Convenient synthesis of hydroxytyrosol and its lipophilic derivatives from tyrosol or homovanillyl alcohol

Article abstract of DOI:10.1021/jf801558z

Hydroxytyrosol, a naturally occurred c-phenolic compound exhibiting antioxidant properties, was synthesized by a three-step high-yielding procedure from natural and low-cost compounds such as tyrosol or homovanillyl alcohol. First, the efficient chemoselective protection of the alcoholic group of these compounds was performed by using dimethyl carbonate (DMC) as reagent/solvent; second, the oxidation with 2-iodoxybenzoic acid (IBX) or Dess-Martin periodinane reagent (DMP) and in situ reduction with sodium dithionite (Na ₂S₂O₄) allowed the preparation of carboxymethylated hydroxytyrosol; finally, by a mild hydrolytic step, hydroxytyrosol was obtained in high yield and purity, as confirmed by NMR spectra and HPLC profile. By using a similar methodology, lipophilic hydroxytyrosol derivatives, utilized as additives in pharmaceutical, food, and cosmetic preparations, were prepared. In fact, at first the chemoselective protection of the alcoholic group of tyrosol and homovanillyl alcohol was performed by using acyl chlorides without any catalyst to obtain the corresponding lipophilic derivatives, and then these compounds were converted in good yield and high purity into the hydroxytyrosol derivatives by oxidative/reductive pathway with IBX or DMP and Na₂S ₂O₄.

Full text of DOI:10.1021/jf801558z

J. Agric. Food Chem. 2008, 56, 8897–8904 8897
Convenient Synthesis of Hydroxytyrosol and Its
Lipophilic Derivatives from Tyrosol or Homovanillyl
Alcohol
ROBERTA BERNINI,* ENRICO MINCIONE, MAURIZIO BARONTINI, AND
FERNANDA CRISANTE
Dipartimento di Agrobiologia e Agrochimica, Universita` degli Studi della Tuscia,
Via S. Camillo De Lellis snc, 01100 Viterbo, Italy
Hydroxytyrosol, a naturally occurred o-phenolic compound exhibiting antioxidant properties, was
synthesized by a three-step high-yielding procedure from natural and low-cost compounds such as
tyrosol or homovanillyl alcohol. First, the efficient chemoselective protection of the alcoholic group of
these compounds was performed by using dimethyl carbonate (DMC) as reagent/solvent; second,
the oxidation with 2-iodoxybenzoic acid (IBX) or Dess-Martin periodinane reagent (DMP) and in situ
reduction with sodium dithionite (Na2S2O4) allowed the preparation of carboxymethylated hydroxy-
tyrosol; finally, by a mild hydrolytic step, hydroxytyrosol was obtained in high yield and purity, as
confirmed by NMR spectra and HPLC profile. By using a similar methodology, lipophilic hydroxytyrosol
derivatives, utilized as additives in pharmaceutical, food, and cosmetic preparations, were prepared.
In fact, at first the chemoselective protection of the alcoholic group of tyrosol and homovanillyl alcohol
was performed by using acyl chlorides without any catalyst to obtain the corresponding lipophilic
derivatives, and then these compounds were converted in good yield and high purity into the
hydroxytyrosol derivatives by oxidative/reductive pathway with IBX or DMP and Na2S2O4.
KEYWORDS: Hydroxytyrosol; lipophilic hydroxytyrosol; oxidation; 2-iodoxybenzoic acid (IBX); Dess-Martin
periodinane (DMP)
INTRODUCTION
are, generally, hydroxytyrosol esters with long saturated or
unsaturated alkylic chains. These compounds show a good
solubility in oils and emulsions and are used as additives in
food and cosmetic products as well as in pharmaceutical
preparations (12). The simplest of these derivatives is hydroxy-
tyrosol acetate [2-(3′,4′-dihydroxyphenyl)ethyl acetate 3; Figure
1] found in olive oil (13). The antioxidant activity of this
compound in oil and emulsions is much higher than those of
R-tocopherol and oleuropein and similar to that of hydroxyty-
rosol (14). Recently, it has been reported that lipophilic phenol
derivatives having amphiphilic structure and self-organizing
properties are potentially interesting for possible applications
in nanotechnology (15).
