An efficient total synthesis of mulberrofuran B and L

Article abstract of DOI:10.1002/bkcs.10442

An efficient approach has been developed for the synthesis of mulberrofuran B and L from 2,4-dihydroxybenzaldehyde and 5-bromoresorcinol. The key steps of the synthesis are neutral Al₂O₃-mediated regioselective geranylation, Ramirez gem-dibromoolefination, and the Suzuki coupling.

Full text of DOI:10.1002/bkcs.10442

Article
DOI: 10.1002/bkcs.10442
BULLETIN OF THE
C. G. Kim and J.-G. Jun
KOREAN CHEMICAL SOCIETY
An Efficient Total Synthesis of Mulberrofuran B and L
*
Cheol Gi Kim and Jong-Gab Jun
Department of Chemistry and Institute of Applied Chemistry, Hallym University, Chuncheon 200-702, Korea.
*E-mail: jgjun@hallym.ac.kr
Received February 22, 2015, Accepted May 18, 2015, Published online August 17, 2015
An efficient approach has been developed for the synthesis of mulberrofuran B and L from 2,4-dihydroxyben-
zaldehyde and 5-bromoresorcinol. The key steps of the synthesis are neutral Al2O3-mediated regioselective
geranylation, Ramirez gem-dibromoolefination, and the Suzuki coupling.
Keywords: 2,4-Dihydroxybenzaldehyde, Regioselective geranylation, Miyaura borylation,
Ramirez gem-dibromoolefination, Suzuki coupling, Mulberrofuran
Introduction
prepared by means of regioselective geranylation of 2,4-dihy-
droxybenzaldehyde followed by Ramirez gem-dibromoolefi-
nation and intramolecular cyclization sequence. Intermediate
5 could be obtained from 5-bromoresorcinol by Miyaura
borylation.
Heterocyclic structures have significant roles in the biological
activities of pharmaceuticals. Benzofurans and their derivatives
in particular are important scaffolds for drug development.1
Several natural and non-natural 2-substituted benzofurans
have been investigated as antifungal,2 antioxidant,3 anti-
inflammatory,4 antimicrobial,5 peroxisome proliferator-
activated receptor (PPAR-δ) agonists,6 anti-HIV, antitumor
and antiplatelet agents.7 Some benzofurans showed pesticidal
and insecticidal activity.8 In supramolecular chemistry,
extended molecular frameworks of benzofurans can be used
as bowl-shaped hosts.9 Recently, 18F and 99mTc-labeled ben-
zofuran derivatives were tested by positron emission tomog-
raphy (PET) and single-photon emission computed
tomography (SPECT) imaging, respectively, for β-amyloid
plaques in Alzheimer's disease.10 Their wide range of biolog-
ical and pharmacological properties has triggered extensive
and enduring efforts toward the syntheses of these important
heterocyclic compounds.
Accordingly, we commenced the synthesis from 2,4-dihy-
droxybenzaldehyde (9). As shown in Scheme 2, neutral alu-
mina (Al2O3)-mediated regioselective geranylation of
9 with 1-bromo-3-methyl-2-butene gave the geranylated alde-
hyde 10.14 Treatment of about half portion of 10 with MeI and
the remaining portion with chloromethyl ethyl ether in acetone
in the presence of K2CO3 afforded 6 and 7 in high yields,
respectively. 5-Bromoresorcinol (8) was protected as its
ethoxy methylene ether 11 in 79% yield using chloromethyl
ethyl ether in the presence of N,N-diisopropylethylamine
(DIEA). Miyaura borylation15 of compound 11 using
bis(pinacolato)diboron, KOAc, and catalytic amount of
PdCl2(dppf ) afforded 5 in 95% yield, which is a common
key intermediate for the synthesis of mulberrofuran B and L.
Next, compounds 6 and 7 were subjected to Ramirez gem-
dibromolefination.16 Preformation of the active PPh3CBr2
ylide from PPh3 and CBr4 in CH2Cl2 at 0 ꢀC, followed by slow
addition of NEt3 and aldehyde 6, provided the gem-dibromoo-
lefin 12 while with the aldehyde 7, the corresponding
gem-dibromoolefin 13 was obtained. A mild and ligand-free
copper-catalyzed cross-coupling of compounds 12 and 13
ensued 2-bromobenzofurans 3 and 4 and the yields were
89 and 85%, respectively.17 Compounds 3 and 4 were then
subjected to Suzuki coupling18 reaction with compound
5 using K2CO3 (2.0M aq. solution) as base and catalytic
Pd(PPh3)4 in THF to furnish 2-aryl benzofurans 14 and 15,
respectively. Finally, deprotection of 2-aryl benzofurans 14
and 15 using Dowex resin in MeOH at room temperature gave
the target molecules, mulberrofuran B (1) and L (2) in 67 and
77%, respectively.
