Modular synthesis of polyphenolic benzofurans, and application in the total synthesis of malibatol A and shoreaphenol

Article abstract of DOI:10.3390/molecules15095909

A modular strategy for the synthesis of hexacyclic dimeric resveratrol polyphenolic benzofurans is reported. The developed synthetic technology was applied to the total synthesis of malibatol A, shoreaphenol, and other biologically relevant polyphenols.

Full text of DOI:10.3390/molecules15095909

Molecules 2010, 15, 5909-5927; doi:10.3390/molecules15095909
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Modular Synthesis of Polyphenolic Benzofurans, and
Application in the Total Synthesis of Malibatol A
and Shoreaphenol
David Y.-K. Chen *, Qiang Kang and T. Robert Wu
Chemical Synthesis Laboratory at Biopolis, Institute of Chemical and Engineering Sciences (ICES),
Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block,
No. 03-08, 138667, Singapore
* Author to whom correspondence should be addressed; E-Mail: david_chen@ices.a-star.edu.sg;
Tel.: +65-6799-8502; Fax: +65-6874-5869.
Received: 29 July 2010; in revised form: 26 August 2010 / Accepted: 27 August 2010 /
Published: 27 August 2010
Abstract: A modular strategy for the synthesis of hexacyclic dimeric resveratrol
polyphenolic benzofurans is reported. The developed synthetic technology was applied to
the total synthesis of malibatol A, shoreaphenol, and other biologically relevant poly-
phenols.
Keywords: cascade reaction; polyphenol; resveratrol; Friedel-Crafts; natural product;
total synthesis
1. Introduction
Polyphenolic secondary metabolites have attracted growing interest from the scientific community
in recent years [1-6]. However, despite their fascinating molecular architectures and diverse biological
properties, chemical syntheses of these natural products and/or designed analogues have been scarce
[7,8]. With this in mind, and as a continuation of our chemical and biological investigations of
polyphenolic natural products [9,10], we set out to develop a general strategy for the synthesis of
dimeric, resveratrol-derived benzofurans represented by generic structure 1, as shown in Figure 1. We
further demonstrated the developed technology in the total synthesis of malibatol A (2) and

Molecules 2010, 15
5910
shoreaphenol (3), two dimeric resveratrol polyphenolic benzofurans isolated from Hopea malibato and
Shorea robusta, respectively [11-13].
Figure 1. Generic molecular structure of polyphenolic benzofuran 1 and structures of
malibatol A (2) and shoreaphenol (3).
2. Results and Discussion
Recognizing the hexacyclic structure represented by 1 containing four substituted phenyl rings, we
envisaged a modular approach where each one of the phenyl rings can be installed independently and
sequentially. Therefore, as outlined in Scheme 1, the proposed synthesis begin with stilbene aldehyde
4, a building block with two aromatic domains brought together through a Horner-Wadswoth-Emmons
(HWE) olefination reaction [14] and a subsequent Vilsmeier formylation [15]. Introduction of a third
aromatic domain through the addition of an organometallic aryl species 5 to aldehyde 4, followed by
subsequent oxidation (IBX) should give ketone 6. The intermediate benzylic alcohol obtained prior to
IBX oxidation has previously been demonstrated by Snyder and co-workers as a versatile intermediate
to access a number of resveratrol derived natural products [7,8]. Carbonyl-directed selective
demethylation of 6 should lead to phenol 7, setting the stage for the attachment of the final aromatic
moiety through an alkylation with benzyl halide 8 or a Mitsunobu reaction [16] with benzyl alcohol 9.
With benzyl ether 10 in hand, the formation of the benzofuran ring is anticipated through its initial
benzylic deprotonation (LiTMP), followed by an intramolecular cyclization (11 to 12) and subsequent
dehydration (12 to 13, p-TsOH•H2O), to deliver pentacyclic benzofuran 13 [17]. Finally, the olefinic
functionality in stilbene 13 should serve as a versatile handle for either direct seven-membered ring
formation, or further transformation (14, e.g. epoxidation) leading to functionalized hexacycles 1 upon
ring closure.
With this general strategy in mind, its realization to generate a library of benzofuran polyphenols is
illustrated in Tables 1. As shown in Table 1, aryl ketones 16 and benzyl ethers 17 were efficiently
prepared in 8590% yield (over the two steps from 15) and 7195% yield (over the two steps from
16), respectively. Next, benzofuran formation from keto benzyl ethers 17 under the two-step procedure
generally proceeded in good yields (7185% yield, Table 2), apart from the failure of p-bromo
substrate to participate in the cyclization (entry 3, Table 2) and the less satisfactory dehydration for the
acid sensitive furanyl substrate (entry 5, Table 2).

Molecules 2010, 15
Scheme 1. General, modular strategy for the construction of hexacyclic benzofuran 1
5911
R
O
R3
OMe
H
R3
R1
HWE
R1
M
5
a)
O
O
b) IBX
formylation
R2
R2
c) BCl3
R = Me
R = H
4
d)
HO
R4
R4
X
or
R4
R4
R3
9
8: (X = Cl, Br)
H
B
R3
e)
O
O
O
Me
Me
Me
Me
R1
R1
N
Li
O
R2
R2
11
10
R4
R4
O
O
R1
R1
f) p-TsOH
OH
R3
R3
R2
R2
12
13
g) functionalization
R1
R4
R4
O
O
R1
h) ring closure
R5
Fn
R2
R3
R3
R2
1
14
Fn = functional group

Molecules 2010, 15
5912
Table 1. Preparation of ketone 16 and benzyl ether 17.
Entry R
Ar1
Ar2
16 Yield (%)b
85%
17 Yield (%)b
1(a)
2(b)
3(c)
4(d)
5(e)a
6(f)
7(g)
8(h)
9(i)
H
A
A
A
A
A
A
A
B
C6H5
C6H5
C6H5
89%
95%
92%
90%
71%
91%
95%
90%
87%
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
C6H5
3,4,5-(MeO)3C6H2
3,4-(MeO)2C6H3
3,5-(MeO)2C6H3
88%
88%
88%
88%
85%
90%
87%
86%
4-(Br)C6H4
4-(MeO)C6H4
2-furyl
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
Reagents and conditions: (a) Ar1MgBr (1.5 equiv), THF, 0 °C, 0.5 h; (b) IBX (2.0 equiv), DMSO,
23 °C, 2 h; (c) BCl3 (1.0 M in CH2Cl2, 1.5 equiv), CH2Cl2, 0 °C, 1 h; (d) NaH (2.0 equiv), Ar2CH2X
a
(entry 13, X = Br; entry 4, 69, X = Cl; 1.4 equiv), DMF, 0 °C. furanyl alcohol (3.0 equiv), PPh3
b
(3.0 equiv), DEAD (3.0 equiv), THF, 0 → 23 °C, 12 h. Yields refer to chromatographically and
spectroscopically homogeneous material. DMF
= N,N'-dimethylformamide, IBX = o-
iodoxybenzoic acid; DEAD = diethyl azodicarboxylate.
Table 2. Preparation of benzofuran 19.
Entry
R
H
A
A
A
A
A
A
A
B
Ar1
C6H5
Ar2
C6H5
19 Yield (%)a
83
71
0
87
38
80
85
81
85
1(a)
2(b)
3(c)
4(d)
5(e)
6(f)
7(g)
8(h)
9(i)
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
C6H5
3,4,5-(MeO)3C6H2
3,4-(MeO)2C6H3
3,5-(MeO)2C6H3
C6H5
4-(Br)C6H4
4-(MeO)C6H4
2-furyl
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
Reagents and conditions: (a) LiTMP (0.5 M in THF, 5 equiv), THF, 0 °C, 2 h; (b) p-TsOH•H2O (1.0
equiv), CH2Cl2, 23 °C, 1 h. aYields refer to chromatographically and spectroscopically homogeneous
material. LiTMP = Lithium 2,2,6,6-tetramethylpiperidide; p-TsOH = toluenesulfonic acid.

Molecules 2010, 15
5913
Finally, closure of the seven-membered ring was carried out under acidic conditions (p-TsOH•H2O)
to give cyclized compound 20 in high yields (9095% yield, entries 1, 2, 57, Table 3). The
incompatibility of the furanyl functionality under the acidic conditions was once again observed (entry
3, Table 3), and the electronically less favoured substrate 19d failed to participate in the FriedelCrafts
type cyclization (entry 4, Table 3).
Table 3. FriedelCrafts type cyclization of benzofurans 20
Entry
1(a)
2(b)
3(c)
4(d)
5(e)
6(f)
R
A
A
A
A
A
A
B
R1
3,5-(MeO)2
3,5-(MeO)2
3,5-(MeO)2
H
3,4,5-(MeO)3
3,4-(MeO)2
3,4-(MeO)2
Ar2
20 Yield (%)a
C6H5
95
90
0
0
92
90
4-(MeO)C6H4
2-furyl
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
7(g)
95
a
Reagents and conditions: (a) p-TsOH•H2O (3.0 equiv), CH2Cl2, 40 °C, 8 h. Yields refer to
chromatographically and spectroscopically homogeneous material.
In addition, we demonstrated a one-pot procedure to prepare hexacyclic benzofuran 20b directly
from keto benzyl ether stilbene 17d (Scheme 2). This highly efficient, cascade process involving
deprotonation-cyclization (LiTMP), dehydration and FriedelCrafts ring-closure (p-TsOH) illustrated
the utility of the developed methodology in the synthesis of highly functionalized, polycyclic
polyphenols, a useful structural class for both chemical and biological investigations.
Scheme 2. One-pot preparation of hexacyclic benzofuran 20b.
MeO
MeO
O
OMe
OMe
MeO
O
O
a) LiTMP
OMe
OMe
b) p-TsOH
O
Me
MeO
17d
20b
OMe
Reagents and conditions: (a) LiTMP (5.0 equiv), THF, 0 °C, 0.5 h; (b) p-TsOH•H2O (3.0 equiv),
CH2Cl2, 23 → 45 °C, 8 h, 80% for the two steps.

