Syntheses and anti-inflammatory activity of natural 1,3-diarylpropenes

Article abstract of DOI:10.1248/cpb.c16-00089

First syntheses of five natural 1,3-diarylpropenes (cinnamylphenols) 2-4, 7, and 8 along with synthesis of two other natural 1,3-diarylpropenes 1 and 5 and E-isomer of mucronulastyrene (6) were achieved by Friedel- Crafts alkylation as a key step. Subsequ

Full text of DOI:10.1248/cpb.c16-00089

632
Chem. Pharm. Bull. 64, 632–637 (2016)
Vol. 64, No. 6
Regular Article
Syntheses and Anti-inflammatory Activity of Natural 1,3-Diarylpropenes
,a
Jong-Woon Jung,a Jin-Kyung Kim,b and Jong-Gab Jun*
a Department of Chemistry and Institute of Natural Medicine, Hallym University; Chuncheon 24252, Korea: and
b Department of Biomedical Science, College of Natural Science, Catholic University of Daegu; Gyeungsan-si 38430,
Korea.
Received January 27, 2016; accepted March 8, 2016; advance publication released online March 30, 2016
First syntheses of five natural 1,3-diarylpropenes (cinnamylphenols) 2–4, 7, and 8 along with synthesis of
two other natural 1,3-diarylpropenes 1 and 5 and E-isomer of mucronulastyrene (6) were achieved by Friedel–
Crafts alkylation as a key step. Subsequently, their anti-inflammatory effects were also investigated in lipo-
polysaccharide (LPS)-induced RAW264.7 macrophages. The compounds exhibited significant inhibition of
inflammatory mediated nitric oxide (NO) production with no cytotoxicity except compound 8 (dalberatin B)
at 10µM concentration and IC50 values were found in the range from 4.05 to 16.76µM.
Key words 1,3-diarylpropene; Friedel–Crafts alkylation; inflammation; nitric oxide (NO)
Flavonoids are naturally occurring low molecular weight
Aldehydes 12–14 and benzaldehyde (15) were then sub-
phytochemicals possessing many biological properties use- jected to Grignard reaction with vinylmagnesium bromide and
ful to human health.1) 1,3-Diarylpropenes (cinnamylphenols) the corresponding allyl alcohols 16–19 were obtained in high
acquire C6+C3+C6 chemical subunit and belong to the fla- yields, respectively. Compound 20 was protected with acetyl
vonoid family, are distinguished class of naturally occurring group (electron withdrawing group) in order to avoid Frie-
bioactive compounds. These small templates have been shown del–Crafts (FC) alkylation at 4-position. Next, we considered
to exhibit potential pharmacological properties including anti- the FC alkylation between compounds 17 and 21 as model
cancer,2–4) anti-oxidant,5) anti-inflammatory,6) anti-platelet,7) reaction.
and anti-malarial.8) They can also serve as key intermediates
Treatment of 1.0eq. of 17 with 2.0eq. of 21 using 0.1eq. of
in the synthesis of natural products and the evolution of bio- various metal triflates (Table 1) as catalysts and 4Å molecular
logically active compounds.9–11) In recent years, there has been sieves (MS) as water scavengers to get the product 24 and
increasing interest around the globe in the synthesis of these the best results (60% yield) were obtained with copper(II)
privileged scaffolds.12,13)
trifluoromethane sulfonate (Cu(OTf)2). Lowering the catalyst
1,3-Diarylpropenes under the current study are depicted in loading led to the decrease of the yield. Next, the reaction
Fig. 1. Isomucronustyrene (1) was isolated from the heartwood was carried out in methylene chloride (CH2Cl2), chloroform
of Dalbergia odorifera (Leguminosae),6) dalparvinene (2) iso- (CHCl3), tetrahydrofuran (THF) and diethyl ether solvents
lated from Dalbergia parviflora14) and dalberatins A–D (7, 8, using 0.1eq. of Cu(OTf)2 as a catalyst and better yields were
3, 4) were also from the Dalbergia species.15) Mucronustyrene obtained in CH2Cl2. Hence, we utilized Cu(OTf)2 as a catalyst
(5) was isolated from the wood of Machaerium mucronulatum with 0.1eq. loading and CH2Cl2 as solvent for the remain-
(Fabaceae) whereas compound 6 is synthetic E-isomer of mu- ing 1,3-diarylpropenes preparation. The allyl alcohols 19, 17,
cronulastyrene.16)
and 18 were underwent FC alkylation with 21 and the cor-
As part of our continuous interest in the synthesis of bio- responding products 22, 23, and 25 were obtained in moderate
active natural products and their analogues,17–19) herein we yields. Deacetylation of 22–25 offered mucronustyrene (1) and
describe an efficient synthesis and anti-inflammatory activity compounds 26–28 in high yields, respectively. Finally, EOM-
evaluation of natural 1,3-diarylpropenes 1–5, 7, and 8 along group deprotection of 26–28 using Dowex® resin in anhyd.
with a synthetic compound 6.
