Efficient synthesis of hydroxytyrosol from 3,4-dihydroxybenzaldehyde

Article abstract of DOI:10.1080/00397911.2010.531369

Hydroxytyrosol is a naturally occurred orthodiphenolic component of olive oil. A variety of biological functions for this molecule have been reported. We report herein an efficient and practical method for the chemical synthesis of hydroxytyrosol from 2,3-dihydroxybenzaldehyde. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.531369

This article was downloaded by: [University of Arizona]
On: 10 August 2012, At: 04:31
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Efficient Synthesis of Hydroxytyrosol
from 3,4-Dihydroxybenzaldehyde
Zhao-Li Zhang a , Jinglei Chen a , Qiongming Xu a , Cui Rao a &
Chunhua Qiao a
a College of Pharmaceutical Science, Soochow University, Suzhou,
China
Accepted author version posted online: 24 Aug 2011. Version of
record first published: 11 Nov 2011
To cite this article: Zhao-Li Zhang, Jinglei Chen, Qiongming Xu, Cui Rao & Chunhua Qiao (2012):
Efficient Synthesis of Hydroxytyrosol from 3,4-Dihydroxybenzaldehyde, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:6, 794-798
To link to this article: http://dx.doi.org/10.1080/00397911.2010.531369
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 42: 794–798, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.531369
EFFICIENT SYNTHESIS OF HYDROXYTYROSOL FROM
3,4-DIHYDROXYBENZALDEHYDE
Zhao-Li Zhang, Jinglei Chen, Qiongming Xu, Cui Rao, and
Chunhua Qiao
College of Pharmaceutical Science, Soochow University, Suzhou, China
GRAPHICAL ABSTRACT
Abstract Hydroxytyrosol is a naturally occurred orthodiphenolic component of olive oil. A
variety of biological functions for this molecule have been reported. We report herein an
efficient and practical method for the chemical synthesis of hydroxytyrosol from 2,3-
dihydroxybenzaldehyde.
Keywords Antioxidant; hydroxytyrosol; synthesis
INTRODUCTION
Hydroxytyrosol has been reported to exhibit a variety of biological activities,
including protection against oxidative DNA damage and low-density lipoprotein
(LDL) oxidation,[1] scavenging of free radicals,[2] antibacterial activity,[3] and preven-
tion of platelet aggregation.[4] Most of these functions are related to its antioxidant
capability. Hydroxytyrosol displayed 10 times more radical absorbance capacity
than green tea and two times more than CoQ10.[5]
Like other catechols, the mechanism of antioxidant activity of hydroxytyrosol
was attributed to the formation of the initial o-hydroxyquinone intermediate,[6]
which could be further oxidized to quinone or attacked by another molecular of
hydroxytyrosol to form a dimer.
Despite the reported biological importance of hydroxytyrosol, it is commer-
cially available only for research purposes, and the approximate cost is $1000 per
gram,[7] which is very expensive for a simple small molecule with a molecular weight
Received September 5, 2010.
Address correspondence to Chunhua Qiao, College of Pharmaceutical Science, Soochow
University, Suzhou 215123, Jiangsu, China. E-mail: qiaochunhua@suda.edu.cn
794

