Synthesis of new L-ascorbic ferulic acid hybrids

Article abstract of DOI:10.3390/12112533

A feasibility and chemical study of the coupling conditions of L-ascorbic acid with ferulic acid derivatives are described on the basis of the known synergistic effects of mixtures of various antioxidants. Novel L-ascorbic ferulic hybrids linked at the C-3 hydroxyl group were prepared with the aim to protect the alcohol function and the enediol system.

Full text of DOI:10.3390/12112533

Molecules 2007, 12, 2533-2545
molecules
ISSN 1420-3049
© 2007 by MDPI
www.mdpi.org/molecules
Full Paper
Synthesis of New L-Ascorbic Ferulic Acid Hybrids
Anne Sophie Voisin-Chiret, Marc-Antoine Bazin, Jean-Charles Lancelot and Sylvain Rault *
Université de Caen Basse-Normandie, U.F.R. des Sciences Pharmaceutiques, Centre d’Etudes et de
Recherche sur le Médicament de Normandie, UPRES EA-3915, 5, rue Vaubénard, 14032 CAEN
Cedex, France
* Author to whom correspondence should be addressed; E-mail: sylvain.rault@unicaen.fr;
Tel: +33 (0)2 31 93 64 58; Fax: +33 (0)2 31 93 11 88.
Received: 30 October 2007; in revised form: 15 November 2007 / Accepted: 15 November 2007 /
Published: 17 November 2007
Abstract: A feasibility and chemical study of the coupling conditions of L-ascorbic acid
with ferulic acid derivatives are described on the basis of the known synergistic effects of
mixtures of various antioxidants. Novel L-ascorbic ferulic hybrids linked at the C-3
hydroxyl group were prepared with the aim to protect the alcohol function and the enediol
system.
Keywords: Ascorbic acid, ferulic acid, hybridization, antioxidant, oxidative stress.
Introduction
Oxidative stress is thought to play an important contributory role in the pathogenesis of numerous
degenerative or chronic diseases, such as cancer. Besides, experimental evidence links the production
of reactive oxygen species to biological damage that can potentially provide a mechanistic basis for
their initiation and/or progression. For this reason we were especially interested in the use of
antioxidants in this context of photoprotection and we have already developed a synthesis program that
was aimed at the preparation of antioxidant trans-1,2-diarylethenes from cinnamic acids [1].

Molecules 2007, 12
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Under normal conditions, cells and tissues are protected from the attack of active oxygen species
and free radicals by various enzymes such as catalase, superoxide dismutase and glutathione
peroxidase [2-5].
In the experiments, corroborated in clinical studies on volunteers, L-ascorbic acid (1) protects
against photoperoxidation of serum lipids, membrane lipids and collagen and increases the
neosynthesis of collagens [6-10]. Moreover, L-ascorbic acid prevents against mutation and
immunosuppression (responsible for the skin becoming cancerous), and inflammation (through
reactive oxygen species) attributable to UV radiations [11-12]. Finally, L-ascorbic acid counteracts
skin aging in promoting collagen formation and in stimulating elastic fiber element synthesis [10].
Therefore, the protective effect of L-ascorbic acid allows considering it as one of the most potent
naturally occurring antioxidants.
These biological characteristic activities are derived from the enediol structure, with its strong
electron-donating ability. L-ascorbic acid is reversibly metabolized to dehydro-L-ascorbic acid (2) via
monodehydro-L-ascorbic acid in a series of oxidative processes (Scheme 1).
Scheme 1: L-Ascorbic acid (1) and dehydro-L-ascorbic acid (2).
HO
HO
6
5
6
5
2 H+
O
O
1
1
O
O
4
3
4
3
HO
HO
H
H
2
2
HO
OH
O
O
2
1
However, L-ascorbic acid loses its biological activities because of its reducing power, its low
stability under aqueous conditions and its high sensitivity to oxidation. The well-known susceptibility
of L-ascorbic acid to thermal and oxidative degradation has led to interest in its analogs with increased
in vitro stability, while maintaining the inherent in vivo biological activity. To overcome this problem,
L-ascorbic acid was chemically modified by protecting alcohol functions or the enediol system.
On the one hand, we were particularly interested in the chemical modifications of hydroxyl groups
in C-2 and C-3 positions of L-ascorbic acid so as to protect the enediol structure. Among these
derivatives, ascorbic acid/kojic acid and ascorbic acid/α-tocopherol hybrids 3 and 4 have been
described (Scheme 2) that were more stable and have shown biological properties of both ascorbic acid
and active substances [13].
In the same way, 2-O-α-D-glucopyranosylascorbic acid (5, Scheme 2) has good stability and the
same biological properties as L-ascorbic acid. This compound has been widely used in cosmetics for
its L-ascorbic acid-like activity [14-15]. Then, salts of ascorbyl 2-phosphoric esters, 6 (Scheme 2) have
been largely studied to be less sensitive than L-ascorbic acid after dephosphorylation [16-18].
On the other hand, several studies such as the one by Pinnell et al. [19] suggest that mixtures of
various antioxidants may have synergistic effects, yielding a greater efficiency than individual
antioxidant compounds used alone. In fact, Pinnell et al. have examined ferulic acid mixed with L-
ascorbic acid and α-tocopherol and have shown that this combination seemed to provide meaningful
synergistic protection against oxidative stress in skin. Although the hydroxycinnamic acids, as ferulic
acid, cafeic acid or p-coumaric acid, have been studied for their antioxidative potency which is related

