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XXXIV CONVEGNO NAZIONALE
DIVISIONE DI CHIMICA ORGANICA
sotto il Patrocinio di
Regione Lombardia
Comune di Pavia
Provincia di Pavia
Università degli Studi di Pavia
10-14 settembre 2012
1
con il contributo di
2
Comitato Scientifico
Prof. Paolo Scrimin
Prof. Raffaele Riccio
Prof. Roberto Ballini
Prof. Valeria Conte
Prof. Marco D’Ischia Prof. Gianluca Farinola
Prof. Francesco Sannicolò
Dott. Pietro Allegrini
Comitato Organizzatore
Prof. Angelo Albini
Prof. Giovanni Vidari
Prof. Giuseppe Faita
Prof.ssa Mariella Mella
Prof. Paolo Quadrelli
Prof. Giuseppe Zanoni
Dott. Alessio Porta
Dott. Filippo Doria
Dott.ssa Laura Legnani
Dott. Stefano Protti
3
La Divisione di Chimica Organica della Società Chimica Italiana e l'Università di
Pavia sono liete di invitare i Chimici Organici Italiani a partecipare al XXXIV
Convegno Nazionale della Divisione che si terrà dal 10 al 14 Settembre 2012 presso
le Aule Storiche del Palazzo Centrale dell’Università degli Studi di Pavia. Il XXXIV Convegno della Divisione sarà aperto ai contributi di tutti i
ricercatori che operano nelle varie discipline riconducibili alla Chimica
organica a livello accademico e industriale. Il Convegno sarà inoltre
occasione per stimolare nuovi contatti e collaborazioni tra i ricercatori,
fornendo in particolare agli studiosi più giovani l’occasione di esporre e discutere il proprio lavoro.
Proseguendo la tradizione dei precedenti Convegni, la XXXIV edizione si
propone di evidenziare il ruolo della Chimica Organica per la soluzione
delle problematiche della società moderna ove la Ricerca costituisce la
base per lo Sviluppo produttivo e sociale di un paese che guarda alla
Sostenibilità delle sue attività produttive.
Pavia è geograficamente al centro di un’area ricca di attività culturali e produttive ove, nel raggio di poche decine di chilometri, operano una
decina di Università e numerose Industrie di medie e piccole dimensioni
che producono intermedi di sintesi e prodotti per la chimica farmaceutica.
Prof. Paolo Scrimin Presidente del Comitato Scientifico.
4
PROGRAMMA DEL CONVEGNO
5
Lunedì 10 Settembre
ore 15.00 – Aula Magna
APERTURA DEL CONVEGNO
Saluto delle Autorità
Proclamazione dei vincitori delle medaglie A. Mangini, G. Ciamician e A. Quilico
Presiede: Ottorino De Lucchi
PL1 – B. M. Trost
The Alkyne Strategy For the Synthesis of Bioactive Targets
Conferenza del vincitore della medaglia “A. Quilico”
M1 – A. Brandi
Experiences of thirtyfive years along with azaheterocycles: more delight than frustration
ore 17.00 Intervallo
Tavola rotonda
Il futuro della Chimica nell’industria europea
ore 19.00 Fine Sessione
ore 20.00 Cocktail di benvenuto presso il Castello Visconteo
6
Presiede: Bartolo Gabriele
F1 – I. Mulani, O. Bortolini, A. De Nino, L. Maiuolo, G. Stabile, B. Russo
Synthesis and biological activity of effective gem- hydroxyl -amino bisphosphonate.
F2 – G. Giacomelli, G. Nieddu
A mild approach to the dehalogenation of aromatic halides.
F3 – L. Troisi, M. M. Carrozzo, C. Citti, A. Falcicchio, R. Mansueto, F. Rosato, G. Cannazza
Oxidation of different iminic bonds by 3-chloroperbenzoic acid.
F4 – S. Montanaro, D. Ravelli, D. Merli, M. Fagnoni, A. Albini
Polyoxometalates as photoredox catalysts in C-C bond formation. Decatungstate salt
photocatalyzed benzylation of electron-poor olefins.
F5 – F. Berti, V. Di Bussolo, M. Pineschi
Synthesis of new piperidinyl enamides and enecarbamates
by unconventional elaboration of NDA cycloadducts.
F6 – C. Zona, C. Airoldi, S. Mourtas, E. Sironi, A. Niarakis, M. Canovi, M. Gregori,
I. Cambianica, S. Sesana, F. Re, M. Gobbi, M. Masserini, S.G. Antimisiaris, F. Nicotra, B. La Ferla
Going toward the development of new therapeutic
and diagnostic nanotools for Alzheimer's disease.
F7 – S. Bugoni, V. Merlini, A. Porta, G. Zanoni, G. Vidari
Dual mechanism of Au-promoted rearrangements of 1,5-enynes.
F8 – M. Sassi, L. Beverina, F. Rosciano, R. Ruffo and M. Salamone
New polymeric active material for energy storage with improved specific capacity
by embedding redox active naphthalene diimide centres in a PEDOT matrix
F9 – F. Leonelli, V. Latini, A. Trombetta, G. Bartoli, F. Ceccacci, A. La Bella,
A. Sferrazza, D. Lamba, L. M. Migneco, R. Marini Bettolo
Regio and diastereoselective synthesis and X-ray structure determination of (+)-2-deoxyoryzalexin S
ore 14.30 – Cortile Sforzesco
Prima Sessione Poster: F1 – F9 e P01 – P48
Presiede: Alessandro Bagno
Conferenza del vincitore del premio per la ricerca in chimica organica
nei suoi aspetti sintetici (metodologie e prodotti)
PR1 – M. Taddei
Microwave dielectric heating, hydrogenation, hydroformylation, carbonylation,
asymmetric synthesis….. and beyond
ore 16.30
NT1 – F. Benevelli
Improved NMR software and hardware solutions for organic chemists.
8
Presiede: Ugo Azzena
O9 – F. De Sarlo, L. Guideri, F. Machetti
Conjugate addition versus cycloaddition-condensation of nitro compounds in water.
O10 – M. Salamone, M. Milan, L. Mangiacapra, G. A. Di Labio, M. Bietti
Effetti strutturali e del solvente sulle reazioni di trasferimento di atomo di idrogeno
da legami CH ad alcossi radicali. Il ruolo delle interazioni di legame idrogeno.
O11 – M. Pelà, S. Salvadori, R. Guerrini, C. Trapella
Mechanistic studies of a non usual Wittig reaction.
O12 – M. Bruschini, A. Dalla Cort , P. A. Gale, J. R. Hiscock
Novel anion receptors for the fluorescent sensing of L-lactate.
O13 – C. Talotta, C. Gaeta, R. Ciao, P. Neri
Stereoprogrammed interlocked structures based on calixarene threading.
Presiede: Enrico Marcantoni
ore 17.10 – Aula del ‘400
O14 – S. Lentini, V. Armuzza, E. Gatto, V. Conte,
B. Floris, M. Venanzi, P. Galloni
Photophysical properties in solution and on ITO surface of a new class of polyquinoid compounds.
O15 – A. Bonetti, S. Pellegrino, M. L. Gelmi
Alpha-diazocarbonyl-piperidine derivatives: chemoselective rhodium catalysed transformation.
O16 – F. Bellina, M. Lessi, A. Pucci, G. Ruggeri,
S. Barondi, L. Perego, P. Minei
Heteroaromatic-based fluorophores for smart materials via palladium-catalyzed coupling reactions
O17 – D. Donati, S. Fusi, F. Ponticelli
Tetrathienyltetrathiafulvalenes, efficient “suicide” sensitizers of singlet oxygen: synthesis and
properties of thienyl substituted 1,2,5,8-tetrathiecine-6,7-dione, a new heterocyclic system.
O18 – R. De Marco, A. Tolomelli, M. Campitiello, P. Rubini, S. Rupiani, A. Greco, L. Gentilucci
One-step synthesis of constrained peptidomimetics including oxazolidinones and/or Δ-amino acids,
and application to the design of bioactive compounds.
9
Mercoledì 12 Settembre
Presiede: Stefano Menichetti
PL3 – E. Beccalli
Pd-catalyzed reactions of indole derivatives
Presiede: Gabriele Fontana
O19 – L. Bartali, A. Casini, E. G. Occhiato, D. Scarpi
A general approach to the synthesis of polyhydroxylated piperidine alkaloids
for the discovery of new drugs.
O20 – M. Mari, F. Bartoccini, G. Piersanti
Concise synthesis of indole alkaloid (-)-Indolactam V
via intramolecular Buchwald-Hartwig amination.
O21 – R. Gaggeri, K. Mahmood, G. Gilardoni, A. Avanzini,
D. Rossi, S. Collina
Phytochemical and biological profile of Eremurus persicus Boiss root extract:
isolation of the main phytocomponents.
O22 – A. Cimmino, A. Andolfi, A. Evidente
Phytotoxic nonenolides produced by fungi pathogenic for crops and weeds.
Presiede: Andrea Goti
O23 – A. Bassoli, G. Borgonovo, G. Morini, L. De Petrocellis, A. Schiano Moriello, V. Di Marzo
TRPA1 high potency analogues of perillaketone.
O24 – A. Barozza, J. Roletto, P. Paissoni
Thermal safety of chemical processes for industrial scale-up.
O25 – T. Tedeschi, A. Tonelli, S. Sforza, R. Corradini, A. Dossena, R. Marchelli
Design and synthesis of new fluorescent PNAs for diagnostic purposes.
O26 – S. Cicchi, G. Giambastiani, L. Luconi, L. Lascialfari,
A. Rossin, M. Melucci, F. Mercuri, A. Brandi
1,3-Dipolar cycloaddition of nitrones to MWCNTs: the role of the CNT sidewall effects.
10
Presiede: Paolo Crotti
O27 – L. Battistini, P. Burreddu, P. Carta, A. Sartori, G. Rassu, C. Curti,
G. Casiraghi, F. Zanardi
Synthesis and characterization of aminoproline-based
RGD semipeptides targeting V3 integrins and their utility in medicine.
O28 – A. Frongia, P. P. Piras, F. Secci
Catalytic asymmetric tandem intramolecular rearrangement-protonation:
an approach to optically active -acyloxy-, -amino thioester and ketones.
O29 – S. Diomedi, R. Cipolletti, M. Di Nicola,
R. Giovannini, D. Hamprecht, L. Marsili,
E. Marcantoni, M. S. Jadhav, R. Properzi, F. Sorana
Exploiting Ce(III) salt properties in the synthesis of polysubstituted heterocycles
by cyclization reaction: microwave irradiation and co-catalyst effect.
O30 – G. Belogi
Industrial scale synthesis of SN38 via photochemical rearrangement
Presiede: Emanuela Licandro
F10 – C. Troise, A. Andolfi, A. Cimmino, M. Vurro, A. Berestetskiy,
M. C. Zonno, A. Motta, A. Evidente
Agropyrenol and agropyrenal, phytotoxins from Ascochyta agropyrina var. nana,
potential herbicides for Elytrigia repens control.
F11 – P. P. Righetti, S. Angioni, D. C. Villa, L. Garlaschelli
New synthetic strategies of polybenzimidazoles for fuel cell application.
F12 – A. Manicardi, A. Bertucci, R. Marchelli, R. Corradini
Nucleobase- and backbone-modified monomers for the construction of multifunctional PNA.
F13 – A. Coletti, A. M. Valerio, A. D’Angelo, O. Scialdone, E. Vismara
Electrochemical synthesis of C-glycosides as non-natural mimetics
of biologically active oligosaccharides.
F14 – L. Gazzera, M. Cametti, P. Metrangolo, G. Resnati
Novel Fluorinated Compounds as Smart Reporter Agents in 19F MRI.
F15 – A. Bertolani, G. Cavallo, P. Metrangolo, G. Resnati
Intermolecular recognition features of bioactive polyhalogenated compounds.
F16 – E. Petricci, M. Taddei, M. Pizzetti
Optimization of MW-assisted “sustainable” carbonylation reactions.
F17 – C. Samorì, P. Galletti, E. Tagliavini
Green technologies for algae treatment.
11
Presiede: Giorgio Cevasco
PL4 – S. Garattini
Open problems in drug discovery and development
Presiede: Giovanni Petrillo
O31 – G. Barreca, L. Carcone, E. Cini, G. Marras, M. Rasparini,
A. Russo, M. Taddei, A. Zanotti-Gerosa
Process development of generic Aliskiren.
O32 – C. Pozzoli
6-Fluoro corticosteroids synthetic approaches and industrial synthesis of fluticasone propionate.
O33 – F. Borin, C. De Faveri, F. A. Martin Huber, F. Tessari, M. Stivanello
Raman spectroscopy: a versatile PAT tool in pharmaceutical process R&D
O34 – A. Toppino, A. Deagostino, S. Geninatti-Crich, D. Alberti, S. Aime, P. Venturello
Synthetic strategies for the preparation of lipophilic MRI/GdBNCT agents.
O35 – S. Alcaro, G. Costa, S. Distinto, F. Moraca, F. Ortuso, L. Parrotta, A. Artese
The polymorfisms of DNA G-quadruplex investigated by docking experiment
with telomestatin enantiomers.
Presiede: Lucio Pellacani
O36 – G. Dell’Anna, E. Attolino, P. Allegrini
A novel enantioselective enzymatic synthesis of Sitagliptin.
O37 – R. Mancuso, B. Gabriele, I. Ziccarelli, G. Salerno
New synthesis of isoindolinone and isoquinolinone derivatives
by Pd-catalyzed carbonylation of 2-alkynylbenzamides.
O38 – M. C. Bellucci, A. Volonterio
Multi-component domino process for the synthesis of glyco-conjugates and glyco-mimetics.
O39 – M. Benotti, M. Freccero, G. Fogliato, A. Manca, M. Bassanini
1,3 Imidazolidine derivatives and their use in the production of carbapenem.
O40 – R. Fretta
The use of iodine/iodic acid in the synthesis of iodinated contrast agents.
Presiede: Marco Lucarini
nei suoi aspetti sintetici di determinazione strutturale e interazioni molecolari
PR2 – A. Casnati
Multivalent calixarene ligands for lectins and nucleic acids
ore 18.10 – ASSEMBLEA
DELLA DIVISIONE DI CHIMICA ORGANICA
12
Giovedì 13 Settembre
Presiede: Pietro Allegrini
nei suoi aspetti di applicazione industriale
PR3 – L. Lattuada
Twenty years of research and development in Bracco Imaging
Presiede: Agostino Casapullo
O41 – P. Fabbrizzi, G. Menchi, A. Trabocchi, A. Guarna, A. Bottoncetti, A. Pupi, S. Raspanti
Design, synthesis and biological evaluation of non peptide integrin antagonists
synthesized via Cu(I) catalyzed azide-alkyne cycloaddition.
O42 – V. Sepe, S. De Marino, R. Ummarino, M. V. D’Auria,
G. Bifulco, B. Renga, S. Fiorucci, A. Zampella
Marine steroids as modulators of pregnane-X-receptor:
isolation, design, total synthesis and potential therapeutic application.
O43 – F. Doria, C. Percivalle, M. Petenzi, L. Germani, S. N. Richter, M. Freccero
Mild alkylation and cross-linking of DNA by quinone methides.
Presiede: Fernando Formaggio
O44 – C. Cimarelli, D. Fratoni, G. Palmieri
Synthesis of indolyl and pyrrolyl-glicine derivatives by catalyzed three components reactions.
O45 – N. Castellucci, C. Tomasini
One-pot synthesis of tetramic acid derivates for the preparation of -turn mimics.
O46 – L. Banfi, A. Basso, M. Bella, L. Moni, F. Morana, R. Riva
Organocatalytic asymmetric processes and multicomponent reactions: a fruitful coalition.
Presiede: Rosa Lanzetta
O47 – F. Micheli
A few synthetic approaches to bridged scaffolds useful as triple reuptake inhibitors.
O48 – C. Spatafora, V. Barresi, V. Bhusainahalli, S. Di Micco, N. Musso,
R. Riccio, G. Bifulco, D. Condorelli, C. Tringali
Bio-inspired benzo[kl]xanthene lignans: design, synthesis,
DNA-interaction and antiproliferative properties.
O49 – A. Bochicchio, L. Chiummiento, M. Funicello, P. Lupattelli, S. Choppin, F. Colobert
First enantioselective approach to the synthesis of (+)-aR,11S-myricanol,
a potent microtubule-associated protein Tau destabilizing
13
Presiede: Luigino Troisi
O50 – G. Strappaveccia, D. Lanari, F. Pizzo, L. Vaccaro
Preparation of -cyano ketones via a two-step catalyzed efficient addition of
trimethylsilyl cyanide to ,-unsaturated ketones.
O51 – A. Porcheddu
A new strategy for amine activation via hydrogen transfer.
O52 – A. Palumbo Piccionello, A. Guarcello, A. Martorana, A. Pace, S. Buscemi
New Boulton-Katritzky rearrangements of azoles
Presiede: Domenico Spinelli
PL5 – B. Stanovnik
Thermal [2+2] cycloadditions of electron poor acetylenes to enaminones
and further transformations of polysubstituted butadienes
ore 13.00
NT2 – S. Bubici, R. Steele, G. Ferrante
Field Cycling Relaxometry – Application in Materials Science
ore 14.40 – Cortile Sforzesco
Seconda Sessione Poster: F10 – F17 e P49 – P97
Presiede: Francesco Nicotra
O53 – E. Bedini, C. De Castro, M. De Rosa, A. Di Nola, C. Schiraldi, M. Parrilli
Semi-synthetic chondroitin sulfate polysaccharides.
O54 – L. Panzella, L. Verotta, L. Goya, S. Ramos, M. A. Martín,
L. Bravo, A. Napolitano, R. Amorati, L. Valgimigli, M. d’Ischia
Synthesis and activity profile of a family of 5-S-lipoylhydroxytyrosol-based
multi-defence antioxidants with sizeable (poly)sulfide chain.
O55 – S. Serra
Chemoenzymatic approaches towards the enantioselective synthesis
of the bisabolane sesquiterpenes
Presiede: Barbara Floris
O56 – A. Lattanzi, C. De Fusco, A. Russo
Organocatalytic stereoselective routes to three-membered rings.
O57 – A. Nacci, A. Monopoli, P. Cotugno, N. Cioffi, M. Manica, G. Tatulli,
O. Iacovelli, F. Lozito, M. V. Divincenzo, F. Ciminale
Metal nano-Catalysts for Green Organic Synthesis.
O58 – C. Santi, C. Tidei, C. Scalera, L. Incipini, F. Marini, L. Bagnoli, L. Testaferri
Bioinspired catalytic oxidation reactions in water: not simply green chemistry.
14
Presiede: Claudia Tommasini
O59 – M. DellaGreca, M. R. Iesce, L. Previtera, S. Zuppolini, A. Zarrelli
Synthesis of lignan-like compounds through highly functionalized diarylfuranones.
O60 – C. F. Morelli, D. Ubiali, I. Serra, C. D. Serra, A. M. Albertini, G. Speranza
Synthesis of purine ribonucleosides via transglycosylation reaction catalyzed
by a purine phosphorylase from A. hydrophila.
O61 – L. Margarucci, M. C. Monti, C. Cassiano, R. Riccio, A. Casapullo
Marine drugs target discovery by chemical proteomics.
O62 – A. Porta, E. Mattia, V. Merlini, G. Zanoni, G. Vidari
One-pot consecutive reactions via oxo-Re-catalysed Meyer-Schuster rearrangement.
Presiede: Luca Banfi
O63 – O. Rosati, F. Messina, M. Curini, M. C. Marcotullio
Improved microwave assisted synthesis of tetrahydrocannabinol analogues catalyzed by Yb(OTf)3.
O64 – A. Sacchetti, F. Gatti, M. Moretti, A. Silvani
Use of Ugi MCR for the synthesis of 4-amino-1,2,3,4-tetrahydroisoquinoline1,3-dione-based peptidomimetics.
O65 – M. Bonchio, M. Carraro, G. Casella, V. Causin, F. Rastrelli, G. Saielli
Ionic liquid crystals based on viologens and viologen dimers.
O66 – L. Meazza, J. A. Foster, K. Fucke, P. Metrangolo, G. Resnati, J. W. Steed
Halogen bonded supramolecular gels.
ore 20.00 Cena Sociale presso il Collegio F.lli Cairoli
15
Venerdì 14 Settembre
PL6 – G. Sartori, R. Maggi
Fine chemical synthesis through heterogeneous catalysis
under batch and continuous flow conditions
nei suoi aspetti meccanicistici e teorici
PR4 – R. Noto
Organic salts: from ionic liquids to gels
Presiede: Michelangelo Gruttadauria
O67 – L. Di Bari
Enhancement of Vibrational Circular Dichroism spectra using lantanide auxiliaries
O68 – S. Riva
Biocatalysis: an efficient and sustainable tool to solve industrial problems?
O69 – A. Massi, A. Cavazzini, O. Bortolini
Silica-supported organocatalysts: development of stereoselective processes
from batch to continuous-flow conditions.
12.00 – 12.30 – Chiusura del Convegno
16
CONFERENZE MEDAGLIE
“A. Quilico”
“G. Ciamician”
“A. Mangini”
17
M1
The experiences of thirtyfive years along with azaheterocycles:
more delight than frustration
Alberto Brandi
University of Florence, Department of Chemistry “Ugo Schiff”,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI)
alberto.brandi@unifi.it
Azaheterocycles are privileged structures for the synthesis of natural products. They represent the
main skeleton of several families of natural products, or they are the tool for selective reactions
leading to total syntheses of more complex molecules. 1,3-Dipolar cycloadditions of nitrones and
nitrile oxides are an extremely potent mean for the build up of functionalised azaheterocycles with
high control of the diastereo- and enantioselectivity. Isoxazole, isoxazoline, or isoxazolidine
heterocycles, deriving from the cycloadditions, allow a large number of selective transformations
originating from the easy cleavage of the N-O bond. Our group has developed several processes,
multistep domino or tandem, thermal, acid, or Pd-catalysed for the synthesis of pyrrolidine,
piperidine, pyrrolizidine, indolizidine, and quinolizidine heterocycles that represent the skeleton of
several classes of natural products.1 Among the most important results is the use of five-membered
cyclic hydroxylated enantiopure nitrones for the synthesis of indolizidine compounds that belong to
the family of azasugar glycosidase inhibitors. One natural compound of this class, Lentiginosine,
has shown very interesting biological properties for both enantiomers, the natural and the
nonnatural one, that suggest a deeper investigation of them and their derivatives, either in vitro or in
vivo.
In this seminar a new synthesis of racemic lentiginosine and diastereomeric 1,2dihydroxyindolizidines will be presented starting from 1-(2-pyridyl)-2-propen-1-ol, a compound
endowed with various interesting reactivity that will be briefly discussed.2
(1) a) A. Brandi, F. Cardona, S. Cicchi, F.M. Cordero, A. Goti Chem. Eur. J. 2009, 15, 7808-7821. b) A. Brandi, S.
Cicchi, F. M. Cordero, Chem. Rev., 2008, 108, 3988–4035. c) J. Revuelta, S. Cicchi, A. Goti, A. Brandi
Synthesis, 2007, 485-504. d) F. M. Cordero, F. De Sarlo, A. Brandi, Monatshefte für Chemie 2004, 135, 649-669.
e) A. Brandi, S. Cicchi, F. M. Cordero, A. Goti. Chem. Rev., 2003, 103, 1213-1269.
(2) D. Giomi, R. Alfini, A. Micoli, E. Calamai, C. Faggi, A. Brandi J. Org. Chem. 2011, 76, 9536-9541.
18
M2
Microbial glycoconjugates and eukaryotic innate immunity
Alba Silipo
Dipartimento Scienze Chimiche, Università di Napoli Federico II,
via Cintia 4, I-80126, Napoli, Italy.
silipo@unina.it
Innate immunity is the first line of defence against invading microorganisms in vertebrates and the
only line of defence in invertebrates and plants and therefore plays a crucial role in the early
recognition and subsequent triggering of a pro-inflammatory response to invading pathogens.
This mechanism relies on recognition of evolutionarily conserved structures on pathogens, termed
microbe-associated molecular patterns (MAMPs), through a limited number of germ line-encoded
pattern recognition receptors. MAMPs are characterized by being invariant among entire classes of
pathogens, essential for the survival of the pathogen, and distinguishable from "self".
Gram negative lipopolysaccharide and peptidoglycan are two very important cell wall glycoconjugates and act as MAMPs in eukaryotic/bacteria interactions. Besides their general architectural
principle, a number of subtle chemical variations are at the basis of the dynamic host-guest
recognition that in case of pathogens is followed by the innate response and in case of symbiosis is
followed by its suppression. Therefore, the structural study of such glyco-conjugates involved as
virulence factors in animal or plant infections is a pivotal pre-requisite for the comprehension at
molecular level of the innate immunity mechanisms.
Significant examples of isolation, structure determination and elicitation and/or suppression of plant
and animal innate immunity by peptidoglycan and lipopolysaccharides from pathogen and
symbiotic Gram negative bacteria will be here illustrated.
19
M3
Switching between supramolecular assemblies of guanosine derivatives
triggered by external stimuli
Gian Piero Spada
Alma Mater Studiorum – Università di Bologna, Dipartimento di Chimica Organica “A. Mangini”
via San Giacomo 11, 40126 Bologna
gianpiero.spada@unibo.it
Depending on the experimental conditions, lipophilic guanosines (LipoG’s) can undergo different self-assembly pathways based on different H-bonded motifs, e.g. the cyclic discrete G-quartet and
the “infinite” tape-like G-ribbon1.
The switching between different supramolecular motifs have been obtained by a variety of external
stimuli. A first example is represented by chemical stimuli: addition of an alkali metal ion stabilizes
the G-quartet while its removal shifts the equilibrium toward the G-ribbon2.
R
R
R
R
stimulus
R
R
R
R
Stimuli: cations addition/removal; UV/Vis light; solvent polarity variation
A second type of stimuli is represented by light: the photocontrolled self-assembly of a modified
guanosine nucleobase with a photoactive unit at C8 is obtained3 selecting the appropriate
wavelength. Finally, a lipoG armed with a terthiophene unit undergoes a pronounced variation of its
supramolecular organisation by changing the polarity of the solvent:4 in chloroform the derivative
assembles via H-bonding in a Guanosine directed structure, while in the more polar (and H-bond
competing) acetonitrile different aggregates are observed, where the terthiophene chains are -
stacked in a helicoidal arrangement.
(1)
(2)
(3)
(4)
Davis, J. T.; Spada, G. P. Chem. Soc. Rev. 2007, 36, 296
Ciesielski, A.; Lena, S.; Masiero, S.; Spada, G. P.; Samorì, S. Angew. Chem. Int. Ed. 2010, 49, 1963-1966
Lena, S.; Neviani, P.; Masiero, S.; Pieraccini, S.; Spada, G. P. Angew. Chem. Int. Ed. 2010,49, 3657-3660
Pieraccini, S.; Bonacchi, S.; Lena, S.; Masiero, S.; Montalti, M.; Zaccheroni, N.; Spada, G. P. Org. Biomol. Chem.
2010, 8, 774-781
20
CONFERENZE PLENARIE
21
PL1
The alkyne strategy for the synthesis
of bioactive targets
Barry M. Trost
Job & Gertrud Tamaki Professor
Department of Chemistry, Stanford University, Stanford, CA 94305-5080
A major challenge for synthesis is the enhancement of efficiency. While most attention has focused
on selectivity, the question of how much of what goes into the pot actually ends up as product,
which I refer to as atom economy, is equally significant. This goal addresses the twin issues of
better use of raw materials in order to conserve valuable resources and minimization of the
generation of waste to reduce disposal issues. There are two strategic aspects. In one, efforts are
made to improve existing processes. A second and, even more challenging one, is to invent new
processes. This latter alternative also has the advantage of providing for new strategic concepts for
constructing complex molecules that could further streamline syntheses.
The first step is to invent reactions that theoretically are capable of having maximal atom economy
or nearly so. The ideal reaction is an addition. A description of a research program that asks the
question of whether new addition reactions can be rationally invented is explored. A key element is
the utilization of alkynes as key building blocks. The chemistry largely involves simple additions
wherein anything else is needed only catalytically. Using a mechanism based approach, a number
of new catalytic reactions is under development. The applications of some of these to interesting
biomolecular targets is prominently considered.
22
PL2
New artificial receptors: synthesis and molecular recognition studies
Bruno Botta, Ilaria D’Acquarica, Francesca Ghirga, Sara Toscano and Andrea Calcaterra
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma (Italy)
bruno.botta@uniroma1.it
For potential applications in sensing technology, receptor molecules must be readily linkable on
solid supports or surfaces. To this purpose, spherical Daisogel SP-300-5P silica gel was
functionalized with 3-aminopropyltriethoxysilane to give the corresponding 3-aminopropylated
silica gel. Cone-shaped resorc[4]arene 1, containing bromoundecyl moiety in the four axial
pendants, readily reacted with the above aminopropyl functionalized silica gel to give the
corresponding immobilized system 1a.1
N-linked peptidoresorc[4]arenes were synthesized by functionalization at the feet of resorc[4]arene
octamethyl ethers with valyl-leucine (Val-Leu) and leucyl-valine (Leu-Val) methyl esters and
applied to enantiodiscrimination studies of the homologue dipeptides as guests both in the gas phase
and in solution.2 We synthesized several derivatives by varying sequence, nature, and
stereochemistry of the peptide chains to be applied in protein surface recognition. From this family
of receptors we have identified noncompetitive inhibitors of -chymotrypsin (ChT), which function
by binding to the surface of the enzyme in the neighborhood of the active site cleft.3
We are currently engaged in extensive mass spectrometric studies of the interactions between
bis(diamido)-bridged basket resorc[4]arenes and some representative chiral biomolecules in the gas
phase, where interference from the solvent is excluded.4
NH2
MeO
OMe
MeO
OMe
MeO
MeO
OMe
O
O
ACN, TEA,
O reflux, 4h
O
MeO
(CH2)3
OMe
OMe
OM
e
O
O
O
O
O
O
O
O
O
Br
Br
Br
OMe
MeO
O
O
O
OMe
MeO
MeO
Br
Br
Br
HN
Br
(CH2)3
1
1a
N-linked peptidoresorc[4]arenes
(CH2)3 NH2 = 3-aminopropyl
silica gel
Besides, some recent results regarding the employment of enzyme systems as “reagents” in the biotransformation of synthetic substrates to desired end products will be shown. Such conversions
are often superior to those utilizing chemical reagents, with the result that the overall synthetic route
is more efficient. Alternatively, the use of the above enzymes in the evaluation of biosynthetic
pathways can often afford important information for synthetic design. The overall strategy
illustrating such an approach will be presented herein with specific examples.
(1) Botta, B.;; D’acquarica, I.;; Delle Monache, G.; Nevola, L.; Tullo, D.; Ugozzoli, F.; Pierini, M. J. Am. Chem. Soc.
2007, 129, 11202-11212.
(2) Botta, B.; D'acquarica, I.; Delle Monache, G.; Subissati, D.; Uccello-Barretta, G.; Mastrini, M.; Nazzi, S.;
Speranza, M. J. Org. Chem. 2007, 72, 9283-9290.
(3) D’acquarica, I;; Cerreto, A;; Delle Monache, G;; Subrizi, F;; Boffi, A;; Tafi, A;; Forli, S;; Botta, B. J. Org. Chem.
2011, 76, 4396-407.
(4) (a) Botta, B.;; Tafi, A.;; Caporuscio, F.;; Botta, M.;; Nevola, L.;; D’acquarica, I.;; Fraschetti, C.;; Speranza, M. Chem.
Eur. J. 2008, 14, 3585-3595. (b) Botta, B.; Fraschetti, C.; Novara, F. R.; Tafi, A.; Sacco, F.; Mannina, L.; Sobolev,
A. P.; Mattay, J.; Letzel, M. C.; Speranza, M. Org. Biomol. Chem. 2009, 7, 1798-1806.
23
PL3
Intramolecular Pd-catalyzed reactions of indole derivatives
Egle M. Beccalli
DISFARM, Sezione di Chimica Generale e Organica "A. Marchesini",
Università degli Studi di Milano, via Venezian 21, 20133 Milano
egle.beccalli@unimi.it
Indole is probably the most ubiquitous heterocycle in nature. Owing to the great structural diversity
of biologically or synhetically relevant indoles, this nucleus has become an important skeleton
endowed with pharmacological and agrochemical activities.1 For over a hundred years, synthesis
and functionalization of indoles have been a relevant area for synthetic organic chemists. In some
cases, specific substitution patterns remain difficult to obtain by standard indole-forming reactions,
thus, all the new emerging methodologies are of great interest.2 Palladium complexes have been
used in the synthesis and derivatization of complex organic molecules, including indoles. Within
these synthetic protocols, besides more classical Pd(0)-catalyzed reactions, several oxidative
reactions based on Pd(II) catalysis have been used for indole functionalization, some of which
represent a convenient tool for the direct elaboration of the indole core motif.3 Undoubtedly, C-H
activation/functionalization has received increased attention as an alternative strategy, due to the fact
that it offers improved atom and step-economy compared to the traditional cross-coupling-based
methods where extra steps are needed for pre-activation of the substrates.4
Following our interest towards Pd-catalyzed reactions as well as towards the synthesis of complex
heteropolycyclic systems, we developed several Pd-catalyzed methodologies applied to variously
substituted indole derivatives providing selective access to different heteropolycyclic systems
containing the indole skeleton.
(1) a) Sundberg, R. J., Indoles; Ed. Academic Press: London, 1996. b) Joule, J. A. Indole and its Derivatives. In
Science of Synthesis:Houben-Weyl Methods of Molecular Transformations; George Thieme Verlag: Stuttgart,
Germany, 2000; Vol. 10, Chapter 10.13.
(2) a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist, Pergamon,
New York, 2000; b) Cacchi, S.; Fabrizi, G.; Chem. Rev. 2011, 111, PR215-PR283; c) Humphrey, G. R.; Kuethe, J.
T.; Chem. Rev. 2006, 106, 2875-2911; d) Bandini, M.; Eichholzer, A.; Angew. Chem. Int. Ed. 2009, 48, 96089644; e) Bartoli, G. Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449-4465.
(3) Beck, E. M. Gaunt, M. J. Top. Curr. Chem. 2010, 292, 85-121.
(4) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318-5365.
24
PL4
Open problems in drug discovery and development
Silvio Garattini
Istituto di Ricerche Farmacologiche Mario Negri, Milan (Italy)
Despite the increasing cost of research the number and the innovative characteristics of new drugs
available on the market is decreasing. The promises of the genomics are still slow to become reality
although partial results have been obtained. Most of the discoveries are concentrated in few areas
while unmet needs of patients, such as mental disorders and rare diseases, receive scarse interest.
Most of the drugs are obtained by comparison with placebo rather than the best treatment available;
clinical trials with design of non-inferiority are increasing; several drugs are withdrawn postmarketing for insufficient evaluation of adverse reactions; surrogate parameters are utilized instead
of therapeutic end-points. Thus new products do not represent real advantages in respect to drugs
already available in terms of efficacy and cost-effectiveness.
More collaboration is needed between industry and academia to improve drug discovery and
development.
25
PL5
Thermal [2+2] cycloadditons of electron-poor acetylenes to enaminones
and further transformations of polysubstituted butadienes
Branko Stanovnik
Faculty of Chemistry and Chemical Technology, University of Ljubljana,
Aškerčeva 5, 1000 Ljubljana, Slovenia
branko.stanovnik@fkkt.uni-lj.si
Recently, we demonstrated the wide applicability of 3-(dimethylamino)propenoates and related
enaminones in heterocyclic synthesis,1 including natural products and their analogues.2
Regiospecific
microwave-assisted
[2+2]
cycloadditions
of
substituted
2-amino-3(dimethylamino)propenoates with acetylenedicarboxylates, afforded highly functionalized 1-amino4-(dimethylamino)buta-1,3-dienes.3 The research has been extended also to metal-free preparation
of 2-alkyl, cycloalkyl, aryl, and heteroaryl substituted pyridines and their N-oxides, 1-aryl (or
heteroaryl)imidazol-2-ones, [2+2] cycloadditions of iminium salts to enaminones, ring-expansion
reactions, rearrangements of heterocyclic systems and other transformations.
(1) a) Stanovnik, B.; Svete, J. Chem. Rev., 2004, 104, 2433;; b) Stanovnik, B.;; Grošelj, U. Adv. Heterocycl. Chem.
2010, 100, 145.
(2) Wagger, J.;; Grošelj, U.;; Svete, J.;; Stanovnik, B. Synlett 2010, 1197 and references cited therein.
(3) a) Uršič, U.;; Grošelj, U.;; Meden, A.;; Svete, J.;; Stanovnik, B. Tetrahedron Lett., 2008, 49, 3775;; b) Uršič, U.;; Svete, J.; Stanovnik, B. Tetrahedron, 2008, 64, 9937;; c) Uršič, U.;; Grošelj, U.;; Meden, A.;; Svete, J.;; Stanovnik, B. Helv. Chim. Acta, 2009, 92, 481; d) Uršič, U.;; Svete, J.;; Stanovnik, B. Tetrahedron, 2010, 66, 4346;; e) Bezenšek, J.;; Koleša, T.;; Grošelj, U.;; Wagger, J.;; Stare, K.;; Meden, A.;; Svete, J.;; Stanovnik, B. Tetrahedron Lett 2010,
3392;; f) Bezenšek, J.;; Koleša, T.;; Grošelj, U.;; Meden, A.;; Stare, K.; Svete, J.; Stanovnik, B. Curr. Org. Chem.
2011, 15, 2530;; g) Bezenšek, J.;; Grošelj, U.;; Stare, K.;; Svete, J.;; Stanovnik, B. Tetrahedron 2012, 68, 516; h)
Bezenšek, j.;; Prek, B.;; Grošelj, U.;; Kasunič, M.;; Svete, J.;; Stanovnik, B. Tetrahedron 2012, 68, 4719.
26
PL6
Fine chemical synthesis through heterogeneous catalysis
under batch and continuous flow conditions
Giovanni Sartori, Raimondo Maggi
Dipartimento di Chimica, Università degli Studi di Parma,
Parco Area delle Scienze 17A, I-43124 Parma
giovanni.sartori@unipr.it
As well underlined by Basset1 “Catalysis remains a strategic field of chemistry because of its
implication in many fields, which include industry, energy, environment, and life sciences. Whether
it is homogeneous or heterogeneous (or even enzymatic), catalysis is primarily a molecular
phenomenon since it involves the chemical transformation of molecules into other molecules”.
In the last decades many efforts have been devoted to bring down the gap between these two
important sectors of the chemistry. Even if nowadays this challenging goal has not been reached, as
homogeneous catalysis is mainly related to the molecular and organometallic chemistry and the
heterogeneous one is closer to the surface science and solid state chemistry, nevertheless the
growing number of studies dealing with the application of heterogeneous and supported catalysts to
the (stereo)selective synthesis of fine chemicals and pharmaceuticals, has made possible to smooth
the way between the two sectors and to realize fruitful cooperation.
Since 1990 the goal of the “Clean Synthetic Methodology” Group has been the combination of the process efficiency and eco-compatibility in the fine chemical synthesis through heterogeneous
catalysis.
At the beginning the solid catalysts utilized were commercially available clays and zeolites;
successively more elaborated catalysts, prepared in the laboratories of the group, such as (chiral)
organic catalysts or transition metal complexes supported onto organic and inorganic polymers have
been applied.
These solid catalysts have been employed under batch and continuous flow conditions.
The tight cooperation with experts in surface chemistry, material characterization and reactor
assembling has allowed to face interesting challenges at both laboratory and industrial level.
Some interesting results will be briefly discussed.
(1) Copéret, C.; Chabanas, M.; Petroff Saint-Arroman, R.; Basset, J.-M. Angew. Chem. Int. Ed. 2003, 42, 156-181.
27
CONFERENZE PREMI PER LA RICERCA
28
PR1
Microwave dielectric heating, hydrogenation, hydroformylation, carbonylation,
asymmetric synthesis….. and beyond
Maurizio Taddei
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena,
Via A. Moro 2, 53100 Siena
maurizio.taddei@unisi.it
Since the initial experiments in 1980s, the application of microwave dielectric heating to organic
reactions has led a tremendous benefit to organic synthesis in terms of time saved and reaction
quality. However, as microwaves are always associated to heating, this technique has been seldom
used for enantioselective transformations, with many reports describing poor stereochemical control
and moderate enantiomeric excess. Analogously, the use of gaseous reagents in a microwave oven
has been for long time a taboo due to the microwave gas transparency. After developing an efficient
protocol to carry out microwave assisted reactions under gas pressure,1 we decided to investigate
the possibility to extend the process to asymmetric transformations.2 The versatility of
hydroformylation associated with a chiral auxiliary has been exploited in a series of domino and
multicomponent reactions for a rapid approach to piperidine based natural products or biologically
active compounds. On the other hand, catalytic asymmetric hydrogenation was also an obvious
choice for the huge number of catalytic systems available and for the synthetic versatility of the
reaction. In connection with a project for the total synthesis of the direct Renin inhibitor Aliskiren,
we developed a highly efficient process for the enantioselective hydrogenation of (E)-enol acetates
under microwave dielectric heating that shows several advantages respect to standard autoclave
hydrogenation presenting a valuable alternative to classic Ru catalyzed dynamic kinetic resolutions,
especially in the case of complex molecules.
(1) E. Petricci, M. Taddei Chimica Oggi. 2007, 25, 45-49.
(2) G. Arena, N. Zill, J. Salvadori, N. Girard, A. Mann, M. Taddei Org. Lett. 2011, 13, 2294-2297. N. Zill, A.
Schoenfelder, N. Girard, M. Taddei, A. Mann J. Org. Chem. 2012, 77, 2246-2253.
29
PR2
Multivalent calixarene ligands for lectins and nucleic acids
Alessandro Casnati.
Dip.to di Chimica, Università degli Studi di Parma,
Parco Area delle Scienze 17/a, 43124 Parma
casnati@unipr.it
Calixarenes1 are ideal scaffolds for the synthesis of multivalent ligands2,3 since the valency, distance
and stereochemical disposition of their ligating units might be easily varied exploiting well
consolidated synthetic procedures.
The lecture will give an overview of the supramolecular properties of the multivalent calixarenes
ligands
bearing
carbohydrates,
glycocalixarenes,4-6
or
guanidinium
head-groups,
guanidinocalixarenes.6-8 Glycocalixarenes having lactosyl units at their upper rim (e.g. 1) are able
to efficiently bind galectins, thus inhibiting their adhesion to the surface of tumor cells 5 and are
therefore potentially useful to develop site-specific drug-delivery systems or contrast agents.
Guanidinocalixarenes (e.g. 2) can bind, condense and deliver DNA inside cells with efficiency
superior to those of some important commercially available nonviral transfecting agents. 8 The
remarkable binding properties shown by these ligands certainly propose them as main characters in
Bionanotechnology.6
HO
OH
OH
OH
HO
OH
HO
O
HO
HO
O
OH
HO
NH
S
1
O
OH
HO
OH
NH
S
NH
O
HO
O OH
O
O
HO
HO
O
OH
OH
HO
OH
HO
HO
O
O
OH
HN
O O
O
HO
HO
HN
O O
O O
O
HN
S
HN
HO
HN
Cl
S
2
NH
H 2N
+
NH 2
H 2N
Cl
O O
HN
HN NH
2
NH 2
+
NH H N +
2
H 2N
+ NH
2
Cl
Cl
(1) Baldini, L.; Sansone, F.; Casnati, A.; Ungaro, R. Calixarenes In Molecular Recognition in Supramolecular
Chemistry: From Molecules to Nanomaterials, 2012, Vol. 3, 863-894.
(2) Casnati, A.; Sansone, F.; Ungaro, R. Acc. Chem. Res. 2003, 36, 246-254.
(3) Baldini, L.; Casnati, A.; Sansone, F.; Ungaro, R. Chem. Soc. Rev. 2007, 36, 254-266
(4) Sansone, F.; Rispoli, G.; Casnati, A.; Ungaro, R. Multivalent Glycocalixarenes, in “Synthesis and Biological Applications of Glycoconjugates”, Eds. O. Renaudet and N. Spinelli, Bentham Science Publishers, 2011, p. 36-63
(open access).
(5) André, S.; Sansone, F.; Kaltner, H.; Casnati, A.; Kopitz, J.; Gabius, H.-J.; Ungaro, R. ChemBioChem 2008, 9,
1641-1661.
(6) Baldini, L.; Sansone, F.; Casnati, A. Ungaro, R. Proteins and Nucleic Acids Targeting in “Applications of supramolecular chemistry”, H.-J. Schneider ed., CRC Press, 2012 cap. 15, 363-390.
(7) Sansone, F.;; Dudič, M.;; Donofrio, G.;; Rivetti, C.;; Baldini, L.;; Casnati, A.;; Cellai, S.;; Ungaro, R. J. Am. Chem.
Soc. 2006, 128, 14528 – 14536.
(8) Bagnacani,V.; Franceschi, V.; Fantuzzi, L.; Casnati, A.; Donofrio, G.; Sansone, F.; Ungaro, R. Bioconj. Chem.
2012, 23, 993-1002.
30
PR3
Twenty years of research and development in Bracco Imaging
Luciano Lattuada
Bracco Imaging S.p.A., CRB/Chemistry Dept., Via Ribes 5, Colleretto Giacosa (TO), Italy.
luciano.lattuada@bracco.com
Medical imaging is the technique to create images of the human body for clinical purposes, mainly
for the diagnosis of diseases.1
The first example dates back to 1895 when the W. C. Röntgen’s discovery of X-rays allowed to get
the image of the skeleton inside a living human. Since then, many other modalities, such as
Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Positron Emission
Tomography (PET), Single Photon Emission Computed Tomography (SPECT), Ultrasound, Optical
Imaging have been developed and applied in medicine.2,3
Moreover, the administration to the patient of an exogenous compound, usually called contrast
agent, greatly improve the quality of the images and expand the application of medical imaging.
Bracco Imaging is a worldwide leader in the manufacturing and marketing of contrast agents for
medical imaging. Iodinated molecules, such as Iopamidol and Iomeprol, employed in x-ray scans,
or gadolinium complexes, such as Multihance and Prohance, used in MRI techniques, are the most
known examples of contrast agents provided by Bracco Imaging.
HO
OH
OH
CONH
I
CONH
OH
I
I
I
HO
OH
OH
CONH
CONH
HO
OH
Me
Iopamidol
Ph
O
N
N
-
COO
I
Iomeprol
COO-
COO-
CONH
CON
OH
I
2 Meg+
N
Gd
Multihance
3+
-
N
N
Gd3+
N
N
COO-
COO
-
COO-
OOC
OH
OOC
Prohance
In this communication, few selected cases of R&D projects carried out in Bracco Research Centre
in the last twenty years will be presented and discussed.
(1) Braddock, M. Biomedical Imaging – The Chemistry of Labels, probes and Contrast Agents, RSC Publishing,
Cambridge, 2012.
(2) Merbach, A. E.; Tóth, É. The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging, Wiley, New
York, 2001.
(3) Krause,W.; Schneider; P. W. Top. Curr. Chem. 2002, 221, 1-235; W. Krause, P. W. Schneider. Top. Curr. Chem.
2002, 222, 1-278.
31
PR4
Organic salts: from ionic liquids to gels
Renato Noto
Dipartimento STEMBIO-Sezione di Chimica Organica “E. Paternò”
Università degli Studi di Palermo,
Viale delle Scienze-Parco d’Orleans II, 90128 Palermo
renato.noto@unipa.it
The “solvent action” has been frequently considered as one of the main topics of physical organic
chemistry. Lots of papers have tried to understand if and how a given solvent may affect the
outcome of a target reaction both in terms of rate and selectivity. As recently stated in literature, in
the last decades the intellectual foundations, strategies and methods of physical organic chemistry
have been adapted and applied to extremely complex and diverse supramolecular systems such as
materials science and biological sciences.1
The study of properties and applications of organic salts represents one of the examples in which
the above statement can be applied. Organic salts give rise to one of the most widely used class of
solvents in the last years: the ionic liquids “family”. Moreover, as a consequence of their structural features (Coulomb and hydrogen bond interaction sites, alkyl chains able to give hydrophobic and
van der Waals interactions, less or more extended -surface area etc.) they are also able to favor the
formation of conductive gel phases that, as well as ionic liquids, could be used as highly polar and
organized reaction media.
N
[NTf 2 ]
N
N
[NTf2 ]
N
N
[NTf 2 ]
N
C8 H16 N
2 [NTf 2 ]
N
[NTf2 ]
N
N
N
N
C8 H17
SO3
O3S
In this communication a fast “journey” across the research activity developed in the last decade,
going from ionic liquids to gels, will be carried out. Particular attention will be devoted to all
methods and “probe” systems that belong to physical organic chemistry and have allowed to have a better understanding of microscopic properties of these neoteric solvents.2 Then, on the whole, an
investigation of supramolecular systems using the instruments of physical organic chemistry will be
showed.
(1) Turro, N. J. J. Org. Chem. 2011, 76, 9863-9890.
(2) Noto, R. et al. a) J. Org. Chem. 2005, 70, 2828-2831. b) Tetrahedron 2006, 62, 1690-1698. c) J. Org. Chem. 2008,
73, 3397-3403. d) Chem. Eur. J. 2009, 15, 13059-13068. e) J. Org. Chem. 2010, 75, 767-771. f) Eur. J. Org.
Chem. 2011, 5681-5689. g) ChemPhysChem 2012, 13, 1877-1884.
32
COMUNICAZIONI ORALI
33
OC01
A low-molecular weight halogen-bonded complex showing
highly efficient photoalignment and Surface Relief Grating formation
Marco Saccone,1 Gabriella Cavallo,1 Pierangelo Metrangolo,1,2 Tullio Pilati,1 Giuseppe Resnati1,2
1
NFMLab – DCMIC “Giulio Natta”;; Politecnico di Milano, via Mancinelli 7, 20131 Milan, Italy;
2
Center for Nano Science and Technology, Istituto Italiano di Tecnologia,
Politecnico di Milano, via Pascoli 70/3, 20133 Milan, Italy.
marco.saccone@chem.polimi.it
Organic molecules capable of undergoing efficient and reversible photoisomerization upon
irradiation have attracted a huge scientific interest, since they offer the unique possibility to control
the properties of a system with light. Such photo-switching has been implemented in a variety of
materials ranging from optical devices to smart polymers and liquid crystals (LCs).1 It is wellknown that doping mesomorphic materials with photoactive azobenzene molecules results in a
system in which the LC-to-isotropic, and viceversa, can be controlled with light.2 It is also known
that in supramolecular small molecule complexes, liquid crystallinity promotes photoalignment of
molecules.3 Halogen bonding,4 namely the noncovalent interaction wherein halogen atoms function
as electrophilic species,5 has already been used to design supramolecular photoresponsive
polymers.6
In this communication we report on the first halogen-bonded low molecular weight complex that
exhibits both efficient Surface Relief Grating (SRG) formation and photoalignment upon irradiation
with polarized light. The obtained complex features a stilbazole derivative7 that self-assembles with
a photoactive azobenzene molecule bearing an iodotetrafluorophenyl ring as halogen-bonding donor
site. The obtained self-assembled complex may have potential for applications in imaging and data
storage.
(1)
(2)
(3)
(4)
(5)
Russew, M.-M.; Hecht, S. Adv. Mater. 2010, 23, 2149-2180.
Yu, H.; Ikeda T. Adv. Mater. 2011, 22, 3348-3360.
Zakrevskyy, Y.; Stumpe , J.; Faul, C. F. J. Adv. Mater. 2006, 18, 2133-2136.
Metrangolo, P.; Resnati, G. Science 2008, 321, 918-919.
An IUPAC Task Group set up to examine the definition of halogen bonding has not reported, yet, so that given
here should be taken as temporary (see www.iupac.org/web/ins/2009-032-1-100 and www.halogenbonding.eu).
(6) Priimagi, A.; Cavallo, G.; Forni, A.; Gorynsztejn–Leben, M.; Kaivola, M.; Metrangolo, P.; Milani R.; Shishido,
A.; Pilati, T.; Resnati, G.; Terraneo, G. Adv. Funct. Mater. 2012, 22, 2572-2579.
(7) Nguyen, H. L.; Horton , P.N.; Hursthouse, M.B.; Legon, A.C.; Bruce, D.W. J. Am. Chem. Soc. 2004, 126, 16–17.
34
OC02
From phenyl cations to ,n-didehydrotoluenes (,n-DHTs).
An alternative to enyne-allene cyclization.#
Stefano Protti,1 Davide Ravelli,1 Barbara Mannucci,2 Maurizio Fagnoni,1 Angelo Albini1
1
PhotoGreen Lab, Department of Chemistry, University of Pavia,
Viale Taramelli 12, 27100 Pavia, Italy
2
Centro Grandi Strumenti (CGS), University of Pavia, Via Bassi 21, 27100 Pavia (Italy)
prottistefano@gmail.com
The activation of a chemotherapeutic prodrug requires that an aggressive intermediate is generated
in situ by some mild mechanism. This in turn should be able to abstract hydrogens from DNA and
induce DNA cleavage and subsequent apoptosis. Among the few chemical classes that come close
to this paradigm are highly unsaturated hydrocarbons, such as enyne-allenes present in some natural
compounds (e.g. the antibiotic Neocarzinostatin).1 These moieties cyclize under physiological
conditions by converting two  bonds into a  one through the Myers-Saito reaction to a ,3didehydrotoluene (,3-DHT), the only isomer accessible by this approach (Scheme 1a).2 The
mechanism leading to this intermediate is still under debate.3
a)
3
4
C2-C7 cyclization
6
CH2
100 °C
1
5
.
CH3OH/H2O 9:1
2
.
,3-DHT
7
b)
CH2SiMe3
Cl
h -ClProtic
Solvent
3
.
CH2SiMe3
+
-SiMe3+
CH2
.
,n-DHT
Scheme 1
An alternative route to the generation of all of the ,n-DHT isomers involves the photochemical
generation of a triplet phenyl cation via heterolytic cleavage of the Aryl-Chloro bond occurring in
(n-chlorobenzyl)trimethylsilanes (Scheme 1b) followed by the loss the trimethylsilyl cation. The
photochemistry of the examined substrates and of the involved intermediates has been investigated
by means of a combined experimental/computational approach.4 This is the first report of DHTs
generation in solution starting from an aromatic precursors and, contrary to the Myers-Saito
protocol that is valid only for ,3-DHT, all of the isomers are generated in this way.
(1)
(2)
(3)
(4)
#
Enediyne Antibiotics as Antitumor Agents (Eds: D. B. Borders, T. W. Doyle), Marcel Dekker, New York, 1995.
Myers, A. G.; Parrish, C. A. Bioconjugate Chem. 1996, 7, 322-331.
Hughes, T. S.; Carpenter, B. K. J. Chem. Soc., Perkin Trans. 2 1999, 2291-2298.
Protti,S.; Ravelli, D.; Mannucci, B.; Fagnoni, M.; Albini, A. Angew. Chem. Int. Ed. 2012, 51, 8577-8580.
This work has been supported by Fondazione Cariplo (grant n° 2011-1839). S.P. acknowledges MIUR, Rome
(FIRB-Futuro in Ricerca 2008 project RBFR08J78Q) for financial support.
35
OC03
A new class of conformationally constrained bicyclic silylated diarylprolinol
organocatalysts
Marco Lombardo, Elisa Montroni, Arianna Quintavalla, Claudio Trombini
Università degli Studi di Bologna, Dipartimento di Chimica “G. Ciamician”,
via Selmi 2, 40126, Bologna - Italy.
marco.lombardo@unibo.it
Among the class of “privileged” organocatalysts, Jørgensen-Hayashi silylated diarylprolinols (1)
have been successfully used in a variety of useful synthetic transformations, almost invariably with
very high stereoselectivity values.1
One of the major drawback of this class of compounds is their lability towards desilylation
reactions, confirmed by the fact that also commercially available catalysts contain at least 10–15%
of their deprotected analogues.2 The corresponding desilylated diarylprolinols are much less active
catalysts, due to the almost irreversible reaction with carbonyl compounds to afford oxazolidines.
Finally, the free rotation of diarylmethanol group around C-C bond can bring to the formation of
different preferred conformations of the active intermediates.
Here we wish to report a new family of conformationally constrained bicyclic silylated
diarylprolinol analogues (2), deriving from natural L-4-hydroxy-proline, characterized by a superior
hydrolitic stability towards desilylation and by a very good catalytic efficiency.
Their preparation and their activity in different organocatalytic transformations based on the
iminium ion/enamine reactivity-type will be thoroughly presented.
(1) a) M. Marigo, D. Fielenbach, A. Braunton, A. Kjaersgaard and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44,
3703–3706. b) M. Marigo, T. C. Wabnitz, D. Fielenbach and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44,
794–797. c) Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., Int. Ed., 2005, 44, 4212–4215. d) M.
Marigo, J. Franzén, T. B. Poulsen, W. Zhuang and K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127, 6964–6965. e)
A. Mielgo and C. Palomo, Chem.–Asian J., 2008, 3, 922–948. f) C. Palomo and A. Mielgo, Angew. Chem., Int.
Ed., 2006, 45, 7876–7880. g) L. W. Xu, L. Li and Z. H. Shi, Adv. Synth. Catal., 2010, 352, 243–279. h) D. Enders,
C. Grondal and M. R. M. Hüttl, Angew. Chem., Int. Ed., 2007, 46, 1570–1581. i) D. Enders, C. Wang and J. W.
Bats, Angew. Chem., Int. Ed., 2008, 47, 7539–7542.
(2) M. H. Haindl, M. B. Schmid, K. Zeitler and R. M. Gschwind, RSC Advances, 2012, 2, 5941–5943.
36
OC04
A complete characterization of the 3D properties of the
CCR5 antagonist Vicriviroc
Laura Legnani,1 Diego Colombo,2 Fiorella Meneghetti,3 Stefania Villa,3 Lucio Toma1
1
2
Dipartimento di Chimica, Università di Pavia, Via Taramelli 12, 27100 Pavia, Italy.
Dipartimento di Chimica, Biochimica e Biotecnologie per la Medicina, Università di Milano,
Via Saldini 50, 20133 Milano, Italy.
3
Dipartimento di Scienze Farmaceutiche, Università di Milano,
Via Mangiagalli 25, 20133 Milano, Italy.
laura.legnani@unipv.it
Vicriviroc 1 is a piperazine-based CCR5 receptor antagonist, that showed better oral availability,
potency, safety, and pharmacological properties than its precursor SCH-C, but whose development
has been stopped.1 A full evaluation of the 3D properties of Vicriviroc was carried out, in order to
achieve a complete knowledge of its conformational behavior and, consequently, identify the
parameters necessary to design new, possibly better, analogs. The theoretical study was performed
at the B3LYP/6-31G(d) level of calculations.2 Particular attention was focused on the arrangement
at the planar amido function and on the conformational preferences of the piperazine and piperidine
rings.
H3CO
H3CO
2"

3"
N

F3C
N

1A
F3C
N
N
1"
4"
5"
6"
2a
1
1a N
2
5'
6'
N
3'
2'
N
O
3
6 5 4N
4'
1B
1'
O
1'a
5"'
6"'
4"'
N
3"'
N 1"'
2"'
Several conformational families, characterized by different through space contacts and comparable
energy values, were located and confirmed by high field NMR spectroscopy. Two distinct series of
signals, originated by the barrier to rotation of the amido function, were observed in the NMR
spectrum. Moreover, a NOESY experiment put in evidence all the close contacts present assuring
the coexistence, in solution, of numerous conformations in equilibrium, characterized by different
chair geometries of the heterocyclic rings.3
(1) Tagat, J. R.; McCombie, S. W.; Nazareno, D.; Labroli, M. A.; Xiao, Y.; Steensma, R. W.; Strizki, J. M.; Baroudy,
B. M.; Cox, K.; Lachowicz, J.; Varty, G.; Watkins, R. J. Med. Chem. 2004, 47, 2405-2408.
(2) a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652; b) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37,
785.
(3) Legnani, L.; Colombo, D.; Villa, S.; Meneghetti, F.; Castellano, C.; Gelain, A.; Marinone Albini, F.; Toma, L.
Eur. J. Org. Chem., 2012, DOI:10.1002/ejoc.201200586.
37
OC05
Investigation of mixed-monolayer-protected nanoparticles by NMR:
the use of Lanthanides for multi-component distribution mapping#
Gaetano Guarino, Fabrizio Mancin, Alessandro Bagno and Federico Rastrelli.
Dipartimento di Scienze Chimiche, Università degli Studi di Padova,
via Marzolo 1, 35131 Padova
federico.rastrelli@unipd.it
Monolayers of organic molecules coating nanoparticles (NPs) are known to produce different
patterns1 depending on the chemical nature of the grafted molecules (Fig.1). In principle, if such
patterns could be turned into specific motifs, they may result in cooperation of functional groups to
obtain molecular recognition: the potential of such topologically-controlled monolayers in every
field where NPs are applied, from nanomedicine2 to catalysis3 and materials development,4 is
virtually endless. Opposite to the nanocrystal core, however, there exist few experimental methods
that can provide information on the monolayer structure itself. In this challenging framework, we
exploit lanthanide-based NMR spectroscopy to investigate the properties of mixed monolayers.
(a)
(b)
(c)
Figure 1: Representative patterns of mixed-monolayer protected gold nanoparticles: (a) Janus, (b) stripes, (c) patches.
Gd3+ ions are well known to induce a paramagnetic relaxation enhancement (PRE) that broadens
and eventually cancels the signals of nuclear spins located nearby. Similarly, when Gd 3+ ions bind
to nanoparticles coated with mixed monolayers, the signals arising from the different coating
molecules experience a different PRE, depending on their distance from the binding site. As a
consequence, observation of the patterns of signal broadening provides direct information on the
monolayer organization.5 The study is complemented with a computational investigation of the 13C
chemical shifts of the grafted thiol alkyl chains, in order to better understand the still elusive nature
of the Au-S bond.
(1)
(2)
(3)
(4)
(5)
#
(a) Centrone, A.; Hu, Y.; Jackson, A. M.; Zerbi, G.; Stellacci, F. Small 2007, 3, 814. (b) Jackson, A. M.; Myerson,
J. W.; Stellacci, F. Nat. Mater. 2004, 3, 330.
Giljohann, D. A.; Seferos, D. S.; Daniel, W. L.; Massich, M. D.; Patel, P. C.; Mirkin, C. A. Angew. Chem., Int. Ed.
2010, 49, 3280-3294.
Schatz, A.; Reiser, O.; Stark, W. J. Chem. Eur. J. 2010, 16, 8950-8967.
Nie, Z. H.; Petukhova, A.; Kumacheva, E. Nat. Nanotechnol. 2010, 5, 15-25.
Guarino, G; Rastrelli, F; Scrimin, P.; Mancin, F. J. Am. Chem. Soc. 2012, 134, 7200-7203.
This project was granted by the European Reseach Council, Grant ERC-StG 259014 MOSAIC
38
OC06
Color tuning in multichromophoric heteroaromatic electrochromic conjugated
polymers. Highly stable materials for all plastic electrochromic devices.
L. Beverina, M. Sassi, M. M. Salamone, R. Ruffo, C. M. Mari, G. A. Pagani.
University of Milano-Bicocca and INSTM, Department of Material-Science,
Via R. Cozzi 53, Milano 20125, ITALY.
luca.beverina@unimib.it
Recent years registered a constantly increasing demand of highly performing conjugated materials
for technological applications including displays, solar cells and field effect transistors. In particular
organic electrochromic materials (OEMs) offer a low power input and potentially low cost solution
for displays and shading technologies.1 The organic electrochromic palette nowadays includes all
primary colors as well as neutral tints, most notably black.2,3 Such exceptional achievement is
ascribed to the successful Donor-Acceptor (D-A) strategy.4 Poly(3,4-ethylenedioxythiophene)
(PEDOT) bearing discrete monodisperse electrochromic single molecule as side chain substituents
are a viable alternative to D-A polymers. Most relevant advantages are a easy synthetic access,
compatible with multi grams scale preparations, color tunability, high stability and complete
colorlessness in the oxidized form. We here present the design, synthesis, polymerization and full
electrochemical and spectroelectrochemical characterization of a series of new DE-functionalized
PEDOT materials. These new polymers show exceptionally high redox reversibility, efficient
switching between red/purple/brown gray colored states and a completely colorless bleached state
characterized by a transmittance above 80 %. These materials are compatible with both chemical
and electrochemical deposition, feature cheap starting materials and mild reaction conditions.
Relevant results about solid-state devices will also be discussed.5
Figure 1: A) Capacity retention as a function of the cycle number for a representative polymer.
Inset: CV plots as a function of the cycle number for the first 1000 cycles. B) Polymer color as a
function of the applied bias.
(1)
(2)
(3)
(4)
(5)
Sönmez, G. Chem. Commun. 2005, 5251–5259.
Beaujuge, P. M.; Reynolds, J. R. Chem. Rev. 2010, 110, 268–320.
Gunbas, G.; Toppare, L. Chem. Commun. 2012, 48, 1083–1101.
Beaujuge, P. M.; Amb, C. M.; Reynolds, J. R. Accounts Chem. Res. 2010, 43, 1396–1407.
Sassi, M.; Salamone, M. M.; Ruffo, R.; Mari, C. M.; Pagani, G. A.; Beverina, L. Adv. Mater. 2012, 24, 2004–
2008.
39
OC07
Organic chemistry contribution to biomaterial science: case studies
Laura Cipolla
Department of Biotechnology and Biosciences, University of Milano-Bicocca,
P.zza della Scienza 2, 20126 Milano-Italy
laura.cipolla@unimib.it
Research on biomaterials surface has become one of the hottest topics in biomaterials and
biomedical engineering.1 Modern biomaterials science is characterized by a growing need to
integrate biomaterials design with new insights emerging from studies of cell–matrix interactions,
cellular signalling processes,2 towards the design of bioactive materials that can modulate and
control cell behaviour (smart biomaterials).
One of the critical issues in the design of biomaterials for tissue engineering is the possibility to
recreate conditions that mimic the natural extra-cellular matrix (ECM) environment for particular
cell types in order to support their function and proliferation. Since cell contact with the
biomaterial surface is a key point, in recent years, biomaterial designs have focused on the
functionalisation of material surfaces with biomolecules,3 that are, of course, organic compounds.
Thus biomaterial science needs continuous input from organic chemistry, and organic chemistry
may find challenging and unprecedented synthetic methodologies targeted to biomaterial
functionalisation.
Recent examples of organic chemistry methodologies applied to material surface functionalisation
will be presented,4-8 including the application of chemoselective and bio-orthogonal approaches.
