First total synthesis of Boehmenan

Article abstract of DOI:10.1007/s12039-014-0599-7

The first total synthesis of dilignan Boehmenan has been achieved. A biomimetic oxidative coupling of the ferulic acid methyl ester in the presence of silver oxide is the crucial step in the synthesis sequence, generating the dihydrobenzofuran skeleton. Hydroxyl group was protected with DHP and reducted with LiAlH ₄ to afford the intermediate diol. The diol was condensated with the derivative of ferulic acid, then removed the protecting groups, to get Boehmenan. Meanwhile, a study on the ring-opening reaction of the intermediate dihydrobenzofuran neolignan under base conditions was described.

Full text of DOI:10.1007/s12039-014-0599-7

c
J. Chem. Sci. Vol. 126, No. 3, May 2014, pp. 813–820. ꢀ Indian Academy of Sciences.
First total synthesis of Boehmenan
YAMU XIAa,∗, XIAOLI DAIa,∗, HAIXIN LIUa and CHEN CHAIb
aCollege of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042,
People’s Republic of China
bThe first Affiliated Hospital of Lanzhou University, Gansu 730000, People’s Republic of China
e-mail: xiaym@qust.edu.cn; dxlqust@163.com
MS received 27 April 2013; revised 29 July 2013; accepted 14 November 2013
Abstract. The first total synthesis of dilignan Boehmenan has been achieved. A biomimetic oxidative coup-
ling of the ferulic acid methyl ester in the presence of silver oxide is the crucial step in the synthesis sequence,
generating the dihydrobenzofuran skeleton. Hydroxyl group was protected with DHP and reducted with LiAlH4
to afford the intermediate diol. The diol was condensated with the derivative of ferulic acid, then removed the
protecting groups, to get Boehmenan. Meanwhile, a study on the ring-opening reaction of the intermediate
dihydrobenzofuran neolignan under base conditions was described.
Keywords. Boehmenan; dihydrobenzofuran neolignan; dilignan; biomimetic oxidative coupling;
ring-opening reaction mechanism.
1. Introduction
application prospect have been found in nature, only a
few have been synthesized. In 2010, our team devel-
oped a novel synthetic route of dilignan threo-( )-
diferuloysecoisolariciresinol. The method involved two
Stobbe reactions to construct the skeleton of lignan, and
then condensed with ferulaic acid to give threo-( )-
diferuloysecoisolariciresinol.11
Here, we report the first total synthesis of another
dilignan Boehmenan. The synthesis was based on a
strategy involving biomimetic oxidative coupling to
give the key intermediate dihydrobenzofuran neolig-
nan, and then treated with derivative of ferulic acid
to obtain the natural product Boehmenan as shown in
scheme 1. Furthermore, the reaction conditions of
biomimetic oxidative coupling are described, and the
possible ring-opening reaction mechanisms of dihy-
drobenzofuran compound are discussed in this paper.
The structurally novel lignan Boehmenan (1) was first
isolated in 2001 by Seca et al. from the bark of Kenaf
(Hibiscus cannabinus), which is an annual dicotyle-
donous herbaceous plant and well-known in Asia and
Africa.1 In 2005, Wu et al. reported that Boehmenan
was isolated from the stems of Hibiscus taiwanensis,
co-occurring with a structurally diverse set of natural
products.2 Rudiyansyah et al. isolated it together with
another nine compounds by the phytochemical explo-
ration of a wood bark extract from Durio zibethinus in
2006.3 Cytotoxicity-guided fractionation of the stems
of Helicteres hirsuta, led to the isolation and identifi-
cation of Boehmenan by Chin et al. in the same year.4
In addition, Sasaki et al. extracted it from the whole
plants of Sambucus adnata and reported the evalua-
tion of the PTP1B inhibitory activities of it in 2011.
The kinetic analysis indicated that Boehmenan in hibits
PTP1B activity in a competitive manner.5
2. Experimental
Boehmenan, with a dihydrobenzofuran skeleton, is
formed by polymerization of four phenylpropanoid
units. This compound belongs to the very interest-
ing class of dilignan on account of their great num-
ber of structural possibilities. Dilignan family are
found in all part of plants6,7 and display biologi-
cal activities including antioxidant8 and antituberculo-
sis activities9 and inhibitory effects on the growth of
dicotyledons.10 Although many dilignans with broad
2.1 Materials and apparatus
The reagents and the solvents used in this study were of
analytical grade and were used without further purifica-
tion. Melting points were determined in open capillar-
ies and are uncorrected. The purity of the compounds
was checked by TLC on silica gel GF254 plates using
UV/Iodine as visualizing agent and silica gel (200–300
mesh) was used for column chromatographic purifica-
tion. The 1HNMR and 13CNMR spectra were recorded
∗For correspondence
813

814
Yamu Xia et al.
