Synthesis and evaluation of water-soluble resveratrol and piceatannol via BGLation

Article abstract of DOI:10.1016/j.bmcl.2012.06.019

Synthesis of four water-soluble resveratrol and piceatannol derivatives bearing symmetrically branched glyceryl trimer (BGL003) with a non-biocleavable linkage, and their biological evaluation as a mitochondrial fusion-inducing agent with cellular fat-reducing effect from cells, is described. The effect of Piceatannol-BGL003 conjugate was as high as that of original stilbenoids.

Full text of DOI:10.1016/j.bmcl.2012.06.019

Supplementary Material
Synthesis and Evaluation of Water-soluble Resveratrol and
Piceatannol via BGLation
Hisao Nemoto a,*, Ayato Katagiri a, Masaki Kamiya a, Tsuyoshi Matsushita a, Hatsuhiko
Hattori a, Kosuke Matsumura a, Tomohiro Itou a, Tomoyuki Kawamura a, Toshiyuki
Kita b, Hana Nishida b, Naokatu Arakaki b
a Department of Pharmaceutical Chemistry, Institute of Health Biosciences, Graduate School of The University of Tokushima, 1-78,
Sho-machi, Tokushima 770-8505, Japan
b Department of Molecular Cell Biology and Medicine, Institute of Health Biosciences, Graduate School of The University of
Tokushima, 1-78, Sho-machi, Tokushima 770-8505, Japan
1
IR spectra were recorded by FT-IR 6200 spectrometer. H NMR and 13C NMR spectra were
measured by JEOL JMN-AL300 Spectrometer at 300 MHz, or 75 MHz, respectively. Chemical
shifts were indicated by δ value (ppm) with tetramethylsilane as an internal standard. High
Resolution Mass spectra (HRMS) were measured by Waters LCT PREMIER. Dichloromethane
(CH2Cl2) was distilled over phosphorous pentoxide. Pyridine was distilled over potassium hydroxide.
N,N-Dimethylformamide (DMF) was distilled over calcium hydride under reduced pressure.
Acetone was distilled over potassium carbonate (K2CO3). Anhydrous tetrahydrofuran (THF) was
purchased from Kanto Chemical Co., Inc. All the reaction was carried out under argon atmosphere
unless otherwise noted.
1-(bromomethyl)-3-(methoxymethoxy)-5-(prop-2-ynyloxy)benzene (11): To a solution of 921)
(4.04 g, 22.0 mmol) in acetone (100 mL) were added propargyl bromide (3.14 g, 26.4 mmol) and
K2CO3 (5.70 g, 44.0 mmol), and the resulting suspension was heated at reflux for 4 h. The resulting
suspension was cooled to room temperature, and filtered. The filtrate was concentrated in vacuo to
afford crude 10 (4.90 g), which was used in the next step without further purification.
To a solution of the crude 10 (4.90 g) in CH2Cl2 (100 mL) were added 2,6-lutidine (2.56 ml, 22.0
mmol), carbon tetrabromide (9.48 g, 28.6 mmol) and triphenylphosphine (7.50 g, 28.6 mmol), and
the mixture was stirred for 30 min at 0˚C. The resulting solution was diluted with ether (100 mL),
and the suspension was filtered. The filtrate was concentrated in vacuo. The residue was purified by
silica gel column chromatography eluted with hexane/ethyl acetate (4/1) to afford 11 (4.78 g, 16.8
mmol, 76% yield from 9). FT-IR (neat): 3228, 2956, 1596, 1459, 1294, 1213, 1147, 1081, 1054,
1031, 933, 844 cm–1; 1H NMR (CDCl3, 400 MHz): δ 6.73 (s, 1H), 6.67 (s, 1H), 6.63 (s, 1H), 5.16 (s,
2H), 4.68 (d, J = 2.4 Hz, 2H), 4.42 (s, 2H), 3.48 (s, 3H), 2.54 (t, J = 2.3 Hz, 1H); 13C NMR (CDCl3,
75 MHz): δ 158.5 (C), 158.3 (C), 139.7 (C), 109.9 (CH), 108.9 (CH), 103.5(CH), 94.3 (CH2), 78.0
1

(C), 75.7 (CH), 56.0 (CH), 55.8 (CH2), 33.1 (CH2); HRMS (ESI-TOF) m/z calcd for C12H14O3Br [M
+ H]+ 285.0126, found 285.0125.
