An efficient method for the synthesis of lignans

Article abstract of DOI:10.1016/j.tet.2006.03.111

An efficient approach for the synthesis of several types of lignans (dibenzylbutanediols, dibenzylbutanes, substituted tetrahydrofurans, aryldihydronaphthalenes, arylnaphthalenes, and aryltetralins) was developed. The regioselective oxidative coupling of ethyl ferulate was used as the key step.

Full text of DOI:10.1016/j.tet.2006.03.111

Tetrahedron 62 (2006) 6107–6112
An efficient method for the synthesis of lignans
*
Qian Wang, Yong Yang, Ying Li, Wei Yu and Zi Jie Hou
Department of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
Received 29 November 2005; revised 29 March 2006; accepted 30 March 2006
Available online 2 May 2006
Abstract—An efficient approach for the synthesis of several types of lignans (dibenzylbutanediols, dibenzylbutanes, substituted tetrahydro-
furans, aryldihydronaphthalenes, arylnaphthalenes, and aryltetralins) was developed. The regioselective oxidative coupling of ethyl ferulate
was used as the key step.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
R
R
R
.
R
β
α
Lignans, one class of the oldest known natural products,
have attracted much interest over the years on account of
their broad range of biological activities. The structural
diversity of lignans has attracted much attention and many
elegant syntheses have been reported. One classical route
toward lignan structure utilizes the direct oxidative coupling
reaction of structurally simple precursors. Though this
1
4
H+ -e
-
6
5
2
3
.
OMe
OMe
OMe
OMe
OH
O
O
O
1
–7
.
Mβ
M5
4
MΟ
6
Scheme 1.
method is very attractive as it could offer quick access to the
skeletons of a wide range of lignans, its application is limited
because of the lack of selectivity on the coupling sites.
Herein we report an efficient modified strategy hinged on
the oxidative coupling reaction for the synthesis of secoiso-
lariciresinol (1), dihydroguaiaretic acid (2), and divanillyl-
tetrahydrofuran (3). Previous attempts to synthesize these
compounds using coupling reactions are not successful due
to the complexity of coupling pattern and the low yield of
As a result, six coupling modes for the mesomers are pos-
sible (b–b, b–5, b–O, 5–5, 5–O, and O–O), leading to com-
plex products. The major product was reported to be b–5
9
linked compound. This is verified by our own experiment.
Et) with alkaline
2
Oxidation of ethyl ferulate (4: R¼CO
potassium ferricyanide in benzene–water two phase system
gave rise to b–5 linked 5 as the main product. The desired
1
2,13
b–b coupling product 6
yield (Scheme 2).
was only obtained in very low
8
–11
the desired product.
It is expected that other lignan com-
pounds, e.g., arylnaphthalene and aryltetralin derivatives,
may also be prepared by this strategy.
EtO2C
CO2Et
H
O
K3[Fe(CN)6], KOH,
C6H6-H2O, rt, 0.5 h
OH
OCH3
2
. Results and discussion
5
(84%)
OMe
+
It is known that during the course of oxidative coupling of
phenols, phenoxyl radicals are generated as intermediates.
In the case of 4 (R¼CH , CH OH), the formed radical
CO2Et
MeO
HO
OH
CO2Et
3
2
4
EtO C
2
OMe
has five mesomeric forms, three of which, designated as
M , M , and M , are relevant to the coupling reactions
6
(9%)
O
5
b
(
Scheme 1).
Scheme 2.
The chance of b–b coupling could be increased if the b–5
coupling is blocked by another substituent at the 5 position
1
4
of the phenyl ring. Accordingly, a strategy was developed
based on substrate modification. A tert-butyl group was in-
troduced to the 5 position of the phenyl ring before oxidation
Keywords: Lignan; Synthesis; Regioselective oxidative coupling.
*
Corresponding author. Tel.: +86 931 891 3193; fax: +86 931 891 2582;
e-mail: houzj@lzu.edu.cn
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.111

6108
Q. Wang et al. / Tetrahedron 62 (2006) 6107–6112
to obstruct the side b–5 coupling. The tert-butyl group could
be removed afterwards using the method reported by Tashiro
et al. It was hoped that this maneuver could improve
the yield of desired oxidative coupling product greatly,
thus providing a simple concise route for the synthesis of
OMe
CO2Et
t-Bu
CO2Et
t-Bu
OH
1
5
K3[Fe(CN)6],
HO
KOH, C6H6/H2O HO
rt, 0.5 h, 92%
t-Bu
EtO C
2
MeO
11
MeO
12
1
, 2, and 3.
MeO
HO
CO Et MeO
CO Et
2
2
Our syntheses started from the commercially available 7.
Hydrogenation of 7 afforded 8, which was transformed to
9
later step was not complete, but the substrate 8 can be re-
covered and recycled. Oxidation of 9, followed by the Wittig
reaction, readily gave the desired compound 11, which
CO2Et HO
CO2Et
t-Bu
t-Bu
t-Bu
t-Bu
13b OH
(59%)
H2, Pd/C (10%),
rt, 24 h
+
16,17
by subsequent reaction with t-BuOH in H PO .