Molecules 2007, 12
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to the structure, in particular to electron delocalization of the aromatic nucleus [20], the mechanism of
ferulic acid’s stabilizing effect on L-ascorbic acid and α-tocopherol is still unknown, and their
chemical linkage with L-ascorbic acid has never been studied previously.
Scheme 2: Ascorbic acid derivatives.
HO
HO
HO
HO
O
O
O
O
O
O
OH
HO
O
O
HO
OH
3
4
O
O
CH2OH
O
HO
HO
HO
HO
mMk+
M = Na, K, Ca, Mg, Al
OH
O
HO
O
P = PO32-, P2O63-, P3O9
k.m = 3, 4, 5
4-
H
O
OH
O
O
P
OH
O
5
6
O
Therefore, we decided to study hybridization methodology conditions to synthesize new L-ascorbic
acid/ferulic ester hybrids connected at the C-3 position, which is crucial for both stability and
biological activity, with a view to simultaneously improving the stability and preventing diminution of
activity (Scheme 3).
Scheme 3: L-ascorbic acid / ferulic ester hybrids 20, 21 and 22.
HO
O
O
HO
H
O
OH
HO
O
20, R = -CH3,
21, R = -CH2-CH3,
22, R = -(CH2)11-CH3
MeO
CO2R
So, this paper emphasizes a feasibility study concerning the coupling conditions via a glycidyl ether
spacer of L-acid ascorbic and ferulic derivatives and we realized a chemical study in order to prepare
compounds 20, 21 and 22.
At the beginning of our works, only mono- and di-esters of cinnamic acids 7 and L-ascorbic acid
(Scheme 4) have been prepared [21]. Nevertheless, the two patterns, cinnamic and L-ascorbic acids,
were linked at the C-2 hydroxyl group whereas the biologically active site was reported to be placed

Molecules 2007, 12
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on the C-3 hydroxyl group. It is the reason why we studied the synthesis of new hybrids linked at the
C-3 hydroxyl group via an ether spacer more stable than an ester group. So, we have chosen the
glycidyl ether methodology previously described by Morisaki [13] which moreover can offer a greater
molecular diversity.
Scheme 4: Ascorbic acid / cinnamic acid hybrids 7.
R4
O
O
O
HO
H
O
R1, R2, R3 = H, OH, OR
R1
R2
HO
O
R4 = H or COR5 and R5 = C1-C20 or R5 =
7
R3
R3
R1
R2
Even if L-ascorbic acid can be considered as one of the most potent naturally occurring
antioxidants, its high hydrophilicity limits this latter property. These hybrids have different lipophilic
properties than L-ascorbic acid (Table 1) which allows a good penetration into the stratum corneum. In
fact, they could be considered as excellent vehicles of L-ascorbic acid in which the length of the alkyl
chain modulates the octanol/water partition coefficient log Po/w (see hybrids 20, 21 and 22).
Table 1: Octanol/water partition coefficient log Po/w [22].
Compounds
L-ascorbic acid 1
Ferulic acid 9
Methyl ferulate 10
Ethyl ferulate 11
Dodecyl ferulate 13
Hybrid 20
Log Po/w
-2.34
1.86
2.60
2.94
6.97
-0.63
-0.23
3.75
Hybrid 21
Hybrid 22
Results and Discussion
Protection of the C-5 and C-6 positions of L-ascorbic acid
First of all, the hydroxyl groups at the C-5 and C-6 positions were protected with acetone in the
presence of acetyl chloride according to Jung’s procedure [23] to afford (R)-5-((S)-2,2-dimethyl-[1,3]-
dioxolan-4-yl)-3,4-dihydroxy-5H-furan-2-one (8) in 74% yield (Scheme 5).

Molecules 2007, 12
Scheme 5: Protection of the C-5 and C-6 positions of L-ascorbic acid.
2537
HO
O
O
H3C
H3C
O
O
O
O
i
HO
H
H
HO
OH
HO
OH
8
1
Reagents and conditions: i) CH3COCl 0.25 equiv., acetone, rt, 3h.
Synthesis of ethyl, methyl and dodecyl (2E)-3-(4-hydroxy-3-methoxyphenyl)acrylates 10, 11 and 13
The esterification of ferulic acid (9) was carried out in the presence of methanol and sulfuric acid
(95%) by a classical method to afford methyl ferulate 10 in 97% yield. The same procedure was used
in the presence of ethanol to afford ethyl ferulate 11 (80%). With the previous method, we did not
obtain the expected dodecyl ester (Scheme 6), so we have perfected the esterification reaction using a
different methodology. Indeed, the activation of the acid function of ferulic acid with 1,1'-
carbonyldiimidazole (CDI) led to (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(1H-imidazol-1-yl)prop-2-
en-1-one (12) (76%), then the esterification with 1-dodecanol allowed us to obtain the dodecyl (2E)-3-
(4-hydroxy-3-methoxyphenyl)acrylate 13 (66%).
Scheme 6: Synthesis of ferulate derivatives 10, 11 and 13.
HO
i
MeO
CO2CH3
HO
10, R = -CH3
11, R = -CH2-CH3
MeO
CO2H
9
HO
HO
ii
iii
N
N
MeO
MeO
CO2(CH2)11-CH3
12
13
O
Reagents and conditions: i) MeOH or EtOH, H2SO4 (95%), reflux, 24h; ii) CDI 2 equiv.,
anhydrous THF, reflux, 3.5h; iii) 1-dodecanol 1 equiv., DBU 1 equiv., anhydrous THF, reflux,
48h;
Synthesis of methyl, ethyl and dodecyl 2(E)-3-(4-(3-((R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-
2,5-dihydrofuran-3-yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)acrylates 20, 21 and 22
Hybrids 20, 21 and 22 were synthesized in three steps from the corresponding ferulates 10, 11 and
13, as described in Scheme 7. Alkylation with (±)-epichlorohydrin in the presence of NaOH in a
water-acetone medium (1:1) gave the corresponding ethers 14, 15 and 16 in 70%, 45% and 83%
yields, respectively.