(diethyl 3-(methoxymethoxy)-5-(prop-2-ynyloxy)benzylphosphonate) (8)
A mixture of 11 (4.78 g, 16.8 mmol) and triethyl phosphite (5.75 mL, 33.5 mmol) was heated at
100˚C for 3 h. After being cooled to room temperature, the resulting mixture was purified by silica
gel column chromatography eluted with hexane/ethyl acetate (1/3) to afford 8 (5.59 g, 16.3 mmol,
1
97% yield). FT-IR (neat): 3284, 2982, 1597, 1459, 1391, 1246, 1148, 1028, 965, 858, 782 cm–1; H
NMR (CDCl3, 400 MHz): δ 6.63 (s, 1H), 6.58 (s, 2H), 5.14 (s, 2H), 4.66 (d, J = 2.4 Hz, 2H), 4.05
(dq, JH–H = 7.2 Hz, JH–P = 7.2 Hz, 4H), 3.46 (s, 3H), 3.10 (d, J = 21.7 Hz, 2H), 2.52 (s, 2H), 1.27 (t, J
= 7.1 Hz, 6H); 13C NMR (CDCl3, 75MHz): δ 158.3 (d, JC–P = 3.0 Hz, C), 158.0 (d, JC–P = 3.0 Hz, C),
133.5 (d, JC–P = 8.8 Hz, C), 110.6 (d, JC–P = 6.7 Hz, CH), 109.4 (d, JC–P = 6.4 Hz, CH), 101.8 (d, JC–P
= 3.47 Hz, CH), 94.0 (CH2), 78.0 (C), 75.3 (CH), 61.7 (d, JC–P = 6.8 Hz, CH2 × 2), 55.5 (CH3), 55.4
(CH2), 33.4 (d, JC–P = 138 Hz, CH2), 15.8 (d, JC–P = 6.8 Hz, CH3 × 2); HRMS (ESI-TOF) m/z calcd
for C16H24O6P [M + H]+ 343.1131, found 343.1316.
5,5'-(2-azidopropane-1,3-diyl)bis(oxy)bis(2,2-dimethyl-1,3-dioxane) (5): To a solution of 1215d)
(303 mg, 0.946 mmol) in pyridine (1.5 mL) were 4-toluenesulfonyl chloride (270 mg, 1.42 mmol)
and 4-(N,N-dimethylamino)pyridine (11.6 mg, 0.0946 mmol), and the mixture was stirred for 24 h at
room temperature. The resulting mixture was poured into a saturated aqueous solution of copper(II)
sulfate (CuSO4aq, 100 mL), and extracted with three portions of ethyl acetate (100 mL × 3). The
combined organic layers were washed with a saturated aqueous solution of sodium hydrogen
carbonate (NaHCO3aq, 100 mL), brine (100 mL), dried over anhydrous sodium sulfate (Na2SO4),
and concentrated in vacuo. The residue (crude 13, 470 mg) was used in the next step without further
purification.
To a solution of the crude 13 (470 mg) in DMF (10 mL) was added sodium azide (184 mg, 2.84
mmol), and the mixture was heated at 100˚C for 2 h. After being cooled to room temperature, the
resulting mixture was poured into NaHCO3aq (100 mL), and extracted with two portions of ethyl
acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over
Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography
eluted with hexane/ethyl acetate (1/1) to afford 5 (309 mg, 0.896 mmol, 95% yield from 12). FT-IR
(neat): 3585, 2991, 2873, 2360, 2100, 1652, 1455, 1373, 1338, 1251, 1228, 1199, 1153, 1099, 1043,
1
997, 939, 829, 732 cm–1; H NMR (CDCl3, 400 MHz): δ 4.0–3.95 (m, 5H), 3.78-3.56 (m, 9H),
3.50–3.45 (m, 2H), 1.44 (s, 6H), 1.41 (s, 6H); 13C NMR (CDCl3, 75 MHz): δ 97.9 (C × 2), 70.9 (CH
× 2), 68.1 (CH2 × 2), 62.0 (CH2 × 4), 60.2 (CH), 23.6 (CH3 × 2), 22.7 (CH3 × 2); HRMS (ESI-TOF)
m/z calcd for C15H27N3O6Na [M + Na]+ 368.1798, found 368.1802
(E)-1,2-bis(methoxymethoxy)-4-(3-(methoxymethoxy)-5-(prop-2-ynyloxy)styryl)benzene (15a’):
2

To a solution of 8 (157 mg, 0.455 mmol) in THF (1.0 mL) was added sodium hydride [57.9 mg of
55% in mineral oil (net weight: 31.9 mg), 1.33 mmol] in some portions, and the mixture was stirred
