
R2
(+/-)-1 R1=OMe, R2=OH
(+/-)-2 R1=OH, R2=OMe
(+/-)-3 R1=OH, R2=H
Scheme 1.
The synthetic route is following (Sch. 2). 7,30-Dihydroxy-40-methoxy-
flavan (1) was firstly isolated from Dracaena cinnabari by Mohamed
Masaoud et al. in 1994. Dracaena cinnabari, which is called dragon’s
blood, has been known for a long time in folk medicine as an astringent
in diarrhoea and dysentery, as well as an antiseptic, haemostatic and an-
tiulcer remedy.[10] The synthesis of 1 was commenced from isovanilin (4),
which was readily prepared from selective methylation of 4-OH of 3,4-
dihydroxybenzaldehyde with dimethyl sulfate and K2CO3 in dry acetone
under reflux. Methoxymethylation of 4 with MOMCl and K2CO3 in acet-
one was followed by Grignard reaction of 6 with CH3MgI in ethyl ether,
which gave 1-(3-methoxymethoxy-4-methoxyphenyl) ethanol (8).

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Studies on Flavans. III
3529
O
OH
CHO
b
c
R1
R1
R1
R2
R2
R2
R1=OMOM, R2=OCH3
10 R1=OMOM, R2=OCH3
4
6
5
7
R1=OH, R2=OCH3
8
a
R1=OMOM, R2=OCH3
R1=OCH3, R2=OH
11 R1=OCH3, R2=OMOM
9 R1=OCH3, R2=OMOM
a
R1=OCH3, R2=OMOM
O
OMOM
MOMO
OMOM
R2
+
d
R1
R1
OMOM
R2
CHO
O
10 R1=OMOM, R2=OCH3
11 R1=OCH3, R2=OMOM
12 R1=H, R2=OMOM
14 R1=OMOM, R2=OCH3
15 R1=OCH3, R2=OMOM
16 R1=H, R2=OMOM
13
R2
MOMO
OMOM
R2
R1
MOMO
O
R1
f
e
OH
17 R1=OMOM, R2=OCH3
18 R1=OCH3, R2=OMOM
19 R1=H, R2=OMOM
20 R1=OMOM, R2=OCH3
21 R1=OCH3, R2=OMOM
22 R1=H, R2=OMOM
g
(+/-)-1, (+/-)-2, (+/-)-3
Scheme 2. Reagents and conditions: (a) CH3OCH2Cl, K2CO3, acetone, reflux;
(b) CH3MgI, THF, reflux; (c) PCC, CH2Cl2, r. t.; (d) KOH, CH3OH (abs.), r. t.;
(e) H2/Pd-C (5%), EtOH, r. t.; (f) BF3ꢁEt2O, 1, 4-dioxane, r. t.; (g) 3M HCl,
CH3OH.
Oxidation of 8 by PCC in methylene dichloride yielded 30-methoxy-
methoxy-40-methoxyacetophenone (10). This is a new approach to
30-methoxymethoxy-40-methoxyactophenone, from which 30-hydroxy-40-
methoxyacetophenone could be obtained in one step. 13 was readily
prepared from 2,4-dihydroxybenzaldehyde by methoxymethylation
method previously reported by us.[9] Condensation of 10 and 13 proceeded
in a solution of KOH (20.0 equiv.) in absolute methanol gave chalcone 14.
In opposition to the condensation in KOH-EtOH-H2O reported by us in
previous work,[9] this condensation has higher yield, more simple result

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3530
Xue et al.
and its product is easier to purify. The key precursor for the formation of
benzopyran, alcohol 17 comes from reduction of 14 with H2/Pd-C. 17
was treated with BF3ꢁEt2O in 1,4-dioxane at room temperature to give
flavan 20, which is the key step. The condition is very gentle and the
yield is satisfying. Deprotection of methoxymethyl group of 20 by treat-
ment with 3M HCl in CH3OH led to the first target product (ꢀ)-1.