3
The
4
OMe
OMe
1
3a OH
40%)
(
1
8,19
MeO
HO
2
CO Et
MeO
CO2Et
2
served as our key precursor (Scheme 3).
CO2Et HO
CO Et
OH
OH
AlCl3, C6H6,
0 °C, 1 h, 79%
+
OMe
OMe
t-BuOH,
5
8
5%H3PO4,
OMe
OMe
H2, Pd/C (10%),
rt, 24 h, 99%
7
3-76 °C,
1
4a
14b
OH
OH
1
0 h, 80%
CHO
7
CH3
8
MeO
HO
CH2OH MeO
CH2OH
2
OH
OH
t-Bu
OMe
t-Bu
OMe
CH OH HO
CH OH
2
Br , t-BuOH,
2
rt, 1 h, 85%
+
LiAlH4, Et2O,
10
-15 °C, 2 h, 85%
9
CH3
CHO
OMe
OMe
1
a
OH
1b OH
t-Bu
HO
CO2Et
meso-ꢀeꢁoiꢂolariꢁireꢂinol
(±)-ꢀeꢁoiꢂolariꢁireꢂinol
Ph3PCHCOOEt,
CH3OCH2CH2OCH3,
reflux, 2 h, 96%
MeO
MeO
11
(i) p-TꢂCl,
OMe
pyridine,
HO
HO
0
°C, 4 h;
+
Scheme 3.
(ii) LiAlH , THF,
4
reflux, 6 h;
(
iii) KOH, EtOH-H2O,
OMe
OMe
The stage was now set for the crucial coupling step. As
expected, on treatment with alkaline potassium ferricyanide
in benzene–water two phase system, 11 was transformed to
reflux, 10 h, (49%)
2a
2b
OH
OH
meso-Dihydroguaiaretiꢁ aꢁid (±)-Dihydroguaiaretiꢁ aꢁid
1
2,13
b–b coupling product 12
in excellent yield. Hydrogena-
Scheme 4.
tion of 12 gave 13 as a mixture of two diastereomers,
erythro-13a and threo-13b, which could be separated by
flash chromatography and each obtained in pure form. The
ratio of these two compounds was 2:3 as determined by
integration of corresponding signals in the H NMR spectra.
The relative configurations of 13a and 13b were identified
by comparing the spectroscopic data of the terminal product
group might overcome this obstacle, but the introduction of
a protective group and its removal afterwards would detract
from the overall yield and most likely would lead to the
generation of byproducts, thus reducing the efficiency of
this approach for the preparation of those compounds.
1
1a and 1b with literature data. The tert-butyl group was then
removed at this stage. Using the method reported by Tashiro
The synthesis of divanillyltetrahydrofuran (3a or 3b) was
also achieved by refluxing a methanolic solution of secoiso-
lariciresinol (1a or 1b) under acidic conditions (Scheme 5).
et al., the tert-butyl groups were transferred from 13a (13b)
to solvent benzene via AlCl catalyzed Friedel–Crafts reac-
tion. Reduction of 14a (14b) using LiAlH afforded 1a
4
3
1
5
(
1b). The Compound 2a (2b) was obtained from 1a (1b)
MeO
HO
MeO
by tosylation of the hydroxy groups, reduction with LiAlH4
in THF, and final deprotection of phenol hydroxyl groups
with KOH in EtOH–H O (Scheme 4).
O
O
2
0,21
HO
+
2
1
a
HCl, MeOH
reflux, 18h, 96%
+
It should be noted that 2,3-dibenzylidenesuccinates, may be
in principle readily produced via a double Stobbe condensa-
tion, starting from a succinate ester and the appropriate aro-
OMe
OMe
1
b
OH
OH
3a
3
b
1
2
matic aldehyde. However, the use of Stobbe condensation
reaction for the synthesis of 2,3-dibenzylidenesuccinates
containing unprotected phenol hydroxyl group (e.g., com-
pounds 6 and 12) has not been reported so far to the best
of our knowledge. Probably the presence of active phenol
hydroxyl group in the starting aromatic aldehyde would ham-
per the effective condensation. The protection of hydroxyl
meso-Divanillyltetrahydrofuran (±)-Divanillyltetrahydrofuran
Scheme 5.
Treatment of 12 with AlCl in benzene directly afforded
3
aryldihydronaphthalene 15 (Scheme 6). The unreacted start-
ing material 12 can be recovered and recycled.

Q. Wang et al. / Tetrahedron 62 (2006) 6107–6112
6109
OH
TLC inspections on silica gel GF254 plates with petroleum
ether/ethyl acetate.
t-Bu
OMe
MeO
HO
CO2Et
CO2Et
EtO2C
4
.1.1. Oxidative coupling of ethyl (E)-3-(4-hydroxy-3-
AlCl3, C6H6
0°C, 1h, 50%
methoxyphenyl)-propenoate (4). The compound 4 (500 mg,
2.25 mmol) in benzene (22.5 mL) was vigorously stirred
with an aqueous solution (4.5 mL) containing potassium
ferricyanide (1.80 g) and potassium hydroxide (700 mg) for
5
CO2Et
OMe
OH
MeO
t-Bu
OH
12
15
0.5 h under nitrogen. The organic layer was washed with water,
brine, and dried over MgSO . The solvent was evaporated in
Scheme 6.
