Posters
118
Session Poster 1 (PC1-PC62):
1) Catalisi
2) Chimica Fisica Organica
3) Chimica Supramolecolare
4) Foldameri
5) Fotosica e Fotochimica
6) Green Chemistry
7) Sostanze Naturali
Session Poster 2 (PC63-PC122):
1) Medicinal Chemistry – Chimica Bioorganica
2) Nanotecnologie
3) Sintesi Organica
119
A - Catalisi
120
PC1
Aerobic C-C Cleavage Catalyzed by Vanadium(V)-Amino
Triphenolate Complexes
Emanuele Amadio, Rosalia Di Lorenzo, Cristiano Zonta, Giulia Licini*
Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131, Padova, Italy.
e-mail: [email protected]
Oxidative carbon-carbon bond cleavage of vicinal diols to carbonyl compounds
is a fundamental and important reaction in fine chemical synthesis as well as in the
renewable feedstock transformations such as in the oxidative valorization of lignin or
cellulose.1
Since the earliest discovery in 1928,2 the cleavage of 1,2-diols has been
traditionally performed with stoichiometric high-valent inorganic oxidants, like
periodates or lead tetracarboxylates. However, most of these oxidants suffer from severe
drawbacks in terms of toxicity and issues related to their storage, handling, cost and
solubility. Therefore, one of the main goals in this area is the design of more efficient,
environmentally benign and cleaner processes.
Recently, the use of vanadium complexes as catalysts has emerged as a new
effective method for the C-C oxidative bond cleavage using only air as final oxidant and
with the corresponding formation of water as the only by-product (Scheme 1).1
Scheme 1. Aerobic C-C oxidative cleavage of diols to the corresponding carbonyl
derivatives.
Here we will show that vanadium(V)-amino triphenolate complexes3 are
effective catalysts for this transformation. The correct tuning of the reaction conditions
(catalyst, solvent, and temperature) allows the obtainment of carbonyl derivatives with
high conversion and chemical yields with catalyst loading down to 0.2%. The
methodology is effective with a large series of diols.
The authors acknowledge the Università di Padova for funding [PRAT-CPDA123307,
and Assegni Senior 2014, GRIC141OVJ. (E. A. fellowship)].
1)
2)
3)
Amadio, E.; Di Lorenzo, R.; Zonta, C.; Licini, G. Coord. Chem. Rev. 2015 and references there
in.
Malaprade, L.; Hebd, C. R.; Seances Acad. Sci. 1928, 186, 382.
Mba, M., Pontini, M.; Lovat, S.; Zonta, C.; Bernardinelli, G; Kündig, E.P.; Licini, G. Inorg.
Chem. 2008, 47, 8616-8618
121
PC2
Highly Enantioselective Mannich Reactions of Aldehydes with
Quinoline-N,O-acetals by Synergistic Catalysis
Francesco Berti1, Federico Malossi1, Fabio Marchetti2, Mauro Pineschi*1
1
Dipartimento di Farmacia, Sede di Chimica Bioorganica e Biofarmacia, Università di Pisa (Via
Bonanno 33, 56126 Pisa, Italy).
2
Dipartimento di Chimica e Chimica Industriale, Università di Pisa (Via G. Moruzzi 3, 56124, Pisa,
Italy).
e-mail: [email protected]
Enantioselective Mannich-type reactions represent a straightforward method for the
synthesis of β-amino-carbonyl derivates. Recently, several organocatalytic approaches
have been developed for an asymmetric functionalization of the key intermediate Nacyliminium ion exploiting mainly chiral Brønsted acids.1 On the other hand, the use of
chiral enamine as nucleophile remains a challenging task due to the deactivation of the
amine organocatalyst.2
We herein report an highly enantioselective functionalization of quinoline
derivatives with the formation of two stereocenters with moderate to good
diastereoselectivity.
Scheme 1
The reaction exploits easily available N,O-acetals of type 1 (Scheme 1) activated in
situ with Lewis or Brønsted acids in combination with Hayashi-Jørgensen catalyst L
and aldehydes, according to a synergistic catalysis. The absolute configuration of
compound 2 was determined by single crystal X-ray analysis indicating a lk (Si, Si)
addition of the enamine to the intermediate quinolinium ion.3 Studies are ongoing in
order to apply this simple and practical procedure to other challenging substrates.
1) Lee, Y. S.; Alam, M.M.; Keri, R. S. Chem. Asian J. 2013, 8, 2906.
2) For a solution to this problem, see: Mengozzi, L.; Gualandi, A.; Cozzi, P. G. Chem. Sci. 2014, 5, 3915
3) Manuscript under preparation.
122
PC3
The first enantioselective synthesis of 3-spiro--methylene-γbutyrolactoneoxindoles
Lucia Cerisoli, Arianna Quintavalla, Marco Lombardo, Claudio Trombini
Department of Chemistry ”G.Ciamician”, University of Bologna
e-mail: [email protected]
In recent years, spiro-fused oxindoles have been identified as potential bioactive
compounds due to the fact that this skeleton is present in a huge amount of natural
bioactive products, such as spirotryprostatins etc. For this reason the synthetic
community started to investigate their chemical modification to obtain new biologically
active classes of compounds.1 At the same time macrolides with -methylene-γbutyrolactone moiety have been recognized in different natural products, as
sesquiterpene lactones, that presented biological activities as antitumour, phytotoxic and
antibacterial compounds.2 Our purpose is the union of oxindole scaffold with the methylene-γ-butyrolactone fragment, to obtain a new class of promising highly
functionalized spiro compounds.3Inspired by our previous works4 concerning the
oxindoles reactivity, we investigated a new synthetic strategy for the first stereoselective
synthesis of 3-spiro--methylene-γ-butyrolactoneoxindoles 4.
1)
2)
3)
4)
(a) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104-6155. (b) Galliford, C. V.; Scheidt, K.
A. Angew. Chem., Int. Ed. 2007, 46, 8748- 8758. (c) Marti, C.; Carreira, E. M. Eur. J. Org.
Chem. 2003, 2209-2219.
(a) Ogura, M.; Cordell, G. A.; Fransworth, N. R. Phytochemistry1978, 17, 957-961. (b) Kitson,
R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem., Int. Ed.2009, 48, 9426-9451. (c)
Bachelier, A.; Mayer, R.; Klein, C. D. Bioorg. Med. Chem. Lett. 2006, 16, 5605-5609.
(a) Shanmugam, P.; Vaithiyanathan, V. Tetrahedron, 2008,64,3322-3330. (b)Shanmugam, P.;
Viswambharan, B. Synlett, 2008, 2763-2768.
(a) Quintavalla, A.; Lanza, F.; Montroni,E.; Lombardo, M.; Trombini, C. J. Org. Chem.2013, 78,
12049-12064. (b) Monari, M.; Montroni,E.; Nitti, A.; Lombardo, M.; Trombini, C.; Quintavalla,
A.Chem. Eur. J.2015, 21, early view.
123
PC4
CeCl3 catalyzed imino Diels-Alder reactions: hydrated vs anhydrous
Enrico Marcantoni1, Samuele Bordi1, Gabriele Lupidi1, Cristina Cimarelli1
1
School of Science and Technology - Chemistry division - University of Camerino
e-mail: [email protected]
Aza-Diels-Alder reaction is a straightforward way to synthesize useful nitrogen
containing heterocyclic structures.1 In particular, the known reaction between imines
and Danishefsky’s diene has proved to be an excellent way to obtain the 1,2-substituted2,3-dihydropyridinone scaffold, widely present in bioactive small molecules and
versatile building block for the synthesis of more complex structures.2
The reaction of Danishefsky’s diene with aromatic imines has been widely studied in
last years, anyway less examples of the same reaction involving imines derived from
aliphatic amines or aldehydes are present. For this reason the possibility to extend the
potentiality of this reaction performing it on a large variety of imines was studied, under
the Lewis acid promoting system CeCl3.7H2O/CuI, previously applied with success3 in
many other synthetic methodologies.
Imines 3 were prepared by direct condensation of aliphatic or aromatic amines and
aldehydes and then the diene was added together with the catalyst, obtaining
dihydropyridinones 4 with good to excellent yields in short reaction times. To extend
the scope of this work, also imines derived from aminoacids were tested as dienophiles.
Scheme 1
1
R
O
CHO + H2N R*
1a-b
1a: R1 = Ph
1b: R1 = COOEt
2a-d
MgSO4
CH3CN, r.t.
N
R*
Danishefsky's diene
CeCl3.7H2O/CuI 50% mol
CH3CN, r.t.
1
R
3aa-ad
R1
N
R*
4aa-ad
2a: (R)-1-phenylethylamine
2b: (R)-phenylglycine methylester
2c: (L)-valine methylester
2d: (L)-tryptophan methylester
The only moderate diastereoselectivity and the long time needed with some homochiral
dienophiles prompted us to have a deeper insight into the mechanism, with the
conclusion that the reaction proceed also through a slower competitive MannichMichael pathway, favoured by the presence of water in the catalyst.
1) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099-6138.
2) Cant, A. A.; Sutherland, A. Synthesis 2012, 44, 1935-1950.
3) Bartoli, G.; Marcantoni, E.; Marcolini, M.; Sambri, L. Chem. Rev. 2010, 110, 6104-6143.
124
PC5
Bioinspired Mn and Fe catalysed oxidations in Ionic media
(ILs and DESs)
Miquel Costas1, Marco Cianfanelli1,2, Barbara Floris2, Valeria Conte2
1
Departament de Quimica and Institute of Computational Chemistry and Catalysis (IQCC), University of
Girona,Campus de Montilivi, Girona 17071 (Spain)).
2
Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, via della Ricerca
Scientifica, snc, 00133 Roma, Italy.
e-mail: [email protected]
ILs with different physicochemical properties were used in epoxidation reaction of
model alkenes with hydrogen peroxide, in particular cis-β-methylstyrene and 2cyclohexenone;1 with the ambition to recover the catalytic phase, to replace the
molecular solvent and to improve the efficiency. The chiral catalyst employed were
[Fe(CF3SO3)2-(S,S)-dMMPDP], [Fe(CF3SO3)2-(S,S)-dMMPDP] and [Mn(CF3SO3)2-(S,S)Me2N
PDP].2
Fe catalyst provided results
similar to those obtained in
MeCN while, with Mn
catalysts (2-3), an appreciable
increase of the yield was
obtained with respect to that
observed
in
acetonitrile,
accompanied
by
similar
enantiomeric excesses.
Using cis-β-methylstyrene with
Mn and Fe catalysts, a more hydrophobic medium appears crucial.
In recyclability experiments the yield decreased significantly after two cycles, however
an improvement in the recycling procedure was obtained recharging the catalytic phase
with a further amount of the catalyst.
Deep eutectic solvents, a new class of “green” solvents,3 was also tested for the first
time in epoxidation reactions with interesting results, even if Fe catalyst did not provide
substrate conversion. Epoxide formation was observed with Mn catalyst with yields
from moderate to good. The 1:2 mixture choline chloride/glycerol gave the best results
in terms of yield and ee, (86% Y, 66% ee) with respect to the more viscous choline
chloride/urea mixture, using cis-β-mehylstyrene as substrate. A preliminary substrates
scope was performed with encouraging results.
1) The present work has been carried out within European Project COST Action: CM1003 “Biological
oxidation reactions - mechanisms and design of new catalysts” between “Università di Roma Tor
Vergata” and “Universitat de Girona”.
2) Cussò, O.; Garcia-Bosch, I.; Ribas, X.; Lloret-Fillol, J.; Costas, M. J. Am. Chem. Soc. 2013,135,
14871.
3) Abbott, A. P.; Capper, G.; Davies, D. L.; Rasheed, R. K.; Tambyrajah, V. Chem. Commun. 2003, 70.
125
PC6
Gold supported on silica catalyzes the aerobic oxidation of N,Ndisubstituted hydroxylamines to nitrones
G. D’Adamio,1 F. Cardona,1 C. Parmeggiani,2 A. Goti1
1 Dipartimento di Chimica “Ugo Schiff”, Università degli Studi di Firenze, Via della Lastruccia 3-13,
50019 Sesto Fiorentino (FI), Italy.
2 CNR-INO and European Laboratory for Non-Linear Spectroscopy (LENS), University of Florence, Via
N. Carrara 1, Sesto Fiorentino (FI), Italy.
[email protected]
Oxygen or air are ideal oxidants from a green chemistry point of view,1 since they are
safe and inexpensive and produce only water as a co-product. The implementation of a
transition metal catalyst in combination with oxygen for the oxidation of alcohols to the
corresponding carbonyl compounds represents an emerging more sustainable alternative
to the traditional procedures.2 The related oxidation of N,N-disubstituted
hydroxylamines to nitrones is much less studied, despite the growing importance of
these compounds as spin traps in biological studies and drugs for age-related
diseases3,4 or as key intermediates for the synthesis of nitrogen containing biologically
active compounds.5
Although bulk gold has being regarded for a long time as an inert catalyst, recently it
has been recognized as surprisingly active in the form of nanoparticles.6
In this work we report our preliminary results on the oxidation of N,N-disubstituted
hydroxylamines to nitrones catalyzed by a supported gold catalyst on silica previously
described.7 N,N-dibenzylhydroxylamine (1) was selected as the model substrate in order
to study the best conditions for the aerobic oxidation.
After careful optimization of the reaction conditions, the reactivity of a series of both
aliphatic and benzylic hydroxylamines, including cyclic and enantiopure ones, was
examined.
1) Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437-1451; 2) Cardona, F.; Parmeggiani, C. “Transition
Metal Catalysis in Aerobic Alcohol Oxidation” RSC Green Chemistry Book Series, Cambridge, 2015; 3)
Dhainaut, A.; Tizot, A.; Raimbaud, E.; Lockhart, B.; Lestage, P.; Goldstein, S. J. Med. Chem. 2000, 43,
2165-2175; 4) Floyd, R. A.; Chandru, H. K.; He, T.; Towner, R. AntiCancer Agents Med. Chem. 2011,
11, 373-379; 5) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Eur. J., 2009, 15,
7808-7821; 6) Zhang, Y.; Cui, X.; Shi, F.; Deng, Y. Chem. Rev. 2012, 112, 2467-2505. 7) Biella, S;
Rossi, M. Chem. Comm., 2003, 378-379.
126
PC7
Highly efficient Proline-catalysed enantioselective aldol reaction
A. Tamburrini, A. Quintavalla, L. Cerisoli, M. Lombardo, C. Trombini, M. G. Emma
Dipartimento di Chimica “G. Ciamician”, Università degli Studi di Bologna
via Selmi 2, 40126, Bologna, Italy
e-mail: [email protected]
The first results obtained in the proline-catalysed direct aldol reaction represented a real
breakthrough in the field of the asymmetric catalysis, paving the way to a strong
development of this research area1. On the other hand, high catalyst loading, long
reaction times and highly polar solvents have to be used in this reaction, mainly since
proline is insoluble in commonly used organic solvents.2 In order to optimize the
efficiency of this reaction, many efforts have been directed towards the design and
synthesis of new more soluble and more reactive proline derivatives. Other strategies
rely on the use of additives like inorganic salt, for example CoCl2,3 or organic
molecules, for example thioureas,4 in order to complex proline increasing both
selectivity and solubility. Unfortunately both strategies leads to an increase of the costs,
because both proline-derivatives and additives are not as cheap as simple proline.
In this communication, a new simple protocol for the highly efficient proline-catalysed
aldol reaction will be presented, using only a certain amount of water and methanol,
instead of other additives. While methanol allows proline to be dissolved in the reaction
mixture, increasing the reactivity, water plays a key-role in the reaction mechanism,
increasing the selectivity of the reaction.
Scheme 1: Aldol reaction between cyclohexanone and aromatic aldehydes in the
presence of water and methanol as additives.
The new protocol has been applied first using cyclohexanone as donor, aromatic
aldehydes as acceptors and only 10% of proline as the catalyst (Scheme 1). The results
are very satisfactory with almost quantitative conversions, reaction time up to 4 hours
and very good selectivities, with enantiomeric excess up to 99%. The scope of the
reaction has been successfully expanded to different donors, like cyclopentanone and
acetone, and also on less activated acceptors like aliphatic aldehydes.
Since the aldol reaction is one of the most useful organic reaction in building a carboncarbon bond, this protocol may be a very useful both in scientific and in industrial
applications. The reaction may be performed easily, with cheap reagents, low catalytic
loadings and fast reaction times.
1)
2)
3)
4)
B. List, R. A. Lerner, C. F. Barbas, J. Am. Chem. Soc. , 2000, 122, 2395.
M. Bhanushali. C. Zhao, Synthesis (Stuttg). 2011, 12, 1815.
A. Karmakar, T. Maji, S. Wittmann, O. Reiser, Chem. Eur. J., 2011, 17, 11024.
N. El-Hamdouni, X. Company, R. Rios, A. Moyano, Chem. Eur. J., 2010, 16, 1142.
127
PC8
Enantioselective tools for the total synthesis of marine bioactive
metabolites containing tetrahydrofuran moiety
Mattia Fredditori, Alessio Porta, Giuseppe Zanoni and Giovanni Vidari
Department of Chemistry, University of Pavia, Viale Taramelli, 10-27100, Italy
[email protected]
During the last years a large number of highly bioactive THF-containing macrolides has
been isolated from algae and other marine invertebrates [1].
Our research group has developed an enantioselective stereodivergent methodology [2]
to two key THF cores, named AC and ST compounds, starting from a single achiral
precursor, the meso diol (1).
The absolute configuration of the THF cores, was secured by a Pd-catalyzed
asymmetric allylic alkylation using (S,S)-L1 and (R,R)-L2 ligands, respectively.
Now, we are developing new catalysts in order to improve the stereoselectivity of this
reaction and we are trying to extend the methodology to other meso diols bearing
different substituents at C5, such as methyl, methylidene and hydroxymethyl groups.
1) A. Lorente, J. Lamariano-Merketegi, F. Albericio, and M. Álvarez, Chem. Rev., 113 (7), 2013, pp
4567–4610 .
2) M.Valli, P. Bruno, D. Sbarbada, A. Porta, G. Vidari, and G. Zanoni, JOC, 78, 2013, pp 5556-5567.
128
PC9
The mechanism of the aerobic Cu-catalysed oxidative cross-coupling of
tertiary amines. An experimental and computational study.
Giovanni Ghigo,1 Stefano Dughera,1 Pierpaolo Morgante1
1
Dipartimento di Chimica, Università di Torino, via P. Giuria 7-10125 Torino.
e-mail: [email protected]
Cross-Coupling reactions catalysed by transition metals are used since several years in
the synthesis of organic molecules and applied to a wide spectrum of substrates.1
Among them, we focused our interest on the Aerobic Oxidative Cross-Coupling
catalysed by copper and in particular, the reaction involving the tertiary amines.2
In this poster, we presents the preliminary results of a combined experimental and
computational study of the mechanism of this reaction. Although the reaction has been
extensively tested from the synthetic point of view2 the details of the reaction are still
unknown. The mechanistic studies are still limited to a few experimental3 and
computational4 works that have allowed only to verify the role as the oxidant of copper
(Cu++) in the formation of the iminium as intermediate for the reaction with some
nucleophilic reactant HNu (Scheme 1).
Scheme 1
What is the real process leading to the iminium (Scheme 2), i.e. what is the specie that
actually completes the oxidation through the hydrogen-abstraction (STEP 2 in Scheme
2) is still unknown. The ignorance of these details prevents an efficient application,
extension and optimization of this reaction. For this reason we challenged to fill this
gap with the combined use of computational and experimental methods. In particular,
the roles of the counter-ion of Cu+/++ and of the molecular oxygen used as oxidant (a
part from the oxidation of Cu+ to Cu++ regenerating the catalyser) are the subject of our
study. The preliminary results indicate, in fact, that the commonly accepted mechanism
is too naive and that it does not take in account a possible role for these species.
Scheme 2
1) Yeung C. S., Dong V. M. Chem. Rev. 2011, 111, 1215–1292.
2) Zhang C., Tang C., Jiao N. Chem. Soc. Rev. 2012, 41, 3464–3484; Klussmann M., Jones. K. M.
SYNLETT 2012, 23, 159–162.
3) (a) Boess, E.; Schmits, C.; Klussmann M. J. Am. Chem. Soc. 2012, 134, 5317–5325; (b) Scott, M.;
Sud, A.; Boess, E.; Klussmann, M. J. Org. Chem. 2014, 79, 12033–12040.
4) Cheng, G. J.; Song, L. J.; Yang, Y. F.; Zhang, X.; Wiest, W.; Wu, Y.-D. ChemPlusChem 2013, 78,
943–951.
129
P10
Tuning of the electronic properties of armchair graphene nanoribbons
by mild functionalization. Theoretical study of the 1∆g O2 border
addition.
Giovanni Ghigo,1 Andrea Maranzana,1 Glauco Tonachini1
1
Dipartimento di Chimica, Università di Torino, via P. Giuria 7-10125 Torino.
e-mail: [email protected]
Armchair graphene nanoribbons (a-GNRs) are finite strips of graphite sheets cut along a
specific direction with a width < 10 nm and a length/width ratio > 10.1 They feature
peculiar electronic and optical properties so they have been touted as a promising
material for everything from solar cells to computers.2 The energies of their HOMOs
and LUMOs, along with their difference (gap) are some of the most important
parameters to be controlled in the design of organic electronic devices mechanisms.3 In
this this work we propose a modification of their electronic properties through the
oxidation of a-GNRs with 1∆g O2 in mild conditions.4 This process should bring about
a decoration with vicinal dialdehydic groups (Figure 1) of the border of the a-GNRs via
endoperoxide "1,2".
Figure 1
The new material should present LUMO energies lowered by 0.3 – 0.5 eV with respect
to the original material. As a consequence, the HOMO-LUMO gap should be reduced
by almost the same amount, being the HOMO energy less sensitive to the oxidation.
This method is intended to be alternative or complementary to the simple tuning of the
a-GNRs size.
1) Duttaa, S.; Pati, S. K. J. Mater. Chem. 2010, 20, 8207–8223.
2) Novoselov, K. S.; Geim, A. K.; Morozov, S. V.; Jiang, D.; Zhang, Y.; Dubonos, S. V.; Grigorieva, I.
V.; Firsov, A. A.. Science 2004, 306, 666–669.
3) Brabec, C. J.; Cravino, A.; Meissner, D.; Sariciftci, N. S.; Fromherz, T.; Rispens, M. T.; Snachez, L.;
Hummelen, J. C. Adv. Funct. Mater. 2001, 11, 374–380.
4) Clennan, E. L. ; Pace, A. Tetrahedron 2005, 61, 6665–6691.
130
PC11
Multicomponent Cascade Synthesis of Biaryl-based Chalcones in Pure
Water and in Aqueous Micellar Environment
Nicola Armenise,[a] Danilo Malferrari,[b] Sara Ricciardulli,[a] Paola Galletti,[a,b] and
Emilio Tagliavini[a,b]
[a] Università di Bologna - Dipartimento di Chimica “G. Ciamician” - Via F. Selmi 2, 40126 Bologna (Italy) [b]
Università di Bologna - Centro Interdipartimentale di Ricerca Industriale (CIRI) - Via S. Alberto 163, 48123
Ravenna (Italy)
E-mail: [email protected]
The goal of Green Chemistry is the design of chemical products and processes able to
reduce or avoid the handling and emission of hazardous materials. In particular, the
employment of solvents is highly concerning since it gives rise to toxicity, hazard and
pollution issues. In this context the employment of water as solvent has attracted much
interest in recent years. In fact, water offers many advantages because it is a cheap,
readily available, non-toxic and non-flammable solvent, thus being very attractive from
both an economical and an environmental point of view.
Among the organic reactions that can be conducted in water, cross-coupling and aldol
condensation reactions play an outstanding role; moreover, these kind of reactions can
be coupled together with one-pot and sequential procedures.
In particular, the one-pot synthesis of biarylchalcones in aqueous medium, through the
sequential Suzuki–Miyaura coupling and aldol condensation reactions, is a challenging
but attractive synthetic route. Unfortunately, the poor solubility of many substrates in
water, the formation of β-arylated ketones as side product and other drawbacks still
limit the exploitation of this strategy.
Looking for the sustainability of the synthetic processes, we have developed an highly
efficient protocol aimed to the multicomponent cascade synthesis of
biaryl(hetero)chalcones and of their functionalized derivatives, in pure water or in
aqueous micellar system, overcoming the existing drawbacks. The first step of our
protocol is a simple Pd-catalyzed, ligand-free and aerobic Suzuki-Miyaura reaction in
aqueous medium, which has proved to be extremely efficient for the coupling of aryl
and heteroaryl bromides with different arylboronic acids. The second step consists of
the addition of the third substrate (ketone or aldehyde) that undergoes in situ aldol
condensation reaction.
When the protocol was applied to highly lipophilic or less reactive reagents, micellar
catalysis was required for achieving good performances. To this aim we successfully
employed a new surfactant that we recently designed from renewable resources.
Furthermore, thanks to this additive, the catalytic system could be repeatedly recycled
without significant loss of activity.
131
PC12
The Osmium-Catalysed Tethered Aminohydroxylation of Glycals: A
Stereodirected Access to 2- and 3-Aminosugars
Stefania Mirabella1, Francesca Cardona1, Andrea Goti1
1
Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 3-13, Sesto
Fiorentino (FI), Italy.
[email protected]
The aminohydroxylation reaction is an extremely useful method for the oxidation of
alkenes to form 1,2-aminoalcohols. This moiety is present in important synthetic
pharmaceutical targets like aminosugars, key constituents of a wide variety of natural
substances.1 In 2001, Donohoe and co-workers introduced an innovative method to
obtain vicinal aminoalcohols through an intramolecular aminohydroxylation of olefins,
called “tethered aminohydroxylation”.2 This method is an adaptation of the Os-mediated
Sharpless aminohydroxylation, but it guarantees a full regiocontrol by tethering the
nitrogen source to the allylic alcohol. We describe herein the results of the application
of this method on D-glucal and D-galctal and on their derivatives, in order to obtain 2amino and 3-aminosugars with different configurations at the stereogenic carbon atoms
depending on the starting glycals.3 Glucals and galactals showed complementary
reactivity in dependence of the stage at which the reaction was performed, i.e., directly
or after double-bond shift consequent to a Ferrier rearrangement. This method allows
access to both classes of 2-amino (compound 1-2) and 3-amino (compound 3) sugar
derivatives (Scheme 1). The oxazolidinone moiety of the compound 3 was easily
removed with a basic treatment to obtain the free 3-aminosugar with excellent yield.
Scheme 1
1) Rai, R.; McAlexander, I.; Chang, C. T. Org. Prep. Proced. Int. 2005, 37, 337-375.
2) a. Donohoe, T. J.; Johnson, P. D.; Helliwell, M.; Keenan, M. Chem. Commun. 2001, 2078-2079.
b. Donohoe, T. J.; Callens, C. K. A.; Lacy, A. R.; Winter, C. Eur. J. Org. Chem. 2012, 655-663.
3) Mirabella, S.; Cardona, F.; Goti, A. Org. Lett. 2015, 17, 728-731.
132
PC13
Synthesis of β-Amino -Nitro β-Trifluoromethyl Ketones by NitroMannich Reactions on Fluorinated Imines
Stefania Fioravanti, Alessia Pelagalli, Lucio Pellacani
Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”
e-mail: [email protected]
Trifluoromethyl ketones are compounds of considerable interest due to their importance
as synthetic intermediates of other trifluoromethyl-containing targets (1) as well as for
biological activity (2).
Of even greater importance and interest is the synthesis of nitrogenated trifluoromethyl
carbonyl compounds and here we report our first results on the -nitro ketone (3)
additions to trifluoromethyl N-protected aldimines (4) by nitro-Mannich reactions (5).
The nitro-Mannich additions were performed under solvent-free conditions and without
added catalyst and can be considered a good example of green chemistry. In fact, the
reactions took place at room temperature, with very low environmental impact, no
work-up was needed and they proceeded with total atom economy.
Starting from optically pure primary amines, even the stereochemical reaction outcome
was successfully studied.
1)
2)
3)
4)
5)
(a) Zhang, P.; Wolf C. J. Org. Chem. 2012, 77, 8840–8844; (b) Gao, J.-R.; Xiang, H. Wu, B.;
Yu, W.-B.; Han, L.; Jia Y.-X. J. Am. Chem. Soc. 2013, 135, 2983–2986.
(a) Kelly, C. B.; Mercadante, M. A.; Leadbeater N. E. Chem. Commun. 2013, 49, 11133–11148;
(b) Ilies, M.; Dowling, D. P.; Lombardi, P. M.; Christianson D. W. Bioorg. Med. Chem. Lett.
2011, 21, 5854–5858; (c) Kokotos, G.; Hsu, Y.-H.; Burke, J. E.; Baskakis, C.; Kokotos, C. G.;
Magrioti, V.; Dennis E. A. J. Med. Chem. 2010, 53, 3602–3610.
Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A. Tetrahedron 2005, 61, 8971–8993.
Carroccia, L.; Fioravanti, S.; Pellacani, L.; Tardella, P. A. Synthesis 2010, 4096–4100.
Nobel, A.; Anderson, J. C. Chem. Rev. 2013, 113, 2887–2939.
133
PC14
Combining flow technology and microwave heating towards
sustainable Metal-catalyzed transformations
Chiara Petrucci1, Elena Petricci2, Ferdinando Pizzo1, Luigi Vaccaro1
1
Laboratory of Green Synthetic Organic Chemistry, CEMIN, Università di Perugia, Via Elce di Sotto, 8 –
Perugia; http://www.dcbb.unipg.it/greensoc.
2
Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via Aldo Moro, 2 – Siena
e-mail: [email protected]
In the development of new synthetic strategies towards interesting molecules the
sustainability aspect cannot be neglected, i.e. the number of steps, the waste and the
energy required should be minimized, while efficiency and selectivity must be
enhanced. Our research activity aims at the development of sustainable synthetic
processes, through the use of safer reaction media (water, azeotropes, biomass-derived)
or SolFC, and the preparation of novel organic/inorganic supports for heterogeneous
catalysis.1 The final optimization of the processes can be achieved with the flow
technology, which enables us to exploit the features of the selected medium and
catalyst.2
In this contribution, we present the results of the application of green synthetic
strategies to several metal-catalyzed reactions, fundamental tools that enable the access
to molecular moieties often found in the preparation of pharmaceutical targets and
organic semiconductors.
The use of heterogeneous catalysts in combination with the flow technology and
microwave heating proved effective in minimizing waste, simplifying experimental
procedures and in safety improvement. Moreover, with the use of flow reactors we were
able to limit the effect related to the formation of hotspots during microwave heating.
1) Pavia, C.; Ballerini, E.; Bivona, L. A.; Giacalone, F.; Aprile, C.; Vaccaro, L.; Gruttadauria, M. Adv.
Synth. Catal. 2013, 355, 2007; Petrucci, C.; Strappaveccia, G.; Giacalone, F.; Gruttadauria, M.; Pizzo, F.;
Vaccaro, L. ACS Sustainable Chem. Eng.2014,2, 2813; Ismalaj, E.; Strappaveccia, G.; Ballerini, E.;
Elisei, F.; Piermatti, O.; Gelman, D.; Vaccaro, L. ACS Sustainable Chem. Eng. 2014, 2, 2461;
Strappaveccia, G.; Ismalaj, E.; Petrucci, C.; Lanari, D.; Marrocchi, A.; Drees, M.; Facchetti, A.; Vaccaro,
L. Green Chem. 2015, 17, 365; Strappaveccia, G.; Luciani, L.; Bartollini, E.; Marrocchi, A.; Pizzo, F.;
Vaccaro, L. Green Chem. 2015, 17, 1071; Petrucci, C.; Cappelletti, M.; Piermatti, O.; Nocchetti, M.; Pica,
M.; Pizzo, F.; Vaccaro, L. J. Mol. Catal. A: Chem. 2015, 401, 27.
2) Vaccaro, L.; Lanari, D.; Marrocchi, A.; Strappaveccia, G. Green Chem. 2014, 16, 3680.
134
PC15
Exploiting Ethanolamines as Green and Sustainable Alkylating Agents
in Iridium-Catalyzed Alkylation of C−H Bonds Using Borrowing
Hydrogen Methodology
Giovanni Di Gregorio, Silvia Bartolucci, Michele Mari, Giovannni Piersanti
Department of Biomolecular Sciences, University of Urbino “Carlo Bo”
e-mail: [email protected]
Carbon−carbon bond formation reactions are fundamentally important transformations
in organic synthesis.1 The formation of C−C bonds by the electrophilic alkylation of an
alkyl halide/pseudohalide with a nucleophile results in the production of a
stoichiometric amount of salt as well as the desired alkylation product. The use of
alcohols as direct alkylating agents is generally limited due to the poor electrophilicity
of most alcohols, although such a procedure is appealing since the only reaction
byproduct is water.2 The use of the hydrogen autotransfer (or hydrogen borrowing)
strategy overcomes the lack of reactivity by reversible changes in the oxidation state of
the reacting partners. In essence, a catalyst (generally transition-metal such as Ir, Pd,
Rh, Ru, etc.) alters the reactivity of a compound (tipically alcohols) by removing two
hydrogen atoms in a formal oxidation of the substrate. This temporarily generates a
highly reactive intermediate and permits bond formation to take place. Finally, the
intermediate is reduced with the redelivery of two hydrogen atoms, giving a product
without a net change in the overall oxidation state.3 Hydrogen borrowing represents
already a promising alternative approach for the formation of C−C bonds of carbonyl
compounds, as well as relatively unactivated substrates bearing fewer acidic αhydrogens, such as nitriles, esters, malonates using simple alcohols as the alkylating
agent.4 However, the direct alkylation of nonacidic C−H bonds, such as aromatic or
heteroaromatic C−H bonds, with alcohols has scarcely been reported.5 In addition, very
little is know about the use of alcohols containing aminoethylene moieties although they
could be suitable two-carbon nitrogen-containing electrophiles highly desiderable for
C2N unit that is found in a number of drug and is a common motif in countless naturally
occurring compounds. (Scheme 1)
Scheme 1
1) Caine, D. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Patternden, G. Eds.;
Pergamon Press: Oxford, 1991; Vol. 3, pp 1.
2) The Functional group interconversion (FGI) of nonderivatized alcohols was recently voted as the
second most desired reaction that pharmaceutical companies wanted a greener version of. See : Green
Chem. 2007, 9, 411.
3) (a) Gunanathan, C.; Milstein, D. Science 2013, 341, 249. (b) Watson, A. J. A.; Williams, J. M. J.
Science 2010, 329, 635.
4) (a) Obora, Y. ACS Catal. 2014, 4, 3972. (b) Pan, S.; Shibata, T. ACS Catal. 2013, 3, 704.
5) Bartolucci, S.; Mari, M.; Bedini, A.; Piersanti, G.; Spadoni G. J. Org. Chem. 2015, 80, 3217.
135
PC16
Enantioselective Organocatalyzed Vinylogous Mannich-Type Reaction
Involving Isatin
G. Rainoldi, G. Lesma, A. Silvani, M. Stucchi
Dipartimento di Chimica, Università di Milano, via Golgi 19, 20133, Milano, Italy.
e-mail: [email protected]
The reactions at the C-3 carbonyl group of isatins, by nucleophilic addition or
spiroannulation, transform them into 2-oxindole derivatives, featuring in a large number
of natural and unnatural compounds with important biological activities.1
Going on with our interest in the asymmetric synthesis of 3,3-disubstituted oxindoles,2
we are developing a project aimed to explore the applicability of organocatalysis,
particularly chiral Brønsted acid catalysis,3 to the enantioselective synthesis of
quaternary 3-aminooxindole butenolides, through the vinylogous Mannich-type reaction
of trimethylsilyloxyfuran and isatin-derived ketimines. The application of such reaction
to ketimines remains to date largely unexplored,4 due to the steric challenge inherent in
the stereocontrolled formation of a quaternary stereogenic center consecutive with a
bulky tertiary one.
Reaction of trimethylsilyloxyfurans with various preformed imines, derived from Nprotected isatins and benzhydrylamine, allowed us to access a small family of highly
functionalized diastereoisomeric compounds, in high yields and enantiomeric eccesses.
To demonstrate the synthetic utility of the Mannich-type adducts, transformation
reactions are presently in progress, in order to increase the number of potentially useful
compounds. The assignment of the absolute and syn/anti relative configuration through
X-ray diffraction is currently underway on selected compounds, as well as
computational studies aimed to explain the stereochemical outcome of this
organocatalyzed process.
1) 1. Singh, G.S.; Desta, Z.Y. Chem. Rev. 2012, 112, 6104.
2) Lesma, G.; Meneghetti, F. Belstein J. Org. Chem. 2014, 10, 1383.