7,40-Dihydroxy-30-methoxyflavan (2) was isolated firstly[11] in 1980 from
Iryanthera elliptica Duke, a slender tree which occurs in the Brazilian region
of the Amazon. In 1996,[12] it was isolated from the monocotyledon Mariscus
psilostachys C. B. Clarke by Eliane G. again. This small herb belongs to the
Cyperaceae and its distributed throughout tropical Africa. Although no uses
for M. psilostachys are directly reported in the traditional pharmacopoea of
Zimbabwe, it is well known[12] that other species of the same genus are
commonly used by West Africa healers to treat different affections (gonor-
rhoes, Infected wounds, etc.). 2 was synthesized in analogue manner from
vanillin (5) and 13 as the starting materials through the steps of protection of
phenolic hydroxyl, Grignard reaction, oxidation, condensation, reduction,
cyclization, and deprotection. In the key step, if BF3ꢁEt2O, not the solution
of BF3ꢁEt2O in 1,4-dioxane, was added directly to the solution of 18 in 1,4-
dioxane, the MOM protective group would be removed and monoMOM-
protecting flavan formed. But it is not clear which MOM was removed. In
order to make sure of the result of the key step, the solution of BF3ꢁEt2O in
1,4-dioxane was added dropwise very slowly to the substrate so that the
MOM groups were kept. After deprotecting the MOM group of 21 with
3 M HCl in MeOH, another target, the flavan (ꢀ)-2 was formed.
7,40-Dihydroxyflavan (3) is a phytoalexin. In 1980,[13] David T.
Coxon et al. found that it could be isolated from the lesions of
inoculation of Narcisses pseudonarcisses L. bulb, but it was absent
from fresh or frozen and thawed healthy tissues. The synthesis of 3 was
started from 13 and 12, which were condensated in KOH alcoholic
solution to yield chalcone 16. Hydrogenation of 16 using Pd-C (5%) as
the catalyst in ethanol afforded propanol 19, which was treated with
BF3ꢁEt2O to give flavan 22. Demethxoymethylation of 22 with 3 M
HCl in methanol under reflux led to the target (ꢀ)-3.
EXPERIMENTAL
General Experimental Procedures
Melting points were measured on a Kofler hot stage and are uncor-
rected. For column chromatography, 100–200 mesh silica gel was used.

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Studies on Flavans. III
3531
1
Infrared spectra were obtained on a FT-170SX spectrometer. H NMR
spectra were recorded on DRX-200 instrument in CDCl3. Chemical
shifts were reported in ppm units with TMS as the internal standard.
EIMS were measured on a HP-5988A spectrometer by direct inlet at
70 eV.
1-(4-Methoxy-3-methoxymethoxyphenyl) ethanol (8). A mixture of
Mg (58 mg, 2.4 mmol) and CH3I (0.15 mL, 2,4 mmol) in dry ethyl ether
(10 mL) was heated to reflux for 30 min. Then it was cooled to 0ꢂC,
stirred and a solution of 6 (392 mg, 2.0 mmol) in dry ether (5 mL) was
added dropwise to it. And after it was refluxed for 30 min, the mixture
was quenched with saturated aqueous ammonium chloride solution and
extracted with ethyl acetate. The combined organic layer was washed
with brine, dried over MgSO4, filtered and evaporated under reduced
pressure. The residue was purified by silica gel column chromatography
eluting with petroleum ether-EtOAc (v/v, 4:1) to give 8 (322 mg, 76%
yield) as a colorless oil. IR (KBr) ꢀ 3391, 2968, 1593, 1511, 1441, 1131,
1
809 cmꢃ1. H NMR ꢁ 2.67 (3H, d, J ¼ 6.0 Hz, CH3), 3.67, 4.00 (3H each,
s, CH3O), 4.94 (1H, q, J ¼ 6.0 Hz, 1-H), 5.34 (2H, s, OCH2O), 6.94 (1H,
d, J ¼ 8.0 Hz, 50-H). 7.30 (1H, dd, J ¼ 8.0, 2.0 Hz, 60-H), 7.03 (1H, d,
J ¼ 2.0 Hz, 20-H). EIMS m/z [M]þ 212 (1.8), 198 (2.7), 168 (12.4), 150
(2.5), 125 (16.2), 77 (10.9), 45 (100).