Molecules 2007, 12
2538
Condensation of 14, 15 and 16 with the protected L-ascorbic acid derivative 8 in the presence of
NaHCO3 and a catalytic amount of 4-dimethylaminopyridine (4-DMAP) in 1,4-dioxane afforded 17,
18 and 19 in 50%, 49% and 66% yields, respectively; considering that the most acidic hydrogen is the
hydroxyl in the C-3 position, the condensation will take place on this position, involving the enediol
system. Subsequent removal of the protecting group was achieved by acid hydrolysis to yield methyl,
ethyl and dodecyl 2(E)-3-(4-(3-((R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-
yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)acrylates 20, 21 and 22 (71%, 61% and 75%).
Scheme 7: Synthesis of hybrids 20, 21 and 22.
O
HO
O
i
MeO
CO2R
MeO
CO2R
10, R = -CH3
14, R = -CH3
11, R = -CH2-CH3
15, R = -CH2-CH3
13, R = -(CH2)11-CH3
16, R = -(CH2)11-CH3
ii
HO
HO
O
H3C
H3C
O
O
O
O
O
H
H
O
OH
O
OH
iii
HO
HO
O
O
MeO
CO2R
MeO
CO2R
20, R = -CH3
17, R = -CH3
21, R = -CH2-CH3
18, R = -CH2-CH3
22, R = -(CH2)11-CH3
19, R = -(CH2)11-CH3
Reagents and conditions: i) (±)-Epichlorohydrin 5 equiv., NaOH 1 equiv., water/acetone:1/1,
reflux, 8h; ii) 8 1.2 equiv., 4-DMAP 0.1 equiv., NaHCO3 1 equiv., 1,4-dioxane, reflux, 24h; iii)
HCl 12N, 1,4-dioxane, rt, 4h.
Conclusions
We have studied the feasibility and the conditions of the hybridization methodology for the
synthesis of three new L-ascorbic ferulic acid hybrids. This methodology led us to introduce a
chemical spacer connected to the hydroxyl in the C-3 position of the L-ascorbic acid and the phenol of
the ferulic ester. The junction could be crucial for both stability and biological activity insofar as the
enediol system is protected.

