Synthesis of bio-based epoxy monomers from natural allyl- and vinyl phenols and the estimation of their affinity to the estrogen receptor α by molecular docking

Article abstract of DOI:10.1039/c6nj00782a

Diepoxydized diphenyls from eugenol, 4-vinyl guaiacol and 4-vinyl syringol (canolol) were synthesized as sustainable alternatives to the diglycidyl ether of bisphenol A (DGEBA). In the first step, glycidylated derivatives were produced by reaction with epichlorohydrin. Then, the dimerization of these derivatives was performed by cross metathesis (CM) reaction in the presence of the Grubbs II catalyst. From the CM reaction, a set of epoxy phenolic dimers was obtained in good yields with a high diastereoselectivity. Estimation by molecular docking calculations of the affinity of the synthesized products and their hydrolysed structures to the intranuclear estrogen receptor ERα showed that the epoxy forms presented a moderate affinity to the antagonistic conformation of the receptor (six to forty times lower than bisphenol A and in the same order of magnitude as DGEBA) and mostly no binding in the agonist conformation. The hydrolysed forms of the epoxy products, which are expected to be predominant in the human body cells, exhibited a relatively weak affinity to the ERα LBD in its both agonistic and antagonistic conformations.

Full text of DOI:10.1039/c6nj00782a

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DOI: 10.1039/C6NJ00782A
Synthesis of bio-based epoxy monomers from
natural allyl- and vinyl phenols and the
estimation of their affinity to the estrogen
receptor α by molecular docking.
Erika Zago a, Eric Dubreucq b, Jérôme Lecomte a, Pierre Villeneuve a, Frédéric Fine c, Hélène
Fulcrand d and Chahinez Aouf d*
a: Centre de Coopération Internationale en Recherche Agronomique et Développement, CIRAD,
UMR IATE, F-34398 Montpellier, France.
b: Montpellier SupAgro, UMR IATE, F-34060 Montpellier, France.
c: Terres Inovia, 11 rue Monge, 33600 Pessac, France.
d: Institut National de Recherche Agronomique, INRA, UMR SPO 1083, F-34060 Montpellier,
France.
Corresponding Author
*Email: aouf@supagro.inra.fr. Phone: +33 (0) 499612454.
1

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ABSTRACT:
Diepoxydized diphenyls from eugenol, 4-vinyl guaiacol and 4-vinyl syringol (canolol) were
synthesized as sustainable alternatives to the diglycidyl ether of bisphenol A (DGEBA). In a first
step, glycidylated derivatives were produced by reaction with epichlorohydrin. Then, the
dimerization of these derivatives was performed by cross metathesis (CM) reaction in the
presence of Grubbs II catalyst. From the CM reaction, a set of epoxy phenolic dimers was
obtained in good yields with a high diastereoselectivity. Estimation by molecular docking
calculations of the affinity of the synthesized products and their hydrolysed structures to the
intranuclear estrogen receptor ERα showed that the epoxy forms presented a moderate affinity to
the antagonistic conformation of the receptor (six to forty times lower than bisphenol A and in
the same order of magnitude as DGEBA) and mostly no binding in the agonist conformation.
The hydrolysed forms of the epoxy products, which are expected to be predominant in the human
body cells, exhibited a relatively weak affinity to the ERα LBD in its both agonistic and
antagonistic conformations.
KEYWORDS: epoxy monomers, natural polyphenols, cross metathesis, bioactivity.
INTRODUCTION
Bisphenol A (BPA) is one of the highest volume chemicals produced worldwide, with 6.3
million metric tons produced in 2010 and a 6-10% growth in demand expected per year1. This
petroleum-based product is classified as an endocrine-disruptor. It can interact with the ligand
binding domain (LBD) of several nuclear hormone receptors such as estrogen, androgen and
thyroid hormone receptors2, giving rise to disorders in downstream signalling pathways. Because
2

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nuclear receptors regulate the expression of a large number of genes, BPA is suspected to have
profound effects on organisms. Indeed, this chemical has been associated to diseases such as
cancer, osteoporosis and obesity2, 3 The current concerns surrounding BPA began in the early
1990s when researchers from Stanford University realized that the chemical was migrating from
the plastic laboratory bottles into the water they were using4. Nowadays, exposure to bisphenol A
is proven to be nearly universal. Indeed, a recent study has reported that BPA was detected in the
urine samples from 92.6% of the population in USA5 .Consequently, responding to expressions
of public concern and pressure from certain media, some countries such as Canada, France and
some US states decided to ban BPA from baby bottles and to extend this prohibition to all food
and beverage containers6, 7.
However, no one can overlook the excellent properties of BPA which allowed it to become a key
ingredient in several polymer and non-polymer processes. Indeed, this compound is mainly used
for the production of polycarbonate resins (71%), epoxy resins (27%), unsaturated polyesters,
polysulfone, polyetherimide and polyarylate resins8, 9. In the epoxy resins industry,
manufacturers are producing a very large variety of products bearing different properties from a
single molecule, the diglycidyl ether of BPA (DGEBA). Indeed, in combination with a judicious
selection of curing agents and appropriate modifiers, epoxy resins can be specifically tailored to
fit a broad range of applications10-13. For example, cured epoxy resin is used for coatings such as
corrosion protectors, lacquers in the automotive industry, housings for electrical equipment,
laminates, industrial floorings, construction parts, adhesives as well as in dental products14-16
.
This broad range of applications is related to the characteristic properties that BPA chemical
structure provides. Indeed, this aromatic, bulky diol affords excellent thermal, mechanical,
optical and electrical properties, especially upon incorporation into polymers11, 17
.