for 10 min at room temperature. To the resulting mixture was added a solution of 14a’22) (166 mg,
0.486 mmol) in THF (1.0 mL). The resulting solution was stirred for 3 h at room temperature,
poured into a saturated aqueous solution of ammonium chloride (NH4Claq) (30 mL), and extracted
with three portions of ethyl acetate (30 mL × 3). The combined organic layers were washed with
brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with hexane/ethyl acetate (4/1) to afford 15a’ (144 mg, 0.346 mmol,
76% yield). FT-IR (neat): 2360, 1590, 1508, 1449, 1258, 1150, 1074, 1033, 993, 922, 832, 683 cm–1;
1H NMR (CDCl3, 400 MHz): δ 7.35 (d, J = 1.8 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.8,
1.8 Hz, 1H), 7.00 (d, J = 16.2 Hz, 1H), 6.90 (d, J = 16.3 Hz, 1H), 6.84 (s, 1H), 6.76 (s, 1H), 6.58 (t, J
= 2.1 Hz, 1H), 5.27 (s, 2H), 5.23 (s, 2H), 5.17 (s, 2H), 4.69 (d, J = 2.4 Hz, 2H), 3.54 (s, 3H), 3.51 (s,
3H), 3.48 (s, 3H), 2.56 (t, J = 2.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 158.5 (C), 158.3 (C),
147.2 (C), 146.8 (C), 139.4 (C), 131.6 (C), 128.7 (CH), 126.9 (CH), 121.0 (CH), 116.4 (CH), 114.2
(CH), 107.1 (CH), 106.1 (CH), 102.7 (CH), 95.2 (CH2), 95.1 (CH2), 94.2 (CH2), 78.3 (C), 75.5 (CH),
56.0 (CH3), 55.9 (CH3), 55.8 (CH3), 55.6 (CH2); HRMS (ESI-TOF) m/z calcd for C23H26O7Na [M +
Na]+ 437.1576, found 437.1569.
(E)-1-(1,3-bis(2,2-dimethyl-1,3-dioxan-5-yloxy)propan-2-yl)-4-((3-(3,4-bis(methoxymethoxy)sty
ryl)-5-(methoxymethoxy)phenoxy)methyl)-1H-1,2,3-triazole (16a’): To a solution of 15a’ (113
mg, 0.272 mmol) in tert-butanol/water (0.3 mL/0.3 mL) were added copper(II) sulfate pentahydrate
(6.8 mg, 0.027 mmol) and sodium ascholbate (10.8 mg, 0.0545 mmol), and the mixture was stirred
for 6 h at room temperature. The resulting solution was poured into NH4Claq (30 mL), and extracted
with three portions of ethyl acetate (30 mL × 3). The combined organic layers were washed with
brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with hexane/ethyl acetate (1/3) to afford 16a’ (127 mg, 0.168 mmol,
73% yield). FT-IR (neat): 2993, 2827, 1733, 1590, 1510, 1449, 1373, 1256, 1151, 827, 755, 686,
666, 520, 442 cm–1; 1H NMR (CDCl3, 400 MHz): δ 7.91 (s, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.14 (d, J
= 8.4 Hz, 1H), 7.10 (dd, J = 8,4, 1.9 Hz, 1H), 6.98 (d, J = 16.3 Hz, 1H), 6.89 (d, J = 16.2 Hz, 1H),
6.81 (t, J = 1.6 Hz, 1H), 6.79 (t, J = 1.8 Hz, 1H), 6.60 (t, J = 2.2 Hz, 1H), 5.28 (s, 2H), 5.25 (s, 2H),
5.22 (s, 2H), 5.18 (s, 2H), 4.92 (quint, J = 5.6 Hz, 1H), 4.01–3.88 (m, 8H), 3.76-3.65 (m, 4H), 3.56
(s, 3H), 3.53 (s, 3H), 3.50 (s, 3H), 3.37–3.32 (m, 2H), 1.40 (s, 6H), 1.39 (s, 6H); 13C NMR (CDCl3,
75 MHz): δ 159.1 (C), 158.2 (C), 147.1 (C), 146.8 (C), 143.2 (C), 139.2 (C), 131.5 (C), 128.5 (CH),
126.8 (CH), 123.1 (CH), 120.8 (CH), 116.4 (CH), 114.3 (CH), 106.8 (CH), 105.9 (CH), 102.5 (CH),
97.8 (C × 2), 95.1 (CH2), 95.0 (CH2), 94.1 (CH2), 70.9 (CH × 2), 66.8 (CH2 × 2), 61.8 (CH2 × 2),
61.7 (CH2), 61.5 (CH2 × 2), 60.4 (CH), 55.8 (CH3 × 2), 55.6 (CH3), 24.1 (CH3 × 2), 22.3 (CH3 × 2);
HRMS (ESI-TOF) m/z calcd for C38H53N3O13Na [M + Na]+ 782.3276, found 782.3461.