1-(3-Methoxy-4-methoxymethoxyphenyl) ethanol (9) was prepared
from 7 in analogue manner in 70% yield. IR (KBr) ꢀ 3406, 2968, 1594,
1
1513, 1463, 1157, 818 cmꢃ1. H NMR ꢁ 1.42 (3H, d, J ¼ 6.4 Hz, CH3),
3.46, 3.83 (3H each, s, CH3O), 4.78 (1H, q, J ¼ 6.4 Hz, 1-H), 5.15 (2H, s,
OCH2O), 6.80 (1H, dd, J ¼ 2.0, 8.2 Hz, 50-H), 6.92 (1H, d, J ¼ 2.0 Hz,
20-H), 7.04 (1H, d, J ¼ 8.2 Hz, 60-H). EIMS m/z [M]þ 212 (9.3), 167 (7.6),
150 (9.9), 135 (11.6), 121 (16.4), 93 (8.4), 45 (100).
3-Methoxymethoxy-4-methoxyacetophenone (10). To a mixture of
PCC (1.60 g, 7.5 mmol) in dry CH2Cl2 (10 mL) was added dropwise the
solution of 8 (1.06 g, 5 mmol) in CH2Cl2 (5 mL). After stirred for 1.5 h at
room temperature, the mixture was filtered with a short silica gel column.
The filtrate was concentrated and the residue was purified with silica gel
column chromatography eluting with petroleum ether-EtOAc (v/v, 8:1)
to give 10 (890 mg, 85% yield) as a colorless oil. IR (KBr) ꢀ 2957, 1675,
1595, 1511, 1429, 1152, 812 cmꢃ1. 1H NMR ꢁ 2.53 (3H, s, CH3CO), 3.48,
3.93 (3H each, s, OCH3), 5.31 (2H, s, OCH2O), 6.89 (1H, d, J ¼ 8.4 Hz,
5-H), 7.61 (1H, dd, J ¼ 2.0, 8.4 Hz, 6-H), 7.72 (1H, d, J ¼ 2.0 Hz, 2-H).
EIMS m/z [M]þ 210 (16.9), 180 (7.8), 119 (5.5), 91 (4.6), 45 (100).
3-Methoxy-4-methoxymethoxyacetophenone (11) was prepared by
oxidation of 9 in the same way in 85% yield as a pale yellow oil. IR
1
(KBr) ꢀ 2958, 1676, 1592, 1509, 1463, 1139, 814 cmꢃ1. H NMR ꢁ 2.52

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3532
Xue et al.
(3H, s, CH3CO), 3.47, 3.89 (3H each, s, CH3O), 5.26 (2H, s, OCH2O),
7.13 (1H, d, J ¼ 8.8 Hz, 6-H), 7.49 (1H, dd, J ¼ 2.0, 8.8 Hz, 5-H), 7.50
(1H, d, J ¼ 2.0 Hz, 2-H). EIMS m/z [M]þ 210 (7.3), 180 (3.7), 165 (5.0),
149 (1.2), 137 (1.1), 91 (2.7), 45 (100).
2,30,4-Trimethoxymethoxy-40-methoxychalcone (14). A well-stirred
solution of 10 (420 mg, 2 mmol) and KOH (2.24 g, 40 mmol) in absolute
CH3OH (10 mL) was cooled by ice-bath. Then 13 (452 mg, 2 mmol) in
CH3OH (6 mL) was added dropwise. Stirred for 16 h at room tempera-
ture, the solution was poured into 20 mL ice-water, acidified to pH ¼ 2
and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with
water and brine, dried over anhydrous MgSO4, filtered and concentrated.