Molecules 2010, 15
5914
Next, the developed methodology was applied to the total synthesis of malibatol A (2) [18] and
shoreaphenol (3), as shown in Scheme 3 [19]. In this instance, with pentacyclic benzofuran 19d in
hand, construction of the oxygen-substituted, seven-membered ring in the malibatol A (2) and
shoreaphenol (3) framework called for an intramolecular FriedelCrafts type epoxide-opening process.
Thus, epoxidation of stilbene 19d under the bromohydrin protocol (NBS, NaOH), followed by
treatment of the resulting epoxide (21) with BBr3 resulted the concomitant cyclization and global
demethylation as a one-pot process, presumably through the intermediacy of 22, giving racemic
malibatol A (2) as a single diastereoisomer in 20% yield. Oxidation of malibatol A (2) in the presence
of PDC then afforded shoreaphenol (3), despite the modest yield of 46%. Both malibatol A (2) and
shoreaphenol (3) exhibited spectroscopic data (1H- and 13C-NMR) and mass spectrometry data
matching those reported for the natural substances [11-13].
Scheme 3. Total synthesis of malibatol A (2) and shoreaphenol (3).
Reagents and conditions: (a) NBS (1.1 equiv), DMSO/H2O (5:1), 0 °C, 0.5 h; then NaOH (4.0 M
aq.), PhEt3NCl (1.0 equiv), Et2O, 23 °C, 2 h, 75%; (b) BBr3 (1.0 M in CH2Cl2, 12 equiv), CH2Cl2,
78 → 23 °C, 2 h, 20%; (c) PDC (1.2 equiv), THF, 0 → 23 °C, 1 h, 46%. NBS = N-
bromosuccinimide, DMSO = dimethylsulfoxide, PDC = pyridinium dichromate.
3. Experimental
3.1. General
All reactions were carried out under a nitrogen or argon atmosphere with dry solvents under
anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran (THF) and methylene chloride

Molecules 2010, 15
5915
(CH2Cl2) were obtained by passing commercially available pre-dried, oxygen-free formulations
through activated alumina columns. Methanol (MeOH), N,N'-dimethylformamide (DMF), dimethyl-
sulfoxide (DMSO) and benzene were purchased in anhydrous form and used without further
purification. Acetone, water, ethyl acetate (EtOAc), diethyl ether (Et2O), methylene chloride (CH2Cl2),
and hexanes were purchased at the highest commercial quality and used without further purification,
unless otherwise stated. Reagents were purchased at the highest commercial quality and used without
further purification, unless otherwise stated. Yields refer to chromatographically and spectroscopically
(1H-NMR) homogeneous materials, unless otherwise stated. Reactions were monitored by thin-layers
chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as
visualizing agent and an ethanolic solution of ammonium molybdate and anisaldehyde and heat as
developing agents. E. Merck silica gel (60, particle size 0.0400.063 mm) was used for flash column
1
chromatography. H and 13C-NMR spectra were recorded at 600 and 150 MHz, respectively, on a
Bruker AV-600 instrument and calibrated using residual undeuterated solvent as an internal reference.
The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, quint = quintet, m = multiplet, pent = pentet, hex = hexet, br = broad. IR spectra were
recorded on a Perkin-Elmer Spectrum One FTIR spectrometer with diamond ATR accessory. Melting
points (m.p.) are uncorrected and were recorded on a Buchi B-540 melting point apparatus. High-
resolution mass spectra (HRMS) were recorded on an Agilent ESI TOF (time of flight) mass
spectrometer at 3500 V emitter voltage.
3.2. General procedure A (Preparation of diaryl ketones 16, Table 1)
To a solution of aldehyde 15 (2.0 mmol) in THF (20 mL) at 0 °C was added the appropriate
Grignard reagent (0.5 M in THF, 3.0 mmol). The resulting mixture was stirred for 0.5 h before it was
quenched with NH4Cl (5 mL, sat. aq.). The layers were separated and the aqueous layer was extracted
with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried
(Na2SO4) and concentrated in vacuo to afford the crude benzyl alcohol, which was used directly
without further purification. To the solution of crude benzyl alcohol (obtained as above) in DMSO
(5 mL) at 23 °C was added IBX (1.15 g, 4.1 mmol) in one portion. The resulting mixture was stirred
for 2 h before it was quenched with Na2S2O3 (5 mL, sat. aq.). The layers were separated and the
aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic layers were washed with
brine (30 mL), dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel)
afforded diaryl ketone 16. Using this general procedure the following compounds were prepared:
(2,4-Dimethoxyphenyl)(phenyl)methanone (16a). From 2,4-dimethoxybenzaldehyde and phenyl-
magnesium bromide. Flash column chromatography (silica gel, hexanes-EtOAc 4:1) afforded ketone
16a (412 mg, 85%) as a pale yellow foam. All physical properties of this compound were identical to
those reported in literature [20].
(E)-(2,4-Dimethoxy-6-(4-methoxystyryl)phenyl)(3,5-dimethoxyphenyl)methanone (16b). From (E)-2,4-
dimethoxy-6-(4-methoxystyryl)benzaldehyde and 3,5-dimethoxyphenylmagnesium bromide. Flash

Molecules 2010, 15
5916
column chromatography (silica gel, hexanes-EtOAc 2:1) afforded ketone 16b (764 mg, 88%) as a pale
yellow foam. All physical properties of this compound were identical to those reported in literature [8].
(E)-(2,4-Dimethoxy-6-(4-methoxystyryl)phenyl)(phenyl)methanone (16f). From (E)-2,4-dimethoxy-6-
(4-methoxystyryl)benzaldehyde and phenylmagnesium bromide. Flash column chromatography (silica
gel, hexanes-EtOAc 2:1) afforded ketone 16f (636 mg, 85%) as a pale yellow foam. 16f: Rf = 0.45
(silica gel, hexanes-EtOAc 2:1); IR (film) νmax 2938, 1661, 1595, 1510, 1253, 1161, 1078, 920, 830,
1
721 cm1; H-NMR (CD3CN):  = 7.807.78 (m, 2 H), 7.587.55 (m, 1 H), 7.467.43 (m, 2 H), 7.25
(d, J = 9.0 Hz, 2 H), 7.13 (d, J = 16.2 Hz, 1 H), 6.97 (d, J = 1.8 Hz, 1 H), 6.81 (d, J = 9.0 Hz, 2 H),
6.70 (d, J = 16.2 Hz, 1 H), 6.56 (d, J = 1.8 Hz, 1 H), 3.89 (s, 3 H), 3.71 (s, 3 H), 3.63 ppm (s, 3 H);
13C-NMR (CD3OD):  = 197.2, 161.6, 159.7, 158.3, 138.3, 137.4, 133.5, 131.2, 129.4, 129.1, 128.7,
127.9, 122.4, 121.0, 114.1, 101.4, 97.7, 55.5, 55.3, 54.9 ppm; HRMS (ESI): calcd for C24H22O4Na+ [M
+ Na+] 397.1410, found 397.1406.
(E)-(2,4-Dimethoxy-6-(4-methoxystyryl)phenyl)(3,4,5-trimethoxyphenyl)methanone (16g). From (E)-
2,4-dimethoxy-6-(4-methoxystyryl)benzaldehyde and 3,4,5-trimethoxyphenylmagnesium bromide.
Flash column chromatography (silica gel, hexanes-EtOAc 2:1) afforded ketone 16g (836 mg, 90%) as
a pale yellow foam. 16g: Rf = 0.25 (silica gel, hexanes-EtOAc 2:1); IR (film) νmax 2938, 1661, 1578,
1
1511, 1413, 1327, 1156, 1126, 834 cm1; H-NMR (CD3CN):  = 7.28 (d, J = 8.4 Hz, 2 H), 7.13 (d,
J = 16.2 Hz, 1 H), 7.08 (s, 2 H), 6.95 (d, J = 2.4 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 2 H), 6.67 (d,
J = 16.2 Hz, 1 H), 6.56 (d, J = 2.4 Hz, 1 H), 3.89 (s, 3 H), 3.77 (s, 3 H), 3.75 (s, 6 H), 3.74 (s, 3 H),
13
3.68 ppm (s, 3 H); C-NMR (CD3OD):  = 195.8, 161.5, 159.7, 158.2, 153.3, 142.7, 137.5, 133.6,
131.1, 129.4, 127.9, 122.6, 120.8, 114.1, 106.6, 101.4, 97.7, 60.0, 55.7, 55.5, 55.3, 54.9 ppm; HRMS
(ESI): calcd for C27H28O7Na+ [M + Na+] 487.1727, found 487.1712.
(E)-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)(3,4-dimethoxyphenyl)methanone (16h). From (E)-2,4-
dimethoxy-6-(4-methoxystyryl)benzaldehyde and 3,4-dimethoxyphenylmagnesium bromide. Flash
column chromatography (silica gel, hexanes-EtOAc 2:1) afforded ketone 16h (755 mg, 87%) as a pale
yellow foam. 16h: Rf = 0.20 (silica gel, hexanes-EtOAc 2:1); IR (film) νmax 2937, 1739, 1653, 1595,
1
1511, 1267, 1158, 835 cm1; H-NMR (CD3CN):  = 7.50 (d, J = 1.8 Hz, 1 H), 7.26 (d, J = 9.0 Hz,
2 H), 7.20 (dd, J = 8.4, 2.4 Hz, 1 H), 7.13 (d, J = 16.2 Hz, 1 H), 6.94 (d, J = 2.4 Hz, 1 H), 6.90 (d,
J = 8.4 Hz, 1 H), 6.83 (d, J = 9.0 Hz, 2 H), 6.65 (d, J = 16.2 Hz, 1 H), 6.55 (d, J = 1.8 Hz, 1 H), 3.89
(s, 3 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.74 (s, 3 H), 3.67 ppm (s, 3 H); 13C-NMR (CD3CN):  = 195.5,
161.3, 159.7, 158.0, 153.8, 149.2, 137.1, 131.3, 130.9, 129.4, 127.8, 125.1, 122.5, 121.3, 114.1, 110.5,
110.1, 101.1, 97.7, 55.5, 55.5, 55.3, 55.2, 54.9 ppm; HRMS (ESI): calcd for C26H26O6Na+ [M + Na+]
457.1621, found 457.1610.
(2,4-Dimethoxy-6-((4-methoxyphenyl)ethynyl)phenyl)(3,5-dimethoxyphenyl)methanone (16i). From
2,4-dimethoxy-6-[(4-methoxyphenyl)ethynyl]benzaldehyde and 3,5-dimethoxyphenylmagnesium
bromide. Flash column chromatography (silica gel, hexanes-EtOAc 2:1) afforded ketone 16i (743 mg,
86%) as a pale yellow foam. 16i: Rf = 0.28 (silica gel, hexanes-EtOAc 2:1); IR (film) νmax 2938, 1671,
1590, 1569, 1510, 1247, 1153, 1065, 832 cm1; 1H- NMR (CD3CN):  = 7.10 (d, J = 9.0 Hz, 2 H), 6.92

