Fluorinated resveratrol and pterostilbene

Article abstract of DOI:10.1016/S0040-4039(01)01800-7

A general method for the synthesis of polyhydroxylated stilbene monofluorinated on the central double bond based on the Suzuki reaction between a bromofluoroolefin and a phenylboronic acid is described. Synthesis of fluorinated analogues of resveratrol an

Full text of DOI:10.1016/S0040-4039(01)01800-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9127–9130
Fluorinated resveratrol and pterostilbene
Said Eddarir,a,b Zouanate Abdelhadib and Christian Rolandoa,*
aUniversite´ des Sciences et Technologies de Lille, UPRESA CNRS 8009, Chimie Organique et Macromole´culaire, 59655
Villeneuve d’Ascq Cedex, France
bUniversite´ Cadi Ayyad, Faculte´ des Sciences et Technique Gue´liz, BP 618 Marrakech, Maroc
Received 1 August 2001; accepted 30 August 2001
Abstract—A general method for the synthesis of polyhydroxylated stilbene monofluorinated on the central double bond based on
the Suzuki reaction between a bromofluoroolefin and a phenylboronic acid is described. Synthesis of fluorinated analogues of
resveratrol and pterostilbene was achieved using this strategy. © 2001 Elsevier Science Ltd. All rights reserved.
Resveratrol, and more generally polyhydroxylated stil-
benes are natural compounds which exhibit many bio-
logical properties. As they are widely distributed in
plants, especially in grape they are very often found in
human diet. Since the pioneering discovery of their
anti-carcinogenic1 and anti-oestrogenic2 properties a
great number of studies has been devoted to understand
their biological effects.3
So we decided to synthesize resveratrol fluorinated on
the stilbene double bond in order to test its biological
activity against oxidation enzymes. Most of the previ-
ously described syntheses of resveratrol and analogues
rely on the Wittig or Wittig–Horner reactions.7–14 The
coupling of a benzyl anion with a benzaldehyde fol-
lowed by the dehydration of the alcohol may equally
lead to the central double bond.15 The hydroxyl
groups are protected on both precursors as methyl
ethers, which are cleaved under harsh acidic (pyri-
dinium hydrochloride at reflux,7–9 BBr3,11,12 MeMgI at
100–160°C15) or basic (lithium diphenylphosphide)11,12
conditions. More recently a synthesis of piceid using
ter-butyldimethylsilyl ethers as protecting group for the
resorcinol ring has been described, but the phenol
group was still protected by a methyl group, which
required the use of sodium ethanethiolate in DMF for
cleavage.13,14 In our target molecule the fluorinated
double bond is by far too sensitive to either such basic
In grapevines polyhydroxylated stilbenes are strong
protectors of the plant against the attack by pathogen
fungi like Botrytis cinerea.4 Pterostilbene has been
shown to be the more efficient phytoalexin and this
activity is well correlated with its strong inhibition of
Botrytis cinerea laccase.5 Most of the time, the intro-
duction of a fluorine atom on a key double bond of a
natural compound leads to a strong inhibitor of the
enzymatic system responsible for its metabolization.
For example fluoroconiferylic alcohol, injected as its
glycoside, fluoroconiferine, which is the transported
form in the plant, is a strong inhibitor of lignification.6
or acidic conditions. So we decided to use
a
methoxymethyl ether as a protecting group for its ease
of deprotection in slightly acidic conditions, as most
phenols are very unstable in basic medium and as
methoxymethyl ethers has been reported to be stable
under organometallic reaction conditions.16,17
* Corresponding author. Tel.: +33-3 20 43 49 77; fax:+33-3 20 33 61
36; e-mail: christian.roland@univ-lille1.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01800-7

