Radical-scavenging polyphenols: New strategies for their synthesis

Article abstract of DOI:10.1211/jpp.59.12.0013

New strategies for the synthesis of polyphenols, compounds with antioxidant properties contained in every kind of plants, are discussed. Syntheses of different classes of polyphenols, namely ubiquinones, present in many natural systems in which electron-transfer mechanisms are involved, hydroxytyrosol, one of the main components of the phenol fraction in olives, and flavonoids, widespread in the plant kingdom, were approached by simple and environmentally sustainable methods.

Full text of DOI:10.1211/jpp.59.12.0013

JPP 2007, 59: 1703–1710
© 2007 The Authors
Received February 19, 2007
Accepted June 15, 2007
DOI 10.1211/jpp.59.12.0013
ISSN 0022-3573
Radical-scavenging polyphenols: new strategies for
their synthesis
Paolo Bovicelli
Abstract
New strategies for the synthesis of polyphenols, compounds with antioxidant properties contained
in every kind of plants, are discussed. Syntheses of different classes of polyphenols, namely ubiqui-
nones, present in many natural systems in which electron-transfer mechanisms are involved, hydroxy-
tyrosol, one of the main components of the phenol fraction in olives, and flavonoids, widespread in
the plant kingdom, were approached by simple and environmentally sustainable methods.
Introduction
Many chronic degenerative diseases in adults and the parallel aging process are in many
cases directly related to oxidative stress. This condition is the result of an imbalance
between oxidative processes and defence systems (Kaikkonen et al 1997). It occurs because
of an overproduction of free radicals in the organism, a deficit in the defence system, or,
most commonly, both factors together.
Natural antioxidants can be divided into two types: enzymatic (including peroxy
dismutase, catalase, glutathione peroxidase) and non-enzymatic (Gatto et al 2002). From the
latter, relatively small molecules are believed able to prevent development of some patholo-
gies, and to protect tissues from biological damage caused by the formation of free radicals.
Many beverages and plant extracts, as well as vegetables and some types of fruit, are there-
fore believed to be important dietary constituents because they contain antioxidant com-
pounds.
Institute of Biomolecular
Chemistry, CNR, Department of
Chemistry, University ‘La
Sapienza’, P.le A. Moro, 5-00185
Rome, Italy
Paolo Bovicelli
Correspondence: Paolo
Ascorbic acid (vitamin C), tocopherols (vitamin E), carotenoids, phenolic and polyphe-
nolic substances are particularly important among these compounds. Currently, the most
widely used preservatives are synthetic (t-butylhydroxyanisole, toluene, t-butylhydroquinone,
etc.), whereas it would be desirable to use natural substances or their derivatives to preserve
products intended for human use or animal feed.
Bovicelli, Institute of
Biomolecular Chemistry, CNR,
Department of Chemistry,
University ‘La Sapienza’, P.le A.
Moro, 5-00185 Rome, Italy.
E-mail:paolo.bovicelli@uniroma1.it
Unfortunately, the production of natural substances invariably requires their extraction
from the organisms of origin, which may not be viable either because of the small amount
of extract that can be obtained and/or the high costs of extraction procedures. Furthermore,
every extraction procedure involves the destruction of a product meant for human and/or
animal consumption. Recovery from waste products or using modestly polluting synthetic
methods is therefore preferred to extraction, and may also control or improve yields. The
availability of controlled methods for the synthesis of these compounds is preferable since it
opens up the possibility of obtaining derivatized molecules with improved or specific prop-
erties for the preservation of a given product.
Polyphenols are molecules with antioxidant properties contained in every kind of plant.
The specific properties of these molecules are due to the presence of aromatic moieties and
of many hydroxyl groups (Fernandez-Bolanos et al 1998). The antioxidant effect may be
brought about in many ways, one of which is the so-called ‘free-radical scavenging’ mecha-
nism, whereby the unpaired electron becomes delocalized over the aromatic ring, acquiring
the possibility of forming strong hydrogen bonds. Natural antioxidants endowed with such
structural characteristics (such as flavonoids, gallic acid, resveratrol, ubiquinones and
hydroxytyrosol) are important for their potential use in foods and drugs.