4
vacuo and the residue was purified by column chromatography
using petroleum ether and ethyl acetate (5:1, v/v) to afford 5
Compound 15 could be converted to a wide variety of aryl-
naphthalenes and aryltetralins, thus our method reported
here might be used for the preparation of these types of
(
1
301 mg, 84%) and 6 (45 mg, 9%); 5, colorless crystals, mp
ꢁ
1
11 C; H NMR (CDCl ) d 1.36 (3H, t, J¼7.2 Hz), 1.44
3
2
2,23
(3H, t, J¼7.2 Hz), 4.05 (3H, s), 4.29 (2H, q, J¼7.2 Hz), 4.42
natural products.
(
2H, q, J¼7.2 Hz), 6.46 (1H, d, J¼15.9 Hz), 7.04 (1H, s),
2
4–27
7.79 (1H, d, J¼15.9 Hz), 7.82 (1H, s), 8.26 (1H, s). MS m/z:
The synthetic secoisolariciresinol (1),
aretic acid (2),
dihydroguai-
divanillyltetrahydrofuran (3), and aryl-
+
2
8–31
32
318 (M ), 273, 246, 227. HRMS: C H O +Na calcd
17 18 6
1
3
3
1
13
341.0996, found 341.0992; 6, yellow oil; H NMR (CDCl )
3
dihydronaphthalene 15 have identical H and C NMR
spectra to those of the corresponding natural products
reported in the literatures.
d 1.11 (6H, t, J¼6.9 Hz), 3.74 (6H, s), 4.15 (4H, q,
J¼6.9 Hz), 6.06 (2H, s), 6.84 (2H, d, J¼8.1 Hz), 7.06 (2H,
1
3
dd, J¼1.8, 8.1 Hz), 7.13 (2H, d, J¼1.8 Hz), 7.86 (2H, s).
C
NMR (CDCl ) d 14.0, 55.6, 61.0, 111.3, 114.5, 124.6, 125.1,
3
+
3. Conclusions
127.3, 142.2, 146.3, 147.3, 167.3. MS m/z: 442 (M ), 296,
260, 151, 137.
In summary, concise and highly efficient syntheses of di-
benzylbutanediol1, dibenzylbutane2, substitutedtetrahydro-
furan 3, and aryldihydronaphthalene 15 have been achieved
by employing phenol oxidative coupling reaction as the
key step. Modification of the substrate (5–H/5–t-butyl)
forced the oxidative coupling to undergo an otherwise unfa-
vorable coupling pathway, which dramatically improved the
yield of the desired dimer. The tert-butyl group can be read-
ily removed via Friedel–Crafts reactions after the coupling.
4.1.2. Synthesis of 2-methoxy-4-methyl-phenol (8). A
mixture of compound 7 (200 mg, 1.31 mmol) and 10%
Pd/C (5:1, substrate/catalyst) in acetic acid was stirred at
ꢁ
55 C under hydrogen atmosphere for 24 h, Pd/C was filtered
and the solvent was evaporated in vacuo to give 8 (180 mg,
1
99%) as a colorless oil. H NMR data were consistent with
literature values.
3
6 1
H NMR (CDCl ) d 2.21 (3H, s), 3.74
3
(3H, s), 5.84 (1H, s), 6.61 (1H, d, J¼8.7 Hz), 6.62 (1H, s),
3
4,35
+
Compared with other methods
used to synthesize these
6.80 (1H, d, J¼8.7 Hz). MS m/z: 138 (M ), 123, 95, 67.
natural products, secoisolariciresinol (1), dihydroguaiaretic
acid (2), and divanillyltetrahydrofuran (3), the strategy
described in this paper is convenient and efficient. Further-
more, this route can be applied in the preparation of other
lignans, e.g., arylnaphthalenes and aryltetralins via structural
modifications. Further investigations will be directed toward
stereoselective synthesis of lignan molecules through this
methodology.
4.1.3. Synthesis of 2-tert-butyl-6-methoxy-4-methyl-
phenol (9). To a well-stirred emulsion of compound 8
(860 mg, 6.23 mmol) and 85% phosphoric acid (3.20 g,
1.90 mL), t-BuOH (1.11 equiv, 0.65 mL) was added at 73–
ꢁ
76 C. The mixture was stirred at the same temperature for
10 h, then the reaction was quenched with water, extracted
with ethyl acetate and the combined organic layers were
washed with brine, dried over MgSO . The solvent was
4
evaporated in vacuo and the residue was purified by column
chromatography using petroleum ether and ethyl acetate
4
. Experimental
(20:1, v/v) to afford 9 (967 mg, 80%) as a yellowish oil,
the unreacted starting material 8 can also be recovered and
4
.1. General procedures
1
13
recycled. H and C NMR data were consistent with litera-
ture values. H NMR (CDCl ) d 1.53 (9H, s), 2.40 (3H, s),
3
7 1
All reagents and chemicals were of reagent grade and used
as received from commercial suppliers. Melting points
were measured on a Kofler apparatus and were uncorrected.
IR spectra were obtained in liquid films or KBr disks on an
FTIR spectrometer. H NMR and C NMR spectra were
recorded with 300 MHz spectrometer. The chemical shifts
are referenced in parts per million relative to TMS. Low-
resolution mass spectra were recorded in the ES mode.
