Synthesis of resveratrol, DMU-212 and analogues through a novel Wittig-type olefination promoted by nickel nanoparticles

Article abstract of DOI:10.1016/j.tetlet.2009.04.023

A novel synthesis of resveratrol, DMU-212 and analogues is presented using benzyl alcohols as phosphorus ylide partners in a one-pot Wittig-type olefination reaction promoted by nickel nanoparticles.

Full text of DOI:10.1016/j.tetlet.2009.04.023

Tetrahedron Letters 50 (2009) 3070–3073
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Synthesis of resveratrol, DMU-212 and analogues through a novel
Wittig-type olefination promoted by nickel nanoparticles
*
*
Francisco Alonso , Paola Riente, Miguel Yus
Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthesis of resveratrol, DMU-212 and analogues is presented using benzyl alcohols as phospho-
rus ylide partners in a one-pot Wittig-type olefination reaction promoted by nickel nanoparticles.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 10 March 2009
Revised 3 April 2009
Accepted 6 April 2009
Available online 11 April 2009
Keywords:
Resveratrol
DMU-212
Wittig olefination
Nickel nanoparticles
Resveratrol [1, (E)-3,40,5-trihydroxystilbene] is
a naturally
OH
OMe
occurring phytoalexin present in vine bark, leaves and grapes, as
well as in many other plants.1 In recent years, this polyphenol
has attracted the attention of an important part of the scientific
community because of its remarkable biological properties and
therapeutic potential including chemoprevention of cancer,1,2
inflammation,1 aging,1,3 obesity,1,4 cardiovascular diseases1 and
neurodegeneration.1,5 Antioxidant,1,6 radio-protective,1 phyto-
oestrogen,1 antibacterial1 and antifungal1 activities have also been
attributed to this special molecule. The methoxylated analogues of
resveratrol possess increased lipophilicity and a pharmacological
profile comparable or even superior to that of resveratrol.7 Among
them, DMU-212 [2, (E)-3,4,40,5-tetramethoxystilbene] has recently
disclosed a strong anti-cancer activity with higher chemoprotec-
tive activity than resveratrol (Chart 1).8
Many approaches have been designed in order to prepare this
kind of structures primarily through Wittig7b,9 or Horner–Em-
mons–Wadsworth7a and Heck10 reactions. Other methodologies
involving lithiation–condensation,11 Perkins,12 Ramberg–Bäckl-
und,13 or Diels–Alder/Wittig14 reactions have also been reported.
In many cases, however, the synthetic sequence is rather long, con-
sequently leading to low product yields, while it can also be diffi-
cult to control the stereo- and regiochemistry of the process.
Therefore, the development of alternative strategies to synthesise
these valuable molecules is welcome.
HO
MeO
MeO
OH
resveratrol (1)
OMe
DMU-212 (2)
Chart 1. Chemical structures of resveratrol and DMU-212.
methodology for the synthesis of nickel(0) nanoparticles (NiNPs),
from different nickel(II) chloride-containing systems in THF, using
lithium powder and a catalytic amount of an arene as reducing
agent.16 These nanoparticles were applied to different functional
group transformations,17 and more recently, to the hydrogen-
transfer reduction of carbonyl compounds18 and reductive amina-
tion of aldehydes.19 We also reported for the first time that nickel,
in the form of nanoparticles, was a potential alternative to the use
of catalysts based on noble metals for the
and indirect aza-Wittig reaction with alcohols.20 In these reactions,
hydrogen transfer from the alcohol to the intermediate ,b-unsat-
urated ketone or imine, respectively, took place in short reaction
times and in the absence of any added ligand, hydrogen acceptor
or base, under mild conditions.
a-alkylation of ketones
a
Very recently,21 we have discovered that NiNPs, readily pre-
pared from NiCl2, lithium metal, and a catalytic amount of DTBB
(4,40-di-tert-butylbiphenyl) in THF, are able to promote a Wittig-
type olefination of benzyl alcohols with benzylidenetriphenyl-
phosphorane. We want to present herein a novel synthesis of res-
veratrol, DMU-212 and analogues, including a one-pot Wittig-type
On the other hand, and due to our ongoing interest on the prep-
aration and reactivity of active metals,15 we studied a mild and fast
* Corresponding authors. Fax: +34 965903549 (F.A.).
E-mail addresses: falonso@ua.es (F. Alonso), yus@ua.es (M. Yus).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.023