Scheme 1. Synthesis of Boehmenan.
on a Brucker AM-500 MHz spectrometers. HRMS stream of hydrogen chloride is continued for two or
were obtained on a Bruker Daltonics APEXII47e three hours longer until the solution is saturated. The
spectrometer.
layer of chloromethyl ether is then separated. The water
layer is saturated with calcium chloride, and more ether
separates. This is added to the main portion, which is
then dried over calcium chloride and fractionally dis-
tilled. The yield of MOMCl boiling at 55–60◦C is about
150 g.
2.2 Synthesis of (E)- ferulic acid methyl ester (3)
A mixture of vanillin (8.58 g, 56.4 mmol), methyl
hydrogen malonate (13.32 g, 112.8 mmol) and piperi-
dine (0.72 g, 8.5 mmol) in pyridine (13 mL) were heated
at 100◦C for 4 h. The residue was poured into diluted
hydrochloric acid solution which was cooled at 0◦C.
After three days, the crude product obtained was fil-
tered and recrystallized from ethanol to give compound
3 (10.40 g).
2.3b The synthesis of methyl (E)-4-methoxymethyl-
3-methoxycinnamate (4): A mixture of compound 3
(2.81 g, 13.5 mmol), potassium carbonate (5.59 g,
40.5 mmol) in acetone (20 mL), was stirred for 1 h at
room temperature. Then, MOMCl (2.18 g, 27.1 mmol)
was added drop-wise. Stirring was continued for 3 h and
the reaction mixture was then quenched with aqueous
ammonium chloride. The mixture was extracted with
ethyl acetate, dried over MgSO4, concentrated under
vacuum to give 4 (3.15 g).
2.2a (E)- ferulic acid methyl ester (3): This com-
pound was obtained as a white solid, mp: 63–64◦C;
89% yield; HRMS calcd for C11H12O4 208.0737, found
1
208.0751; H NMR (500 MHz, CDCl3) δ 3.69 and
3.91 (s, 6H, 2 × OCH3), 6.39 (d, 1H, J = 16.0 Hz,
ArCH=CH), 6.87–7.30 (m, 3H, ArH), 7.59 (d, 1H, J
= 16.0 Hz, ArCH=CH), 8.11 (s, 1H, OH); 13C NMR
(125 MHz, CDCl3) δ 51.49, 56.36, 111.42, 115.55,
116.06, 123.75, 127.42, 145.66, 148.67, 149.98, 167.87
(C=O). The data are consistant with the literature.12
2.3c Methyl (E)-4-methoxymethyl-3-methoxycinnamate
(4): This compound was obtained as a colourless oil,
93% yield; HRMS calcd for C13H16O5 252.0998, found
252.1004; 1H NMR (500 MHz, CDCl3) δ 3.46 (s, 3H,
OCH3), 3.70 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 5.23
(s, 2H, OCH2O), 6.43 (d, 1H, J = 16.5 Hz, ArCH=CH),
6.80–7.10 (m, 3H, ArH), 7.52 (d, 1H, J = 16.5 Hz,
ArCH=CH).
2.3 Synthesis of methyl (E)-4-methoxymethyl-3-
methoxycinnamate (4)13,14
2.3a The preparation of MOMCl: In a 1 L round-
bottomed flask fitted with a stopper carrying a reflux
condenser and a glass tube reaching nearly to the bot-
2.4 Synthesis of (E)-4-methoxymethyl-3-methoxycinnamic
acid (5)
tom of the flask are placed methyl alcohol (100.00 g, To the compound 4 (0.94 g, 3.7 mmol) in ethanol
3.1 mol) and formaldehyde (72.00 g, 2.4 mol). A rapid (20 mL), 20 mL aqueous solution of NaOH (0.18 g,
stream of hydrogen chloride is run into the mixture, 4.5 mmol) were added, then the mixture was heated
which is cooled with running water. In about two hours under reflux for 3 h. After that the reaction mixture was
a layer of chloromethyl ether begins to appear. The cooled and poured in acetic acid, which has been cooled

First total synthesis of Boehmenan
815
in an ice bath. The solid product obtained was filtered and DHP (0.21 g 2.5 mmol). After the mixture was
and recrystallised (petroleum/acetic ether = 1/15) to stirred for 4 h at room temperature, the reaction com-
give the compound 5 (0.84 g).