The high-resolution mass spectra (HRMS) were recorded
in the FAB mode. The preparative HPLC separations were
3
3.94 (3H, s), 5.96 (1H, s), 6.69 (1H, d, J¼1.8 Hz), 6.81 (1H,
1
3
d, J¼1.8 Hz). C NMR (CDCl ) d 21.7, 29.7, 34.8, 56.3,
3
109.6, 119.6, 128.1, 135.4, 142.2, 146.7. MS m/z: 194
(M ), 179, 151, 119, 91.
1
13
+
4.1.4. Synthesis of 3-tert-butyl-4-hydroxy-5-methoxy-
benzaldehyde (10). Bromine (4 equiv, 0.25 mL) was added
dropwise with stirring to compound 9 (220 mg, 1.14 mmol)
+
ꢁ
in t-BuOH (3.5 mL) at 25 C. After stirred for 1 h, the mix-
Ò
ꢁ
with water, extracted with ethyl acetate, and the combined or-
performed using a Nova-pak Silica 6 mm 7.8ꢀ300 mm col-
ture was cooled to 20 C, then the reaction was quenched
umn. The flow rate was 2.5 mL/min utilizing an n-hexane/
ethyl acetate mobile phase. Flash column chromatography
was generally performed on silica gel (200–300 mesh) and
ganic layers were washed with 10% NaHSO , distilled water,
3
brine, and dried over MgSO . The solvent was evaporated
4

6110
Q. Wang et al. / Tetrahedron 62 (2006) 6107–6112
1
3
in vacuo and the residue was purified by column chromato-
graphy using petroleum ether and ethyl acetate (7:1, v/v) to
afford 10 (200 mg, 85%) as colorless crystals; mp 102–
5.87 (2H, s), 6.43 (2H, s), 6.65 (2H, s). C NMR (CDCl3)
d 14.1, 29.3, 34.5, 35.7, 48.1, 55.9, 60.5, 108.8, 119.7,
+
128.2, 134.6, 142.6, 146.4, 173.7. MS m/z: 558 (M ), 279,
193, 149, 57. HRMS: C H O +H calcd 559.3265, found
559.3267.
ꢁ
1
1
03 C; H NMR (CDCl ) d 1.44 (9H, s), 3.97 (3H, s), 6.61
3
32 46 8
(
(
1
1
1H, s), 7.32 (1H, d, J¼1.8 Hz), 7.45 (1H, d, J¼1.8 Hz), 9.82
1
3
1H, s). C NMR (CDCl ) d 29.1, 34.7, 56.3, 106.7, 125.3,
3
+
28.3, 135.6, 147.2, 150.3, 191.4. MS m/z: 208 (M ), 193,
65. HRMS: C H O +H calcd 209.1172, found 209.1170.
4.1.8. Synthesis of diethyl bis(4-hydroxy-3-methoxy-
benzyl)succinate (14). To a solution of compound 13 (13a
1
2 16 2
and 13b, 330 mg, 0.59 mmol) in benzene (20 mL) was
ꢁ
4
5
.1.5. Synthesis of ethyl (E)-3-(3-tert-butyl-4-hydroxy-
-methoxyphenyl)-propenoate (11). solution of
added AlCl (8 equiv, 631 mg) at 50 C. The mixture was
3
A
stirred at the same temperature for 1 h, and then the reaction
was quenched with ice, extracted with benzene. The com-
bined organic layers were washed with brine, dried over
Na SO . The solvent was evaporated in vacuo and the resi-
Ph PCHCOOEt (2 equiv, 719 mg) in ethylene glycol
3
dimethyl ether (20 mL) was added dropwise to the solution
of 10 (215 mg, 1.03 mmol) in ethylene glycol dimethyl ether
2
4
(
10 mL), and the mixture was heated under reflux for 2 h.
due was purified by column chromatography using benzene
and ethyl acetate (8:1, v/v) to afford 14 (208 mg, 79%); 14a,
Then the reaction was quenched with water, extracted with
ethyl acetate, and the combined organic layers were washed
with brine, dried over MgSO . The solvent was evaporated
ꢁ
2924, 1724, 1515 cm ; H NMR (CDCl ) d 1.11 (6H, t,
83 mg, colorless crystals, mp 180 C; IR (KBr) nmax: 3422,
ꢂ1
1
4
3
in vacuo and the residue was purified by column chromato-
graphy using petroleum ether and ethyl acetate (7:1, v/v) to
J¼6.9 Hz), 2.72–2.83 (4H, m), 2.98–2.99 (2H, m), 3.85
13
(6H, s), 4.02 (4H, q, J¼6.9 Hz), 5.48 (2H, s), 6.64 (4H, s),
ꢁ
1
afford 11 (276 mg, 96%) as white crystals; mp 69–70 C; H
NMR (CDCl ) d 1.32 (3H, t, J¼6.9 Hz), 1.40 (9H, s), 3.90
6.80 (2H, d, J¼8.7 Hz). C NMR (CDCl ) d 14.1, 36.3,
3
50.2, 55.9, 60.5, 111.3, 114.1, 121.7, 130.2, 144.2, 146.3,
173.6. MS m/z: 446 (M ), 223, 177, 137, 57. HRMS:
3
+
(
6
3H, s), 4.26 (2H, q, J¼6.9 Hz), 6.29 (1H, d, J¼15.6 Hz),
.30 (1H, s), 6.69 (1H, s), 7.09 (1H, s), 7.63 (1H, d,
C H O +Na calcd 469.1833, found 469.1848. 14b,
2
4 30 8
+
J¼15.6 Hz). MS m/z: 278 (M ), 263, 235, 217, 95. HRMS:
125 mg, colorless oil; IR (KBr) nmax: 3429, 2934, 1727,
1516 cm ; H NMR (CDCl ) d 1.21 (6H, t, J¼7.2 Hz),
ꢂ1
1
C H O +Na calcd 301.1410, found 301.1414.