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Therefore, scientists face a dilemma as, on one hand they need to substitute this hazardous fossil-
based product, and on the other hand, the high performance of BPA must be preserved. In the
present work, we describe the synthesis of some epoxidized phenolic compounds, which could
represent a bio-based alternative to DGEBA. Thus, natural phenolic compounds bearing alkenyl
chain on their aromatic ring have first undergone a glycidylation reaction to introduce the epoxy
group. Then, the resulting products were dimerized through the cross metathesis (CM) coupling,
producing diglycidylated diphenyl compounds. The resulting epoxy monomers exhibit a
structural similarity with DGEBA, which will undoubtedly lead to approach the versatile
properties of this latter. However, care must be taken to ensure that these new compounds do not
show comparable health effects as BPA. Hence, the second part of this work was dedicated to the
assessment of the affinity of the synthesized diphenyls and some of their derivatives to the
intranuclear estrogen receptor ERα by means of molecular docking simulations. This would give
indications on the potential relative risks associated to the various structures obtained and
represent a crucial step before epoxy resins production. Three natural phenolic compounds were
selected for this study: eugenol (4-allyl guaiacol) 1, 4-vinylguaiacol 2 and canolol (4-
vinylsyringol) 3 (scheme 1). Eugenol 1 is a phenylpropene, mainly extracted from clove oil
(80%)18 and widely used in food, pharmaceutical, cosmetic and active packaging applications 18,
19. 4-vinyl guaiacol 2, a styrene type molecule, is a valuable starting material for fragrances,
flavours, oxygenated biodegradable polymers and is an intermediate for organic synthesis20. This
molecule is produced by the either bio-catalytic or thermal decarboxylation of ferulic acid21, 22, a
hydroxycinnamic acid widely present in the cell wall of several cereal grains23, 24. A few years
ago, canolol 3 was isolated from crude rapeseed oil and identified as the decarboxylation product
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of sinapic acid25, 26. Canolol 3 is mainly formed under high temperatures arising during rapeseed
processing 27 and is of interest for the food industry due to its flavour and antioxidant property28.
The relative abundance of the biomass-derived compounds 1, 2 and 3 prompted us to consider
them as starting materials in the synthesis of bio-based epoxy monomers.
Scheme 1: Chemical structures of compounds 1, 2 and 3.
EXPERIMENTAL
Chemicals
Eugenol (99%), syringaldehyde (≥98%), vanillin (99%), malonic acid (99%), piperidine
(≥99.5%), sodium carbonate (≥99.5%), epichlorohydrin (99%), sodium hydroxide (≥98%),
benzyltriethylammonium chloride (≥98.0%), Grubbs II catalyst, dichloromethane (≥99.5)%,
N,N-dimethylformamide (99.8%) were purchased from Sigma-Aldrich France.
Methods
All the reactions were monitored by TLC performed on pre-coated silica gel 60 F254 plates
purchased from Merck (Germany).
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Excepted for 3, all compounds were dissolved in DMSO-d6 and analysed using an Agilent
VNRMS DD2 500MHz spectrometer, operating at 500.05 MHz for 1H and 125.75 MHz for 13C,
using a 5mm indirect detection Z-gradient probe. The chemical shifts were reported to that of
1
internal DMSO at 2.5 ppm and 39.5 ppm for H and 13C respectively. Assignments of both
proton and carbon resonances, identification and structure characterization of products were
1
performed using 1D and 2D NMR spectrum analyses using homonuclear H and heteronuclear
1H/13C experiments. Data were processed and analysed using both VNMRJ and ACD/Labs
software. Compound 3 in solution in CDCl3 was analysed on a Bruker 600 MHz spectrometer,
1
operating at 600 MHz for H and 150 MHz for 13C. Chemical shifts were referenced using
residual internal CHCl3 signals at 7.26 ppm and 77.0 ppm for 1H and 13C respectively.
Melting points were measured on Stuart SMP10 apparatus. Samples were heated with a rate of
20 °C per minute to plateau, then 2 °C per minute to melt.
Computational structural analysis of interactions with estrogen receptors
The protein structure of the complex of the human estrogen receptor alpha (hER alpha) ligand-
binding domain recognition bound either to agonist diethylstilbestrol and a peptide derived from
the NR box II region of the coactivator GRIP1 (PDB accession code: 3ERD) or to the antagonist
4-hydroxytamoxifen (PDB accession code: 3ERT) were downloaded from the RCSB Protein
Data Bank [http://www.pdb.org]. Ligands were drawn and converted to 3D structures using
Marvin
Sketch
15.4.6.0
[ChemAxon
(2015)
http://www.chemaxon.com].
Docking simulations were carried out using Autodock Vina 1.1.229 within UCSF Chimera
version 1.10.130 , using the default options for receptor’s and ligand’s preparation scripts and for
docking parameters. The maximum number of binding modes was set to 10, with a maximum
energy difference of 3 kcal•mol-1.
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Docking coordinates were determined through a centered grid box enclosing the whole ligand-
binding domain. Interactive visualization, analysis and imaging of molecular structures were
performed using UCSF Chimera. The computations were performed on a PC with a 17-4650U
Intel CPU and 8 GB RAM, running 64 bits Windows 8.1 Professional.
Synthesis of 4-vinylguaiacol 2 and canolol 3
Vanillin (3-methoxy-4-hydroxybenzaldehyde) and syringaldehyde (3,5-dimethoxy-4-
hydroxybenzaldehyde) were used as 4-vinyl-guaiacol and canolol precursors respectively. In a
100 mL round bottom flask were added 20 mL of toluene, 5 mmol of 4-hydroxybenzaldehyde
derivative, 7.5 mmol of malonic acid and 25 mmol of piperidine. The reaction medium was kept
under stirring and heated to reflux (115 °C) until the total solubilisation of the reagents. The
kinetics of the reactions were followed by TLC-densitometry at 280 nm, using a CAMAG TLC
scanner 3 (Muttenz, Switzerland). The conversion of vanillin into 4-vinyl guaiacol and
syringaldehyde into canolol required respectively 100 min and 240 min. After completion of the
reaction, the medium was cooled down to room temperature and the solvent was evaporated at
reduced pressure. In order to eliminate any trace of piperidine, the crude product was washed
twice with 20 mL of toluene followed by vacuum drying until complete solvent removal.