Examples of material functionalisation will range from natural and un-natural organic polymers
such as collagen and polypropylene to inorganic materials such as hydroxypatatite.
(1) Leeuwenburgh, S.C.G.; Jansen, J.A.; Malda, J.; Wouter, A.D.; Rouwkema, J.; Van Blitterswijk, C.A.; Kirkpatrick,
C.J.; Williams, D.F. Biomaterials 2008, 29, 3047.
(2) Langer, R.; Tirrell, D. Nature 2004, 428, 487.
(3) Bacáková, L.; Filova, E.; Rypacek, F.; Svorcik, V.; Stary, V. Physiol Res 2004, 53, 35.
(4) Russo, L.; Zanini, S.; Riccardi, C.; Nicotra, F.; Cipolla, L. Materials today, 2011, 14, 164-169.
(5) Russo, L.; Landi, E.; Tampieri, A.; Natalello, A.; Doglia, S.M.; Gabrielli, L.; Cipolla, L.; Nicotra, F. Carbohydr.
Res. 2011, 346, 1564-1568.
(6) Sandri, M.; Natalello, A.; Bini, D.; Gabrielli, L.; Cipolla, L.; Nicotra, F.. Synlett 2011, 1845-1848.
(7) Russo, L.; Zanini, S.; Giannoni, P.; Landi, E.; Villa, A.; Sandri, M.; Riccardi, C.; Quarto, R.; Doglia, S.M.;
Cipolla, L.; Nicotra, F. J. Material Sci. 2012, accepted for publication after revisions.
(8) Taraballi, F.; Zanini, S.; Lupo, C.; Panseri, S.; Cunha, C.; Riccardi, C.; Marcacci, M.; Campione, M.; Cipolla,
Biomacromolecules 2012, submitted.
40
OC08
Lactames and cyclic imides: new building blocks for semiconducting polymers
and their applications in polymeric solar cells
Luciano Miozzo,1,2 Ramona Gironda,1,2 Antonio Papagni,2 Abderrahim Yassar,1
Jin-Woo Choi,1 Yvan Bonnassieux,1 Bernard Geffroy1 Denis Tondelier.1
1
LPICM, Ecole Polytechnique, UMR 7647 CNRS, route de Saclay, 91128 Palaiseau Cedex, France.
2
Dipartimento di Scienza dei Materiali, Università degli Studi di Milano Bicocca,
via R. Cozzi 53, 20125, Milano.
luciano.miozzo@mater.unimib.it
Bulk heterojunction solar cells (BHJSCs) are a possible solution to the need for low cost, renewable
energy sources. Record efficiencies close to 10% have been recently reported for BHJSCs, making
organic photovoltaics (OPV) competitive with amorphous silicon technologies.1 The recent increase
in power efficiency of OPV cells has been obtained mainly by the design of new semiconducting
polymers and materials and even higher efficiencies (15-20%) are envisaged for the next 5-10
years.2 This goal requires a huge effort in terms of synthesis of new materials (mainly new
semiconducting polymers) and development of new device architectures. Low-bandgap
copolymers, based on the internal donor–acceptor (D–A) interactions, are the most promising
choice to develop new semiconducting polymers for BHJSCs, thanks to the possibility to tune their
optical and electronic properties by proper combinations of D and A units. Among the wide number
of acceptor units, cyclic imides and amides, such as 2,5-diketopyrrolo-[3,4-c]pyrrole (DPP)
derivatives, have emerged as promising building blocks for the synthesis of these low-bandgap,
donor-acceptor copolymers.
Here we present our results about the synthesis and the application in BHJSCs of new D-A
copolymers, incorporating disubstitued-N-alkyl-maleimides (a) and pyrrolo[3,2-b]pyrrole-2,5-dione
(b), an isomer of DPP, as accepting units (See figure). We developed efficient syntheses of
symmetrical 3,6-di(thienyl)pyrrolo[3,2-b]pyrrole-2,5-dione and of disubstituted N-alkyl-maleimide,
which were used to prepare D-A copolymers by Stille cross-coupling polymerization. These
polymers present broad absorption spectra, extending close to the NIR region, and values of
HOMO/LUMO energy levels suitable for their application in BHJSCs. We fabricated BHJSCs
using these D-A copolymers, mixed with PC60BM (a soluble fullerene derivative, used as acceptor
material) and we investigated their photovoltaic properties.
S
S
Ar
N
S
n
O
N
R
O
O
N
Ar
O
S
n
a
b
(1) Li, G.; Zhu, R. Yang, Y. Nature Photonics 2012, 6, 153–161
(2) Koster L. J. A.; Shaheen, S. E.; Hummelen J. C. Adv. Energy Mater. 2012, 10.1002/aenm.201200103
41
OC09
Conjugate addition versus cycloaddition-condensation
of nitro compounds in water#
Francesco De Sarlo,1 Luca Guideri,2 Fabrizio Machetti2
1
Dipartimento di Chimica Ugo Schiff dell’Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino Firenze
2
Istituto di Chimica dei Composti Organo Metallici del Consiglio Nazionale delle Ricerche
c/o Dipartimento di Chimica Ugo Schiff
fabrizio.machetti@unifi.it
Activated primary nitro compounds, like ethyl nitroacetate, have been shown to undergo in
chloroform base-catalysed condensations with unsaturated substrates (dipolarophiles) to isoxazole
derivatives in competition with conjugate addition (Scheme 1).1-3
NO2
EtO2C
catalyst
EWG
O2 N
CO2Et +
EWG
catalyst
EtO2C
H2O
EWG
N O
Scheme 1
The ratio between the two products was found to depend mainly on the base employed and on its
concentration: the results were rationalised considering that condensations to isoxazolines occur
after
considerable
induction
times.
Condensations are in general largely
predominant if Cu(II) salt is added to the
catalytic system. In this communication we
consider how the solvent (water vs
chloroform) affects the selectivities
observed in the above reactions. In general,
high selectivity towards condensation is
observed in water, with shorter induction
periods than in chloroform (see Figure 1).
In water, condensations slowly occur even
without base: kinetic profiles evidence the
catalytic effect of the base, that should be
related to the conversion to the tautomeric
nitronic acid. Condensations in water4 are
useful as a convenient access to isoxazole
derivatives bearing various functional
groups: e. g. N-aminoethylnitroacetamide hydrochloride and methacrylamide give the condensed
cycloadduct in good yield (Scheme 2).
H3N
Cl-
H
N
NO2 +
O
O water
catalyst
NH2
H3N
Cl-
O
O
N
H
N O
NH2
+ H2O
92%
Scheme 2
(1)
(2)
(3)
(4)
#
Machetti F.; Cecchi L.; Trogu E.; De Sarlo F. Eur. J. Org. Chem. 2007, 4352 – 4359.
Cecchi L.; De Sarlo F.; Machetti F.Chem. Eur. J. 2008, 14, 7903 – 7912.
Trogu E.; De Sarlo F.; Machetti F. Chem. Eur. J. 2009, 15, 7940 – 7948.
Vinattieri C.; Trogu E.; De Sarlo F.; Machetti F. Chem. Eur. J. 2012, 18, 2081 – 2093.
The authors thank the Ministero dell’Istruzione, Università e Ricerca (MIUR, Italy project COFIN 2008 – prot.
200859234J) for financial support.
42
OC10
Structural and medium effects on hydrogen abstraction reactions
from C-H bonds by alkoxyl radicals. The role of hydrogen bond interactions
Michela Salamone,1 Michela Milan,1 Livia Mangiacapra,1 Gino A. DiLabio,2 Massimo Bietti1
1
Dipartimento di Scienze e Tecnologie Chimiche, Università "Tor Vergata",
Via della Ricerca Scientifica, 1 00133 Roma
2
National Institute for Nanotechnology, National Research Council of Canada,
11421 Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2M9.
bietti@uniroma2.it
Hydrogen atom abstraction is one of the most fundamental chemical reactions and plays a major
role in a variety of important chemical and biological processes. These reactions are involved in
processes such as lipid peroxidation, the antioxidant activity of vitamin E and other natural and
synthetic phenolic and non-phenolic antioxidants, enzymatic reactions, the degradation of volatile
organic compounds in the atmosphere, as well as in a large number of synthetically useful
procedures. Among the abstracting radicals, highly reactive oxygen centered radicals such as
alkoxyls (RO) have received considerable attention, as these radicals are able to abstract an
hydrogen atom from a large variety of substrates, and accordingly their hydrogen abstraction
reactivity has been studied in detail. Limited information is instead available on the role of radical
structure on these reactions.
In view of the relevance of these reactions and to develop a deeper mechanistic understanding on
hydrogen abstraction reactions by alkoxyl radicals, we have carried out a detailed time-resolved
kinetic study on the hydrogen abstraction reactions from a variety of CH atom donors by two
selected alkoxyl radicals: the cumyloxyl (PhC(CH3)2O, CumO) and benzyloxyl radicals
(PhCH2O, BnO). Particular attention has been devoted to the role of structural effects in both the
radical and the substrate and of medium effects in these reactions.
These studies have shown the existence of very large differences in reactivity between the two
radicals in their reactions with substrates characterized by high hydrogen bond acceptor abilities. 1
Sizable kinetic solvent effects have been also observed in the reactions of CumO with a series of
hydrogen atom donors.2
These effects have been explained on the basis of the important role played by specific
substrate/radical hydrogen bond interactions and, for what concerns solvent effects, of
substrate/solvent and radical/solvent hydrogen bond interactions.
(1) Salamone, M.; DiLabio, G. A.; Bietti, M. J. Am. Chem. Soc. 2011, 133, 16625-16634. Salamone, M.; DiLabio, G.
A.; Bietti, M. J. Org. Chem. 2011, 76, 6264-6270. Salamone, M.; Anastasi, G.; Bietti, M.; DiLabio, G. A. Org.
Lett. 2011, 13, 260-263.
(2) Bietti, M.; Martella, R.; Salamone, M. Org. Lett. 2011, 13, 6110-6113. Salamone, M.; Giammarioli, I.; Bietti, M.
J. Org. Chem. 2011, 76, 4645-4651. Bietti, M.; Salamone, M. Org. Lett. 2010, 12, 3654-3657.
43
OC11
Mechanistic studies of a non usual Wittig reaction
Michela Pelà, Severo Salvadori, Remo Guerrini and Claudio Trapella
Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara, 17/19, 44121 Ferrara
trap@unife.it
The mitochondria associated granulocyte–macrophage colony stimulating factor signaling molecule
(MAGMAS) is a crucial protein for mitochondria function and cell survival1 and this complex
seems to be involved in different endocrine associated tumours.2
Our research group started a medicinal chemistry campaign aimed at the identification of novel
MAGMAS inhibitors. In this frame, the molecule identified by Jubinsky et al. (figure 1) has been
selected as reference molecule for in vitro biological assays.3
Figure 1
Its synthesis has been successfully performed following the synthetic methodology proposed by
Jubinsky’s group. In addition, our curiosity was attracted by the uncommon mechanism of the Wittig reaction proposed in the original paper that envisioned an intramolecular proton shift to
explain the product formation.4 (Scheme 1)
Br
OH
H shift
tBuONa
PPh3HBr
PPh3
Ph
2
A
P
Ph
Ph
B
PPh3
C
PPh3
D
PPh3
Scheme 1
E
We deeply investigated the mechanism of this reaction and in this communication we describe
evidences supporting the formation of 6 following Scheme 2
Scheme 2
Thus, treatment of the secondary alcohol 2 with triphenylphosphine hydrobromide in methanol
furnished the secondary carbocation 3 that underwent proton elimination to stabilize itself as a diene
4 (confirmed by NMR). The subsequent attack of the phosphorus lone pair at the less hindered
position of the diene gave the phosphonium salt 5 that was easily stabilized by treatment with BuLi
in THF. The formation of this compound instead of the quaternary phosphonium salt (B) described
by Das et al.4 has been fully confirmed through complete NMR analysis.
(1) a) N. Wiedemann, A. E. Frazier, N. Pfanner. Journal of Biological Chemistry. 2004, 279, (15), 14473–14476. b) P.
T. Jubinsky, A. Messera, J. Bender, R. E. Morris, G. M. Ciraolo, D. P. Witte, R. G. Hawley, M. K. Short.
Experimental Hematology. 2001, 29, 1392–1402.
(2) P. T. Jubinsky, M. K. Short, G. Mutema, R. E. Morris, G. M. Ciraolo, M. Li. J Mol Hist. 2005, 36, 69–75.
(3) P. T. Jubinsky, M.K. Short, M. Ghanem, B. C. Das. Bioorganic & Medicinal Chemistry Letters. 2011, 21, 3479–
3482.
(4) B. C. Das, S. M. Mahalingam, T. Evans, G. W. Kabalka, J. Anguiano, K. Hema. Chem. Commun. 2009, 2133–
2135.
44
OC12
Novel anion receptors for the fluorescent sensing of L-lactate#
Michele Bruschini,1 Antonella Dalla Cort,1 Philip A. Gale,2 Jennifer R. Hiscock2
1
Dipartimento di Chimica, Sapienza Università di Roma-Piazzale Aldo Moro 5, 00185 Roma
2
Chemistry, University of Southampton, Southampton, SO17 1BJ, UK
michele.bruschini@uniroma1.it
L-Lactate plays an extremely important role not only in biological systems, but also in industrial
manufacturing. In the human body, it is found naturally as a product of anaerobic respiration, while
on the industrial scale it is synthesized and used for the preservation of food1 and the production of
biomaterials.2
The concentration of this anion in blood can be indicative of several life threatening conditions.3
Due to its important medicinal relevance, the design of receptors capable of selectively and
quantitatively sensing L-lactate over structurally similar anions like pyruvate (Figure 1) is a very
challenging task.
Figure 1 Schematic representations of the two anions
Here we report the synthesis of four novel benzoimidazole-based receptors functionalized with a
naphthalene moiety (5-8, Figure 2). The results of the sensing studies with tetrabutylammonium
lactate and pyruvate, carried out in aqueous mixtures by means of fluorescence spectroscopy, will
be also discussed.
Figure 2 Schematic representation of the four receptors 5-8
(1) a) Shrestha, B.M.; Mundorff, S.A.; Bibby, B.G. Caries Research 1982, 16, 12-17; b)
http://www.foodditive.com/additive/calcium-lactate.
(2) a) Middleton, J.C.; Tipton, A.J. Biomaterials, 2000, 21, 2335-2346; b) Södergård, A.; Stolt, M. Prog. Polym. Sci.
2002, 27, 1123–1163.
(3) Bakker, J.; Pinto de Lima, A. Critical Care 2004, 8, 96-98.
#
Work done in the frame of the European COST Action CM1005 “Supramolecular Chemistry in Water”
45
OC13
Stereoprogrammed interlocked structures based
on calixarene threading
Carmen Talotta, Carmine Gaeta, Roberta Ciao, Placido Neri
Dipartimento di Chimica e Biologia and NANO_MATES Research Center, Università di Salerno,
Via Ponte don Melillo, I-84084 Fisciano (Salerno), Italy
ctalotta@unisa.it
Recently, we have introduced an efficient method to obtain endo-cavity complexation and throughthe-annulus threading of large calix[6-7]arenes exploiting the inducing effect of a weakly
coordinating anion, tetrakis [3,5-bis (trifluoromethyl) phenyl]borate (TFPB-).1 This approach has
been used for the synthesis of [2]rotaxanes,2 which showed an unprecedented inversion of the wheel
orientation.
Subsequently, it was extended to the synthesis of pseudo[3]rotaxane systems in which two
calix[6]arene macrocycles are threaded by a bis(benzylalkylammonium) axle.3 Because of the threedimensional nonsymmetrical nature of the calix[6]arene wheels, in these instances three sequence
stereoisomers could be obtained, which were termed as head-to-head (H,H), head-to-tail (H,T) and
tail-to-tail (T,T).
Taking advantage of these systems, it was possible to obtain the stereoprogrammed synthesis of the
first examples of calixarene-based [3]rotaxane architectures. The base/acid treatment demonstrated
that these systems act as molecular shuttles, which move on a nanometer scale level.4
The directionality of the threading and the observed high stereoselection have enabled the synthesis
of directional calix[6]arene-based catenane. All these aspects represent interesting peculiar features
of calixarene threading, which could be exploited for designing molecular machines with new
properties or functions.
(1) a) Gaeta, C.; Troisi, F.; Neri, P. Org. Lett. 2010, 12, 2092. b) Gaeta, C.; Talotta, C.; Farina, F.; Camalli, M.;
Campi, G.; Neri, P. Chem.−Eur. J. 2012, 18, 1219.
(2) Pierro, T.; Gaeta, C.; Talotta, C.; Casapullo, A.; Neri, P. Org. Lett. 2011, 13, 2650.
(3) Talotta, C.; Gaeta, C.; Pierro, T.; Neri, P. Org. Lett. 2011, 13, 2098.
(4) Talotta, C.; Gaeta, C.; Neri, P. Org. Lett. 2012, DOI:10.1021/ol3011997.
46
OC14
Photophysical properties in solution and on ITO surface
of a new class of polyquinoid compounds
Sara Lentini, Valentina Armuzza, Emanuela Gatto, Valeria Conte,
Barbara Floris, Mariano Venanzi and Pierluca Galloni.
Dipartimento di Scienze e Tecnologie Chimiche, University of Rome Tor Vergata
sara.lentini@uniroma2.it
The study of the electron transfer processes and their possible applications in organic photovoltaic
technology is of great interest for the engineering of new and efficient solar energy devices.
Langmuir Blodgett (LB) films in light-utilizing devices represent an useful technique to easily
obtain mono and multi layers using different molecules.1 Recently we discovered a new class of
quinoid compounds2 that show very interesting photo- and electrochemical properties such as a
broad absorption spectra in visible region and a very low reduction potential. For these reasons we
used these diquinoid molecules in LB deposition of mono and multi layers films on ITO surface.
The results in terms of photocurrent generation and films stability are promising and they will be
discussed as a function of layers number.
HO
LB
CHCl3/H2O
O
ITO
O
OH
O
=
(1) a) Yam, V.; W.-W.; Li, B.; Yang, Y.; Chu, B. W.-K.; Wong, K. M.-C.; Cheung, K.-K. Eur. J. Inorg. Chem. 2003,
4035. b) Vivo, P.; Vuorine, T.; Chukharev, V.; Tolkki, A.; Kaunisto, K.; Ihalaine, P.; Peltonen, J.; Lemmetyinen,
H. J. Phys. Chem. C 2010, 114, 8559 c) Marczak, R.;; Sgobba, V.;; Kutner, W.;; Gadde, S.;; D’Souza, F.;; Guldi, D.
M. Langmuir 2007, 23, 1917.
(2) Coletti, A.; Lentini, S.; Conte, V.; Floris, B.; Bortolini, O.; Sforza, F.; Grepioni, F.; Galloni, P. submitted.
47
OC15
Alpha-diazocarbonyl-piperidine derivatives:
chemoselective rhodium catalysed transformation.
Andrea Bonetti, Sara Pellegrino, Maria Luisa Gelmi,
University of Milan
Andrea.bonetti@unimi.it
Several natural compounds or compounds of biological interest contain the piperidine nucleus that,
in many cases, is inserted in complex structures or simply condensed with other rings.
Our interest is address to the preparation of different piperidine systems using a very interesting
chemistry that combines the use of -diazocarbonyl compounds and rhodium (II) dimer catalysts.
Our studies were focused on the synthesis of piperidine derivatives, or their benzocondensed
analogues as well as of more complex structures such as hexahidrobenzophenanthidine alkaloids or
crinine derivatives.
Several piperidine, all functionalized with diazo-keto function, characterized by a different
substitution pattern and stereochemistry, were used as starting materials. These key intermediates
when treated with a rhodium catalyst afford electrophilic carbenes that could give a chemoselective
C-H or N-H insertion, or reactions with an aromatic ring depending on the nature of the catalyst.
Simple diazoketo-piperidine afforded CH insertion giving tropone derivatives. More complex
compounds could be obtained from tetrahydroisoquinoline derivatives as shown in Scheme 1.
(1)
(2)
(3)
(4)
Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou L. Chem. Rev. 2010, 110, 704–724 and references cited therin. (b) Ye, T.;
McKervey A. Chem. Rew. 1994, 94, 1091-1160. (c) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072–3081. (d) Doyle, M. P. ;
McKervey, M. A.; Ye, T. in Modern Catalytic Methods for Organic Synthesis With Diazo Compounds, Wiley- Interscience,
New York, 1998.
Meerwein, H.; Rathjen, H.; Wemer, H. Ber. Dtsch. Chem. Ges. 1942, 75, 1610.
a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int Ed. 1998, 37, 1044. b) Suresh, S.; Periasamy, M. Tetrahedron Lett.
2004, 45, 6291. c) Funatomi, T.; Nakazawa, S.; Matsumoto, K.; Nagase, R.; Tanabe, Y. Chemm. Com. 2008, 771.
a) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215. b) Ager, D. J.;
Prakash, I.; Schaad; D. Aldrichimica Acta 1997, 30, 3. c) Seebach, D.; Schaeffer, L.; Gessier, F.; Bindschädler, P.; Jäger, C.;
Josin, D.; Kopp, S.; Lelais, G.; Mahajan, Y. R.; Micuch, P.; Sebesta, R.; Schweizer, B. W. Helv. Chim. Acta 2003, 86, 1852.
(d) Periasamy, M.; Ganesan, S. S.; Suresh, S. Tetrahedron: Asimmetry 2010, 21, 385-392.
48
OC16
Heteroaromatic-based fluorophores for smart materials
via palladium-catalyzed coupling reactions
F. Bellina,1 M. Lessi,1 A. Pucci,1,2 G. Ruggeri,1,3 S. Barondi,1 L. Perego,1,4 P. Minei.1
1
Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Italy.
2
CNR NANO, Istituto Nano Scienze-CNR, Pisa. Italy.
3
Istituto per Processi Chimico Fisici-CNR, Pisa, Italy.
4
Scuola Normale Superiore, Pisa, Italy.
marcol@ns.dcci.unipi.it
Stimuli-responsive materials, nowadays called also "smart" materials, are able to detect thermal,
mechanical, optical or chemical solicitations. These smart materials are generally obtained by
properly combining chemical functional species (fluorophores) into a multiphase systems (polymer
composite) whose distinct responses could be effectively modulated, in terms of intensity and
selectivity, by controlling interphase interactions.1
Organic fluorophores featuring heteroaromatics as the main π-conjugated backbones usually display
high polarizability, stability and thermal and chemical robustness required for fabrication processes.
During our studies on the selective and efficient C–C bond forming reactions using palladium
catalysts2 we became interested in preparing new heteroaromatic fluorophores to be used for the
preparation of stimuli-responsive materials.3
In this communication we will focus on the application of selective Pd-catalyzed reactions to the
synthesis of novel organic fluorophores containing sulfur- and nitrogen-based heteroaromatics as
relevant conjugated moieties (Figure 1).
R1
R
N
S
N
R2
N
N
R3
N
N
N
1
R2
N
N
2
3
Figure 1
In details, 1,4-bis-ethynylbenzenes 1, end-capped with a thienyl ring on one side and with a
nitrogen-containing heteroaromatic core on the other side, were prepared via sequential palladiumcatalyzed Sonogashira-type couplings.4 On the other hand, imidazole-based fluorophores 2 and 3
were synthesized using selective palladium-catalyzed direct C-H arylation protocols.5
The optical properties of compounds 1-3 in relation to their structures, and their behaviour at the
variation of pH will be also discussed.
(1) Pucci, A.; Bizzarri, G.; Ruggeri, G. Soft Matter 2011, 7, 3689-3700.
(2) a) Bellina, F.; Cauteruccio, S.; Di Fiore, A; Rossi, R. Eur. J. Org. Chem. 2008, 5436-5445. b) Bellina, F.;
Cauteruccio, S.; Di Fiore, A.; Marchetti, C.; Rossi, R. Tetrahedron 2008, 64, 6060-6072.
(3) Barone, V.; Bellina, F.; Biczysko, M.; Cappelli, C.; Carta, L.; Lessi, M.; Prampolini, G.; Pucci, A.; Ruggeri, G. J.
Am. Chem. Soc. Submitted.
(4) Bellina, F.; Lessi, M.; SynLett. 2012, 23, 773-777.
(5) Bellina, F.; Rossi, R. Adv. Synth. Catal. 2010, 352, 1223-1276.
49
OC17
Tetrathienyltetrathiafulvalenes, efficient “suicide” sensitizers of singlet oxigen:
synthesis and properties of thienyl substituted 1,2,5,8-tetrathiecine-6,7-dione,
a new heterocyclic system
Donato Donati, Stefania Fusi, Fabio Ponticelli
Dipartimento di Chimica, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena, Italy
Stefania.fusi@unisi.it
Tetrathiafulvalene derivatives are largely investigated for their potential involvement in organic
polymeric conducting materials, useful for transistors and solar cells.1 In particular, tetrathienyl
substituted analogues 1a,b were synthesized and considered for electrochemical investigations.2
Following our interest on photooxidative processes of thienyl substituted systems,3 here we report
the photochemical behaviour of 1a,b in presence of oxygen to give ciclic disulfides 3a,b in good
yields.
O
R
R
S
S
S
S
1a,b
a) R = 2-Thienyl
b) R = 3-Thienyl
R
R
O2, C6D6
570 nm
R
R
SO OS
S
S
2a,b
R
O
S
S
R
R
R
R
S S
R
3a,b
Our results, based on sensitizations and quenching experiments, indicate that
tetrathienyltetrathiafulvalenes 1a,b are able to produce singlet oxigen, which undergoes
cycloaddition on the double bond of 1a,b to give the unstable dioxetanes 2a,b. These compounds
finally rearrange to the cyclic dithiooxalates 3a,b, a new type of heterociclic system. Analogous
singlet oxigen cycloaddition-rearrangement sequence was previously reported for some
tetrathioethenes, but in that case the presence of an independent sensitizer is required.4
The X-ray structure of compound 3b is reported below.
Some data on spectroscopic properties and chemical behaviour of 3a,b will be also reported.
(1) a) Beaujuge, P.M., Fréchet, J.M.J., J. Am. Chem. Soc., 2011, 132, 20009-20029; b) Song, C., Swager, T., J.
Org. Chem., 2010, 75, 999-1005.
(2) a) Charlton, A., Underhill A.E., Williams G., Kalaji M., Murphy P.J., Malik K.M. Abdul, Hursthouse M.B., J.
Org. Chem., 1997, 62, 3098-3102; b) Charlton, A., Kalaji M., Murphy P.J., Salmaso, S., Underhill A.E.,
Williams G., Hursthouse M.B., Malik K.M. Abdul, Synthetic Metals, 1998, 95, 75-78.
(3) Blencowe, A., Celli A.M., Donati D., Hayes W.C., Martin C., Murphy P.J., Ponticelli, F., Melville-Richards
J.K.. Tetrahedron, 2009, 65, 3858-3862 and references therein.
(4) Adam, W, Ju-Chao L., J. Am. Chem. Soc., 1972, 94, 1206-1209.
50
OC18
One-step synthesis of constrained peptidomimetics including oxazolidinones
and/or-amino acids, and application to the design of bioactive compounds
R. De Marco, A. Tolomelli, M. Campitiello, P. Rubini, S. Rupiani, A. Greco, L. Gentilucci
Dept. Of Chemistry “G. Ciamician”, University of Bologna, via Selmi 2,40126, Bologna, Italy.
rossella.demarco2@unibo.it
We present a new methodology for the straightforward preparation of peptides containing 2-oxo1,3-oxazolidine-4-carboxylate (in short: Oxd) peptides and/or -amino acids, by treatment of
arylsulfonyl peptides containing L or D-configured -hydroxy amino acids with DSC and a base.
To expand the scope of the methodology, we introduced in a single step two Oxd rings, consecutive
or separated by other amino acids, from peptides containing Ser/Thr/PhSer. The synthesis of the
linear precursors and the cyclization reaction was performed either in solution or in the solid phase,
making the entire process a convenient method for the preparation of constrained peptidomimetics.
Further, the elaboration of the -amino acids allows preparing different unnatural aminoacids.
Interestigly, the procedure gave in a single step the -amino acids equipped with a effective
oxazolidinone chiral auxiliary for asymmetric syntheses.
The cyclization mechanism has been investigated by varying the reaction conditions, and the results
were rationalized with the aid of theoretical computations.
The Oxd residues can be regarded to as suitable constrained pseudo-Pro. The peptides containing
the Oxd show an all-trans conformation instead of mixtures of cis and trans conformers.
Homochiral sequences tend to adopt extended conformations, while the presence of a D-Oxd ring
induces folded conformations, giving rise to different types of γ- or -turn or inverse turns.
Oxd-peptides have been the subject of much interest as self-assembling scaffolds forming
nanostructures, and in the preparation of foldamers,2 short synthetic oligomers which have a
tendency to form well-defined secondary structures, stabilized by noncovalent interactions.3,4
Among the potential applications in medicinal chemistry, we utilized these peptidomimetics for the
design of constrained analogues of the opioid peptides endomorphins, for the preparation of antiinflammatory integrin inhibitors, or of analogues of the antibiotic Linezolid.
(1)
(2)
(3)
(4)
A. B. Mauger, J. Nat. Prod., 1996, 59, 1205.
S. J. Buhrlage, B. Chen, and A. K. Mapp, Tetrahedron, 2009, 65, 3305;
W. S. Horne and S. H. Gellman, Acc. Chem. Res., 2008, 41, 1399;
T. A. Martinek and F. Fülöp, Chem. Soc. Rev., 2012, Advance Article DOI: 10.1039/C1CS15097A
51
OC19
A general approach to the synthesis of polyhydroxylated piperidine
alkaloids for the discovery of new drugs
Laura Bartali, Andrea Casini, Ernesto G. Occhiato, Dina Scarpi
Dipartimento di Chimica “U. Schiff”, Università degli Studi di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
ernesto.occhiato@unifi.it
A general approach to the synthesis of polyhydroxylated piperidine alkaloids based on Pd-catalyzed
carbonylative reactions of lactam derivatives is reported. Suitable protected lactams 1 are converted
into the corresponding enol phosphates which are then subjected to methoxycarbonylation in the
presence of a Pd(0) catalyst. This affords enamide esters 2 which can be then converted into a series
of different natural and unnatural polyhydroxylated piperidine derivatives. Hydroboration of the
enamide double bond, after ester reduction, affords polyhydroxylated piperidine iminosugars 3,
hydrogenation produces pipecolic acids 4, and cyclopropanation generates conformationally
constrained pipecolic acids 5. Piperidine iminosugars are known for their inhibitory activity against
various glycosidases, a property which can be exploited for the development of antiviral and
anticancer therapies, as well as for the treatment of metabolic disorders.1 We report here the
enantiodivergent chemo-enzymatic synthesis of fagomine, 1-deoxymannojirimycin and 1deoxynojirimycin, three of the most important piperidine iminosugars.2 Hydroxy- and polyhydroxysubstituted pipecolic acids in particular and their derivatives play an increasingly important role in
medicinal chemistry as molecular scaffolds and -amino acid analogues for the preparation of
pharmaceutically active compounds. Their scope can be widened by introducing additional
conformational restrictions which could be crucial for the design of highly selective and potent
peptide analogues in peptide-receptor recognitions. We report herein the synthesis of new
cyclopropanated polyhydroxypipecolic acids which are currently studied for the generation of
cyclic peptides targeting specific proteins.3 Finally the synthesis of another natural compound, the
Streptomyces 4-epi-SS20846A piperidine 6, based on the same approach from 1, is also described.
(HO)n
(HO)n
N
H
1
N
R
2
O
(HO)n
(HO)n
CO2Me
CO2H
N
H
3
OH
OH
(HO)n
N
H
4
OH
N
H
5
CO2H
N
H
6
(1) a) P. Compain and O. R. Martin, Iminosugars: From Synthesis to Therapeutic Applications; Wiley: Chichester,
2007; b) A. E. Stütz, Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-VCH: Weinheim,
1999.
(2) a) Scarpi,D.; Bartali, L.; Casini, A.; Occhiato, E. G. Eur. J. Org. Chem. 2012, 2597-2605; b) Bartali, L.; Casini,
A.; Guarna, A.; Occhiato, E. G.;Scarpi, D. Eur. J. Org. Chem. 2010, 5831-5840.
(3) Occhiato, E. G.; Casini, A.; Guarna, A.; Scarpi, D. Eur. J. Org. Chem. 2011, 6544-6552.
52
OC20
Concise synthesis of indole alkaloid (-)-Indolactam V
via intramolecular Buchwald-Hartwig amination
Michele Mari, Francesca Bartoccini and Giovanni Piersanti
Department of Biomolecular Sciences, University of Urbino,
P.zza del Rinascimento 6, 61029 Urbino (PU), Italy
giovanni.piersanti@uniurb.it
(-)-Indolactam V (ILV)1 (Figure 1) is a potent activator of various protein kinase C (PKC) isozymes
and is a specific inducer of human embryonic stem cell differentiation to pancreatic cell types.2 Due
to the potent activity and peculiar structure involving a 9-membered lactam ring bridging the indole
3- and 4-positions, ILV has attracted much attention in the area of organic and medicinal
chemistry.3 In nearly all previous syntheses of ILV,3 the nine-membered ring is fashioned by latestage amide bond formation.
Me
Me
Intramolecular
transition-metal-catalyzed
N-arylation
Me
H
N
N
4
OH
O
3
Friedel-Crafts alkylation
with dehydroalanine
N
H
(-)-Indolactam V
Figure 1. Structure of (-)-Indolactam V and the main disconnections of the synthetic strategy.
We envisioned a strategically distinct approach to ILV, which involved initial C3 functionalization
using our previously reported Friedel-Craft alkylation with dehydroalanine,4 followed by transitionmetal-catalyzed N-aryl bond formation/ring closure at C4. While N-arylation of simple aromatic
halides by simple amines5 works with many of the described methods in high yield, the reactions
require detailed optimization if applied to the synthesis of complex molecules with additional
functional groups, such as natural products. We compared the three main catalytic N-arylation
methods in their application to the synthesis of ILV: Palladium-catalyzed Buchwald–Hartwig-type
reactions, copper-catalyzed Ullmann-type and Chan–Lam-type intramolecular N-arylation
reactions. The discussed examples show that palladium-catalyzed coupling reactions (Buchwald–
Hartwig amination reaction) using Buchwald’s mono phosphine ligands and Pd-precatalyst systems,
are favoured, in this particular case, because tolerate sterically demanding and coordinating
substituents and can easily be applied for gram-scale application.
(1) Irie, K.; Hirota, M.; Hagiwara, N.; Koshimizu, K.; Hayashi, H.; Murao, S.; Tokuda, H.; Ito, Y. Agric. Biol. Chem.
1984, 48, 1269-1274. For a pertinent review on indolactam isolation, tumor-promoting activity, and derivatives,
see: Irie, K.; Koshimizu, K. Comments Agric. Food Chem. 1993, 3, 1-25.
(2) Chen, S.; Borowiak, M.; Fox, J. L.; Maehr, R.; Osafune, K.; Davidow, L.; Lam, K.; Peng, L. F.; Schreiber, S. L.;
Rubin, L. L.; Melton, D. Nat. Chem. Biol. 2009, 5, 258-265.
(3) a) Endo, Y.; Shudo, K.; Itai, A.; Hasegawa, M.; Sakai, S. Tetrahedron 1986, 42, 5905-5924. b) de Laszlo, S. E.;
Ley, S. V.; Porter, R. A. J. Chem. Soc., Chem. Commun. 1986, 344-346. c) Meseguer, B; Alonso-Díaz, D.;
Griebenow, N.; Herget, T.; Waldmann, H. Chem.—Eur. J. 2000, 6, 3943-3957. d) Xu, Z.; Zhang, F.; Zhanga, L.;
Jia Y. Org. Biomol. Chem. 2011, 9, 2512-2517. e) Bronner, S. M.; Goetz, A. E.; Garg N. K. J. Am. Chem. Soc.
2011, 133, 3832-3835
(4) a) Angelini, E.; Balsamini, C.; Bartoccini, F.; Lucarini, S.; Piersanti, G. J. Org. Chem. 2008, 73, 5654-5657. b)
Lucarini, S.; Bartoccini, F.; Battistoni, F.; Diamantini, G.; Piersanti, G.; Righi, M.; Spadoni, G. Org. Lett. 2010,
12, 3844-3847. c) Bartolucci, S.; Bartoccini, F.; Righi, M.; Piersanti, G. Org. Lett. 2012, 14, 600-603.
(5) a) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.; Buchwald, S. L. Chem. Sci. 2011, 2, 27-57. b) Hartwig,
J. F. Acc. Chem. Res. 2008, 41, 1534-1544. c) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 69546971. d) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829-856.
53
OC21
Phytochemical and biological profile of Eremurus persicus Boiss root extract:
isolation of the main phytocomponents.#
R. Gaggeri,1,2 Karzan Mahmood,1 G. Gilardoni,2,3 A. Avanzini,4 D. Rossi,1 S. Collina1,2
1
Department of Drug Sciences, via Taramelli 12, 27100 Pavia
Center for Studies and Researches in Ethnopharmacy (C.I.St.R.E.), University of Pavia,
via Taramelli 12, 27100, Pavia, Italy.
3
Department of Chemistry, via Taramelli 10, 27100 Pavia
4
Pediatric Hematology/Oncology Department, Fondazione IRCCS Policlinico San Matteo,
Piazzale Golgi 19, 27100 Pavia, Italy
raffaella.gaggeri@unipv.it
2
Plants of genus Eremurus (Liliaceae), consisting of nearly 50 species, are mainly restricted to the
mountains of central and western Asia. Among them, Eremurus persicus (Jaub & Spach) Boiss,
distributed in Iran/Kurdistan area, has been traditionally used as herbal remedy by native people
since ancient time.1 Actually in Kurdistan folk herbal medicine still represents the first choice for
primary healthcare in towns, villages as well as in rural area.2 In this ethnomedical tradition
Eremurus persicus root extracts are employed to cure several diseases having a common
pathophysiological factor related to inflammation (folk use).
As a part of our ongoing search of novel anti-inflammatory agents, we applied the ethnobotanical
directed approach of drug discovery to Eremurus persicus Boiss. In this context, the phytochemical
characterization of Eremurus persicus root extracts as well as the assessment of its folk medicinal
use were investigated. Eremurus persicus was collected in Iran/Iraq area and, basing on our
previous experiences,3 different root extracts were prepared using various extraction procedures.
The phytochemical fingerprint of extracts was drawn by both TLC and HPLC-PD-CD analyses.
Then, a preliminary biological screening was performed on all crude extracts by testing their free
radical scavenging effect (FRS), given that reactive oxygen species (ROS) are involved in
inflammatory process.4 Finally, the most active extract (called hit extract) was subjected to a deeply
investigation of anti-inflammatory properties as well as to a purification aimed at isolating the main
phytocomponents.
In summary, herein we report for the first time: 1) the preliminary phytochemical fingerprint of the
Eremurus persicus extracts; 2) the biological profile of the hit extract 3) the isolation and structure
elucidation of its main phytocomponents.
(1) Safar K.N.; Osaloo S.K.; Zarrei M. Iran. J. Bot. 2009, 15, 27-35.
(2) Mati E.; de Bore H. J. Ethnopharmacol. 2011, 133, 490-510.
(3) Gaggeri, R.; Rossi, D.; Hajikarimian, N.; Martino, E.; Bracco, F.; Grisoli, P.; Dacarro, C.; Leoni, F.; Mascheroni,
G.; Collina, S. The Open Natural Products Journal 2010, 3, 20-25.
(4) Young, C.N.; Koepke, J.I.; Terlecky, L.J.; Borkin, M.S.; Boyd, S.L.; Terlecky, S.R. J. Invest. Dermatol. 2008,
128, 2606-2614.
#
The Authors would like to thank Regione Lombardia (Astil-PROKURDUP Project) for financial support.
54
OC22
Phytotoxic nonenolides produced by fungi pathogenic for crops and weeds
Alessio Cimmino, Anna Andolfi and Antonio Evidente
Dipartimento di Scienze del Suolo, della Pianta, dell’Ambiente e delle Produzioni Animali,
Università di Napoli Federico II, Via Università 1000, 80055 Portici, Italy
alessio.cimmino@unina.it
Pinolidoxin, 2-hexadionoyloxy-7-hydroxy-9-propyl-5-nonen-9-olide, is the first phytotoxic
nonenolide, isolated from some of us on 1993, together three minor ones as the main toxin produced
by Ascochyta pinodes.1 This is the fungal causal agent of pea anthracnose.
Successively, phytotoxic nonenolide as putaminoxin, the main one, the close related putaminoxins
B-D were also isolated from Phoma putaminum, the fungus proposed as mycoherbicide to
biological control Erigeron annuus, a widespread weed in the pasture of northern emisphere.2 Later,
stagonolide, a new nonenolide, was also isolated as the main toxin from liquid culture of
Stagonospora cirsii proposed for the biological control of Cirsium arvense and Sonchus arvensis,
two very noxious perennial weeds of several agrarian crops, essentially cereals. Successively nine
related new nonenolides were isolated together to the well known modiolide A, from solid cultures
of the same fungus.3 So that some studies were carried out using the toxins some their natural
analogues and hemisynthetic derivatives to carry out studies on the structure-activity relationships
and on their mode of action.4
Recently, from a strain of Ascochyta pinodes isolated in Spain from infected pea and grown in
liquid culture were isolated herbarumin II, and 2-epi-herbarumin II together with a new nonenolide,
named pinolide.
In this communication an overview on the phytotoxic fungal nonenolides will be illustrated as well
as the chemical and biological characterization of pinolide and the potential practical application of
some of them as natural eco-friendly herbicides.
HO
O
O
O
HO
n-Pr
O
Pinolidoxin
(1) Evidente, A.; Capasso, R.; Abouzeid, A.M.A.; Lanzetta, R.; Vurro M.; Bottalico, A J. Nat. Prod. 1993, 56, 19371943.
(2) Evidente, A.; Capasso, R.; Andolfi, A.; Vurro, M.; Zonno, M.C. Phytochemistry, 1998, 48, 941-945.
(3) Evidente, A.; Cimmino, A.; Berestetskiy, A.; Andolfi, A.; Motta, A. J. Nat. Prod. 2008, 71, 1897-1901.
(4) Berestetskiy, A.; Dmitriev, A.; Mitina, G.; Lisker, I.; Andolfi, A.; Evidente, A. Phytochemistry, 2008, 69, 953-960.
55
OC23
TRPA1 high potency analogues of perillaketone
Angela Bassoli ,1 Gigliola Borgonovo,1 Gabriella Morini,2 Luciano De Petrocellis,3
Aniello Schiano Moriello3 and Vincenzo Di Marzo4
1
University of Milano – Department of Food, Environmental and Nutritional Sciences- DeFENS,
Via Celoria 2, Milano 20133, Italy
2
University of Gastronomic Sciences, Pollenzo (CN), Italy
3
Endocannabinoid Research Group, Institute of Cybernetics, “Eduardo Caianiello”,
CNR, Pozzuoli (NA), Italy
4
Endocannabinoid Research Group, Institute of Biomolecular Chemistry,
CNR, Pozzuoli (NA), Italy
angela.bassoli@unimi.it
Transient Receptor Potential (TRP) channels represent interesting molecular target structures
involved in a number of different physiological and pathophysiological systems.1,2
In particular, TRPA1 channel is involved in nociception3 and in sensory perception of many
pungent chemesthetic compounds,4 which are diffuse in spices and food plants, included the Korean
food plant Perilla frutescens.
A natural compound from P. frutescens (isoegomaketone) and sixteen synthetic derivatives of
perillaketone has been prepared and tested in vitro on rTRPA1 expressed in HEK293 cells and their
potency, efficacy and desensibilization activity measured.
O
O
O
O
perillaketone
and 16 synthetic analogues
isoegomaketone
The new synthetic and natural derivatives of perillaketone resulted in general effective in targeting
TRPA1. Among eighteen compounds, eleven resulted more effective than the lead compound, and
eight are both more potent and more effective than the lead. In some cases, the potency is two order
of magnitude higher than the lead and higher than that of most known natural agonists of TRPA1.
These furylketones derivatives represent therefore a new class of chemical structures active on
TRPA1 with many potential applications in agrifood and pharmaceutical industry.
(1) Moran, M.M.; McAlexander, M.A. ; Bíró, T.; Szallasi, A.; Nat. Rev. Drug Disc. 2011, 10, 601-620.
(2) Clapham, D.E. ; Nature 2003, 426, 517-524.
(3) Akopian, A.N. ; Ruparel, N.B. ; Jeske, N.A.; Patwardhan, A.; Hargreaves, K.M.; Trends Pharmacol. Sci. 2008, 30
79-84.
(4) Bassoli,A.; Borgonovo, G.; Caimi,S.; Scaglioni, L.; Morini,G.; Schiano Moriello,A.; Di Marzo,V.; De
Petrocellis,L.; J. Biorg. Med. Chem. 2009, 17 , 1636-1639.
56
OC24
Thermal safety of chemical processes for industrial scale-up
Alessandro Barozza, Jacopo Roletto, Paolo Paissoni
CBC-PROCOS S.p.A. – R&D Department – Via G.Matteotti 249 – Cameri (NO) – Italy
barozza@procos.it
Safety of a chemical process can be approached and realized in several ways. From an industrial
point of view, the concept has to include several aspects: quantities, toxicity and handling of
materials, design of chemical plants, performances of utilities, and compliance with the regulations
in place.
Planning a scale-up, especially to pilot and industrial plants where large amounts of reactants are
involved, the chemist should characterize every aspects of a reaction as deeply as possible.
The thermal characterization of reactive system, from both thermodynamic and kinetic points of
view, is one of the main elements to be investigated.
The complete understanding of the reaction mechanism, the optimization of yield, productivity and
quality are important, but when approaching an industrial production the deep knowledge of the
energy involved in the chemical transformation is essential in order to avoid serious incident which
may involve people, plants and environment.
In this presentation some case studies will be described, focusing on some equipment and
procedures needed to characterize a chemical process from a thermal point of view. The final point
is to scale-up an inherently safe1 and optimized procedure, reducing its dependency on the hardware
where it will be carried out and minimizing the use of special protection equipment against
unexpected events.
(1) Barton, J.; Rogers, R. Chemical Reaction Hazards - A guide to safety - Second edition - Gulf Publishing
Company, Houston Texas, 1997
57
OC25
Design and synthesis of new fluorescent PNAs for diagnostic purposes
Tullia Tedeschi, Alessandro Tonelli, Stefano Sforza, Roberto Corradini,
Arnaldo Dossena and Rosangela Marchelli
Dipartimento di Chimica Organica e Industriale, Università di Parma,
Parco Area delle Scienze 17/A, 43125 Parma.
tullia.tedeschi@unipr.it
The development of novel, sensitive and selective sensors for the detection of DNA and RNA has
become a very active research field in recent years.
The selective detection of specific DNA and RNA sequences can be achieved by using
oligonucleotide analogue hybridization probes. Generally these probes are made by an
oligonucleotide sequence, complementary to the target sequence, containing a reporter group that
can be monitored using a spectroscopic technique, such as fluorescence spectroscopy. During the
last years, new generations of fluorescent oligonucleotide probes have emerged with interesting
properties and have been employed to target important issues, ranging from in vitro PCR
monitoring to in vivo mRNA detection. Fluorescent oligonucleotide probes can improve their
performance if they are chemically modified in order to enhance sequence specificity and
selectivity. One of the most successful example of these chemically modified probes are peptide
nucleic acids (PNAs). Several fluorescent probes based on PNA structure have been reported,
showing improved properties if compared to the homologous oligonucleotides: molecular beacons,
lightUP probes, FIT probes.
In the first part of this work, two Thiazole Orange-conjugated PNAs for genogroup II noroviruses
(NoV GII) detection were designed and synthesized. The spectroscopic properties of the two PNA
probes were studied and their applicability to NoVs detection, using an isothermal assay, was
investigated.1
The second part of this comunication is focused on the development of new fluorescent PNA probes
based of carboxymethyl pyrene residues, which behave as excimers after hybridization with the
complementary DNA and RNA target. The two probes were derivatized with pyrene molecules in
proper orientation, inserted in the backbone of a lysine modified PNA monomer, in order to provide
excimer formation upon simultaneous hybridization. The system was targeted to the PTPN22
C1858T polymorphism sequence, implicated in several human autoimmune diseases including type
1 diabetes; the dual-probe system was designed to be sequence specific with single-nucleotide
resolution. The fluorecence emission signal occured only upon ternary complex formation with the
fullmatch DNA or RNA sequence. However, in order to be effective, the system requires the
presence of a co-solvent in the buffer which resulted crucial for the fine-tuning of the mismatch
recognition capability.
The results here presented underline the potential of using PNA probes for end-point analysis of
single stranded DNA or RNA targets or for real time monitoring of amplification events in
isothermal assays.
(1) A. Tonelli, T. Tedeschi, A. Germini, S. Sforza, R. Corradini, M. C. Medici, C. Chezzi and R. Marchelli, Mol.
Biosystems, 2011, 7, 1684.
58
OC26
1,3-Dipolar cycloaddition of nitrones to MWCNTS:
the role of the CNT sidewall defects
Stefano Cicchi,1,2 Giuliano Giambastiani,2 Lapo Luconi,2 Luisa Lascialfari,1 Andrea Rossin,2
Manuela Melucci,2 Francesco Mercuri,3 Alberto Brandi.1,2
1
Dipartimento di Chimica “U. Schiff”, University of Florence, Via della Lastruccia 13,
50019 - Sesto Fiorentino (Fi), Italy.
2
Istituto di Chimica dei Composti Organometallici ICCOM-CNR, Via Madonna del Piano 10,
50019, Sesto Fiorentino (Fi), Italy
3
Istituto di Scienze e Tecnologie Molecolari (ISTM-CNR) and UdR INSTM, Via Elce di Sotto 8,
06123 (Perugia), Italy
stefano.cicchi@unifi.it
Carbon nanotubes (CNTs) have attracted growing attention in nanotechnology because of their
outstanding high mechanical, thermal, and electrical properties. At present, much interest is being
paid to the covalent attachment of functional groups through reactions involving the -conjugated
skeleton of single-walled (SW) or multi-walled (MW) CNTs. Among the possible reactions, 1,3dipolar cycloadditions play an important role in the sidewall functionalization of CNTs.
Azomethine ylides and nitrile imines are very reactive intermediates for the organic
functionalization of SWCNTs, whereas no examples of nitrone 1,3-cycloadditions to the sp2
network have been reported so far. This has been theoretically rationalized, invoking a too-high
activation energy barrier and a relatively low energy associated with the retro-cycloaddition
process. Consistent with theory, all our attempts to functionalize SWCNTs using cyclic nitrones
were unsuccessful. In contrast, we have surprisingly discovered that the same nitrones reacts with
MWCNTs to give highly functionalized materials (f-MWCNTs) with unique properties.1 In this
communication, we report on the effective grafting of nitrones to the sidewalls of MWCNTs. The
protocol developed yields highly functionalized materials with unprecedented solubility in DMF
(close to 10 mg of f-MWCNTs per mL of DMF) so as to obtain stable inks with no apparent CNT
rebundling over a period of weeks.
Raman scattering, in combination with complementary XRPD and Active Surface Area (ASA)
measurements, has provided unambiguous evidence of the key role played by the structural “carbon disorder” in the nitrone cycloaddition reaction.2 Density functional theory (DFT) calculations on the
reactivity of selected topological defects at the CNT sidewalls have finally contributed to trace out a
“defect-based” sidewall reactivity trend.
(1) Ghini, G.; Luconi, L.; Rossin, A.; Bianchini, C.; Giambastiani, G.; Cicchi, S.; Lascialfari, L.; Brandi, A.; Giannasi,
A. Chem. Commun. 2010,46, 252-254.
(2) Giambastiani, G.; Cicchi, S.; Giannasi, A.; Luconi, L.; Rossin, A.; Mercuri, F.; Bianchini, C.; Brandi, A.; Melucci,
M.; Ghini, G.; Stagnaro, P.; Conzatti, L.; Passaglia, E.; Zoppi, M.; Montini, T.; Fornasiero, P. Chem. Mater. 2011,
23, 1923-1938.
59
OC27
Synthesis and characterization of aminoproline-based RGD semipeptides
targeting V3 Integrins and their utility in medicine
Lucia Battistini,1 Paola Burreddu,2 Paola Carta,2 Andrea Sartori,1 Gloria Rassu,2 Claudio Curti,1
Giovanni Casiraghi,1 and Franca Zanardi1
1
Dipartimento Farmaceutico, Università degli Studi di Parma, Parco Area delle Scienze 27A, I43124 Parma, Italy
2
Istituto di Chimica Biomolecolare del CNR, Traversa La Crucca 3, I-07100 Li Punti, Sassari, Italy
lucia.battistini@unipr.it
In recent past years, integrin receptors have been the focus of intense and vivid research directed to
elucidate their structure, function and regulation.1 In the cancer-related field, the expression of
particular integrins is correlated with disease progression and decreased patient survival in various
tumor types, rendering these integrin families appealing targets for cancer therapy.
The V3 integrins, among others, have been identified as useful biomarkers of tumor angiogenesis
and tumor progression, invasion and metastasis, being overexpressed on proliferating endothelial
cells as well as various tumor-related cells.2 Given the appeal these integrins have as therapeutic
targets, a number of specific, highly potent V3-targeting small molecule ligands have been
developed so far, which contain or mimic the essential RGD binding motif.3
Notable results from our laboratory in the design, synthesis and characterization of aminoprolinebased integrin binders (AmpRGD) will be presented, which displayed nanomolar binding affinity
toward the isolated V3 integrin receptor. The preparation and evaluation of both covalent and
nanostructured assemblies will also be discussed, wherein appropriate cytotoxic or imaging cargos
are consigned to the AmpRGD semipeptide vectors, to be used as novel anti-angiogenic
therapeutic/diagnostic tools.
(1) Cox, D.; Brennan, M.; Moran, N. Nature Rev. Drug Discovery 2010, 9, 804-820.
(2) Desgrosellier, J. S. and Cheresh, D. A. Nature Rev. Cancer 2010, 10, 9-22.
(3) Auzzas, L.; Zanardi, F.; Battistini, L.; Burreddu, P.; Carta, P.; Rassu, G.; Curti, C.; Casiraghi, G. Curr. Med.
Chem. 2010, 17, 1255-1299.
60
OC28
Catalytic asymmetric tandem intramolecular rearrangement-protonation:
an approach to optically active -acyloxy-, -amino thioester and ketones
Angelo Frongia, Pier Paolo Piras, Francesco Secci
Università degli Studi di Cagliari, Dipartimento di Scienze Chimiche, Cittadella Universitaria di
Monserrato, S.S. 554, Bivio per Sestu, Cagliari
afrongia@unica.it
Asymmetric protonation of prochiral enolates have received great attention as efficient methods for
the construction of optically active -substituted carbonyl compounds. Recent research witnesses
an increasing application of organocatalysis1 in enantioselective protonation reactions2 and notably,
some enantioselective protonations have been successfully incorporated into tandem or cascade
processes3 to give access to structurally complex molecules. These methods are based on the use of
an enol or enolate prepared in situ from a suitable precursor in the absence of metal components. In
particular, only a few examples of organocatalytic tandem intramolecular rearrangementenantioselective protonation have been reported.4 In this connection, we have developed a simple
and efficient organocatalytic new tandem reaction for the synthesis of -acyloxy-,5 -amino6
thioesters and ketones through an enantioselective protonation-terminated organocatalytic
intramolecular rearrangement. Applying this newly developed organocatalytic tandem reaction we
prepared important synthetic building blocks in high yield and with good to excellent
enantioselectivities.
O
Quinidine (20 mol%)
O

R'S
R
O
R'S
O
2
ee up to 92%
R
O
O
1
O
Rac
R'
Quinidine (20 mol%)
(S)-BDHP (20 mol%)
R'NH2
N

PhS
R
O
3
ee up to 76%
OH
O
R'
4
O
R'
R''
R
Rac
Quinidine or (DHQD)2PHAL
(30 mol%)
R'''
NH

R''
N R'''
R
5
ee up to 81%
(1) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli, Angew. Chem. Int. Ed. Engl. 2008, 47, 6138.
(2) J. T. Mohr, A. Y. Hong, B. M. Stolts, Nature Chem. 2009, 1, 359-369.
(3) a) B. Wang, F. Wu, Y. Wang, X. Liu, L. Deng, J. Am. Chem. Soc. 2007, 129, 768-769; b) T. Seitz, J. Baudoux, H.
Bekolo, D. Cahard, J. C. Plaquevent, M. C. Lasne, J. Rouden, Tetrahedron 2006, 62, 6155-6165; c) M. Rueping,
W. Ieawsuwan, Adv. Synth. Catal. 2009, 351, 78-84.
(4) a) E. Schmitt, I. Schiffers, C. Bolm, Tetrahedron Lett. 2009, 50, 3185-3188; b) M. Hayashi, S. Nakamura, Angew.
Chem. Int. Ed. 2011, 50, 2249-2252.
(5) F. Capitta, A. Frongia, P. P. Piras, P. Pitzanti, F. Secci, Adv. Synth. Catal., 2010, 352, 2955-2960.
(6) F. Capitta, A. Frongia, P. P. Piras, P. Pitzanti, F. Secci, Org. Biomol. Chem., 2012, 10, 490-494.
61
OC29
Exploiting Ce(III) salt properties in the synthesis of
polysubstituted heterocycles by cyclization reaction:
microwave irradiation and Co-catalyst effect.
S. Diomedi,1,2 R. Cipolletti,1 M. Di Nicola,1 R. Giovannini,2 D. Hamprecht, 2 L. Marsili,1 E.
Marcantoni,1 M. S. Jadhav,1 R. Properzi,1 F. Sorana.1,2
1
School of Science and Technology, Chemistry Division, University of Camerino,
Via S. Agostino 1, 62032 Camerino
2
BIRIT S.a.s. di BI IT S.r.l., via Lorenzini 8, 20139Milano.
federico.sorana@unicam.it
In last years cerium(III) derivatives have been attracting considerable attention because of its broad
application as catalysts in organic chemistry. In particular, CeCl3 was found to be efficient catalyst
for several organic transformations,1 and acquired a central position with the increasing relevance of
eco-friendly reaction both in academia and industry.
Recently, during our study, we have been exploring different approaches for the construction of
polysubstituted small ring heterocycles by cyclization of suitable precursors using CeCl3∙7H2O.
Exploiting the unconventional heating of microwave irradiation,2 and CeCl3∙7H2O/NaI system
ability to interact with multiple bond,3 we were able to synthesize polysubstituted furans (1) and
oxazoles (2), important scaffold in numerous natural products.4 In addition, since the CeCl3∙7H2O
activity increases dramatically in presence of an iodide source, we are studying the use of iodine
salt co-catalyst containing different counter-ion to create lanthanide/transition metal multi-catalyst
systems, of great interest in one-pot reaction.5 The two catalyst compounds (CeCl3/CuI) firstly used
are commercially available and air stable; they are also compatible with a variety of functional
groups, and we improved useful procedures for obtaining nitrogen containing heterocycles, such as
benzimidazole derivatives (3) and dihydro-4-pyridone compounds (4), both interesting building
block in medicinal chemistry.6
1
2
3
4
(1) Bartoli, G.; Marcantoni, E.; Marcolini, M.; Sambri, L. Chem. Rev. 2010, 110, 6104-6143.
(2) Kappe, O. C. Angew. Chem. Int. Ed. 2004, 43, 6250-6284.
(3) Bartoli, G.; Cipolletti, R.; Di Antonio, G.; Giovannini, R.; Lanari, S.; Marcolini, M.; Marcantoni, E. Org. Biomol.
Chem. 2010, 8, 3509-3517.
(4) a) Bartoli, G.; Cimarelli, C.; Cipolletti, R.; Diomedi, S.; Giovannini, R.; Mari, M.; Marsili, L.; Marcantoni, E. Eur.
J. Org. Chem. 2012, 3, 630-636. b) Hou, X. L.; Yang, Z.; Wong, H. N. C. In Progress in Heterocyclic Chemistry;
Gribble, G. W.; Gilchrist, T. L., Eds.; Pergamon: Oxford, 2003, Vol. 15, pp 167-205.
(5) a) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai, M.; Uemura, S. Angew. Chem. Int. Ed. 2003,
42, 2681-2684. b) Wang, H.; Denton, J. R.; Davies, H. M. L. Org. Lett. 2011, 13, 4316-4319.
(6) a) White, A.W.; Almassy, R.; Calvert, N.J. J. Med. Chem. 2000, 43, 2430-2437. b) Buonora, P.; Olsen, J.C; Oh, T.
Tetrahedron 2001, 57, 6099-6138.
62
OC30
Industrial scale synthesis of SN38 via photochemical rearrangement
Gianluca Belogi
Olon S.p.A.; R&D, Rodano (Milan)
GBelogi@OlonSpA.it
SN38, the active metabolite of the anticancer drug Irinotecan, can be prepared through different
routes, either by total synthesis or by semisynthesis from available Camptothecins as starting
materials. The presentation will illustrate the synthetic routes that exploit the natural product
Camptothecin as a starting material, with emphasis to those that involve a photochemical step. We
will also show how such a process has been selected and scaled-up to an industrial scale at the Olon
Rodano plant.
N
HO
O
N
N
O
N
N
O
OH O
Camptothecin
(CPT)
O
N
O
OH O
7-Ethyl CPT
7-Ethyl CPT N-oxide
10-Hydroxy-7-ethyl CPT
(SN38)
63
OC31
Process development of generic Aliskiren
Giuseppe Barreca,1 Luca Carcone,1 Elena Cini,2 Giovanni Marras,1 Marcello Rasparini,1
Adele Russo,2 Maurizio Taddei2 and Antonio Zanotti-Gerosa3
1
Chemessentia Srl, Via Bovio 6, 28100 Novara (Italy)
Via A. Moro 2, 53100 Siena, Italy
3
Johnson Matthey Catalysis and Chiral Technologies, 28 Cambridge Science Park,
Milton Road, Cambridge, CB4 0FP, United Kingdom.
marcello.rasparini@chemessentia.it
2
Aliksiren (Novartis) (1) is an antihypertensive with a novel mode of action1 (i.e. blockade of the
renin-angiotensin cascade) and is the first direct renin inhibitor launched on the market. Due to its
clinical potential, Aliskiren has generated a great commercial interest, resulting in a large number of
syntheses appearing in the patent and academic literature.2
From the chemical point of view, (1) is a challenging structure featuring four stereocentres, all of Sconfiguration, on an acyclic chain of pseudo C2 symmetry.
Our route to (1) underwent several rounds of evolution, starting from a stereochemically unselective
synthesis, to one based on chiral auxiliaries and chromatographic purifications and culminating on a
totally catalytic and perfectly stereoselective synthesis based on asymmetric hydrogenations.
From a process point of view, extremely low catalytic loadings were used and very few
purifications (mostly by extraction) were necessary, resulting on a synthesis that is being validated
on pilot plant at 15 Kg/batch scale.
(1) Jensen, C.; Herold, P.; Brunner, H. R. Nature Rev. Drug. Disc. 2008, 7, 399-410.
(2) Hanessian, S.; Guesné, S.; Chénard, E. Org. Lett. 2010, 12, 1816-1819.
64
OC32
6-Fluoro corticosteroid synthetic approaches
and industrial synthesis of Fluticasone propionate
Claudio Pozzoli
R&D Manager – Farmabios (Zellbios Group) – Gropello Cairoli (PV)- Italy
claudio.pozzoli@farmabios.com
Fluticasone propionate (Flovent, or Flonase, GSK) is certainly the main fluoro-corticosteroid on the
pharmaceutical market. Only considering the 2011 year, its sales have generated a turnover
exceeding 11.5 billion of dollars
Originated from Glaxo research, Fluticasone Propionate is mainly used for the treatment of asthma
and more generally as antiinflammatory-acting local.
Chemically it is a -carbotio androstane derivative fluorinated in position 6and it is generally
obtained from flumethasone through various chemical reactions.
O
OH
O
CH2F
S
HO
HO
OH
F
O
OCOEt
F
O
F
Flumetasone
F
Fluticasone
Propionate
Farmabios is a company active in the field of corticosteroids and produces since 1969 active
pharmaceutical ingredients (API) off-patent for the generic market.
This presentation shows results of Farmabios' studies obtained in its R&D laboratories along the
time with the aim to develop industrial synthesis methods suitable to produce both fluticasone
propionate and flumethasone
The presentation also contains an overview of the corticosteroids chemistry starting from
phytosterols biotransformation with special focus to the regio and stereoselective fluorination
reaction at the C6 position.
65
OC33
Raman spectroscopy: a versatile PAT tool in pharmaceutical process R&D
Fabrizio Borin, Carla De Faveri, Florian Anton Martin Huber,
Franco Tessari and Mariano Stivanello.
Lundbeck Pharmaceuticals Italy SpA, Quarta Strada, 2- 35129-Padova, Italy.
msti@lundbeck.com
Pharmaceutical products are of excellent and totally controlled quality, but it is also true that drug
manufacturing processes occasionally lack of robustness and could be improved through an
increased process and product understanding, in order to identify and appropriately manage the
critical sources of variability.
According to the current guidelines of International Conference on Harmonization (ICH) for the
manufacturing of pharmaceutical products, quality of a drug cannot in fact be tested only into the
final product, but should be built in the production process by design (Quality by Design approach).
The thorough knowledge of critical process parameters (CPPs) affecting the final product quality is
thus of paramount importance for assuring the robustness of the final manufacturing processes.
In this regard, Process Analytical Technology (PAT) is an excellent toolbox commonly used by
Pharmaceuticals Companies for designing, analyzing, and controlling manufacturing process
through timely measurements of critical “quality attributes” with the goal of ensuring final product quality.
Various PAT tools are nowadays available, among which statistical methods and modern on-line
process analyzers are the most used in pharmaceutical companies. In this regard, on-line RAMAN
spectroscopy proved to be a really versatile technique used in Lundbeck both for general process
optimization and for the development of robust crystallization processes of final active
pharmaceutical ingredient (API), including identification and characterization of new polymorphs,
solvates or hydrates.
A few selected case studies will be presented where on-line RAMAN spectroscopy, if necessary
combined with other analytical techniques, has been used to detect and analyze different hydrate
forms of a new API under clinical development in Lundbeck, to optimize and develop a kineticallycontrolled classical resolution process of a key intermediate, currently running efficiently in full
production scale, to achieve a polymorphic transformation of an API in a solid suspension and to
optimize an extractive work-up of an polycyclic ketone prone to form a highly water soluble gemdiol.