1
6
22
4
3
2
.80–2.87 (3H, m), 2.91–2.96 (3H, m), 3.78 (6H, s), 4.10
4
.1.6. Synthesis of diethyl (E,E)-bis(3-tert-butyl-4-
(4H, q, J¼7.2 Hz), 5.49 (2H, s), 6.48 (2H, d, J¼1.8 Hz),
1
3
hydroxy-5-methoxybenzylidene)succinate (12). The com-
pound 11 (200 mg, 0.719 mmol) in benzene (7.2 mL) was
vigorously stirred with an aqueous solution (1.45 mL) con-
taining potassium ferricyanide (600 mg) and potassium
hydroxide (220 mg) for 0.5 h under nitrogen. The organic
layer was washed with water, brine, and dried over
6.59 (2H, dd, J¼1.8, 8.1 Hz), 6.79 (2H, d, J¼8.1 Hz).
C
NMR (CDCl ) d 14.1, 35.3, 47.5, 55.6, 60.6, 111.2, 114.0,
3
+
121.9, 130.5, 144.1, 146.3, 179.5. MS m/z: 446 (M ), 277,
223, 177, 149, 137, 124, 91. HRMS: C H O +H calcd
447.2013, found 447.2021.
2
4 30 8
MgSO . The solvent was evaporated in vacuo and the residue
4
was purified by column chromatography using petroleum
ether and ethyl acetate (5:1, v/v) to afford 12 (183 mg,
4.1.9. Synthesis of secoisolariciresinol (1). To a suspension
of LiAlH4 (1.2 equiv, 6.5 mg) in dry THF (10 mL),
compound 14 (14a and 14b, 65 mg, 0.15 mmol) was added
ꢁ
9
1
2%) as a yellow oil; IR (KBr) nmax: 3412, 2957, 1366,
H NMR (CDCl ) d 1.10 (6H, t,
at ꢂ15 C, and stirred at same temperature for 2 h. Then the
ꢂ1
1
700, 978 cm
;
reaction was quenched with water, extracted with ethyl ace-
tate, and the combined organic layers were washed with
brine, dried over MgSO . The solvent was evaporated
3
J¼6.9 Hz), 1.34 (18H, s), 3.77 (6H, s), 4.14 (4H, q,
J¼6.9 Hz), 6.17 (2H, s), 7.03 (2H, s), 7.11 (2H, s), 7.85
4
+
(
calcd 577.2772, found 577.2790.
2H, s). MS m/z: 554 (M ), 278, 57. HRMS: C H O +Na
2 42 8
in vacuo and the residue was purified by column chromato-
graphy using petroleum ether and ethyl acetate (1:1, v/v) to
give the compound 1 (45 mg, 85%); 1 was further purified
by HPLC eluting with n-hexane and ethyl acetate (1:3, v/v)
to afford 1a (18 mg), colorless oil; 1b (27 mg), white solid,
3
4
.1.7. Synthesis of diethyl bis(3-tert-butyl-4-hydroxy-5-
methoxybenzyl)succinate (13). A mixture of compound 12
200 mg, 0.36 mmol) and 10% Pd/C (5:1, substrate/catalyst)
ꢁ
ꢂ1
(
mp 116–117 C; 1b, IR (KBr) n : 3351, 2933, 1515 cm ;
max
1
in EtOH (15 mL) was stirred at room temperature under
hydrogen atmosphere for 24 h, Pd/C was filtrated and the
solution was evaporated in vacuo. The residue was purified
by column chromatography using benzene to afford 13a
H NMR (CDCl ) d 1.85 (2H, s), 2.64 (2H, dd, J¼6.9,
3
13.5 Hz), 2.74 (2H, dd, J¼8.1, 13.5 Hz), 3.54 (2H, dd,
J¼4.2, 12 Hz), 3.80–3.83 (2H, m), 3.81 (6H, s), 6.58 (2H,
1
3
s), 6.62 (2H, d, J¼8.4 Hz), 6.80 (2H, d, J¼8.4 Hz).
C
NMR (CDCl ) d 35.9, 43.8, 55.8, 60.8, 111.4, 114.1, 121.7,
(
81 mg, 40%) and 13b (119 mg, 59%); 13a, white solid, mp
50–151 C; IR (KBr) nmax: 3526, 2956, 1726, 1367 cm
3
ꢁ
ꢂ1
+
1
;
132.4, 143.8, 146.4. MS m/z: 362 (M ), 277, 189, 137.
