Unified syntheses of gramniphenols F and G, cicerfuran, morunigrol C and its derivative

Article abstract of DOI:10.1016/j.tetlet.2016.02.006

The first syntheses of natural benzofurans, gramniphenols F and G, morunigrol C and its 3′,5′-di-O-methyl analogue along with the synthesis of cicerfuran are achieved by a unified synthetic sequence using 7-hydroxycoumarin, 5-bromoresorcinol, 2,4-dihydroxybenzaldehyde, and sesamol as building blocks. Ramirez gem-dibromoolefination, Miyaura borylation, Suzuki coupling have been successfully exploited in the synthesis. Additionally, their anti-inflammatory effects were also investigated in lipopolysaccharide (LPS)-induced RAW-264.7 macrophages. The compounds exhibited significant inhibition of iNOS mediated nitric oxide (NO) production with no cytotoxicity at 10 μM concentration and IC₅₀ values are found in the range from 9.1 to 25.2 μM.

Full text of DOI:10.1016/j.tetlet.2016.02.006

Tetrahedron Letters 57 (2016) 1183–1186
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unified syntheses of gramniphenols F and G, cicerfuran, morunigrol
C and its derivative
Kongara Damodar a, Jin-Kyung Kim b, Jong-Gab Jun a,
⇑
a Department of Chemistry and Institute of Natural Medicine, Hallym University, Chuncheon 200-702, Republic of Korea
b Department of Biomedical Science, College of Natural Science, Catholic University of Daegu, Gyeungsan-Si 700-702, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
The first syntheses of natural benzofurans, gramniphenols F and G, morunigrol C and its 30,50-di-O-methyl
analogue along with the synthesis of cicerfuran are achieved by a unified synthetic sequence using 7-
hydroxycoumarin, 5-bromoresorcinol, 2,4-dihydroxybenzaldehyde, and sesamol as building blocks.
Ramirez gem-dibromoolefination, Miyaura borylation, Suzuki coupling have been successfully exploited
in the synthesis. Additionally, their anti-inflammatory effects were also investigated in lipopolysaccha-
ride (LPS)-induced RAW-264.7 macrophages. The compounds exhibited significant inhibition of iNOS
Article history:
Received 23 December 2015
Revised 29 January 2016
Accepted 2 February 2016
Available online 2 February 2016
Keywords:
Gramniphenols F & G
Cicerfuran
mediated nitric oxide (NO) production with no cytotoxicity at 10
l
M concentration and IC50 values are
found in the range from 9.1 to 25.2 M.
l
Ó 2016 Elsevier Ltd. All rights reserved.
Morunigrol C
Suzuki coupling
anti-Inflammatory
Introduction
mosaic virus activity.7 Morunigrol C (3) (Fig. 1) was isolated from
the bark of Morus nigra.8 Compound 4 is a synthetic analogue of
3. Cicerfuran (5) (Fig. 1) was isolated from Cicer bijugum and dis-
played potent antifungal activity.9 Few groups reported the syn-
thesis of cicerfuran (5).10
Benzofuran core is a prominent structural unit in a variety of
bioactive natural products as well as synthetic materials. In partic-
ular, 2-substituted benzofurans are acknowledged as important
scaffolds for drug development.1 Numerous natural and non-natu-
ral 2-substituted benzofurans have been investigated as antioxi-
dant, antifungal, anti-inflammatory, antimicrobial, PPAR-d
agonists, anti-HIV, anti-tumor, and anti-platelet agents.1,2 Some
benzofurans showed pesticide and insecticidal activity.3 Recently,
18F and 99mTc labeled benzofurans were applied in positron emis-
sion tomography (PET) and single photon emission computed
tomography (SPECT) imaging, respectively, for b-amyloid plaques
in Alzheimer’s disease.4 In supramolecular chemistry, extended
molecular frameworks of benzofurans are useful as bowl-shaped
hosts.5 Some benzofuran derivatives were explored in organic
semiconductors including organic field effect transistors (OFETs),
phosphorescent organic light-emitting diodes (PhOLEDs), and
organic photovoltaic cells (OPVCs).6 Their wide range of pharmaco-
logical and physical properties have triggered extensive and endur-
ing efforts toward the synthesis of these important heterocyclic
compounds.