MeOH led to the isolation of natural 1,3-diarylpropenes 2–4,
respectively.
Synthesis of 1,3-diarylpropenes 5–8 were commenced with
Results and Discussion
Chemistry Syntheses of 1,3-diarylpropenes 1–8 were il- the protection of 2-hydroxybenzaldehyde (29), 10, and 11 with
lustrated in Charts 1 and 2. Chart 1 deals with the synthesis benzyl bromide and resulting benzyl protected aldehydes
of 1,3-diarylpropenes originated from 2,6-dimethoxyphenol 30–32 were subjected to Grignard reaction with vinylmagn-
(syringol) (20) (B ring) i.e., compounds 1–4 whereas Chart 2 esim bromide to yield the allyl alcohols 33–35, respectively
deals with the synthesis of 1,3-diarylpropenes generated from (Chart 2). 2,3-Dimethoxyphenol (36) was protected with ben-
2,3-dimethoxyphenol (36) i.e., 5–8. Synthesis of compounds zyl (–Bn) group.
1–4 began with the protection of 4-hydroxybenzaldehyde (9),
Next, FC alkylation of 37 with 19 and 33–35 using
2-methoxy 3-hydoxybenzaldehyde (10), and 2-hydroxy 5-me- Cu(OTf)2/4Å MS system in anhyd. CH2Cl2 produced the
thoxybenzaldehyde (11). Treatment of 9–11 with chloromethyl benzyl-protected 1,3-diarylpropenes 38–41 as major products,
ethyl ether (EOM-Cl) using potassium carbonate (K2CO3)/ respectively. Due to the bulkiness of the benzyl group, FC
tetrabutylammonium iodide (TBAI) system in acetone pro- alkylation favored at ortho to –OMe group rather than ortho
duced the ethoxymethyl (EOM)-protected aldehydes 12–14, to –OBn. We tried the FC alkylation with tert-butyldimethyls-
respectively.
ilyl (TBS)- and trityl-protected components, but, lower yields
*To whom correspondence should be addressed. e-mail: jgjun@hallym.ac.kr
© 2016 The Pharmaceutical Society of Japan

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Chem. Pharm. Bull.
633
Fig. 1. Structures of 1,3-Diarylpropenes (1–8)
Reagents and conditions: a) chloromethyl ethyl ether (EOM–Cl), TBAI, K2CO3, anhyd. acetone, rt 4h. b) 1.0M vinylMgBr solution, anhyd. THF, 0°C–rt 2h. c) acetic
anhydride, 4-(dimethylamino)pyridine (DMAP), triethylamine (Et3N), anhyd. CH2Cl2, rt overnight. d) Cu(OTf)2, 4Å MS, anhyd. CH2Cl2, 0°C, 5–6h. e) aq. K2CO3, MeOH,
rt 2h, f) Dowex® resin, anhyd. MeOH, 40°C, 48h.
Chart 1. Synthesis of Diarylpropenes 1–4
were obtained than benzyl-protection FC alkylation. The the target compounds 1–8 were settled from their NMR (1H-
lower yields with TBS- and trityl-protected components were and 13C-) and MS data.
due to their partial deprotection during the reaction. Finally,
Anti-inflammatory Activity Inflammation is part of the
benzyl-deprotection of 39–41 was carried out by treatment body’s immune response and it is a protective attempt of the
with 1.0M boron trichloride (BCl3) solution at −40°C and the host to remove the injurious stimuli including damaged cells,
products 5–8 were obtained in high yields, respectively. All irritants or pathogens that leads to the restoration of the nor-

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Reagents and conditions: a) Benzyl bromide, K2CO3, dimethylformamide (DMF), 40°C, 4h. b) 1.0M vinylMgBr solution, anhyd. THF, 0°C–rt 2h. c) Benzyl bromide,
K2CO3, acetone, 40°C, 6h. d) Cu(OTf)2, 4Å MS, anhyd. CH2Cl2, rt 3h. e) 1.0M BCl3 solution, anhyd. CH2Cl2, −40°C, 1h.