Molecules 2010, 15
5917
(d, J = 2.4 Hz, 2 H), 6.84 (d, J = 9.0 Hz, 2 H), 6.73 (d, J = 2.4 Hz, 1 H), 6.72 (t, J = 2.4 Hz, 1 H), 6.66
(d, J = 2.4 Hz, 1 H), 3.86 (s, 3 H), 3.77 (s, 6 H), 3.75 (s, 3 H), 3.72 ppm (s, 3 H); 13C-NMR (CD3CN):
 = 195.7, 162.3, 162.0, 161.0, 158.8, 140.7, 133.6, 125.0, 123.2, 115.0, 114.8, 108.6, 107.7, 106.1,
100.3, 94.2, 86.4, 56.5, 56.3, 56.2, 55.9 ppm; HRMS (ESI): calcd for C26H24O6Na+ [M + Na+]
455.1465, found 455.1467.
3.3. General procedure B (Preparation of benzyl ethers 17, Table 1)
To a solution of diaryl ketone 16 (1.0 mmol) in CH2Cl2 (10 mL) at 0 °C was added BCl3 (1.0 M in
CH2Cl2, 1.5 mL, 1.5 mmol) dropwise. The resulting mixture was stirred for 1 h before it was quenched
with NH4Cl (10 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4)
and concentrated in vacuo to afford the crude phenol, which was used directly without further
purification. To a solution of the crude phenol (obtained as above) in DMF (5 mL) at 0 °C was added
NaH (80 mg, 60% wt/wt in mineral oil, 2.0 mmol). The resulting mixture was stirred for 0.5 h before
benzyl bromide (or chloride) (1.4 mmol) was added. The reaction mixture was warmed to 23 °C and
the progress was monitored by TLC analysis. Upon completion of the reaction (<4 h for most cases),
the reaction mixture was quenched with NH4Cl (20 mL, sat. aq.). The layers were separated and the
aqueous layer was extracted with Et2O (3 × 20 mL). The combined organic layers were washed with
brine (30 mL), dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel)
afforded the desired benzyl ether 17. Using the described general procedure the following substances
were prepared:
(2-(Benzyloxy)-4-methoxyphenyl)(phenyl)methanone (17a). From ketone 16a and benzyl bromide.
Flash column chromatography (silica gel, hexanes-EtOAc 4:1) afforded benzyl ether 17a (283 mg,
89%) as a yellow foam. 17a: Rf = 0.35 (silica gel, hexanes-EtOAc 4:1); IR (film) νmax 1651, 1601,
1
1579, 1501, 1446, 1272, 1166, 1120, 737, 697 cm1; H-NMR (CD3CN):  = 7.737.72 (m, 2 H),
7.577.55 (m, 1 H), 7.467.41 (m, 3 H), 7.217.16 (m, 3 H), 6.936.92 (m, 2 H), 6.69 (d, J = 2.4 Hz,
1 H), 6.64 (dd, J = 8.4, 2.4 Hz, 1 H), 4.97 (s, 2 H), 3.84 ppm (s, 3 H); 13C-NMR (CD3CN):  = 195.6,
163.4, 158.3, 139.2, 136.5, 132.5, 131.6, 129.2, 128.3, 128.2, 127.6, 126.9, 121.7, 105.6, 99.7, 69.8,
55.4 ppm; HRMS (ESI): calcd for C21H18O3Na+ [M + Na+] 341.1148, found 341.1156.
(E)-(2-(Benzyloxy)-4-methoxy-6-(4-methoxystyryl)phenyl)(3,5-dimethoxyphenyl)methanone
(17b).
From ketone 16b and benzyl bromide. Flash column chromatography (silica gel, hexanes-EtOAc 2:1)
afforded benzyl ether 17b (485 mg, 95%) as a yellow foam. 17b: Rf = 0.45 (silica gel, hexanes-EtOAc
2:1); IR (film) νmax 1667, 1594, 1511, 1301, 1204, 1156, 1065, 829 cm1; 1H-NMR (CD3CN):  = 7.31
(d, J = 9.0 Hz, 2 H), 7.247.23 (m, 3 H), 7.14 (d, J = 16.2 Hz, 1 H), 7.047.02 (m, 2 H), 6.96 (d,
J = 2.4 Hz, 1 H), 6.88 (d, J = 2.4 Hz, 2 H), 6.86 (d, J = 9.0 Hz, 2 H), 6.736.70 (m, 2 H), 6.59 (d,
13
J = 1.8 Hz, 1 H), 4.99 (s, 2 H), 3.88 (s, 3 H), 3.76 (s, 3 H), 3.75 ppm (s, 6 H); C-NMR (CD3CN):
 = 196.8, 161.5, 161.1, 159.8, 157.2, 140.8, 137.7, 136.6, 131.3, 129.4, 128.3, 127.9, 127.8, 127.2,
122.4, 121.3, 114.1, 106.7, 105.1, 101.7, 99.0, 70.0, 55.3, 55.3, 54.9 ppm; HRMS (ESI): calcd for
C32H30O6Na+ [M + Na+] 533.1934, found 533.1951.