66
OC34
Synthetic strategies for the preparation of lipophilic MRI/GdBNCT agents
Antonio Toppino, Annamaria Deagostino, Simonetta Geninatti-Crich, Diego Alberti, Silvio Aime,
Paolo Venturello
1
Dipartimento di Chimica, Università degli Studi di Torino,
Via Pietro Giuria, 7 - 10125, Torino.
annamaria.deagostino@unito.it
BNCT (boron neutron capture therapy) is a binary radiation therapy for the treatment of cancer,
based on the capture of thermal neutrons by 10B nuclei that have been selectively delivered to
tumour cells. The neutron capture event results in the formation of excited 11B nuclei that undergo
fission to yield highly energetic 4He2+ and 7Li3+ ions. Cell death is triggered by the release of these
charged particles which create ionisation tracks along their trajectories, resulting in cellular damage.
It has been estimated that approximately 10−30 µg of boron per gram of tumour mass is needed to attain an acceptable therapeutic advantage.1 An important task relies on the possibility of delivery
high payloads of 10B at the target sites and polynuclear boron derivatives are potential candidates
for BNCT applications. Several functionalised carboranes have been employed to construct boron
delivery vehicles for BNCT, because of their high content of boron and their stability in vivo. In
recent years our research group has been working on the preparation of dual agents for BNCT/MRI
applications. In these systems a carborane cage is linked to a lipophilic unit, in order to exploit
LDLs as biological vectors, and a MRI probe (AT101).2 In vivo MR image acquisition showed that
the amount of B taken up in the tumour region was above the threshold for successful NCT
treatment.3 With the goal of achieving an effective MRI/GdBNCT agent in a relatively few
synthetic passages in mind, we have recently applied the Huisgen reaction carried out in
heterogeneous conditions to the suitable substituted carborane cage. MRI images performed on
tumour melanoma cells incubated in the presence of the Gd/B dual probe have demonstrated that
the high amount of intracellular B necessary to perform BNCT can be reached using a relatively
low B containing labelled LDL concentration.
(1)
(2)
(3)
R. F. Barth, Journal of Neuro-Oncology 2003, 62, 1.
S. Aime, A. Barge, A. Crivello, A. Deagostino, R. Gobetto, C. Nervi, C. Prandi, A. Toppino, P. Venturello,
Organic & Biomolecular Chemistry 2008, 6, 4460.
S. Geninatti-Crich, D. Alberti, I. Szabo, A. Deagostino, A. Toppino, A. Barge, F. Ballarini, S. Bortolussi, P.
Bruschi, N. Protti, S. Stella, S. Altieri, P. Venturello, S. Aime, Chemistry-a European Journal 2011, 17, 8479.
67
OC35
The polymorfisms of DNA G-quadruplex investigated
by docking experiments with Telomestatin enantiomers
Stefano Alcaro, Giosuè Costa, Simona Distinto, Federica Moraca,
Francesco Ortuso, Lucia Parrotta, Anna Artese.
Dipartimento di Scienze Farmacobiologiche Università "Magna Græcia" di Catanzaro,
Complesso Ninì Barbieri, 88021 Roccelletta di Borgia (Catanzaro - Italy)
gcosta@unicz.it
Human telomeres are comprised of d(TTAGGG) repeats involved in the formation of G-quadruplex
DNA structures. Ligands stabilizing these G-quadruplex DNA structures are potential inhibitors of
the cancer cell-associated enzyme telomerase. In human cells, telomerase adds multiple copies of
the 5ʹ-GGTTAG-3ʹ motif to the end of the G-strand of the telomere and in the majority of tumor
cells it results over-expressed.1 Several structural studies have revealed a diversity of topologies for
telomeric quadruplexes, which are sensitive to the nature of the cations present, to the flanking
sequences, and probably also to concentration, as confirmed by the different conformations
deposited in the Protein Data Bank (PDB). The existence of different polymorphisms in the DNA
quadruplex and the absence of a uniquely precise binding site prompted us to carefully compare the
two different docking approaches: MOLINE2 and AutoDock.3 As target we have selected six
different experimental models of the human telomeric sequence d[AG3(T2AG3)3] based on three Gtetrads and as ligands the telomestatin isomers, whose the S enantomer is experimentally known to
recognize the G-quadruplex better than the R one. In this communication we discuss the different
binding modes of the well known strong telomestatin G-quadruplex binder form the thermodynamic
and the geometrical points of view. With respect to this last issue we propose an easy approach to
classify binding modes of G-quadruplex ligands based on a single angle descriptor as tool for the
quick analysis of the binding modes.
Fig. 1: MOLINE best pose superimposition of the two 1 stereoisomers (R in yellow and S in red)
against the 2HY9 PDB model. Central guanine quartets are displayed in blue cartoon and wireframe
rendering.
(1) Patel, D.J; Phan, A.T.; Kuryavyi, V. Human telomere, oncogenic promoter and 5′-UTR G-quadruplexes: diverse
higher order DNA and RNA targets for cancer therapeutics. Nucleic Acids Res, 2007, 35, 7429-7455.
(2) Alcaro, S.; Gasparrini, F.; Incani, O.; Mecucci, S.; Misiti, D.; Pierini, M.; Villani, C. A "quasi-flexible" automatic
docking processing for studying stereoselective recognition mechanisms. Part I. Protocol validation. J Comput
Chem, 2000, 21, 515-530.
(3) Morris, G.M.; Goodsell, D.S.; Halliday, R.S.; Huey, R.; Hart, W.E.; Belew, R.K.; Olson, A.J. Automated docking
using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem, 1998, 19,
1639-1662.
68
OC36
A novel enantioselective enzymatic synthesis of Sitagliptin
Gianmaria Dell’Anna, Emanuele Attolino, Pietro Allegrini.
Dipharma Francis s.r.l. via Bissone 5, 20021 Baranzate (MI), Italy.
emanuele.attolino@dipharma.it
In recent years, dipeptidyl peptidase IV (DPP-4) inhibitors have emerged as a new class of anti
hyperglycemic agents for the treatment of Type 2 diabetes mellitus (T2DM) because they show
several advantages over other already existing anti-diabetic agents. 2(R)-4-Oxo-4-[3(trifluoromethyl)-5,6-dihydro[1,2,4]triazol[4,3-a]-7(8H)-pyrazinil]-1-(2,4,5-trifluorophenyl)-2butanamine, namely Sitagliptin, is one of the most potent and selective DPP-4 inhibitors. It has
been developed by Merck and is commercialized as phosphate monohydrate salt, under the trade
name Januvia®.
Hansen and co-workers, from Merck, reported two different processes1,2 for the preparation of
Sitagliptin, both characterized by an asymmetric hydrogenation key step. The enantioselective
hydrogenations were run on two different unsaturated intermediates promoted by efficient but rather
expensive Rh(I) complexes. Recently, also a biocatalytic asymmetric synthesis of Sitagliptin has
been published.3
With the aim of preparing Sitagliptin starting from low cost starting materials and making use of
safe procedures, we recently developed a new synthetic approach4 (Scheme 1) which allowed us to
obtain Sitagliptin in eight synthetic steps, with good yield and excellent enantiomeric purity.
COOEt
O
Cl
CHO
COOEt
F
F
F
1
3
F
N
F
F
N
N
N
F
F
OMe
O
O
CF3
F
F
2
4
N
N
N
N
N
F
CO2H O
N
N
N
F
5
CF3
CF3
F
F
*H3PO4
NH2
O
F
O
F
N
N
N
F
Sitagliptin
H
N
SC12H25
O
N
CF3
N
N
N
F
6
N
CF3
Scheme 1
In our synthesis, commercially available aldehyde 1 is first converted into malonate 2 via
Knoevenagel condensation and reduction. Subsequently malonate 2 is alkylated using
chloroacetamide 3, easily prepared from the commercially available free amine. After classical
hydrolysis-decarboxylation sequence, the esterification of the so obtained carboxylic acid gives amido ester 4 as a racemate. The highly efficient enantioselective enzymatic hydrolysis of the
racemic ester 4 yields -amido acid 5 which is then transformed into the dodecylthio carbamate 6
via Curtius rearrangement of the acyl azide intermediate in presence of dodecanethiol. Hydrolysis
of thiocarbamate 6 yields finally Sitagliptin.
(1) Hansen, K.B.; Balsells, J; Dreher, S.; Hsiao, Y.; Kubryk, M.; Palucki, M.; Rivera, N.; Steinhebel, D.; Armstrong,
J.D. III, Askin, D.; Grabowski, E.J.J. Org. Process. Res .Dev. 2005, 9, 634.
(2) Hansen, K.B.; Hsiao, Y.; Xu, F.; Rivera, N.; Clausen, A.; Kubryk, M.; Krska, S.; Rosner, T.; Simmons, B.;
Balsells, J; Ikemoto, N.; Sun, Y.; Spindler, F.; Malan, C.; Grabowski, E.J.J.; Armstrong, J.D. III J. Am. Chem .Soc.
2009, 131, 8798.
(3) Savile, C.K. et al. Science 2010, 329, 305.
(4) Allegrini, P.;; Attolino, E.;; Dell’Anna, G.;; Michieletti, M. U.S. Patent 8,097,724 January 17, 2012.
69
OC37
New synthesis of isoindolinone and isoquinolinone derivatives
by Pd-catalyzed carbonylation of 2-alkynylbenzamides
Raffaella Mancuso,1 Bartolo Gabriele,2 Ida Ziccarelli,1 Giuseppe Salerno1
1
2
Dip. di Chimica, Università della Calabria, Arcavacata di Rende (CS)
Dip. di Scienze Framaceutiche, Università della Calabria, Arcavacata di Rende (CS)
raffaella.mancuso@unical.it
PdI2-catalyzed oxidative carbonylation of acetylenic substrates bearing a suitably placed
nucleophilic group is a powerful methodology for the direct synthesis of carbonylated
heterocycles.1
In this communication, we report a novel method for the direct synthesis of functionalized
isoindolinone derivatives (2, 3) and isoquinolinones derivatives (4) based on PdI2-catalyzed
oxidative heterocyclization-carbonylation processes (1) (Scheme 1).
O
R2
R2
OR'
Pdcat
H
N
R1
NR1
CO, O2, R'OH
2
1 O
Pdcat
CO,O2, Pdcat
R'OH
CO2R'
R2
NR1
4
O
R = alkyl, aryl; R2=H
R' = Me, Et
1
R' = Me, Et
O
R2
CO, O2,
R''2NH
O
R1, R2 = alkyl, aryl
NR1
R''
N
R''
O 3
R = alkyl, aryl; R2=H
1
R''2NH = morpholine, piperidine, pyrrolidine
Scheme 1
Reactions are carried out at 100 °C and under 40 atm of a 4:1 mixture of CO-air, in the presence of
catalytic amounts of PdI2 (1 mol %) in conjunction with KI (10 mol %). Products are obtained in
fair to good isolated yields (50-80%). Different mechanistic pathways are followed, depending on
the substrate substitution pattern and reaction conditions.
(1) For reviews, see: a) Gabriele, B.; Salerno, G.; Costa, M. Top. Organomet. Chem. 2006, 18, 239-272. b) Gabriele,
B.; Salerno, G. PdI2. In e-EROS (Electronic Encyclopedia of Reagents for Organic Synthesis); Chrich, D., Ed.;
Wiley-Interscience: New York, 2006. c) Gabriele, B.; Salerno, Costa, Synlett 2004, 2468-2483. d) Gabriele, B.;
Salerno, G.; Costa, M.; Chiusoli, G. P. Curr. Org. Chem. 2004, 8, 919-946. e) Gabriele, B.; Salerno, G.; Costa, M.;
Chiusoli, G. P. J. Organomet. Chem. 2003, 687, 219-228. f) Gabriele, B.; Salerno, G. Cyclocarbonylation. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York,
2002.
70
OC38
Multi-component domino process for the synthesis
of glyco-conjugates and glyco-mimetics
Maria Cristina Bellucci1 and Alessandro Volonterio2
1
Dipartimento di Scienze Molecolari Agroalimentari, Università degli Studi di Milano,
via Celoria 2, 20133, Milano, Italy.
2
Dipartimento di Chimica, Materiali, e Ingegneria Chimica “Giulio Natta”, via Mancinelli 7, 20131, Milano, Italy.
alessandro.volonterio@polimi.it
The complexity of organic target molecules is constantly increasing and novel strategies allowing
the efficient formation of new carbon-carbon and carbon-heteroatom bonds between functionalized
moieties are needed. Domino reactions1 allow the efficient construction of complex molecules from
simple precursors in a minimum number of steps and may are ideally suited for the generation of
structurally diverse libraries of small molecules. An important subclass of domino reactions are
multi-component reactions (MCRs),2 which became very popular because they offer a wealth of
products, while requiring only a minimum effort combining many elements of an ideal synthesis,
such as operational simplicity, atom economy, bond-forming efficiency, and the access to molecular
complexity from simple starting materials. As such, multi-component reactions have become the
cornerstones of both combinatorial chemistry and diversity-oriented synthesis and thus playing a
central role in the development of modern synthetic methodology for pharmaceutical and drug
discovery research.
This communication is intended to highlight our work in the development of new carbodiimidemediated MCRs for the synthesis of biologically relevant structures incorporating the carbodiimide
framework such as glyco-conjugates and glyco-mimetics.3
F3 C
O
Sugar
N
H
CF 3
N
Sugar O
O
H
N
COOX or
Sugar
R1
N
H
COOR 2
N
Sugar O
H
N
COOR 2
O
H
COX or Sugar
N
N
N
Sugar
H
1
R
Sugar O
R 1 = H, alkyl; R2 = Et, Bn, t er t-Bu; X = O-alkyl, NH-alkyl, NH-AA-OEt
domino
process
R 1 -NCO(S)
+
Sugar-N3
Ph 3P
R1
organic
solvent
domino
process
N C N Sugar
R1
N
H
3
O
H
N
COOX or
R1
N R
Sugar
Sugar
or
O
N
R2
3
O
N R
Sugar
R 1 = ter t-Bu, aryl
CF 3
N
Sugar O
R2
N
O
domino
process
F3 C
O
O
N
H
COOR 2
N
Sugar O
H
N
COX
R1
R 1 = H, alkyl; R2 = Et, Bn, t er t-Bu; X = O-alkyl, NH-alkyl, NH-AA-OEt
(1) A. Domling, Chem. Rev. 2006, 106, 17-89.
(2) For some reviews on MC reaction see a) B. Ganem, Acc. Chem. Res. 2009, 42, 463-472; b) E. Ruijter, R.
Scheffelaar, R. V. Orru, Anew. Chem. Int. Ed. 2011, 50, 6234-6246.
(3) a) M. C. Bellucci, A. Volonterio, Adv. Synth. Catal. 2010, 352, 2791-2798; b) M. C. Bellucci, A. Ghilardi, A.
Volonterio, Org. Biomol. Chem. 2011, 9, 8379-8392.
71
OC39
1,3 Imidazolidine derivatives and their use
in the production of carbapenem
Michele Benotti,1 Mauro Freccero,2 Giovanni Fogliato,1
Antonio Manca,1 Michele Bassanini.1
1
2
ACS DOBFAR S.p.A., Tribiano (MI)
Dipartimento di Chimica, Università di Pavia, V.le Taramelli 10, 27100 Pavia, Italy
michele.benotti@acsdobfar.net
The present invention relates to 1,3-imidaziolidine intermediates useful in the stereoselective
synthesis of carbapenem, in particular of 1b-methylcarbapenem. The heterocyclic compounds of
this invention are represented in formula (I).
As they are derived from a 2-halopropionic acid (CH3-CHX-COOH in which X is an halogen
chosen from cholorine, bromine and iodine), the compounds of formula (I) are used for the
steroselective synthesis of the advanced intermediate of formula (II), a key chiral intermediate for
the synthesis of varius 1b-methylcarbapenem with antimicrobic activity (G = protective group).
Compounds of formula (II) are known to have been synthesized in various strategies,1 by
derivatives of a 2-halopropionic acid binding heterocycles different from those described in the
present invention. Inventors shown that compounds of formula (I) also react as enolates of 2halopropionc acid derivative with azetedinone intermediates of formula (III),
where L is a nucleofuge functional on the condensation between the species (I), activate as enolate,
and the species (III), to obtain the new intermediate species (IIIb). The present inventors have
surprisingly verified that the intemediate (IIIb) is isolated steroisomerically pure by a sterospecific
and stereoselective reaction mechanism.2 The species (IIIb) presents four contiguos stereocenters
identifiable by the common grapic ligand describers used in the relative structural formulas, each
characterized by a graphically explicit unequivocal absolute configuration.
(1) EP232786B1
(2) Berks, A.B. Tetrahedron. 1996, 52, 331-375.
72
OC40
The use of iodine/iodic acid in the synthesis of iodinated contrast agents
Roberta Fretta
Bracco Imaging S.p.A., CRB/Chemistry Dept., Via Ribes 5, Colleretto Giacosa (TO), Italy.
roberta.fretta@bracco.com
Iodinated contrast agents are widely used in several different X-ray diagnostic procedures. Most of
them are non ionic, water soluble molecules containing a triiodinated aromatic nucleus, which
provides the enhanced contrast effect.1
Iopamidol,2 patented in 1974, was a pioneer molecule in this field and is still one of the most
employed worldwide; nowadays its production has reached thousand tons per years.
OH
CONH
O
I
I
OH
OH
NH
OH
CONH
OH
I
Iopamidol
The industrial manufacturing processes currently in use comprise the synthesis of the intermediate
5-amino-2,4,6-triiodoisophtalic acid, that is commonly prepared by iodination of 5-aminoisophtalic
acid with a hydrochloric solution of ICl.3
One of the main drawbacks of ICl is related to concerns about its manufacturing process, that
requires the use of chlorine, classified as toxic and highly dangerous for the environment according
to the GHS classification. Due to the key role of the iodination reaction, several studies were
dedicated to find other possible iodinating systems alternative to ICl.
The couple iodine/iodic acid was identified as an interesting candidate for ICl replacement,
potentially applicable on a large scale process, and a new procedure was optimized to obtain
triiodinated anilines with high quality and yields.4
In addition to safety and environmental benefits, the use of iodine/iodic acid has a positive impact
on the impurity profile of the product as it avoids the formation of some by-products commonly
formed in presence of ICl; finally both iodine and iodic acid are commercially available on the
suitable scale.
COOH
COOH
I2/HIO 3
H2N
COOH
H2SO4/ H2O
I
I
H2N
COOH
I
(1) W. Krause, P. W. Schneider. Top. Curr. Chem. 222, 107 (2002).
(2) a) Felder, E.; Grandi, M.; Pitrè, D.; Vittadini, G. Analytical Profiles of Drug Substances, Vol 17, K. Florey (Ed.),
Academic Press, San Diego, pp 115-154 (1988). b) Pitrè, D.; Felder, E. Invest. Radiol. 15, S301 (1980). c) Felder,
E.; Pitrè, D. E. US Patent 4001323 (1977).
(3) Felder, E. Invest. Radiol. 19, S164 (1984).
(4) Citterio, A.; Lattuada, L.; Ferrigato, A.; Fretta, R.; Mazzon, R.; Meli, G.; Leonardi, G.; Uggeri, F. WO
2010/121904 (2009).
73
OC41
Design, synthesis and biological evaluation of non peptide integrin antagonists
synthesized via Copper (I) catalyzed azide-alkyne cycloaddition
Pierangelo Fabbrizzi,1 Gloria Menchi,1 Andrea Trabocchi,1 Antonio Guarna,1
Anna Bottoncetti,2 Alberto Pupi,2 Silvia Raspanti.2
1
Department of Chemistry “U. Schiff” – University of Florence,
Via della Lastruccia, 13. I-50019 Sesto Fiorentino (FI), Italy.
2
Department of Clinical Physiopathology, Nuclear Medicine Unit – University of Florence,
Viale G. Pieraccini 6, I-50134 Firenze, Italy.
pfabbrizzi@gmail.com
Integrins are cell surface ahdesion proteins that play main roles in cell-cell and cell-matrix
interactions. Subgroup ανβ3 is involved in angiogenesis and tumor cell migration, interacting with vitronectin on the extracellular matrix mainly through the recognition of the tripeptide sequence
RGD (Arg-Gly-Asp).1 Developing integrin ligands is a promising way to develop tumor
therapeutics, tumor targeted probes for imaging and tumor targeted drug delivery systems. RGD
sequence was first incorporated into various linear and cyclic peptides; recently, research has been
focused on the synthesis of selective non peptide integrin antagonists, because of their enhanced
metabolic stability, bioavailability and biological absorption.
In recent years Sharpless and Kolb2 proposed the triazole ring as a non-classical bioisostere of
peptidic bond. Triazolic rings can be synthesized via an high yield reaction that can be performed in
mild conditions, the so-called CuAAC (Copper (I) catalyzed azide-alkyne cycloaddition), the main
reaction of the “Click Chemistry” concept.3 Considering also the stability of such ring, we focused
our synthetic efforts in producing a library of triazole derivatives bearing isosteres of the basic and
acidic groups of the RGD sequence. After a first library of compounds was synthesized and their
biological effects were evaluated,4 other structures were then designed, synthesized and evaluated
also as radiolabeled compounds for imaging applications.
N
N
N
B
A
R
n
B: Basic Isostere A: Acidic Isostere
Screened molecules shown remarkable properties in both in vitro and in vivo assays. In particular,
structures suitable for radiolabeling seem to be very promising candidates in the field of
theranostics.
(1)
(2)
(3)
(4)
Hynes, R.O. Cell, 1992, 69, 11-25.
Kolb, H. C. Sharpless, K. B. Drug Discovery Today, 2003, 8, 24, 1128-1137.
Kolb, H. C. Finn, M. G. Sharpless, K. B. Angew. Chem. Int. Ed. 2001,40, 2004-2021.
Trabocchi, A. Menchi, G. Cini, N. Bianchini, F. Raspanti, S. Bottoncetti, A. Pupi, A. Calorini, L. Guarna, A. J.
Med. Chem. 2010, 53, 19, 7719-7128.
74
OC42
Marine steroids as modulators of pregnane-X-receptor:
isolation, design, total synthesis and potential therapeutic application
Valentina Sepe,1 Simona De Marino,1 Raffaella Ummarino, 1 Maria Valeria D’Auria,1 Giuseppe
Bifulco, 2 Barbara Renga,2 Stefano Fiorucci,2 and Angela Zampella1
1
Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli “Federico II” 2
Dipartimento di Scienze Farmaceutiche, Università di Salerno, Fisciano (SA)
3
Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia,
S. Andrea delle Fratte, Perugia
azampell@unina.it
Nuclear receptors represent important drug targets in terms of potential therapeutic application,
playing a role in every aspect of development, physiology and disease in humans. Among these,
PXR regulates the inflammatory response in inflammatory bowel disease (IBD) and therefore its
ligands represent new therapeutic leads in the clinical treatment of immune-mediated diseases.
During our systematic study on secondary metabolites from marine organisms, we isolated from
Theonella swinhoei two family of steroids, 4-methylenesteroids and sulfated steroids,
solomonsterols A and B.
4-methylenesteroids are 24-alkylated steroids, unique biomarkers in Theonella sponges and for the
first time we proved their ability to modulate PXR transcription activity. Among these molecules,
by means of a deep in vitro pharmacological analysis and docking calculations we have
demonstrated that the different functionalization of the tetracyclic nucleus determines a different
mode of action, ranging from a selective agonistic activity on PXR, to a dual agonistic activity on
PXR and FXR.
Solomonsterols A and B represent the first example of trisulfated C24 and C23 5-cholane
derivatives from marine environment and notably the first report of potent and selective PXR
agonists from sea, useful in the pharmacological treatment of IBD.
In this talk we report the isolation, preliminary in vitro pharmacological evaluation, total synthesis,
deep in vivo pharmacological investigation and the first SAR on the pharmacoforic role played by
the sulfate groups on the side chain and on the tetracyclic nucleus.
(1) Festa, C.;; De Marino, S.;; D’Auria, M. V.;; Bifulco, G.;; Renga, B.; Fiorucci, S.; Petek, S.; Zampella, A. J. Med.
Chem. 2011, 54, 401-405.
(2) Sepe, V.; Ummarino, R.; D'Auria, M. V.; Mencarelli, A.; D'Amore, C.; Renga, B.; Zampella, A.; Fiorucci, S. J.
Med. Chem. 2011, 54, 4590-4599.
(3) De Marino, S.;; Ummarino, R.;; D’Auria, M. V.;; Chini, M. G.;; Bifulco, G.;; Renga, B.;; D’Amore, C.;; Fiorucci, S.;; Debitus, C.; Zampella, A. J. Med. Chem. 2011, 54, 3065-3075.
(4) De Marino, S.;; Sepe, V.;; D’Auria, M. V.;; Bifulco, G.;; Renga, B.;; Petek, S.;; Fiorucci, S.;; Zampella, A. Org.
Biomol. Chem. 2011, 9, 4856-4862.
(5) De Marino, S.; Ummarino, R.; D'Auria, M. V.; Chini, M. G.; Bifulco, G.; D'Amore, C.; Renga, B.; Mencarelli, A.;
Petek, S.; Fiorucci, S, Zampella A. Steroids 2012, 77, 484-495.
(6) Chini, M. G.; Jones, C. R.; Zampella, A.; D'Auria, M. V.; Renga, B.; Fiorucci, S.; Butts, C. P.; Bifulco, G. J. Org.
Chem. 2012, 77, 1489-1496.
(7) Sepe, V.; Ummarino, R.; D'Auria, M. V.; Chini, M. G.; Bifulco, G.; Renga, B.; D'Amore, C.; Debitus, C.;
Fiorucci, S.; Zampella, A. J. Med. Chem. 2012, 55, 84-93.
75
OC43
Mild alkylation and cross-linking of DNA by quinone methides
Filippo Doria,1 Claudia Percivalle,1 Michele Petenzi,1 Luca Germani,1
Sara N. Richter,2 Mauro Freccero1
1
2
Dipartimento di Chimica, Università di Pavia, V.le Taramelli 10, 27100 Pavia, Italy.
Dip. di Medicina Molecolare, Università di Padova, via Gabelli 63, 35121 Padua, Italy.
mauro.freccero@unipv.it
In the last decade there has been increasing interest in the design of novel chemical agents capable
of nucleic acid alkylation and cross-linking. Particular emphasis has been placed upon those
compounds which can be activated starting from unreactive substrates, by redox processes, by light
or mild digestion. Among the alkylating species generated by activation processes, our attention has
been focused on a class of reactive electrophilic intermediates known as quinone methides (QMs).1
Benzo-, naphtho- and Binol-QMs, particularly those with an ortho geometry (o-QMs), have been
successfully used to accomplish nucleoside and DNA monoalkylations and cross-linking. 2 The
selectivity of the alkylation has been implemented using QMs conjugated to amino acids, amino
esters and naphthalenediimides. 3 The reactivity and selectivity of the QM intermediates toward
simple nucleophiles and nucleosides have also been investigated by laser flash photolysis (LFP).
(1) “Quinone Methides”. Wiley Series of Reactive Intermediates in Chemistry and Biology, Volume 1. Edited by
Steven E. Rokita (University of Maryland, College Park). Chap. 2 Freccero, M.; Doria, F.
(2) a) Weinert, E. E.; Dondi, R.; Colloredo-Melz, S.; Frankenfield, K. N.; Mitchell, C. H.; Freccero, M.; Rokita, S. E.
J. Am. Chem. Soc. 2006, 128, 11940-11947. b) Verga, D.; Nadai, M.; Doria, F.; Percivalle, C.; Di Antonio, M.;
Palumbo, M.; Richter, S. N.; Freccero, M. J. Am. Chem. Soc. 2010, 132, 14625-14637. c) Doria, F.; Percivalle, C.;
Freccero, M. J. Org. Chem. 2012, 77, 3615-3619.
(3) a) Di Antonio, M.; Doria, F.; Richter, S. N.; Bertipaglia, C.; Mella, M.; Sissi, C.; Palumbo, M.; Freccero, M. J.
Am. Chem. Soc. 2009, 131, 13132-13141. b) Doria, F.; et al. Org. Biomol. Chem. 2012, 10, 2798-2806.
76
OC44
Synthesis of indolyl and pyrrolyl-glicine derivatives
by catalyzed three components reactions
Cristina Cimarelli, Davide Fratoni, Gianni Palmieri.
University of Camerino - School of Science and Technology - Chemistry Division
Via S. Agostino 1 - 62032 Camerino (MC)
cristina.cimarelli@unicam.it
Indolylglycines are an important class of non-proteinogenic amino acids, which are very useful
building blocks for the synthesis of many biologically important compounds.
The direct asymmetric addition of organic nucleophiles (electron rich aromatic compounds) to
preformed or in situ generated -imino esters has emerged as one of the most promising and
intensely investigated routes to enantiomerically enriched -amino acid derivatives.1,2 In particular,
imines derived from ethyl glyoxylate are excellent electrophiles for the stereoselective construction
of optically active arylglycine derivatives.3
The unprecedented asymmetric synthesis of N-alkylated indolylglycine derivatives is performed by
a three components catalysed Friedel-Crafts reaction among functionalized indoles, a chiral
enantiopure amine and ethyl glyoxalate. This methodology has been extended also to pyrrole
derivatives. Furthermore the use of a chiral enantiopure urea instead of the amine allows the
diastereoselective synthesis of chiral indolyl and pyrrolyl urea derivatives, widely studied as chiral
organocatalysts in several classes of reactions.
R4HN
COOEt
O
R1
N
R3
R1= H, OMe, Br
2
R = H, Me, Ph
R3= H, Me
4
R2 + H2NR + H
cat.
CH3CN
OEt
O
Ph
O
R1
R2
N
R3
Ph
4
R =
Me ,
N
H
Me
(1) Taggi, A. E.; Hafez, A. M.;.Lectka, T. Acc. Chem. Res. 2003, 36, 10-19.
(2) Cordova, A. Acc. Chem. Res. 2004, 37, 102-112.
(3) Cimarelli, C.; Fratoni, D.; Mazzanti, A.; Palmieri, G Tetrahedron: Asymmetry 2011, 22, 591-596.
77
OC45
One-pot synthesis of tetramic acid derivates
for the preparation of -turn mimics
Nicola Castellucci and Claudia Tomasini
Dipartimento di Chimica “G. Ciamician” - Alma Mater Studiorum Università di Bologna
Via Selmi 2, I–40126 Bologna (Italy)
nicola.castellucci2@unibo.it
The tetramic acid (2,4-pyrrolidin-2,4-dione) heterocycle system was found to be a key structural
unit in many natural products due to its interesting biological activities.1 Tetramic acids are polar
and quite unreactive; for this reason the functionalization of these heterocycles is often a difficult
task.
We are interested in the synthesis and the application of N-acyl 2-carboxy tetramic acids, because
they may be applied to the formation of pseudopeptides foldamers, as these interesting structures
are constrained amino acid mimetics, containing an endocyclic carbonyl group which forces the two
exocyclic carbonyls in the trans conformation, following the same effect that we have observed for
the 4-carboxy-oxazolidin-2-one.2
O
R
R'O
O
O
N
H
O
N
R
N
O
NH
O
O
4-carboxy-oxazolidin-2-one
N-acyl 2-carboxy tetramic acids
Thus we synthesize polysubstitued 4-hydroxy-2-oxo-1H-pyrrole-5,6-dihydropyridine-1,3(2H)dicarboxylates (five membered rings) and 4-hydroxy-2-oxo-1H-pyrrole-1,3(2H,5H)-dicarboxylates
(six membered rings) starting from both - and-amino acids activated in the carbossilic group
with O-succinimidyl unit. After the treatment of these compounds with the sodium anion of the
benzyl malonate, the reaction proceeded directly to the formation of the heterocyclic ring.
Finally, after the synthesis of this small library of products, we decided to derivatized the achiral
molecule (R=H, n=1, R’=H, n’=1) with L-Ala-OMe to check its ability to promote the formation of
-turn.
OH
O
O
O
OBn
n
N
R
O
a: R = H; R' = CH2Ph; n = 0; n' = 0
b: R = CH2Ph; R' = CH3; n = 0; n' = 0
c: R = H; R' = CH2Ph; n = 1; n' = 0
d: R = H; R' = H; n = 1; n' = 1
O
O
N
H
O
N
O
O
n' NHBoc
R'
O
N
H
O
e
(1) Schobert, R.; Schlenk, A. Bioorg. Med. Chem. 2008, 16, 4203-4221.
(2) Tomasini, C.; Luppi, G.; Monari, M. J. Am. Chem. Soc. 2006, 128, 2410-2420.
(3) Castellucci N.; Gentilucci L.; Tomasini C. Tetrahedron, 2012, 68, 4506-4512.
78
OC46
Organocatalytic asymmetric processes and multicomponent reactions:
a fruitful coalition
Luca Banfi,1 Andrea Basso,1 Marco Bella,2 Lisa Moni,1
Fabio Morana,1 and Renata Riva1
1
Dipartimento di Chimica e Chimica Industriale, Università di Genova,
via Dodecaneso 31, 16146 Genova
2
Dipartimento di Chimica, Università "Sapienza", p.le A. Moro 5, 00185 Roma
banfi@chimica.unige.it
Isocyanide-based multicomponent reactions are a very efficient tool for the diversity-oriented
assembly of collections of potential drug candidates, granting high step- and atom-economy and a
dramatic increase of structural complexity in just one step. Further manipulation of the MCR
adducts, i.e. through post-condensation cyclization steps, allows an entry to a huge variety of druglike heterocyclic scaffolds.1 While exploration of decoration and scaffold diversity is therefore
easily achieved, the efficient control of absolute and relative stereochemistry of the final products is
still troublesome. In particular, chiral enantiopure components have been used seldom, and they
have been mostly obtained starting from the natural chiral pool.
In the last years my group has been active in searching for new biocatalytic2 or organocatalytic
strategies to prepare (in both enantiomeric pure forms) chiral inputs to be used in isocyanide-based
MCRs.
R1
R1
Ar
*
CN
1
CO2 Et
R2
N
1
CHO
R2
Boc
2a: R = H
2b: R1 = OBn
2c: R1 = CH2N3
R3
NHBoc
1
3a: R = H
3b: R1 = OBn
3c: R1 = CH2N3
In this presentation I will focus only on the organocatalytic methodologies.The development of a
new organocatalytic phase-transfer methodology to access enantiopure β-isocyanoesters of general
formula 1, and their use in diastereoselective Ugi reactions will be described.3 The aldehydes 3a,b,
derived from organocatalytic Mannich-type reactions4 of Boc imines 2a-b, have been subjected to
Passerini reactions, followed by one or two post-condensations transformations, leading to acylamino-α-hydroxyamides, -acylamino-α-ketoamides or dihydrobenzopyrans. Finally, aldehydes
3c have been used in a one-pot protocol involving Staudinger-aza-Wittig and Ugi reactions to afford
stereoselectively tetrahydrobenzazepines.
(1) Banfi, L.; Basso, A.; Riva, R. In Synthesis of Heterocycles via Multicomponent Reactions I; Orru, R. V. A.;
Ruijter, E. Eds.; Springer Berlin / Heidelberg, 2010; pp. 1-39; Banfi, L.; Riva, R.; Basso, A., Synlett 2010, 23-41.
(2) Cerulli, V.; Banfi, L.; Basso, A.; Rocca, V.; Riva, R., Org. Biomol. Chem. 2012, 10, 1255-1274.
(3) Morana, F.; Basso, A.; Bella, M.; Riva, R.; Banfi, L., Adv. Synth. Cat. 2012, in press.
(4) Yang, J. W.; Stadler, M.; List, B., Angew. Chem. Int. Ed. Engl. 2007, 46, 609-611.
79
OC47
A few synthetic approaches to bridged scaffolds useful
as triple reuptake inhibitors
Fabrizio Micheli
Aptuit Verona s.r.l. Via Fleming,4 37135 Verona
fabrizio.micheli@aptuit.com
Depression is terrible illness characterized by low mood, low self-esteem, and loss of interest or
pleasure in usually enjoyable activities. Different drugs have been used for many years to treat
depressed patients: in particular, chemicals able to interfere with either the uptake or with the
metabolism of aminergic neurotransmitters found substantial application. Monoamino oxidase
(MAO) inhibitors or tricyclic antidepressants achieved a large diffusion in the early days. In recent
times, drugs which selectively block the neurotransmitter re-uptake in either serotoninergic neurons
(SSRI, e.g. paroxetine) or noradrenergic neurons (SNRI e.g. reboxetine) became the “gold
standard” therapy. Additionally, drugs blocking the re-uptake at both serotoninergic and
noradrenergic transporters (e.g. venlafaxine) or at both noradrenergic and dopaminergic neurons
(e.g. bupropion), also demonstrated clinical efficacy and acceptable tolerability.
Quite recently, the structures of new compounds named “Triple” Re-uptake Inhibitors (TRUI) were
disclosed. Among these derivatives, a few exemplars are endowed with bicyclic or spiro
structures.1-4
Their properties and their synthesis will be reported.
(1)
(2)
(3)
(4)
F. Micheli et al. J. Med. Chem. 2010, 53, 2534–2551
F. Micheli et al. J. Med. Chem. 2010, 53, 4989–5001
F. Micheli et al. ChemMedChem 2010, 5, 361 – 366
V. Elitzin et al. J. Org. Chem. 2011, 76, 712–715
80
OC48
Bio-inspired benzo[kl]xanthene lignans:
design, synthesis, DNA-interaction and antiproliferative properties
Carmela Spatafora,1 Vincenza Barresi,1 Vedamurthy Bhusainahalli,1 Simone Di Micco,2 Nicolò
Musso,1 Raffaele Riccio,2 Giuseppe Bifulco,2 Daniele Condorelli,1 Corrado Tringali.1
1
Dipartimento di Scienze Chimiche, Università degli Studi di Catania,
Viale A. Doria 6, I-95125 Catania, Italy
2
Dipartimento di Scienze Farmaceutiche e Biomediche, Università degli Studi di Salerno,
Via Ponte Don Melillo, 84084 Fisciano (SA), Italy
cspatafo@unict.it
Many anticancer drugs today available have been developed from natural leads, and a number of
new anticancer candidates derived from natural products is currently in Phase II or Phase III clinical
trial. Thus, many families of natural products have been investigated in the effort to discover or
develop of new bio-inspired antitumor agents and hundreds of promising synthetic analogues have
been obtained. Nevertheless, some groups of compounds rarely found in nature have been only
marginally evaluated or are almost unexplored for their biological properties; among these,
benzo[k,l]xanthene lignans have been recently made available by some of us through a simple
biomimetic methodology,1 in the frame of our studies on natural-derived compounds as potential
antitumor agents. These compounds were evaluated, both for their DNA-interaction (studied by
means of molecular docking and STD-NMR experiments) and for their antiproliferative activity
towards SW480 (colon) and HepG2 (hepatic) cancer cells.2 This study highlighted the important
role of the ester pendant in the DNA minor groove binding.
Thus, we have now synthesized a small library of bio-inspired benzoxanthene lignans, using as
starting material caffeic esters or amides bearing different pendants, with a longer acyl chain or
including an aromatic ring; we included pendants bearing polar groups with donor or acceptor
properties in the formation of hydrogen bonds, or bearing an amide function as isosteric substitution
of the ester function. We report here the synthesis of these benzoxanthene lignans, based on a
biomimetic oxidative coupling reaction; the study of their interaction with DNA by STD-NMR
experiments paralleled with molecular docking ; and finally the evaluation of their antiproliferative
activity against human cancer cell lines.
(1) Daquino, C; Rescifina, A.; Spatafora, C.; Tringali, C. Eur. J. Org. Chem. 2009, 6289-6521.
(2) Di Micco, S.; Daquino, C.; Spatafora, C.; Mazué, F.; Delmas, D.; Latruffe, N.; Tringali, C.; Riccio, R.; Bifulco, G.
Org. Biomol. Chem. 2011, 9, 701-710.
81
OC49
First enantioselective approach to the synthesis of (+)-aR, 11S-myricanol,
a potent microtubule-associated protein Tau destabilizing
Antonella Bochicchio,1 Lucia Chiummiento,1 Maria Funicello,1
Paolo Lupattelli,1 Sabine Choppin2 and Françoise Colobert2
1
Dipartimento di Chimica “A.M.Tamburro”, Università della Basilicata,
Via dell’Ateneo Lucano 10, 85100 Potenza. Italy
2
Laboratoire de Stéréochimie, Ecole de Chimie Polymères et Matériaux (ECPM),
CNRS UMR 7509, 25 Rue Becquerel, 67087 Strasbourg cedex 2, France.
lucia.chiummiento@unibas.it
The diarylheptanoid (+)-aR,11S-myricanol, an extract from Myrica cerifera (bayberry/southern wax
myrtle) potently reduces both endogenous and overexpressed Tau protein levels in cells (anti
Alzheimer effect) and murine brain slices. It is the most effective anti-Tau component in the extract,
with potency approaching the best targeted lead therapies biaryls compounds (Scheme 1).1
Scheme 1
From a retrosynthetic perspective, we envisioned the installation of the axial chirality using an
intramolecular Suzuki-Miyaura reaction starting from compound 2, followed by deprotection of the
hydroxyl group and hydrogenation of the C=C double bond. We proposed to prepare the linear
diarylhetptanoid 2 by a metathesis reaction between the north fragment 3 and the south fragment 4.
The aromatic core 3 could be prepared from the corresponding iodinated and Claisen rearranged
allylic ether. Insteed, the chiral subunit 4 could be obtained using a Grignard reagent in the
regioselective opening of the corresponding enantiopure epoxide.2 Insteed, the correct configuration
on C11 derives from the well-known stereocontrolled reduction of (R)--ketosulfoxide with DibalH/ZnBr2.3
(1) Jones, J. R., Lebar, M. D.; Jinwal, U. K.; Abisambra, J. F.; Koren, J., III; Blair, L.; O'Leary, J. C.; Davey, Z.;
Trotter, J.; Johnson, A. G.; Weeber, E.; Eckman, C. B.; Baker, B. J.; Dickey, C. A. J. Nat. Prod. 2011, 74, 38–44.
(2) Bonini, C.; Chiummiento,L.; Lopardo, M. T.; Pullez, M.; Colobert, F.; Solladié, G. Tetrahedron Lett. 2003, 44,
2695–2697
(3) Miokowski, C.; Solladié, G. Tetrahedron Lett. 1975, 16, 3341.
82
OC50
Preparation of β-cyano ketones via a two-step catalyzed efficient addition
of trimethylsilyl cyanide to α,β-unsaturated ketones.
Giacomo Strappaveccia, Daniela Lanari, Ferdinando Pizzo, Luigi Vaccaro
Laboratory of Green Synthetic Organic Chemistry,
CEMIN - Dipartimento di Chimica, Università degli Studi di Perugia,
via Elce di Sotto 8, 06123 Perugia
email: giacomo.strappa@gmail.com
Our research intends to contribute to the development of a new sustainable organic synthesis
focusing on the replacement of toxic organic solvents and on the design and synthesis of
recoverable heterogeneous catalysts in order to define waste-minimized synthetic procedures.1
We have recently directed our attention on the reactions involving CN as nucleophile. They are
generally useful due to the possible transformation of cyanide into a plethora of possible functional
groups such as amino, carboxylic, amide, or ester.2
In this communication we will report our recent results on the solvent free synthesis of β-cyano
ketones3 3 starting from the corresponding α,β-unsaturated ketones 1 and Amberlite IRA900F
(Amb-F) as catalyst. Our protocol proved to be generally efficient and allowed the preparation of a
variety of β-cyano ketones in satisfactory to excellent yields (53-99%).
To optimize the recovery and reuse of Amb-F we have studied the reaction mechanism and finally
defined two-step protocol using triphenylphosphine supported on polystyrene (PS-TPP) as catalyst
to promote the initial 1,2 addition of CN- (product 2) and then Amb-F to promote the rearrangement
to product 3. This approach allowed us to define a flow procedure featuring a very high chemical
efficiency and low waste production.
Scheme 1 - Preparation of β-cyano ketones via two-step route
(1) For some recent references: a) Bonollo, S.; Lanari, D.; Longo, J. M.; Vaccaro, L. Green Chem. 2012, 14, 164-169;
b) Angelini, T.; Lanari, D.; Maggi, R.; Pizzo, F.; Sartori, G.; Vaccaro, L. Adv. Synth. & Catalyst 2012, 354, 908916; c) Bonollo, S.; Lanari, D.; Vaccaro, L. Eur. J. of Org. Chem. 2011, 2587-2598.
(2) Gregory R. J. H., Chem. Rev., 1999, 99, 3649-3682.
(3) a) Yang, J.; Shen, Y.; Chen, F.-X. Synthesis, 2010, 1325–1333; b) Yang, J.; Wang,Y.; Wu, S.; Chen, F.-X.;
Synlett, 2009, 3365–3367; c) Tanaka, Y.; Kanai, M.; Shibasaki, M. Synlett, 2008, 2295–2298.
83
OC51
A new strategy for amine activation via hydrogen transfer
Andrea Porcheddu
1
Università degli Studi di Sassari, Dipartimento di Chimica e Farmacia
via Vienna 2, 07100 Sassari.
anpo@uniss.it
The selective and direct conversion of an amine into a carbonyl compound is a natural biological
process that still remains a key challenge in organic synthesis. It would be very noteworthy to
achieve this objective by promoting new sustainable procedures that replace the use of strong
stoichiometric oxidative agents. Amines, bearing α and β hydrogen atoms on adjacent nitrogen atom, might become promising substrates as they are readily dehydrogenated by transition-metal
catalysts to generate a metal hydride-iminium complex. Notwithstanding the impressive multitude
of active soluble catalysts developed for C–H activation, often they are not attractive for industrial
application owing to stringent environmental requirements for removal of residual metal. In this
regards, C–H activation via heterogeneous catalysis may represent an original improvement.
Following our interest on “borrowing hydrogen” strategy,1 a simple, and efficient method for the
preparation of a library of nitrogen-containing derivatives based on the Pd/C catalysed C–H
activation of tertiary amines will be described.2
R2
R4
H
N
N
R3
R1
R1
N
R1
R3
R2
N
R1
N
R1
O
R1
N
R2
(1) Lubinu, M. C.; De Luca, L.; Giacomelli, G.; Porcheddu, A. Chem. Eur. J. 2011, 17, 82–85.
(2) Porcheddu, A; De Luca, L Eur. J. Org. Chem. 2011, 5791-5795.
84
OC52
New Boulton-Katritzky rearrangements of azoles
Antonio Palumbo Piccionello, Annalisa Guarcello, Annamaria Martorana,
Andrea Pace, Silvestre Buscemi.
Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari-STEMBIO,
Università degli Studi di Palermo, Viale delle Scienze Ed. 17, 90128, Palermo, Italy.
antonio.palumbopiccionello@unipa.it
Heterocyclic ring rearrangements are reactions that have been well documented in the literature.
Among these, the Boulton-Katritzky rearrangement (BKR) represents one of the most investigated
ring-transformation reactions as a result of its synthetic applications and intriguing mechanistic
aspects.1 It consists of an interconversion between two five-membered heterocycles where a pivotal
annular nitrogen is involved (Fig 1). This rearrangement typically occurs on 1-oxa-2-azoles (D=O),
such as isoxazoles2 and 1,2,4-oxadiazoles.3 When the nucleophilic Z atom (for instance, O, N, S,
C), in the side-chain attacks the electrophilic N(2), the O(1) ring oxygen acts as an internal leaving
group, and the O-N bond is cleaved; the process could be irreversibile and the driving force is the
“leaving group ability” of the sequence ABD and the formation of a more stable bond (N-N, S-N,
or C-N) replacing the less stable O-N bond.
A
B
D
B A
D
H
N
X Y
Z H
N
1
Z
X
Y
2
Fig. 1: General scheme of the BKR
In this communication our recent efforts toward synthetic applications of the BKR through the
investigations of new side-chains (XYZ) will be presented. In particular, the application of azoles
containing a CNC side-chain for the synthesis of imidazole derivatives (Fig. 2) and the first
example of BKR of 1,2,4-oxadiazole derivatives, containing a saturated CCO side chain, into 3acylamino-isoxazoline derivatives (Fig. 3) will be highlighted.
Ph
N
X
Ph
N
O
3 X= N, CH
Ar t-BuOK
Ph
H
X
Ph
O
HN
DMF
O
N for X= CH
Ar
4
t-BuOK/Air
DMF
Ph
Ph
O
HN
5
N
Ar
t-BuOK/Air
for X= CH
DMF
Fig. 2: General scheme of the BKR of azoles containing a CNC side-chain
R'
R''
R'
H
R
N
N
OH t-BuOK
R''
O
N
N O
R
O
DMSO
6
7
Fig. 3: General scheme of the BKR of 1,2,4-oxadiazoles containing a CCO side-chain
(1) a) Vivona, N.; Buscemi, S.; Frenna, V.; Cusmano, G. Adv. Heterocycl. Chem. 1993, 56, 49–154. b) Pace, A.;
Pierro, P. Org. Biomol. Chem. 2009, 7, 4337-4348.
(2) a) Pace, A.; Pierro, P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org. Chem. 2009, 74, 351–358. b) Martorana, A.;
Palumbo Piccionello, A.; Buscemi, S.; Giorgi, G.; Pace, A. Org. Biomol. Chem. 2011, 9, 491-496.
(3) a) Pace, A.; Pibiri, I.; Palumbo Piccionello, A.; Buscemi, S.;Vivona, N.; Barone, G. J. Org. Chem. 2007, 72,
7656–7666. b) Palumbo Piccionello A.; Pace A.; Buscemi S.; Vivona N. Org. Lett. 2009, 11, 4018-4020. c)
Palumbo Piccionello, A.; Pace, A.; Buscemi, S.; Vivona, N. Org. Lett. 2010, 12, 3491-3493.
85
OC53
Semi-synthetic chondroitin sulfate polysaccharides
Emiliano Bedini,1 Cristina De Castro,1 Mario De Rosa,2 Annalida Di Nola,1
Chiara Schiraldi,2 Michelangelo Parrilli1
1
Dipartimento di Chimica Organica e Biochimica, Università di Napoli “Federico II”, Complesso Universitario Monte S.Angelo, via Cintia 4, 80126 Napoli, Italy
2
Dipartimento di Medicina Sperimentale, Seconda Università di Napoli,
via De Crecchio 7, 80138 Napoli, Italy
ebedini@unina.it
Chondroitin sulfate (CS) is a glycosaminoglycan found in both vertebrates and invertebrates,
ubiquitously distributed in extracellular matrices and at cell surfaces. CS polysaccharide is
constituted of a 4)--GlcA-(13)--GalNAc-(1 (GlcA = glucuronic acid; GalNAc = N-acetylgalactosamine) disaccharide repeating unit, with a variable sulfation pattern. The most common
sulfation patterns are listed in Figure 1: the position 4 and/or 6 of the GalNAc units is commonly
sulfated while position 2 or 3 of the GlcA units is sulfated to a minor extent. However, CSs
extracted from animal sources often possess a combination of different sulfation patterns.
Recent studies suggested that CS may be capable of
S O O S
encoding functional information in a sequence-specific
COO Na
O
O
manner, mainly through the sequence of sulfate sites
O
O
O
S O
pattern on the saccharide backbone.1 This sequence
NHAc
S O
seems to be strictly regulated in vivo and is tissue/age
0: GlcA-GalNAc
K: GlcA(3S)-GalNAc(4S)
A: GlcA-GalNAc(4S)
specific. However, the details of this “sulfation code” C: GlcA-GalNAc(6S)
L: GlcA(3S)-GalNAc(6S)
have yet to be fully elucidated. Because of the
D: GlcA(2S)-GalNAc(6S) M: GlcA(3S)-GalNAc(4,6S)
involvement in many biological processes, CS has some
E: GlcA-GalNAc(4,6S)
R: GlcA(2,3S)-GalNAc
applications in therapeutics, mainly for the therapy of
Figure 1
articular cartilage osteoarthritis, for which a CS
polysaccharide composed of A and C disaccharide units is extracted from bovine and porcine
tracheal cartilage. Other different potential pharmaceutical applications have been recently
proposed for CS oligo- and polysaccharides.2
The systematic production of synthetic CS species attracted the attention of several research groups
in the last two decades. They focused mainly on the obtainment of CS oligosaccharides by chemical
or chemoenzymatic syntheses, but semi-synthetic approaches toward the obtainment of CS
polysaccharides by chemical manipulation of natural products have been also reported.3 With
regard to the latter approach, we developed some regioselective protections of a chondroitin
polysaccharide (produced by a suitably optimized biotechnological fermentation of Escherichia coli
O5:K4:H4),4 followed by sulfation of the unprotected hydroxyls and final global deprotection.5
Among the obtained CS products, a polysaccharide containing both CS-A and CS-C units on the
same polymer chain was demonstrated to be very closely resembling commercial CS used for
osteoarthritis treatment.6
-
+
(1) Gama, C.I.; Tully, S.E.; Sotogaku, N.; Clark, P.M.; Rawat, M.; Vaidehi, N.; Goddard III, W.A.; Nishi, A.; HsiehWilson, L.C. Nat. Chem. Biol. 2006, 2, 467-473.
(2) Two recent reviews: a) Yamada, S.; Sugahara, K. Curr. Drug Discov. Techn. 2008, 5, 289-301; b) Schiraldi, C.;
Cimini, D.; De Rosa, M. Appl. Microbiol. Biotechnol. 2010, 87, 1209-1220.
(3) Two very recent reviews: a) Vibert, A.; Jacquinet, J.-C.; Lopin-Bon, C. J. Carbohydr. Chem. 2011, 30, 393-414;
b) Bedini, E.; Parrilli, M. Carbohydr. Res. 2012, 356, 75-85.
(4) Cimini, D.; Restaino, O.F.; Catapano, A.; De Rosa, M.; Schiraldi, C. Appl. Microbiol. Biotechnol. 2010, 85, 17791787.
(5) Bedini, E.; De Castro, C.; De Rosa, M.; Di Nola, A.; Restaino, O.F.; Schiraldi, C.; Parrilli, M. Chem. Eur. J. 2012,
18, 2123-2130.
(6) Bedini, E.; De Castro, C.; De Rosa, M.; Di Nola, Iadonisi, A.; Restaino, O.F.; Schiraldi, C.; Parrilli, M. Angew.
Chem. Int. Ed. 2011, 50, 6160-6163.
86
OC54
Synthesis and activity profile of a family of 5-S-lipoylhydroxytyrosol-based
multi-defence antioxidants with sizeable (poly)sulfide chain
Lucia Panzella,1 Luisella Verotta,2 Luis Goya,3 Sonia Ramos,3 María Angeles Martín,3
Laura Bravo,3 Alessandra Napolitano,1 Riccardo Amorati,4 Luca Valgimigli,4 Marco d’Ischia1
1
Department of Chemical Sciences, University of Naples “Federico II”,
Via Cintia 4, I-80126 Naples, Italy
2
Department of Chemistry, Via C. Golgi 19, I-20133, Milan, Italy
3
Dep. of Metabolism and Nutrition, ICTAN, CSIC, José Antonio Novais 10, 28040-Madrid, Spain
4
Department of Organic Chemistry “A. Mangini”, University of Bologna,
Via S. Giacomo 11, 40126 Bologna, Italy
panzella@unina.it
Hydroxytyrosol occupies a prominent position among natural polyphenols because of its
antioxidant potency and the wide range of biological properties. Several efforts have therefore been
directed toward the preparation of hydroxytyrosol derivatives with improved antioxidant and
pharmacological activities and different solubility properties, particularly enhanced lipophilicity.
Along this line 5-S-lipoylhydroxytyrosol (1) was prepared by conjugation of hydroxytyrosol with
dihydrolipoic acid. The expedite synthetic procedure involves regioselective oxidation of tyrosol
with 2-iodoxybenzoic acid (IBX) to hydroxytyrosol o-quinone, followed by addition of
dihydrolipoic acid. Further aim of the study was the preparation of polysulfide derivatives of 1, as
polyfunctional compounds combining the potential of the catechol moiety with that of the
polysulfide functionality, typically associated to remarkable chemical, biological, and
pharmacological properties. Specific conditions to obtain each polysulfide, namely the disulfide 2,
the trisulfide 3 and the tetrasulfide 4, were developed relying on a fine tuning of the reaction
parameters such as the absence or presence of sulfur in different solvents. All the polysulfides 2-4
were found to have stronger hydrogen donor ability than Trolox in the DPPH assay. In the FRAP
assay, 1 exhibited the best reducing activity. All compounds 1-4 acted as efficient hydroxyl radical
scavengers at concentration as low as 10 M in a Fenton reaction inhibition assay and showed
peroxyl radical trapping activity in inhibited autoxidation studies. The antioxidant activity of
compound 1, disulfide 2 and tetrasulfide 4 was also tested in human hepatocarcinoma cell line
(HepG2). Direct treatment of cells with the compounds induced significant changes in cellular
intrinsic antioxidant status, reducing ROS imbalance. Moreover, pretreatment of cells with the
compounds counteracted cell damage induced by t-BOOH by decreasing ROS generation. All the
compounds proved more active than the parent hydroxytyrosol.
OH
HO
tyrosol
O O
HO I
O
IBX
phosphate buffer
pH 7.4
OH
O
2
OH HO
HO
OH
OH
HO
OH
HO
O
o-quinone
HO
O
SH
OH
SH
SH
S
sulfur
3
methanol/
phosphate buffer pH 7.4
1:2 v/v
5-S-lipoylhydroxytyrosol
(1)
dihydrolipoic acid
O
sulfur
methanol
OH
4
S
S
(S)n
S
S
COOH HOOC
2: n=0; 3: n=1; 4: n=2
87
OC55
Chemoenzymatic approaches towards the enantioselective synthesis
of the bisabolane sesquiterpenes
Stefano Serra
C.N.R. Istituto di Chimica del Riconoscimento Molecolare, Via Mancinelli 7, 20131 Milano, Italy.
stefano.serra@cnr.it
The monocyclic sesquiterpenes of the bisabolane family have been isolated from many natural
sources. Most of these compounds possess an asymmetric centre in position C(7) of the bisabolane
framework 1 and display a wide range of biological activities which are strictly related to their
absolute configuration.
14
3
2
7
4
13

9
8
11
12
10
5
15
6
BISABOLANE FRAMEWORK
(bisabolane numbering)
1
Due to the difficulty associated with the stereoselective introduction of the aforementioned centre,
only few of the reported syntheses afford the sesquiterpenes in high enantiomeric purity.
In this context we have developed some chemoenzymatic approaches that turned out to be very
effective in the bisabolane syntheses allowing the preparation of both of their enantiomeric forms in
high optical purity.
microbial
reduction
R
R
O
OH
R
OH
(S)-1
R= Aryl, Cyclohexenyl
lipase-cat.
resolution
R
OAc
(R)-1
As illustrated in the scheme, two main methods were accomplished: The first is based on the
microbial-mediated reduction of substituted 3-aryl-(cyclohexenyl)-but-2-enals to give saturated (S)3-aryl-(cyclohexenyl)-butanols.1-3 A further approach was hence devised in order to prepare also the
(R) isomers. We found that 2-aryl-(cyclohexenyl)-propanol can be efficiently resolved by means of
the lipase-catalysed irreversible acetylation reaction,4,5 provided the substrates meet some specific
structural requirements.
These approaches, as well as a number of their applications in the natural products synthesis, will be
illustrated comprehensively.
(1)
(2)
(3)
(4)
(5)
Fuganti, C.; Serra, S. J. Chem. Soc. Perkin Trans. 1 2000, 3758-3764.
Fuganti, C.; Serra, S. J. Chem. Soc. Perkin Trans. 1 2000, 97-101.
Serra, S. Nat. Prod. Commun. 2012, 7, 455-458.
Serra, S. Tetrahedron: Asymmetry 2011, 22, 619-628.
Serra, S.; Nobile, I. Tetrahedron: Asymmetry 2011, 22, 1455-1463.
88
OC56
Organocatalytic stereoselective routes to three-membered rings
Alessandra Lattanzi,1 Claudia De Fusco,1 Alessio Russo2
1
Dipartimento di Chimica e Biologia, Università di Salerno,
Via Ponte don Melillo, 84084, Fisciano, Italy
2
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, UK
lattanzi@unisa.it
Recently, a lot of attention has been paid to the development of asymmetric organocatalytic
methodologies which make use of easily available and low cost catalysts coupled with simplicity of
the reaction conditions. Among the different organocatalysts available, L-proline and their
derivatives have been the subject of deep investigantion in processes where covalent intermediates,
such as enamines and iminium ions, are generated with carbonyl compounds as the reagents.1 In
this context, ,-L-diaryl prolinols have been employed in some processes as classical
aminocatalysts likewise L-proline.2 Nevertheless, they proved to be chameleonic promoters, being
able to activate the reagents via noncovalent interactions, typically via general base and acid
catalysis in analogy to cinchona alkaloids, their thiourea derivatives, and derivatives thereof.2
We have recently disclosed that this type of activation provided by ,-L-diaryl prolinols and
cinchona thioureas can be exploited in the nucleophilic asymmetric epoxidation of electron-poor
alkenes to give novel synthetically useful classes of epoxides bearing contiguous tertiary and
quaternary stereocenters or exclusively quaternary stereocenters with high diastereo- and good to
high enantioselectivity.3 The MIRC (Michael initiated ring closure) approach has also been
exploited to access enantiomerically enriched cyclopropanes and aziridines (Scheme 1).4
Scheme 1
(1) a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471-5569; b) Erkkilä, E.; Majander,
I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416-5470.
(2) For a review see: Lattanzi, A. Chem. Commun. 2009, 1452-1463.
(3) a) De Fusco, C.; Tedesco, C.; Lattanzi, A. J. Org. Chem. 2011, 76, 676-679; b) Russo, A.; Galdi, G.; Croce, G.;
Lattanzi, A. Chem. Eur. J. 2012, 18, 6152-6157.
(4) a) Russo, A.; Meninno, S.; Tedesco, C.; Lattanzi, A. Eur. J. Org. Chem. 2011, 5096-5103; b) Russo, A.; Lattanzi,
A. Org. Biomol. Chem. 2011, 9, 7993-7996; (c) De Fusco, C.; Fuoco, T.; Croce, G.; Lattanzi, A. submitted.
89
OC57
Metal nano-catalysts for green organic synthesis
Angelo Nacci,1,2 Antonio Monopoli,1 Pietro Cotugno,1 Nicola Cioffi,1 Marilena Manica,1 Giuseppina
Tatulli,1 Onofrio Iacovelli,1 Francesco Lozito,1 M. Vittoria Divincenzo1 and Francesco Ciminale1
1
Department of Chemistry - University of Bari, Via Orabona 4, 70126-Bari, Italy
2
CNR – ICCOM - Department of Chemistry - University of Bari,
Via Orabona 4, 70126-Bari, Italy.
nacci@chimica.uniba.it
Transition-metal nanoparticles (NPs) are attracting a great deal of attention in almost any
scientific and technological field, including catalysis, where nanoscale materials are becoming more
prevalent in a wide range of applications such as fuel conversion, pollution abatement and fine
chemical production.1
An increasing interest is also devoted nowadays to properly exploit the high activity and
selectivity of nanocatalysts in order to develop greener and waste-minimized processes. From the
Green Chemistry standpoint, new nanocatalysts must be designed to operate under environmentally
friendly (for instance phosphine-free) conditions or in neoteric green solvents (e.g. ionic liquids,
supercritical fluids, fluorous phases, water and so on).2
In this context, during the last decade, we exploited the use of nanostructured metal catalysts
based on palladium, copper, and gold, to perform a wide range of C-C bond forming reactions, like
for example Heck, Suzuki, Stille, acrylate dimerization, and Ullmann couplings, using
tetraalkylammonium ionic liquids and water as green reaction media.3
Hydrodechlorination
RO2C
Ar-H
CO2R
Ar-Ar
dimerization
CO2R
R
Ar-X
Ar-Ar'
Ar'SnBu3
solvents: IL or water
Ar
CO2R
Stille
Ar-X
Ar'B(OH)2
Ar'X
R
Ar'
Heck
Ar-X
cat.= metal-NPs
oxidative coupling
(C-Cl activation)
Ar-Cl
R
R
Ar
H2
Ullmann
Ar-Ar'
CO2R
Suzuki
R
C-H activation
This communication deals with our recent advances in controlling the catalyst performances by
choosing appropriately the nature of the ionic liquid or the aqueous medium.
(1) Astruc, D.; Lu, F.; Aranzaes J. R. Angew. Chem. 2005, 117, 8062; Angew. Chem. Int. Ed. 2005, 44, 7852.
(2) Pârvulescu, V. I.; Hardacre, C.; Chem. Rev. 2007, 107, 2615.
(3) a) Calò, V.; Nacci, A.; Monopoli, A.; Cotugno, P. Angew. Chem. Int. Ed. 2009, 48, 6101; b) Monopoli, A.; Calò,
V.; Ciminale; F.; Cotugno, P.; Angelici, C.; Cioffi, N.; Nacci, A. J. Org. Chem. 2010, 75, 3908.
90
OC58
Bioinspired catalytic oxidation reactions in water:
not simply green chemistry
Claudio Santi, Caterina Tidei, Claudia Scalera, Loredana Incipini,
Francesca Marini, Luana Bagnoli, Lorenzo Testaferri
Group of Catalysis & Green Chemistry – Dip. Chimica e Tecnologia del Farmaco
Università degli Studi di Perugia – via del liceo 1- 06134 Perugia
santi@unipg.it
The idea of ‘‘green’’ solvents expresses the goal to minimize the environmental impact resulting from the use of organic solvents in chemical production. Finding environmentally benign greenalternatives is a top priority of the organic chemist. Togheter with solvent-free reactions and
biphasic technologies, the use of water as naturally abundant solvent present nowadays a series of
interesting attractive features: environmental benefits, safety, synthetic efficienct, simple operation
and reduced costs.
During the last five years we developed a series of new reagents and metodologies devoted to
increase the greenest of the reactions involving organoselenium compounds. We sinthetized a series
of PhSeZn-halides,1 a class of new bench stable selenolates, that showed interesting rate
accelleration in some nucleophilic selenenylation reactions when these were effected in ”on-water
conditions. In these communication we describe bioinspired oxidation reactions catalyzed by
organoperselenenic acids effected at room temperature, using diluited hydrogen peroxide as
stoichiometric oxidant and a recyclable catalyst containing aqueous medium. The sinthesis of
derivatives like 1-6 will be described.