The residue was purified with petroleum ether-EtOAc (v/v, 4:1) to give a
yellow oil 14 (3.56 g, 85% yield). IR (KBr) ꢀ 2922, 1653, 1598, 1505, 1432,
1
1260, 1154, 996, 923, 807 cmꢃ1. H NMR ꢁ 3.37, 3.41, 3.43, 3.82 (3H
each, s, CH3O), 5.08, 5.16, 5.20 (2H each, s, OCH2O), 6.63 (1H, dd,
J ¼ 2.0, 8.6 Hz, 5-H), 6.76 (1H, d, J ¼ 2.0 Hz, 3-H), 6.85 (1H, d,
J ¼ 8.6 Hz, 6-H), 7.50 (1H, d, J ¼ 15.4 Hz, Hb), 7.52 (1H, d, J ¼ 9.0 Hz,
60-H), 7.65 (1H, dd, J ¼ 2.4, 9.0 Hz, 50-H), 7.80 (1H, d, J ¼ 2.4 Hz, 20-H),
8.04 (1H, d, J ¼ 15.4 Hz, Ha). EIMS m/z [M]þ 418 (0.2), 373 (3.5), 357
(13.9), 313 (1.8), 283 (0.7), 195 (42.5), 151 (6.7), 45 (100).
2,40,4-Trimethoxymethoxy-30-methoxychalcone (15) was obtained by
condensation of 13 and 11 in analogue manner in 85% yield as a yellow
oil. IR (KBr) ꢀ 2924, 1663, 1601, 1505, 1433, 1261, 1151, 1078, 808 cmꢃ1
.
1H NMR ꢁ 3.24, 3.27, 3.28, 3.75 (3H each, s, OCH3), 4.97, 5.06, 5.10 (2H
each, s, OCH2O), 6.52 (1H, dd, J ¼ 2.2, 8.6 Hz, 5-H), 6.65 (1H, d,
J ¼ 2.2 Hz, 3-H), 7.00 (1H, d, J ¼ 8.6 Hz, 6-H), 7.39 (1H, d, J ¼ 15.8 Hz,
Hb), 7.42 (1H, d, J ¼ 8.6 Hz, 60-H), 7.43 (1H, dd, J ¼ 2.0, 8.6 Hz, 50-H),
7.43 (1H, d, J ¼ 2.0 Hz, 20-H), 7.93 (1H, d, J ¼ 15.8 Hz, Ha). EIMS m/z
[M]þ 418 (0.3), 357 (7.4), 195 (11.9), 45 (100).
2,40,4-Trimethoxymethoxychalcone (16) was prepared in the same
way from 13 and 12 in 90% yield as a yellow oil. IR (KBr) ꢀ 2930,
1
1680, 1618, 1600, 1500, 1453, 1150, 1078, 810 cmꢃ1. H NMR ꢁ 3.44,
3.45, 3.50 (3H each, s, CH3O), 5.16, 5.21, 5.23 (2H each, s, OCH2O),
6.70 (1H, dd, J ¼ 2.4, 8.6 Hz, 5-H), 6.82 (1H, d, J ¼ 2.4 Hz, 3-H), 7.08
(2H, d, J ¼ 8.8 Hz, 30, 50-H), 7.51 ( 1H, d, J ¼ 15.8 Hz, Hb), 7.99 (1H, d,
J ¼ 8.6 Hz, 6-H), 8.10 (1H, d, J ¼ 15.8 Hz, Ha), 7.58 (2H, d, J ¼ 8.8 Hz, 20,
60-H). EIMS m/z [M]þ 388 (0.4), 327 (12.8), 283 (1.5), 241 (1.4), 165
(36.6), 135 (13.1), 121 (1.7), 45 (100).