Aknowledgements: Many
people have been involved in the
work described herein, including
my colleagues Dr R. Antonioletti,
Dr G. Nicolosi, and Dr R. Bernini
and Professor E. Mincione
(DABAC, University of Viterbo).
Collaborators who played a key
role in several of the projects
discussed briefly in this article
are Dr S. Ammendola, Dr M.
Barontini, Dr G. Borioni, Dr V.
D’Angelo and Dr D. Fabbrini.
The financial support from the
Italian Ministry for University
and Research, General
Management for Strategies and
Development of
Internationalization of Scientific
and Technological Research is
gratefully acknowledged.
In the last few years we have reviewed strategies for simple, efficient and economi-
cally viable syntheses of bioactive polyphenols, such as ubiquinones, hydroxytyrosol and
1703

1704
Paolo Bovicelli
derivatives, together with flavonoid derivatives. Recently, we previously prepared from solanesol. The limitations of this
developed an efficient and selective method for halogenating method are probably the high cost of the starting materials
activated aromatic compounds by using dimethyldioxirane and the difficulties in preparing the reagents.
(Bovicelli et al 2002), both in its isolated form or generated
Our approach to the synthesis of these compounds makes
in-situ, as an oxyfunctionalizing reagent or as an oxidant of use of iridol as a key intermediate, exploiting a Lewis-acid-
halide anions to produce electrophilic species. The method promoted shift of an ethereal allyl chain. Iridol is a naturally
was applied to a range of complex natural compounds, such occurring phenol (De Laire & Tiemann 1893) and is commer-
as flavones and flavanones, with excellent results, and a cially available, but at high cost. To make our approach eco-
number of halogenated flavonoids have been prepared using nomically viable we needed to develop a low-cost synthesis
this method (Bovicelli et al 2001). Halogenation of aromatics of iridol, since the syntheses reported to date use severe con-
proved compatible with sensitive functional groups, and the ditions and expensive and environmentally unfriendly rea-
amount of the added oxidant determines the degree of halo- gents (Merz & Rauschel 1993).
genation (Mincione et al 2003). Halogenated derivatives of
We proposed a high-yield synthesis based on simple reac-
aromatic systems are the key intermediates for the prepara- tions, using environmentally sustainable and affordable rea-
tion of higher oxidized compounds and derivatives. In par- gents (Figure 2) (Bovicelli et al 2005).
ticular, a bromination–methoxylation pathway, developed in
Bromination of activated aromatic rings by the oxone/
our laboratories over recent years, for introducing oxygenated NaBr system to produce a highly electrophilic halogenating
functions into aromatic rings allows already known or prom- species has been developed over recent years and applied to a
ising powerful antioxidant polyhydroxylated aromatic deriva- series of natural compounds, showing high efficiency and
tives to be obtained.
selectivity (Bovicelli et al 2001, 2002). This method does not
require the use of molecular halogen or metal catalysts and
can be considered as non-polluting. The methoxylation step,
in which a bromine atom is substituted by a methoxy group,
was likewise developed by strictly controlling the reaction
conditions, since the procedure previously described in the
literature (Capdevielle & Maumy 1993) proved ineffective on
our substrates.
To verify the usefulness of iridol in the synthesis of ubiqui-
nones, we described the synthesis of CoQ3 (Figure 3). The
sodium salt of iridol was etherificated by reaction with bromo-
farnesyl, previously prepared by treatment of farnesol with
PBr3. Treatment of the ether obtained with a Lewis acid such
as etherate BF3 in very mild conditions afforded an allyl shift
to the relative ortho position. The final step, an oxidation pro-
moted by Co(salen) (Lipshutz 2002) yielded a good amount
of ubiquinone Q3.
Good yields of the rearranged product were accomplished
by the shift of the allyl chain into the relative para position.
This rearrangement became much more important when
longer chains were used, such as when a solanesyl group was
used to synthesize CoQ9, in which case the para shift was the
only observed phenomenon.