(1) Santi, C. Phenylselenenylzinc halides (2011), Encyclopaedia of Reagents for Organic Synthesis, John Wiley &
Sons Ltd., http://onlinelibrary.wiley.com/book/10.1002/047084289X [3/10/2011], DOI:
10.1002/047084289X.rn01352
91
OC59
Synthesis of lignan-like compounds through highly
functionalized diarylfuranones
Marina DellaGreca, Maria Rosaria Iesce, Lucio Previtera,
Simona Zuppolini and Armando Zarrelli
University of Federico II, Department of Chemical Sciences,
Via Cintia 4, I-80126, Naples-Italy
zarrelli@unina.it
Furans are a class of heterocycles widely distributed in a large number of natural compounds, in
aromatic forms, reducted forms as tetrahydrofurans, and oxidated forms as furanones.1 Furans also
have a prominent role in synthetic chemistry due to their ability to undergo a wide range of
reactions, for example oxidation to versatile 1,4-enediones or furanones. Actually, polysubstituted
furans are important building blocks for the synthesis of natural and non-natural products.
In this communication we describe the use of readily accessible 2-aryl-3,4-dicarboxymethyl furans
(1)2 in novel synthetic approaches to lignan-like compounds. Lignans are widespread plant
secondary metabolites holding a large series of bioactivities.3 The isolation of these natural
compounds is a laborious and expensive process and the yields are generally low. Hence several
routes to natural and synthetic derivatives have been proposed over the years.
Selective basic hydrolysis of diesters 1 followed by the use of the corresponding 4-furoic acids in
the Friedel-Crafts (FC) acylation of aromatic substrates in the presence of Tf2O leads to aryl
ketones 2 that show a suitable C6C3-C3C6 scaffold for the elaboration of lignan structures.
Application of the Tf2O-mediated acylation using acids 3 leads to lactones 4 with rare lignanstructure.4 Monoacids 3 have been obtained by singlet oxygenation of furans 1 followed by in situ
treatment of the corresponding endo-peroxides with an amine. Their formation is an unexpected
reaction. Although the power of the reaction of furans with 1O2 is widely recognized, novel findings
are often found due to versatility of the furan endoperoxide intermediates.5
O
MeO2C
Ar
R
O
2
MeO2C
basic
hydrolysis
Tf2O
Ar
R
CO2Me
1) 1O2
2) Amine
O
1
MeO2C
CO2Me
Ar
OH
O O
3
MeO2C
Ar'H
Tf2O
CO2Me
Ar
Ar'
O
O
4
(1) Keay, B. A.; Hopkins, J. M.; Dibble, P. W. in Comprehensive Heterocyclic Chemistry III, Katritzky, A. R.;
Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. (Eds), Elsevier, Oxford, 2008, 3.
(2) Mingji, F.; Zeyi, Y.; Weimin, L.; Yongmin, L. J. Org. Chem. 2005, 70, 8204-8215.
(3) a) Pan, J.-Y.; Chen, S.-L.; Yang, M.-H.; Wu, J.; Sinkkonen, J.; Zou, K. Nat. Prod. Rep. 2009, 26, 1251-1292. b)
Saleem, M.; Kim, H. J.; Ali, M. S.; Lee Y. S. Nat. Prod. Rep. 2005, 22, 696-716.
(4) Gan, L.-S.; Yang, S.-P.; Fan, C.-Q.; Yue, J.-M. J. Nat. Prod. 2005, 68, 221-227.
(5) a) Iesce, M. R.; Cermola, F.; Temussi, F. Curr. Org. Chem. 2005, 9, 109-139. b) Montagnon, T.; Tofi, M.;
Vassilikogiannakis, G. Accounts of Chemical Research 2008, 41, 1001-1011.
92
OC60
Synthesis of purine ribonucleosides via transglycosylation reaction
catalyzed by a purine phosphorylase from A. hydrophila
Carlo F. Morelli,1 Daniela Ubiali,2 Immacolata Serra,2 Carla D. Serra,1
Alessandra M. Albertini,3 Giovanna Speranza1
1
Dip. di Chimica, Università degli Studi di Milano, via Golgi, 19 – 20133 Milano
Dip. di Scienze del Farmaco, Università degli Studi di Pavia, via Taramelli, 12 – 27100 Pavia
3
Dip. di Biologia e Biotecnologie, Università degli Studi di Pavia, via Ferrata, 1 – 27100 Pavia
carlo.morelli@unimi.it
2
Nucleoside phosphorylases (NPs, E.C. 2.4.2) catalyze the reversible cleavage of the glycosidic bond
of (deoxy)ribonucleosides in the presence of inorganic phosphate to afford the nucleobase and -D(deoxy)ribose-1-phosphate (Scheme 1).1
Scheme 1
If a second nucleobase is added to the reaction medium, the formation of a new nucleoside can
result through a transglycosylation reaction. NPs have been therefore proposed as biocatalysts for
the chemoenzymatic synthesis of natural and unnatural purine nucleosides, as an alternative to
conventional chemical methods, which generally require multi-step procedures and can be plagued
by low stereoselectivity.2
Starting from the results of a microbiological screening,3 we investigated the potential of a purine
nucleoside phosphorylase (PNP, E.C. 2.4.2.1) from Aeromonas hydrophila as
a biocatalyst for synthetic purposes. A. hydrophila PNP was cloned,
overexpressed in E. coli and isolated. Phosphorolysis experiments performed
on a library of nucleoside analogues (1) showed that 1-, 2-, 6- and 7-modified
purine nucleosides act as substrates, whereas 8-substituted nucleosides are not
accepted.4 Because of this broad substrate specificity, A. hydrophila PNP has
been now exploited for the regio- and stereoselective synthesis of nucleosides analogues by a “one pot–one enzyme” transglycosylation strategy (Scheme 2).5
Scheme 2
(1) Pugmire, M., Ealick, S. E. Biochem. J. 2002, 361, 1-25.
(2) Vorbrüggen, H., Ruh-Pohlenz, C. In Organic Reactions, Vol. 55 (Eds: L. A. Paquette et al.), John Wiley & Sons,
Hoboken, NJ, 2000, pp 1-51.
(3) Trelles, J. A., Valino, A. L., Runza, V., Lewcowicz, A. S., Iribarren, A. M. Biotechnol. Lett. 2005, 27, 759.
(4) Ubiali, D., Serra, C. D., Serra, I., Morelli, C. F., Terreni, M., Albertini, A. M., Manitto, P., Speranza, G. Adv.
Synth. Catal. 2012, 354, 96-104.
(5) Morelli, C. F., Ubiali, D., Serra, I., Albertini, A. M., Speranza, G., Manuscript in preparation.
93
OC61
Marine drugs target discovery by chemical proteomics
Luigi Margarucci, Maria Chiara Monti, Chiara Cassiano,
Raffaele Riccio and Agostino Casapullo
Department of Pharmaceutical and Biomedical Sciences, University of Salerno,
via Ponte don Melillo, 84084, Fisciano, Italy
lmargarucci@unisa.it
Although the therapeutic potential of the most promising compounds is being evaluated in
preclinical and clinical trials, often their intracellular targets and the interaction profile remain
largely unknown. In recent years, mass spectrometry-based chemical proteomic- approaches have
been applied to the macromolecular targets discovery and to the characterization of drug–targets
interactions under physiological condition.1,2
Since natural products from marine source have acquired a central role in the drug discovery
research, we have focused our attention onto the application of the chemical proteomics based
approach for the interactome identification of several bioactive natural compounds, such as
petrosaspongiolide M,3 bolinaquinone,4 perthamide.5
The experimental procedure usually requires three steps :1) preparation of solid support bearing the
molecule of interest, 2) isolation of the potential targets, through affinity chromatography of the
crude cell extract, 3) SDS-PAGE of the eluting proteins and the identification by MS of the
interacting target(s). Finally, a panel of in vitro and/or in vivo based assays is required to validate
the proteomic data. Some of our recent results will be discussed herein to fully clarify how chemical
proteomics can help us in the discovery of unknown natural drug target(s).
(1)
(2)
(3)
(4)
Rix, U., Superti-Furga, G., (2009), Nature Chemical Biology, 5, 616 – 624
Margarucci, L., Monti, M. C., Tosco, A., Riccio, R., Casapullo, A., (2010), Angew. Chem. Int. ed., 49, 3960-3963
Margarucci, L., Monti, M. C., Fontanella, B., Riccio, R., Casapullo, A., Mol Biosyst. (2011), 7(2),480-485
Margarucci, L., Monti, M.C., Cassiano, C., Mencarelli, A., Fiorucci, S., Riccio, R., Zampella, A., Casapullo A.,
Mol. Biosyst. 2012, 8, 1412-1417
(5) Shimizu, N., Sugimoto, K., Tang, J., Nishi, T., Sato, I., Hiramoto, M., Aizawa, S., Hatakeyama, M., Ohba, R.,
Hatori, H., Yoshikawa, T., Suzuki, F., Oomori, A., Tanaka, H., Kawaguchi, H., Watanabe, H., Handa, H., Nature
Biotechnology, (2000), 18, 877-81.
94
OC62
One-pot consecutive reactions
via oxo-Re-catalysed Meyer-Schuster rearrangement
Alessio Porta, Elio Mattia, Valentina Merlini, Giuseppe Zanoni, and Giovanni Vidari.
University of Pavia, Department of Chemistry, Via Taramelli 12, 27100 Pavia, Italy.
alessio.porta@unipv.it
Conjugated enones are one of the most used building blocks in synthetic organic chemistry1 and an
important moiety in natural products and biologically active compounds. Given to its high synthetic
versatility, the enone system is involved both in several carbon-carbon bond forming reactions, such
as cyclopropanation, Michael-additions, Diels-Alder and 1,3-dipolar cycloaddition reactions, as
well as in the conversion to other functional groups, such as allylic alcohols, epoxides, and amines.2
Recently, using the readily available complex ReOCl3(OPPh3)(SMe2),4 we have developed a novel
general catalytic procedure for the rapid and efficient M–S rearrangement of free secondary and
tertiary propargylic alcohols to the corresponding α,β-unsaturated carbonyl compounds.3 The
reaction proceeded under neutral conditions, showing virtually complete (E)-stereoselectivity and
preserving the configurational integrity of potentially enolizable stereocenters.3
In this work we have developed an unprecedented atom-economical strategy, which allows
conversion of readily accessible starting materials to products of increased molecular complexity
through one-pot consecutive reactions based on the Meyer-Schuster rearrangement. Thus, alkyne
deprotonation by BuLi, followed by addition of the lithium acetylide to a carbonyl compound, and
subsequent Re (V)-catalyzed Meyer-Schuster rearrangement of intermediate alkynol, afforded the
corresponding α,ß-unsaturated enone in high yield. In further experiments, the Meyer-Schuster
rearrangement was coupled in situ with a hydride reduction or with a Diels-Alder reaction of the
formed enone, yielding products with complete stereoselectivity in good-high overall yields.
(1) a) S. Patai, Z. Rappoport, The Chemistry of Enones; Wiley, Chichester, 1989; b) C. E. Foster, P. R. Mackie, In
Comprehensive Organic Functional Group Transformations II, Vol..3 (Eds. A. R. Katritzky, R. J. K. Taylor)
Elsevier, Oxford, 2005; pp. 215–266; c) J. Otera, Modern Carbonyl Chemistry; WILEY–VCH, Weinheim, 2000.
(2) For reviews, see: a) M. E. Jung, in Comprehensive Organic Synthesis; Vol..4 (Eds. B. M. Trost, I. Fleming, M. F.
Semmelhack,); Pergamon: Oxford, 1991; pp. 1–67; b) V. J. Lee, in Comprehensive Organic Synthesis, Vol. 4
(Eds. B. M. Trost, I. Fleming, M. F. Semmelhack); Pergamon, Oxford, 1991; pp. 69–137 and 139–168; c) J. A.
Kozlowski, in Comprehensive Organic Synthesis; Vol. 4 (Eds. B. M. Trost, I. Fleming, M. F. Semmelhack);
Pergamon, Oxford, 1991, 169–198.
(3) M. Stefanoni, M. Luparia, A. Porta, G. Zanoni, G. Vidari, Chem. Eur. J. 2009, 15, 3940–3944.
(4) a) B. D. Sherry, R. N. Loy, F. D. Toste, J. Am. Chem. Soc. 2004, 126, 4510–4511; b) M. M. Abu-Omar, S. I.
Khan, Inorg. Chem. 1998, 37, 4979–4985.
95
OC63
Improved microwave assisted synthesis of tetrahydrocannabinol
analogues catalyzed by Yb(OTf)3
Ornelio Rosati, Federica Messina, Massimo Curini, Maria Carla Marcotullio.
Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi,
Via del Liceo 06123 Perugia, Italy
ornros@unipg.it
Tetrahydrocannabinols are important natural occurring compounds that recently claimed some
important therapeutic use in pain therapy, multiple sclerosis, atherosclerosis and several other
pathologies.1 A wide range of syntheses of natural tetrahydrocannabinols and analogues are
reported in the literature since 1940.2 Many of these processes show poor yields, long reaction time
and hard conditions, along with the formation of several side products. Furthermore, a lack in the
field of heterogeneous synthetic approach to tetrahydrocannabinols and analogues exists.
In order to develop a new heterogeneous synthetic approach to tetrahydrocannabinol analogues,
microwave assisted Yb(OTf)33 mediated reactions of pulegone and resorcinol derivatives have been
investigated. The reaction can be improved by the combined use of some carboxylic acids that
probably are involved in the formation of a more active ytterbium-carboxylate catalytic complex.
Microwave assisted one pot reaction led to a significant shortening of reaction time. The yields of
desired products are sufficient despite the presence of xanthenes as up to date not-avoidable sideproducts. The use of ytterbium-carboxylate catalytic complex lead to an evident improvement in the
tetrahydrocannabinol analogues yield and in the tetrahydrocannabinol analogues/xanthene ratio if
compared with the data previously reported in the literature.4 A pentacyclic system by a second
pulegone molecule addition to the already formed tetrahydrocannabinol analogues and/or xanthenes
is also obtained. Further improvements of this process can be envisaged by the minimization of this
byproduct formation.
R1
R1
R2
Yb(OTf)3
+
R3
O
OH
R1
R2
R2
+
MW
R3
O
R3
O
(1-4 a)
(1-4 b)
OH
O
OH
O
R
O
Yb(OTf), MW
O
R
O
Yb(OTf), MW
R
O
3,4 b
3,4 c
3,4 a
1-a,b R1=R2=H, R3=OH; 2-a,b R1=H, R2=CH2CH3, R3=OH; 3-a,b R1=OH, R2=H, R3=
CH3; 4-a,b R1=OH, R2=H, R3=C5H11; 3c R=CH3; 4c R=C5H11.
(1) Iskedjian, M.; Bereza, B.; Gordon, A.; Piwko, C.; Einarson, T.R. Curr. Med. Res. Opin. 2007, 23, 17-24.
Papathanasopoulos, P.; Messinis, L.; Lyros, E.; Kastellakis, A.; Panagis, G. J. Neur. Clin. Neurosci. 2008, 20, 3651.
(2) Razdan, R. “Total synthesis of Cannabinoids”, in Total Synthesis of NaturalProducts, Vol. 4, Wiley, 1981, 185260. Ballerini, E.; Minuti, L.; Piermatti, O. J. Org. Chem. 2010, 75, 4251-4260. Trost, B.; Dogra, M. K. Org. Lett.
2007, 9, 861-863. Adams, R.; Smith, C. M.; Loewe, S. J. Am. Chem. Soc. 1941, 63, 1973-1976. Gosh, R.; Todd,
A. R.; Wright, D. C. J. Chem Soc. 1941, 137-143.
(3) Epifano, F.; Pelucchini, C.; Rosati, O.; Genovese, S.; Curini, M. Catal. Lett. 2011, 141, 844-849.
(4) Chazan, J. B.; Ourisson, G. Bull. Soc. Chim. Fra. 1968, 4, 1374-1393. Claussen, U.; Mummenhoff, P.; Korte, F.
Tetrahedron 1968, 24, 2897-2898.
96
OC64
Use of Ugi MCR for the synthesis of 4-amino-1,2,3,4tetrahydroisoquinoline-1,3-dione-based peptidomimetics
Alessandro Sacchetti,1 Francesco Gatti, Marcella Moretti1 and Alessandra Silvani2
1
Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”,
Politecnico di Milano, P.zza Leonardo Da Vinci 32, 20133, Milano (Italy).
2
Dipartimento di Chimica, Università degli Studi di Milano,
via Golgi 19, 20133 Milano, Italy.
alessandro.sacchetti@polimi.it
The atom economy of multicomponent reactions (MCRs), their convergent character, and
operational simplicity make this chemistry exceptionally useful for drug discovery.1 In particular,
isonitrile based multicomponent reactions (IMCR’s), such as the Ugi MCR, have found numerous
applications due to the high degree of structural diversity and complexity of the resulting products
which can be accomplished in a single reaction step.2 With the aim of designing new
pharmacophore-based combinatorial libraries3 for identification of new peptidomimetic scaffolds,4
we report here on the use of 4-amino-1,2,3,4-tetrahydroisoquinoline-1,3-dione-based compounds 1
as molecular targets for the synthesis of peptidomimetics by means of multicomponent
methodologies.
The MCR of methyl 2-formylbenzoate 2 with different isonitriles, amines and carboxylic acids,
followed by an intramolecular amidation, allowed to obtain a library of 1. The selected compound 3
was further investigated by computational and spectroscopy tools to evaluate its ability to mimic a
β-turn structure.
(1) a) Zhu, J.; Bienayme´, H. Multicomponent Reactions, Wiley-VCH, Weinheim, 2005. b) Hulme, C.; Gore, V. Curr.
Med. Chem. 2003, 10, 51. c) Akritopoulou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324.
(2) a) Dömling, A. Chem. Rev., 2006, 106, 17. b) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(3) Danieli, B.; Giovanelli, P.; Lesma, G.; Passarella, D.; Sacchetti, A.; Silvani, A. J. Comb. Chem. 2005, 7, 458-462.
(4) a) Lesma, G.; Landoni, N.; Sacchetti, A.; Silvani, A. Tetrahedron 2010, 66, 4474–4478. b) Lesma, G.; Landoni,
N.; Pilati, T.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74, 8098–8105. c) Lesma, G.; Landoni, N.; Sacchetti,
A.; Silvani, A. J. Org. Chem. 2007, 72, 9765–9768. d) Lesma, G.; Meschini, E.; Recca, T.; Sacchetti, A.; Silvani,
A. Tetrahedron 2007, 63, 5567–5578.
97
OC65
Ionic liquid crystals based on viologens and viologen dimers
M. Bonchio,1 M. Carraro,2 G. Casella,3 V. Causin,2 F. Rastrelli,2 G. Saielli1
1
CNR Institute on Membrane Technology, Unit of Padova, Italy.
Department of Chemical Sciences, University of Padova, Italy.
3
Department of Chemistry University of Palermo, Italy.
giacomo.saielli@unipd.it
2
Ionic liquid crystals (ILC) are expected to combine the properties and technological applications of
ionic liquids and liquid crystals.1,2 We have investigated how structural modifications of the
viologen cation (1,1′-dialkyl-4,4′-bipyridinium) affect the stability and temperature range of the ILC
mesophases. Thus we report the synthesis and characterization of the compounds of Figure 1: i)
unsymmetric viologen salts (nBPm, with n ≠ m);; ii) symmetric salts of tetramethylviologen (nBLn);
iii) dimeric viologen salts (nBPmBPn). In most cases the counteranion is
bis(trifluoromethanesulfonyl)amide (Tf2N–), but also dodecatungstosilicates have been investigated
in details. The various phases exhibited have been characterized by means of TGA, DSC, X-ray
diffraction, polarized optical microscopy and solid state NMR, while the behaviour in solution has
been characterized by cyclic voltammetry.3-5 The modulation of the length of the alkyl chains
allowed the fine tuning of the transition temperatures and temperature range of stability of the ILCs.
Monomers and dimers with short alkyl chains only have a melting transition, thus exhibiting no
mesomorphism. Unsymmetric monomeric salts show a stable room temperature smectic phase from
about 0 °C up to about 130 °C with a mosaic textures under crossed polarisers, suggesting an
ordered smectic phase. In contrast, for dimers with relatively long lateral alkyl chains and short
middle chains, a SmA phase was observed, see Figure 1. The thermal behaviour is then rationalized
in terms of the overall flexibility and degree of disorder brought into the system by the combination
of cation and anion.
Fig. 1. Left: viologen systems investigated. Right: POM textures of the SmA phase of 14BP4BP14(Tf2N)4.
(1) Binnemans, K. Chem. Rev. 2005, 105, 4148.
(2) Causin, V.; Saielli, G. Ionic Liquid Crystals in „Green Solvents II. Properties and Applications of Ionic Liquids“, A. Mohammad, Inamuddin Eds, Springer-UK (2012).
(3) Causin, V.; Saielli, G., J. Mol. Liq. 2009, 145, 41.
(4) Causin, V.; Saielli, G., J. Mater. Chem. 2009, 19, 9153.
(5) Bonchio, M.; Carraro, M.; Casella, G.; Causin, V.; Rastrelli, F.; Saielli, G. Phys. Chem. Chem. Phys. 2012, 14,
2710.
98
OC66
Halogen bonded supramolecular gels
Lorenzo Meazza,1 Jonathan A. Foster,2 Katharina Fucke,2 Pierangelo Metrangolo,1
Giuseppe Resnati,1 Jonathan W. Steed2
1
NFMLab-DCMIC "Giulio Natta", Politecnico di Milano, Via L. Mancinelli 7, IT-20131, and
CNST-IIT@POLIMI, Via G. Pascoli 70/3, IT-20133, Milano, Italy.
2
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE
lorenzo.meazza@chem.polimi.it
Tuneable gel phase materials are an emerging topic of interest in potential applications in many
various fields.1-3 Within this context low molecular weight supramolecular gelators (LMWG), with
their reversible and dynamic intermolecular interactions, are achieving increasing prominence.
Works on switchable gels include systems involving photo- and pH and redox based switching,
ultrasound induced gelation and switchable catalysis.4-6
As a starting point for this work we focused our attention on the usage of metallogels in which the
metal coordination results in metal binding to the pyridyl group of pyridyl-urea compounds, which
suppresses the alternative, gel-inhibiting, urea-pyridyl hydrogen bonding interaction, freeing the
urea groups to form fibrils (urea tape hydrogen bonding motif) and hence gels (Figure 1a).7-8
In this communication we will show that halogen bonding is sufficiently strong to competitively
interfere with inhibitory urea-pyridyl hydrogen bonding in order to favour fibre formation and
hence gelation in a similar way to metal coordination giving the first example of application of
halogen bonding in order to control and “switch on” gelation (Figure 1b).9
Once demonstrated that halogen bonding induced gelation is a general phenomenon we designed a
halogen bonding donor gelator combining bis(urea) and perfluoroaryliodide components in the
same molecule (Figure 1c) and we “turned on” gelation simply by adding 4,4’-bipyridine, a strong
halogen bonding acceptor (Figure 1c,d).10
Figure 1: a) Metal coordination frees the urea moieties to produce parallel gel-forming α-tape motifs. b) X-ray crystal structure of
the halogen bonded gel showing the gel-forming urea-tape interaction and the halogen bonding cross-links involving the pyridyl
groups (using 1,4-diiodotetrafluorobenzene as halogen bonding-donor molecule). c) Chemical structure of the new halogen
bonding donor gelator (XB-Gelator) and the acceptor 4,4’-bipyridine. d) A 1% solution of the XB-Gelator (left) and the same
solution with the addition of 4,4’-bipyridine which drives the gel formation (right).
(1)
(2)
(3)
(4)
(5)
(6)
(7)
Smith, D. K. in Organic Nanostructures eds J. L. Atwood & J. W. Steed 111-154 (Wiley-VCH, 2008).
Li, H., Fujiki, Y., Sada, K. & Estroff, L. A. CrystEngComm, 2011, 13, 1060-1062.
Escuder, B., Rodríguez-Llansola, F. & Miravet, J. F. New J. Chem. 2010, 34, 1044-1054.
Terech, P. & Weiss, R. G. Chem. Rev. 1997, 97, 3133-3160.
Steed, J. W. Chem. Commun. 2011, 47, 1379-1383.
Rodríguez-Llansola, F., Escuder, B. & Miravet, J. F. J. Am. Chem. Soc. 2009, 131, 11478-11484.
Byrne, P., Lloyd , G. O., Applegarth, L., Anderson, K. M., Clarke, N. & Steed, J. W. New J. Chem. 2010, 34,
2261-2274.
(8) Piepenbrock, M.-O. M., Clarke, N. & Steed, J. W, Soft Matter, 2010, 6, 3541–3547.
(9) Metrangolo, P., Meyer, F., Pilati, T., Resnati, G. & Terraneo, G. Angew. Chem, 2008, Int. Ed. 47, 6114-6127.
(10) Meazza, L., Foster, J. A., Fucke, K., Metrangolo, P., Resnati, G. & Steed, J. W. Nature Chem. 2012, in press.
99
OC67
Enhancement of Vibrational Circular Dichroism spectra
using lantanide auxiliaries
Lorenzo Di Bari
Dipartimento di Chimica e Chimica Industriale, Università di Pisa,
Via Risorgimento 35, 56126 PISA
ldb@dcci.unipi.it
Vibrational Circular Dichroism is one of the most powerful methods for characterizing molecular
chirality and its main limitation still consists in its low sensitivity, which enforces the use of
extremely concentrated solutions and very long acquisition times. Metal ions endowed with Low
Lying Electronic States (LLES) can deeply alter VCD spectra of ligands.1,2 We use this principle in
conjunction with some peculiar properties of lanthanide ions, well known from old-times NMR
spectroscopy to obtain Lanthanide-Induced VCD Enhancement (LIVE).
Different regions of the mid-IR VCD are highlighted by various Ln3+ ions, according to their
electronic configuration and as a function of the normal modes associated to the transition.
These enhancement allows one to work with more dilute solutions and to shorten the acquisition
time, while maintaining optimal signal-to-noise. The shape of VCD spectra (sequence of signs and
their relative amplitudes) remains practically identical, which allows one to compare the spectrum
directly with a non-enhanced one (e.g. taken from the literature) or with the result of application of
computational methods.
Applications to various synthetic and natural substrates will be discussed.
(1) He, Y.N.; Cao X.L.; Nafie L.A.; Freedman T.B. J. Am. Chem. Soc. 2001, 123, 11320-11321
(2) Nafie L.A. J. Phys. Chem. A 2004, 108, 7222-7231.
100
OC68
Biocatalysis: an efficient and sustainable tool
to solve industrial problems?
Sergio Riva
Istituto di Chimica del Riconoscimento Molecolare, C.N.R.,
via Mario Bianco 9, 20131 Milano.
sergio.riva@icrm.cnr.it
Exploitation of enzymes in organic synthesis is nowadays a well-accessed methodology in chemical
synthesis, both in the laboratory and on an industrial scale.1
Over the past ten years, our group has been involved in several research projects sponsored by
Italian Companies. The outcome of these efforts is documented by scientific articles and patents. In
addition to these “paper” products, one of these biotransformations is presently used in an industrial process and the development of two of them for large scale productions is in an advanced
phase.
In this presentation the following topics will be briefly discussed and exemplified:
 Exploitation of the enantioselectivity of hydrolases for the synthesis of chiral synthons.1c
 The use of laccase-catalyzed reactions for the selective hydroxylation of ergot alkaloids and for
the synthesis of the bisindole alkaloid anhydrovinblastine.2
 The use of hydroxysteroid dehydrogenases (HSDHs) to catalyze the reversible oxidoreduction of
the hydroxyl-keto groups of bile acids. Suitable regeneration systems have been coupled to these
enzymes to provide the driving force to shift the overall equilibrium towards the desired
products.3
(1) a) Bornscheuer, U. T.; Huisman, G. W.; Kazlauskas, R.J.; Lutz, S.; Moore, J.C., Robins, K Nature, 2012, 485,
185-194. b) Monti, D.; Ottolina, G.; Carrea, G.; Riva, S. Chem. Rev. 2011, 111, 4111-4140. c) Carrea, G.; Riva,
S. Angew. Chem. Int. Ed., 2000, 39, 2226-2254.
(2) a) Chirivì, C.; Fontana, G.; Monti, D.; Ottolina, G.; Danieli, B.; Riva, S. Chem. Eur. J., 2012, in press. b) Sagui,
F.; Chirivì, C.; Fontana, G.; Nicotra, S.; Passerella, D.; Riva, S.; Danieli, B. Tetrahedron, 2009, 65, 312–317.
(3) Monti, D.; Ferrandi, E.E.; Zanellato, I.; Hua, L.; Polentini, F.; Carrea, G.; Riva, S. Adv. Synth. Catal. 2009, 351,
1303-1311, and references therein.
101
OC69
Silica-supported organocatalysts: development of stereoselective
processes from batch to continuous-flow conditions
Alessandro Massi, Alberto Cavazzini, and Olga Bortolini
Dipartimento di Chimica dell’Università di Ferrara,
Via L. Borsari 46, I-44121, Ferrara, Italy
alessandro.massi@unife.it
In a context where time, cost, and sustainability issues play an increasingly important role even at a
research stage, chemical efficiency has become one of the leading concepts for synthetic chemists
working in both industry and academia. Key criteria include intrinsic (yield, selectivity, atom
economy) and extrinsic (time, waste, equipment, environment, safety) factors of the synthetic
process. Hence, the booming field of asymmetric organocatalysis is opening new and unique
opportunities towards efficient and highly stereoselective metal-free catalytic syntheses. On the
other hand, microreactor technology is offering safe, environmentally benign, and high throughput
processes typically intensified by a fast postreaction phase and direct scalability. Very recently, we
have embarked on a research program aimed at preparing and testing organocatalytic packed-bed
microreactors to prove the potential benefits arising from the combination of the above synthetic
methodology and production technology.1 This program is currently being developed on the basis of
the following general thread: i) heterogeneization of a successful asymmetric organocatalyst on
silica and optimization of its performance under batch conditions; ii) preparation of the
corresponding packed-bed microreactor and preliminary testing in continuous-flow regime; iii)
development of a suitable in-line analysis method, and iv) final optimization of the continuous-flow
process based on kinetic and thermodynamic characterization thereof. Recent results of this study
are herein reported.
(1) O. Bortolini, L. Caciolli, A. Cavazzini, V. Costa, R. Greco, A. Massi, L. Pasti, Green. Chem. 2012, 14, 992-1000.
102
“NOTE TECNICHE”
103
NT01
Improved NMR software and hardware solutions for organic chemists
Francesca Benevelli
Bruker Italia Srl Unipersonale - Milano
francesca.benevelli@bruker.it
Nuclear Magnetic Resonance (NMR) is a very valuable tool to characterise, recognise and quantify
molecules. In the recent years a big effort has been done in improving the efficiency of NMR
systems for such challenges. This include the development of high sensitivity probeheads, new
generation electronic consolle, more capable sample changer and user friendly software that allows
easier and reliable acquisition of the spectroscopic data. Now software tools are dedicated to the
data analysis and search for consistency between structure and spectrum.
Here we will present an overview of these novelties.
104
NT02
Fast Field Cycling Relaxometry – Application in material science
Salvatore Bubici,1 Rebecca Steele,2 Gianni Ferrante2
1
2
Invento srl, via Nizza, 52 10126 Torino
Stelar srl, via E. Fermi, 4 27035 Mede (PV)
salvatore.bubici@invento-lab.com
80
-1
TBVM
12 years old
60
50
40
30
20
0,01
0,1
1
300
250
PI
200
150
100
PB
50
0
10
0.01
Proton Larmor Frequency, MHz
NMRD profiles were highly
informative for characterization of
the age of balsamic vinegar
(Traditional Balsamic Vinegar of
Modena). (Baroni et al. J Agric
Food Chem. 2009;57(8):3028-32)
T = 296 K
350
Suspected counterfeit
TBVM
70
Longitudinal Relaxation Rate, s
Longitudinal relaxation rate , s
-1
Fast Field Cycling Relaxometry (FFCR) is a NMR technique used to determine the longitudinal
relaxation time (T1) over a range of B0-fields spanning about six decades, from about 10-6 T up to ~
1 T without varying the frequency of spectrometer.1 The main information expected from the
relaxation dispersion curves ,T1 or R1=1/ T1 versus the Larmor frequency ω (ω=γB0, γ is the
gyromagnetic ratio) concerns molecular motions characterized by temperature-activated frequencies
and described by means of spectral density J(ω ).
The data obtained may, therefore, be correlated directly to physical/chemical proprieties of complex
materials. The use of radio frequency allows the easy penetration of most materials, thus permitting,
the exploration of slow dynamics which are often difficult to study by other spectroscopic method
in heterogeneous materials, that may include both liquids and solids.
Furthermore, the benefit of exploring the range of low Larmor frequencies is to detect typical
relaxation features associated with molecular processes characterized by very long correlation
times, such as molecular surface dynamics and collective effects.
In this presentation we show developments in the FFCR method and discuss some contributions of
NMRD towards a fundamental understanding of classes of materials and of phenomena predicted
by theoretical models. We show in practice how relaxation experiments on protons, as well as
deuterons or other nuclei can be applied for qualitative structural diagnostics in solutions,
quantitative structural determinations, recognitions of weak intermolecular interactions and studies
of molecular mobility. The findings that have been established more recently are noteworthy for
their potential use in quality assessment and off-line process monitoring.
0.1
1
10
Proton Larmor Frequency, MHz
Protein aggregation detected via
rotational
diffusion.
Bovine
pancreatic trypsin inhibitor (BPTI)
self-association as a function of salt
concentration (Gottschalk et al.
Biophys J. 84,39
The frequency dependence of
proton NMR longitudinal relaxation
times
was
determined
in
polyisoprene melts compared to
polybutadiene melts
(Kariyo S., et al Macromol. Chem.
Phys. 2005, 206 , 1292 – 1299)
(1) Ferrante and Sycora Adv. Ino. Chem. Vol. 57, pag. 405
105
COMUNICAZIONI FLASH
106
F01
Synthesis and biological activity of effective
gem- hydroxyl α-amino bisphosphonate
I. Mulani,1 O. Bortolini,2 A. De Nino,1 L. Maiuolo,1 G. Stabile,1 B. Russo1
1
Dipartimento di Chimica, Università della Calabria, Via P. Bucci 12 C, 87036, Rende (CS) Italy.
2
Dipartimento di Chimica, Università di Ferrara, Via Borsari 46, 44100, Ferrara (FE) Italy.
iqbal.mulani@unical.it
Biphosphonates (BPs) are hydrolytically stable analogs of pyrophosphate, which inhibit bone
resorption as a consequence of affecting osteoclast and probably osteoblast activity.1 Recently, a
heterocyclic nitrogen-containing BPs has shown significantly increased potency compared in both
in vitro and in vivo bone resorption models. BPs have been fully inhibits osteoclastic activity and
bone resorption at low doses that do not adversely affect bone formation and mineralization, and
have no appreciable impact on renal function, resulting in an improved ratio of antiresorptive versus
renal effects.2 Furthermore, BPs are being developed for the treatment of tumour induced
hypercalcemia, bone metastases arising from any cancer, and for the prevention of bone metastases
associated with advanced breast cancer and locally advanced prostate cancer.
Accordingly, earlier we synthesized of a new class of bisphosphonates having in gem position an
isoxazolidine ring that holds simultaneously the required basic nitrogen and an oxygen atom in
place of the hydroxyl group, acting as third hook.3 In view of importance of gem hydroxyl amino
bisphosphonate, we thought of interest to have such compounds. Though, there are several methods
for oxidative and reductive cleavage of N-O bond,4 our sensitive isoxazolidine ring were reductively
cleaved under very mild condition to afford bisphosphonate bearing 1,3 amino alcohol. As a result
we could able to synthesis the compounds which are similar to existing biological active
bisphosphonate.
In this communication we have described an efficient and general synthetic approach to amino
bisphosphonates bearing in geminal position a hydroxyl group. The biological tests for the activity
of these compounds are currently under way.
(1) a) Jung, A.; Bisaz, S.; Fleisch, H. Calcif. Tissue Res, 1973, 11, 69–280; b) Fleisch, H.; Biphosphonates - history
and experimental basis, Bone, 1987, 8, 523–528.
(2) a) Boonekam, P.; Van der Wee-pals, L;. Van Wijk-van Lennep, M. Bone Mineral, 1986, 1, 27–39; b) Green, J.;
Muller, K.; Jaeggi, K. J. Bone Miner. Res, 1994, 9, 745–751.
(3) Bortolini, O.; Mulani, I.; De Nino, A..; Maiuolo, L.; Nardi, M.; Russo, B.; Avnet, S. Tetrahedron, 2011, 67, 56355641.
(4) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; Sarlo, F. D. Tetrahedron Lett. 1990, 31, 3351–3354.
107
F02
A mild approach to the dehalogenation of aromatic halides
Giampaolo Giacomelli, Giammario Nieddu.
Dipartimento di Chimica, Università degli Studi di Sassari,
via Vienna 2, I-07100, Sassari.
gmrnd@uniss.it
POPs (persistent organic pollutants) are a class of pollutants, really dangerous for the environment
and human health.1 This class of pollutants includes DDT, PCBs (polychlorinated biphenyls),
PCDDs (polychlorinated dibenzo- p-dioxins) and PCDFs (polychlorinated dibenzofurans). POPs
are halogenated compounds and the high percentage of carbon-bond halogen gives them chemical
stability and high resistance to environmental biodegradation, causing an almost global diffusion of
these products.
Most of these compounds have been introduced in the environment as pesticides (aldrin, dieldrin,
chlordane, endrin, heptachlor, DDT) or in industrial applications (PCBs). Differently, dioxins
(PCDDs) are found in the environment as byproducts of industrial processes or because of
municipal waste incineration. Environmental contamination continue to be the subject of news
reports like Seveso in 1976, Campania in 2007, Ilva (Taranto) in 2008 and meat from Ireland in
2008.
Disposal by incineration of POPs is problematic because of toxic byproducts formation. An
alternative approach to their degradation is based on reductive dehalogenation. This kind of
reactions are well known in literature but very often they require toxic reagents and/or solvents.2
Following an “environmental friendly” approach, we studied a dehalogenation method based on Pd/C and glucose. The method gave good results and was further investigated. We finally
developed a dehalogenation process under mild conditions, carried out in water and using natural
substances as reducing agents, making it a potential starting point for the treatment of polluted
waters.
The process is efficient and allowed the treatment of a wide number of organic halides with good to
quantitative yields. Furthermore, the method has been successfully used for treatment of
polihalogenated dioxins.
(1) Harrad, S. Persistent Organic Pollutants, John Wiley & Sons Ltd, Chichester (UK), 2009.
(2) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev., 2002, 102, 4009
108
F03
Oxidation of different iminic bonds by 3-chloroperbenzoic acid
Luigino Troisi,1 Marina Maria Carrozzo,1 Cinzia Citti,1,* Aurelia Falcicchio,2
Rosmara Mansueto,1 Francesca Rosato1 and Giuseppe Cannazza3
1
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento,
via Prov.le Lecce-Monteroni, 73100 – Lecce, Italy
2
Istituto di Cristallografia (IC-CNR), via Amendola 122/o, 70125 – Bari, Italy
3
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia,
via Campi 183, 41125 – Modena, Italy
cinzia.citti@unisalento.it
Imines are one of the most representative organic molecules of biological and pharmaceutical
interest.
It is reported that benzyliden-alkylamines, reacting with peracids like m-CPBA,1 urea-hydrogen
peroxide2 or cobalt mediated molecular oxygen,3 lead to the corresponding oxaziridines (Scheme 1).
Scheme 1
In this contribution it will be shown that a heteroatom (O, N, S) beared to the nitrogen of the iminic
function does not allow the oxidation of π-bond. On the contrary, when a heteroatom like oxygen,
nitrogen or sulfur and carbon also is linked to the carbon of the iminic function, it makes the iminic
double bond more reactive (Scheme 2). Specifically, oxaziridines, amides, oximes, nitroso-, nitroand azodioxy compounds or no products could be formed depending on the substituents at the C=N
bond and on the imine/m-CPBA stoichiometric ratio.
Scheme 2
(1) a) Widmer J.; Keller-Schierlein W. Helv. Chem. Acta 1974, 57, 657. b) Emmons W. D. J. Am. Chem. Soc. 1956,
78, 6208.
(2) Lin Y.; Miller M. J. J. Org. Chem. 2001, 66, 8282.
(3) Damavandi J. A.; Karami B.; Zolfigol M. A. Synlett 2002, 933.
* Partecipazione con borsa di studio offerta da Dipharma.
109
F04
Polyoxometalates as photoredox catalysts in C–C bond formation.
Decatungstate salt photocatalyzed benzylation of electron-poor olefins
Sara Montanaro, Davide Ravelli, Daniele Merli, Maurizio Fagnoni, Angelo Albini
Viale Taramelli 12, 27100 Pavia - www.unipv.it/photochem
davide.ravelli@unipv.it
Polyoxometalates (POMs) are metal-oxygen clusters showing an amazing variety of properties.1
Some POMs show interesting photochemical activity and, among them, the most widely studied is
the decatungstate anion ([W10O32]4-),2,3 usually employed as tetrabutylammonium salt (TBADT).
Accurate photophysical investigations led to the conclusion that two photochemical processes can
compete upon TBADT excitation, viz. hydrogen atom transfer (HAT) and electron transfer (ET).4
The goal of the present work is exploiting TBADT as photoredox catalyst for the benzylation of
electron-poor olefins by using benzyltrimethylsilanes as the electron donors. The trimethylsilyl
group (TMS) has the double role to decrease the oxidation potential of the aromatic and to be
eliminated during the reaction as a very stable cation upon fragmentation of the resulting radical
cation. Since benzyl radicals are quite stable and difficult to trap a way to improve the success of
the reaction often requires the coupling with a radical anion likewise formed in the PET process. In
the present work the olefin radical anion is generated from the reduced form of the photocatalyst
(W10O325-). As a result, the TBADT is regenerated and the olefin radical anion is prone to be
trapped by the benzyl radicals to give the end benzylated derivatives (Scheme 1).
The process met some success providing that the radical cation fragmentation with the concomitant
regeneration of the photocatalyst were
efficient avoiding back electron transfer
(BET) reactions. The efficiency was
improved by increasing the nucleophilic
character and the ionic strength of the
reaction medium, substituting MeCN with
a 0.5 M LiClO4 MeCN/H2O (5/1 v/v)
solution. Another important advantage of
the present approach is the chemoselective
derivatization of the silanes since only
products deriving from an electron transfer
pathway rather than a HAT pathway were observed. This report is the first example of a TBADTphotocatalyzed synthesis exploiting an ET mechanism and allowed for a smooth benzylation of
electron-poor olefins. Moreover, this is one of the few examples of a clean radical benzylation of
alkenes via benzyl radicals. The scope of the reaction is limited to the use of olefins with suitable
redox properties, while different substituents on the aromatic ring of the benzylsilanes are well
tolerated.5
(1) Long, D.-L.; Tsunashima, R.; Cronin, L. Angew. Chem. Int. Ed. 2010, 49, 1736-1758.
(2) Tzirakis, M. D.; Lykakis, I. N.; Orfanopoulos, M. Chem. Soc. Rev. 2009, 38, 2609-2621.
(3) Ravelli, D.; Montanaro, S.; Zema, M.; Fagnoni, M.; Albini, A. Adv. Synth. Catal. 2011, 353, 3295-3300 and
references cited therein.
(4) Texier, I.; Delaire, J. A.; Giannotti, C. Phys. Chem. Chem. Phys. 2000, 2, 1205-1212.
(5) Montanaro, S.; Ravelli, D.; Merli, D.; Fagnoni, M.; Albini, A. Org. Lett. 2012, 14, 4218-4221
110
F05
Synthesis of new piperidinyl enamides and enecarbamates
by unconventional elaboration of NDA cycloadducts.
Francesco Berti,* Valeria Di Bussolo, Mauro Pineschi
Dipartimento di Scienze Farmaceutiche, Sede di Chimica Bioorganica e Biofarmacia,
Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy
francescoberti86@gmail.com
Nitroso cycloadducts, derived from nitroso Diels-Alder (NDA) reactions, are valuable synthetic
intermediates as they serve as a general scaffold to create unique structural and functional
diversity.1 Apart from seminal contributions,2 the application of NDA chemistry to 1,2dihydropyridines as the diene component have been relatively neglected. We recently found a new
regioselective introduction of a 2-methoxycarbonyl methyl group at the C2 position of unsubstituted
pyridine to give 1,2-dihydropyridines.3 We now report the synthesis of new piperidinyl enamides
and enecarbamates by simple elaborations of some NDA cycloadducts obtained with a variety of
1,2-dihydropyridines. In particular, the treatment of acyl-NDA cycloadducts in CH3CN at 75 °C in
the presence of H2O gave substituted enamides and enecarbamates, comprising the valuable 4hydroxypiperidines scaffold, in a stereoselective fashion (eq. a, Scheme).
OH
R3
ONH
N
R1
R2
R3= acyl
R2
R1 N
(eq. a)
O
N
R3
NHPh
(eq. b)
R3= Ph, R1=Ac
N
Ac
R2
Only when particular substitution patterns were present, the reductive cleavage of phenyl-NDA
with Cp2Ti(III)Cl gave new 3-amino-substituted 1,2-dihydropyridines, instead of the amino
alcohols commonly obtained in these reaction conditions (eq. b). The newly prepared enamides and
enecarbamates are potentially useful nucleophilic substrates for accessing a variety of
polyhydroxylated piperidines and azasugars.
(1) Bodnar, B. S.; Miller, M. J. Angew. Chem. Int. Ed. 2011, 50, 5630.
(2) For a review, see: Streith, J.; Defoin, A. Synlett 1996, 189.
(3) Crotti, S.; Berti, F.; Pineschi, M. Org. Lett. 2011, 13, 5152.
* Partecipazione con borsa di studio offerta da Lundbeck.
111
F06
Going toward the development of new therapeutic
and diagnostic nanotools for Alzheimer's disease
1
C. Zona, C. Airoldi,1 S. Mourtas,2 E. Sironi,1 A. Niarakis,2 M. Canovi,3 M. Gregori,4
I. Cambianica,4 S. Sesana,4 F. Re,4 M. Gobbi,3 M. Masserini,4
S.G. Antimisiaris,2,5 F. Nicotra1 and B. La Ferla1
1
P.zza della Scienza 2, Milano, Italy
2
Laboratory of Pharmaceutical Technology, Department of Pharmacy, University of Patras,
Rio 26510, Patras, Greece
3
Department of Biochemistry and Molecular Pharmacology,
Istituto di Ricerche Farmacologiche “Mario Negri”, 20156 Milano, Italy
4
Department of Experimental Medicine, University of Milano-Bicocca,
via Cadore 48, Monza, Italy
5
Institute of Chemical Engineering and High Temperatures, FORTH/ICE-HT,
Rio 26504, Patras, Greece
c.zona@campus.unimib.it
Nanoparticles (NPs) are attractive tools in biomedical applications thanks to their biocompatibility,
non-immunogenicity, non-toxicity, biodegradability, high physical stability, possibility of drug
loading and releasing, and high surface functionalization possibilities; in particular, liposomes are
being extensively explored for their potentialities in the medical field.
This work deals with the synthesis of different type of nanoparticles functionalized with amyloidbeta ligands (Aβ-ligands), imaging tools and/or blood brain barrier-transporters (BBB-transporters)
for the therapy and the diagnosis of Alzheimer’s disease (AD).
Amyloid β (Aβ) aggregates are considered possible targets in the war against AD. It has been
previously shown that some small molecules target Aβ plaques and, in particular, curcumin interacts with their precursores, suggesting a potential role for the prevention of AD. Herein, a
chemoselective ligation procedure was used to generate nanoliposomes decorated with new
potential Aβ peptide ligands, designed to maintain all the features required for interaction with Aβ.
Our approach starts from the molecular design and synthesis of functionalized phosholipid
analogues monomers suitable for the assembly of new functionalized NPs. The monomers and the
Abeta ligands present functional groups suitable for the chemoselective decoration of the NPs
surface by covalent conjugation. In particular, the synthesized compounds show triple bond or
azide group that can be reacted exploiting the chemoselective click chemistry.
This work describes the preparation and characterization of novel curcumin decorated nanotools
with improved affinity (KD = 1.7 nM) for Aβ peptide and ability to pass the BBB. They could be exploited as ligands and/or vectors for the targeted delivery of new diagnostic and therapeutic
molecules for AD (theragnosis).
The NPs preparations and the biological results were obtained in collaboration with scientists
involved in a joint European project: NAD - Nanoparticles for therapy and diagnosis of
Alzheimer’s Disease - 2008-2012, FP7-NMP-2007-LARGE-1-Large-scale integrating project
NMP-2007-4.0-4 Substantial innovation in the European medical industry: development of
nanotechnology-based systems for in-vivo diagnosis and therapy.
(1) Masserini, M.; Antimisiaris, S.G.; Nicotra, F.; La Ferla, B.; Zona, C.; Mourtas, S.; Niarakis, A. Greek patent n.
20100100563.
(2) Mourtas, S.; Canovi, M.; Zona, C.; Aurilia, D.; Niarakis, A.; La Ferla, B.; Salmona, M.; Nicotra, F.; Gobbi, M.;
Antimisiaris, S.G. Biomaterials 2011, 32, 1635-1645
(3) Le Droumaguet, B.; Nicolas, J.; Brambilla, D.; Mura, S.; Maksimenko, A.; De Kimpe, L.; Salvati, E.; Zona, C.;
Airoldi, C.; Canovi, M.; Gobbi, M.; Noiray, M.; La Ferla, B.; Nicotra, F.; Scheper, W.; Flores, O.; Masserini, M.;
Andrieux, K.; Couvreur P. ACS Nano 2012 (in press), DOI:10.1021/nn3004372
112
F07
Dual mechanism of Au-promoted rearrangements of 1,5-enynes
Serena Bugoni, Valentina Merlini, Alessio Porta, Giuseppe Zanoni, and Giovanni Vidari
Università degli Studi di Pavia, Dipartimento di Chimica, Sezione di Chimica Organica,
Via Taramelli 10, 27100 Pavia
e-mail: serena.bugoni01@ateneopv.it
The NHC-gold-mediated Meyer-Schuster rearrangement of propargylic alcohols and esters is
receiving an increasing attention as a useful tool for the synthesis of α,β-unsaturated ketones.1 For
example, this methodology was successfully employed for the synthesis of α-ionone, an important
natural product responsible of the pleasant smell of blooming violet flowers and one of the most
important raw materials in the fragrance industry.2
The same catalytic reaction performed on the free propargylic alcohol, under dry conditions, led to
a completely different mixture of products, suggesting a mechanism involving an unexpected oxyCope-like rearrangement:
Starting from these observations, the rearrangements of different propargylic alcohol and ester
derivatives, containing an 1,5-enyne moiety, were examined. We observed that the sigmatropic-like
rearrangement was favoured on the free alcohol, under dry conditions, especially when the
rearrangement involved a trisubstituted olefin. In stark contrast, the preferred outcome of the
reaction could be shifted towards the Meyer-Schuster product using a propargylic ester, in a wet
solvent, and in presence of a nucleophilic base like NaHCO3; indeed, the amount of water (1-5%)
drammatically influenced the success of the reaction. A rational explanation of this dual mechanism
has been proposed. Moreover, this study led us to develop a new and short synthesis of -ionone,
the most valuable ionone derivatives in terms of odor threshold and notes.
(1) Nolan, S. P. Acc. Chem. Res. 2011, 44, 91-100.
(2) Merlini, V.; Gaillard, S.; Porta, A.; Zanoni, G.; Vidari, G.; Nolan, S. P. Tetrahedron Letters 2011, 52, 1124-1127.
113
F08
New polymeric active material for energy storage with
improved specific capacity by embedding
redox active naphthalene diimide centres in a PEDOT matrix
Mauro Sassi,1 Luca Beverina,1 Fabio Rosciano,2 Riccardo Ruffo1 and Matteo Salamone1
1
Università degli Studi di Milano-Bicocca, Dipartimento di Scienza dei Materiali,
Via Cozzi, 53, I-20125 Milano
2
AT1 Division, Toyota Motor Europe, Zaventem, Belgium.
mauro.sassi@mater.unimib.it
The interest in renewable energy sources and the development of electric or hybrid vehicles leads to
an increasing demand of energy storage technologies. In particular, materials with better
performances in terms of energy density and specific power are required to overcome the market
requests. Conjugated polymers represent an interesting class of active materials for batteries as a
consequence of their unique characteristics: tunable electrochemical properties, pseudocapacitive
behaviour, morphological control and low cost. However, the maximum specific capacity of these
materials is limited by their low doping level. In this respect, the incorporation of discrete redox
active centres with high specific
capacity in a conductive polymer
matrix could represent a viable
strategy overcome this limitation.
We have designed and synthesized
a new redox active naphthalene
diimide (NDI) based monomer
carrying
polymerogenic
3,4Figure 1
ethylenedioxythiophene (EDOT)
units
(Figure
1)
and
the
corresponding polymer.1 In this system the electroactive NDI unit, responsible for the ionic energy
storage, is embedded in a conductive PEDOT matrix that ensures a fast electronic transfer to the
current collector. The resulting material has been tested both in conventional Li-ion half cells and in
Li-free environments, thus removing all metals from the battery. Good reversibility and long-term
performances were also observed.
This contribution will provide a description of the synthesis and the characterization of the
aforementioned polymer. An outlook on the design principles of this class of materials and possible
future developments will also be given.
(1) Sassi, M.; Salamone, M. M.; Ruffo, R.; Mari, C. M.; Pagani, G. A.; Beverina, L.;. Advanced Materials 2012, 24,
2004-2008.
114
F09
Regio and diastereoselective synthesis and X-ray structure
determination of (+)-2-deoxyoryzalexin S
Francesca Leonelli,1Valentina Latini,1Andrea Trombetta,1Gabriele Bartoli,1
Francesca Ceccacci,1Angela La Bella,1 Alessio Sferrazza,1 Doriano Lamba,2
Luisa Maria Migneco,1 Rinaldo Marini Bettolo1
1
Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le Aldo Moro, 5, I-00185 Roma, Italy
2
Istituto di Cristallografia – C.N.R., Unità Organizzativa di Supporto, Sede di Trieste,
Area Science Park- Basovizza, Strada Statale 14 – Km 163.5, I-34149 Trieste, Italy.
francesca.leonelli@uniroma1.it
In 1990 Garbarino and co-workers isolated in Chile from Calceolaria species (1-3) a diterpenoid to
which the structure of 2-deoxyoryzalexin S 1 was attributed on the basis of the 1H and 13C spectra.
To this compound the absolute ent-stemarane configuration, opposite to that of the other known
stemarane diterpenes, was assigned on biogenetic grounds. Nominal 2-deoxyoryzalexin S 1 was
characterized as its acetylderivative (-)-2.1-3 The structure and absolute configuration of (-)-1 was
never confirmed neither by chemical correlation nor by X-ray diffraction.
Now we report, after having recently disclosed a very simple solution for the construction of the
C/D ring system of stemarane diterpenes,4 the regio and diastereoselective synthesis from
podocarpic acid of (+)-2-deoxyoryzalexin S 1. (+)-2-Deoxyoryzalexin S 1 was characterized also as
its acetylderivative (+)-2 whose structure was confirmed by X-ray crystallographic analysis.
Surprisingly, the comparison between the data recorded for (+)-2, and those reported for the natural
product derivative, to which structure (-)-2 was assigned, showed some differences indicating that
the latter does not possess the proposed structure. Further work on the diterpenoids 1 isolated from
Chilean Calceolaria appears, therefore, necessary to establish unambiguously its structure.
H
R
H
(-)-1 R = OH
(-)-2 R = OAc
(1)
(2)
(3)
(4)
H
R
H
(+)- 1 R = OH
(+)- 2 R = OAc
Chamy, M. C.; Piovano, M.; Garbarino, J. A.; Miranda, C.; Gambaro, V. Phytochemistry 1990, 29, 2943-2946.
Garbarino, J. A.; Molinari, A. Phytochemistry 1990, 29, 3037-3039.
Chamy, M. C.; Piovano, M.; Garbarino, J. A.; Gambaro, V. Phytochemistry 1991, 30, 3365-3368.
Leonelli, F.; Blesi, F.; Dirito, P.; Trombetta, A.; Ceccacci, F.; La Bella, A.; Migneco, L. M.; Marini Bettolo, R. J.
Org. Chem., 2011, 76, 6871–6876.
115
F10
Agropyrenol and agropyrenal, phytotoxins from Ascochyta agropyrina var.
nana, potential herbicides for Elytrigia repens control
Ciro Troise,1,* Anna Andolfi,1 Alessio Cimmino,1 Maurizio Vurro,2 Alexander Berestetskiy,3
Maria Chiara Zonno,2 Andrea Motta,4 Antonio Evidente1
1
Dipartimento di Scienze del Suolo, della Pianta, dell’Ambiente e delle Produzioni Animali, Università di Napoli Federico II, 80055 Portici, Italy
2
Istituto di Scienze delle Produzioni Alimentari, CNR, Via Amendola 122/O, 70125 Bari, Italy
3
All-Russian Institute of Plant Protection, Russian Academy of Agricultural Sciences,
Pushkin, Saint-Petersburg 196608, Russia
4
Istituto di Chimica Biomolecolare, CNR, Comprensorio Olivetti, Edificio 70,
Via Campi Flegrei 34, 80078 Pozzuoli, Italy
cirotroise84@libero.it
Elytrigia repens L. Desv. ex Nevski (commonly known as quack grass), is a perennial weed
widespread through the cold temperate regions all over the world. It is managed only by chemical
herbicides1,2 because it easily spreads by seed and rhizomes and produces allelopathic metabolites
suppressing the growth of other plants.
In surveys carried out with the aim to find pathogens of this species, which could have potential as
biological agents for its control, a fungus was isolated from naturally diseased leaves of this species
and identified as Ascochyta agropyrina (Fairman) Trotter var. nana Punith. Due to the interest of
the authors in studying species belonging to the genus Ascochyta as sources of biologically active
metabolites, a previous study led to the isolation of a main phytotoxin from the solid culture of this
fungus and to its identification as papyracillic acid.3
On liquid medium A. agropyrina produces different toxins the main one of which, named
agropyrenol, was characterized as a new disubstituted benzaldehyde on the basis of its chemical and
spectroscopic properties. Other two new minor metabolites were isolated from the same culture and
named agropyrenal and agropyrenone, respectively. They were characterized as a trisubstituted
naphthalene carbaldehyde and a pentasubstituted 3H-benzofuranone, respectively. When assayed on
leaves of some weedy plants, i.e. Mercurialis annua, Chenopodium album and Setaria viridis,
agropyrenol proved to be phytotoxic, causing the appearance of necrotic lesions, agropyrenal was
less active, while agropyrenone was inactive. None of compounds showed antibiotic, fungicidal or
zootoxic activity.
In this communication the production, isolation, and chemical and biological characterization of the
metabolites produced by A. agropyrina var. nana in liquid culture will be illustrated and their
potential as safe herbicides will be discussed.
(1) Curran, W.S.; Edward, L.; Nathan, L. Weed Technol. 1994, 2, 324-330.
(2) Ivany, J.A.; Doohan, D.J. Weed Technol. 1997, 2, 744-747.
(3) Evidente, A.; Berestetskiy, A.; Cimmino, A.; Tuzi, A.; Superchi, S.; Melck, D.; Andolfi, A. J. Agr. Food Chem.
2009, 57, 11168-11173.
* Partecipazione con borsa di studio offerta da Sifavitor.
116
F11
New synthetic strategies of polybenzimidazoles for fuel cell application
Righetti Pier Paolo, Angioni Simone, Villa Davide Carlo, Garlaschelli Luigi.
University of Pavia, Department of Chemistry, viale Taramelli 10, 27100 Pavia, Italy
davidecarlo.villa01@universitadipavia.it
Solid polymer electrolytes for fuel cell applications have gained much attention recently as a
promising technology. In the last decade, acid-doped polybenzimidazole (PBI) membranes have
been studied for PEMFC (Proton Exchange Membrane Fuel Cell) use, showing good properties that
allow them to be used in PEMFC at temperatures as high as 200 °C without humidification.1
We have devised two alternative synthetic strategies to obtain new complex dicarboxylic acids
suitable to be polymerized by reaction with a commercial tetramine (3,3’-diaminobenzidine). The
first one was successfully accomplished,2 and is outlined below:
The arylethereal moieties in the monomers have been easily mono- or poly-sulfonated, thus
improving the proton conductivity of the membranes obtained from the corresponding polymers.
The second strategy consists in the synthesis of modified isophtalic acids, whose -5- position has
been linked to triazolic rings , with different type of spacers, as shown in the figure below:
The increased number of basic sites and/or proton donor/acceptor sites in the polymer chain should
enhance the proton conductivity of the membranes obtained thereof, once doped with phosphoric
acid. Indeed the polymerization of some of these monomers suffered from difficulties caused by the
sudden rise of the viscosity of the reacting mixture. The electrochemical properties of the polymers
were studied: some of them have shown excellent proton conductivity and/or good mechanical
properties.
(1) a) Kondratenko, M.S.; Gallyamov, M. O.; Khokhlov, A. R. Int. J. Hydrogen Energy 2012, 37, 2596; b): Li, Q.;
Jensen, J. O.; Savinell, R. F.; Bjerrum, N. J. Prog Polym Sci 2009, 34, 449
(2) Angioni, S.; Righetti, P. P.; Quartarone, E.; Dilena, E.; Mustarelli, P.; Magistris, A. Int. J. Hydrogen Energy 2011,
36, 7174
117
F12
Nucleobase- and backbone-modified monomers
for the construction of multifunctional PNA
Alex Manicardi, Alessandro Bertucci, Rosangela Marchelli, Roberto Corradini.
Dipartimento di Chimica Organica e Industriale Università di Parma,
Parco Area delle Scienze 17/A, 43100, Parma, Italy.
alex.manicardi@unipr.it
The peptide nucleic acid (PNA) structure,1 on account of its excellent nucleic acid recognition
properties and its high chemical and biological stability, has served as a model and a robust scaffold
for the synthesis of new compounds aimed at specific applications in diagnostics2 and in the
development of gene-targeting drugs,3,4 and, more recently, for the construction of nanostructured
materials (4). Modified PNA have been used to improve the PNA properties, such as DNA and
RNA affinity, selectivity, water solubility, and cellular uptake.5,6
In this work we describe the use of the masked amino function of 5-azidomethyluracil (Figure 1a)
and orthogonally protected functional groups on the backbone side chains of Fmoc and Boc
protected PNA monomers.
Fig.1: a) general structure of the modified monomers; b) Schematic representation of multi-functionalization along the
PNA chain: i) lysine side chain at the C-term, ii) nucleobase and backbone modification, iii) single nucleobase or
backbone modification and/or conjugation at N-term.
Both backbone and nucleobase modifications were exploited to expand the range of possible
dispositions of functional groups along the PNA strand (Figure 1b).
Different solid-phase synthetic strategies were tested in order to evaluate the application of these
type of monomers for the solid-phase synthesis of bearing different functional groups along the
chain.7 Several examples of applications of this strategy for the synthesis of specific PNA probes
and potential drugs will be discussed.
(1) Nielsen, P.E.; Egholm, M.; Berg, R.H.; Buchardt, O. Science 1991, 254, 1497-1500.
(2) Bertucci, A.; Manicardi, A.; Corradini, R. Advanced Molecular Probes for Sequence-Specific DNA Recognition,
in Detection of non-amplified Genomic DNA, Springer, 2012.
(3) Gambari, R.; Fabbri, E.; Borgatti, M.; Lampronti, I.; Finotti, A.; Brognara, E.; Bianchi, N.; Manicardi, A.;
Marchelli, R.; Corradini, R. Biochemical Pharm 2011, 82, 1416-1429.
(4) Tonelli, R.; McIntyre, A.; Camerin, C.; Walters, Z.S. et al. Clinical Cancer Res 2012, 18,796-807.
(5) Corradini, R.; Sforza, S.; Tedeschi, T.; Totsingan, F.; Manicardi, A.; Marchelli, R. Curr Top Med Chem 2011 , 11,
1535-1554.
(6) Manicardi, A.; Fabbri, E.; Tedeschi, T.; Sforza, S.; Bianchi, N.; Brognara, E.; Gambari, R.; Marchelli, R.;
Corradini, R. ChemBiochem 2012, 13, 1327-1337.
(7) Manicardi, A.; Accetta, A.; Tedeschi, T.; Sforza, S.; Marchelli, R.; Corradini, R. ADNA 2012, 3 (2),
http://dx.doi.org/10.4161/adna.20158
118
F13
Electrochemical synthesis of C-glycosides as non-natural mimetics
of biologically active oligosaccharides
Alessia Coletti,1 Antonio Marco Valerio,1 Adriana D’Angelo,2
Onofrio Scialdone,2 Elena Vismara. 1
1
Dipartimento di Chimica, Materiali e Ingegneria Chimica “G. Natta”,
Politecnico di Milano, via L. Mancinelli 7, 20131 Milano
2
Dipartimento di Ingegneria Chimica, Gestionale, Informatica, Meccanica,
Università degli Studi di Palermo, Viale delle Scienze, 90128 Palermo
alessia.coletti@chem.polimi.it
Natural oligosaccharides inhibitors of heparanase and selectins are emerging as promising drugs for
cancer therapy. As an alternative tool to the natural ones, sulfated tri maltose C-C-linked dimers
( and  STMCs) were prepared by bromo-maltotriose electroreduction on silver cathode,1
followed by sulfation. The presence of an interglycosidic C-C bond makes STMCs less vulnerable
to metabolic processing then their O-analogues. For this reason, STMCs have been studied as drug
candidates and inhibitors of carbohydrate processing enzymes. Their activity as inhibitor of Pselectin in vivo and in the attenuation of metastasis both on B16-BL6 melanoma cells and on MC38 carcinoma cells2 prompted to the optimization of their synthetic process. Therefore, the
electrochemical process for the C-C coupling of the model molecule acetobromoglucose has been
investigated by changing various reaction conditions such as solvent and arrangement of the
electrolytic cell, aiming at the final scale-up of the reaction.
Target
:
OSO3-
O
O
(-)
O
-O3SO
-O3SO
-O3SO
OSO3-
-O3SO
-O3SO
O
-O3SO
O
OSO3-
OSO3-
OSO3-
O
OSO3- O
OSO3-
O
OSO3-
-O3SO
 STMC
OSO3O
-O3SO
O
OSO3-
OSO3OSO3-
-
e
Br
-
(1) Guerrini, M.; Guglieri, S.; Santarsiero, R.; Vismara, E. Tetrahedron Asymmetry, 2005, 16, 243-253.
(2) Borsig, L.; Vlodavsky, I.; I-Michaeli, R.; Torri, G.; Vismara, E. Neoplasia, , 2011, 13, 445-452.
