[Show abstract][Hide abstract] ABSTRACT: C-glucosidic ellagitannins constitute a subclass of bioactive polyphenolic natural products with strong antioxidant properties, as well as promising antitumoral and antiviral activities that are related to their capacity to interact with both functional and structural proteins. To date, most synthetic efforts toward ellagitannins have concerned glucopyranosic species. The development of a synthetic strategy to access C-glucosidic ellagitannins, whose characteristic structural feature includes an atropoisomeric hexahydroxydiphenoyl (HHDP) or a nonahydroxyterphenoyl (NHTP) unit that is linked to an open-chain glucose core by a C-aryl glucosidic bond, is described herein. The total synthesis of the biarylic HHDP-containing 5-O-desgalloylepipunicacortein A (1 β) was achieved by either using the natural ellagic acid bis-lactone as a precursor of the requested HHDP unit or by implementing an atroposelective intramolecular oxidative biarylic coupling to forge this HHDP unit. Both routes converged in the penultimate step of this synthesis to enable a biomimetic formation of the key C-aryl glucosidic bond in the title compound.
[Show abstract][Hide abstract] ABSTRACT: The first total synthesis of a member of the C-glucosidic subclass of ellagitannins, 5-O-desgalloylepipunicacortein A, was accomplished by relying on a biomimetic aldol-type formation of its characteristic C-aryl glucosidic bond through the exploitation of the inherent chemical reactivity of a glucopyranosic hemiacetal precursor.
Chemical Communications 02/2011; 47(5):1628-30. · 6.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study, we have designed novel chromanyl derivatives that share with alpha-tocopherol a chromanyl head but differ in the lateral chain in: (i) length and saturation (FEBL-45, 50, 70), (ii) position of double bonds in Z or E (FEBL-50 and 53 and their respective 6-chromanyl methyl derivatives FEBL-161 and 162), or (iii) presence of additional antioxidant molecules, such as the catechol compound hydroxytyrosol (FEBL-80) or dopamine (FEBL-82, 95). The efficiency of these compounds in preventing free-radical-induced oxidative stress was investigated in isolated membranes as well as intact cells. The results of this study clearly show that all compounds synthesized were active in: (i) inhibiting AAPH- or tert-BOOH-induced lipid peroxidation in microsomes and (ii) preventing H2O2-induced ROS production, cell damage, and heat-shock protein expression in immortalized RAT-1 fibroblasts. Such effects were dose- and time-dependent. Independent of the kind of pro-oxidant used, differences in the antioxidant potency of these compounds were found in relation to the chemical structure with respect to the natural alpha-tocopherol: (1) The concomitant presence of a chromanyl head and an additional aromatic ring markedly increased the antioxidant potency of the molecule. In particular, FEBL-82 and FEBL-95, resulting from the molecular combination of trolox and dopamine, were much more potent than alpha-tocopherol, alpha-tocotrienol, and the other synthetic compounds. Moreover, they were also more potent than trolox and dopamine, used alone or in combination, suggesting synergistic cooperative interactions in the molecule between chromanyl and catechol moieties. (2) The length of the side chain affected the antioxidant properties of the molecule: FEBL-70, which displays a bulky squalene side chain, was less effective than the natural alpha-tocotrienol and the synthetic FEBL-45 and FEBL-50. (3) The presence of polyunsaturated double bonds in the side chain in the Z configuration (FEBL-53, FEBL-162) increased the antioxidant potency of the molecule with respect to the E configuration (FEBL-50, FEBL-161).
Free Radical Biology and Medicine 05/2008; 44(7):1452-64. · 5.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemical or enzymatic oxidation of 5,6-dihydroxyindole (1) leads to the rapid deposition of a black solid resembling eumelanin pigments by way of a complex oligomerization/polymerization process that proceeds in the early stages via dimers 2-3 and trimers 5-6 characterized by 2,4'- and 2,7'-couplings. Despite extensive efforts, the structures of the higher oligomers, which define the structural architecture and physicochemical properties of the eumelanin particles, have so far defied elucidation. Using a dimer-dimer coupling strategy that has recently allowed the first successful entry to a tetramer of 1, we report now three additional tetramers obtained by oxidation of 5,5',6,6'-tetrahydroxy-2,7'-biindolyl (3) with the peroxidase/H2O2 system. On the basis of extensive 2D NMR and mass spectrometric analysis, the products were identified as 5,5',5'',5''',6,6',6'',6'''-octaacetoxy-7,2':3',3'':2'',7'''-tetraindolyl (acetylated 8, 3%), 5,5',5'',5''',6,6',6'',6' ''-octaacetoxy-2,7':4',4'':7'',2'''-tetraindolyl (acetylated 9, 4%), and 5,5',5'',5''',6,6',6'',6'''-octaacetoxy-2,7':2',3'':2'',7'''-tetraindolyl (acetylated 10, 5%), in which the inner units are linked through unexpected 3,3'-, 4,4'-, and 2,3'-linkages. If verified in further studies, the newly uncovered coupling patterns would entail important consequences for current models of eumelanin structure based on one-dimensional structural chains with extended pi-electron conjugation or pi-stacked flat oligomer aggregates.