pleted. The residue was chromatographed on a silica
gel column (petroleum/acetic ether = 4/1) to give the
compound 7 (0.85 g).
2.4a (E)-4-methoxymethyl-3-methoxycinnamic acid
(5): This compound was obtained as a white solid,
mp: 135–137◦C; 95% yield; HRMS calcd for C12H14O5
238.0841, found 238.0848; 1H NMR (500 MHz,
CDCl3) δ 3.52 (s, 3H, OCH3), 3.92 (s, 3H, OCH3),
5.28 (s, 2H, OCH2O), 6.33 (d, 1H, J = 16.0 Hz,
ArCH=CH), 7.10–7.28 (m, 3H, ArH), 7.71 (d, 1H, J =
16.0 Hz, ArCH=CH).
2.6a
Methyl (E)-3-{2-[4-(tetrahydro-2H-pyran-2-
yloxy)-3-methoxyphenyl]-7- methoxy-3-methoxycarbonyl-2,
3-dihydro-1-benzofuran-5-yl}-prop-2-enoate (7): This
compound was obtained as a pale yellow oil, 85% yield;
HRMS calcd for C27H30O9 498.1889, found 498.1995;
1H NMR (500 MHz, CDCl3) δ 1.59–1.94 (m, 6H,
CH2CH2CH2), 3.56–3.73 (m, 2H, OCH2), 3.72 and
3.84 (s, 6H, 2 × OCH3), 3.88 and 3.92 (s, 6H, 2 ×
OCH3), 4.35 (d, 1H, J = 8.0 Hz, H-8), 5.39 (t, 1H,
OCHO), 6.12 (d, 1H, J = 8.0 Hz, H-7), 6.30 (d, 1H, J =
16 Hz, H-8ꢁ), 6.77–7.19 (m, 5H, ArH), 7.63 (d, 1H, J =
16 Hz, H-7ꢁ). 13C NMR (125 MHz, CDCl3) δ 18.79,
25.23, 30.28, 51.65, 52.90, 55.45, 55.62, 56.16, 62.12,
87.33, 97.02, 110.37, 112.18, 115.57, 117.80, 117.97,
118.80, 125.74, 128.64, 133.65, 144.45, 144.78,
146.63, 150.02, 150.52, 167.63 (C=O), 170.77 (C=O).
2.5 Synthesis of methyl (E)-3-[2-(4-hydroxy-3-
methoxyphenyl)-7-methoxy-3-methoxycarbonyl-2,
3-dihydro-1-benzofuran-5-yl]-prop-2-enoate (6)15–17
Fresh silver oxide (1.56 g, 6.7 mmol) was added to a
solution of compound 3 (2.81 g, 13.5 mmol) in dry ace-
tone (20 mL) and toluene (30 mL) under a nitrogen
atmosphere at −20◦C. After stirring for 30 h, the mix-
ture was filtered and evaporated under reduced pressure.
The residue was purified by a short silica gel column
chromatography (petroleum/acetic ether = 3/1) to give
the compound 6 (1.27 g).
2.7 Synthesis of 3-{2-[4-(Tetrahydro-2H-pyran-2-
yloxy)-3-methoxyphenyl]-3-hydroxymethyl-7-methoxy-
2,3-dihydro-1-benzofuran-5-yl}propan-1-ol (8) 12,20
2.5a Methyl (E)-3-[2-(4-hydroxy-3-methoxyphenyl)-7-
methoxy-3-methoxycarbonyl-2,3-dihydro-1- benzofuran-
5-yl]-prop-2-enoate (6): This compound was obtained
as a white crystals, mp: 151–152 ◦C; 45% yield; HRMS
calcd for C22H22O8 414.1315, found 414.1328; 1H
NMR (500 MHz, CDCl3) δ 3.74 and 3.82 (s, 6H, 2
× OCH3), 3.83 and 3.94 (s, 6H, 2 × OCH3), 4.49 (d,
1H, J = 8.0 Hz, H-8), 6.03 (d, 1H, J = 8.0 Hz, H-7),
6.46 (d, 1H, J = 16.0 Hz, H-8ꢁ), 6.85–7.34 (m, 5H,
ArH), 7.64 (d, 1H, J = 16.0 Hz, H-7ꢁ) 7.69 (s, 1H, OH).