CHEMICAL SYNTHESIS OF HYDROXYTYROSOL
795
of only 154.16. Therefore, chemical synthesis of hydroxytyrosol at a competitive
price should be investigated extensively.
In 1949, Schopf et al. reported the first chemical synthesis of hydroxytyrosol.
This synthesis employed 3,4-dihydroxyphenyl acetic acid as the starting material,
which was reduced with LiBH4 to afford hydroxytyrosol in a one-step reaction.[8]
Later on, LiAlH4 in tetrahydrofuran (THF) was employed as reductant, and the
total reaction yield was improved from 40% to 82.8%.[9] However, the high cost of
the starting material (i.e., 3,4-dihydroxyphenyl acetic acid,) limited the practical
application of this method. Recently, Bovicelli et al. achieved the chemical synthesis
of hydroxytyrosol from tyrosol in seven steps,[10] involving monobromination, sub-
stitution, diacetylation, and deprotection, to give an overall yield of 37%. However,
the practicality of this synthetic route is compromised by the required selective
monobromination, demethylation using expensive nasty, BBr3, low reaction
temperature, and final deprotection using enzymes.
We report herein a new, efficient, and practical method for the synthesis of
hydroxytyrosol from commercially available 2,3-dihydroxybenzaldehyde (1), which
as an important and widely used intermediate in food and pharmaceutical
industries that is inexpensive and readily commercially available. As shown in
Scheme 1, the two free hydroxyl groups of 1 were first protected by the benzyl
group. Subsequently, one carbon homologation of the protected aldehyde 2 was
achieved by an established method employing a-(N-methylanilino)acetonitrile as a
one-carbon building block,[11] which was the key step for this synthesis. Specific
ally, the reaction between 2 and a-(N-methylanilino)acetonitrile afforded a-cyano
enamines 3, which was readily converted to the carboxylic acid under acidic con-
ditions. The resulting carboxylic acid 4 was then readily transformed to the corre-
sponding alcohol 5 upon sodium boron hydride treatment under acidic conditions.
Hydroxytyrosol 6 was finally obtained by hydrogenolysis under Pd-C=H2
conditions.
In summary, a new synthetic method for hydroxytyrosol is described, which
has the advantages of mild reaction conditions, high efficiency, and low cost. The
key step of this synthesis is one-carbon homologation of 2 to afford carboxylic acid
4 employing a-(N-methylanilino) acetonitrile as the one-carbon building block.
Scheme 1. Synthesis of hydroxytyrosol 6 from 3,4-dihydroxybenzaldehyde.

796
Z.-L. ZHANG ET AL.
EXPERIMENTAL
3,4-(O-Dibenzylhydroxy)benzaldehyde (2)
Benzyl bromide (0.24 mL, 2.0 mmol) was added to a solution of 3,4-dihydrox-
ybenzaldehyde (138.0 mg, 1.0 mmol) and K2CO3 (288.0 mg, 2.1 mmol) in 10.0 mL
acetone. The reaction mixture was refluxed for 20 h. Acetone was removed, and
the remaining residue was diluted by 25 mL of ethyl ether. The ether was washed
with water (10 mL ꢀ 2), dried (Na2SO4), and concentrated under reduced pressure
to afford the product as a white solid (292.0 mg, 92%). 1H NMR (400 MHz, CDCl3)
d 9.81 (s, 1H), 7.49–7.37 (m, 12H), 7.02 (d, 1H, J ¼ 8.0 Hz), 5.26 (s, 2H), 5.22 (s, 2H);
13C NMR (75 MHz, CDCl3) d 190.8, 154.1, 148.9, 136.4, 136.1, 130.1, 128.6, 128.5,
128.0, 127.9, 127.2, 126.9, 126.7, 112.8, 111.9, 70.8, 70.6.
a-(N-Methylanilino)acetonitrile (7)
This intermediate was prepared according to reported method[11] with slightly
modification. Briefly, K2CO3 (1380 mg, 10.0 mmol, 2.0 equiv.) was added to a solution
of N-methylaniline (0.5 mL, 5.0 mmol, 1.0 equiv.) and 2-chloroacetonitrile (0.35 mL,
5.0 mmol, 1.0 equiv.) in 25 mL toluene. The reaction mixture was refluxed overnight,
washed with H2O (10 mL ꢀ 2), dried (Na2SO4), and concentrated under reduced press-
ure with flash chromatography (petroleum ether–ethyl ether ¼ 10:1) afford the product
as a brown oil (510.0 mg, 80%). 1H NMR (400 MHz, CDCl3) d 7.33–7.29 (m, 2H), 6.92
(t, J ¼ 8.0 Hz, 1H), 6.87 (d, J ¼ 8.0 Hz, 2H), 4.15 (s, 2H), 2.99 (s, 3H). 13C NMR
(75 MHz, CDCl3) d 147.3, 128.9, 119.4, 115.4, 114.1, 41.4, 38.5.
a-(N-Methylanilino)-3,4-dibenzylhydroxycinnamonitrile (3)
KH (80.0mg, 1.2 equiv.) was added under N2 atmosphere to a solution of
a-(N-methylanilino)acetonitrile (104.0 mg, 0.71mmol, 1.2 equiv.) and 3,4-(O-dibenzyl-
hydroxy)benzaldehyde (188.7 mg, 0.59mmol, 1.0 equiv.) in 10.0mL tetrahydrofuran
(THF). The reaction mixture was stirred for 2 h at room temperature, and diluted with
2.0 mL water. The reaction mixture was partitioned with ethyl acetate and water
(20:10); organic phase was dried (Na2SO4) and concentrated under reduced pressure.
Flash chromatography (petroleum ether–ethyl acetate 20:1) afforded the product (E-
1
and Z-mixture) as a light yellow oil (240mg, 85%). H NMR (400MHz, CDCl3) d:
7.42 (d, J ¼ 8.0 Hz, 3H), 7.37 (t, J ¼ 4.0 Hz, 3H), 7.32 (d, J ¼ 8.0Hz, 3H), 7.23 (s,
2H), 7.04–6.93 (m, 3H), 6.84 (t, J ¼ 8.0 Hz, 3H), 6.76 (s, 1H), 5.19 (s, 2H), 4.95 (s,
2H), 3.24 (s, C CH of Z, 1H), 3.02 (s, C CH of E, 1H), 2.93 (s, 3H); 13C NMR
(100MHz, CDCl3) d: 151.0, 150.0, 149.1, 148.7, 146.8, 145.5, 138.8, 137.2, 137.2,
137.0, 136.8, 131.4, 129.7, 129.6, 128.9, 128.8, 128.8, 128.8, 128.3, 128.2, 128.2, 128.1,
127.7, 127.5, 127.4, 127.2, 126.5, 126.1, 125.3, 122.9, 122.7, 120.7, 119.9, 117.7, 117.2,
116.7, 115.9, 115.1, 115.1, 114.7, 113.9, 113.8, 71.4, 71.2, 71.0, 70.9, 40.4, 37.7.
=
=
3,4-(Dibenzylhydroxy)phenyl Acetic Acid (4)
To a solution of 3 (617.0 mg, 1.47 mmol) in 12.0 mL THF was added 10% HCl
(12.0 mL). The reaction mixture was refluxed overnight and concentrated. The