The products were purified by silica gel chromatography using petroleum ether/ethyl acetate
(70:30, v/v) as the mobile phase to yield:
2-methoxy-4-vinylphenol (4-vinylguaiacol) 2: dark yellow oil, 74% yield (3.70 mmol). 1H NMR
(500 MHz, DMSO-d6) δ = 3.79 (s, 3H, Me), 5.06 (d, J= 11.1 Hz, 1H, H8), 6.63 (d, J= 16.8 Hz,
1H, H8), 6.61 (dd, J= 17.6, 10.9 Hz, 1H, H7), 6.72 (d, J= 8.1 Hz, 1H, H5), 6.85 (d, J= 8.1 Hz,
1H, H6), 7.04 (s, 1H, H3), 9.07 (s, 1H, OH) ppm. 13C NMR (125 MHz, DMSO-d6) δ = 55.3
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(Me), 109.4 (C3), 110.7 (C8), 115.02 (C6), 119.4 (C5), 128.5 (C4), 136.3 (C7), 146.3 (C1),
147.6 (C2) ppm. C9H10O2 calcd. C 71.98, H 6.71; found. C 72.08, H 6.60.
2,6-dimethoxy-4-vinylphenol (canolol) 3: dark green oil, 47% yield (2.35 mmol). 1H NMR (600
MHz, CDCl3) δ = 3.91 (s, 6H, Me), 5.15 (d, J= 10.9 Hz, 1H, H8), 5.53 (s, 1H, OH), 5.60 (d, J=
17.5 Hz, 1H, H8), 6.62 (dd, J= 17.5, 10.9 Hz, 1H, H7), 6.65 (s, 1H, H3,H5) ppm. 13C NMR (150
MHz, CDCl3) δ = 56.7 (Me), 103.3 (2C, C3 and C5), 112.0 (C8), 129.5 (C4), 135.3 (C1), 137.1
(C7), 147.5 (2C, C2 and C6) ppm.C10H12O3 calcd. C 66.65, H 6.54; found. C 66.42, H 6.54.
General procedure for the glycidylation of phenolic compounds
A 250 mL two-necked round bottom flask equipped with a condenser, a Teflon septum cap and a
magnetic stirring bar was charged with 1 g of 1, 2 or 3 in epichlorohydrin (4 molar eq). The
suspension was then heated to 100°C and benzyltriethylammonium chloride (BnEt3NCl, 0.05
molar eq) was added. After 90 min, the resulting mixture was cooled down to 30°C and an
aqueous solution of NaOH 200 g•L-1 (2 molar eq) containing the same previous amount of phase
transfer catalyst (BnEt3NCl) was added. The reaction medium was stirred vigorously for 90 min.
The organic layer was separated, dried over anhydrous MgSO4 and concentrated under vacuum.
The crude product was purified by silica gel chromatography using petroleum ether/ethyl acetate
(70:30, v/v) to yield the following products:
From 1:
2-((4-allyl-2-methoxyphenoxy)methyl)oxirane 4: colourless oil, 84% yield (5.12 mmol). 1H NMR
(500 MHz, DMSO-d6) δ = 2.67 (dd, J= 5.1, 2.7 Hz, 1H, Hγ'), 2.82 (m, 1H, Hγ ), 3.29-3.30 (m,
2H, H7 and Hβ), 3.75 (s, 3H, Me), 3.77 (m, 1H, Hα'), 4.24 (dd, J= 11.3, 2.7 Hz, 1H, Hα), 5.04
(dd, J= 12.5, 8.0 Hz, 2H, H9), 5.93 (tdd, J= 16.8, 10.0, 6.8 Hz, 1H, H8), 6.68 (d, J= 8.1 Hz, 1H,
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H5), 6.80 (s, 1H, H3), 6.87 (d, J=8.1 Hz, 1H, H6) ppm. 13C NMR (125 MHz, DMSO-d6) δ =
39.3(C7), 44.0 (Cγ), 50.0 (Cβ), 55.6 (Me), 70.2 (Cα), 112.7 (C3), 113.9 (C6), 115.7 (C9), 120.3
(C5), 133.1 (C4), 138.0 (C8), 146.2 (C1), 149.1 (C2) ppm. C13H16O3 calcd. C 70.89, H 7.32;
found. C 70.57, H 7.21.
From 2:
2-((2-methoxy-4-vinylphenoxy)methyl)oxirane 5: light yellow solid (MP = 129°C), 80% yield
(5.32 mmol). 1H NMR (500 MHz, DMSO-d6) δ = 2.68 (dd, J= 5.0, 2.6 Hz, 1H, Hγ'), 2.83 (m,
1H, Hγ ), 3.32 (qd, J= 6.8, 3.1 Hz, 1H,Hβ), 3.78-3.82 (m, 1H, Hα'), 3.71 (s, 3H, Me), 4.27 (dd,
J= 11.3, 2.7 Hz, 1H, Hα), 5.13 (d, J= 11.0 Hz, 1H, H8), 5.74 (d, J= 17.6 Hz, 1H, H8), 6.65 (dd,
J= 17.6, 11.0 Hz, 1H, H7), 6.92 (d, J= 8.3 Hz, 1H, H5), 6.94 (d, J=8.3 Hz, 1H, H6), 7.11 (s, 1H,
H3) ppm. 13C NMR (125 MHz, DMSO-d6) δ = 43.8 (Cγ), 49.7 (Cβ), 55.4 (Me), 69.8 (Cα), 109.3
(C3), 112.2 (C8), 113.1 (C6), 119.1 (C5), 130.7 (C4), 136.4 (C7), 147.7 (C1), 149.0 (C2) ppm.
C12H14O3 calcd. C 69.88, H 6.84; found. C 69.98, H 6.96.