13C NMR (125 MHz, CDCl3) δ 51.67, 53.07, 55.92,
56.35, 56.54, 87.54, 110.97, 113.46, 116.03, 116.29,
119.02, 120.19, 127.36, 129.42, 131.81, 145.50,
145.80, 148.21, 148.75, 151.01, 167.86 (C=O), 171.73
(C=O). The data are consistant with the literature.12
In a 50 mL dried three-necked flask, LiAlH4 (0.19 g,
5.0 mmol) was dissolved in 30 mL of dry THF, and
compound 7 (0.50 g, 1.0 mmol) was added slowly.
The mixture was stirred at 0◦C under a nitrogen atmo-
sphere for 3 h. H2O (0.19 mL) was added, followed
by treatment with HCl, and the mixture was extracted
with AcOEt (3 × 10 mL). Then the organic phase was
washed with saturated NaCl solution (20 mL), dried
over MgSO4 and evaporated. The residue was chro-
matographed on a silica gel column (petroleum/acetic
ether = 1/1) to give the compound 8 (0.34 g).
2.7a 3-{2-[ 4-( Tetrahydro-2H-pyran-2 - yloxy ) - 3 -
methoxyphenyl]-3-hydroxymethyl-7-methoxy-2,3- dihydro-
1-benzofuran-5-yl}propan-1-ol (8): This compound
was obtained as a yellow oil, 77% yield; HRMS
calcd for C25H32O7 444.2148, found 444.2156; 1H
NMR (500 MHz, CDCl3) δ 1.60–1.96 (m, 6H,
CH2CH2CH2), 1.86–2.08 (m, 2H, H-8ꢁ), 2.56 (t, 2H,
H-7ꢁ), 3.50–3.53 (m, 2H, OCH2), 3.55–3.56 (d, 1H, J =
7.0 Hz, H-8), 3.70 (t, 2H, H-9ꢁ), 3.81 (s, 3H, OCH3),
2.6 Synthesis of methyl (E)-3-{2-[4-(tetrahydro-2H-
pyran-2-yloxy)-3-methoxyphenyl]-7-methoxy-3-
methoxycarbonyl-2,3-dihydro-1-benzofuran-5-yl}-
prop-2-enoate (7)18,19
A 25 mL dried round-bottom flask containing anhy- 3.82 (s, 3H, OCH3), 4.03–4.09 (m, 2H, H-9), 5.30
drous dichloromethane 5 mL was charged with com- (t,1H,OCHO), 5.47 (d, 1H, J = 7.0 Hz, H-7), 6.59-7.01
pound 6 (0.83 g, 2.0 mmol), PPTS (0.05 g, 0.2 mmol) (m, 5H, ArH). 13C NMR (125 MHz, CDCl3) δ: 18.85,

816
Yamu Xia et al.
25.22, 30.28, 31.91, 34.48, 53.85, 56.01, 56.12, 60.87, 2.9 Synthesis of 2-(4-hydroxy-3-methoxyphenyl)-5-[3-
62.36, 63.91, 87.60, 97.60, 109.92, 110.38, 116.39, (4-hydroxy-3-methoxycinnamoyloxy) propyl]-3-(4-
118.03, 118.62, 128.20, 135.40, 135.84, 143.97, hydroxy-3-methoxycinnamoyloxmethyl)-7-
145.28, 145.92, 150.27.
methoxybenzodihydrofuran (Boehmenan)
In a 25 mL round-bottom flask, a mixture of 9 (0.097 g,
0.11 mmol) and PPTS (2.52 g, 0.011 mmol) in anhy-
drous ethanol (8 ml) were stirred for 2 h at 55◦C. The
solvent was removed in vacuo to give a crude pro-
duct. To the residue of 25 ml (round-bottomed flask),
hydrochloric acid (4 ml) in THF solution was added.