The Journal of Organic Chemistry 12/2007; 72(24):9225-30. · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The chemical and spectroscopic characterization of 5,6-indolequinones and their semiquinones, key transient intermediates in the oxidative conversion of 5,6-dihydroxyindoles to eumelanin biopolymers, is a most challenging task. In the present paper, we report the characterization of a novel, relatively long-lived 5,6-indolequinone along with its semiquinone using an integrated chemical, pulse radiolytic, and computational approach. The quinone was obtained by oxidation of 5,6-dihydroxy-3-iodoindole (1a) with o-chloranil in cold ethyl acetate or aqueous buffer: it displayed electronic absorption bands around 400 and 600 nm, was reduced to 1a with Na2S2O4, and reacted with o-phenylenediamine to give small amounts of 3-iodo-1H-pyrrolo[2,3-b]phenazine (2). The semiquinone exhibited absorption maxima at 380 nm (sh) and 520 nm and was detected as the initial species produced by pulse radiolytic oxidation of 1a at pH 7.0. DFT investigations indicated the 6-phenoxyl radical and the N-protonated radical anion as the most stable tautomers for the neutral and anion forms of the semiquinone, respectively. Calculated absorption spectra in water gave bands at 350 (sh) and 500 nm for the neutral form and at 310 and 360 (sh) nm for the anion. Disproportionation of the semiquinone with fast second-order kinetics (2k = 1.1 x 1010 M-1 s-1) gave a chromophore with absorption bands resembling those of chemically generated 1a quinone. Computational analysis predicted 1a quinone to exist in vacuo as the quinone-methide tautomer, displaying low energy transitions at 380 and 710 nm, and in water as the o-quinone, with calculated absorption bands around 400 and 820 nm. A strong participation of a p orbital on the iodine atom in the 360-380 nm electronic transitions of the o-quinone and quinone-methide was highlighted. The satisfactory agreement between computational and experimental electronic absorption data would suggest partitioning of 1a quinone between the o-quinone and quinone-methide tautomers depending on the medium.
The Journal of Organic Chemistry 04/2007; 72(5):1595-603. · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: C-arylglucosidic ellagitannins represent a unique sub-class of hydrolyzable tannins. Polyphenols
such these have attracted considerable interest in the past fifteen years because of possible
benefits in human health care and prevention of diseases such as carcinogenesis and
arteriosclerosis. However, this class of natural product, with such unique structural architectures
and potent biological activities, has not yet been fully explored for therapeutic potential. From here
our interest in developing a synthetic strategy for generation of these compounds and their
analogues with enhanced pharmacological properties.
Our synthetic efforts were so focused on the synthesis of 5-O-degalloyl epipunicacortein A (1) as
simple structures of this class of natural compounds. C-arylglucosidic ellagitannins constitute a
tannin subclass in which a C–C bond links the C-1 atom of an “open-chain” glucose core to the C-
2’ atom of a galloyl-derived unit esterified to the 2-position of the glucose core. Their C-1-linked
galloyl-derived unit is either part of a HHDP ester group bridging the 2- and 3-positions of the
It is possible to identify three key issues that must be addressed in order to accomplish the
synthesis of C-arylglucosidic ellagitannins:
- Opening of the sugar
- C-arylglucosidation reaction
- Atroposelective intramolecular biaryl coupling for the HHDP construction
In the end of this work we managed to obtain a route to access the C-arylglucosidic ellagitannins. In the meantime an intramolecular atroposelective methodology for the construction of the
hexahydroxyterphenolyl unit (HHDP) was developed, inspired to the Yamada’s total synthesis of
corilagin. We are confident it could be successfully applied to the NHTP construction. This strategy
required the preparation of a precursor featuring a para-protected galloyl units.
Our methodology for the C-arylglucosidic bond formation into biomimetic conditions resulted
applicable even on differently protected substrates. So a biomimetic route to C-glucosidic
ellagitannins have been developed.
The introduction of a conveniently protected galloyl unit on the intermediates A gives access to the
a product that could be further submitted to an oxidative coupling in the Yamada’s conditions to
give, after deprotection, the NHTP-bearing C-arylglucosidic ellagitannin vescalin (17) First galloylation attempts on compound 17 resulted unsatisfactory. Studies are still on going to
address this point.
At this point of the synthesis it was possible to obtain a first member of the C-arylglucosidic
The benzylidene cleavage of compound 7 delivered the degalloyl epi-punicacortein A 1 (1).
This molecule has not yet isolated form a natural source, but it is reasonable to suppose that its
structure corresponds to a natural compound. The hydrolysis of esters is the most frequent
modification incurred by ellagitannins so O-5-degalloyl epipunicacortein A could derive from
epipunicacortein A as O-5-degalloyl punicacortein A derives from hydrolysis of its precursor