From 3:
2-((2,6-dimethoxy-4-vinylphenoxy)methyl)oxirane 6: light green solid (MP = 138°C), 90% yield
(5.0 mmol). 1H NMR (500 MHz, DMSO-d6) δ = 2.56 (dd, J= 5.1, 2.7 Hz, 1H, Hγ'), 2.73 (m, 1H,
Hγ ), 3.24 (dt, J= 6.8, 2.9 Hz, 1H,Hβ), 3.74 (dd, J= 11.5, 6.5 Hz, 1H, Hα'), 3.80 (s, 6H, Me), 4.07
(dd, J= 11.5, 3.0 Hz, 1H, Hα), 5.21 (d, J= 11.0 Hz, 1H, H8), 5.80 (d, J= 17.6 Hz, 1H, H8), 6.66
(dd, J= 17.6, 11.0 Hz, 1H, H7), 6.79 (s, 2H, H5 and H3) ppm. 13C NMR (125 MHz, DMSO-d6) δ
= 43.3 (Cγ), 50.3 (Cβ), 56.0 (Me), 63.9 (Cα), 103.5 (2C, C3 and C5), 113.7 (C8), 133.0 (C4),
136.3 (C7), 136.7 (C1), 153.0 (2C, C2 and C6) ppm. C13H16O4 calcd. C 66.09, H 6.83; found. C
65.88, H 6.62.
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General procedure for 4, 5 and 6 dimerization by cross metathesis
A mixture of 4, 5 or 6 (1 mmol) and Grubbs II catalyst (5 mol%, 0.05 mmol) in CH2Cl2 (1 mL)
was heated at 42°C under argon for 48 h. The mixture was concentrated under vacuum. The
residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (50:50,
v/v) to give the following products:
From 4:
4,4'-(but-2-ene-1,4-diyl)bis(2-methoxyphenol) 7: light yellow solid (MP = 234°C), 56% yield
1
(0.28 mmol). H NMR (500 MHz, DMSO-d6) δ = 2.67 (dd, J= 5.1, 2.7 Hz, 1H, Hγ'), 2.82 (m,
1H, Hγ ), 3.26 (d, J= 4.8 Hz, 2H,H7), 3.30 (td, J= 9.4, 4.8 Hz, 1H, Hβ), 3.73 (s, 3H, Me), 3.76
(dd, J= 11.0, 6.4 Hz, 1H, Hα´),4.23 (dd, J= 11.4, 2.7 Hz, 1H, Hα), 5.63 (t, J= 3.8 Hz, 1H, H8),
6.66 (d, J= 8.2 Hz, 1H, H5), 6.79 (s, 1H, H3), 6.86 (d, J= 8.2 Hz, 1H, H6) ppm. 13C NMR (125
MHz, DMSO-d6) δ = 37.8 (C7), 43.9 (Cγ), 50.0 (Cβ), 55.5 (Me), 70.2 (Cα), 112.6 (C3), 114.0
(C6), 120.2 (C5), 130.4 (C8), 133.9 (C4), 146.1 (C1), 149.1 (C2) ppm. C24H28O6 calcd. C 69.88,
H 6.84; found. C 69.73, H 6.68.
4,4'-(ethene-1,2-diyl)bis(2-methoxyphenol) 8: light yellow solid (MP = 263°C), 10% yield (0.05
mmol). 1HNMR (500 MHz, DMSO-d6) δ = 2.70 (dd, J= 5.0, 2.6 Hz, 1H, Hγ'), 2.85 (m, 1H, Hγ ),
3.34 (m, 1H,Hβ), 3.82 (dd, J= 10.0, 5.1 Hz, 1H, Hα´), 3.84 (s, 3H, Me), 4.30 (dd, J= 11.4, 2.7
Hz, 1H, Hα), 6.95 (d, J= 8.3 Hz, 1H, H6), 7.05 (d, J= 8.3 Hz, 1H, H5), 7.08 (s, 1H, H7), 7.23 (s,
13
1H, H3) ppm. C NMR (125 MHz, DMSO-d6) δ = 43.0 (Cγ), 49.3 (Cβ), 54.9 (Me), 69.3 (Cα),
109.0 (C3), 112.7 (C6), 118.8 (C5), 125.8 (C7), 130.3 (C4), 146.7 (C1), 148.6 (C2) ppm.
C22H24O6 calcd. C 68.74, H 6.29; found. C 68.52, H 6.18.
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2,2'-(4,4'-(prop-1-ene-1,3-diyl)bis(2-methoxy-4,1-phenylene))bis(oxy)bis(methylene)dioxirane 9:
yellow solid (MP = 237°C), 14% yield (0.07 mmol). 1HNMR (500 MHz, DMSO-d6) δ = 2.67 (m,
2H, Hγ'), 2.83 (m, 1H, Hγ ), 3.32 (m, 2H,Hβ), 3.43 (d, J= 6.4 Hz, 2H, H9), 3.75 (m, 2H, Hα´),
3.77 (s, 3H, Me),3.78 (s, 3H, Me), 4.26 (dd, J= 11.0, 2.7 Hz, 1H, Hα), 6.31 (m, 1H, H8), 6.37 (d,
J= 15.8 Hz, 1H, H7), 6.74 (d, J= 8.0 Hz, 1H, H5B), 6.87-6.91 (m, 4H, H5A, H6A, H6B and H3B),
7.05 (s, 1H, H3A) ppm. 13C NMR (125 MHz, DMSO-d6) δ = 38.0 (C9), 43.5 (2C, Cγ), 49.5 (2C,
Cβ), 55.2 (2C, Me), 69.5 (2C, Cα), 108.9 (C3A), 112.2 (C3B), 113.0 (C6A), 113.4 (C6B), 118.6
(C5A), 120.0 (C5B), 127.5 (C8), 129.5 (C7), 133.2 (2C, C4A and C4B), 145.8 (C1B), 146.8 (C1A),
148.7 (C2B), 148.8 (C2A) ppm. C23H26O6 calcd. C 69.33, H 6.58; found. C 69.08, H 6.13.
From 5:
8: 76% yield (0.38 mmol).