Mulberrofuran B and L (Figure 1), 2-arylbenzofuran deri-
vatives isolated from the root bark of the cultivated mulberry
tree (Japanese name “Rosô” a cultivated variety of Morus lhou
(ser.) koidz.) displayed moderate cytotoxic activity.11 Previ-
ously, Mann et al. developed a method for the synthesis of
mulberrofuran B that utilizes chromium and toxic tin
reagents.12
In continuation of our work13 on the synthesis of bioactive
natural products and their derivatives, herein wewish todescribe
a straightforward synthesis of mulberrofuran B and L utilizing
Al2O3-mediated regioselective geranylation, Ramirez gem-
dibromoolefination, and the Suzuki coupling as the key steps.
Results and Discussion
Retrosynthetic approach for mulberrofuran B and L synthesis
is depicted in Scheme 1. We envisaged that the target mole-
cules could be achieved from intermediates 3, 4, and 5 by
Suzuki coupling reaction, in which 3 and 4 could easily be
In conclusion, we have developed an efficient approach
for the synthesis of mulberrofuran B (1) and L (2). Neutral
Al2O3-mediated regioselective geranylation, Ramirez gem-
dibromoolefination, and the Suzuki coupling are the key
Correction added on 01 October 2015, after first online publication: ISSN (Print) has been corrected.
Bull. Korean Chem. Soc. 2015, Vol. 36, 2278–2283
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
2278

Article
BULLETIN OF THE
ISSN (Print) 0253-2964 | (Online) 1229-5949
KOREAN CHEMICAL SOCIETY
transformations of the present method. Application of the
present method for the synthesis of other prenyl(geranyl)-sub-
stituted natural 2-aryl benzofurans is in progress and will be
disclosed in due course.
backed silica gel plates and visualized by UV light (254
nm) or staining with p-anisaldehyde.
3-(3,7-Dimethylocta-2,6-dien-1-yl)-2,4-dihydroxyben-
zaldehyde (10). To a stirred suspension of 2,4-dihydroxyben-
zaldehyde, 9 (0.2 g, 1.45 mmol) and neutral Al2O3 (10.0 g) in
diethyl ether (100 mL) was added 1-bromo-3-methyl-2-
butene under nitrogen atmosphere andthe suspensionwasstir-
red for 3 days at room temperature. Al2O3 was filtered off,
washed with ether (50 mL), and the filtrate was concentrated
invacuo. Theresiduewaspurifiedbycolumnchromatography
(EtOAc/hexane = 1/5) to yield the product 10 (0.138 g, 35%)
as white solid. Rf = 0.32 (EtOAc/hexane = 1/3); mp
Experimental
All chemicals were purchased from Sigma-Aldrich (Munich,
Germany) and Alfa Aesar Chemicals (Lancashire, UK) and
were used without further purification unless noted otherwise.
1H-NMR spectra were recorded at Varian Mercury-300 MHz
FT-NMR (Varian, Palo Alto, CA, USA) and 75 MHz for 13C,
with the chemical shift (δ) reported in parts per million (ppm)
relative toTMS and thecouplingconstants (J)quoted in Hertz.
CDCl3 was used as a solvent and an internal standard. Mass
spectra were recorded using a JMS-700 (JEOL) spectrometer
(JEOL Ltd, Tokyo, Japan). Melting points were measured on a
MEL-TEMP II apparatus (Laboratory Devices, Inc Holliston
MA, USA) and were uncorrected. Thin-layer chromatography
(TLC) was performed on DC-Plastikfolien 60, F254 (layer
thickness 0.2 mm; Merck, Darmstadt, Germany) plastic-
1
119–121 ꢀC; H NMR (300 MHz, CDCl3) δ 11.75 (1H, s),
9.65 (1H, s), 7.29 (1H, d, J = 8.7 Hz), 6.46 (1H, d, J = 8.7
Hz), 6.35 (1H, s), 5.25 (1H, t, J = 6.9 Hz), 5.03 (1H, t, J =
6.5 Hz), 3.45 (2H, d, J = 6.9 Hz), 2.08 (4H, br s), 1.81 (3H,
s), 1.66 (3H, m), 1.58 (3H, s); 13C NMR (75 MHz, CDCl3)
δ 194.4, 162.5, 161.5, 139.9, 133.4, 132.1, 123.5, 120.5,
115.0, 113.5, 109.0, 39.7, 26.4, 25.8, 21.4, 17.8, 16.4.