Up until some years ago, hydroxytyrosol was commercially
unavailable. More recently, it has been commercialized by some
chemical companies but at high prices. Several protocols have
been optimized to recover hydroxytyrosol from olive oil waste
waters (16). Sometimes, it is isolated in a mixture with other
phenolic compounds, in particular, with tyrosol 4 [or 2-(4′-
hydroxyphenyl)ethanol; Figure 1]. Several synthetic procedures
of hydroxytyrosol have been reported in the literature, but many
of them required various steps and proceeded with no satisfac-
tory yields (17). Recently, some enzymatic or chemical conver-
sions of natural oleuropein 2 (18) or tyrosol 4 into hydroxyty-
rosol have been described (19). In fact, tyrosol 4 is a very
Hydroxytyrosol 1 [or 2-(3′,4′-dihydroxyphenyl)ethanol; Fig-
ure 1] is a natural phenolic compound found in olive fruits,
leaves, virgin olive oil (1), and olive oil waste waters, also
known as vegetable waters (2). It is released by hydrolysis of
the glycoside oleuropein 2 (Figure 1) by means of cellular
esterases or acidic catalysis during olive storage and pressing
(3). A recent study has identified and quantified hydroxytyrosol
in several Italian white and red wines.
The antioxidant property of hydroxytyrosol has been claimed
in more papers, and it has been attributed to the o-diphenolic
moiety (4). Moreover, it possesses many biological and phar-
macological properties. For example, hydroxytyrosol protects
human erythrocytes against oxidative damages and low-density
lipoprotein (LDL) oxidation (5); it induces cytochrome c-
dependent apoptosis (6) and prevents cardiovascular diseases
(7), certain types of cancer (8), and platelet aggregation (9).
Hydroxytyrosol is also utilized for the treatment of inflamma-
tions and protection against neurodegenerative diseases (10) and
in cosmetic applications such as skin care preparations and
bathing agents (11). The industrial applications of hydroxyty-
rosol have been extended using its lipophilic derivatives that
* Author to whom correspondence should be addressed (telephone
+39 0761 357452; fax +39 0761 357242; e-mail berninir@unitus.it).
10.1021/jf801558z CCC: $40.75  2008 American Chemical Society
Published on Web 09/05/2008

8898 J. Agric. Food Chem., Vol. 56, No. 19, 2008
Bernini et al.
to 40:60 during the following 30 min. GC-MS analyses were performed
on a Shimadzu VG 70/250S apparatus equipped with a CP-SIL 8 CB-
MS column (25 m × 0.25 mm and 0.25 mm film thickness). The
analyses were performed using an isothermal temperature profile of
100 °C for 2 min, followed by a 10 °C/min temperature gradient to
280 °C for 15 min. The injector temperature was 280 °C. HRMS were
recorded with a Micromass Q-TOF micro mass spectrometer (Waters).
1H and 13C NMR spectra were recorded in CDCl3 (99.8% in deuterium)
and in CD3OD (99.8% in deuterium) using a Bruker 200 MHz
spectrometer. All chemical shifts are expressed in parts per million (δ
scale) and are referenced to either the residual protons or carbon of
the solvent. Only the spectral data of new compounds are described
here, but all 1H and 13C NMR data of lipophilic phenols are available
as Supporting Information.
Figure 1. Chemical structures of some low molecular weight phenolic
compounds present in olive oil and in olive oil waste waters.
Carboxymethylation of Tyrosol 4 and Homovanillyl Alcohol 5.
This reaction was performed following two different methods.
Method a. Either tyrosol 4 (138 mg, 1.0 mmol) or homovanillyl
alcohol 5 (168 mg, 1.0 mmol) was dissolved in DMC (3 mL), and
then H2SO4 96% (10.7 µL, 0.2 mmol) was added. The solution was
stirred at reflux (T ) 90 °C) for 7 h until disappearance of the substrate.
At the end, it was cooled to room temperature, and DMC was
evaporated under vacuum as an azeotropic mixture with methanol
(DMC/CH3OH ) 1:3) boiling at 64 °C. The residue was extracted with
ethyl acetate, washed with a saturated solution of NaCl, and dried over
Na2SO4. After filtration and evaporation under vacuum, 2-(4′-hy-
droxyphenyl)ethyl methyl carbonate 6 and 2-(4′-hydroxy-3′-methoxy-
phenyl)ethyl methyl carbonate 7 were obtained as colorless oils in
quantitative yields.
Method b. A mixture of either tyrosol 4 (138 mg, 1.0 mmol) or
homovanillyl alcohol 5 (168 mg, 1 mmol), DBU (1,8-diazabicyclo[5.4.0]-
undec-7-ene, 1.2 mmol), and DMC (3 mL) was heated to reflux (T )
90 °C) for 7 h. The reaction was monitored by thin layer chromatog-
raphy (TLC) and by gas-mass analysis (GC-MS). After the disap-
pearance of the substrate, the reaction mixture was cooled to room
temperature, and DMC was evaporated under vacuum with methanol.