F. Alonso et al. / Tetrahedron Letters 50 (2009) 3070–3073
3071
i) PPh3, PhMe
Cl reflux, 6 h, 84%
PPh3
OMe
OH
i) cat. I2, hexane
reflux, 48h
100% E (M5)
ii) n-BuLi, THF
0 °C, 20 min
MeO
MeO
MeO
MeO
HO
3
4
NiNPs , THF
reflux , 12 h
52%
ii) BBr3, CH2Cl2
0°C-rt, 5 h, 70%
OH
OMe
OH
resveratrol (1)
6 (Z/ E 44:56)
OMe
5
MeO
i) PPh3, PhMe
Br reflux, 6 h, 90%
MeO
PPh3
OMe
OH
i) (PhS)2, AIBN
THF, reflux
ii) n-BuLi, THF
0 °C, 20 min
OMe
MeO
HO
OMe
NiNPs, THF
8 h, 100% (M5)
E
8
7
reflux , 8 h
81%
ii) BBr3, CH2Cl2
0 °C-rt, 5 h, 70%
OH
OMe
OH
resveratrol (1)
6 (
41:59)
Z/ E
MeO
9
Scheme 1. Two syntheses of resveratrol through a Wittig-type olefination promoted by nickel nanoparticles.
reaction of properly substituted benzyl alcohols and phosphorus
ylides, in the presence of nickel nanoparticles as the key step. To
the best of our knowledge, this is the first synthesis of resveratrol
derivatives through a Wittig-type olefination with alcohols (in-
stead of aldehydes) in which there is no standard redox step.
We focused first on the synthesis of resveratrol, for which two
approaches were devised from the commercially available starting
materials 3 and 7 (Scheme 1). In the first approach, 1-(chloro-
methyl)-4-methoxybenzene (3) was transformed into the corre-
sponding phosphonium salt in good yield, followed by
deprotonation with n-BuLi. The resulting benzyl phosphorus ylide
4 was reacted with 3,5-dimethoxybenzyl alcohol (5) in the pres-
ence of 1 equiv NiNPs at reflux for 12 h.22 Methylated resveratrol
(6) was obtained as a 44:56 Z/E mixture of diastereoisomers in
moderate yield. It is well known that semi-stabilised ylides, such
as benzyl ylides, yield mixtures of Z and E isomers with practically
no selectivity.23 Fortunately, isomerisation of (Z)-6 to (E)-6 (M5)
could be quantitatively accomplished under iodine catalysis.7b Fi-
nal demethylation with BBr3 furnished resveratrol (1) in 31% over-
all yield.
In the search for a more effective resveratrol synthesis, we
decided to change the Wittig-type partners 4 and 5 into 8 and 9,
respectively (Scheme 1). Following the above-described methodol-
ogy, 3,5-dimethoxybenzyl bromide (7) was converted into the cor-
responding phosphonium salt in higher yield compared to 3.
Wittig-type olefination of 8 and 4-methoxybenzyl alcohol (9) pro-
ceeded in shorter time and in higher yield in comparison with that
in the first approach. Moreover, the reaction time for the Z to E
isomerisation of 6 was substantially reduced by using diphenyl
disulfide in the presence of a catalytic amount of AIBN.24 Final
treatment with BBr3 led to resveratrol in 51% overall yield. This
yield is higher than those obtained with previously reported meth-
odologies9–12 and is comparable to that obtained from resorcylic
acid using a decarbonylative Heck approach.10b
Following a similar strategy, we focused next on the synthesis of
DMU-212 (2) (Scheme 2). In the first synthetic variant, 3,4,5-tri-
methoxybenzyl bromide (11), which is not commercially available,
had to be prepared by bromination of alcohol 10. This step, as well as
the formation of the corresponding phosphorus ylide (12), pro-
ceeded in high yield. NiNPs-promoted Wittig-type reaction of 12
MeO
MeO
MeO
MeO
MeO
i) PPh3, PhMe
reflux, 6 h, 90%
OH
Br
PPh3
PBr3, CH2Cl2
OMe
ii) n-BuLi, THF
0 °C, 20 min
MeO
0 °C-rt, overnight
86%
OMe
OMe
OMe
MeO
MeO
NiNPs, THF
10
11
12
reflux, 12 h
64%
OH
OMe
2 (Z/ E 46:54)
MeO
9
i) PPh3, PhMe
reflux, 6 h, 84%
Cl
PPh3
OH
OMe
ii) n-BuLi, THF
MeO
MeO
°
0
C, 20 min
3
4
MeO
MeO
NiNPs, THF
reflux, 12 h
100%
MeO
MeO
OMe
DMU-212 (2)
OMe
10
Scheme 2. Two syntheses of DMU-212 through a Wittig-type olefination promoted by nickel nanoparticles.

