Efficient total synthesis of piceatannol via (e)-selective wittig-horner reaction

Article abstract of DOI:10.1080/00397910802528944

Efficient and practical total synthesis of piceatannol via (E)-selective Wittig-Horner reaction is demonstrated with six steps in overall 40% yield from a commercially available, cheap starting material, 3,5-dihydroxybenzoic acid. Wittig-Horner reaction o

Full text of DOI:10.1080/00397910802528944

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Efficient Total Synthesis of
Piceatannol via (E)-Selective
Wittig–Horner Reaction
Su Young Han a , Hyun Suck Lee a , Da Hye Choi a ,
Jung Woon Hwang a , Deok Mo Yang a & Jong-Gab
Jun a
a Department of Chemistry and Institute of Applied
Chemistry , Hallym University , Chuncheon, Korea
Published online: 19 Mar 2009.
To cite this article: Su Young Han , Hyun Suck Lee , Da Hye Choi , Jung Woon Hwang ,
Deok Mo Yang & Jong-Gab Jun (2009) Efficient Total Synthesis of Piceatannol via (E)-
Selective Wittig–Horner Reaction, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:8, 1425-1432, DOI:
10.1080/00397910802528944
To link to this article: http://dx.doi.org/10.1080/00397910802528944
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Synthetic Communications1, 39: 1425–1432, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802528944
Efficient Total Synthesis of Piceatannol via
(E)-Selective Wittig–Horner Reaction
Su Young Han, Hyun Suck Lee, Da Hye Choi, Jung Woon Hwang,
Deok Mo Yang, and Jong-Gab Jun
Department of Chemistry and Institute of Applied Chemistry,
Hallym University, Chuncheon, Korea
Abstract: Efficient and practical total synthesis of piceatannol via (E)-selective
Wittig–Horner reaction is demonstrated with six steps in overall 40% yield
from a commercially available, cheap starting material, 3,5-dihydroxybenzoic
acid. Wittig–Horner reaction of diethyl phosphonate with aldehyde showed a
superior (E)-selectivity compare to Wittig reaction using triphenylphosphine.
We optimized the Wittig–Horner reaction condition by using NaH (6 equiv) in
tetrahydrofuran (THF) at reflux 1 h to give 99% yield of single (E)-stilbene.
Keywords: (E)-Selective Wittig–Horner reaction, piceatannol, polyphenol, stilbene
(E)-3,30,4,50-Tetrahydroxystilbene (piceatannol, 1), which is a natural
polyhydroxy stilbene, was first isolated by King et al. from Vouacapoua
Americana[1] and has been known to have many biological activities
such as anti-inflamatory,[2] anti-oxidative,[3] anti-carcinogenic,[4] and
antiviral[5] activities. To characterize the biological activities of piceatan-
nol, enough sample should be synthesized because of the limited supply
of piceatannol from nature. Recently, we developed a new synthesis of
piceatannol by using Sonogashira coupling reaction from vanillin includ-
ing six steps in 29% overall yield.[6] Even though many (E)-stilbene synth-
esis have been reported by using Wittig,[7] Heck,[8] and Suzuki[9] coupling
reactions, the practical preparation of piceatannol was difficult because
Received July 11, 2008.
Address correspondence to Jong-Gab Jun, Department of Chemistry and
Institute of Applied Chemistry, Hallym University, Chuncheon 200-702, Korea.
E-mail: jgjun@hallym.ac.kr
1425