The residue was extracted with ethyl acetate and washed with a solution
of 1N HCl. The organic extracts were treated with a saturated solution
of NaCl and dried over Na2SO4, then filtered and concentrated under
vacuum. Compounds 6 and 7 were isolated as colorless oils in
quantitative yields. Their spectroscopic data have been already described
by us (28).
Esterification of Tyrosol 4 and Homovanillyl Alcohol 5. Either
tyrosol 4 (138 mg, 1.0 mmol) or homovanillyl alcohol 5 (168 mg, 1.0
mmol) was dissolved in DMC (3 mL), and then acyl chloride (acetyl,
hexanoyl, palmitoyl, oleoyl, linoleyl chloride, 1.2 mmol) was added.
The solution was stirred at room temperature for 24 h until disappear-
ance of the substrate. DMC was evaporated under vacuum to afford a
mixture that was solubilized with ethyl acetate and washed with a
saturated solution of NaCl. The aqueous phase was extracted with ethyl
acetate, washed with a saturated solution of NaCl, and dried over
Na2SO4. Purification on silica gel of the mixture by elution with hexane/
ethyl acetate ) 2:1 gave 2-(4′-hydroxyphenyl)ethyl acetate 9 (white
solid, 90% yield); 2-(4′-hydroxy-3′-methoxyphenyl)ethyl acetate 10
(colorless oil, quantitative yield); 2-(4′-hydroxyphenyl)ethyl hexanoate
11 (yellow oil, 80% yield); 2-(4′-hydroxy-3′-methoxyphenyl)ethyl
hexanoate 12 (yellow oil, 83% yield); 2-(4′-hydroxyphenyl)ethyl
palmitate 13 (colorless oil, 75% yield); 2-(4′-hydroxy-3′-methoxyphe-
nyl)ethyl palmitate 14 (colorless oil, 75% yield); 2-(4′-hydroxyphe-
nyl)ethyl oleate 15 (yellow oil, 86% yield); 2-(4′-hydroxy-3′-
methoxyphenyl)ethyl oleate 16 (yellow oil, 75% yield); 2-(4′-
hydroxyphenyl)ethyl linoleate 17 (yellow oil, 60% yield); and 2-(4′-
hydroxy-3′-methoxyphenyl)ethyl linoleate 18 (yellow oil, 70% yield).
NMR data of compounds 9, 10, 14, 15, and 17 were coherent with
those reported in the literature (29-33).
Figure 2. Chemical structures of IBX and DMP.
attractive natural starting material, being the monophenolic
precursor of hydroxytyrosol.
Considering the industrial applications of hydroxytyrosol as
well its studies on the biological properties, it is important to
have at hand simple and efficient synthethic procedures at
competitive prices to prepare this compound. Therefore, in this
paper we report a new convenient oxidative procedure to obtain
hydroxytyrosol as well as its lipophilic derivatives starting from
either tyrosol 4 or homovanillyl alcohol 5 [2-(4′-hydroxy-3′-
methoxyphenyl)ethanol], natural phenols present in olive oil mill
waste waters (20), and commercially available inexpensive
chemicals. The critical step, that is, the selective protection of
the alcoholic hydroxyl group in the presence of phenolic
hydroxyl group, was accomplished by using dimethyl carbonate
(DMC) as reagent/solvent as well as acyl chlorides. The oxidants
of choice were 2-iodoxybenzoic acid (1-hydroxy-1-oxo-1H-1λ5-
benz[d][1,2]iodoxol-3-one, IBX; Figure 2) and the correspond-
ing 1,1,1-triacetoxy derivative (Dess-Martin periodinane, DMP;
Figure 2) (21). Some examples of reactivity of IBX and DMP
include oxidative demethylation of simple phenolic methyl aryl
ethers (22) and oxidation of phenols to o-quinones (23). When
the use of IBX or DMP has been combined with an in situ
reduction, several natural and synthethic catecholic compounds
have been prepared (24). Therefore, the utilization of IBX and
DMP and in situ reduction permitted an efficient selective
conversion of either protected tyrosol or homovanillyl alcohol
into the corresponding hydroxytyrosol derivatives. In fact, we
observed that IBX and DMP oxidized the phenolic compounds
with a selectivity similar to that of a polyphenol oxidase.
Furthermore, we optimized a one-pot synthesis of carboxy-
methylated hydroxytyrosol. The new procedures described in
the present paper have been deposited for two patents (25).
MATERIALS AND METHODS
Reagents. Tyrosol [2-(4′-hydroxyphenyl)ethanol], homovanillyl
alcohol [2-(4-hydroxy-3-methoxyphenyl)ethanol] were purchased from
Sigma Aldrich as were all other solvents and reagents. All chemicals
used were of analytical grade. IBX and DMP were prepared in the
laboratory as described in the literature (26, 27). Silica gel 60 F254
plates and silica gel 60 were furnished by Merck.