Results and discussion
Continuing our interest11 in the synthesis of natural bioactive
compounds and their derivatives, we have realized that
R2
R1
O
O
R2
Gramniphenol F
R1 = OH, R2 = H;
( )
Gramniphenol G 2
1
2
R1 = OMe, R = H;
( )
R1 = H, R2 = OH; Morunigrol C (3)
R1 = H, R2 = OMe; 3',5'-Di-O-methylmorunigrol C (4)
O
Gramniphenols F (1) and G (2) (Fig. 1) have recently been iso-
lated from Arundina gramnifolia and they displayed anti-tobacco
O
O
HO
MeO
Cicerfuran 5
( )
⇑
Corresponding author. Tel.: +82 33 248 2075; fax: +82 33 256 3421.
E-mail address: jgjun@hallym.ac.kr (J.-G. Jun).
Figure 1. Structures of natural (1–3 and 5) and synthetic (4) benzofurans.
http://dx.doi.org/10.1016/j.tetlet.2016.02.006
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

1184
K. Damodar et al. / Tetrahedron Letters 57 (2016) 1183–1186
R2
R2
A
OH
Suzuki
O
R1
O
Br
gramniphenol F (1)
O
coupling
O
O
O
6
1 R1 = OH, R2 = H
2 R1 = OMe, R2 = H
3 R1 = H, R2 = OH
4 R1 = H, R2 = OMe
Br
Br
CsF/Pd(PPh3)4
B
C
6
OMe
DME, 80 o
C
O
O
OH
O
7 h
gramniphenol G (2)
8
CHO
OMe
OH
O
O
OH
Br
O
12
O
10
9
O
OMe
CHO
OH
3',5'-di-O-methylmorunigrol C (4)
Br
OH
O
HO OH
MOEO
HO
HO
OH
HO
OH
B
B
B
11
O
B =
MOEO
A =
Suzuki
coupling
C =
MeO
O
Br
OMe
O
HO
OMe
OH
MeO
EOM = -CH2OEt
Scheme 1. Retrosynthetic analysis of benzofurans 1–5.
7
5
Scheme 3. Synthesis of benzofurans 1, 2, and 4.
K3PO4/CuI produced 2-bromobenzofurans 6 and 7 in high yields,
respectively.14
Compound 6 was subjected to Suzuki coupling15 with commer-
cially available 4-hydroxyphenylboronic acid, 4-methoxyphenyl-
boronic acid, and 3,5-dimethoxyphenylboronic acid using cesium
fluoride (CsF) as a base and dimethoxyethane (DME) as a solvent
medium to furnish the desired benzofurans 1, 2, and 4 in 90%,
84%, and 89% yields, respectively (Scheme 3). All of the products
were obtained as white solids (see the Supplementary material).
Demethylation of compound 4 to achieve compound 3 using BCl3
as well as BBr3 was not successful.
benzofurans 1–5 can be accessed by a common synthetic route
involving Ramirez gem-dibromoolefination and Suzuki coupling
as key steps (Scheme 1).
Accordingly, we commenced the synthesis with the protection
of compound 11 (Scheme 2). Treatment of 11 with chloromethyl
ethyl ether (EOM-Cl) using K2CO3/tetrabutylammonium iodide
(TBAI) system provided compound 13 in 79% yield. Construction
of benzofurans 1–4 began from chromene aldehyde 10, which
was available from 7-hydroxycoumarin 12 in four pots and 56%
yield.12
Next, compounds 10 and 13 were subjected to Ramirez gem-
dibromoolefination13 using triethylamine (Et3N) as a scavenger to
yield 8 and 9 in moderate yields, respectively. Intramolecular
O
O
Br
Br
B
cross-coupling of gem-dibromoolefins
8
and
9
using anhyd
b
a
CHO
HO
OH
OH
MOEO
OEOM
MOEO
OEOM
O
16
14
15
O
O
OH
HO
OH
12
11
O
B
Br
OMe
O
O
a
ref . 12
O
O
O
O
c, d
b
CHO
OH
OMe
CHO
OH
17
18
19
MOEO
O
OEOM
OEOM
13
10
f
b
e
morunigrol C (3)
cicerfuran (5)
b
6 + 16
Br
Br
Br
Br
O
O
20
O
OH
MOEO
MOEO
OH
O
O
9
8
f
e
O
c
c
7 + 19
O
MOEO
MeO
Br
21
EOM = -CH2OEt
Br
O
O
7
6
Scheme 4. Synthesis of morunigrol
C
(3) and cicerfuran (5). Reagents and
EOM= -CH2OEt
conditions: (a) chloromethyl ethyl ether, K2CO3, TBAI, acetone, rt, 20 h, 76%. (b)
Bis(pinacolato)diboron, anhyd KOAc, PdCl2(dppf)ꢀCH2Cl2, 1,4-dioxane, 80 °C, over-
night. 69% (16), 66% (19). (c) 1.5 M tetraethylammonium hydroxide, dimethyl
sulfate, 0 °C–rt, 1 h, 100%. (d) Bromine (Br2), THF, 0 °C, 5–10 min, 95%. (e) Aq 2.0 M
K2CO3, Pd(PPh3)4, THF, 80 °C, 48 h, sealed tube, 85%. (20), 89% (21). (f) DowexÒ
50WX8, MeOH, 35 °C, 24 h, 97% (3), 18 h, 98% (5).
