Easy synthesis of polyphenolic 4-thiaflavans with a 'double-faced' antioxidant activity

Article abstract of DOI:10.1039/b100359n

Inverse electron demanding Diels-Alder reactions of o-thioquinones with styrenes, followed by simple manipulations of the obtained cycloadducts, allowed the synthesis of polyphenolic 4-thiaflavans which showed antioxidant activity miming either flavonoid

Full text of DOI:10.1039/b100359n

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Easy synthesis of polyphenolic 4-thiaflavans with a ‘double-faced’ antioxidant
activity
Giuseppe Capozzi,*a Pierandrea Lo Nostro,b Stefano Menichetti,*c Cristina Nativia and Paolo Sarria
a Centro C.N.R. ‘Chimica dei Composti Eterociclici’, Dipartimento di Chimica Organica, Università di Firenze, Via
G. Capponi 9, I-50121, Firenze, Italy
b Dipartimento di Chimica e CSGI, Università di Firenze, Via G. Capponi 9, I-50121, Firenze, Italy
c
Dipartimento di Chimica Organica e Biologica, Università di Messina, Salita Sperone 31, I-98166, Messina, Italy.
E-mail: menichet@isengard.unime.it
Received (in Cambridge, UK) 9th January 2001, Accepted 12th February 2001
First published as an Advance Article on the web 28th February 2001
Inverse electron demanding Diels–Alder reactions of o-
thioquinones with styrenes, followed by simple manipula-
tions of the obtained cycloadducts, allowed the synthesis of
polyphenolic 4-thiaflavans which showed antioxidant activ-
ity miming either flavonoid or tocopherol behaviour.
required cycloadducts which were transformed into the hydroxy
derivatives 6–12 by direct fluoro desilylation using wet TBAF
in THF at 0 °C.‡ For sulfoxides 7, 11 and 12 the oxidation with
mCPBA of the corresponding sulfides was performed before the
deprotection of the silyl ethers (Scheme 1).§
The antioxidant activity of compounds 6–12 was evaluated,5
as fading of the purple colour of commercially available DPPH
radical measured at 517 nm. Thus the value of the absorbance of
a 1024 M solution of DDPH in absolute ethanol (A0) and the
absorbance after 20 min from its mixing with an equimolar
solution of the thiaflavans (A1), were used for calculating the
reducing activity RA as: RA = [(A0 2 A1)/A0] 3 100. The
obtained RA for derivatives 6–12 and the one measured for
commercially available (+)-catechin hydrate are reported in
Scheme 1.
Flavonoids, natural products containing the 2-phenylchromane
skeleton, are almost ubiquitous in higher plants and have been
related to a huge number of biological effects1 including anti-
inflammatory, anti-viral and anti-cancer activity. Flavonoids
bearing OH groups on A, B and C rings (Fig. 1) represent one
of the most important families of natural antioxidants, able to
prevent oxidation by oxyl radicals.2 A high polyphenolic
flavonoid content in the diet has been indicated as the reason
why certain populations show statistically low levels of
cardiovascular disease (the so-called French paradox) and most
types of cancer.3
We have reported that o-hydroxy-N-thiophthalimides, pre-
pared by N-phthalimidesulfenylation of activated phenols, are
suitable precursors of ortho-thioquinones, a synthetically useful
class of electron-poor heterodienes, which react with styrenes
giving rise to the formation of aryl-substituted benzoxathiin
cycloadducts with complete regioselectivity.4
This hetero Diels–Alder approach, can be involved in the
preparation of 4-thiaflavan derivatives as shown in Fig. 1. Thus
we decided to exploit this procedure for access to polyphenolic
4-thiaflavans with the aim of verifying their potential perform-
ance as antioxidants.
We focused our attention on the 5,7,3A,4A and 5,7,4A
substitution patterns, two of the more common structural
characteristics in natural flavonoids.1
The sulfenylation of 3,5-dimethoxyphenol and 3,5-(di-
methyl-tert-butylsilyloxy)phenol with phthalimidesulfenyl
chloride gave, as expected, the sulfenamide derivatives 1 and 2
as suitable precursors of the corresponding o-thioquinones.†
The reaction of compounds 1 or 2 with styrenes 3–5 in CHCl3
at 60 °C, in the presence of TEA,4 allowed the isolation of the
Scheme 1 Reagent and conditions. i: TEA (1 equiv.), CHCl3, 60 °C, 20–120
h; ii (only for 7, 11 and 12): mCPBA (1 equiv.) CH2Cl2, 0 °C, 0.5–2h; iii:
TBAF (1–4 equiv.), THF, 0 °C, 1–2 h.
Fig. 1 Flavan skeleton and access to 4-thiaflavan structure.
DOI: 10.1039/b100359n
Chem. Commun., 2001, 551–552
This journal is © The Royal Society of Chemistry 2001
551