Instrumental Analysis. HPLC analyses were performed on a Varian
Prostar 325 apparatus equipped with a Varian Pursuit 5u C18 column
(150 × 4.6 mm) and a dual wavelength UV-vis detector selected on
λ ) 280 nm. Elutions were carried out at a 1 mL/min flow rate using
a H2O/CH3CN mixture (90:10, v/v) for the first minute and a gradient
2-(4′-Hydroxyphenyl)ethyl hexanoate 11: 1H NMR (CDCl3) δ 0.85
(m, 3H, CH3), 1.19-1.32 (m, 4H, 2 × CH2), 1.50-1.65 (m, 2H, CH2),
2.24 (t, 2H, J ) 7.7 Hz, COCH2), 2.83 (t, 2H, J ) 7.1 Hz, Ph-CH2),
4.23 (t, 2H, J ) 7.1 Hz, CH2O), 6.76 (d, 2H, J ) 8.4 Hz, H-ar), 7.06
(d, 2H, J ) 8.4 Hz, H-ar); 13C NMR (CDCl3) δ 13.9, 22.3, 24.6, 31.2,
34.2, 34.3, 65.2, 115.4, 129.6, 130.0, 154.5, 174.5. HRMS found:
236.3120; C14H20O3 requires 236.3122.

Synthesis of Hydroxytyrosol and Lipophilic Derivatives
J. Agric. Food Chem., Vol. 56, No. 19, 2008 8899
Figure 3. 1H NMR, 13CNMR, and HPLC profiles of hydroxytyrosol 1 synthesized as reported in Scheme 1.
2-(4′-Hydroxy-3′-methoxyphenyl)ethyl hexanoate 12: 1H NMR
(CDCl3) δ 0.83 (3H, m, CH3), 1.20-1.29 (4H, m, 2 × CH2), 1.53-1.61
(2H, m, CH2), 2.25 (2H, t, J ) 7.7 Hz, COCH2), 2.82 (2H, t, J ) 7.1
Hz, Ph-CH2), 3.81 (3H, s, OCH3), 4.22 (2H, t, J ) 7.1 Hz, CH2O),
6.66 (2H, m, J ) 8.4 Hz, H-ar), 6.82 (d, 1H, J ) 7.2 Hz, H-ar); 13C
NMR (CDCl3) δ 13.9, 22.3, 24.6, 31.2, 34.3, 34.8, 56.0, 64.9, 111.4,
114.5, 121.6, 129.6, 144.3, 146.5, 173.8. HRMS found: 266.3388;
C15H22O4 requires 266.3386.
2.28 (2H, t, J ) 7.3 Hz, COCH2), 2.84 (2H, t, J ) 7.1 Hz, Ph-CH2),
4.23 (2H, t, J ) 7.1 Hz, CH2O), 6.75 (2H, d, J ) 8.5 Hz, H-ar), 7.03
(2H, d, J ) 8.5 Hz, H-ar); 13C NMR (CDCl3) δ 14.1, 22.7, 24.9, 29.1,
29.2, 29.3, 29.4, 29.6, 29.7, 31.9, 34.2, 34.4, 65.3, 115.4, 129.5, 130.0,
154.6, 174.6. HRMS found: 376.5825; C24H40O3 requires 376.5822.
2-(4′-Hydroxy-3′-methoxyphenyl)ethyl oleate 16: 1H NMR (CDCl3)
δ 0.86 (3H, m, CH3), 1.15-1.25 (20H, m, 10 × CH2), 1.97 (4H, m, 2
× CH2), 1.60 (2H, m, CH2), 2.26 (2H, t, J ) 7.6 Hz, COCH2), 2.83
(2H, t, J ) 7.1 Hz, Ph-CH2), 3.85 (3H, s, OCH3), 4.23 (2H, t, J ) 7.1
Hz, CH2O), 5.33 (2H, m, CHdCH), 6.67-6.70 (2H, m, H-ar), 6.82
1
2-(4′-Hydroxyphenyl)ethyl palmitate 13: H NMR (CDCl3) δ 0.86
(3H, m, CH3); 1.24-1.29 (24H, m, 12 × CH2), 1.55 (2H, m, CH2),

8900 J. Agric. Food Chem., Vol. 56, No. 19, 2008
Bernini et al.
yield), 2-(3′,4′-dihydroxyphenyl)ethyl oleate 21 (orange oil, 68% yield),
and 2-(3′,4′-dihydroxyphenyl)ethyl linoleate 22 (orange oil, 62% yield)
were obtained.
Scheme 1. Synthetic Procedure To Obtain Hydroxytyrosol 1 from Tyrosol
4 or Homovanillyl Alcohol 5
Oxidation of Compounds 6, 9, 11, 13, 15, and 17 with DMP.
