Synthesis of pterostilbene by julia olefination

Article abstract of DOI:10.1080/00397911.2013.775308

A simple, E-stereoselective route for the synthesis of the biologically active compounds trans-pterostilbene and tetramethoxy stilbene from the readily available starting materials 3,5-dimethoxy benzyl alcohol and 4-hydroxy benzaldehyde was developed using Julia olefination as a key reaction. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2013.775308

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Synthesis of Pterostilbene by Julia
Olefination
Prabhakar Peddikotla a , Amar G. Chittiboyina a & Ikhlas A. Khan a b
a National Center for Natural Products Research, School of
Pharmacy, University of Mississippi , University , Mississippi , USA
b Department of Pharmacognosy, School of Pharmacy , University of
Mississippi, University , Mississippi , USA
Accepted author version posted online: 03 Jul 2013.Published
online: 04 Sep 2013.
To cite this article: Prabhakar Peddikotla , Amar G. Chittiboyina & Ikhlas A. Khan (2013) Synthesis
of Pterostilbene by Julia Olefination, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:23, 3217-3223
To link to this article: http://dx.doi.org/10.1080/00397911.2013.775308
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Synthetic Communications1, 43: 3217–3223, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.775308
SYNTHESIS OF PTEROSTILBENE BY JULIA
OLEFINATION
Prabhakar Peddikotla,1 Amar G. Chittiboyina,1 and
Ikhlas A. Khan1,2
1National Center for Natural Products Research, School of Pharmacy,
University of Mississippi, University, Mississippi, USA
2Department of Pharmacognosy, School of Pharmacy, University of
Mississippi, University, Mississippi, USA
GRAPHICAL ABSTRACT
Abstract A simple, E-stereoselective route for the synthesis of the biologically active com-
pounds trans-pterostilbene and tetramethoxy stilbene from the readily available starting
materials 3,5-dimethoxy benzyl alcohol and 4-hydroxy benzaldehyde was developed using
Julia olefination as a key reaction.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resources: Full
experimental and spectral details.]
Keywords 3,5-Dimethoxy benzyl alcohol; 4-hydroxy benzaldehyde; Julia olefination;
tetramethoxy stilbene; trans-pterostilbene
INTRODUCTION
Polyhydroxy stilbenes, such as pterostilbene and resveratrol, have been
reported to exhibit a wide range of biological activities including anticancer, induc-
tion of peroxisome proliferator activated receptor-a (PPAR-a),[1] antioxidant,[2] anti-
inflammatory,[3] antibacterial,[4] antifungal, antiplatelet aggregation, and vasodilator
activities and other potential health benefits.[5] Pterostilbene is found in nature in a
variety of grapes and berries as well as plants commonly used in traditional folk
medicine. Pterostilbene was isolated for the first time from Pterocarpus santalinus
by Spath and Kromp[6] in 1941. Because of its potential health benefits, significant
interest in the synthesis of pterostilbene by using Wittig, Wittig–Horner,[1] Perkin,[7]
or transition-metal-catalyzed reactions[8] has been generated in recent years. Herein
Received December 21, 2012.
Address correspondence to Amar G. Chittiboyina, 3040 TCRC, National Center for Natural
Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
E-mail: amar@olemiss.edu
3217