From 6:
4,4'-(ethene-1,2-diyl)bis(2,6-dimethoxyphenol) 10: light yellow solid (MP = 291°C), 78% yield
(0.39 mmol). 1HNMR (500 MHz, DMSO-d6) δ = 2.58 (dd, J= 5.0, 2.7 Hz, 1H, Hγ'), 2.75 (m, 1H,
Hγ ), 3.25 (dt, J= 6.8, 2.9 Hz, 1H,Hβ), 3.76 (dd, J= 11.5, 6.5 Hz, 1H, Hα´), 3.84 (s, 6H, Me),
4.10 (dd, J= 11.5, 2.9 Hz, 1H, Hα), 6.92 (s, 2H, H3 and H5), 7.18 (s, 1H, H7) ppm. 13C NMR
(125 MHz, DMSO-d6) δ = 43.3 (Cγ), 50.3 (Cβ), 55.9 (Me), 74.0 (Cα), 103.6 (2C, C3 and C5),
127.9 (C7), 133.0 (C4), 136.0 (C1), 153.0 (C2) ppm. C24H28O8 calcd. C 64.85, H 6.35; found. C
65.06, H 6.19.
Coupling of 4 with 5, 4 with 6 and 5 with 6 by cross metathesis
A mixture (0.5 mmol each) of 4 and 5, 4 and 6 or 5 and 6 with 0.025 mmol (5 mol%) Grubbs II
catalyst in 1 mL CH2Cl2 was heated at 42°C under argon for 48 h. The solvent was evaporated
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under vacuum. The crude product was purified by silica gel chromatography using petroleum
ether/ethyl acetate (45:55, v/v) mixture to give the following products:
From 4 + 5:
9 (36% yield, 0.09 mmol) and 7 (10% yield, 0.025 mmol) and 8 (44% yield, 0.11 mmol).
From 4 + 6:
((2,6-dimethoxy-4-(3-(3-methoxy-4-(oxiran-2-ylmethoxy)phenyl)prop-1-
enyl)phenoxy)methyl)oxirane 11: light yellow solid (MP = 234°C), 48% yield (0.12 mmol).
1HNMR (500 MHz, DMSO-d6) δ = 2.55 (dd, J= 5.2, 2.7 Hz, 1H, Hγ'), 2.67 (dd, J= 5.0, 2.6 Hz,
1H, Hγ´), 2.72 (m, 1H,Hγ), 2.82 (m, 1H, Hγ), 3.23 (m, 1H, Hβ), 3.30 (m, 1H, Hβ), 3.44 (d, J=
5.1 Hz, 2H, H9), 3.71 (dd, 2H, Hα´), 3.76 (s, 3H, Me), 3.77 (s, 6H, Me), 4.05 (dd, J= 11.4, 3.0
Hz, 1H, Hα), 4.24 (dd, J= 11.3, 2.5 Hz, 1H, Hα), 6.38 (s, 2H, H7 and H8), 6.71 (s, 2H, H3A and
13
H5A), 6.73 (d, J= 8.2 Hz, 1H, H5B), 6.86 (s, 1H, H3B), 6.90 (d, J= 8.2 Hz, 1H, H6B) ppm. C
NMR (125 MHz, DMSO-d6) δ = 37.8 (C9), 42.8 (CγA), 43.2 (CγB), 49.4 (CβA), 49.7 (CβB), 55.3
(MeB), 69.5 (CαB), 73.4 (CαA), 55.3 (2C, MeA), 103.0 (2C, C3A and C5A), 112.4 (C3B), 113.2
(C6B), 120.0 (C5B), 128.7 (C8), 129.8 (C7), 132.7 (C4A), 132.8 (C4B), 145.2 (C1A), 145.7 (C1B),
148.5 ( C2B), 152.4 (2C, C2A and C6A)ppm. C24H28O7 calcd. C 67.28, H 6.59; found. C 66.90, H
6.28.
7 (16% yield, 0.04 mmol) and 10 (16% yield, 0.04mmol)
2-((2,6-dimethoxy-4-(3-methoxy-4-(oxiran-2-ylmethoxy)styryl)phenoxy)methyl)oxirane 12: light
1
yellow solid (MP = 278°C), 5% yield (0.012 mmol). HNMR (500 MHz, DMSO-d6) δ = 2.57
(dd, J= 5.0, 2.6 Hz, 1H, Hγ'A), 2.70 (dd, J= 5.0, 2.6 Hz, 1H, Hγ´B ), 2.74 (m, 1H,HγA), 2.84 (m,
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1H, HγB), 3.25 (m, 1H, HβA), 3.34 (m, 1H, HβB), 3.75 (dd, J= 11.5, 6.5 Hz, 1H, Hα´A),3.82 (m,
1H, Hα´B), 3.83 (s, 6H, MeA), 3.85 (s, 3H, MeB), 4.10 (dd, J= 11.6, 3.0 Hz, 1H, HαA), 4.30 (dd,
J= 11.4, 2.7 Hz, 1H, HαB), 6.90 (s, 2H, H5A and H3A), 6.96 (d, J= 8.3 Hz, 1H, H6B), 7.07 (d, J=
13
8.7 Hz, 1H, H5B), 7.10 (d, J= 16.3Hz, 2H, H7 and H8), 7.24 (s, 1H, H3A) ppm. C NMR (125
MHz, DMSO-d6) δ = 43.0 (CγA), 43.5 (CγB), 49.3 (CβB), 50.0 (CβA), 55.1 (MeB), 55.5 (2C,
MeA), 69.6 (CαB), 73.6 (CαB), 103.1 (2C, C3A and C5A), 108.9 (C3B), 112.9 (C6B), 119.2 (C5B),
126.1 (C7), 127.5 (C8), 130.3 (C4B), 132.8 (C4A), 135.4 (C1A), 147.1 (C1B), 148.3 (C2B), 152.6
(2C, C2A and C6A) ppm. C23H26O7 calcd. C 66.65, H 6.32; found. C 67.02, H 6.63.
From 5 + 6:
12 (30% yield, 0.075 mmol) and 10 (33% yield, 0.082 mmol) and 8 (24% yield, 0.06 mmol).