Chart 2. Synthesis of Diarylpropenes 5–8
Table 2. Anti-inflammatory Activities of 1,3-Diarylpropenes (1–8)
Table 1. Catalyst Screening for Friedel–Crafts Alkylation Reaction be-
tween 17 and 21a)
NO Production (% Inhibition)
S. No
Catalyst
% Yieldb)
Compound
1µM
10µM
1
2
3
4
5
Zn(OTf)2
Cu(OTf)2
Yb(OTf)3
AgOTf
50
60
25
37
26
Medium (MED)
1.21 0.01 (98.79)***
80.28 0.73 (19.72)***
70.57 1.87 (24.43)***
99.12 1.20 (0.88)
1.21 0.01 (98.79)***
60.73 1.00 (39.27)***
63.48 0.42 (36.52)***
73.19 1.99 (26.81)***
65.91 2.69 (34.09)***
62.07 3.40 (37.93)***
41.34 1.83 (58.66)***
86.09 1.99 (13.91)**
46.23 0.63 (53.77)***
7.6 4.0 (92.4)***
1
2
3
La(OTf)3
4
92.73 1.04 (7.27)
a) Reaction conditions: 17 (1.0eq.), 21 (2.0eq.), 4Å MS and catalyst (0.1eq.) in
CH2Cl2 at 0°C for 6h. b) Isolated yields after column chromatography.
5
75.64 2.50 (24.36)***
68.42 0.28 (31.58)***
88.80 1.72 (11.2)
6
7
8
mal tissue structure and function.20) In order to evaluate the
anti-inflammatory effects of the prepared 1,3-diarylpropenes
1–8, we measured the amount of nitric oxide (NO) which is
one of the essential mediators on inflammation, in lipopoly-
saccharide (LPS)-stimulated RAW264.7 macrophages21) using
NG-monomethyl-L-arginine acetate (L-NMMA)22,23) as a posi-
tive control.
69.80 1.12 (30.2)***
79.1 4.1 (20.9)
L-NMMA
The results are reported as the mean value S.E.M. 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.
1 (39.3%), and 5 (37.9%). The cell viability assay at 10µM con-
Effect of compounds 1–8 on NO generation by induced centration was not affected by any compound excluding com-
macrophages was monitored (Table 2). In this study, four pound 8 indicating no cytotoxicity as shown in Table 3. Com-
compounds i.e., compounds 6 (mucronulastyrene E-isomer), pound 8 showed toxicity at 10µM concentration. IC50 values
8 (dalberatin B), 1 (isomucronustyrene), and 5 (mucronusty- of compounds 1–8 were evaluated by using GraphPad Prism
rene) showed significant activities at 10µM. Among the 8 4.0 software and showed 11.48, 8.98, 15.28, 12.96, 10.48, 4.05,
compounds, the maximum inhibitory activity was observed 16.76, and 5.04µM, respectively (Table 3).
with compound 6 (58.7%) followed by compounds 8 (53.8%),
From these pharmacological results, we can conclude that

Vol. 64, No. 6 (2016)
Chem. Pharm. Bull.
635
Table 3. Proliferation Effect and IC50 (µM) Values of 1,3-Diarylpropenes
(1–8)
solution (2mL) was added slowly and extracted with CH2Cl2
(2×30mL). The combined organic layer was washed with
brine (2×30mL), dried over anhyd. Na2SO4 and concentrated
in vacuo. The crude was purified by column chromatography
(EtOAc–Hexane=1:20–1:10) to afford the product [Note: FC
reactions of allyl alcohol (19, 33–35) and 37 were carried out
at room temperature instead of 0°C and the reaction time was
3 h].
(E)-3-Cinnamyl-2,6-dimethoxyphenyl Acetate (22) Yield:
61%; Colorless liquid; Rf=0.44 (EtOAc–hexane=1:4);
1H-NMR (300MHz, CDCl3) δ: 7.34–7.14 (5H, m), 7.02 (1H,
d, J=8.7Hz), 6.66 (1H, d, J=8.7Hz), 6.41 (1H, d, J=15.6Hz),
6.30 (1H, dt, J=15.6, 6.3Hz), 3.78 (6H, s), 3.50 (2H, d,
J=6.3Hz), 2.35 (3H, s); 13C-NMR (75MHz, CDCl3) δ: 168.9,
151.0, 137.7, 133.4, 131.2, 129.2, 128.8, 128.7, 127.3, 127.2,
126.5, 126.3, 107.7, 61.7, 56.5, 33.1, 21.0.
Proliferationa)
Compound
IC50 (µM)
1µM
10µM
Medium (MED)
100.0 2.06
105.3 11.82
112.7 9.62
95.60 2.72
117.7 9.70
93.08 2.03
105.5 7.56
100.3 9.97
94.36 3.12
98.6 2.9
100.0 2.06
105.9 8.37
112.0 6.19
121.7 8.32
107.6 10.19
110.9 5.07
109.1 6.20
99.48 8.60
79.54 3.66**
97.6 5.6
1
11.48
8.98
2
3
15.28
12.96
10.48
4.05
4
5
6
7
8
16.76
5.04
L-NMMA
2.69
a) The results are reported as the mean value S.E.M. for n=3. Statistical signifi-
cance is based on the difference when compared with medium groups (**p<0.01).