Scheme 2. Synthesis of 2-bromobenzofurans 6 and 7. Reagents and conditions: (a)
chloromethyl ethyl ether, K2CO3, TBAI, acetone, rt, overnight, 79%. (b) carbon
tetrabromide/triphenylphosphine, Et3N, CH2Cl2, 0 °C–30 min then rt–2 h, 57% (8),
58% (9). (c) Anhyd K3PO4/CuI, THF, sealed tube, 80 °C, 6 h, 80% (6), 87% (7).

K. Damodar et al. / Tetrahedron Letters 57 (2016) 1183–1186
1185
M)
Table 1
Anti-inflammatory activities and proliferation effects of benzofurans 1–5
Compound
No production (% inhibition)a,b
10 mol/L
Proliferation
IC50 (l
1
lmol/L
l
1
lmol/L
10 lmol/L
Medium
0.13 0.87 (99.87)
93.46 8.36 (6.54)
90.43 3.06 (9.57)
88.47 6.34 (11.53)
100.00 1.73 (0.0)
93.77 11.20 (6.23)
79.10 4.10 (20.9)
0.13 0.87 (99.87)
76.04 2.01 (23.96)⁄
84.34 7.12 (15.66)⁄
67.75 8.68 (32.25)
60.89 8.70 (39.11)⁄⁄
57.50 11.20 (42.5)⁄⁄
7.60 4.00 (92.4)⁄⁄
100 1.25
100 1.25
96.12 2.98
93.93 5.61
95.58 3.23
93.98 3.11
93.92 3.56
97.61 5.63
1
2
3
4
5
93.03 1.12
96.46 2.46
97.47 3.37
92.63 4.45
96.44 4.21
98.64 2.92
16.0
25.2
12.9
9.1
10.6
2.69
L
-NMMA
a
The results are reported as mean value SEM for n = 3. Statistical significance is based on the difference when compared with LPS-treated groups (*P <0.01, **P <0.001).
Inhibition is based on LPS as shown in parenthesis.
b
For the synthesis of morunigrol C (3) and cicerfuran (5), the
macrophages was indicated by the amount that was measured in
RAW264.7 cell culture supernatant. RAW264.7 cells were plated
at a density of 5 ꢁ 104 cells in a 96-well cell culture plate with
other coupling partners, that is, boronic esters were prepared from
5-bromoresorcinol (14) and sesamol (17), respectively (Scheme 4).
Treatment of 14 with chloromethyl ethyl ether (EOM-Cl) fol-
lowed by Miyaura borylation16 using catalytic [1,10-bis
200 lL of culture medium and incubated for 12 h. They were then
treated with indicated concentrations of the benzofurans 1–5 plus
LPS (500 ng/mL) and incubated for another 18 h. The amount of
nitrite was measured using the Griess reagent system (Promega,
Madison, MI, USA) according to the manufacturer’s instructions.