To improve the efficiency of our approach based on the
allyl shift, we changed strategy and followed a scheme in
which 3,4,5-trimethoxytoluene, submitted to a formylation–
oxidation procedure, gave the suitable phenol derivative so
that the only free position for the allyl chain to migrate to is
the relative ortho (alpha) position (Figure 4) (Bovicelli etal 2006).
The sodium salt of the new phenol was reacted with a suitable
allyl bromine to give the corresponding ether, and further
Synthesis of ubiquinones
Ubiquinones, also known as coenzyme Qn (CoQn;
n = number of isoprene units in the side chain), are lipophilic
molecules comprising a highly functionalized benzoquinone
moiety and an all-trans polyisoprene hydrophobic chain,
which ensures solubility in organic media. In a redox system,
these compounds are present as p-benzoquinones (CoQ) and
p-hydroquinones (ubiquinonols, CoQH2) (Lipshutz et al
2002) (Figure 1).
Ubiquinones are present in many natural systems in which
electron-transfer mechanisms are involved (Anderson et al
2005) and they also function as antioxidants and scavengers
of free radicals (Kalen et al 1987; Mordente et al 1993;
Georgellis et al 2001). Natural CoQn are those with n from
6 to 10, the minor members of the family being synthetic.
CoQ10 is the endogenous compound in humans. All other
members of the family are known as powerful antioxidants
and could be used as dietary supplements, and as anti-aging
factors and nutrients in creams to preserve the epithelium
from damage due to aggressive environmental oxidants.
Many methods are known to produce ubiquinones, includ-
ing the fermentation process for CoQ10, and syntheses starting
from CoQ0 (Lipshutz et al 2005), with a final low-yield oxi-
dation to quinone (Merz & Rauschel 1993). Today, the best
synthesis of CoQ10 is that reported by Lipshutz & Mollard
(2003), in which the key step is the coupling between a
benzyl chloride derivative and an allyl-dimethyl-alane,
O
HO
+
–
2e + 2H
n–2
n–2
CH3O
CH3O
O
CH3O
CH3O
OH
CoQn
CoQnH2
Figure 1 Redox equilibrium of coenzyme Q (CoQn) and ubiquinonols (CoQnH2); n = number of isoprene units in the side chain.

Synthesis of radical-scavenging polyphenols
1705
MeI, K2CO3
acetone, 45°C
MCPA, pTSOH
CHCl3 , 50°, 3 h
NaBr, oxone
O
O
O
acetone, H2O
Br
Br
OH
OH
CH3O
2-hydroxy-5-methyl
acetophenone
3-bromo-2-hydroxy-5-
methyl acetophenone
3-bromo-2-methoxy-5-
methyl acetophenone
MeONa, CuBr (5%)
DMF, H2O, 130°C
Na, MeOH
r.t.
Br
OAc
Br
OH
CH3O
OH
CH3O
CH3O
CH3O
iridol
3-bromo-2-methoxy-5-
methylphenol acetate
3-bromo-2-methoxy-5-
methylphenol
90% overall yield
Figure 2 Synthesis of iridol.
H
BF3*ET2O / Et2O
H
Br
3
O–Na+
H3CO
O
H3CO
3
–20°, conv. 90%, 75%
THF, 10°, 95%
OCH3
OCH3
sodium
2,3-dimethoxy-5-
methylphenolate
2,3-dimethoxy-5-methyl-
phenyl farnesyl ether
H
3
O
H
3
Na2CO3/Pyr/toluene
H3CO
OH
OCH3
H3CO
O
O2/CoSalen/CH3CN
r.t., 70%
OCH3
2,3-dimethoxy-5-methyl-
6-farnesyl phenol
CoQ3
Figure 3 Synthesis of ubiquinone Q3.
treatment with a Lewis acid led to the correct product, is present as a free molecule or as a substructure of more
rearrangement occurring only on the free position. Using this complicated compounds, such as oleuropein, present in
strategy we obtained good results for every allyl side chain large quantities in the leaves and in unripe olives. Unfortu-
we used. In the case of the solanesyl group, yields were lower nately, being a hydrophilic molecule and thus poorly soluble
than obtained with shorter chains but were still good. Worthy in lipid matrices, most of the hydroxytyrosol contained in
of note is that in no case was there evidence of epimarization the fruits ends up in the waste water at the end of the manu-
of the allyl chain from our analytical methods.
facturing process (Visioli et al 1999). In olive oil, in which
it plays an important role as an antioxidant preserving
against the degradation of fatty acids, it is present in very
small quantity, the least being in extra-virgin olive oil
(Gutfinger 1981).
