Journal of Natural Products
Article
were recorded on a Varian (100 MHz) spectrometer. The values of the
chemical shifts are expressed in δ values (ppm), and the coupling
constants (J) are reported in Hertz (Hz). Mass spectra were recorded
using high-resolution mass spectrometry (HRMS, ESI-MS), obtained
on a G2 QTOF mass spectrometer (Waters Corp, Milford, U.S.A.).
Products were purified by column or flash chromatography (Biotage,
Sweden) using silica gel 60 (230−400 mesh Kieselgel 60). TLC on
0.25 mm silica plates (E. Merck; silica gel 60 F254) was used to
monitor the reactions. Spots were detected by viewing under UV light
and colorized with charring after dipping in anisaldehyde or basic
KMnO4 solution.
(E)-2-Bromo-5-(3,5-dimethoxystyryl)-1,3-dimethoxybenzene (6).
Triethyl phosphite (5.76 g, 34.0 mmol) was added to 3,5-
dimethoxybenzyl bromide (4) (5.00 g, 21.0 mmol) containing a
catalytic amount of tetrabutylammonium iodide (0.79 g, 2.10 mmol),
and the reaction mixture was heated at 130 °C for 6 h. Excess triethyl
phosphite was removed by heating at 80 °C under vacuum. Diethyl
3,5-dimethoxybenzylphosphonate (5) was obtained as a colorless oil
(5.60 g, 90%). Compound 5 was used for the next step without further
purification.
Diethyl 3,5-dimethoxybenzylphosphonate (5) (5.00 g, 17.0 mmol)
was dissolved in THF (20.0 mL), and the mixture was stirred at 0 °C
under Ar. NaH (60% dispersion in mineral oil, 3.40 g, 86.0 mmol) was
slowly added. After 30 min, a solution of 4-bromo-3,5-dimethox-
ybenzaldehyde (3.82 g, 15.0 mmol) in THF (8.0 mL) was added
dropwise. The reaction mixture was stirred for 12 h at rt and
monitored by TLC. After completion of the reaction, the mixture was
cooled to 0 °C, and excess NaH was destroyed with water. The
reaction mixture was poured on ice, followed by the addition of 2.0 N
HCl until pH 6, and the product was extracted with EtOAc (3 × 30
mL). The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography (silica gel, 0−5% EtOAc in hexanes),
producing 6 as a white solid (3.90 g, 66% yield): mp 161−162 °C; IR
(neat) νmax 1587.62, 1572.65, 1455.67, 1426.66, 1245.10, 1150.58,
1119.69, 1056.99, 964.34, 829.58 cm−1; 1H NMR (CDCl3, 400 MHz)
δ 7.05 (d, J = 16.4 Hz, 1H), 7.00 (d, J = 16.0 Hz, 1H), 6.71 (s, 2H),
6.68 (d, J = 2.4 Hz, 2H), 6.42 (t, J = 2.4 Hz, 1H), 3.95 (s, 6H), 3.83 (s,
6H); 13C NMR (CDCl3, 100 MHz) δ 161.1, 157.2, 138.8, 137.6,
129.5, 128.7, 104.7, 102.9, 100.5, 100.4, 56.5, 55.4; HRMS m/z
379.0606 (calcd for C18H20BrO4 [M + H]+, 379.0545).
(E)-5-(3,5-Dimethoxystyryl)-1,3-dimethoxy-2-vinylbenzene (7).
Tributyl(vinyl)tin (0.53 mL, 1.80 mmol), CsF (0.36 g, 2.40 mmol),
and Pd(t-Bu3P)2 (6.00 mg, 0.01 mmol) were added to a solution of
stilbene 6 (0.46 g, 1.20 mmol) in toluene (8.0 mL). The solution was
refluxed for 12 h and monitored by TLC. After completion of the
reaction, the solution was cooled and filtered through a silica pad to
remove a fine tan powder, which was thoroughly washed with Et2O.