(E)-3-(3-(4-(Ethoxymethoxy)phenyl)allyl)-2,6-di-
methoxyphenyl Acetate (23) Yield: 61%; Colorless liquid;
1,3-diarylpropene 6 can be considered as a new lead to de- Rf=0.48 (EtOAc–hexane=1:2); 1H-NMR (300MHz, CDCl3)
velop impressive anti-inflammatory agents.
δ: 7.25 (2H, d, J=8.4Hz), 6.94 (2H, d, J=8.4Hz), 6.67 (1H,
d, J=8.4Hz) 6.59 (1H, d, J=8.4Hz), 6.35 (1H, d, J=15.6Hz),
6.17 (1H, dt, J=15.6, 6.3Hz) 5.19 (2H, s) 3.79 (3H, s), 3.78 (3H,
Conclusion
We have developed an efficient approach for the synthe- s), 3.70 (2H, q, J=7.1Hz), 3.48 (2H, d, J=6.3Hz), 2.35 (3H, s)
sis of 1,3-diarylpropenes 1–8 using FC alkylation as a key 1.21 (3H, t, J=7.1Hz); 13C-NMR (75MHz, CDCl3) δ: 168.8,
step. Additionally, their anti-inflammatory effects were also 156.7, 152.5, 151.0, 131.6, 130.5, 127.4, 127.3, 127.1, 126.5,
investigated in LPS-induced RAW264.7 macrophages. The 116.5, 107.7, 105.1, 93.4, 64.5, 61.6, 56.4, 33.0, 20.8, 15.5.
compounds exhibit significant inhibition of inflammatory me-
(E)-3-(3-(3-(Ethoxymethoxy)-2-methoxyphenyl)-
diated NO production with no cytotoxicity except compound 8 allyl)-2,6-dimethoxyphenyl Acetate (24) Yield: 60%;
(dalberatin B) at 10µM concentration and IC50 values are found Colorless liquid; Rf=0.32 (EtOAc–hexane=1:3); 1H-NMR
in the range from 4.05 to 16.76µM.
(300MHz, CDCl3) δ: 7.12 (1H, dd, J=7.8, 1.5Hz), 7.05 (1H,
d, J=8.7Hz), 7.04 (1H, d, J=8.7Hz), 6.96 (1H, t, J=7.8Hz),
6.78 (1H, d, J=15.9Hz), 6.69 (1H, d, J=7.8Hz), 6.33 (1H,
Experimental
Chemistry All chemicals were obtained from commercial dt, J=15.9, 6.9Hz), 5.27 (2H, s), 3.82 (9H, s), 3.77 (2H, q,
suppliers and were used without further purification unless J=6.9Hz), 3.56 (2H, d, J=6.9Hz), 2.37 (3H, s), 1.25 (3H, t,
noted otherwise. All solvents used for reactions were freshly J=6.9Hz); 13C-NMR (75MHz, CDCl3) δ: 168.4, 150.6, 150.4,
distilled from proper dehydrating agents under nitrogen gas. 146.7, 132.9, 131.6, 130.1, 126.6, 126.0, 124.9, 123.8, 119.1,
All solvents used for chromatography were purchased and 114.9, 107.2, 93.6, 64.2, 61.1, 60.8, 56.1, 33.1, 20.5, 15.1.
directly used without further purification. TLC was performed
(E)-3-(3-(2-(Ethoxymethoxy)-5-methoxyphenyl)-
on DC-Plastikfolien 60, F254 (Merck, layer thickness 0.2mm) allyl)-2,6-dimethoxyphenyl Acetate (25) Yield: 59%;
plastic-backed silica gel plates and visualized by UV light Colorless liquid; Rf=0.30 (EtOAc–hexane=1:5); 1H-NMR
(254nm) or staining with p-anisaldehyde and phosphomolyb- (300MHz, CDCl3) δ: 7.03 (1H, d, J=8.4Hz), 7.00 (1H, d,
dic acid (PMA) stain. Chromatographic purification was car- J=9.0Hz), 6.95 (1H, d, J=8.4Hz), 6.76 (1H, s), 6.70 (1H,
1
ried out using Kieselgel 60 (60–120 mesh, Merck). H-NMR d, J=9.0Hz), 6.68 (1H, d, J=15.9Hz), 6.27 (1H, dt, J=15.9,
spectra were recorded at Varian Mercury-300MHz FT-NMR 6.9Hz) 5.14 (2H, s), 3.79 (6H, s), 3.75 (3H, s), 3.71 (2H, q,
and 75MHz for 13C, with the chemical shift (δ) reported in J=6.9Hz), 3.52 (2H, d, J=6.9Hz), 2.36 (3H, s), 1.22 (3H, t,
parts per million (ppm) downfield relative to tetramethylsilane J=6.9Hz); 13C-NMR (75MHz, CDCl3) δ: 168.5, 154.4, 150.6,
(TMS) and the coupling constants (J) quoted in Hz. Peak 148.3, 133.0, 129.7, 128.3, 126.7, 126.1, 125.4, 116.8, 113.3,
splitting patterns were abbreviated as s (singlet), d (doublet), 111.0, 107.2, 94.4, 64.1, 61.3, 56.1, 55.6, 33.1, 20.6, 15.2.