Molecules 2007, 12
2539
The thermal stability and the inhibitory effects of the products on tyrosinase activity, and on active
oxygen species and free radicals in vitro, are currently under investigation and the results will be
published elsewhere.
Experimental
General
Commercial reagents were purchased from Aldrich, Acros Organics and Alfa Aesar and used
without additional purification. Melting points were determined on a Kofler heating bench and are
uncorrected. IR spectra were recorded on a Perkin Elmer BX FT-IR spectrophotometer. Optical
1
13
rotations were obtained on a Perkin-Elmer 343 polarimeter. H-NMR (400 MHz) and C-NMR (100
MHz) spectra were recorded in DMSO-d6 on a JEOL Lambda 400 spectrometer. Chemical shifts are
expressed in parts per million downfield from tetramethylsilane as an internal standard and coupling
constants in hertz. Mass spectra were taken on a JEOL JMS GCMate spectrometer at ionising potential
of 70 eV (EI) or were performed using a spectrometer LC-MS Waters alliance 2695 (ESI+).
Chromatography was carried out on a column using flash silica gel 60 Merck (0.063-0.200 mm) as the
stationary phase. Thin-layer chromatography was performed on 0.2 mm precoated plates of silica gel
60F-264 (Merck) and spots were visualized using an ultraviolet-light lamp.
Synthesis of (R)-5-((S)-2,2-dimethyl-[1,3]-dioxolan-4-yl)-3,4-dihydroxy-5H-furan-2-one (8)
Acetyl chloride (1 mL, 14.2 mmol) was added dropwise under nitrogen to a solution of L-ascorbic
acid 1 (10 g, 56.8 mmol) in acetone (40 mL) and the solution was then stirred at room temperature for
3 h. The resulting white mixture was cooled to 4°C, filtered and then washed with acetone (2 x 20 mL)
to afford 9.1 g of (R)-5-((S)-2,2-dimethyl-[1,3]-dioxolan-4-yl)-3,4-dihydroxy-5H-furan-2-one (8) as a
white solid (yield: 74%); m.p.: 210°C; IR (cm-1): 3242 (OH), 1754 (C=O), 1663 (C=C), 1333
(C(CH3)2), 1140 (dioxolane); 1H-NMR: 11.29 (bs, 1H, OH), 8.48 (bs, 1H, OH), 4.70-4.69 (m, 1H, H4),
4.25-4.23 (m, 1H, H5), 4.08-4.06 (m, 1H, H6), 3.87-3.86 (m, 1H, H6), 1.24 (s, 6H, CH3); 13C-NMR:
173.4, 157.1, 117.8, 110.4, 76.6, 76.4, 65.1, 26.3, 25.7; MS (ESI+) m/z 219 (M++1).
Synthesis of methyl (2E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (10)
Ferulic acid 9 (30.0 g, 154.0 mmol) and 5 drops of H2SO4 (95%) were refluxed in methanol for 24
h. The crude product was then evaporated to dryness and re-dissolved in dichloromethane. The organic
layer was washed with saturated NaHCO3 solution (2 x 50 mL), dried (MgSO4), and concentrated in
vacuo. The residue was chromatographed on silica gel (cyclohexane-ethylacetate: 8/2) to afford 31.2 g
of methyl (2E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (10) as a white solid (yield: 97%); m.p.: 68°C;
IR (cm-1): 3399 (OH), 2947 (CH3), 1718 (C=O), 1264-1160 (C-O); 1H-NMR: 9.62 (bs, 1H, OH), 7.55
3
3
3
(d, Jtrans=15.9 Hz, 1H, H2), 7.31 (s, 1H, H2’), 7.11 (d, J=8.1 Hz, 1H, H6’), 6.78 (d, J=8.1 Hz, 1H,
3
13
H5’), 6.47 (d, Jtrans=15.9 Hz, 1H, H3), 3.80 (s, 3H, CO2CH3), 3.68 (s, 3H, OCH3); C-NMR: 167.5,
149.8, 148.3, 145.5, 125.9, 123.5, 115.9, 114.6, 111.7, 53.1, 51.6; MS (ESI+) m/z 209 (M++1).

Molecules 2007, 12
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Synthesis of ethyl (2E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (11)
Ferulic acid 9 (50.0 g, 257.0 mmol) and 10 mL of H2SO4 (95%) were refluxed in ethanol for 24h.
The crude product was then evaporated to dryness and re-dissolved in dichloromethane. The organic
layer was washed with saturated NaHCO3 solution (2 x 50 mL), dried (MgSO4), and concentrated in
vacuo. The residue was chromatographed on silica gel (cyclohexane-ethyl acetate: 8/2) to afford 45.8 g
of ethyl (2E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (11) as a white solid (yield: 80%); m.p.: 67°C;
1
IR (cm-1): 3180 (OH), 2952 (CH3), 1711 (C=O), 1256 (C-O); H-NMR: 9.58 (bs, 1H, OH), 7.53 (d,
3
3
3Jtrans=15.9 Hz, 1H, H2), 7.31 (s, 1H, H2’), 7.10 (d, J=8.1 Hz, 1H, H6’), 6.77 (d, J=8.1 Hz, 1H, H5’),
3
6.45 (d, Jtrans=15.9 Hz, 1H, H3), 4.15 (q, J=7.0 Hz, 2H, CH2), 3.76 (s, 3H, OCH3), 1.23 (t, J=7.0 Hz,
13
3H, CH3); C-NMR: 166.9, 148.8, 148.3, 145.1, 126.9, 123.9, 116.5, 115.6, 110.7, 60.3, 56.4, 14.3;
MS (ESI+) m/z 223 (M++1).
Synthesis of (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(1H-imidazol-1-yl)prop-2-en-1-one (12)
To a solution of ferulic acid (9, 5.0 g, 25.8 mmol) in freshly distilled THF (60 mL) was added 1,1'-
carbonyldiimidazole (8.3 g, 51.5 mmol) and the mixture was refluxed for 3.5 h (CaCl2 guard tube).
The resulting mixture was cooled down to room temperature and concentrated in vacuo. The residue
was chromatographed on silica gel (ether) to afford 4.8 g of (E)-3-(4-hydroxy-3-methoxyphenyl)-1-
(1H-imidazol-1-yl)prop-2-en-1-one (12) as a white solid (yield: 76%); m.p.: 156°C; IR (cm-1): 3124
1
(OH), 2841 (CH3), 1772 (C=O), 1320-1243 (C-O); H-NMR: 8.78 (bs, 1H, Himidazole), 8.50 (bs, 1H,
3
3
Himidazole), 8.03 (d, Jtrans=15.5 Hz, 1H, H2), 7.94 (s, 1H, H2’), 7.62 (d, J=8.0 Hz, 1H, H5’), 7.70 (d,
3Jtrans=15.5 Hz, 1H, H3), 7.55 (d, 3J=8.0 Hz, 1H, H6’), 7.17 (bs, 1H, Himidazole), 3.90 (s, 3H, OCH3); 13C-
NMR: 163.3, 149.5, 147.8, 138.2, 129.9, 129.2, 128.2, 124.3, 115.5, 115.3, 111.8, 111.4, 57.0; MS
(EI) m/z: 244 (M+ •, 100).
Synthesis of dodecyl (2E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (13)
To a solution of (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(1H-imidazol-1-yl)prop-2-en-1-one (12, 4.8
g, 19.7 mmol) in freshly distilled THF (60 mL) were added DBU (3.0 g, 19.7 mmol) and 1-dodecanol
(3.7 g, 19.7 mmol) and the mixture was refluxed for 48 h. The resulting mixture was cooled down to
room temperature and concentrated in vacuo. The crude product was diluted with water (40 mL) and
extracted with ethyl acetate (3 x 50 mL). The organic layer was dried (MgSO4), and concentrated in
vacuo. The residue was chromatographed on silica gel (cyclohexane-ethyl acetate: 7/3) to afford 4.7 g
of dodecyl (2E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (13) as a white solid (yield: 66%); m.p.:
1
46°C; IR (cm-1): 3534 (OH), 3131, 2923 (CH3), 2849, 1746 (C=O), 1269-1190 (C-O); H-NMR: 9.58
(bs, 1H, OH), 7.52 (d, 3Jtrans=15.9 Hz, 1H, H2), 7.29 (s, 1H, H2’), 7.08 (d, 3J=8.1 Hz, 1H, H6’), 6.77 (d,
3
3
3J=8.1 Hz, 1H, H5’), 6.44 (d, Jtrans=15.9 Hz, 1H, H3), 4.09 (t, J=6.5 Hz, 2H, OCH2), 3.80 (s, 3H,
OCH3), 1.60-1.58 (m, 2H, CH2), 1.31-1.21 (m, 18H, (CH2)9), 0.82 (t, 3J=6.4 Hz, 3H, CH3); 13C-NMR:
167.4, 147.8, 146.8, 144.6, 127.2, 123.0, 115.6, 114.6, 110.1, 64.6, 56.1, 31.9, 30.4, 29.8, 29.6, 29.5,
29.4, 29.3, 28.7, 25.9, 22.7, 15.1; MS (EI) m/z: 362 (M+ •, 95).