Molecules 2010, 15
5918
(E)-(2-((4-Bromobenzyl)oxy)-4-methoxy-6-(4-methoxystyryl)phenyl)(3,5-dimethoxyphenyl)methanone
(17c). From ketone 16b and 4-bromobenzyl bromide. Flash column chromatography (silica gel,
hexanes-EtOAc 2:1) afforded benzyl ether 17c (542 mg, 92%) as a yellow foam. 17c: Rf = 0.41 (silica
1
gel, hexanes-EtOAc 2:1); IR (film) νmax 2837, 1666, 1593, 1510, 1300, 1156, 1066, 806 cm1; H-
NMR (CD3CN):  = 7.37 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 9.0 Hz, 2 H), 7.15 (d, J = 16.2 Hz, 1 H),
6.97 (d, J = 2.4 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 2 H), 6.86 (d, J = 9.0 Hz, 2 H), 6.84 (s, 2 H), 6.72 (d,
J = 16.2 Hz, 1 H), 6.70 (t, J = 2.4 Hz, 1 H), 6.58 (d, J = 2.4 Hz, 1 H), 4.95 (s, 2 H), 3.88 (s, 3 H), 3.75
13
(s, 3 H), 3.74 ppm (s, 6 H); C-NMR (CD3CN):  = 196.8, 161.5, 161.1, 159.8, 157.1, 140.9, 137.9,
135.9, 131.3, 131.3, 129.4, 129.1, 127.9, 122.3, 121.3, 121.1, 114.1, 106.6, 105.1, 101.9, 99.0, 69.3,
55.3, 55.3, 54.9 ppm; HRMS (ESI): calcd for C32H29BrO6Na+ [M + Na+] 611.1039, found 611.1033.
(E)-(3,5-Dimethoxyphenyl)(4-methoxy-2-((4-methoxybenzyl)oxy)-6-(4-methoxystyryl)phenyl)-methan-
one (17d). From ketone 16b and 4-methoxybenzyl chloride. Flash column chromatography (silica gel,
hexanes-EtOAc 4:1) afforded benzyl ether 17d (486 mg, 90%) as a pale yellow solid. 17d: Rf = 0.40
(silica gel, hexanes-EtOAc 2:1); m.p. = 118119 °C (hexanes-EtOAc); IR (film) νmax 2970, 1738,
1594, 1512, 1352, 1302, 1249, 1204, 1156, 1065, 834 cm1; 1H-NMR (CDCl3):  = 7.31 (d, J = 9.0 Hz,
2 H), 7.03 (d, J = 15.0 Hz, 1 H), 6.98 (d, J = 2.4 Hz, 2 H), 6.92 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 2.4
Hz, 1 H), 6.85 (d, J = 14.4 Hz, 1 H), 6.82 (d, J = 9.0 Hz, 2 H), 6.74 (d, J = 9.0 Hz, 2 H), 6.66 (t, J = 2.4
Hz, 1 H), 6.45 (d, J = 2.4 Hz, 1 H), 4.88 (s, 2 H), 3.87 (s, 3 H), 3.77 (s, 6 H), 3.76 (s, 3 H), 3.75 ppm
13
(s, 3 H); C-NMR (CDCl3):  = 197.3, 161.1, 160.6, 159.3, 158.9, 157.3, 140.9, 137.8, 130.8, 129.4,
128.4, 128.2, 127.9, 122.8, 121.6, 113.8, 113.4, 106.9, 105.3, 101.2, 98.9, 69.8, 55.4, 55.3, 55.1, 55.0
ppm; HRMS (ESI): calcd for C33H32O7Na+ [M + Na+] 563.2040, found 563.2037.
(E)-(3,5-Dimethoxyphenyl)(2-(furan-2-ylmethoxy)-4-methoxy-6-(4-methoxystyryl)phenyl)methanone
(17e). To a solution of phenol 16b (420 mg, 1.0 mmol) in THF (10 mL) at 23 °C was added PPh3
(786 mg, 3.0 mmol). The resulting mixture was cooled to 0 °C before a solution of DEAD (522 mg,
3.0 mmol) and furfuryl alcohol (294 mg, 3.0 mmol) in THF (2 mL) were added. The resulting mixture
was warmed to 23 °C and stirred for 12 h before it was quenched with NH4Cl (5 mL, sat. aq.). The
layers were separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. Flash
column chromatography (silica gel, hexanes-EtOAc 4:1) afforded furanyl ether 17e (355 mg, 71%) as
a yellow oil. 17e: Rf = 0.72 (silica gel, benzene-EtOAc 8:1); IR (film) νmax 2937, 1667, 1592, 1510,
1
1456, 1300, 1155, 1063, 819 cm1; H-NMR (CD3CN):  = 7.38 (d, J = 1.2 Hz, 1 H), 7.28 (d,
J = 9.0 Hz, 2 H), 7.13 (d, J = 16.2 Hz, 1 H), 6.97 (d, J = 2.4 Hz, 1 H), 6.85 (d, J = 9.0 Hz, 2 H), 6.82
(d, J = 2.4 Hz, 2 H), 6.69 (t, J = 2.4 Hz, 1 H), 6.68 (d, J = 2.4 Hz, 1 H), 6.65 (t, J = 16.2 Hz, 1 H),
6.336.32 (m, 1 H), 6.28 (d, J = 3.6 Hz, 1 H), 4.95 (s, 2 H), 3.90 (s, 3 H), 3.75 (s, 3 H), 3.74 ppm (s,
13
6 H); C-NMR (CD3CN):  = 197.4, 162.2, 161.9, 160.6, 157.6, 150.7, 144.2, 141.3, 138.5, 132.2,
130.2, 128.8, 123.1, 122.3, 115.0, 111.3, 111.1, 107.6, 106.0, 103.0, 100.1, 63.5, 56.2, 56.1, 55.8 ppm;
HRMS (ESI): calcd for C30H28O7Na+ [M + Na+] 523.1727, found 523.1725.
(E)-(4-Methoxy-2-((4-methoxybenzyl)oxy)-6-(4-methoxystyryl)phenyl)(phenyl)methanone (17f). From
ketone 16f and 4-methoxybenzyl chloride. Flash column chromatography (silica gel, hexanes-EtOAc

Molecules 2010, 15
5919
2:1) afforded benzyl ether 17f (437 mg, 91%) as a yellow foam. 17f: Rf = 0.50 (silica gel, hexanes-
EtOAc 2:1); IR (film) νmax 1661, 1595, 1511, 1249, 1163, 1033, 827, 721 cm1; 1H-NMR (CD3CN): 
= 7.777.75 (m, 2 H), 7.627.59 (m, 1 H), 7.47 (t, J = 7.8 Hz, 2 H), 7.28 (d, J = 9.0 Hz, 2 H), 7.14 (d,
J = 16.2 Hz, 1 H), 6.97 (d, J = 1.8 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 2 H), 6.83 (d, J = 9.0 Hz, 2 H), 6.74
(d, J = 8.4 Hz, 2 H), 6.72 (d, J = 16.2 Hz, 1 H), 6.61 (d, J = 1.8 Hz, 1 H), 4.89 (s, 2 H), 3.89 (s, 3 H),
13
3.74 (s, 3 H), 3.71 ppm (s, 3 H); C-NMR (CD3CN):  = 198.5, 162.8, 161.0, 160.6, 158.7, 139.9,
139.0, 134.7, 132.5, 130.7, 130.4, 130.3, 130.0, 129.7, 129.2, 123.7, 122.8, 115.4, 114.9, 103.0, 100.4,
71.2, 56.6, 56.2, 56.1 ppm; HRMS (ESI): calcd for C31H28O5Na+ [M + Na+] 503.1829, found
503.1817.
(E)-(4-Methoxy-2-((4-methoxybenzyl)oxy)-6-(4-methoxystyryl)phenyl)(3,4,5-trimethoxyphenyl)methan-
one (17g). From ketone 16g and 4-methoxybenzyl chloride. Flash column chromatography (silica gel,
hexanes-EtOAc 2:1) afforded benzyl ether 17g (542 mg, 95%) as a yellow foam. 17g: Rf = 0.30 (silica
gel, hexanes-EtOAc 2:1); IR (film) νmax 1655, 1595, 1512, 1413, 1327, 1249, 1157, 1126, 832 cm1;
1H-NMR (d6-acetone):  7.35 (d, J = 9.0 Hz, 2 H), 7.22 (d, J = 15.6 Hz, 1 H), 7.08 (s, 2 H), 7.05 (d,
J = 2.4 Hz, 1 H), 6.97 (d, J = 8.4 Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 15.6 Hz, 1 H), 6.77
(d, J = 8.4 Hz, 2 H), 6.68 (d, J = 2.4 Hz, 1 H), 4.99 (s, 2 H), 3.91 (s, 3 H), 3.81 (s, 3 H), 3.77 (s, 9 H),
3.74 ppm (s, 3 H); 13C-NMR (d6-acetone):  = 195.3, 161.4, 159.8, 159.3, 157.5, 153.4, 142.8, 137.7,
134.4, 130.8, 129.6, 128.7, 128.6, 127.9, 122.7, 121.6, 114.0, 113.4, 106.6, 101.4, 99.0, 69.6, 59.8,
55.6, 54.9, 54.6, 54.5 ppm; HRMS (ESI): calcd for C34H34O8Na+ [M + Na+] 593.2145, found
593.2137.
(E)-(3,4-Dimethoxyphenyl)(4-methoxy-2-((4-methoxybenzyl)oxy)-6-(4-methoxystyryl)phenyl)methan-
one (17h). From ketone 16h and 4-methoxybenzyl chloride. Flash column chromatography (silica gel,
hexanes-EtOAc 2:1) afforded benzyl ether 17h (486 mg, 90%) as a yellow foam. 17h: Rf = 0.25 (silica
gel, hexanes-EtOAc 2:1); IR (film) νmax 1652, 1594, 1510, 1265, 1249, 1159, 1121, 1024, 833 cm1;
1H-NMR (CD3CN):  7.45 (d, J = 1.8 Hz, 1 H), 7.27 (d, J = 9.0 Hz, 2 H), 7.20 (dd, J = 8.4, 1.8 Hz, 1
H), 7.13 (d, J = 16.2 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 2 H), 6.95 (d, J = 2.4 Hz, 1 H), 6.89 (d, J = 8.4 Hz,
1 H), 6.83 (d, J = 9.0 Hz, 2 H), 6.76 (d, J = 9.0 Hz, 2 H), 6.70 (d, J = 16.2 Hz, 1 H), 6.60 (d, J = 2.4
Hz, 1 H), 4.91 (s, 2 H), 3.87 (s, 3 H), 3.83 (s, 3 H), 3.80 (s, 3 H), 3.73 (s, 3 H), 3.72 ppm (s, 3 H); 13C-
NMR (CD3CN):  = 195.7, 161.2, 159.7, 159.3, 157.1, 153.8, 149.2, 137.3, 131.6, 130.9, 129.4, 129.0,
128.5, 127.8, 124.9, 122.5, 121.9, 114.1, 113.6, 110.5, 110.2, 101.4, 99.2, 69.9, 55.6, 55.3, 55.3, 54.9,
54.8 ppm; HRMS (ESI): calcd for C33H32O7Na+ [M + Na+] 563.2040, found 563.2057.
(3,5-Dimethoxyphenyl)(4-methoxy-2-((4-methoxybenzyl)oxy)-6-((4-methoxyphenyl)ethynyl)phenyl)
methanone (17i). From ketone 16i and 4-methoxybenzyl chloride. Flash column chromatography
(silica gel, hexanes-EtOAc 2:1) afforded benzyl ether 17i (468 mg, 87%) as a yellow foam. 17i:
Rf = 0.27 (silica gel, hexanes-EtOAc 2:1); IR (film) νmax 2937, 1671, 1591, 1511, 1300, 1248, 1155,
1063, 832 cm1; 1H -NMR (CD3CN):  = 7.12 (d, J = 8.4 Hz, 2 H), 7.07 (d, J = 9.0 Hz, 2 H), 6.88 (d,
J = 2.4 Hz, 2 H), 6.84 (d, J = 9.0 Hz, 2 H), 6.81 (d, J = 8.4 Hz, 2 H), 6.74 (d, J = 2.4 Hz, 1 H), 6.72 (t,
J = 2.4 Hz, 1 H), 6.71 (d, J = 2.4 Hz, 1 H), 4.97 (s, 2 H), 3.85 (s, 3 H), 3.77 (s, 6 H), 3.76 (s, 3 H), 3.74
13
ppm (s, 3 H); C-NMR (CD3CN):  = 195.8, 162.2, 162.0, 161.0, 160.3, 157.8, 140.9, 133.6, 130.0,