3

(E)-2,2'-(2-(4-((3-(3,4-dihydroxystyryl)-5-hydroxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl)propa
ne-1,3-diyl)bis(oxy)dipropane-1,3-diol (3a): A solution of 16a’ (22.2 mg, 29.2 µmol) in methanol
(0.3 mL) in the presence of a catalytic amount of Amberlyst 15 (6.2 mg) was stirred for 35 h at room
temperature. The resulting suspension was filtered, and the filtrate was concentrated in vacuo. The
residue was purified by silica gel column chromatography eluted with chloroform/methanol (4/1) to
afford 3a (12.1 mg, 22.1µmol, 76% yield). FT-IR (neat): 3309, 2938, 2360, 1595, 1524, 1455, 1340,
1280, 1159, 1117, 1048, 966, 830, 683 cm–1; 1H NMR (CD3OD, 400 MHz): δ 8.28 (s, 1H), 7.01 (d, J
= 1.8 Hz 1H), 6.96 (d, J = 16.3 Hz, 1H), 6.87 (dd, J = 8.1, 1.9 Hz, 1H), 6.82 (d, J = 16.2 Hz, 1H),
6.76 (d, J = 8.1 Hz, 1H), 6.67 (s, 1H), 6.58 (s, 1H), 6.35 (t, J = 2.0 Hz, 1H), 5.17 (s, 2H), 5.02 (quint,
J = 5.5 Hz, 1H), 4.18–4.07 (m, 4H), 3.67–3.48 (m, 8H), 3.44 (quint, J = 5.0 Hz, 2H); 13C NMR
(CD3OD, 75 MHz): δ 161.3 (C), 159.9 (C), 146.8 (C), 146.7 (C), 144.9 (C), 141.6 (C), 131.1 (C),
130.3 (CH), 126.9 (CH), 125.8 (CH), 120.4 (CH), 116.5 (CH), 114.0 (CH), 107.3 (CH), 105.3 (CH),
102.4 (CH), 83.4 (CH × 2), 70.2 (CH2 × 2), 63.1 (CH), 62.6 (CH2 × 2), 62.4 (CH2 × 3); HRMS
(ESI-TOF) m/z calcd for C26H33N3O10Na [M + Na]+ 570.2064, found 570.2062.
((E)-1-(methoxymethoxy)-3-(4-(methoxymethoxy)styryl)-5-(prop-2-ynyloxy)benzene) (15b’):
To a solution of 8 (205 mg, 0.600 mmol) in THF (2.0 mL) was added sodium hydride [65.5 mg of
55% in mineral oil (net weight: 36.0 mg), 1.50 mmol] in some portions, and the mixture was stirred
for 10 min at room temperature. To the resulting mixture was added a solution of 14b’23) (36.5 mg,
0.243 mmol) in THF (0.5 mL). The resulting solution was stirred for 15 h at room temperature,
poured into NH4Claq (30 mL), and extracted with three portions of ethyl acetate (30 mL × 3). The
combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated in
vacuo. The residue was purified by silica gel column chromatography eluted with hexane/ethyl
acetate (4/1) to afford 15b’ (135 mg, 0.381 mmol, 76% yield). FT-IR (neat): 3284, 2954, 1591, 1509,
1450, 1291, 1238, 1201, 1150, 1080, 1034, 922, 838, 681 cm–1; 1H NMR (CDCl3, 400 MHz): δ 7.44
(d, J = 8.7 Hz, 2H), 7.03 (d, J = 16.1 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 16.3 Hz, 1H),
6.84 (t, J = 2.2 Hz, 1H), 6.77 (t, J = 1.9 Hz, 1H), 6.59 (t, J = 2.2 Hz, 1H), 5.19 (s, 4H), 4.71 (d, J =
2.4 Hz, 2H), 3.50 (s, 3H), 3.49 (s, 3H), 2.54 (t, J = 2.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 158.6
(C), 158.4 (C), 156.8 (C), 139.6 (C), 130.8 (C), 128.7 (CH), 127.6 (CH × 2), 126.5(CH), 116.2 (CH
× 2), 107.2 (CH), 106.2 (CH), 102.5 (CH), 94.3 (CH2), 94.2 (CH2), 78.3 (C), 75.5 (CH), 55.8 (CH3 ×
2), 55.7 (CH2); HRMS (ESI-TOF) m/z calcd for C21H22O5Na [M + Na]+ 377.1365, found 377.1357.