Synthesis of hydroxytyrosol and its derivatives
Hydroxytyrosol may be extracted from waste water, but
the process does not seem economically viable (Fernandez-
Bolanos et al 2004), or may be obtained by synthetic proc-
esses, including reduction of 3,4-dihydroxyphenylacetic acid
(Tuck et al 2000), hydrolysis of oleuropein (Alcudia
Gonzalez et al 2004) and by enzymatic conversion of tyrosol
Hydroxytyrosol (3,4-dihydroxy-phenethyl alcohol) is bel-
ieved to be the antioxidant with the highest free-radical-
scavenging capacity: double that of quercetin and more than
three times that of epicatechin. Hydroxytyrosol is one of the
main components of the phenol fraction identified in the
fruit of the olive, a widespread tree in the Mediterranean. It

1706
Paolo Bovicelli
CHO
OH
Cl2CHOCH3
AlCl3, THF
H2O2, MeOH
MeO
OMe
OMe
MeO
MeO
OMe
OMe
OMe
OMe
3,4,5-trimethoxy-5-methyl
formaldehyde
3,4,5-trimethoxy-5-
methylphenol
3,4,5-trimethoxytoluene
NaH
THF
ONa
MeO
OMe
OMe
sodium
3,4,5-trimethoxy-5-
methylphenolate
O
H
OH
OMe
H
n
BF3.Et2O
n
MeO
OMe
MeO
OMe
OMe
Br
H
n
FeCl3
PBr3
H
O
OH
H
n
n
O
OMe
OMe
Coenzyme Qn
a) n = 1, b) n = 2 c) n = 3 d) n = 9
Figure 4 Improved synthesis of ubiquinones starting from 3,4,5-trimethoxytoluene.
(Espin et al 2001) and oleuropein (Briante et al 2004). None One of the most critical problems in using hydroxytyrosol as
of the methods described is suitable for industrial applica- preservative or drug, as well as its high cost, is its ready deg-
tions, partly because of the high cost of the starting materials, radation in the presence of external oxidants, light and base
increasing the market price of these molecules.
media. The corresponding ester derivative on the side chain
Tyrosol (4-hydroxy-phenethyl alcohol) is also widely proved to be very stable for long periods in almost any condi-
present in the waste water. It is easily separated from these tions except in hydrolytic or reducing media. For this reason,
waters as a solid material but this material is acidic and highly such derivatives can be used in formulations as precursors of
polluting and must therefore be destroyed before disposal, the active principle.
which is expensive. Tyrosol is not biologically active and,
A new compound with promising biological properties has
being a phenol and thus an acidic material, is considered a been synthesized by a similar procedure (Figure 6). 2,5-Dihy-
pollutant. The development of simple systems to transform droxytyrosol has been shown to have powerful antibacterial
tyrosol into hydroxytyrosol is therefore attractive for the activity, and, owing to its structure, is a potentially good anti-
added value it might give to waste water.
oxidant. The biological properties of this new molecule are
Using our expertise in oxyfunctionalization of aromatic currently being investigated.
rings, we proposed a synthetic scheme using easy transformation
and highly eco-friendly, economically and environmentally
sustainable processes (Figure 5) (Bovicelli et al 2007). By this
method, hydroxytyrosyl acetate and any other ester derivative
Derivatives of natural flavonoids
can be synthesized, giving the possibility of obtaining prod-
rugs, since the esters are easily transformed into the parent
alcohols by a number of hydrolases present in the organism.