3) Mahalau, M.; List, B. Angew. Chem. Int. Ed. 2013, 52, 518.
4) Bhaskara Rao V.U., Jadhav P.A., Org. Lett., 2014, 16, 648; Hermange P., Dodd R.H., Org. Lett., 2009,
11, 4044; Wieland L.C., Hoveyda A.H., J. Am. Chem. Soc., 2009, 131, 570; Hayashi M., Nakamura S.,
Angew. Chem. Int. Ed., 2013, 52, 5557; Shy Y.H., Wang Z., Tetrahedron, 2012, 68, 3649.
136
PC17
V-catalyzed oxidation of thymol with hydrogen peroxide
Federica Sabuzi, Paola Pesce, Valeria Conte, Pierluca Galloni, Barbara Floris
Università di Roma Tor Vergata, Via della Ricerca Scientifica, 00133, Roma, Italia
e-mail: [email protected]
The reaction between Vanadium (V) derivatives and hydrogen peroxide or alkyl
hydroperoxide leads to the formation of peroxocomplexes which are the effective
oxidating species of organic and inorganic substrates in both, stoichiometric and
catalytic conditions1.
In this context, recently good results have been achieved in the oxidative bromination of
thymol2, a monoterpenoid phenol compound, main component of the Thymus vulgaris
essential oils. Bromination reaction proceeded with no organic solvents, in very mild
conditions and using sustainable reactants. The process showed high substrate
conversion and selectivity toward the formation of 4-bromothymol.
Occasionally, among reaction products, the presence of the oxidation product,
thymoquinone, has been detected. Considering the great importance of such quinoid
compound in medical field3 and the lack of effective synthetic methods in the literature4,
our interest has been focused on the possibility to oxidize thymol in water, using
hydrogen peroxide as primary oxidant and a commercially available V-catalyst.
OH
O
H2O2
NH4VO3
O
Scheme 1: V-catalyzed oxidation of thymol
The oxidative procedure has been explored and results will be reported.
1) Conte V.; Floris B. Dalton Trans., 2011, 40, 1419-1436; Conte V.; Coletti A.; Floris B.; Licini G.;
Zonta C. Coord. Chem. Rev., 2011, 255, 2165-2177; Conte V.; Coletti A.; Mba M.; Zonta C.; Licini
G. Coord. Chem. Rev., 2011, 255, 2345–2357.
2) Sabuzi F.; Churakova E.; Galloni P.; Wever R.; Hollmann F.; Floris B.; Conte V. Eur. J. Inorg.
Chem., 2015, in press DOI:10.1002/ejic.201500086.
3) Guimarães A. G.; Quintans J. S. S.; Quintans-Júnior L. J. Phytother. Res., 2012, 27, 1-15; Vieira
Sobral M.; Lira Xavier A.; Cardoso Lima T.; Pergentino de Sousa D. Scientific World J., 2014, 2014,
1-35; Razavi B. M.; Hosseinzadeh H. J. Endocrinol. Invest., 2014, 37, 1031–1040.
4) Henderson G. G.; Boy R. J. Chem. Soc. Trans., 1910, 97, 1659-1669; Dockal E. R.; Cass Q. B.;
Brocksom T. J.; Brocksom U.; Correa A. G. Synth. Commun., 1985, 15, 1033-1036.
137
PC18
One-pot, four-step organocatalytic asymmetric synthesis of
functionalized nitrocyclopropanes
Anna Zaghi, Tatiana Bernardi, Valerio Bertolasi, Olga Bortolini, Alessandro Massi,
Carmela De Risi
Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17,
44121 Ferrara (Italy)
e-mail: [email protected]
Nitrocyclopropanes represent a special class of cyclopropane compounds,1 which are
present in some natural products and used as precursors of pharmacologically relevant
targets. In the last few decades, there has been a renewed interest in the stereoselective
synthesis of nitrocyclopropanes, which is most frequently achieved through Michael
initiated ring closure (MIRC) reactions between electrophilic alkenes and suitable
nucleophiles bearing a good leaving group.2
Recently, it has been reported that racemic 2,5-dihydrothiophene-3-carbaldehydes 2,
obtained by secondary amine-catalyzed domino sulfa-Michael/aldol condensations of
1,4-dithiane-2,5-diol 1 with ,-unsaturated aldehydes, are convenient substrates for
diastereoselective cyclopropanations with bromonitromethane to give the bicyclic
nitrocyclopropanes 3 via domino Michael/-alkylation reactions catalyzed by
3
DLproline. As a logical extension of this work, it has been investigated an asymmetric
version of the above process by using a chiral proline surrogate as catalyst, with the aim
at combining the two catalytic domino sequences to access the target nitrocyclopropane
scaffolds by a challenging four reaction, one-pot process.
Our studies led to disclose a one-pot, four-step method wherein chiral
dihydrothiophenes 2, prepared by an organocatalytic domino sulfa-Michael/aldol
condensation reaction, are treated in-situ with bromonitromethane anion to provide the
target compounds 3 with good diastereo- and enantioselectivies (Scheme 1). This
process is efficiently carried out by using (S)-diphenylprolinol TMS ether 4 as the only
and one organocatalyst triggering both the domino sulfa-Michael/aldol condensation
step and the following domino Michael/-alkylation reaction.
Scheme 1
1)
2)
3)
For reviews on synthesis and use of nitrocyclopropanes, see: a)E. B. Averina; N. V. Yashin; T.
S. Kuznetsova; N. S. Zefirov Russ. Chem. Rev. 2009, 78, 887-902; b) R.Ballini;A.Palmieri;D.
Fiorini,Arkivoc2007,vii,172‐194.
G. Bartoli; G. Bencivenni; R. Dalpozzo Synthesis 2014, 46, 979-1029.
De Risi, C.; Benetti, S.; Fogagnolo, M.; Bertolasi V. Tetrahedron Lett. 2013, 54, 283-286.
138
B – Chimica Fisica Organica
139
PC19
Stable diarylmethylium salts as reagents and catalysts
Margherita Barbero1, Silvano Cadamuro1, Stefano Dughera1, Giovanni Ghigo1,
Domenica Marabello2
1
Dipartimento di Chimica (Università di Torino, Via P. Giuria 7, 10125 Torino) 2Dipartimento di
Chimica e CrisDi (Università di Torino, Via P. Giuria 7, 10125 Torino)
e-mail: [email protected]
We have recently reported the synthesis of a representative number of bench-stable and
ready to use non-symmetric diarylcarbenium tetrafluoroborates via the direct coupling
of aryl (or heteroaryl) aldehydes and N-heteroarenes (Scheme 1).1 Some of them have
been previously isolated as long shelf life o-benzenedisulfonimides,2 which have been
recently employed in a direct organocatalyzed asymmetric alkylation of aldehydes.3
The presence of the azole moiety (whether isolated or benzene-fused) is the crucial
framework for the high stability of these diarylcarbenium ions due to the vinylogous
iminium (alkylideneindoleninium) substructure stabilization.
Scheme 1
The easy preparation procedure, ready to use availability, high stability and structure
variety of these normally highly reactive intermediates, along with the commercial
availability of the tetrafluoroborate anion, make them a tool of great synthetic relevance
in organic chemistry for the synthesis of more complex structures.
On the other hand, carbocations represent an hitherto almost completely neglected but
very versatile Lewis acid class.4
Researches are currently under way on our laboratory on suitable reactions of these
reactive species as electrophilic reagents in reactions with nucleophiles such as
activated aromatics and cyclic silyl enol ethers, where good yields and diastereomeric
ratio are observed. Meanwhile, they are tested in catalytic amounts in Lewis acid
catalyzed organic reactions (e.g. Michael additions, dehydrative coupling).
1) Barbero, M.; Buscaino, R.; Cadamuro, S.; Dughera, S.; Gualandi, A.; Marabello, D.; Cozzi, P. G. J.
Org. Chem. 2015, 80, 47914796.
2) Barbero, M.; Cadamuro, S.; Cauda, F.; Dughera, S.; Gervasio, G.; Venturello, P. J. Org. Chem. 2012,
77, 427887.
3) Armenise, N.; Dughera, S.; Gualandi, A.; Mengozzi, L.; Barbero, M.; Cozzi, P. G. Asian J. Org.
Chem. 2015, 4, 337345.
4) Bah, J; Naidu, V. R.; Teske, J.; Franzen, J. Adv. Synth. Catal. 2015, 357, 148158.
140
PC20
Peptide-based Low Molecular Weight Gelators:
their versatility and applications
S. Bartocci1, M. Mba1
1
Department of Chemical Sciences, University of Padova
Via Marzolo 1, 35131 Padova, Italy
e-mail: [email protected]
Supramolecular gels derived from low molecular weight gelators (LMWGs)1 received
great attention in recent years and it is possible to design many different gelators with
very different structures but, despite the structural variety, the self-assembly into fibrous
networks is always driven by non-covalent interactions like van der Waals interactions,
π-interactions, hydrogen bonding and so on. The reason of such an interest is not only to
study and understand the fundamental aggregates structures but also to explore their
technological applications. Indeed, a clever incorporation of sensitive units as part of the
gelator molecule lead to obtain stimuli-responsive gels that respond to the change in
their surroundings such as solvent, temperature, pH, light, ultrasound etc. that can be
exploited as smart materials which have sensor, processor and actuator functions.
Among the different small organic compounds able to form supramolecular gels,
peptides are really good low molecular weight gelators since they give secondary
structures through hydrogen bond formation moreover the synthetic protocol is well
established and is possible to choose in a pool of 20 natural amino acids. In this work
we report our last achievements in this field showing the ease of synthesis of these
systems and their versatility2, 3.
Scheme 1
1) Abdallah, J.; Weiss, R. G. Adv. Mater. 2000, 17, 1237-1247.
2) Bartocci, S.; Mazzier, D.; Moretto, A.; Mba, M. Org. Biomol. Chem. 2015, 13, 348-352.
3) Morbioli, I.; Bartocci, S.; Maggini, M.; Mba, M. J. Pept. Sci. submitted
141
PC21
Predictions of the nucleofugality of carbanionic leaving groups based
upon NMR chemical shifts in the enantioselective synthesis of
sulfoxides
Maria Annunziata M. Capozzi1, Cosimo Cardellicchio2
1
2
Dipartimento di Chimica, Università di Bari, via Orabona 4, Italy.
CNR ICCOM; Dipartimento di Chimica, Università di Bari, via Orabona 4, Italy..
e-mail: [email protected]
Our sequential coupling of Grignard reagents with suitable sulfinyl compounds
involving the displacement of carbanionic leaving groups is now a well established
procedure1 for the synthesis of enantiopure sulfoxides.
Scheme 1
After our synthetic and mechanistic investigation on the straightforward synthesis of
selected sulfinyl precursors through a highly enantioselective oxidation of the sulfides
with hydroperoxide in the presence of a complex between titanium and hydrobenzoin,
more than 40 enantiopure aryl benzyl sulfoxides are now easily available as starting
materials.2 Thus, we decided to give a deep insight into the reaction of organometallic
reagents with the enantiopure items of this chemical library.
We found that the nucleofugality of the leaving groups, and the order in the sequence of
substitution, can be tuned by choosing the aryl benzyl sulfoxide that bears appropriate
substituents on both the phenyl groups.
We report now that the nucleofugality of the carbanionic leaving groups can be
predicted by comparing analogous NMR chemical shifts of signals of the starting
sulfoxides. The agreement between the experimental results and the expectations will be
briefly surveyed.
(1) Wojaczyńska, E.; Wojaczyński, J. Chem. Rev. 2010, 110, 4303-4356. O’ Mahony, G. E.; Kelly, P.;
Lawrence, S. E.; Maguire, A. R. ARKIVOC 2011, 1-110.
(2) Naso, F., Capozzi, M.A.M.; Bottoni, A.; Calvaresi, M.; Bertolasi, V.; Capitelli, F. Chem. Eur. J. 2009,
10, 13417-13426. Capozzi, M.A.M.; Centrone, C.; Fracchiolla, G.; Naso, F.; Cardellicchio, C. Eur. J.
Org. Chem. 2011, 4327-4334. Capozzi, M.A.M.; Capitelli, F.; Bottoni, A.; Calvaresi, M.;
Cardellicchio, C. ChemCatChem 2013, 5, 210-219. Capozzi, M.A.M.; Terraneo, G.; Cavallo, G.;
Cardellicchio, C. Tetrahedron, 2015, 4810-4816 and references therein.
142
PC22
Stability study of synthetic organic pigments and dyes used in
contemporary paintings
Alessandro Ciccola1, Marcella Guiso1, Armandodoriano Bianco1
1
Dipartimento di Chimica, “Sapienza” Università di Roma, Piazzale Aldo Moro 5, 00185 Roma,
e-mail: [email protected]
Industrial revolution represented a threshold of complete change also in artistic
field: the synthesis of new colouring molecules offered new colours to the artists, who
could obtain new painting materials, less expensive and easy to use.1
These compounds, like azopigments, quinacridones, anthraquinones and
pthalocyanines, are typically organic and they have replaced the inorganic historical
pigments. However, because of their industrial and recent origin, their stability in a
pictorial film is unknown. After all, it is plausible that the organic nature of these
molecules could be responsible of their susceptibility to chemical degradation.2
Figure 1: examples of structures of common synthetic pigments.
In this study, part of a PhD project, we monitor and characterize the degradation
products of some selected organic pigments. Starting from the preparation of standard
samples of pictorial films, combining the pigments with organic binders used in
contemporary art (oil, acrylic, etc.), we monitor their accelerated aging process, using
UVA and UVB lamps. This process causes the formation of degradation products, which
would be characterized with mass spectrometry and NMR techniques. The identification
of their structures could result useful to understand reactions involved in pictorial film
alteration and to identify optimal conditions for conservation of contemporary artworks.
Besides, these samples will be analysed with several analytical techniques used in
cultural heritage, as Raman spectroscopy3 and chromatography.4 Synergy among all
these techniques would supply useful information for the analysis of art objects.
1)
Herbst W., Hunger K., Industrial Organic Pigments, WILEY-VCH Verlag GmbH & Co. KGaA, 2004
2)
Papliaka Z. E., Andrikopoulos K. S., Varella E. A., Study of the stability of a series of synthetic colorants
applied with styrene-acrylic copolymer, widely used in contemporary paintings,concerning the effects of accelerated
ageing, Journal of Cultural Heritage 2010, 11 () 381–391
3)
Schulte F., Brzezinka K., Lutzenberger K., Stege H., Panne U., Raman spectroscopy of synthetic organic
pigments used in 20th century works of art, J. Raman Spectrosc. 2008; 39, 1455–1463
4)
Brosseau C. L., Gambardella A., Casadio F., Grzywacz C. M., Wouters J., Van Duyne R. P., Ad-hoc
Surface-Enhanced Raman Spectroscopy Methodologies for the Detection of Artist Dyestuffs: Thin Layer
Chromatography-Surface Enhanced Raman Spectroscopy and in Situ On the Fiber Analysis, Anal. Chem., 2009, 81,
3056–3062
143
PC23
SOMO-HOMO Conversion in Distonic Radical Anions: An
Experimental Test in Solution by EPR Radical Equilibration
Technique
Marco Lucarini1, Elisabetta Mezzina1, Paola Franchi1
1
Department of Chemistry “G. Ciamician” (University of Bologna, Via San Giacomo 11, I-40126
Bologna, Italy)).
e-mail: [email protected]
Knowledge of the energy required to break bonds and energy released on making bonds
are basic to our understanding of chemical reactivity. This is definitely true for reactions
involving free radical intermediates. For these reactions, knowledge of the dissociation
energies (BDEs) of the bonds that are being broken and made is generally sufficient to
predict their thermochemistry and thus their feasibility. In this context it is of great
relevance the recent report of Coote and co-authors who predicted by theoretical
calculations an unexpected radical stabilization in distonic radical anions where a truly
remote negative charge (such as carboxylate, sulfate or phosphate) and a stable radical
center (aminoxyl, peroxyl or aminyl) are separated by more than 5 Å and are not πconjugated.1-2 This effect was ascribed to an inversion of SOMO and HOMO energy
levels of the radical.1-2
In order to verify under real conditions (i.e. in solution) Coote’s computational
predictions, we decided to measure the BDEs of O-H bonds in hydroxylamines deriving
from neutral and deprotonated forms of 4-carboxy-TEMPO in solution (acetonitrile and
dimethylsulfoxide) by using the EPR radical equilibration technique (see Scheme 1).3
Scheme 1
The experimental results indicated that the stabilizing interaction between a remote
negative charge and a stable radical center, predicted in gas phase, is completely lost in
polar solvents.4
1)
2)
3)
4)
Grin’ova, G.; Marshall, D. L.; Blanskby, S. J.; Coote, M. L. Nat. Chem. 2013, 5, 474.
Grin’ova, G.; Coote, M. L. J. Am. Chem. Soc. 2013, 135, 15392.
Lucarini, M.; Pedulli, G.F. Chem. Soc. Rev. 2010, 39, 2106.
Franchi, P.; Lucarini, M.; Mezzina, E. J. Am. Chem. Soc. 2014, 136, 1250.
144
PC24
Characterization of compounds present in the ammonia extract of
Madder lake, using NMR, ESI-MS and HPTLC-SERS
L. Lombardi1,2, C. Fasolato3, I. Serafini1,2, M. Guiso1, F. Sciubba1, P. Postorino3, A.
Bianco1
1
Dipartimento di Chimica, 2Dipartimento di Scienze della Terra,3Dipartimento di Fisica Università di
Roma “La Sapienza” , Piazzale A. Moro 5, Roma ( Italy)
<[email protected]>
Until the introduction of synthetic dyes in the XIX century, artworks were realized
using lakes prepared from natural raw materials. The precipitation of lake pigments
occurs due to the formation of a complex with different cations. The complexes thus
obtained are particularly stable and therefore insoluble in water or common organic
solvents. This work was aimed at the identification of compounds present in the
ammonia extract of Madder lake. To perform the analysis, it is necessary the breakdown
of the complex and then extract the compounds. The most common method used until
now had been a mixture of organic solvent with strong acid as HCl or H2SO4 [1]. This
method ensured high yield of extraction producing, however, hydrolysis, alteration of
original compounds in the sample and allowing only the identification of the main
aglycones. Our new extraction method [2], was developed in order to preserve the
glycoside compounds present and then to get closer to the real molecule pattern
involved in lake precipitation. In fact, understanding the chemical nature of the
compounds is very important in order to adequately respond to questions regarding for
example the proper storage conditions, the dating or the provenance of an artwork.
The first step of the research was the preparation of
samples of Madder lake from Rubia tinctorum L.,
following the recipes contained in the ancient and
medieval recipes [3,4]. Then a chromatographic
separation of ammonia extract was performed. In
order to identify the isolated compounds, NMR, ESIMS and HPTLC-SERS (Surface Enhanced Raman
Spectroscopy) analysis were carried out (example in
Fig.1).
Fig. 1 – Example of HPTLC-SERS results
To identify these compounds in artworks, it is very important to apply a technique that
allow a rapid, minimally invasive and highly sensitive identification of these natural
organic dyes. We developed a new analytical protocol, the micro-sampling with Ag-gel
matrix associated with SERS analysis [4] that presents these characteristics and, for this
reason, could be very useful in the field of diagnostic for Cultural Heritage. To interpret
the SERS spectra of micro-samples on Ag-gel matrix, we use as reference spectra those
obtained from HPTLC-SERS analyses.
1) Wouters J. Stud. Conservation. 1985, 30, 119-128.
2) Lombardi L. ; Serafini I. ;Guiso M. ; Sciubba F. ; Bianco A. , 2015, Tetrahedron Letters, submitted to
3) Merrifield M. P., London 1849
4) Lombardi L. , Guiso M., Santamaria U. , Bianco A. , Book of abstracts TECHNART 2015
145
PC25
Stereochemical lability of 2,5-diphenyl-1,3,4 oxadiazoline and -1,3,4
thiadiazoline chiral derivatives: effects of solvent and substituent
groups.
Roberto Cirilli1, Simona Distinto2, Maria L. Sanna2, Elias Maccioni2, Sergio Menta3,
Marco Pierini3
1
Dipartimento del Farmaco (Istituto Superiore di Sanità, V.le Regina Elena, 299, 00161 Rome, Italy). 2
Dipartimento Farmaco Chimico Tecnologico (Università di Cagliari, Via Ospedale 72, 09124 Cagliari,
Italy). 3 Dipartimento di Chimica e Tecnologie del Farmaco (Sapienza, University of Rome, P.le Aldo
Moro 5, 00185 Rome, Italy).
e-mail: [email protected]
The 1,3,4 oxadiazole and 1,3,4-thiadiazole rings, two five-membered heterocycles, as
well as their totally or partially reduced forms (i.e. the -diazolidine or -diazoline cycles),
characterize molecules endowed with a wide spectrum of pharmacological activities1,2
(e.g. antimicrobial, fungicidal, anticancer, antiviral, analgesic and anti-inflammatory
activity, etc.). Accordingly, these peculiar structural frameworks can be observed in a
variety of medicinal agents, thus that their insertion within suitable molecular structures
can constitute a successful strategy for the synthetic development of new drugs. With
attention to the particular cases of the 1,3,4 oxadiazoline and 1,3,4 thiadiazoline rings as
pharmacologically significant scaffolds, we performed a study concerning the
stereochemical lability expressed by 2,5-diphenyl-substituted chiral derivatives of these
heterocycles (Scheme 1). The tendency to lose the stereo-integrity at the asymmetric
carbon C2 has been experimentally investigated on compound 1 by determining the
relevant enantiomerization rate constant within eleven solvents endowed with very
different polarities and proticities. The obtained findings have been rationalized by
resorting to extensive LSER analyses and molecular modelling investigation. Through
DFT calculations, information have also been achieved about the effects exercised on
the enantiomerization barrier by electron-donor and -withdrawing groups substituting
the 2-phenyl ring and/or the 3-nitrogen atom of both the oxadiazoline and thiadiazoline
structures. The overall results have been discussed in the perspective to make rational
the design of new chiral pharmacological agents based on these heterocycles which are
endowed with high configurational stability.
R3
R1
N N
X
R4
Br
X=O
1,3,4 oxadiazoline derivative
X=S
1,3,4 thiadiazoline derivative
X=O
R1 =
R2
Compound 1:
Scheme 1
R2 = R3 =
R4 =
R1
O
R2 = R 3
O
Cl
CN
O
R4
H
Cl
O
H
CH3
NO2
OCH3
NH2
1) Abu-Zaied, M.A.Z.; Nawwar, G.A.M.; Swellem1, R.H.; El-Sayed, S.H. Pharmacology & Pharmacy,
2012, 3, 254-261.
2) Asif M. American Journal of Current Organic Chemistry 2014, 1, 17-36
146
PC26
Acid-base equilibria in ionic liquids
Gabriella Siani, Romina Zappacosta, Antonello Di Crescenzo, Antonella Fontana
Dipartimento di Farmacia, Università “G. d’Annunzio”
via dei Vestini, 31- 66100 Chieti.
e-mail: [email protected]
Ionic liquids (ILs) are low temperature molten organic salts, with melting points lying
often below room temperature. Due to their peculiar properties, such as low volatility,
low flammability and high stability, they have been widely used in the last two decades
as alternative reaction media to conventional organic solvents for many organic
reactions.1
Aliphatic amines2,3 and pyridines4 have been used as nucleophiles or bases in organic
reactions performed in ILs. In some cases, rate constants are higher than those expected
on the basis of the pKa values in water, suggesting a higher nucleophilicity/basicity of
amines in ILs than in conventional organic solvents.
It is well known that the acid-base strength depends on the solvent and it is reasonable
to expect that acids and bases can differently interact with a molecular solvent and an
ionic solvent. Hence, particular caution is necessary if pKa values determined in water
are used to rationalize quantitative results obtained in ILs.
In a previous work5 we have determined the equilibrium constants for ion pair
formation, Kip, of some pyridines with trifluoroacetic acid in different ionic liquids. It
turned out that the basicity order is the same in ionic liquids and in water and pyridine
basicity is less sensitive to the substituent effect in ionic liquids than in water.
In the present work we have determined the ion-pair basicity in ILs of various
substituted anilines and other bases as a further extension of the earlier established
basicity scale for pyridines. The ion-pair basicity has been estimated quantitatively from
the aptitude of the base to take a proton from trifluoroacetic acid. The values of Kip have
been measured in ILs, obtained from the combination of different cations and anions, by
spectrophotometric titration, adding increasing amounts of TFA to a solution of the
base.
The effects of the different ILs cation/anion compositions on the ion-pair basicities have
been discussed.
To compare more rigorously the basicities in ILs and in water, the experimental Kip
values have been corrected for ion-pairing using the Fuoss equation to obtain relative
ionic basicities, Ka
1) Chiappe, C.; Pieraccini, D. Eur. J. Org. Chem. 2002, 2831-2837.
2) D’anna, F.; Noto, R. Tetrahedron. 2007, 63, 11681-11685.
3) D’anna, F.; Frenna, V.; La Marca, S.; Noto, R.; Pace, V.; Spinelli, D. Tetrahedron. 2008, 64, 672680.
4) Angelini, G.; De Maria, P.; Chiappe, C.; Fontana, A.; Gasbarri, C.; Siani, G. J. Org. Chem. 2009, 74,
6572-6576.
5) Angelini, G.; De Maria, P.; Chiappe, C.; Fontana, A.; Pierini, M.; Siani, G. J. Org. Chem. 2010, 75,
3912-3915.
147
C – Chimica Supramolecolare
148
PC27
Reversible Mechanical Switching of Magnetic Interactions in a
Molecular Shuttle
Valentina Bleve, Christian Schäfer, Paola Franchi, Serena Silvi, Elisabetta Mezzina,
Alberto Credi, Marco Lucarini
Dipartimento di Chimica “G. Ciamician”
Università di Bologna
Via Selmi 2, 40126, Bologna (Italy).
e-mail: [email protected]
An acid-base switchable molecular shuttle based on a [2]rotaxane incorporating stable
radical units in both the ring and dumbbell components is reported. The [2]rotaxane
comprises a dibenzo[24]crown-8 ring (DB24C8) interlocked with a dumbbell
component that possesses a dialkylammonium and a 4,4’-bipyridinium (Bpym2+)
recognition sites. In the rotaxane deprotonation of the NH2+ centre of the guest effects a
quantitative displacement of the DB24C8 macroring to the Bpym2+ recognition site, a
process that can be reversed by acid treatment. Interaction between stable 2,2,6,6tetramethylpiperidine-1-oxyl (TEMPO) radicals connected to the ring and dumbbell
components could be switched between noncoupled (three-line EPR spectrum) and
coupled (five-line EPR spectrum) upon displacement of the spin-labelled DB24C8
macroring.1 A system of this kind can represent a first step towards a new generation of
nanoscale magnetic switches that may be of interest for ICT applications.2 Spin
labelling in molecular machines is also interesting because correlations between radical
pairs, monitored by pulsed EPR methods, enable detailed conformational analyses,
dynamics studies and precise measurements of nanoscale distances.3
Scheme
1) Bleve, V.; Schäfer, C.; Franchi, P.; Silvi, S.; Mezzina, E.; Credi, A.; Lucarini, M. ChemistryOpen
2015, 4, 18-21.
2) Sato, O.; Tao, J.; Zhang, Y. Angew. Chem. Int. Ed. 2007, 46, 2152-2187, and references therein.
3) Pievo, R.; Casati, C.; Franchi, P.; Mezzina, E.; Bennati, M.; Lucarini, M. ChemPhysChem, 2012, 13,
2659-2661; Mezzina, E.; Manoni, R.; Romano, F.; Lucarini M. Asian J. Org. Chem, 2015, 4, 296-310.
149
PC28
Solvent molding of organic morphologies made of supramolecular
chiral polymers
Luka Đorđević,1 Tomas Marangoni,1 Tanja Miletić,1 Jenifer Rubio-Magnieto,2 Mathieu
Surin2,* and Davide Bonifazi1,3*
1Department of Chemical and Pharmaceutical Sciences, INSTM UdR Trieste, University of
Trieste, Piazzale Europa 1, 34127 Trieste, Italy
2Laboratory for Chemistry of Novel Materials, Center for Innovation in Materials and
Polymers, University of Mons – UMONS, 20 Place du Parc, B-7000 Mons, Belgium
3Namur Research College (NARC) and Department of Chemistry, University of Namur
(UNamur) Rue de Bruxelles 61, 5000 Namur, Belgium
e-mail: [email protected]
The self-assembly and self-organization behavior of uracil-conjugated enantiopure (R)
or (S) 1,1’-binaphthyl-2,2’-diol (BINOLs) and an hydrophobic oligo(para-phenylene
ethynylene) (OPE) chromophore exposing 2,6-di(acetylamino)pyridine termini are
reported.1 Systematic spectroscopic (UV-Vis, CD, fluorescence, NMR and SAXS) and
microscopic studies (TEM and AFM) showed that BINOL and OPE compounds
undergo triple H-bonding recognition generating different organic nanostructures in
solution. Depending on the solvophobic properties of the liquid media (Toluene, CHCl3,
CHCl3/CHX and CHX/THF), spherical, rod-like, fibrous and helical morphologies were
obtained, with the latter being the only nanostructures expressing chirality at the
microscopic level. SAXS analysis combined with molecular modeling simulations
showed that the formation of the helical superstructures is composed of dimeric doublecable tape-like structures that, in turn, are supercoiled at the microscale. This behavior is
interpreted as a consequence of an interplay between the degree of association of the Hbonded recognition, the vapour pressure of the solvent and the solvophobic/solvophilic
character of the supramolecular adducts in the different solutions under static and
dynamic conditions, namely during solvent evaporation conditions at room temperature.
1)
L. Đorđević, T. Marangoni, T. Miletić, J. Rubio-Magnieto, J. Mohanraj, H. Amenitsch, D.
Pasini, N. Liaros, S. Couris, N. Armaroli, et al., J. Am. Chem. Soc. 2015, doi: 10.1021/jacs.5b02448.
150
PC29
New Chiral Rotaxanes for Asymmetric Catalysis
Andrea Gualandi1, Elisabetta Manoni1, Serena Silvi1, Alberto Credi1, Pier Giorgio
Cozzi1
1
ALMA MATER STUDIORUM-Università di Bologna, Dipartimento di chimica “G. Ciamician”,
Bologna, Italy.
e-mail: [email protected]
Nowadays, rotaxanes incorporating catalytic centers are emerging as new catalysts in
catalytic transformations. Inspired by nature, where external stimuli are able to control
the enzymatic processes, numerous synthetic systems have been developed. In these
systems a stimulus (e.g. pH, light) can be used to turn a catalyst's activity 'on' or 'off'.1 In
particular, switchable rotaxane-based organocatalysts have been synthesized, where the
catalytic activity can be switched by addition of acid or base, which acts to move the
rotaxane ring to either conceal or reveal the catalytic site.2
The rotaxane systems is also suitable for the addition of multiple catalytic active sites in
the various components of rotaxane, thus creating multi-functional catalyst. The two or
more active sites can work cooperatively or individually, through an external stimulus
that controls the activity. Furthermore, the high structural flexibility of rotaxanes allows
to the different groups, taking part in the catalytic process, to spatially arranged in the
best way, thus increasing the efficiency of process. Furthermore, the possibility to insert
in a rotaxane two or more sites capable to coordinate transition metals, open the way to
the use of these structures in asymmetric metal-catalysed reaction.3
Here we report the synthesis of new chiral catalysts based on rotaxane architectures able
to act as switchable catalysts or ligands for transition metals in asymmetric
transformations.
Acknowledgments: This work was financially supported by ALMA MATER
STUDIORUM-Università di Bologna through the SLAMM FARB project.
1) For an highlight see: Angew. Chem. Int. Ed. 2012, 51, 8163. For some selected examples: Science
2011, 331, 1429; ACS Catal. 2013, 3, 1874; Chem. Commun. 2013, 49, 5453; Chem. Commun. 2012,
48, 11730.
2) Angew. Chem. Int. Ed. 2012, 51, 5166; J. Am. Chem. Soc. 2014, 136, 4905.
3) J. Am. Chem. Soc. 2007, 129, 12930.
151
PC30
Supramolecular Control of Spin Exchange in Spin Labelled
[2]Rotaxane Incorporating a Tetrathiafulvalene Unit
Lorenzo Gualandi, Francesco Romano, Roberta Manoni, Valentina Bleve, Paola
Franchi, Elisabetta Mezzina and Marco Lucarini
Department of Chemistry “G. Ciamician”University of Bologna, Via S. Giacomo 11, 40126, Bologna,
Italy
e-mail: [email protected]
Exchange-coupled oligoradicals are of great importance and interest in many fields of
chemistry and related sciences.1 An essential parameter in such structures is represented
by the magnitude and sign of the spin−spin coupling interaction (J). This interaction can
be through-bond and/or through-space, and its value depends on the extent of electronic
communication which is sensitive to their relative orientation between molecules. In
this contest, mechanically interlocked molecules (MIMs), such as catenanes and
rotaxanes, containing paramagnetic species provided stimulating framework in
consideration of their capacity to vary the relative positions of the dumbbell and ring
components in response to external stimuli.2 Very recently, we prepared a [2]rotaxane,
where spin exchange between two nitroxide units located both at the ring and the
dumbbell could be switched on/off by changing the pH.3
In the present communication, differently from the previous paramagnetic MIM,3 we
report novel examples of nitroxide-spin-labelled bistable rotaxanes containing both
tetrathiafulvalene (TTF) and 1,5-dioxynaphthalene (DNP) units, and cyclobis(paraquatp-phenylene) ring (CBPQT4+) in which the paramagnetic centers are directly involved
in the shuttling process. In this case the movement of the ring induced by single electron
oxidation of the TTF station provides important differences in the electronic
communication between TTF+ radical cation and a spin label introduced “ad hoc” as a
stopper in the dumbbell, highlighting the effect of rotaxanation on through-space
magnetic interactions between radical fragments.4 Introduction of a spin label also on
the CBPQT4+ ring in the rotaxane structure will also be discussed.
Scheme 1
1) Abe, M. Chem. Rev. 2013, 113, 7011-7088.
2) Bleve, V.; Schäfer, C.; Franchi, P.; Silvi, S.; Mezzina, E.; Credi, A.; Lucarini, L. ChemistryOpen
2015; 4, 18-21.
3) Coskun, A.; Spruell, J. M.; Barin, G.; Dichtel, W. R.; Flood, A. H.; Botrosghi, Y. Y.; Stoddart, J. F.
Chem. Soc. Rev. 2012, 41, 4827-4859.
4) Romano, F.; Manoni, R.; Franchi, P.; Mezzina, E.; Lucarini, M. Chem. Eur. J. 2015; 21, 2775-2779.
152
PC31
Unique binding behavior of water-soluble polycationic
oxacalix[4]arene tweezers towards the paraquat dication
G. Gattuso,a G. Lando,a N. Manganaro,a A. Notti,a S. Pappalardo,b M. F. Parisia and I.
Pisagattia
a
b
Dipartimento di Scienze Chimiche, Università di Messina, 98166 Messina, Italy.
Dipartimento di Scienze Chimiche, Università di Catania, 95125 Catania, Italy.
E-mail: [email protected]
After four decades of oblivion, oxacalix[4]arenes1 are finally emerging as a promising
class of macrocyclic receptors.2 As part of our studies on these old yet new
macrocycles,3 in this communication, we report on a unique water-soluble
oxacalix[4]arene, the tetraammonium derivative 14HCl (Figure 1), able to recognize
and bind the methyl viologen dication under acidic conditions.
A combined UV-Vis and 1H NMR study demonstrates that the tri- (13H+) and tetra
protonated (14H+) forms predominate at pH < 2, but only 13H+ is able to efficiently
bind the paraquat dication (Ka = 253 ± 50 M–1), overcoming the repulsion between the
positive charges on both host and guest.
2D ROESY spectra reveal that the guest is nestled within the -rich cleft generated by
the two resorcinol moieties. Moreover, DFT calculations show that protonation
preorganizes the oxacalixarene tweezers: the increasing repulsion between the
ammonium groups (on the facing amino-bearing aromatic rings) results in a narrowing
of the resorcinol-resorcinol interplanar angle, thus making this saddle-shaped
oxacalixarene a good receptor for aromatic guest molecules.
+
Figure 1. Tricationic oxacalix[4]arene 13H acts as molecular tweezers for the paraquat
dication.
1) Sommer, N.; Staab, H. A. Tetrahedron Lett. 1966, 7, 2837–2841.
2) a) Maes, W.; Dehaen, W. Chem. Soc. Rev. 2008, 37, 2393–2402; b) Wang, M.-X. Acc. Chem. Res.