Molecules 2010, 15
5920
129.1, 125.5, 123.4, 115.0, 114.8, 114.5, 108.9, 107.6, 106.0, 101.8, 94.1, 86.4, 70.9, 56.3, 56.2, 55.9,
55.7 ppm; HRMS (ESI): calcd for C33H30O7Na+ [M + Na+] 561.1883, found 561.1883.
3.4. General procedure C (Preparation of benzofurans 19, Table 2)
To a solution of benzyl ether 17 (0.2 mmol) in THF (2 mL) at 0 °C was added LiTMP (0.5 M in
THF, 2 mL, 1.0 mmol). The resulting mixture was stirred at 0 °C and the progress was monitored by
TLC analysis. Upon completion of the reaction (~ 2 h for most cases), the reaction mixture was
quenched with NH4Cl (5 mL, sat. aq.). The layers were separated and the aqueous layer was extracted
with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried
(Na2SO4) and concentrated in vacuo to afford crude tertiary alcohol 18, which was used directly
without further purification. To a solution of the crude tertiary alcohol 18 (obtained as above) in
CH2Cl2 (3 mL) at 23 °C was added p-TsOH•H2O (38 mg, 0.2 mmol). The resulting mixture was stirred
for 1 h before it was quenched with NaHCO3 (3 mL, sat. aq.). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with
brine (5 mL), dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel)
afforded the desired benzofuran 19. Using this general procedure the following compounds were
prepared:
6-Methoxy-2,3-diphenylbenzofuran (19a). From benzyl ether 17a. Flash column chromatography
(silica gel, hexanes-EtOAc 4:1) afforded benzofuran 19a (50 mg, 83%) as a pale yellow oil. All
physical properties of this compound were identical to those reported in literature [21].
(E)-3-(3,5-Dimethoxyphenyl)-6-methoxy-4-(4-methoxystyryl)-2-phenylbenzofuran (19b). From benzyl
ether 17b. Flash column chromatography (silica gel, hexanes-EtOAc 4:1) afforded benzofuran 19b
(70 mg, 71%) as a yellow oil. 19b: Rf = 0.42 (silica gel, hexanes-EtOAc 2:1); IR (film) νmax 1601,
1
1510, 1420, 1249, 1204, 1143, 1064, 1033, 808, 693 cm1; H-NMR (CD3CN):  = 7.587.57 (m, 2
H), 7.327.25 (m, 3 H), 7.15 (d, J = 2.4 Hz, 1 H), 7.06 (d, J = 2.4 Hz, 1 H), 7.01 (d, J = 16.2 Hz, 1 H),
6.99 (d, J = 8.4 Hz, 2 H), 6.83 (d, J = 9.0 Hz, 2 H), 6.79 (d, J = 16.2 Hz, 1 H), 6.72 (t, J = 2.4 Hz, 1 H),
6.65 (d, J = 2.4 Hz, 2 H), 3.88 (s, 3 H), 3.77 (s, 3H), 3.74 ppm (s, 6 H); 13C-NMR (CD3CN):  = 163.1,
160.8, 159.9, 156.3, 150.6, 138.0, 133.6, 131.9, 131.2, 130.1, 129.8, 129.3, 128.8, 127.1, 123.4, 122.8,
119.3, 115.3, 109.9, 108.0, 101.0, 96.1, 56.8, 56.6, 56.3 ppm; HRMS (ESI): calcd for C32H28O5Na+ [M
+ Na+] 515.1829, found 515.1837.
(E)-2-(4-Bromophenyl)-3-(3,5-dimethoxyphenyl)-6-methoxy-4-(4-methoxystyryl)benzofuran
(19c).
From benzyl ether 17c. The desired benzofuran 19c was not obtained in this reaction.
(E)-3-(3,5-Dimethoxyphenyl)-6-methoxy-2-(4-methoxyphenyl)-4-(4-methoxystyryl)benzofuran (19d).
From benzyl ether 17d. Flash column chromatography (silica gel, hexanes:-EtOAc 2:1) afforded
benzofuran 19d (91 mg, 87%) as a yellow solid. 19d: Rf = 0.52 (silica gel, hexanes-EtOAc 2:1);
m.p. = 6162 °C (hexanes-EtOAc); IR (film) νmax 2936, 1603, 1509, 1250, 1153, 1143, 1033, 833, 808
cm1; 1H-NMR (CD3CN):  = 7.43 (d, J = 8.4 Hz, 2 H), 7.07 (d, J = 2.4 Hz, 1 H), 6.956.89 (m, 4 H),

Molecules 2010, 15
5921
6.786.75 (m, 5 H), 6.68 (t, J = 2.4 Hz, 1 H), 6.59 (d, J = 2.4 Hz, 2 H), 3.82 (s, 3 H), 3.73 (s, 3 H),
13
3.70 (s, 6 H), 3.69 ppm (s, 3 H); C-NMR (CD3CN):  = 161.6, 159.4, 159.3, 158.1, 154.8, 149.4,
137.0, 131.8, 130.0, 128.4, 127.4, 127.3, 123.1, 122.4, 121.7, 116.2, 113.9, 113.8, 108.7, 106.4, 99.5,
94.7, 55.3, 55.2, 54.9, 54.8 ppm; HRMS (ESI): calcd for C33H30O6Na+ [M + Na+] 545.1934, found
545.1951.
(E)-3-(3,5-Dimethoxyphenyl)-2-(furan-2-yl)-6-methoxy-4-(4-methoxystyryl)benzofuran (19e). From
furanyl ether 17e. Flash column chromatography (silica gel, hexanes-EtOAc 2:1) afforded benzofuran
19e (36 mg, 38%) as a yellow oil. 19e: Rf = 0.40 (silica gel, hexanes-EtOAc 2:1); IR (film) νmax 2936,
1600, 1510, 1421, 1250, 1152, 1064, 819 cm1; 1H-NMR (CD3CN):  = 7.50 (d, J = 1.2 Hz, 1 H), 7.16
(d, J = 2.4 Hz, 1 H), 7.06 (d, J = 2.4 Hz, 1 H), 7.02 (d, J = 15.6 Hz, 1 H), 7.01 (d, J = 8.4 Hz, 2 H),
6.846.82 (m, 3 H), 6.70 (t, J = 2.4 Hz, 1 H), 6.62 (d, J = 2.4 Hz, 2 H), 6.46 (q, J = 1.8 Hz, 1 H), 6.38
13
(d, J = 3.0 Hz, 1 H), 3.88 (s, 3 H), 3.77 (s, 3 H), 3.76 ppm (s, 6 H); C-NMR (CD3CN):  = 162.2,
160.4, 159.5, 156.1, 146.2, 143.9, 143.4, 136.3, 133.1, 130.7, 129.8, 128.3, 123.0, 121.5, 114.9, 112.5,
109.4, 107.7, 100.6, 95.8, 56.4, 56.1, 55.8 ppm; HRMS (ESI): calcd for C30H26O6Na+ [M + Na+]
505.1621, found 505.1603.
(E)-6-Methoxy-2-(4-methoxyphenyl)-4-(4-methoxystyryl)-3-phenylbenzofuran (19f). According to
General Procedure C using benzyl ether 17f. Flash column chromatography (silica gel, hexanes-EtOAc
4:1) afforded benzofuran 19f (74 mg, 80%) as a yellow oil. 19f: Rf = 0.60 (silica gel, hexanes-EtOAc
1
2:1); IR (film) νmax 1605, 1511, 1251, 1175, 1144, 1033, 833, 702 cm1; H-NMR (d6-acetone):
 = 7.627.59 (m, 3 H), 7.527.50 (m, 2 H), 7.45 (d, J = 9.0 Hz, 2 H), 7.18 (d, J = 2.4 Hz, 1 H), 7.09
(d, J = 2.4 Hz, 1 H), 7.03 (d, J = 16.2 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 2 H), 6.86 (d, J = 9.0 Hz, 2 H),
13
6.80 (d, J = 8.4 Hz, 2 H), 6.73 (d, J = 16.2 Hz, 1 H), 3.91 (s, 3 H), 3.77 ppm (s, 6 H); C-NMR (d6-
acetone):  = 159.5, 159.5, 158.4, 155.0, 149.7, 135.1, 131.9, 130.7, 129.9, 129.3, 128.6, 128.0, 127.6,
127.3, 123.2, 121.9, 121.8, 116.4, 113.8, 113.8, 106.5, 94.7, 55.2, 54.7, 54.6 ppm; HRMS (ESI): calcd
for C31H26O4Na+ [M + Na+] 485.1723, found 485.1713.
(E)-6-Methoxy-2-(4-methoxyphenyl)-4-(4-methoxystyryl)-3-(3,4,5-trimethoxyphenyl)benzofuran (19g).
According to General Procedure C using benzyl ether 17g. Flash column chromatography (silica gel,
hexanes:EtOAc 2:1) afforded benzofuran 19g (94 mg, 85%) as a yellow oil. 19g: Rf = 0.34 (silica gel,
1
hexanes:EtOAc 2:1); IR (film) νmax 2936, 1604, 1511, 1409, 1250, 1126, 1033, 838 cm1; H-NMR
(CD3CN):  = 7.50 (d, J = 9.0 Hz, 2 H), 7.14 (d, J = 1.8 Hz, 1 H), 7.056.99 (m, 4 H), 6.86 (d,
J = 9.0 Hz, 2 H), 6.81 (d, J = 16.2 Hz, 1 H), 6.78 (d, J = 9.0 Hz, 2 H), 6.75 (s, 2 H), 3.88 (s, 3 H), 3.86
13
(s, 3 H), 3.76 (s, 3 H), 3.75 (s, 3 H), 3.68 ppm (s, 6 H); C-NMR (CD3CN):  = 159.5, 159.4, 158.2,
154.8, 154.0, 149.7, 137.9, 132.0, 130.1, 130.0, 128.8, 127.4, 127.3, 123.2, 122.3, 121.7, 116.4, 114.0,
113.9, 107.9, 106.6, 94.8, 60.3, 55.9, 55.4, 54.9, 54.9 ppm; HRMS (ESI): calcd for C34H32O7Na+ [M +
Na+] 575.2040, found 575.2048.
(E)-3-(3,4-Dimethoxyphenyl)-6-methoxy-2-(4-methoxyphenyl)-4-(4-methoxystyryl)benzofuran (19h).
From benzyl ether 17h. Flash column chromatography (silica gel, hexanes-EtOAc 2:1) afforded
benzofuran 19h (85 mg, 81%) as a yellow oil. 19h: Rf = 0.35 (silica gel, hexanes-EtOAc 2:1); IR (film)

