Selective esterification of the polyphenol resveratrol at the 4′-position

Article abstract of DOI:10.1016/j.tetlet.2013.12.019

Selective esterification of the polyphenol resveratrol was performed under thermodynamic conditions using NaH and acid anhydrides to directly access 4′-esters. Standard conditions with acetyl chloride and pyridine showed poor selectivity, favoring esterification at the 3-position. The extended 4′-phenolate anion is generated in preference to the 3-phenolate under the new anhydride-sodium hydride-DMSO conditions. Acylation occurs to access the 4′-ester products with modest selectivity and yield with minimal formation of the 3-monoester, 3,5-diester, and triester products.

Full text of DOI:10.1016/j.tetlet.2013.12.019

Accepted Manuscript
Selective esterification of the polyphenol resveratrol at the 4’-position
Mark J. Acerson, Merritt B. Andrus
PII:
S0040-4039(13)02094-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.12.019
TETL 43933
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 October 2013
3 December 2013
6 December 2013
Please cite this article as: Acerson, M.J., Andrus, M.B., Selective esterification of the polyphenol resveratrol at the
4’-position, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.12.019
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Selective esterification of the polyphenol
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Mark J. Acerson, Merritt B. Andrus

1
Tetrahedron Letters
journal homepage: www. elsevier. com
Selective esterification of the polyphenol resveratrol at the 4’-position
Mark J. Acerson, Merritt B. Andrus*
Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN, Provo, UT, 84602, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Selective esterification of the polyphenol resveratrol was performed under thermodynamic
conditions using NaH and acid anhydrides to directly access 4’-esters. Standard conditions with
acetyl chloride and pyridine showed poor selectivity, favoring esterification at the 3-position.
The extended 4’-phenolate anion is generated in preference to the 3-phenolate under the new
anhydride-sodium hydride-DMSO conditions. Acylation occurs to access the 4’-ester products
with modest selectivity and yield with minimal formation of the 3-monoester, 3,5-diester and
triester products.
Available online
Keywords:
Acylation
Analog
2009 Elsevier Ltd. All rights reserved.
Anhydride
Bioavailability
Esterification
Phenol
Polyphenol
Resveratrol
Thermodynamic
Selective functionalization of natural products allows for
modifications that can lead to improvements in biological
activity, stability, availability, solubility, and metabolism.1 Many
natural products have potent in vitro activity, as seen in cell-
based assays, and yet suffer from poor bioavailability in whole
organisms being rapidly cleared with low cell permeability and
transport. Poor pharmacodynamics are often due to low
solubility, and oxidation or glycosylation leading to rapid
clearance.2 Covalent attachment of suitable functionality can be
used to address these drawbacks by modulating the polarity of
the compound to improve transport and blocking sights of
oxidation and glycosylation to lower clearance. Selective
modification can also allow for unmasking of active functionality
in a pro-drug manner once target proximity is achieved.3 Added
functionality holds potential to minimize off target interactions
by lowering affinity with unwanted receptors. Plant polyphenols
possess numerous beneficial activities as demonstrated with in
vitro assays, yet they show poor bioavailability characteristics
with rapid clearance.4 Resveratrol (RV), 3,5,4’-trihydroxystilbene
1, a phytoalexin polyphenol present in various plants (Figure 1),5
has a short ½-life (30 min) due to rapid glycosylation and sulfate
formation.6 Yet, reports show that this compound holds promise
with potent activity as an activator of the protein deacetylase
SIRT1 that controls gene silencing, cell cycle regulation, and
longevity.7 Resveratrol is also an inhibitor of quinone reductase
II8 and apurinic endonuclease I (APE/Ref-I),9 a DNA repairase.
Previously, we reported the synthesis of RV esters, including
2 and 3, and diesters using a palladium-N-heterocyclic carbene
catalysis decarbonylative Heck approach with protected benzoyl
chlorides and 4-acetoxystyrenes in four steps.10 We now report
the development of a selective acylation approach to 4’-RV esters
through direct treatment of RV
thermodynamic deprotonation.
1 with anhydrides via
———
* Corresponding author, Tel: 1 801 422-8171, fax: 1 801 422-0153
E-mail address: mbandrus@chem.byu.edu