2012, 45, 182–195.
3) a) Capici, C.; Garozzo, D.; Gattuso, G.; Messina, A.; Notti, A.; Parisi, M. F.; Pisagatti, I.; Pappalardo,
S. Arkivoc 2009, (viii), 199–211; b) Capici, C.; Gattuso, G.; Notti, A.; Parisi, M. F.; Bruno, G.;
Nicolò, F.; Pappalardo, S. Tetrahedron Lett. 2011, 52, 1351–1353; c) Gargiulli, C.; Gattuso, G.; Notti,
A.; Pappalardo, S.; Parisi, M. F.; Puntoriero, F. Tetrahedron Lett. 2012, 53, 616–619.
153
D – Foldameri
154
PC32
A new synthetic route towards the fully-extended conformation and its
employment as peptide spring
Marta De Zotti1, Jonathan Clayden2
1
ICB CNR, Padova Unit, Department of Chemistry, University of Padova, via Marzolo 1, 35131 Padova,
Italy
2
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
e-mail: [email protected]
Peptides consisting of Cα-tetrasubstituted α-amino acids1 can adopt stable and well
defined helical conformations even with very short sequences (4-6 residues).
Homopeptides made of diethylglycine (Deg) residues undergo reversible spring-like
conformational transitions between a 2.05 (fully extended) and a 310-helix upon
changing a single environmental paramater.2 The 2.05-helix has an axial translation per
residue of about 3.7 Å, the longest possible for a single α-amino acid (for the 310-helix,
this translation is only 1.9 Å).
Poly-Deg peptide springs are however difficult to synthesize, owing to the very poor
reactivity of Deg. In this contribution, we describe a novel strategy that employs more
reactive 4-amino-tetrahydrothiopyran-4-carboxylic acid (Thp)3 residues as Deg
precursors. After synthesis of the Thp homopeptides, hydrogenolysis of the C–S bonds
with hydrogen and Raney-Ni provides, quantitatively, the corresponding Deg homopeptides.
S
S
Ac
N
H
O
H
N
N
H
O
S
O
H
N
1) Raney-Ni, H2
O
2) reflux o.n., quant.
O
Ac
N
H
H
N
O
O
N
H
H
N
O
O
O
S
A comprehensive conformational analysis of our systems will also be discussed.
1) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Biopolymers (pept. Sci.) 2001, 60, 396-419.
2) Peggion, C.; Crisma, M.; Toniolo, C.; Formaggio, F. Tetrahedron 2012, 68, 4429-4433.
3) Lewis, N.J.; Inloes, R. L.; Hes, J.; Matthews, R.H.; Milo, G. J. Med. Chem. 1978, 21, 1070-1073.
155
PC33
Synthesis , Conformational Analysis And Biological Evaluation Of
Pseudopeptide Foldamers
Benedetta Del Secco , Lorenzo Milli, Nicola Zanna, Claudia Tomasini
Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum Università di Bologna, - Via Selmi 2,
40126, Bologna, Italia
e-mail: [email protected]
The aim of this work is the synthesis, the conformational analysis and the biological
evaluation of a series of foldamers all containing the D-Oxd unit (5-carboxy-4-methyloxazolidin-2-one) alternating with a valine or a lysine unit. These compounds may used
to prepare nanoparticles ready available for the human body (Figure 1).
Figure 2 Schematic rapresentation of the synthesis of decored nanoparticles
The introduction of the Oxd moiety is very useful in
the preparation of organized oligomers because it
imparts rigidity to the pseudopeptide chain,1 as we
could demonstrate by X-Ray analysis of a Boc-L-LeuD-Oxd-OBn unit (Figure 2).
By peptide coupling reactions we have obtained BocL-Val-D-Oxd-L-Lys(2Cl-Z)-D-Oxd-OBn,
Boc-(-LVal-D-Oxd-L-Lys(2Cl-Z)-D-Oxd-)2-OBn and Boc-(L-Val-D-Oxd-L-Lys(2Cl-Z)-D-Oxd-)3-OBn
that
have been analyzed by IR, NMR and ECD.
Figure 3 X-Ray structure of
Boc-L-Leu-D-Oxd-OBn
These compounds have been fully deprotected for biological evaluation, that was
performed on HeLa cells and proved the effective non-toxicity of all three compounds.
1) Tomasini, C.; Castellucci, N. et al., Eur. J. Org. Chem., 2013, 3567 – 3573
156
PC34
Synthesis and conformation of a peptide with two pendant nitronyl
nitroxide free radical units
Karen Wright1, Edouard d’Aboville1, Antonio Toffoletti2, Marta De Zotti2,
Fernando Formaggio2, Claudio Toniolo2
1
Institute Lavoisier de Versailles, UMR 8180, University of Versailles St-Quentin en Yvelines, 78035
Versailles, France
2
ICB, Padova Unit, CNR, Department of Chemistry, University of Padova, 35131 Padova, Italy
e-mail: [email protected]
The blue-colored Ullman imidazolinyl nitronyl nitroxide (NN) monoradicals1 have been
extensively investigated, in particular as spin probes and organic magnetic materials.
Recently, we reported synthesis, configurational and conformational assignments, and
physico-chemical properties of a tripeptide with a central (R)-Aic(NN), where Aic(NN)
is the helicogenic 2-amino-5-nitronylnitroxideindan-2-carboxylic acid.2 Here, we
discuss the synthesis and spectroscopic/conformational properties of the hexapeptide
Boc-[Ala-(R)-Aic(NN)-Ala]2-OMe (Figure 1), with the spin labels at positions i and
i+3.
Figure 1. Molecular structure of the hexapeptide Boc-[Ala-(R)-Aic(NN)-Ala]2-OMe
The preparation of this peptide was performed from the precursor with two Aic(CN)
units, which in turn was synthesized by N-to-C chain elongation in solution. Reduction
of the two cyano groups to aldehydes, followed by condensation with 2,3-diamino-2,3dimethylbutane, afforded the bis-tetramethyl-imidazoline hexapeptide. Oxidation gave
the target bis-nitronyl nitroxide compound.
The results of our solution conformational analysis, carried out by use of the UV-Vis
absorption, CD, FT-IR absorption, fluorescence, NMR, and EPR spectroscopic
techniques, will also be described.
1) Osiecki, J.H.; Ullman, E.F. J. Am. Chem. Soc. 1968, 90, 1078-1079.
2) Wright, K.; d’Aboville, E.; Scola, J.; Margola, T.; Toffoletti, A.; De Zotti, M.; Crisma, M.;
Formaggio, F.; Toniolo, C. Eur. J. Org. Chem. 2014, 1741-1752.
157
PC35
Spherical shape supramolecular structure of serum stable selfassembled pentapeptides containing the constrained norbornene
amino acid
Marco Zuccoloa, Alessandro Ruffonia, Maria Vittoria Cavannab, Simona Argentiereb,
Francesca Clericia
a
DISFARM, Sez. di Chimica Generale e Organica “A. Marchesini”, Università degli Studi di Milano, V.
Venezian 21, Milano; b Fondazione Filarete, V. Ortles 22, Milano
e-mail: [email protected]
Self-assembly is a spontaneous process by which unordered systems of monomers
organize into ordered structures as the result of non-covalent interactions and lies
behind a number of biological nanostructures. The concept of self-assembly has also
been used in many disciplines for constructing useful materials. Supramolecular
spontaneous assembly of high molecular weight peptides or peptides conjugated with
non-peptidic molecules has been reported. Less is known on the self-assembly of short
peptides alone which self-organize predominantly into nanotubes and nanofibers.
Spherical (micellar and vesicle-like) architectures are rarely described although they
appear very attractive, due to promising applications in biomedicine and
nanotechnology.1 Besides the numerous advantages of using peptides containing natural
amino acids for nanostructures, they present some limitations such as low bio-stability
and unstable conformation especially when they are short or medium-sized. The
insertion of unnatural amino acids in the peptide sequences is a well-known tool to
overcome these problems.2 Here we report on the preparation and self-assembly of short
hydrophobic peptides able to stabilize the formation of supramolecular spherical shape
assemblies in water. Two diastereoisomeric pentapeptides AcAla-NRB-Ala-AibAlaNH2 1 and 2, containing the unnatural constrained norbornene amino acid (NRB) 3,
were prepared. Interestingly, peptides 1 and 2 are insoluble in organic solvent but
completely soluble in water despite the presence of hydrophobic non polar norbornene
scaffold.
Me
H
N
AcHN
O
Me
O
N
H
H
N
O Me
Me
O
Me
N
H
Me
NH2
O
H
N
AcHN
O
O
Me
N
H
2
1
H
N
O Me
O
Me
Me
N
H
R*
COOH
R*
NH2
NH2
R*
O
3
The formation of a supramolecular assembly in water was assessed by DLS analyses for
both 1 and 2 either as pure compounds or as a mixture. In all cases, the obtained
assemblies showed almost monomodal distributions in the size range of 320-370 nm
with low polidispersity. To assess their stability in conditions mimicking the in vivo
environment, they were suspended in fetal bovine serum. Interestingly, peptide
assemblies were found to keep their size and shape. An interesting feature of these
peptides is also the presence of the C-C double bond in the norbornene scaffold, which
could allow the easy labeling of the system introducing a variety of useful biotag.
1. Panda, J. J.; Chauhan, V. S. Polym. Chem. 2014, 5, 4418
2. Ruffoni, A. et al. RSC Adv., 2015, 5, 32643-32656
158
E – Fotofisica e Fotochimica
159
PC36
Influence of structural variations over the synthesis and fluorescent
properties of new thermochemiluminescent labels
Luca Alfio Andronico1, Massimo Di Fusco1,2, Arianna Quintavalla1, Marco Lombardo1,
Massimo Guardigli1, Mara Mirasoli1,2, Claudio Trombini1, Aldo Roda1
1
2
Department of Chemistry ‘‘G. Ciamician’’, Alma Mater Studiorum, University of Bologna, Via
Francesco Selmi 2, 40126 Bologna,
CIRI-MAM, Alma Mater Studiorum, University of Bologna, Viale Risorgimento 2, 40136 Bologna
e-mail: [email protected]
Thermochemiluminescence (TCL) is the process by which a thermolabile molecule
generates a light emission after heating above a threshold temperature. It was proposed
in the late 1980s as an innovative reagentless detection technique for immunoassays.
However, it was quickly abandoned owing to the high decomposition temperatures
(200-250 °C) and poor detectability of early employed substrates. Recently, we
synthesized new 1,2-dioxethane derivatives, characterized by remarkably TCL
properties in terms of lower triggering temperature and high fluorescence efficiency1-3.
The synthesis of these new TCL-labels consists of two steps, as shown in Scheme 1a.
After heating, these substrates decompose giving two carbonyl fragments, one of which
in its singlet excited state. Consequently, the excited fragment relaxes to its ground state
generating light emission (Scheme 1b).
a)
b)
Scheme 1. a) Scheme of the synthesis of 1,2-dioxethane derivatives; b) Schematic
representation for a typical TCL process.
We will present the impact of structural modifications both on the photo-oxygenation
step and on TCL properties of a small library of dioxetanes, and preliminary results on
the employment of these molecules for TCL-based immunoassay.
1.
2.
3.
A. Roda, M. Di Fusco, A. Quintavalla, M. Guardigli, M. Mirasoli, M. Lombardo, C. Trombini Anal.
Chem. 2012, 84, 9913−9919.
M. Di Fusco, A. Quintavalla, C. Trombini, M. Lombardo, A. Roda, M. Guardigli, M. Mirasoli J.
Org. Chem. 2013, 78, 11238-11246.
M. Di Fusco, M. Guardigli, M. Lombardo, M. Mirasoli, A. Quintavalla, A. Roda, C. Trombini Patent
WO2014024106 A1 (2014).
160
PC37
Benzodithiophene Based Organic Dyes for DSSC: Effect of Alkyl
Chain Substitution on Dye Efficiency
Clara Baldoli,1 Stefania Bertuolo,2 Ivan Andreosso,3 Emanuela Licandro,2
Gabriele Marotta,4 Paolo Salvatori,4,5 Filippo De Angelis,4
Paola Manca,4 Norberto Manfredi,6 Alessandro Abbotto6
1
2
CNR - Istituto di Scienze e Tecnologie Molecolari (ISTM). Via C. Golgi 19. 20133 Milano
Dipartimento di Chimica. Università degli Studi di Milano. Via C. Golgi 19. 20133 Milano
3
SmartMatLab Centre - Dipartimento di Chimica. Via C. Golgi 19. 20133 Milano
4
Computational Laboratory for Hybrid Organic Photovoltaics (CLHYO)-CNR-ISTM.
Via Elce di Sotto 8. 06123 Perugia
5
D3-Computation, Istituto Italiano di Tecnologia. Via Morego 30. 16163 Genova
6
Dipartimento di Scienze dei Materiali and Solar Energy Research Center MIB-SOLAR; INSTM MilanoBicocca Unit. Università di Milano-Bicocca. Via Cozzi 55. 20125 Milano
e-mail: [email protected].
A series of push-pull triarylamine organic dyes containing the benzo[1,2-b:4,5b’]dithiophene unit as a spacer and bearing alkyl chains in different positions of the
molecule were synthesized. The new dyes 1-4 were characterized by optical and
electrochemical measurements and density functional theory calculations and tested as
sensitizers in liquid dye-sensitized solar cells (DSSC).
The effect of the alkyl chain
position on the dye properties and
their photovoltaic performance
were investigated. The best PCE
was recorded for dye 1 (6.6% at
0.5 sun), this value was only
~20% less than the benchmark dye
N719 (8.1%) under the same
fabrication conditions.
The best LHE profile, in
agreement with optical properties,
and the APCE values, greater than 80%, suggested that the efficiency of 1 originates
from high light harvesting and charge formation and collection efficiency.
In addition, it was found that photovoltaic performance were dramatically dependent on
the choice of the solvent used for the dye-sensitizing bath. The results were correlated,
through extensive optical studies in different solvents and acid/base additives, with
protonation equilibrium of COOH/COO- group of dyes. This study clearly demonstrated
the strategic importance of selecting an appropriate solvent for dye absorption in the
DSSC fabrication, even in the case of performing sensitizers.
1
Baldoli, C.; Abbotto, A.; Licandro, E.; De Angelis, F.; et al. Dyes and Pigments 2015, 121, 351-362
Acknowledgements: CNR and Accordo Quadro Regione Lombardia-CNR (Times Project). Regione
Lombardia-Fondazione CARIPLO "SmartMatLab Centre" project.
161
PC38
Versatile dibenzofulvene structures as dyes for efficient DSSCs and
HTM perovskite solar cells
A.-L. Capodilupo,1 G. Gigli,1,2 and G. Ciccarella1,3
1
2
3
CNR NANOTEC - Istituto di Nanotecnologia, Polo di Nanotecnologia c/o Campus Ecotekne, via
Monteroni - 73100 Lecce
Dipartimento di Matematica e Fisica “Ennio De Giorgi”, Università del Salento, Via Monteroni, 73100,
Lecce, Italy.
Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Via Monteroni, 73100, Lecce, Italy.
e-mail: [email protected]
DSSCs and perovskite solar cells (PSCs) represent the most promising photovoltaic
devices.
They have been attracting a great interest thanks to high performance and low-cost
production. In these devices the organic component play a key role: is the lightharvesting antenna in the DSSCs and the hole transporting material in the PSCs.
Design and synthesize new organic molecules with improved performance is
demanding in order to increase cell efficiency. Moreover, easy, versatile and low cost
synthetic strategies are necessary to ensure an effective low cost production of final
devices. Here we present the results of our study of a new class of organic molecules for
solar cells based on the dibenzofulvene structure. The main aspects of the work lie in
the versatility of the molecular structure, that allows, by a proper functionalization, to
obtain different derivatives which have been successfully used in DSSCs and PSCs
devices.
Scheme 1
We have prepared dyes for DSSCs with power conversion efficiency of 7.45% and hole
transporting materials for PCEs with power conversion efficiency of 10.9%.
References
1. A.-L. Capodilupo, L. De Marco, E. Fabiano, R. Giannuzzi, A. Scrascia, C. Clarlucci, G. A. Corrente,
M. P. Cipolla, G. Gigli and G. Ciccarella J. Mater. Chem. A 2, 14181 (2014).
162
PC39
Tunable photogeneration of reactive intermediates from
chlorobenzylphosphonic acids in aqueous media.
Stefano Crespi, Stefano Protti, Davide Ravelli and Maurizio Fagnoni
PhotoGreen Lab, Department of Chemistry, University of Pavia
Viale Taramelli 12, 27100 Pavia, Italy.
e-mail: [email protected]
The photoreactivity of the three isomeric chlorobenzylphosphonic acids (I) has been
investigated and found to be tunable by modifying the pH of the reaction medium.
Thus, irradiation of I in aqueous/organic solvent mixtures at pH = 2.5 results in the
formation of a highly electrophilic triplet aryl cation (3II) after chloride anion
detachment (path a).1 Two main competing pathways departing from 3II are observed,
viz. the reduction upon hydrogen abstraction from the solvent (path b) and Intersystem
Crossing (ISC) to singlet phenyl cation (1II) and the subsequent solvolysis to phenol
(path c). In contrast, when moving to basic pH (pH = 11) formation of 3II from the
corresponding phosphonate is followed by detachment of a phosphate ion, with the
subsequent generation of a ,n didehydrotoluene diradical (,n DHTs, path d).2 At
physiological pH (pH = 7.2) a competition between the aforementioned pathways has
been observed.
In the aim of fully characterize the nature and the role of the involved intermediates,
different factors including the polarity of the solvent and the presence of triplet
sensitizer (acetone) have been considered, and the experimental data have been
supported by computational analyses.
1) Raviola, C.; Ravelli, D.; Protti, S.; Albini, A.; Fagnoni, M. Synlett 2015, 26, 471-478.
2) Protti, S.; Ravelli, D.; Mannucci, B.; Fagnoni, M.; Albini, A. Angew. Chem. Int. Ed. 2012, 51,
8577-8580; Crespi, S.; Ravelli, D.; Protti, S.; Albini, A.; Fagnoni, M. Chem. Eur. J. 2014, 20,
17572-17578.
Acknowledgement: We are grateful to the Fondazione Cariplo (grant 2011-1839) for support.
163
PC40
Photogeneration of methanesulfonic acid from aromatic
bis(methanesulfonylimides): Application in cationic
photopolymerization
Maurizio Fagnoni,1 Edoardo Torti,1 Stefano Protti,1 Daniele Merli,1 Gioia Della
Giustina,2 Giovanna Brusatin.2
1
PhotoGreen Lab, Department of Chemistry, University of Pavia, Italy.
2
Department of Industrial Engineering, University of Padova, Italy
e-mail: [email protected]
Mild generation of strong acids is a crucial issue for material chemistry. Compounds
able to release acid upon light absorption (photoacid generators, PAGs) find wide
application in photoresists and other similar devices.1 Thus, the study of innovative
PAGs is a prominent challenge in microelectronic field. In the last few years our group
demonstrated that aryl sulfonates such as mesylates, tryflates and tosylates are able to
release the corresponding sulfonic acid under UV irradiation.2,3 Aryl tosylates have been
exploited as PAGs in epoxy based hybrid organic-inorganic materials.3 We present
herein a detailed photochemical investigation of N-aryl bis(methanesulfonylimides (1).
Irradiation of 1 in N2 saturated acetonitrile resulted in the formation of different
photoproducts (including N-aryl methanesulfonamides, anilines and thia-Fries
rearrangement products) along with methanesulfinic acid (0-116%). In O2 saturated
media, methanesulfonic acid was released in high yields (up to 2 equiv for one equiv of
1). The photochemical behaviour is consistent with a homolytic cleavage of the ArNS
bond with the formation of a radical pair (2); trapping of the methanesulfonyl radical by
O2 leads then to strong CH3SO3H. Compounds 1 were tested as photoinitiators for
cationic polymerization and incorporated in an epoxy based hybrid organic-inorganic
material obtained from 3-glycidoxypropyltrimethoxysilane (GPTMS) and germanium
tetraethoxide (TEOG).4 The devices were exposed to UV light and the structural
modifications induced were quantified by FT-IR spectroscopy. The results obtained
show that 1 are able to induce polymerization of the epoxy groups, making these
compounds good candidates as PAGs for hybrid organic-inorganic photoresists.
This work has been supported by the Fondazione Cariplo (grant no. 2012-0186).
1) Moon, S. Y.; Kim, J. M. J. Photoch. Photobio. C, 2007, 8, 157-173.
2) Terpolilli, M.; Merli, D.; Protti, S.; Dichiarante, V.; Fagnoni, M.; Albini, A. Photochem. Photobiol.
Sci., 2011, 10, 123-127.
3) Torti, E.; Della Giustina, G.; Protti, S.; Merli, D.; Brusatin, G.; Fagnoni, M.RSC Adv.,2015,5, 3323933248.
4) Brusatin, G.; Della Giustina, G. J. Sol-Gel Sci. Technol., 2011, 60, 299-314.
164
PC41
Photoresponsive supramolecular architecture based on α-cyclodextrine
functionalized with azobenene
M. Stefania Ferrito1, Stefano Masiero1, Yoshinori Takashima2, Akihito Hashidzume2,
Akira Harada2
1
Department of Chemistry «Giacomo Ciamician» Via S. Giacomo, 11, 40127 Bologna Italy;
Department of Macromolecular Science, Graduated School of Science, Osaka University, Toyonaka,
Osaka 560-0043, Japan
2
Email: [email protected]
Abstract
Photoresponsive assembling/disassembling behavior of a supramolecular architecture in
aqueous solution based on α-cyclodextrine functionalized with an azobenzene (Azo) moiety (2AzoH-αCD) has been studied. A model system consisting of azobenzene sodium carboxylate
and α-CD has been studied(1,2). CDs can form inclusion complexes with organic compounds
improving the host solubility, and their binding abilities have been shown to be changed by light
when an azobenezene moiety is incorporated (3,6). In this project we have focused on the use of
supramolecular system based on azobenezene-CD interactions as photoresponsive host-guest
assembling. Two-dimensional NMR, diffusion coefficient, ESI-MS and circular dichroism
indicated that the trans-isomer of 2-AzoH-αCD formed a supramolecular oligomer in aqueous
solution even at lower concentrations (< 1 mM). On the contrary the cis-Azo moiety was
excluded from the cavity of αCD.
Reference
1) Pietro Bortulus, Sandra Monti J.Phys.Che. 1987, 91, 5046-5050
2) Di Motta, Avellini, Silvi, Venturi, Ma, Tian, Credi and Negri, Chem. Eur. J. 2013, 19, 3131-3138
3) Shinkai,S.;Shigematsu,K.; Sato,M; Manabe, O.J. Chem. Soc., Perkin trans. 1 1982, 2735-2745
4) Shiki Yagai, Akihide Kitamura, Chem.Soc.Rev. 2008, 37, 1520–1529
5) A. Harada, Y. Takashima, and M. Nakahata, Acc. Chem. Res., 2014, 47 (7), 2128–2140.
6) Yamaguchi, H.;Kobayashi, Y.; Kobayashi, R.; Takashima,Y.; Hashidzume, A.; Harada, A. Nature
Communications 2012, 3, 603.
165
PC42
PC43
Blue emitting nanostructured silica by in vivo functionalization of
diatom algae shells with an aryleneethynylene fluorophore
M. Lo Presti,a R. Ragni,a D. Vona,a S. R. Cicco,a O Hassan Omar,b G. M. Farinola*a
a
Dipartimento di Chimica, Università degli Studi di Bari “Aldo Moro”, via Orabona 4, 70126 Bari (Italy)
b
CNR-ICCOM, Dipartimento di Chimica, Università degli Studi di Bari“Aldo Moro”, via Orabona 4,
70126 Bari (Italy).
e-mail: [email protected]
Hybrid systems in which organic luminescent molecules are covalently bound or embedded into
mesoporous nanostructured silica have recently attracted scientific and technological interest as versatile
multifunctional materials with applications in photonics, sensing and bioimaging.[1] Diatoms are a class
of single cell photosynthetic algae bearing a three-dimensional silica skeleton (frustule) whose size and
morphology is strictly dependent on the algal species: these microorganisms are a natural and low cost
source of biosilica with highly hierarchically ordered nanostructure behaving as natural photonic crystal.
Hence, the integration of organic fluorophores into diatom frustules represents a very promising strategy
to afford new bio-hybrid luminescent materials for laser technology or light emission modulation.
In the frame of our studies on new functional bioorganic materials,[2] here we present the synthesis of a
new blue emitting arylenethynylene fluorophore (Figure 1a) properly designed to be a model compound
with sterically unhindered structure and a triethoxysilyl group allowing its in vivo incorporation into
frustules of the Thalassiosira weissflogii centric diatom (figure 1b).
Figure 1
Our results demonstrate the possibility to in vivo convey the dye into the biosilica and to isolate, by
proper oxidative treatment, new hybrid luminescent materials with the natural frustules retained
morphology (Figure 1c). This approach discloses intriguing possibilities in the massive biotechnological
production of photoactive nanostructured materials, whose properties can be finely tailored by chemical
design of the light emitting molecule and by selecting and modifying the characteristics of the
microorganism used.
1) Wenrong Yang, et Al; “Diatoms: Self assembled silica nanostructures, and templates for
bio/chemical sensors and biomimetic membranes” ; Analyst, 2011, 136, 42
2) Stefania R. Cicco, Gianluca M. Farinola et Al; ”Chemically Modified Diatoms Biosilica for
Bone Cell Growth with Combined Drug-Delivery and Antioxidant Properties” ; ChemPlusChem,
2015.
167
PC44
SiC/SiO2 NWs conjugated with porphyrins for Photodynamic therapy
Elena Bedogni1, Cecilia Loffi1, Marco Negri2, Giovanni Attolini2, Giovanna Benecchi3,
Tiziano Rimoldi4, Luigi Cristofolini4, Silvana Pinelli5, Rossella Alinovi5, Francesca
Rossi4, Giancarlo Salviati4 and Franca Bigi1
1
2
Chemistry Department (Parma University)
IMEM-CNR (Parco Area delle Scienze 37/A, Parma).
3
4
5
Health Physics (Parma Hospital)
Department of Physics and Heart Science (Parma University)
Unit of Experimental Oncology, (Parma University and CERT)
e-mail: [email protected]
In recent years, increasing attention has been devoting in the literature to the preparation
of nanosystems for biomedical applications, such as drug delivery, bio-separation,
immunoassays, and in particular for alternative approaches in cancer treatment, such as
photodynamic therapy (PDT).
In this communication we report the preparation of a novel nanosystem obtained by
functionalization of core-shell SiC@SiO2 nanowires with porphyrins for application in
nanomedicine. Due to its high biocompatibility, cubic SiC is a promising material for
biomedical applications and recently we evidenced that SiC/SiO2 NWs can easily
penetrate the cell membrane and that they are cytocompatible.1
Porphyrins are an important class of photosensitizers largely employed in PDT,
absorbing light and producing singlet oxygen. We decided to conjugate porphyrins to
the SiC/SiO2 NWs to obtain nanosystem able to promote Xray-excited PDT for deep tumor treatment.2
Here we present a conjugation strategy based on the
formation of amidic bonds.
The efficient anchorage of tetracarboxyphenylporphyrin
(H2TCPP) to the nanowires surface was performed through
covalent amidic bonds by reacting the porphyrin with the
nanowires previously functionalized with amino groups. To
increase the dispersion of the nanosystem in aqueous medium
short PEG chains were linked to the porphyrins.
The hybrid nanosystem was characterized by fluorescence
spectroscopy, that confirmed the successful porphyrin conjugation. In vitro studies on
tumor cell lines are in progress and will be presented.
1) Cacchioli, A.; Ravanetti, F.; Alinovi, R.; Pinelli, S., Rossi, F.; Negri, M.; Bedogni, E.; Campanini, M.;
Galetti, M.; Goldoni, M.; Lagonegro, P.; Alfieri, R.; Bigi, F.; and G. Salviati, Nano Lett., 2014, 14 (8),
4368–4375.
2) Rossi, F.; Bedogni, E.; Bigi, F., Rimoldi, T.; Cristofolini, L.; Pinelli, S.; Alinovi, R.; Negri, M.;
Dhanabalan, S.C.; Attolini, G.; Fabbri, F. M. Goldoni, A. Mutti, G. Benecchi, C. Ghetti, S. Iannotta and
G. Salviati Scientific Reports 2015, 5:7606.
168
PC45
Synthesis and optical properties of novel azole-based fluorophores
F. Bellina,1 M. Lessi,1 G. Marianetti,2 P. Minei,2 L. A. Perego,2 C. Pezzetta,2 A. Pucci1,
Chiara Manzini1
1
Dipartimento di Chimica e Chimica Industriale, Università di Pisa, via Moruzzi 3, 56124, Pisa, Italy.
2
Scuola Normale Superiore, Università di Pisa, Piazza dei Cavalieri 7, 56126, Pisa, Italy.
e-mail: [email protected]
Heteroaromatic fluorophores with electron-donor and –acceptor architectures have
attracted growing interest for both the understanding of fundamental chemistry and
physics and promising applications in diverse fields, ranging from solar energy
conversion1 to optoelectronic devices2 and chromogenic materials.3 These fluorophores
show interesting intramolecular charge-transfer (ICT) properties and the presence in
their structure of azole rings, such as imidazole and thiazole, confers them chemical and
thermal robustness, as well as good solubility in common organic solvents.
Furthermore, heteroatoms can enhance the donor/acceptor character of the groups and
improve the overall polarizability of the chromophore. In continuation of our studies on
the synthesis of new classes of organic fluorophores,4 we recently focused our attention
on the design of azole-based fluorescent molecules to be used in luminescent solar
concentrator (LSC) devices.
In this communication we will describe the synthesis of novel fluorophores of general
formula 1-3 (Figure 1),4a,5 obtained through an innovative and operationally simple
reaction protocol consisting in two sequential Pd-catalyzed direct arylation reactions.6
N
N
N
Me
N
Me
Y
N
N
N
Me
S
R
Z
1
N
N
S
S
2
Y = -Me, -MeO, -CN
Z = -Me, -MeO, -CN, -O(2-ethyl)hexyl
R = H, -CH=C(CN)2
Z
3
Figure 1: General structure of organic fluorophores.
The optical properties of these new interesting classes heteroaromatic fluorophores will
be also shown and discussed in details.
1)
2)
3)
4)
A. Hagfeldt, G. Boschloo, L. Sun, L. Kloo, H. Pettersson, Chem. Rev., 2010, 110, 6595-6663.
G. S. He, L.-S. Tan, Q. Zheng, P. N. Prasad, Chem. Rev., 2008, 108, 1245-1330.
F. Ciardelli, G. Ruggeri, A. Pucci, Chem. Soc. Rev., 2013, 42, 857-870.
a) M. Lessi, C. Manzini, P. Minei, L. A. Perego, J. Bloino, F. Egidi, V. Barone, A. Pucci, F. Bellina,
ChemPlusChem, 2014, 79, 366-370; b) G. Prampolini, F. Bellina, M. Biczysko, C. Cappelli, L. Carta,
M. Lessi, A. Pucci, G. Ruggeri, V. Barone, Chem. Eur. J., 2013, 19, 1996-2004; c) I. Platonova. A.
Branchi, M. Lessi, G. Ruggeri, F. Bellina, A. Pucci, Dyes and Pigments, 2014, 110, 249-255.
5) C. Manzini, PhD Thesis, 2015, Università di Pisa.
6) F. Bellina, M. Lessi, C. Manzini, Eur. J. Org. Chem., 2013, 5621-5630.
169
PC46
2,5-Diaryl substituted azoles as promising organic fluorescent dyes for
luminescent solar concentrators.
V. Barone,a F. Bellina,b M. Lessi,b P. Minei,a A. Pucci,b G.
Marianettia
a
b
Scuola Normale Superiore. Piazza dei Cavalieri 7, 56126 Pisa, Italy
Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Moruzzi 3, 56124 Pisa, Italy
In the past two decades lot of research has focused on Luminescent Solar Concentrators (LSCs)
as a way to decrease the cost of solar photovoltaics.1 LSC devices usually consist in a thin slab
of transparent material (glass or polymer) doped with a fluorescent dye. Upon solar irradiation,
a fraction of the luminescence emitted by the dye remains trapped inside the slab though means
of internal reflection and is collected at the edges of the device by photovoltaic cells. Compared
to traditional concentrators, which make use of mirrors and lenses, this kind of devices show
numerous advantages, such as theoretical higher concentration factors, the ability to work with
both diffuse and incident light and no need for tracking devices or cooling apparatuses.1,2
Moreover, the simplicity and the low cost of this devices make them particularly appealing. In
this insight, efforts can be directed towards the synthesis of novel organic dyes which not only
display interesting optical features, but are also attainable through cheap and scalable
procedures.
Organic fluorescent dyes bearing -conjugated electron-donor and -acceptor moieties exhibit
intramolecular charge-transfer (ICT) properties,3 and can therefore show the optical properties
required by LSCs such as high quantum yield and high Stokes shift.
On account of this, in the present communication it will be discussed the synthesis and UV-Vis
characterization of a set of novel symmetrical push-pull azole-based dyes of general structure 1.
These compounds are characterized by a central 1,3-azole core substituted at its 2 and 5
positions with two aromatic rings bearing typical electron withdrawing (EWG) functional
groups. Remarkably, the heteroatoms have a positive impact on the overall polarizability
properties, and the introduction of a -heteroaromatic ring usually improves the thermal and
chemical stability required for fabrication processes of the final device.
The 2,5-diaryl substituted azoles 1 were prepared through a robust synthetic pathway involving
a palladium-catalyzed direct arylation reaction as key step. In order to rationalize the
experimental results we carried out TD-DFT studies is solution and in a polymeric matrix, with
the aim of selecting the best candidate to be employed in LSC devices.
References
1.
Van Sark, W. et al. Optics Express 2008, 16 (26), 21773-21792.
2.
Reisfeld, R.; Jørgensen, K. C. Solar Energy Materials 1982, 49, 1-36.
3.
Hagfeldt, A.; Boschloo, G.; Sun, L.; Kloo, L.; Pettersson, H. Chem. Rev. 2010, 110, 6595-6663.
170
F – Green Chemistry
171
PC47
Solvent-Free Synthesis and Characterization of Spiro-isoxazolidines at
Potential Biological Activity.
Vincenzo Algieri1, Antonio De Nino1, Loredana Maiuolo1, Monica Nardi, Beatrice
Russo1.
1
Dipartimento di Chimica e Tecnologie Chimiche (CTC), Università della Calabria, Ponte Bucci Cubo
12/C, 87036 Rende (CS), IT.
e-mail: [email protected]
The discovery of new pharmacological agents is one of the biggest challenges for
chemists. One of these is the synthesis of spiro-isoxazolidines pharmacologically active.
In recent years it has been developed the synthesis of spiro compounds by 1,3-dipolar
cycloaddition reactions, in which the isoxazolidinic core product is an interesting
pharmacophore that could be the future in biology and pharmacology fields.
Isoxazolidines are cyclic molecules that mimic natural nucleosides exerting antiviral
activity; for example, the furanopirimidine N,O-nucleosides inhibit the replication of
DNA and RNA of poliovirus 1. The presence of a nucleobase on the oxazolidine ring
leads to the formation of modified N,O-nucleosides which greatly increase the
cytotoxicity of these molecules making them excellent candidates as antitumor agents1,2.
In addition, the asymmetric character of the molecules that have one or more spiro
carbon is one of the most important factors that determine the biological activities3,4.
The indole compounds are further relevant since their spiro derivatives are excellent
anti-cancer agents, antibiotics, inhibitors of the receptor NK-15 and inhibitors of p53MDM2 interaction. In this context, the object of this work is the synthesis of a new
class of indolyl spiro-isoxazolidine N,O-nucleosides variously functionalized that can
enclose all the pharmacological properties of each class of molecules above described.
The synthesis of these chiral compounds is carried out with simple and "Solvent-free"
methodologies, by diastereoselective and microwave assisted 1,3-dipolar cycloaddition
reaction between a chetonitrone derived from 1-indanone and a vinylnucleobase
(Scheme 1). The synthetic methodology is innovative in that the two precursors are
reacted in the solid phase and without solvent.
Scheme 1
The reaction products were obtained with high reaction yields and excellent
diasteroisomeric ratio. Moreover, all products are been subjected to a subsequent test
phase to evaluate the pharmacological activity.
1) O. Bortolini, M. D’agostino, A. De Nino, L. Maiuolo, M. Nardi, G. Sindona. Tetrahedron, 2008, 64, 8078-8081.
2) R. Romeo, S. V. Giofrè, A. Garozzo, B. Bisignano, A. Corsaro, M. A. Chiacchio. Biorganic & Medicinal
Chemistry, 2013, 21, 5688-5693.