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Satisfactorily, derivatives 6 and 7 showed the same activity as
catechin. The high efficiency as antioxidants of natural
flavonoids showing a catechol-like ring B, has been explained
on the basis of the formation of a stable o-quinone species
arising from two consecutive hydrogen abstractions by the
radical reagent.2 Clearly thiaflavans 6 and 7 could show a
similar behaviour demonstrating that the above mentioned
catechol-like mechanism is maintained with the introduction of
a sulfide or a sulfoxide sulfur into the C ring.
Surprisingly compound 8, bearing only one hydroxy group
on C4A of ring B, was even more efficient than previously
considered 4-thiaflavans and catechin. This is in sharp contrast
with the literature data on antioxidant activity of flavonoids2
and prompted us to envisage a different oxidation mechanism
probably involving the A and C rings. This hypothesis was
corroborated by the substitution of hydroxy by methoxy groups
on the A ring which caused a complete loss of consumption of
DPPH colour for derivative 9, while compound 10, bearing a
methoxy group on the B ring but hydroxy groups on the A ring,
exhibited the same activity as 8. Moreover the transformation of
sulfides 8 and 10 into the corresponding sulfoxides 11 and 12
gave rise to an almost complete loss of activity. Thus the
observed antioxidant activity of compounds 8 and 10 requires
both hydroxy groups on the A ring and a sulfide sulfur in the C
ring (Scheme 1).
makes these thiaflavans very stimulating and promising new
‘double-faced’ antioxidant derivatives.
Moreover, since several 4-thiaflavans, including derivatives
8–10, appeared active against Staphylococcus aureus, Pseudo-
monas aeruginosa and Candida albicans growth,10 more
detailed studies on the activity of 4-thiaflavans as antioxidants
and antimicrobials are in progress in these laboratories.
This work was carried out under the auspices of the National
Project: ‘Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni’ supported by the Ministero dell’Università e della
Ricerca Scientifica e Tecnologica, Rome, and by the University
of Florence.
Notes and references
† 3,5-(Dimethyl-tert-butylsilyloxy)phenol was prepared by direct silylation
of 1,3,5-trihydroxybenzene hydrate (fluorglucinol hydrate) with t-Bu-
Me2SiCl and imidazole in DMF.
‡ Representative experimental procedure: to a solution of 2 (150 mg, 0.28
mmol) and p-methoxystyrene (5) (38 mg, 0.28 mmol) in dry CHCl3 (3 mL),
TEA (28 mg, 0.28 mmol) was added and the mixture heated at 60 °C for 22
h. Evaporation of the solvent and flash chromatography afforded the
required cycloadduct (145 mg, 60%), which was directly desilylated by
reaction with TBAF hydrate (146 mg, 0.56 mmol) in THF (5 mL) for 35 min
at 0 °C. Evaporation of the solvent and flash chromatography gave
derivative 10 (57 mg, 70%) as a white solid; mp 169 °C.
§ Sulfoxides 7, 11 and 12 were obtained, and tested, as 82+18, 86+14 and
93+7 mixtures of trans and cis isomers, respectively. For the synthesis and
geometry of related sulfoxides see: G. Capozzi, P. Fratini, S. Menichetti and
C. Nativi, Tetrahedron, 1996, 52, 12233. Using 1 equiv. of mCPBA the
formation of sulfones is not observed, the latter can be easily prepared
carrying out the oxidation with 2 equiv. of mCPBA at rt for 2–12 h.