RESULTS AND DISCUSSION
Diglycidyl ether of BPA (DGEBA) is synthesized by reaction of bisphenol A with
epichlorohydrin. Structurally, it consists of two aromatic derivatives each bearing a methyl
oxirane group. In order to reach a similar chemical structure and to synthesize a wide range of
potential DGEBA substitutes, the following synthetic strategy was adopted: i) the O-
glycidylation of compounds 1, 2 and 3 by epichlorohydrin. ii) the homo- and heterodimerization
of compounds 4, 5 and 6 assisted by the cross metathesis (CM) reaction.
Synthesis of 4-vinyl guaiacol 2 and canolol 3
Contrary to eugenol 2, which is commercially available with a relatively low price ($ 5 Kg-1)31,
4-vinyl guaiacol 2 and canolol 3 had to be prepared. To avoid the time-consuming extraction and
purification from biomass for this laboratory-scale study, these compounds were synthesized
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according to the procedure described by Simpson et al32, using vanillin and syringaldehyde as
precursors respectively. The reported reaction based on Knoevenagel-Doebner condensation
afforded 4-vinyl guaiacol 2 and canolol 3 in 74% and 47% yields respectively (scheme 2). In
spite of the total conversion of syringaldehyde into canolol 3, the latter was isolated in relatively
low yield. This arose from the rapid degradation of the canolol crude product during the
purification step, as indeed this product has proved to be air and light sensitive.
Scheme 2: 4-vinyl guaiacol 2 and canolol 3 synthesis.
O-glycidylation reaction of compounds 1, 2 and 3
Based on our previous studies related to the production of bio-based epoxy polymers33, 34; the O-
glycidylation reaction of compounds 1, 2 and 3 was carried out using epichlorohydrin in alkaline
medium. It is worth mentioning that the use of bio-based epichlorohydrin, commercially
available from DOW or Solvay35 might strengthen the sustainability of the process.
In alkaline medium and in the presence of a catalytic amount of BnEt3NCl, a large excess of
epichlorohydrin was reacted with compounds 1, 2 and 3 to give the glycidylated derivatives 4, 5
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and 6 respectively (scheme 3). The substitution of the phenolic hydroxyl proton by the methyl
oxirane group was clearly established by 1H NMR analysis. Indeed, the disappearance of signals
corresponding to the phenolic hydroxyl protons was accompanied by the occurrence of several
aliphatic signals arising from the glycidyl group. The methylene and methyne ring proton signals
appear in the 2.55-2.84 ppm and 3.23-3.32 ppm ranges respectively and the CH2–O protons give
resonance signals in the 3.67-4.30 ppm spectral range.
Scheme 3: The O-glycidylation reaction of compounds 1, 2 and 3.
Cross metathesis reactions of compounds 4, 5 and 6
The CM dimerization of the glycidylated derivatives 4, 5 and 6 was carried out in refluxing
CH2Cl2, in the presence of 5 mol% of Grubbs II catalyst (C46H65Cl2N2PRu) during 48 h. In order
to produce differently substituted diphenyls, CM reactions of 4 with 5, 4 with 6 and 5 with 6
were also performed under the same reaction conditions. The reaction products are summarised
in both table 1 and scheme 4.
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As shown in scheme 4, three kinds of linkages resulted from the CM reactions of 4, 5 and 6:
“allyl-allyl” (compound 7), “vinyl-vinyl” (compounds 8, 10 and 12) and “vinyl-allyl”
(compounds 9 and 11).
1
Depending on the linkage type, the H NMR signals arising from the olefinic protons of the
intercyclic chain exhibited different patterns and chemical shifts. The structural characterisation
of all dimer products was performed from several NMR 1D and 2D analyses which allowed all
1H and 13C resonances to be assigned. The spectra showed that, for each dimer, only one
stereoisomer was formed since only one set of signals could be observed. The determination of
the double bond relative configuration was only possible for dimers 9, 11 and 12, for which the
olefinic proton coupling constants were found to be equal to ~16Hz, a value characteristic of an
E configuration. In molecules 7, 8 and 10, the olefinic protons are chemically and magnetically
equivalent, precluding the olefinic coupling constant measurements and consequently the
determination of the geometric configuration of the double bond. According to the computational
study of Bahri-Laleh et al.36 on the origin of the Z-E selectivity of the CM reaction, it has been
established that the (E)-stereoisomers are preferentially formed. Indeed, the transition state
leading to the formation of the (Z)-stereoisomer is of similar energy or even favoured, relative to
that leading to the (E)-stereoisomer. Thus, the CM reaction should kinetically lead first to the
formation of the (Z)-stereoisomer, which is gradually converted into the more stable (E)-
stereoisomer. However, the key step to rationalize the preferential formation of the (E)-
stereoisomer is the product releasing step, since the (E)-stereoisomer has a higher tendency to be
released from the catalyst at the end of the CM reaction. In other words, all the (Z)-stereoisomers
remain linked to the catalyst until they are converted to (E)-stereoisomers and eventually
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released. Based on this study, it could be assumed that compounds 7, 8 and 10 were (E)-
stereoisomers.
Table 1: Products of the cross metathesis of the glycidylated derivatives 4, 5 and 6.
CM products
Entry
Monomers
Yield (%)
Homodimers
Heterodimers
56
10
14
76
78
44
10
36
16
16
48
5
7
8
i
4
9
ii
5
6
8
10
8
iii
iv
v
4+5
4+6
5+6
7
9
7
10
11
12
33
24
30
10
8
vi
12
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Scheme 4: cross metathesis products obtained from 4, 5 and 6.
As displayed in table 1 (entries ii and iii), the CM dimerization of 5 and 6 led to the
diglycidylated diphenyl products 8 and 10 respectively with approximately same yields (76%
and 78%). In the case of compound 4 (entry i), the CM reaction gave the expected homodimer 7
in the highest yield (56%) along with two dimers identified as 8 (10%) and 9 (14%). The
formation of these two unexpected dimers is very likely related to the double bound
isomerization of compound 4. Indeed, it is well known that ruthenium-based olefin metathesis
catalysts can isomerise double bonds37, 38. The mechanism leading to the formation of the
ruthenium-hydride species that are responsible for this isomerisation is discussed in detail in the
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literature39. Furthermore, this isomerisation activity is not specific to ruthenium; it may be
catalysed by several transition-metal complexes40. In the case of compound 4, the action of the
ruthenium catalyst, associated to the conjugated system created by the migration of the double
bond, favoured the partial conversion of 4 into 4a (scheme 5). The homodimerization of the
latter led to the formation of product 8, whereas diphenyl 9 was the heterodimer product arising
from the reaction of 4 and 4a. In both cases, prop-1-ene molecules are released.