The filtrate was concentrated in vacuo to give a crude product, which
was purified by flash chromatography (silica gel, 0−4% EtOAc in
hexanes), to give 7 as a light green solid (0.35 g, 88% yield): mp 120−
121 °C; IR (neat) νmax 1585.16, 1557.82, 1453.17, 1422.05, 1401.31,
1359.83, 1198.61, 1144.87, 1115.64, 1054.36, 998.73, 941.22, 819.60
cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.02 (s, 2H), 6.97 (dd, J = 17.8,
12.2 Hz, 1H), 6.69 (s, 2H), 6.67 (d, J = 2.0 Hz, 2H), 6.40 (s, 1H), 6.10
(dd, J = 18.0, 2.8 Hz, 1H), 5.44 (dd, J = 12.2, 2.6 Hz, 1H), 3.90 (s,
6H), 3.83 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 161.0, 158.7,
139.1, 137.2, 129.3, 128.8, 127.2, 118.5, 114.8, 104.6, 102.3, 100.2,
55.7, 55.4; HRMS m/z 327.1681 (calcd for C20H23O4 [M + H]+,
327.1596).
chromatography (silica gel, 0−50% EtOAc in hexanes) yielded alcohol
8 (0.03 g, 33% yield) as a white solid.
b. Hydroboration−Oxidation. A solution of compound 7 (0.44 g,
1.34 mmol) in dry THF (10.0 mL) was cooled to 0 °C, and 0.5 M 9-
BBN in THF (13.0 mL, 6.70 mmol) was added. The reaction mixture
was kept in an ice bath for 30 min, and left at rt for 20 h. The reaction
progress was monitored by TLC. After the reaction was complete, the
solution was cooled to 0 °C, and MeOH (2.0 mL) was added
dropwise. When gas evolution had ceased, H2O (2.0 mL) was added,
followed by a mixture of 2.0 M NaOH (2.0 mL, 3.20 mmol) and H2O2
(30% (w/w) in H2O, 1.06 mL, 9.30 mmol). The ice bath was
removed, and the mixture was stirred vigorously at rt for 4 h. The
mixture was filtered to remove the precipitate and the filtrate was
diluted with EtOAc (20.0 mL). The organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo. The
resulting residue was purified by flash chromatography (silica gel, 0−
50% EtOAc in hexanes), furnishing 8 as a white solid (0.33 g, 72%
yield): mp 153−154 °C; IR (neat) νmax 3324.59, 1585.15, 1445.19,
1
1416.31, 1154.18, 1125.30, 956.46, 814.28 cm−1; H NMR (CDCl3,
400 MHz) δ 7.05 (d, J = 16.4 Hz, 1H), 6.99 (d, J = 16.0 Hz, 1H), 6.71
(s, 2H), 6.68 (d, J = 2.4 Hz, 2H), 6.40 (s, 1H), 3.88 (s, 6H), 3.84 (s,
6H), 3.77 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 6.6 Hz, 2H), 1.83 (br, 1H);
13C NMR (CDCl3, 100 MHz) δ 161.0, 158.6, 139.2, 136.8, 129.5,
128.5, 115.3, 104.5, 102.2, 100.1, 62.8, 55.8, 55.4, 26.6; HRMS m/z
345.1787 (calcd for C20H25O5 [M + H]+, 345.1702).
(E)-5-(3,5-Dihydroxystyryl)-2-(2-hydroxyethyl)benzene-1,3-diol
[Gramistilbenoid A, (1)]. To a stirred solution of 8 (0.23 g, 0.67
mmol) in CH2Cl2 (5.0 mL), at −40 °C under Ar, BBr3 (0.33 mL, 3.40
mmol) was added. The temperature was gradually increased to rt over
a period of 1 h and stirring was continued until completion of the
reaction. The unreacted BBr3 was destroyed by adding ice at 0 °C. The
mixture was warmed to rt, stirred for 40 min, and concentrated in
vacuo. The residue was diluted with EtOAc (20 mL), washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (silica gel, 0−50% EtOAc in
hexanes) afforded 1 as a brown semisolid (0.12 g, 64% yield): IR
(neat) νmax 3186.61, 2916.30, 1585.57, 1429.62, 1354.25, 1291.87,
1
1141.12, 1021.56, 974.78, 816.24, 759.06 cm−1; H NMR (DMSO-d6,
400 MHz) δ 9.42 (s, 2H), 9.22 (s, 2H), 6.81 (d, J = 16.0 Hz, 1H), 6.72
(d, J = 16.0 Hz, 1H), 6.48 (s, 2H), 6.39 (d, J = 1.6 Hz, 2H), 6.14 (s,
1H), 3.77 (br, 1H), 3.47 (t, J = 8.2 Hz, 2H), 3.05 (t, J = 8.0 Hz, 2H);
13C NMR (methanol-d4, 100 MHz) δ 159.6, 157.8, 140.6, 138.3, 129.5,
129.2, 113.4, 105.6, 105.4, 103.0, 31.4, 28.8; HRMS m/z 289.1101
(calcd for C16H17O5 [M + H]+, 289.1076).