Compounds acting as free-radical scavengers are able to pro-
duce stable radical species. Many studies on the effect of
substituents on the aromatic moiety have been reported

Synthesis of radical-scavenging polyphenols
1707
OH
OH
OH
NaBr, Oxone
MeONa, MetOH
OMe
Br
CuBr, DMF
120°C, 90–95%
acetone, H2O
0°C, >95%
OH
tyrosol
OH
OH
3-bromotyrosol
3-methoxytyrosol
OH
OAc
OAc
Ac2O, AcOH
50°C, 95%
BBr3, CH2Cl2
–20°C, 80%
a), b) or c)
OH
OH
OMe
OH
OH
OAc
3-methoxytyrosol
diacetate
3,4-dihydroxy-phenetyl
acetate
3-hydroxytyrosol
a) LiAlH4, THF, r.t., 4h, 78% b) CH2Cl2, 30% HCl, r.t., 12h, 94%
c) wheat germ lipase, pH 7.5, 37°C, 1h, complete conv.
Figure 5 Synthesis of hydroxytyrosol from tyrosol.
OAc
OAc
OAc
O
H2O2, NaHSO4
HO
Cl2CHOCH3, AlCl3
CH3OH, r.t., 75%
CH2Cl2, t.a., 90%
OMe
OMe
OMe
OMe
OMe
OMe
acetic acid 2-(3,4-dimethoxy-
phenyl) ethyl ester
acetic acid 2-(2-acyl-4,5-
dimethoxyphenyl) ethyl ester
acetic acid 2-(2-hydroxy-4,5-
dimethoxyphenyl) ethyl ester
OAc
OAc
OH
Ac2O, Py
LiAlH4
THF, r.t., 55%
AcO
BBr3, CH2Cl2
–20°C,65%
OMe
AcO
HO
r.t., >95%
OH
OH
OH
OH
OMe
acetic acid 2-(2-acetoxyethyl)- acetic acid 2-(2-acetoxy-4,5-
4,5-dimethoxyphenyl ester dihydroxyphenyl) ethyl ester
2,4,5-trihydroxytyrosol
Figure 6 Synthesis of 3,5-dihydroxytyrosol.
(Balasundram et al 2006), with the main focus on oxygenated
Flavonoids are widespread in nature, occurring in many
groups and their relative positions. All the factors able to sta- vegetables (Geissman 1962), and in particular in grapes
bilize a radical species contribute to improving the scaveng- (Amiot et al 1986), olive leaves (Heimler et al 1992) and
ing properties of the molecule, and from these factors the plants of the citrus genus (Kefford & Chandler 1970).
closeness between a hydroxyl group with other oxygenated
Over 4000 flavonoids have been identified in the vegeta-
moieties (hydroxyl, methoxyl, etc.) seems to be of great ble kingdom, and every plant possesses a complex mixture of
importance. This situation is often found in natural com- these compounds, which describes a characteristic chemical
pounds (Hotta et al 2001; Leopoldini et al 2004), including profile. Flavonoids participate in many physiological and bio-
the flavonoid class (Heim et al 2002).
chemical processes, for example as enzyme inhibitors, in

1708
Paolo Bovicelli
Br
O
O
O
O
Oxone/NaBr1:4
Br
acetone, H2O,
15min, r.t., 80%
CH3O
CH3O
5-methoxyflavanone
6,8-dibromo-5-methoxyflavanone
Br
O
O
O
Oxone/NaBr 1:4
+
acetone, H2O,
30 min, r.t.
Br
CH3O
70%
O
CH3O
O
CH3O
O
15%
5-methoxyflavanone
6-bromo-5-methoxyflavanone 8-bromo-5-methoxyflavanone
OCH3
OCH3
Br
CH3O
O
O
CH3O
O
O
oxone/NaBr 1:2
acetone, H2O
r.t., 45 min, >95%
CH3O
CH3O
5,7,4'-trimethoxyflavanone
8-bromo-5,7,4'-trimethoxyflavanone
OCH3
OCH3
Br
CH3O
O
O
CH3O
Br
O
O
oxone/NaBr1:4
acetone, H2O
r.t., 45 min, 90%
CH
CH3O
3O
5,7,4'-trimethoxyflavanone
6,8-dibromo-5,7,4'-trimethoxyflavanone
OCH3
OCH3
Br
Br
CH3O
O
CH3O
O
O
Br
oxone/NaBr 1:2
acetone, H2O
r.t., 2 h, 85%
Br
Br
CH3O
O
CH3O
6,8-dibromo-5,7,4'-trimethoxyflavanone
Figure 7 Selective bromination of flavanones.