Scheme 5: The partial isomerisation of 4 in the presence of the Ru-based catalyst.
In spite of this side reaction, the higher yield of homodimer 7 compared to those of diphenyls 8
and 9 implies that dimerization reaction occurs faster than double bond migration.
In addition to the homodimerization of 4, 5 and 6, each compound reacted with the other under
the CM reaction conditions cited above. Generally, the cross metathesis of two different alkenes
proceeds to yield three unique products: one desired heterodimeric product and two undesired
homodimeric products. This pattern was reproduced during the CM reaction of 5 with 6 (entry
vi) which produced heterodimer 12 in 30% yield along with homodimers 10 and 8 in 33% and
24% yield respectively. It was observed that both homodimer 10 and heterodimer 12 were
obtained with a similar yield, suggesting that the CM reaction was not very selective in this case.
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The cross coupling of 4 and 5 (entry iv) led to the formation of products 7, 8 and 9, i.e. the same
as those obtained from the CM reaction of 4, in 10%, 44% and 36% yield respectively. The
homodimer 8 was the most abundant product formed. This can be explained by the increase of
the proportion of 4ain the reaction medium due to the isomerization of compound 4 as explained
above.
The cross metathesis reaction between 4 and 6 gave the heterodimer product 11 in 48% yield,
beside homodimers 7 and 10 which were obtained in equal amounts (16% yield each). The
recovery of heterodimer 11 in the highest yield was in accordance with the literature data which
have shown that cross metathesis of alkenes bearing allylic (or more distant) groups gives mainly
unsymmetrical coupling products41. On the other hand, the isomerisation phenomenon did not
seem to be very significant in this case. Indeed, dimer 12 was formed in very low yield (5%) and
the product arising from the reaction of 4 with 4a (compound 9) was not observed.
In summary, the homodimerization of the glycidylated derivatives 4, 5 and 6 led to the
corresponding symmetrical dimers 7, 8 and 10 respectively in good yields and high
diastereoselectivity. During the CM of compound 4, double bond isomerisation occurred, leading
also to the heterodimer 9. By cross coupling 6 with both 4 and 5, two new dimers (11 and 12
respectively) were obtained in fair yields. Before envisioning the epoxy resins production from
the synthesized diphenyl (which will be a subject of a future study), it seems worth to assess their
safety. Indeed, the structural similarities between DGEBA and the synthesized epoxy precursors
bring up questions about the possible bioactivity of the latter. Hence, we conducted a
computational study to estimate the affinity of these compounds and the substrates that they
originated from (phenols 1 to 3 and their glycidylated derivatives 4 to 6) toward the ligand
binding domain (LBD) of one of the most studied estrogen receptor for such cases, ERα.
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The affinity of the synthesized diphenyl ethers and some of their derivatives to the ERα
LBD
Estrogen receptor α (ERα), with 17-β-estradiol as a natural endogen ligand, regulates the
differentiation and maintenance of neural, skeletal, cardiovascular and reproductive tissues. All
ERα ligands bind exclusively to the C-terminal ligand binding domain. The LBD recognizes a
variety of compounds, diverse in their sizes, shapes and chemical properties. Some of these
ligands function as agonist, whereas others are antagonist42. When an agonist binds to ERα LBD,
the positioning of helix 12 (H12, in brown on figure 1) allows the formation of the coactivator
binding surface. In contrast, when an antagonist binds to LBD, the coactivator binding surface is
not formed because H12 is preventing from reaching its correct position43.
Using available three-dimensional structures of ERα LBD, estimates of the binding affinity of
the compounds of interest were calculated from the binding energy of best ligand-receptor
configurations obtained by molecular docking with either agonistic or antagonistic
conformations of the receptor. The study included phenolic compounds 1 to 3, their glycidylated
derivatives 4 to 6, as well as the CM products 7 to 12. It also involved all the structures resulting
from the hydrolysis of the glycidylated derivatives. Indeed, it is well known that, once penetrated
in the organism, epoxy groups are converted into diols by the action of epoxide hydrolases44, 45
.
Hence, epoxidized structures are supposed to be practically inexistent in the human body cells.
The chemical structures arising from the hydrolysis of the glycidylated compounds are depicted
in scheme 6. The hydrolysis of compounds 4, 5 and 6 would lead to derivatives 13, 14 and 15
respectively. Structures 16 to 21 correspond to the hydrolysis products of diglycidylated
diphenyls 7 to 12.
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OMe
MeO
OMe
OMe
O
O
O
OH
OH
OH
HO
HO
HO
13
14
15
OH
OH
HO
O
HO
O
MeO
O
OH
O
OH
HO
MeO
OMe
OMe
HO
16
17
OH
MeO
O
OH
OMe
O
HO
O
O
OH
OH
HO
OH
OMe
OMe
MeO
OMe
OH
18
19
OH
MeO
O
OMe
O
OH
HO
O
O
OH
HO
HO
OMe
OMe
OH
MeO
OMe
20
21
OH
Scheme 6: hydrolysis products of the glycidylated compounds.
Dissociation constants (Kd) of all the structures cited above are summarized in table 2. BPA
which has been proven to have an estrogenic effect was included in the calculations as a
reference. Interactions of DGEBA and its hydrolysis product with receptor LBD were also
evaluated.
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Table 2: the binding affinity of the different ligands to ERα LBD. Agonist and antagonist
interactions were computed using PDB structures 3ERD and 3ERT, respectively. Empty cells
indicated the absence of binding poses interfering with the ligand binding pocket or helix H12.