3-(3,7-Dimethylocta-2,6-dien-1-yl)-2-hydroxy-4-meth-
oxybenzaldehyde (6). To a stirred suspension of 10 (0.465 g,
1.69 mmol) and K2CO3 (0.281 g, 2.03 mmol) in acetone (15
mL) were added methyl iodide (0.13 mL, 2.03 mmol) under
nitrogen atmosphere at room temperature. The suspension
was stirred for 8 h at room temperature. Reaction mixture
was filtered through celite pad, washed with acetone (30
mL), and the filtrate was concentrated in vacuo. EtOAc (30
mL) and H2O (20 mL) were added to the residue and two
layers separated. The aqueous layer was extracted with EtOAc
(2 × 30 mL). The combined organic layer was washed with
brine (2 × 40 mL), dried over anhydrous Na2SO4, and concen-
trated in vacuo. The crude was purified by column chromatog-
raphy (EtOAc/hexane = 1/6) to yield the product 6 (0.459 g,
94%) as a colorless liquid. Rf = 0.52 (EtOAc/hexane = 1/5);
1H NMR (300 MHz, CDCl3) δ 11.40 (1H, s), 9.69 (1H, s),
OH
OH
OH
OH
O
O
MeO
HO
mulberrofuran B (1)
mulberrofuran L (2)
Figure 1. Structures of mulberrofuran B (1) and L (2).
OH
OR''
O
Br
B
+
O
O
RO
RO
O
R'
3 R = Me, R' = geranyl
R'
OH
OR''
5 R'' = CH2OEt
1R = Me, R' = geranyl; mulberrofuran B
2 R = H,R' = geranyl; mulberrofuran L
4R = CH2OEt, R' = geranyl
OH
H
C O
Br
R
O
H
O
OH
R'
8
6 R = Me, R' = geranyl
7 R = CH2OEt, R' = geranyl
CHO
HO
OH
9
Scheme 1. Retrosynthetic analysis for the synthesis of mulberrofuran B and L.
Bull. Korean Chem. Soc. 2015, Vol. 36, 2278–2283
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2279

BULLETIN OF THE
Article
Synthesis of Mulberrofuran B and L
KOREAN CHEMICAL SOCIETY
CHO
b
c
RO
OH
R'
CHO
OH
CHO
OH
a
6 R = Me, R' = geranyl
HO
HO
CHO
9
R'
10 R' = geranyl
RO
OH
R'
7 R = CH2OEt, R' = geranyl
HO
R''O
R''O
O
B
O
e
d
Br
Br
HO
R''O
11 R'' =CH2OEt
R''O
8
5 R'' = CH2OEt
Br
Br
CHO
OH
Br
g
h
f
RO
O
RO
OH
RO
R'
6 R = Me, R' = geranyl
7 R = CH2OEt, R' = geranyl
R'
R'
12 R = Me, R' = geranyl
3 R = Me, R' = geranyl
4 R = CH2OEt, R' = geranyl
13 R = CH2OEt, R' = geranyl
OR''
OH
i
O
O
RO
RO
OR''
OH
R'
R'
1 R = Me, R' = geranyl; mulberrofuran B
14 R = Me, R' = geranyl, R'' = CH2OEt
15 R,R'' = CH2OEt, R' = geranyl
2 R = H, R' = geranyl; mulberrofuran L
Scheme2. Reagentsandconditions:(a)geranylbromide, neutralAl2O3, ether, roomtemperature(rt), 72 h, 35%;(b)MeI, K2CO3, acetone, rt, 8 h,
94%; (c) chloromethyl ethyl ether, K2CO3, TBAI, acetone, rt, overnight, 72%; (d) chloromethyl ethyl ether, N,N-diisopropylethylamine,
CH2Cl2, rt, 6 h, 79%; (e) bis(pinacolato)diboron, KOAc, PdCl2(dppf ), 1,4-dioxane, 80 ꢀC, 11 h, 95%; (f ) CBr4, PPh3, NEt3, CH2Cl2, 0 ꢀC,
30 min, then rt, 1 h, 45%; (12), 46% (13); (g) K3PO4, CuI, THF, 80 ꢀC, 11 h, 89% (3), 85% (4); (h) 5, K2CO3 (2.0 M aq. Solution),
Pd(PPh3)4, THF, 80 ꢀC, 48 h, 50% (14), 60% (15); (i) Dowex resin, MeOH, rt, 3 days, 67% (1), 77% (2).
7.35(1H, d, J = 8.7 Hz), 6.54(1H, d, J = 8.7 Hz), 5.17 (1H, t, J
= 7.2 Hz), 5.04 (1H, t, J = 6.5 Hz), 3.90 (3H, s), 3.34 (2H, d, J
= 7.2 Hz), 2.03–1.98 (4H, m), 1.77 (3H, s), 1.63 (3H, s), 1.56
(3H, s); 13C NMR (75 MHz, CDCl3) δ 194.5, 163.9, 160.6,
135.4, 133.5, 131.1, 124.2, 121.3, 117.1, 115.5, 103.0,
55.9, 39.8, 26.7, 25.7, 21.4, 17.7, 16.2.