1426
S. Y. Han et al.
Figure 1. Structure of piceatannol and resveratrol.
of the oxidizing sensitivity of the polyphenolic groups and inherent diffi-
culties of controlling trans-selectivity. The commercial price of piceatan-
nol at Sigma is 40 times more expensive than similar natural stilbene
resveratrol (Fig. 1). We report herein the total synthesis of piceatannol
(1) in six steps from a relatively cheap starting material, 3,5-dihydroxy-
benzoic acid (2), by using Wittig–Horner reaction, which was reported
by Piao et al.[10] in seven steps with 26% overall yield from same starting
material, but that article did not show any experimental details and
(E)-selectivity of the reaction.
Reaction of 3,5-dihydroxybenzoic acid in acetone at reflux with ben-
zyl bromide and potassium carbonate produced 97% yield of benzylated
ester 3, which was then reduced with LiAlH4 in tetrahydrofuran (THF)
at room temperature to give benzyl alcohol 4 in 88% yield (Scheme 1).
Bromination of alcohol 4 with PBr3 in acetonitrile at room temperature
yielded benzyl bromide 5 in 99% yield. Phosphonation of 5 with triethyl
phosphite in xylene at reflux afforded 92% yield of diethyl phosphonate 6.
Wittig–Horner reaction of 6 with benzylated vanillin 7 by using NaH in
THF at reflux gave only the desired (E)-stilbene 8 in 99% yield selectively.
The Wittig reaction, however, with triphenylphosphine derivative 6a with
Scheme 1. Reagents and conditions: (a) BnBr (3.2 eq), K2CO3 (6 eq), acetone,
reflux, 97%; (b) LAH (1.5 eq), THF, rt, 88%; (c) PBr3 (3.1 eq), MeCN, rt,
99%; (d) P(OEt)3 (3.5 eq), xylene, reflux, 92%; (e) NaH (6 eq), THF, reflux,
99%; (f) BBr3 (6 eq), CH2Cl2, rt, 52%.

Synthesis of Piceatannol
1427
aldehyde 7 using n-BuLi or t-BuOK as a base produced a lower yield of
(E)- and (Z)-stilbene mixtures (Table 1, entries 10–12), but the use of
NaH as a base produced only (E)-stilbene in low yield (entries 8 and 9).
The structural analysis of (E)- and (Z)-stilbenes was confirmed by the inte-
gration of 1H NMR at a methoxy group, and its chemical shift showed at
d 3.94 of (E)-stilbene compare to d 3.63 of (Z)-stilbene. The Wittig–Horner
reaction of 6 with NaH (6 equiv) in THF (entry 5) at reflux showed 99%
yield of (E)-stilbene as a single product within 1 h compare to 24 h reaction
using CH2Cl2 as a solvent (entry 4). In this Wittig reaction, we realized
that the reaction conditions including Wittig reagent, base, and solvent
were very important to control the yield, reaction time, and stereoselectiv-
ity of product. We are not sure of the reasons for each factor of reaction
conditions, but the solubility could be the most important role in the
Table 1. Wittig–Horner reaction of 6 and 6a compounds with aldehyde 7 compound
Entry Reagents
Base
NaH
NaH
NaH
NaH
NaH
t-BuLi
t-BuLi
NaH
Equiv. Solventa Time (h) Yield (%) (8:8a)b
1
2
6
6
2
3
4
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH2Cl2
THF
THF
CH2Cl2
CH2Cl2
Benzene
DMF
10
24
24
24
1
10 (100:0)
30 (100:0)
60 (100:0)
92 (100:0)
99 (100:0)
35 (100:0)
—
<10 (100:0)
<10 (100:0)
30 (67:33)
<10 (50:50)
<10 (50:50)
3
6
4
6
5
6
6
6
6
1.6
1.6
3
0.5
7
6
24
24
24
4
8
9
10
11
12
6a
6a
6a
6a
6a
NaH
3
n-BuLi
n-BuLi
t-BuOK
1.6
1.6
1.6
4
4
aDistilled solvent. All reaction conditions are refluxed under an N2 atmosphere.
b(E)- and (Z)-stilbene ratio was analyzed by the integration of 1H NMR
methoxy group (trans; d 3.94, cis; d 3.63).