Molecules 2007, 12
2541
Synthesis of methyl (2E)-3-[3-methoxy-4-(oxiran-2-ylmethoxy)phenyl]acrylate (14)
To a water-acetone medium (1:1, 80 mL) were added methyl (2E)-3-(4-hydroxy-3-
methoxyphenyl)acrylate (10, 3.1 g, 15.0 mmol) and NaOH (0.6 g, 15.0 mmol). The mixture was stirred
at room temperature for 10 min. (±)-Epichlorohydrin (12.8 g, 75.0 mmol) was added and the resulting
mixture was refluxed for 8 h. Then, acetone was concentrated in vacuo and the aqueous layer was
diluted with 70 mL of cold water and extracted with ethyl acetate (3 x 40 mL). The organic layer was
dried (MgSO4), and concentrated in vacuo. Recrystallization from diethyl ether afford 2.8 g of methyl
(2E)-3-[3-methoxy-4-(oxiran-2-ylmethoxy)phenyl]acrylate (14) as a white solid (yield: 70%); m.p.:
1
100°C; IR (cm-1): 2943-2925 (CH3), 2837 (CH2), 1717 (C=O), 1264-1161 (C-O); H-NMR: 7.58 (d,
3
3
3Jtrans=15.9 Hz, 1H, H2), 7.37 (s, 1H, H2’), 7.22 (d, J=8.1 Hz, 1H, H6’), 6.98 (d, J=8.1 Hz, 1H, H5’),
3
6.57 (d, Jtrans=15.9 Hz, 1H, H3), 4.34-4.33 (m, 1H, Hoxirane), 3.81 (s, 3H, CO2CH3), 3.70 (s, 3H,
13
OCH3), 3.33-3.32 (m, 2H, CH2), 2.84-2.83 (m, 1H, Hoxirane), 2.82-2.81 (m, 1H, Hoxirane); C-NMR:
167.9, 149.5, 147.8, 144.2, 128.8, 122.8, 117.5, 113.0, 111.3, 70.2, 55.7, 51.5, 49.8, 44.6; MS (EI)
m/z: 264 (M+ •, 41), 179 (37), 15 (100).
Synthesis of ethyl (2E)-3-[3-methoxy-4-(oxiran-2-ylmethoxy)phenyl]acrylate (15)
The same procedure as compound 14 starting from ethyl (2E)-3-(4-hydroxy-3-
methoxyphenyl)acrylate (11, 20.0 g, 90.0 mmol) and (±)-epichlorohydrin (76.7 g, 450.0 mmol) was
used to prepare 11.3 g of ethyl (2E)-3-[3-methoxy-4-(oxiran-2-ylmethoxy)phenyl]acrylate (15) as a
white solid (yield: 45%); m.p.: 75°C; IR (cm-1): 2980 (C-H), 1703 (C=O), 1600 (C=C), 1309-1273 (C-
O); 1H-NMR: 7.56 (d, 3Jtrans=15.9 Hz, 1H, H2), 7.37 (s, 1H, H2’), 7.21 (d, 3J=8.2 Hz, 1H, H6’), 6.97 (d,
3
3J=8.2 Hz, 1H, H5’), 6.56 (d, Jtrans=15.9 Hz, 1H, H3), 4.34-4.33 (m, 1H, Hoxirane), 4,16 (q, J=7.0 Hz,
2H, CH2), 3.81 (s, 3H, OCH3), 3.33-3.32 (m, 2H, CH2), 2.84-2.83 (m, 1H, Hoxirane), 2.70-2.69 (m, 1H,
Hoxirane), 1.24 (t, J=7.0 Hz, 3H, CH3); 13C-NMR: 166.9, 149.5, 147.8, 144.6, 128.3, 122.9, 116.6,
113.2, 111.3, 70.2, 60.3, 55.7, 51.5, 49.8, 44.6, 14.4; MS (ESI+) m/z 279 (M++1).
Synthesis of dodecyl (2E)-3-[3-methoxy-4-(oxiran-2-ylmethoxy)phenyl]acrylate (16)
The same procedure as compound 14 starting from dodecyl (2E)-3-(4-hydroxy-3-
methoxyphenyl)acrylate (13, 1.8 g, 5.0 mmol) and (±)-epichlorohydrin (2.3 g, 25.0 mmol) gave 1.7 g
of dodecyl (2E)-3-[3-methoxy-4-(oxiran-2-ylmethoxy)phenyl]acrylate (16) as a white solid (yield:
1
83%); m.p.: 69°C; IR (cm-1): 2919-2849 (CH3, CH2), 1713 (C=O), 1265-1171 (C-O); H-NMR: 7.58
3
3
3
(d, Jtrans=16.0 Hz, 1H, H2), 7.38 (s, 1H, H2’), 7.22 (d, J=8.1 Hz, 1H, H6’), 6.98 (d, J=8.1 Hz, 1H,
H5’), 6.57 (d, 3Jtrans=16.0 Hz, 1H, H3), 4.34-4.33 (m, 1H, Hoxirane), 4.12 (t, 3J=7.2 Hz, 2H, OCH2), 3.83
(s, 3H, OCH3),3.63-3.62 (m, 2H, CH2oxirane), 2.86-2.84 (m, 1H, Hoxirane), 2.71-2.69 (m, 1H, Hoxirane);
3
13
1.64-1.62 (m, 2H, CH2), 1.28-1.18 (m, 18H, (CH2)9), 0.86 (t, J=6.4 Hz, 3H, CH3); C-NMR: 167.4,
149.5, 147.8, 144.5, 128.2, 122.9, 115.6, 113.6, 111.3, 70.2, 64.6, 55.7, 49.8, 44.6, 31.9, 30.4, 29.8,
29.6, 29.5, 29.4, 29.3, 28.7, 25.9, 22.7, 14.1; MS (EI) m/z: 418 (M+ •, 37), 169 (100).