= 0.42 (EtOAc/hexane = 1/5); 1H NMR (300 MHz, CDCl3) δ
11.44 (1H, s), 9.69 (1H, s), 7.32 (1H, d, J = 8.7 Hz), 6.76 (1H,
d, J = 8.7 Hz), 5.31(2H, s), 5.18(1H, t, J = 7.2 Hz), 5.04(1H, t,
J = 6.5 Hz), 3.71 (2H, q, J = 6.9 Hz), 3.36 (6H, s), 2.20–1.88
(4H, m), 1.78 (3H, s), 1.63 (3H, s), 1.56 (3H, s), 1.21 (2H,
t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 194.7, 161.6,
160.9, 135.4, 133.1, 131.2, 124.2, 121.3, 117.8, 115.8,
105.8, 92.6, 64.7, 39.8, 26.7, 25.8, 21.6, 17.7, 16.2, 15.2.
1-Bromo-3,5-bis(ethoxymethoxy)benzene (11). To a stir-
red solution of 5-bromoresocinol, 8 (0.809 g, 4.28 mmol) in
CH2Cl2 (15 mL) was added DIEA (2.98 mL, 17.12 mmol)
under nitrogen atmosphere at room temperature. After stirring
for 15 min, chloromethyl ethyl ether (0.21 mL, 2.19 mmol)
wasaddeddropwise andthemixture wasstirred for6 hatroom
temperature. After completion of the reaction, H2O (10 mL)
was added and two layers separated. The aqueous layer was
extracted with CH2Cl2 (2 × 40 mL). The combined organic
layer was washed with brine (2 × 30 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude was pur-
ified by column chromatography (EtOAc/hexane = 1/6) to
yield the product 11 (1.03 g, 79%) as a colorless liquid. Rf
3-(3,7-Dimethylocta-2,6-dien-1-yl)-4-(ethoxymethoxy)-
2-hydroxybenzaldehyde (7). To a stirred suspension of 10
(0.5 g, 1.82 mmol) and K2CO3 (0.655 g, 4.74 mmol) in ace-
tone (20 mL) were added chloromethyl ethyl ether (0.21
mL, 2.19 mmol) and tetrabutylammonium iodide (TBAI)
(0.034 g, 0.09 mmol) under nitrogen atmosphere at room tem-
perature. The suspension was stirred for overnight at room
temperature. Reaction mixture was filtered through celite
pad, washed with acetone (40 mL), and the filtrate was con-
centrated in vacuo. EtOAc (30 mL) and H2O (20 mL) were
added to the residue and two layers separated. The aqueous
layer was extracted with EtOAc (2 × 30 mL). The combined
organic layer was washed with brine (2 × 40 mL), dried over
anhydrous Na2SO4, and was concentrated in vacuo. The crude
was purified by column chromatography (EtOAc/hexane = 1/
8)toyieldtheproduct 7(0.436 g, 72%)asacolorless liquid. Rf
1
= 0.7 (EtOAc/hexane = 1/5); H NMR (300 MHz, CDCl3) δ
Bull. Korean Chem. Soc. 2015, Vol. 36, 2278–2283
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2280

BULLETIN OF THE
Article
Synthesis of Mulberrofuran B and L
KOREAN CHEMICAL SOCIETY
7.08 (2H, d, J = 2.4 Hz), 6.82 (1H, t, J = 2.4 Hz), 5.21 (4H, s),
3.72 (4H, q, J = 6.9 Hz), 1.32 (12H, s), 1.22 (6H, t, J = 6.9 Hz);
13C NMR (75 MHz, CDCl3) δ 157.8, 115.3, 108.2, 93.1, 83.8,
64.3, 24.9, 15.2.
(1H, t, J = 6.5 Hz), 3.72 (2H, q, J = 6.9 Hz), 3.45 (2H, d, J =
7.2 Hz), 2.17–1.99 (4H, m), 1.82 (3H, s), 1.68 (3H, s), 1.60
(3H, s), 1.23 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3)
δ 155.6, 153.2, 139.5, 132.2, 132.1, 126.9, 123.4, 121.2,
117.1, 115.5, 106.1, 93.4, 88.7, 64.5, 39.7, 26.3, 25.8, 22.7,
17.8, 16.2, 15.2.