Molecules 2010, 15
5922
νmax 2923, 1604, 1509, 1247, 1138, 1026, 833, 734 cm1; 1H-NMR (CD3CN):  = 7.49 (d, J = 9.0 Hz,
2 H), 7.12 (d, J = 1.8 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 7.03 (d, J = 2.4 Hz, 1 H), 7.02 (d, J = 2.4 Hz,
1 H), 6.996.96 (m, 4 H), 6.85 (d, J = 9.0 Hz, 2 H), 6.79 (d, J = 9.0 Hz, 2 H), 6.73 (d, J = 16.2 Hz,
1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.77 (s, 3 H), 3.76 (s, 3 H), 3.67 ppm (s, 3 H); 13C-NMR (CD3CN):
 = 159.4, 159.4, 158.2, 154.8, 149.9, 149.8, 149.3, 132.0, 130.0, 128.5, 127.5, 127.3, 126.9, 123.3,
122.9, 122.3, 122.0, 116.3, 114.2, 113.9, 113.9, 112.2, 106.4, 94.8, 55.6, 55.5, 55.4, 54.9 ppm; HRMS
(ESI): calcd for C33H30O6Na+ [M + Na+] 545.1934, found 545.1946.
3-(3,5-Dimethoxyphenyl)-6-methoxy-2-(4-methoxyphenyl)-4-((4-methoxyphenyl)ethynyl)benzofuran
(19i). From benzyl ether 17i. Flash column chromatography (silica gel, hexanes-EtOAc 4:1) afforded
benzofuran 19i (88 mg, 85%) as a yellow oil. 19i: Rf = 0.70 (silica gel, hexanes-EtOAc 2:1); IR (film)
νmax 2935, 1604, 1510, 1485, 1248, 1152, 1035, 831 cm1; 1H-NMR (CD3CN):  = 7.47 (d, J = 9.0 Hz,
2 H), 7.16 (d, J = 2.4 Hz, 1 H), 7.02 (d, J = 8.4 Hz, 2 H), 6.99 (d, J = 2.4 Hz, 1 H), 6.87 (d, J = 9.0 Hz,
2 H), 6.85 (d, J = 8.4 Hz, 2 H), 6.64 (d, J = 2.4 Hz, 2 H), 6.56 (t, J = 2.4 Hz, 1 H), 3.87 (s, 3 H), 3.79
13
(s, 3 H), 3.77 (s, 3 H), 3.70 ppm (s, 6 H); C-NMR (CD3CN):  = 161.8, 160.7, 160.6, 158.5, 155.4,
151.5, 135.8, 133.7, 128.6, 123.9, 123.7, 117.3, 116.4, 116.0, 115.5, 114.8, 114.7, 109.9, 100.4, 97.6,
94.6, 86.1, 56.5, 55.9, 55.8 ppm; HRMS (ESI): calcd for C33H28O6Na+ [M + Na+] 543.1778, found
543.1773.
3.5. General procedure D (Preparation of hexacyclic benzofurans 20, Table 3)
To a solution of benzofuran 19 (0.04 mmol) in CH2Cl2 (6 mL) at 23 °C was added p-TsOH•H2O
(22.8 mg, 0.12 mmol). The resulting mixture was heated to 40 °C and stirred for 8 hours before it was
quenched with NaHCO3 (3 mL, sat. aq.). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried
(Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel) afforded the desired
hexacyclic benzofuran 20. The following compounds were prepared via this general procedure:
1,3,8-Trimethoxy-11-(4-methoxyphenyl)-5-phenyl-10,11-dihydrobenzo[6,7]cyclohepta[1,2,3-cd]benzo-
furan (20a). From benzofuran 19b. Flash column chromatography (silica gel, hexanes-EtOAc 4:1)
afforded hexacyclic benzofuran 20a (18.7 mg, 95%) as a yellow oil. 20a: Rf = 0.57 (silica gel,
hexanes-EtOAc 2:1); IR (film) νmax 2933, 1598, 1509, 1461, 1248, 1144, 1065, 853, 696 cm1;
1H- NMR (CD3CN):  = 7.667.64 (m, 2 H), 7.477.41 (m, 3 H), 7.01 (d, J = 8.4 Hz, 2 H), 6.78 (d,
J = 1.8 Hz, 1 H), 6.71 (d, J = 1.8 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 2 H), 6.58 (d, J = 2.4 Hz, 1 H), 6.53 (d,
J = 2.4 Hz, 1 H), 5.44 (d, J = 5.4 Hz, 1 H), 3.81 (s, 3 H), 3.78 (s, 3 H), 3.72 (dd, J = 16.2, 5.4 Hz, 1 H),
13
3.58 (s, 3 H), 3.44 (s, 3 H), 3.37 ppm (d, J = 16.2 Hz, 1 H); C-NMR (CD3CN):  = 158.6, 158.3,
158.1, 157.2, 154.2, 150.6, 135.4, 134.1, 133.9, 131.7, 128.9, 128.7, 128.7, 128.3, 123.9, 119.8, 112.9,
112.6, 107.2, 97.8, 92.7, 55.8, 55.2, 54.5, 54.4, 36.7, 36.6 ppm; HRMS (ESI): calcd for C32H28O5Na+
[M + Na+] 515.1829, found 515.1835.
1,3,8-Trimethoxy-5,11-bis(4-methoxyphenyl)-10,11-dihydrobenzo[6,7]cyclohepta[1,2,3-cd]benzofuran
(20b). From benzofuran 19d. Flash column chromatography (silica gel, hexanes-EtOAc 4:1) afforded