Molecules 2007, 12
2542
Synthesis of methyl 2(E)-3-(4-(3-((R)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-5-oxo-2,5-
dihydrofuran-3-yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)acrylate (17)
To a solution of methyl (2E)-3-[3-methoxy-4-(oxiran-2-ylmethoxy)phenyl]acrylate (14, 2.2 g, 8.3
mmol) and (R)-5-((S)-2,2-dimethyl-[1,3]-dioxolan-4-yl)-3,4-dihydroxy-5H-furan-2-one (8, 2.2 g, 10.0
mmol) in 1,4-dioxane (30 mL) were added NaHCO3 (0.8 g, 8.3 mmol) and 4-dimethylaminopyridine
(0.1 g, 0.8 mmol). The resulting mixture was refluxed for 24 h. The organic layer was concentrated in
vacuo and the crude product was diluted with water (100 mL) and extracted with ethyl acetate (3 x 40
mL). The organic layer was dried (MgSO4), and concentrated in vacuo. Recrystallization from diethyl
ether afforded 2.0 g of methyl 2(E)-3-(4-(3-((R)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-5-
oxo-2,5-dihydrofuran-3-yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)acrylate (17) as a white solid
(yield: 50%); m.p.: 73°C; IR (cm-1): 3445 (OH), 2988-2950 (CH), 1760 (C=O), 1699 (C=C), 1260
1
3
(C(CH3)2); H-NMR: 9.03 (bs, 1H, OH), 7.58 (d, Jtrans=15.9 Hz, 1H, H2), 7.35 (s, 1H, H2), 7.22 (d,
3J=8.1 Hz, 1H, H6), 6.99 (d, J=8.1 Hz, 1H, H5), 6.55 (d, Jtrans=15.9 Hz, 1H, H3), 5.43 (bs, 1H, OH),
3
3
4.78-4.77 (m, 1H, H4), 4.43-4.40 (m, 1H, H5), 4.21-4.20 (m, 1H, H6), 4.14-3.97 (m, 6H), 3.80 (s, 3H,
13
CO2CH3), 3.70 (s, 3H, OCH3), 1.24-1.22 (m, 6H, CH3); C-NMR: 170.3, 167.5, 149.8, 149.2, 148.8,
148.6, 144.4, 127.9, 122.2, 119.6, 115.6, 113.1, 110.1, 74.9, 71.9, 69.9, 69.5, 68.4, 64.9, 55.6, 51.4,
25.5, 25.2; MS (EI) m/z: 480 (M+ •, 8), 280 (56), 206 (66), 194 (100).
Synthesis of ethyl 2(E)-3-(4-(3-((R)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-5-oxo-2,5-
dihydrofuran-3-yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)acrylate (18)
The same procedure as compound 17 starting from ethyl (2E)-3-[3-methoxy-4-(oxiran-2-
ylmethoxy)phenyl]acrylate (15, 2.2 g, 8.3 mmol) and (R)-5-((S)-2,2-dimethyl-[1,3]-dioxolan-4-yl)-3,4-
dihydroxy-5H-furan-2-one (8, 2.2 g, 10.0 mmol) was used to give 1.6 g of ethyl 2(E)-3-(4-(3-((R)-2-
((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-yloxy)-2-hydroxypropoxy)-
3-methoxyphenyl)acrylate (18) as a white solid (yield: 49%); m.p.: 71°C; IR (cm-1): 3432 (OH), 2985
1
3
(CH), 1770 (C=O), 1698 (C=C), 1259 (C(CH3)2); H-NMR: 8.90 (bs, 1H, OH), 7.49 (d, Jtrans= 15.9
Hz, 1H, H2), 6.98 (s, 1H, H2), 6.96 (d, 3J=8.3 Hz, 1H, H6), 6.79 (d, 3J= 8.3 Hz, 1H, H5), 6.22 (d, 3Jtrans
=
15.9 Hz, 1H, H3), 4.58 (bs, 1H, OH), 4.51 (m, 1H, H4), 4.30 (m, 1H, H5), 4.22 (m, 1H, H6), 4,16 (q,
J=7.0 Hz, 2H, CH2), 4.10-3.86 (m, 6H), 3.78 (s, 3H, OCH3), 1.35-1.33 (m, 3H, CH3), 1.27-1.23 (m,
6H, CH3); 13C-NMR: 174.4, 172.2, 166.9, 149.3, 146.5, 144.5, 128.3, 126.7, 123.1, 116.6, 112.8,
111.4, 110.6, 77.7, 76.1, 72.0, 70.4, 70.3, 65.1, 60.3, 55.7, 26.4, 26.0, 14.4; MS (ESI+) m/z 495
(M++1).
Synthesis of dodecyl (2E)-3-(4-(3-((R)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-5-oxo-2,5-
dihydrofuran-3-yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)acrylate (19)
The same procedure as compound 17 starting from dodecyl (2E)-3-[3-methoxy-4-(oxiran-2-
ylmethoxy)phenyl]acrylate (16, 1.7 g, 4.1 mmol) and (R)-5-((S)-2,2-dimethyl-[1,3]-dioxolan-4-yl)-3,4-
dihydroxy-5H-furan-2-one (8, 1.1 g, 5.0 mmol) gave 1.7 g of dodecyl (2E)-3-(4-(3-((R)-2-((S)-2,2-
dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-yloxy)-2-hydroxy-propoxy)-3-