Then the mixture was stirred for 0.5 h at room tem-
perature and it was concentrated in vacuum. The crude
product was purified by flash chromatography to afford
Boehmenan (59.05 mg).
2.8 Synthesis of 2-[4-(tetrahydro-2H-pyran-2-yloxy)-
3-methoxyphenyl]-5-[3-(4-methoxymethyl-3-
methoxycinnamoyloxy)propyl]-3-[(4-methoxymethyl-3-
methoxycinnamoyloxy)propyl]-
7-methoxybenzodihydrofuran (9)21
Under a nitrogen atmosphere, a 50 mL, oven dried,
round-bottom flask containing anhydrous dichloro-
methane (20 mL) was charged with acid 5 (0.119 g,
0.5 mmol), compound 8 (0.111 g, 0.25 mmol), dicyclo-
hexyl carbodiimide (DCC, 0.105 g, 0.5 mmol), and 4-
dimethylaminopyridine (DMAP, 0.021 g, 0.165 mmol)
at 0◦C. The ice bath was removed after the addition
was completed, and the resulting solution was stirred
for 6 h at room temperature. The reaction mixture was
filtrated and the solvent was distilled off. The residue
was purified by flash column chromatography to afford
compound 9 (0.103 g).
2.9a 2-(4-Hydroxy-3-methoxyphenyl)-5-[3-(4-hydroxy-
3 - methoxcinnamoyloxy)propyl] - 3 - hydroxymethyl - 7-
methoxybenzodihydrofuran (Boehmenan): This com-
pound was obtained as yellow oil, 75% yield; HRMS
calcd for C40H40O12 712.2520, found 712.2536; 1H
NMR (500 MHz, CDCl3) δ 1.97–2.06 (m, 2H,
H-2ꢁꢁꢁ), 2.71 (t, 2H,J = 7.6 Hz, H-1ꢁꢁꢁ), 3.83 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3), 3.93 (s, 6H, 2 × OCH3),
3.84–3.93 (m, 1H, H-3), 4.23 (t, 2H, J = 6.5 Hz, H-
3ꢁꢁꢁ), 4.43 (dd, 1H, J = 7.7 and 11.2 Hz, H-1ꢁꢁ), 4.59
(dd, 1H, J = 5.1 and 11.2 Hz, H-1ꢁꢁ), 5.50 (d, 1H, J
= 7.8 Hz, H-2), 5.65 (s, 1H, OH), 5.91 (s, 1H, OH),
5.92 (s, 1H, OH), 6.23 (d, 1H, J = 15.9 Hz, H-a),
6.30 (d, 1H, J = 15.9 Hz, H-aꢁ), 6.69–7.09 (m, 11H,
ArH), 7.49 (d, 1H, J = 15.9 Hz, H-b), 7.61 (d, 1H, J =
15.9 Hz, H-bꢁ). 13C NMR (125 MHz, CDCl3) δ 30.71,
32.13, 50.67, 55.90 (2 × OCH3), 56.01 (2 × OCH3),
63.68, 65.42, 88.89, 108.76, 109.32, 109.39, 112.38,
114.21, 114.71, 114.72, 114.73, 115.37, 116.12,
119.71, 122.97, 123.14, 126.67, 126.94, 127.43,
132.50, 134.89, 144.08, 144.92, 145.48, 145.66,
146.23, 146.64, 146.71, 146.73, 147.94, 148.12, 167.02
(C=O), 167.34 (C=O). The data are consistant with the
literature.1
2.8a
2 - [ 4 - ( Tetrahydro-2H-pyran-2-yloxy )-3-
methoxyphenyl]-5-[3-(4-methoxymethyl-3-methoxcinnamoyloxy)
propyl]-3-[(4-methoxymethyl-3-methoxcinnamoyloxy)
propyl ] - l - 7 -methoxybenzodihydrofuran (9): This
compound was obtained as a yellow oil, 47% yield;
HRMS calcd for C49H56O15 884.3619, found 884.3628;
1H NMR (500 MHz, CDCl3) δ 1.54–2.17 (m, 6H,
CH2CH2CH2), 1.92–2.04 (m, 2H, H-2ꢁꢁꢁ), 2.72 (t, 2H,
H-1ꢁꢁꢁ), 3.49 (s, 3H, OCH3), 3.51 (s, 3H, OCH3), 3.60–
3.64 (m, 2H, OCH2), 3.75 (m, 1H, H-3), 3.85 (s, 3H,
OCH3), 3.91 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.93
(s, 3H, OCH3), 4.05 (dd, 1H, J = 7.0 and 12.0 Hz,
H-1ꢁꢁ), 4.43 (dd, 1H, J = 7.0 and 12.0 Hz, H-1ꢁꢁ),
4.84 (t, 2H, J = 6.5 Hz, H-3ꢁꢁꢁ), 5.07 (s, 1H, OCHO),
5.27 (s, 4H, 2 × OCH2O), 5.60 (d, 1H, J = 6.5 Hz,
H-2), 6.27 (d, 1H, J = 16.0 Hz, H-a), 6.35 (d, 1H, J =
16.0 Hz, H-aꢁ), 6.67–7.16 (m, 11H, ArH), 7.50 (d, 1H,
J = 16.0 Hz, H-b), 7.61 (d, 1H, J = 16.0 Hz, H-bꢁ).