3) P. Das, A. O. Omollo, L. J. Sitole, E. McClendon, E. J. Valente, D. Raucher, L. R. Walcher, A. T. Hamme II.
Tetrahedron Letters, 2015, 56, 1794-1797.
4) M. Mehrdad, L. Rafaji, K. Jadidi, P. Eslami, H. Sureni. Monaths Chem, 2011, 142, 917-921.
5) T. Okita, M. Isobe, Tetrahedron, 1994, 50, 11143-11152.
172
PC48
Task-specific dicationic ionic liquids used as reaction media for
Michael addition.
Carla Rizzo1, Francesca D’Anna1, Salvatore Marullo1, Paola Vitale1, Renato Noto1
1
Dipartimento STEBICEF, Sezione di Chimica, Viale delle Scienze-Parco d’Orleans II, 90128 Palermo,
Italy.
e-mail: [email protected]
Nowadays one of the main goals in organic chemistry is the research of
increasing efficiency in chemical processes taking care of the environmental impact.
In this context the choice of the right catalysts and solvents for organic reactions
becomes crucial. For this reason in the last decades, ionic liquids have been applied
as alternative solvents thanks to their low flammability, vapor pressure and high
structural organization.1 If a catalyst is tethered in the cation or in the anion of the
ionic liquids, they are called “task-specific ionic liquids”. The ensemble of catalyst
and solvent in one compound increases the kinetic mobility and allows a large
operational surface area.2
We have recently studied the properties and the catalytic ability of novel
diimidazolium ionic liquids bearing an imidazole as basic functionality.3 Properties
of these ionic liquids, such as thermal stability, catalytic ability and recyclability are
strongly dependent on the nature of the anion used.
With this in mind, we are now interested in the study of Michael addition of
malonitrile to trans-calchone (Scheme 1), a base catalyzed reaction that leads to a
key precursor for the synthesis of some biological and pharmaceutical products. In
addition to the basic functionality present on the cationic unit, chiral anions such as
tartrate, proline, phenilalanine, (R)-(-)-1,1’binaphtyl-2,2’diyl-phosphate, have been
used in order to analyze stereochemical aspects of the reaction, studying their effects
on reaction time, percentage yields and enantiomeric excess.
Scheme 1 Task-specific ionic liquids used for the study of Michael addition.
References:
1. Dupont, J.; Acc. Chem. Res. 2011, 44, 1223.
2. a) Lee, S.-G.; Chem. Commun. 2006, 1049. b) Sawant, A. D.; Raut, D. G.; Darvatkar, N. B.;
Salunkhe, M. M.; Green Chem. Lett. Rev. 2011, 4, 41.
3. a) D’Anna, F.; Gunaratne, N. H. Q.; Lazzara, G.; Noto, R.; Rizzo, C.; Seddon, K. R.; Org. Biomol.
Chem. 2013, 11, 5836. b) Rizzo, C.; D’Anna, F.; Marullo, S.; Noto, R.; J. Org. Chem. 2014, 79, 8678.
173
PC49
Catalytic Hunsdiecker Reaction in Continuous-Flow
Graziano Fusinia, Adriano Carpitaa, Federico Galloa, Cosimo Boldrinia
a
Department of Chemistry and Industrial Chemistry, University of Pisa, Via G.Moruzzi, 13, 56124 Pisa,
Italy
e-mail: [email protected]
The decarboxylative halogenation of carboxylic acids is a synthetically useful route to
various organic halides. Various modifications of the classical Hunsdiecker1 reaction are
testimony to the unabated interest of organic chemists in this reaction.2 Currently, simple
strategy to employ a catalytic metal or ammonium salt pool, mediating an catalytic Hunsdiecker
for the synthesis of β-halo styrenes from corresponding α,β-unsaturated aromatic carboxylic
acids using N-halosuccinimides.3 However, until recently, despite the fact that a large number of
publications describing the Catalytic Hunsdiecker reaction are available, the reaction has major
limitations of safety and cost in the industrial application, due release of a variable amount of
CO2 depending on the reaction conditions.
Therefore, the use of continuous-flow tecnology can make such application much simple,
safe and cheap.4 Herein we wish to report our recent results in the Catalytic Hunsdiecker
reaction under continuous-flow conditions, compared to results obtained in batch mode, by
using NBS as brominating agent and LiOAc as catalyst in mild homogeneous conditions.
In a first approach, the experiments were performed in the batch mode with homogeneous
condition using the LiOAc when catalyst at 70°C. Then, an effective continuous mini-reactor was
developed, by filling pieces of Teflon tubing (2-4 mm internal diameter) with appropriate inert
material to allow an efficient mixing. The resulting device was employed for carrying out the
reactions in the flow mode, with pneumatic pumping.
R1
R
1
O
NX
2
COOH
R1
LiOAc (cat.)
- CO2
CH3CN/H2O
(7:1)
70°C
X
R
3
O
R = H, 4-Me, 2-OMe, 4-NO2, 4-Cl, 4-OH, 4-TBDMSO
R1 = H, Me
X = I, Br
The efficiency of this reaction in continuous mode will be compared with those in classical
bath mode in terms of reaction time, productivity and Space Time Yield.
1) (a) Borodin, B. Liebigs Ann. 1861, 119, 121. (b) Hunsdiecker, H. C. Chem. Ber. 1942, 75, 291.
2) (a) Sheldon, R. A.; Kochi, J. K. Org. React. (NY) 1972, 19, 326. (b) Zerong Wang Comprehensive Organic
Name Reactions and Reagents; 2010, 338, 1511. (c) Chrich, D. In Comprehensive Organic Synthesis; Trost, B.
M., Steven, V. L. Eds.; Pergamon: Oxford, 1991; Vol. 7, pp. 723–734. (d) Hassner, A.; Stumer, C. Organic
Synthesis based on Name Reactions and Unnamed Reactions; Pergamon: Oxford, 1994; p 183. (e) Camps, P.;
Lukach, A. E.; Pujol, X.; Vazquez, S. Tetrahedron 2000, 56, 2703.
3) (a) Das J. P.; Roy S. J. Org. Chem. 2002, 67, 7861. (b) Chowdhury S.; Roy S. J. Org. Chem. 1997, 62, 199. (c)
Kuang C. X.; Senboku H.; Tokuda M. Synthesis 2005, 1319. (d) Graven, A.; Jorgensen, K. A.; Dahl, S.;
Stanczak, A. J. Org. Chem. 1994, 59, 3543. (e) Naskar, D.; Roy, S. Tetrahedron 2000, 56, 1369. (f) Rajanna K.
C.; Reddy N. M.; Reddy M. R. J. Disp. Sci. Techn. 2007, 28, 613
4) (a) Wiles C.; Watts P. Micro Reaction Technology in Organic Synthesis, 2011, CRC Press: Boca Raton. (b) B.
Ahmed-Omer, J. C. Brandt, T. Wirth, Org. Biomol. Chem. 2007, 5, 733 (c) D. M. Roberge, L. Ducry, N. Bieler,
P. Cretton, B. Zimmermann, Chem. Eng. Techn., 2005, 28, 318. (d) Wegner J.; Ceylan S.; Kirschning A. Adv.
Synth. Catal. 2012, 354, 17
174
PC50
Room Temperature Ionic Liquids as Reaction Media for the
Isomerization of Azobenzene Derivatives
Guido Angelini1, Nadia Canilho2, Mélanie Emo3, Molly Kingsley4, Carla Gasbarri1
1
Department of Pharmacy, University “G. d’Annunzio” of Chieti – Pescara, Italy
2
University of Lorraine, Vandœuvre-lès-Nancy Cedex, France
3
Institut J. Barriol, University of Lorraine, Vandœuvre-lès-Nancy Cedex, France
4
University of Colorado Denver, Anschutz Medical Campus, USA
e-mail: [email protected]
Room temperature ionic liquids (RTILs) have attracted much attention in the last years
for their unique properties and their potential high recyclability1. The effect of a para
substituent (OtBu, OCH3, F and Br) on the azobenzene isomerization has been
investigated by using BMIM+ / Tf2N- based RTILs as reaction media2.
Typical V-shape Hammett plots for the cis – trans isomerization have been obtained in
EMIM Tf2N, BMIM Tf2N and HMIM Tf2N, showing that both the rotation and the
inversion mechanisms occur, according to the electronic nature of the substituent, but
only rotation takes place in BMIM BF4, BMIM PF6 and BM2IM Tf2N.
Small-wide angle X-ray scattering (SWAXS) has been performed before and after UV
irradiation to determine the effect of the azobenzene isomers on the structural network
formed by cations and anions in the RTILs.
Finally, the cis population in the photostationary state and the hardness parameter  of
the trans isomer have been calculated to compare the reactivity of the investigated
azobenzene derivatives in the trans – cis isomerization.
Hammett plot for the cis – trans isomerization of the azobenzene derivatives
1) Seddon, K.R. J. Chem. Technol. Biotechnol. 1997, 68, 351-356.
2) Angelini, G.; Canilho, N.; Emo, M.; Kingsley, M.; Gasbarri, C. submitted 2015.
175
PC51
Synthesis of (-)-oseltamivir by the use of supported organocatalysts
Luca Mengozzi1, Carles Rodriguez2, Pier Giorgio Cozzi1, Miquel A. Pericàs2,3
1
Dipartmento di Chimica “G. Ciamician”ALMA MATER STUDIORUM
Università di Bologna, Via Selmi 2, 40126, Bologna, Italy
2
Institute of Chemical Research of Catalonia (ICIQ),
Av. Països Catalans 16, 43007 Tarragona, Spain
3
Departament de Química Orgànica, Universitat de Barcelona (UB),
08028 Barcelona, Spain
e-mail: [email protected]
The use of immobilized catalyst and the development of continuous flow processes that
allow either for the catalyst recovery and re-use have emerged as a powerful strategy to
develop sustainable chemical processes.1
Six membered cyclohexenes bearing several stereocenters with a high density of
functional groups can be retrieved in the core of important pharmaceutical compounds
such as (-)-oseltamivir2,3 zanamivir and laninamivir.4
The synthesis of key intermediate 4, a direct precursor of (-)-oseltamivir, through a nitro
Michael reaction promoted by supported proline derived catalyst 35 will be presented.
Scheme 1. Synthesis of (-)-oseltamir using supported organocatalysts.
Acknowledgements: Bologna University through a Marco Polo fellowship and ICIQ,
Institut Català d’Investigatiò Quimica are acknowledged for financial support.
1)
2)
3)
4)
5)
Brzozowski, M.; O’Brien, M.; Ley, S.V.; Polyzos, A. Acc. Chem. Res. 2015, 48, 349-362
Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem. Int. Ed. 2009, 49, 1330-1333.
Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem. Int. Ed. 2010, 53, 4656-4660.
Tian, J.; Zhong, J.; Li, Y.; Ma, D. Angew. Chem. Int. Ed. 2014, 53, 13885-13888.
Alza, E.; Pericas, M. A. Adv. Synth. Cat. 2009, 351, 3051-3056.
176
PC52
Biomass valorization using ionic liquids
Cinzia Chiappe1, Maria Jesus Rodriguez-Douton1, Barbara Masciocchi2, Alessio
Gentile2, Andrea Mezzetta1
1
Dipartimento di Farmacia, Università di Pisa, via Bonanno 33, 56126 Pisa, Italy.
2
Processi Innovativi Srl, Via Guido Polidoro 1,67100 L’Aquila, Italy.
e-mail: [email protected]
Nowadays, conversion of biomass into bio-fuels or value-added compounds is one of
the most possible alternatives to alleviate the environmental and economic burdens
associated with the depletion and consumption of fossil-based resources 1.
Ionic liquids (ILs) are not only able to dissolve important biomacromolecules such as
cellulose and chitin but, due to their negligible vapor pressure and thermal stability, they
have been considered as “greener” alternative media to use as solvents and/or catalysts
in several fields, including also the industrial processes for generating fuels from
renewable feedstock.
Herein, we report some selected examples showing the efficacy of ILs to affect the
dissolution and transformation of biomass (based on cellulose or other biopolymers) and
the possibility to develop new industrial processes. In particular, we discuss the
extraction of fatty acids from micro-algae for biodiesel production and the conversion of
cellulose (present in the biomass) into sugars and subsequently into their degradation
compounds, such as 5-hydroxymethylfurfural (5-HMF), levulinic acid and formic acid.
1) Baliban, R, C.; Elia, J. A. Y.; Floudas, C, A. Energy Environ. Sci. 2013, 6, 267-287
177
PC53
Microwave assisted synthesis of lipophilic hydroxytyrosol fatty esters
Emanuela Vitale1, Manuela Oliverio1, Luca Cariati1, Monica Nardi2, Antonio Procopio1.
1
Università Magna Græcia di Catanzaro, Campus Salvatore Venuta, 88100 Germaneto (CZ)
2
Università della Calabria, Ponte Bucci, cubo 12C, 87036 Arcavacata di Rende (CS)
e-mail: [email protected]
Natural products display various biological activities and, therefore, constitute
important targets for drug synthesis. Hydroxytyrosol is natural antioxidant largely
investigated owing to his safety and his usefulness in food, cosmetic and
pharmaceuticals. Hydroxytyrosol fatty esters, compared with hydroxytyrosol, show a
better skin permeability [1] and have a greater antioxidant activity in biological models
[2]. In a previous report, we developed a mild method for the synthesis of lipophilic
hydroxytyrosol esters at room temperature using THF dry and Er(OTf)3 as a catalyst
[1]. In this report, instead, we explain a new green protocol developed for the synthesis
of these compounds. This new method expect the use of fatty chlorides and
hydroxytyrosol acetonide, a protected form of hydroxytyrosol where the oxidation
during the storage is avoided, reacted by a microwave assisted one-pot synthesis. [3] In
particular, because of the acetonide can be removed from hydroxytyrosol in acid
environment, we thought that the hydroxytyrosol fatty ester synthesis and the
hydroxytyrosol deprotection may occur simultaneously thanks to the HCl formed in the
first reaction step.
This new economic and eco-friendly protocol allows to synthetize hydroxytyrosol fatty
esters not using any catalyst and toxic organic solvent. It is critical to note that neither
the reagents nor the products are soluble in water, thus creating an oil/water interface
where the reaction could take place allowing eater to play a pivotal role in accelerating
the reaction thanks to the so-called “on-water effect”. This compounds are synthetized
by one-pot reaction with a slightly molar excess of acyl chloride with a yield higher
than the 60%.
1)
2)
3)
Procopio A., Celia C., Nardi M., Oliverio M., Paolino D., and Sindona G., J Nat. Prod., 2011,
74, 2377-2381.
rujillo M., Meteos R., Collantes de Teran L., Espartero J. L., Cert R., Jover M., Alcudia F.,
Bautista J, Cert A. and Parrado J., J. Agric. Food. Chem., 2006, 54, 3779-3785.
orres de Pinedo A., Peñalver P., Rondón D. and Morales J. C., Tetrahedron, 2005, 61, 7654-7
660.
178
G – Sostanze Naturali
179
PC54
Phytotoxins by Phoma chenopodicola as potential herbicides to
biological control of Chenopodium album
Marco Evidentea, Maria Chiara Zonnob, Alessio Cimminoa, Marco Masia, Maurizio
Vurrob, Alexander Berestetskiyc, Antonio Evidentea
a
Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte S.
Angelo, Via Cintia 4, 80126 Napoli; bIstituto di Scienze delle Produzioni Alimentari, Consiglio
Nazionale delle Ricerche, Via Amendola 122/O, 70125 Bari, Italy; cAll-Russian Institute of Plant
Protection, Russian Academy of Agricultural Sciences, Pushkin, Saint-Petersburg 196608, Russia
[email protected]
Chenopodium album, also known as common lambsquarters or fat hen, is a worldwide
weed of arable crops such as sugar beet and maize (1). The difficulties in managing this
weed have increased the interest in the use of fungal pathogens as a suitable option for
its biological control. The first mycoherbicide proposed for the control of C. album was
Ascochyta caulina (2, 3). More recently, another pathogenic Sphaeropsidales, Phoma
chenopodicola, was proposed as a potential mycoherbicide for the control of the same
weed. Taking into account that leaf and stem pathogenic Sphaeropsidales are well
known as toxin producers, it was considered to be worthwhile studying the production
of toxic metabolites by culture filtrates of P. chenopodicola. This study led to the
isolation and the chemical and biological characterization of the main toxin, a new
unrearranged ent-pimaradiene diterpene, named chenopodolin (4). This compound
showed to have phytotoxic activity, causing necrotic lesions to leaves of different
weeds, namely Mercurialis annua, Cirsium arvense and Setaria viridis. In order to
figure out the structural features responsible for the activity, a structure-activity
relationship study was carried out by using five derivatives obtained by chemical
modification of the main functional groups of the toxin (4). Moreover, a successive
investigation of the organic extract allowed to isolate three new tetrasubstituted
furopyrans, named chenopodolans A, B and C, together with the well known fungal
metabolite (-)-(R)-6-hydroxymellein (5).
Considering that the organic extract obtained from the culture filtrates showed a
phytotoxicity higher than the expected by chenopodolin and chenopodolans A-C
content, a further analysis of the organic extracts of the fungus allowed to ascertain the
presence of further bioactive metabolites, whose isolation, and chemical and biological
characterization will be discussed in this communication.
1)
2)
3)
4)
5)
L. G. Holm, D. L. Pluckett, J. V. Pancho, J. P. Herberger, The World’s Worst Weeds
(Distribution and Biology); University Press of Hawaii: Honoloulou, HI, 1977; pp 84−91.
C. Kempenaar, Studies on the Biological Control of Chenopodium album by Ascochyta caulina.
Doctoral Thesis, University of Wageningen, The Netherlands, 1995.
C. Kempenaar, P. J. F. M. Horsten, P. C. Scheepens, Eur. J. Plant Pathol., 1996, 102, 143−153.
A. Cimmino, A. Andolfi, M.C. Zonno, F. Avolio, A. Santini, A. Tuzi, A. Berestetskiy, M. Vurro
& A. Evidente, J. Nat. Prod., 2013, 76, 1291-1297.
A. Cimmino, A. Andolfi, M.C. Zonno, F. Avolio, A. Berestetskiy, M. Vurro & A. Evidente,
Phytochemistry, 2013, 96, 208-213.
180
PC55
Secondary metabolites from Scrophularia canina L.
A. Vendittia,b, C. Frezzab*, M. Nicolettib , A. Biancoa, M. Serafinib
a) Università di Roma “La Sapienza”, Dipartimento di Chimica, Piazzale Aldo Moro, 5 00185 Roma
(Italia)
b) Università di Roma “La Sapienza”, Dipartimento di Biologia Ambientale, Piazzale Aldo Moro, 5
00185 Roma (Italy)
*e-mail: [email protected]
Scrophularia canina L. is a herbaceous perennial plant belonging to Scrophulariaceae
and growing abundantly in Italy1. In this work we report the composition of the polar
fraction of the ethanolic extract of S. canina harvested in the pre-park area of National
Park of Abruzzo, Lazio and Molise (Central Italy).
This study allowed the isolation and the identification of a total of six compounds: one
phenyl-propanoid, verbascoside2; one acyclic diterpenic alcohol called phytol3; four
iridoid glucosides namely aucubin4, harpagide5, 8-O-acetyl-harpagide5 and 8-epiloganic
acid6.
Verbascoside is a quite common compound which is often identified as a constituent of
species of the Asterideae subclass and has a taxonomic relevance when evidenced
together with iridoids7.
Also phytol is a widespread compound since it’s part of the chlorophyll structure.
Aucubin, harpagide and 8-O-acetyl-harpagide have already been evidenced in this
species8 while the other three compounds were recognized for the first time in this
study.
From a biosynthetic point of view, it’s important to underline the presence of 8epiloganic acid since it is considered the biogenetic precursor of a wide series of
substances owning an iridoidic skeleton which are generally found in Scrophulariaceae
and in other families of the Lamiales order and for this reason they are considered of
chemotaxonomical relevance.
1) Pignatti, S. Flora d’Italia, 1982, 2, 590-596.
2) Venditti, A.; Bianco, A.; Nicoletti, M.; Quassinti, L.; Bramucci, M.; Lupidi, G.; Vitali, L.A.; Papa, F.;
Vittori, S.; Petrelli, D.; Maleci Bini, L.; Giuliani, C And Maggi, F. Chemistry & Biodiversity, 2014,
11, 245-261.
3) Li, G.; Dumaa, M.; Xiang, P.; Jinhai, Y.; Guolin, Z.; Yinggang, L. Chin. J. Appl. Environ. Biol. 2012,
18(6), 924-927.
4) Paris, Mm.R. And Chaslot, M. Ann. Pharm. Franc., 1955, 13, 648.
5) Scarpati, M.L.; Guiso, M.; Panizzi, L. Tethraedron Lett., 1965, 39, 3439.
6) Coscia, C.J. And Guarnaccia, R. Chem Comm., 1968, 138.
7) Jensen, S.R. Annales Of The Missouri Botanical Garden Press, 1992, 79(2), 284-302.
8) Berdini, R.; Bianco, A.; Guiso, M.; Marini, E.; Nicoletti, M.; Passacantilli, P.; Righi, G. Journal of
Natural Products. 1991, 54(5), 1400-1403.
181
PC56
Secondary metabolites content of two Stachys species: S. germanica
subsp germanica and S. annua subsp. annua
A. Vendittia,b, C. Frezzab*, F. Maggic, K. Cianfaglioned, A. Biancoa, M. Serafinib
a) Università di Roma “La Sapienza”, Dipartimento di Chimica, Piazzale Aldo Moro, 5 00185 Roma
(Italia)
b) Università di Roma “La Sapienza”, Dipartimento di Biologia Ambientale, Piazzale Aldo Moro, 5
00185 Roma (Italy)
c)
Scuola di Farmacia, Università di Camerino, Camerino, Italia
d) Scuola di Bioscienze e Medicina Veterinaria, Università di Camerino, Camerino, Italia
*e-mail: [email protected]
Stachys is an important and large genus belonging to the Lamiaceae family comprising
31 species in Italy out of 450 with characteristics not common and specific among
themselves1.
In this work we report the contents of the polar fractions of Stachys germanica L. subsp.
germanica and S. annua L. subsp. annua.
The study of the ethanolic extract of the former allowed the isolation and identification
of two flavonoids, isoscutellarein derivates2,3, a phenyl-propanoid, stachysoside3, a
caffeoylquinic derivative, clorogenic acid3 and lastly one iridoid, harpagide4. They all
have been already evidenced in this genus5 and some are considered chemotaxonomic
markers.
On the other hand, the study of the latter led to the isolation and identification of two
flavonoids, again isoscutellarein derivates2,3.
These last compounds containing allose have been often evidenced in several genera of
the Lamiaceae family such as Sideritis and even Stachys itself6,7, thus confirming their
own chemotaxonomic proximity.
Making a comparison between the two studied plants it can be noted that only a
compound, one of the isoscutellarein derivates, was found in both species: in particular
the observed composition of S. germanica resulted in accordance with those reported
for several Stachys species5,6, while S. annua showed only the presence of flavonoids,
instead. Such fact might be a starting basis for a reconsideration of the systematic
collocation of this species.
1) Tomás-Barberan, F.A.; Gil, M.I.; Ferreres, F.; Tomás-Lorente, F. Phytochemistry. 1992, 31(9), 30973102.
2) Lenherr, A. And Mabry, T.J. Phytochemistry, 1987, 26, 1185.
3) Venditti, A.; Bianco, A.; Nicoletti, M.; Quassinti, L.; Bramucci, M.; Lupidi, G.; Vitali, L.A.; Papa, F.;
Vittori, S.; Petrelli, D.; Maleci Bini, L.; Giuliani, C And Maggi, F. Chemistry & Biodiversity, 2014,
11, 245-261.
4) Scarpati, M.L.; Guiso, M.; Panizzi, L. Tethraedron Lett., 1965, 39, 3439.
5) Venditti, A.; Bianco, A.; Maggi, F.; Nicoletti, M. Natural Product Research, 2013, 27(15), 14081412.
6) Venditti, A.; Bianco, A.; Nicoletti, M.; Quassinti, L.; Bramucci, M.; Lupidi, G.; Vitali, L.A.; Papa, F.;
Vittori, S. Et Al. Fitoterapia, 2013, 90, 94-103.
7) Serrilli, A.M.; Ramunno, A.; Piccioni, F.; Serafini, M.; Ballero, M.; Bianco, A. Natural Product
Research, 2006, 20(6), 648-652.
182
PC57
Bioactive metabolites produced by Diplodia species pathogens of forest
plants
Wanda D’Amico,1 Marco Masi,1 Benedetto T. Linaldeddu,2 Marco Evidente,1 Lucia
Maddau,2 Alessio Cimmino,1 Antonio Evidente1
1
Dipartimento di Scienze Chimiche, Universita’ di Napoli Federico II, Complesso Universitario Monte S.
Angelo, Via Cintia 4, 80126 Napoli
2
Dipartimento di Agraria, Sezione di Patologia vegetale ed Entomologia, Università degli Studi di
Sassari, Viale Italia 39, 07100 Sassari, Italy
e-mail: [email protected]
Several studies have pointed out the important role of fungi belonging to Diplodia
genus in the aetiology of serious disease affecting forest trees worldwide. Among them,
the infections of D. cupressi, D. africana D. quercivora, and D. corticola have a heavy
impact on forest ecosystems, compromising both vitality and productivity of trees.
Several Diplodia species are well-known for their ability to produce in vitro a wide
range of secondary metabolites, exhibiting a variety of biological activities such as
phytotoxic, cytotoxic, and antimicrobial which have drawn the attention in application
studies. Sphaeropsidin A, an ent-pimarane isolated from D. cupressi, has been studied
as a novel therapeutic strategy to combat drug-resistant cancers.1
Two new phytotoxic dihydrofuropyran-2-ones, named afritoxinones A and B, and
oxysporone were isolated from Diplodia africana, a pathogen directly involved in the
aetiology of juniper die-back in Italy.2 A new phytotoxic nor-ent-pimarane, namely
diplopimarane, was isolated together with sphaeropsidin A and epi-epoformin from D.
quercivora, a pathogen recently found on declining Quercus canariensis trees in
Tunisia.3 Diplodia corticola, an aggressive cork oak pathogen, produced in liquid
culture monocyclic and bicyclic substituted furanones and a new phytotoxic
tetrahydropyranpyran-2-one, namely diplopyrone as well as the sphaeropsidin A.4
A re-investigation of the culture filtrates of D. corticola allowed us to isolate new
metabolites, which appear, from preliminary spectroscopic investigations, to be closely
related to sphaeropsidins and furanones. In addition, for the first time bioactive
secondary metabolites were isolated from two other pathogenic Diplodia species,
namely Diplodia olivarum and Diplodia fraxini. Their organic extracts showed
phytotoxicity. The results will be illustrated in this communication.
1) Mathieu, V.; Chantome, A.; Lefranc, L.; Mohr, T.; Maddau, L.; Berger, W.; Evidente, A.;
Vandier, C.; Delpire, E.; Kiss, R. Cmls 2015, In Press.
2) Evidente, A.; Masi, M.; Linaldeddu, B.T.; Franceschini, A.; Scanu, B.; Cimmino, A.; Andolfi,
A., Motta, A.; Maddau, L. Phytochemistry, 2012, 77, 245-250.
3) Andolfi, A.; Maddau, L.; Basso, S.; Linaldeddu, B.T.; Cimmino, A.; Scanu, B.; Deidda, A.;
Tuzi, A.; Evidente, A. J. Nat. Prod., 2014, 77, 2352-2360.
4) Evidente, A.; Andolfi, A.; Fiore, M.; Spanu, E.; Maddau, L.; Franceschini, A., Marras, F.; Motta,
A. J. Nat. Prod., 2006, 69, 671-674.
183
PC58
Natural dyes from Rubia tinctorum L., used in tapestries
Ilaria Serafini1,2, Livia Lombardi1,2, Fabio Sciubba1, Marcella Guiso1, Armandodoriano
Bianco1
1
Dipartimento di Chimica, 2Dipartimento di Scienze della Terra,
Università di Roma “La Sapienza”, Piazzale Aldo Moro 5, 00185 Roma.
e-mail: [email protected]
Plants and insects had been used for a long time in the ancient period as source for dyes
for art materials. On many tapestries, there is a widespread state of decay in charge of
the colour of many yarns. This phenomenon may be due to presence of alteration
products or total destruction of dye molecules. If we consider madder root, for example,
contains a large number of compounds characterized by anthraquinone structures,
thought as the main chromophores [1]. However, it is worth to notice that the analyses
of madder’s extract, obtained in the same condition of dyeing bath [2], reveal also the
presence of other types of molecules (not necessarily anthraquinones), present in the
matrix. Some of them can be fixed on the yarn and, probably, these are involved in the
degradation processes. During this work, it has carried out extraction of dyes from
R.tinctorum L. and analysed by HPTLC (Fig. 1), 1H-NMR (Fig. 2). and ESI-MS With
ESI-MS/MS, in both positive and negative mode, it has been possible to draw a
structural profile of the compounds. These compounds are compared to those extracted
by yarns [3] [4], dyed following the ancient recipes [2], in order to evaluate which
molecules are fixed on the textile .
Fig.1 Chromatographic separation of madder extract
Fig.2 1H-NMR of madder yarn extract .
1) G. C. H. Derksen, H.A.G. Niederländer, T.A. Van Beek, J. Chromatogr, 2002, 978, 119–127.
2) D. Cardon, Natural Dyes: Sources, Tradition, Technology and Science, 2007, Archetype Publications
Ltd, London.
3) Lombardi L., Serafini I., Guiso M., Sciubba F, Bianco A., Tetrahedron Letters, Submitted, 2015.
4) Valaniou, L., Karapanagiotis I., Chryssoulakis, Anal Bioanal Chem, 2007, 395, 2175 -2189.
184
PC59
Anthemis cretica subsp. petraea (Ten.) Oberpr. & Greuter from
Majella National Park.
Alessandro Venditti1,2, Mirella Di Cecco3, Giampiero Ciaschetti3, Armandodoriano
Bianco1
1
2
3
Dipartimento di Chimica Sapienza Università di Roma (P.le A. Moro 5, 00185 Roma).
Dipartimento di Biologia Ambientale Università di Roma (P.le A. Moro 5, 00185 Roma).
Ente Parco Nazionale della Majella, Via Occidentale 6, 66016 Guardiagrele (CH),(Italy)
e-mail: [email protected]
Anthemis cretica subsp. petraea (Ten.) Oberpr. & Greuter (Asteraceae) is an endemic
species of central Italy which grows between 110 and 2600 m a.s.l.. In Italy it is present
only in Abruzzo and Molise regions. We studied a sample collected from the Majella
National Park, where this species represent a rare entity. The preliminary study of the
ethanolic fraction led to the identification of partenolide (1) already evidenced in
Anthemis melampodina Delile2 and in other Asteraceae, kaempferol (2), a common
flavonoid in Anthemideae and Cichorideae3,4,5 and a cycloexenetetraol named
leucanthemitol (3) previously evidenced in Anthemis nobilis L. and in Chrysanthemum
leucanthemum L., together with several other compounds under study. Compound (3) is
a quite rare compound and represent a molecular evidence of the botanical proximity
among these correlated genera of Asteraceae.
1) Conti, F.; Abbate, G.; Alessandrini, A.; Blasi, C., An Annotated Checklist of the Italian Vascular
Flora. 2005, Palombi Press: Rome.
2) Sarg, T.; El-Dahmy, S.; Salem, S., Scientia Pharmaceutica, 1990, 58(1), 33-35.
3) Wollenweber, E.; Dorr, M.; Fritz, H.; Valant-Vetschera, K.M., Z Naturforsch C, 1997, 52(3/4), 137143.
4) Valant-Vetschera, K.M.; Wollenweber, E.; Faure, R.; Gaydou, E., Biochem Syst Ecol, 2003, 31(5),
545-548.
5) Guimaraes, R.; Barros, L.; Duenas, M.; Calhelha, R.C.; Carvalho, A.M.; Santos-Buelga, C.; Queiroz,
M.J.R.P.; Ferreira, I.C.F.R., Food Chem., 2013, 136(2), 718-725.
6) Plouvier, V., Compt. Rend., 1962, 255, 360-362.
185
PC60
Secondary metabolites from flowers of Genista cilentina Vals.
Alessandro Venditti1,2, Mauro Serafini2, Claudio Frezza2, Armandodoriano Bianco1
1
2
Dipartimento di Chimica Sapienza Università di Roma (P.le A. Moro 5, 00185 Roma).
Dipartimento di Biologia Ambientale Università di Roma (P.le A. Moro 5, 00185 Roma).
e-mail: [email protected]
Genista cilentina Vals. is an Italian endemic species belonging to Fabaceae which is
characteristic of Cilento, a territory of Campania region overlooking the Tyrrhenian
Sea1.
The phytochemical analysis of the ethanolic extract from the flowers revealed the
presence of several flavonoid and isoflavonoid yet evidenced in this genus, and resulted
in accordance with the flavonoidic pattern reported by Harborne for Genisteae tribe2. In
particular were identified genistein (1) the main isoflavonoid, biochanin A (2), luteolin
(3) and apigenin (4) as aglycones, while several glycosidated derivatives are currently
under study. Is worth of mention the conspicuous presence of liquiritigenin (5) a
chalcone evidenced as the only synthesized compound in Genista tinctoria hairy root
cultures3 treated with abscissic acid. Compound (5) is also endowed with interesting
biological activities, i.e. gastroprotective4, antiviral5 and counteracting the Alzheimer
disease progression6.
1) Conti, F.; Abbate, G.; Alessandrini, A.; Blasi, C., An Annotated Checklist of the Italian Vascular
Flora. 2005, Palombi Press: Rome.
2) Harborne, J.B., Phytochemistry, 1969, 8(8), 1449-1456.
3) Luczkiewicz, M.; Kokotkiewicz, A., Z Naturforsch. C, 2005, 60(11/12), 867-875
4) Choi, Y.H.; Kim, Y-J.; Chae, H-S.; Chin, Y-W., Planta Med. 2015, 81(7), 586-593.
5) Li, Z.; Zhao, Y.; Lin, W.; Ye, M.; Ling, X., J Pharmaceut Biomed., 2015, 111, 28-35.
6) Link, P.; Wetterauer, B.; Fu, Y.; Wink, M., Planta Med., 2015, 81(5), 357-362.
186
PC61
Anti-inflammatory effects of dihydroasparagusic acid in
lipopolysaccharide-activated microglial cells
Adele Salemme1,Anna Rita Togna1,Vittoria Cammisotto1, Armandodoriano Bianco2,
Alessandro Venditti2,3
1
Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, P.le
A. Moro 5, 00185 Rome, Italy
2
Department of Chemistry, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
3
Department of Environmental Biology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
[email protected]
The activation of microglia and resulting elevated levels of pro-inflammatory and
neurotoxic mediators, is crucially associated with neurodegenerative diseases, including
Alzheimer and Parkinson diseases and multiple sclerosis1,2. Dihydroasparagusic acid
(DHAA) is a natural dimercaptanic acid, a sulfur-containing flavor component produced
by Asparagus plants. It has two thiolic functions able to coordinate metal ions, and a
carboxylic moiety, which may enhance excretion of the complexes. Indeed a protective
effect of DHAA toward Hg2+ poisoning has been demonstrated in an in vitro study4.
Thiol functions are also present in several biomolecules with important physiological
antioxidant role as glutathione. DHAA has been recently reported to exert several
interesting biological activities, including radical scavenging and antioxidant activities
and an inhibitory action on mushroom tyrosinase3.
The aim of this study was to investigate the in vitro anti-inflammatory potential of
DHAA on LPS-activated primary rat microglia cultures. LPS was used as a stimulus,
being capable of causing a wide variety of pathophysiological effects, i.e. release of proinflammatory cytokines and mediators, increased ROS production, which cause
oxidative stress5.
Our results suggest that DHAA significantly prevented LPS-induced production of proinflammatory and neurotoxic mediators such as NO, TNF-α, PGE2, as well as iNOS and
COX-2 protein expression and LOX activity in microglia cells, suggesting that DHAA
can effectively inhibit inflammation and oxidative processes that are typical of activated
microglia. So it can be a valuable source for further development of agents designed for
prevention or treatment of neuroinflammation, an important part of the etiopathogenesis
of neurodegenerative diseases.
1) Block, M.L., Zecca, L., Hong, J.S. Nat. Rev. Neurosci. 2007, 8, 57-69.
2) Kim, E.A., Han, A.R., Choi, J., Ahn, J.Y., Choi, S.Y., Cho, S.W. Int. Immunopharmacol. 2014, 22,
73-83
3) Venditti, A., Mandrone, M., Serrilli, A.M., Bianco, A., Iannello, C., Poli, F., Antognoni F. J. Agric.