1428
S. Y. Han et al.
reaction, and also the use of strong base such as n-BuLi or t-BuLi might
decompose the reagent to give low yield of the product. Finally, dealkyla-
tion of 8 by BBr3 in CH2Cl2 at room temperature gave piceatannol (1) in
52% yield. Polymethoxy aryl ether has been known to be difficult for
demethylation using BBr3 or other reagents, probably because of suscept-
ibility for oxidation of polyphenolic substances.[11] Synthetic piceatannol
was easily oxidized to give decomposed mixture at rt within 1 week even
with tight storage. However, it was quite stable while frozen with light
protection for a relatively long period.
In conclusion, the six-step reaction procedure including benzylation,
metal hydride reduction, bromination, phosphonation, Wittig–Horner
reaction, and dealkylation gave piceatannol from 3,5-dihydroxybenzoic
acid in 40% overall yield, which showed a practical and economical
synthesis of piceatannol and could be utilized easily for the synthesis of
many other stilbene derivatives.
EXPERIMENTAL
All chemicals used were purchased from commercial sources and used as
received unless otherwise stated. NMR spectra were recorded on a Varian
1
Mercury Fourier transform (FT) NMR at 300 MHz for H and 75 MHz
for 13C, with the chemical shifts (d) reported in parts per million (ppm)
relative to tetramethylsilane (TMS) and the coupling constants (J) quoted
in hertz (Hz). CDCl3 was used as a solvent and an internal standard.
Flash chromatography was carried out using Merck 60 silica gel
(230–400 mesh). Thin-layer chromatography (TLC) was performed on
DC-Plastikfolien 60, F254 (Merck, layer thickness 0.2 mm) plastic-backed
silica-gel plates with visualization by UV light (254 nm) or by treatment
with p-anisaldehyde. Melting points were measured on a Mel-Temp II
apparatus and were uncorrected.
Benzyl 3,5-Dibenzyloxybenzoate (3)
K2CO3 (11.0 g, 78.0 mmol) was added to a solution of 3,5-dihydroxy-
benzoic acid 2 (2.0 g, 13.0 mmol) in acetone (80 mL) under nitrogen
atmosphere, stirred for 0.5 h at rt, and refluxed for 24 h after addition
of benzyl bromide (4.8 mL, 41.6 mmol). Solvent was removed by evapora-
tion, and the organic product was extracted with ethyl acetate, washed
with brine, dried, and concentrated to give the solid. The solid was chro-
matographed (EtOAc–hexane 1:9) to give the white solid3 (5.3 g, 97%).
1
Rf 0.50 (EtOAc–hexane 1:3); mp 49–51 ꢀC; H NMR (300 MHz, CDCl3)

Synthesis of Piceatannol
1429
d 5.05 (4H, s, benzyl CH2), 5.33 (2H, s, benzyl CH2), 6.79 (1H, t,
J ¼ 2.3 Hz, 4-H), 7.03–7.18 (2H, m, 2,6-H), 7.24-7.42 (15H, m);
13C NMR (75 MHz, CDCl3) d 67.19 (benzyl CH2), 70.59 (2 ꢁ benzyl
CH2), 107.37 (C4), 108.73 (C2,6), 127.43, 127.82, 128.06, 128.36, 128.65,
128.80, 132.17, 136.07, 136.56 (C1), 159.88 (C3,5), 166.24 (C ¼ O).
3,5-Dibenzyloxybenzyl Alcohol (4)
LiAlH4 (0.2 g, 5.3 mmol) was added to a solution of benzoate 3 (1.5 g,
3.5 mmol) in THF (20 mL) under a nitrogen atmosphere at 0 ꢀC and
stirred for 2 h at rt. Water was added to this reaction bottle at 0 ꢀC,
and the mixture was filtered using Celite 545, extracted with diethyl ether,
washed with brine, dried, and concentrated to give the solid. The solid
was chromatographed (EtOAc–hexane 1:5) to give the white solid 4
(1.0 g, 88%). Rf 0.21 (EtOAc–hexane 1:3); mp 73–75 ꢀC; 1H NMR
(300 MHz, CDCl3) d 4.61 (2H, d, J ¼ 4.5 Hz, CH2OH), 5.02 (4H, s, benzyl
CH2), 6.53 (1H, t, J ¼ 2.4 Hz, 4ꢂH), 6.60 (2H, d, J ¼ 2.1 Hz, 2,6-H), 7.33–
7.39 (10H, m); 13C NMR (75 MHz, CDCl3) d 65.63 (CH2OH), 70.36
(2 ꢁ benzyl CH2), 101.49 (C4), 105.93 (C2,6), 127.74 (4 ꢁ C20), 128.22
(2 ꢁ C40), 128.80 (4 ꢁ C30), 135.97 (2 ꢁ C10), 143.57 (C1), 160.28 (C3,5).
3,5-Dibenzyloxybenzyl Bromide (5)
Phosphorous tribromide (0.03 mL, 0.29 mmol) was added to a solution of
benzyl alcohol 4 (0.03 g, 0.09 mmol) in acetonitrile (3 mL) under nitrogen
atmosphere at 0 ꢀC and stirred for 2 h in an ice bath. After stirring further
for 3 h at rt, the solvent was removed by evaporation, and the organic
product was extracted with diethyl ether, washed with brine, dried, and
concentrated to give the solid. The solid was chromatographed
(EtOAc–hexane 1:4) to give the white solid 5 (0.035 g, 99%). Rf 0.79
1
(EtOAc–hexane 1:3); mp 63–65 ꢀC; H NMR (300 MHz, CDCl3) d 4.40
(2H, s, CH2Br), 5.00 (4H, s, benzyl CH2), 6.53 (1H, t, J ¼ 2.3 Hz, 4ꢂH),
6.62 (2H, d, J ¼ 2.1 Hz, 2,6ꢂH), 7.31–7.41 (10H, m); 13C NMR
(75 MHz, CDCl3) d 34.00 (CH2Br), 70.45 (2 ꢁ benzyl CH2), 102.40 (C4),
108.37 (C2,6), 127.80, 128.31, 128.84, 136.78 (C1), 139.96, 160.20 (C3,5).
Diethyl 3,5-Dibenzyloxybenzylphosphonate (6)
Triethyl phosphite (0.54 mL, 3.1 mmol) was added to a solution of
benzyl bromide 5 (0.67 g, 1.75 mmol) in xylene (10 mL) under nitrogen