2-(3,5-Bis(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (5). To a 15 mL sealed tube equipped
with a magnetic stir bar were added compound 11 (0.1 g,
0.33 mmol), bis(pinacolato)diboron (0.125 g, 0.49 mmol),
KOAc (0.096 g, 0.98 mmol), and 1,4-dioxane (2 mL), and
the mixture was degassed for 3 min. PdCl2(dppf ) (0.026 g,
0.04 mmol) was added to the mixture and degassed for another
3 min. The reaction was then stirred at 80 ꢀC for 11 h. Solvent
was removed under reduced pressure and the crude was pur-
ified by column chromatography (EtOAc/hexane = 1/7) to
yield the product 5 (0.109 g, 95%) as a colorless liquid. Rf
2-Bromo-7-(3,7-dimethylocta-2,6-dien-1-yl)-6-methox-
ybenzofuran (3). To a 15 mL sealed tube equipped with a
magnetic stir bar were added the gem-dibromoolefin 12
(0.222 g, 0.50 mmol), CuI (0.004 g, 0.02 mmol), and K3PO4
(0.212 g, 1.00 mmol). The tube was flushed with nitrogen
for 3 min, after which THF (2.5 mL) was added at room tem-
perature. The mixture was then stirred at 80 ꢀC for 11 h, after
which it was allowed to cool to room temperature. The con-
tents werefiltered over apadofcelite andwashedwith copious
amounts of Et2O. The filtrate was concentrated under reduced
pressure. The crude was purified by column chromatography
(EtOAc/hexane = 1/8) to yield the product 3 (0.161 g, 89%) as
a colorless liquid. Rf = 0.59 (EtOAc/hexane = 1/10); 1H NMR
(300 MHz, CDCl3) δ 7.23 (1H, d, J = 7.8 Hz), 6.83 (1H, d, J =
7.8 Hz), 6.60 (1H, s), 5.29 (1H, t, J = 7.5 Hz), 5.04 (1H, t, J =
6.9 Hz), 3.86 (3H, s), 3.56 (2H, d, J = 6.9 Hz), 2.09–1.92 (4H,
m), 1.81(3H, s), 1.62(3H, s), 1.56(3H, s); 13CNMR(75 MHz,
CDCl3) δ 155.0, 154.6, 135.6, 131.2, 126.4, 124.2, 122.3,
121.4, 116.8, 113.8, 108.1, 108.0, 56.7, 39.8, 26.7, 25.7,
22.7, 17.7, 16.2.
2-Bromo-7-(3,7-dimethylocta-2,6-dien-1-yl)-6-(ethoxy-
methoxy)benzofuran (4). Following the procedure used
for compound 3 preparation, where compound 13 (0.19 g,
0.39 mmol) was used instead of 12. The crude was purified
by column chromatography (EtOAc/hexane = 1/8) to yield
the product 4 (0.135 g, 85%) as a colorless liquid. Rf = 0.65
(EtOAc/hexane = 1/10); 1H NMR (300 MHz, CDCl3) δ 7.22
(1H, d, J = 8.7 Hz), 7.04 (1H, d, J = 8.7 Hz), 6.61 (1H, s),
5.28 (1H, t, J = 7.2 Hz), 5.23 (2H, s), 5.03 (1H, t, J = 6.5
Hz), 3.74 (2H, q, J = 6.9 Hz), 3.57 (2H, d, J = 7.2 Hz),
2.10–1.92 (4H, m), 1.82 (3H, s), 1.61 (3H, s), 1.55 (3H, s),
1.23 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ
154.9, 152.3, 135.6, 131.2, 126.6, 124.1, 123.0, 121.4,
116.9, 114.9, 111.8, 108.1, 94.2, 64.3, 39.8, 26.7, 25.7,
23.0, 17.7, 16.2, 15.2.
2-(3,5-Bis(ethoxymethoxy)phenyl)-7-(3,7-dimethylocta-
2,6-dien-1-yl)-6-methoxybenzofuran (14). To a 15 mL
sealed tube equipped with a magnetic stir bar were added com-
pound 3 (0.033 g, 0.09 mmol), compound 5 (0.044 g, 0.12
mmol), 2.0 M K2CO3 aqueous solution (0.13 mL), and THF
(1 mL), and the mixture was degassed for 3 min. Pd(PPh3)4
(0.01 g, 0.01 mmol) was added and degassed for another
3 min. The reaction mixture was then stirred at 80 ꢀC for
48 h. Solvent was removed under reduced pressure. The
crude was purified by column chromatography (EtOAc/hex-
ane = 1/8) to yield the product 14 (0.023 g, 50%) as a colorless
liquid. Rf = 0.51 (EtOAc/hexane = 1/5); 1H NMR (300 MHz,
CDCl3) δ 7.30 (1H, d, J = 9.0 Hz), 7.16 (2H, d, J = 2.4 Hz),
6.92 (1H, s), 6.85 (1H, d, J = 9.0 Hz), 6.72 (1H, t, J = 2.4
Hz), 5.40 (1H, t, J = 7.2 Hz), 5.28 (4H, s), 5.07 (1H, t,
1
= 0.65 (EtOAc/hexane = 1/5); H NMR (300 MHz, CDCl3)
δ 7.08 (2H, d, J = 2.4 Hz), 6.82 (1H, t, J = 2.4 Hz), 5.21
(4H, s), 3.72 (4H, q, J = 6.9 Hz), 1.32 (12H, s) 1.22 (6H, t,
J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 157.8, 115.3,
108.2, 93.1, 83.8, 64.3, 24.9, 15.2.