1-(4-Methoxy-3-methoxymethoxyphenyl)-3-(2,4-dimethoxymethox-
yphenyl)-1-propanol (17). A well-stirred solution of 14 (418 mg, 1.0 mol)
and Pd-C (5%) (40 mg) in EtOH (10 mL) was kept for 24 h at room
temperature under 2 atm atmosphere of hydrogen. The reaction mixture

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Studies on Flavans. III
3533
was filtered and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel eluting with
petroleum ether-EtOAc (v/v, 4:1) to give 17 (418 mg, 99% yield) as a
colorless gum. IR (KBr) ꢀ 3430, 2962, 2929, 2822, 1610, 1444, 1153,
1
1127, 811, 736 cmꢃ1. H NMR ꢁ 1.88–2.09 (2H, m, 2-H), 2.61 (2H, t,
J ¼ 7.4Hz, 3-H), 3.45, 3.47, 3.50, 3.87 (3H each, s, CH3O), 4.51 (2H,
dd, J ¼ 2.6, 7.8 Hz, 1-H), 5.13, 5.16, 5.20 (2H each, s, OCH2O), 6.64
(1H, dd, J ¼ 2.4, 8.4 Hz, 60-H), 6.78 ( 1H, d, J ¼ 2.4 Hz, 20-H), 6.83
(1H, dd, J ¼ 1.8, 8.2 Hz, 500-H), 6.94 (1H, d, J ¼ 1.8 Hz, 300-H), 7.05
(1H, d, J ¼ 8.4 Hz, 50-H), 7.14 (1H, d, J ¼ 8.2 Hz, 600-H). EIMS m/z
[M]þ 422 (0.5), 197 (3.3), 181 (2.5), 167 (5.7), 151 (3.6), 137 (6.9), 105
(1.1), 91 (3.1), 45 (100).
1-(3-Methoxy-4-methoxymethoxyphenyl)-3-(2,4-dimethoxymethoxy-
phenyl)-1-propanol (18) was prepared in analogue manner by hydrogena-
tion of 15 in 99% yield as a colorless oil. IR (KBr) ꢀ 2960, 1610, 1588,
1
1505, 1445, 1151, 1011, 811 cmꢃ1. H NMR ꢁ 1.88–2.09 (2H, m, 2-H),
2.67 (2H, t, J ¼ 8.0 Hz, 3-H), 3.38, 3.44, 3.48, 3.85 (3H each, s, CH3O),
4.57 (1H, dd, J ¼ 5.4, 8.0 Hz, 1-H), 5.11, 5.14, 5.18 (2H each, s, OCH2O),
6.63 (1H, dd, J ¼ 2.4, 8.4 Hz, 60-H), 6.77 (1H, d, J ¼ 2.4 Hz, 20-H), 6.81
(1H, dd, J ¼ 2.0, 8.4 Hz, 500-H), 6.93 (1H, d, J ¼ 2.0 Hz, 300-H), 7.03 (1H,
d, J ¼ 8.4 Hz, 50-H), 7.07 (1H, d, J ¼ 8.4 Hz, 600-H). EIMS m/z [M]þ 422
(0.4), 360 (3.4), 212 (3.3), 197 (1.8), 167 (3.9), 150 (1.5), 91 (2.4), 45 (100).
1-(4 -Methoxymethoxyphenyl)-3-(2,4-dimethoxymethoxyphenyl)-1-
propanol (19) was prepared by hydrogenation of 16 in 99% yield as a
colorless oil. IR (KBr) ꢀ 2925, 1610, 1506, 1447, 1402, 1152, 1114, 837.
1H NMR ꢁ 1.92–2.08 (2H, m, 2-H), 2.67 (2H, t, J ¼ 8.0 Hz, 3-H), 3.46,
3.47, 3.48 (3H each, s, CH3O), 4.59 (1H, dd, J ¼ 5.4, 7.8 Hz, 1-H), 5.14,
5.15, 5.18 (2H each, s, OCH2O), 6.65 (1H, dd, J ¼ 2.4, 8.2 Hz, 500-H), 6.79
(1H, d, J ¼ 2.4 Hz, 300-H), 7.02 (2H, d, J ¼ 8.6 Hz, 30, 50-H), 7.03 (1H, d,
J ¼ 8.2 Hz, 600-H), 7.28 (2H, d, J ¼ 8.6 Hz, 20, 60-H). EIMS m/z [M]þ 392
(35), 347 (15), 330 (75), 285 (35), 167 (54), 151 (22), 45 (100).
(1)-7,30-Dimethoxymethoxy-40-methoxyflavan
(20).