2
Tetrahedron Letters
Figure 1. Stilbene polyphenol RV 1 and acetates 2 and 3
Plant polyphenols typically possess at least three aryl hydroxyls
appended on two benzenes, as with the flavones and isoflavones,
quercetin, genistein, which readily undergo oxidation to the para-
quinone, glycosylation, uronylation, or sulfation generating polar
metabolites.11 RV 1 lacking a 1,4-diol needed for para-quinone
formation undergoes glycolsylation and sulfation primarily
Mild Lewis acid catalyzed conditions were also explored for
selective RV esterification (Table 2). Use of iron(III) chloride (1
mol%) with acetic anhydride (1.5 equiv.)19 gave a mixture of
products with slight selectivity for 4’-acetyl-RV 2. Unreacted RV
1 remained and the reaction did not proceed further after 45 min.
Catalytic nickel(II) chloride20 proceeded at a slower rate with
higher selectivity for 2, 3 to 1 over 3, yet RV 1 remained as the
major product. Other catalysts attempted, TiCl3•4H2O,21 ErCl3,22
TiO2,23 and InCl3 in acetonitrile24 as solvent, all showed moderate
selectivity for 3-acetyl RV 3 over 2. TiCl3•4H2O was best,
requiring 48 hr to give 3 2.4 to 1 over 2. TiO2 conditions rapidly
gave products, 3 again being slightly favored, with RV 1
remaining largely unreacted.
through the 4’-hydroxyl.6 The multi-drug resistance transport
proteins, MRP2 and BCRP, also contribute to the low
bioavailability of RV.12 The synthesis of various 3, 5, and 4’-
ester analogs and fluoro variants of RV 1 have been reported
together with anticancer activity and longevity promotion
assays.10 4’-Acetyl RV 2 (4AR, Figure 1) was modestly more
active (ED50 17 μM) compared to RV (22 μM) with HL-60
cells10b and was found to be more effective with melanoma
cells.10a 4’-Acetyl RV
2 was resistant to decomposition,
remaining stable as a pure white solid over extended time,
compared to RV which rapidly yellows. Longevity studies with
yeast using 4’-acetyl RV 2 also showed improved stability and
activity compared to RV 1 by extending lifespan at a reduced
dose.13 Direct access, now in one step from RV 1, to improved
analogs offers the potential for new therapeutic applications with
enhanced stability and bioavailability.2 Selective esterification
also holds potential for improving related polyphenols that show
similar poor availability.14 Enzymatic based approaches to direct
RV acylation require vinyl acetate and are limited in scope with
low yields and poor selectivity.15
Initial efforts for direct RV 1 esterification focused on the use
of standard conditions with acetyl chloride and pyridine in
methylene chloride (Table 1).16 In all cases with various
equivalents, solvent, and temperature changes, the undesired
triacetate was found to be the dominant product. Use of less
reactive acetic anhydride with NaOH in water,17 the mono-RV
esters could be obtained with the 3-acetate 3 dominant 1.2:1.0
over the desired 4’-acetate 2. Unreacted RV was also obtained in
these cases. Potassium carbonate as base in ethanol showed
similar selectivity for 3. A significant improvement was finally
achieved using acetic anhydride in excess (1.5 equiv) at rt to
provide selective 4’-mono-acetate formation with 2 dominant 4.6
to 1.0 over 3. Excess sodium hydride in THF18 at elevated
temperature led to further improvement to 5 to 1 for the 4’-
acetate 2, however, the problem of unreacted starting material
remained.
The analysis of the product distribution in these cases was
made straightforward due to our experience with the synthesis of
individual RV esters and diesters reported previously.10b Analysis
1
of the H NMR (500 MHz) 6 to 8 ppm shift range of the crude
material allowed for product identification and quantification due
to well resolved C4 proton signals for the esters and the starting
material RV (Figure 2). TLC readily distinguished RV 1 from
mono-, di-, the tri-ester formation and 1H NMR allowed for
reliable monoester differentiation due to a C4 proton shift
difference of 0.2 ppm between 3 and 2. The example shown
corresponds to the conditions of acetic anhydride and potassium
carbonate in ethanol (Table 1.)