(E)-5-(3,5-Dimethoxystyryl)-2-(2-hydroxyethyl)benzene-1,3-diol
[Gramistilbenoid C, (3)]. The experimental procedure for the
synthesis of 3 was the same as for 1. The crude product was purified
by silica gel column chromatography (0−50% EtOAc in hexanes) to
yield 3 as a brown semisolid (80.0 mg, 58% yield): IR (neat) νmax
3449.26, 3380.20, 1586.62, 1425.49, 1262.60, 1197.09, 1154.60,
1128.04, 1071.38, 1035.97, 958.06, 821.73 cm−1
;
1H NMR
(methanol-d4, 400 MHz,) δ 6.94 (d, J = 16.4 Hz, 1H), 6.90 (d, J =
16.4 Hz, 1H), 6.65 (d, J = 2.4 Hz, 2H), 6.49 (s, 2H), 6.38 (t, J = 2.2
Hz, 1H), 3.79 (s, 6H), 3.46 (t, J = 8.4 Hz, 2H), 3.14 (t, J = 8.4 Hz,
2H); 13C NMR (methanol-d4, 100 MHz) δ 162.5, 157.8, 140.8, 138.3,
130.3, 129.1, 113.6, 105.8, 105.4, 100.7, 55.8, 31.4, 28.9; HRMS m/z
317.1408 (calcd for C18H21O5 [M + H]+, 317.1389).
(E)-2-Bromo-5-(3,5-dimethoxystyryl)-1,3-bis(methoxymethoxy)-
benzene (18). The experimental procedure for the synthesis of 18 was
the same as for 6. The crude product was purified by flash
chromatography (silica gel, 0−10% EtOAc in hexanes), yielding 18
as a white solid (0.26 g, 54% yield): mp 77−78 °C; IR (neat) νmax
1583.93, 1452.59, 1398.16, 1332.49, 1240.49, 1140.67, 1108.7,
1072.41, 1012.79, 918.61 cm−1; 1H NMR (CDCl3, 400 MHz) δ
7.03 (d, J = 16.0 Hz, 1H), 6.99 (s, 2H), 6.98 (d, J = 16.4 Hz, 1H), 6.66
(d, J = 2.4 Hz, 2H), 6.41 (t, J = 2.2 Hz, 1H), 5.30 (s, 4H), 3.82 (s,
6H), 3.55 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 160.9, 155.1,
138.8, 137.6, 129.7, 128.3, 170.5, 104.5, 102.9, 100.5, 95.1, 56.4, 55.3;
(E)-2-[4-(3,5-Dimethoxystyryl)-2,6-dimethoxyphenyl]ethanol (8).
a. Lithium−Halogen Exchange. To a stirred solution of bromos-
tilbene 6 (0.10 g, 0.26 mmol) in THF (8.0 mL) at −78 °C, 2.5 M n-
BuLi in hexanes (0.21 mL, 0.54 mmol) was added dropwise. After
stirring for 30 min, ethylene epoxide (0.73 mL, 1.82 mmol) was added
dropwise and stirred for 1 h at 0 °C. The reaction mixture was
carefully quenched with NH4Cl (sat. aq., 10 mL), followed by
extraction with EtOAc (3 × 10 mL). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. Purification of the residue by flash
+
HRMS m/z 439.3065 (calcd for C20H24BrO6 [M + H] , 439.0756).
F
J. Nat. Prod. XXXX, XXX, XXX−XXX