13C NMR (125 MHz, CDCl3) δ 19.19, 24.96, 25.21,
30.27, 33.91, 50.51, 55.94 (2 × OCH3), 56.16 (2 ×
2.10 The formation of the dihydrobenzofuran
neolignan (10–12)
OCH3), 56.34 (2 × OCH3), 62.12, 63.78, 65.27, 88.72, 2.10a The formation of methyl (E,E)-4,4ꢁ-dihydroxy-
95.14, 97.50, 104.20, 110.25, 110.45, 110.86, 115.60, 3,5ꢁ-dimethopxy-ß-3ꢁ-bicinnamate (10): The com-
115.64, 115.91, 116.23, 116.24, 117.75, 118.85, pound 6 (82.9 mg, 0.2 mmol) was dissolved in acetone
121.36, 122.28, 122.51, 127.76, 128.49, 128.86, (10 ml) with KOH (22.4 mg, 0.4 mmol) and stirred at
134.44, 134.75, 144.19, 144.82, 145.33, 145.53, room temperature for 4 h. The solution was acidified
146.37, 148.22, 148.51, 148.74, 149.74, 149.88, 166.89 with HCl and partitioned between EtOAc and saturated
(C=O), 167.01 (C=O).
NaCl. The organic layer was dried over MgSO4, and

First total synthesis of Boehmenan
817
then crystallized (petroleum/acetic ether = 2/1) to give organic layer was dried over MgSO4, and then crystal-
compound 10 (62.1 mg).
lized (petroleum/acetic ether = 2/3) to give compound
12 (36.9 mg).
2.10b Methyl (E,E)-4,4ꢁ-dihydroxy-3,5ꢁ-dimethopxy-
ß-3ꢁ-bicinnamate (10): This compound was obtained
as pale yellow solid, 75% yield; mp. 148–149 C;
2.10f
(E)- 4 - hydroxy -3-( 2-[(E) -4- hydroxy -3-
◦
methoxystyryl]-}5-methoxycinnamic acid (12): This
compound was obtained as pale yellow oil, 54% yield;
HRMS calcd for C19H18O6 342.1103, found 342.1109;
1H NMR (500 MHz, CDCl3) δ 3.74 (s, 3H, OCH3),
3.83(s, 3H, OCH3), 6.46 (d, 1H, J = 15.5 Hz, H-8ꢁ),
6.76–7.52 (m, 5H, Ar-H), 7.21(d, 1H, J = 15.5 Hz, H-7),
7.22(d, 1H, J = 15.5 Hz, H-8), 7.53(d, 1H, J = 15.5 Hz,
H-7ꢁ), 9.14 (s, 1H, Ph-OH), 9.40 (s, 1H, Ph-OH), 12.20
HRMS calcd for C22H22O8 414.1315, found 414.1326;
1H NMR (500 MHz, CDCl3) δ 3.50 (s, 3H, OCH3),
3.78 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.94 (s,
3H, OCH3), 5.74 (s, 1H, OH), 6.00 (s, 1H, OH), 6.26
(d, 1H, J = 16.0 Hz, H-8ꢁ), 6.57–7.07 (m, 5H, Ar-H),
7.56 (d, 1H, J = 16.0 Hz, H-7ꢁ), 7.83 (s, 1H, H-7).