6-(2,2-Dibromovinyl)-2-(3,7-dimethylocta-2,6-dien-1-
yl)-3-methoxyphenol (12). To a stirred solution of PPh3
(2.281 g, 8.7 mmol) in CH2Cl2 (8.7 mL) at 0 ꢀC was added
a solution of CBr4 (1.443 g, 4.35 mmol) in CH2Cl2 (4.5
mL). After 10 min, NEt3 (1.21 mL, 8.7 mmol) was added
dropwise and stirred for an additional 5 min, after which a
solution of compound 6 (0.417 g, 1.45 mmol) in CH2Cl2
(1.5 mL) was added dropwise over 10 min. The internal
temperature was maintained below 10 ꢀC, over the
additionofallreagents. Thevesselwasstirredforanadditional
30 min at 0 ꢀC, after which it was allowed to warm to
room temperature and stirred for an additional 1 h. The reac-
tion was quenched by addition of saturated aqueous NH4Cl
solution. The phases were then separated, and the aqueous
layer was extracted with CH2Cl2 (2 × 40 mL). The combined
organic layer was washed with brine (2 × 30 mL), dried over
anhydrous Na2SO4 and was concentrated in vacuo. The crude
was purified by column chromatography (EtOAc/hexane = 1/
5) to yield the product 12 (0.289 g, 45%) as a pale orange color
liquid. Rf = 0.59 (EtOAc/hexane = 1/5); 1H NMR (300 MHz,
CDCl3) δ 7.55 (1H, d, J = 8.7 Hz), 7.53 (1H, s), 6.49 (1H, d, J
= 8.7 Hz), 5.70(1H, s), 5.20(1H, t, J = 7.2 Hz), 5.03(1H, t, J =
6.5 Hz), 3.81 (3H, s), 3.43 (2H, d, J = 7.2 Hz), 2.17–2.04 (4H,
m), 1.81(3H, s), 1.69(3H, s), 1.60(3H, s); 13CNMR(75 MHz,
CDCl3) δ 157.7 153.3, 139.5, 132.2, 132.1, 126.9, 123.5,
121.2, 116.4, 114.4, 102.5, 88.2, 55.7, 39.7, 26.3, 25.8,
22.4, 17.8, 16.2.
6-(2,2-Dibromovinyl)-2-(3,7-dimethylocta-2,6-dien-1-
yl)-3-(ethoxymethoxy)phenol (13). Following the procedure
used for compound 12 preparation, where compound 7 (222
mg, 0.67 mmol) was used instead of 6. The crude was purified
by column chromatography (EtOAc/hexane = 1/5) to yield the
product 12 (0.15 g, 46%) as a pale orange color liquid. Rf =
1
0.55 (EtOAc/hexane = 1/5); H NMR (300 MHz, CDCl3) δ
7.52 (1H, s), 7.50 (1H, d, J = 8.7 Hz), 6.70 (1H, d, J = 8.7
Hz), 5.67 (1H, s), 5.23 (2H, s), 5.21 (1H, t, J = 7.2 Hz), 5.03
Bull. Korean Chem. Soc. 2015, Vol. 36, 2278–2283
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2281

BULLETIN OF THE
Article
Synthesis of Mulberrofuran B and L
KOREAN CHEMICAL SOCIETY
J = 6.3 Hz), 3.92 (3H, s), 3.79 (4H, q, J = 6.9 Hz), 3.68 (2H,
d, J = 7.2 Hz), 2.12–1.97 (4H, m), 1.93 (3H, s), 1.62 (3H,
s), 1.56 (3H, s), 1.28 (6H, t, J = 6.9 Hz); 13C NMR
(75 MHz, CDCl3) δ 158.5, 155.0, 154.6, 154.1, 135.2,
132.6, 131.1, 124.3, 122.7, 121.8, 117.7, 113.8, 108.0,
106.0, 104.5, 101.9, 93.2, 64.4, 56.7, 39.8, 26.8, 25.7, 22.9,
17.7, 16.3, 15.2.
(4H, m), 1.87 (3H, s), 1.66 (3H, s), 1.57 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 157.0, 154.0, 153.8, 152.4, 139.1,
133.0, 132.0, 123.6, 122.1, 120.8, 118.6, 112.9, 110.2,
104.1, 102.6, 102.3, 39.7, 26.5, 25.8, 23.2, 17.8, 16.4; EI-
MS m/z 378 (M+, base), 293, 254, 207, 123. HRMS
(EI) calcd. for C24H26O4 M+ 378.1831, found 378.1831.