Compound
Dissociation constant Kd (μM)
Antagonist
1
Agonist
BPA
DGEBA
2
50*
40
-
20
7
10
7
8
7
-
-
9
10
11
12
30*
6
20*
-
40
10
Hydrolysed DGEBA
40*
-
30
16
17
18
19
20
21
1
2
3
4
5
50*
10
-
-
-
50*
40
100*
-
20
260*
220
130
30
110
40
40
40
40
30
40
50
40
300*
60
6
70
13
14
15
100
130*
*: these ligands are predicted to interact with helix H12 but not inside the ligand-binding pocket.
The results displayed in table 2 show that, except for compound 7, the diglycidylated diphenyls
(8 to 12) and their hydrolysed derivatives (17 to 21) are not predicted to bind to the agonistic
conformation of ERα LBD. In contrast, BPA shows a dual action as agonist and antagonist with
the same affinity (which is in accordance with literature data46).
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Compound 10 resulting from the CM reaction of the glycidylated canolol did not show a
significant affinity neither to the agonistic nor to the antagonistic conformations of the receptor.
Indeed, binding poses were predicted by the docking calculations with an affinity constant of 30
μM for the antagonistic conformation, but the molecule did not fit within the ligand-binding
pocket and was located between Helix 12 and the pocket. Docking the glycidylated compounds
8, 9, 11 and 12 showed a certain affinity as antagonists but weaker than that of BPA. For
instance, compounds 9 and 12 should be respectively 7-fold and 35-fold more concentrated than
BPA to reach a similar effect, according to these estimations.
Compound 7, produced from the glycidylated eugenol metathesis, exhibits a binding affinity to
both agonistic and antagonistic conformations of the receptor LBD, with a marked preference for
the antagonistic one. Compared to compound 10 (for which no relevant binding pose was found),
compound 7 shows a less hindered and a less constrained structure that may contribute to
facilitate its penetration in the ligand binding pocket of the receptor.
According to this computational study, the hydrolysis of the glycidylated diphenyls would
modify their respective binding affinities to the antagonistic conformation of the receptor.
Indeed, the binding affinities of compounds 8 and 11 become weaker after hydrolysis of their
epoxy groups, especially for compound 11, whereas, the oxirane ring opening of compound 12
would enhance its affinity (as antagonist) to the receptor. Interestingly, the tetrahydroxy
derivative generated from the hydrolysis of compound 7 was not found to bind to the agonistic
conformation of the receptor, while requiring a concentration 25 times higher than that of BPA to
bind to the receptor antagonist form. The only diphenyl that preserved its strong affinity to the
receptor antagonistic form after hydrolysis was compound 9. Indeed, as depicted in figures 1a
and 1b, the resulting compound 18 would partially penetrate the receptor binding pocket,
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adopting a similar configuration than that of 4-hydroxytamoxyfen (which is well known for its
ERα antagonistic activity). Excluding compound 18, if we assume that the diglycidylated
diphenyls are transformed into tetrahydroxy derivatives when penetrating the human organism,
these latter would show a weak activity towards ERα. On the other hand, the antagonistic
dissociation constant of compounds 17 and 19 (Kd = 50 µM) perfectly matches with the in vitro
estimated IC50 value of resveratrol47 (IC50 = 58.5 µM), a phenolic diphenyl with a similar
chemical structure as 17 and 19. This brings solid evidence on the computational study
efficiency.
Figure 1: a) antagonist configuration of human estrogen receptor ERα ligand-binding domain
(pdb structure 3ERT) in complex with compound 18. b) antagonist configuration of human
estrogen receptor ERa ligand-binding domain (pdb structure 3ERT) in complex with 4-
hydroxytamoxifen (orange) and compound 18 (green). Helix 12 is depicted in brown.
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Besides the final products, it was also worth evaluating the potential risk associated to the
exposure to the reactants (phenolic compounds 1 to 3), intermediates (glycidylated derivatives 4
to 6) and their hydrolysis products (13 to 15).
As shown in table 2, all these compounds display a potential agonist interaction with ERα LBD
but with binding affinities 15 to 50 times lower than that of BPA.
The same way, their predicted affinity for the receptor in the antagonist conformation is more
than 100 times lower than that of BPA, with the exception of the O-glycidylation products of
eugenol 1 (product 4) and canolol 3 (product 6) and the hydrolysis product of 4 (compound 13),
which affinities are higher but still 30 to 70 times lower than that of BPA.
CONCLUSIONS
In this work, we have provided a facile synthetic strategy for producing diglycidylated diphenyls
from renewable resources. The epichlorohydrin-assisted glycidylation of eugenol 1, 4-vinyl
guaiacol 2 and canolol 3, followed by the cross metathesis reaction of the glycidylated
derivatives converted the three natural phenolic compounds into a set of homo- and hetero-
phenolic dimers (7-12) in good yields and with a high diastereoselectivity. The bio-based
synthetized diphenyls comprise two aromatic rings each bearing a methyl oxirane group, which
make them good candidates for the substitution of DGEBA.
Molecular docking calculations of their binding to the ligand-binding domain of ERα suggested
that diglycidylated diphenyls 7 to 12 present a moderate affinity to the antagonistic conformation
of the receptor (6-40 times lower than that of BPA) . However, their hydrolysed forms, which are
expected to be predominant in the human organism, exhibit a relatively weak affinity towards
ERα LBD in its both agonistic and antagonistic conformations. Obviously, this computational
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approach could be used to give a first indication on the potential risk associated to the
synthesized dimers towards the endocrine receptor and must be consolidated and completed
through in vitro and in vivo tests. Compared to DGEBA, which is synthesised from BPA, all the
potential substitutes 7 to 12 proposed here are synthesised using reactants or intermediates with a
predicted affinity for the ERα LBD much lower than that of BPA. Although this has to be
confirmed by in vivo studies, this is, besides its bio-based character, another advantage of the
proposed synthesis.
Supporting information
1D and 2 D NMR spectra of all the synthesized products. This material is available free of
charge via the internet
ACKNOWLEDGEMENT
The authors are grateful to Christine Le Guernevé from INRA (Montpellier) for her assistance in
NMR characterizations.
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