13C NMR (125 MHz, CDCl3) δ 52.02, 52.06, 55.22,
56.62, 110.59, 113.47, 115.58, 115.73, 124.53, 125.19,
125.63, 125.66, 126.13, 126.22, 140.68, 145.07,
147.58, 147.66, 148.72, 148.78, 167.02 (C=O), 167.40
(C=O).
(s, 1H, COOH). 13C NMR (125 MHz, CDCl3)
δ
56.06, 56.56, 109.55, 110.26, 116.17, 116.70, 119.95,
120.09, 120.37, 125.09, 125.90, 129.60, 129.89,
145.19, 146.37, 147.11, 148.32, 148.58, 168.50 (C=O).
The data are consistant with the literature.22
2.10c The formation of (E,E)-4,4ꢁ-dihydroxy-3,5ꢁ-
dimethopxy-ß-3ꢁ-bicinnamic acid (11): The com-
pound 6 (82.9 mg, 0.2 mmol) was dissolved in 10%
NaOH (10 ml) and stirred at room temperature for
4 h. The mixture was acidified with HCl and parti-
tioned between EtOAc and saturated NaCl. The organic
layer was dried over MgSO4, and then crystallized
(petroleum/acetic ether = 2/1) to give compound 11
(70.3 mg).
3. Results and discussion
The analytic and spectroscopic data of Boehmenan and
the intermediate products are given in experimental
section.
Our approach to the synthesis of natural product
Boehmenan 1 is outlined in scheme 2. Vanillin was used
as starting material. Compound 3 was formed through
Knoevenagel condensation between vanillin and methyl
hydrogen malonate. The 4-hydroxyl group of 3 was pro-
tected with MOMCl to afford the product 4, which was
hydrolysed to form compound 5.
The preparation of compound 6 from ferulic acid
methyl ester 3 by biomimetic oxidative coupling with
Ag2O to construct the skeleton of dihydrobenzofuran
lignan was the key step in our method. The reaction
gave different yield dependent on the reaction condi-
tions. As shown in table 1, freshly prepared Ag2O was
used in the reaction into compound 7 with higher yield
than that of conventional Ag2O and recycling Ag2O.
The solvent system had only small effect on the yield
of 7, but the reaction temperature and time had signif-
icant influence in the reaction. A decrease in the reac-
tion temperature increased the yield of compound 6,
2.10d (E,E)-4,4ꢁ-dihydroxy-3,5ꢁ-dimethopxy-ß-3ꢁ-bici-
nnamic acid (11): This compound was obtained as
pale yellow oil, 91% yield; HRMS calcd for C20H18O8
386.1002, found 386.1013; 1H NMR (500 MHz,
CDCl3) δ 3.88 (s, 3H, OCH3), 3.92 (s, 3H, OCH3),
6.37 (d, 1H, J = 16.0 Hz, H-8ꢁ), 6.71–7.37 (m, 5H,
Ar-H), 7.60 (d, 1H, J = 16.0 Hz, H-7ꢁ), 7.82 (s, 1H,
H-7), 12.15 (s, 2H, 2 × COOH). 13C NMR (125 MHz,
CDCl3) δ 55.93, 56.45, 110.27, 113.27, 116.24,
125.14, 125.62, 126.34, 126.37, 127.26, 127.59,
141.81, 145.81, 147.85, 148.02, 148.96, 149.12,
155.64, 168.56 (C=O), 169.18 (C=O). The data are
consistant with the literature.22
2.10e The formation of (E)-4-hydroxy-3-(2-[(E)-4- while the by product was decreased. Moreover, in the
hydroxy-3-methoxystyryl]-}5-methoxycinnamic acid process of the reaction, the yield increased to a maxi-
(12): The compound 6 (82.9 mg, 0.2 mmol) was mum and began to decrease as the time increased fur-
dissolved in 10% NaOH (10 ml) and stirred for 4 h ther. The optimum reaction conditions were obtained as
under reflux. Then the reaction solution was cooled and follows: freshly prepared Ag2O, dry acetone (20 mL)
◦
concentrated. The mixture was acidified with HCl and and toluene (30 mL), 30 h and −20 C. Under above
partitioned between EtOAc and saturated NaCl. The conditions, the yield of compound 6 was 45%.23,24

818
Yamu Xia et al.
Scheme 2. Formation of the stilbene 10 and diacid 11 from diester 6.