The inhibitory activities of 1–5 on iNOS mediated NO production
in LPS-stimulated RAW 264.7 cells were evaluated and the results
are shown in Table 1. The compounds exhibited up to 42% inhibition
of iNOS mediated nitric oxide (NO) production with no cytotoxicity
(diphenylphosphino)ferrocene]dichloropalladium(II)
complex
with dichloromethane (PdCl2(dppf)ꢀCH2Cl2) afforded boronic ester
16. Methylation of 17 followed by bromination17 and subsequent
Miyaura borylation provided the boronic ester 19 in 66% yield.
Next, Suzuki coupling of 2-bromobenzofurans 6 and 7 with the
corresponding boronic esters 16 and 19 using aq. 2.0 M K2CO3/Pd
(PPh3)4 accomplished compounds 20 and 21 in 85% and 89% yields,
respectively. Finally, deprotection of the EOM-ether group of 20
and 21 with DowexÒ 50WX8 resin led to the natural products 3
and 5 in 97% and 98% yields, respectively. All the products 1–5
were settled from their spectral (1H, 13C NMR and MS) data.
at 10 lM concentration. IC50 (lM) values of these compounds 1–5
were evaluated using Prism 4.0 software (GraphPad Software, San
Diego, CA, USA) and the values were 16.0, 25.2, 12.9, 9.1 and 10.6.
In summary, we have applied a unified strategy for the first syn-
theses of natural benzofurans gramniphenols F and G, morunigrol
C and its 30,50-di-O-methyl derivative along with the synthesis of
cicerfuran using commercially feasible 7-hydroxycoumarin, 2,4-
dihydroxybenzaldehyde, 5-bromoresorcinol and sesamol as build-
ing blocks. Ramirez gem-dibromoolefination, Miyaura borylation,
Suzuki coupling have been successfully exploited in the synthesis.
In addition, their anti-inflammatory effects were also investigated
in lipopolysaccharide (LPS)-induced RAW-264.7 macrophages.
The compounds exhibited significant inhibition of iNOS mediated
anti-Inflammatory activity
Inflammation is a protective attempt of host to eradicate injuri-
ous stimuli and initiate healing.18 In this process, activated inflam-
matory cells (neutrophils, eosinophils, mononuclear phagocytes
and macrophages) secrete increased amounts of nitric oxide
(NO), prostaglandins (PGs) and cytokines, such as interleukin
(IL)-1ß, IL-6, and tumor necrosis factor (TNF). Among these, one
of the most prominent is NO which is a small, lipophilic and tran-
nitric oxide (NO) production with no cytotoxicity at 10 lM concen-
tration and IC50 values are found in the range from 9.1 to 25.2 lM.
sient free-radical species generated from L-arginine by three types
of nitric oxide synthase (NOS) enzymes viz. endothelial (eNOS) and
neuronal (nNOS) (both expressed constitutively) and inducible
(iNOS). Excess NO production causes inflammation, asthma, dia-
betes, cancer, stroke, and neurodegenerative disorders.19 There-
fore, control of the excess NO production may exert anti-
inflammatory effects.
Acknowledgments
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), South Korea.
Inhibition of iNOS mediated NO production in LPS-stimulated
RAW 264.7 cells by benzofurans 1–5 was determined using NG-
monomethyl-
L
-arginine acetate (
L
-NMMA)20 as a positive control
Supplementary data
following the similar procedure to our previous method.21 Briefly,
RAW 264.7 murine macrophages obtained from Korean Cell Bank
(Seoul, Korea) were cultured in Dulbecco’s modified Eagle’s med-
ium (DMEM), supplemented with 10% fetal bovine serum (FBS),
Supplementary data (experimental procedures and characteri-
zation data and copies of 1H and 13C NMR spectra) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2016.02.006.
100 U/mL penicillin and 100 lg/mL streptomycin (obtained from
Hyclone, Logan, UT, USA) at 37 °C in 5% CO2. The effects of the var-
ious compounds on cell viability were tested using the CellTiter
96Ò AQueous One Solution (Promega, Madison, MI, USA) assay of
cell proliferation. This assay was used to determine the number
of viable cells remaining after the culturing process was complete.
RAW264.7 cells were plated at a density of 2 ꢁ 104 cells in a 96-
well flat-bottom plate, and each compound was added to each
plate at indicated concentrations. After a 24 h incubation period,
the number of viable cells were counted according to the manufac-
turer’s instructions. The amount of nitrite produced by mouse
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