(E)-1-(1,3-bis(2,2-dimethyl-1,3-dioxan-5-yloxy)propan-2-yl)-4-((3-(methoxymethoxy)-5-(4-(met
hoxymethoxy)styryl)phenoxy)methyl)-1H-1,2,3-triazole (16b’): To a solution of 15b’ (135 mg,
0.381 mmol) in THF (2.0 mL) were added 8 (158 mg, 0.457 mmol), copper(I) iodide (7.3 mg 0.038
mmol) and diisopropylethylamine (0.13 mL, 0.762 mmol), and the mixture was stirred for 15 h at
room temperature. The resulting solution was poured into NH4Claq (30 mL), and extracted with
three portions of ethyl acetate (30 mL × 3). The combined organic layers were washed with brine
(20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel
4

column chromatography eluted with hexane/ethyl acetate (1/3) to afford 16b’ (202 mg, 0.289 mmol,
1
83% yield). FT-IR (neat): 2938, 1590, 1509, 1454, 1373, 1247, 1151, 827, 732 cm–1; H NMR
(CDCl3, 400 MHz): δ 7.92 (s, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 7.03 (d, J =
8.8 Hz, 2H), 6.90 (d, J = 16.3 Hz, 1H), 6.84 (t, J = 1.7 Hz, 1H), 6.81 (t, J = 1.8 Hz, 1H), 6.60 (t, J =
2.2 Hz, 1H), 5.22 (s, 2H), 5.19 (s, 2H), 5.18 (s, 2H), 4.92 (quint, J = 5.7 Hz, 1H), 4.01-3.88 (m, 8H),
3.76–3.65 (m, 4H), 3.50 (s, 3H), 3.49 (s, 3H), 3.37–3.32 (m, 2H), 1.40 (s, 6H), 1.39 (s, 6H); 13C
NMR (CDCl3, 75 MHz): δ 159.2 (C), 158.2 (C), 156.7 (C), 143.3 (C), 139.4 (C), 130.7 (C), 128.6
(CH), 127.5 (CH × 2), 126.4 (CH), 123.2 (CH), 116.2 (CH × 2), 106.9 (CH), 106.1 (CH), 102.4
(CH), 98.0 (C × 2), 94.3 (CH2), 94.1 (CH2), 71.1 (CH × 2), 67.0 (CH2 × 2), 62.0 (CH2 × 2), 61.9
(CH2), 61.8 (CH2 × 2), 60.7 (CH), 55.9 (CH3), 55.8 (CH3), 24.4 (CH3 × 2), 22.5 (CH3 × 2); HRMS
(ESI-TOF) m/z calcd for C36H49N3O11Na [M + Na]+ 722.3265, found 722.3255.
(E)-2,2'-(2-(4-((3-hydroxy-5-(4-hydroxystyryl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)propane-1
,3-diyl)bis(oxy)dipropane-1,3-diol (3b): A solution of 16b’ (35.2 mg, 50.3 µmol) in methanol (1.0
mL) in the presence of a catalytic amount of Amberlyst 15 (1.3 mg) was stirred for 5 days at room
temperature. The resulting suspension was filtered, and the filtrate was concentrated in vacuo. The
residue was purified by silica gel column chromatography eluted with chloroform/methanol (4/1) to
afford 3b (23.7 mg, 44.6 µmol, 89% yield). FT-IR (neat): 3353, 2939, 1591, 1514, 1455, 1345, 1241,
1
1155, 1049, 966, 839, 682 cm–1; H NMR (CD3OD, 400 MHz): δ 8.17 (s, 1H), 7.27 (d, J = 8.6 Hz,
2H), 6.92 (d, J = 16.3 Hz, 1H), 6.76 (d, J = 16.3 Hz, 1H), 6.67 (d, J = 8.6 Hz, 2H), 6.57 (s, 1H), 6.48
(s, 1H), 6.23 (s, 1H), 5.06 (s, 2H), 4.91 (quint, J = 5.9 Hz, 1H), 4.05–3.96 (m, 4H), 3.55–3.38 (m,
8H), 3.32 (quint, J = 5.0 Hz, 2H); 13C NMR (CD3OD, 75 MHz): δ 160.9 (C), 159.6 (C), 158.3 (C),
144.6 (C), 141.4 (C), 130.2 (C), 129.8 (CH), 128.8 (CH × 2), 126.7 (CH), 125.5 (CH), 116.4 (CH ×
2), 107.2 (CH), 105.2 (CH), 102.3 (CH), 83.3 (CH × 2), 70.1 (CH2 × 2), 63.0 (CH), 62.5 (CH2 × 2),
62.4 (CH2 × 3); HRMS (ESI-TOF) m/z calcd for C26H33N3O9Na [M + Na]+ 554.2214, found
554.2119.