Molecules 2007, 12
methoxyphenyl)acrylate (19) as a colourless oil (yield: 66%); IR (cm-1): 3440 (OH), 2924-2854 (CH),
2543
1
3
1769 (C=O), 1700 (C=C), 1260 (C(CH3)2); H-NMR: 9.03 (bs, 1H, OH), 7.56 (d, Jtrans=16.0 Hz, 1H,
H2), 7.35 (s, 1H, H2), 7.20 (d, 3J=7.8 Hz, 1H, H6), 6.98 (d, 3J=7.8 Hz, 1H, H5), 6.55 (d, 3Jtrans=16.0 Hz,
1H, H3), 5.43 (bs, 1H, OH), 4.77-4.76 (m, 1H, H4), 4.43-4.39 (m, 2H), 4.21-4.20 (m, 1H, H6), 4.14-
3.97 (m, 5H), 4.10-4.09 (m, 2H, OCH2), 3.80 (s, 3H, OCH3), 1.64-1.62 (m, 2H, CH2), 1.24 (s, 6H,
13
CH3), 1.23-1.21 (m, 18H, (CH2)9), 0.84-0.82 (m, 3H, CH3); C-NMR: 174.4, 172.3, 167.4, 149.3,
146.5, 144.5, 128.2, 126.6, 123.1, 115.7, 112.8, 111.5, 110.7, 77.7, 76.1, 70.5, 72.0, 70.1, 65.1, 64.6,
53.7, 31.9, 30.4, 29.8, 29.6, 29.5, 29.4, 29.3, 28.7, 26.3, 26.1, 25.9, 22.7, 14.1; MS (EI) m/z: 635 (M+ •,
5), 436 (69), 362 (65), 194 (100).
Synthesis of methyl 2(E)-3-(4-(3-((R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-
yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)acrylate (20)
To a solution of methyl 2(E)-3-(4-(3-((R)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-5-
oxo-2,5-dihydrofuran-3-yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)acrylate (17, 2.0 g, 4.2 mmol) in
1,4-dioxane (30 mL) was added HCl (12 N, 0.6 mL) and the resulting mixture was stirred at room
temperature for 4 h. The organic layer was neutralized with saturated NaHCO3 solution (100 mL), and
extracted with ethyl acetate (3 x 40 mL), dried (MgSO4), and concentrated in vacuo. The residue was
chromatographed on silica gel (ethyl acetate) to afford 1.3 g of methyl 2(E)-3-(4-(3-((R)-2-((S)-1,2-
dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)-
acrylate (20) as a white solid (yield: 71%); m.p.: 69°C; [α]20 = +21.0 (c 0.5, C2H5OH); IR (cm-1): 3452
D
1
(OH), 2953 (CH), 1765 (C=O), 1692 (C=C), 1259 (C-O); H-NMR: 8.82 (bs, 1H, OH), 7.58 (d,
3
3
3Jtrans=15.9 Hz, 1H, H2), 7.35 (s, 1H, H2), 7.22 (d, J=8.1 Hz, 1H, H6), 7.00 (d, J=8.1 Hz, 1H, H5),
6.56 (d, 3Jtrans=15.9 Hz, 1H, H3), 5.43 (bs, 1H, OH), 4.96-4.78 (m, 2H, H4, H5), 4.43-4.41 (m, 2H, H6),
4.00-3.99 (m, 5H), 3.80 (s, 3H, CO2CH3), 3.70 (s, 3H, OCH3); 13C-NMR: 170.5, 167.0, 150.41 149.2,
144.7, 127.2, 122.9, 119.3, 118.1, 115.4, 112.9, 110.8, 74.6, 71.9, 69.7, 68.6, 67.6, 61.7, 55.7, 51.3.
MS (ESI+) m/z 441 (M++1).
\Synthesis of ethyl 2(E)-3-(4-(3-((R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-
yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)acrylate (21)
The same procedure as compound 20 starting from ethyl 2(E)-3-(4-(3-((R)-2-((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)-
acrylate (18, 0.3 g, 0.5 mmol) was used to prepare 8.6 mg of ethyl 2(E)-3-(4-(3-((R)-2-((S)-1,2-
dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)-
acrylate (21) as a white solid (yield: 61%); m.p.: 68°C; [α]20 = +21.0 (c 0.5, C2H5OH); IR (cm-1): 3419
D
1
(OH), 2936 (CH), 1760 (C=O), 1694 (C=C), 1259 (C-O); H-NMR: 8.83 (bs, 1H, OH), 7.56 (d,
3
3
3Jtrans=15.9 Hz, 1H, H2), 7.34 (s, 1H, H2), 7.20 (d, J=8.0 Hz, 1H, H6), 6.99 (d, J=8.0 Hz, 1H, H5),
3
6.53 (d, Jtrans=15.9 Hz, 1H, H3), 5.44 (bs, 1H, OH), 4.97-4.38 (m, 2H, H4, H5), 4.18-4.00 (m, 5H),
13
3.80 (s, 3H, OCH3), 1.23 (t, J=7.0 Hz, 3H, CH3); C-NMR: 170.9, 166.0, 150.7, 149.6, 144.9, 127.7,
123.2, 119.8, 118.7, 116.2, 113.4, 111.2, 75.0, 72.3, 70.3, 69.0, 67.9, 62.2, 60.2, 56.1, 14.5; MS (ESI+)
m/z 455 (M++1).