3218
P. PEDDIKOTLA ET AL.
we report a simple, economical alternative method for the gram-scale preparation of
pterostilbene using Julia olefination[9] as a key reaction (Figure 1).
Pterostilbene is a naturally occurring dimethyl ether analog of resveratrol. To
synthesize these biologically active stilbenes, the majority of the reported patented
and unpatented methods have involved Wittig-type olefinations. However, in this
particular type of classical method for the synthesis of biologically important
stilbenes, several adverse factors such as geometrical isomers[10] (E=Z isomers), harsh
conditions, expensive starting materials, and lengthy sequences are often encoun-
tered. Alternatively, the Julia or modified Julia olefination reaction is a powerful
and versatile synthetic transformation, widely utilized in the construction of complex
natural products with excellent control of geometrical isomerism. Herein we report
an amenable route for the synthesis of biologically active stilbenes including
pterostilbene and tetramethoxy stilbene[11,12] using Julia olefination as a key
reaction.
RESULTS AND DISCUSSION
As shown in Scheme 1, readily available and inexpensive 3,5-dimethoxy
benzyl alcohol 2 was treated with mercapto benzothiazole under Mitsunobu reaction
conditions[13] to give the known sulfide intermediate 4 in excellent yield. Ammonium
heptamolybdate–catalyzed oxidation[14] of the sulfide yielded a white, crystalline sul-
fone 5 with 95% yield. On the other hand, treatment of 4-hydroxy benzaldehyde 6 with
acetic anhydride or dihydropyran yielded the corresponding protected benzaldehydes
7a or 7b. Treatment ofthe sulfone 5 with lithium hexamethyldisilazide (LiHMDS) at
0 ꢀC, followed by addition of aldehyde 7b, produced the unexpected compound tetra-
methoxy stilbene 8 in almost quantitative yield. After conducting several experiments,
the exclusive formation of tetramethoxy stilbene was attributed to the unstable and
reactive nature of sulfonyl ylide under basic conditions and=or at elevated tempera-
tures. The ylide intermediate underwent self-dimerization with another molecule of
5 to give tetramethoxy stilbene 8. The sulfone, when treated with LiHMDS in the
absence of aldehyde at 0 ꢀC, furnished exclusively compound 8 within 30min. How-
ever, when the sulfone was treated with LiHMDS at ꢁ78ꢀC, a very small amount
of 8 (<5%, based on thin-layer chromatography; TLC) was observed after 1.5 h of
reaction.
To minimize self-dimerization of sulfone 5, the reaction was conducted at
ꢁ78 ꢀC with increased amounts (1.25–1.5 equiv.) of the aldehyde in a modified
Julia olefination. Under these conditions with aldehyde 7a, the expected product,
E-4-acetylpterostilbene (9) was formed in 53% yield along with 19% of deacetylated
product (E-pterostilbene, 1) and 12% of E-8. The noteworthy feature of the current
method is the absence of Z-isomer of 4-acetylpterostilbene (9), stilbene 1, and tetra-
methoxy stilbene 8. Moreover, addition of aldehyde solution to sulfone ylide gave
superior yields of 4-acetylpterostilbene (9) than the slow, dropwise addition of sul-
fone to aldehyde. In the case of reverse addition (addition of sulfone ylide to alde-
hyde), increased amount of side product 8 was observed. When the sulfone ylide
was added to 1.25 or 1.50 equivalents of aldehyde, no significant amount of products
distribution was observed at ꢁ78 ꢀC. Finally, potassium carbonate–mediated saponi-
fication of the resulting 4-acetylpterostilbene (9) furnished the target pterostilbene (1)

SYNTHESIS OF PTEROSTILBENE
3219
ꢀ
=
Scheme 1. Reagents and conditions: (a) PPh3, EtO2CN NCO2Et, THF, 6 h, 0 C ! rt, 90%; (b)
(NH4)6Mo7O24 ꢂ 4H2O, H2O2, NaOAc, EtOH–CHCl3 (7:3), rt, 24 h, 95%; (c) Ac2O, TEA, DMAP,
DCM, 0 ꢀC, 1 h, 95% (for 7a) or DHP, PPTS, DCM, 0 ꢀC–rt, 4 h, 80% (for 7b); (d) LiHMDS, THF,
ꢁ78 ꢀC, 4 h, 53%; (e) LiHMDS, THF, 0 ꢀC, 4 h, 90%; (f) K2CO3, MeOH, rt, 1 h, 95%.
in 95% yield. Alternatively, the crude product obtained via Julia olefination was sub-
jected to saponification without further purification and furnished 11% of E-8 and
69% of pterostilbene (1) with excellent geometrical selectivity.
Figure 1. Structures of biologically significant stilbenes.