Molecules 2010, 15
5923
hexacyclic benzofuran 20b (18.8 mg, 90%) as a yellow oil. 20b: Rf = 0.49 (silica gel, hexanes-EtOAc
1
2:1); IR (film) νmax 2933, 1599, 1508, 1460, 1248, 1143, 1067, 1032, 834 cm1; H-NMR (CD3CN):
 = 7.57 (d, J = 9.0 Hz, 2 H), 7.006.98 (m, 4 H), 6.75 (d, J = 1.8 Hz, 1 H), 6.69 (d, J = 1.8 Hz, 1 H),
6.61 (d, J = 2.4 Hz, 1 H), 6.58 (d, J = 9.0 Hz, 2 H), 6.51 (d, J = 2.4 Hz, 1 H), 5.43 (d, J = 6.0 Hz, 1 H),
3.83 (s, 3 H), 3.80 (s, 3 H), 3.76 (s, 3 H), 3.69 (dd, J = 16.2, 6.0 Hz, 1 H), 3.57 (s, 3 H), 3.47 (s, 3 H),
13
3.35 ppm (d, J = 16.2 Hz, 1 H); C-NMR (CD3CN):  = 160.2, 158.6, 158.3, 157.8, 157.2, 154.0,
150.7, 135.2, 134.2, 134.1, 130.2, 128.3, 123.9, 123.8, 119.9, 116.1, 114.1, 112.9, 112.3, 106.9, 97.6,
92.6, 55.8, 55.2, 55.1, 54.5, 54.4, 36.7, 36.6 ppm; HRMS (ESI): calcd for C33H30O6Na+ [M + Na+]
545.1934, found 545.1948.
5-(Furan-2-yl)-1,3,8-trimethoxy-11-(4-methoxyphenyl)-10,11-dihydrobenzo[6,7]cyclohepta[1,2,3-cd]-
benzofuran (20c). From benzofuran 19e. The desired product 20c was not obtained in this reaction.
8-Methoxy-5,11-bis(4-methoxyphenyl)-10,11-dihydrobenzo[6,7]cyclohepta[1,2,3-cd]benzofuran (20d).
From benzofuran 19f. The desired product 20d was not obtained in this reaction.
1,2,3,8-Tetramethoxy-5,11-bis(4-methoxyphenyl)-10,11-dihydrobenzo[6,7]cyclohepta[1,2,3-cd]benzo-
furan (20e). From benzofuran 19g. Flash column chromatography (silica gel, hexanes-EtOAc 4:1)
afforded hexacyclic benzofuran 20e (20.3 mg, 92%) as a yellow oil. 20e: Rf = 0.48 (silica gel, hexanes-
EtOAc 2:1); IR (film) νmax 2933, 1611, 1508, 1316, 1248, 1143, 1037, 835 cm1; 1H-NMR (CD3CN): 
= 7.60 (d, J = 8.4 Hz, 2 H), 7.027.00 (m, 4 H), 6.89 (s, 1 H), 6.75 (s, 1 H), 6.69 (s, 1 H), 6.58 (d,
J = 8.4 Hz, 2 H), 5.31 (d, J = 5.4 Hz, 1 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.76 (s, 3 H), 3.74 (dd, J = 16.2,
5.4 Hz, 1 H), 3.73 (s, 3 H), 3.40 (d, J = 16.2 Hz, 1 H), 3.39 ppm (s, 3 H); 13C-NMR (CD3CN):
 = 160.2, 157.9, 157.2, 154.0, 152.2, 151.2, 150.1, 141.4, 134.9, 134.1, 130.1, 129.4, 128.3, 128.0,
123.9, 119.9, 115.8, 114.1, 112.9, 112.4, 110.2, 92.7, 61.2, 60.2, 55.2, 55.1, 54.8, 54.5, 38.0, 36.8 ppm;
HRMS (ESI): calcd for C33H30O6Na+ [M + Na+] 545.1934, found 545.1948.
2,3,8-Trimethoxy-5,11-bis(4-methoxyphenyl)-10,11-dihydrobenzo[6,7]cyclohepta[1,2,3-cd]benzofuran
(20f). From benzofuran 19h. Flash column chromatography (silica gel, hexanes-EtOAc 2:1) afforded
hexacyclic benzofuran 20f (18.8 mg, 90%) as a yellow oil. 20f: Rf = 0.35 (silica gel, hexanes-EtOAc
1
2:1); IR (film) νmax 2934, 1610, 1511, 1499, 1251, 1177, 1143, 1035, 834, 793 cm1; H-NMR
(CD3CN):  = 8.07 (d, J = 9.0 Hz, 2 H), 7.23 (s, 1 H), 7.08 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 8.4 Hz,
2 H), 6.70 (d, J = 8.4 Hz, 2 H), 6.64 (d, J = 2.4 Hz, 1 H), 6.57 (s, 1 H), 6.21 (d, J = 2.4 Hz, 1 H), 4.63
(dd, J = 6.6, 2.4 Hz, 1 H), 3.90 (s, 3 H), 3.74 (s, 3 H), 3.69 (s, 3 H), 3.66 (s, 3 H), 3.65 (s, 3 H), 3.62
13
(dd, J = 14.4, 2.4 Hz, 1 H), 3.15 ppm (dd, J = 14.4, 6.6 Hz, 1 H); C-NMR (CD3CN):  = 193.6,
165.3, 165.0, 162.1, 158.8, 153.5, 150.5, 148.4, 139.9, 139.6, 136.3, 132.9, 131.8, 130.4, 127.8, 122.6,
114.9, 114.6, 114.1, 113.4, 112.7, 107.6, 56.3, 56.3, 56.2, 56.1, 55.6, 49.7, 41.4 ppm; HRMS (ESI):
calcd for C33H30O6Na+ [M + Na+] 545.1934, found 545.1943.
1,3,8-Trimethoxy-5,11-bis(4-methoxyphenyl)benzo[6,7]cyclohepta[1,2,3-cd]benzofuran (20g). From
benzofuran 19i. Flash column chromatography (silica gel, hexanes-EtOAc 4:1) afforded hexacyclic
benzofuran 20g (19.8 mg, 95%) as a yellow oil. 20g: Rf = 0.70 (silica gel, hexanes-EtOAc 2:1); IR

Molecules 2010, 15
5924
1
(film) νmax 2919, 1738, 1606, 1505, 1462, 1365, 1247, 1199, 833 cm1; H-NMR (CD3CN):  = 7.82
(d, J = 9.0 Hz, 2 H), 7.21 (d, J = 9.0 Hz, 2 H), 7.08 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 9.0 Hz, 2 H), 6.78
(d, J = 1.8 Hz, 1 H), 6.64 (d, J = 1.8 Hz, 1 H), 6.62 (d, J = 2.4 Hz, 1 H), 6.59 (s, 1 H), 6.29 (d, J = 2.4
Hz, 1 H), 3.86 (s, 3 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 3.43 (s, 3 H), 3.17 ppm (s, 3 H); 13C-NMR
(CD3CN):  = 161.4, 161.4, 161.3, 159.8, 158.8, 155.0, 151.9, 141.9, 141.7, 138.2, 133.8, 132.4,
131.0, 127.4, 127.1, 125.0, 120.6, 116.4, 115.1, 114.1, 111.9, 106.2, 100.3, 94.6, 56.2, 56.0, 56.0, 55.7,
55.3 ppm; HRMS (ESI): calcd for C33H30O6Na+ [M + Na+] 543.1784, found 543.1745.
3.6. One-pot preparation of hexacyclic benzofuran 20b
To a solution of benzyl ketone 17d (100 mg, 0.185 mmol) in THF (3 mL) at 0 °C was added
LiTMP (0.5 M in THF, 1.9 mL, 0.93 mmol). The resulting mixture was stirred at 0 °C for 30 min
before it was quenched with NH4Cl (5 mL, sat. aq.). The layers were separated and the aqueous layer
was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL),
dried (Na2SO4) and concentrated in vacuo to afford crude alcohol, which was used directly without
further purification. To a solution of the crude alcohol (obtained as above) in CH2Cl2 (3 mL) at 23 °C
was added p-TsOH•H2O (105 mg, 0.56 mmol). The resulting mixture was heated to 45 °C and stirred
for 8 h before it was quenched with NaHCO3 (3 mL, sat. aq.). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with
brine (5 mL), dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel,
hexanes-EtOAc 2:1) afforded the desired hexacyclic benzofuran 20b (77 mg, 80%) as a yellow oil.
(E)-(3,5-Dimethoxyphenyl)(2-hydroxy-4-methoxy-6-(4-methoxystyryl)phenyl)methanone (16b'). To a
solution of ketone 16b (13.0 g, 30 mmol) in CH2Cl2 (100 mL) at 0 °C was added BCl3 (1 M in CH2Cl2,
45 mL, 45 mmol) dropwise. The resulting mixture was stirred for 1 h before it was quenched with
NaHCO3 (50 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with CH2Cl2
(3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and
concentrated in vacuo. Flash column chromatography (silica gel, hexanes-EtOAc-CH2Cl2 4:1:1)
afforded phenol 16b' (12 g, 95%) as a yellow solid. 16b': Rf = 0.45 (silica gel, hexanes-EtOAc 2:1);
m.p. = 139140 °C (hexanes-EtOAc); IR (film) νmax 2939, 1600, 1511, 1457, 1254, 1204, 1157, 1064,
840, 808 cm1; 1H-NMR (CDCl3):  = 11.5 (br s, 1 H), 6.89 (d, J = 8.4 Hz, 2 H), 6.74 (d, J = 8.4 Hz,
2 H), 6.72 (d, J = 2.4 Hz, 2 H), 6.67 (d, J = 2.4 Hz, 1 H), 6.65 (d, J = 16.2 Hz, 1 H), 6.48 (t, J = 2.4 Hz,
1 H), 6.47 (d, J = 2.4 Hz, 1 H), 6.46 (d, J = 15.6 Hz, 1 H), 3.88 (s, 3 H), 3.78 (s, 3 H), 3.68 ppm (s,
6 H); 13C-NMR (CDCl3):  = 200.1, 164.7, 164.6, 160.6, 159.4, 142.7, 142.7, 130.0, 129.5, 127.7,
126.9, 113.8, 113.3, 106.9, 106.3, 104.4, 99.9, 55.6, 55.2 ppm; HRMS (ESI): calcd for C25H24O6Na+
[M + Na+] 443.1465, found 443.1454.
3-(3,5-Dimethoxyphenyl)-6-methoxy-2-(4-methoxyphenyl)-4-(3-(4-methoxyphenyl)oxiran-2-yl)benzo-
furan (21). To a solution of benzofuran 19d (4.20 g, 8.04 mmol) in DMSO (50 mL) and water (10 mL)
at 0 °C was added NBS (1.57 g, 8.84 mmol) in one portion. The resulting mixture was stirred for 0.5 h
before it was quenching with Na2S2O3 (50 mL, sat. aq.). The layers were separated and the aqueous
layer was extracted with Et2O (3 × 100 mL). The combined organic layers were washed with brine