A simple rationalization of these results can be obtained by
considering that a 5,7-dihydroxy-4-thiaflavan moiety, like in 8
or 10, could behave as an antioxidant with the same mechanism
operative in tocopherols and related compounds, which, with
flavonoids, represent the most important families of natural
antioxidants (Fig. 2).
Literature data regarding the activity of modified tocopher-
ols6 are in perfect agreement with the observed high efficiency
of 4-thiaflavans 8 and 10. Actually it is known that the
introduction of electron donating groups in the aromatic ring
(i.e. OH on C5) facilitates hydrogen abstraction by the oxyl
radical, while the substitution of the oxygen by the sulfur atom,
on the saturated condensed ring, increases the stability of the
intermediate radical7 (Fig. 2).
1 J. B. Harborne, The Flavonoids Advances in Research Since 1986,
Chapman & Hall, London, 1994; N. C. Cook and S. Samman,
Nutritional Biochemistry, 1996, 7, 66; B. A. Bohm, Introduction to
Flavonoids, Harwood Academic Publishers, Amsterdam, 1998; L.
Bravo, Nutr. Rev., 1998, 56, 317 and references cited therein.
2 S. V. Jovanovic, S. Steenken, M. Tosic, B. Marjanovic and M. G. Simic,
J. Am. Chem. Soc., 1994, 116, 4846; O. Dangles, G. Fargei and C.
Dufour, J. Chem. Soc., Perkin Trans. 2, 1999, 1387 and references cited
therein.
3 O. Dangles, G. Fargeix and C. Dufour, J. Chem. Soc., Perkin Trans. 2,
2000, 1653 and references cited therein.
4 G. Capozzi, C. Falciani, S. Menichetti and C. Nativi, J. Org. Chem.,
1997, 62, 2611.
5 P. Lo Nostro, G. Capuzzi, N. Mulinacci and A. Romani, Langmuir,
2000, 16, 1744.
6 G. W. Burton, T. Doba, E. J. Gabe, L. Hughes, F. L. Lee, L. Praasad and
K. U. Ingold, J. Am. Chem. Soc., 1985, 107, 7053.
Fig. 2 4-Thiaflavan and tocopherol skeletons.
The oxidation of the sulfide sulfur causes the decrease of
activity exhibited by sulfoxides 11 and 12 since it introduces an
electron withdrawing group which, at the same time, is known
to possess less ability in stabilizing radicals.8
These results seem to indicate that both the flavonoid-like
and the tocopherol-like mechanisms are operative in compound
6. Recent observations indicate that ‘in vivo’ these two classes
of natural polyphenols have to operate synergistically for a fast
and safe protection against LDL (low density lipoprotein)
damaging radicals.9 Thus the possibility of joining in a single
compound the very fast reaction of flavonoids with oxyl
radicals and the high chain breaking ability of tocopherols,
7 H. A. Zahalka, B. Robillard, L. Hughes, J. Lusztyk, G. W. Burton, E. G.
Janzen, Y. Kotake and K. U. Ingold, J. Org. Chem., 1988, 53, 3739; L.
Engman, M. J. Laws, J. Malmstrom, C. H. Schiesser and L. M. Zugaro,
J. Org. Chem., 1999, 64, 6764.
8 I. Biddles, A. Hudson and J. T. Wiffen, Tetrahedron, 1972, 28, 867;
D. D. M. Wayner and D. R. Arnold, Can. J. Chem., 1984, 62, 1164; D.
Griller, D. C. Nonhebel and J. C. Walton, J. Chem. Soc., Perkin Trans.
2, 1984, 1817; A. E. Luedtke and J. W. Timberlake, J. Org. Chem.,
1985, 50, 268.
9 O. Dangles, G. Fargeix and C. Dufour, J. Chem. Soc., Perkin Trans. 2,
2000, 1215.
10 G. Capozzi, A. Lo Nostro, S. Menichetti, C. Nativi and P. Sarri,
unpublished results.
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Chem. Commun., 2001, 551–552