(E)-5-(3-(methoxymethoxy)-5-(prop-2-ynyloxy)styryl)benzo[d][1,3]dioxole (15c): To a solution
of 8 (100 mg, 0.292 mmol) in THF (1.0 mL) was added sodium hydride [31.9 mg of 55% in mineral
oil (net weight: 17.5 mg), 0.73 mmol] in some portions, and the mixture was stirred for 10 min at
room temperature. To the resulting mixture was added a solution of piperonal (14c) (36.5 mg, 0.243
mmol) in THF (0.5 mL). The resulting solution was stirred for 5 h at room temperature, poured into
NH4Claq (30 mL), and extracted with three portions of ethyl acetate (30 mL × 3). The combined
organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The
residue was purified by silica gel column chromatography eluted with hexane/ethyl acetate (4/1) to
afford 15c (59.2 mg, 0.175 mmol, 72% yield). FT-IR (neat): 3287, 2900, 2121, 1589, 1490, 1446,
1
1253, 1147, 931, 854, 757, 682 cm–1; H NMR (CDCl3, 400 MHz): δ 7.02 (d, J = 1.5 Hz, 2H), 6.96
(d, J = 16.2 Hz, 1H), 6.91 (dd, J = 8.0, 1.5 Hz, 1H), 6.82 (d, J = 16.1 Hz, 1H), 6.81 (s, 1H), 6.77 (d, J
5

= 8.0 Hz, 1H), 6.73 (s, 1H), 6.58 (t, J = 2.1 Hz, 1H), 5.93 (s, 2H), 5.17 (s, 2H), 4.68 (d, J = 2.4 Hz,
2H), 3.48 (s, 3H), 2.54 (t, J = 2.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 158.7 (C), 158.4 (C),
148.0 (C), 147.3 (C), 139.5 (C), 131.4 (C), 129.0 (CH), 126.5 (CH), 121.5(CH), 108.2 (CH), 107.3
(CH), 106.3 (CH), 105.4 (CH), 102.6 (CH), 101.0 (CH2), 94.3 (CH2), 78.4 (C), 75.5 (CH), 55.8 (CH3,
CH2); HRMS (ESI-TOF) m/z calcd for C20H18O5Na [M + Na]+ 361.1069, found 361.1052
(E)-4-((3-(2-(benzo[d][1,3]dioxol-5-yl)vinyl)-5-(methoxymethoxy)phenoxy)methyl)-1-(1,3-bis(2,
2-dimethyl-1,3-dioxan-5-yloxy)propan-2-yl)-1H-1,2,3-triazole (16c): To a solution of 15c (59.2
mg, 0.175 mmol) in THF (1.0 mL) were added copper(I) iodide (3.3 mg 0.018 mmol) and
diisopropylethylamine (0.061 mL, 0.35 mmol), and the mixture was stirred for 6 h at room
temperature. The resulting solution was poured into NH4Claq (30 mL), and extracted with three
portions of ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL),
dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column
chromatography eluted with hexane/ethyl acetate (1/3) to afford 16c (106 mg, 0.154 mmol, 88%
yield). FT-IR (neat): 2879, 1589, 1490, 1446, 1372, 1253, 1148, 1039, 929, 826, 732 cm–1; 1H NMR
(CDCl3, 400 MHz): δ 7.92 (s, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.98 (d, J = 16.0 Hz, 1H), 6.93 (dd, J =
8.1, 1.5 Hz, 1H), 6.85 (d, J = 16.2 Hz, 1H), 6.81–6.77 (m, 3H), 6.60 (t, J = 2.1 Hz, 1H), 5.98 (s, 2H),
5.22 (s, 2H), 5.18 (s, 2H), 4.92 (quint, J = 5.7 Hz, 1H), 4.01–3.88 (m, 8H), 3.76–3.65 (m, 4H), 3.49
(s, 3H), 3.37–3.32 (m, 2H), 1.40 (s, 6H), 1.39 (s, 6H); 13C NMR (CDCl3, 75 MHz): δ 159.5 (C),
158.6 (C), 147.4 (C), 143.7 (C), 139.6 (C), 131.5 (C), 129.1 (CH), 126.6 (CH), 123.4 (CH), 121.6
(CH), 108.3 (CH), 107.0 (CH), 106.2 (CH), 105.5 (CH), 102.6 (CH), 101.1 (CH2), 98.2 (C × 2), 94.4
(CH2), 71.2 (CH × 2), 67.1 (CH2 × 2), 62.1 (CH2 × 2), 62.0 (CH2), 61.8 (CH2 × 2), 60.7 (CH), 55.9
(CH3), 24.3 (CH3 × 2), 22.5 (CH3 × 2); HRMS (ESI-TOF) m/z calcd for C35H45N3O11Na [M + Na]+
706.2949, found 706.2952