Substrate (1.0 mmol) was dissolved in THF (4 mL), and then DMP
(509 mg, 1.2 mmol) was added. The solution was stirred at room
temperature until disappearance of the substrate (1 h). At the end,
H2O (4 mL) and Na2S2O4 (348 mg, 2.0 mmol) were added, and the
solution was under stirring for 5 min. After evaporation of the
solvent under vacuum, the residue was solubilized with ethyl acetate
and treated with a saturated solution of NaHCO3. The aqueous phase
was extracted with ethyl acetate. The organic phases were washed
with a saturated solution of NaCl and dried on Na2SO4. After
evaporation of the solvent, 2-(3′,4′-dihydroxyphenyl)ethyl methyl
carbonate 8 (colorless oil, 85% yield); 2-(3′,4′-dihydroxyphenyl)ethyl
acetate 3 (colorless oil, 80% yield), 2-(3′,4′-dihydroxyphenyl)ethyl
hexanoate 19 (yellow oil, 82% yield), 2-(3′,4′-dihydroxyphenyl)ethyl
palmitate 20 (orange oil, 92% yield), 2-(3′,4′-dihydroxyphenyl)ethyl
oleate 21 (orange oil, 89% yield), and 2-(3′,4′-dihydroxyphenyl)ethyl
linoleate 22 (orange oil, 77% yield) were obtained.
Oxidation of Compounds 7, 10, 12, 14, 16, and 18 with DMP.
The experimental procedure is the same. After evaporation of the
solvent, 2-(3′,4′-dihydroxyphenyl)ethyl methyl carbonate 8 (colorless
oil, 85% yield), 2-(3′,4′-dihydroxyphenyl)ethyl acetate 3 (colorless oil,
72% yield), 2-(3′,4′-dihydroxyphenyl)ethyl hexanoate 19 (yellow oil,
62% yield), 2-(3′,4′-dihydroxyphenyl)ethyl palmitate 20 (orange oil,
88% yield), 2-(3′,4′-dihydroxyphenyl)ethyl oleate 21 (orange oil, 65%
yield), and 2-(3′,4′-dihydroxyphenyl)ethyl linoleate 22 (orange oil, 58%
yield) were obtained.
One-Pot Synthesis of Compound 8 in Dimethyl Carbonate.
Tyrosol 4 (138 mg, 1.0 mmol) was dissolved in DMC, and then H2SO4
96% (10.7 µL, 0.2 mmol) was added. The solution was stirred at reflux
(T ) 90 °C) for 7 h until disappearance of the substrate. After cooling
at room temperature, H2O (2 mL) and DMP (1.2 mmol) were added.
After 50 min, Na2S2O4 (2.0 mmol) was added, and the mixture was
carried out under magnetic stirring for 5 min. After evaporation of the
solvent at reduced pressure, the residue was solubilized with ethyl
acetate and treated with a saturated solution of NaHCO3. The aqueous
phase was washed with ethyl acetate; then the organic phases were
washed with a saturated solution of NaCl until neutral pH and dried
over Na2SO4. After evaporation of the solvent, compound 8 was isolated
as yellow oil (82% yield).
Hydrolysis of 2-(3′,4′-Dihydroxyphenyl)ethyl Methyl Carbonate
8. To a solution of substrate (226 mg, 1.0 mmol) in THF was added
KOH 1 M (3 mL, 3.0 mmol). The mixture was stirred at room
temperature for 30 min. After evaporation of the solvent, the residue
was solubilized with ethyl acetate and treated with 1 M HCl. The
aqueous phase was extracted with ethyl acetate. Organic phases were
washed with a saturated solution of NaCl and dried over Na2SO4. After
evaporation of solvent, colorless oil was obtained (85% yield).
Spectroscopic data are reported in Figure 3 and were consistent with
those reported in the literature (16b).
(d, 1H, J ) 8.6 Hz, H-ar); 13C NMR (CDCl3) δ 14.0, 22.6, 24.9, 27.1,
27.2, 29.0, 29.1, 29.3, 29.5, 29.6, 29.7, 31.9, 34.3, 34.8, 55.8, 64.9,
111.3, 114.3, 121.6, 129.6, 129.7, 130.0, 144.3, 146.4, 173.8. HRMS
found: 432.6470; C27H44O4 requires 432.6466.