119
F14
Novel fluorinated compounds as smart reporter agents in 19F MRI
Lara Gazzera,1,* Massimo Cametti,1 Pierangelo Metrangolo,1,2 Giuseppe Resnati1,2
1
NFMLab – DCMIC “Giulio Natta”;; Politecnico di Milano, via Mancinelli 7, 20131 Milan Italy;
2
Center for Nano Science and Tecnology of IIT@Polimi, via Pascoli 70/3, 20133 Milan, Italy;
e-mail: lara.gazzera@mail.polimi.it
The aim of this project is the design, synthesis, and study of an entirely new generation of
fluorinated smart reporter agents for neurological pre-clinical research. In particular, our interest is
centred over the investigation of cerebral ischemia mechanism1 and cell-tracking of dendritic cells.2
The use of fluorinated reporter molecules could avoid troubles relative to classical 1H contrast
agents.3 Indeed, the nominal biological abundance of 19F in tissues permits to detect only the signals
belonging to the reporter. However, the inherently low sensitivity of the MR technique is
particularly critical in 19F-MRI studies, considering the low concentrations of 19F atoms that can be
attained in biological samples. Therefore, to fully exploit the potentialities offered by 19F-MR in
molecular imaging, it is necessary to optimize data collection strategies in order to overcome
detection limits and obtain images with a suitable Signal to Noise Ratio (SNR).
To date, hexafluorobenzene (HFB) and perfluoro-15-crown-5-ether (PFCE)4 are the perfluorinated
compounds (PFCs) most commonly used in 19F MRI research, due to the high fluorine content and
the single fluorine resonance. Moreover, PFCs are not typically degraded in vivo and have no
known intracellular biological activity5. On the other hand, these compounds have poor solubility in
water and, as such, need to be administered into lipid micro/nanoparticle emulsions.6
In this work we will present a data acquisition strategy tuned on the specific gyromagnetic features
of the investigated 19F compound. We have chosen a potassium salt with a perfluorinated
counteranion, KPF6. It is water soluble, and it has two sets of equivalent F atoms. Simulation and
phantom experimental studies were carried out with various sequences. By numerical simulations,
changes of relative SNR were mapped versus the repetition time (TR) and the number of echoes,
with and without the flip back (FB) pulse. Phantom studies were carried out embedding the sample
within different supports: agar mixture, ex-vivo perfused rat brain, and in water solution. A
detection limit of 1.53x1016 fluorine atoms per voxel was detected. T1 and T2 were measured, thus
finding a dramatic T2 drop in both agar and ex-vivo tissue, compared to water solution.
Figure 1. 19F MRI of KPF6 water solution phantoms at different
concentrations.
Finally, we will present some preliminary results on the design and synthesis of novel branched
fluorinated MRI reporter compounds possessing a very high fluorine content.
(1) Flögel, U.; Ding, Z.; Hardung, H.; Jander, S.; Reichmann, G.; Jacoby, C.; Schubert, R.; Schrader, J.
Circulation 2008, 118, 140–148.
(2) Srinivas, M.; Morel, P.A.; Ernst, L.A.; Laidlaw; D.H.; Ahrens, E.T. Magn. Reson. Med. 2007, 58, 725734.
(3) Bulte, J. W. M.; Kraitchman, D. L. NMR Biomed. 2004, 17, 484-499.
(4) Ahrens, E.T.; Flores, R.; Xu, H.; Morel, P.A. Nature Biotech. 2005, 23, 983–987.
(5) Spahn, D.; Kocian, R. Curr. Pharm. Des. 2005, 11, 4099-4114.
(6) Cametti, M.; Benoit, C.; Metrangolo, P.; Milani, R.; Resnati, G. Chem. Soc. Rev. 2012, 41, 31-42.
120
F15
Intermolecular recognition features of bioactive polyhalogenated compounds
Arianna Bertolani,1 Gabriella Cavallo,1 Pierangelo Metrangolo,1,2 Giuseppe Resnati1,2
1
NFMLab – DCMIC “Giulio Natta”, Politecnico di Milano, via Mancinelli 7, 20131 Milan, Italy;
Center for Nano Science and Technology, Istituto Italiano di Tecnologia, Politecnico di Milano,
via Pascoli 70/3, 20133 Milan, Italy.
arianna.bertolani@mail.polimi.it
2
Halogen bonding (XB) is the noncovalent interaction involving halogen atoms as acceptors of
electron density.1 The term “halogen bonding” has been suggested to emphasize the similarity with hydrogen bonding, which is the key noncovalent interaction in chemistry, biology and materials
science. XB is strong, specific and directional enough to direct the formation of well-defined
supramolecular systems.2 In particular, it can be used to modulate the aggregation of organic
molecules in solid,3 liquid,4 liquid crystalline,5 and gas phases.6 As an example, recognition in
solution mediated by XB has been proven to result in the successful separation of
diiodoperfluoroalkane mixtures by means of adduct formation and size matching.7 Recently, the
role of XB in fundamental biological processes, such as activation/inactivation of thyroid hormones,
has also been highlighted.8
Organo-halogenated contaminants, such as brominated flame retardants, have been widely
detected in the European marine environment. For this reason, the OSPAR (Oslo and Paris
Conventions for the protection of the marine environment of the North-East Atlantic) have recently
widened their scope by including these emerging contaminants. Polybrominated diphenyl ethers
(PBDEs) have, in fact, highly accumulated in sediments and water. Structural similarities between
thyroid hormones and PBDEs strongly suggest similar receptorial activity and mechanism of action
(see Figure).
In this project we are taking inspiration from Mother Nature by designing novel plastic
antibodies targeted to the multivalent recognition of polyhalogenated molecules. Molecular
imprinted polymer (MIP) techniques are used to imprint size and shape of a template molecule in a
polymer receptor matrix.9 Here we report some preliminary results on the use of MIPs as prospect
materials for the recognition, binding, and remediation of polyhalogenated organic pollutants.
T4
PBDE 73
(1) Metrangolo P.; Resnati G. Science 2008, 321, 918–919.
(2) a) Metrangolo P.; Resnati G. Chem. Eur. J. 2001, 7, 2511-2519; b) Metrangolo P.; Neukirch H.; Pilati T.; Resnati
G. Acc. Chem. Res. 2005, 38, 386-395.
(3) Corradi E.; Meille S. V.; Messina M. T.; Metrangolo P.; Resnati G. Angew. Chem., Int. Ed. 2000, 39, 1782-1786.
(4) a) Messina M. T.; Metrangolo P.; Panzeri W.; Ragg E.; Resnati G. Tetrahedron Lett. 1998, 39, 9069-9072; b)
Metrangolo P.; Panzeri W.; Recupero F.; Resnati G. J. Fluorine Chem. 2002, 114, 27-33.
(5) Nguyen H. L.; Horton P. N.; Hursthouse M. B.; Legon A. C.; Bruce D. W. J. Am. Chem. Soc. 2004, 126, 16-17.
(6) Legon A. C. Angew. Chem., Int. Ed. 1999, 38, 2686-2714.
(7) Metrangolo P.; Carcenac Y.; Lahtinen M.; Pilati T.; Rissanen K.; Vij A.; Resnati G. Science, 2009, 323, 14611464.
(8) Metrangolo P.; Resnati G. Nature Chem. 2012, 4, 437-438.
(9) a) Komiyama M.; Takeuchi T.; Mukawa T.; Asanuma H. Molecular Imprinting, Wiley-VCH, Weinheim, 2002; b)
Wulff G. Chem Rev. 2002, 102, 1-28; (c) Takeuchi T.; Mukawa T.; Shinmori H. Chem. Records 2005, 5, 263-275.
121
F16
Optimization of MW-assisted “sustainable” carbonylation reactions
Elena Petricci, Maurizio Taddei, Marianna Pizzetti
Via A. Moro, 53100, Siena, Italy
pizzetti4@unisi.it
The development of new, milder, more environmentally friendly and economically sustainable
processes as well as the search for efficient alternative synthetic methodologies are still challenging
targets in organic chemistry. Microwave dielectric heating driven transformations represent an ever
growing tool to the modern chemist since this methodology is really versatile and can be applied to
many different branches of chemistry. In many instances MW technology has shown to
dramatically reduce reaction times, increase the products yields and purity of the products if
compared to traditionally processed experiments. Nevertheless the debate about the energy
efficiency of MW heating with respect to traditional heating protocols is still open in the scientific
community.1
The application of MW to the Pd/C catalyzed carbonylation of aryl halides was investigated giving
an easy access to amides and esters in a very efficient way (Scheme 1).2
Scheme 1
The nucleophiles (alcohols and amines) were used in a stoichiometric amount and the catalyst can
be reused up to three times without changes in the reaction yields.
Looking for more economical and environmentally friendly catalysts for carbonylation reactions,
iron-carbonyls represent a good alternative which has been increasingly used in organic synthesis in
recent years. Ynamides were chosen as the model substrates to optimize a MW-assisted
carbonylation procedure in the presence of primary amines or alcohols as the nucleophiles and
Fe3(CO)12 as the catalyst (Scheme 2).
Scheme 2
The reaction can be easily run using a stoichiometric amount of the nucleophile and the cheap and
easily available TEA as the ligand, under low pressure of CO giving regioselectively the E isomer.3
The 3-amido acrylamides and esters thus obtained represent a versatile new class of compounds
which can eventually undergo further functionalization to give biologically interesting scaffolds.
The same procedure can also be applied to terminal alkynes giving regioselectively E-acrylcinnamides and esters in milder and more simple reaction conditions with respect to classical
autoclave procedures with remarkable reductions in terms of time, temperature and gas pressure.
(1) Moseley, J. D.; Kappe, C. O. Green Chem. 2011, 13, 794-806.
(2) Salvadori, J.; Balducci, E.; Zaza, S.; Petricci, E.; Taddei, M. J. Org. Chem., 2010, 75 (6), 1841–1847.
(3) Pizzetti, M.; Russo, A.; Petricci, E. Chem. Eur. J. 2011, 17, 4523-4528.
122
F17
Green technologies for algae treatment
Chiara Samorì,1 Paola Galletti,1,2 Emilio Tagliavini.1,2
1
Centro Interdipartimentale di Ricerca Industriale (CIRI), Università di Bologna,
via S. Alberto 163, 48123 Ravenna
2 Dipartimento di chimica ”Giacomo Ciamician”, Università di Bologna,
via Selmi 3, 40126 Bologna
chiara.samori3@unibo.it
Microalgae represent a very promising source of third generation biofuels. Benefits rising from the
utilisation of aquatic over terrestrial biomasses are varied, however lipid extraction is currently a
critical step in the industrial development of these biofuels.
Here we propose a new green procedure based on switchable-polarity and switchable hydrophilicity
solvents (SPS and SHS) for the extraction of algal lipids from both dried samples and concentrated
cultures. SPS and SHS are capable to turn from a non-ionic form, suitable for lipid extraction, to an
ionic liquid, suitable for a recovery step, by simply bubbling CO2, and to be reconverted in the nonionic form by bubbling N2 or by heating.1 We present the results obtained with two switchable
systems: i) one SPS based on 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU) and alcohols (ROH),
switchable in alkylcarbonate salts;2 ii) and one SHS based on alkyl amines (as
N,Ndimethylcyclohexylamine,
DMCHA) and water, switchable in hydrogen carbonate salts.3 The two switchable systems were
tested for the extraction of lipids from freezedried samples and directly from aqueous growth
medium of several microalgae, as Botryococcus braunii, rich in unsaturated hydrocarbons,4 and
other freshwater and marine species rich in triacylglycerols (Nannochloropsis sp., Tetraselmis sp.
and Desmodesmus sp.).
The best results in the extraction of B. braunii hydrocarbons freeze-dried samples were obtained
with the DBU/octanol system with an effectiveness better than that of volatile organic solvents (e.g.
chloroform or hexane). On the contrary, DMCHA/H2O system were slightly less efficient than
organic solvents in the extraction of freeze-dried algae rich in triacylglycerols. Algal hydrocarbons
and lipids could be also extracted directly from aqueous growth medium: in this case the use of the
SPS DBU/octanol as well as the SHS DMCHA/H2O gave much better results than performing a
liquid-liquid extraction with volatile organic solvents. The use of a green technology suitable for
extracting lipids from both dried microalgal biomass and directly from aqueous growth medium is
an important issue considering that the harvest and the dewatering of algal biomass have a large
impact on overall costs and energy balance. Besides the efficiency in lipid extraction, SPS and SHS
have the great advantage to be recyclable nonvolatile/non-inflammable systems, therefore suitable
for non-hazardous small plants for biofuel production located nearby algal cultivation sites.
(1) Jessop, P. Heldebrant, D.J.; Li, X.; Eckert, C.A.; Liotta, C.L. Nature 2005, 436, 1102.
(2) Phan, L.; Chiu, D.; Heldebrant, D.J.; Huttenhower, H.; John, E.; Li, X.; Pollet, P.; Xiaowang, R.; Eckert, C.A.;
Liotta, C.L.; Jessop, P.G. Ind. Eng. Chem. Res. 2008, 47, 539-545.
(3) Jessop, P.G.; Kozycz, L.; Ghoshouni Rahami, Z.; Schoenmakers, D.; Boyd, A.R.; Wechsler, D.; Holland, A.M.
Green Chem. 2011, 13, 619-623.
(4) Samorì, C.; Torri, C.; Samorì, G.; Fabbri, D.; Galletti, P.; Guerrini, F.; Pistocchi, R.; Tagliavini, E. Bioresource
Technol. 2010, 101, 3274-3279.
123
COMUNICAZIONI POSTER
124
P01
Synthesis of shikonin aza-analogs as
potential inhibitors of topoisomerases
Francesco Cascio, Alessandro D’Alfonso, Matteo Valli,
Alessio Porta, Giuseppe Zanoni, Giovanni Vidari
Università degli Studi di Pavia, Dipartimento di Chimica,
Via Taramelli 12, 27100 Pavia
e-mail: alessio.porta@unipv.it
Compounds having a naphthoquinone core are ubiquitous in nature and possess importnt biological
activities, such as antimalarial, antitumor, molluscididal, anti-fungal, anti-inflammatory properties,
and so on. A few years ago, a few shikonin derivatives were shown to exhibit potent inibitory
activity against topoisomerases I and II, two enzymes which, being critical for DNA replication,
transcription, and recombination are, therefore, important biological targets in cancer
chemotherapy. In this context, we considered it interesting to synthesize unprecedented aza-analogs
of prenylated naphthoquinones, such as compounds 8 and 9, as potential inhibitors of the
topoisomerases. The two compounds have been identified considering the mechanisms of
topoisomerase inhibition and the data of biological activities reported for structurally related
compounds.1
O
OH O
N
O
OH O
OH
shikonin
OR
8R=H
9 R = Ac
Scheme 1
The synthetic route to 8 and 9 is shown in the following scheme:
Scheme 2
Most of the synthetic intermediates have been tested against three tumor cell lines (A549, U87,
Caco-2). Preliminary data of cell growth inhibitory activity are promising, in particular for
compounds 2 and 8.
(1) a) Ahn, B. Z. et al., Archiv der Pharmazie, 2001, 334, 318-322; b) Ahn, B. Z. et al., Archiv der Pharmazie, 2000,
333, 87-92; c) Ahn, B. Z. et al., Eur. J. Med. Chem, 2000, 35, 291-298; d) Ahn, B. Z. et al., J. Med. Chem, 1995,
38, 1044; e) Couladouros, E. A., Papageorgiou, V. P. et al., BioOrg. Med. Chem., 1998, 8, 3385-3390.
125
P02
Total synthesis of A1- and B1-type phytoprostanes
Umberto Pennè,1 Marco Quaroni,1 Juan Fernando Gil,2 Alessio Porta,1
Giuseppe Zanoni,1 GiovanniVidari1
1
2
Università di Pavia, Dipartimento di Chimica, via Taramelli 12, 27100 Pavia
Instituto de Quimica, SIU-Universidad de Antioquia, A.A. 1226, Medellin, Colombia
a.porta@unipv.it
Phytoprostanes (PP) are bioactive products generated in plant tissues from the non-enzymatic freeradical mediated peroxidation of α-linolenic acid, like the oxidation of arachidonic acid to
isoprostanes in mammals. Phytoprostanes elicite the production of molecules related to the immune
system, such as phytoalexins, and upregulate gene expression in order to protect plants against the
attack of external organisms and dangerous effects caused by oxidative stress conditions.1 However,
the biochemical mechanisms are far from having been fully elucidated and the amounts of products
required for biological assays are available only by total synthesis. Moreover, product structures are
challenging from a synthetic point of view. In this work we describe the first synthesis of PPA 1 (8)
and PPB1 type II (12), and an improved synthesis of PPB1 type I (4).
Compound 4 was synthesized from an efficient organocatalysed coupling between aldehyde 1, and
diketone 2, followed by enol bromination, Heck coupling, and enzymatic ester hydrolysis.
Synthesis of PPA1 type II 8 started from lactone 5, readily elaborated to sulphone 6,2 on which the
lower side-chain was installed by Julia-Lythgoe reaction with enantiopure aldehyde 7. Finally, total
synthesis of PPB1 type II 12 departed from commercially available monomethyl azelate 9, which
was converted into stannane 10 in six steps; subsequently, Stille coupling between 10 and 11,
followed by standard reactions, afforded 12 in high yield.
The execution of in vivo biological tests with our synthetic samples are ongoing.
(1) Mueller M.J.; Plant Biol. 2004, 7, 441.
(2) Zanoni G.; Porta A.; Brunoldi E.; Vidari G.; J.Org.Chem. 2006, 71, 8459.
126
P03
Plakilactones: a new class of marine agonists of the peroxisome
proliferator-activated receptor  from Plakinastrella mamillaris
C. Festa,1,* S. De Marino,1 M. V. D’Auria,1 G. Lauro,2 G. Bifulco,2 C. D’Amore,2 B. Renga,3
A. Mencarelli,3 S. Petek,4 S. Fiorucci,3 A. Zampella.1
1
Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli “Federico II”,
via D. Montesano 49, 80131 Napoli, Italy;
2
Dipartimento di Scienze Farmaceutiche e Biomediche, Università di Salerno,
via Ponte don Melillo, 84084 Fisciano (SA), Italy;
3
Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia, Nuova Facoltà di
Medicina e Chirurgia, Via Gerardo Dottori 1, S. Andrea delle Fratte, 06132 Perugia, Italy;
4
Institut de Recherche pour le Développement (IRD), UMR7138, CPRBI, BP529,
98713 Papeete, French Polynesia
carmen.festa@unina.it
Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator in adipogenesis, implicated in whole-body glucose homeostasis and insulin sensitivity and expressed in various
tissues or cells involved in the control of several physiological responses including inflammation,
bone homeostasis, and blood pressure.1,2
Therefore PPARγ agonists have been proved effective in the treatment of diabetes, cancer and of various inflammatory disorders including atherosclerosis, rheumatoid arthritis and bowel disease.
Pursuing our search for human nuclear receptors modulators from marine organisms,3-6 we found
the sponge Plakinastrella mamillaris, collected at Fiji Islands, an extraordinary source of polyketide
metabolites as a new chemotype of PPAR agonists.
In this communication we will present details on the isolation procedures, structural characterization
and pharmacological evaluation of this family of oxygenated polyketides. The bioactivity on nuclear
receptor PPAR of these compounds was rationalized by docking experiments, suggesting a possible
mechanism of action based on a covalent Michael addition assisted by a set of fundamental weak
interactions required for the activation of PPAR.
OH
600000
Gr
ac
il i o
500000
O
eth
e
rC
*
O
O
*
RLU/  gal
400000
300000
200000
100000
0
Naive
Rosiglitazone Gracilioether C
(1)
(2)
(3)
(4)
Heikkinen, S.; Auwerx, J.; Argmann, C. A. Biochim.Biophys. Acta 2007, 1771, 999-1013.
Tontonoz, P.; Spiegelman, B. M. Annu. Rev. Biochem. 2008, 77, 289-312.
Sepe, V.;; Bifulco, G.;; Renga, B.;; D’Amore, C.;; Fiorucci, S.;; Zampella, A. J. Med. Chem. 2011, 54, 1314-1320.
Festa, C.;; De Marino, S.;; D’Auria, M. V.;; Bifulco, G.; Renga, B.; Fiorucci, S.; Petek, S.; Zampella, A. J. Med.
Chem. 2011, 54, 401-405.
(5) Sepe, V.; Ummarino, R.; D'Auria, M. V.; Mencarelli, A.; D'Amore, C.; Renga, B.; Zampella, A.; Fiorucci, S. J.
Med. Chem. 2011, 54, 4590-4599.
(6) De Marino, S.;; Sepe, V.;; D’Auria, M. V.;; Bifulco, G.;; Renga, B.;; Petek, S.;; Fiorucci, S.;; Zampella, A. Org.
Biomol. Chem. 2011, 9, 4856-4862.
(7) De Marino, S.;; Ummarino, R.;; D’Auria, M. V.;; Chini, M. G.;; Bifulco, G.;; Renga, B.;; D’Amore, C.;; Fiorucci, S.;; Debitus, C.; Zampella, A. J. Med. Chem. 2011, 54, 3065-3075.
(8) De Marino, S.; Ummarino, R.; D'Auria, M. V.; Chini, M. G.; Bifulco, G.; D'Amore, C.; Renga, B.; Mencarelli, A.;
Petek, S.; Fiorucci, S, Zampella A Steroids 2012, 77, 484-495.
* Partecipazione con borsa di studio offerta da Sifavitor.
127
P04
Theonella swinhoei as a source of anti-inflammatory cyclopeptides
C. Festa,1 S. De Marino,1 M. V. D’Auria,1 M. C. Monti,2 M. Bucci,3
V. Vellecco,3 C. Debitus,4 A. Zampella.1
1
2
via Ponte don Melillo, 84084 Fisciano (SA), Italy;
3
Dipertimento di Farmacologia Sperimentale Università di Napoli “Federico II”,
4
Institut de Richerche puor Developpement (IRD), Polynesian Reaserch Center on the Island
Biodiversity, BP529, 98713 Papeete, Tahiti, French Polynesia.
carmen.festa@unina.it
Cyclic peptides and cyclodepsipeptides from sponges have been
extensively studied for their significant biological activities and
structurally unique features incorporating several modified
amino acid residues.1,2 Whereas many of these compounds were
proved to be antifungal, antiviral and antiproliferative, few
examples of anti-inflammatory peptides from sponges or, more
generally, from marine habitats have been so far reported.3-5
As a part of our systematic study on secondary metabolites from
marine organisms collected at Solomon Islands, we found a
single specimen of the sponge Theonella swinhoei as an
extraordinary source of anti-inflammatory cyclic cyclopeptides, such as perthamides C-K6-9 and
solomonamides.10
Perthamides C-K are a family of cyclic octapeptides, characterized by several unprecedented amino
acid units and endowed of promising anti-inflammatory activity measured as a dose-dependent
reduction of mouse carrageenan-induced paw oedema and, for perthamide C, as a down-regulation
of TNF- and IL-8 release, two key biomarkers in the inflammatory response of primary human
keratinocytes cells.9
Structural characterization of these peptides were performed by interpretation of NMR spectroscopy
and mass spectrometry analysis and the configuration of amino acid residues was secured through
an integrated approach combining NMR analysis, chemical degradation, stereoselective synthesis,
LC/MS analysis and NMR-QM calculated chemical shifts. The isolation of this small library of
peptides allowed us to delineate a structure-activity relationship.
(1) Rawat, D. S.; Joshi, M. C.; Joshi, P.; Atheaya, H. Anti Canc. Agents Med. Chem. 2006, 6, 33-40.
(2) Andavan, G.S. B; Lemmens-Gruber, R. Mar Drugs 2010, 8, 810-834.
(3) Renner, M. K.; Shen, Y. C.; Cheng, X. C.; Jensen, P. R.; Frankmoelle, W.; Kauffman, C. A.; Fenical, W.;
Lobkovsky, E.; Clardy, J. J. Am. Chem. Soc. 1999, 121, 11273-11276.
(4) Moore, B. S.; Trischman, J. A.; Seng, D.; Kho, D.; Jensen, P. R.; Fenical, W. J. Org. Chem. 1999, 64, 1145-1150.
(5) Randazzo, A.; Bifulco, G.; Giannini, C.; Bucci, M.; Debitus, C.; Cirino, G.; Gomez-Paloma, L. J. Am. Chem. Soc.
2001, 123, 10870-10876.
(6) Festa, C.;; De Marino, S.;; Sepe, V.;; Monti, M. C.;; Luciano, P.;; D’Auria, M. V.;; Debitus, C.;; Bucci, M.;; Vellecco, V.; Zampella, A. Tetrahedron 2009, 65,10424-10429.
(7) Sepe, V.;; D’Auria, M. V;; Bifulco, G.;; Ummarino, R.;; Zampella, A. Tetrahedron 2010, 66, 7520-7526.
(8) Festa, C.; De Marino, S.; Sepe, V.; D'Auria, M. V.; Bifulco, G.; Andres, R.; Terencio, M. C.; Paya, M.; Debitus,
C.; Zampella, A. Tetrahedron 2011, 67, 7780-7786.
(9) Festa, C.;; De Marino, S.;; D’Auria, M.V.;; Monti, M.C.;; Bucci, M.;; Vellecco, V.;; Debitus, C.;; Zampella, A. Tetrahedron 2012, 68, 2851-285.
(10) Festa, C.; De Marino, S.; Sepe, V.; D'Auria, M. V.; Bifulco, G.; Debitus, C.; Bucci, M.; Vellecco, V.; Zampella,
A. Org. Lett. 2011, 13, 1532-1535.
128
P05
o-Benzenedisulfonimide as Brønsted acid catalyst in the Strecker reaction.
Synthetic and mechanistic aspects.
Giovanni Ghigo, Stefano Dughera, Margherita Barbero, Silvano Cadamuro
Università di Torino, Dipartimento di Chimica, V. Giuria 7, 10125 Torino.
giovanni.ghigo@unito.it
o-Benzenedisulfonimide (1) has efficiently catalysed the one-pot three-component Strecker1
reaction (Scheme 1) of ketones (2) and aromatic amines (3) with trimethylsilyl cianide (TMSCN, 4)
giving the corresponding α-amino nitriles (5) in excellent yields. Reaction conditions were very
simple, green and efficient.
Scheme 1
O
O
S
NH
O
S
O
R
O
R'
R''
2
1
NC
1
+
NH2
+ TMSCN
3
R'
R
4
NH R''
5
The reaction (Scheme 2) is known to start with the nucleophilic attack of the aniline 3 to the
carbonyl group of 2 giving rise to the amino alcohol 7. After this step, two different pathways have
been proposed for the formation of the product 5. In pathway (a), the amino alcohol 7 dehydrates to
the imine intermediate 8 then it affords 5 by the subsequent addition of CN-. In pathway (b), the
nucleophilic attack of CN- occurs directly on 7. Some authors conjectured that the two mechanisms
can coexist.3
Scheme 2
(a)
acid catalysts
O
R
R'
2
+
6
R''
NH2
3
HO
- H2O
R'
R
NH R''
7
R'
N
R
?
TMSCN
4
(b)
R''
8
TMSCN
4
NC
R'
R
NH R''
5
Theoretical calculations have allowed us to discriminates between the two mechanism and to
explain the fundamental role of the o-benzenedisulfonimide (1) as Brønsted acid catalyst.
(1) Strecker, A. Ann. Chem. Pharm., 1850, 75, 27-45.
(2) Barbero, M.; Bazzi, S.; Cadamuro, S.; Dughera, S. Curr. Org. Chem., 2011, 15, 576-599.
(3) Zhang,G.-W.; Zheng, D.-H.; Nie, J.; Wang, T.; Ma, J.-A. Org. Biomol. Chem., 2010, 8,1399-1405.
129
P06
From second to third order kinetics acid-catalyzed benzidine rearrangemet.
A theoretical study.
Giovanni Ghigo,1 Stefania Cagnina,1,2 Silvio Osella,1,3
Andrea Maranzana,1 Glauco Tonachini1
1
2
Università di Torino, Dipartimento di Chimica, V. Giuria 7, 10125 Torino.
Present add.: CNRS UMR-7575, Chimie Paris-Tech, 11 r. Curie, 75231 Paris - France.
3
Present add.: CNM, University of Mons, Pl. du Parc 20, B-7000 Mons - Belgium.
giovanni.ghigo@unito.it
The benzidine rearrangement consists in the acid-catalyzed conversion of hydrazobenzenes in
benzidines, diphenylines and semidines.1
Despite the number of experimental evidences, some mechanistic aspects still remain unsolved.
One of them is its kinetics law that shows, depending on the nature of the substrate S, first or
second order dependence on the acid concentration (second and third order on the whole). This
dicotomy is due to the occurrence of two competing mechanisms: the first one is a second order
monoprotonated mechanism with rate constant km; the second one is a third order diprotonated
mechanism with rate constant kd:
v = km [S] [H+] + kd [S] [H+]2
The mechanism for the hydrazobenzene (R=R'=H, above) follows a third order kinetics and it has
been unraveled by our group last year.2 The present poster will illustrate the results of the recent
study on the monoprotonated mechanism for the same substrate3 and of the current exploration of
the reaction mechanisms for the second order rearrangement of the 2,2'-dimethoxyhydrazobenzene.
(1) March, J. March's Advanced Organic Chemistry John Wiley & Sons, Inc., 2001, Chap. 18-36, pp. 1455-1456.
(2) Ghigo, G.; Osella, S.; Maranzana, A.; Tonachini, G. Eur. J. Org. Chem. 2011, 2326-2333.
(3) Ghigo, G.; Maranzana, A.; Tonachini, G. Tetrahedron 2012, 68, 2161-2165.
130
P07
Conicasterol E, a small heterodimer partner sparing farnesoid-X-receptor
modulator endowed with a pregnane-X-receptor agonistic activity,
from the marine sponge Theonella swinhoei
Valentina Sepe,1 Raffaella Ummarino,1 Maria Valeria D’Auria,1 Maria Giovanna Chini,2
Giuseppe Bifulco,2 Barbara Renga,3 Claudio D’Amore,3 Stefano Fiorucci,3 Angela Zampella1
1
via D. Montesano 49, 80131 Napoli, Italy
2
Dipartimento di Scienze Farmaceutiche, Università di Salerno,
via Ponte don Melillo, Fisciano (SA), 84084 Italy
3
Dipartimento di Medicina Clinica e Sperimentale,Università di Perugia, Nuova Facoltà di
Medicina e Chirurgia, Via Gerardo Dottori 1, S. Andrea delle Fratte, 06132 Perugia, Italy
valentina.sepe@unina.it
Nuclear receptors are key regulators of various processes including reproduction, development, and
metabolism of xeno- and endobiotics. They represent one of the most important drug targets in
terms of potential therapeutic application. There are 48 genes in the human genome that code for
the NRs superfamily.
Among nuclear receptors, farnesoid-X-receptor (FXR) has emerged as a valuable pharmacological
target due to its role in regulating bile acids (BAs), lipid and glucose homeostasis. Activation of
FXR, highly expressed in the liver, intestine, kidney and adrenals, leads to complex responses, the
most relevant of which is the inhibition of bile acids synthesis. The discovery of FXR modulators
represents an important answer to the urgent demand of new drugs for the treatment of relevant
human diseases including dyslipidemia, cholestasis, non-alcoholic steatohepatitis (NASH) and type2 diabetes.
In this communication we report the isolation and
characterization of a new 4-methylenesterol, conicasterol E,
isolated from the marine sponge Theonella swinhoei.
Pharmacological characterization of this steroid in
OH
comparison to CDCA, a natural FXR ligand, and 6-ECDCA, a HO
OH
H
synthetic FXR agonist generated by an improved synthetic
Conicasterol E
strategy, and rifaximin, a potent pregnane-X-receptor (PXR)
agonist, demonstrated that conicasterol E is an FXR
modulator endowed with PXR agonistic activity.
Conicasterol E induces the expression of genes involved in
bile acids detoxification without inducing the expression of
small heterodimer partner (SHP), thus sparing the expression
of genes involved in bile acids biosynthesis. SHP activation
by FXR is responsible for some unwanted effects including
inhibition of bile acids synthesis, which leads to bile acid pool
shrinking.
(1)
(2)
(3)
(4)
(5)
(6)
Fiorucci, S.; Mencarelli, A.; Distrutti, E.; Palladino, G.; Cipriani S. Curr. Med. Chem. 2010, 17, 139-159.
Fiorucci, S.; Cipriani, S.; Baldelli, F.; Mencarelli, A.. Prog. Lipid Res. 2010, 49, 171-185.
Fiorucci, S.; Mencarelli, A.; Palladino, G.; Cipriani, S. Trends Pharmacol. Sci. 2009, 30, 570-580.
Fiorucci. S.; Baldelli, F. Curr. Opin. Gastroenterol. 2009, 25, 252-259.
Fiorucci, S.; Rizzo, G.; Donini, A.; Distrutti, E.; Santucci, L. Trends Mol. Med. 2007, 13, 298-309.
Sepe, V.;; Ummarino, R.;; D’Auria, M. V.; Chini, M. G.; Bifulco, G.; Renga, B.;; D’Amore, C.;; Fiorucci, S.;; Zampella, A. J. Med. Chem. 2012, 55, 84-93.
131
P08
Theonellasterol: a highly selective
FXR antagonist that protects against liver injury in cholestasis
Barbara Renga,1 Andrea Mencarelli,1 Claudio D’Amore,1 Sabrina Cipriani,1
Maria Valeria D’Auria,2 Valentina Sepe,2 Maria Giovanna Chini,3 Maria Chiara Monti,3
Giuseppe Bifulco,3 Angela Zampella,2 Stefano Fiorucci1
1
Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia, Nuova Facoltà di
Medicina e Chirurgia, Via Gerardo Dottori 1, S. Andrea delle Fratte, 06132 Perugia, Italy
2
via D. Montesano 49, 80131 Napoli, Italy
3
via Ponte don Melillo, Fisciano, Salerno, 84084 Italy
valentina.sepe@unina.it
Among natural sources, marine environment represents a greater promise to provide original
molecules for treatment of human diseases. Sponges of the genus Theonella have attracted the
interest from the scientific community for the impressive variety of bioactive secondary metabolites
with unusual structures and powerful biological effects.
In the course of our research for novel metabolites from marine sponges we had the opportunity to
isolate from Theonella swinhoei unique sterols. Decodification of these non conventional
metabolited has allowed the identification of 24-ethyl-4-methylenesterols endowed with potent
activity towards nuclear receptors including the farnesoid-X-receptor (FXR) and pregnane-Xreceptor (PXR).
In this communication we report recent results obtained by transactivation and microarray analyses
carried out in HepG2 cells, a human hepatocyte cell line. We have found that theonellasterol is a
selective FXR antagonist. Exposure of HepG2 cells to theonellasterol antagonizes the effect of
natural and synthetic FXR agonist on a number of FXR target genes, including SHP, OSTα, BSEP and MRP4. In particular, we demonstrates that theonellasterol is an FXR antagonist that increases
the liver expression of MRP4 and protects against liver injury induced by bile duct ligation in a
animal model of cholestasis.
HO
H
Theonellasterol
(1) Nishimura, S.; Arita, Y.; Honda, M.; Iwamoto, K.; Matsuyama, A.; Shirai. A.; Kawasaki, H.; Kakeya, H.;
Kobayashi, T.; Matsunaga, S.; Yoshida, M. Nat. Chem. Biol. 2010, 6, 519-526.
(2) Kobayashi, M.; Tanaka, J.; Katori, T.; Kitagawa, I. Tetrahedron Lett., 1989, 30, 2963-2966.
(3) De Marino, S.;; Ummarino, R.;; D’Auria, M.V.;; Chini, M.G.;; Bifulco, G.;; Renga, B.; D'Amore, C.; Fiorucci, S.;
Debitus, C.; Zampella, A. J. Med. Chem. 2011, 54, 3065-3075
(4) De Marino, S.; Ummarino, R.; D'Auria, M.V.; Chini, M.G.; Bifulco, G.; D'Amore. C.; Renga, B.; Mencarelli, A.;
Petek, S.; Fiorucci. S.; Zampella, A. Steroids 2012, 77, 484-495.
(5) Renga, B.; Mencarelli, A.; D'Amore, C.; Cipriani, S.; D'Auria, M.V., Sepe, V.; Chini, M.G.; Monti, M.C.; Bifulco,
G.; Zampella, A.; Fiorucci, S. PLoS One 2012, 7(1):e30443
132
P09
Isolation and characterization of iridoid secondary metabolites from kurdish
plants Verbascum calvum Boiss & Kotschy and Teucrium parviflorum Schreb.#
Hawraz I. M. Amin,5 Fuad O. Abdullah,5 Gianluca Gilardoni,1,2 Davide Gozzini,1,2
Solveig Tosi,2,3 Daniela Buonocore,4 Faiq H. S. Hussain,5 Gloria Brusotti,6
Paola Vita Finzi,1,2 and Giovanni Vidari1,2
1
Dipartimento di Chimica, Università di Pavia, Via Taramelli 10, 27100 Pavia, Italy
2
C.I.St.R.E., Università di Pavia, Via Taramelli 10, 27100 Pavia, Italy
3
Dipartimento di Scienze della Terra e dell’Ambiente, Università di Pavia,
Via S. Epifanio 14, 27100 Pavia, Italy
4
Dipartimento di Medicina Legale, Università di Pavia, Via Ferrata 9, 27100 Pavia, Italy
5
Department of Chemistry, College of Science, University Salahaddin, Erbil, Iraq
6
Dipartimento di Scienze del Farmaco, Università di Pavia, Via Taramelli 12, 27100 Pavia, Italy
gianluca.gilardoni@unipv.it
Verbascum calvum belongs to the family of Scrophulariaceae, which comprises about 2500 species
growing worldwide; many of them have been thoroughly investigated. Chemical and biological
aspects of Verbascum calvum have not been reported so far; on the other hand, this plant is
commnly employed in the Kurdish traditional medicine for the treatment of burns and other skin
diseases. T. parviflorum belongs to the family of Lamiaceae, which comprises about 300 species; 11
of them are present in Iraq. Like Verbascum, also the genus Teucrium is very well known from a
phytochemical point of view; however, the components of T. parviflorum have not yet been
investigated. The plant is employed in the Kurdish traditional medicine for the treatment of
jaundice, stomach pains, liver disorders, and for lowering the level of cholesterol in blood.
Dry flowers of V. calvum (210 g) and dry aerial parts of T. parviflorum (550 g) were exhaustively
extracted by maceration at room temperature, in solvents of increasing polarity: hexane, methanol,
methanol/water 70:30.
Chlorophylls were removed from the methanolic extracts by filtration on a C-18 reversed phase
column, while tannins were not present in significant amounts. Subsequently, the chlorophyll free
extracts were separtely fractionated by repetitive preparative MPLC, on a C-18 reversed phase,
affording four glucosylated iridoids as the major products: aucubin (1) and ajugol (2) from V.
calvum, and harpagide (3) and 8-acetylharpagide (4) from T. parviflorum.
OH
OH
OH
O
O
O
HO
OH
OH
O HO
(2)
O
OH
O HO
OH
(4)
O
OH
O
OH
O HO
(1)
O
OH
OH
HO
OH
O
OH
O
OH
HO
OH
OH
O HO
(3)
O
OH
OH
These iridoids are well-known and show a characteristic high anti-inflammatory activity; in
contrast, they had no activity against the growth of several tumor cell lines. The chlorophyll free
extracts were strongly active in the DPPH anti-radical test and in the Folin-Ciocalteu assay; the
phenolic compounds are under investigation.
#
This paper is one of the first investigations on the composition of Iraqi Kurdistan medicinal plants and has been
financed by a generous grant from Regione Lombardia (ASTIL-PROKURDUP project 2010-2012)
133
P10
Novel monoterpenoid esters isolated from the Ecuadorian plant
Hedyosmum scabrum (Ruiz & Pav.) Solms
Vladimir Morocho,3 Gianluca Gilardoni,1,2 Davide Gozzini,1,2 Omar Malagòn,3
Paola Vita Finzi,1,2 and Giovanni Vidari1,2
1
Dipartimento di Chimica, Università di Pavia, Via Taramelli 10, 27100 Pavia, Italy
2
C.I.St.R.E., Università di Pavia, Via Taramelli 10, 27100 Pavia, Italy
3
Departamento de Quimica, Universidad Técnica Particular de Loja, San Cayetano Alto, 11 01 608
Loja, Ecuador
gianluca.gilardoni@unipv.it
Hedyosmum scabrum (Ruiz & Pav.) Solms, belonging to the family of Chloranthaceae, is a plant
growing on the andean regions of South America, known also with the synonymous name of
Tafalla scabra Ruiz & Pav. The plant occurs widely in several provinces of Ecuador, at altitudes
between 1800 and 3500 m A.M.S.L.1 With the names of Guayusa del cerro, Granizo and Tarqui,
Hedyosmum scabrum is employed as an aqueous infusion in the local traditional medicine for the
treatment of stomach pains; moreover, the fruits are used to prepare flavoring drinks.2
Nor chemical and farmacological data were published so far on this plant, except for the
composition of the essential oil.3,4
For this phytochemical study, concerning the non volatile components, dry leaves (200 g), collected
at the time of fructification, were exhaustively extracted by repeated maceration at room
temperature in solvents of increasing polarity. Subsequently, ethyl acetate and methanol extracts
were deprived of chlorophylls by chromatography on a C-18 reversed phase column; and the
chlorophyll-free mixtures where then fractionated by preparative liquid chromatography, at first on
C-18 reversed phase, followed by silica gel columns. The structures of six novel cinnamic esters of
the monoterpenoid alcohols pinocarveol and chrysanthenol, shown below, were established by MS
and NMR spectra, and analysis of the products obtained by basic hydrolysis.
(1) Jorgensen, P.; Leon, S. Catalogue of vascular plants of Ecuador. Missouri Botanical Garden Press. St. Louis.
U.S.A. 1999.
(2) de la Torre, L.; Navarrete, H.; Muriel, P.; Macía, M. J.; Balsle, H. Enciclopedia de las Plantas Útiles del Ecuador.
Herbario QCA & Herbario AAU. Quito & Aarhus. 2008.
(3) De Feo, V.; Soria, R. U. J. of Essential Oil-Bearing Plants 2007, 10, 41-45.
(4) Lorenzo, D.; Loayza, I.; Dellacassa, E. Flavour and Fragrance Journal 2003, 18, 32-35.
134
P11
Formic Acid: a Promising Bio-Renewable Feedstock for Fine Chemicals
Manuel G. Mura, Andrea Porcheddu
Università degli Studi di Sassari, Dipartimento di Chimica e Farmacia
via Vienna 2, 07100 Sassari.
anpo@uniss.it
Nowadays, the dramatic rise in the consuming of fossil resources is irreversibly impacting climate
change. In light of finite nature of these fossil resources coupled with concerns for global warming,
carbon dioxide is becoming increasingly attractive as organic carbon source.1 Although CO2 is one
of the cheapest and most abundant carbon-containing raw materials in nature, several drawbacks
limit its use in organic synthesis: costs, capture, separation, purification, storage, and transportation.
We believe that formic acid could be an interesting solution to store, transport, and activate carbon
dioxide for the synthesis of value-added chemicals.2 In this perspective, HCOOH can be
successfully used as C1-building block for the synthesis of a library of alcohols. This “concept” may be further developed and found application in every field where organic synthesis is involved.
HCOOH
Syngas Source
RCH=CH2
[Ru]
H2 source
RCH2CH2CHO
[Ru]
RCH2CH2CH2OH
(1) Sakakura, S.; Choi, J. C.; Yasuda, H. Chem. Rev. 2007, 107, 2365–2387.
(2) Laurenczy, G.; Grasemann, M: Energy Environ. Sci. 2012, (DOI: 10.1039/C2EE21928J).
135
P12
Chemoenzymatic synthesis of monodeprotected carbohydrates
for glycoprotein preparation
Teodora Bavaro,1 Francesco Fasanella,2 Pierangelo Francescato,2
Carlo F. Morelli,2 Giovanna Speranza,2 Marco Terreni1
1
Italian Biocatalysis Center (IBC), Department of Drug Sciences,
University of Pavia, Pavia, Italy
2
University of Milan, Department of Chemistry, Milan, Italy
teodora.bavaro@unipv.it
The increasing importance of glycoproteins as therapeutic agents in the recent years has placed
increasing emphasis on their synthesis and extensive characterization of their chemical structures.
However, preparation of glycoconjugates is hampered by difficulties related to obtain pure
oligosaccharides.1 The carbohydrate synthesis, based on the orthogonal protective/deprotective
pathway, involves cumbersome multistep sequences to introduce modifications at a specified
position. Enzymes can be exploited in this frame to develop highly selective transformations and
straightforward synthetic routes.
In this work, we have developed a chemoenzymatic approach based on the regioselective enzymatic
hydrolysis of different peracetylated sugars (1) catalyzed by different immobilized lipases2 to obtain
the selectively monodeprotected acyl pyranose 2 bearing only a free hydroxyl group in C-6
position. These compounds have been used as starting material for the preparation of the activated
disaccharides (3) for protein conjugation.
Scheme 1
AcO
AcO
AcO
HO
OAc
O
AcO
AcO
R
1
HO
OAc
O
R
O
OH
2
R = SCH2CN, OAc
OH
O
OH
O
HO
HO
R = SCH2CN, OAc
R
3
NH
R= S
HO
O
R= O
OH
H2N
OH
HO
HO
O
OMe
O
N
H
O
O
NO2
OH
O
X
On this basis, we have investigated the preparation of antigenic glycoconjugates obtained with
oligosaccharides structurally related to lipoarabinomannan (LAM), the major surface antigen of
Mycobacterium tuberculosis. The synthesis and conjugation of cancer antigens of the “lacto series” has been also studied.
(1) Seeberger, P. H.; Werz, D. B. Nature. 2007, 446, 1046-1051.
(2) Terreni, M.; Bavaro, T.; Abu alassal, Qais. Italian Patent Application. 2011, MI2011A001064 and
MI2011A001065.
136
P13
Reactivity of densely functionalized cyclopentadienes with nitroso derivatives:
unexpected synthesis of fulvenes and dihydrofuranes
Stefania Fusi, Fabio Ponticelli
Dipartimento di Chimica, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena, Italy
stefania.fusi@unisi.it
Recently1 we have explored the reactivity of 1 towards dienophiles characterized by the double
bond C=C e N=N. In general the cyclopentadiene system 1 shows low reactivity and the
cycloaddition reaction occurs only by heating or heating under microwave irradiation. In this
communication we present the results obtained using nitroso derivatives as dienophiles. The
reaction does not proceed with nitroso benzene, whatever the experimental conditions.
The compound 1 reacts N,N-dimethyl nitroso aniline at room temperature or heating under
microwave irradiation and unexpectedly gives compounds 2 and 3
R
N
R
N
CN
O
NC
O
O
RT
+
N
2, 2',2"
NC
NHCOCF3
N
MW
NC
HN
N
1, 1',1"
R
CN
3, 3',3"
2,3 R =
1 R=
1' R =
NO2
2',3' R =
NO2
1"R=
NO2
2",3" R=
NO2
O2N
O2N
(1) Fusi,S.;Ferrini,S.;Ponticelli,F. Tethaedron Letters 2011, 52, 6911-6915.
137
P14
Photochemical synthesis of benzo[a]carbazoles
via 2-aryl-3-(1-arylsulfonylalkyl)-indoles#
Stefano Protti,1 Alessandro Palmieri,2 Marino Petrini,2
Roberto Ballini,2 Angelo Albini,1 Maurizio Fagnoni1
1
Viale Taramelli 12, 27100 Pavia, Italy.
2
Green Chemistry Group, School of Science and Technology, Chemistry Division, University of
Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy
fagnoni@unipv.it
Despite the poor availability in nature, the benzocarbazole moiety has gained significant attention in
recent years, since its considerable biological activity. In particular, different benzo[a]carbazoles
have shown enhanced in vivo antitumour activity towards mammary colon and renal tumor and
leukemia.1 Furthermore, benzo[a]carbazoles have found extensive application as photographic and
photoconductive materials (1). In view of these applications, different multi-step strategies for the
synthesis of these derivatives have been proposed in literature.1,2
We recently investigated the photoreactivity of 2-aryl-3-(1-arylsulfonylalkyl)-indoles, finding that
the irradiation of such substrates affords a benzo[a]carbazole derivative, as the main product. In the
aim of exploiting the synthetic potentialities of the reaction, different reaction conditions (choice of
the solvent, irradiation wavelentgh, presence of oxygen) have been investigated.
Thus, irradiation of such easy synthesizable3 substrates ( = 355 nm) in polar solvents such as
acetonitrile, acetone and tetrahydrofuran led to differently substituted benzo[a]carbazole from
discrete to satisfactory yields (Scheme 1). The reaction mechanism as well as the nature of the
involved intermediates have been also investigated.
TolO2S
R
R
FG
N
R1
h
Solvent
FG
N
R1
Solvent = MeCN, Acetone, THF
R = CH3, CH2C6H5, C4H9, C6H13, C7H15
R1 = H, CH3
FG = H, CH3, OCH3, CF3
Scheme 1
(1) Knölker H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303-4427.
(2) Schmidt, A. W. Reddy, K. R.;; Knölker, H.-J. Chem. Rev. 2012, 112, 3193-3328.
(3) Ballini, R.; Palmieri, A.; Petrini, M.; Torregiani A. Org. Lett. 2006, 8, 4093-4096.
#
We acknowledge MIUR, Rome (FIRB-Futuro in Ricerca 2008 project RBFR08J78Q) for financial support.
138
P15
Synthesis of new enzimatic inhibitors based on a β-lactam structure
Roberto Soldati, Paola Galletti, Matteo Pori, Daria Giacomini
Department of Chemistry “G. Ciamician”, University of Bologna, Italy
roberto.soldati3@unibo.it
-Lactam compounds are really “evergreen” molecules. Beside bicyclic -lactam substrates such as
penicillins, cephalosporins, and carbapenems, monocyclic compounds (azetidinones) emerged for
their interesting and variegated biological activities.1 For instance, 4-alkyliden-azetidinones proved
to be interesting scaffolds for antibiotics against resistant bacteria2 and effective enzymatic
inhibitors against Human Leukocyte Elastase (HLE) and matrix metallo-proteases (MMPs), and as
antiaggregating agents.3 Moreover, our interest in the design of new β-lactam compounds with
specific biological activities recently allowed us to extend our strategies to the synthesis of new
monocyclic derivatives with specific inhibitory potency against integrins and histone deacetylase
enzymes (HDAC).4
Furthermore, we recently developed the synthesis of new -lactam peptides specifically designed as
integrin inhibitors, which should work as mimetic of the RGD (Arg-Gly-Asp) peptide. The study of
integrin inhibitors is generally devoted to the design and development of structures able to mimic
the RGD sequence, key portion in the recognition process of proper integrin ligands. 5 Our
optimized strategy involved the use of the commercially available 4-acetoxy-azetidin-2-one as
starting material, and efficiently allowed specific modifications at the C-4 and the nitrogen atom of
the -lactam ring (Figure 1).
Figure 1
(1) Galletti, P.; Giacomini, P.; Curr. Med. Chem., 2011, 18, 4265-4283.
(2) Broccolo, F.; Cainelli, G.; Caltabiano, G.; Cocuzza, C. E A.; Fortuna, C. G.; Galletti, P.; Giacomini, D.;
Musumarra, G.; Musumeci, R.; Quintavalla, A.; J. Med. Chem., 2006, 49, 2804-2811.
(3) a) Cainelli,G.; Galletti, P.; Garbisa, S.; Giacomini, D.; Sartor, L.; Quintavalla, A.; Bioorg. Med. Chem., 2005, 13,
6120-6132;; b) Dell’Aica, I.;; Sartor, L.;; Galletti, P.; Giacomini, D.; Quintavalla, A.; Calabrese, F.; Giacometti, C.;
Brunetta, E.; Piazza, F.; Agostini, C.; Garbisa, S.; J. Pharmacol. Exp. Ther., 2006, 316, 539-546; c) Cainelli, G.;
Angeloni, C.; Cervellati, R.; Galletti, P.; Giacomini, D.; Hrelia, S.; Sinisi R.; Chem. Biodivers., 2008, 5, 811-829.
(4) a) Galletti, P.; Quintavalla, A.; Ventrici, C.; Giannini, G.; Cabri, W.; Penco, S.; Gallo, G.; Vincenti, S.; Giacomini,
D.; ChemMedChem, 2009, 4, 1991-2001; b) Galletti, P.; Quintavalla, A.; Ventrici, C.; Giannini, G.; Cabri, W.;
Giacomini, D.; New J. Chem., 2010, 34, 2861-2866.
(5) Plow, E. F.; Haas, T. A.; Zhang, L.; Luftus, J.; Smith, J. W.; J. Biol. Chem., 2000, 275, 21785-21788.
139
P16
Syntheses of sugar mimetics as new antitumoral agents
Franca M. Cordero, Carolina Vurchio,
Bhushan B. Khairnar, Paola Bonanno, Alberto Brandi
Consorzio Interuniversitario Nazionale “Metodologie e Processi Innovativi di Sintesi" CINMPIS
and Dipartimento di Chimica“Ugo Schiff”, Università di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino(FI)
carolina.vurchio@unifi.it
Polyhydroxylated indolizidine alkaloids are interesting compounds because of their structural
analogy with sugars and their biological activity as inhibitors of glycosidase enzymes. (+)Lentiginosine (1) is a natural iminosugar with only two hydroxylic groups that displays a potent
amyloglucosidase inhibition activity. Recently, it was proved that 1 is also an Hsp90 inhibitor1 and
that the enantiomeric (–)-lentiginosine 2 and its derivative (–)-7S-OH-lentiginosine 3 are potent
proapoptotic agents against different cancer cell types, with low cytotoxicity towards normal cells.
Indolizidine 3 can be prepared with high stereoselectivity through a 1,3-dipolar cycloaddition
between a suitable alkene and the enantiopure hydroxylated pyrroline N-oxide 5 in turn, easily
derived from a “chiral pool” compound such as tartaric acid.2
The interesting biological profile of lentiginosine suggests its derivatization3,4 to improve the
potency and to study its interaction with the receptors, not yet known, involved in the bioactivity.
For this purpose in this communication, besides a revisited stereoselective synthesis of intermediate
6, the synthesis of 7-substituted lentiginosine derivatives functionalized with different moieties,
such as halides, thiols, carboxylic esters, sulfonates, and carbamates linked to carbon hydrophobic
chains or conjugated with aromatic, heteroaromatic, and polar groups, or markers such as biotin and
fluoresceine will be presented.
(1) Dal Piaz, F.; Vassallo, A.; Chini, M. G.; Cordero, F. M.; Cardona, F.; Pisano, C.; Bifulco, G.; De Tommasi, N.;
Brandi, A. PLoS One in press.
(2) 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.
(3) Cordero, F. M.; Bonanno, P.; Neudeck, S.; Vurchio, C.; Brandi, A. Adv. Synth. Catal. 2009, 351, 1155-1161.
(4) Cordero, F. M.; Bonanno, P.; Chioccioli, M.; Gratteri, P.; Robina, I.; Moreno Vargas, A. J.; Brandi A.
Tetrahedron, 2011, 67, 9555-9564.
140
P17
Synthesis of benzolentiginosines and a new approach to tetrahydroquinolines
Franca M. Cordero, Bhushan B. Khairnar, Andrea Martinelli, Alberto Brandi
Department of Chemistry “Ugo Schiff”, University of Florence,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
khairnarbhushan2008@gmail.com
Iminosugars are a class of natural products characterized by a polyhydroxylated monocyclic or
bicyclic structure containing a nitrogen atom in the ring. These compounds are able to inhibit
glycosidases. Among the natural indolizidine iminosugars, (+)-lentiginosine [(+)-1] is potent
amyloglucosidases inhibitor.1 In addition an interesting alternative bioactivity of this compound as
inhibitor of the HSP90 protein was recently revealed.2 The bioactivity of the enantiomeric (–)lentiginosine [(–)-1] is completely different as proved by its proapoptotic activity against different
strains of cancer cells associate with a very low cytotoxicity.3
HO H
H OH
N
OH
(+)-1
natural lentiginosine
amyloglucosidase inhibitor
Hsp90 inhibitor
HO
N
(-)-1
non-natural enantiomer
proapoptotic agent
The important activity of (+)- and (–)-1 encouraged the collection of several differently
functionalised derivatives to modulate bioactivity and study their interaction with bioreceptors.
Computational docking studies with glucoamylase suggested that an aromatic ring fused on the ebond of (+)-1 could be favorably accommodated in the enzyme cavity and increase the affinity of
the ligand to the enzyme.
Our approach to benzolentiginosines 4 is based on the 1,3-dipolar cycloadditon (1,3-DC) of
pyrrolidine N-oxides 2 with 2-halogenated styrene derivatives, followed by isoxazolidine reduction
and metal catalyzed intramolecular N-C coupling.
In this communication a new synthesis of nitrone 2 (R = t-Bu)4 will be presented along with the
study of the conversion of intermediates 3 to substituted benzo-indolizidines. Finally, the study of
the three-step sequence 1,3-DC/N-O reduction/N-C intramolecular coupling as a new general
approach to tetrahydroquinolin-4-ols starting from acyclic nitrones will be discussed.
(1) Goti, A.; Cardona, F.; Brandi. A.; Picasso, S.; Vogel, P. Tetrahedron: Asymmetry 1996, 7, 1659-1674
(2) Dal Piaz, F.; Vassallo, A.; Chini, M. G.; Cordero, F. M.; Cardona, F.; Pisano, C.; Bifulco, G.; De Tommasi, N.;
Brandi, A. PLoS One in press
(3) Macchi, B.; Minutolo, A.; Grelli, S.; Cardona, F.; Cordero, F. M.; Mastino, A.; Brandi A. Glycobiology 2010, 20,
500–506
(4) Cordero, F. M.; Bonanno, P.; Khairnar, B. B.; Cardona, F.; Brandi, A.; Macchi, B.; Minutolo, A.; Grelli, S.;
Mastino, A. ChemPlusChem 2012, 77, 224-233
141
P18
Synthesis of spirocyclic compounds
via organocatalytic Michael addition to vinyl selenones
Benedetta Battistelli, Silvia Sternativo, Luana Bagnoli,
Claudio Santi, Lorenzo Testaferri, Francesca Marini
Dip.to di Chimica e Tecnologia del Farmaco, Università di Perugia,
Via del Liceo 1, 06123 Perugia
benedettabattistelli@yahoo.it
Spirocyclic compounds are attractive targets in organic synthesis, not only because of their unique
structural properties with potential application in asymmetric synthesis, but also because of their
broad distribution in biologically active natural products and pharmaceuticals.1 Among the methods
for the enantioselective construction of spirocyclic frameworks, cascade processes involving
Michael additions are particularly appreciated making the asymmetric assembly of structurally
diverse spirocyclic compounds possible from simple and readily available precursors.2 In
continuation of our efforts to expand the scope of privileged organocatalysts in the field of selenium
chemistry,3 we herein report the unprecedented enantioselective synthesis of spiro compounds
starting from racemic cyclic -ketoesters or amides and phenyl vinyl selenone. The one-pot Michael
addition/cyclization sequences catalyzed by bifunctional cinchona-derived catalysts proceed in
good yields and excellent stereocontrol under mild reaction conditions. The method is based on the
peculiar properties of the phenylselenonyl unit, which plays a dual role as an activating electronwithdrawing group, during the addition step, and as an excellent leaving group, during the
cyclization.
(1) a) Bartoli, A.; Rodier, F.; Commeiras, L.; Parrain, J.-L.; Chouraqui, G. Nat. Prod. Rep. 2011, 28, 763; b) Kotha,
S.; Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009, 165; c) R. Pradhan, M. Patra, A. K. Behera, B. K.
Mishra, R. K. Becera Tetrahedron, 2006, 62, 779.
(2) Rios R. Chem. Soc. Rev. 2012, 41, 1060.
(3) a) Tiecco, M.; Carlone, A.; Sternativo, S.; Marini, F.; Bartoli, G.; Melchiorre, P. Angew. Chem. Int. Ed. 2007, 46,
6882; b) Marini, F.; Sternativo, S.; Del Verme, F.; Testaferri, L.; Tiecco, M. Adv. Synth. Catal. 2009, 351, 103; c)
Marini, F.; Sternativo, S.; Del Verme, F.; Testaferri, L.; Tiecco, M. Adv. Synth. Catal. 2009, 351, 1801; d)
Sternativo, S.; Calandriello, A.; Costantino, F.; Testaferri, L.; Tiecco, M.; Marini, F. Angew. Chem. Int. Ed. 2011,
50, 9382.
142
P19
Synthesis of new mixed sulfonyl diaryl derivatives
and their use in the preparation of important biological targets
S. Lancianesi, A. Palmieri, M. Petrini
School of Science and Technology, Chemistry Division, University of Camerino,
Via S. Agostino 1, 62032 Camerino
e-mail: stefano.lancianesi@unicam.it
Heterocyclic systems often constitute the core of biologically active compounds. In particular
the bisindolylmethane framework is present in many natural and synthetic products successfully
used as drugs for the treatment of various diseases (cancer, fibromyalgia, chronic fatigue, etc.). 1
Following our ongoing research on the chemistry of sulfonylalkylindoles and their analogues, 2
we devised a new method for the preparation of bisindolylmethanes. Our strategy provides a
rapid entry to unsymmetrical bisindolylmethanes3 in which interesting mixed bicyclic structures
containing an indazole or an azaindole core are present (Scheme 1). Moreover, the presence of ptoluenesulfonyl moiety acting as leaving group gives the possibility of further functionalization
using different nucleophilic systems.
Scheme 1
(1) a)Shiri, M.; Zolfigol, M.A.; Kruger, H.G.; Tanbakouchian, Z. Chem. Rev. 2010, 110, 2250. b) Safe, S.; Papineni,
S.; Chintharlapalli, S. Cancer Lett. 2008, 269, 326; c) Shertzer, H.G.; Sainsbury, M. Food Chem. Toxicol. 1991,
29, 237. d) Giannini, G. et al.; Bioorg. And Med. Chem. Lett. 2009, 19, 2840. e) Chintharlapalli, S. et al. Mol.
Pharmacol. 2005, 68, 1782
(2) a) Palmieri A.; Petrini, M.; Shaikh, R.R. Org. Biomol. Chem. 2010, 8, 1259; b) Martinelli, F.; Palmieri A.; Petrini,
M. Phosphorus Sulfur and Silicon 2011, 186, 1032; c) Palmieri A.; Petrini, M. Org. Biomol. Chem. 2012, 10,
3486.
(3) a) Chen, D.; Yu, L.; Wang, P.G. Tetrahedron Lett. 1996, 37, 4467; b) Firouzabadi, H.; Iranpoor, N.; Jafarpour, M.;
Ghaderi, A. J. Mol. Catal. A 2006, 253, 249.
143
P20
Efficient synthesis of heterocycles by intramolecular
ruthenium-catalyzed hydroamination reactions
Gianluigi Broggini, Andrea Fasana, Silvia Gazzola
Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell’Insubria, via Valleggio 11, 22100 Como
andrea.fasana@uninsubria.it
The intramolecular direct formation of a new carbon-nitrogen bond by addition of a N-H group to
an unsaturated carbon-carbon bond, usually defined as hydroamination,1 is a well established route
for the synthesis of nitrogen-containing heterocycles. Cyclization of allenes with tethered amines
represents a valuable procedure for this purpose. Some alternative strategies based upon basic or
transition metal catalysis have been used for obtaining this goal.2 Ruthenium complexes are known
to be effective catalysts for the cyclization of allenes3 but only in rare cases intramolecular
ruthenium-catalyzed reactions have been reported in the literature. These procedures involve
cyclocarbonylations and domino reactions providing differently functionalized nitrogen-containing
heterocycles.4
Our recent studies towards hydroamination reactions,5 prompted us to investigate cyclizations of Nprotected amminoallenes in the presence of an inexpensive catalyst such as ruthenium trichloride in
combination with an additive for the synthesis heterocyclic products.
These investigations provided mild and efficient procedures for intramolecular hydroamination
reactions which involve selectively the internal double bond of the allene moiety, giving vinyl and
chloro-vinyl substituted heterocycles. Further investigations are in progress to have evidences on
the mechanism of the reaction.
(1) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795-3892.
(2) a) Ohno, H.; Kadoh, Y.; Nobutaka, F.; Tanaka, T. Org. Lett. 2006, 8, 947-950. b) Bates, R. W.; Satcharoen, V.
Chem. Soc. Rev. 2002, 31, 12-21.
(3) a) Trost, B. M.; Pinkerton, A. B. J. Am. Chem. Soc. 1999, 121, 10842-10843. b) Trost, B. M.; McClory, A Org.
Lett. 2008, 8, 3627-3629.
(4) a) Beccalli, E. M.; Bernasconi, A.; Borsini, E.; Broggini, G.; Rigamonti, M.; Zecchi, G. J. Org. Chem. 2010, 75,
6923. b) Manzo, A. M.; Perboni, A. D.; Broggini, G.; Rigamonti, M. Tetrahedron Lett. 2009, 50, 4696.
(5) a) Kang, S.-K.; Kim, K.-J.; Yu, C.-M.; Hwang, J.-W.; Do, Y.-K. Org. Lett. 2001, 3, 2851-2853. b) Trost, B.
M.; Pinkerton, A. B.; Kremzow, D. J. Am. Chem. Soc. 2000, 122, 12007-12008.
144
P21
Synthesis of dibenzylcarbonate: towards a green catalytic approach
Giulia Fiorani, Alvise Perosa and Maurizio Selva
Dipartimento di Scienze Molecolari e Nanosistemi, Università Ca' Foscari Venezia
Calle Larga S. Marta, 2137 - 30123 Venezia, Italy
giulia.fiorani@gmail.com
Sustainability has become a key parameter for the development and optimization of synthetic
protocols, where “Twelve Principles of Green Chemistry” are an established and useful toolbox.1,2
In this context, dialkyl carbonates [RO(CO)OR] emerged as a promising class of sustainable
compounds being: i) non toxic; ii) biodegradable; iii) polar aprotic molecules, not requiring the use
of additional solvents; iv) capable of generating reusable or innocuous byproducts (alcohols and
CO2); v) highly selective reagents, which can be activated through catalysis;3-5 vi) used in
replacement of hazardous compounds like alkyl halides, phosgene or chloroformates.6,7
The synthesis of dialkylcarbonates can be carried out by simple transesterification on lighter
homologues (such as dimethylcarbonate, DMC).8 For dibenzylcarbonate, the efficiency of this
protocol is somehow limited, requiring poorly selective and non-quantitative two-step processes.9-11
We describe a methodology for the straight forward synthesis of dibenzylcarbonate by
transesterification of DMC with benzyl alcohol using the homogeneous organocatalyst
methyltrioctylphosphonium methylcarbonate, [P8881][O(CO)OCH3],12,13 and a previously reported
heterogeneous catalyst, CsF supported on -Al2O3 (Scheme).14,15
Scheme. Synthesis of dibenzylcarbonate by catalyzed transesterification of DMC.