Food Chem. 2013, 61, 6848-6855
4) Bianco, A., Bottari, E., Festa, M.R., Gentile, L., Serrilli, A.M., Venditti, A. Monatsh Chem., 2013,
144, 1767-1773
5) Hou, X., Zhang, J., Ahmad, H., Zhang, H., Hu, Z., Wang, T. PLoS One, 2014, 9(9):e108314. doi:
10.1371/journal.pone.0108314
187
PC62
Molecular traits of hemiparasitism in Odontites lutea (L.) Clairv.
Alessandro Venditti1,2, Mauro Serafini2, Marcello Nicoletti2, Sebastiano Foddai2,
Armandodoriano Bianco1
1
2
Dipartimento di Chimica Sapienza Università di Roma (P.le A. Moro 5, 00185 Roma).
Dipartimento di Biologia Ambientale Università di Roma (P.le A. Moro 5, 00185 Roma).
e-mail: [email protected]
Odontites lutea (L.) Clairv. is an erect hemiparasitic plant traditionally comprised in
Scrophulariaceae which was recently moved in Orobanchaceae1. In this study we
reported the analysis of the monoterpene glycoside fraction obtained following the
procedure of an our recent patent2. The studied sample was collected from a
spontaneous population growing in a cultivated olive field (Olea europaea, Oleaceae)
bordering a Mediterranean forest represented mainly by Arbutus unedo (Ericaceae), to
verify the influence of the environmental conditions on the secondary metabolite
content.
After repeated chromatographic purification fourteen iridoidic compounds were isolated
and identified. Besides iridoids already evidenced in Odontites as melampyroside (1),
bartsioside (2), aucubin (3), 6-O-glucosyl-aucubin (4) and aucubigenin-1-O-cellobioside (5), shanzhiside methyl ester (6), mussaenoside (7), 8-epiloganin (8) and
adoxosidic acid (9), and currently considered chemotaxonomical markers for the
Scrophulariaceae family since recognized in many genus belonging to this
family3,4,5,6,7,8, were also evidenced compounds peculiar of different families which
were not reported before as constituents of Scrophulariaceae or Orobanchaceae. In
particular were recognized: monotropein (10) and 6,7-dihydromonotropein (11) which
are characteristic of Ericaceae9,10; agnuside (12), previously found in Verbenaceae11;
methyl oleoside (13) and methyl gluco-oleoside (14)11, two secoiridoids usually found
in Oleaceae12,13. The occurrence of these unusual compounds (10-14) in the studied
species is a molecular evidence of the parasitic behaviour of O. lutea, which
demonstrates a host-guest metabolites exchange.
1) APG II. The Angiosperm Phylogeny Group.: APG II. Bot. J. Linn. Soc., 2003; 141: 399–436.
2) Ballero, M.; Bianco A.; Serrilli A. M., Italian Patent, 2009, MI2009A000720
3) Bianco, A.; Francesconi, A; Passacantilli, P., Phytochemistry 1981, 20(6), 1421-1422.
4) Bianco, A.; Bolli, D.; Passacantilli, P., Gazz. Chim. Ital. 1981, 111(3-4), 91-94.
5) Bianco, A.; Bolli, D.; Passacantilli, P., 6 Planta Med. 1982, 44(2), 97-99.
6) Venditti, A.; Serrilli, A.M.; Bianco, A., Nat. Prod. Res., 2013, 27(15), 1413-1416.
7) Venditti, A.; Ballero, M.; Serafini, M.; Bianco, A., Nat. Prod. Res. 2015, 29(7), 602-606.
8) Mead, E.W.; Stermitz, F.R., Phytochemistry 1993, 32(5), 1155-1158.
9) Karikas, G.A.; Euerby, M.R.; Waigh, R.D., Planta Med. 1987, 53(2), 223-224.
10) Jensen, H.D.; Krogfelt, K.A.; Cornett, C.; Hansen, S.H.; Christensen, S.B., J. Agr. Food Chem., 2002,
50(23), 6871-6874.
11) Sridhar, C.; Subbaraju, G.V.; Venkateswarlu, Y.; Venugopal, R.T., J. Nat. Prod., 2004, 67(12), 20122016.
12) Bianco, A.; Buiarelli, F.; Cartoni, G.; Coccioli, F.; Muzzalupo, I.; Polidori, A.; Uccella, N. Anal. Lett,
2001, 34(6), 1033-1051.
13) Takenaka, Y.; Tanahashi, T.; Shintaku, M.; Sakai, T.; Parida N.N., Phytochemistry 2000, 55(3), 275284.
188
H – Medicinal Chemistry e Chimica BioOrganica
189
PC63
Self-assembly of amphiphilic anionic calix[4]arene and encapsulation
of poorly soluble naproxen and flurbiprofen.
L. Barbera,a G. Gattuso,a F.H. Kohnke,a A. Notti,a M. F. Parisi,a I. Pisagatti,a S.
Pappalardo,b S. Patanè,c N. Micali,d and V. Villarid
a
Dipartimento di Scienze Chimiche, Universita` di Messina,
Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy.
b
Dipartimento di Scienze Chimiche, Universita` di Catania, Viale A. Doria 6,
95125 Catania, Italy.
c
Dipartimento di Fisica e di Scienze della Terra, Universita` di Messina,
Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy.
d
CNR-IPCF Istituto per i Processi Chimico-Fisici, Viale F. Stagno d’Alcontres 37, 98158 Messina, Italy.
E-mail: [email protected]
Calixarenes-based surfactants represent a new class of amphiphiles with unique and
intriguing properties assigned by the presence of an aromatic cavity, which may offer,
together with the other hydrophobic and hydrophilic characteristics, additional
interactions.1 The present work describes the synthesis of a water-soluble calix[4]arere 1
bearing 4-butylsulfonato pendant groups at the lower rim and the analysis of its selfassembling properties by a combination of NMR, DLS and AFM techniques, thus
revealing their complementarity in the study of amphiphilic systems. Surfactant
formulations are finding growing applications as drug delivery systems in
pharmaceutical and clinical fields, owing to their ability to encapsulate and transport a
hydrophobic pharmaceutically active drug to its therapeutic target. In this context the
ability of the micellar aggregates of calixarene 1 to encapsulate the non steroidal antiinflammatory naproxen 2 and flurbiprofen 3 in their environment was investigated, and
the results showed that calixarene-type surfactants might be employed in the design of
novel drug delivery systems.
1)
a) Shinkai S.; Mori S.; T. Tsubaki; Sone T.; Manabe O. Tetrahedron Letters 1984, 25, 5315; b)
Shinkai S. Pure Appl. Chem 1986, 58, 1523.
190
PC64
Synthesis and Preclinical Evaluation of a Novel, Selective 111In-labelled
Aminoproline-RGD-peptide For Non-invasive Tumor Imaging
Andrea Sartori,1 Francesca Bianchini,2 Paola Burreddu,3 Claudio Curti,1 Franca
Zanardi,1 Lucia Battistini1
1
2
Dipartimento di Farmacia, Università degli Studi di Parma, Parma 43124, Italy
Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, “Mario Serio” Università degli Studi di
Firenze, Firenze 50134, Italy
3
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Li Punti Sassari 07100, Italy
e-mail: [email protected]
In recent years, many efforts have been addressed to develop new techniques enabling
the early diagnosis and non-invasive monitoring in primary tumors and metastasis.
Integrins V3 and 51 have been characterized as prototypic molecules of angiogenic
tumor associated-endothelial cells and their overexpression in tumor cells has been
correlated to different stages of progression in various tumor types.1,2 The chemical and
radiochemical synthesis, characterization and preclinical evaluation of a 111In-labelled
DOTA conjugate embodying a cyclic aminoproline-RGD semipeptide [c(AmpRGD)] as
a competent dual V3/51 integrin ligand will be reported.3
Evaluation of the 111In-labelled bioconjugate as SPECT tracer in a xenograft model of
human melanoma will be described, as well as displacement experiments assessing the
V3/51 integrin specificity of tumor uptake. The 111In-labelled c(AmpRGD)-DOTA
conjugate holds promise as SPECT-imaging small-molecular probe for non-invasive
visualization of human melanoma and other V3/51-positive tumors.
1) Zhou, Y.; Chakraborty, S.; Liu, S. Theranostics. 2011, 1, 58-82.
2) Auzzas, L.; Zanardi, F.; Battistini, L.; Burreddu, P.; Carta, P.; Rassu, G.; Curti, C.; Casiraghi, G. Curr.
Med. Chem. 2010, 17, 1255-1299.
3) Battistini, L.; Burreddu, P.; Carta, P.; Rassu, G.; Auzzas, L.; Curti, C.; Zanardi, F.; Manzoni, L.;
Araldi, E.M.V.; Scolastico, C.; Casiraghi, G. Org. Biomol. Chem. 2009, 7, 4924-4935.
191
PC65
Design, synthesis and characterization of helical oligopeptides
inhibiting the VEGF/VEGFR protein-protein interaction
Laura Belvisi1, Gianfranco Bocchinfuso2, Stefano Raniolo2, Antonio Palleschi2, Marta
De Zotti3, Giacomo Panighel3, Fernando Formaggio3, Daniela Arosio4, Umberto
Piarulli5, Simone Zanella1, Luca Pignataro1, Cesare Gennari1, Lorenzo Stella2
1
Department of Chemistry, University of Milan, 20133 Milan, Italy
2
Department of Chemical Sciences and Technologies, University of Rome ‘Tor Vergata’, 00133 Rome,
Italy
3
Department of Chemistry, University of Padova, 35131 Padova, Italy
4
ISTM CNR, 20133 Milan, Italy
5
Department of Science and High Technology, 22100 Como, Italy
e-mail: [email protected]
Protein-protein interactions modulate most biological processes, but their inhibition by
small organic molecules is challenging, due to the large interacting protein interfaces.
One example is provided by the association between vascular endothelial growth factors
(VEGFs) and their receptors (VEGFRs). It is crucial in regulating angiogenesis and
therefore constitutes a key target in cancer therapy. Oligopeptides mimicking a VEGF
interface helix represent a promising strategy to inhibit this interaction.1
Receptor (VEGFR, D2 VEGF (dimer)
Here we report in silico design, synthesis, structural and functional characterization of
several short peptides (9-15 residues) targeting VEGFRs. In particular, we exploited the
known helix-inducing capabilities of Cα-tetrasubstituted α-amino acids to stabilize the
secondary structure of our peptides.2
We gratefully acknowledge MIUR for financial support (PRIN project 2010NRREPL: Synthesis and
biomedical applications of tumor-targeting peptidomimetics).
1) Basile, A.; Del Gatto, A.; Diana, D.; Di Stasi, R.; Falco, A.; Festa, M.; Rosati, A.; Barbieri, A.;
Franco, R.; Arra, C.; Pedone, C.; Fattorusso, R.; Turco, M. C.; D'Andrea, L. D. J. Med. Chem. 2011,
54, 1391-1400.
2) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Biopolymers 2002, 60, 396-419.
192
PC66
Stereoselective synthesis of carba analogs of Manα1-2Man as potential
DC-SIGN ligands
Vittorio Bordoni,1 Alessia Nocciolini,1 Lucilla Favero,1 Paolo Crotti,1 Anna Bernardi,2
Franck Fieschi3, Valeria Di Bussolo1
1
2
Dipartimento di Farmacia, Università di Pisa, via Bonanno 33, 56126 Pisa
Dipartimento di Chimica, Università degli studi di Milano, via Golgi 19, 20133 Milano
3
Institut de Biologie Structurale, 41 rue Jules Horowitz, 38027 Grenoble (France)
e-mail: [email protected]
DC-SIGN is a novel DC-specific adhesion receptor on human Dendritic cells, which is
essential in binding antigens and in transfecting the infection to T cells. DC-SIGN binds
ligand motifs through a terminal carbohydrate recognition domain (CRD).1 The main
carbohydrate ligand recognized by DC-SIGN is the high mannose glycan
(Man)9(GlcNAC)2, in which the terminal disaccharide portion Manα1-2Man binds DCSIGN almost as efficiently as the entire high mannose glycan (Man)9(GlcNAC)2. This
suggests an important role of the nonreducing end Manα1-2Man fragment of Man9 in
DC-SIGN recognition.2
Recently, Bernardi’s group synthesized pseudodisaccharide 1 having a threedimensional structure and a conformational behavior corresponding to that of the
natural disaccharide Manα1-2Man. It also showed a significant anti-viral activity.3 a,b,c
On the basis of this result, we achieved the synthesis of the new pseudomannobiosides 2
and 3, mimics of the natural Manα1-2Man, with an amino and an azido functionality at
the end, respectively. These compounds are conceptually corresponding to the
previously pseudodisaccharide 1, but with the important difference of the presence of a
real D-carbamannose unit instead of a simplified mimic structure. The synthetic project
proceeds through the obtainment of the (+)-6-O-benzyl-5a-carba-D-glucal (4), as a key
intermediate, which was subjected to two different type of elaborations to afford the
carbaglycosylating agents (+)-tri-O-benzyl-β-epoxide (5), and the (+)-tri-O-acetyl-βepoxide (6), precursors of the pseudomannobiosides 2 and 3, respectively.
1) Gejtenbeek, T. B. H.; Engering, A.; van Kooyk, Y. J. J. Leuk. Bio. 2002, 921-931.
2) Engering, A.; Gejtenbeek, T. B. H. J. Immunol. 2002, 168: 2118-2126.
3) (a) Bernardi, A.; Arosio, D.; Dellavecchia, D.; Micheli, F. Tetrahedron: Asymmetry 1999, 10, 34033407. (b) Reina, J. J.; Sattin, S.; Invernizzi, D.; Mari, S.; Mart nez-Prats, L.; Tabarani, G.; Fieschi, F.;
Delgado, R.; Nieto, P. M.; Rojo J.; Bernardi, A. ChemMedChem 2007, 2, 1030-1036. (c) Thépaut, M.;
Guzzi, C.; Sutkeviciute, I.; Sattin, S.; Ribeiro-Viana, R.; Varga, N.; Chabrol, E.; Rojo, J.; Bernardi,
A.; Angulo, J.; Nieto, P. M.; Fieschi, F. J. Am. Chem. Soc. 2013, 135, 2518-2529.
193
PC67
Guanosine-based hydrogen-bonded Scaffolds: G-ribbons and Gquartets Formed in the Absence of a Templating Metal Cation
Mohamed El Garah,[a] Rosaria C. Perone,[b] Alejandro Santana Bonilla,[c,d] Sébastien
Haar,[a] Marilena Campitiello,[b] Rafael Gutierrez,[c] Gianaurelio Cuniberti,*[c,e] Stefano
Masiero,*[b] Artur Ciesielski*[a] and Paolo Samorì*[a]
[a]
[b]
ISIS & icFRC, Université de Strasbourg & CNRS, Strasbourg (France)
Alma Mater Studiorum - Università di Bologna Dipartimento di Chimica “G. Ciamician”, Bologna
(Italy)
[c] Institute for Materials Science and Max Bergmann Center of Biomaterials Dresden University of
Technology (Germany)
[d] Max Planck Institute for the Physics of Complex Systems (Germany)
[e] Dresden University of Technology (Germany)
e-mail: [email protected]
Here we describe the design and synthesis of novel alkyl substituted guanosine
derivatives equipped with a ferrocene1 moiety on the C(5’) position of the sugar, and
their self-assembly at the solid/liquid interface on highly oriented pyrolitic graphite
(HOPG). Scanning Tunneling Microscopy imaging at the graphite/solution interface
revealed that the functionalization of the C(8) position of the guanine core rules the type
of 2D pattern at surfaces.2 In particular, when the C(8) position of the guanine core is
exposing either a proton or a Br atom, the molecule was found to form different 1D
supramolecular nanoribbons on graphite.3 On the other hand, upon functionalization of
the C(8) with a sterically demanding substituent like a phenol group, cyclic G-quartet
motifs were formed.4 This result represents the first example of the formation and
visualization at the solid/liquid interface of metal-free G-quartets, a structure of
biological significance, in the frame of nucleic acid telomerase. The tunability of the
structural motif of the guanosine based assembly via simple substitution in the C(8)
position also opens perspectives towards the use of ferrocene based ordered
architectures for applications in (opto)elecronics.
1)
2)
3)
4)
D. Astruc, C. Ornelas, J. Ruiz, Acc. Chem. Res. 2008, 41, 841-856
a) G. P. Spada, S. Lena, S. Masiero, S. Pieraccini, M. Surin, P. Samorì, Adv. Mater. 2008,
20, 2433-2438; b) T. F. A. Greef, E. W. Meijer, Nature 2008, 453, 171-173.
S. Masiero, S. Pieraccini, G. P. Spada, in Guanine Quartets: Structure and Application, The
Royal Society of Chemistry, 2013, pp. 28-39
V. Andrisano, G. Gottarelli, S. Masiero, E. H. Heijne, S. Pieraccini, G. P. Spada, Angew.
Chem. Int. Ed. 1999, 38, 2386-2388.
194
PC68
Discovery of gymnemic acids as a new class of liver X receptor
antagonists
Carmen Festa1, Barbara Renga2, Simona De Marino1, Simone Di Micco3, Maria Valeria
D’Auria1, Giuseppe Bifulco3, Stefano Fiorucci2, Angela Zampella1
1
Department of Pharmacy (University of Naples “Federico II”, Via D. Montesano 49, I-80131 Naples,
Italy). 2Department of Surgery and Biomedical Sciences (Nuova Facoltà di Medicina, P.zza L. Severi, I06132 Perugia, Italy). 3Department of Pharmacy (University of Salerno, Via Giovanni Paolo II, 132,
84084, Fisciano, Italy)
e-mail: [email protected]
Liver X receptor- and - are ligand-activated transcription factors belonging to the
nuclear receptor superfamily that controls biological responses by coordinating
regulation of gene transcription. These receptors are critical modulators of lipid and
glucose
metabolism,
inflammatory
responses
and
innate
immunity.1-3
Within our interest in nuclear receptor modulators from natural sources,4,5
we proceeded in the isolation and pharmacological decodification of gymnemic acids
from a commercial available preparation of Gymnema sylvestre extracts.
Gymnema sylvestre is considered a relevant medicinal plant, especially for its
antidiabetic properties, but also for the treatment of a broad range of ailments including
asthma, eye complaints, family planning, colic pain, cardiopathy, constipation,
dyspepsia, hemorrhoids, and hyperlipidemic
conditions.6-9 We demonstrated for the first
time that individual gymnemic acids are potent
and selective antagonists for the  isoform of
LXR. Deep pharmacological investigation
Gymnestrogenin
demonstrated that gymnestrogenin, reducing
the expression of SREBP1c and ABCA1 in
vitro, is able to decrease lipid accumulation in
HepG2 cells. The results of this study
substantiate the use of Gymnema sylvestre
extract in LXR-mediated dislypidemic
diseases.
1) Kalaany, N.Y.; Mangelsdorf, D.J. Annu Rev Physiol 2006; 68; 159-91.
2) Tontonoz, P.; Mangelsdorf, D.J. Mol Endocrinol 2003;17;985-93.
3) Swanson, H.I.; Wada, T.; Xie, W.; Renga, B.; Zampella, A. et al. Drug Metab Dispos 2013;41;1–11.
4) D'Auria, M.V.; Sepe, V.; Zampella, A. Curr Top Med Chem 2012;12;637–69.
5) Fiorucci, S.; Distrutti, E.; Bifulco, G.; D'Auria, M.V.; Zampella, A. Trends Pharmacol Sci
2012;33;591–601.
6) Kanetkar, P.; Singhal, R.; Kamat, M. J Clin Biochem Nutr 2005;1;77–81.
7) Saneja, A.; Sharma, C.; Aneja, K.R.; Pahwa, R. Der Pharmacia Lettre 2010;2;275–84.
8) Porchezhian, E.; Dobriyal, R.M. Pharmazie 2003;58;5–12.
9)Shigematsu N, Asano R, Shimosaka M, Okazaki M. Biol Pharm Bull 2001;24;713–17.
195
PC69
Targeting Microsomal Prostaglandin E2 Synthase 1 For The
Development Of New Potential Anti-inflammatory Drugs.
Antonio Foglia, Stefania Terracciano,Gianluigi Lauro, Carmela Saturnino,
Raffaele Riccio, Ines Bruno, Giuseppe Bifulco.1
1
Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, Italy
e-mail: [email protected]
Arachidonic acid metabolism is a critical process mediated by several enzymes, which
lead to the formation of different classes of eicosanoids.1 Prostaglandin E2 (PGE2) is the
most prominent prostanoid and it elicites a wide range of biological effects associated
with inflammation, pain, fever and cancer.2 The synthesis of this bioactive lipid is
mediated by three terminal Prostaglandin E2 synthases (PGES): a cytosolic isoform
(cPGES) and two microsomal isomerases (mPGES-1 and mPGES-2).3 In contrast to
mPGES-2 and cPGES, the expression of mPGES-1 is inducible and therefore
responsible for enhanced PGE2 levels during inflammation processes. Therefore,
mPGES-1 has emerged as a promising target for therapeutic application in light of the
possibility of overcoming the classical side effects commonly associated with use of
traditional anti-inflammatory drugs (NSAIDs and Coxibs).5 This membrane protein is
structurally a homotrimer and the active site is located at the interfaces of the three
asymmetric monomers, which are formed by four α-helices and are partially occupied
by the glutathione (GSH) cofactor.4 Although many structurally different compounds
able to efficiently inhibit mPGES-1 have been developed, the discovery of new and
more potent mPGES-1 inhibitors is strongly required. With the aim of discovering a
new potential class of mPGES-1 inhibitors, we have accomplished a virtual screening
on a huge number of synthetically accessible molecules in order to select the best
candidates for the subsequential steps of chemical synthesis and biological evaluation.
Computational calculations were performed by using the X-ray crystallographic
structure of mPGES-1 solved in 20146 and results will enable the selection of scaffolds
displaying the most promising binding affinity toward the target protein.
1)
2)
3)
4)
5)
6)
Smith, W. L.; Urade, Y.; Jakobsson, P.-J.; Chemical Reviews, 2011, 111, 5821-5865
Park, JY.; Pillinger, MH.; Abramson, SB. Clinical Immunology, 2006, 119, 3, 229-240.
Nakanishia, M.; Gokhaleb, V.; Meuilletc, E.J.; Rosenberg D.W. Biochimie, 2010, 92, 660-664.
Chang, H.; Meuillet, E.J.; Future Med Chem, 2011, 3, 1909–1934.
T. Sjögren, J. Nord, M. Ek, P. Johansson, G. Liu, S. Geschwindner Proc. Natl. Acad. Sci. U.S.A.,
2013, 110, 3806-3811.
Li, D.; Howe, N.; Dukkipati, A.; Shah, S. T.; Bax, B. D.; Edge, C.; Bridges, A.; Hardwicke, P.;
Singh, O. M.; Giblin, G.; Pautsch, A.; Pfau, R.; Schnapp, G.; Wang, M.; Olieric, V.; Caffrey, M.
Cryst Growth Des 2014, 14, 2034-2047.
196
PC70
Targeting integrins with new beta-lactam derivatives
Paola Galletti,1 Giulia Martelli,1 Monica Baiula,2 Samantha Deianira Dattoli,2 Santi
Spampinato,2 Daria Giacomini.1
1
Department of Chemistry “G. Ciamician”, University of Bologna, Via Selmi 2, 40126 Bologna, Italy
Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126 Bologna,
Italy
b
[email protected]

-Lactam compounds are really evergreen molecules. Because of the unique properties
of the azetidinone ring, which is particularly strained and activated towards nucleophilic
acyl substitution, the β-lactam structure is a versatile building block in the synthesis of
several biologically active compounds. Notably, in the last decades monocyclic βlactams gained importance as effective enzymatic inhibitors; among them there are only
few examples of azetidinones that demonstrated activity against integrins.1 Integrins are
heterodimeric α/β transmembrane receptors that mediate dynamic adhesive cell-cell and
cell-matrix interactions. Because of their important roles in intracellular signalling,
immune responses, leukocyte traffic, haemostasis and cancer, their potential as a
therapeutic target is now widely recognized. We have actively contributed to this field
with the design and synthesis of new monocyclic β-lactams specifically designed to
target integrins, thus acting like mimetics of the RGD (Arg-Gly-Asp) peptide sequence,
the key portion for the recognition of ligands. The new molecules contain the
azetidinone as the only cyclic framework armed with carboxylic acid and amine
terminals spaced from 9 to 14 atoms to switch on recognition by integrins. We recently
reported the synthesis of some biologically active derivatives which showed good
affinity and specificity towards αvβ3 and α5β1 integrin classes. All tested molecules
showed a concentration-dependent enhancement in fibronectin-mediated adhesion of
K562 and SK-MEL-24 cells.2 After first biological data, a library of new beta-lactams
derivatives with a wider structural variability was developed. The biological activity,
indeed, is always related to the residues present on the β-lactam scaffolds. New
compounds were designed especially to deepen a preliminary SAR study on their
agonist or antagonist activities and to develop new promising active molecules that can
be selective towards different integrin isoforms. Moreover, we also evaluated some
structural parameters in selected compounds such as the formation of intramolecular Hbonds through VT NMR studies.
O
H
N
COOH
H
N
N
O
O
NH3
N
O
NH
COOH
COOH
O
O
H
N
N
O
NH3
CF3COO
CF3COO
NH3
CF3COO
1)
2)
Aizpurua, J.M.; Ganboa, J.I.; Palomo, C.; Loinaz, I.; Oyarbide, J.; Fernandez, X.; Balentova, E.; Fratila, R.M.; Jimenez,
A.; Miranda, J.I.; Laso, A.; Avila, S.; Castrillo, J.L.; ChemBioChem, 2011, 12, 401- 405. Aizpurua, J.M.; Oyarbide, J.;
Fernandez, X.; Miranda, J.I.; Ganboa, J.I.; Avila, S.; Castrillo, J.L.; Eur. Pat. Appl., 2012, EP 2407478 A1 20120118.
Aizpurua, J.M.; Ganboa, J.I.; Palomo, C.; Loinaz, I.; Miranda, J.I.; PCT Int. Appl., 2006, WO 2006048473 A1 20060511
Galletti, P.; Soldati, R.; Pori, M.; Durso, M.; Tolomelli, A.; Gentilucci, L.; Dattoli, S.D.; Baiula, M.; Spampinato, S.;
Giacomini, D.; Eur.J. Med. Chem., 2014, 83, 284-293
197
PC71
Scaffold optimisation and activity evaluation of multimeric MBL
antagonists
G. Goti1, A. Palmioli1, M. Stravalaci2, M. Gobbi2, A. Bernardi1
1
Università degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133 Milano, Italy.
2
Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, 20156 Milano, Italy.
e-mail: [email protected]
Mannose Binding Lectin (MBL) is a circulating multimeric calcium dependent (Clectin) protein that acts as a first-line host defence by selectively recognizing and
binding to polyglycosylated surfaces of invading pathogens or damaged self cells.1
MBL is also able to modulate inflammation and it is likely involved in reperfusion
damage in acute stroke,2 therefore representing an attractive target for the development
of new drugs against this disease.
Our groups have already reported that pseudoglycosylated tetravalent dendrons based
on a polyester scaffold such as 1a,b are good antagonists of MBL, with kd values in the
low micromolar range. They were shown to supply a protective effect in a mouse model
of brain stroke, reducing the reperfusion damage with a surprisingly wide therapeutic
window.3 Unfortunately, these constructs proved to be rather chemically unstable: the
polyester scaffold does not survive silica gel chromatography in either direct or reverse
phase and slowly hydrolyses in water solution at physiological pH (27% hydrolysis in
6h).
Here we present the synthesis of two new dendrons characterised by an optimised
scaffold that allows to obtain still water soluble compounds with an improved chemical
stability. Preliminary results of in vitro SPR binding assays of the new dendrons to
MBL will also be discussed.
Figure 1. - Polyester tetravalent dendrons 1a,b and monovalent ligands 2, 3 employed
as MBL antagonists.
1) Weis, W. I.; Drickamer, K.; Hendrickson, W. A. Nature 1992, 360, 127-134.
2) Osthoff, M.; Katan, M.; Fluri, F. et al. PLoS One 2011, 6, e21338.
3) Orsini, F.; Villa, P.; Parrella, S. et al. Circulation 2012, 126, 1484-1494.
198
PC72
New Silibinin glyco conjugates: synthesis, characterization and
preliminary evaluation of antioxidant properties
Raffaele Gravante1, Valeria Romanucci1,Valeria Sgambati2, Elio Pizzo2,
Daniele D’Alonzo1, Annalisa Guaragna1, Armando Zarrelli1 and Giovanni Di Fabio1.
1
Department of Chemical Sciences; 2Department of Biology, University of Naples "Federico II", Via
Cintia 4, I-80126, Napoli, Italy
e-mail: [email protected]
Medicinal nutrients derived from plants have been used for health maintenance and
disease management since the dawn of history. Today, natural products still represent a
precious building blocks and an inspiration for the synthesis of medicinal drugs. In this
way, an interesting plant is the milk thistle (Silybum. marianum L. Gaertn., Asteraceae);
in particular its main component: the Silibinin1. Silibinin is a diastereoisomeric mixture
of two flavonolignans, Silybin A and B, extracted from the seeds of the milk thistle.
This metabolite presents multiple biological activities operating at various cell levels,
however its therapeutic efficiency is rather limited by its low water solubility2.
In order to improve its solubility, and therefore bioavailability and permeability to cell
membranes, we present here the preliminary results of an efficient synthetic procedure
to obtain new 9''-phosphodiester Silibinin conjugates with different mono- and disaccharide labels. The introduction of the phosphate group is generally used to bring
great pharmaceutical and pharmacokinetic benefits. In our approach 9''-phosphoramidite
(I)3 have been used as Silibinin substrate and fully protected 6-OH mono- and disaccharide derivatives (Glucose, Galactose, Mannose, Lactose, Glucosamine,
Trehalose) chosen as sugar starting materials.
All derivatives were obtained as a mixture of diastereoisomers and as expected they
showed a water solubility well above that of Silibinin. All compounds were obtained in
good yields after RP-18 HPLC purification, and characterized by NMR and ESI-MS
analysis. All conjugates were subjected to several biological assays to evaluate their
cytotoxicity and antioxidative properties.
1) Gažák, R.; Walterová, D.; Křen, V. Curr. Med. Chem. 2007, 14, 315.
2) Zhan, T.; Digel, M.; Küch, E.-M. J. Cell. Biochem. 2011, 112, 849 and references therein.
3) Zarrelli, A.; Romanucci, V.; Tuccillo, C.; Federico, A.; Loguercio, C.; Gravante, R.; Di Fabio, G.
Bioorg. Med. Chem. Lett. 2014, 24, 5147.
199
PC73
GEM-DCA: synthesis of a novel codrug
Raffaele Gravante1, Daniele D’Alonzo1, Valeria Romanucci1, Armando Zarrelli1,
Giovanni Di Fabio1, Giovanni Palumbo1 and Annalisa Guaragna1
1
Department of Chemical Sciences, Università di Napoli "Federico II", Via Cintia 21,
I-80126, Napoli, Italy
e-mail: [email protected]
One of the most efficient approaches in the field of prodrug antitumor therapy is the use
of codrugs or mutual drugs.1 They consist of two or more pharmacologically active
agents coupled together via a covalent chemical linkage, generating prodrugs in which
drugs and promoieties are both pharmacophores. The resulting molecules will be
inactive until methabolic processes will enable their chemical conversion to the active
forms. Codrug approach is usually used to improve physicochemical, biopharmaceutical
and drug delivery properties of therapeutic agents. In the frame of our interest of
nucleoside analogues,2 herein we reported the synthesis of a novel codrug consisting of
Gemcitabine (GEM)-Dichloroacetate (DCA) moieties in 1:1, 1:2, 1:3 ratio (Figure 1).
O
O
NH 2
DCA
Cl
N
Cl
O
Cl
O
N
O
Cl
O
GEM
N
NH
Cl
N
Cl
N
Cl
O
F
1
NH
Cl
O F
OH
Cl
O
O F
OH F
2
N
O
Cl
O
O
O F
Cl
O
Cl
O
F
3
Figure 1. GEM-DCA codrugs.
Gemcitabine (2′,2′-difluorodeoxycytidine) is an established and highly potent cytotoxic
drug with a broad spectrum of cancer targets.3 The main disadvantage in its use is its
rapid inactivation due to the conversion, by cytidine deaminase, to its inactive
metabolite 2,2′-difluorodeoxyuridine. Furthermore, the prolonged use of GEM typically
results in the onset of different forms of drug resistance after initial tumor regression.3
DCA is an orphan drug,4 a small molecule already used in humans for the treatment of
lactic acidosis, which has been shown to shift cancer cell metabolism from glycolysis to
glucose oxidation, inducing apoptosis leading to a decrease in proliferation, and
inhibiting tumor growth, without affecting healthy cells.
Taking into account of some recent results on the anticancer activity of a DCA codrug,4
we are expected to obtain a complementary synergistic and selective capability to stall
malignant cells.
1) Das, N.; Dhanawat, M.; Dash, B.; Nagarwal, R. C.; Shrivastava, S. K. Eur. J. Pharm. Sci. 2010, 41,
571–588.
2) Caso, M. F.; D'Alonzo, D.; D'Errico, S.; Palumbo, G.; Guaragna, A. Org. Lett. 2015, 17, 2626-2629.
3) Bergmann, A. M.; Peters, G. J. In Deoxynucleosides in Cancer Therapy; Peters, G. J. Ed.; Humana
Press: Totowa, NJ, 2006.
4) Saha, S.; Ghosh, M.; Dutta, S. K. Sci. Rep. 2015, 5, 7762-7772.
200
PC74
Cellulose Nanocrystals: Novel Nanotools Targeting Bone Tissue
Barbara La Ferla1, Luca Zoia2, Laura Colombo3, Francesco Nicotra1, Marco Orlandi2,
Mario Salmona3, Paolo Bigini3
1
University of Milano-Bicocca, Dep. Biotechnology and Bioscience, Piazza della Scienza 2, Milan, ZIP
20126, ITALY
2
University of Milano-Bicocca, Dep. Earth and Environmental Science, Piazza della Scienza 1, ZIP
20126 Milan, ITALY;
3
IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri”, via La Masa 19, ZIP 20156, Milan, ITALY.
e-mail: [email protected]
The physico-chemical properties and its relative inexpensive costs, make Cellulose
Nano-Crystals (CNCs) as a potential target for a future large-scale production in many
fields, including nanomedicine. These CNCs, along with the dimensions in the
nanometer range [1], possess a typical rod-shape that, from a pharmacokinetic point of
view, has been observed to present a reduced risk of NP uptake by monocytes and also
an enhanced extravasation [2,3]. However, robust and reliable data concerning their
safety and biocompatibility and their tissue distribution should be provided prior to a
sustained and responsible development as theranostic agents. In the present study the
interaction between CNCs, extracted from Whatman filters and functionalized with a
fluorescent dye, and living organisms has been deeply assessed. Our experimental
evidence demonstrated that CNCs: 1) are well tolerated by healthy mice after systemic
injection; 2) are rapidly up taken by excretory organs and progressively cleared thus
avoiding bioaccumulation; 3) are able to penetrate in the cytoplasm of cells without
detrimental effects in terms of survival; 4) show a peculiar localization in bones. The
tropism to the bones is likely due to the chemical interaction between the Ca2+ of the
bone matrix and the active surface of CNCs. These properties could be exploited for the
development of new nanodevices for theranostics purposes, mainly in the field of bone
diseases[4].
Figure 1
1)
2)
3)
4)
Y. Habibi, L.A. Lucia, O.J. Rojas, Chem Rev, 2010, 110(6),3479-500
J.S. Ananta, B. Godin, R. Sethi, L. Moriggi, X. Liu, R.E. Serda, R. Krishnamurthy, R. Muthupillai,
R.D. Bolskar, L. Helm, M. Ferrari, L.J. Wilson, P. Decuzzi. Nat Nanotechnol, 2010, 5(11), 815-21.
J. Key, S. Aryal, F. Gentile, J.S. Ananta, M. Zhong, M.D. Landis, P. Decuzzi. Biomaterials. 2013,
34(21), 5402-10.