1430
S. Y. Han et al.
atmosphere and refluxed for 10 h at 140 ꢀC. The reaction mixture was
concentrated and chromatographed (EtOAc–hexane 2:1) to give the
1
colorless liquid 6 (0.71 g, 92%). Rf 0.50 (EtOAc–hexane 5:1); H NMR
(300 MHz, CDCl3) d 1.24 (6H, t, J ¼ 7.2 Hz, CH3), 3.08 (2H, d,
J ¼ 21.6 Hz, PCH2), 3.97 (4H, q, J ¼ 7.4 Hz, OCH2), 5.01 (4H, s, benzyl
CH2), 6.51 (1H, d, J ¼ 2.1 Hz, 4-H), 6.55 (2H, d, J ¼ 2.4 Hz, 2,6-H),
7.34 (10H, m); 13C NMR (75 MHz, CDCl3) d 16.83 (d, J ¼ 0.08 Hz,
CH3), 34.38 (d, J ¼ 1.83 Hz, PCH2), 62.48 (d, J ¼ 0.09 Hz, OCH2),
70.28 (benzyl CH2), 101.14 (C4), 109.21 (C2,6), 127.70, 128.16, 128.76,
139.90 (C1), 137.00, 160.01 (C3,5).
(E)-30,4,50-Tribenzyloxy-3-methoxystilbene (8)
NaH (0.16 g, 4.09 mmol) was added to a solution of phosphonate 6 (0.30 g,
0.68 mmol) in dry THF (10 mL) under nitrogen atmosphere at 0 ꢀC and stir-
red for 0.5 h at rt. 4-Benzyloxy-3-methoxybenzaldehyde 7 (0.20 g, 0.82 mmol)
was added to the reaction mixture in dry THF (10 mL) and refluxed for 1 h at
70–75 ꢀC. The pH was adjusted to 3–4 by addition of 1 N HCl (4 mL) to the
reaction mixture in ice bath, and the solvent was filtered using Celite 545 and
removed by evaporation. The organic product was extracted with CH2Cl2,
washed with brine, dried and chromatographed (EtOAc–hexane 1:10) to give
the white solid 8 (0.36 g, 99%). Rf 0.45 (EtOAc–hexane 1:3); mp 73–75 ꢀC;
1H NMR (300 MHz, CDCl3) d 3.94 (3H, s, OCH3), 5.06 (4H, s, benzyl
CH2), 5.16 (2H, s, benzyl CH2), 6.52 (1H, t, J¼ 2.1 Hz, 40-H), 6.74 (2H, d,
J¼ 1.8 Hz, 20,60-H), 6.84 (1H, d, J¼ 8.1 Hz, 5-H), 6.87 (1H, d, J ¼ 16.2 Hz,
olefinic H), 6.94 (1H, br d, J ¼ 8.1 Hz, 6-H), 6.98 (1H, d, J¼ 16.2 Hz, olefinic
H), 7.05 (1H, d, J¼ 2.4 Hz, 2-H), 7.27-7.45 (15H, m); 13C NMR (75MHz,
CDCl3) d 56.35 (OCH3), 70.42 (2 ꢁ benzyl CH2), 71.31 (benzyl CH2),
101.56, 105.85, 109.68, 114.20, 120.10, 127.06, 127.44, 127.74, 128.06,
128.76, 128.80, 130.91, 137.08, 137.21, 139.79, 148.34, 149.94, 160.30.
(Z)-30,4,50-Tribenzyloxy-3-methoxystilbene (8a): Rf 0.56 (EtOAc–
1
hexane 1:3); colorless liquid; H NMR (300 MHz, CDCl3) d 3.63 (3H, s,
OCH3), 4.89 (4H, s, benzyl CH2), 5.12 (2H, s, benzyl CH2), 6.44 (1H, d,
J ¼ 11.7 Hz), 6.46 (1H, d, J ¼ 8.1 Hz, 5-H), 6.53 (2H, d, J ¼ 2.1 Hz,
20,60-H), 6.74 (1H, br s, 40-H), 6.75 (1H, d, J ¼ 8.1 Hz, 6-H), 6.82 (1H,
br s, 2-H), 7.26 (1H, d, J ¼ 11.4 Hz), 7.28–7.45 (15H, m).
Piceatannol (1)
Boron tribromide (1.0 M solution in dichloromethane, 1.13 mL) was
added to a solution of alkoxystilbene 8 (0.10 g, 0.19 mmol) in CH2Cl2