Reaction conditions were optimized in terms of time, temperature, benzyl alcohol/DMC ratio,
nature and catalysts’ quantity and selectivity towards the formation of the symmetric carbonate.
Green chemistry metrics for this protocol were evaluated and will be compared with the ones
derived for known literature procedures.16
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, 1998.
Tang, S. L. Y.; Smith, R. L.; Poliakoff, M. Green Chem. 2005, 7, 761-762.
Shaikh, A.-A. G.; Sivaram, S. Chem. Rev. 1996, 96, 951-976.
Tundo, P.; Selva, M. Acc. Chem. Res. 2002, 35, 706-716.
Selva, M. Pure Appl. Chem. 2007, 79, 1855-1867.
Parrish, J. P.; Salvatore, R. N.; Jung, K. W. Tetrahedron 2000, 56, 8207-8237.
Selva, M.; Perosa, A.; Fabris, M. Green Chem. 2008, 10, 1068-1077.
Peng, W.; Zhao, N.; Xiao, F.; Wei, W.; Sun, Y. Pure Appl. Chem. 2012, 84, 603-620.
Williams, J. L. R.; Reynolds, D. D.; Dunham, K. R.; Tinker, J. F. J. Org. Chem. 1959, 24, 64-68.
Selva, M.; Marques, C. A.; Tundo, P. J. Chem. Soc., Perkin Trans. 1 1995, 1889-1893.
Loris, A.; Perosa, A.; Selva, M.; Tundo, P. J. Org. Chem. 2004, 69, 3953-3956.
Fabris, M.; Lucchini, V.; Noè, M.; Perosa, A.; Selva, M. Chem. Eur. J. 2009, 15, 12273-12282.
Selva, M.; Perosa, A.; Noè, M.; Gottardo, M. Org. Biomol. Chem. 2012, doi:10.1039/C2OB25447F
Veldurthy, B.; Clacens, J.-M.; Figueras, F. J. Catal. 2005, 229, 237-242.
Veldurthy, B.; Clacens, J.-M.; Figueras, F. Eur. J. Org. Chem. 2005, 1972-1976.
Selva, M.; Perosa, A. Green Chem. 2008, 10, 457-464.
145
P22
Unravelling unidirectional threading of -cyclodextrin
in a [2]rotaxane through spin labelling approach
Costanza Casati, Paola Franchi, Roberta Manoni,* Elisabetta Mezzina, Marco Lucarini
Department of Organic Chemistry ‘A. Mangini’, Faculty of Pharmacy,
University of Bologna, Italy
roberta.manoni3@unibo.it
The possibility to control the extent of spin-spin communication in biradicals has been recently
attained through supramolecular complexation of nitroxide biradicals by cyclodextrins (CDs)1 or
cucurbiturils (CBs).2 Due to our interest in the construction of paramagnetic mechanically
interlocked molecules (MIMs), and in order to extend the investigation of supramolecular
architectures in controlling spin communication between two nearby radical centers, we report here
the synthesis of a diradical -cyclodextrin-based [2]rotaxane 3, in which both the -CD macrocycle
and the axle component of the assembly, bring 2,2,6,6-tetramethylpiperidin-N-oxyl (TEMPO) units.
By combining molecular dynamic calculations and information extracted from the ESR spectra we
were able to determine the geometrical nature of the isolated isomer.
(1) Mezzina, E.; Fani, M.; Ferroni, F.; Franchi, P.; Menna, M.; Lucarini, M. J. Org. Chem. 2006, 71, 3773-3777.
Ionita, G.; Meltzer, V.; Pincu, E.; Chechik, V. Org. Biomol. Chem. 2007, 5, 1910-1914. Ionita, G.; Chechik, V.
Chem. Commun. 2010, 46, 8255-8257.
(2) Mileo, E.; Casati, C.; Franchi, P.; Mezzina, E.; Lucarini, M. Org. Biomol. Chem. 2011, 9, 2920-2924. Yi, S.;
Captain, B.; Ottaviani, M. F.; Kaifer, A. Langmuir 2011, 27, 5624-5632. Porel, M.; Ottaviani, M. F.; Jockusch, S.;
Jayaraj, N.; Turro, N. J.; Ramamurthy, V. Chem. Commun. 2010, 46, 7736-7738.
146
P23
New uranyl-salen complexes for anion recognition:
a colorimetric assay#
S. Bartocci,1 F. Keymuelen,2 F. Yafteh Mihan,1 K. Bartik,2 A. Dalla Cort1
1
2
Dipartimento di Chimica, Università La Sapienza, Rome, Italy.
Université Libre de Bruxelles, Matière et Matèriaux, Bruxelles, Belgium.
silvia.bartocci@uiroma1.it
Lately anion recognition is a target of major importance for research. This is mainly due to the role
they play in several biological processes.1 A fundamental class of receptors able to detect anions are
salen-type complexes, 1. The corresponding salen ligands are characterized by a very easy synthetic
accessibility and they are able to coordinate a series of metal dications.
Uranyl salen complexes are strong Lewis acid that binds anions in organic solvents2 and, if properly
functionalized, also in water.3 The recognition event is easily detected by variations in the UV-Vis
and NMR spectra. Obviously it would be very practical if the association could be also correlated
with a color changes, visible by naked eye. The introduction of appropriate fluorophores in the
ligand backbone can in principle give raise to such phenomenon. To this purpose we have
synthesized receptor 2.
Preliminary binding studies show that color changes from purple to blue when fluoride anion is
added to the solution. The phenomenon is not observed with other halides. Here we report the
synthesis of 2 and the association studies with selected anions in different organic solvents.
R
N
R
NC
N
N
M
O
O
1
CN
N
UO2
O
O
2
(1) Kim S. K., Lee D. H., Hong J.-H., Yoon J. Acc. Chem. Res., 2009, 42, 23-31.
(2) Dalla Cort A., De Bernardin P., Forte G., Yafteh Mihan F. Chem. Soc. Rev., 2010, 39, 3863
(3) Dalla Cort A. Forte G., Schiaffino L. J. Org. Chem., 2011, 76, 7569
#
Work carried out within the frame of COST Action 1005
147
P24
Synthesis and biological evaluation of new dual agents
for MRI/BNCT applications
Antonio Toppino, Annamaria Deagostino, Simonetta Geninatti,
Diego Alberti, Paolo Venturello, and Silvio Aime.
Dipartimento di Chimica, Università degli Studi di Torino,
Via Pietro Giuria, 7, 10125, Torino, Italy.
antonio.toppino@unito.it
BNCT (Boron Neutron Capture Therapy) is a binary therapy for the treatment of cancer based on
the selective uptake of the stable 10B isotope by tumor cells, followed by irradiation with low energy
thermal neutrons. In order to be effective BNCT requires 15–30 μg of 10B per g of tumor, therefore,
in vivo visualization of 10B distribution is important.1 Thanks to its superb spatial resolution MRI
appears to be one of the most appropriate technique to tackle this task. In this work the synthesis
and the in vitro and in vivo biological evaluation of a panel of new dual agents for MRI/BNCT
applications is reported. Those agents are obtained starting form a versitile dicarbaclosododecaborane intermediate, which assures a high payload of 10B atoms and can be
functionalized with different biological vectors and different MRI probes. On one side the
carborane cage has been functionalized with lipophilic moieties, like palmityl chains2,3 (AT101) or
double-tailed moiety (AT102) or colesterol (AT103) in order to bind the carborane cage to the
nanosized vector represented by LDL or liposomes (the real biological vectors). On the other side
the carborane has been funtionalized with a Gd-DOTA complex, which allow the boron
concentration in cell by means of MRI detection to be quantified.
(1) R. F. Barth, Journal of Neuro-Oncology 2003, 62, 1.
(2) S. Aime, A. Barge, A. Crivello, A. Deagostino, R. Gobetto, C. Nervi, C. Prandi, A. Toppino, P. Venturello,
Organic & Biomolecular Chemistry 2008, 6, 4460.
(3) S. Geninatti-Crich, D. Alberti, I. Szabo, A. Deagostino, A. Toppino, A. Barge, F. Ballarini, S. Bortolussi, P.
Bruschi, N. Protti, S. Stella, S. Altieri, P. Venturello, S. Aime, Chemistry-a European Journal 2011, 17, 8479.
148
P25
Structure-based approach for the discovery of potent inhibitors
of the Hsp90 molecular chaperone bearing the triazole scaffold
Stefania Terracciano, Maria Strocchia, Maria Giovanna Chini, Ines Bruno,
Fabrizio Dal Piaz, Giuseppe Bifulco and Raffaele Riccio
Dipartimento di Scienze Farmaceutiche e Biomediche, Università degli Studi di Salerno,
Via Ponte Don Melillo, 84084, Fisciano (Salerno), Italy
mstrocchia@unisa.it
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that plays a key role in
the correct folding, stabilization and function of a wide number of cellular proteins.1 Hsp90 “client proteins” include over-expressed or mutant oncogenic proteins, most of which are involved in the
control of cell homeostasis, proliferation, differentiation and apoptosis2 and are associated with the
six hallmarks of cancer.3
Alterations in the signaling pathways of Hsp90 client proteins are involved in malignant
transformations:4 the inhibition of the Hsp90 protein folding machinery results thus in misfolded
clientf proteins and in the disruption of numerous oncogenic pathways, representing a valid strategy
in cancer therapy.5 Basing on these considerations we decided to undertake a project on the design,
synthesis and biological evaluation of potential inhibitors of Hsp90, bearing the triazole scaffold.
Virtual screening performed on a collection of triazole derivatives
allowed us to select the most promising compounds that have been
efficiently synthesised through “click chemistry” approaches;; their interaction with Hsp90 was evaluated through a Surface Plasmon
Resonance based binding assay. Among the molecules that showed
to efficiently interact with the immobilized target protein,
compound 1 turned out to be the most potent binder with a KD
value of 3.6 nM, almost comparable with that measured for
radicicol, a well known Hsp90 inhibitor. Further biological investigation on this new emerging hit
disclosed more details on his mode of interaction with the molecular chaperone and established that
triazole scaffold can be considered a molecular platform useful for the development of new efficient
Hsp90 inhibitors as promising anticancer drug candidates.
(1) LH Pearl, C Prodromou, Annu. Rev. Biochem. 2006, 75, 271-294. L Neckers, J. Biosci. 2007, 32, 517–530.
(2) M Taipale, DF Jarosz, S. Lindquist, Nat. Rev. Mol. Cell. Biol. 2010, 11, 515–28. H Zhang, F Burrows, J. Mol.
Med. 2004, 82, 488-499.
(3) D Hanahan, RA Weinberg, Cell 2000, 100, 57-70.
(4) MP Goetz, DO Toft, MM Ames, C Erlichman, Ann. Oncol. 2003, 14, 1169–1176.
(5) R Bagatell, L Whitesell, Mol. Cancer. Ther. 2004, 3, 1021-1030.
149
P26
Characterization of spiropyran modified liposomes.
Influence of the molecular switch on vesicles stability
Romina Zappacosta, Antonella Fontana
Dipartimento di Scienze del Farmaco, Università “G. d’Annunzio”,
Via dei Vestini 13, 66100 Chieti, Italy
r.zappacosta@unich.it
Photoresponsive membrane-based ion gating devices are particularly interesting because they
have numerous potential applications to optical sensors, information storage, energy conversion and
storage, and optoelectronics devices.1-3 In this work we describe the influence of the insertion of a
photochemical molecular switch on the characteristics of the phospholipid bilayer of liposomes
consisting of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocoline (POPC, diameter ~100 nm).
The molecular switch used belongs to the class of spiropyrans. Spiropyran consists of two ring
systems connected at a spiro carbon in a closed orthogonal fashion (SP). Upon irradiation by UVlight, the C-O bond in the pyran ring breaks resulting in the formation of an open planar molecule
that absorbs visible light (ME). The addition of an acid to this solution induces the formation of a
merocyanine protonated form (MEH).4 The photoinduced ring closing transforms MEH into the
initial SP with the concomitant release of a proton.5
The kinetic stability of the POPC extruded large unilamellar vesicles (LUV) was evaluated by
investigating the time-dependent leakage of the 5(6)-carboxyfluorescein anionic dyes from the
liposomes in the presence and in the absence of spiropyran guest.6
The viscosity and the micropolarity of the membrane have been measured fluorimetrically by
using pyrene as the probe.7
(1)
(2)
(3)
(4)
(5)
(6)
(7)
J.M. Lehn; Supramolecular Chemistry: Concepts and Perspectives; VCH: Weinheim, 1995.
R.W. Cattrall; Chemical Sensors; Oxford University Press: Oxford, 1997.
T. Ikeda, O. Tsutsumi; Science, 1995, 268, 1873-1874.
F. Raymo, S. Giordani; J. Am. Chem. Soc., 2001, 123, 4651–4652.
S. Giordani, M.A. Cejas, F. Raymo; Tetrahedron, 2004, 60, 10973-10981.
R. Zappacosta et al.; Small, 2010, 6, N°8, 952-959.
A.K. Soutar, H.J. Pownall, A.S. Hu, L.C. Smith, Biochemistry, 1974, 13, 2828-2836.
150
P27
Wrapping of lipophilic guanosine to single-walled carbon nanotubes
Antonello Di Crescenzo,1 Ilona Kopf,2 Silvia Pieraccini,3 Stefano Masiero,3
Elisa Del Canto,2 Gian Piero Spada,3 Silvia Giordani,2 Antonella Fontana1
1
2
Dipartimento di Farmacia, Università “G. d’Annunzio”, Chieti, Italy
School of Chemistry/CRANN, Trinity College Dublin, Dublin 2, Ireland
3
Dipartimento di Chimica Organica “A. Mangini”
Alma Mater Studiorum – Università di Bologna, Italy
fontana@unich.it
The tendency of lipophilic guanosines (LipoGs) to self-assemble in organic solvents into ribbonlike structures1 induced us to investigate their potential wrapping and thus their potential selectivity
towards single walled carbon nanotubes (SWCNTs) of elected diameter size or chirality. Indeed the
capacity to wrap around SWCNTs has already been demonstrated for long chains macromolecules
such as DNA,2 polymers or proteins.3 The novelty of the present ribbon-like dispersing agent is the
fact that the self-assembly is a H-bonded driven process from relatively small units. The possibility
to selectively disperse SWCNTs would be particularly important for their manageability and
applications in material science as well as in biomedical fields.
Different spectroscopic, photoluminescence and electron microscopy measurements highlighted the
capacity of the investigated LipoGs to exfoliate SWCNTs, whereas fluorescence and AFM
measurements demonstrated the adsorption and the wrapping of LipoGs onto SWCNT sidewalls,
respectively. We demonstrate4 that the ability of LipoGs to disperse SWCNTs depends on their Hbonded driven self-assembly while different super-organization of these supramolecular structures
control the homogeneity of the dispersion. Wrapping of SWCNTs by LipoGs was found to depend
on LipoG structure.
(1) Davis, J. T.; Spada, G. P. Chem. Soc. Rev. 2007, 36, 296-313.
(2) Tuncel, D. Nanoscale 2011, 3, 3545-3554.
(3) Zheng, M.; Jagota, A.; Strano, M. S.; Santos, A. P.; Barone, P.; Chou, S. G.; Diner, B. A.; Dresselhaus, M. S.;
Mclean, R. S.; Onoa, G. B.; Samsonidze, G. G.; Semke, E. D., Usrey, M.; Wallset, D. J. Science 2003, 302, 1545–
1548.
(4) Di Crescenzo, A.; Kopf, I.; Pieraccini, S.; Masiero, S.; Del Canto, E.; Spada, G. P.; Giordani, S.; Fontana, A.
Carbon 2012 (accepted).
151
P28
Synthesis and STM studies of thiophene functionalized guanosines
Lucia Gramigna,1 Stefano Masiero,1 Artur Ciesielski,2 Paolo Samorì,2 Gian Piero Spada.1
1
Dipartimento di Chimica Organica “A. Mangini”Alma Mater Studiorum - Università di Bologna
Via S.Giacomo, 11 – 40126 – Bologna
2
ISIS & International Center for Frontier Research in Chemistry, Université de Strasbourg,
8 allée Gaspard Monge, 67000 Strasbourg (France)
lucia.gramigna@unibo.it
The ability of functionalized guanosines to self-assemble into supramolecular structures allows the
preparation of complex architectures with a variety of potential technological applications, for
example the fabrication of electronic nanodevices. In particular our group1 synthesized a
terthiophene derivative (A) which can form H-bonded ribbonlike or quartet-based supramolecular
architectures in solution, depending on the conditions. Additional Scanning Tunneling Microscopy
studies at the solid-liquid interface demonstrated that A self-assembles into ordered monolayer thick
films on graphite, which could be used to control the position of the electrically active
oligothiophene moieties in 2D with a sub-nm precision (Fig 1).
Fig 1: Terthiophene derivative A and molecular model of two adjacent ribbons (each made from 8
molecules), fitting the unit cell parameters of the STM images.
The major problem that emerged from this study is that the functonalization of the ribose with a
single oligothiophene led to a remarkably high distance between adjacent oligothiophenes once the
molecules are adsorbed on a solid substrate, thus minimizing any electronic cross-talk. Such a
feature renders the system of modest interest for applications in organic electronics. To overcome
this problem, we synthetized different thiophene substitued guanosine derivatives (1a-d), as shown
in Fig. 2, for preliminary studies of self-assembly in solution and at the solid-liquid interface on
graphite using STM techniques.
Fig 2: New thiophene functionalized guanosines 1a-d
(1) G. P. Spada, S. Lena, S. Masiero, S. Pieraccini, M. Surin, P. Samorì, Adv. Mater. 2008, 20, 2433–2438
152
P29
Intramolecular Pd-catalysed hydro- and carboaminations
as a route to N-containing bicyclic systems
Egle M. Beccalli, Alice Bernasconi, Marta Meazza
DISFARM, Sezione di Chimica Generale e Organica "A. Marchesini",
Università degli Studi di Milano, via Venezian 21, 20133 Milano
alice.bernasconi@unimi.it
During the past decades, intramolecular Pd-catalysed reactions have became a versatile tool to
prepare carbo- and heterocycles endowed with different kind of properties.1 Among them, reactions
involving C-N bond formation on easily available substrates containing C-C multiple bonds
represent useful methodology to achieve nitrogenated cyclic structures.2 In particular, transition
metal-catalyzed cyclization of functionalized allenes is an interesting tool to prepare carbo- and
heterocycles endowed with highly substituted olefin groups,3 which can be useful intermediates for
natural and pharmaceutical product synthesis. Despite the few examples reported in the literature,4 a
successful Pd-catalysed method of hydroamination of allenes has been recently developed in our
laboratories following a convenient procedure using mild conditions under microwave irradiation.5
In the present work, we describe hydroamination and carboamination processes on allenyl ethers
and amines, converted into benzooxazolidines and benzoimidazoles bearing vinyl or styryl
moieties. Both carboamination and hydroamination pathways involve the attack of the nitrogen to
the inner carbon of a π-allyl-Pd(II) unity.
(1) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist, Pergamon,
New York, 2000
(2) a) Beccalli, E. M.; Broggini, G.; Fasana, A.; Rigamonti, M. J. Organomet. Chem. 2010, 696, 277, b) Kotov, V.;
Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007, 46, 1910 c) Beccalli, E. M., Broggini, G., Martinelli, M.,
Sottocornola, S. Chem. Rev. 2007, 107, 5318
(3) Krause, N.; Hashmi, A. S. K. Modern Allene Chemistry; Wiley-VCH: Weinheim, Germany, 2004
(4) a) Qiu, S.; Wei, Y.; Liu, G. Chem. Eur. J. 2009, 15, 2751. b) Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1998,
39, 5421
(5) Beccalli, E. M., Bernasconi, A., Borsini, E., Broggini, G. Rigamonti, M., Zecchi, G. J. Org. Chem, 2010, 75, 6923
153
P30
Lipophilic guanosine derivatives as carbon nanotube dispersing agents
Antonello Di Crescenzo,1,* Ilona Kopf,2 Silvia Pieraccini,3 Stefano Masiero,3
Elisa Del Canto,2 Gian Piero Spada,3 Silvia Giordani,2 Antonella Fontana1
1
Dipartimento di Scienze del Farmaco, Università “G. d’Annunzio”, Chieti, Italy
2
School of Chemistry/CRANN, Trinity College Dublin, Dublin 2, Ireland
3
Dipartimento di Chimica Organica “A. Mangini”,
Alma Mater Studiorum – Università di Bologna, Bologna, Italy
a.dicrescenzo@unich.it
The exfoliation and dispersion of carbon nanotubes (CNTs) is widely recognized as an important
step for their multiple applications. Non covalent functionalization is a useful approach to obtain the
individualization of CNTs preserving their structure and properties. Lipophilic guanosine
derivatives (LipoGs) have shown to exhibit a rich supramolecular chemistry in organic solution:
they are able to self-assemble into different structures based on ribbon-like or G-quartet motifs.1
Besides, guanosines have already been reported in the literature as good dispersing agents for
CNTs.2 The lipophilicity and the tendency to self-assemble make LipoGs suitable to interact with
CNTs in organic solution. In this context, we investigated the ability of two specific LipoGs which
differ for the presence of one or two decanoyl chains respectively, to act as CNT dispersing agents.
The study focused on the development of the best dispersion protocol, assessing the effect of
various solvents and different concentrations of the dispersants.
UV-vis-NIR spectrophotometry, Raman spectroscopy and NIR-photoluminescence measurements
as well as AFM and SEM highlighted a well debundling of CNTs (Fig.1).
The disaggregation has been demonstrated to depend on the tendency of LipoGs to generate ribbonlike supramolecular structures. Such super-organization appears to control also the homogeneity
and the stability of the CNT dispersions.3
Fig. 1 CNT dispersions in chloroform in the absence (A) and in the
presence of 10 mM GACE C10 (B), and of 10 mM dG(C10)2 (C).
(1) Lena, S.; Brancolini, G.; Gottarelli, G.; Mariani, P.; Masiero, S.; Venturini, A.; Palermo, V.; Pandoli, O.; Pieraccini,
S.; Samorì, P.; Spada, G. P. Chemistry – A European Journal 2007, 13, 3757-3764.
(2) McGown, L.; Nalamasu, O.; Yu, Y.; Nakamaura, D. Patent Int appl WO 2008;2008048352:A2.
(3) Di Crescenzo, A.; Kopf, I.; Pieraccini, S.; Masiero, S.; Del Canto, E.; Spada, G.P.; Giordani, S.; Fontana, A.
Carbon 2012 (accepted).
154
P31
Stereochemical determination of plakilactone G
by quantitative NMR-derived interproton distances combined with
quantum mechanical calculations of 13C chemical shifts
Simone Di Micco,1 Angela Zampella,2 Raffaele Riccio,1 Craig P. Butts,3 Giuseppe Bifulco.1
1
via Ponte don Melillo, 84084 Fisciano (SA), Italy.
2
via D. Montesano 49, 80131 Napoli, Italy.
3
Department of Chemistry, University of Bristol, Cantocks Close,
BS8 1TS Bristol, United Kingdom.
sdimicco@unisa.it
In recent years the quantum mechanical calculation of NMR parameters1,2 has been demonstrated to
be a valid tool for the stereostructural determination of organic compounds,3,4 especially for high
flexible systems. Recently, a further method has been proposed for relative configuration
assignment based on experimental inter-protons distances derived from a quantitative and accurate
NOEs analysis.5,6 Until recently, these quantitative measured NOEs have only been applied to
stereochemical assignments relatively to rigid molecular frameworks, as the NOE analysis is
complicated by multiconformers equilibria for flexible molecules.
We report the stereostructural investigation of the marine natural product plakilactone G, isolated
from the sponge Plakinastrella mamillaris Kirkpatrick, 1900 (Homoscleromorpha) collected at Fiji
Islands.
The structural studies have been carried out by a combination of the NOE-based protocol in parallel
with quantum mechanical calculation of 13C chemical shifts. In particular in the present contribution
we extended the application of NMR-derived interproton distances to a highly flexible molecular
system.
(1) Barone, G.; Gomez-Paloma, L.; Duca, D.; Silvestri, A.; Riccio, R.; Bifulco, G. Chem. Eur. J. 2002, 8, 3233−3239.
(2) Barone, G.; Duca, D.; Silvestri, A.; L. Gomez-Paloma, L.; Riccio, R.; Bifulco, G. Chem. Eur. J. 2002, 8,
3240−3245.
(3) Bifulco, G.; Dambruoso, P.; Gomez-Paloma, L.; Riccio, R. Chem. Rev. (Washington, DC, U. S.) 2007, 107,
3744−3779.
(4) Di Micco, S.; Chini, M. G.; Riccio, R.; Bifulco, G. Eur. J. Org. Chem. 2010, 8, 1411−1434.
(5) Chini, M.G.; Jones, C. R.; Zampella, A; D'Auria, M.V.; Renga, B; Fiorucci, S; Butts, C.P.; Bifulco, G. J. Org
Chem. 2012, 77, 1489-1496.
(6) Butts, C. P.; Jones, C. R.; Towers, E. C.; Flynn, J. L.; Appleby, L.; Barron ,N. J. Org. Biomol. Chem., 2011, 9,
177–184.
155
P32
Revisitation of (+)-usnic acid reactivity, an interesting natural β-triketone.#
Beatrice Trucchi, Laura Mesiano, Luisella Verotta
Department of Chemistry, University of Milan, Via Golgi 19, 20133, Milano (Italy).
beatrice.trucchi@unimi.it
One of the most investigated lichen substance is the secondary metabolite usnic acid, a yellow
cortical pigment easily isolated from Cladonia, Usnea or Romalina species where it occurs up to
26%.1 Usnic acid is a benzofurandione, phloroglucinol like2,3 which exists in two enantiomers,
depending on the stereochemistry of the methyl group at the stereogenic center. The absolute
configuration of (+)-usnic acid has been determined by X-ray analysis to be R, less toxic and more
active than the S isomer. In spite of its recognized and proved in vitro activities,1,2 usnic acid
potential has been so far underestimated due to its rapid metabolism, poor water solubility and in
vivo toxicity. On this basis, we have synthesized a small library of (+)-usnic acid derivatives to
improve its biological profile, and, with this purpose, we have investigated (+)-usnic acid reactivity,
prevalently at the β-triketone moiety.
Nucleophilic additions to the acylic methyl ketone at C-2 position easily led to hydrazones 1 or
stable enamines 2;4 intramolecular cyclizations gave stable heterocyclic systems, like 1,5benzodiazepines (3), or isoxazoles (4 and 5) and oxazocines (6).
Finally, the reactions with thiourea and urea, led, despite of the expected pyrimido derivatives, rapid
degradations to enaminousnic acid 7 and a thermal retro-electrocyclic rearrangement (8a,b).
O
O
HO
HO
O
O
O
O
OH
O
7
O
OH
HO
O
OH
OH
O
O
NH2
O
O
HO
+
OH
O
8a
OH
O
8b
Depending on the type of substituent, the synthesized products were tested on different targets and
showed remarkable biological properties.
(1)
(2)
(3)
(4)
#
Ingólfsdóttir, K. Phytochemistry 2002, 61, 729-736.
Cocchietto, M.; Skert, N.; Nimis, P.L.; Sava, G. Naturwissenschaften 2002, 89, 137-146.
Verotta, L. Phytochem. Rev. 2003, 1, 389-407.
Verotta L.; Monti D. Università degli Studi di Milano, PCT/EP2009/006960, WO2010/034512.
Work supported by University of Milan, PRIN 2008, Johns Hopkins University (Baltimore) (NIH grant n.
R01AI082587) with the post-doc fellowship to B.T.
156
P33
Solvent and ligand free Pd-catalyzed N-arylation of nitrogen nucleophile
using low catalyst loadings
Egle M. Beccalli,1 Elena Borsini,1 Gianluigi Broggini2
1
DISFARM– Sezione di Chimica Generale e Organica "A. Marchesini"
Università degli Studi di Milano, via Venezian 21,20133 Milano, Italy
2
Dipartimento di Scienza e Alta Tecnologia,
Università dell’Insubria, via Valleggio 11, 22100 Como, Italy.
elena.borsini@unimi.it
Palladium-catalyzed amination reaction is one of the most important tool to obtain C-N bond
formation.1 In our recent work2 we described a protocol for amination of indolines with aryl halides,
using low catalyst loadings, in the absence of solvent and under microwave heating. Solvent free
reaction conditions are a crucial point for sustainability in organic synthesis3 because it circumvents
the need for their supply, purification, and disposal. The combination of solvent-free reaction
conditions and microwave irradiation led to significantly reduced reaction times, enhanced
conversions, and offered several advantages for the coupling reaction. With the aim to pursue more
attractive protocols in both academic and industrial demains the ligandless conditions are of
particular interest.
In this communication we describe a new synthetic protocol for the amination of some different
nitrogen nucleophiles (aryl and heteroaryl substituted amines) with aryl bromides without the use of
solvent and phosphine ligand requiring only the 0,5% mol Pd-catalyst suspended in K2CO3.
X
R'
H
N
R + Ar Br
Pd catalyst
K2CO3
MW
X
R'
Ar
N
R
(1) a) Beccalli, E.M.; Broggini, G.; Fasana, A.; Rigamonti, M. J. Organomet. Chem. 2010, 696, 277-295. b) Kienle,
M.; Dubbaka, S.R.; Brade, K.; Knochel, P. Eur. J. Org. Chem. 2007, 4166-4176. c) Kotov, V.; Scarborough, C.C.;
Stahl, S.S. Inorg. Chem. 2007, 46, 1910-1923. d) Wolfe, J.P. Eur. J. Org. Chem. 2007, 571-582. e) Beccalli, E.M.;
Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318-5365.
(2) Basolo, L.; Bernasconi, A.; Borsini, E.; Broggini, G.; Beccalli, E.M. ChemSusChem 2011, 4, 1637-1642.
(3) a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, Oxford University Press, Oxford, 1998; b)
Winterton, N. Green Chem. 2001, 3, G73–G75; c) Anastas, P. T.; Zimmermann, J. B. Environ. Sci. Technol. 2003,
37, 94 A-101 A; d) Tang, S. L. Y.; Smith, R. L. S.; Poliakoff, M. Green Chem. 2005, 7, 761–762; e) P. Tundo, A.
Perosa, F. Zecchini, Methods and Reagents For Green Chemistry, John Wiley & Sons, Oxford, 2007
157
P34
Diastereodivergent synthesis of polyhydroxy-2,3-methanopipecolic acids
as conformationally constrained amino acid analogues
Andrea Casini,* Ernesto G. Occhiato, Dina Scarpi, Antonio Guarna
Dipartimento di Chimica “Ugo Shiff”, Università di Firenze,
Via della Lastruccia 13, 50019, Sesto Fiorentino, Italy
casini.and@gmail.com
Hydroxypipecolic acids and their derivatives play an important role in medicinal chemistry as
amino acid analogues for the synthesis of pharmaceutically active peptidomimetics.1 Amino acid
analogues containing a cyclopropane skeleton, including prolines and pipecolic acids, have attracted
much attention as the three-membered ring introduces severe constraints in the proximal backbone
torsion angles,2 possibly leading to profound changes in the peptide conformation and biological
activity. On these grounds, we focused our interest on the introduction of a cyclopropane ring in
polyhydroxy pipecolic acids.
Convenient methods for the diastereodivergent synthesis of cyclopropanated 4-hydroxypipecolic (1
Scheme 1) and 4,5-dihydroxypipecolic acid derivatives 2 with high optical purity is here reported.3,4
These compounds were obtained by stereoselective cyclopropanation of the double bond in
enantiopure 4-hydroxy- and 4,5-dihydroxytetrahydropyridine derivatives 3 and 4. Both enantiomers
of 3 were prepared by highly enantioselective lipase-catalyzed kinetic resolution of the racemic
compound, while 4 was synthesized from a commercially available sugar from the chiral pool.
Under the best conditions of yield and facial selectivity (> 99:1), cis-1 and cis-2 were obtained by
OH-directed cyclopropanation with Charette’s Zn-carbenoid.
Trans derivatives trans-1 and trans-2 were obtained via Michael-type addition of
dimethylsulfoxonium methylide to OH-protected precursors 3 and 4. The facial selectivity were 7:1
for trans-1 and 6:1 for trans-2. Diasteropure trans compounds were obtained by chromatography
after OH-deprotection.
OH
OH
HO
N
H
CO2Me
N
H
OH
N
H
N
R
CO2Me
trans-1
OH
cis-2
cis-1
OH
CO2Me
CO2Me
N
H
O
3
OH
N
CO2Me
Cbz
HO
N
H
R = CO2Me, Cbz
TBSO
CO2Me
4
trans-2
Scheme 1
(1)
(2)
(3)
(4)
Purkayastha, N.; Shendage, D. M.; Frölich, R.; G. Haufe.; J. Org. Chem. 2010, 75, 222
Hanessian, S.; Auzzas, L.; Acc. Chem. Res. 2008, 41, 1241
Occhiato, E. G.; Casini, A.; Guarna A.; Scarpi D.; Eur. J. Org. Chem. 2011, 6544
manuscript in preparation
* Partecipazione con borsa di studio offerta da Lundbeck.
158
P35
Copolyacrylates containing porphyrin units as pendant groups:
synthesis, characterization and their use as sensors.
Emilio Scamporrino,1 Placido Mineo,1 Fabiola Spitaleri,1 Sandro Dattilo,2
Emanuela Spina,2 Daniele Vitalini2
1
Dipartimento di Scienze Chimiche, Università di Catania;
Viale A. Doria, 6; 95125 Catania, Italy
2
Istituto per la Chimica e la Tecnologia dei Polimeri (ICTP-CNR);
Via Paolo Gaifami, 18; 95126 Catania, Italy
escamporrino@unict.it
Porphyrins are highly-conjugated organic molecules having useful properties for some functional
devices as photodiodes, catalysts, artificial solar energy conversion systems and, particularly, for
sensor devices.1,2
Obviously, their use as sensing of specific analytes (as acid vapours or NO2) requires a direct
contact, so that only chromophore units present on sensor surfaces are active. In previous works,3
good results were obtained assembling porphyrin monolayer on a quartz surface, but both materials
and synthetic procedure were expensive.
The present work regards the construction of an inexpensive sensor device obtained depositing a
thin layer of a MMA/porphyrin copolymer on PMMA plates, with the hope of reducing both the
amount of sensitive material and the cost
CH 3
of the support.
C
(CH2 )x (CH2 CH)1-x
By reaction between MMA and an
C
C
Acrylic comonomer, obtained by
O
O O
O
O (CH 2 CH 2 O) CH 3
condensation of a porphyrin derivative
3
CH 3
(having
three
triethylene
glycol
monomethyl ether branches and a freeN
hydroxyl group) and acryloil chloride,
H
N
N
copoly-porphyrin-acrylates of different
H
N
compositions were prepared.
Sensor devices were then assembled
stratifying very thin layers of these
O (CH2 CH2 O) CH3
CH 3 (O CH 2 CH 2) O
3
3
materials on transparent commercial
PMMA plates by immersion of these last
Copoly(porphyrinacrylate-methylmethacrylate)
in very diluted solutions of copolymers.
The efficiency of the devices was tested by exposition to trifluoroacetic and hydrochloric acid
vapours or NO2 gas. Under exposition, as expected, the Soret porphyrin band (at 424 nm) rapidly
and totally disappears (substituted, in both cases, by a new band at about 450 nm) to be quickly
recovered by treatment of the devices with ammonia or hot air, respectively.
(1) Senge, M. O.; Fazekas, M.; Notaras, E. G. A.; Blau, W. J.; Zawadzka, M.; Locos, O. B.; Ni Mhuircheartaigh, E.
M. Adv. Mater, 2007, 19, 2737-2774
(2) a) Monti, D.;; Nardis, S.;; Stefanelli, M.;; Paolesse, R.;; Di Natale, C.;; D’Amico, A. Journal of Sensors, 2009, Vol.
2009, Article ID 856053, doi:10.1155/2009/856053. b) McDonagh, C.; Burke, C. S.; MacCraith, B. D. Chem.
Rev., 2008, 108, 400-422.
(3) Gulino, A.; Mineo, P.; Scamporrino, E.; Vitalini, D.; Fragalà. I.; Chem. Mater. 2006, 18, 2404-2410.
159
P36
Graphene and ionic liquid nanocomposites
for the assembly of new electrochemical devices
V. Conte, F. Valentini, D. Roscioli, F. Possanza, M. Carbone, B. Floris, G. Palleschi
Università di Roma Tor Vergata, Dipartimento di Scienze e Tecnologie Chimiche,
via della Ricerca Scientifica 1, 00133 Roma
valeria.conte@uniroma2.it
Dispersions of graphene oxide (GO1) nanoribbons in ionic liquids, ILs (i.e. 1-butyl-3methylimidazolium chloride (bmimCl); 1-butylpyridinium chloride (bupyCl); 1-methyl-2,3dimethylimidazolium bromide (bdmimBr); 1-butyl-3-methylimidazolium bromide (bmimBr)) have
been used to assemble modified screen printed electrodes (SPEs). The graphene oxide/ionic liquid
dispersions have been morphologically and structurally characterized using X-ray photoelectron
spectroscopy (XPS), Fourier transform-infrared (FT-IR), high-resolution-transmission electron
microscopy (HR-TEM). The modified SPEs resulted very sensitive and specific towards several
interesting organic and inorganic targets. In all cases high peak currents were recorded for the
electro-active probes, together with significant potential shifts, especially in the detection of
catecholamines and NADH, compared with the bare SPE and the conventional electrodes, such as
glassy carbon (GC) and highly oriented pyrolitic graphite (HOPG). This opens the way to the
assembly of new sensors and biosensors.2 The enhanced performances observed are attributed to the
electrocatalytic effects related to the high electrode surface area, to oxygen-functional groups, able
to catalyze electron transfer processes, and to the disordering effect of the ILs. This latter is likely
related to the favorable π−π interactions with the ILs and the GO plane. When the hydrophobic ILs
were used, such as bis (trifluoromethanesulfonyl) imide of 1-butyl-3- methylimidazolium
(bmimNTf2), carbon paste based electrodes were used as alternative electrochemical devices, very
sensitive for the detection of biomolecules. In conclusion, the electrochemical techniques were also
able to synthesize graphene gels, covalently functionalized with ILs (e.g. (bmimBF4) and
(bmimCl)), selective towards the irreversible electrochemical oxidation of several different
carboxylic acids, having anti-oxidant properties.
-6
6,0x10
-6
I / [A]
3,0x10
0,0
-6
-3,0x10
-6
-6,0x10
-0,6
-0,4
-0,2
0,0
0,2
0,4
0,6
E / [V]
(a)
(b)
(c)
Figure 1. (a): SPE-based device; (b): Carbon Paste-based electrodes (CPEs); and (c): cyclic voltammograms of 1mM
of K3Fe(CN)6 recorded at () IL, () SPE, () IL/target elettroattivo, ( ) SPE/GN, () GN/target/IL.
(1) Cataldo, F.; Compagnini, G.; Patané, G.; Ursini, O.; Angelini,G.; Ribice, P. R.; Margaritondo, G.; Cricenti, A.;
Palleschi, G.; Valentini, F. Carbon 2010, 48(9), 2596–2602.
(2) Valentini, F.; Roscioli, D.; Carbone, M.; Conte, V.; Floris, B.; Palleschi, G.; Flammini, R.; Bauer, E. M.;
Nasillo,G.; and Caponetti, E. Anal. Chem. 2012, DOI: 10.1021/ac301285e.
160
P37
Methyl(trifluoromethyl)oxaziridines: new reagents in organic synthesis
Serena Perrone, Catia Granito, Francesca Rosato, Luigino Troisi
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento,
via Prov.le Lecce-Monteroni, 73100-Lecce, Italy.
serena.perrone@unisalento.it
Dioxiranes 1 and oxaziridines 2 are small heterocycles prepared by oxidation of ketones1 and
imines2 with peroxomonosulfate and meta-chloroperbenzoic acid, respectively.
Both heterocycles are important reagents involved in several reactions of organic synthesis.
Dioxiranes are widely used as oxidizing agents capable of oxidation of many substrates (alkanes,
alkenes, alcohols, ethers, etc.).3 Oxaziridines are used as sources of both electrophilic oxygen and
nitrogen for a wide variety of nucleophiles; in addition, a large variety of heterocycles can be
synthesized by cycloaddition reactions of oxaziridines with alkenes, alkynes and nitriles.4
However, it is known that methyl(trifluoromethyl)dioxirane (TFDO) is an oxidizing agent more
effective than dimethyldioxirane (DDO). The substitution of a methyl- with a trifluoromethylgroup results in a higher electrophilicity of the TFDO.
The introduction of trifluoromethyl group on the oxaziridine ring could lead to similar results: a) the
reactivity as oxidizing or aminating agents could be increased; b) a large variety of new fivemembered heterocycles could be prepared via cycloaddition reactions.
For this reason several novel methyl(trifluoromethyl)oxaziridines were synthesized and their
reactivity, under investigation, will be reported.
R
O
N
CF3
HSO5-
O O
CF3
m-CPBA
O N
CF3
1
R
CF3
2
(1) Murray, R. W.; Singh, M.; Jeyaraman, R. J. Am. Chem. Soc. 1992, 114 (4), 1346-1351; Mello, R.; GonzálezNúñez, M. E.; Asensio, G. ChemInform 2007, 38 (19).
(2) Emmons, W. D. J. Am. Chem. Soc. 1956, 78, 6208-6209; Widmer, J.; Keller- Schierlein, W. Helv. Chim. Acta
1974, 57, 657-664.
(3) Annese, C.;; D’Accolti, L.;; Dinoi, A.;; Fusco, C.;; Gandolfi, R. and Curci, R. J. Am. Chem. Soc. 2008, 130, 11971204.
(4) Fabio, M.; Ronzini, L.; Troisi L. Tetrahedron 2007, 63 (52), 12896-12902.
161
P38
Synthesis of fluorinated vicinal diamines as precursors of peptidomimetics
Stefania Fioravanti, Alessia Pelagalli, Lucio Pellacani, Maria Cecilia Vergari
Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”
lucio.pellacani@uniroma1.it
The synthesis of fluorinated nitrogenated compounds is a goal of relevant significance considering
that these kind of molecules are interesting synthetic targets widely used in different fields, i.e.
organic, bioorganic, pharmaceutical, and medicinal chemistry.1
Special interest is being directed towards obtainment of trifluoromethyl nitrogenated molecules and
in this context the synthesis of new trifluoromethyl vicinal diamines 2 is here presented (Scheme 1).
MeNO2,
ZrCl4 (50%M)
R
N
CF3
r.t., 3h,
solvent-free
H
N *
R
NO2
CF3
1
HCO2-NH4+,
Pd/C (10%)
1.5h
H
N *
R
NH2
CF3
2
Scheme 1
Compounds 1 were obtained through a new ZrCl4-catalyzed aza-Henry reaction starting from
trifluoromethyl imines and nitromethane. The selective reduction2 of the corresponding β-nitro αtrifluoromethyl amines 1 was performed under strict anhydrous conditions and inert atmosphere, in
the presence of 10% Pd/C as catalyst and ammonium formate as reducing agent.
Starting from a benzylamine derivative, we succeeded in preparing new peptidomimetics
characterized by the presence of a CHCF3 group, known as C=O isoster. In fact, a first peptide bond
has been introduced by a DCC coupling reaction3 between a suitable N-protected L-α-amino acid
and a mono-N-benzyl α-trifluoromethyl β-diamine. Then, the hydrogenolysis of the benzylic
residue4 allowed to obtain a primary amino function as a new site for further possible molecular
growth (Scheme 2).
O
H
N
NH2
H2N *
CF3
CF3
N
H
H
* N
R
O
O
Scheme 2
(1) a) Yamazaki, T.;; Taguchi, T.;; Ojima, I. “Fluorine in Medicinal Chemistry and Chemical Biology”, Ojima, I., Ed., John Wiley & Sons, Ltd: Chichester, UK, 2009; pp 3-46. b) Kukhar, V. P.; Sorochinsky, A. E.; Soloshonok, V. A.
Future Med. Chem. 2009, 1, 793-819. c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev.
2008, 37, 320-330. d) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305-321.
(2) a) Chi, Y.; Guo, L.; Kopf, N. A.; Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 5608-5609. b) Pitts, R. M.;
Harrison, R. J.; Moody, J. C. J. Chem. Soc., Perkin Trans. 1 2001, 955-977.
(3) a) Fioravanti, S.; Gasbarri, S.; Morreale, A.; Pellacani, L.; Ramadori, F.; Tardella, P. A. Amino Acids 2010, 39,
461-470. b) Fioravanti, S.; Morreale, A.; Pellacani, L.; Ramadori, F.; Tardella, P. A. Synlett 2007, 2759-2761.
(4)
Grishina, G. V.; Luk’yanenko, E. R.;; Borisenko, A. A. Russ. J. Org. Chem. 2005,
162
P39
Synthesis of fast water exchange GdIII complexes for the development
of macromolecular and nanosized MRI Contrast Agents
Luca Gaino, Lorenzo Tei, Giuseppe Gugliotta, Mauro Botta
Dipartimento di Scienze ed Innovazione Tecnologica, Università degli Studi del Piemonte Orientale
”Amedeo Avogadro”, Viale T. Michel 11, 15121 Alessandria, Italy
(luca.gaino@mfn.unipmn.it)
Many bifunctional chelating agents (BFCA) for the conjugation of Magnetic Resonance Imaging
(MRI) contrast agents to biomolecules are based on DOTA monoamide derivatives as they are
relatively easy to synthesise and they form neutral and thermodynamically and kinetically stable
complexes with Gd3+ ions.1 However, the low water exchange rate (kex) values in these monoamide
derivatives represents a serious limiting factor for the relaxivity of their conjugates to
macromolecular scaffolds. We have recently demonstrated that increasing the length of the
carboxyamide arm from acetic to propionic (DOTAMAP) accelerates kex by nearly two orders of
magnitude; the 1H relaxivity of the corresponding macromolecular derivatives was remarkably
enhanced in the case of aggregated micellar systems.2
In order to increase the sensitivity of the MRI technique, various macromolecular or nanosized
systems such as liposomes, dendrimers, inorganic nanoparticles with Gd(III) chelates attached have
been developed.3 We herein report on the synthesis of a 3-amino-3,7-dideoxycholic acid derivative
of DOTAMAP (Figure) and the relaxometric study of its Gd(III) complex and of its adduct with
Human Serum Albumin (HSA). In fact, several liver-specific Gd-based contrast agents in which a
bile acid conjugated to a Gd-DOTA or DTPA derivative have been reported demonstrating their
ability to target the hepatocytes and to bind HSA or lipoproteins.4 At the same time, the formation
of liposomes with the incorporation of the C18 alkyl chain derivative of GdDOTAMAP (Figure) in
the lipidic bilayer and their 1H relaxometric behavior have been studied. In both cases, the optimal
kex value of GdDOTAMAP results in very high relaxivity values of the macromolecular and
nanosized probes useful for future MRI applications.
OH
O
HOOC
HOOC
N
N
N
N
N
H
H
N
O
COOH
DOTAMAP-cholic acid
COOH
O
H
OH
HOOC
HOOC
N
N
N
N
N
H
H
N
O
16
COOH
DOTAMAP-En-C18
(1) a) A. Barge, G. Cravotto, G. B. Giovenzana, L. Lattuada, L. Tei, Chem. Soc. Rev. 2011, 40, 3019–3049; b) A.
Barge, L. Tei, D. Upadhyaya, F. Fedeli, L. Beltrami, R. Stefania, S. Aime and G. Cravotto, Org. Biomol. Chem.,
2008, 6, 1176-1184.
(2) L. Tei, G. Gugliotta, Z. Baranyai, M. Botta, Dalton Trans. 2009, 9712–9714.
(3) M. Botta, L. Tei, Eur. J. Inorg. Chem., 2012, 1945-1960.
(4) P. L. Anelli, L. Lattuada, V. Lorusso, G. Lux, A. Morisetti, P. Morosini, M. Serleti, F. Uggeri, J. Med. Chem.
2004, 47, 3629-3641.
163
P40
A novel strategy for quinone methide generation:
the photo-induced electron transfer approach
Claudia Percivalle,1 Filippo Doria,1 Marco Di Antonio2 and Mauro Freccero1
1
Dipartimento di Chimica , Università di Pavia , V.l e Taramelli 10, 27100 Pavia , Italy
2
Dipartimento di Scienze Farmaceutiche, Università di Padova,
Via Marzolo 5, 35131 Padova, Italy
claudia.percivalle01@ateneopv.it
Quinone methides (QMs) are electrophilic transient species which can be generated from stable
precursors (QMPs) such as o,p-hydroxybenzyl derivatives. The formation of these masked Michael
acceptors have shown a strong dependence on (i) the leaving group attached at the benzylic position
of their precursor (QMP) and on (ii) the electronic nature of the aromatic ring (electronwithdrawing and electron-donating groups).1 Several mild generation protocol have been developed
ranging from mild thermal digestion2, photoactivation by ESIPT3,4, and monoelectronic
reduction5. In the present work we describe the synthesis and the unexpected photochemical
reactivity of a new class of water-soluble 1,8-naphthalimide derivatives (NIs) bearing two different
QMPs at the imide moiety (1,2 in Scheme). Reactivity in aqueous and neat acetonitrile has been
extensively investigated by laser flash photolysis (LFP) at 355 nm, as well as by steady-state
preparative irradiation at 310 nm in the presence of water, amines, thiols, and ethyl vinyl ether. The
photogeneration of the transient QM was rationalized through a Photo-Induced Electron transfer
(PET) mechanism from the phenolic precursors to the NI core, by a laser flash photolysis (LFP)
investigation. Briefly, after irradiation of the NI moiety (λ > 300nm), a PET mechanism involving
the NI triplet excited state (λmax 470 nm) of the NI core and the tethered quinone methide
precursor (QMP) generated a radical ions pair NI-• (λmax 410 nm) and a QMP•+. The latter underwent fast deprotonation in water to generate a detectable phenoxyl radical (λmax 390 and 700
nm), which was efficiently reduced by the radical anion NI•-, generating a detectable QM. Such
reactivity represents the first case of photo-activation of QMs via PET involving a tethered
peripheral moiety.
(1) Weinert, E.E.; Dondi, R.; Colloredo-Melz, S.; Frankenfield, K.N.; Mitchell, C.H.; Freccero, M; Rokita, S.E. J Am
Chem Soc. 2006, 128, 11940-11947
(2) Di Antonio, M.; Doria, F.; Richter, S. N.; Bertipaglia, C.; Mella, M.; Sissi, C.; Palumbo, M.; Freccero, M. J. Am.
Chem. Soc. 2009, 131, 13132-13141.
(3) Verga, D.; Nadai, M.; Doria, F.; Percivalle, C.; Di Antonio, M.;Palumbo, M.; Richter, S. N.; Freccero, M. J. Am.
Chem. Soc. 2010, 132, 14625-14637.
(4) Doria, F.; Percivalle, C.; Freccero, M. J. Org. Chem. 2012, 77, 3615-3619.
(5) Di Antonio, M.; Doria, F.; Mella, M.; Merli, D.; Profumo, A.; Freccero, M. J. Org. Chem. 2007, 72, 8354-8360.
164
P41
Configurational stability of chiral
N-(4-acetyl-6- or 7-alkyl-1-thia-3,4-diazaspiro[4.5]dec-2-en-2-yl)acetamides:
the role of the alkyl substituent on the cyclohexyl fragment
S. Menta,1 D. Secci,2 S. Carradori,2 R. Ferretti,1 C. Faggi,3 M. Pierini2 and R. Cirilli1
1
Istituto Superiore di Sanità, Dipartimento del Farmaco,
Viale Regina Elena 299, 00161 Rome, Italy
2
Dipartimento di Chimica e Tecnologie del Farmaco,
Università “La Sapienza” di Roma, P.le A. Moro 5, 00185 Rome, Italy
3
Università degli studi di Firenze, Dipartimento di Chimica Organica,
Sesto Fiorentino, Florence, Italy
rcirilli@iss.it
The spiro structures are constituted by two rings having in common one atom of carbon with sp3
hybridization. Due to the tetrahedral nature of the junction carbon atom, the planes of the two rings
are not coplanar but twisted almost perpendicularly to each other. This particular arrangement,
sterically bound, markedly characterizes the biological activity of many synthetic and natural
substances. Among novel biologically active compounds, spiro compounds containing a
heterocyclic ring have showed interesting in vitro antitumor activity.
Starting from this premise, some of us have developed a series of chiral spiro-compounds
O
containing the 1,3,4-thiadiazoline nucleus joined, by spiro junction,
to a cyclohexyl fragment mono-alkyl substituted either in the 6- or
N
R = 6-Me (1)
the 7-position (Compounds 1-3, Figure 1). The enantiomers and
N
6-t-Bu (2)
diastereomers of 1-3 were simultaneously separated by HPLC on a
S
7-Me (3)
NH
polysaccharide-based chiral stationary phase under normal phase
R
conditions. The stereoisomers isolated on semipreparative scale were
O
subjected to classical batch wise kinetic determinations in various
solvents and over the temperature range 55-95°C. The kinetic study
Figure 1. Structure of 1-3.
has highlighted as: i) the stereoisomers of the compounds 1-3, under
certain experimental conditions, undergo diastereomerization
without concomitant racemization, a phenomenon due to the
inversion of the chirality of the spirocenter, without any
involvement of the asymmetric carbon atom of the cyclohexyl
fragment; ii) the rate of the diastereomerization process depends
on the nature of the substituent of the cyclohexyl fragment and
its position with respect to the spirocenter, and also on the
nature of solvent and temperature; iii) the half-lives of the
reaction (less stable diastereoisomer)→(more stable Figure 2. Crystal structure of (6R,7S)-(+)-2.
diastereoisomer) were about 200-300 lower than those of the backward reaction. Structural studies
by theoretical calculations and X-ray diffraction analysis suggest that the lower stability of one
component of the diastereomeric pair could be due to the anomalous arrangement of the alkyl group
in the strained axial position of the chair conformation, which also occurs in the case of a
substituent sterically very demanding as the t-butyl group (Figure 2).
165
P42
A biophotonic approach for DNA detection:
PNA-modified photonic crystal fibers combined with
oligonucleotide-functionalized gold nanoparticles (ON-AuNPs)
Alessandro Bertucci,1 Alex Manicardi,1 Emanuela Cavatorta,1 Alessandro Candiani,2
Michele Sozzi,2 Annamaria Cucinotta,2 Stefano Selleri,2 Roberto Corradini1
1
Parco Area delle Scienze 17/A, 43124, Parma, Italy;
2
Dipartimento di Ingegneria dell’Informazione, Università di Parma,
Parco Area delle Scienze 181/A, 43124, Parma, Italy
alessandro.bertucci@nemo.unipr.it
Biophotonics represents a very attractive and promising field of interest integrating ICTs with
biological systems and bioprobes. Hybrid optical fibers bearing specific probes for DNA detection
are advanced tools in which the sensing element can be integrated in a microfluidic device for the
generation of optical signals. Label-free DNA detection can be achieved using this strategy and,
with signal amplification tools, potentially PCR-free detection can be performed.1 Photonic crystal
fibers (PCFs) have the unique feature of presenting a cross-section defined by air-hole arrays
running throughout the fiber, allowing to perform internal functionalization.2 Peptide nucleic acid
(PNA) is an oligonucleotide (ON) mimic that, due to its exceptional properties in DNA
hybridization and its high chemical and biological stability, is well suited for specific DNA target
sequences detection.3-5 In this work, the feasibility of a novel specific DNA sensing system, based
on the use of photonic crystal fibers combined with very specific PNA probes is described. The
inner surface of a grapefruit geometry microstructured optical fiber (MOF) was modified using an
in-house built apparatus. The hybrid sensing element was tested for optical DNA biosensing:
changes in the refractive index were monitored by shift of the reflection band of the Bragg grating
fiber itself.2,5 ON-functionalized AuNPs were used for signal amplification. Thus, the target DNA,
once captured on the functionalized fiber surface, was hybridized with the ON-AuNPs to form a
sandwich-like system. A systematic study on the behaviour of this sensing system using targets of
relevance in biomedical and food-analysis will be presented.
a)
b)
Fig.1: a) scheme of the linkage of the PNA probe to the fiber internal surface; b) scheme of the sandwich-like system
used for DNA detection.
(1) Bertucci, A.; Manicardi, A.; Corradini, R. Advanced Molecular Probes for Sequence-Specific DNA Recognition,
in: Detection of non-amplified Genomic DNA, Spoto, G.; Corradini, R. Eds. Springer, Dordrecht, The Netherlands
2012.
(2) Corradini, R.; Selleri, S. Photonic Crystal Fiber for Physical, Chemical and Biological Sensing 2010, 80-84 in
“Photonic Cystal Fibers for Physical, Chemical and Biological Sensing” Prisco, M.;; Cutolo, A.;; Cusano, A. Eds. Bentham Publisher, in press
(3) Coscelli, E.; Sozzi, M.; Poli F., Passaro, D.; Cucinotta, A.; Selleri, S.; Corradini, R.; Marchelli, R. IEEE
J.Sel.Top.Quant. 2010, 16, 967-962.
(4) D’Agata, R.;; Corradini, R.; Ferretti, C.; Zanoli, L.; Gatti, M.; Marchelli, R.; Spoto, G. Biosens. Bioelectron. 2010,
25, 2095–2100.
(5) Candiani, A.; Sozzi, M.; Cucinotta, A.; Selleri, S.; Veneziano, R.; Corradini, R.; Marchelli, R.; Childs, P.;
Pissadakis, S. IEEE J.Sel.Top.Quant. 2012, 18, 1176-1183.
166
P43
An uncommon aldehyde-enamine condensation.
Synthesis and antiproliferative activity of
new berberine-derived (hetero)aryl amides#
G. Fiorillo,1 F. Buzzetti,1 L.M. Guamán Ortiz,2,3 F. Orzi,1 M. Parks,2 M. Tillhon,2
A.I. Scovassi,2 and P. Lombardi1
1
Naxospharma srl, via G. Di Vittorio 70, 20026 Novate Milanese, Italy;
2
IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy;
3
UTPL, Loja, Ecuador.
staff@naxospharma.eu
Berberine (I), an isoquinoline plant quaternary alkaloid (or a 5,6-dihydrodibenzo [a,g]quinolizinium
salt derivative), possesses a variety of diverse biological and pharmacological properties. The
alkaloid has a definite potential as drug in a wide spectrum of clinical applications as come out of
scientific and patent literature and 10 ongoing clinical trials (www.clinicaltrials.gov). Anticancer
properties of berberine have been studied.1 Berberine represents a biologically important skeleton
and an attractive natural lead compound for the introduction of chemical modifications to search for
selective medical indications. Esters and amides of 13-carboxymethylberberine (II) are of interest.
These classes of compounds have been prepared starting from a 13-ethoxycarbonylmethyl precursor
(IIa) obtained by the reaction of ethyl bromoacetate with either i) the enamine 7,8-dihydroberberine
(III), followed by reduction of the resulting unstable iminium intermediate to the corresponding
7,8,13,13a-tetrahydro derivative, and final halogen oxidation; or ii) the enamines 8acetonyldihydroberberine (IIIa) or 8-allyldihydroberberine (IIIb), followed by thermal elimination
of the 8-groups to regenerate the quinolizinium salt.2,3 We will report the unprecedented direct
preparation of 13-carboxymethylberberine (II) by the simple condensation reaction of the enamine
(III) with glyoxylic acid OCHCOOH, and the antiproliferative effects of some new (hetero)aryl
amides (IIb’s) on human colon carcinoma HCT116 and SW613-B3 cell lines, which are normally
refractory to chemotherapy (e.g. etoposide treatment).
-
O
+
7N
O
13
Cl
O
8
O
-
+
O
X
N
OCH3
O
N
OCH3
OCH3
COR
I
OCH3
Berberine chloride
II:
R = - OH
IIa:
R = - OEt
OCH3
OCH3
IIb's: R = (hetero)aryl-NH-
R'
III:
R' = H
IIIa:
R' = -CH2COCH3
IIIb:
R' = -CH-CH=CH2
(1) Sun, Y., Xun, K., Wang, Y., & Chen, X., Systematic review of the anticancer properties of berberine, a natural
product from Chinese herbs, Anti-Cancer Drugs, 2009, 20, 757-769
(2) Samosorn, S., Development of berberine-based derivatives as novel antimicrobial agents, 2005 University of
Wollongong Thesis Collection.
(3) Brenner, J.B. & Samorson, S., 8-allyldihydroberberine as an alternative precursor for the synthesis of 13substituted berberine derivatives, Aust. J. Chem., 2003, 56, 871-873.
#
Research supported by Regione Lombardia, Italy (Bando ATP2009, Project: Plant Cell, grant No. 13810040 to
Naxospharma srl and IGM-CNR).
167
P44
Binding properties of polyaminocyclodextrin materials
towards polyanions and p-nitroaniline derivatives
Paolo Lo Meo, Daniele La Corte, Marco Russo, Francesca D’Anna,
Michelangelo Gruttadauria, Serena Riela, Renato Noto.
Dip. STEMBIO, sez. di Chimica Organica”E. Paternò” – Università degli Studi di Palermo
V.le delle Scienze pad. 17; 90128 - PALERMO.
paolo.lomeo@unipa.it
Polyaminocyclodextrin materials CD1-CD5 (figure 1) have been obtained by reacting the heptakis(6-deoxy)-(6-iodo)--cyclodextrin with different polyamines.1 The reaction afforded complex
mixtures of not separable compounds, partly hydroiodides, having a different degree of substitution.
Nevertheless, these mixtures were fully characterized by means of ESI-MS, NMR and
potentiometric techniques. Our materials are found to be analitically equivalent to a mixture of four
independent weak bases.
(figure 1)
In view of their possible application as economically appealing polycationic ligands for cell
transfection of polynucleotides,2 able to exploit at the same time the drug carrier abilities of the
cyclodextrin cavity, the binding properties of our materials towards sodium alginate and some
suitable p-nitroaniline derivatives3 1-5 (figure 2) were evaluated by means of polarimetry,4 at
different pH values both in the presence or absence of a supporting electrolyte. In particular,
alginate (chosen as a model polyanion) afforded in the presence of polycationic CD1-CD5 jelly-like
insoluble aggregates. The polarimetric technique allowed us to evaluate the composition of the
aggregates obtained.
(figure 2)
(1)
(2)
(3)
(4)
Lo Meo, P.; D’Anna, F.; Gruttadauria, M.; Riela, S.; Noto, R. Carbohyd. Res. 2012, 347, 32-39.
Ortiz Mellet, C.; Benito, J. M.; García Fernández, J. M. Chem Eur. J. 2010, 16, 6728-6742.
Lo Meo, P.;; D’Anna, F.;; Gruttadauria, M.;; Riela, S.;; Noto, R. Tetrahedron 2004, 60, 9099-9111.
Lo Meo, P.;; D’Anna, F.;; Riela, S.;; Gruttadauria, M.;; Noto, R. Tetrahedron 2007, 63, 9163-9171.
168
P45
Anion and ionic liquid effects on ionogel phases formation
Francesca D’Anna, Carla Rizzo, Salvatore Marullo, Paola Vitale, Renato Noto
Dipartimento STEMBIO-Sezione di Chimica Organica “E. Paternò”
Università degli Studi di Palermo, Viale delle Scienze-Parco d’Orleans II, 90128 Palermo
francesca.danna@unipa.it
Geminal organic salts have been recently introduced as the third generation of ionic liquids. 1 Like
their monocationic precursors they generally show high thermal stability and low corrosiveness, as
well as high polarity and structural order degree.2 All these features make them good candidates to
be used in the formation of conductive gel phases, that afterwards may find application as organized
reaction media or in the preparation of dye sensitized solar cells.3
In this context, we have recently synthesized some task specific geminal organic salts and
investigated their behaviour as gelators.
N
N
X2
2X
N
N
N
N C 8 H17
C 8H 17
N
2X
X2
N
C 8H 17
N
C 8H 17
X = Br, [1,5-NDS], [2,6-NDS], [2,6-NDC]
The obtained salts were able to gel ionic liquid solutions. In order to have information about the
opacity and the size of the aggregates characterizing the gel phases, UV-vis, resonance light
scattering and SEM measurements were carried out. The whole of collected data shed light on the
role played by the different nature of the anion in the ionogels formation and the relationship
between the ionogelator and the ionic liquid structure.
(1) Anderson, J. L.; Ding, R.; Ellern, A.; Armstrong, D. W. J. Am. Chem. Soc. 2005, 127, 593-604.
(2) a) D’Anna, F.;; Ferrante, F.;; Noto, R. Chem. Eur. J. 2009, 15, 13059-13068; b) D’Anna, F.;; Marullo, S.;; Vitale, P.;; Noto, R. Eur. J. Org. Chem. 2011, 5681-5689.
(3) Kim, J. Y.; Kim, T. H.; Kim, D. Y.; Park, N.-G.; Ahn, K.-D. J. Power Sources 2008, 175, 692-697.
169
P46
Microwave-assisted functionalization of halloysite nanotube surface
Marina Massaro,1 Serena Riela,1 Giuseppe Cavallaro,2 Michelangelo Gruttadauria,1
Giuseppe Lazzara,2 Stefania Milioto,2 Renato Noto1
1
Dipartimento STEMBIO, Sezione di Chimica Organica “E. Paternò”,
Università degli Studi di Palermo, Viale delle Scienze - Parco d’Orleans II, Ed. 17,
90128 Palermo (Italy).
2
Dipartimento di Chimica “S. Cannizzaro”, Università degli Studi di Palermo,
Viale delle Scienze-Parco d’Orleans II, Ed. 17, 90128 Palermo (Italy)
serena.riela@unipa.it
Halloysite, Al2Si2O5·2H2O, is a naturally occurring two-layered alluminosilicate, chemically similar
to kaolin, which has a predominantly high-aspect-ratio hollow tubular structure in the
submicrometer range and an internal diameter in the nanometer range.1 The size of halloysite
nanotubes (HNTs), generally varies from 50 to 70 nm in external diameter, ca. 15 nm diameter
lumen, and 0.5 to 1 μm in length. Halloysite tubes have aluminol (Al-OH) groups on the internal
surface and siloxan groups (Si-O-Si) on the external surface.2
The very large diameter of the halloysite lumen makes it potentially suitable for the accommodation
of a range of guests. In recent reports, for example, the mesoporous lumen of HNTs was used as a
nanoreactor to host reactants for nanosynthesis and biomimetic synthesis.3,4
Application of halloysite is severely limited by its hydrophilic internal and external surfaces.