2-(4′-Hydroxy-3′-methoxyphenyl)ethyl linoleate 18: 1H NMR
(CDCl3) δ 0.87 (3H, m, CH3), 1.27-1.37 (14H, m, 7 × CH2), 1.58
(2H, m, CH2), 2.01 (4H, m, 2 × CH2), 2.27 (2H, t, J ) 7.7 Hz, CH2),
2.76 (2H, t, J ) 5.9 Hz, CH2), 2.84 (2H, t, J ) 7.1 Hz, Ph-CH2), 3.84
(3H, s, OCH3), 4.23 (2H, t, J ) 7.1 Hz, CH2O), 5.24-5.38 (4H, m, 2
× CHdCH), 6.65-6.70 (2H, m, H-ar), 6.81 (1H, d, J ) 8.6 Hz, H-ar);
13C NMR (CDCl3) δ 14.0, 22.6, 25.0, 25.7, 27.2, 29.1, 29.2, 29.3, 29.6,
31.1, 34.3, 34.8, 55.8, 65.0, 111.3, 114.4, 121.6, 127.9, 128.0, 129.6,
130.0, 130.2, 144.3, 146.4, 173.7. HRMS found: 430.6310; C27H44O4
requires 430.6306.
Oxidation of Compounds 6, 9, 11, 13, 15, and 17 with IBX.
Substrate (1.0 mmol) was dissolved in CH3OH (4 mL), and then IBX
(336 mg, 1.2 mmol) was added. The solution was stirred at 0 °C until
disappearance of the substrate (30 min). At the end, water (4 mL) and
Na2S2O4 (348 mg, 2.0 mmol) were added, and the solution was stirred
for 5 min at room temperature. After evaporation of the solvent under
vacuum, the residue was solubilized with ethyl acetate and treated with
a saturated solution of NaHCO3. The aqueous phase was extracted with
ethyl acetate. The organic phases were washed with a saturated solution
of NaCl and dried over Na2SO4. After evaporation of the solvent,
2-(3′,4′-dihydroxyphenyl)ethyl methyl carbonate 8 (colorless oil, 86%
yield), 2-(3′,4′-dihydroxyphenyl)ethyl acetate 3 (colorless oil, 85%
yield), 2-(3′,4′-dihydroxyphenyl)ethyl hexanoate 19 (yellow oil, 84%
yield), 2-(3′,4′-dihydroxyphenyl)ethyl palmitate 20 (orange oil, 88%
yield), 2-(3′,4′-dihydroxyphenyl)ethyl oleate 21 (orange oil, 89% yield),
and 2-(3′,4′-dihydroxyphenyl)ethyl linoleate 22 (orange oil, 73% yield)
were obtained. To recover 2-iodobenzoic acid, the aqueous phase
deriving from the oxidation reaction was acidified with HCl 37% until
pH 1 and then extracted with ethyl acetate. The organic phase was
dried on Na2SO4. After filtration, the solvent was evaporated under
vacuum. 2-Iodobenzoic was recovered in 85% yield.
Validation of Experimental Data. All conversions and yields are
the average of at least five different experiments.
RESULTS AND DISCUSSION
1
2-(3′,4′-Dihydroxyphenyl)ethyl hexanoate 19: H NMR (CDCl3) δ
The procedure optimized to obtain hydroxytyrosol 1 is
depicted in Scheme 1. To avoid a possible competitive oxidation
on the alcoholic chain of tyrosol 4 and homovanillyl alcohol 5,
the first step was the chemoselective protection of this functional
group. We performed it by using DMC, a cheap and green
carboxymethylating agent having properties as an ecofriendly
solvent as well as an environmentally benign substitute for
hazardous and toxic reagents such as phosgene, methyl halides,
and methyl sulfate (35). In our experimental conditions, by using
catalytic amounts of sulfuric acid or 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU), we obtained 2-(4′-hydroxyphenyl)ethyl methyl
carbonate 6 (tyrosol carboxymethylated) and 2-(4′-hydroxy-3′-
methoxyphenyl)ethyl methyl carbonate 7 (homovanillyl alcohol
0.85 (3H, m, CH3), 1.18-1.27 (4H, m, 2 × CH2), 1.49-1.64 (2H, m,
CH2), 2.26 (2H, t, J ) 7.6 Hz, COCH2), 2.78 (2H, t, J ) 7.1 Hz, Ph-
CH2), 4.18 (2H, t, J ) 7.1 Hz, CH2O), 6.58 (1H, dd, J ) 8.0 and 1.9
Hz, H-ar), 6.70 (2H, d, J ) 1.9 Hz, H-ar), 6.76 (2H, d, J ) 8.0 Hz,
H-ar); 13C NMR (CDCl3) δ 13.8, 22.3, 24.6, 31.2, 34.4, 65.2, 115.3,
115.8, 121.2, 130.3, 142.5, 143.8, 174.9. HRMS found: 252.3120;
C14H20O4 requires 252.3116. NMR data of compounds 3 and 20-22
were consistent with those reported in the literature (13, 34).