Manuscript submitted
201
PC75
Inverse Virtual Screening: A New Computational Approach For The
Identification of The Interacting Targets of Bioactive Compounds
Gianluigi Lauro, Raffaele Riccio, Giuseppe Bifulco
Department of Pharmacy, University of Salerno, Fisciano (SA), Italy
e-mail: [email protected]
Inverse Virtual Screening approach represents a new and fast computational method
allowing the analysis of different binding hypotheses between a single ligand and a high
number of targets by means of molecular docking experiments.1 It represents a fast and
inexpensive tool for the identification and selection of possible ligand-receptor favorite
complexes among a set of numerous other theoretical possibilities. It has been applied
to several natural bioactive molecules to screen their efficacy on proteins involved in
cancer processes successfully directing subsequent experimental assays. New insights
and applications of Inverse Virtual Screening are here reported.2,3,4,5
1) Lauro, G.; Romano, A.; Riccio, R.; Bifulco, G. J. Nat. Prod. 2011, 74, 1401-1407.
2) Lauro, G.; Masullo, M.; Piacente, S.; Riccio, R.; Bifulco, G. Bioorg. Med. Chem. 2012, 20,
3596-3602.
3) Cheruku, P.; Plaza, A.; Lauro, G.; Keffer, J.; Lloyd, J. R.; Bifulco, G.; Bewley, C. A. J. Med.
Chem. 2012, 55, 735-742.
4) Scrima, M.; Lauro, G.; Grimaldi, M.; Di Marino, S.; Tosco, A.; Picardi, P.; Gazzerro, P.; Riccio,
R.; Novellino, E.; Bifulco, M.; Bifulco, G.; D’Ursi, A. M. J. Med. Chem. 2014, 57, 7798-7803.
5) Gong, J.; Sun, P.; Jiang, N.; Riccio, R.; Lauro, G.; Bifulco, G.; Li, T.-J.; Gerwick, W.; Zhang,
W. Org. Lett. 2014, 16, 2224-2227.
202
PC76
Hydrosoluble Oligo-Heteroaromatic Ligands Targeting G-Quadruplex
Folded Nucleic Acids
Alberto Lena, Filippo Doria, Vincenzo Grande and Mauro Freccero
Dipartimento di Chimica, Università di Pavia, V.le Tramelli 10, 27100 Pavia, Italy
[email protected]
G-quadruplexes are secondary structures adopted by guanine-rich DNA
oligonucleotides containing short G tracts 1. Many guanine-rich sequences capable
of G4 formation have been found concentrating in areas of human genome involved
in regulational processes, such as gene expression, transcription and cell immortality
2
. The significant biological role of G4 gives rise to the developement of many
ligands targeting G4 as anticancer drugs 3. Among these, the polyoxazole-based
natural product telomestatin has played a major role, since it first showed potent
telomerase inhibitory activity through stabilization of G4 structures in telomeres and
great selectivity over duplex DNA 4. With the aim to design telomestatine-like
synthetic analogues, a small library of new hydrosoluble oligo-heteroaromatic class
of G4 selective ligands has been synthesized, focusing on the development of an
efficient and versatile synthetic pathway. Particular efforts have been devoted to
optimize the critical steps of amidoxime acylation (a) and the subsequent cyclization
of the resulting O-acyloxime (b). Qualitative in vitro affinity for G4 structures has
been inferred by FRET-melting assay. This preliminary data are consistent with the
assignment of exceptionally good binding properties towards G4 for the new
scaffold, revealing a much higher stabilization in comparation to related nonhydrosoluble compounds.5 We demonstrated for the first time that individual
gymnemic acids are potent and selective antagonists for the  isoform of LXR. Deep
pharmacological investigation demonstrated that gymnestrogenin, reducing the
expression of SREBP1c and ABCA1 in vitro, is able to decrease lipid accumulation
in HepG2 cells. The results of this study substantiate the use of Gymnema sylvestre
extract in LXR-mediated dislypidemic diseases.
1. S. Neidle, Curr. Opin. Struct. Biol., 2009, 19, 239.
2. G. W. Collie and G. N. Parkinson, Chem. Soc. Rev., 2011, 40, 5867.
3. S. Balasubramanian, L. H. Hurley and S. Neidle, Nat. Rev. Drug Discov., 2011, 10, 261.
4. M. Y. Kim et al., J. Am. Chem. Soc., 2002, 124, 2098.
5. F. Hamon et al., Angew. Chem. Int. Ed., 2011, 50, 8745.
203
PC77
Bile acids derivatives in the selective modulation of FXR and GPBAR1
Dario Masullo,a Claudia Finamore,a Valentina Sepe,a Claudio D’Amore,b Carmen
Festa,a Barbara Renga,b Simona De Marino,a Angela Zampella,a Stefano Fioruccib
a Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano, 49, I-80131 Napoli,
Italy;
b Department Experimental and Clinical Medicine, University of Perugia, Via Gambuli 1, S. Andrea
delle Fratte, 06132 Perugia, Italy;
[email protected]
Farnesoid-X-receptor (FXR) and GP-BAR1 are bile acids receptors mainly expressed in
entero-hepatic tissues that regulates some metabolic and non-metabolic functions [1]. In
the last ten years, this two receptors gained an increasing importance because they are
involved in many physiological and physio-pathological human conditions. One of the
main problem of these receptors is that bile acids are promiscuous ligand for both
receptors. Even if the dual activation could be a promising pharmacological opportunity
for several metabolic deseases, often it is associated to several side effects. Starting
from the results obtained in several our previous works, [2, 3] in this contest, we decide
to manipulate bile acids scaffold in order to produce new selective FXR and GP-BAR1
modulators.
1)
Fiorucci, S.; Cipriani, S.; Mencarelli, A.; Baldelli, F.; Bifulco, G.; Zampella A. Farnesoid, Mini
Rev. Med. Chem. 2011, 11, 753–762
2)
Sepe, V.; Renga, B.; Festa, C.; D’Amore, C.; Masullo, D.; Cipriani, S.; Di Leva, F. S.; Monti,
M.C.; Novellino, E.; Limongelli, V.; Zampella, A. and Fiorucci, S. J. Med. Chem 2014, 57 (18), pp 7687–
7701
3)
Festa, C.; Renga, B.; D’Amore, C.; Sepe, V.; Finamore, C.; De Marino, S.; Carino, A.; Monti, M.
C.; Zampella, A. Fiorucci, S. J Med Chem. 2014, 57 (20), pp 8477-95
204
PC78
Amphiphilic calix[4]arenes for the modulation of TLR4 activity
I. Morbioli1, S. Sestito2, F. Sansone1, A. Casnati1, F. Peri2
1
2
Department of Chemistry, University of Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2,
20126 Milano, Italy.
e-mail: [email protected]
Toll-like receptor 4 (TLR4) is a transmembrane protein that selectively recognizes
bacterial lypopolysaccharides (LPS) and their portions like lipid A and immediately
induces the innate immune response in the organism.1 It is a significant biological and
pharmacological target because the modulation of the receptor activation pathway
allows the control of the inflammatory response. Therefore, on one hand molecules able
to activate the receptor have interest as vaccines or immunotherapeutics, on the other
hand molecules that inhibit the receptor acting as antagonists can work as antisepsis and
anti-inflammatory agents.2 Different natural and synthetic molecules are known to act
as agonists or antagonists in the TLR4 activation process and they present generally an
amphiphilic structure with the hydrophilic domain that can bear both positively and
negatively charged groups.3 The aggregation ability of the compound can also have a
significant role in determining its biological activity. Starting from this point, we have
synthesized different calix[4]arenes bearing at the lower rim alkyl chains of different
length and at the upper rim guanidinium or carboxylic moieties (Figure 1). The
tendency of these molecules to self-assemble has been investigated by NMR, Dynamic
Light Scattering and Fluorescence Spectroscopy. At the same time, biological tests
aimed at studying their activity in TLR4 modulation have been performed evaluating
the effects of the compounds on the receptor activity stimulated through administration
of LPS doses to properly modified HEK-Blue cells. Micro and submicromolar IC50
values have been found for some of the calixarenes closely related to nature of charge
and chain length (Figure 1).
The first results regarding the self-assembling properties and the biological activity of
the amphiphillic calix[4]arenes will be shown.
Figure 1. Calix[4]arenes synthesized for this work and inhibition curve relative to 1a.
1) Beutler, B. Curr. Top. Microbiol. Immunol. 2002, 270, 109-120.
2) Peri, F.; Piazza, M. Biotechnol Adv. 2012, 30, 251-260.
3) Peri, F.; Calabrese, V. J. Med. Chem 2014, 57, 3612-3622.
205
PC79
Extraction, fractionation and HPLC-MS-MS analysis of the main
antioxidative constituents from an oak wood (Quercus robur)
commercial tannin
Vera Muccilli, Nunzio Cardullo, Carmela Spatafora, Vincenzo Cunsolo,
Corrado Tringali
Department of Chemical Science, University of Catania, V.le A. Doria 6, 95125 Catania
e-mail: [email protected]
Nowadays there is a growing interest in plant polyphenols and in their exploitation in
the fields of agro-food, cosmetic and over-the-counter (OTC) drug industry.1
Polyphenols were originally considered equivalent to ‘vegetable tannins’. The two main
groups of vegetable tannins are generally known as ‘condensed tannins’ (oligomers of
the structural unit of flavan-3-ols) and ‘hydrolyzable tannins’ (‘gallotannins’ and
‘ellagitannins’). Both hydrolyzable and condensed tannins have promising antioxidative
and other healthy properties; some ellagitannins have been recently cited for their
chemopreventive or antitumor properties. Commercial tannins are widely used in
enology, tanning and other industrial sectors. Thus, we planned to examine some
commercial tannins widely exploited for commercial purposes. As first sample for this
study, we selected a commercial hydrolizable tannin obtained from roasted oak wood,
because Quercus spp. and Quercus robur in particular are widely reported as a source
of bioactive polyphenols. In this study we privileged a fractionation guided by DPPH
radical scavenging activity, in view of both the known antioxidant properties of plant
polyphenols, and the well-known relationship between antioxidant activity and
chemoprevention of degenerative diseases. Extraction followed by DPPH-guided
chromatographic fractionation, afforded sub-fractions showing enhanced antioxidant
activity. The main polyphenols in the extract/fractions were identified by means of
HPLC-ESI/MSMS in order to establish a possible relationship between composition and
antioxidant activity.
1. Quideau, S.; Deffieux, D.; Douat-Casassus, C.; Pouységu, L. Angew. Chem. Int. Ed. 2011, 50, 586–621
206
PC80
High resolution mass spectrometry in the analysis of site-specific
donkey milk lactoferrin glycosylation
Serafina Gallina1,Rosaria Saletti1, Vincenzo Cunsolo1, Vera Muccilli1
Antonella Di Francesco1, Salvatore Foti1, Peter Roepstorff2
1DepartmentofChemicalSciences,UniversityofCatania,V.leA.Doria6,
IT‐95123,Catania,Italy
2ProteinResearchGroup,DepartmentofBiochemistryandMolecularBiology,UniversityofSouthern
Denmark,Campusvej55,DK‐5230OdenseM,Denmark
e-mail: [email protected]
Donkey milk is considered the best mother milk substitutes for allergic newborns for its
reduced or absent allergenic properties, coupled to excellent palatability and nutritional
value. Lactoferrin (LF) is one of the most important milk glycoproteins, member of the
transferrin family, present in the whey protein fraction. It shows an array of biological
properties, including antibacterial, antiviral, antioxidant activities, iron-binding and
immunomodulation. Glycosylation, one of the most common post-translational
modifications, can modify the structural conformation of the protein and consequently
its biological activity. Within the frame of our research line aimed at the systematic
investigation of donkey milk protein composition,1-4 we isolated LF from the milk of an
individual donkey belonging to the Ragusano breed and investigated by nanoflow liquid
chromatography/mass spectrometry (Nano-LC-MS/MS) in order to identify a
comprehensive glycosylation profile. The protein isolated by ion exchange high
performance liquid chromatography (IEC-HPLC), was digested by chymotrypsin and
the glycopeptides were enriched by TiO2,5 in order to enrich acid glycopeptides, and by
Hydrophilic Interaction Liquid Chromatography (HILIC),6 in order to enrich neutral
glycopeptides. Analysis by nano-reversed phase high performance liquid
chromatography (nRP-HPLC) coupled on-line with a hybrid ESI-MS LTQ/Orbitrap
mass spectrometrer (Q-Exactive Plus), identified at least 29 different glycan
compositions at three N-glycosylation sites on donkey LF. To identify the
glycopeptides, mass spectral data were processed by an in-house developed software
(MassAI Bioinformatics)7. All identified glycopeptides were manually validated.
Preliminary results indicate that N-glycolylneuraminic acid, which is absent in human
LF and is considered a potential allergen, is less abundant in the donkey milk glycans in
comparison with other animal species.
1) Cunsolo, V.; Muccilli, V.; Fasoli, E,; Saletti, R.; Righetti, P.G.; Foti, S. J. Proteomics 2011, 74, 20832099
2) Cunsolo, V.; Muccilli, V.; Saletti, R.; Foti, S. Eur. J. Mass Spectrom. 2011, 17, 305-320
3) Cunsolo, V.; Costa, A.; Saletti, R.; Muccilli, V.; Foti, S. Rapid Commun. Mass Spectrom. 2007, 21,
1438-1446
4) Cunsolo, V.; Muccilli, V.; Saletti, R.; Foti, S. J. Mass Spectrom. 2007, 42, 1162-1174
5) Larsen, M.R.; Jensen, S.S.; Jakobsen, L.A.; Heegaard, N.H. Mol. Cell. Proteomics. 2007,6, 1778-1787
6) Hägglund, P.; Bunkenborg, J.; Elortza, F.; Jensen, O.N.; Roepstorff, P. J. Proteome Res. 2004, 3,
556-566
7) Mass AI-Bioinformatics. MassAI. At <http://massai.dk/index.html>
207
PC81
Integrated bottom-up/top-down ms-based approach for sequence
determination of a donkey’ CSN1S2 duplicate gene products
Vincenzo Cunsolo, Vera Muccilli, Rosaria Saletti, Serafina Gallina,
Antonella Di Francesco, Salvatore Foti
Department of Chemical Sciences, University of Catania, V.le A. Doria 6,
IT-95123 Catania, Italy
e-mail: [email protected]
Cow’s milk represents the main source of allergens in early childhood, affecting about
3% of infants, and therefore constitutes a problem of social relevance. In the last few
years, milk from different mammalian species (goat, donkey, mare, camel) have been
studied to identify the best natural substitute for human milk. On this respect, several
clinical trials indicate the positive effects of donkey milk in nutrition of infants allergic
to cow’s milk proteins (CMPs).1 However, although composition, physico-chemical and
nutritional properties of donkey’s milk are well known, the information available for its
proteins and their polymorphism are still scant,2 and the data available for the casein
(CN) fraction, constituted by αs1-, αs2-, - and κ-CN, are at a relatively early stage of
progress.3-5
In this study, a casein component with experimentally high resolution measured Mr
16316.175 was detected by capillary reversed-phase high-performance liquid
chromatography (RP-HPLC) coupled on-line with an hybrid ESI-MS LTQ/Orbitrap
mass spectrometry in the dephosphorylated casein fraction of a milk sample collected
from an individual donkey belonging to the Ragusano breed.
By coupling both top-down and bottom-up approaches, the unknown casein component
was identified as a gene product of the duplicate gene CSN1S2 II. Primary structure of
this protein was characterized using the m-RNA derived amino acid sequence of the
donkey’s s2-CN variant B as reference (GenBank Acc. No. CAX65660.2), which
should be encoded at CSN1S2 II locus.
The MS data derived sequence revealed that the investigated protein differs from the
GenBank reported sequence for amminoacid point substitution, insertion and absence of
short peptides.
1) Vita, D.; Passalacqua, G.; Di Pasquale, G.; Caminiti, L.; Crisafulli, G.; Rulli, I.; Pajno, G.B. Pediatr.
Allerg. Immunol. 2007, 18, 594.
2) Criscione, A.; Cunsolo, V.; Bordonaro, S.; Guastella, A.M.; Saletti, R.; Zuccaro, A.; D’Urso, G.,
Marletta, D. Int. Dairy J. 2009, 19, 190.
3) Cunsolo, V.; Cairone, E.; Muccilli, V.; Saletti, R.; Foti, S. Rapid Commun. Mass Spectrom.2009, 23,
1907.
4) Cunsolo, V.; Cairone, Fontanini, D.; Criscione, A.; Muccilli, V.; Saletti, R.; Foti, S. J. Mass Spectrom.
2009, 44, 1742.
5) Saletti, R.; Muccilli, V.; Cunsolo, V.; Fontanini, D.; Capocchi, A.; Foti, S. J. Mass Spectrom. 2012,
47, 1150
208
PC82
Parallel Synthesis of Analogs of Permethylated Anigopreissin A
Palmina Nigro, Eugenio D’Amato, Maria Funicello, Paolo Lupattelli, Lucia
Chiummiento
Dipartimento di Chimica, Università della Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
[email protected]
Permethylated Anigopreissin A (PAA)1 is a protected form of naturally occurring
Anigopreissin A2 which belongs to the class of oligomeric stilbenes containing a
benzofuran ring system. PAA kills different types of human cancer cells without
affecting non-tumorigenic cells; particularly, hepatic cancer cell line show the highest
sensitivity to it (IC50=0.24± 0.05 μM)3. Biological activity of PPA and its
pharmacological potential has generated extensive efforts toward the syntheses of its
analogs in order to evaluate structure-activity relationship. We planned to synthesize
two classes of analogs with single modifications to aryl group on C3 (series A analogs)
and to styryl moiety on C6 (series B analogs). The key retrosynthetic steps are outlined
below.
To insert the aryl groups on C3 of the benzo[b]furan ring we perform Suzuki crosscoupling reactions between A and different phenylboronic acids, whilst the styryl
groups are introduced via Wittig olefinations between aldehyde B and different
phosphonium salts; synthon C would be constructed through the 5-endo-dig cyclization
of the corresponding diaryl alkyne, which could, in turn, arise from the Sonogashira
reaction.
1) Chiummiento, L.; Funicello, M.; Lopardo, M. T.; Lupattelli, P.; Choppin, S.; Colobert, F. Eur. J. Org.
Chem. 2012, 188-192.
2) a) Holsche, D.; Schneider, B. Phytochemistry 1996, 44, 471– 473; b) Schneider, B. Phytochemistry
2003, 64, 459– 462. 192
3) Convertini, P.; Tramutola, F.; Iacobazzi, V.; Lupattelli, P.; Chiummiento, L.; Infantino, V. Submitted
Manuscript.
209
PC83
“Two is better than one”: probes for dual-modality molecular imaging
approach. Design, synthesis and characterization of a mini-library of
NOTA derivatives
Claudia Riccardi, Domenica Musumeci, Daniela Montesarchio
Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Via Cintia 21,
I-80126, Napoli, Italy
[email protected]
The increasing incidence of cancer pathologies more and more requires an early diagnosis of the
disease to achieve effective therapeutic results. The use of a single diagnostic technique is often
insufficient, not being able to provide complete structural and functional information. Thus
different imaging modalities such as PET-CT, PET-MRI or PET-fluorescence can be used in
combination to overcome the inherent disadvantages of each single methodology and to obtain a
timely detection of neoplastic cells1. The interest in this field is strongly growing and many
new, more efficient radio-pharmaceuticals have been recently proposed to improve tumour
identification and localization2-3. In this context, we here describe the synthesis and
characterization of a mini-library of lipophilic derivatives of NOTA - which is a well-known
68
Ga chelator used for PET analyses - differing for the functional tails, i.e. an oleic acid, a lipoic
acid and a biotin moiety (NOTA-OL, NOTA-Lip and NOTA-Bio, respectively, Figure 1).
These functionalizations have been designed to allow the subsequent immobilization of NOTA
onto different nanoplatforms, each
carrying a suitable coating, so to
perform bimodal “two-in-one” imaging
investigations4-6. In our future studies,
these derivatives will be anchored on
nanoparticles
(NPs)
intrinsically
sensitive to MRI, fluorescence or other
sensitive imaging techniques (as iron
oxide or zinc oxide-based NPs).
Oleic acid has a 18-carbon atoms chain
which allows its immobilization onto
lipid-functionalized
NPs
through
hydrophobic interactions. The disulfide
bond of lipoic acid, thanks to its high affinity for metals, provides covalent bonds with metal or
metal-oxide NPs. Finally, biotin is useful to functionalize avidin or streptavidin-coated NPs
exploiting the high affinity of these proteins for biotin molecules. Furthermore, upon insertion
on the NPs’ surface also of suitable therapeutic agents, exploiting different recognition schemes
(hydrophobic interactions, covalent bonds or specific recognition), multi-functional tools7 can
be easily obtained in a modular or one-step approach. This design will open the way to a variety
of theranostic agents, concomitantly able to provide early diagnosis and therapy of a disease.
1. Velikyan, I. Theranostics. 2014, 4, 47-80.
2. Chong, H. S. et al. Bioorg. Med. Chem. 2015, 23, 1169–1178.
3. Frigell, J.et al. J. Am. Chem. Soc. 2014, 136, 449−457.
4. Paeng, J. C. et al. The Open Nuclear Medicine Journal 2010, 2, 145-152.Open Access
5. Louie, A. Chem. Rev. 2010, 110, 3146–3195.
6. Schober, O. et al. Eur J Nucl Med Mol Imaging. 2009 36, 302–314.
7. Cheon, J. et al. Acc Chem Res. 2008, 41, 1630-1640. Open Access
210
PC84
Discovery of potential modulators of Macrodomain proteins MacroD1
and MacroD2
Alessandra Russo, Stefania Terracciano, Gianluigi Lauro, Giuseppe Bifulco,
Raffaele Riccio, Ines Bruno
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084, Fisciano, Salerno
e-mail: [email protected]
Macrodomains are a family of evolutionarily conserved protein structural domains
(130-190 a.a.) which bind several NAD+ products, such as mono-ADP-ribose, polyADP-ribose and O-acetyl-ADP-ribose (OAADPr).1
ADP-ribosylation is an important, reversibile, protein post-translational modification
that regulates different biological processes, catalyzed by a variety of enzymes,
implicated in important cellular functions including transcription, DNA repair,
chromatin remodeling and apoptosis.2
Recent studies demonstrated that a family of Macrodomains enzymes, such as:
MacroD1, MacroD2 and C6orf130, act as mono ADP hydrolases capable of removing
from proteins the last glutamate-linked ADPr releasing ADPr and the unmodified
aminoacidic product that is readily available for the next cycle of ADP-ribosylation.2
Consequently,it has been demonstrated that the dysregulation of Macrodomain function
can affect both reversible cellular mono-ADP-ribosylation and OAADPr homeostasis.
In fact, human MacroD1 and MacroD2 cellular levels are, also,
overexpressed in a range of tumors such as endometrial carcinoma, gastric carcinoma,
colorectal carcinoma and breast carcinoma.3
In this context, our project is focused on the identification of potential Macrodomains
modulators as new promising anticancer agents. With this aim we performed a
preliminary virtual screening, through molecular docking calculations using the recently
crystallized structure of MacroD and the X-ray crystallographic structure of MacroD2 in
complex with ADP-ribose.4 This screening started from libraries of syntetically
accessible molecules that will allow us to identify different scaffolds that display a high
binding affinity for the target enzymes.
The subsequent step will consist in the biological evaluation of synthetized compounds
in order to obtain the key structural information for the binding with the catalytic site of
the protein.
References:
1) Rosenthal F. et al Nature Structural & Molecular Biology, 2013, 20, (4)
2) Li N., Chen J., Mol. Cells. 2014, 37, 9-16
3) Weidong H. et al, Review, Mutation Research, 2011, 727 , 86-103
4) Chen D., et al J.Biol.Chem. , 2011, 286, 13621-13271
211
PC85
Activation of Hsp90 enzymatic activity and conformational dynamics
through rationally designed allosteric ligands
Sara Sattin,1 Jiahui Tao,2 Gerolamo Vettoretti,3 Laura Morelli,1 Matteo Panza,1
Elisabetta Moroni,3 David A. Agard,2 Giorgio Colombo,3 Anna Bernardi1
1
2
Università degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133 Milano, Italy
Howard Hughes Medical Institute and Dept. of Biochemistry & Biophysics, University of California, San
Francisco, 94158 USA)
3
Istituto di Chimica del Riconoscimento Molecolare - CNR, Via Mario Bianco, 9, 20131 Milan, Italy
e-mail: [email protected]
Hsp90 is a chaperone that mediates the folding and activation of diverse client proteins
essential for a variety of signal-transduction pathways1 and an established anti-apoptotic
target in cancer therapy.2
Instead of targeting the Hsp90 N-terminal domain inhibiting its ATPase activity,3 we
aim to target the protein C-terminal domain (CTD) through the allosteric modulation of
its chaperone activity, hopefully avoiding important secondary effects. Eupomatenoid-2
(1, Figure 1) has been identified as a potential lead targeting a CTD allosteric pocket
that control interdomain communication.4
(Glyco)diversification of the benzofuran core5 at R’’ and preliminary work on the
chemical expansion at R’ allowed to obtain about 40 derivatives that are mostly
activators of the chaperone ATPase activity. The peculiarity of these compounds is that,
in selected cancer cell lines, they retain the cytotoxic activity showed by small molecule
ATPase inhibitors.
Synthetic approaches to the benzofuran derivatives will be presented along with
biochemical and biological data of their effects on the Hsp90 chaperone machinery.
Figure 4: Lead compound 1 (Eupomatenoid-2).
1)
2)
3)
4)
5)
Jackson, S. E. In Molecular Chaperones; Jackson, S., Ed.; Springer Berlin Heidelberg: 2013;
Vol. 328, p 155-240.
Trepel, J.; Mollapour, M.; Giaccone, G. and Neckers, L., Nat Rev Cancer 2010, 10, 537-549.
Kitson, R. R. A. and Moody, C. J., J. Org. Chem. 2013, 78, 5117-5141.
Morra, G.; Neves, M. A. C.; Plescia, C. J.; Tsustsumi, S.; Neckers, L.; Verkhivker, G.; Altieri, D.
C. and Colombo, G., J. Chem. Theory Comput. 2010, 6, 2978-2989.
Morelli, L.; Bernardi, A. and Sattin, S., Carbohydr. Res. 2014, 390, 33-41.
212
PC86
9H-Purine Derivatives as New Modulators of non-BET Human
Bromodomains
Maria Strocchia1, Stefania Terracciano1, Gianluigi Lauro1, Sarah Picaud2, Jacqui
Mendez3, Danette Daniels3, Raffaele Riccio1, Giuseppe Bifulco1, Panagis
Filippakopoulos2, Ines Bruno1
1
Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084
Fisciano, Italy.
2
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford,
Roosevelt Drive, Oxford OX3 7DQ, U.K.
3
Promega Corporation, 2800 Woods Hollow Road, Madison, Wisconsin 53711, USA.
e-mail: [email protected]
Bromodomains (BRDs) are structurally conserved modules which act as readers of
acetyl-lysine residues on histone tails.1 The involvement of BRD containing proteins in
a variety of human diseases has recently emerged.2 Here we report the design and
synthesis of some 9Hpurine-based derivatives which showed nanomolar affinity
towards the BRD9 bromodomain and only weak residual micromolar affinity for BRD4.
High-resolution X-ray crystal structure of our molecules in complex with BRD9
revealed extensively structural re-arrangements of the Kac binding cavity of BRD9,
resulting in an unprecedented cavity shape arrangement.3 Finally, we assessed the
ability of these compounds to competitively displace the BRD9 bromodomain from the
chromatin in cellular environment through bioluminescence proximity assays.3
1)
2)
3)
Filippakopoulos, P.; Knapp, S. FEBS Letters 2012, 586, 2692-2704.
Filippakopoulos, P.; Knapp, S. Nat Rev Drug Discov 2014, 13, 337-56.
Picaud, S.; Strocchia, M.; Terracciano, S.; Lauro, G.; Mendez, J.; Daniels, D. L.; Riccio, R.;
Bifulco, G.; Bruno, I.; Filippakopoulos, P. J. Med. Chem. 2015, 58, 2718–2736.
213
PC87
Discovery of innovative Hsp90 C-terminal modulators: synthesis and
biological evaluation of 3,4- dihydropyrimidinone derivatives
Stefania Terracciano, Maria Strocchia, Fabrizio Dal Piaz, Maria Carmela Vaccaro,
Antonio Foglia, Maria Giovanna Chini, Antonietta Leone, Raffaele Riccio, Giuseppe
Bifulco, Ines Bruno
Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano,
Italy.
e-mail: [email protected]
Heat shock protein 90 (Hsp90) is a molecular chaperone that controls the folding of key
proteins in multiple cancer signaling networks. Its pivotal role in human tumor
development and progression has attracted much interest in order to identify new potent
inhibitors of this protein.1 Traditional inhibitors of Hsp90 target the N-terminal domain,
however this type of modulation induces undesiderable side effects and the deleterious
pro-survival heat shock response (HRS).2
Although less explored, C-terminal inhibition of Hsp90 is a very promising approach
for developing new potential anti-cancer drugs lacking the known drawbacks of the Nterminal ligands.3 Recently, our research group focused the attention on the chemically
accessible dihydropyrimidinone (DHPM) scaffold, as a new template for the discovery
of innovative Hsp90 C-terminal inhibitors.4 In the course of our study we identified a
new promising hit showed antiproliferative activity in two different cancer cell lines,
without any apparent cytotoxic effect in non-tumor cells.4 On the basis of these
encouraging findings, we decided to expand our collection of DHPM derivatives in
order to get further structural information and to identify more powerful and safer
Hsp90 inhibitors.
1) Miyata, Y.; Nakamoto, H.; Neckers, L. Curr. Pharm. Des. 2013, 19, 347-365.
2) Kim, Y. S.; Alarcon, S. V.; Lee, S.; Lee, M. J.; Giaccone, G.; Neckers, L.; Trepel, J. B. Curr. Top
Med. Chem. 2009, 9, 1479-1492; Bhat, R.; Tummalapalli, S. R.; Rotella, D. P. J. Med. Chem. 2014,
57, 8718-8728; Neckers, L.; Workman, P. Clin. Cancer Res. 2012, 18, 64-76.
3) Conde, R.; Belak, Z. R.; Nair, M.; O'Carroll R. F.; Ovsenek, N. Biochem. Cell Biol. 2009, 87, 845851; Wang Y.; McAlpine, S. R. Chem. Commun. 2015, 51, 1410-1413.
4) Strocchia, M.; Terracciano, S.; Chini, M. G.; Vassallo, A.; Vaccaro, M. C.; Dal Piaz, F.; Leone, A.;
Riccio, R.; Bruno, I.; Bifulco, G. Chem. Commun. 2015, 51, 3850-3853.
214
PC88
Design and synthesis of integrin ligands as “Molecular Shuttles” for
drug and fluorescent molecules delivery
Alessandra Tolomelli, Lucia Ferrazzano, Angelo Viola
Alma Mater Studiorum - University of Bologna, Department of Chemistry
“G. Ciamician” (Via Selmi 2, 40138 Bologna, Italy)
e-mail: [email protected]
In the field of cancer theranostic, one of the main goal of medicinal chemistry is the
development of systems for selective and targeted delivery of drugs and diagnostic
molecules towards the pharmacologic target, for the reduction of side effects associated
to an uncontrolled distribution of drugs during treatments and the localization of
tumours, using fluorescent molecules and nanoparticles. This is possible through
overexpression on cancer cells of several receptors, which became the anchoring points
of cancer therapy. Among them, integrins are receptors involved in cell signalling, cell
adhesion and cell motility, three of the upregulated phenomena in cancer cells.1 Since
integrins recognize RGD sequence, our purpose is to develop an RGD peptidomimetic
functionalized with drugs, fluorescent molecules and nanoparticles.2 The RGD mimetic
have been designed to have an alkyne side chain to link amino-, acidic- and PEG-azides
but also selected dipeptides by Click chemistry.
NH2
NH2
HN
NH
N
H
O
H
N
R
G
O
NH2
O
OH
OH
N
H
D
O
O
O
HO
OH
O
O
N O
HO
N N
R N
NH
NH2
O
H
N
O
O
O
H
N
O
RGD sequence
O
N
O
R=
NH
O
OH
O
O
O
O
NH2
O
O
NH2
OH
RGD peptidomimetic
H
N
AA1
AA2
O
H
N
1) K. Chenr, X. Chen, Theranostics, 2011, 1, 189–200.
2) F. Danhier, A. Le Breton, V. Préat, Mol. Pharmaceutics, 2013, 9, 2961-2973.
215
AA2
AA1
NH2
COOH
PC89
Red-NIR G-quadruplex sensing harvesting blue light by a coumarinnaphthalene diimide dyad
Michela Zuffo1, Filippo Doria1, Vincenzo Spalluto1, Sylvain Ladame2 and Mauro
Freccero1
1
2
Dipartimento di Chimica, Università di Pavia. V.le Taramelli 10, 27100 Pavia, Italy
Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7
2AZ, U.K.
[email protected]
G-quadruplex (G-4) are non-canonical structures formed by guanine rich nucleic acids
strands1, located in genomic regions relevant for a number of pathologies2. After their
validation as suitable therapeutic targets3, the need of selective methodologies for their
sensing became urgent. In this perspective, fluorescence light-up chemosensors
represent a valuable tool4. A conceptually new light-up fluorescent probe will be
presented. Two moieties, a coumarin (C) and a naphthalene diimide (NDI), have been
conjugated through a flexible alkyl spacer. The dyad exhibits a single wavelength
emission at 494 nm when free in solution, due to the complete quenching of the NDI
emission via an electron transfer (eT) process. The same molecule, when bound to a G4, exhibits an additional red-NIR emission upon excitation of the coumarin moiety. The
emission centred at 666 nm is due to an energy transfer (ET) process from the coumarin
to the NDI. This light up response is highly specific for quadruplex DNA when
compared to duplex DNA or to RNA quadruplexes.
N
O
O
O
H
N
H
N
O
N
H
O
1.
2.
3.
4.
(CH 2) 3NMe2
N
O
R
N
O
(CH 2) 3NMe2
S. Neidle, Curr. Opin. Struct. Biol., 2009, 19, 239.
(a) A.T. Phan, FEBS J., 2010, 277, 1107; (b) R. Rodriguez and K. M. Miller, Nat. Rev. Genet.,
2014, 15, 783.
S. Balasubramanian, L.H. Hurley and S. Neidle, Nat. Rev. Drug. Discov., 2011, 10, 261.
(a) D.-L. Ma, H.-Z. He, K.-H. Leung, H.-J. Zhong, D. S.-H. Chan and C.-H. Leung, Chem.
Soc. Rev., 2013, 42, 3427; (b)L.D. Lavis and R.T. Raines, ACS Chem. Biol., 2008, 3, 142.
216
I – Nanotecnologia
217
PC90
Single-walled carbon nanotubes dispersions in high viscous solvents
Carla Gasbarri, Fausto Croce, Ida Meschini, Guido Angelini
Department of Pharmacy, University “G. d’Annunzio” of Chieti – Pescara, Italy
e-mail: [email protected]
The properties induced by single-walled carbon nanotubes (SWNTs) in three high
viscous solvents, as BMIM BF4, Pluronic L121 and Triton X-100 have been studied by
using UV-Vis-NIR spectroscopy, electrochemical impedance spectroscopy and optical
microscopy.
The size of the SWNTs aggregates and the dispersion degree in the three systems
depend on the sonication time as highlighted by optical microscopy (Fig. 1) and UvVis-NIR spectra.
A non-linear increasing in electronic conductivity as a function of the nanotubes
concentration can be observed by electrochemical impedance spectroscopy
measurements. Moreover, in the case of SWNTs-BMIM BF4 dispersions ionic
conductivity has also been observed.
A critical percolation threshold has been determined by using a classical percolation
power-law1, suggesting the generation of a three-dimensional network of SWNTs in the
investigated systems.
(a)
(b)
Fig. 1 Micrographs of SWNTs-L121 dispersion (5 mg/mL)
before sonication (a) and after 5 hours of sonication (b).
The obtained results show that Triton-X100 is the best dispersing solvent in comparison
to L121 and BMIM BF4, because of the presence of an aromatic hydrophobic moiety
and an hydrophilic polyoxyethylene chain.
1)
Martins J.N.; Bassani, T. S.; Barra, G. M. O.; Oliveira, R. V. B., Polym. Int. 2011, 60, 430-435.
218
PC91
Carbon nanotubes-polymer electrospun nanofibers as biocompatible
scaffolds for neuronal cells differentiation
Nicola Vicentini1, Teresa Gatti1, Patrizio Salice1, Giorgia Scapin2, Carla Marega1,
Francesco Filippini2, Enzo Menna1
1
Dipartimento di Scienze Chimiche (Università di Padova).