t (triplet), q (quartet), dt (doublet of triplet) and m (multiplet)
1-(Benzyloxy)-4-cinnamyl-2,3-dimethoxybenzene
(38)
and CDCl3/CD3OD was used as a solvent and an internal Yield: 61%; Colorless liquid; Rf=0.65 (EtOAc–hexane=1:5);
standard. Mass spectra were recorded on an Agilent-5977E 1H-NMR (300MHz, CDCl3) δ: 7.46–7.16 (10H, m), 6.87 (1H,
spectrometer. High resolution mass spectra were recorded on d, J=8.7Hz), 6.64 (1H, d, J=8.7Hz), 6.35 (1H, d, J=15.6Hz),
a JMS-700 (JEOL, Japan) spectrometer. Melting points were 6.22 (1H, dt, J=15.6, 6.6Hz), 5.06 (2H, s), 3.89 (3H, s), 3.86
measured on a MEL-TEMP II apparatus and were uncor- (3H, s), 3.44 (2H, d, J=6.6Hz); 13C-NMR (75MHz, CDCl3)
rected.
δ: 151.7, 151.2, 137.4, 137.0, 130.5, 129.2, 128.4, 128.3, 127.7,
General Procedure for FC Alkylation To a stirred solu- 127.1, 126.8, 126.5, 126.3, 125.9, 123.8, 109.3, 70.9, 61.1, 60.8,
tion of allyl alcohol (1.0mmol) and 21 (0.39g, 2.0mmol) in 33.1
anhyd. CH2Cl2 (8mL) were added Cu(OTf)2 (0.04g, 0.1mmol)
(E)-1-(Benzyloxy)-4-(3-(2-(benzyloxy)phenyl)allyl)-2,3-
and molecular sieves 4Å (0.39g) at 0°C under nitrogen atmo- dimethoxybenzene (39) Rf=0.65 (EtOAc–hexane=1:5);
sphere. The reaction mixture was then stirred for 5–6h. After 1H-NMR (300MHz, CDCl3) δ: 7.44-723 (11H, m), 7.13 (1H, td,
completion of the reaction of the reaction, aq. sat. NH4Cl J=8.4, 1.8Hz), 6.90–6.78 (4H, m), 6.63 (1H, d, J=8.7Hz), 6.33

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(1H, dt, J=15.9, 6.9Hz), 5.07 (2H, s), 5.05 (2H, s), 3.88 (3H, s), δ: 7.09 (1H, dd, J=7.8, 1.8Hz), 6.98 (1H, dd, J=7.8, 1.8Hz),
3.85 (3H, s), 3.49 (2H, dd, J=6.9, 1.2Hz); 13C-NMR (75MHz, 6.92 (1H, t, J=7.8Hz), 6.68–6.60 (3H, m), 6.34 (1H, dt,
CDCl3) δ: 155.7, 152.1, 151.5, 143.3, 137.5, 137.4, 130.3, 129.1, J=16.2, 6.6Hz), 5.21 (2H, s), 3.81 (3H, s), 3.80 (3H, s), 3.73
128.7, 128.5, 128.1, 128.0, 127.9, 127.5, 127.4, 127.3, 126.8, (3H, s), 3.66 (2H, q, J=7.0Hz), 3.47 (2H, d, J=6.6Hz), 1.19
125.7, 124.2, 121.2, 112.8, 109.9, 71.4, 70.7, 61.4, 61.2, 33.8.
(3H, t, J=7.0Hz); 13C-NMR (75MHz, CD3OD) δ: 150.6, 147.5,
(E)-1-(Benzyloxy)-4-(3-(3-(benzyloxy)-2-methoxyphen- 147.0, 146.0, 139.4, 132.0, 131.0, 126.0, 124.4, 123.9, 119.1,
yl)allyl)-2,3-dimethoxybenzene (40) Yield: 32%; Colorless 115.2, 107.0, 93.7, 64.4, 60.1, 59.8, 55.5, 33.3, 14.4.
