Synthesis of polyhydroxylated ester analogs of the stilbene resveratrol using decarbonylative Heck couplings

Article abstract of DOI:10.1016/j.tetlet.2006.05.065

Protected 3,5-hydroxy-benzoyl chlorides 3 were coupled with styrenes 4 to give hydroxylated stilbenes, analogs of resveratrol, an important antioxidant disease preventative agent isolated from grape skins and other dietary sources. Levulinate and chloroacetate protecting groups allowed for the selective production of mono- and di-acetate variations under palladium-N-heterocyclic carbene (NHC) catalyzed decarbonylative coupling conditions. Fluorinated analogs were also produced using Heck conditions with bromofluorobenzenes. Human HL-60 cell assays showed the 4′-acetoxy variant 11 to have improved activity (ED₅₀ 17 μM) relative to resveratrol (24 μM).

Full text of DOI:10.1016/j.tetlet.2006.05.065

Tetrahedron Letters 47 (2006) 5811–5814
Synthesis of polyhydroxylated ester analogs of the stilbene
resveratrol using decarbonylative Heck couplings
Merritt B. Andrus* and Jing Liu
Brigham Young University, Department of Chemistry and Biochemistry, C100 BNSN, Provo, UT 84602, United States
Received 12 April 2006; revised 11 May 2006; accepted 11 May 2006
Abstract—Protected 3,5-hydroxy-benzoyl chlorides 3 were coupled with styrenes 4 to give hydroxylated stilbenes, analogs of resve-
ratrol, an important antioxidant disease preventative agent isolated from grape skins and other dietary sources. Levulinate and chloro-
acetate protecting groups allowed for the selective production of mono- and di-acetate variations under palladium-N-heterocyclic
carbene (NHC) catalyzed decarbonylative coupling conditions. Fluorinated analogs were also produced using Heck conditions with
bromofluorobenzenes. Human HL-60 cell assays showed the 40-acetoxy variant 11 to have improved activity (ED50 17 lM) relative
to resveratrol (24 lM).
Ó 2006 Published by Elsevier Ltd.
We previously reported a short, efficient synthesis of the
antioxidant disease preventative stilbene resveratrol 1
using a palladium catalyzed decarbonylative coupling
of a benzoyl chloride derived from resorcylic acid 3
(X, Y = OH) and acetoxystyrene 4 (Scheme 1).1 Interest
continues to grow concerning the biological activity and
therapeutic potential for this phytoalexin compound iso-
lated from grape skins (50 lg/g) and other sources.2
Resveratrol has been identified as the causative agent
of the ‘French Paradox,’ and the ‘Mediterranean Diet’
in that moderate consumption of wine is associated with
lower incidence of heart disease and cancer.3 Recently,
resveratrol has also been shown to extend lifetime in
yeast and Caenorhabditis elegans through activation of
sirtuin (SIRT-1, 2) an NAD dependent histone deacetyl-
ase that has been shown to directly correlate with cellu-
lar longevity.4 While various biological targets have
been implicated and identified, the mechanism of resve-
ratrol’s integrated effect on various cellular pathways re-
mains unclear.5 To facilitate these efforts, we now report
the systematic, selective syntheses of acetate and fluoro
analogs6 of resveratrol 2 using decarbonylative Heck
couplings7 with protected resorcylic acid derivatives
and styrenes under palladium-N-heterocyclic carbene
conditions. Resorcylic acid is an ideal, inexpensive start-
ing material as it has the requisite 3,5-substitution
pattern and it is easily converted to acid chloride
derivatives. Suitable protecting groups on this template
can now be employed that allow for efficient cross-cou-
plings with appropriate partners for the selective synthe-
sis of specific resveratrol analogs.
OH
resveratrol
Z
HO
X
2
1
OH
X
Y
O
Z
Cl
4-Acetoxyresveratrol was synthesized in five steps begin-
ning with resorcylic acid 5 (3,5-dihydroxybenzoic acid).
Treatment with sodium hydride followed by MOMCl
(methoxymethyl chloride) and exposure to sodium
hydroxide gave 6 in 91% isolated yield (Scheme 2). Thio-
nyl chloride with added benzotriazole provided acid
chloride 7.8 Thionyl chloride on its own, without added
benzotriazole, was found to be ineffective for this trans-
formation. Decarbonylative Heck coupling with 4-acet-
oxy styrene 8 was performed using palladium acetate
+
Y
3
4
Scheme 1.
Keywords: Resveratrol; Stilbene; Decarbonylative Heck; Palladium
catalysis.
*
Corresponding author. Tel.: +1 801 422 8171; fax: +1 801 422 0153;
e-mail: mbandrus@chem.byu.edu
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.05.065