2-(3,5-Bis(ethoxymethoxy)phenyl)-7-(3,7-dimethylocta-
2,6-dien-1-yl)-6-(ethoxymethoxy)benzofuran (15). Follow-
ing the procedure used for compound 14 preparation, where
compound 4 (0.03 g, 0.07 mmol) was used instead of 3. The
crude was purified by column chromatography (EtOAc/hex-
ane = 1/8) to yield the product 15 (0.024 g, 60%) as a colorless
liquid. Rf = 0.57 (EtOAc/hexane = 1/5); 1H NMR (300 MHz,
CDCl3) δ 7.29 (1H, d, J = 8.4 Hz), 7.15 (2H, d, J = 2.4 Hz),
7.05 (1H, d, J = 8.4 Hz), 6.92 (1H, s), 6.71 (1H, t, J = 2.4
Hz), 5.37 (1H, t, J = 7.2 Hz), 5.26 (2H, s), 5.25 (4H, s), 5.03
(1H, t, J = 6.5 Hz), 3.75 (4H, q, J = 7.2 Hz), 3.74 (2H, q, J =
7.2 Hz), 3.66 (2H, d, J = 7.2 Hz), 2.09–1.93 (4H, m), 1.89
(3H, s), 1.59 (3H, s), 1.52 (3H, s), 1.25 (9H, t, J = 7.2 Hz);
13C NMR (75 MHz, CDCl3) δ 158.6, 154.8, 154.0, 152.6,
135.3, 132.5, 131.2, 124.2, 123.4, 121.7, 117.9, 114.8,
111.6, 106.0, 104.6, 102.0, 94.3, 93.2, 64.4, 39.8, 26.7,
25.7, 23.1, 17.7, 16.4, 15.2.
5-(7-(3,7-Dimethylocta-2,6-dien-1-yl)-6-methoxybenzo-
furan-2-yl)benzene-1,3-diol; mulberrofuran B (1). To a
stirred solution of compound 14 (0.014 g, 0.03 mmol)
in MeOH (2 mL) was added Dowex resin (40 mg) under nitro-
gen atmosphere and the mixture was stirred at room
temperature for 3 days. The resin was filtered, washed with
EtOAc (10 mL), and the filtrate was concentrated in vacuo.
The crude was purified by column chromatography (EtOAc/
hexane = 1/3) to yield the product 1 (0.007 g, 67%) as a white
solid. Rf = 0.15 (EtOAc/hexane = 1/5); mp 65–67 ꢀC; 1H
NMR (300 MHz, CDCl3) δ 7.31 (1H, d, J = 8.4 Hz), 6.89
(1H, s), 6.88 (2H, d, J = 2.4 Hz), 6.86 (1H, d, J = 8.4 Hz),
6.31 (1H, t, J = 2.4 Hz), 5.38 (1H, t, J = 6.9 Hz), 5.04 (1H, t,
J = 6.3 Hz), 3.89 (3H, s), 3.64 (2H, d, J = 6.9 Hz), 2.09–1.93
(4H, m), 1.88 (3H, s), 1.60 (3H, s), 1.54 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 156.9, 155.0, 154.2, 154.1, 135.3,
133.0, 131.3, 124.2, 122.6, 121.8, 117.8, 113.7, 108.0,
104.1, 102.5, 102.0, 56.8, 39.8, 26.7, 25.7, 23.1, 17.8,
12.4; EI-MS m/z 392 (M+, base), 269, 207, 165, 123.
HRMS (EI) calcd. for C25H28O4 M+ 392.1988, found
392.1987.
Acknowledgements.
This research was financially
supported by Priority Research Centers Program through
the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology
(NRF-2009-0094071), and by Hallym University Research
Fund, 2015 (HRF-201501-012).
References
1. (a) B. A. Keay, P. W. Dibble, In Comprehensive Heterocyclic
Chemistry II, Vol. 2, A. R. Katritzky, C. W. Rees,
E. F. V. Scriven Eds., Elsevier, Oxford, UK, 1996, p. 395;
(b)X.-L. Hou, Z. Yang, H. N. C. Wong, Prog. Heterocycl. Chem.
2002, 14, 139.
2. (a) S. Zacchino, G. Rodriguez, G. Pezzenati, G. Orellana,
R. Enriz, S. M. Gonzalez, J. Nat. Prod. 1997, 60, 659;
(b) S. Sogabe, M. Masubuchi, K. Sakata, T. A. Fukami,
K. Morikami, Y. Shiratori, H. Ebiike, K. Kawasaki, Y. Aoki,
N. Shimma, A. D'Arcy, F. K. Winkler, D. W. Banner,
T. Ohtsuka, Chem. Biol. 2002, 9, 1119.
3. D. H. S. Silva, F. C. Pereira, M. V. B. Zanoni, M. Yoshida, Phy-
tochemistry 2001, 57, 437.