At
room
2
temperature, to a well-stirred solution of 17 (84 mg, 0.2 mmol) in dry
1,4-dioxane was added dropwise a solution of BF3ꢁEt2O (0.08 mL,
0.96 mmol) in dry 1,4-dioxane (10 mL). The resulting mixture was stirred
for 30 min, quenched by the addition of saturated aqueous NaHCO3, and
extracted with ethyl ether. The organic extracts were washed with water
and brine, dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column chroma-
tography eluting with petroleum ether-EtOAc (v/v, 16:1) to yield 20
(65 mg, 90% yield) as a colorless gum. IR (KBr) ꢀ 2924, 1616, 1502,
1
1461, 1382, 1259, 1151, 906, 759 cmꢃ1. H NMR ꢁ 2.00–2.08 (2H, m,

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3534
Xue et al.
3-H), 2.70–2.86 (2H, m, 4-H), 3.35, 3.45, 3.81 (3H each, s, OCH3), 4.88
(1H, dd, J ¼ 9.2, 2.8 Hz, 2-H), 5.06, 5.17 (2H each, d, OCH2O), 6.52 (1H,
dd, J ¼ 2.4, 10.4 Hz, 6-H), 6.81 (1H, d, J ¼ 2.4 Hz, 8-H), 6.85 (1H, d,
J ¼ 2.0 Hz, 20-H), 6.91 (1H, d, J ¼ 8.4 Hz, 5-H), 6.97 (1H, d, J ¼ 2.0 Hz,
60-H), 7.17 (1H, dd, J ¼ 2.0, 9.8 Hz, 50-H). EIMS m/z [M]þ 360 (2.7), 315
(1.9), 283 (1.1), 194 (3.4), 147 (3.0), 45 (100).
(1)-7,40-Dimethoxymethoxy-30-methoxyflavan (21) was obtained by
2
cyclization of 18 with Lewis acid BF3ꢁEt2O in 10 min in 60% yield as a
colorless gum. IR (KBr) ꢀ 2932, 1618, 1503, 1463, 1151, 806 cmꢃ1
.
1H NMR ꢁ 2.00–2.20 (2H, m, 3-H), 2.80–2.96 (2H, m, 4-H), 3.49, 3.53,
3.92 (3H each, s, CH3O), 4.99 (1H, dd, J ¼ 2.8, 9.8 Hz, 2-H), 5.17, 5.27
(2H each, s, OCH2O), 6.63 (1H, dd, J ¼ 2.4, 8.2 Hz, 6-H), 6.68 (1H, d,
J ¼ 2.4 Hz, 8-H), 6.94 (1H, d, J ¼ 2.2 Hz, 20-H), 7.01 (1H, d, J ¼ 8.2 Hz,
5-H), 7.02 (1H, dd, J ¼ 2.2, 8.2 Hz, 60-H), 7.20 (1H, d, J ¼ 8.2 Hz, 50-H).
EIMS m/z [M]þ 360 (7.2), 316 (2.8), 283 (3.2), 149 (9.8), 137 (8.2), 105
(8.0), 45 (100).
(1)-7,40-Dimethoxymethoxyflavan (22) was obtained in analogue
2
manner from 19 in 95% yield as a colorless oil. IR (KBr) ꢀ 2925, 1624,
1
1507, 1152, 1109. H NMR ꢁ 2.03–2.18 (2H, m, 3-H), 2.77–2.94 (2H, m,
4-H), 3.48, 3.49 (3H each, s, OCH3), 4.97 (1H, dd, J ¼ 1.4, 11.2 Hz, 2-H),
5.15, 5.20 (2H each, s, OCH2O), 6.61 (1H, dd, J ¼ 2.6, 8.2 Hz, 6-H), 6.63
(1H, d, J ¼ 8.2 Hz, 5-H), 7.36 (2H, d, J ¼ 8.8 Hz, 20, 60-H), 7.10 (2H, d,
J ¼ 8.8 Hz, 30, 50-H), 7.04 (1H, d, J ¼ 2.6 Hz, 8-H). EIMS m/z [M]þ 330
(100), 285 (13.3), 269 (2.7), 253 (6.5), 165 (2.7), 139 (14.6), 91 (2.9), 77
(2.5).