9128
S. Eddarir et al. / Tetrahedron Letters 42 (2001) 9127–9130
The organometallic synthesis of phenols is well docu-
mented.18 The total synthesis of Combrestatin A-4 illus-
trates the scope of this approach.19 Furthermore
recently a series of cross coupling reactions of resor-
cinol has been described.20 So we chose to construct the
fluorinated double bond by coupling the required bro-
mofluoroolefin with an organometallic reagent using
palladium catalysis. We previously described such a
strategy for the synthesis of fluoroolefins, dienes and
enynes based on the Stille reaction using organotin
reagent.21–23 Recently, McCarthy extended this synthe-
sis to the Suzuki reaction.24–27 The palladium-catalyzed
In our hands, only zinc activated by cupric sulfate40
gave good results, which are reported in Table 1.
coupling reaction between either
a
fluorinated
organometallic and an aromatic or a vinylic halide, or
between an organometallic and a fluorinated iodo,
bromo or chloroolefin is quite general, working on a
wide scope of substrates, even on polyfluorinated com-
pounds.28–31 In order to avoid the introduction of tin in
compounds dedicated to biochemical experiments we
decided to use a phenylboronic acid for the coupling
step.
4-(Methoxymethyl)oxyphenylboronic acid was pre-
pared according to the procedure described by Hibino
and co-workers using triisopropyl borate as the trap-
ping reagent17 whereas 4-methoxy or 3,5-dimethoxy-
phenylboronic acids were synthesized using standard
procedures. Among the various conditions used for the
Suzuki reaction,41,42 McCarthy and co-workers used
Pd(PPh3)4 along with sodium carbonate in benzene,
ethanol–water for the coupling of bromofluoroolefin
with phenylboronic acids.24–27 At the sight of: (i) the
acceleration of the Suzuki reaction in presence of
fluoride ions,43 when fluoroarylborates are used;44 (ii)
the ease of transformation of boric acid to fluoroborate
by potassium hydrogenfluoride;45 (iii) the improved
yield using phase transfer catalyst46 we chose to use the
PdCl2(PPh3)2/PPh3 system in presence of the non-basic
reagent n-Bu4N+, HF2− in THF,47 we used previously for
the Stille reaction.48 After 4 h at reflux, TLC indicated
a near complete transformation of the starting bromo-
fluoroolefin.
There are three main synthetic pathways leading to the
required bromofluoroolefins: (i) transformation of the
corresponding fluoroacrylate by bromine addition fol-
lowed by dehydrogenative decarboxylation;21–23 (ii)
condensation of LiCFBr2 on an aldehyde followed by
water elimination;32,33 (iii) reaction of fluorotri-
bromethane with aldehyde in presence of a tertiary
phosphine according to the procedure developed for the
synthesis of dibromoolefins by Corey34 and adapted to
bromofluoroolefins by Burton.35–37 We chose this later
strategy, as it is compatible with functionalized
molecules like carbohydrates38 or nucleotides.39 Hap-
pily this procedure appeared to be compatible with the
methoxymethyl ether protecting group. However, using
2 equiv. of triphenylphosphine we always got a 50/50
mixture between the gemdibromo compound derived
from the aldehyde (reported here for the first time in
this reaction to the best of our knowledge) and the E/Z
bromofluorolefin mixture.
Table 1. Synthesis of protected b,b-bromofluoro-hydroxy-
styrenes
This reaction can be readily explained from the stoi-
chiometry of the reaction leading to the intermediate
phosphorane.
R (meta)
R% (para)
R%% (meta)
Isolated yield (%)
MeO
CH3C(O)O
CH3OCH2O
H
H
H
H
H
H
MeO
CH3OCH2O
NO2
MeO
CH3C(O)O
CH3OCH2O
H
H
H
55
41
46
52
48
56
CFBr3+2PPh3“Ph3PCFBr+Ph3PBr2
As the gemdibromo compound and the bromofluoro-
lefins were very difficult to isolate by chromatography,
we chose to use alternative conditions using one equiv-
alent of triphenylphosphine in the presence of zinc dust.

S. Eddarir et al. / Tetrahedron Letters 42 (2001) 9127–9130
Table 2. Synthesized polyhydroxylated fluorostilbenes
9129
R1=R2
R3
Suzuki coupling yield (%)
Deprotection isolated yield (%)
Me
Me
CH3OCH2O
CH3OCH2O
Me
86
83
71
84
–
CH3OCH2O
CH3OCH2O
Me
76
73
80
Our first attempt to deprotect the fluororesveratrol
blocked by three MOM groups using trifluoroacetic acid
in dichloromethane49 at room temperature led to the
formation of the ketone resulting from the hydrolysis of
the fluorinated enol. The ketone was identified by its
ESI–MS/MS spectrum, which exhibits peaks at m/z 121
and 151 corresponding to the acylium ion and the benzyl
cation.
In summary, the synthesis of fluorinated analogues of
resveratrol and pterostilbene was achieved based on the
Suzuki reaction between a bromofluoroolefin and a
phenylboronic acid. The choice of the protecting group
was rather critical duetothesensitivity ofthe fluoroolefins
to hydrolysis. The methoxymethyl protecting group
appeared to be both stable under coupling conditions and
easily cleaved under mild acidic conditions, opening the
way to a general synthesis of polyhydroxylated stilbenes
monofluorinated on the central double bond. The synthe-
sized fluorinated compounds are currently tested in
various in vitro biological experiments.
Acknowledgements
This work was supported by the European Community
(European Contract QLK1-CT-199-00505 POLYBIND)
and the Conseil Re´gional Nord, Pas-de-Calais. S.E.
thanks the Universite´ Cadi Ayyad, Faculte´ des Sciences
et Technique Gue´liz for a sabbatical leave. Professor
Florence Charbonnier, Universite´ Joseph Fourier,
Grenoble, France, is gratefully thanked for helpful
discussions on zinc activation.
We were delighted that using milder conditions, aqueous
HCl 0.1N in MeOH at reflux, the three MOM groups
could be cleaved without hydrolysis of the carbonꢀ
fluorine bond. After optimization of the reaction time
(36 h) a near quantitative yield of fluoresveratrol has been
achieved.50
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