In order to improve the dispersion of HNTs in polymer matrix and synthesize great promise organic
composites, a surface modification of halloysite is required. In this work we have developed a new
synthetic method, that consists in the grafting of organosilanes on the external surface by
microwave irradiation. The f-HNTs can be employed as polymer filler and they can be subjected to
further chemical modification by organic molecules such as ionic liquids.
(1) Guimaraes, L.; Enyashin, A. N.; Seifert, G.; Duarte, H. A. J Phys Chem C 2010, 114, 11358-11363.
(2) a) Hendricks, S. B. Am. Mineral. 1938, 23, 295−301; b) Bates, T. F.; Hildebrand, F. A.; Swineford, A. Am.
Mineral. 1950, 35, 463−484.
(3) Liu, G. Y.; Kang, F. Y.; Li, B. H.; Huang, Z. H.; Chuan, X. Y. J. Phys. Chem. Solids 2006, 67, 1186-1189.
(4) Shchukin, D. G.; Sukhorukov, G. B.; Price, R. R.; Lvov, Y. M. Small 2005, 1, 510-513.
170
P47
Photochemistry of drugs: from phototoxicity to photoactivation
Valentina Dichiarante, Luca Pretali, Elisa Fasani, Angelo Albini
Department of Chemistry, University of Pavia, v. Taramelli, 10 – 27100 Pavia, Italy
elisa.fasani@unipv.it
Many examples of drugs that undergo some reaction upon exposure to UV, but often also visible,
light have been reported in the literature over the last three decades. This fostered investigations
aimed at identifying the products formed and the mechanism involved in such reactions.
Furthermore, an increasing number of photosensitization cases resulting from the use of largely
prescribed drugs were reported and encouraged the study of the biological mechanism underlying
the observed effect. Clearly, a detailed knowledge of the chemistry occurring under irradiation in
vivo and of the biological chain of the events that leads to the observed clinically phototoxic effect
are required for an effective rationalization and for establishing a structure-effect correlation. In this
way, safe drugs with minimal side-effects may be developed.
On the other hand, understanding how the phototoxic effect is generated on the cell and which is the
‘active’ species (being it either an excited state of the drug or produced by sensitization, e.g. singlet
oxygen, or rather a photoproduct or an intermediate) making the combination drug/light toxic, may
open a new perspective, that is using such photoatovated drugs for te selective killing af specific
cells, in particular tumour cells. This paradigm could be achieved if the drug localizes specifically
in the tumour vs normal cells with a preferential intracellular distribution, resulting in an action
tunable upon excitation. In this perspective we have considered fluoroquinolones. Detailed
mechanistic studies support that these heteroaromatic derivatives, largely used as antibacterials and
known for their phototoxic behavior, generate aggressive intermediates, such as aryl cations and
radicals. The most reactive compounds of this series undergo photoheterolysis of a C-F bond
generating an aryl cation in the triplet state. This intermediate exhibits a varied chemistry,
depending on structure and medium, which includes oxidation (and thus formation of radicals) and
arylation (including of DNA bases) reactions. These should thus be suitable models for the work
mentioned above.
We thus designed a study aimed at verifying the feasibility of this approach through a multi
disciplinary investigation. The study is devoted to: determining the interaction of selected
fluoroquinolones with biological molecules, in particular with DNA; performing the rationale
design of new terms of the series guided by the understanding of the photochemical reaction
mechanism; investigating the subcellular localization and the chemistry occurring in vivo.
Preliminary results will be presented.
171
P48
Recycling and remediation of natural matrices with
simultaneous photocatalytic production of hydrogen
Andrea Speltini, Michela Sturini, Federica Maraschi, Andrea Serra,
Antonella Profumo, Daniele Dondi, Armando Buttafava, Angelo Albini
Department of Chemistry, University of Pavia, via Taramelli 12-27100 Pavia (Italy)
michela.sturini@unipv.it
The demand for hydrogen (H2) as an alternative and clean fuel is expected to increase substantially
in the near future. H2 can be obtained via water splitting in the presence of a photocatalyst, under
anoxic conditions; the efficiency of this process is very low but strongly improved by organic
substances undergoing oxidation, e.g. methanol and glycerol. The combination of water splitting
with photoreforming of organic compounds is therefore a powerful strategy for such purpose; 1
moreover, the possibility of recycling various biomasses1,2 is very interesting in the perspective of a
sustainable chemistry.
Here we present the first results on the photocatalytic production of H2 from swine sewage (COD
46 g/L, pH 7.9), in presence of Pt/TiO2 as the catalyst.
Experiments were carried out on stirred nitrogen-purged aqueous solutions under UV-A irradiation
(30 W) at room temperature. Analytical determination of evolved H2 was performed by packedcolumn gas chromatography coupled to thermal conductivity detector.
Raw and biogas plant-effluent sewage samples were irradiated after proper dilution (final volume
30 mL). The amounts of H2 obtained from 100 L of sample was in the range 2-15 mol depending
on the reaction conditions. A general increase in H2 production was achieved by increasing pH (2.510) and catalyst concentration (0.5-2 g/L). Control tests undertaken both in pure water (0.5 g/L
Pt/TiO2) and in presence of organic substances (0.5 g/L Pt-free TiO2) did not produce H2.
Further, we are exploring the possibility to combine H2 production with remediation of
environmental waters, such as wastewaters from pharmaceutical industries. Interestingly,
photocatalytic irradiation of water samples spiked at the milligrams per litre level with
fluoroquinolones and phenols, chosen as model contaminants, gave H2 at different amounts
(micromole levels).
In view of such promising outcomes, we will optimize experimental conditions to improve reaction
yields, and evaluate the possibility to recycle the catalyst too; other matrices and organic substances
will be tested as well, to assess their potential exploitation for H2 production.
(1) Kondarides, D.I.; Daskalaki, V.M; Patsoura, A.; Verykios, X.E. Catal. Lett. 2008, 122, 26-32.
(2) Xu, Q.; Ma, Y.; Zhang, J.; Wang, X.; Feng, Z.; Can, L. J. Catal. 2011, 278, 329-335.
172
P49
NIR Squaraines: all-organic sensitizers for DSSC
Jinhyung Park,1 Nadia Barbero,1 Claudia Barolo,1 Roberto Buscaino,1
Pierluigi Quagliotto,1 Guido Viscardi,1
2
Jun-ho Yum, Lioz Etgar,2 Md. K. Nazeeruddin2 and Michael Graetzel2
1
Dipartimento di Chimica, Centro di Eccellenza NIS, Università di Torino,
Via P. Giuria, 7; I-10125, Torino, Italy.
2
Laboratoire de Photonique et Interfaces, Institut des Sciences et Ingénierie Chimiques, Ecole
Polytechnique Fédérale de Lausanne (EPFL), Station 6, CH-1015, Lausanne, Switzerland.
guido.viscardi@unito.it
The strong request for renewable energy sources has recently boosted the interest in photovoltaic
devices. Among all the organic and hybrid organic-inorganic solar cells, Dye sensitized solar cells
(DSSC) have demonstrated the highest conversion efficiencies and a mature research and
development plan. Compared to traditional photovoltaics, DSSC have several advantages, such as
improved performances at low light intensities and diffuse light, color tunabilty, and transparency,
which make DSSC very appealing for building-integrated photovoltaics (BIPV).
When a visible photon is absorbed by the sensitizer (S) in its ground state, anchored to a TiO2
anatase nanoparticle, an electron is first promoted to an excited state and then injected into the
conduction band of the TiO2 semiconductor. The thus oxidized sensitizer (S+) needs to be
regenerated by a mediator, typically an iodide ion. The most successful charge-transfer sensitizers
employed are Ru(II) complexes but Zn porphyrin derivatives yielded 12% solar-to-electric power
conversion efficiencies.1
The majority of these metal complexes show: i) absorption in the visible region at around 500 nm,
i.e. not ideal matching of the absorption spectra to the solar radiation; ii) high costs; iii) tedious
purification. Metal-free organic sensitizers are accessible by simple synthetical approaches and well
established purification approaches. They can be simply modified structurally and functionalised in
order to obtain the desired spectroscopic properties between 400–700 nm, but NIR dyes are
particularly interesting because of their possible applications in transparent solar cells, tandem cells
and exciton Quantum Dots (QDs) solar cells.
Squaraines have been extensively investigated for their sensitization
properties as highly stable dyes with intense absorption in the NIR
regions. In general, these dyes are prepared by direct condensation
reaction of electron rich aromatic heterocyclic compounds or
heterocyclic quaternized salts with squaric acid. Since a number of
heterocyclic systems with varying π-framework are available, there
are miscellaneous possibilities to design tunable squaraine dyes and
absorption in the far red to near infrared domain.2
We present synthesis and photovoltaic properties of squaraines,3 also
employed as a co-sensitizer in QDs solar cell to obtain a
panchromatic response.4 Moreover, it is also possible to exploit
energy transfer between organic dyes and QDs. Very efficient photon
capture of QDs is combined to very efficient electron injection of dye
to TiO2 conduction band.
(1) Yella, A.; Lee, H.W.; Tsao, H.N.; Yi, C.; Chandiran, A.K.; Nazeeruddin, M.K.; Diau, E.W.G.; Yeh, C.Y.;
Zakeeruddin, S.M.; Grätzel, M. Science., 2011, 334, 629-634.
(2) McEwen, J.J.; Wallace, K.J. Chem. Comm., 2009, 6339-6351.
(3) Park, J.; Barolo, C.; Sauvage, F.; Barbero, N.; Benzi, C.; Quagliotto, P.; Coluccia, S.; Di Censo, D.; Grätzel, M.;
Nazeeruddin, M.K.; Viscardi, G. Chem. Comm., 2012, 2782-2784.
(4) Etgar, L.; Park, J.; Barolo, C.; Lesnyak, V.; Panda, S. K.; Quagliotto, P.; Hickey, S. G.; Nazeeruddin, M.K.;
Eychmüller, A.; Viscardi, G.; Grätzel, M.; RSC Adv., 2012, 2, 2748-2752.
173
P50
Tetrathia[7]helicene mono and dinuclear Gold(I) complexes
Silvia Cauteruccio,1 Davide Dova,1 Maria Camila Blanco Jaimes,2
A. Stephen K. Hashmi,2 Stefano Maiorana,1 Emanuela Licandro1
1
Dipartimento di Chimica. Università di Milano, Via Golgi 19, 20133 Milano, Italia
2
Organisch-Chemisches Institut,Universitat Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
silvia.cauteruccio@unimi.it
Tetrathia[7]helicenes (7-TH) are polyconjugated -systems in which four thiophene rings are
orthofused to alternating arene rings to generate a non planar, chiral, stable helix which allows the
existence of M and P enantiomers. The 7-TH systems are very interesting structures1 even because
they can be easily and selectively functionalized in the alpha positions of the terminal thiophene
rings,2 making it possible the introduction of appropriate substituents.
In the course of our studies on the synthesis of phosphane derivatives of 7-TH as potential
innovative chiral ligands in asymmetric organometallic catalysis,3 gold(I) complexes of the
phosphines of 7,8-di-n-propyl-tetrathia[7]helicene 1 and 2 (Figure 1) provided promising results in
some cycloisomerization reactions.
S
S
S AuCl
PPh2
PPh2
S AuCl
S
S AuCl
PPh2
S
S
1
2
Figure 1.
Encouraged by these results, the two P and M enantiomers of gold(I) complex 1 have been
synthesized, and completely characterized.
The use of gold in homogeneous catalysis has witnessed tremendous activity in recent years. 4
Thanks to gold(I) phosphine-based catalysts, various organic transformations have been accessible
with both high yields and chemo- and stereoselectivity. In particular, asymmetric gold catalysis
represents a very hot topic in catalytic research,5 and several efforts have been made by various
research groups in this field.
(1)
(2)
(3)
(4)
(5)
Collins, S. K.; Vachon, M. P. Org. Biomol. Chem. 2006, 4, 2518-2524.
Licandro, E.; Baldoli, C.; Maiorana, S. et al. Synthesis 2006, 3670-3678.
Cauteruccio, S.; Maiorana, S.; Licandro, E. et al. Eur. J. Org. Chem. 2011, 5649-5658.
Hashmi, A. S. K.. Chem. Rev. 2007, 107, 3180-3211.
Sengupta, S.; Shi, X. ChemCatChem 2010, 2, 609-619.
174
P51
Copper-catalyzed three-component coupling of benzyne,
allylic aziridines, and terminal alkynes
Francesco Berti, Paolo Crotti, Giulio Cassano, Mauro Pineschi
Dipartimento di Scienze Farmaceutiche, Sede di Chimica Bioorganica e Biofarmacia,
Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy
pineschi@farm.unipi.it
The transition-metal-catalyzed three-component sequential coupling of electrophiles and
nucleophiles to carbon-carbon -systems is an ideal method in organic synthesis to create two
different consecutive carbon-carbon bonds from very simple precursor in a single operation. In
particular, the use of benzyne as a carbon-carbon -component for the construction of two different
carbon-carbon bonds ortho to each other has recently attracted considerable attention.1 A
cooperative copper- and palladium-catalyzed three-component coupling of benzynes, allylic
epoxides, and terminal alkynes recently reported,2 stimulated our curiosity as no three-component
coupling reaction occurred in the absence of palladium catalyst.
In our continued interest in the regio- and stereoselective arylative cross-coupling type reactions
of aziridines without using precious metal catalysts,3 we now report that benzyne constitute a
suitable arylation partner of allylic aziridines by the use of simple copper catalysts in one pot. For
example, the use of o-trimethylsilyltriflate as benzyne precursor in combination with CsF, phenyl
acetylene (R = Ph), and N-Ts allylic aziridine derived from 1,3-cyclohexadiene (n = 2) in CH3CN at
55 °C for 18 h afforded the corresponding three-component SN2’ adduct with high regioselectivity as single trans diastereoisomer by the use of catalytic amounts of CuI and PPh3 (Scheme).
Ts
N
OTf
+
TMS
R
+
CuI (5 mol%)
PPh3 (10 mol%)
n
CsF ( 3.0 eq)
CH3CN, 55 °C, 18h
R
n
NHTs
Other combinations of terminal alkynes and allylic aziridines were used with variable degree of
success, but importantly, the use of palladium catalysts was not necessary in all cases examined. In
this Communication, our preliminary results about this chemistry will be discussed in detail.
(1) For a recent review, see: Worlikar, S. A.; Larock, R. C. Curr. Org. Chem. 2011, 15, 3214.
(2) Jeganmohan, M.; Bhuvaneswari, S.; Cheng, C.-H. Angew. Chem. Int. Ed. 2009, 48, 391-394.
(3) Bertolini, F.; Crotti, P.; Macchia, F.; Pineschi, M. Org. Lett. 2006, 8, 2627-2630.
175
P52
Nanocapsules with core-shell structure for delivery of polyphenols
Massimo Carraro,1 Andrea Mattarei,2 Michele Azzolini,3 Lucia Biasutto,2,3
Mario Zoratti,2,3 Cristina Paradisi.1
1
Department of Chemical Sciences, University of Padova,
via Francesco Marzolo 1 , 35131 Padova, Italy.
2
CNR Institute of Neuroscience, Italy (viale G. Colombo 3 , 35131 Padova, Italy).
3
Department of Biomedical Sciences, University of Padova,
viale G. Colombo 3 , 35131 Padova, Italy.
massimo.carraro@unipd.it
Polyphenols are a class of plant secondary metabolites. More than 8000 molecules of this category
have been described, sharing the characteristic of having multiple phenol groups. Polyphenols
interaction with a great variety of proteins explains their positive effects against cardiovascular and
aging-related diseases as well as their chemopreventive and chemotherapic effects.1-3 Dietary intake
of many polyphenols is limited by their low bioavailability due to solubility characteristics and
rapid conversion to metabolites. It is therefore desirable to bypass the solubility problems of
molecules such as quercetin (and derivatives) and to protect them from metabolism with the aim of
an effective and possibly specific targeting to relevant biological systems. Microencapsulation
allows to enclose molecules inside a shell and separate them from the environment. The technique
has been intensively studied and applied in pharmacology for metabolic protection and controlled
release of drugs. Polyphenols encapsulation has already been achieved relying on different
methods: emulsion evaporation,4 layer-by-layer assembly5 and spray drying;6 nevertheless it is
appealing to pursue a more resilient advanced system such as core-shell structures with the
possibility of a selective post-functionalization between the capsule contents and its surface shell.7
We developed a method based on nano-emulsions generated by spontaneous emulsification of
ternary mixtures of solvents. These templates allow to synthesize a shell of cross-linked polymer
surrounding a core made of functional polymer. The core is a useful scaffold to anchor polyphenols.
Such monodispersed nanocapsules have been characterized for size, morphology and composition
by DLS, fluorescence microscopy, ATR-FTIR, DSC and TGA. The devices hold a good potential to
improve the bioavailability of polyphenols and their derivatives.
(1)
(2)
(3)
(4)
(5)
Opie, L. H.; Lecour, S. Eur. Heart J. 2007, 28, 1683-1693.
Spencer, J. P. Proc. Nutr. Soc. 2008, 67, 238-252.
Ramos, S. Mol. Nutr. Food Res. 2008, 52, 507-526.
Li, Y.; Huang, C.; Cen, Y.; Xu, S.; Xu, S.; Zhong Yao Cai. 2000, 23, 281-284.
Shutava, T. G.; Balkundi, S. S.; Vangala, P.; Steffan, J. J.; Bigelow, R. L.; Cardelli, J. A.;; O’Neal, P.;; Lvov, Y. M. ACS Nano 2009, 3, 1877–1885.
(6) Gavini, E.; Alamanni, M. C.; Cossu M.; Giunchedi, P. J. Microencapsul. 2005, 22, 487-499.
(7) Mason, B. P.; Hira, S. M.; Strouse, G. F.; McQuade, D. T. Org. Lett. 2009, 11, 1479-1482.
176
P53
Synthesis of acetal derivatives of Resveratrol: a method to improve
the oral bioavailability of polyphenols
Mattarei A.,1,2,* Bradaschia A.,3 Biasutto L.,1,3 Azzolini M.,3 Carraro M.,2 Marotta E.,2
Garbisa S.,3 Paradisi C.,2 Zoratti M.1,3
1
CNR Institute of Neuroscience
Department of Chemical Sciences, University of Padova,
3
Department of Biomedical Sciences , University of Padova
andrea.mattarei@unipd.it
2
Plant polyphenols exhibit potentially useful effects in a wide variety of pathophysiological settings.
We focus here on resveratrol; this is the preferred model compound for our studies because it is one
of the most effective and interesting members of the family and because of its relatively simple
chemistry. A partial list of the pathologies for which a positive impact by resveratrol has been
reported includes cancer, aging and cognitive impairment associated with aging, metabolic
syndrome, obesity, arterial wall hardening, inflammatory ailments.
However, pharmacological exploitation of polyphenols is unfortunately hindered by their low
bioavailability, rapid metabolism (hydroxyls are ideal targets for conjugating enzymes), and often
by unfavourable physico-chemical properties, e.g. a generally low water solubility.
We are thus developing polyphenol pro-drugs, with the goals of increasing absorption from the
gastrointestinal tract and permeation of the blood-brain barrier, and of providing temporary
protection from Phase II metabolism. In the ideal pro-drug, hydroxyls are protected by capping
groups which a) help or at least not hinder permeation of epithelia; b) prevent conjugative
modification during absorption and first-pass through the liver; c) can be eliminated with opportune
kinetics to regenerate the parent compound.
We report here the synthesis, stability tests and pharmacokinetic studies of resveratrol derivatives
incorporating acetal-type bonds; capping groups were ethyleneglycol olygomers with increasing
chain length. 4-units oligomers provided the best absorption, but acetal bonds proved to be too
stable. Future efforts will be directed to developing analogous pro-drugs with more labile chemical
bonds.
177
P54
Hydrogen-Bonding Bronsted acid chemoselective oxidation of sulfides
Angelo Frongia, Pier Paolo Piras, Francesco Secci.
Dipartimento di Scienze Chimice, Università degli Studi di Cagliari.
Complesso Universitario di Monserrato, SS554, bivio per Sestu, Monserrato (Ca).
fsecci@unica.it
Sulfoxide derivatives1 represent a useful class of compounds due to their ability to promote
different organic transformations useful for the synthesis of drugs and sulphur carrying natural
products,2,3 being also important synthetic intermediates in the production of a considerable number
of fine chemical building blocks and of a considerable number of pharmaceutical molecules.2-4
Strategies based on direct sulfide oxidation5 doubtless are the most common and easy approaches to
synthetize these compounds. Despite several oxidants have been developed for the conversion of
sulphides to the corresponding sulfoxides, most of them require careful control of the reaction
conditions to minimize the formation of the sulfones as side products.6 Selective formation of
sulfoxides has been reported with many oxidants both in the presence of metals, mainly transition
metals,5 than using metal free oxidants6. However, the growing attention to chemical eco-friendly
approaches, stimulate the investigation of challenging new synthetic strategies. For this reason, the
design and optimization of new synthetic strategies have to bind together a) the limitation of
polluting reagents, b) work efficiently at room temperature, maximizing chemo-regio and
enantioselectivity accompained by satisfactory yields. Despite the resistance to oxidants of the
tetrazole ring no use has been reported on their use in the sulphide oxidations. Due to the
commercial availability of 5-aminotetrazole 2 we envisaged the possibility of preparing the
corresponding amides by reaction with different carboxylic acids with the aim of mimicking the
active part of the most commonly used ureas and thioureas. For this aim we prepared the three
tetrazole derivedamides 3a-c and tested them in the oxidation of differently functionalized sulfides
and disulfides affording the corresponding sulfoxides with high chemo- and diastereoselectivity
(>99%) and high yields.
CF3
CF3
S
F3C
N
H
N
H
CF3
1
2
N N
O
N
N
N
H
H
3b
1)
2)
3)
4)
5)
6)
N N
O
N
N
N
H
H
N N
N
N
NH2
H
NO2
NO2
N N
O
N
N
N
H
H
3c
3a
N N
N
N
H
HN
O
4
R
S
5
3a-c 10%
R'
Ox. 1.1 eq.
solvent, rt
R
O
S
6
O
R'
R
S
O
R'
7
TBHP/CH2Cl2 conv. >98%, 6/7 ratio >99:1
H2O2/H2O
conv. 95%, 6/7ratio 95:5
a) J. Legros, J.R. Dehli; C. Bolm, Adv. Synth. Catal. 2005, 347, 19; b) I. Fernandez, N. Khiar, Chem. Rev. 2003,
103, 3651; c) M. C. Carreno, Chem. Rev. 1995, 95, 1717.
H. L. Holland Chem. Rev. 1988, 88, 473.
E. Block Angew. Chem. Int. Ed. Engl. 1992, 31, 1135.
C. M. Spencer, D. Faulds, Drugs. 2000, 103, 321.
a) M. Palucki, P. Hanson, E. N: Jacobsen Tetrahedron Lett. 1992, 33, 7111; b) M. Mba, L. J. Prins, G. Licini Org.
Lett. 2007, 9, 21.
a) F. Shi, M. K. Tse, H. M. Kaiser, M. Beller Adv. Synth. Catal. 2007, 349, 2425. b) R. E. del Rio, B. Wang, S.
Achab, L. Bohè Org. Lett. 2007, 9, 2265.
178
P55
Orthogonal self-assembly of a purely organic framework driven
by simultaneous hydrogen and halogen bonding
Pierangelo Metrangolo,1,2 Luca Colombo,1,2 Javier Martí-Rujas,2 Tullio Pilati,1
Giuseppe Resnati,1,2 Giancarlo Terraneo1,2
1
NFMLab – DCMIC “Giulio Natta”;; Politecnico di Milano, via Mancinelli 7, 20131 Milan, Italy;
Center for Nano Science and Technology, Istituto Italiano di Tecnologia, Politecnico di Milano,
via Pascoli 70/3, 20133 Milan, Italy.
pierangelo.metrangolo@polimi.it
2
Self-assembly of metals (nodes) and organic ligands (linkers) is a widely exploited strategy for the
synthesis of porous materials known as metal-organic frameworks (MOFs).1 Metal coordination
provides strong and directional metal-ligand bonds that help to design MOFs with particular
topologies. Such predictability along with ligand tunability, porosity, and robustness have
contributed significantly to the recent upsurge of MOFs and their industrial applications. Metal-free
materials are also being studied and have found applications in gas adsorption,2 conductivity,3 and
molecular transport.4 However, unlike MOFs, organic porous crystals containing large voids are
less common due to their tendency to collapse upon guest removal as a consequence of the weak
nature of the non-covalent interactions used (i.e., hydrogen bonding and van der Waals
interactions).
Halogen bonding (XB) is a powerful new tool in supramolecular chemistry. 5 Most often XB is seen
in competition with the most used HB. Wee will show that XB could cooperate orthogonally with
HB in building up more complex and functional organic frameworks, provided that optimized selfassembling structures and geometries are chosen. Herein we report that a purely organic framework
was obtained by relying on the use of a ligand possessing moieties able to engage in simultaneous
XB and HB, in a chemically and geometrically orthogonal manner.6 The open framework consists
of 2Dintersecting channel network with a void volume of 19 % of the unit cell volume(probe radius
1.2 Å) (Figure 1). The network can undergo single-crystal-to-single-crystal (SCSC) guest exchange
from liquid and gas phases. To the best of our knowledge, this is the first report of an open
framework with a 2D porosity self-assembled via orthogonal HB and XB. We believe that the
reported strategy will lead to the development of unique materials and will attract considerable
attention of various scientists studying porous systems, smart materials, supramolecular chemistry.
Figure 1. Single crystal X-ray structure of an open framework synthesized by the orthogonal self-assembly of a ligand
with moieties able to engage in simultaneous HB and XB with hydroiodic acid (HI).
(1) M. Eddaoudi, D. B. Moler, H. Li, B. Chen, T. M. Reineke, M. O. O’Keeffe, O. M. Yaghi, Acc. Chem. Res., 2001
34, 319–330.
(2) H. Kim, Y. Kim, M. Yoon, S. Lim, S. M. Park, G. Seo, K. Kim, J. Am. Chem. Soc., 2010, 132, 12200–12202.
(3) T. Hasell, M. Schmidtmann, A. I. Cooper, J. Am. Chem. Soc., 2011, 133, 14920–14923.
(4) J. Martí-Rujas, A. Desmedt, K. D. M. Harris, F. Guillaume, J. Am. Chem. Soc., 2004, 126, 11124–11125.
(5) P. Metrangolo, F. Meyer, T. Pilati, G. Resnati, G. Terraneo, Angew. Chem. Int. Ed., 2008, 47, 6114–6121.
(6) J. Marti-Rujas, L. Colombo, J. Lü, A. Dey, G. Terraneo, P. Metrangolo, T. Pilati, G. Resnati, Chem. Commun.,
2012, in press.
179
P56
Synthesis of a heterogeneous metalloenzyme mimic based on Er[III] chemistry
1
1
P. Costanzo,1 A. Procopio,1 S. Bonacci,2 G. De Luca,1 M.Nardi,2 M. Oliverio1
Università degli Studi Magna Graecia, Campus “C. Venuta”, Loc. Germaneto, CZ
2
Università della Calabria, Ponte Bucci, Arcavacata di Rende, CS
m.oliverio@unicz.it
A bifuctional catalyst is a system characterized by cooperatively working general base and acid
groups. The main natural example of a polyfunctional system are the enzymes. Metalloenzymes are
an interesting subset of polyfunctional catalysts that employ metal ions as Lewis acids and/or redox
centers, in conjunction with “organic” functional groups, to enhance reaction rates.1 Acids and
bases are antagonists and the cooperative use of both of them in a spatial proximity could generate a
self quenching reaction. This problem has been avoided choosing a right combination such as an
hard metal ion and a soft base.2 A recent work of Tiseni and Peters3 suggests that the oxophilic
lanthanide Er(III) triflate, which combine low price with a relatively small radius, should be
advantageous to achieve a rigid transition state. In this work we present the synthesis (Scheme) of
an asymmetric heterogeneous bifunctional catalyst characterized by the presence of Er(III) in spatial
proximity with an amine group.
OH
APTES
OH
dry Tol,
MW,
130°C
NH 2
N-Fmoc-S-trytil-cysteine
(5 eq)
HOBT, DIC,
DCM/DMF
r.t., 72h
O
N
H
Ph
Fmoc
HN
S
Ph
Ph
CH2Cl2, r.t. TIS/TFA
2h
O
N
H
Cl2ErO3 S
NH2
3)
1) H2O2 30%
r.t., 24h
2) ErCl CH CN
3,
3
80°C, 24h
DMF,DBU
r.t..
O
Fmoc
HN
N
H
HS
Scheme
The catalyst, after full Ft-IR, Raman, ICP-MS and porosimetric characterization, has been tested on
the Michael reaction of diethyl malonate and cicloexanone. Data concerning its activity,
enentioselectivity, TOF/TON values, recovery and recycling are discussed.
(1) Pérez-Quintanilla D.; del Hierro, I; Fajardo, M; Sierra, I. J. Haz. Mat. B, 2006, 134, 245-256
(2) a) Aggarwal, V. J. Org. Chem. 1998, 63, 7183-7189; b) Aggarwal, V.J. Org. Chem. 2002, 67, 510-514
(3) Tiseni, T.S.; Peters, R. Angew. Chem. Int. Ed. 2007, 46, 5325 –5328
180
P57
D-Allal- and D-galactal-derived vinyl N-mesylaziridines: regio- and
stereoselectivity in addition reactions of O-, C-, N-, and S-nucleophiles
Valeria Di Bussolo, Ileana Frau, Mauro Pineschi, Paolo Crotti
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy
ileana.frau@farm.unipi.it
Glycosides having differently functionalized amino groups in different positions
(aminosugars) are an important category of modified carbohydrate units present in several
oligosaccharides and glycoconjugates.1 Furthermore, aminosugars are important as essential
components of bacterial capsular polysaccharides and as structural elements of aminoglycoside
antibiotics with antiviral and antitumor activity.2 Because of the biological importance of natural
products containing aminosugars,3 the development of efficient synthetic routes to these
carbohydrates is an attractive goal.
In this context, our interest was directed toward D-allal- and D-galactal-derived vinyl N-mesyl
aziridines 1 and , respectively, as useful tools for the regio- and stereoselective introduction of a
nitrogen functionality at the C(4) carbon of a glycal system with simultaneous glycosylation.4
Aziridines 1 and  were prepared from epoxides 2 and 2,(5) repectively, with opposite
configuration and their chemical behavior was examined with several O- (alcohols, acetate,
methoxide and hydroxide ions), C- (organometallic compounds), N- (amines, azide ion) and Snucleophiles (thiols). Our aim was to find simple procedures for glycosylating as many nucleophiles
as possible with aziridines 1 and with high levels of regio- and stereocontrol.
O
BnO
O
BnO
O
Ms
2
O
BnO
N
Ms
1
O
BnO
N
O
1
2
The results have indicated the marked tendency of these activated vinyl aziridines to show a
high-to-complete degree of 1,4-regioselectivity in association with complete syn-stereoselectivity
(coordination product) in nucleophilic addition reactions when the nucleophile can coordinate the
aziridine nitrogen through a metal or by means a hydrogen bond (route a).
syn-1,4-addition product
BnO
O
Nu
route a
MsHN
coordination product
Ms
BnO
OBn
O
+
N
1'
O
1
a
+
Y Nu
3
Ms
anti-1,2-addition product
O
BnO
route b
MsHN
Nu
Nu-X
b
N
1''
noncoordination product
NuY = coordinating nucleophile
NuX = no coordinating nucleophile
On the other hand, the use of reaction conditions where no coordinating agent (metal or protic
species) is present leads to complete 1,2-regio- and anti-stereoselectivity (noncoordination product)
(route b), in a nice regioalternating process.
(1) Van den Bos, L. J.; Codée, J. D. C.; van Boom, J. H.; Overkleeft, H. S.; van der Marel, G. A. Org. Biomol. Chem.
2003, 1, 4160.
(2) Choi, Y.-H; Roehrl, M. H.; Kasper, D. L.; Wang, J. Y. Biochemistry 2002, 41, 15144.
(3) Knapp, S Chem. Soc. Rev. 1999, 28, 61.
(4) a) Di Bussolo, V.; Romano, M. R.; Pineschi, M.; Crotti, P. Org. Lett. 2005, 7, 1299. b) Di Bussolo, V.; Favero, L.;
Romano, M. R.; Pineschi, M.; Crotti, P. J. Org. Chem. 2006, 71, 1696. See also: c) Di Bussolo, V.; Romano, M.
R.; Pineschi, M.; Crotti, P. Tetrahedron 2007, 63, 2482.
(5) Di Bussolo, V.; Caselli, M.; Romano, M. R.; Pineschi, M.; Crotti, P. J. Org. Chem. 2004, 69, 7383 and 8702.
181
P58
Petrosapongiolide M, a new proteasome inhibitor:
from chemical proteomics to mechanistic insights
Luigi Margarucci, Maria Chiara Monti, Alessandra Tosco,
Raffaele Riccio, Agostino Casapullo
via Ponte don Melillo, 84084, Fisciano, Italy
casapullo@unisa.it
One of the main questions affecting the new era of chemical biology is the comprehension of the
action mechanisms of small bioactive molecules on their macromolecular targets. Although the
therapeutic potential of the most promising lead compounds is being evaluated in preclinical and
clinical trials, often their intracellular partners and their interaction profiles remain largely
unknown.1 Chemical proteomics consists in the versatile combination of affinity purification and
mass spectrometry, that has been recently applied for the identification of macromolecular partners
which specifically bind to an immobilized small drug.2
Here, we report the chemical proteomics analysis of Petrosaspongiolide M (PM), an antiinflammatory marine metabolite. The multi-component 20S-PA28 complex of the enzymatic
proteasome machinery emerged as the major specific partner of this marine compound.3 We also
report an in-deep investigation on the biological role of PM and the characterization of the
molecular mechanism of inhibition on 20S-PA28 active complex by a combination of biochemical
approaches and mass spectrometry. Our data revealed a covalent modification of the activator
complex PA28 by PM through a specific Schiff base formation between the amino group of Lys236
and the γ-hydroxybutenolide masked aldheyde onto the marine metabolite skeleton. Lys236 is
located into the so-called ‘PA28 activation loop’, and has a key role in the 20S activation mediating the conformational changes of the proteasome core subunits responsible for the proteolytic activity
of the enzyme.
(1)
(2)
(3)
(4)
Sleno, L.; Emili A. Curr. Opin. Chem. Biol., 2008, 12, 46–54.
Aebersold, R.; Mann M. Nature 2003, 422, 198-208.
Margarucci, L.; Monti, M.C.; Tosco, A.; Riccio, R.; Casapullo, A. Angew. Chem. 2010, 49, 3960-3963.
Posadas, I.; Terencio, M.C; Randazzo, A.; Gomez-Paloma, L.; Payá, M.; Alcaraz M.J. Biochem. Pharmacol. 2003,
165, 887-895.
182
P59
Design and synthesis of new camptothecin-Pt (II) “dual-drugs”
Sabrina Dallavalle,1 Raffaella Cincinelli,1 Loana Musso,1 Roberto Artali2
1
Department of Food, Environmental and Nutritional Sciences
Università di Milano, Via Celoria 2, 20133, Milano
2
Scientia Advice, R&D in Science, Lissone (MB)
sabrina.dallavalle@unimi.it
The antitumor activity of cis-diaminedichloro-platinum (II) (DDP) was first reported by Rosenberg
et al in 1969.1 The success of cisplatin paved the way for the second- and third-generation
platinum(II) drugs, carboplatin and oxaliplatin, and presently platinum-based coordination
complexes are among the most widely used antitumour agents in the clinic. Recently, many efforts
have been made to overcome severe and sometimes life-threatening toxic side effects of Pt (II)
complexes, low cellular uptake and relatively poor pharmacokinetic profiles, often correlated to the
activation of drug resistance mechanisms by tumour cells.
In this context we synthesised new Camptothecin-Pt complexes with different Pt-containing linkers
ad we modelled their binding to the Topo I covalent complex with DNA. Camptothecin (CPT) is
among the most promising agents for the treatment of human cancers. It exhibits a unique
mechanism of action because it targets the nuclear enzyme topoisomerase I,2 forming a ternary
complex with this enzyme and DNA. The stabilization of the complex results in DNA breaks by
preventing DNA religation. and it can be converted to lethal double-strand breaks during DNA
replication. The potential advantages of using CPT-Pt combinations could be multiple. On one side
they could promote adequate cellular accumulation and nuclear localisation of the Pt(II)-complex
by virtue of the hydrophobicity and the DNA interacting properties of CPTs; on the other side, the
incorporation of a chemical function able to covalently bind to DNA, like a Pt complex, could
stabilize the CPT-DNA-enzyme ternary complex, improving the drug-target interaction
Several criteria have guided the design of the CPT–Pt (II) conjugates: a) a CPT moiety endowed
with high activity; b) a short linker between the Pt center and CPT chosen to ensure enough
conformational flexibility while maintaining proximity of the reactive metal center to the DNAselective scaffold; and c) a chelating diamine selected to secure Pt (II)coordination to the CPT
moiety. Recently, a series of potent camptothecins substituted in position 7 have been synthesized
in our laboratory. The highest activity was shown by oxyiminomethyl derivatives.3 Thus, Pt (II)
conjugates of 7-oxyminomethylCPTs through different linkers were synthesized as a firstgeneration of CPT-Pt (II) hybrid drugs.
(1) Rosenberg, B.; Van Camp, L.; Trosko, J. E.; Mansour, V.H. Nature 1969, 222, 385-386
(2) Hsiang, Y.-H.; Hertzberg, R.; Hecht, S.M.; Liu, L.F. J. Biol. Chem. 1985, 260, 14873.
(3) Dallavalle, S.; Ferrari, A.; Biasotti, B.et al. J. Med. Chem. 2001, 44, 3264.
183
P60
Synthesis, structural characterization and molecular dynamics
of neutral liposomes able to complex DNA
Roberta Galeazzi,1 Luca Massaccesi,1 Milvia Marini,2
Giovanna Mobbili,1 Michela Pisani2
1
Di.S.V.A. Università Politecnica delle Marche, Ancona, Italy
SIMAU, Università Politecnica delle Marche, Ancona, Italy
l.massaccesi@univpm.it
2
Gene therapy is considered a promising approach for the treatment of a wide range of diseases such
as cancer, AIDS, neurodegenerative and cardiovascular pathologies and is expected to be of
paramount importance in the treatment of genetic disorders. The possibility of a successful transfer
of genetic material to targeted cells or tissues is closely dependent on the choice of the appropriate
delivery system, which can be viral or synthetic. Between the synthetic carriers cationic liposomes
are the most studied, although some inherent cytotoxicity and the low stability of their complexes
with plasmid DNA in serum are serious drawbacks and still limit their application. Our group
started few years ago studying neutral liposomes that we demonstrated in some in vitro experiments
being able either to form stable complexes with plasmid DNA in the presence of bivalent metal
cations (Ca, Mg, Mn), either to transfect this material to cells.1 In order to improve the ability of
neutral liposomes to complex DNA, our strategy has been to develop liposomal gene delivery
systems containing new synthetic lipids lacking in positive charge but acting as effective cationic
lipids.2
For this purpose we are studying neutral synthetic vectors containing lipids functionalized with
groups able to coordinate bivalent metals and to form stable complex with plasmidic DNA. With
the aim to optimize the structure of the chelating agent lipids with different polar heads have been
synthesized, in particular we report here the synthesis of a cholesteryl-2(picolinamido)phenylcarbamate together with the results of high level DFT calculations aimed to
establish its conformational preferences and to investigate its propensity to complex metal cations
(cation- complexes).
The neutral synthetic lipid has been mixed with commercial zwitterionic lipids (DOPC and DOPE)
in different percentage and employed in the preparation of multilamellar liposome. The ability of
these systems to form stable complexes with plasmid DNA in the presence of bivalent metal cations
(Ca, Mg, Mn) has been investigated by means of synchrotron X-ray diffraction, and the structural
parameters are deduced from experimental electron density profiles. Size and z-potential of the selfaggregated nanoparticles and their complexes with DNA were studied using dynamic and
electrophoretic light scattering. In the next future, all atoms Molecular Dynamics calculations will
be carried out in order to both predict at atomistic level the interactions between lipids in these
mixed bilayer and to study its mechanism of complexation with DNA.
(1) Bruni, P., Pisani, M.,. Amici, A, Marchini, C., Montani, M., Francescangeli, O., Appl. Phys. Lett., 2006, 88,
073901-3.
(2) Pisani, M., Mobbili, G., Placentino, I.F., Smorlesi, A., Bruni, P., J. Phys. Chem. B, 2011,115, 10198-10206.
184
P61
Characterization of neo-glycoproteins by
liquid chromatography-mass spectrometry peptide mapping
Caterina Temporini,1 Francesco Fasanella,2 Teodora Bavaro,1 Immacolata Serra,1
Sara Tengattini,1 Carlo Morelli,2 Giovanna Speranza,2 Marco Terreni1
1
Department of Drug Sciences and Italian Biocatalysis Center,
University of Pavia, Italy
2
Department of Chemistry, University of Milan, Italy
caterina.temporini@unipv.it
The fundamental role of glycoproteins in many biological processes is now well appreciated and
has intensified the development of innovative synthetic and analytical characterization strategies. 1
When neo-glycoproteins are produced by synthesis, neither the degree nor the resulting N- or Oglycosylation sites can be predicted because no consensus sequences exist as in the case of enzymecatalyzed glycosylation in mammalian cells. The accurate and detailed structural characterization of
the produced therapeutic protein becomes, thus, mandatory.
In this work we exploited different synthetic strategies to obtain neo-glycoproteins using
carbohydrates (mannose and N-acetylglucosammine) with modelled chemical activation. In
particular, synthetic monosaccharides contained the IME (2-iminomethoxymethyl) or
homobifunctional (adipate 4-nitrophenyl diester) aglycone were considered to evaluate the
influence of the coupling reagent in the reaction of glycosylation of proteins. Two proteins were
used as models, TB10.4 and Ribonuclease A, containing single and multiple glycosylation sites,
respectively.
The glycosylation degree was monitored by direct infusion of intact proteins in a linear ion trap
mass spectrometer (ESI-LIT-MS). A more detailed characterization of both N-linked and O-linked
sites of glycosylation were directly identified by liquid chromatography mass spectrometry peptide
mapping after an appropriate proteolytic cleavage of the synthesised glycoproteins. Briefly, pronase
digests were produced in order to verify the amino acid occupancy, while chymotriptic digests of
the same glycoproteins were analysed to define the exact glycosylation sites.2 In both cases,
glycopeptides were selectively enriched by on-line SPE on hypercarb trap column, and
subsequently separated by HILIC-MS/MS. The detailed characterization allowed the study of the
effect of the different chemical activations on the reactivity, the selectivity and the efficiency of the
glycosylation process.
(1) Gamblin D. P.; Scanlan E. M.; Davis B. G. Chem. Rev. 2009, 109, 131–163.
(2) Temporini C.;Perani E.; Calleri E.; Dolcini L.; Lubda D.; Caccialanza G.; Massolini G. Anal. Chem. 2007, 79,
355-363.
185
P62
Preparation and characterization of stable diarylmethylium salts
Margherita Barbero, Silvano Cadamuro, Stefano Dughera, Paolo Venturello
Università di Torino, Dipartimento di Chimica, Via P. Giuria 7 -10125 TORINO
margherita.barbero@unito.it
We have reported a number of synthetic transformations catalyzed by the strong Brønsted acid obenzenedisulfonimide (1).1 Recently we carried out a simple and efficient method for the
preparation of triarylmethanes, bis- and trisindolylmethanes using activated aryl aldehydes and
activated arenes via a multistep Friedel–Crafts hydroxyalkylation.2
We decided to study the reaction mechanism, with an eye to preparing, isolating and characterizing
the carbocation intermediates, whose significance as intermediates in organic chemistry has long
been recognized. Several types of stable carbocations have been studied, normally obtained at low
temperature in superacidic systems and in the presence of a nucleophile which should trap them
immediately after the formation.3
Owing to results previously obtained in our researches, it was expected that o-benzenedisulfonimide
would provide a counteranion of well-known stabilizing power.4
A number of stabilized aryl or heteroaryl(3-indolyl)carbenium ions, never previously prepared in
the solid state, have been isolated in excellent yields as highly stable o-benzenedisulfonimide salts.
Their purity has been proven by spectroscopic methods, chemical reduction with NaBH4 and X-ray
crystal structure analysis. They are ready to use and have a long shelf-life. Researches are currently
under way on suitable reactions of these reactive species with various nucleophiles.
(1) Barbero M., Bazzi S., Cadamuro S., Dughera S., C. Magistris, A. Smarra, P. Venturello Org. Biomol. Chem. 2011,
9, 2192-2197 and references therein.
(2) Barbero, M.; Cadamuro, S.; Dughera, S.; Magistris, C.; Venturello, P. Org. Biomol. Chem. 2011, 9, 8393-8399.
(3) Olah, G. A. J. Org. Chem. 2001, 66, 5943-5957.
(4) Barbero, M.; Crisma, M.; Degani, I.; Fochi R.; Perracino, P. Synthesis 1998, 1171-1175.
186
P63
Ethyl lactate: a green solvent for the synthesis of
colored Maillard reaction products from 2-furaldehyde
M. Nardi,1 P. Costanzo,2 M. Oliverio,2 A. Procopio,2 G. Sindona. 1
1
Department of Chemistry University of Calabria Ponte Bucci, cubo 12C,
87036 Arcavacata di Rende (CS) Italy.
2
Department of Pharmacobiology University of Magna Graecia
Complesso Ninì Barbieri, 88021 Roccelletta di Borgia (CZ), Italy.
nardi@unical.it
Furan-2-carboxaldehyde is known as one of the main reaction products formed from pentoses
during thermal treatment.1 Severin and Kro¨nig (1972) reported that this aldehyde reacts easily with
4-hydroxy-5-methyl-3(2H)-furanone also derived from carbohydrate dehydration, giving rise to a
yellow condensation product.2 Although as yet not investigated, it might be possible that the
reaction of 2-furaldehyde with amino acids might contribute to color development present in the
different foods.3
Lewis acid catalyzed reaction of 2-furaldehyde and secondary amines results in the formation of
4,5-diaminocyclopent-2-enones exclusively as the trans diastereomers.4
Li and Batey developed a method for exclusive formation of 4,5-diaminocyclopent-2-enones using
lanthanide (III).5 Ethyl lactate is approved by the FDA as a food additive, is derived from renewable
resources, and is biodegradable.6 In this paper, we describe a summary of the greenest 4,5diaminocyclopent-2-enones with ethyl L-lactate (EL) as solvent. The reactions are complete within
minutes at room temperature.
Scheme 1
O
O
O
O
H +2
HN
O
Er(III)
N
EL
N
O
Yield 100%
(1)
(2)
(3)
(4)
(5)
(6)
Ledl, F.; Schleicher, E. Angew. Chem. 1990, 102, 597-734.
Ledl, F.; Severin, Th. Z. Lebensm. Unters.Forsch. 1978, 167, 410-413.
T. Hofmann J. Agric. Food Chem. 1998, 46, 932-940
J. Stenhouse, Justus Liebigs Ann. Chem., 1850, 74, 278.
S. Li; R. A. Batey Chem. Commun., 2007, 3759–3761
a) J. J. Clary, V. J. Feron and J. A. van Velthuijsen, Regul Toxicol.Pharmacol., 1998, 27, 88; b) C. T. Bowner and
R. Hooftman, Chemosphere, 1998, 37, 1317
187
P64
Characterization of new aza-sesquiterpenoids
from the fungus Clavicorona divaricata
Loana Musso,1 Raffaella Cincinelli,1 Sabrina Dallavalle,1 Gianluca Nasini2
1
Department of Food, Environmental and Nutritional Sciences
Università di Milano, Via Celoria 2, 20133, Milano
2
C.N.R, Istituto di Chimica del Riconoscimento Molecolare, Politecnico,
via Mancinelli 7, 20131, Milano
loana.musso@unimi.it
Mushrooms have proved to be a rich source of secondary metabolites with unusual structures as
well as interesting biological activities.1 Despite their potential for drug development, few bioactive
metabolites have been reported from mushrooms as compared with higher plants and microbes.
In our screening project on bioactive metabolites of Basidiomycetes we have investigated the
metabolites produced by the fungus Clavicorona divaricata in MPG agar cultures and isolated
divaricatine A and B together with the nor-sesquiterpenoids tsugicoline L and M.2
Successively, the fermentation of the fungus in different conditions, one week still and two weeks
shaken at 180 rpm gave rise to complex mixtures, from which new aza-sesquiterpenoids were
isolated. The poster describes the isolation, structure elucidation and absolute configuration
assessment of two novel metabolites: divaricatine C and divaricatine D. The skeleton of these
compounds was never found before among the sequiterpenes of protoilludane origin, except for
illudinine, a metabolite isolated from some strains of Clitocybe illudens. A possible mechanism of
their formation is also suggested.
The new metabolites showed a weak antibacterial activity against Bacillus cereus and Sarcinea
lutea (50µg/disc), and inhibited the growth of Lepidum sativum.
(1) Zaidman, B.Z., Yassin, M., Mahajna, J., Wasser, S.P., Appl. Microbiol. Biotechnol. 2005, 67, 453–468.
(2) Arnone, A., Candiani, G., Nasini, G., Sinisi, R., Tetrahedron, 2003, 59, 5033–5038.
188
P65
Heterogeneization of a basic ionic liquid on magnetic nanoparticles
and its use as catalyst in nitro-Michael additions.
A. Mega and F. Bigi
Dipartimento di Chimica Organica e Industriale dell’Università,
Parco Area delle Scienze17/A,43124 Parma, Italy
antonio.mega@studenti.unipr.it
Environmental and economic considerations have created great interest, in both academic and
industrial research, in designing synthetic procedures that are clean, selective, high-yielding, and
manipulatively easy. In this respect, the heterogeneous catalysis plays a fundamental role. Indeed,
solid catalysts can be easily separated from the reaction products by simple filtration and
quantitatively recovered in the active form.
In recent years, the nanoparticles have been studied by many research groups not only for their
specific properties, but also as new matrices to support homogeneous catalysts for organic
reactions. They present the advantage of having a large surface area and they can be functionalized,
consequently higher loading values can be achieved respect to the supports traditionally employed.
A particular attention has been addressed to the magnetic nanoparticles (MNPs) conveniently
coated and functionalized. These nanoparticles respond to an external magnetic field without
retaining any magnetization property when the field is removed. This enables to recover the catalyst
from the reaction mixture by the application of an external magnetic field.
Here we report the heterogeneization of a ionic liquid containing the Hünig’s base1 by anchoring
on core-shell Fe3O4/SiO2 nanoparticles. The activity of this new catalyst was investigated in the
reaction of nitroalkanes with electronpoor alkenes, and compared with the activity of the same basic
ionic liquid supported on silica.
The conjugate addition of various nitroalkanes to methyl vinyl ketone was successfully carried out
under solventless conditions at room temperature (yields >80%, selectivity 94-99%). Preliminary
results show the catalyst recyclability.
MeO
MeO Si
MeO
+
O
N
+
N
N
Br-
EWG + O2N
O
N
Br-
R
NO2
R
EWG
(1) Paun, C.; Barklie, J.; Goodrich, P.; Gunaratne, H. Q. N.; McKeowna, A.; Pârvulescu, V. I.; Hardacre, C. J. Mol.
Catal. A: Chem., 2007, 269, 64-71.
189
P66
Kinetic quantities determined by dynamic chromatography:
effective correction for stationary phase influence
S. Carradori,1 R. Cirilli,2 S. Dei Cicchi,1 R. Ferretti,2 F. Gasparrini,1 S. Menta,2
M. Pierini,1 D. Secci,1 C. Villani.1
1
Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Università di Roma,
P.le A. Moro 5, 00185 Rome, Italy.
2
Istituto Superiore di Sanità, Dipartimento del Farmaco,
Viale Regina Elena 299, 00161 Rome, Italy
marco.pierini@uniroma1.it
It is now well consolidated that, when employable (i.e. when a chemical equilibrium to be studied
under a kinetic point of view can be “captured” as the plateau of dynamic chromatograms),
Dynamic Chromatography (DC) proposes itself as the most convenient method in terms of required
time and experimental effort (especially about both purity and amount of the involved compounds).
Reliable kinetic information (i.e. values of forward and backward rate constants of the process to be
studied, as well as their associated free energy activation barriers) may in fact be obtained by
suitable line shape analysis of chromatographic profiles displaying plateau zones between resolved
peaks, which, in general, are expression of secondary equilibria concomitant to the chromatographic
partition of the resolved
species.1-3 However, rate
constants measured by such
an approach are necessarily
perturbed
(although,
commonly, in quite little
extent) by direct action of the
employed
chromategraphic
stationary phase (SP).1,2
The present communication
deals with the possible and
effective correction of these
kinds of SP perturbative
effects, by resorting to
thermodynamic information
directly obtainable from the chromatographic capacity factors of the species involved within the
dynamic profiles. Several examples of stereoisomerizations are analyzed according to the here
proposed correction procedure1-4 and some indications, suggesting the more convenient choice of
operative conditions to adopt in order to reduce in origin the influence of SP, are also provided.
(1) D’Acquarica I.; Gasparrini F.; Pierini M.; Villani C.; Zappia G. J. Sep. Sci. 2006, 29, 1508-1516.
(2) Cirilli R.; Costi R.; Di Santo R.; La Torre F.; Pierini M.; Siani G. Anal. Chem. 2009, 81, 3560-3570.
(3) Gasparrini F.; Lunazzi L.; Mazzanti A.; Pierini M.; Pietrusiewicz K. M.; C. Villani J. Am. Chem. Soc. 2000, 122,
4776-4780.
(4) S. Carradori, R. Cirilli, S. Dei Cicchi, R. Ferretti, S. Menta, M. Pierini, D. Secci J. Chromatogr. A, submitted
190
P67
A short-cut synthesis of non-classical nucleosides
through pericyclic reactions of fleeting intermediates
Dalya Al-Saad, Paolo Quadrelli
Dipartimento di Chimica, Università degli Studi di Pavia,
Viale Taramelli 12, 27100 – Pavia (Italy)
dalia_nimri@hotmail.com
Organic transformations that result in the formation of multiple covalent bonds within the same
reaction are some of the most powerful tools in synthetic organic chemistry. Nitrosocarbonyl
hetero-Diels–Alder (HDA) reactions allow for the simultaneous stereospecific introduction of
carbon–nitrogen and carbon–oxygen bonds in one synthetic step, and provide direct access to 3,6dihydro-1,2-oxazines.1 Our recent methodology to generate nitrosocarbonyls from Nmethylmorpholine N-oxide (NMO) mediated oxidation of nitrile oxides provides a convenient
source of these fleeting intermediates bearing a variety of heterocyclic rings as substituents. The
easy trapping with cyclic dienes afforded the corresponding HDA cycloadducts in fair yields.2
Cl
Het
O
O
Het
n
NMO, Et3N
DCM, r.t., 48h
N
N
N
OH
n = 1, 2
Het
O
O
Al(Hg)
THF/H2O
R
N
S
N
Het
HO
HN
O
N
The HDA cycloadducts were then cleaved using Al(Hg) under mild conditions in order to obtain
five- and six-membered cyclic olefins with heterocyclic substituents as novel nucleoside
analogues.3
These new compounds have been tested against a variety of viruses. In the present communication
the synthesis, characterization and synthetic elaboration will be discussed along with the biological
activities.
(1) Bodnar, B. S.; Miller, M. J. Angew. Chem. Int. Ed. 2011, 50, 5630-5647.
(2) Quadrelli, P.; Mella, M.; Gamba Invernizzi, A.; Caramella, P. Tetrahedron 1999, 55, 10497-10510.
(3) Keck, G. E.; Fleming, S.; Nickell, D; Weider, B. Synth. Commun. 1979, 9, 281-286.
191
P68
Targeting G-quadruplex by hybrid ligand-alkylating agents with a NDI scaffold
Luca Germani,1 Filippo Doria,1 Matteo Nadai,2 Claudia Percivalle,1
Sara N. Richter,2 Mauro Freccero1
1
Dipartimento di Chimica, Università di Pavia, V.le Taramelli 10, 27100 Pavia, Italy,
2
Dipartimento di Istologia, Microbiologia e Biotecnologie Mediche,
via Gabelli 63, 35121 Padova, Italy.
luca.germani01@ateneopv.it
Guanine rich oligonucleotides are capable of folding into supramolecular structures called Gquadruplex (G-4). The growing interest on G-4 structures is justified by their potential role in
anticancer strategy. Stabilization and selective recognition of G-4 conformations is the key aspect of
this strategy and it has been achieved by small molecules acting as G-4 reversible selective ligands.1
In the present work we report the synthesis2,3 and the reactivity of a new class of hybrid
ligand/alkylating NDIs. The ligand structures in the Scheme exhibit two -(CH2)2NMe2 solubilizing
side chains, tethered to both the imide moieties. An additional phenol moiety has been linked to the
NDI aromatic core by alkyl-amido spacers, with modular length. The key structural feature of the
synthesized library is the presence of orto-CH2OH group which can be embedded in the phenol
moiety. Its presence confers alkylating properties to the NDIs 1-6. In fact, the o-hydroxy benzyl
alcohol acts as masked electrophilic quinone methides (QM). QMs can be very useful for G-4
targeting by covalent interactions. These differences open the way for two distinctive subclasses
among the NDI library in Scheme: (i) potential reversible G-4 binders (lacking the orto-CH2OH
group) and (ii) hybrid ligand-alkylating NDIs. QMs have to be generated by the mild thermal
digestion (40°C). The introduction of a covalent linkage would result in both a direct covalent
damage and a stabilization of the G-4 structure.4,5
(1) Xu, Y. Chem. Soc.Rev. 2011, 40, 2719-2740.
(2) Nadai,M.; Doria, F.; Di Antonio, M.; Sattin, G..; Germani, L.; Percivalle, C.; Palumbo,M.; Richter, S.N.; Freccero,
M.; Biochimie 2011, 93, 1328-1340 .
(3) a) Di Antonio, M.; Doria, F.; Mella, M.; Merli, D.; Profumo, A.; Freccero, M. J. Org. Chem. 2007, 72, 8354-8360.
b) Doria, F.; Di Antonio, M.; Benotti, M.; Verga, D; Freccero, M. J. Org. Chem. 2009, 74, 8616-8625.
(4) Di Antonio, M.; Doria, F.; Richter, S. N.; Bertipaglia, C.; Mella, M.; Sissi, C.; Palumbo, M.; Freccero, M. J. Am.
Chem. Soc. 2009, 131, 13132-13141.
(5) Doria, F.; Nadai, M.; Folini, M.; Di Antonio, M.; Germani, L.; Percivalle, C.; Sissi, C.; Zaffaroni, N.; Alcaro, S.;
Artese, A.; Richter, SN.; Freccero, M. Org Biomol Chem. 2012, 10, 2798-2806.
192
P69
Water Soluble Terpyridine containing 1,2,4-oxadiazoles moieties
as selective G-Quadruplex Ligands
Michele Petenzi,1 Filippo Doria,1 Mariella Mella,1 Marie-Paule Teulade-Fichou,2 Mauro Freccero.1
1
2
Dipartimento di Chimica, Università di Pavia, V.le Taramelli 10, 27100 Pavia, Italy
UMR176 CNRS, Institut Curie, Centre de Recherche. Centre Universitaire, 91405 Orsay (France).
mikiiron@gmail.com
G-Quadruplexes (G4) are secondary DNA structures generated from guanine-rich repetitive
sequence, involved in some important biological roles. During last 20 years stabilisation of G4
structures has become a promising anticancer strategy1. In fact, small organic molecules could be
used as G4 binders exploiting selective reversible interactions. Using a solvent free microwaveassisted synthesis we have created a new family of water-soluble selective G4 ligands. Inspiring to
natural macrocycle telomestatin2, that exhibits a remarkable antitumor activity, we have prepared
and studied a family of acyclic poly-heterocyclic compounds similar to the recently published
groove binder TOxaPy (Scheme).3
Scheme: TOxaPy, BOxaPys and BOxAzaPys structures.
The new BOxAzaPy4 series, with 1,2,4-oxadiazoles moieties instead the 1,3-oxazole moieties of
BoxaPys compounds, show a nitrogen binding cavity like telomestatin, in the bent conformation.
Moreover the cationic side chains, introduced by an efficient microwave-assisted protocol, seem to
favourably affect the binding to G4. Stabilization of the telomeric sequences by BOxaPys (810)and BOxAzaPys (1-7) series was investigated by FRET-melting assay, HT-G4-FID and circular
dichroism experiments. Our data reveal that the oxadiazole core and lateral cationic chains highly
controlled the binding to G4. The results (especially the induced circular dichroism, ICD) suggest
that a specific interaction may be established in the grooves of the G4. Furthermore the FRET
experiments show that the ligands prefer the stabilization of the parallel G4 topology (Figure).
Figure: G4 FRET-melting experiments in the presence of several BOxAzaPys
A) potassium-rich buffer; B) sodium rich-buffer.
(1) a)S. Balasubramanian, S. Neidle, Curr. Opin. Chem. Biol. 2009, 13, 345-353; b) D. Monchaud, M.P. TeuladeFichou. Org. Biomol. Chem. 2008, 6, 627-636.
(2) J. Linder, T.P. Garner, H.E.L. Williams, M.S. Searle, C.J. Moody, J.Am.Chem.Soc. 2011, 133, 1044-1051.
(3) Marie-Paule Teulade-Fichou, Angew. Chem. Int. Ed. 2011, 50, 8745-8749
(4) M. Petenzi, D. Verga, E. Largy, F. Hamon, F. Doria, M.P. Teulade-Fichou, A. Guédin, J.L. Mergny, M. Mella, M.
Freccero, Chem. -Eur. J. 2012 Submitted.
193
P70
Anti-miR PNA for gene regulation
Roberto Corradini,1 Alex Manicardi,1 Fabio Aimi,1 Tullia Tedeschi,1 Stefano Sforza,1
Rosangela Marchelli1, Enrica Fabbri,2 Eleonora Brognara,2 Nicoletta Bianchi,2 Roberto Gambari2
1
Parco Area delle Scienze 17/A, 43124, Parma
2
BioPharmaNet, Dipartimento di Biochimica e Biologia Molecolare,
Università di Ferrara, Via Fossato di Mortara n.74, 44100 Ferrara.
roberto.corradini@unipr.
Peptide nucleic acids (PNA), and their modification (Figure 1) are extensively used for targeting
mRNA in the antisense1 or anti-gene approaches.2 Micro-RNAs (miRs) are regulatory short (19-23
bp) dsRNA which modulate gene expression of highly relevant biological functions such as
differentiation, cell cycle and apoptosis. Inhibition of miR activity by PNA and their analogues
(anti-miR PNA) is of great interest in drug development, and is a tool for the up-regulation of genes
targeted by miR.3 The use of PNA internally modified in the backbone at C2 or C5 or at the
nucleobase level (Figure 1A) allows to introduce further contributions to the stability and
selectivity.
A
Base modfication
B
Active element
PNA
PNA conjugate
Backbone modfication
Internally modified
PNA
PNA
Figure 1 A: Structure of PNA and modified PNA; B: Scheme of end-conjugated or internally modified PNAs.
We here describe the synthesis of anti-miR PNA of high affinity and high specificity for miR210
and miR221, involved in erythroid differentiation and tumor progression, respectively. Modified
PNA showed improved biovailability and exerted anti-miR activity, leading to up-regulation of
genes.4,5 Internally-modified PNAs, bearing arginine side chains either at C2 or C5 carbon atom of
the PNA backbone showed improved cellular uptake, and higher biostability than the peptideconjugated, and effectiveness of these compounds was shown to depend on the type and position of
substitution. Perspectives in the use of this approach, and new strategies for the elaboration of PNA
structure during the solid phase synthesis either at the backbone or at the nucleobase level, thus
introducing new functionalities for RNA/DNA binding or catalysis, will be discussed.
(1) R Corradini, R.; Sforza, S.; Tedeschi, T.; Totsingan, F.; Manicardi, A.; Marchelli, R. Curr Top Med Chem 2011 ,
11, 1535-1554.
(2) Tonelli, R.; McIntyre, A.; Camerin, C.; Walters, Z.S. et al. Clinical Cancer Res 2012, 18,796-807.
(3) Fabbri, E.; Manicardi, A., Tedeschi, T.; Sforza, S.; Bianchi, N.; Brognara, E.; Finotti, A.; Breveglieri G.; Borgatti,
M.; Corradini, R.; Marchelli, R.; Gambari, R. ChemMedChem 2011, 6, 2192-2202.
(4) Brognara, E.; Fabbri, E.; Aimi, F.; Manicardi, A.; Bianchi, N.; Finotti A.; Breveglieri, G.; Borgatti, M.; Corradini,
R.; Marchelli, R.; Gambari, R. Int. J Oncol. 2012, in press
(5) Manicardi, A.; Fabbri, E.; Tedeschi, T.; Sforza, S.; Bianchi, N.; Brognara, E.; Gambari, R.; Marchelli, R.;
Corradini, R. ChemBiochem 2012, 13, 1327-1337.
194
P71
Pyridyl methanol derivatives as new Hantzsch ester mimics
in metal-free reductions
Renzo Alfini, Alberto Brandi, Donatella Giomi
Dipartimento di Chimica ‘Ugo Schiff’, Università di Firenze, Polo Scientifico e Tecnologico
Via della Lastruccia 3-13, I-50019 Sesto Fiorentino, Italy
donatella.giomi@unifi.it
1-(2-Pyridyl)-2-propen-1-ol (1) showed a peculiar behaviour as C-1, C-2, or C-3 carbon
nucleophile, depending on the experimental conditions, likely associated to the weak acidity of the
‘picoline type’ hydrogen atom.1,2 On the other hand, reactions of the above alcohol with nitrosubstituted aromatic and heteroaromatic compounds as electrophiles evidenced for 1 a surprising
reactivity as Hantzsch ester (HEH) 1,4-dihydropyridine mimic, allowing the metal-free reduction of
nitro compounds to the corresponding amino derivatives.2,3 Moreover, the redox mechanism, again
ascribed to the ‘mobility’ of the hydrogen atom on the C-1 carbon of 1, is part of a domino process
leading to the one-pot formation of new functionalised aminoacylpyridines 2, through aza-Michael
addition of the amino derivatives to the vinyl ketone intermediate coming from the oxidation of 1.
Unluckily, the multifacet reactivity of alcohol 1 is often responsible for competitive reaction
pathways leading to mixtures of products with low selectivities.