6,8,3'-tribromo-5,7,4'-trimethoxyflavanone
defending plants from bacteria and fungi, in fixing nitrogen, interest in these molecules, methods for their synthesis and
in growth regulation and in oxy-reductive processes in cells structural modification are the goals of several research
(Harborne 1982).
groups. Our interest in this field is to exploit our experience
Given that flavonoids are present in many beverages and in the functionalization of aromatic compounds to prepare
food, they are constituents of the human diet (Kyle & Duthie new flavonoids that are potentially useful as drugs or food
2006; Nemeth & Piskula 2007). They carry out several bio- preservatives. Synthesis of flavonoids is usually performed
logical functions in the organism (Kyriakydis et al 1986; by the ring closure of chalcones (Stermitz et al 1975;
Okura et al 1988; Ferriola et al 1989), including that as anti- Sanicanin & Tabakovic 1986); however, yields are not
oxidant (Lemanska et al 2001). Because of the increasing always satisfactory.

Synthesis of radical-scavenging polyphenols
1709
Br
HO
Br
O
O
HO
O
O
H2O2, NaBr
EtOH, 50°C, 24 h, 90%
OH
OH
crysine
6,8-dibromocrysine
Figure 8 Soft bromination of flavanones.
OH
OH
OMe
OH
Br
HO
MeO
O
O
HO
Br
O
O
MeONa/MeOH
CuBr, DMF
110°C,1 h, 80%
OH
6,8-dibromoapigenin
Figure 9 Methoxylation of bromoflavanones.
demethoxysudachitin
Given the high degree of aromatic ring oxygenation, the their importance for human health, studies on biological
bromination–methoxylation procedure already used in the activities of flavonoids are inadequate, because of their scar-
synthesis of ubiquinones and hydroxytyrosol was then con- city and high cost, apart from some very common com-
sidered in the oxy-functionalization of natural flavonoids in pounds. With our approach a number of rare or new
order to obtain more active molecules.
flavanoids can be prepared starting from cheap material.
The bromination procedure proved efficient and selective
on flavanones (Figure 7), and a number of derivatives were
prepared. However, this failed when applied to flavones,
Conclusion
because of the sensitivity of the enonic double bond on the C The development of simple sequences of reactions, such as
ring to the reaction conditions.
bromination–methoxylation and formylation–oxidation pro-
Bromo-flavanones were easily converted into the corre- cedures, allows selective functionalization of aromatic com-
sponding flavones by an I2/DMSO-promoted oxidation (Fatma pounds and gains access to classes of highly biologically
et al 1984). When the A ring is sufficiently activated for elec- active products for which the previous syntheses are complex
trophilic attack, a softer method can be used for bromination or low yielding. Some of the compounds that we prepared are
to avoid the interaction with the enonic double bond, and the expensive, and our approach makes it possible to obtain them
H2O2/NaBr system in ethanol successfully converted chry- at low cost with eco-friendly reactions, readily manipulated
sine to the corresponding dibromo derivative (Figure 8).
reagents, and almost always environmentally sustainable
All these bromo-flavanones were converted into the corre- processes. Three classes of compounds – ubiquinones,
sponding methoxy-derivatives by an improved substitution hydroxytyrosol derivatives and flavonoids – can be obtained
procedure of the bromine atoms (Figure 9). Until now, this using the chemistry introduced here.
reaction was not reproducible and thus little used in synthesis,
its success being dependent on the nature of the substrates.
With our optimized procedure the reaction is suitable for
almost every transformation, including for very sensitive sub-
strates such as flavanoids. In practice, a blue resulting mix-
ture between MeONa, CuBr (the catalyst) and DMF was
prepared separately at room temperature and added to the
warm solution of the substrate in DMF. In this way the
decomposition of DMF was prevented and the reagent
worked correctly.
The closeness of methoxyl and hydroxyl groups on aro-
matic rings is a common situation in natural compounds,
which provides several biological properties (Saroglou et al
2005; Nakagawa et al 2006). Such a situation is readily
achieved using the procedure that we propose. In spite of
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