(E)-2,2'-(2-(4-((3-(2-(benzo[d][1,3]dioxol-5-yl)vinyl)-5-hydroxyphenoxy)methyl)-1H-1,2,3-triazo
l-1-yl)propane-1,3-diyl)bis(oxy)dipropane-1,3-diol (3c): A solution of 16c (11.0 mg, 16.0 µmol) in
methanol (0.5 mL) in the presence of a catalytic amount of Amberlyst 15 (0.34 mg) was stirred for
21 h at room temperature. The resulting suspension was filtered, and the filtrate was concentrated in
vacuo. The residue was purified by silica gel column chromatography eluted with
chloroform/methanol (4/1) to afford 3c (5.8 mg, 9.7 µmol, 64% yield). FT-IR (neat): 3352, 2929,
1
1589, 1503, 1446, 1337, 1254, 1157, 1039, 930, 826, 683 cm–1; H NMR (CD3OD, 400 MHz): δ
8.16 (s, 1H), 7.00 (d, J = 1.5 Hz, 1H), 6.91 (d, J = 16.3 Hz, 1H), 6.86 (dd, J = 8.1, 1.5 Hz, 1H), 6.78
(d, J = 16.3 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.58 (s, 1H), 6.49 (s, 1H), 6.25 (t, J = 2.1 Hz, 1H),
5.84 (s, 2H), 5.05 (s, 2H), 4.90 (quint, J = 6.5 Hz, 1H), 4.05–3.96 (m, 4H), 3.56–3.38 (m, 8H), 3.32
(quint, J = 5.3 Hz, 2H); 13C NMR (CD3OD, 75 MHz): δ 161.2 (C), 159.8 (C), 149.7 (C), 148.8 (C),
144.8 (C), 141.2 (C), 133.3 (C), 129.8 (CH), 128.0 (CH), 125.7 (CH), 122.7 (CH), 109.3 (CH),
107.5 (CH), 106.5 (CH), 105.2 (CH), 102.7 (CH), 102.5 (CH2), 83.4 (CH × 2), 70.2 (CH2 × 2), 63.1
6

(CH), 62.6 (CH2 × 2), 62.5 (CH2 × 3); HRMS (ESI-TOF) m/z calcd for C27H33N3O10Na [M + Na]+
582.2064, found 582.2065.
(E)-1-methoxy-3-(4-methoxystyryl)-5-(prop-2-yn-1-yloxy)benzene (15d): To a solution of 8 (205
mg, 0.600 mmol) in THF (2.0 mL) was added sodium hydride [65.5 mg of 55% in mineral oil (net
weight: 36.0 mg), 1.50 mmol] in some portions, and the mixture was stirred for 10 min at room
temperature. To the resulting mixture was added a solution of anisaldehyde (14d) (0.061 mL, 0.50
mmol) in THF (1.0 mL). The resulting solution was stirred for 3 h at room temperature, poured into
NH4Claq (30 mL), and extracted with three portions of ethyl acetate (30 mL × 3). The combined
organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The
residue was purified by silica gel column chromatography eluted with hexane/ethyl acetate (4/1) to
afford 15d (151 mg, 0.466 mmol, 93% yield). FT-IR (neat): 3275, 2934, 1589, 1512, 1451, 1279,
1252, 1147, 1082, 1057, 1029, 965, 931, 836, 681 cm–1; 1H NMR (CDCl3, 400 MHz): δ 7.44 (d, J =
8.7 Hz, 2H), 7.03 (d, J = 16.3 Hz, 1H), 6.92-6.87 (m, 3H), 6.83 (s, 1H), 6.76 (s, 1H), 6.58 (t, J = 2.2
Hz, 1H), 5.19 (s, 2H), 4.70 (d, J = 2.4 Hz, 2H), 3.82 (s, 3H), 3.49 (s, 3H), 2.54 (t, J = 2.4 Hz, 1H);
13C NMR (CDCl3, 75 MHz): δ 159.3 (C), 158.7 (C), 158.4 (C), 139.8 (C), 129.7 (C), 128.9 (CH),
127.7 (CH × 2), 126.1 (CH), 114.0 (CH × 2), 107.3 (CH), 106.3 (CH), 102.6 (CH), 94.4 (CH2), 78.4
(C), 75.4 (CH), 55.9 (CH3), 55.8 (CH2), 55.1 (CH3); HRMS (ESI-TOF) m/z calcd for C20H20O4Na
[M + Na]+ 347.1259, found 347.1259
(E)-1-(1,3-bis(2,2-dimethyl-1,3-dioxan-5-yloxy)propan-2-yl)-4-((3-(methoxymethoxy)-5-(4-meth
oxystyryl)phenoxy)methyl)-1H-1,2,3-triazole (16d): To a solution of 15d (50 mg, 0.150 mmol) in
THF (2.0 mL) were added 8 (64 mg, 0.180 mmol) copper(I) iodide (3.0 mg 0.015 mmol) and
diisopropylethylamine (40 mg, 0.31 mmol), and the mixture was stirred for 3 h at room temperature.