3
Figure 2. 1H NMR analysis of RV 1 acetylation showing key C4
proton shifts at 6.18 ppm for RV 1, 6.20 ppm for 4'-Ac-RV 2 and
6.40 for 3-Ac-RV 3.
The moderately selective result for 4’-acylation giving 2 over
3 using the conditions reported by Rappoport with NaH in THF18
was further explored over a wide temperature range (Table 3).
NaH (1 equiv.) used at -78 °C with RV 1 (30 min) followed by
addition of Ac2O gave 2 with slight 2 to 1 selectivity over 3.
After 3.5 hr with gradual warming to rt, unreacted RV remained
dominant. With n-butyllithium as base under comparable
conditions25 the selectivity for 2 increased and it was now found
to be the major product. Prolonged reaction times and use of
excess base or anhydride gave more 3-ester 3 and 3,5-diester
products in these cases. Using 2 equiv. of NaH at 0 °C, the
product 2 was further enhanced. Further increases in the
temperature, from 25 °C to 65 °C, increased reactions rates,
improved selectivity for 2, and lowered the amount of unreacted
RV 1.
Selective RV 1 acylation using acetic anhydride at this point
appeared to be governed primarily by the nature of the solvent
and to a lesser extent by the base and reaction temperature. Use
of protic solvents, ethanol and water, provided the 3-acetate 3 in
slight preference 1.3 to 1 over the 4’-product 2 (Table 1).
Switching to acetone and THF showed a dramatic shift in
selectivity to the desired 4’-RV acetate 2, 5 to 1. The pKa values
for RV have been measured showing the 4’-hydroxyl to be most
acidic at 8.9 (H2O), followed by the 3-hydroxyl at 10.26 The 4’-
phenolate is an extended anion that benefits from delocalization
through the stilbene alkene (Scheme 1) and can be considered the
thermodynamic site of deprotonation leading to 2 following
acylation. The 3-phenolate is cross conjugated to the alkene and
is not fully delocalized. Due to the presence of the two
hydroxyls, at C3 and C5, this site of deprotonation is statistically
more probable and can be considered a kinetic pathway giving 3.
In addition, with protic solvents reversible deprotonation is
facilitated generating more 3-phenolate leading to more 3-acetyl
Scheme 1. 3- versus 4’-deprotonation.
Building on the observed 4’-selectivity, developed using THF
as solvent, the process was optimized with other anhydrides to
provide access to a range of RV ester products (Table 4). Modest
isolated yields were obtained for these products using a slight
excess of anhydride (1.5 equiv.) in THF or DMSO. Following
standard work-up and chromatography 4’-RV acetate 2 (R=Me)
was obtained in 40% yield using NaH in THF as developed in
previous experiments. The 65 °C reaction temperature proved
critical to minimize remaining starting material RV 1. Use of
triethylamine in DMSO showed an improved isolated yield of
47% for product 2. Less reactive isobutyryl anhydride (R=i-Pr) in
THF with NaH base gave the 4’-ester 4 in 37% yield. Use of
DMSO further improved the yield to 43%. These conditions also
provided a useful yield of the n-butyryl ester 5 in 46% following
chromatography. The slower reacting pivalic anhydride was
employed in DMSO with NaH to give the pivaloyl ester product
6 in reasonable 58% yield. Again, use of THF or switching the
base to K2CO3 gave reduced yields. The corresponding benzoate
RV ester 7 was also investigated. Benzoyl chloride with K2CO3
gave the best results with a lower 32% yield in this case.
RV
3
formation. In aprotic solvents, equilibration of
deprotonation is less favored promoting the 4’-phenolate to give
4-acetyl RV 2 as the major product. Faster acylation at the 4’-
position also leads to lower amounts of diester formation. When
the 3-acetate 3 is favored in protic solvents, higher amounts of
3,5-diester was observed. A proximity effect for a second
deprotonation shows that the 3-acetate 3 reacts faster than the 4’-
acetate 2 when excess anhydride and base are present. Having an
ester at the 3-position thus lowers the pKa of the 5-hydroxyl,
while the 4’-ester, being more remote, has less of an effect on
diester formation.

4
Tetrahedron Letters
The selective mono esterification of the polyphenol RV has
been developed using anhydrides in DMSO as solvent to access a
variety of 4’-esters. Modest isolated yields of pure products are
obtained with 5 to 1 selectivity over the 3-ester and unreacted
RV. The process appears to be consistent with a thermodynamic
deprotonation and acylation pathway through the 4’-phenolate
anion. Use of protic solvents switched the selectivity giving
preference for the 3-ester product through reversible formation of
the phenolate intermediate. Other types of acyl functionality,
including carbonates and carbamates, can now be installed in
similar fashion using this one-step approach to directly access
new RV variations. The method should also extend to other
polyphenols for selective monoacylation and related
transformations.
2.
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Acknowledgments
We are grateful for support provided by the Brigham Young
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Supplementary Material
Experimental procedures, characterization, including NMR
spectra. Supplementary data associated with this article can be
found, in the online version, at ScienceDirect.

Highlights
Selective esterification of the polyphenol resveratrol at the 4’-position
Mark J. Acerson, Merritt B. Andrus1
Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN,
Provo, UT, 84602, USA
Highlights
• The polyphenol resveratrol was selectively acylated at the 4’-position using simple
reagents.
• Various 4’-esters of resveratrol are now available in moderate yields.
• Selective esterification is due primarlity to the stability of the fully delocalized
phenolate ion intermediate.
• Optimal conditions include use of sodium hydride or triethylamine in DMSO.
1 Corresponding author, Tel: 1 801 422-8171, fax: 1 801 422-0153
E-mail address: mbandrus@chem.byu.edu