HRMS: C H O +NH calcd 380.2068, found 380.2061.
1
H NMR (CDCl ) d 1.09 (6H, t, J¼6.9 Hz), 1.37 (18H, s),
3
20 26
6
4
2
4
.76–2.82 (4H, m), 3.01 (2H, d, J¼3.9 Hz), 3.84 (6H, s),
.01 (4H, q, J¼6.9 Hz), 5.87 (2H, s), 6.54 (2H, s), 6.63
4.1.10. Synthesis of dihydroguaiaretic acid (2). A solution
of compound 1 (1a and 1b, 420 mg, 1.16 mmol) in pyridine
1
3
(
2H, s). C NMR (CDCl ) d 14.1, 29.3, 34.3, 36.6, 50.4,
3
ꢁ
5
6.1, 60.4, 108.9, 119.3, 128.5, 135.9, 142.7, 146.6, 173.7.
(1.50 mL) was stirred at 0 C for 20 min, p-TsCl (8 equiv,
+
MS m/z: 558 (M ), 279, 233, 193, 149, 57. HRMS:
C H O +Na calcd 581.3085, found 581.3083. 13b, yellow
oil; IR (KBr) nmax: 3526, 2956, 1730, 1595, 1372 cm ; H
1.77 g) was added. The mixture was stirred at same temper-
ature for other 4 h, and then the reaction was quenched with
2 N HCl (5 mL). The oil was separated, extracted with ethyl
acetate, and the combined organic layers were washed with
3
2 46 8
ꢂ1
1
NMR (CDCl ) d 1.18 (6H, t, J¼6.9 Hz), 1.36 (18H, s), 2.88
3
(
2H, s), 2.92 (4H, s), 3.77 (6H, s), 4.08 (4H, q, J¼6.9 Hz),
brine, dried over MgSO . The solvent was evaporated
4

Q. Wang et al. / Tetrahedron 62 (2006) 6107–6112
6111
in vacuo. The residue and LiAlH (5 equiv, 182 mg) was
4
(200 mg, 0.36 mmol) in benzene (20 mL) was added AlCl
3
ꢁ
added to the solution of dry THF (20 mL), and the mixture
was refluxed for 6 h. The reaction was quenched with water,
extracted with ethyl acetate, and the combined organic layers
(12 equiv, 578 mg) at 50 C. The mixture was stirred at same
temperature for 1 h, and then the reaction was quenched with
ice, extracted with benzene. The combined organic layers
were washed with brine, dried over Na SO . The solvent
were washed with brine, dried over MgSO . The solvent was
4
2
4
evaporated in vacuo and a solution (15 mL) of potassium
hydroxide (9.0 g) in H O (150 mL)–EtOH (150 mL) was
added to the residue in three 5 mL portions at 15 min inter-
vals. After reflux for 10 h, the solution was cooled, neutral-
ized with acetic acid, and extracted with ether. The organic
was evaporated in vacuo and the residue was purified by col-
umn chromatography using petroleum ether and ethyl ace-
tate (1:1, v/v) to afford 15 (80 mg, 50%), white solid, mp
2
ꢁ
ꢂ1
153 C; IR (KBr) nmax: 3402, 2931, 1697, 1512, 731 cm
;
1
H NMR (CDCl ) d 1.14 (3H, t, J¼7.2 Hz), 1.29 (3H, t, J¼
3
layers were washed with brine, dried over MgSO . The sol-
4
7.2 Hz), 3.80 (3H, s), 3.91 (3H, s), 3.97 (1H, d, J¼4.2 Hz),
4.08 (2H, q, J¼7.2 Hz), 4.21 (2H, q, J¼7.2 Hz), 4.53 (1H,
d, J¼4.2 Hz), 5.53 (1H, s), 5.84 (1H, s), 6.45 (1H, dd,
J¼8.1, 1.8 Hz), 6.63 (1H, d, J¼1.8 Hz), 6.68 (1H, s), 6.73
vent was evaporated in vacuo and the residue was purified by
column chromatography using petroleum ether and ethyl
acetate (10:1, v/v) to afford 2 (188 mg, 49%); 2 was further
purified by HPLC eluting with n-hexane and ethyl acetate
1
3
(1H, d, J¼8.1 Hz), 6.84 (1H, s), 7.64 (1H, s). C NMR
(
less crystals, mp 88–89 C; IR (KBr) nmax: 3445, 2925,
9:1, v/v) to afford 2a (75 mg) and 2b (113 mg); 2a, color-
(CDCl ) d 14.0, 14.2, 45.7, 47.4, 55.8, 56.0, 60.7, 61.1,
3
ꢁ
110.1, 111.1, 114.1, 115.4, 120.5, 123.0, 123.9, 131.2,
134.3, 137.3, 144.3, 145.6, 146.3, 147.5, 166.7, 172.6. MS
m/z: 442 (M ), 368, 323, 69, 43. HRMS: C H O +H calcd
ꢂ1
1
1
513, 1458 cm
J¼6.3 Hz), 1.71–1.78 (4H, m), 2.28 (2H, dd, J¼9.6,
3.5 Hz), 2.73 (2H, dd, J¼5.1, 13.5 Hz), 3.86 (6H, s), 6.61
2H, d, J¼1.8 Hz), 6.65 (2H, d, J¼8.4 Hz), 6.82 (2H, d,
;
H NMR (CDCl ) d 0.84 (6H, d,
3
+
2
4 26 8
1
(
443.1700, found 443.1698.