The resulting solution was poured into NH4Claq (30 mL), and extracted with three portions of ethyl
acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over
Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography
eluted with hexane/ethyl acetate (1/3) to afford 16d (82.0 mg, 0.120 mmol, 80% yield). FT-IR
(neat): 3439, 2992, 1598, 1512, 1449, 1373, 1252, 1148, 1039, 827, 732 cm–1; 1H NMR (CDCl3, 400
MHz): δ 7.92 (s, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.92-6.85 (m, 3H), 6.81 (s,
1H), 6.78 (s, 1H), 6.60 (t, J = 2.2 Hz, 1H), 5.22 (s, 2H), 5.18 (s, 2H), 5.18 (s, 2H), 4.92 (quint, J =
5.6 Hz, 1H), 4.01–3.88 (m, 8H), 3.83 (s, 3H), 3.76–3.65 (m, 4H), 3.50 (s, 3H), 3.37–3.32 (m, 2H),
1.40 (s, 6H), 1.39 (s, 6H); 13C NMR (CDCl3, 75 MHz): δ 159.3 (C × 2), 158.3 (C), 143.5 (C), 139.7
(C), 129.7 (C), 128.8 (CH), 127.7 (CH × 2), 126.1 (CH), 123.3 (CH), 114.0 (CH × 2), 106.9 (CH),
106.1 (CH), 102.4 (CH), 98.1 (C × 2), 94.3 (CH2), 71.1 (CH × 2), 67.0 (CH2 × 2), 62.1 (CH2 × 2),
62.0 (CH2), 61.8 (CH2 × 2), 60.7 (CH), 55.9 (CH3), 55.2 (CH3), 24.3 (CH3 × 2), 22.5 (CH3 × 2);
HRMS (ESI-TOF) m/z calcd for C35H47N3O10Na [M + Na]+ 692.3159, found 692.3157.
7

(E)-2,2'-(2-(4-((3-hydroxy-5-(4-methoxystyryl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)propane-1
,3-diyl)bis(oxy)dipropane-1,3-diol (3d): A solution of 16d (49.3 mg, 76.3 µmol) in methanol (1.0
mL) in the presence of a catalytic amount of Amberlyst 15 (1.6 mg) was stirred for 48 h at room
temperature. The resulting suspension was filtered, and the filtrate was concentrated in vacuo. The
residue was purified by silica gel column chromatography eluted with chloroform/methanol (4/1) to
afford 3d (30.6 mg, 56.1 µmol, 76% yield). FT-IR (neat): 3438, 2956, 2924, 2853, 1725, 1646, 1465,
1378, 1287, 1124, 1075 cm–1; 1H NMR (CD3OD, 400 MHz): δ 8.26 (s, 1H), 7.45 (d, J = 8.7 Hz, 2H),
7.04 (d, J = 16.3 Hz, 1H), 6.93–6.85 (m, 3H), 6.68 (s, 1H), 6.60 (s, 1H), 6.35 (t, J = 2.0 Hz, 1H),
5.15 (s, 2H), 5.05–4.96 (m, 1H), 4.15–4.04 (m, 4H), 3.79 (s, 3H), 3.66–3.39 (m, 10H); 13C NMR
(CD3OD, 75 MHz): δ 161.3 (C), 161.1 (C), 159.9 (C), 144.9 (C), 141.5 (C), 131.5 (C), 129.7 (CH),
129.0 (CH × 2), 127.6 (CH), 125.8 (CH), 115.2 (CH × 2), 107.5 (CH), 105.4 (CH), 102.6 (CH), 83.4
(CH × 2), 70.1 (CH2 × 2), 63.1 (CH), 62.6 (CH2 × 2), 62.4 (CH2 × 3), 55.7 (CH3); HRMS (ESI-TOF)
m/z calcd for C27H35N3O9Na [M + Na]+ 568.2271, found 568.2274.
8