3220
P. PEDDIKOTLA ET AL.
CONCLUSION
In summary, the synthesis of pterostilbene on a gram scale by Julia olefination
has been achieved with good yield from inexpensive and readily available starting
materials. In the future, we plan to continue to explore other potential synthetic
alternatives including metal-catalyzed reactions to prepare biologically significant
stilbenes in a fewer number of steps with improved overall yields.
EXPERIMENTAL
1H and 13C NMR spectra were measured in CDCl3 on 400 MHz (100 MHz) or
500 MHz (125 MHz) instruments. Chemical shifts were reported in parts per million
(ppm) downfield from tetramethylsilane (d) as the internal standard, and coupling
constants are reported in hertz (Hz). Assignment of proton resonances was confirmed
by correlation spectroscopy. Infrared (IR) spectra were recorded using a universal
attenuated total reflection sampling accessory with a diamond ATR (attenuated total
reflectance) on an Agilent Cary 630 Fourier transform (FT)–IR spectrometer. The
reaction progress was monitored on precoated silica-gel TLC plates. Spots were
visualized under 254 nm UV light and=or by dipping the TLC plate into a solution
of 2 ml anisaldehyde, 10 ml of glacial acetic acid, and 5 ml of H2SO4 in 340 ml MeOH
followed by heating with a hot gun. Column chromatography was performed with sil-
ica gel (230–400 mesh). All the solvents (hexanes, ethyl acetate, CH2Cl2, Et2O) were
distilled prior to use. All reactions were performed under an atmosphere of argon
using oven-dried glassware and standard syringe=septa techniques. The solvent tetra-
hydrofuran (THF) was distilled from sodium benzophenone, and CH2Cl2 was dried
over P2O5. Triethylamine was distilled from CaH2.
2-((3,5-Dimethoxybenzyl)thio)benzo[d]thiazole (4)
A solution of a mixture of mercapto benzothiazole 3 (6.4 g, 38.6 mmol) and
diethyl azodicarboxylate (4.8 mL, 40.2 mmol) in THF (30 mL) was added at 0 ꢀC a
solution of 3,5-dimethoxy benzyl alcohol 2 (5.0 g, 29.7 mmol) and triphenylphosphine
(10.1 g, 38.5 mmol) in anhydrous THF (30 mL) to and stirred for 6 h at the same tem-
perature. After completion of the reaction (monitored by TLC), the reaction mixture
was quenched with saturated NH4Cl, extracted with EtOAc (3 ꢃ 50 mL), and evapo-
rated under vacuum, and the resulting residue was purified by silica-gel column
chromatography (20% of EtOAc in hexane) to yield sulfide (8.4 g, 90% yield). IR
1
(cmꢁ1) 2934, 2834, 1592, 1423, 1344, 780. H NMR (400 MHz, CDCl3) d 7.88 (dd,
J ¼ 8.1, 1.0 Hz, 1H), 7.72 (d, J ¼ 8.4 Hz, 1H), 7.40 (ddd, J ¼ 8.4, 7.3, 1.3 Hz, 1H),
7.27 (ddd, J ¼ 8.3, 7.3, 1.2 Hz, 1H), 6.61 (d, J ¼ 2.4 Hz, 2H), 6.37 (t, J ¼ 2.3 Hz,
1H), 4.52 (s, 2H), 3.75 (s, 6H). 13C NMR (101 MHz, CDCl3) d 166.37, 160.93,
153.14, 138.35, 135.35, 126.07, 124.29, 121.51, 121.03, 107.10, 99.90, 55.34, 37.92.
HRMS-ESI calcd. C16H16NO2S2 318.0612; found 318.0606.
2-((3,5-Dimethoxybenzyl)sulfonyl)benzo[d]thiazole (5)
Initially 30% of H2O2 (17.8 mL) was added to a solution of sulfide 4 (5.0 g,
15.7 mmol) in ethanol and chloroform (200 mL, 3:1). Ammonium molybdate