5812
M. B. Andrus, J. Liu / Tetrahedron Letters 47 (2006) 5811–5814
ously employed MOM ether. Chloroacetate 13 was
MOMO
CO2H
1) NaH,
MOMCl
2) NaOH
HO
CO2H
5
formed in high yield using chloroacetyl chloride. 3,5-
Diacetoxybenzoate, reported previously for the synthe-
sis of resveratrol,1 was reacted under palladium–NHC
9 conditions to give stilbene 15 (70%). Efficient removal
of the chloroacetate, in the presence the 3,5-diacetates,
was performed using 50% aqueous pyridine (pH 6.7)
to give 3,5-acetoxy resveratrol 16 in 90% isolated yield.
6
MOMO
HO
91%
COCl
OAc
8
MOMO
SOCl2
benzotriazole
Pd(OAc)2 1%
Cl-
7
MOMO
9
N
N+
To begin the synthesis of 3-acetoxy resveratrol, resor-
cylic acid was mono-acetylated in 60% yield using acetic
anhydride (1 equiv) and sodium hydroxide (3 equiv) to
give 17 (Scheme 4).12 Protection of the 5-hydroxyl was
found to be most efficient using the seldom employed
levulinate (Lev, 4-oxopentanoate) group.13 This group
was found to be stable to various reaction conditions,
including acid chloride formation and the palladium
coupling step, and is readily removed using sodium sul-
fite via the hydroxysulfite adduct. Mono-acetate 17 was
treated with levulinic anhydride in the presence of pyri-
dine to give 18 in 96% isolated yield. Formation of the
acid chloride 19 was then performed using thionyl chlo-
ride again with added benzotriazole. Coupling under
palladium–9 conditions, as before, generated levulinic
ester 20 (70%). The Lev group was then removed by
sodium sulfite and thiosulfate to access the desired
3,40-diacetoxy resveratrol analog 21.
Ar
Ar
Ar=2,6-di-i-PrPh
NEM, xyl. 120 °C
OAc
MOMO
MOMO
NaI, TMSCl
10
56% (2 steps)
72%
OAc
HO
11
HO
Scheme 2.
(1 mol %) and N,N-bis-2,6-diisopropylphenyl-4,5-di-
hydro chloride 9 (H2IPr) as an N-heterocyclic carbene
(NHC) ligand9 with NEM (N-ethylmorpholine) as base
in xylenes at 120 °C following the previous route.1 The
di-MOM stilbene 10 was isolated in 56% yield for the
two steps, from 6. The MOM groups were removed
using TMSI, generated from TMSCl and sodium iodide,
to give 40-acetoxy-resveratrol 11.
The levulinate strategy also proved to be most effective
for the synthesis of the 3-acetoxy analog (Scheme 5).
4-Hydroxystyrene was treated with levulinic anhydride
to give the Lev-protected 22. Coupling with 19 under
the decarbonylative Heck conditions gave the protected
stilbene 23 in 72% yield. Removal of the two Lev groups
gave 3-acetoxy resveratrol.
The 3,5-diacetoxy analog was generated from the unsta-
ble intermediate, 4-vinylphenol 12,10 which was accessed
from acetoxy 8 (Scheme 3). To differentiate between the
3,5 and 40-hydroxyls in this case, the chloroacetate pro-
tecting group11 was found to be superior to the previ-
Fluoro analogs were also produced using the decarb-
onylative coupling reaction (Scheme 6). Resveratrol
has been found to have a limited cellular lifetime.4b,14
O
OH
Cl
KOH
60%
Cl
O
8
Ac2O
NaOH
O
Et3N
HO
CO2H
12
AcO
2
O
5
COCl
17
O
60%
AcO
pyr. 96%
Cl
14
O
AcO
LevO
COCl
LevO
CO2H
SOCl2
benzotriazole
92%
13
Pd(OAc)2 1%
9
19
18
NEM, xyl. 120 °C
AcO
45%
AcO
O
OAc
70%
Cl
8
50% aq.
pyr., pH 6.7
AcO
O
LevO
Pd(OAc)2 1%
NEM, xyl. 120 °C
15
9
20
90%
OH
70%
AcO
AcO
AcO
HO
OAc
Na2SO3
Na2S2O5
16
73%
21
AcO
AcO
Scheme 3.
Scheme 4.