3072
MeO
MeO
F. Alonso et al. / Tetrahedron Letters 50 (2009) 3070–3073
MeO
MeO
OH
PPh3
(see Scheme 2)
OMe
OH
i) (PhS)2, AIBN
THF, reflux
8 h, 100% E
OMe
OMe
OH
OH
OMe
OMe
NiNPs, THF
MeO
MeO
HO
HO
10
12
reflux, 24 h
61%
ii) BBr3, CH2Cl2
-30 °C-rt, 2 h
45% (ref. 27)
OMe
dehydrobrittonin A (13, Z/ E 46:54)
OH
M8 (14)
Scheme 3. Synthesis of dehydrobrittonin A and M8.
with benzyl alcohol 9 led to 2 in 64% yield as a 46:54 Z/E diastereo-
meric mixture. A 50% overall yield of 2 was achieved after three syn-
thetic steps. Before trying the Z to E isomerisation in a fourth
synthetic step, however, we decided to study the alternative variant.
We were very delighted to discover that by changing 12 and 9 into 4
and 10, respectively, the Wittig-type olefination reaction proceeded
quantitatively. Moreover, DMU-212 (2) was obtained as a single
diastereoisomer25 in 84% overall yield after two synthetic steps
from commercially available 3. In view of the results obtained in
other Wittig-type olefinations with benzyl ylides and alcohols, the
high diastereoselectivity observed in the synthesis of 2 was cer-
tainly unexpected. At the moment, we have no explanation for this
result, since one would expect the presence of an additional meth-
oxy group in 10, when compared to the structure 5 (Scheme 1), not
to be so essential in driving the diastereoselectivity of the reaction.
In order to study the scope of this methodology, we decided to
deal with highly polymethoxylated derivatives. It is worthwhile
mentioning that the symmetrically substituted target molecule,
dehydrobrittonin A (13),26 could be synthesised from only one
starting material (Scheme 3). Thus, benzyl alcohol 10 served both
as the precursor of the ylide 12 and as its partner in the Wittig-type
olefination. The latter reaction was slower in comparison with the
homologues with less methoxy substituents, leading to the ex-
pected stilbene in moderate yield as a mixture of diastereoisomers.
Quantitative Z to E isomerisation, followed by demethylation27
afforded the resveratrol analogue M8 [14, (E)-3,30,4,40,5,50-
hexahydroxystilbene].
References and notes
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K. E.; Schmalz, H.-G.; Polunina, I. A. Russ. Chem. Bull. 2002, 51, 1319–1324.
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2563–2576; (b) Alonso, F.; Yus, M. Chem. Soc. Rev. 2004, 33, 284–293; (c)
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The remarkable manifold biological effects of M8 (14) have
been recently studied and include: (a) highly selective cyclooxy-
genase-2 inhibition,27 (b) much higher antioxidant activity than
resveratrol in different leukemic cell lines,28 (c) apoptosis induc-
tion at concentrations significantly lower than resveratrol in HL-
60 human promyelocytic leukaemia cells29 and (d) apoptosis
induction and cell cycle arrest in prostate cancer [also observed
for DMU-212 (2)]30 and HT29 human colon cancer cells [also ob-
served for M5, (E)-6)].31
18. (a) Alonso, F.; Riente, P.; Yus, M. Tetrahedron 2008, 64, 1847–1852; (b) Alonso,
In conclusion, we have reported an alternative synthesis of res-
veratrol, DMU-212 and analogues, such as M5, dehydrobrittonin A
or M8, through a novel Wittig-type olefination promoted by nickel
nanoparticles involving benzyl alcohols as phosphorus ylide part-
ners. The polymethoxylated stilbenes were obtained in moder-
ate-to-excellent yields depending on the benzyl alcohol and ylide
couple selected. The diastereomeric mixtures of these compounds
could be easily transformed into the (E)-stilbenes and additionally
demethoxylated to give the corresponding polyhydroxylated ana-
logues. Further research to expand the scope of this methodology
is under way.
F.; Riente, P.; Yus, M. Tetrahedron Lett. 2008, 49, 1939–1942.
19. Alonso, F.; Riente, P.; Yus, M. Synlett 2008, 1289–1292.
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Riente, P.; Yus, M. Eur. J. Org. Chem. 2008, 4908–4914.
21. Alonso, F.; Riente, P.; Yus, M. Synlett, in press.
22. General procedure for the NiNPs-promoted Wittig-type olefination: 1.6 M n-BuLi
(625 lL, 1.0 mmol) was added dropwise to a suspension of the corresponding
methoxylated benzyltriphenylphosphonium halide (1.5 mmol) in THF (2 mL)
at 0 °C. While the corresponding ylide was being formed (ca. 20 min), nickel(II)
chloride (130 mg, 1 mmol) was added over a suspension of lithium (14 mg,
2 mmol) and DTBB (13 mg, 0.05 mmol) in THF (2 mL) at room temperature
under argon. The reaction mixture, which was initially dark blue, changed to
black indicating that nickel(0) was formed. After 10 min, the corresponding
benzyl alcohol (1 mmol) and the initially prepared ylide suspension were
added to the NiNPs suspension. The reaction mixture was warmed up to reflux
and monitored by GLC–MS. The resulting mixture was diluted with EtOAc
(10 mL), filtered through a pad containing Celite, and the filtrate was dried over
MgSO4. The residue obtained after removal of the solvent (15 Torr) was
purified by column chromatography (silica gel, hexane or hexane-EtOAc) to
give the pure product. The diastereomeric ratio was determined on the basis of
the GC and 1H NMR analyses.
Acknowledgements
This work was generously supported by the Spanish Ministerio
de Educación y Ciencia (MEC; Grant No. CTQ2007-65218 and Con-
solider Ingenio 2010-CSD2007-00006). P.R. thanks the MEC for a
predoctoral grant.
23. Yamataka, H.; Nagareda, K.; Ando, K.; Hanafusa, T. J. Org. Chem. 1992, 57, 2865–
2869.

F. Alonso et al. / Tetrahedron Letters 50 (2009) 3070–3073
3073
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isomerisation to the corresponding Z stereoisomer (e.g., in CDCl3). We are
currently studying the parameters that could affect this transformation in
different stilbenes.
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