liquid; Rf=0.52 (EtOAc–hexane=1:5); 1H-NMR (300MHz,
(E)-3-(3-(2-(Ethoxymethoxy)-5-methoxyphenyl)-
CDCl3) δ: 7.49–7.31 (10H, m), 7.11 (1H, dd, J=7.8, 0.9Hz), allyl)-2,6-dimethoxyphenol (28) Yield: 96%; Colorless oil;
1
6.96 (1H, t, J=7.8Hz), 6.88 (1H, d, J=8.4Hz), 6.83 (1H, dd, Rf=0.38 (EtOAc–hexane=1:3); H-NMR (300MHz, CD3OD)
J=7.8, 0.9Hz), 6.82 (1H, d, J=15.9Hz), 6.70 (1H, d, J=8.4Hz), δ: 6.95 (1H, d, J=8.7Hz), 6.94 (1H, d, J=3.0Hz), 6.67 (1H, dd,
6.38 (1H, dt, J=15.9, 7.0Hz), 5.14 (4H, s), 3.95 (6H, s), 3.88 J=8.7, 3.0Hz), 6.65 (1H, d, J=15.9Hz), 6.62 (1H, d, J=8.4Hz),
(3H, s), 3.57 (2H, d, J=7.0Hz); 13C-NMR (75MHz, CDCl3) 6.61 (1H, d, J=8.4Hz), 6.31 (1H, dt, J=15.9, 6.6Hz) 5.08
δ: 152.0, 151.8, 151.3, 147.0, 143.0, 137.2, 137.1, 132.0, 128.3, (2H, s), 3.80 (3H, s), 3.79 (3H, s), 3.70 (3H, s), 3.64 (2H, q,
127.7, 127.2, 127.1, 126.8, 124.9, 123.8, 123.7, 118.6, 113.1, J=7.0Hz), 3.44 (2H, dd, J=6.6, 1.2Hz), 1.15 (3H, t, J=7.0Hz);
109.7, 71.2, 70.9, 61.1, 61.0, 60.8, 33.5.
13C-NMR (75MHz, CD3OD) δ: 155.9, 149.5, 148.5, 147.0,
(E)-1-(Benzyloxy)-4-(3-(2-(benzyloxy)-5-methoxyphen- 140.4, 131.5, 130.0, 127.1, 126.0, 120.3, 118.1, 114.1, 112.0,
yl)allyl)-2,3-dimethoxybenzene (41) Yield: 32%; Colorless 108.1, 95.6, 65.3, 60.9, 56.6, 55.9, 34.3, 15.5.
liquid; Rf=0.56 (EtOAc–hexane=1:5); 1H-NMR (300MHz,
General Procedure for EOM-Deprotection To a stirred
CDCl3) δ: 7.48–7.30 (10H, m), 7.02 (1H, d, J=2.7Hz), 6.85 solution of EOM-protected 1,3-diarylpropene (0.15mmol) in
(1H, d, J=8.4Hz), 6.85 (1H, d, J=8.4Hz), 6.81 (1H, d, anhyd. MeOH (4mL) was added Dowex® resin (150% w/w)
J=15.3Hz), 6.71 (1H, dd, J=8.4, 2.7Hz), 6.36 (1H, dt, J=15.6, under nitrogen atmosphere at room temperature. The reac-
6.9Hz), 6.67 (1H, d, J=8.4Hz), 5.11 (2H, s), 5.02 (2H, s), 3.93 tion was stirred at 40°C for 31–48h. After completion of the
(3H, s), 3.89 (3H, s), 3.78 (3H, s), 3.53 (2H, d, J=6.9Hz); reaction, filtered, washed with MeOH (5mL) and the filtrate
13C-NMR (75MHz, CDCl3) δ: 154.3, 152.1, 151.6, 150.2, 143.3, was concentrated in vacuo. The crude was purified by column
137.6, 137.5, 130.6, 128.7, 128.6, 128.6, 128.0, 127.9, 127.5, chromatography (EtOAc–Hexane=1:4–1:3) to afford the
127.4, 127.1, 125.5, 124.2, 114.7, 113.3, 112.1, 109.9, 71.8, 71.5, product.
61.4, 61.1, 56.0, 33.7.
(E)-3-(3-(4-Hydroxyphenyl)allyl)-2,6-dimethoxyphenol
General Procedure for Acetyl Deprotection To a stirred (Dalparvinene) (2) Yield: 76%; Pale yellow color liquid;
solution of acetyl protected 1,3-diarylpropene (0.4mmol) in Rf=0.33 (EtOAc–hexane=1:2); 1H-NMR (300MHz, CDCl3)
MeOH (4mL) was added aq. 0.7M K2CO3 (3.43mL) and stirred δ: 7.20 (2H, d, J=8.4Hz), 6.73 (2H, d, J=8.4Hz), 6.67 (1H,
for 2h at room temperature. After completion of the reaction, d, J=8.1Hz) 6.59 (1H, d, J=8.1Hz), 6.33 (1H, d, J=16.2Hz),
MeOH was removed under reduced pressure and the pH was 6.16 (1H, dt, J=16.2, 6.3Hz) 5.57 (1H, s) 5.13 (1H, s) 3.87 (3H,
adjusted to 6 with 1N HCl. The crude was extracted with s), 3.86 (3H, s), 3.47 (2H, d, J=6.3Hz); 13C-NMR (75MHz,
EtOAc (2×25mL). The combined organic layer was washed CDCl3) δ: 154.6, 146.2, 145.1, 138.6, 130.5, 130.0, 127.3,
with brine (2×30mL), dried over anhyd. Na2SO4 and concen- 127.1, 126.5, 119.6, 115.3, 106.5, 60.8, 56.3, 32.9; EI-MS m/z
trated in vacuo. The crude was purified by column chromatog- 286 (M+, base), 255, 223; HR-MS: Calcd for C17H18O4 (M+):
raphy (EtOAc–Hexane=1:4–1:2) to afford the product.