Molecules 2007, 12
2544
Synthesis of dodecyl 2(E)-3-(4-(3-((R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-
3-yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)acrylate (22)
The same procedure as compound 20 starting from dodecyl (2E)-3-(4-(3-((R)-2-((S)-2,2-dimethyl-
1,3-dioxolan-4-yl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-yloxy)-2-hydroxypropoxy)-3-methoxyphenyl)-
acrylate (19, 0.4 g, 0.6 mmol) was used to prepare 0.3 g of dodecyl (2E)-3-[4-(3-[2-(1,2-
dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-3-yloxy]-2-hydroxy-propoxy)3-methoxyphenyl]-
acrylate (22) as a white solid (yield: 75%); m.p.: 67°C; [α]20 = +21.6 (c 0.5, C2H5OH); IR (cm-1): 3387
D
1
(OH), 2953-2853 (CH), 1759 (C=O), 1695 (C=C), 1260 (C-O); H-NMR: 8.83 (bs, 1H, OH), 7.56 (d,
3
3
3Jtrans=15.9 Hz, 1H, H2), 7.35 (s, 1H, H2), 7.20 (d, J=8;1 Hz, 1H, H6), 6.99 (d, J=8.1 Hz, 1H, H5),
6.54 (d, 3Jtrans=15.9 Hz, 1H, H3), 5.42 (bs, 1H, OH), 4.95-4.78 (m, 2H, H4, H5), 4.46-4.45 (m, 2H, H6),
4.12-4.01 (m, 5H), 3.81 (s, 3H, OCH3), 1.61-1.60 (m, 2H, CH2), 1.22-1.19 (m, 20H, (CH2)10), 0.83 (t,
2J=5.8 Hz, 3H, CH3); C-NMR: 170.5, 166.6, 150.5, 150.2, 149.2, 134.9, 127.2, 122.8, 119.4, 115.6,
13
112.7, 110.6, 74.6, 69.7, 68.6, 67.5, 66.4, 63.8, 61.7, 55.7, 31.3, 30.4, 29.0, 28.9, 28.8, 28.7, 28.6, 28.3,
25.4, 22.1, 13.9; MS (ESI+) m/z 596 (M++1).
Acknowledgements
The authors thank the PCAS society for their financial support.
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