1
3
J¼8.4 Hz). C NMR (CDCl ) d 16.2, 30.9, 39.0, 39.2,
3
5
5.9, 111.5, 114.0, 121.8, 133.8, 143.7, 146.4. MS m/z:
Acknowledgements
+
330 (M ), 208, 193, 165, 149, 137. HRMS: C H O ꢂH
calcd 329.1758, found 329.1766. 2b, white solid, mp 87–
8 C; IR (KBr) nmax: 3425, 2925, 1513, 1456 cm ; H
2
0 26 4
This research work was financially supported by the National
Natural Science Foundation of China (Grant No. 20272020).
ꢁ
ꢂ1
1
8
NMR (CDCl ) d 0.82 (6H, d, J¼6.3 Hz), 1.69–1.76 (4H,
3
m), 2.38 (2H, dd, J¼6.9, 13.5 Hz), 2.52 (2H, dd, J¼6.9,
1
3.5 Hz), 3.81 (6H, s), 6.52 (2H, s), 6.58 (2H, d,
References and notes
1
3
J¼8.1 Hz), 6.80 (2H, d, J¼8.1 Hz). C NMR (CDCl3)
d 13.8, 37.4, 41.0, 55.7, 111.2, 113.8, 121.6, 133.6, 143.5,
1
1. Ward, R. S. Nat. Prod. Rep. 1999, 16, 75–96.
2. Ward, R. S. Nat. Prod. Rep. 1997, 14, 43–74.
3. Ward, R. S. Nat. Prod. Rep. 1995, 12, 183–205.
+
46.2. MS m/z: 330 (M ), 137. HRMS: C H O ꢂH calcd
2
0 26 4
3
29.1758, found 329.1759.
4
. Ward, R. S. Nat. Prod. Rep. 1993, 10, 1–28.
4
.1.11. Synthesis of divanillyltetrahydrofuran (3). A solu-
5. Whiting, D. A. Nat. Prod. Rep. 1990, 7, 349–364.
6. Ward, R. S. Chem. Soc. Rev. 1982, 11, 75–125.
7. Kise, N.; Ueda, T.; Kumada, K.; Terao, Y.; Ueda, N. J. Org.
Chem. 2000, 65, 464–468.
8. Sih, C. J.; Ravikumar, P. R.; Huang, F. C.; Buckner, C.;
Whitlock, H. J. Am. Chem. Soc. 1976, 98, 5412–5413.
9. Sarkanen, K. V.; Wallis, A. F. A. J. Chem. Soc., Perkin Trans. 1
1973, 1869–1878.
tion of compound 1 (1a and 1b, 165 mg, 0.46 mmol) in
methanol (50 mL) containing 10 N HCl (0.5 mL) was re-
fluxed for 18 h. The solvent was removed and the residue ad-
sorbed on silica gel. Elution with petroleum ether and ethyl
acetate (3:1, v/v) afforded 3 (151 mg, 96%); 3 was further
purified by HPLC eluting with n-hexane and ethyl acetate
(
solid, mp 113–114 C; IR (KBr) nmax: 3375, 2929, 1603,
3:1, v/v) to afford 3a (60 mg) and 3b (91 mg); 3a, white
ꢁ
514 cm ; H NMR (CDCl ) d 2.47–2.54 (4H, m), 2.80–
10. Eskins, K.; Glass, C.; Rohwedder, W.; Kleiman, R.; Slonekar,
J. Tetrahedron Lett. 1972, 861–864.
ꢂ1
1
1
3
2
.86 (2H, m), 3.64 (2H, dd, J¼4.2, 8.1 Hz), 3.79 (2H, dd,
11. Miller, I. J. Tetrahedron Lett. 1972, 4955–4958.
12. For an example of 2,3-dibenzylidenesuccinates made through
double Stobbe condensation see: Datta, P. K.; Yau, C.; Hooper,
T. S.; Yvon, B. L.; Charlton, J. L. J. Org. Chem. 2001, 66,
8606–8611.
J¼4.2, 8.1 Hz), 3.87 (6H, s), 5.49 (2H, s), 6.65 (2H, d, J¼
1
.2 Hz), 6.68 (2H, dd, J¼1.2, 8.1 Hz), 6.85 (2H, d,
3
1
3
J¼8.1 Hz). C NMR (CDCl ) d 33.1, 43.8, 55.9, 72.0,
1
11.2, 114.3, 121.2, 132.5, 143.8, 146.4. MS m/z: 344
M ), 189, 163, 137. HRMS: C H O calcd 344.1618,
+
1
(
found 344.1622. 3b, colorless crystals, mp 134–135 C; IR
13. The H NMR spectra of compound 6 and compound 12 show
2
0 24 5
ꢁ
H NMR
a singlet for the ethylene protons at d 7.86 and d 7.85, respec-
tively. As calculated by the Tobey–Simon rule, the chemical
shift for the ethylene protons in 6 and 12 should be at d 7.81
for E configuration, and at d 7.33 for Z configuration. There-
fore, the stereochemistry of the ethylene in 6 and 12 is judged
to be of E configuration. For the Tobey–Simon rule see: (a)
Tobey, S. W. J. Org. Chem. 1969, 34, 1281–1298; (b) Pascual,
C.; Meier, J.; Simon, W. Helv. Chim. Acta 1966, 49, 164–168.