Oxidation of Compounds 7, 10, 12, 14, 16, and 18 with IBX. The
experimental procedure is the same. After evaporation of the solvent,
2-(3′,4′-dihydroxyphenyl)ethyl methyl carbonate 8 (colorless oil, 78%
yield), 2-(3′,4′-dihydroxyphenyl)ethyl acetate 3 (colorless oil, 80%
yield), 2-(3′,4′-dihydroxyphenyl)ethyl hexanoate 19 (yellow oil, 60%
yield), 2-(3′,4′-dihydroxyphenyl)ethyl palmitate 20 (orange oil, 85%

Synthesis of Hydroxytyrosol and Lipophilic Derivatives
J. Agric. Food Chem., Vol. 56, No. 19, 2008 8901
Scheme 2. Synthetic Procedure To Obtain Lipophilic Phenols from Tyrosol 4 or Homovanillyl Alcohol 5
Table 1. Chemoselective Esterification of Tyrosol 4 and Homovanillyl
Alcohol 5a
dithionite (Na2S2O4) allowed the isolation of the corresponding
oxidation product, 2-(3′,4′-dihydrophenyl)ethyl methyl carbonate
8 (hydroxytyrosol carboxymethylated), in 86 and 78% yields,
respectively. The oxidation proceeded with a high selectivity
on the ortho-position. The only byproduct of the oxidation was
2-iodobenzoic acid, which we recovered from the solution and
reused for the regeneration of IBX. When the oxidation of 6
and 7 was performed with DMP as oxidant, we observed a
similar efficiency; in fact, hydroxytyrosol carboxymethylated
8 was obtained in 85% yield.
entry
substrate
acylating agent
yield (%)
1
2
3
4
5
6
7
8
9
10
4
5
4
5
4
5
4
5
4
5
CH3COCl
CH3COCl
CH3(CH2)4COCl
CH3(CH2)4COCl
CH3(CH2)14COCl
CH3(CH2)14COCl
CH3(CH2)7CHdCH(CH2)7COCl
CH3(CH2)7CHdCH(CH2)7COCl
CH3(CH2)4(CHdCHCH2)2(CH2)6COCl
CH3(CH2)4(CHdCHCH2)2(CH2)6COCl
9: 90
10: 100
11: 80
12: 83
13: 75
14: 75
15: 86
16: 75
17: 60
18: 70
Successively, we optimized the one-pot synthesis using the
same DMC as carboxymethylating reagent in the first step as
well as solvent in the oxidative/reductive step with DMP and
Na2S2O4. Without any workup and chromatographic purifica-
tions, we isolated the final product in quantitative conversion
and 82% yield. The final step of the synthethic procedure
reported in Scheme 1 was the deprotection of the alcoholic chain
of the hydroxytyrosol carboxymethylated 8. Acidic conditions
(6 M HCl, THF) were ineffective, whereas in basic conditions
(1 M KOH, THF) hydroxytyrosol 1 was obtained in 85% yield.
a Experimental conditions: substrate (1.0 mmol); acylating agent (1.2 mmol);
DMC (3 mL); rt; 24 h; conversions > 98%.
Table 2. Oxidation of Compounds 9-18 with IBX and DMPa
entry
substrate
oxidant
yield (%)
1
2
3
4
5
6
7
8
9
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
3: 85
3: 80
10
11
12
13
14
15
16
17
18
9
10
11
12
13
14
15
16
17
18
1
The H and 13C NMR spectra and the HPLC profile of the
19: 84
19: 60
20: 88
20: 85
21: 89
21: 68
22: 73
22: 62
3: 80
synthesized hydroxytyrosol 1 are reported in Figure 3. On the
basis of the antioxidant activity of hydroxytyrosol carboxy-
methylated 8 measured by the DPPH reduction method (28)
and owing to its lipophilic properties, this compound appears
to be a new antioxidant useful for cosmetic and nutraceutical
applications.
9
IBX
IBX
10
11
12
13
14
15
16
17
18
19
20
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
Finally, we extended this procedure for the preparation of
lipophilic hydroxytyrosol derivative (Scheme 2), up until now
prepared by lipase- or acid-catalyzed esterification of the
precious and expensive hydroxytyrosol (12). We performed the
selective esterification of tyrosol 4 and homovanillyl alcohol 5
with acyl chlorides in DMC as solvent. For example, 2-(4′-
hydroxyphenyl)ethyl acetate 9 and 2-(4′-hydroxy-3′-metho
xyphenyl)ethyl acetate 10 were prepared in 90% and quantitative
yields by using only a little excess of acetyl chloride in DMC
without any catalyst (Table 1, entries 1 and 2). The chemose-
lective acylation of the aliphatic hydroxyl group is an important
and frequently used transformation in organic synthesis (36).