2
Dipartimento di Biologia (Università di Padova).
e-mail: [email protected]
Carbon nanotubes (CNTs) are attractive candidates for the development of scaffolds
able to support neuronal growth and development thanks to their ability to conduct
electrical stimuli, to interface with cells and to mimic the neural environment. We
recently proposed for tissue engineering purposes a freestanding nanocomposite
scaffold that combines the conductive and topographical features of 4-methoxyphenyl
functionalized multi-walled carbon nanotubes (MWCNT-PhOMe) with the
biocompatible and mechanical properties of a poly(L-lactic acid) matrix (PLLA).1 The
functionalization of MWCNTs, necessary for their proper compatibilization into the
polymeric matrix, has been achived through the addition of diazonium salts. We will
present here a novel morphology for the polymeric nanocomposite scaffold, based on
electrospun nanofibers. This particular morphology is characterized by an extremely
high surface to volume ratio and its porosity allows better mimicking of the
extracellular matrix in which neurons normally grow in physiological conditions.
Details on the preparation and characterization of such nanofibers will be given,
together with preliminary evidences of polarized neurite outgrowth along the scaffold
nanofibrous topography and peripheral blood stem cells selective differentiation into
neurons.2
a)
b)
Figure 1. a) TEM image of PLLA electrospun nanofibers containing MWCNT-PhOMe aligned along the
fiber axis. b) Fluorescence microscopy images of SH-SY5Y cells stained with Calcein-AM. White arrows
indicate neurites following the scaffold fibers orientation.
1) Scapin, G.; Salice, P. et al. Nanomed. Nanotechnol. Biol. Med. 2015, 11, 621-632.
2) Submitted
219
J – Sintesi Organica
220
PC92
From nutraceutical to materials: effects of natural hydroxytyrosol on
the performances of PVA-based films for food packaging applications
Roberta Bernini,1 Elena Fortunati,2 Francesca Luzi,2 Luca Santi,1 Chiara Fanali,3 Laura Dugo,3
Giorgio M. Balestra,1 Josè M. Kenny,2 Luigi Torre 2
1
University of Tuscia, Department of Agriculture, Nature, Forests and Energy,
Via S. Camillo De Lellis, 01100 Viterbo
2
University of Perugia, Civil and Environmental Engineering Department,
Strada di Pentima 4, 05100, Terni
3
University Campus Bio-Medico, Center of Integrated Research (CIR),
Via Alvaro del Portillo 21, 00128 Roma
e-mail: [email protected]
Hydroxytyrosol (3,4-dihydroxyphenylethanol, HTyr) is a phenolic compound found in
olive leaves and fruits and extra-virgin olive oil, well-known for its strong antioxidant,
and radical-scavenging properties.1 Pure samples of HTyr were obtained in high yield in
our laboratory by a three-steps procedure using commercial available tyrosol as starting
material, according to the following Scheme.2
Poly(vinyl alcohol) (PVA) is an industrially relevant polymer widely used also for the
production of environment-friendly materials due its excellent chemical and physical
properties, easy processing technique and low cytotoxicity.3 In search of natural
antioxidants to be used in alternative to those synthetic, the potential use of HTyr in
PVA films for food packaging applications was evaluated and described in this
communication. PVA/HTyr-based films were produced by solvent casting in water;
their morphological, thermal, mechanical and swelling in water properties were tested;
the antioxidant and migration properties were also investigated taking into account their
potential application for food packaging.
1) Bernini, R.; Merendino, N.; Romani, A.; Velotti, F. Curr. Med. Chem. 2013, 20, 655-670.
2) Bernini, R.; Mincione, E.; Barontini, M.; Crisante. F. J. Agric. Food Chem. 2008, 56, 8897-8904.
3) Fortunati, E.; Puglia, D.; Luzi, F.; Santulli, C.; Kenny, J. M.; Torre, L. Carbohyd. Polym. 2013, 97, 825-836.
221
PC93
Aerobic oxidation of 1-aryl-isochromans isochromans catalyzed by the
Trametes villosa laccase/1-hydroxybenzotriazole system
Roberta Bernini,1 Fernanda Crisante,1 Patrizia Gentili,2 Emanuele Ussia,2 R. Vadalà 2
1
University of Tuscia, Department of Agriculture, Nature, Forests and Energy,
Via S. Camillo De Lellis, 01100 Viterbo
2
Sapienza, University of Roma, Department of Chemistry,
P.le A. Moro, 00185 Roma
e-mail: [email protected]
Isochromans or 3,4-dihydro-1H-benzo[c]pyran derivatives are a rare class of natural
products and structural motif of several drugs, agrochemicals and fragances. The
presence of the benzyl carbon at C-4 and benzyl ethereal carbon at C-1 in these
compounds has led us to investigate the potentiality of the Trametes villosa laccase in
the presence of 1-hydroxybenzotriazole (HBT) as mediator on the aerobic oxidation
already studied by us on catechin derivatives.2,3 As known, mediators enable laccases to
oxidize substrates with a redox potential above 1.3 V by means of an indirect way
where the active species is the oxidized form of the mediator (Scheme 1).
Scheme 1
Then, we synthetized several 1-aryl-dihydroxyisocromans by the oxa-Pictet-Spengler
reaction.1 After the protection of the phenolic groups by acetylation reaction, the
corresponding 1-aryl-isochromans were oxidized with oxygen in the presence of the
Trametes villosa laccase/1-hydroxybenzotriazole system. The reaction proceeded
selectively at the C-1 position affording novel phenolic compounds (Scheme 2).
Scheme 2
1) Bernini, R.; Crisante, F.; Fabrizi, G.; Gentili, P. Curr. Org. Chem. 2012, 16, 1051-1057
2) Bernini, R.; Crisante, F.; Gentili, P.; Morana, F.; Pierini, M. J. Org. Chem. 2011, 76, 820-832.
3) Bernini, R.; Crisante, F.; Gentili, P.; Menta, F.; Morana, F.; Pierini, M. RSC Adv. 2014, 4, 8183-8190.
222
PC94
Chiral non-racemic aryl-substituted oxetanes: stereoselective chemoenzymatic synthesis and regioselective functionalization by metallation
Paola Vitale, Ruggiero Rizzi, Filippo Maria Perna, Antonio Salomone, Vito Capriati
Dipartimento di Farmacia – Scienze del Farmaco, Università di Bari “Aldo Moro”,
Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy
e-mail: [email protected]
Oxetanes are important four-membered cyclic ethers whose ring was found in many
natural products that exhibit a range of biological activities.1a They find extensive use in
polymer chemistry,1b as versatile building blocks in preparative chemistry for the
synthesis of drugs, materials, and agrochemicals, and also act as interesting
intermediates in ring-opening and rearrangements reactions.1c-f Recently, the reactivity
of 2-aryloxetanes toward organolithium reagents was investigated by our group and
successfully exploited for the regioselective preparation of both - and orthofunctionalized derivatives.2 In this communication, we report the first diastero- and
enantioselective chemo-enzymatic synthesis of chiral 2,4-disubstituted oxetanes 4 and
their regioselective functionalization by lithiation/electrophilic interception to afford the
corresponding 2,2,4-trisubstituted derivatives 5. Optically active 2,4-disubstituted
oxetanes 4 have been synthesized by stereospecific cyclization of optically active 1,3diols 3, in turn prepared by reduction with high stereo-preference of 3-hydroxy-1arylpropan-1-ones 2, obtainable by subjecting to stereoselective reduction 1,3-diketones
1 with different and cheap yeast strains in water at RT, and thus under “green”
conditions (Scheme 1). Stereochemical aspects concerning both the chemo-enzymatic
reductions and the lithiation process, as well as stereospecific ring-opening reactions,
will be discussed as well.
O
yeast
strains
O
R
Ar
1
H2O, RT
O
OH
Ar
CH3CN/CH3COOH
R
-40 °C
2
4
R
Ar
1) (OCH3)3CHCH3, PPTS/CH2Cl2
solvent
Ar
Li
E+
O
Ar
O
E
R
5
Ar
2) AcBr
3) NaH/THF
R
90–98% yield
dr from 87:13 to 98:2
ees=30–80%
RLi
O
OH
3
65–98% yield
ees=60–90%
Ar
OH
(CH3)4BH(OAc)3
O
4
R
69–87% overall yield
(dr from 66:33 to > 95:5)
Stereospecific
ring-opening reactions
R
Scheme 1
1) (a) Hailes, H. C.; Behrendt, J. M. in Comprehensive Heterocyclic Chemistry III. Oxetanes and
Oxetenes: Monocyclic, Katritzky, A. R. Ed., Pergamon, Oxford, 2008, vol. 2, ch. 2.05, p. 321; (b)
Ghosh, B.; Urban, M. W. Science 2009, 323, 1458–1460; (c) Bukhard, J. A.; Wuitschik, G.; RogersEvans, M.; Müller, K.; Carreira, E. M. Angew. Chem. Int. Ed. 2010, 49, 9052–9067; (d) Guo, B.;
Schwarzwalder, G.; Njardarson, J. T. Angew. Chem. Int. Ed. 2012, 51, 5675–5678; (e) Wang, Z.;
Chen, Z.; Sun, J. Angew. Chem. Int. Ed. 2013, 52, 6685–6688; (f) Davis, O.A.; Bull, J. A. Synlett,
2015, DOI: 10.1055/s-0034-1380412.
2) (a) Coppi, D. I.; Salomone, A.; Perna, F. M.; Capriati, V. Chem. Comm. 2011, 47, 9918–9920; (b)
Coppi, D. I.; Salomone, A.; Perna, F. M.; Capriati, V. Angew. Chem. Int. Ed. 2012, 51, 7532–7536.
223
PC95
Diastereoselective Ugi Reaction Followed By Intramolecular
Nucleophilic Substitutions: Convergent Multicomponent Synthesis of
Diverse Heterocyclic Scaffolds.
Samantha Caputo, Luca Banfi, Andrea Basso and Renata Riva
University of Genova, Department of Chemistry and Industrial Chemistry, Via Dodecaneso 31, 16146,
Genova, Italy
e-mail: [email protected]
Multicomponent reactions exhibit many advantages over traditional approaches, allowing the
synthesis of large libraries in highly convergent fashion.
A high level of structural diversity can be achieved with this synthetic approach, providing a
platform for the production of functionalized building blocks for novel bioactive molecules.
However, in some cases, this metod appears to be limited to the smaller availability of
functionalized and chiral substrates; another problem is poor stereochemical control. In
particular, the aim of this project was to explore diastereoselective Ugi reactions to afford
adducts bearing a variety of functional groups that may be employed in subsequent cyclization
reactions for the rapid synthesis of diverse heterocyclic scaffolds. Starting from chiral β-amino
alcohols (1), it was possible to check the best combination of solvent, temperature, potential
Lewis acids, stereochemistry of the amino alcohol and the influence of R1 and R2 groups, to
optimize yeld and diastereoselectivity of the reaction. Chiral β-amino alcohol precursors for the
Ugi reaction are prepared via proline-catalyzed Mannich reaction of aldehydes with Boc-imines,
which gives syn-products in high e.e.s.1 After optimization of the Ugi reaction conditions, these
adducts (2) have been employed as substrates in the synthesis of diverse heterocyclic
compounds, through secondary
transformations.
For
example,
without employing any additional
functional group, complex bicyclic
system (3) was obtained.2 Other
possibilities may be envisaged by
adding additional functional groups,
beside the alcohol. Thus, chromanes
(4) could be obtained by employing
the alcoholic functional group as
electrophilic
substrate
in
a
nucleophilic substitution by an
additional phenol, under Mitsunobu
conditions.3 Finally, the use, as nucleophile, of the secondary amide derived from isocyanide,
and of an additional alkyl chloride, leads to the diketopiperazine scaffold (5).4
1)
2)
3)
4)
Yang, J. W.; Stadler, M.; List, B., Angewandte Chemie-International Edition, 2007, 46, 609611.
Banfi; Basso, A.; Guanti, G.; Kielland, N.; Repetto, C.; L.; Riva, R.; Journal of Organic
Chemistry, 2007, 72, 2151-2160.
Morana, F.; Basso, A.; Riva, R.; Rocca, V.; Banfi, L., Chemistry-a European Journal, 2013,
19, 4563-4569.
Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.; Garcıa-Lo´pez, M. T.; GonzalezMuniz,R.; Journal of Organic Chemistry, 2001, 66, 3538-3547
224
PC96
Comparing the Chemo- and Stereoselectivity of Addition Reactions of
Organolithiums and Grignard Reagents to Carbonyl Compounds in
Deep Eutectic Solvents and in the Water: Synthesis of
Tetrahydrofurans
Luciana Cicco, Rosmara Mansueto, Francesca Claudia Sassone, Antonio Salomone,
Filippo Maria Perna, Vito Capriati
Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari “Aldo Moro”, Consorzio
C.I.N.M.P.I.S
Via E. Orabona 4, I-70125 Bari, Italy
e-mail: [email protected]
In many chemical reactions an organic solvent is often required to favour a better contact
between reactants and to guarantee a convenient separation of products, and those with a low
boiling point are generally preferred because of their easy recovery and recycling. However,
most organic solvents still used in chemistry are volatile, flammable, and hazardous to humans
and to the environment. Among unconventional, more eco-friendly reaction media, the so-called
Deep Eutectic Solvents (DESs) are worth mentioning. DESs are usually formed by the
combination of two or three inexpensive components which are able to engage in hydrogenbond interactions with each other, to form an eutectic mixture with a melting point lower than
either of the individual components. Thanks to their low ecological footprint and attractive low
price, DESs have now become of growing interest both at academic and industrial levels
especially for their unusual solvent properties.1 Recent independent contribution from Hevia and
García-Álvarez groups,2 and our group3 have shown that reactions of simple/functionalized
organolithium compounds can be smoothly performed in DES mixtures at room temperature,
under air, and competitively with protonolysis. Building on these findings, we have started a
systematic investigation of the addition reactions of highly polarized organometallic compounds
to carbonyl derivatives in unconventional solvents. In this communication, the chemo- and
stereoselectivity of the addition reactions of organolithiums and Grignard reagents to γchloroketones (1) aimed at synthesizing tetrahydrofurans (2), which are important structural
components of several natural compounds,4 will be compared and discussed for reactions run
both in DESs and in water, and in the presence of a chiral non racemic ligand (L*). The results
obtained will help pave the way towards a sustainable polar organometallic chemistry, which is
one of the main challenges that chemists must address to face environmental issues.
1) For recent reviews, see: (a) M. Francisco, A. van den Bruinhorst, M. C. Kroon, Angew. Chem.
Int. Ed. 2013, 52, 3074; (b) E. Smith, A. P. Abbott, K. S. Ryder, Chem. Rev. 2014, 114, 11060.
2) C. Vidal, J. Garcìa-Álvarez, A. Hernan-Gòmez, A. R. Kennedy, E. Hevia, Angew. Chem, Int.
Ed., 2014, 53, 5969.
3) (a) V. Mallardo, R. Rizzi, F. Sassone, R. Mansueto, F. M. Perna, A. Salomone, V. Capriati.
Chem Comm. 2014, 50, 8655; (b) F. C. Sassone, F. M. Perna, A. Salomone, S. Florio, V.
Capriati, Chem. Comm., 2015, DOI: 10.1039/C5CC02884a.
4) A. Lorente, J. Lamariano-Merketegi, F. Albericio, M. Alvarez, Chem. Rev. 2013, 113, 4567.
Acknowledgements: This work was finantially supported by Interuniversities Consortium C.I.N.M.P.I.S,
and by the University of Bary.
225
PC97
Chemodivergent entry to enantioenriched (poly)phenolvalerolactone metabolites and their -lactone analogues

1
Claudio Curti,1 Nicoletta Brindani,1,2 Daniele Del Rio,2 Andrea Sartori,1
Lucia Battistini,1 Franca Zanardi1
Dipartimento di Farmacia, Università degli Studi di Parma, Via Parco Area delle Scienze 27/A, 43124,
Parma, Italy 2 Dipartimento di Scienze degli Alimenti, Università degli Studi di Parma, Via Parco Area
delle Scienze 59/A, 43124, Parma, Italy
e-mail: [email protected]
Polyphenols and related compounds are a group of plant-derived secondary metabolites
which epidemiology indicates playing an important role in the protective effects of a
fruit and vegetable-based diet. In particular, flavan-3-ols such as those belonging to the
family of catechins, have attracted considerable attention for the role they seem to play
in the prevention of chronic diseases such as cardiovascular- and diabetes-related
pathologies, as well as neurodegenerative disorders.1 The scientific evidence
accumulated during the last decade though, indicates that the beneficial effect of flavan3-ols in the human organism, could be mainly attributed not to the parent set of
compounds, but rather to the corresponding enteric metabolites, of which chiral
hydroxyphenyl -valerolactone derivatives 1 represents the most significant part.
As part of our ongoing studies on the development of new, catalytic, enantioselective
vinylogous aldol reactions (VMAR) for the construction of functionalized chiral
nonracemic butenolide-type frameworks,2 we report here the implementation of an
expedient and general asymmetric route to valuable -valerolactone metabolites.3 Also,
while conducting these studies, TMSCl/NaI couple was found to promote an
unprecedented, reductive ring-expansion of butanolide A, yielding several valerolactone analogues. The results of our endeavour in understanding the latter
reaction mechanism and substrate viability will be also outlined.
1) Del Rio, D.; Rodriguez-Mateos, A.; Spencer, J.P.E.; Tognolini, M.; Borges, G.; Crozier, A. Antioxid.
Redox Signal. 2013, 1818–1892.
2) Curti, C.; Ranieri, B.; Battistini, L.; Rassu, G.; Zambrano, V.; Pelosi, G.; Casiraghi, G.; Zanardi, F.
Adv. Synth. Catal. 2010, 352, 2011-2022.
3) Curti, C.; Brindani, N.; Zanardi, F.; et al. Manuscript in preparation
226
PC98
Synthesis of pyrimidin-2-one derivatives via thermal decomposition of
uracil-analogues W (0) Fischer carbene complexes
Mariantonietta D’Acunto1, Antonella Carabellese1, Susagna Ricart2, Aldo Spinella1.
1
2
University of Salerno, Department of Chemistry and Biology, Via Giovanni Paolo II, 132, Fisciano
(Salerno).
Laboratorio de Catalisi Homogenea. Institut de Ciencia de Materials de Barcelona (CSIC). Campus de
la UAB. E-08193-Bellaterra. Spain
e-mail: [email protected]
Pyrimidin-2-one substructure is a part of many compounds showing several biological
activities ranging from pharmaceutical to agricultural fields and its preparation has
attracted an increasing research interest.
Starting from carbene complex 1 and substituted ureas, Fischer carbene uracilanalogues 2 and 3 can be easily prepared1, 2 and, subsequently, they can be oxidized
affording uracil derivatives 4 and 5 (Scheme 1). 3
In the course of our study on the reactivity of W(0) alkynyl alkoxy carbene complexes,
the synthesis of pyrimidin-2-one derivatives 6 and 7 has been achieved via base
mediated decomposition of uracil analogues 2 and 3. 4
In this communication, pyrimidin-2-one derivatives 6 and 7 are synthetized from
Fischer carbene uracil-analogues 2 and 3 through thermal elimination under microwave
irradiation.
Scheme1-General preparation of uracil derivatives and pyrimidin-2-one derivatives starting
from alkynyl alkoxy carbene metal complexes
1) Spinella, A.; Caruso, T.; Pastore, U.; Ricart, S. J. Organomet. Chem. 2003, 684, 266-268.
2) Artillo, A.; Della Sala, G.; De Santis, G.; M., Llordes, A.; Ricart, S.; Spinella, A. J. Organomet.
Chem. 2007, 692, 1277-1284.
3) Della Sala, G.; Artillo, A; Ricart, S.; Spinella, A. J. Organomet. Chem. 2007, 692, 1623-1627.
4) C. Bocchino, A. Carabellese, T. Caruso, G. Della Sala, S. Ricart, A. Spinella, J. Organomet.
Chem., 2014, 749, 47-50.
227
PC99
Structural Features of Functionalized Sulphur-Bearing Four
Membered Heterocycles
a
Flavio Fanelli,a,b Laura Carroccia,a Giovanna Parisi,a Marina Zenzola,a Angela
Altomare,b Leonardo Degennaro,a Renzo Luisia
Dipartimento di Farmacia, Università degli Studi di Bari “A. Moro” Via E. Orabona 4, I-70125 Bari
b
Istituto di Cristallografia – CNR, Via G. Amendola 122/O, I-70126 Bari
[email protected]
Four-membered heterocycles (4-MH) with one or two heteroatoms are of great
importance in medicinal chemistry and synthetic organic chemistry.1 This kind of
scaffolds shows peculiar structural features and biological properties. Our recent
research efforts have been focused on the stereoselective synthesis and functionalization
of some almost unexplored 4-MH such as azetidines2 and thietanes. Our interest on this
kind of heterocycles comes from the evidence that effective methodologies for their
direct functionalization are scarce. In this communication, we report some recent
findings concerning the direct regio- and stereoselective functionalization of thietane 1oxides.3 Strategies for the generation of the corresponding polar organometallic
intermediates as well as structural and stereochemical aspects will be highlighted.
1)
2)
3)
a) Rousseau, G.; Robin, S. Four-Membered Heterocycles: Structure and Reactivity, in
Modern Heterocyclic Chemistry, Ed. J. Alvarez-Builla, J. J. Vaquero and J. Barluenga,
Wiley-VCH, ch. 3, 2011, pp. 163–268; b) Four-membered Heterocycles together with all
Fused Systems containing a Four-membered Heterocyclic Ring in Comprehensive
Heterocyclic Chemistry III, Ed. A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J.
K. Taylor, Elsevier Ltd, 2008, vol. 2, pp. 1–989. c) Couty, F.; Drouillat, B.; Evano, G.;
David, O. EurJOC 2013, 11, 2045-2056. d) Guérot, C.; Tchitchanov, B.H.; Knust, H.;
Carreira, E.M. Org.Lett. 2011, 13, 780-783. e) Brandi, A.; Cicchi, S.; Cordero, F.M.
Chemical Reviews 2008, 108, 3988-4035.
a) Luisi, R.; Degennaro, L.; Zenzola, M.; Trinchera, P.; Carroccia, L.; Giovine, A.;
Romanazzi, G.; Falcicchio, A. Chem.Commun., 2014, 50, 1698-1700. b) Zenzola, M.;
Degennaro, L.; Trinchera, P.; Carroccia, L.; Giovine, A.; Romanazzi, G.; Mastrorilli, P.;
Rizzi, R.; Pisano, L.; Luisi, R. Chem. Eur. J. 2014, 20, 12190.
Carroccia, L.; Degennaro, L.; Romanazzi, G.; Cuocci, C.; Pisano, L.; Luisi, R. Org. Biomol.
Chem. 2014, 12, 2180.
228
PC100
Enantioselective enzymatic synthesis of tertiary -hydroxyketones
O. Bortolini1, A. Massi1, G. Di Carmine1,Morena De Bastiani2, P.P. Giovannini1
1
University of Ferrara, Department of Chemistry and Pharmaceutical Science Via L. Borsari 46, 4412,
Ferrara, Italy.
2
University of Ferrara, Department of Life Science and Biotechnology, Via L. Borsari 46, 4412, Ferrara,
Italy.
e-mail: [email protected]
Thiamine diphosphate (ThDP)-dependent enzymes are well-established biocatalysts for
the stereoselective formation of C–C bonds. The members of this enzyme family have
been successfully applied in various carboligation processes like benzoin condensations
and intermolecular Stetter reactions.1 Aldehyde–ketone cross-coupling is another type
of enzymatic reaction that has been recently studied in order to access optically active
tertiary -hydroxy ketones. Only few ThDP-dependent enzyme catalyzed asymmetric
intermolecular aldehyde–ketone cross-carboligations have been reported and the use of
the acetoin dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR), also called
acetylacetoin synthase (AAS), has been recently introduced by our group. This enzyme
has been successfully applied for the enantioselective synthesis of tertiary -hydroxy
ketones through the homo- and cross-coupling of -diketones, either in batch or in
flow-mode.2 In order to extend the catalytic scope of this enzyme, the use of alternative
acyl anion donors was recently explored with a pure recombinant Ao:DCPIP OR.
Inspired by the physiological role of the enzyme, the unprecedented use of
methylacetoin was highlighted.3 The new synthetic strategy has shown a complete
chemoselectivity allowing to prepare in an enantioselective way a broad range of
tertiary -hydroxy ketones, some of which never obtained before through enzymatic
synthesis. Furthermore, some of the products showed the opposite absolute
configuration respect that of the same products obtained with other ThDP-enzymes.
Scheme 1: Ao:DCPIP OR catalysed cross-coupling carboligation reaction
1) Müller, M.; Sprenger, G. A.; Pohl, M. Curr. Opin. Chem. Biol. 2013, 17, 261-270.
2) Giovannini, P. P.; Bortolini, O.; Cavazzini, A.; Greco, R.; Fantin, G.; Massi, A. Green Chem.
2014, 16, 3904-3915.
3) G. Bernacchia, O. Bortolini, M. De Bastiani, L. A. Lerin, S. Loschonsky, A. Massi, M. Müller,
P. P. Giovannini, Angew. Chem. Int. Ed. DOI: 10.1002/anie.201502102R1.
229
PC101
Diversity-Oriented Synthesis of nitrogen-containing heterocycles
through morpholine acetal rearrangement
Elena Lenci, Riccardo Innocenti, Gloria Menchi, Andrea Trabocchi
Department of Chemistry “Ugo Schiff”, University of Florence,
Via della Lastruccia 13, 50019, Sesto Fiorentino (FI), Italy
e-mail: [email protected]
Modern chemical biology requires efficient synthetic processes, able to produce highquality small-molecule collections, as probes to investigate biological pathways.1 Our
efforts in this field are focused on the Diversity-Oriented Synthesis2 of peptidomimetic
molecules, taking advantage of amino acid- and sugar-derived building blocks.
During last years, we reported the successful generation of the bicyclic diketopiperazine
scaffold A and the 2-oxopiperazine ring C, starting from threonine-derived morpholines
and suitable Fmoc-amino acid chlorides (Scheme 1). The skeletal diversity was
obtained tuning the acid-base three-step process, from stepwise to sequential one-pot,
achieving the modulation of the ring rearrangement mechanism.3
Recently, we found that the one-pot synthesis involving serine-derived morpholine
acetals leads to the uncommon dihydropyrazinone heterocycle D. These new
compounds are potential Xaa-Ser dipeptide isosteres, thus they can be applied in the
generation of peptidomimetic libraries for medicinal chemistry.4
Finally, the biological activity of these morpholine-derived scaffolds was evaluated on
yeast deletant strains, using cell growth as a phenotypic screening, in order to identify
novel hit compounds as antifungal and anticancer agents, and to dissect their mode of
action.
Scheme 1
1) Lenci, E.; Guarna, A.; Trabocchi, A. Molecules. 2014, 19, 16506-16528.
2) (a) Schreiber, S. L. Science 2000, 17, 1964-1969; (b) “Diversity-Oriented Synthesis – Basics and
Applications in Organic Synthesis, Drug Discovery, Chemical Biology”, Trabocchi, A.; Wiley, 2013.
3) Ciofi, L.; Trabocchi, A; et al. Tetrahedron Lett. 2010, 51, 6282-6285.
4) Lenci, E.; et al. Org. Biomol. Chem. 2015, 10.1039/C5OB00783F.
230
PC102
Molecular Design and Synthesis of Acetylsalycilic Esters for
Transdermal Delivery
Raffaella Mancuso,a,b Giorgio De Luca c, Elisabetta Conforti,a,c, Bartolo Gabrielea
a
Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Via Pietro Bucci, 12/C,
87036 Arcavacata di Rende (CS), Italy
b
Dipartimento di Ingegneria Meccanica, Energetica e Gestionale,
Università della Calabria, 87036 Arcavacata di Rende (CS), Italy
c
Istituto per la Tecnologia delle Membrane, Consiglio Nazionale delle Ricerche
(ITM-CNR), 87036 Arcavacata di Rende (CS), Italy
[email protected]
Aspirin (acetylsalycilic acid, ASA) is a widely known non-steroidal anti-inflammaatory
drug. A major problem associated with the oral administration of aspirin regards the
gastrointestinal side effects, which may appear even at low doses.
Transdermal delivery of this drug could offer a valid alternative route, more convenient
and safer during long-tem use. Animal and human studies suggest that skin is
moderately permeable to aspirin and its metabolite, salycilic acid.1 With the aim of
developing a novel ASA-like hybrid molecule2 with increased skin permeability, we
have computationally studied, designed then synthesized some alkyl esters of aspirin
with different chain lengths, as shown in Scheme 1.
OH
OH
O
1
HO
CH3
n
DCC
n=4,5,9,13
OH
O
H3C
CH3
O
O
Cl
O
CH3
n
O
O
O
2
3
CH3
n
Scheme 1
The molecular design was carried out analyzing the kinetic diameter of several esters,
according to Samir Mitragotri.3 This molecular descriptor dramatically controls the
transport molecules with low weight through the stratum corneum. A careful
conformational analysis of 10 hybrids, with a different number of methylene groups,
was performed using a in house code.4 In particular, the distribution of the kinetic
diameters was analyzed in addition to the LogP of the target molecules, predicting the
hybrids which best optimizes the considered molecular descriptors regulating the
molecular transport through the skin.
1) Keimowitz, R.M.; Pulvermacher, G.; Mayo, G.; Fitzgerald, D., Circulation, 1993, 88, 556-561
2) Wach, J.; Bonazzi, S.; Gademann, K., Angew. Chem. Int. Ed., 2008, 47, 7123 -7126
3) Mitragroti, S., J. Contr. Rel., 2003, 86, 69-92.
4) Buekenhoudt, A; Bisignano F.; De Luca, G.; Vandezande, P.; Wouters, M;, Verhulst K., J. Membr. Sci.
2013, 439, 36–47.
231
PC103
Coumarin as Backbone for the Production of New Natural-Like
Herbicides
Raffaella Mancuso,a,b Fabrizio Araniti,c Francesco Sunseri,c Maria Rosa Abenavoli,c
Bartolo Gabrielea
a
Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Via Pietro Bucci, 12/C,
87036 Arcavacata di Rende (CS), Italy
b
Dipartimento di Ingegneria Meccanica, Energetica e Gestionale,
Università della Calabria, 87036 Arcavacata di Rende (CS), Italy
c
Dipartimento di Agraria, Università Mediterranea di Reggio Calabria,
89124 Reggio Calabria, Italy
[email protected]
In the search of new compounds with herbicidal activity the natural compound
coumarin, known for its phytotoxic potential,1 was used as backbone for the synthesis of
new coumarin derivatives. 3-[(alkoxycarbonyl)methyl]coumarins 2 have been assayed
in-vitro on germination and root growth of the two noxious weeds Amaranthus
retroflexus and Echinochloa crusgalli. Moreover, in order to identify the possible
physiological targets affected, synthetic coumarins 2 were assayed in-vitro on seedlings
growth of the model species Arabidopsis thaliana.
3-[(alkoxycarbonyl)methyl]coumarins 2 was prepared in good yields starting from
readily available 2-(1-hydroxyprop-2-ynyl)phenols 1 by palladium-catalyzed
dicarbonylation process, in methanol such as solvent and at 25 °C (eq.1).2
R1
R1 OH
R3
PdI2 cat
OH
R3
O
R2
1
CO2Me
CO, MeOH
R2
O
(1)
2
(70%)
R1=R2=H, R3=OMe
R1=H, R2=OMe, R3=H (81%)
(87%)
R1=Me, R2=R3=H
All the assayed molecules strongly affected germination and root growth processes of
both weeds. Interestingly, the effects exerted by the three molecules on weed
germination were higher than that observed in bibliography with the natural coumarin
pointing out ED50 values ranging from 50 to 115 µM. Moreover, all the assayed
molecules showed a strong phytotoxic activity on both Arabidopsis shoot and root
growth. In fact, seedlings treated with synthetic coumarins 2 pointed out a strong
reduction in shoot fresh weight (ED50 values ≤ 60 µM), accompanied by a reduction of
leaf development and pigment content, and a strong alteration of root growth (ED50
values ≤ 170 µM) and morphology with evident alterations of root anatomy (not aligned
cells, gravitropism loss, inhibition of lateral roots and root hairs). Taken together the
results highlight the promising potential herbicidal activity of these new natural-like
molecules.
1) (a) Lupini, A.; Araniti, F.; Sunseri, F.; Abenavoli, M. R.;Plant Growth Regulation, 2014, 74, 23-31.
(b) Abenavoli, M. R.; Lupini, A.; Oliva, S.; Sorgonà, A. Biologia Plantarum, 2010, 54, 149-153.
2) Gabriele, B.; Mancuso R.; Salerno, G; Plastina, P., J. Org. Chem, 2008, 73, 756-759.
232
PC104
A Recyclable Method for the Synthesis of Thiophenes in DES
Raffaella Mancuso, a,b Asif Maner,a Vito Capriati,c Bartolo Gabrielea
a
Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Via Pietro Bucci, 12/C,
87036 Arcavacata di Rende (CS), Italy
b
Dipartimento di Ingegneria Meccanica, Energetica e Gestionale, Università della Calabria, 87036
Arcavacata di Rende (CS), Italy
c
Istituto Dipartimento di Farmacia-Scienze Del Farmaco, Università di Bari Aldo Moro, Consorzio
C.I.N.M.P.I.S., Via E. Orabona 4, Bari, Italy
[email protected]
Deep eutectic solvents (DESs), which can be defined as molecular complexes typically
formed between a simple halide salt (i.e. choline chloride) and a hydrogen bond donor,
have found a wide variety of applications in different fields of modern chemistry,
including organic synthesis, biocatalytic reactions, dissolution of metal oxides,
electrodeposition of metals, and materials chemistry. However the number of studies
reporting the ability of DESs to serve as green and biorenewable reaction media in
metal-catalysed organic reactions is still scarce and no examples of iodocyclization
reactions in DESs are reported in literature.
We report here the first example of iodocyclisation reaction in DES. Readily available
1-mercapto-3-yn-2-ols 1 are converted into the corresponding 3-iodothiophenes 2 under
base-free conditions, at room temperature and in Choline Chloride/Glycerol
(1ChCl/2Gly) such as solvent (eq.1). Products 2 are obtained in good yields (50-85%)
and the DES can be recycled different times without lost of activity.
2
R1 R OH
HS
R2
I2
DES, 25 °C
1
I
(1)
R1
R3
S
2
R3
Starting from 1-mercapto-3-yn-2-ols 1 we have also obtained thiophenes 3 by PdI2catalyzed heterocyclization reaction (eq. 2). The reaction is carried out under air, at
room temperature and in 1ChCl/2Gly such as solvent. Thiophenes 3 are formed in good
to high yields (50-85%) and with the possibility to recycle DES-catalyst system several
times without affecting the reaction.
2
R1 R OH
HS
1
DES, 25 °C
R
R2
PdI2/KI
3
233
(2)
R
1
S
3
R
3
PC105
Design and synthesis of polycyclic aromatic hydrocarbons-based
hetero-doped molecular modules
Domenico Milano1, Tanja Miletić1 and Davide Bonifazi1,2
1
Department of Chemical and Pharmaceutical Sciences, University of Trieste,
Piazzale Europa 1, 34127, Trieste, Italy.
2
Namur Research College (NARC) and Department of Chemistry, University of Namur (UNamur), Rue
de Bruxelles 61, 5000 Namur, Belgium.
e-mail: [email protected]
The design and synthesis of polycyclic aromatic compounds are of great interest owing
to their potential applications as organic semiconductors for electronic devices, such as
organic field-effect transistors (OFETs),1 light emitting diodes (LEDs),2 and
photovoltaic cells.3 In this context peri-Xanthenoxanthene (PXX) derivative,
investigated by Merck and Sony as organic semiconductor, is stable under oxygen,
moisture, light and heat exposure and has an excellent carrier transport capacity.4 The
large π-conjugated system in PXX derivatives is expected to enhance the overlap of
molecular orbitals and the introduction of heteroatoms like oxygens into the π-system,
stabilizing the reactive sites against oxidation, can improve its environmental
stability4,5. From the synthetic chemistry viewpoint, efficient synthetic strategies for
conjugated hexacyclic heteroaromatic compounds containing chalcogens are limited.
In the design of new classes of naphtol-based PXX derivatives, an O-ring closure
through metal-catalyzed C-H activation of binaphthol derivatives has been developed in
our group for the preparation of such new library of PXX derivatives. Here is presented
the design and synthesis of new PAH-based PXX derivatives, in particular pyrenolbased ones, for application as organic emitting systems (Scheme 1).
Scheme 1. Example of a synthethic route to pyrenol-based PXX derivatives.
1) Wang, C.; Dong, H.; Hu, W.; Liu, Y.; Zhu, D. Chem. Rev. 2012, 112, 2208–2267.