SYNTHESIS OF PTEROSTILBENE
3221
[(NH4)6Mo7O24 ꢂ 4H2O] (48.5 g, 39.2 mmol) was added portionwise to this mixture.
Sodium acetate (11.5 g, 140 mmol) was added to the resulting solution and stirred
at room temperature. After 24 h, the mixture was concentrated, diluted with water
(100 mL), extracted with EtOAc (3 ꢃ 50 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure to give crude residue, which was
purified by silica-gel column chromatography (20% of EtOAc in hexane) to give white
crystalline sulfone 5 5.2 g) in 95% yield. IR (cmꢁ1) 2963, 2908, 1592, 1430, 1315, 780.
1H NMR (400 MHz, CDCl3) d 8.22 (d, J ¼ 8.1 Hz, 1H), 7.90 (d, J ¼ 7.9 Hz, 1H),
7.63–7.58 (m, 1H), 7.56–7.51 (m, 1H), 6.33 (d, J ¼ 4.1 Hz, 3H), 4.66 (s, 2H), 3.55 (s,
6H). 13C NMR (101 MHz, CDCl3) d 165.19, 161.97, 160.87, 128.08, 127.73, 125.38,
122.33, 108.87, 101.78, 61.30, 55.25. HRMS-ESI calcd. C16H16NO4S2 350.0512;
found 350.0511.
(E)-1,2-Bis(3,5-dimethoxyphenyl)ethane (8)
LiHMDS (5.0 mL of 1.0 M solution in THF) was added to a solution of sulfone
5 (1.75 g, 5.0 mmol) in anhydrous THF (20 mL) at 0 ꢀC and stirred for 30 min at the
same temperature, and then a solution of aldehyde 7b (930 mg, 4.5 mmol) in THF
(30 mL) was added. Stirring continued for 3 h at 0 ꢀC. After completion of the reac-
tion, the reaction mixture was quenched with saturated NH4Cl solution and
extracted with EtOAc, and the solvent was evaporated under reduced pressure to
give a crude residue. The residue was purified by silica-gel column chromatography
to give compound 8 with 90% yield (1.35 g). IR (cmꢁ1) 2915, 1600, 1515, 1468, 1235,
1185, 960. 1H NMR (400 MHz, CDCl3) d 7.01 (s, 2H), 6.66 (d, J ¼ 2.3 Hz, 4H), 6.31
(t, J ¼ 2.3 Hz, 2H), 3.82 (s, 12H). 13C NMR (101 MHz, CDCl3) d 160.91, 139.07,
129.11, 104.56, 100.05, 55.28. HRMS-ESI calcd. C18H21O4 301.1440; found
301.1442.
(E)-4-(3,5-Dimethoxystyryl)phenol (Pterostilbene) (1)
LiHMDS (17.1 mL of 1.0 M solution in THF, 10.3 mmol) was added to a sol-
ution of sulfone 5 (3.0 g, 8.5 mmol) in anhydrous THF (30 mL) at ꢁ78 ꢀC and stirred
for an additional 30 min at the same temperature. To this cold solution, aldehyde 7a
(1.75 g, 10.63 mmol) in THF (20 mL) was added and stirring continued at ꢁ78 ꢀC.
After 3 h, the mixture was quenched with saturated NH4Cl solution and extracted
with EtOAc (3 ꢃ 25 mL). The combined organic layers were washed with water and
saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced
pressure to yield the crude product. The residue was purified by silica-gel column
chromatography using EtOAc (5–20%) in hexanes to give 4-acetyl pterostilbene
(1.35 g, 53% yield) and pterostilbene (0.42 g, 19% yield). Alternatively, the crude pro-
duct obtained in Julia olefination was subjected to saponification without further
purification using K2CO3 (18.45 mmol) in methanol (20 mL) at room temperature,
followed by purification on silica-gel column chromatography (5–25% EtOAc in hex-
anes) to yield pure 1 in 69% yield (two steps) (1.52 g). IR (cmꢁ1) 3393, 2989, 2941,
1
1661, 1581, 1140, 827. H NMR (400 MHz, CDCl3) d 7.41–7.38 (m, 2H), 7.03 (d,
J ¼ 16.2 Hz, 1H), 6.89 (dd, J ¼ 16.4, 1.6 Hz, 1H), 6.84 (d, J ¼ 8.7 Hz, 2H), 6.66 (t,
J ¼ 1.8 Hz, 2H), 6.41–6.38 (m, 1H), 3.83 (d, J ¼ 1.6 Hz, 6H). 13C NMR (101 MHz,

3222
P. PEDDIKOTLA ET AL.
CDCl3) d 160.86, 155.61, 139.72, 129.87, 128.78, 128.03, 126.41, 115.68, 104.40, 99.61,
55.40. HRMS-ESI calcd. C16H17O3 257.1178; found 257.1178.
SUPPORTING INFORMATION
Supporting information such as general experimental procedures along with
1
spectral data such as IR, H NMR, 13C NMR, and HRMS-ESI for the compounds
is available via the Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
We are grateful for support under the U.S. Department of Agriculture,
Agricultural Research Service, Specific Cooperative Agreement No. 58-6408-2-
0009. C.A.G. and P.P. are grateful to Jon Parcher for his valuable insights and
Bharathi Avula for help with high-resolution mass spectrometry.
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