3-Cinnamyl-2,6-dimethoxyphenol (Isomucronustylene)
286.1205. Found: 286.1213.
(E)-3-(3-(3-Hydroxy-2-methoxyphenyl)allyl)-2,6-di-
(1) Yield: 98%; Colorless oil; Rf=0.42 (EtOAc–hex- methoxyphenol (Dalberatin C) (3) Yield: 74%; Pale yel-
ane=1:2); 1H-NMR (300MHz, CDCl3) δ: 7.30 (5H, m), low color liquid; Rf=0.23 (EtOAc–hexane=1:1); 1H-NMR
6.63 (1H, d, J=8.4Hz), 6.59 (1H, d, J=8.4Hz), 6.36 (1H, d, (300MHz, CD3OD) δ: 6.89 (1H, dd, J=7.8, 1.2Hz), 6.82 (1H, t,
J=15.6Hz), 6.29 (1H, dt, J=15.6, 5.4Hz), 4.90 (1H, s), 3.79 J=7.8Hz), 6.67 (1H, dd, J=7.8, 1.2Hz), 6.63 (1H, d, J=8.1Hz),
(6H, s), 3.43 (2H, d, J=5.4Hz); 13C-NMR (75MHz, CDCl3) 6.62 (1H, d, J=8.1Hz), 6.60 (1H, d, J=17.1Hz), 6.32 (1H, dt,
δ: 147.5, 146.0, 139.4, 137.9, 130.4, 129.5, 128.3, 126.7, 126.0, J=17.1, 6.6Hz), 3.81 (3H, s), 3.80 (3H, s), 3.68 (3H, s), 3.46
125.8, 119.2, 107.1, 59.8, 55.6, 32.9; electron ionization (EI)- (2H, d, J=6.6Hz); 13C-NMR (75MHz, CD3OD) δ: 150.1, 147.5,
MS m/z 270 (M+, base), 239, 207; high resolution (HR)-MS: 146.0, 145.0, 139.4, 131.6, 130.7, 126.0, 124.7, 124.31, 119.2,
Calcd for C17H18O3 (M+): 270.1256. Found: 270.1250.
116.8, 114.7, 107.0, 60.1, 59.8, 55.5, 33.2; EI-MS m/z 316 (M+,
(E)-3-(3-(4-(Ethoxymethoxy)phenyl)allyl)-2,6-di- base), 285, 253; HR-MS: Calcd for C18H20O5 (M+): 316.1311.
methoxyphenol (26) Yield: 98%; Pale yellow color oil; Found: 316.1314.
Rf=0.50 (EtOAc–hexane=1:2); 1H-NMR (300MHz, CDCl3)
(E)-3-(3-(2-Hydroxy-5-methoxyphenyl)allyl)-2,6-di-
δ: 7.25 (2H, d, J=8.4Hz), 6.94 (2H, d, J=8.4Hz), 6.66 (1H, d, methoxyphenol (Dalberatin D) (4) Yield: 77%; Pale yel-
J=8.7Hz) 6.56 (1H, d, J=8.7Hz), 6.35 (1H, d, J=15.9Hz), 6.19 low color liquid; Rf=0.20 (EtOAc–hexane=1:4); 1H-NMR
(1H, dt, J=15.9, 6.3Hz) 5.55 (1H, s) 5.19 (2H, s) 3.86 (3H, s), (300MHz, CD3OD) δ: 6.85 (1H, d, J=3.0Hz), 6.73 (1H, d,
3.85 (3H, s), 3.70 (2H, q, J=6.9Hz), 3.47 (2H, d, J=6.3Hz), J=8.1Hz), 6.68 (1H, d, J=8.1Hz), 6.66 (1H, dd, J=8.1, 3.0Hz),
1.21 (3H, t, J=6.9Hz); 13C-NMR (75MHz, CDCl3) δ: 156.7, 6.60 (1H, d, J=15.6Hz), 6.59 (1H, d, J=8.1Hz), 6.28 (1H, dt,
146.5, 145.5, 138.9, 131.7, 130.2, 127.8, 127.3, 126.7, 119.3, J=15.6, 6.9Hz), 3.80 (3H, s), 3.79 (3H, s), 3.67 (3H, s), 3.44
116.5, 106.7, 93.5, 64.5, 61.0, 56.6, 33.2, 15.5.