CHEMICAL SYNTHESIS OF HYDROXYTYROSOL
797
remaining residue was partitioned with ethyl ether and water (30:15 mL), and
organic phase was washed with 10% Na2CO3 (2 ꢀ 10 mL), dried (Na2SO4), and con-
centrated to afford the product (408.0 mg, 85%). 1H NMR (400 MHz, CDCl3) d 7.43
(t, J ¼ 6.0 Hz, 4H), 7.35 (t, J ¼ 6.0 Hz, 4H), 7.30 (d, J ¼ 6.0 Hz, 2H), 6.90 (d,
J ¼ 8.0 Hz, 1H), 6.88 (s, 1H), 6.80 (d, J ¼ 8.0 Hz, 1H), 5.14 (d, J ¼ 4.0 Hz, 4H),
3.54 (s, 2H); 13C NMR (100 MHz, CDCl3) d 178.3, 149.2, 148.5, 137.5, 137.3,
128.7, 128.7, 128.1, 128.0, 127.6, 127.5, 126.6, 122.6, 116.4, 115.2, 71.5, 71.5, 40.8.
3,4-Dibenzylhydroxyphenethyl Alcohol (5)
NaBH4 (131.0 mg, 3.5 mmol) and methanesulfonic acid (0.17 mL, 2.6 mmol)
were added to a solution of 4 (241.0 mg, 0.75 mmol) in 6.0 mL DMSO. The reaction
mixture was stirred overnight at room temperature. The reaction was quenched by
addition of 10% NaOH (6.0 mL), extracted with diethyl ether (3 ꢀ 15 mL). The organic
extraction was combined, dried (Na2SO4), and concentrated to afford the product as a
white solid (212.0 mg, 92%). 1H NMR (400 MHz, CDCl3) d 7.43–7.41 (m, 4H), 7.33 (t,
J ¼ 8.0 Hz, 4H), 7.29–7.20 (m, 2H), 6.85 (d, J ¼ 8.0 Hz, 1H), 6.79 (s, 1H), 6.69 (d,
J ¼ 8.0 Hz, 1H), 5.11 (d, J ¼ 4.0 Hz, 4H), 3.71 (t, J ¼ 6.4 Hz, 2H), 2.70 (t, J ¼ 6.8 Hz,
2H), 1.85 (s, 1H); 13C NMR (100 MHz, CDCl3) d 149.2, 147.9, 137.6, 137.5, 132.2,
128.7(2C), 128.1, 128.0, 127.7, 127.6, 122.2, 116.4, 115.6, 71.7, 71.6, 63.8, 38.9.
Hydroxytyrosol (6)
Pd-C (3.0 mg) was added to a solution of 5 (85.0 mg, 0.28 mmol) in 2.0 mL THF,
and the reaction was placed under a H2 atmosphere. After 3 h, the reaction mixture
was filtered through a plug of celite, which was further washed with THF (5.0 mL),
and the combined filtrates were concentrated under reduced pressure to afford the
1
product 3,4-dihydroxytyrosol as a colorless oil (42.0 mg, 98%). H NMR (400 MHz,
CD3COCD3) d 7.79 (s, 1H), 6.72 (d, J ¼ 8.0 Hz, 1H), 6.70 (s, 1H), 6.54 (d, J ¼ 8.0 Hz,
1H), 3.86 (s, 1H), 3.68 (t, J ¼ 8.0 Hz, 2H), 3.39 (s, 1H), 2.66 (t, J ¼ 8.0 Hz, 2H); 13C
NMR (100 MHz, CD3COCD3) d 145.4, 143.9, 131.5, 120.8, 116.6, 115.7, 64.1, 39.4.
HRMS calcd. for [M ꢁ H]: 153.0557, found [ESIꢁ]: 153.0554, error 1.96 ppm.
ACKNOWLEDGMENTS
The financial support from Soochow University and the National Science and
Technology Major Project on Key Drug Creation and Manufacturing Program
(2009ZX09103-129) is gratefully acknowledged. We thank Professor Zhongwu
Guo at Wayne State University and Professor Zhengqiang Wang at University of
Minnisota for critical revisions.
REFERENCES
1. Aruoma, O. I.; Kaur, H.; Halliwell, B. Oxygen free radicals and human diseases. J. R. Soc.
Health 1991, 111, 172–177
2. Espin, J. C.; Solar-Rivas, C.; Wichers, H. J. Characterization of the total free radical
scavenger capacity of vegetable oils and oil fractions using 2,2-diphenyl-1-picrylhydrazyl
radical. J. Agric. Food Chem. 2000, 48, 648–656.