(1)-7,30-Dihydroxy-40-methoxyflavan (1). To a well-stirred solution of
2
20 (72 mg, 0.2 mmol) in MeOH (5 mL) was added dropwise 3M HCl
(1 mL). The solution was heated at reflux for 30 min, then H2O (10 mL)
was added, and the solution was extracted with EtOAc. The combined
organic layer was washed with water and brine, dried over anhydrous
MgSO4. After filtered, the solvent was evaporated under reduced pressure
and the residue was purified by silica gel column chromatography eluting
with petroleum ether-EtOAc (v/v, 4:1) to give flavan 1 (43 mg, 80%) as a
white solid. M.p. 151–152ꢂC. IR (KBr) ꢀ 3396, 2977, 2925, 1595, 1509,
1459, 1380, 1152, 1027, 803 cmꢃ1 1H NMR ꢁ 2.0–2.2 (2H, m, 3-H),
.
2.6–2.8 (2H, m, 4-H), 3.81 (3H, s, OCH3), 4.86 (1H, dd, J ¼ 3.0, 9.6
Hz, 2-H), 6.31 (1H, d, J ¼ 2.0 Hz, 8-H), 6.33 (1H, dd, J ¼ 2.0, 8.4 Hz,
6-H), 6.77 (1H, d, J ¼ 8.4 Hz, 50-H), 6.84 (1H, d, J ¼ 8.4 Hz, 5-H), 6.85
(1H, dd, J ¼ 1.6, 8.4 Hz, 60-H), 6.92 (1H, d, J ¼ 1.6 Hz, H-20); EIMS m/z
[M]þ 272 (37.2), 162 (17.9), 150 (100), 137 (49.9), 123 (22.4), 104 (42.7).
(1)-7,40-Dihydroxy-30-methoxyflavan (2) was obtained in analogue
2
manner from 21 in 95% yield as a colorless oil. IR (KBr) ꢀ 3397, 2978,

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©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Studies on Flavans. III
3535
2929, 1731, 1622, 1596, 1510, 1380, 1271, 1112, 1046, 846 cmꢃ1. 1H NMR
ꢁ 1.95–2.11 (2H, m, 3-H), 2.68–2.85 (2H, m, 4-H), 3.84 (3H, s, CH3O),
4.88 (1H, dd, J ¼ 3.0, 9.6 Hz, 2-H), 6.32 (1H, dd, J ¼ 2.4, 8.8 Hz, 6-H),
6.33 (1H, d, J ¼ 2.4 Hz, 8-H), 6.86 (1H, dd, J ¼ 2.0, 8.8 Hz, 50-H), 6.87
(2H, d, J ¼ 8.8 Hz, 5-H), 6.88 (1H, dd, J ¼ 2.1, 8.8 Hz, 60-H), 7.19 (1H, d,
J ¼ 2.0 Hz, 20-H). EIMS m/z [M]þ 272 (36.8), 255 (3.6), 241 (3.4), 150
(100), 137 (45.7), 123 (38.1), 107 (19.1), 91 (16.1), 77 (14.2).
(1)-7, 40-Dihydroxyflavan (3) was obtained in analogue manner from
2
22 in 95% yield as a colorless oil. IR (KBr) ꢀ 2924, 1619, 1511, 1457,
1371, 1152, 1110, 839. 1H NMR ꢁ 1.97–2.07 (2H, m, 3-H), 2.57–2.82 (2H,
m, 4-H), 4.87 (1H, dd, J ¼ 3.2, 9.6 Hz, 2-H), 6.33 (1H, d, J ¼ 2.4 Hz, 8-H),
6.34 (1H, dd, J ¼ 2.4, 8.8 Hz, 6-H), 6.78 (2H, d, J ¼ 8.6 Hz, 30, 50-H), 7.82
(1H, d, J ¼ 8.8 Hz, 5-H), 7.18 (2H, d, J ¼ 8.6 Hz, 20, 60-H). EIMS m/z
[M]þ 242 (100), 225 (6.8), 136 (7.0), 120 (23.5), 107 (5.8), 91 (3.5), 65 (2.7).
ACKNOWLEDGMENTS
This work was financially supported by the National Natural Science
Foundation of China (20272020).
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Received in Japan March 1, 2003