M. B. Andrus, J. Liu / Tetrahedron Letters 47 (2006) 5811–5814
5813
OLev
1) BnOH, NaH
F
22
OLev
LevO
74%
2) Pd(OAc)2 3%
(o-tol)3P 6%
F
F
Br
19
31
23
24
Et3N, DMF
26
Pd(OAc)2 1%
NEM, xyl. 120 ˚C
72%
9
30
AcO
BnO
F
91%
F
OH
F
Na2SO3
Na2S2O5
HO
BBr3
32
86%
HO
70%
AcO
OAc
Pd(OAc)2 3%
(o-tol)3P 6%
F
Br
Scheme 5.
F
Et3N, DMF
8
34
BnO
F
BnO
33
26
88%
F
F
COCl
OH
F
1) BBr3 61%
2) HCl 78%
F
Pd(OAc)2 1%
NEM, xyl. 120 °C
27
9
F
80%
OH
25
F
35
HO
8
Scheme 7.
F
1) Pd(OAc)2 1%
9
25
NEM, xyl. 74%
28
2) HCl 88%
F
Table 1. ED50 of resveratrol analogs with HL-60 cells
F
Z
26
HO
9
1) Pd(OAc)2 1%
X
NEM, xyl. 73%
2) HCl 85%
14
Scheme 6.
29
HO
Y
Compound
X
Y
Z
ED50
1
–OH
–OAc
–OH
–OAc
–OH
–OH
–OH
–OAc
–OH
–OAc
–OAc
–OAc
–OH
–OAc
–OAc
–OH
–OAc
–OH
23
27
17
33
30
24
2
Fluoride is isosteric with hydroxyl and the stability of
the substituted C–F bond can lead to improved activity
and resistance to metabolism.15 3,5-Difluorobenzoyl
chloride 25 reacted with 4-fluorostyrene to give 27
in 80% yield. Coupling of 25 with 4-acetoxystyrene 8
occurred in 74% yield and the difluoro analog 28 was
generated in 88% isolated yield. 3,5-Diacetoxybenzoic
acid 14 was also coupled using 4-fluorostyrene 26 to
generate 40-fluoro resveratrol 29 in good overall yield.
11
16
21
24
100 lM) and ED50 values were determined using an
established protocol.18,5d Triacetoxy 2 and 3-acetoxy
24 were found to be comparable to resveratrol
(23 lM), while the 3,5- and 3,40-diacetoxy analogs were
less potent. Only the 40-acetoxy variant 11 showed some-
what improved anti-cancer activity at 17 lM. In general,
the fluoro analogs were found to be toxic to this and
other cell lines, limiting their potential for future
investigations.
To complete the synthesis of the fluoro analog series, it
was found that use of bromobenzene substrates under
standard Heck coupling conditions known to produce
stilbenes16 was superior to the previous decarbonylative
conditions (Scheme 7). 1-Bromo-3,5-difluorobenzene
was reacted with benzyl alcohol under sodium hydride
conditions to give the benzyloxy substituted product.17
Heck coupling with 4-fluorostyrene and catalytic palla-
dium acetate with tri-o-toluylphosphine gave benzyloxy
stilbene 31. Boron tribromide mediated removal of the
benzyl ether generated the 3,40-difluoro analog 32.
Treatment of the benzyloxy adduct 33, formed from
30, with 8 gave stilbene 34 which was converted to the
3-fluoro analog 35 following protecting group removal.
A new approach to the synthesis of resveratrol analogs
has been developed using efficient decarbonylative cross
couplings with substituted acid chlorides and styrenes.
Chloro acetate and levulinate protecting groups have
been shown to be suitable for this transformation, facil-
itating selective routes to mono and di-acetoxy analogs.
Heck coupling conditions were found to be more effec-
tive for 3-fluoro and 3,40-difluoro resveratrol synthesis.
The 40-acetoxy variant 11 was found to be more potent
than resveratrol using an HL-60 cell assay. Further
investigations of the biological activities of these
compounds, together with the synthesis of a range of
40-analogs, can now be pursued using this approach.
The analogs were tested with human leukemia HL-60
cells to determine anti-cancer potential related to resve-
ratrol (Table 1). The cells were cultured over various
times (24, 48, and 72 h) exposed to compounds (5–

5814
M. B. Andrus, J. Liu / Tetrahedron Letters 47 (2006) 5811–5814
Minutolo, F.; Sala, G.; Bagnacani, A.; Bertini, S.;
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Supplementary data
Experimental and 1H NMR data for all compounds are
included. Supplementary data associated with this
article can be found, in the online version, at
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