798
Z.-L. ZHANG ET AL.
3. Capasso, R.; Evidente, A.; Schivo, I.; Orru, G.; Marcialis, M. A.; Cristinzo, G. Antibac-
terial polyphenols from olive oil mill waste waters. J. Appl. Bacteriol. 1995, 79, 393–398.
4. Petroni, A.; Blasevich, M.; Salami, M.; Papini, N.; Montedoro, G. F.; Galli, C. Inhibition
of platelet aggregation and eicosanoid production by phenolic components of olive oil.
Thromb. Res. 1995, 78, 151–160.
5. Rastrelli, L.; Passi, S.; Ippolito, F.; Vacca, G.; Simone, F. D. Rate of degradation of
a-tocopherol, squalene, phenolics, and polyunsaturated fatty acids in olive oil during
different storage conditions. J. Agric. Food Chem. 2002, 50, 5566–5570.
6. Lucia, M. D.; Panzella, L.; Pezzella, A.; Napolitano, A.; Ischia, M. Oxidative chemistry of
the natural antioxidant hydroxytyrosol: Hydrogen peroxide-dependent hydroxylation and
hydroxyquinone=o-quinone coupling pathways. Tetrahedron 2006, 62, 1273–1278.
7. Obied, K. H.; Allen, S. M.; Bedgood, R. D.; Prenzler, D. P.; Robards, K.; Stochman, R.;
Bioactivity and analysis of biophenols recovered from olive mill waste. J. Agric. Food
Chem. 2005, 53, 823–837.
8. Schopf, C.; Gottmann, G.; Meisel, E. M. Uber b-(3,4-dioxyphenyl)-athylalkohol. Liebigs
Ann. Chem. 1949, 563, 86–93.
9. Capasso, R.; Evidente, A.; Avolio, S.; A highly convenient synthesis of hydroxytyrosol
and its recovery from agricultural waste waters. J. Agric. Food Chem. 1999, 47, 1745–1748.
10. Bovicelli, P.; Antonioletti, R.; Mancini, S.; Causio, S.; Borioni, G.; Ammendola, S.;
Barontini, M. Expedient synthesis of hydroxytyrosol and its esters. Synth. Commun.
2007, 37, 4245–4252.
11. Takahashi, K.; Shibasaki, K.; Ogura, K.; Iida, H. Efficient method for a one-carbon
homologation of aldehydes and benzophenone to carboxylic acids. J. Org. Chem. 1983,
48, 3566–3569.