Synthesis of Piceatannol
1431
(10 mL) at ꢂ20 ꢀC under nitrogen atmosphere and stirred for 1 h. After
the reaction mixture was stirred for 2 h at rt, the solvent was removed
by evaporation, and the organic product was extracted with ethyl acetate,
washed with brine, dried, and concentrated to give the solid. The solvent
was removed by evaporation, and the organic product was chromato-
graphed (EtOAc–hexane 1:1) to give the pale yellow solid1 (0.023 g,
1
52%). Rf 0.47 (diethyl ether); mp 228 ꢀC dec. [lit.,[1] 229 ꢀC dec.]; H
NMR (300 MHz, acetone-d6) d 6.31 (1H, t, J ¼ 2.1 Hz, 40-H), 6.57 (2H,
d, J ¼ 1.8 Hz, 20,60-H), 6.82 (1H, d, J ¼ 16.2 Hz, olefinic H), 6.83 (1H,
d, J ¼ 9.0 Hz, 5-H), 6.90 (1H, dd, J ¼ 8.4, 1.8 Hz, 6-H), 6.95 (1H, d,
J ¼ 16.5 Hz, olefinic H), 7.10 (1H, d, J ¼ 1.8 Hz, 2-H), 8.15 (4H, br s,
13
OH); C NMR (75 MHz, acetone-d6) d 102.12 (C40), 105.21 (C20,60),
113.25 (C2), 115.71 (C5), 119.52 (C6), 126.23 (olefinic), 128.78 (olefinic),
130.05 (C1), 140.17 (C10), 145.24 (C4), 145.27 (C3), 158.64 (C30,50).
ACKNOWLEDGMENT
This work was supported by Grant No. R01-2007-000-20164-0 from the
Basic Research Program of Korea Science and Engineering Foundation
and in part by the Ministry of Commerce, Industry, and Energy through
the Center for Efficacy Assessment and Development of Functional
Foods and Drugs at Hallym University.
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