Molecules 2010, 15
5925
(100 mL), dried (Na2SO4) and concentrated in vacuo to afford the crude bromohydrin, which was use
directly without further purification. To a solution of crude bromohydrin (obtained as above) in Et2O
(100 mL) at 23 °C were added NaOH (4 M, aq., 30 mL) and PhEt3NCl (1.83 g, 8.04 mmol). The
resulting mixture was stirred for 2 h before the layers were separated, and the aqueous layer was
extracted with Et2O (3 × 100 mL). The combined organic layers were washed with brine (100 mL),
dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes-EtOAc
2:1) afforded epoxide 21 (3.25 g, 75%, over the two steps) as a yellow solid. 21: Rf = 0.55 (silica gel,
hexanes-EtOAc 2:1); m.p. = 147148 °C (hexanes/CH2Cl2); IR (film) νmax 2939, 1738, 1611, 1587,
1
1512, 1204, 1154, 1033, 832 cm1; H-NMR (CDCl3):  = 7.47 (d, J = 9.0 Hz, 2 H), 7.02 (d, J = 1.8
Hz, 1 H), 6.89 (d, J = 8.4 Hz, 2 H), 6.86 (d, J = 1.8 Hz, 1 H), 6.80 (d, J = 8.4 Hz, 2 H), 6.79 (d, J = 9.0
Hz, 2 H), 6.54 (br, 1 H), 6.31 (br, 1 H), 6.18 (t, J = 1.8 Hz, 1 H), 3.89 (s, 3 H), 3.83 (s, 3 H), 3.79 (d,
J = 2.4 Hz, 1 H), 3.77 (s, 3 H), 3.74 (br, 3 H), 3.53 (d, J = 2.4 Hz, 1 H), 3.30 ppm (br, 3 H); 13C-NMR
(CDCl3):  = 161.0, 159.7, 159.2, 158.2, 154.2, 149.7, 136.0, 131.5, 128.5, 127.2, 126.9, 123.2, 122.5,
115.4, 113.8, 113.6, 107.7 (br), 105.9, 99.7, 95.3, 63.1, 59.1, 55.8, 55.3, 55.2, 54.7 (br) ppm; HRMS
(ESI): calcd for C33H30O7Na+ [M + Na+] 561.1883, found 561.1898.
Malibatol A (2): To a solution of epoxide 21 (100 mg, 0.19 mmol) in CH2Cl2 (30 mL) at 78 °C was
added BBr3 (1.0 M in CH2Cl2, 2.28 mL, 2.28 mmol). The resulting mixture was warmed to 23 °C and
stirred for 2 h before it was quenched with NaHCO3 (10 mL, sat. aq.). The layers were separated and
the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed
with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica
gel, CH2Cl2-MeOH 9:1) afforded malibatol (2, 17.8 mg, 20%) as a tan oil. Compound 2: Rf = 0.23
(silica gel, CH2Cl2-MeOH 9:1); IR (film) νmax 3323, 2918, 1612, 1510, 1433, 1366, 1231, 1139,
1
833 cm1; H-NMR (CD3OD):  = 7.45 (d, J = 8.6 Hz, 2 H), 7.02 (d, J = 8.6 Hz, 2 H), 7.01 (d,
J = 2.4 Hz, 1 H), 6.80 (d, J = 8.6 Hz, 2 H), 6.57 (dd, J = 2.4, 1.2 Hz, 1 H), 6.51 (d, J = 2.4 Hz, 1 H),
13
6.33 (d, J = 9.0 Hz, 2 H), 6.30 (d, J = 2.4 Hz, 1 H), 5.46 (brs, 1 H), 5.28 ppm (m, 1 H); C-NMR
(CD3OD):  = 159.1, 157.4, 156.7, 156.2, 155.3, 155.1, 151.2, 139.6, 135.8, 133.4, 130.9, 130.6,
124.6, 121.2, 119.0, 117.3, 116.4, 114.7, 109.9, 109.7, 102.1, 95.9, 74.8, 48.9 ppm; HRMS (ESI):
calcd for C28H20O7Na+ [M + Na+] 491.1101, found 491.1092.
Shoreaphenol (3): To a solution of malibatol A (2) (5 mg, 10.7 µmol) in THF (1 mL) at  °C was
added PDC (4.8 mg, 12.8 µmol). The resulting mixture was stirred for 1 h before it was quenched with
Na2S2O3 (1 mL, sat. aq.). The layers were separated and the aqueous layer was extracted with EtOAc
(3 × 2 mL). The combined organic layers were washed with brine (3 mL), dried (Na2SO4) and
concentrated in vacuo. Flash column chromatography (silica gel, CH2Cl2-MeOH 5:1) afforded
shoreaphenol (3, 2.3 mg, 46%) as a yellow oil. Compound 3: Rf = 0.26 (silica gel, CH2Cl2-MeOH 9:1);
1
IR (film) νmax 3339, 1738, 1612, 1366, 1216, 829 cm1; H-NMR (d6-acetone):  = 7.70 (d,
J = 8.4 Hz, 2 H), 7.33 (d, J = 2.4 Hz, 1 H), 7.04 (d, J = 1.8 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 2 H), 6.85 (d,
J = 7.8 Hz, 2 H), 6.70 (d, J = 2.4 Hz, 1 H), 6.57 (d, J = 2.4 Hz, 1 H), 6.55 (d, J = 8.4 Hz, 2 H), 6.12
13
(brs, 1 H), 5.28 ppm (m, 1 H); C-NMR (d6-acetone):  = 196.3, 159.5, 158.3, 157.7, 156.4, 156.1,
154.9, 153.3, 135.2, 131.1, 131.0, 130.6, 128.5, 123.1, 122.4, 116.6, 116.4, 115.6, 114.0, 112.0, 109.0,
103.0, 102.4, 56.1 ppm; HRMS (ESI): calcd for C28H18O7Na+ [M + Na+] 489.0950, found 489.0955.

Molecules 2010, 15
5926
4. Conclusions
In conclusion, a modular and efficient entry to the dimeric resveratrol derived polyphenolic
benzofurans has been developed, and applied to the total synthesis of malibatol A (2) and shoreaphenol
(3). In view of the largely untapped potential of the polyphenolic secondary metabolites, the synthetic
methodology described herein should find wide application in the chemical and biological
investigations of this fascinating class of compounds.
Acknowledgements
We thank Doris Tan (ICES) for high resolution mass spectrometric (HRMS) assistance and Rong-Ji
Sum (CSL-ICES) for his assistance in the biological studies. Financial support for this work was
provided by A*STAR, Singapore.
References and Notes
1. Yang, C.S.; Lambert, J.D.; Sang, S. Antioxidative and anti-carcinogenic activities of tea
polyphenols. Arch. Toxicol. 2009, 83, 1121.
2. Bonfili, L.; Cecarini, V.; Amici, M.; Cuccioloni, M.; Angeletti, M.; Keller, J.N.; Eleuteri, A.M.
Natural polyphenols as proteasome modulators and their role as anti-cancer compounds. FEBS J.
2008, 275, 55125526.
3. Lafay, S.; Gil-Izquierdo, A. Bioavailability of phenolic acids. Phytochem. Rev. 2008, 7, 301311.
4. Habauzit, V.; Horcajada, M.-N. Phenolic phytochemicals and bone. Phytochem. Rev. 2008, 7,
313344.
5. Halliwell, B. Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture
and in vivo studies? Arch. Biochem. Biophys. 2008, 476, 107112.
6. Korkina, L.G.; Pastore, S.; De Luca, C.; Kostyuk, V.A. Metabolism of plant polyphenols in the
skin: Beneficial versus deleterious effects. Curr. Drug Metab. 2008, 9, 710729.
7. Snyder, S.A.; Breazzano, S.P.; Ross, A.G.; Lin, Y.; Zografos, A.L. Total synthesis of diverse
carbogenic complexity within the resveratrol class from a common building block. J. Am. Chem.
Soc. 2009, 131, 17531765.
8. Snyder, S.A.; Zografos, L.; Lin, Y. Total synthesis of resveratrol-based natural products: A
chemoselective solution. Angew. Chem. Int. Ed. 2007, 46, 81868191.
9. Nicolaou, K.C.; Wu, R.T.; Kang, Q.; Chen, D.Y.K. Total synthesis of hopeahainol A and
hopeanol. Angew. Chem. Int. Ed. 2009, 48, 33403343.
10. Nicolaou K.C.; Kang Q.; Wu. R.T.; Lim C.S.; Chen D.Y.K. Total synthesis and biological
evaluation of the resveratrol-derived polyphenol natural products hopeanol and hopeahainol A. J.
Am. Chem. Soc. 2010, 132, 75407548.
11. Dai, J.-R.; Hallock, Y.F.; Cardellina, J.H., II; Boyd, M.R. HIV-Inhibitory and cytotoxic
oligostilbenes from the leaves of Hopea malibato. J. Nat. Prod. 1998, 61, 351353.

Molecules 2010, 15
5927
12. Saraswathy, A.; Purushothaman, K.K.; Patra, A.; Dey, A.K.; Kundu, A.B. Shoreaphenol, a
polyphenol from Shorea Robusta. Phytochemisry 1992, 31, 25612562.
13. Tanaka, T.; Ito, T.; Ido, Y.; Nakaya, K.; Iinuma, M.; Chelladurai, V. Hopeafuran and a C-glucosyl
resveratrol isolated from stem wood of hopea utilis. Chem. Pharm. Bull. 2001, 49, 785787.
14. Boutagy, J.; Thomas, R. Olefin synthesis with organic phosphonate carbanions. Chem. Rev. 1974,
74, 8799.
15. Jones, G.; Stanforth, S.P. The vilsmeier reaction of non-aromatic compounds. Org. React. 1997,
49, 1330.
16. Hughes, D.L. The mitsunobu reaction. Org. React. 1992, 42, 335656.
17. Kraus, G.A.; Gupta, V. A new synthetic strategy for the synthesis of bioactive stilbene dimmers.
A direct synthesis of amurensin. Tetrahedron Lett. 2009, 50, 7180.
18. Kraus, G.A.; Kim, I. Synthetic approach to malibatol A. Org. Lett. 2003, 5, 11911192.
19. Kim, I.; Choi, J. A versatile approach to oligostilbenoid natural products – synthesis of
permethylated analogues of viniferifuran, malibatol A, and shoreaphenol. Org. Biomol. Chem.
2009, 7, 27882795.
20. Hajipour, A.R.; Zarei, A.; Khazdooz, L.; Ruoho, A.E. Simple and efficient procedure for the
Friedel-Crafts acylation of aromatic compounds with carboxylic acids in the presence of
P2O5/Al2O3 under heterogeneous conditions. Synth. Commun. 2009, 39, 27022722.
21. Brady, W.T.; Giang, Y.S.F.; Marchand, A.P.; Wu, A.H. Intramolecular [2 + 2] cycloadditions of
ketenes to carbonyl groups. A novel synthesis of substituted benzofurans. J. Org. Chem. 1987, 52,
3457–3461.
Sample Availability: Contact the authors.
© 2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).