4. S. H. Day, N. Y. Chiu, L. T. Tsao, J. P. Wang, C. N. Lin, J. Nat.
Prod. 2000, 63, 1560.
5. R. Basawaraj, G. Parameshwarappa, S. S. Sangapure, Indian
Drugs 2007, 44, 8.
6. G. F. Filzen, L. Bratton, X. M. Cheng, N. Erasga,
A. Geyer, C. Lee, G. Lu, J. Pulaski, R. J. Sorenson,
P. C. Unangst, B. K. Trivedi, X. Xu, Bioorg. Med. Chem. Lett.
2007, 13, 3630.
7. (a) T. Vang, Y. Xie, W. H. Liu, D. Vidovic, Y. Liu, S. Wu,
D. H. Smith, A. Rinderspacher, C. Chung, G. Gong,
T. Mustelin, D. W. Landry, R. C. Rickert, S. C. Schürer,
S.–. X. Deng, L. Tautz, J. Med. Chem. 2011, 54, 562;
(b) W. J. Song, X. D. Yang, X. H. Zeng, X. L. Xu,
G. L. Zhang, H. B. Zhang, RSC Adv. 2012, 2, 4612.
8. J. A. Findlay, S. Buthelezi, G. Li, M. Seveck, J. Nat. Prod. 1997,
60, 1214.
9. T. Wang, Z.-Y. Li, A.-L. Xie, X.-J. Yao, X.-P. Cao, D. Kuck,
J. Org. Chem. 2011, 76, 3231.
10. (a) M. Ono, Y. Cheng, H. Kimura, M. Cui, S. Kagawa,
R. Nishii, H. Saji, J. Med. Chem. 2011, 54, 2971;
(b) Y. Cheng, M. Ono, H. Kimura, M. Ueda, H. Saji, J. Med.
Chem. 2012, 55, 2279.
11. (a) T. Fukai, T. Fujimoto, Y. Hano, T. Nomura, J. Uzawa,
Heterocycles 1984, 22, 2805; (b) Y.-Q. Shi, T. Fukai,
H. Sakagami, W.-J. Chang, P.-Q. Yang, F.-P. Wang,
T. Nomura, J. Nat. Prod. 2001, 64, 181.
12. I. S. Mann, D. A. Widdowson, J. M. Clough, Tetrahedron 1991,
47, 7991.
5-(7-(3,7-Dimethylocta-2,6-dien-1-yl)-6-methoxybenzo-
furan-2-yl)benzene-1,3-diol (mulberrofuran L) (2). Fol-
lowing the procedure used for compound 1 preparation,
where compound 15 (0.02 g, 0.04 mmol) was used instead
of 14. The crude was purified by column chromatography
(EtOAc/hexane = 1/5) to yield the product 2 (0.01 g, 77%)
as
a
white solid. Rf = 0.12 (EtOAc/hexane = 1/5);
1
mp 148–151 ꢀC; H NMR (300 MHz, CDCl3) δ 7.23 (1H,
d, J = 8.4 Hz), 6.87 (2H, d, J = 2.4 Hz), 6.84 (1H, s), 6.76
(1H, d, J = 8.4 Hz), 6.32 (1H, t, J = 2.4 Hz), 5.40 (4H, br s),
5.04 (1H, t, J = 6.3 Hz), 3.71 (2H, d, J = 7.2 Hz), 2.17–2.02
Bull. Korean Chem. Soc. 2015, Vol. 36, 2278–2283
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2282

BULLETIN OF THE
Article
Synthesis of Mulberrofuran B and L
KOREAN CHEMICAL SOCIETY
13. (a) S.-J. Kim, J. J. Lee, H.-H. Yoon, J.-G. Jun, Bull. Korean
Chem. Soc. 2013, 34, 2815; (b) Y. H. Seo, J.-K. Kim,
J.-G. Jun, Bioorg. Med. Chem. Lett. 2014, 24, 5727.
14. C. G. Kim, J.-H. Jeon, Y. H. Seo, J.-G. Jun, Bull. Korean Chem.
Soc. 2014, 35, 1996.
16. N. B. Desai, N. McKelvie, F. Ramirez, J. Am. Chem. Soc. 1962,
84, 1745.
17. S. G. Newman, V. Aureggi, C. S. Bryan, M. Lautens, Chem.
Commun. 2009, 5236.
18. (a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457;
(b) A. J. J. Lennox, G. C. Lloyd-Jones, Chem. Soc. Rev. 2014,
43, 412.
15. T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem. 1995,
60, 7508.
Bull. Korean Chem. Soc. 2015, Vol. 36, 2278–2283
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2283