(2H, dd, J=6.9, 1.8Hz); 13C-NMR (75MHz, CD3OD) δ: 153.2,
(E)-3-(3-(3-(Ethoxymethoxy)-2-methoxyphenyl)- 148.2, 147.4, 146.0, 139.3, 129.4, 126.3, 125.5, 125.4, 119.3,
allyl)-2,6-dimethoxyphenol (27) Yield: 98%; Colorless oil; 116.1, 113.4, 110.9, 107.1, 59.9, 55.5, 55.0, 33.4; EI-MS m/z
1
Rf=0.65 (EtOAc–hexane=1:2); H-NMR (300MHz, CD3OD) 316 (M+, base), 285, 253; HR-MS: Calcd for C18H20O5 (M+):

Vol. 64, No. 6 (2016)
Chem. Pharm. Bull.
637
316.1311. Found: 316.1306.
Acknowledgments This research was financially support-
General Procedure for Benzyl Deprotection To a stirred ed by Priority Research Centers Program through the National
solution of benzyl protected 1,3-diarylpropene (0.15mmol) Research Foundation of Korea (NRF) funded by the Ministry
in anhyd. CH2Cl2 (5mL) was added BCl3 solution (1.0M in of Education, Science and Technology (NRF-2009-0094071),
CH2Cl2, 0.375mL, 0. 375mmol, 2.5eq.) slowly under nitro- and by the Hallym University Research Fund (HRF-G-2015-2).
gen atmosphere at −40°C. The reaction was stirred for 1h
at −40°C. After completion of the reaction, excess BCl3 was
Conflict of Interest The authors declare no conflict of
quenched by the slow addition of MeOH (1mL) and then sol- interest.
vent was removed under reduced pressure. H2O (5mL) and
CH2Cl2 (15mL) were added to the crude and two layers sepa-
Supplementary Materials The online version of this
rated. Aqueous layer was extracted with CH2Cl2 (2×25mL) article contains supplementary materials (experimental proce-
dried over anhyd. Na2SO4 and concentrated in vacuo. The dures and characterization data).
crude was purified by column chromatography (EtOAc–Hex-
ane=1:4–1:3) to afford the product [Note: For compound 5
preparation from 38, 1.5eq. of BCl3 used instead of 2.5eq.].
4-Cinnamyl-2,3-dimethoxyphenol (Mucronustyrene) (5)
Yield: 89%; Colorless liquid; Rf=0.49 (EtOAc–hexane=1:1);
1H-NMR (300MHz, CDCl3) δ: 7.34–7.13 (5H, m), 6.81 (1H,
d, J=8.4Hz), 6.43 (1H, d, J=15.6Hz), 6.40 (1H, d, J=8.4Hz),
6.35 (1H, dt, J=15.6, 5.7Hz), 5.92 (1H, s), 3.89 (3H, s), 3.82
(3H, s), 3.49 (2H, d, J=5.7Hz); 13C-NMR (75MHz, CDCl3)
δ: 150.7, 147.1, 137.6, 135.4, 130.5, 128.7, 128.3, 126.8, 126.0,
127.1, 119.2, 103.6, 60.9, 55.9, 32.8; EI-MS m/z 270 (M+, base),
239, 207; HR-MS: Calcd for C17H18O3 (M+): 270.1256. Found:
270.1263.
(E)-4-(3-(2-Hydroxyphenyl)allyl)-2,3-dimethoxyphenol
(Mucronulastyrene) (6) Yield: 98%; Pale yellow color
liquid; Rf=0.18 (EtOAc–hexane=1:3); 1H-NMR (300MHz,
CDCl3) δ: 7.30 (1H, dd, J=7.8, 1.5Hz), 7.08 (1H, td, J=7.8,
1.5Hz), 6.86 (1H, d, J=7.8Hz), 6.84 (1H, d, J=8.4Hz), 6.77
(1H, dd, J=7.8, 1.2Hz), 6.68 (1H, d, J=8.4Hz), 6.60 (1H, d,
J=15.6Hz), 6.29 (1H, dt, J=15.6, 6.9Hz), 5.68 (1H, s), 5.20
(1H, s), 3.93 (3H, s), 3.86 (3H, s), 3.50 (2H, dd, J=6.9, 1.5Hz);
13C-NMR (75MHz, CDCl3) δ: 152.8, 150.9, 148.4, 140.1,
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