14. Sarkanen, K. V.; Wallis, A. F. A. J. Chem. Soc., Perkin Trans. 1
ꢂ1
1
(
(
(
KBr) nmax: 3328, 2936, 1606, 1514 cm
;
CDCl ) d 2.13–2.20 (2H, m), 2.48–2.62 (4H, m), 3.53
3
2H, dd, J¼6.0, 8.7 Hz), 3.82 (6H, s), 3.92 (2H, dd, J¼6.0,
8
.7 Hz), 5.50 (2H, s), 6.50 (2H, d, J¼1.5 Hz), 6.58 (2H,
1
3
dd, J¼1.5, 8.1 Hz), 6.80 (2H, d, J¼8.1 Hz). C NMR
(
CDCl ) d 39.2, 46.4, 55.7, 73.2, 111.0, 114.0, 121.3,
3
+
1
32.3, 143.8, 146.4. MS m/z: 344 (M ), 137, 84. HRMS:
C H O ꢂH calcd 343.1551, found 343.1555.
2
0 24 5
1
973, 1878–1881.
4
.1.12. Synthesis of diethyl 1-(4-hydroxy-3-methoxy-
phenyl)-1,2-dihydro-6-methoxy-7-hydroxynaphthalene-
,3-dicarboxylate (15). To a solution of compound 12
15. Tashiro, M.; Yamato, T. J. Org. Chem. 1979, 44, 3037–3041.
16. Harold Vickery, E.; Pahler, L. F.; Eisenbraun, E. J. J. Org.
Chem. 1979, 44, 4444–4446.
2

6112
Q. Wang et al. / Tetrahedron 62 (2006) 6107–6112
1
1
7. Rosenwald, R. H. J. Am. Chem. Soc. 1952, 74, 4602–4605.
8. Coffield, T. H.; Filbey, A. H.; Ecke, G. G.; Kolka, A. J. J. Am.
Chem. Soc. 1957, 79, 5019–5023.
28. Hwu, J. R.; Tseng, W. N.; Gnabre, J.; Giza, P.; Huang, R. C. C.
J. Med. Chem. 1998, 41, 2994–3000.
29. Ikeya, Y.; Taguchi, I.; Yoshida, I. Chem. Pharm. Bull. 1979, 27,
1583–1588.
30. Rao, K. V.; Chattopadhyay, S. K. J. Org. Chem. 1990, 55,
1427–1429.
31. Fo, R. B.; de Carvalho, M. G.; Gottlieb, O. R. Planta Med.
1984, 53–55.
1
2
2
9. Wang, Q.; He, K. K.; Li, Y. Z.; Li, D. W.; Li, Y.; Hou, Z. J.
J. Chem. Res. 2004, 504–505.
0. Xia, Y. M.; Cao, X. P.; Peng, K.; Ren, X. F.; Pan, X. F. Chin.
Chem. Lett. 2003, 14, 359–360.
1. Wolfrom, M. L.; Koos, E. W.; Bhat, H. B. J. Org. Chem. 1967,
3
2, 1058–1060.
32. Fang, J. M.; Hsu, K. C.; Cheng, Y. S. Phytochemistry 1989, 28,
3553–3555.
33. Neudorffer, A.; Deguin, B.; Hamel, C.; Fleury, M. B.; Largeron,
M. Collect. Czech. Chem. Commun. 2003, 68, 1515–1530.
34. Wu, A. X.; Wang, M. Y.; Pan, X. F.; Li, T. X.; Jin, W. Huaxue
Yanjiu Yu Ying Yong 1997, 9, 595–599.
2
2
2. Wallis, A. F. A. Aust. J. Chem. 1973, 26, 585–594.
3. Takei, Y.; Mori, K.; Matsui, M. Agric. Biol. Chem. 1973, 37,
6
37–641.
4. Achenbach, H.; Waibel, R.; Addae-Mensah, I. Phytochemistry
983, 22, 749–753.
5. Umezawa, T.; Davin, L. B.; Lewis, N. G. J. Biol. Chem. 1991,
66, 10210–10217.
6. Agrawal, P. K.; Rastogi, R. P. Phytochemistry 1982, 21, 1459–
461.
7. Fang, J. M.; Lee, C. K.; Cheng, Y. S. Phytochemistry 1992, 31,
659–3661.
2
2
2
2
1
35. Hearon, W. M.; Macgregor, W. S. Chem. Rev. 1955, 55, 957–
1068.
2
1
3
1
36. Pouchert, C. J.; Behnke, J. The Aldrich Library of C and H
FT NMR Spectra, 1st ed.; Aldrich Chemical Company: 1993;
Vol. 2, pp 276.
1
3
37. Cacioli, P.; Reiss, J. A. Aust. J. Chem. 1984, 37, 2525–2535.