Conversion of 6 into intermediate 8 was carried out the attack of the nucleophile at the hydroxy-H seems to
by two steps: protection of dimers 6 with THP group initiate the opening of the dihydrobenzofuran ring to a
and reduction of the resulting compound 7 with LiAlH4. quinone methide intermediate, subsequent elimination
The protection of hydroxyl group as MOM ether is of H-proton and restoration of the aromatic ring system,
a commonly used transformation in synthetic organic followed by the formation of the compound 10 after
chemistry. So the methoxymethyl chloride was firstly acidification at room tempreture in organic solvent. But
chosen as a protecting reagent for free hydroxyl in the in H2O, the saponified products 11 is obtained.
presence of dry K2CO3 and acetone, but no reaction
The mechanism for the formation of compound 12
occurred. When treated with KOH in THF, compound is shown in scheme 3. In aqueous sodium hydroxide
6 was transformed to ring-opening product 10. Finally, solution under heating, the hydrolysis of diester 6
the target products 7 was gained by using DHP with results in the cyclic diacid. After the decarboxylation,
PPTS as protecting reagent. Thus, to research the ring- the acyclic products 12 is obtained with the openning of
openning reaction of compound 6 in the presence of the dihydrobenzofuran ring.
acid and base, various conditions, such as certain base,
solvent, temperature and time, were tested.
The intermediate 8 was condensated with compound
5 in the presence of DCC and DMAP at room tempe-
The results from table 2 show that the ring-openning rature to form compound 9. The removal of the protect-
compound 10 was obtained in the condition of entry 1– ing groups using PPTS and HCl at room temperature
6. When strongly basic with H2O was used as solvent, afforded the target product Boehmenan.
the diacid 11 was formed at room temperature with 91%
yield (entry 11), while at reflux, the monoacid 12 was
gained (entry 12). Treatment of the diester 6 with weak
base K2CO3 in the conditions (entry 7–9) did not pro-
duce any product, but at reflux in H2O, the compound 6
was transformed into 11 with 83% yield (entry 10).
The formation of 10 and 11 is proposed by the me-
chanism presented in scheme 2. At basic conditions,
4. Conclusion
In summary, we have developed an efficient syn-
thesis strategy of Boehmenan which was based on
biomimetic oxidative coupling to construct the skeleton
of lignan. The synthetic method has the advantages of
Table 1. Comparison of different reaction conditions and oxidant effect.
Entry
Preparation of Ag2O
Solvent
T (◦C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
Freshly prepared Ag2O
Freshly prepared Ag2O
Freshly prepared Ag2O
Recycling Ag2O
Acetone/toluene
Acetone/toluene
Acetone/toluene
Acetone/toluene
Acetone/toluene
CH2Cl2
Acetone/toluene
Acetone/toluene
Acetone/toluene
Acetone/toluene
25
25
25
25
25
25
0
8
21
41
33
17
21
37
43
39
45
38
24
32
24
24
24
28
34
30
36
Conventional Ag2O
Freshly prepared Ag2O
Freshly prepared Ag2O
Freshly prepared Ag2O
Freshly prepared Ag2O
Freshly prepared Ag2O
0
−25
−25

First total synthesis of Boehmenan
819
Table 2. The ring-opening reaction of compound 6 under different conditions.
Entry
Base
Reagent
T (◦C)
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
KOH
KOH
KOH
NaH
NaH
C2H5ONa
K2CO3
K2CO3
K2CO3
K2CO3
NaOH
NaOH
PPTS
Acetone
C2H5OH
DMF
THF
DMF
C2H5OH
Acetone
C2H5OH
H2O
H2O
H2O
H2O
CHCl3
–
r.t
r.t
r.t
r.t
r.t
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
10
10
10
10
10
10
–
–
–
11
11
12
–
75
72
65
87
86
94
–
–
–
83
91
65
–
r.t
56
78
r.t
100
r.t
100
r.t
r.t
9
10
11
12
13
14
15
HCl
CH3COOH
–
–
–
–
–
r.t
Scheme 3. Formation of the compound 12 from compound 6.
easy availability of starting materials and simple ope- References
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Acknowledgements
This work was supported by the National Natural Sci-
ence Foundation of Shandong (No. ZR2010HM023),
the Chinese Medicine Administration Bureau of Gansu
Province (No.GZK-2011-62).

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