2) Tao, Y.; Yang, C.; Qin, J. Chem. Soc. Rev. 2011, 40, 2943–2970.
3) Liu, J.; Walker, B.; Tamayo, A.; Zhang, Y.; Nguyen, T.-Q. Adv. Funct. Mater. 2013, 23, 47–56.
4) Kobayashi, N.; Sasaki, M.; Nomoto, K. Chem. Mater. 2009, 21, 552-556.
5) Lv, N.; Xie, M.; Gu, W.; Ruan, H.; Qiu, S.; Zhou, C.; Cui, Z. Org. Lett. 2013, 15, 2382–2385.
234
PC106
An easy route to enantiomerically pure 7- and 8-HSA by an olefin
metathesis-based approach
Carla Boga,1 Sara Drioli,2 Cristina Forzato,2 Gabriele Micheletti,1 Patrizia Nitti,2 Fabio
Prati3
1
Dipartimento di Chimica Industriale «Toso Montanari», Università di Bologna, Viale Risorgimento 4, I40136 Bologna Italy.
2
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, via Licio Giorgieri 1, I-34127
Trieste, Italy.
3
Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, via Giuseppe Campi 183, I41125 – Modena, Italy
e-mail: [email protected]
Synthesis of enantiomerically pure 7- and 8-hydroxystearic acids1 (7- and 8-HSA) has
been accomplished starting from chiral non racemic 1-pentadecen-4-ol 1a and 1tetradecen-4-ol 1b respectively, in accordance with the retrosynthetic procedure
depicted in the Scheme. Access to enantiomerically pure homoallylic alcohols 1a,b was
possible via kinetic resolution of the corresponding racemic acetates, catalyzed by
Novozym 435 (Lipase B from Candida antarctica).
Yamaguchi esterification2 of 1a,b with 4-pentenoic and 5-hexenoic acids 2a,b
respectively afforded the suitable dienic esters 3a,b which were submitted to RingClosing Metathesis Reaction (RCM).3 Hydrogenation of the resulting complex reaction
mixtures followed by hydrolysis under basic conditions afforded the expected chiral non
racemic 7- and 8-HSA in about 40% total yield.
Scheme
1) Ebert, C.; Felluga, F.; Forzato, C.; Foscato, M.; Gardossi, L.; Nitti, P.; Pitacco, G.; Boga, C.; Caruana,
P.; Micheletti, G.; Calonghi, N.; Masotti, L. J. Mol. Catal. B- Enzym. 2012, 83, 38-45.
2) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 19891993.
3) Monfette, S.; Fogg,D. E. Chem. Rev. 2009, 109, 3783-3816.
235
PC107
Metal-Free Reduction of Nitro-Group: a SiCl2-mediated
Transformation of Wide General Applicability
Manuel Orlandi1, Maurizio Benaglia1, Davide Brenna1
1
Università degli Studi di Milano, Via Golgi, 19, Milan
e-mail: [email protected].
Reduction of nitro-group is one of the most straightforward method for the
synthesis of aliphatic or aromatic amines. A great number of methodologies for the
promotion of this reaction exists. Classical protocols use Pd/C, PtO2, Nickel-Raney
or other homogenous metal catalysts under H2 atmosphere or under transfer
hydrogenation conditions. Also SnCl2 or metal dissolving reductions involving Zn,
Fe, In or Sm, have been widely employed as nitro reducing species. However, these
synthetic methods suffer from several drawbacks. For example, the use of high
pressure equipment, flammable hydrogen gas, hazardous reagents (e.g. hydrazine in
transfer hydrogenation reactions), or the presence of potentially toxic transition metal
complexes. Moreover, these protocols lack of functional group compatibility.
Thus, great efforts have been made in order to develop new metal-free
methodologies for the reduction of nitro group.1 Here, a new efficient and green
HSiCl3-mediated methodology for the reduction of aromatic and aliphatic nitrogroups is presented (Figure). This new reaction is highly compatible with a plethora
of functional groups providing a new powerful synthetic tool.
The ability of HSiCl3 to generate SiCl2 in the presence of a tertiary amine was
already reported.2,3 Indeed, mechanistic studies and quantum mechanical calculations
shed light on the reaction mechanism evidencing the involvement of SiCl2 as the
active reducing agent.
1) Sharma, S.; Kumar, M.; Kumar, V.; Kumar, N. J. Org. Chem. 2014, 79, 9433-9439 and references
herein reported.
2) Karsch, H. H.; Schlüter, P. A.; Bienlein, F.; Herker, M.; Witt, E.; Sladek, A.; Heckel, M. Z. anorg.
allg. Chem. 1998, 295-309.
3) Bernstein, S.C., J. Am. Chem. Soc. 1969, 91, 699-700.
236
PC108
A New Flow Chemical Synthesis of 6-Nitroindoles
Roberto Ballini, Serena Gabrielli, Susanna Sampaolesi
Marino Petrini, Alessandro Palmieri
”Green Chemistry Group”, School of Science and Technology, Chemistry Division, University of
Camerino, via S. Agostino 1, 62032 Camerino (MC), Italy
e-mail: [email protected]
The indole ring constitutes a privileged framework in medicinal and in organic
chemistry, due to its presence in many synthetic and naturally occurring biologically
active molecules.1 In this context, over the years, several new methodologies for their
preparation and derivatization have been proposed in literature,2 and in this sense, our
research group has disclosed fruitful contributions to this field (Figure 1).3
Figure 1
Following these studies, we have now developed a new flow chemical synthesis of 6nitroindoles, which have been demonstrated to be useful precursors of dyeing
keratinous fibers (Figure 2).4 Our method exploits the reactivity of substituted pyrrole2-carboxaldehydes 1 in combination with protected β-nitroketones 2 under basic
condition. Using this procedure it has been possible to prepare a wide range of
polysubstituted indoles 3 in good overall yields. It is important to note, that the same
results cannot be obtained by the classic batch approach, due to the instability of the
starting materials under the adopted reaction conditions.
Figure 2
References
1)
(a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-48. (b) Saxton, J. E. In The Alkaloids; Cordell, G.
A., Ed.; Academic Press: New York, 1998. (c) Sundberg, R. J. In Indoles; Academic Press: New
York, 1997. (d) Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559-590.
2)
(a) Gribble, G. W. Contemp. Org. Synth. 1994, 145-172. (b) Gribble, G. W. J. Chem. Soc.,
Perkin Trans. 1 2000, 1045-1075. c) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
2875-2911.
3)
(a) Palmieri, A.; Petrini, M.; Shaikh R. R. Org. Biomol. Chem. 2010, 8, 1259-1270; (b) Palmieri,
A.; Gabrielli, S.; Lanari, D.; Vaccaro, L.; Ballini, R. Adv. Synth. Catal. 2011, 353, 1425-1428.
(c) Palmieri, A.; Gabrielli, S.; Maggi, R.; Ballini, R. Synlett 2014, 25, 128-132.
4)
(a) Patent: US5180400 A1. 1993. (b) Patent: US5752982 A1. 1998. (c) Patent: US5938792 A1,
1999.
237
PC109
A Selenone Mediated Domino Strategy for the Construction of
Variously Functionalized Spirocyclopropyl Oxindoles
Martina Palomba, Luca Rossi, Luca Sancineto, Luana Bagnoli, Claudio Santi,
Francesca Marini
Department of Pharmaceutical Sciences (University of Perugia)
e-mail: [email protected]
Multi bond forming reactions, such as domino and multi component processes, creating
several bonds in a single operation are effective strategies for the concise assembly of
bioactive molecules.1 Herein we report a domino Michael addition/cyclization process
for the construction of spirocyclopropyl oxindoles with different substitution patterns.
Spirocyclopropyl oxindoles were prepared in high yields and good diastereoselectivities
(up to 98% for R=Aryl) using commercially or readily available N-substituted or Nunsubstituted 2-oxindoles and vinyl selenones as bis electrophiles2 by simple treatment
with aqueous NaOH. Spirooxindole ring is a privileged skeleton in several natural
products and drug candidates and our method can provide a facile and effective route to
compounds with promising anti-HIV activity.3
Scheme 1
1) (a) Multibond Forming Reactions: A New Frontier in the Synthesis of Heterocycles. Special Issue.
Curr. Org. Chem. 2013, 17, No 18. Ed Menendez J. C.; (b) Stereoselective Multiple Bond-Forming
Transformations in Organic Synthesis (Eds Rodriguez J., Bonne D.) Wiley & Sons, New Jersey, 2015.
2) (a) Sternativo, S.; Calandriello, A.; Costantino, F; Testaferri, L.; Tiecco, M.; Marini, F. Angew. Chem.
Int. Ed. 2011, 50, 9382-9385; (b) Bagnoli, L.; Scarponi, C.; Rossi, M. G.; Testaferri, L.; Tiecco, M.
Chem. Eur. J. 2011, 17, 993-999; (c) Sternativo, S.; Battistelli, B.; Bagnoli, B.; Santi, C.; Testaferri,
L.; Marini, F. Tetrahedron Lett. 2013, 54, 6755-6757.
3) (a) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Wu, T. Y.-H.;
He, Y. Bioorg. Med. Chem. Lett. 2006, 16, 2105-2108; (b) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.;
Bieza J.; Caldwell, J.; Bursulaya, B.; Tuntland, T, Zhang, K.; Karanewsky, D.; He, Y. Bioorg. Med.
Chem. Lett. 2006, 16, 2109-2112; (c) Kumari, G.; Nutan, Modi, M.; Gupta, S. K.; Singh, R. K. Eur. J.
Med. Chem. 2011, 46, 1181-1188.
238
PC110
Mechanochemical Oxidation Of Perfluoro Anilines To Perfluoro
Azobenzenes
Luca Vaghi1, Giancarlo Cravotto2 and Antonio Papagni*1
1
2
Department of Materials Science, University of Milano-Bicocca, Via Cozzi 55, 20125 Milano, Italy
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, via Giuria 9,
Torino 10125, Italy
e-mail:[email protected]
Aromatic azo compounds have been extensively used in industrial applications mainly
as organic dyes and pigments, but also as food additives, indicators, and therapeutic
agents.1 Moreover, exploiting their peculiar photochemical response, the applications of
azo compounds have been recently extended to a broad range of light-responsive
functional materials, such as liquid crystals, molecular switches, smart polymers and
photochromic ligands.2 A multitude of synthetic methods to affording symmetric azo
compounds are known,3 the most used involve the oxidative coupling of aromatic
amines and the reductive homodimerization of nitroarenes. In the case of anilines
omocoupling the stoichiometric use of toxic and environmentally unfriendly transitionmetal based oxidants, like mercury, lead and manganese derivatives, is often needed to
achieve satisfactory yields, especially with electron-poor aromatic amines. One of our
research efforts entail the synthesis of polifluorinated aromatic compounds as possible
candidates to be used in material science applications.4,5 On the route to target
perfluorinated molecules we needed an efficient method to gain perfluoro azobenzenes,
we focused our attention on the mechanochemical approach.6
Gratifying the use of environmental friendly oxidants in a zirconia mill, without the aid
of milling auxiliaries, afforded the desired products in satisfactory yields. In addition
polyfluoroazobenzenes undergo regiocontrolled aromatic nucleophilic substitutions in
reaction with anilines simply acting on the reaction solvent polarity. Ortho-anilino
substituted derivatives had be proved to be suitable starting material for the synthesis of
polyfluoro phenazines.
[1]
K. Hunger, P. Mischke, W. Rieper, R. Raue, K. Kunde, A. Engel "Azo Dyes" in Ullmann’s
Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2005.
[2]
H. M. D. Bandarab, S. C. Burdette, Chem. Soc. Rev. 2012, 41, 1809-1825.
[3]
E. Merino, Chem. Soc. Rev. 2011, 40, 3835-3853.
[4]
A Papagni, P. Del Buttero, M. Moret, A. Sassella, L. Miozzo, G. Ridolfi, Chem. Mater. 2003, 15,
5010-5018.
[5]
P. Del Buttero, R. Gironda, M. Moret, A. Papagni, M. Parravicini, S. Rizzato, L. Miozzo, Eur. J. Org.
Chem. 2011, 2265–2271.
[6]
R. Thorwirth, F. Bernhardt, A. Stolle, B. Ondruschka, J. Asghari, Chem. Eur. J. 2010, 16, 1323613242.
239
PC111
Thermally Triggered Self-mending in Novel Polyurethanes (PUs)
Antonello Pastore1, Stefania Dello Iacono1,
Maddalena Giordano1, Alfonso Iadonisi2, and Eugenio Amendola1, 3
1
National Research Council (CNR), Institute for Polymers, Composites and Biomaterials (IPCB), P.le E.
Fermi 1 I-80055 Portici (NA) Italy. 2Department of Chemical Sciences, University of Naples “Federico
II”, Via Cintia, I-80126 Napoli, Italy. 3IMAST - Technological District on Engineering of polymeric and
composite Materials and Structures, P.zza Bovio 22, I-80133 Napoli, Italy.
e-mail: [email protected]
Material intrinsic healing is related to the presence of furan and maleimide moieties, insitu generated during damage or by heating above the r-DA reaction temperature; this
mechanism was established for epoxies 1 and polyurethanes.2 In order to ensure
flexibility and mobility of polymeric backbone, semi-flexible structures are required.
Herein 2Ph2Isocyan Diels-Alder adduct (1) was thermally assembled starting from
furfuryl isocyanate and 1,1′-(Methylenedi-4,1-phenylene)bismaleimide (Scheme 1).
Scheme 1 Synthesis of monomer (1).
Compound (1) was subsequently characterized by NMR spectroscopy and its thermal
properties were preliminarily investigated. Metal catalyzed step-growth polymerization
of monomer (1), in the presence of flexible and mobile poly(ethylene glycol) species,
afforded polyurethanes (PUs) films amenable to recover from scratches (Figure 1). An
integrated approach based on solution NMR spectroscopy, Differential Scanning
Calorimetry (DSC), Thermogravimetric analysis (TGA), micromechanical analysis and
optical microscopy allowed a deep characterization of the novel synthesized PUs in
terms of structure, thermo-mechanical properties and morphology. These PUs
satisfactory recover morphological scratch damages, between reaction temperatures of
DA and r-DA processes, and they could promisingly be applied in the field of
adhesives, spray painting and surface coatings.
Figure 1 Scratched PU surface and same location after thermal healing.
1) Peterson, A. M.; Jensen, R. E.; Palmese, G. R. Appl. Mat. & Int. 2010, 2, 1141-1149.
2) Heo, Y.; Sodano, H. A. Adv. Funct. Mater. 2014, 24, 5261-5268.
Acknowledgemets: The activities were performed in the frame of the projects “PRADE - PON02_00029_3205863”
granted to IMAST S.c.a.r.l. and funded by the MIUR and “ALAMSA FP7 Grant Agreement 314768”.
240
PC112
Multicomponent Synthesis of Uracil Analogues by Pd-Catalyzed
Carbonylative Coupling of α-Chloroketones, Isocyanates and Amines
S. Perrone,1 M. Capua,1 C. Granito,1 A. Salomone,1 L. Troisi1
1
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Prov.le LecceMonteroni, Lecce 73100, Italy
e-mail: [email protected]
Multicomponent reactions (MCRs) are a very powerful synthetic tool characterized by
efficiency, selectivity, molecular diversity and, in particular, atom-economy.
Recently we have studied the Pd-catalyzed carbonylation of unsaturated halides such as
allyl-, benzyl-halides, and α-chloroketones. Particularly, these last ones constitute an
efficient method to generate valuable β-dicarbonylpalladium chloride intermediates (B,
Scheme 1). These palladium species, when generated in the presence of triethylamine,
can convert into ketenes (C) that are very useful reagents in cycloaddition reactions. In
fact, the postulated intermediate C was successfully employed in the synthesis of 3acyl-4-hydroxy-2-pyranones (path a) via a dimerizative [4+2] cycloaddition and also
coupled with aromatic imines, to yield, in a [2+2] cycloaddition, (Z)-configured αalkylidene-β-oxoamides (path b) in a high stereoselectivity (Scheme 1).1-2
O
R
1
Cl
Et3N, CO (27 atm)
THF,110 °C
1
R = Alkyl, Aryl
O
O
Pd(AcO)2, Ph3P
R
1
path a
O
PdCl
- HPdCl
R
C
1
R1
O
R
1
OH
O
O
[2+2]
C
B
O
O
[4+2]
dimerization
R2
N
path b
O
R1
R
3
NHR
R
(Z)
3
2
Scheme 1
In this contribution we report a study about the reactivity of the -dicarbonyl palladium
species (B) towards isocyanates as potential partners for the cycloaddition reactions
with in-situ generated ketenes (C). The results obtained are very interesting because
uracil analogues, that exhibit remarkable biological activities, were obtained in high
yields by a multicomponent synthesis (four component reaction, chloroketone,
isocyanate, CO, primary amine, Scheme 2). In addition, a reaction mechanism has been
proposed.3
Scheme 2
1) S. Perrone, A. Salomone, A. Caroli, A. Falcicchio, C. Citti, G. Cannazza, L.Troisi Eur. J. Org. Chem.,
2014, 27, 5932-5938.
2) S. Perrone, A. Caroli, G. Cannazza, C. Granito, A. Salomone, L. Troisi Tetrahedron Lett., 2015, 56,
2773-2776.
3) S. Perrone, M. Capua , A. Salomone, L. Troisi J. Org. Chem. 2015, submitted.
241
PC113
Synthesis and Reductive Elaborations of Piperidinyl Enamides and
Enecarbamates
Francesco Berti, Andrea Menichetti, and Mauro Pineschi*
Dipartimento di Farmacia, Sede di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno
33, 56126, Italy.
[email protected]
Functionalized piperidines are very popular compounds widespread in a number of
biologically active molecules. Therefore, the exploration of new methods to obtain these
scaffolds is an intensive area of research. We recently reported the synthesis and the
elaborations of substituted 1,2-dihydropyridines 1 by means of arylnitroso Diels-Alder
reactions.1,2 We herein report the study of a metal-catalyzed hetero-Cope rearrangement
reaction of acylnitroso Diels-Alder cycloadducts with 1,2-dihydropyridines to give
synthetically valuable six-membered amine activated olefins such as 2 and others not
shown here. Piperidinyl enamides and enecarbamates play an important role as
intermediates in a variety of organic transformations and significant efforts have been
devoted to their synthesis.3
Interestingly, during the elaboration of compound of type 2 in reductive reaction
conditions (H2/Pd(C) or PdCl2(PPh3)2/LiEt3BH), the formation of 3-hydroxypiperidine
derivatives and of a novel [3.3.1]-heterobicyclic structure, respectively, was observed.
(1) Crotti, S.; Berti, F.; Pineschi, M. Org. Lett. 2011, 13, 5152.
(2) Berti, F.; Di Bussolo, V.; Pineschi, M. J. Org. Chem. 2013, 78, 7324.
(3) For typical preparations, see: (a) Gigant, N.; Dequirez, G.; Retailleau, P.; Gillaizeau, I.; Dauban,
P. Chem. Eur. J. 2012, 18, 90. (b) Moriyama, N.; Matsumura, Y.; Kuriyama, M.; Onomura, O.
Tetrahedron: Asymmetry 2009, 20, 2677.
242
PC114
Synthesis of 1,2,3,4-tetrahydro-β-carboline and 1,2,3,4tetrahydroisoquinoline based diketopiperazines by a post Ugi-3CR
cyclization strategy
A. Rossetti1, M. Gatti1, A. Sacchetti1
1
Dipartimento di Chimica, Materiali ed Ing. Chimica ‘Giulio Natta’, Politecnico di Milano, p.zza
Leonardo da Vinci 32, Milan 20133, Italy.
e-mail: [email protected]
Multicomponent reactions (MCRs) are defined as one-pot synthesis reactions, where
more than two starting materials interact to form a product. On the contrary to the
classical assembly line of complex organic molecules, MCRs are convergent reactions,
where the main standard operations, such as reaction set up, work-up, purification and
analyses have to be performed just once. First examples of MCRs appeared in the last
19th century, although a revolution in this field was given in 1921 by the Italian chemist
Passerini, who first reported a reaction based on isocyanide. In 1959 Ivar Ugi
discovered the most useful isonitrile-mediated MCR,1 which can be classified in two
main variations.2 Following our interest in the use of multicomponent reactions3 along
with the study of isoquinoline and carboline based peptidomimetics,4 in this work we
describe a straightforward approach for the synthesis of complex diketopiperazines
through a two steps sequence (Scheme 1). Starting from a 3,4-dihydroisoquinoline or a
β-carboline precursor, a three-component Ugi reaction was performed with chloroacetic
acid and different types of isonitriles. The obtained intermediate was then submitted to
cyclization to form the desired diketopiperazine. Studies on the possibility to achieve
the products in a one-pot sequence were also performed.
Scheme 1: Post Ugi-3CR cyclization synthetic scheme.
1) Ramon, D.J.; Yus, M. Angew. Chem. Int. Ed. 2005, 44, 1602-1634.
2) Chèron,N.; Ramozzi, R.; El Kaїm, L. et al. J. Org. Chem. 2012, 77, 1361-1366.
3) Lesma, G.; Cecchi, R.; Crippa, S.; Giovanelli, P.; Meneghetti, F.; Musolino, M.; Sacchetti, A.; Silvani,
A. Org. Biomol. Chem. 2012, 10, 9004–9012.
4) Airaghi, F.; Fiorati, A.; Lesma, G.; Musolino, M.; Sacchetti, A.; Silvani, A.. Beilstein J. Org. Chem.
2013, 9, 147–154
243
PC115
Continuous-flow stereoselective synthesis in 3D-printed microreactors
Sergio Rossi, Riccardo Porta, Davide Brenna, Maurizio Benaglia
Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy
e-mail: [email protected]
Continuous-flow systems1 have recently emerged as a powerful technology for
performing chemical transformations, since they ensure some advantages over
traditional batch procedures, such as faster reactions, cleaner products, safer reactions,
quick reaction optimization, easy scale-up.
On the other hand, 3D-printing technology allows chemists to build devices with high
precision and well-defined architecture.2 Among the many different 3D-printing
techniques developed in the industrial field, the most known is the Fused Deposition
Modeling (FDM), where a plastic filament is unwound from a coil, heated to a melt, and
fed through a nozzle that can be moved in three-directions to produce objects, according
to the virtual design.
The combination of these two only partially explored technologies in organic synthesis
opens new and intriguing possibilities; the fabrication of ad hoc designed reactors and
other devices, to perform at best different reactions becomes now feasible. In this work,
an in-house designed and 3D-printed reactionware device was realised and employed
for the organocatalytic synthesis of Active Pharmaceutical Ingredients (APIs) such as
(1R,2S)-meta-hydroxyphenylpropanoalmine (MHPA), a potent vasopressor known
under the trade name of Metaraminol. The 3D printed microreactor was fed with
methanol solutions of 3-(benzyloxy)benzaldehyde, nitroethane and a chiral copper
catalyst, leading to the formation of the corresponding nitro-aldol product in high yield
and good diastereo and enantioselectivity (scheme 1).
Scheme 1
References
1) A. Puglisi, M. Benaglia, R. Porta, F. Coccia, Current Organocatalysis, 2015, DOI:
0.2174/2213337202666150513002701
2) a) P. J. Kitson, M. H. Rosnes, V. Sans, V. Dragone, L. Cronin, Lab on a chip 2012, 12, 3267-3271; b)
V. Dragone, V. Sans, M. H. Rosnes, P. J. Kitson, L. Cronin, Beilstein Journal of Organic Chemistry
2013, 9, 951-959.
244
PC116
Synthesis of Novel Neomycin-Sugar Conjugate Antibiotics by a
Domino Multicomponent Process
Aurora Sganappa a, A. Volonterio a, Y. Torb
a Department of Chemistry, Materials, and Chemical Engineering “G. Natta”, Politecnico di Milano,
via Mancinelli 7, 20131 Milano, Italy
b Department of Chemistry and Biochemistry, University of California, San Diego 9500 Gilman Dr., La
Jolla, California 92093, United States
e-mail: [email protected]
The excessive and often unnecessary use of antibiotics has helped the development of
increasingly resistant bacteria. Unfortunately, beside to the constant increase in the
appearance of these resistant strains, there is not a correspondece with the introduction
of new effective drugs. In this scenario, aminoglycoside antibiotics have been identified
and used as scaffolds for the synthesis of different derivatives with a prospective
antibacterial activity.
Recently, we have developed an interesting multicompontent domino process to
sythesize multivalent glycomimetics in high yield and mild condiction.1,2 This
straigthforward process has been also exploited to synthesize a little library of
aminoglycoside-sugar conjugates, in particular neomycine derivatives, as potetntial
novel antibiotics.3 The synthetic pathway as well the results of minimum inhibitory
concentration evaluations will be reported.
1) A. Sganappa et al., ACS Comb. Sci. 2014, 16, 711-720.
2) A. Sganappa et al., Manuscript submitted.
3) A. Sganappa et al., Manuscript in preparation.
245
PC117
Synthesis of Complex Heterocyclic Scaffolds through Cascade
Processes Based on Multicomponent Reactions Followed by Palladium
Mediated SN2' and Ring Closing Metathesis Cyclizations
Martina Spallarossa a, Luca Banfi a, Andrea Basso a, Renata Riva a
a
University of Genova, Department of Chemistry and Industrial Chemistry, Genova
e-mail: [email protected]
The strategy that combines classical isocyanide-based multicomponent reactions
followed by subsequent cyclizations has proved to be one the most effective methods
for the diversity oriented obtainment in few steps (typically 1-3) of a variety of druglike or natural product-like heterocyclic scaffolds.1,2 We envisioned that a 2-step
protocol involving an Ugi reaction followed by a Pd(0) mediated SN2' cyclization could
have a great potential: this latter reaction leaves a terminal double bond that can be
involved in a third organometal catalysed step leading to complex polycyclic
heterocycles. We already previously demonstrated this principle using a custom-made
isocyanide containing an allyl carbonate.3 Now we have decided to access a different
type of alkaloid-like systems, by incorporating the allyl carbonate in the aldehyde
component instead. We have carried out a series of Passerini and Ugi reactions followed
by the SN2' cyclization, where the isocyanide derived NH group acts as nucleophile.
Finally different scaffolds have been prepared exploiting the terminal bond in a Ring
Closing Metathesis based cyclization.
OCO2Me
1) Ugi or Passerini
reactions
R2NC
R3CO2H
O
R1
R4NH
2) Pd(0) cat. SN2'
*
R1
2
N
*
R2
O
Y
O
Y= O or NR4
R3
*
R1
*
N
*
O
Y
O
R3
R1
R5
N
*
O
Y
Further cyclizations
(depending on R 2)
RCM
O
R3
(1) Banfi, L.; Basso, A.; Riva, R. Top. Heterocycl. Chem. 2010, 23, 1.
(2) Banfi, L.; Riva, R.; Basso, A. Synlett 2010, 23.
(3) Riva, R.; Banfi, L.; Basso, A.; Cerulli, V.; Guanti, G.; Pani, M. J. Org. Chem. 2010, 75,
5134.
246
PC118
Helical shaped quinolines through the Povarov reaction
Caterina Viglianisi, Chiara Biagioli, Stefano Menichetti, Lorenzo Tofani
Department of Chemistry “U. Schiff”, University of Florence, Via della Lastruccia 13,
50019 Sesto Fiorentino, Italy.
e-mail: [email protected]
The formal [4+2] cycloaddition reaction of N–aryl imines with electron-rich dienophiles
is known as Povarov reaction and represents one of the most convenient methods for the
preparation of tetrahydroquinolines and quinolines.1
On the other hand, [4+2] cycloadditions represent one of the most commonly used
methodology for the preparation of helical frameworks and several carba- and
heterohelicenes have been synthesized using a Diels-Alder reaction.2 To the best of our
knowledge, however, no report is available describing the preparation of azaheterohelicenes exploiting the Povarov reaction.
In this communication we report a preliminary study on the synthesis of properly
substituted electron-rich alkenes and N-arylimines able to react to give helical shaped
quinolines.
The optimization of the synthetic procedure as well as the structural features of the
tetrahydroquinolines and quinolines so far obtained will be discussed.
1) a) Tetrahedron. 2009, 65, 2721-2750; b) Synthesis 2014, 46, 135-157.
2) Chem. Rev. 2012, 112, 1463-1535.
247
PC119
One-step fast protocol for identification and quantification of Nheterocyclic compounds in corals
Chiara Samorì,1 Federica Costantini,2 Marco Abbiati,2 Paola Galletti,1,3 Emilio
Tagliavini.1,3
1
2
Centro Interdipartimentale di Ricerca Industriale (CIRI), Università di Bologna
Dipartimento di Scienze Biologiche, Geologiche e Ambientali, Università di Bologna
3
Dipartimento di Chimica ”Giacomo Ciamician”, Università di Bologna
[email protected]
Soft corals (Alcyonacea) are a rich source of structurally diverse and pharmacologically active
natural products, including a variety of nitrogen-based metabolites with cytotoxic, antibacterial
and insecticidal activities.1 The typical protocol for isolation and identification of these
metabolites requires the extraction with organic solvents (e.g. haloalkanes and/or alcohols)
followed by the fractionation of the extract by chromatography and by the identification through
NMR and hyphenated techniques (mainly GC-MS and LC-MS). The major limitation of this
approach is probably the relatively large amount of material required for isolating pure
components from the complex mixture of the crude extract and for performing spectroscopic
investigation.2 In fact, since the quantity of secondary metabolites produced by the organisms is
often scarce, a considerable amount of living tissue is needed to get enough material to
accomplish a satisfactory characterization. The present study aims at developing a novel onestep protocol for a fast and simple identification and quantification of N-heterocyclic
compounds from the most common Mediterranean octocorals, applicable to small-size samples
(tens of milligrams) without using concerning or hazardous chemical compounds (e.g.
halogenated solvents). The first qualitative and quantitative analysis of N-heterocyclic
compounds produced by the octocorals Eunicella cavolinii, E. verrucosa, E. singularis,
Paramuricea clavata, Leptogorgia sarmentosa and Corallium rubrum has been provided
(Figure 1). Moreover, an investigation of intraspecific patterns of variability in the amount and
distribution of these compounds by analyzing samples collected in different sites along the
Mediterranean coasts has been performed. Finally, the effectiveness and appropriateness of the
analytical approach here proposed in species identification has been evaluated.
Figure 1. Main N-heterocyclic compounds identified in the Mediterranean octocoral samples analyzed.
Hypoxanthine
Guanine
7-Methylguanine
3,7-Dimethylguanine
Creatinine
1,3,7-Trimethylguanine
Psilocin
Adenosine
1)
2)
J. W. Blunt, B. R. Copp, M. H. G. Munro, P. T. Northcote, M. R. Prinsep. Nat. Prod. Rep.,
2011, 28, 196–268
N. Penez, G. Culioli, T. Perez, J. F. Briand, O. P. Thomas, Y. Blache. J. Nat. Prod. 2011, 74,
2304–2308
248
PC120
One more substituent makes the difference!
Lara Bianchi, Massimo Maccagno, Giovanni Petrillo, Carlo Scapolla and Cinzia Tavani
Dipartimento di Chimica e Chimica Industriale, Università di Genova,
Via Dodecaneso 31, I-16146 Genova, Italy
[email protected], [email protected]
Among the nitrothiophenes which candidate themselves as substrates for ring-opening
by reaction with amines, the polysubstituted -nitroderivative 1 is surely most
synthetically useful as far as X and Y can be varied within a wide range of functional
groups.1
Thus, the nitrobutadiene 2, which can be obtained by proper modification of the initial
ring-opened product from 1 (X = SO2Ph, Y = H or COOMe), enjoys a versatile
reactivity which can be quite rewardingly driven towards structurally different targets
(either open-chain building-blocks or N-heterocycles) by simply varying Y and/or the
reacting amine.
Recent results on the system will be presented.
1) Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.; Cosimelli, B.; Spinelli, D.
Tetrahedron 2001, 57, 8159-8165.
249
PC121
A new domino approach to lentiginosine and indolizine derivatives
Carolina Vurchio, Franca M. Cordero, Alberto Brandi.
University of Florence, Department of Chemistry “Ugo Schiff”, via della Lastruccia 13, 50019 Sesto
Fiorentino (FI), Italy.
[email protected]
(+)-Lentiginosine 1 is a natural iminosugar with important inhibitory activity towards
amyloglucosidases and Hsp90 (Heat Shock Protein 90).1 Interestingly, it has been
proven that the non natural enantiomer (–)-lentiginosine 2 and its 7-hydroxy derivative
3 display a potent proapoptotic activity against different cancer cell lines with a low
toxicity towards healthy cells.2 Other 7-substituted (–)-lentiginosines such as 4 are able
to induce apoptosis (Figure 1).3
Figure 1.
The enantiopure dihydroxylated pyrroline N-oxides 5 have been used as building block
in original highly stereoselective syntheses of hydroxyindolizidines such as
lentiginosine and 7,8-disubstituted derivatives. The synthetic strategy is based either on
nitrone alkylation and 1,3-dipolar cycloaddition with different dipolarophiles followed
by suitable elaboration of the adducts (Scheme 1).
OR
R'O
OR'
HO
N
H
OR
D-tartaric
acid
H
OR
Z
OR
O N
OR
N
O
5
OR
N
EtO2C
RO
OR
H OH
HO
7
MeO2C
HO
H
O N
8
N
OR
OH
OR
Scheme 1.
In this communication synthetic aspects and peculiar reactivities of some intermediates
towards these interesting indolizine derivatives will be discussed.
1)
2)
3)
Dal Piaz, F.; Vassallo, A.; Chini, M. G.; Cordero, F. M.; Cardona, F.; Pisano, C.; Bifulco, G.; De
Tommasi, N.; Brandi, A. PLoS One 2012, 7, e43316.
a) Macchi, B.; Minutolo, A.; Grelli, S.; Cardona, F.; Cordero, F. M.; Mastino, A.; Brandi A.
Glycobiology 2010, 20, 500-506. b) Minutolo, A.; Grelli, S.; Marino-Merlo, F.; Cordero, F. M.;
Brandi, A.; Macchi, B.; Mastino, A. Cell Death. Dis. 2012, 3, e358. c) Cordero, F. M.; Bonanno,
P.; Khairnar, B.; Cardona, F.; Brandi, A.; Macchi, B.; Minutolo, A.; Grelli, S.; Mastino, A. Chem
Plus Chem, 2012, 77, 224-233.
a) Cordero, F. M.; Vurchio, C.; Macchi, B.; Minutolo, A.; Brandi A. ARKIVOC, 2014, 3, 215227. b) Vurchio, C.; Cordero, F. M.; Faggi, C.; Macchi, B.; Frezza, C.; Grelli, S.; Brandi A.
Tetrahedron, 2015, http://dx.doi.org/10.1016/j.tet.2015.03.108.
250
PC122
Phenyl(2-quinolyl)methanol: a New Reagent for Metal-free Reduction
of Nitro Aromatic Compounds
Donatella Giomi, Renzo Alfini, Marino Malavolti, Antonella Salvini, Alberto Brandi
Dipartimento di Chimica ‘Ugo Schiff’, Università di Firenze, Polo Scientifico e Tecnologico, Via della
Lastruccia 3-13, I-50019 Sesto Fiorentino, Italy
e-mail: [email protected]
1-(2-Pyridyl)-2-propen-1-ol (1) showed a peculiar behaviour as C-1, C-2, or C-3 carbon
nucleophile, likely associated to the weak acidity of the ‘picoline type’ hydrogen atom.1
This characteristic also allowed alcohol 1 to react with nitro-aromatic/heteroaromatic
compounds as Hantzsch ester (HEH) 1,4-dihydropyridine mimic, performing the metalfree reduction of nitro compounds to the corresponding amino derivatives.1 The
multifacet reactivity of allyl alcohol 1 was responsible for competitive reaction
pathways leading to mixtures of products with low selectivities. This problem was
resolved exploiting phenyl(2-pyridyl)methanol (2)2 and phenyl(2-quinolyl)methanol (3)
as new reagents for the metal-free reduction of nitro-aromatic/heteroaromatic systems.
They were applied to the synthesis of -amino esters via domino nitro group reduction
and aza-Michael conjugate addition to methyl acrylate, but the quinolyl carbinol 3 was
also efficient in the reductive amination of suitably activated aldehydes and ketones as
well as in new metal-free Friedländer quinoline and Reissert indole syntheses.
Mechanistic aspects as well as applications and limits of these new HEH mimics will be
properly presented.
1) Giomi, D.; Piacenti, M.; Alfini, R.; Brandi, A. Tetrahedron 2009, 65, 7048-7055.
2) Giomi, D.; Alfini, R.; Brandi, A. Tetrahedron 2011, 67, 167-172.
251