Typically, it was performed in dry conditions under homoge-
neous catalysis with acetic acid or acetyl chloride or acetic
anhydride (37). Probably, in our experimental conditions,
operating in no-dry conditions, the in situ generation of traces
of hydrochloric acid deriving from the hydrolysis of the acetyl
chloride (38) and the greater nucleophilicity of the aliphatic
hydroxyl group, compared to the phenolic group, drove the
3: 72
19: 82
19: 62
20: 92
20: 88
21: 89
21: 65
22: 77
22: 58
a Experimental conditions: (a) oxidation with IBX, substrate (1.0 mmol), CH3OH
(3 mL), IBX (1.2 mmol), T ) 0 °C, 30 min; (b) oxidation with DMP, substrate (1.0
mmol), THF (3 mL), IBX (1.2 mmol), rt, 1 h; (c) reduction, H2O (4 mL), Na2S2O4
(2.0 mmol), rt, 5 min. Conversions are quantitative.
carboxymethylated) in quantitative conversions and yields (28).
In these reactions, sulfuric acid increased the electrophilic
character of the carbonyl group of DMC; DBU raised the
nucleophilic character of the alcoholic function. Afterward,
compounds 6 and 7 were oxidized with IBX in methanol at
room temperature. The following in situ reduction with sodium

8902 J. Agric. Food Chem., Vol. 56, No. 19, 2008
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protection on the alcoholic function of 4 and 5. We have
observed a similar selectivity by using several saturated or
unsaturated acyl chloride having longer chains such as hexanoyl
chloride, palmitoyl chloride, oleoyl chloride and linoleoyl
chloride. The corresponding 2-(4′-hydroxyphenyl)ethyl hex-
anoate 11, 2-(4′-hydroxy-3′-methoxyphenyl)ethyl hexanoate 12,
2-(4′-hydroxyphenyl)ethyl palmitate 13, 2-(4′-hydroxy-3′-meth-
oxyphenyl)ethyl palmitate 14, 2-(4′-hydroxyphenyl)ethyl oleate
15, 2-(4′-hydroxy-3′-methoxyphenyl)ethyl oleate 16, 2-(4′-
hydroxyphenyl)ethyl linoleate 17, and 2-(4′-hydroxy-3′-meth-
oxyphenyl)ethyl linoleate 18 were isolated in satisfactory yields
(Table 1, entries 3-10). The following oxidative step with IBX
and reduction with Na2S2O4 of compounds 9-18 allowed us
to obtain the corresponding hydroxytyrosol derivatives such as
2-(3′,4′-dihydroxyphenyl)ethyl acetate 3, 2-(3′,4′-dihydroxyphe-
nyl)ethyl hexanoate 19, 2-(3′,4′-dihydroxyphenyl)ethyl palmitate
20, 2-(3′,4′-dihydroxyphenyl)ethyl oleate 21, and 2-(3′,4′-
dihydroxyphenyl)ethyl linoleate 22 in high yields (Table 2). In
general, the oxidation of tyrosol derivatives proceeded with
higher yields compared to homovanillyl derivatives (Table 2,
compare entries 1, 3, 5, 7, and 9 with entries 2, 4, 6, 8, and 10).
As previously observed, the use of DMP did not modify the
efficiency and selectivity of the oxidation (Table 2, compare
entries 1-10 with entries 11-20).
In conclusion, in this paper we described a short, efficient,
and low-cost synthetic procedure to obtain hydroxytyrosol as
well as its lipophilic derivatives starting from commercially
available and natural compounds such as tyrosol as well as
homovanillyl alcohol. Reactions proceeded quickly, and the final
products were obtained in satisfactory yields and high purity.
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SAFETY
IBX was reported to be explosive under impact or heating to
>200 °C (39). Dess and Martin suggested that the explosive
properties of some samples of IBX were due to the presence of
impurities of potassium bromate utilized during its preparation,
that is, the oxidation of 2-iodobenzoic acid in acidic medium
(40). A safe and convenient preparation of IBX involves the
utilization of oxone in water (26).
Supporting Information Available: 1H and 13C NMR spectra
of lipophilic tyrosol, homovanillyl alcohol, and hydroxytyrosol.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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Received for review May 19, 2008. Revised manuscript received August
5, 2008. Accepted August 6, 2008. We thank the Ministero delle Politiche
Agricole e Forestali (MIPAF, National Project “Estrazione di oli vergini
di oliva da paste denocciolate: miglioramento della qualita` e delle rese
e valorizzazione dei residui - Valorolio”) for financial support.
JF801558Z