R
N
O
R'
RX
R'X
RNO2
N
N
O
R''
R''X
1
OH
R = Ar,Het
H
N
N
O
R
2
N
OH
EtO2C
RNO2
R
N
3
OH
CO2Me
H
N
CO2Me
4 R = Ar,Het
Me
CO2Et
N
Me
H
HEH
In this context, pyridylphenyl4 and quinolylphenyl methanols 3 were studied as Hantzsch ester
mimics for the metal-free reduction of nitro aromatic and heteroaromatic systems. These reagents
resulted more efficient hydrogen donors because the replacement of the vinyl moiety prevents
competitive processes observed for carbinol 1. In particular, multicomponent reactions (3-MCR) of
3 with nitro derivatives and methyl acrylate allowed a facile one-pot synthesis of -amino esters 4.
Mechanistic aspects as well as synthetic applications of these new reactions will be properly
discussed.
(1)
(2)
(3)
(4)
Giomi, D.; Piacenti, M.; Brandi, A. Tetrahedron Lett. 2004, 45, 2113-2115
Giomi, D.; Piacenti, M.; Alfini, R.; Brandi, A. Tetrahedron 2009, 65, 7048-7055.
Giomi, D.; Alfini, R.; Brandi, A. Tetrahedron Lett. 2008, 49, 6977-6979.
Giomi, D.; Alfini, R.; Brandi, A. Tetrahedron 2011, 67, 167-172.
195
P72
A theoretical study of the Julia-Kocienski reaction
Laura Legnani, Alessio Porta, Giuseppe Zanoni, Giovanni Vidari, Lucio Toma
Dipartimento di Chimica, Università di Pavia, Via Taramelli 12, 27100 Pavia, Italy.
laura.legnani@unipv.it
The Julia–Kocienski (J-K) reaction has become an important tool for the synthesis of olefins for its
almost complete E-stereoselectivity, especially in total synthesis of natural products.1 The classical
Julia reaction2 consists of a multi-step sequence comprising nucleophilic attack of an α-metallated
aromatic sulfone on an aldehyde affording a β-hydroxy sulfone, functionalization of the hydroxyl
group, and reductive elimination. The original Julia protocol was then modified with the one-pot
preparation of olefins from carbonyl compounds and benzothiazol-2-yl sulfones (BT sulfones) upon
Smiles rearrangement of the intermediate lithium alkoxide. This new version was developed by
Kocienski who introduced the use of 1-phenyl-1H-tetrazol-5-yl sulfones (PT sulfones).3
S
R1
SO2TB
R2
OM
1
S
N
O
O S
R1
2
H R
M
O
H
N M
MO2S
O SO2
R1 2
R
R1
H
H
2
3
OPT
R1
2
R
SO2M
R2
OTP
4
5
R1
R2
Scheme 1
The commonly accepted mechanism of the J-K (Scheme 1) involves the addition of a metallated
sulfone to an aldehyde to give alkoxide 1, followed by a Smiles rearrangement through spirocyclic
intermediates 3 which affords sulphinate 4. After a conformational change, 4 is converted into 5
that via antiperiplanar β-elimination gives the E-olefin. In order to rationalize the stereochemical
outcome of this reaction, we firstly performed a preliminary mechanistic study on simplified
structures to locate all the intermediates and the transition states along the reaction pathway. Full
geometry optimizations were performed in the gas phase at the B3LYP/6-311+G(d,p) level (6311+G(2df,p) for the S atom). The results were confirmed by IRC analyses at the same level as
above. Solvent effects were considered by single-point calculations, on the gas-phase optimized
geometries, using a self-consistent reaction field (SCRF) method, based on the polarizable
continuum model (PCM).
(1) Zanoni, G.; Brunoldi E.M.; Porta, A.; Vidari, G. J. Org. Chem. 2007, 72, 9698-9703
(2) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 14, 4833-4836.
(3) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26-28.
196
P73
Concanavalin A multivalent recognition by a calixarene-based
glucose functionalized bolaamphiphile included in lipid bilayers
S. Aleandria,1 A. Casnati,2 L. Fantuzzi,2 G. Mancini,1,3 G. Rispoli,2 F. Sansone2
1
Dipartimento di Chimica, Università degli Studi di Roma “Sapienza”,
P.le A. Moro 5, 00185 Roma, Italy.
2
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Parma,
Parco Area delle Scienze 17/A, 43124 Parma, Italy.
3
CNR, Istituto di Metodologie Chimiche, P.le A. Moro 5, 00185 Roma, Italy.
francesco.sansone@unipr.it
Amphiphiles formed by two polar regions connected by one or more hydrophobic chains are named
bolaamphiphiles. Bolalipids are present in the membrane of Archeabacteria living in extreme
habitats and their covalent structure probably participates in conferring to them high chemical and
physical stability under hostile and harsh conditions. Their presence in liposomes was shown to
ascribe them increased rigidity and lower permeability with respect to conventional liposomes, both
features being of great interest in the formulation of liposomes as drug delivery systems.1 We herein
describe the synthesis and the inclusion in lamellar phases and liposomes of a bolaamphiphile built
on a calixarene scaffold (1 in Figure). The macrocycle is shaped in the 1,3-alternate structure and
functionalized with four hydrophobic tails terminating with D-glucose head-groups. The glycoside
units, beyond acting as polar heads, render the bolaform glycocalixarene and its liposome
formulations potentially useful as multivalent ligand for targeting cells and tissues expressing sugar
receptors. Glycocalixarenes2 in fact already demonstrated to be per se interesting multivalent
ligands for lectins.3 In this case, it was found that the new bolaform glucocalixarene 1 perturbs
bilayers of saturated lipids whereas, analogously to cholesterol, it rigidify bilayers of unsaturated
lipids. By optical microscopy and fluorescence experiments it was detected that, when the
macrocycle is inserted in lamellar phases and liposomes, the glucosyl units present in its structure,
not only maintain but also increase with respect to D-glucose their ability to interact with the
multivalent Concanavalin A.
OH OH
HO
OH
HO
HO
O
HO
N
N
N
N
N
N
N
8
HO
O
O
OH
O
O
8
N
N
8
O
O
OH
HO
O
O
O
1
N
8
N
N
O HO
O
OH
HO
OH
OH
(1) Benvegnu, T.; Réthoré, G.; Brard, M.; Richter, W.; Plusquellec, D. Chem. Commun. 2005, 5536–5538.
(2) Baldini, L.; Casnati, A.; Sansone, F.; Ungaro, R. Chem. Soc. Rev. 2007, 36, 254–266. Dondoni, A.; Marra, A.
Chem. Rev. 2010, 110, 4949–4977. Sansone, F.; Rispoli, G.; Casnati, A.; Ungaro, R. in Synthesis and Biological
Application of Glycoconjugates, ed. O. Renaudet and N. Spinelli, Bentham Science Publishers, 2011, Ch. 3, pp
36–63.
(3) André, S.; Sansone, F.; Kaltner, H.; Casnati, A.; Kopitz, J.; Gabius, H.-J.; Ungaro, R. ChemBioChem 2008, 9,
1649–1661; André, S.; Grandjean, C.; Gautier, F.-M.; Bernardi, S.; Sansone, F.; Gabius, H.-J.; Ungaro, R. Chem.
Commun. 2011, 47, 6126–6128; Cecioni, S.; Lalor, R.; Blanchard, B.; Praly, J.-P.; Imberty, A.; Matthews, S. E.;
Vidal, S. Chem.–Eur. J. 2009, 15, 13232–13240.
197
P74
A stereodivergent approach to the enantioselective synthesis of neurofuranes
Davide Sbarbada, Matteo Valli, Alessio Porta, Giuseppe Zanoni, Giovanni Vidari
Università degli Studi di Pavia, Dipartimento di Chimica, Sez. Chimica Organica
Via Taramelli 10, 27100, Pavia (PV)
davide@davidesbarbada.com
Neurofuranes are metabolites formed in the brain of patients affected by Alzheimer’s and Parkinson’s disease in consequence of an increased oxidative stress; in particular, they are produced
by lipid peroxidation of docosahexaenoic acid (DHA) esterified in neuron membranes. These
compounds are particularly promising biomarkers of oxidative stress in neurodegenerative disorders
and are considered as possible diagnostic tools for the early detection of Parkinson’s disease.
During our total synthesis of the 7-epi-ST-8-10-NeuroF neurofurane (Figure 1), a great deal of
efforts were dedicated to assemble the three contiguous stereogenic carbons on the tetrahydrofurane
ring with the desired absolute configuration.
Figure 1
This goal was finally achieved through an intramolecular, Pd(0)-promoted, Tsuji-Trost Asymmetric
Allylic Alkylation of meso diol (S-1), in the presence of the chiral ligand (S,S)-DPPBA, which
afforded the THF core S-2 in high yield and excellent enantiomeric excess (Figure 2).
Figure 2
The work required a methodological screening of a great number of chiral ligands, Pd sources, and
other experimental conditions. Thus, by properly choosing the chiral catalyst, we could achieve
complete control over the desymmetrization process, which occurred though preferential
complexation of the chiral Pd-catalyst to one of the two enantiotopic allylic moieties. In this way
both ST- and AC-type tetrahydrofuran cores were constructed, which paves the way to a
straightforward synthesis of both families of neurofuranes.
198
P75
One-pot synthesis of α-vinyl quaternary amino acids
Massimo Serra, Elena Giulia Peviani, Lino Colombo
Dipartimento di Scienze del Farmaco, viale Taramelli 12, 27100 Pavia, Italy
massimo.serra@unipv.it
Natural amino acids modified by the introduction of a vinyl moiety at the α-position cannot only
induce remarkable conformational changes if introduced in peptides, but also possess important
biological features.1 As a consequence of the concurrent presence of a natural side-chain and a vinyl
moiety, they can act as enzyme inhibitors and, when incorporated in a peptide, increase the
resistance to proteolysis, eventually enhancing the bioavailability of the molecule.2
Furthermore, the impressive application range of olefin metathesis and Pd-catalyzed coupling
reactions (Heck, Suzuki) has aroused new interest in the synthesis of olefinic α-amino acids as
versatile building blocks for the achievement of conformationally constrained or easily
functionalizable peptidomimetics.
In this work we report a fast one-pot protocol suitable for gram scale preparation of α-vinyl, α-alkyl
quaternary α-amino acids (Scheme). The new protocol exploits as a key reaction an aldol
condensation between 2-(phenylselenenyl)acetaldehyde and 4-alkyl-2-phenyloxazolones, readily
accessible by cyclization of the corresponding N-benzoyl amino acids. The generation of the vinyl
moiety was obtained in moderate to good yields by mesylation of the crude alcohols mixture arising
from the aldol addition followed by a microwave-assisted elimination reaction (3 steps, y: 40-75%).
The final acid hydrolysis of the oxazolone ring afforded the desired α-vinyl, α-alkyl quaternary αamino acids in almost quantitative yields.
Scheme
Although our primary aim was the fast (one-working-day) synthesis of α-vinyl quaternary amino
acids, we set up a synthetic scheme that could in principle allow the preparation of enantiomerically
pure compounds. Indeed, the use of chiral bases in the enolate formation step could affect the
stereochemical outcome of the aldol condensation and, as a consequence, the e.e. of the final amino
acids derivatives. Preliminary experiments allowed us to achieve enantiomerically enriched
compounds but the enantioselection is not high yet (49-71%). Therefore, a wider screening of bases
will be performed in order to attain synthetically useful level of enantioselection.
(1) a) Cativiela, C.; Díaz-de-Villegas, M.D. Tetrahedron: Asymmetry 2007, 18, 569-623. b) Cativiela, C.; Ordóñez,
M. Tetrahedron: Asymmetry 2009, 20, 1-63
(2) Berkowitz, D.B.; Charette, B.D.; Karukurichi, K.R.; McFadden, J.M. Tetrahedron: Asymmetry 2006, 17, 869-882.
199
P76
Isolation of novel biologically active triterpenoid derivatives
from the Basidiomycete Tricholoma sejunctum
Davide Gozzini,1 Gianluca Gilardoni,1 Marco Clericuzio,2 Giovanni Vidari.1
1
Dipartimento di Chimica, Università degli Studi di Pavia, via Taramelli 12, Pavia.
2
Dipartimento di Scienze e Innovazione Tecnologica,
Università del Piemonte Orientale, Via T. Michel 11, 15121 Alessandria
davide.gozzini@unipv.it
As a part of our ongoing screening for the discovery of novel natural products from higher
mushrooms, we have investigated Tricholoma sejunctum. This is an inedible and bitter-tasting
mushroom commonly growing in the mountains of the northern part of Italy, in broad-leaved and
coniferous forests.
More than seven kilograms of fresh fruiting bodies were frozen, shredded and extracted in ethyl
acetate; the resulting extract was then purified through different purification steps, using liquidliquid partitions, HPLC separations either on silica gel and reversed phase C18 columns, and
crystallization processes whenever possible. The chemical structures of the obtained pure
compounds were elucidated through extensive NMR experiments and LC-MS analysis.
Several novel triterpenoid derivatives have been identified, related to a few compounds already
isolated from other species of Tricholoma, in particular from T. saponaceum,1-4 but not yet from T.
sejunctum. In accordance with the current literature the new crustinol esters were named
saponaceols D, E, F, G, H, while the other two new terpenoids were named saponaceolides H and I.
Moreover saponaceolides A, B, and C, already described in the literature,2,3 were also isolated from
T. saponaceum for the first time. Typical examples of the structures are:
OH
OH
OH
O
OH
O
OH
O
O
N
H
7
H
OH
H3COOC
OH
O
HO
O
O
Saponaceol D
O
Saponaceolide H
Due to the particular and unusual backbones of these molecules, several tests were performed in
order to determine the bioactivity of the isolated compounds. Indeed the saponaceolides have shown
high cytotoxic activity against different human tumor cell lines.2,3 On the other hand, the close
structural relationship between the saponaceol and the fasciculic acid families5 suggests a possible
calmodulin antagonist activity of these newly isolated compounds.
These bioassays are undergoing.
(1)
(2)
(3)
(4)
Yoshikawa, K.; Kuroboshi, M.; Ahagon, S.; Arihara, S.; Chem. Pharm. Bull. 2004, 52 (7), 886-888.
De Bernardi, M.; Garlaschelli, L.; Gatti, G.; Vidari, G.; Vita Finzi, P.; Tetrahedron, 1988, 44 (1), 235-240.
De Bernardi, M.; Garlaschelli, L.; Toma, L.; Vidari, G.; Vita Finzi, P.; Tetrahedron, 1991, 47 (34), 7109-7116.
Yoshikawa, K.; Kuroboshi, M.; Arihara, S.; Miura, N; Tujimura, N.; Sakamoto, K.; Chem. Pharm. Bull. 2002,
50(12), 1603-1606.
(5) Takahashi, A.; Kusano, G.; Ohta, T.; Ohizumi, Y.; Nozoe, S.; Chem. Pharm. Bull., 1989, 37 (12), 3247-3250.
200
P77
On the stereochemistry of the Mitsunobu reaction of
chiral secondary alcohols with 2,6-diphenylphenol
Ugo Azzena,1 Sarah Mocci,1 Luisa Pisano,1 Mario Pittalis,1
Renzo Luisi,2 Biagia Musio,2 Leonardo Degennaro2
1
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari,
via Vienna 2, 07100 Sassari
2
Dipartimento Farmaco – Chimico Università degli Studi di Bari,
Via E. Orabona 4, 70125 Bari
ugo@uniss.it
We recently reported on the protection of functionalized and non functionalized alcohols as mterphenyl ethers.1 These ethers are easily accessible via an ultrasound stimulated Mitsunobu
reaction,2 are stable under a variety of reaction conditions (e.g., towards basic and organometallic
reagents as well as towards acidic hydrolysis), and can be easily deprotected under SET reaction
conditions using Na metal in THF, as depicted in the example reported below. Later on, we were
able to successfully extend similar procedures to o-biphenyl ethers.
Ph
O
OH
Ph
+
HO
4
O
1. DIAD, Ph 3P, THF
rt, sonication
Ph
Ph
+ -
O
4
2. 1M HCl
THF
O
1. Ph3MeP I , n-BuLi
+
2. Na, THF
Ph
HO
4
CH 2
Ph
We wish now to report the results of a stereochemical investigation aimed to verify the behavior of
chiral secondary alcohols under the above reported reaction conditions. Preliminary results indicate
that protection of these alcohols as m-terphenyl ethers occurs with retention of configuration, whilst
protection as o-biphenyl ethers occurs with inversion of configuration.
Ph
O
Ph
R
Ph
OH
G
+
HO
R
H R'
DIAD, Ph3 P, THF
rt, sonication
H
R'
Ph
O
G = Ph or H
H
R'
R
H
A reaction mechanism accounting for the unusual stereochemical outcome of this synthetic
approach to m-terphenyl ethers will be presented.
(1) Azzena, U.; Mocci, S.; Pisano, L. Synthesis 2011, 1575-1580.
(2) Lepore, S. D.; He, Y. J. Org. Chem. 2003, 68, 8261-8263.
201
P78
Enantioselective synthesis of A- and J-prostanoids via
an asymmetric Diels-Alder cycloaddition of fulvenes
Matteo Valli, Alessio Porta, Francesco Chiesa, Andrea Gandini,
Giuseppe Zanoni and Giovanni Vidari
Università di Pavia, Dipartimento di Chimica, Via Taramelli 10, 27100 Pavia
matteo.valli@unipv.it
The Diels-Alder cycloaddition has always played a fundamental role in organic synthesis. Actually,
this potent methodology has been the key reaction in several enantioselective syntheses of natural
compounds of different types, including prostaglandins and prostanoids. In a precedent
presentation1 we have reported a divergent approach to J- (1) and A-type (2) isoprostanes and
neuroprostanes, featuring a Diels-Alder reaction between fulvene 3 and methyl-acrylate to
efficiently prepare the required starting building block.
COOH
J-Type
O
OH
1
O
COOH
OH
A-Type
2
In order to develop an enantioselective version of these syntheses, we have explored the asymmetric
catalysed Diels-Alder reaction beetween fulvene 3 and Evans oxazolidinone 4. The preliminary
already exciting results (94-96% ee of the endo adduct) obtained with the complex formed between
Mg(ClO4)2 and the chiral ligand 7 as the catalyst, were improved using the complex of Cu(OTf)2
with the chiral ligand 8 (Scheme 1). Thus, we have reached an ee up to 99%. Given its excellent
enantio- and diastereomeric purity, and the high synthetic versatility, we envisage the use of adduct
6 as a pivotal building block in the synthesis of prostanoids and other valuable cyclopentanoid
natural products.
OAc
OAc
OAc
O
O
N
3
4
O
Mg(ClO4)2, BOX1
O
CH2Cl2 dry, -55¡C
Molecular sieves
90%
H
5
O
BOX1 =
Ph
7
O
BOX2=
O
H
O
N
6
O
O
O
O
Ph
N N
Ph
N
ee endo 94%
endo/exo 99:1
Ph
O
N N
t-Bu
8
t-Bu
Scheme 1
(1)
XXXIII Convegno Nazionale della Divisione di Chimica Organica, San Benedetto del Tronto 12-16 Settembre
2010.
202
P79
Ligand free Suzuki cross-coupling for the synthesis of
unconventional cores of HIV-1 protease inhibitors
Lucia Chiummiento, Maria Funicello, Paolo Lupattelli, Francesco Tramutola.
Dipartimento di Chimica “A. M. Tamburro”, Università della Basilicata.
Via dell’Ateneo Lucano 10, 85100, Potenza.
maria.funicello@unibas.it
Metal-catalyzed cross-couplings1 are powerful tools for organic chemists to form new C-C bonds.
Among these cross-coupling processes, Suzuki reaction is one of the most attractive due to the
ready availability of organoboron compounds, their high compatibility toward numerous functional
groups, air-stability and lower toxicity than other organometallic species. In our continuous pursuit
of new HIV-1 protease inhibitors (PIs) bearing unconventional P1-ligands,2-4 we have speculated a
convenient synthetic route to introduce diversity into the common hydroxyethylamino core present
in several approved PIs (e.g. darunavir).
In a simple retrosynthetic approach, variously functionalized aromatic groups can be incorporated
by Suzuki coupling between an activated C(sp3)-bromide (allylic electrophile) and an array of
arylboronic acids to furnish methyl 4-arylcrotonates.
After attempting in different routes we finally elaborated an effective ligand free Suzuki crosscoupling protocol to unite methyl (E)-4-bromobut-2-enoate with several arylboronic acids. Thus a
number of variously functionalized methyl 4-arylcrotonates have been achieved in high to excellent
yields under mild conditions. This method enables to easily prepare various aryl-substituted cores of
potential HIV-1 protease inhibitors. (Scheme 1)
Scheme 1
(1) Suzuki, A. Angew. Chem. Int. Ed. 2011, 50, 6723-6737.
(2) Chiummiento, L.; Funicello, M.; Lupattelli, P.; Tramutola, F.; Campaner, P. , Tetrahedron 2009, 65, 5984–5989.
(3) Bonini, C.; Chiummiento, L.; De Bonis, M.; Di Blasio, N.; Funicello, M.; Lupattelli, P.; Pandolfo, R.; Tramutola,
F.; Berti, F. J. Med. Chem.. 2010, 53, 1451-1457.
(4) Chiummiento, L.; Funicello, M.; Lupattelli, P.; Tramutola, F.; Berti, F.; Marino-Merlo, F. Bioorg. Med. Chem.
Lett. 2012, 22, 2948-2950.
203
P80
A concise synthesis of a novel 10B-Gd derivative for MRI assisted BNCT
Valentina Merlini, Claudia Guanci, Alessio Porta, Giuseppe Zanoni, Giovanni Vidari
Dipartimento di Chimica, Sezione di Chimica Organica,
Università degli Studi di Pavia, viale Taramelli 10, 27100 Pavia
valentina.merlini@unipv.it
Boron Neutron Capture Therapy (BNCT) is an experimental binary anti-cancer therapy that is
designed to exploit the cytotoxic effect of alpha particles and lithium ions released from 10Boron
nuclides following a nuclear reaction induced by thermal neutrons. For this purpose, we have
conceived a novel bimetallic compound made up of a boronophenylalanine moiety, as the 10B
carrier, linked, through an aliphatic chain, to a GdIII-DTPA complex. This would allow the
evaluation of the in vivo boron distribution using MRI, an non invasive imaging method based on
NMR spectroscopy. Thus, boron distribution would be quantified in all the tissues irradiated, just
before irradiation. The good incorporation of our synthesized compound in tumour cells, together
with the application of a non invasive tempo-spatial quantification of 10B, would represent two
important factors which have the potential to greatly promote BNCT as a routine therapy in hospital
settings, for the treatment of tumours that are not responsive to conventional cures.
The short and convenient synthetic strategy which has be developed for the preparation of the
binary 10B/Gd device is shown below:
NH2
HO
B
quantitative
OH
THF, rt, 24 h
MeO
O
N
H
HO
B
NH2
5
PhB(OH)2
O
B
O
B
hexane / MeOH / H2O
10 / 3 / 7 (0.005 M)
O
HO
B
O
NH2
5
O
N
H
O
O
92%
O
H
N
NH2
5
B
O
H
N
S
Et3N
N
DMSO
+
OH
B
O
N
H
TFA (10 eq)
46% (2 steps)
O
70%
O
O
NHBoc
5
DCM, rt, 5 h
O
N
H
MeO
O
DCM, rt, 24 h
O
OH
MeO
O
N
H
Boc-6-Ahx-OH, BOP,
DIEA
pinacol
rt, 48 h
O
NH2
NH2
SOCl2, MeOH
MeO
COOMe
COOMe
COOH
HO
B
OH
OOC OOC
Na
COO
N
N
COO
COO
Gd3+
Na
S C N
S C N
N
HOOCHOOC
COOH
N
N
COOH
COOH
N
GdCl3
H2O
OOC OOC
Na
COO
N
N
COO
COO
Gd3+
Na
This synthetic pathway has required the protection of the free OH groups of the boronic acid of
BPA as pinacol ester, to avoid partial esterification as methyl ester in presence of methanol.
The overall yield of the synthesis is about 20%, over only seven steps, which makes it highly
competitive with the only other process reported in the literature for the synthesis of a related
compound.1
(1) Takahashi, K.; Nakamura, H.; Furumoto, S.; Yamamoto, K.; Fukuda, H.; Matsumura, A.; Yamamoto, Y. Bioorg.
Med. Chem. 2005, 13, 735-743.
204
P81
Free radical multicomponent synthesis of -aminoalcohols and -aminoethers
mediated by TiCl4-Zn/t-BuOOH system
Nadia Pastori, Bianca Rossi, Angelo Clerici, Carlo Punta
Dipartimento di Chimica, Materiali e Ingegneria Chimica "G. Natta", Politecnico di Milano,
Via Mancinelli 7, I-20131 Milano, Italy.
nadia.pastori@polimi.it
Free radical reactions in organic synthesis provide multiple advantages if compared to the classical
ionic reactions, which often require expensive reagents and hazardous operating conditions.1 In
particular, nucleophilic radical addition to the carbon atom of imine derivatives has proved to be an
alternative route to the synthesis of a wide range of polyfunctional molecules and different
procedures have been developed.2
In the last years we reported that the Ti(III)/hydroperoxide (H2O2, t-BuOOH) system was able to
promote both radical Mannich-type reactions and a radical version of the Strecker synthesis, starting
from an aldehyde and an amine in ether, alcohol or formamide co-solvent, respectively.3 More
recently we showed that this nucleophilic free radical addition of formamide could be performed
onto ketimines generated in situ, providing instant access to quaternary α-aminoacid precursors.
The previously reported protocol was optimized by replacing the aqueous solution of TiCl 3 with the
more convenient and efficient Ti(IV)-Zn system.4,5
Here we report two application of the TiCl4-Zn/t-BuOOH system:
a) Nucleophilic radical hydroxymethylation of ketimines, leading to the synthesis of -amino
alcohols by assembling an amine, a ketone and a molecule of methanol in one-pot.
b) α-ethereal radical (cyclic and acyclic) addition to the C-atom of ketimines generated in situ
leading to β-radical aminoalkylation of ethers.
Both cyclic and acyclic ketones resulted suitable for this new procedure, thus confirming its general
applicability. Moreover, this protocol allows to operate under non-anhydrous conditions, requiring
neither the preformation of the ketimine nor the protection of the amino group.
(1) a) Radicals in Organic Synthesis; Renaud, P., Sibi, M.P., Eds. Wiley-VCH: New York, 2001; Vol 1-2. b)
Sibi,M.P., Manyam, S.; Zimmerman, J. Chem.Rev. 2003, 103, 3263-3296. c) Rowlands, G.J. Tetrahedron
2009,65, 8603-8655. (d) Rowlands, G.J. Tetrahedron 2010,66, 1593-1636.
(2) a) Friestad, G. K. Tetrahedron 2001, 57, 5461-5496. b) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 7, 11401157. c) Friestad, G. K. Eur. J. Org. Chem. 2005, 3157-3172. d) Yamada, K; Tomioka,K. Chem. Rev. 2008, 108,
2874-2886. e) Akindele, T.; Yamada, K; Tomioka,K. Acc. Chem. Res. 2009, 42, 345-355. f) Gambarotti, C.;
Punta, C. In Tomorrow’s Chemistry Today;; Pignataro, B., Ed.;; Wiley-VCH: Weinheim, 2008.
(3) a) Cannella, R.; Clerici, A.; Panzeri, W.; Pastori, N.; Porta, O. Tetrahedron 2006, 62, 5986–5994; b) Clerici, A.;
Ghilardi, A.; Pastori, N.; Punta, C.; Porta, O. Org. Lett. 2008,10, 5063–5066; c) Cannella, R.; Clerici, A.; Panzeri,
W.; Pastori, N.; Punta, C.; Porta, O. J. Am. Chem. Soc. 2006, 128, 5358–5359.
(4) Pastori, N.; Greco, C.; Clerici, A.; Porta, O. Org. Lett. 2010,12, 3898–3901.
(5) Prosperini, S.; Pastori, N.; Ghilardi, A.; Clerici, A.; Punta, C. Org. Biomol. Chem., 2011, 9, 3759-3767
205
P82
New peptidomimetic α4β1-integrin antagonists
for reducing inflammation and allergic reactions
A. Greco,1 R. De Marco,1 A. Tolomelli,1 A. Viola,1 S. Spampinato,2
M. Baiula,2 S. Dattoli,2 L. Gentilucci1
1
2
Department of chemistry “G. Ciamician”,
Department of Pharmacology, University of Bologna, Italy
arianna.greco5@unibo.it
The accumulation of leukocytes in various organs contributes to the
pathogenesis of a number of human autoimmune diseases such as asthma,
rheumatoid arthritis, Crohn’s disease, ulcerative colitis, hepatitis C, and
multiple sclerosis.1 The inflammatory processes leading to tissue damage
and disease are mediated in part by the α4β1 integrins expressed on the leukocyte cell surface. These glycoprotein/glycosylated receptors
modulate cell adhesion via interaction with their primary ligands VCAM
and MAdCAM, expressed in the affected tissue. Binding results in firm
adhesion of the leukocytes to the vessel wall followed by entry into the
affected tissue.2 Elevated CAM expression in various organs has been
linked with several autoimmune diseases. In addition, increasing
evidence points to important causative links between inflammation and cancer; in fact, the α4β1 integrin is also involved in the formation of new cancer blood vessels.3
In this work we discuss a library of peptidomimetic inhibitors of α4β1 integrin based on a rigid
central scaffold, β-amino acid residues, and partially modified retro-inverso sequence.
Peptidomimetic integrin antagonists capable of inhibiting the adhesion of leucocytes to their ligands
might represent a new approach for treatment of human inflammatory diseases and cancer,
alternative to the use of monoclonal antibodies.
The pharmacological characterization has been performed by the cell-adhesion inhibition (Jurkat
and eosinophils cells) and SPA assays. The animal model allowed us to study the effect of the
compounds in reducing inflammation and allergic reactions.
We are going to study the recruitment in samples obtained from the animals.
(1)
(2)
(3)
R. O. Hynes. Cell, 1992, 69, 11.
D. Y. Jackson. Curr Pharm Des, 2002, 8, 1229-53.
H. Jin, A. Aiyer, J. Su et al. J. Clin. Invest, 2006, 116, 652-662.
206
P83
(Trimethylsilyl)methyl-chloroanisoles as new precursors
for the photochemical generation of ,n-didehydrotoluenes
Carlotta Raviola, Stefano Protti, Davide Ravelli, Maurizio Fagnoni, Angelo Albini
PhotoGreen Lab, Department of Chemistry, University of Pavia
Viale Taramelli 12, 27100 Pavia, Italy
carlotta.raviola01@ateneopv.it
,n-Didehydrotoluenes (,n-DHTs) are hetero-symmetric diradical species (51) claimed as
potential chemoterapeutic agents1 and their generation in solution has been limited so far to the ,3isomer by the Myers-Saito cyclization of enyne-allenes.2 An alternative route to these intermediates
has been recently proposed by our group3 and involves a photoinduced double elimination process
occurring in (n-chlorobenzyl)trimethylsilanes.
Thus, irradiation of these substrates ( = 254 nm) in protic or polar media causes the heterolytic
cleavage of the Aryl-Cl bond to give a triplet phenyl cation. Loss of the trimethylsilyl cation
(Me3Si+) leads to the desired diradicals and all of the,n-DHT isomers are accessible by using our
approach. We reasoned that the photogeneration and the photoreactivity of ,n-didehydrotoluenes
could be modulated by tuning the nature and the position of the substituent(s) present on the
aromatic ring. Furthermore, the use of substituted (chlorobenzyl)trimethylsilanes allows for the use
of a lower wavelength for their irradiation due to the red shift induced by the substituents.
Since the photogeneration of a triplet phenyl cation from aryl chlorides (the key step in the
generation of ,n-DHTs) is favoured in the presence of strong electron-donating substituents, such
as a methoxy group,4 we decided to synthesize and investigate the photoreactivity of differently
substituted trimethylsilylmethyl-chloroanisoles (Scheme).
Toward this goal, the photoreactivity of these substrates has been examined through a combined
experimental and computational study.
Scheme
(1)
(2)
(3)
(4)
Myers, A. G.; Parrish, C. A. Bioconjugate Chem. 1996, 7, 322-331.
Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am. Chem. Soc. 1992, 114, 9369-9386.
Protti, S.; Ravelli, D.; Mannucci, B.; Fagnoni, M.; Albini, A. Angew. Chem. Int. Ed. 2012, DOI: anie.201202794.
Protti, S.; Mella, M.; Fagnoni, M.; Albini, A. J. Org. Chem. 2004, 69, 3465-3473.
207
P84
Microwave assisted cellulose hydrolysis for bioethanol production
Chiara Pepori, Simone Angioni, Armando Buttafava, Daniele Dondi,
Alberto Zeffiro, Pierpaolo Righetti, Antonio Faucitano.
University of Pavia, Department of Chemistry, Viale Taramelli 12, 27100 Pavia (IT)
armando.buttafava@unipv.it
A study on the optimization of the microwave-assisted cellulose hydrolysis was performed with the
aim of enhance both the glucose production and the cellulose processability for a subsequent
enzyme treatment. Reactions were carried out in closed vessels at different temperatures, acid
concentration and/or mixture of different acids. Sugars produced were quantified via HPLC
equipped with a refractive index detector. A parallel analysis with HPLC-UV was performed in
order to detect unwanted decomposition products that could interfere with the subsequent
fermentation process.
As an example, below is reported the production of the hydroxymethylfurfural depending on the
concentration of sulphuric acid and reaction temperature.
HPLC analysis of hydroxymethylfurfural in samples (3 g dried content) treated with sulphuric acid at different
concentrations and temperatures (1) 160 °C, (2) 170°C and (3) 180°C.
The yields of glucose and degradations products after acid hydrolysis and enzymatic treatment will
be discussed in relation with the severity parameter1 of the acid treatment and physical
characteristics of the starting material.
(1) H. L. Chum, D. K. Johnson, S. K. Black, Ind. Eng. Chem. Res., 1990, 29, 156-162.
208
P85
Determination of degradation mechanism of gamma-irradiated beclometason
Alberto Zeffiro,1 Armando Buttafava,1 Daniele Dondi,1 Raffaella Garzia,2 Antonio Faucitano1
1
University of Pavia, Department of Chemistry, Viale Taramelli 12, 27100 Pavia (IT)
2
Chiesi Farmaceutici S.p.A., Largo Francesco Belloli 11/a, 43122 Parma (IT)
armando.buttafava@unipv.it
The sterilization via gamma or electron irradiation of drugs is a common practice in pharmaceutical
chemistry;1 however, drugs could undergo to a partial degradation with the formation of radicals
and/or radiolytic products. The aim of this work is the study of the effect of gamma irradiation on
crystalline beclometason dipropionate (BDP). Irradiations were performed by a Co-60 gamma
source on glass-sealed samples under vacuum in order to avoid oxygen interference. EPR analysis
of irradiated samples showed a linear relationship between total irradiation dose and radical
concentration in the range considered (0.1-8.35 kGy). Radicals formed in the solid state are
exceptionally stable at room temperature even in the presence of air. Primary radical species and
their behaviour were studied after irradiation of the sample at 77 K and subsequent heating while
recording EPR spectrum. This procedure assessed the presence of the radical anion as primary
radical specie. The radical anion can undergo fragmentation via bond breaking of bonds a or b (see
below).
a
O
O
CH3
b
O
H
CH3
O
HO
CH3
CH3
H
CH3
O
H
Cl
H
O
A parallel pathway involves the electron capture by chlorine atom and the fast fragmentation of CCl bond (even at 77K).
As a conclusion, on the basis of EPR spectroscopy was possible to determine the complete
degradation pathway of BDP leading to the detected species via HPLC-MS.
(1) M. Silindir, A. Y. Ozer, J. Pharm. Sci., 2009, 34, 43-53.
209
P86
Synthesis and biological evaluation of ligands of SGLT1:
a newly identified function for an old receptor
Giuseppe D’Orazio,1 Cristina Airoldi,1 Diego Cardani,2 Claudia Sandri,2 Cristiano Rumio,2
Francesco Nicotra,1 Barbara La Ferla1
1
Università degli Studi di Milano-Bicocca, Dipartimento di Biotecnologie e Bioscienze,
Piazza della Scienza 2, 20126 Milano
2
Humanitas Centro di Ricerche Cliniche, Dipartimento di Biotecnologie Mediche e di Medicina
Traslazionale, Via Manzoni 56, Rozzano, Milano
barbara.laferla@unimib.it
SGLT1 (Sodium Glucose Co-Transporter 1) is a transport protein mainly expressed on the surface
of intestinal epithelial cells (IECs), devoted to the absorption of glucose/galactose in the intestine.
Recently a new immunological role, of a significance similar to its physiological role, has been
associated to this protein. Several works1-3 outline a protective effect of SGLT1 with high Dglucose doses on damages induced by TLRs ligand in IECs, both in vitro and in vivo models of
septic shock and inflammation, liver injury induced by LPS or acetaminophen overdose.4 Recently
we synthesized a C-glucoside (1, Figure), able to block the inflammatory response at
pharmacological concentration.5 Experimental data indicate an involvement of SGLT1 for the
protective role with this compound. In order to develop structure-activity relationship studies and to
characterize the receptor-ligand interaction, we synthesised a series of C-glycoside 1 analogues
(Figure), performed biological evaluations and STD-NMR experiments on hole cells. Moreover, we
are also developing the synthesis of a radiolabelled compound 1 for pharmacokinetic studies.
(1) Yu, L. C. H.; Flynn, A. N.; Turner, J. R.; Buret, A. G. Faseb Journal 2005, 19, 1822.
(2) Yu, L. C. H.; Turner, J. R.; Buret, A. G. Experimental Cell Research 2006, 312, 3276.
(3) Palazzo, M.; Gariboldi, S.; Zanobbio, L.; Selleri, S.; Dusio, G. F.; Mauro, V.; Rossini, A.; Balsari, A.; Rumio, C.
Journal of Immunology 2008, 181, 3126.
(4) Zanobbio, L.; Palazzo, M.; Gariboldi, S.; Dusio, G. F.; Cardani, D.; Mauro, V.; Marcucci, F.; Balsari, A.; Rumio,
C. Am. J. Pathol. 2009, 175, 1066.
(5) La Ferla, B.; Spinosa, V.; D'Orazio, G.; Palazzo, M.; Balsari, A.; Foppoli, A. A.; Rumio, C.; Nicotra, F.
ChemMedChem 2010, 5, 1677.
210
P87
Design and synthesis of inhibitors against
key carbohydrate processing enzymes#
Luca Gabrielli, Davide Bini, Alice Capitoli, Antonella Sgambato, Jessica Scopini,
Silvia Merlo, Cristina Airoldi, Francesco Nicotra, Laura Cipolla
P.zza della Scienza 2, 20126 Milano-Italy.
francesco.nicotra@unimib.it
Enzyme inhibitors are useful tools that can help in the elucidation of biocatalytic mechanisms, in
the development of novel drug candidates and therapeutics in those pathologies where enzyme
disfunctions are involved, or in the design of insecticides with specific activity against insect but
safe for mammals.
Our research group is currently investigating the synthesis of different carbohydrate mimics as
potential inhibitors of three different classes of carbohydrate processing enzymes:
A) Mimetics of arabinose 5-phospate are proposed as tools for the study of the enzyme
requirements of arabinose 5P isomerase, a key enzyme involved in the first committed step of Kdo
biosynthesis in bacteria.1
B) Mimetics of lipid glycosyl diphosphate donors: several glycosyl transferases are involved in
bacterial lipopolysaccharide (LPS) O-antigen portion. The biosynthesis is a multistep process
mediated by several glycosyltransferases using undecaprenyl phosphate (Und-P) activated sugars.2
Among them, a key enzyme is the membrane protein WaaL. The recognition requirements of the
catalytic pocket are still unknown. In order to gain new details obout this, we undertook the
synthesis of lipid pyrophosphate sugar mimics.
C) Mimetics of trehalose: trehalose is a non-reducing disaccharide in which the two glucose units
are linked in an ,-1,1-glycosidic linkage. This sugar is present in a wide variety of organisms
where it may serve as a source of energy and carbon. Trehalose mimetics can find different
biological applications,3 including trehalose processing enzymes inhibitors, such as trehalase4 and
mycobacterial sulfotransferase.5 We report the synthesis of new nojirimycin-based inhibitors
against trehalases.
(1) a) Airoldi, A.; Sommaruga, S.; Merlo, S.; Cipolla, L.; Polissi, A.; Nicotra, F. Chemistry, Eur. J. 2010, 16, 1897;
b) Airoldi, C.; Merlo, S.; Cipolla, L.; Polissi, A.; Nicotra, F. ChemBioChem 2011, 12, 719.
(2) Lehrer, J.;Vigeant, K.A.; Tatar, L.D.; Valvano, M.A. J. Bacteriol. 2007, 189, 2618.
(3) Bini, D.; Cardona, F.; Gabrielli, L.; Russo, L.; Cipolla, L. in Specialist Periodical Reports, SPR Carbohydrate
Chemistry, Vol. 37, cap 10; Royal Society of Chemistry 2011, DOI: 10.1039/9781849732765, ISBN-10:
1849731543, ISBN-13: 978-1849731546
(4) Bini D.; Forcella, M.; Cipolla L.; Fusi P.; Matassini C.; Cardona F. Eur. J. Org. Chem. 2011, 3995
(5) Lin F. L.; van Halbeek H.; Bertozzi C. R. Carbohyd. Res. 2007, 342, 2014
#
This work has been supported by Fondazione Cariplo, grant n° 2010-0653, MIUR, project PRIN2008/24M2HX,
FINLOMBARDA-Regione Lombardia Fondo per la promozione di Accordi Istituzionali- 2009 under project
"Rational Drug Design to target outer membrane biogenesis of Gram-negative pathogenic bacteria".
211
P88
Total synthesis of azasugars through asymmetric dihydroxylation
of optically active vinyl epoxydes
Paolo Bovicelli,1 Emanuela Mandic’,2 Cristina Marucci,2
Gaia Clara Mercedes Naponiello,2 Giuliana Righi,1 Arianna Sisto,2 Michela Tomei.2
1
CNR-Istituto di Chimica Biomolecolare UOS Roma, Dipartimento di Chimica, Sapienza
Università di Roma, P.le A. Moro 5, 00185 Roma.
2
Dipartimento di Chimica, Sapienza Università di Roma, P.le A. Moro 5, 00185 Roma.
emanuela.mandic@uniroma1.it
Azasugars are structural analogues of traditional carbohydrates where the ring oxygen is replaced
by a nitrogen atom.1
Their most valuable property is the ability to inhibit glycosidase and glycosyltransferase enzymes
by mimicking the corresponding natural substrates. Therefore, azasugars show a high therapeutic
potential against a vast array of diseases, from viruses infections to tumoral metastases, leading to
an increasing interest in their synthesis.
Our research group recently developed a procedure to perform the asymmetric dihydroxilation
reaction2 on optically active trans α,β-unsaturated vinyl epoxy esters affording both the matched or
mismatched product in high diastereomeric excess and yields depending on which chiral ligand is
used.
R = propyl
R = cyclohexyl
Ligand
syn/anti
Yield
syn/anti
Yield
-
60:40
89%
55:45
95%
(DHQ)2PHAL
15:85
90%
23:77
80%
(DHQD)2PHAL
83:17
50%
83:17
84%
This reaction, which allows to obtain four contiguous chiral centres with full stereochemistry
control, is the key step in our total synthesis of azasugars.
The epoxyde ring can be opened by a regioselective nucleofilic attack in C-4 or C-5 position
leading respectively to pyrrolidine or piperidine derivatives (when R = CH2OP) and bicyclic
alkaloids (when R = (CH2)nOP).
(1) Afarinkia, K.; Bahar, A. Tetrahedron Asym., 2005, 16, 1239.
(2) Kolb, H.C.; Van Nieuwenhze, M. S.; Sharpless, K.B. Chem. Rev., 1994, 94, 2495.
212
P89
MIRC reactions of hydrazone anions and nitrobutadienes:
an easy access to highly-substituted pyrazoles and pyridazines
L. Bianchi, A. Carloni-Garaventa, M. Maccagno, G. Petrillo, C. Scapolla, C. Tavani
Via Dodecaneso 31, 16146 Genova
cinzia.tavani@unige.it
Nitrobutadienic building blocks, obtained from the initial ring-opening of various nitrothiophenes
with secondary amines in ethanol, show a multi-faceted reactivity not always predictable on the
grounds of the well-known and more exploited behaviour of the isolated nitrovinyl moiety.1
A particularly intriguing application of such building-blocks involves their employment in the
assembling of heterocyclic structures in a highly atom-economic way: thus, starting from a
substituted thiophene, the whole process can be envisaged as a ring-opening/ring-closing protocol
which preserves all of the four original thiophenic carbons.2
Recently we became interested in reactions that build up the heterocycle as a consequence of a
Michael addition: targeted to pyrazolic derivatives, hydrazone anions were the nucleophiles of
choice. While in some cases the system fulfils the expectations, allowing to obtain highly
functionalized pyrazoles, when the 1-(p-tolyl)-2-nitro-4-phenylsulfonyl-1,3-butadiene is involved
an unexpected dichotomy comes out, depending on the nature of the hydrazone, that leads to the
alternative construction of the pyridazine nucleus. Interestingly, related diazines can be obtained,
independently on the hydrazone employed, by simply changing the reaction conditions.
(1) a) Bianchi, L.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.; Spinelli, D.; Tavani, C.; Viale,
M. Versatile Nitrobutadienic Building-Blocks from the Ring-Opening of 2- and 3-Nitrothiophenes. Targets in
Heterocyclic Systems: Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; Società Chimica Italiana:
Rome, 2007; Vol. 11, pp 1-20. b) Bianchi, L.; Maccagno, M.; Petrillo, G.; Sancassan, F.; Spinelli, D.; Tavani, C.
2,3-Dinitro-1,3-butadienes: Versatile Building Blocks from the Ring Opening of 3,4-Dinitrothiophene. In Targets
in Heterocyclic Systems: Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; Società Chimica Italiana:
Rome, 2006; Vol. 10, pp 1-23.
(2) a) Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Scapolla, C.; Tavani, C. Tetrahedron Lett. 2012, 53, 752–
757. b) Bianchi, L.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Spinelli, D.; Tavani, C. Tetrahedron
2011, 67, 8160-8169.
213
P90
Easy access to ring-fused pyrrole-derivatives through a ring-opening/ringclosing protocol starting from 3-nitro-4-(phenylsulfonyl)thiophene
L. Bianchi, M. Maccagno, G. Petrillo, C. Scapolla, C. Tavani, A. Tirocco
Dipartimento di Chimica e Chimica Industriale, Università degli Studi di Genova,
Via Dodecaneso 31, 16146 Genova
lara.bianchi@chimica.unige.it
Nitro and dinitrobutadienes originating from the initial ring-opening of various nitrothiophenes with
secondary amines have proven to be interesting polyfunctionalized molecules which are both
potential pharmacologically-active compounds1 and powerful building blocks to be further
manipulated for the synthesis of various heterocycles.2
We report herein some preliminary results regarding an appealing effective transformation of
3-nitro-4-(phenylsulfonyl)thiophene 1 into ring-fused nitro-substituted pyrroles 4, as described in
the scheme below. A rationalization will be proposed and discussed.
(1) a)Viale, M.; Petrillo, G.; Maccagno, M.; Castagnola, P.; Aiello, C.; Cordazzo, C.; Mariggiò, MA.; Jadhav, S. A.;
Bianchi, L.; Leto, G.; Rizzato, E.; Poggi, A.; Spinelli, D. Eur. J. of Pharmacology 2008, 588, 47-51. b) Petrillo,
G.; Mariggiò, M. A.; Fenoglio, C.; Aiello, C.; Cordazzo, C.; Morganti, S.; Rizzato, E.; Spinelli, D.; Maccagno, M.;
Bianchi, L.; Prevosto, C.; Tavani, C.; Viale, M. Bioorg. & Med. Chem. 2008, 16, 240-247. c) Viale, M.; Petrillo,
G.; Aiello, C.; Fenoglio, C.; Cordazzo, C.; Mariggiò, M. A.; Cassano, A.; Prevosto, C.; Ognio, E.; Maccagno, M.;
Bianchi, L.; Vaccarone, R.; Rizzato, E.; Spinelli, D. Pharmacol. Res. 2007, 56, 318-328.
Rome, 2006; Vol. 10, pp 1-23.
214
P91
Synthesis of indoles and carbazoles from the nitrobutadienic building-blocks
deriving from the ring-opening of nitrothiophenes
Lara Bianchi, Massimo Maccagno, Giovanni Petrillo, Cinzia Tavani
via Dodecaneso 31, I-16146 Genova, Italy
massimo.maccagno@unige.it
Nitrothiophenes such as 2-nitro- (2NT), 3-nitro- (3NT), or 3,4-dinitrothiophene (DNT) undergo a
facile ring-opening process when treated with secondary amines in ethanol, with or without (in the
case of DNT) the assistance of silver nitrate. The so-obtained nitro- or dinitrobutadienic buildingblocks can be further manipulated to eventually obtain a wide range of different homo- and
heterocyclic targets.1,2
Within a more recent research line which exploits the capability of our nitro- or dinitrobutadienes to
behave as Michael-type acceptors,2 their coupling with indole has led to interesting, variously
functionalized heterocycles, whose nature depends on the structure of the diene.3
The formation of the pool of indole derivatives in the Scheme will be presented and discussed,
together with the most intriguing assembling of the carbazole heterocycle when starting from 2,3dinitro-1,3-butadiene. In this case, by a proper adjustment of the reaction conditions, the variable
number of nitrogroups can selectively decorate (by number and/or position) the final carbazole, thus
offering interesting possibilities as far as further manipulation is concerned.
Rome, 2006; Vol. 10, pp 1-23.
(2) Bianchi, L.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Spinelli, D.; Tavani, C. Tetrahedron 2011, 67,
8160-8169, and papers cited therein.
(3) Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Scapolla, C.; Tavani, C. Tetrahedron Lett. 2012, 53, 752–757.
215
P92
Reactivity of dialkyl and diaryl -diketones
with N-heterocyclic carbenes
Salvatore Pacifico, Gloria Guidetti, Daniele Ragno,
Alessandro Massi, and Olga Bortolini
Dipartimento di Chimica dell’Università di Ferrara,
Via L. Borsari 46, I-44121, Ferrara, Italy
salvatore.pacifico@unife.it
In recent years, N-heterocyclic carbenes (NHCs) have attracted considerable interest due to their
unique features, which allow them to be used as ligands for organometallic catalysis, reagents in the
synthesis of heterocycles, and efficient organocatalysts in umpolung transformations. In the latter
sub-area of research many efforts have been devoted to the realization of highly stereoselective
versions of the classical benzoin and Stetter reactions through optimal pre-catalyst design, to the
discovery of new transformations, and to the umpolung of electrophiles alternative to aldehydes and
pyruvates, mainly acylsilanes and Michael acceptors. In this regard, our group has recently
demonstrated the capability of linear and cyclic dialkyl -diketones to undergo polarity reversal
under thiazolium carbene catalysis in benzoin-type1 and Stetter reactions,2 and thus act as a novel
class of acyl anion precursors. Contrarily, it has been observed that diaryl -diketones do not
undergo polarity reversal in the presence of (benzo)thiazolium carbenes but are engaged in a novel
multicomponent reaction with water to efficiently give medicinally relevant 1,4-thiazin-3-one
heterocycles.3 The umpolung reactivity of diaryl 1,2-diones, however, can be effectively triggered
by different NHCs. An overview of this research is herein presented.
R1
O
O
O
Me
Me
OEt
HO
O
OEt
benzoin-type
Me
Ph
O
Ph
Ph
O
Ph
Stetter
S
R3
Ph
multicomponent
reaction (MCR)
O
R
R
O
R2
+ BzOH
H 2O
O
Me
N
O
R = Me, Ph
+ NHCs
O
H
O
Ar
benzoin-type
Ph
* Ar
OBz
(1) O. Bortolini, G. Fantin, M. Fogagnolo, P. P. Giovannini, V. Venturi, S. Pacifico, A. Massi, Tetrahedron 2011, 76,
8110-8115.
(2) O. Bortolini, G. Fantin, M. Fogagnolo, P. P. Giovannini, A. Massi, S. Pacifico, Org. Biomol. Chem. 2011, 9, 84378444.
(3) V. Bertolasi, O. Bortolini, A. Donvito, G. Fantin, M. Fogagnolo, P. P. Giovannini, A. Massi, S. Pacifico, Org.
Biomol. Chem. 2012, DOI:10.1039/C2OB25928A.
216
P93
Molecular dynamics simulations of the Salmonella typhi Vi antigenic
polysaccharide and its zwitterionic analogs
Lucio Toma,1 Laura Legnani,1 Federica Compostella,2 Franca Marinone Albini1
1
Dipartimento di Chimica, Università di Pavia, Via Taramelli 12, 27100 Pavia
2
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale,
Università di Milano, Via Saldini 50, 20133 Milano
lucio.toma@unipv.it
The capsular polysaccharides of several bacteria are important virulence factors and induction of
antibodies specific to them confers protection against bacterial infection.
The Vi antigen capsular polysaccharide I1 is a polymer of α-(1→4)-galacturonic acid, with an Nacetyl at position 2 and variable O-acetylation at C-3, associated with the virulence of Salmonella
typhi, a bacterial pathogen that causes typhoid fever in humans. Studies performed on native Vi
antigen showed that its immunogenicity is closely related to the degree of 3-O-acetylation; indeed,
the partially acetylated polysaccharide is immunogenic while the deacetylated is not.
O
O
COO
COO
O
RO
O
RO
AcNH
n
I: R = H, Ac
R'3N
n
II: R = H, Ac; R' = H
III: R = H, Ac; R' = CH3
The main flaws associated with pure polysaccharide vaccines are their poor immunogenicity and
short-termed, incomplete protection. In fact, they are T-independent antigens. However, it is known
that two polysaccharide components of Bacteroides fragilis are able to activate T cells.2 Their
immunogenic activity is dependent on the presence of a zwitterionic motif. This observation
suggests the possibility to introduce these properties into a polysaccharide by chemical
modification.
Being involved in a project aimed at the design, preparation, and test of structural analogs of the Vi
antigen endowed of T-cell dependent immunogenic properties, a preliminary detailed investigation
of the conformational properties of native Vi polysaccharide, and of the effects of possible chemical
modifications on these properties, is needed. Thus, we used a computational approach to determine
the geometrical properties of the Vi antigen I, as well as of its derivatives II and III containing a
zwitterionic motif and various degrees of acetylation at positions 3. Here we present the results
obtained by molecular dynamics simulations on these compounds carried out with the AMBER 10
package and using explicit water as solvent.
(1) Heyns, K.; Kiessling, G. Carbohydr. Res. 1967, 3, 340-353; Szu, S. C.; Bystricky, S. Methods Enzymol. 2003,
363, 552-567.
(2) Tzianabos, A. O.; Onderdonk, A. B.; Rosner, B.; Cisneros, R. L.; Kasper, D. L. Science 1993, 262, 416-419;
Tzianabos, A. O.; Finberg, R. W.; Wang, Y.; Chan, M.; Onderdonk, A. B.; Jennings, H. J.; Kasper, D. L. J. Biol.
Chem. 2000, 275, 6733-6740; Wang, Y.; Kalka-Moll, W. M.; Roehrl, M. H.; Kasper, D. L. Proc. Natl. Acad. Sci.
U.S.A. 2000, 97, 13478-13483.
217
P94
Synthesis and conformation of fully-thioamidated homo-peptides
Cristina Peggion, Marco Crisma, Alessandro Moretto, Marta De Zotti,
Barbara Biondi, Claudio Toniolo, Fernando Formaggio
ICB, Padova Unit, CNR, Department of Chemistry, University of Padova,
35131 Padova, Italy
fernando.formaggio@unipd.it
The replacement of a peptide bond with amide surrogates1 has been often exploited to produce
compounds with increased resistance to enzymatic hydrolysis and with higher receptor affinity and
specificity. However, often the peptide secondary structure is also seriously affected by such
modifications. The thioamide group, ψ[CS-NH], is one of the closest mimic of an amide (peptide)
linkage, but it exhibits significantly different chemical and physical properties. It is worth
mentioning that its NH moiety is more acidic than that of an amide and, consequently, it is a
stronger H-bonding donor.2 A thioamide can be also isomerized to the cis conformation by
irradiation at about 260 nm3 and may act as a fluorescence quencher.4
Motivated by conflicting literature conclusions,2 we recently started exploring how a thioamide
group may affect peptide folding. For the first time, we synthesized fully thioamidated homopeptides from Gly, Ala and Nle (norleucine) up to the tetramer level. The "all-amide" peptides,
prepared by conventional solution methods, were converted to the corresponding "all-thioamide"
compounds by means of the Lawesson reagent or P2S5. The latter reagent, coupled to an ultrasound
treatment, gave the best results in terms of yields and purity of the products. Interestingly, a solution
conformational analysis, using IR absorption, 2D NMR (Figure 1), and circular dichroism, on these
thiopeptides shows a preference for the uncommon fully-extended conformation ( = 180°,  =
180°). Such a behavior appears to be largely maintained in the crystal state as well, e.g. as inferred
from the X-ray diffraction structure of Z-Gly-ψ[CS-NH]-Gly-ψ[CS-NH]-Gly-OMe, where the
second and third residues adopt the backbone torsion angles typical of the fully-extended structure.
strong
strong
O
H3C
H
H
weak S
H3C
H
N
O
O
N
H
N
S
H3C
H
H weak O
strong
weak
weak
strong
Figure 1. NOESY spectrum in the NH-(αCH) region of Boc-Ala-Ψ[CSNH]-Ala-Ψ[CSNH]-Ala-OMe in CDCl3
solution.
(1) Spatola, A. F. Peptide backbone modifications: structure-activity analysis of peptides containing amide bond
surrogates. In Chemistry and Biochemistry of Amino Acids, Peptides and Proteins; Weinstein, B., Ed.; Dekker,
New York, 1983; pp 267-357.
(2) Chen, P.; Qu, J. J. Org. Chem. 2011, 76, 2994-3004.
(3) Bregy, H.; Heimgartner, H.; Helbing, J. J. Phys. Chem. B 2009, 113, 1756-1762.
(4) Goldberg, J.M.; Wissner, R.F.; Klein, A. M.; Petersson, E.J.J. Chem. Soc., Chem. Commun. 2012, 48, 1550-1552.
218
P95
Essential oil of composition of Artemisia densiflora Viv. from
La Maddalena Archipelago
Luigi Ornano,1 Alessandro Venditti,1 Anna Maria Serrilli,1 Cinzia Sanna,2
Mauro Ballero,2 Filippo Maggi,3 Armandodoriano Bianco.1
1
Sapienza, Università di Roma, Dipartimento di Chimica, P.le Aldo Moro, 5, 00185 Roma.
2
Dipartimento di Scienze della vita e dell’ambiente, Università di Cagliari.
3
Scuola di Scienze Farmaceutiche, Università di Camerino.
luigi.ornano@uniroma1.it
The Artemisia densiflora Viv. (Asteraceae) is one of the many endemic species which grows in
Sardinia-Corsica areal. This species was reported only in the area of Northern Sardinia, in particular
in the La Maddalena Archipelago, and in the Boniface and St. Florent area.1
In the literature data referring to essential oil of certain species of the genus Artemisia2-4 are present,
while no literature references are reported on the molecular composition of A. densiflora. Since it is
known that the molecular heritage plant varies in relation to habitat, we collected a sample of A.
densiflora on the island of La Maddalena, in the area known as Baia Trinita and we undertaken the
study of molecular composition starting from essential oil. Three samples of A.densiflora were
collected in three different periods: on August 2011, at the end of flowering stage, on February
2012, in the winter season, and on May 2012.
The leaf was immediately steam distilled and delivered an oil that has a deep blue color. This
feature is related to the presence in the plant of substantial quantities of artemisinin that change in
chamazulene in the distillation process.
The GC-MS analysis shows that chamazulene (0.8-22%) and β-thujone (48-82.5%) are representing
always the main components of the essential oil of A. densiflora. In fact the other components that
we have highlighted in preliminary way, are present only in lower quantities.
Preliminary examination of the total extract of A. densiflora revealed the presence of caffeoylquinic derivatives.
The research is continuing with the identification of other minor components of the essential oil and
of the polar fraction.
(1) B.Corrias. Bollettino della Società Sarda di scienze naturali, Le piante endemiche della Sardegna. 1996, 25, 187191.
(2) E.Biondi, G.Valentini, B.Bellomaria. Journal of Essential Oil Research. 2000,12(3), 365-371.
(3) Wu, Huaien; Wei, Zhiying; Li, Yaohua; Liang, Chenyan; Liang, Haiyan. Zhongguo Yaofang. 2009, 20(9), 685687.
(4) Wen, Fuji; Yoo, Kyungseun; Eom, Minseop. Xiangliao Xiangjing Huazhuangpin. 2007, 3, 21-23.
219
P96
Ring Opening Cross Metatesis of medium sized olefins. Discovery of a novel
class of cannabinomimetic seco-bishomocaryophillenoids
Diego Caprioglio,1 Alberto Minassi,1 Juerg Gertsch,2 Orazio Taglialatela-Scafati,3
Giovanni Appendino,1 Andrea Chicca,3 Juerg Gertsch3
1
Dipartimento di Scienze del Farmaco, Via Bovio 6, 28100 Novara, Italy.
Dipartimento di ChimicaDipartimento di Chimica delle Sostanze Naturali, Università di Napoli
Federico II, Via D. Montesano 49, 80131 Napoli, Italy.
3
Institute of Biochemistry and Molecular Medicine, National Centre of Competence in Research
NCCR TransCure, Buehlstrasse 28, CH-3012, Bern, Switzerland.
alberto.minassi@pharm.unipmn.it
2

-Caryophyllene (1), the major terpenoid constituent of clove, has played an important role in
shaping our ideas on transannular chemistry and the synthesis of medium-sized compounds.1 The
surprising discovery that -caryophyllene is a potent and selective activator of the peripheral
cannabinoid receptors (CB2)2 has renewed interest in this compound, spurring studies aimed at
establishing the structure-activity relationships of this cannabinomimetic lead. The chemistry of caryophyllene has been extensively investigated,3 but mostly towards electrophilic and acidid
reagents, and the potential of transition metals remains still untapped. In the context of a SARs
study on the cannabinonimetic action of -caryophyllene, we have discovered that the medium-size
ring of the natural product can be selectively opened and bis-homologated using a ring opening
cross-metatesis (ROCS) approach. Surprisingly, and despite the very strict SAR reported so far on
this the cannabinomimetic action of 1, retention or even potentiation of activity was displayed by
some of these dihomo-secocaryophillanes (general formula 3). The mechanistic aspects of the
ROCS reaction and the cannabinomimetic SARs of a series of -caryophyllene derivatives will be
discussed.
(1) O. V. Laronov, E. J. Corey. J.Am. Chem. Soc. 2008, 130, 2954-2955.
(2) J. Gertsch, M. Leonti, S.Raduner, I. Racz, J.Z. Chen, X. Q. Xie, K. H. Altmann, M. Karsak, A. Zimmer, Proc.
Natl. Acad. Sci. USA 2008, 105, 9099-9104.
(3) J. P. Morgan, C. Morill, R. H. Grubbs, Org. Lett. 2002, 4, 67-70.
220
P97
Artefact compounds produced during acid hydrolysis
of triterpenic pentacyclic saponins
Aldo Tava,1 Mariella Mella,2 Elisa Biazzi,1 Pinarosa Avato3
1
CRA-FLC Centro di Ricerca per le Produzioni Foraggere e Lattiero Casearie,
viale Piacenza 29, 26900 Lodi - Italy.
2
Dipartimento di Chimica Università di Pavia, viale Taramelli 12, 27100 Pavia, Italy.
3
Dipartimento Farmaco-Chimico Università di Bari, via Orabona 4, 70125 Bari, Italy.
mariella.mella@unipv.it
Saponins are a large group of plant metabolites, particularly abundant in the Leguminose family and
in the genus Medicago.1-4 In the recent years the number of studies on the biosynthesis of saponins
has increased (5) due to the particular chemical, physical and physiological characteristics of these
compounds making them important starting material for pharmaceutical1 and agro-industry
applications.6
The GC analysis of sapogenins is one of the most used methods to evaluate the saponin content in
saponin-rich plants. Sapogenins are released after acid hydrolyses of saponins, functionalised
(methylated and acetylated or silylated) and than identified by GC/MS, NMR and quantified by
GC/FID using an internal standard. It is well known that during the acidic treatment some artefact
compounds can be obtained, as reported for saponins of soyasapogenol B.2-4
Recently, GC investigation of hydrolyses products of zanhic acid glycosides, revealed the presence
of unknown compounds, in addition to the peak attributed to zanhic acid.4 The artefact formation
from glycosides of soyasapogenol B and zanhic acid (Figure 1), during hydrolyses performed in
acidic condition are investigated. Their identification and their quantitative evaluation during 10
hours hydrolyses are reported. The mechanism of their formation involving anchimeric assistance is
also proposed and discussed.
OH
COOR1
HO
RO
OH
R = H: sapogenin (soyasapogenol B)
R = sugar or sugar chain: saponin
RO
HOOC
OH
R = R1 = H: sapogenin (zanhic acid)
R = R1 = sugar or sugar chain: saponin
Figure 1. Chemical structure of saponins and sapogenins
(1) Tava, A.; Avato, P. Nat. Prod. Commun. 2006, 1, 1159-1180.
(2) Tava, A.; Mella, M.; Avato, P.; Biazzi, E.; Pecetti, L.; Bialy, Z.; Jurzysta, M.; .J. Agric. Food Chem. 2009, 57,
2826-2835.
(3) Bialy, Z.; Jurzysta, M.; Mella, M.; Tava, A.; J. Agric. Food Chem. 2006, 54, 2520-2526.
(4) Tava, A.; Mella, M.; Avato, P.; Argentieri, M.P.; Bialy, Z.; Jurzysta, M.; .J. Agric. Food Chem. 2005, 53, 99549965.
(5) Tava, A.; Scotti, C.; Avato, P. Phytochem. Rev. 2011, 10, 459-469.
(6) D’addabbo, T.;; Carbonara, T.;; Leonetti, P.;; Radicci, V.;; Tava, A.;; Avato, P. Phytochem. Rev. 2011, 10, 503-519.
221
P98
Total synthesis of natural alkaloid taspine and study of its binding to Gquadruplex DNA by ESI-MS
Alessandro Altieri, Antonello Alvino, Marco Franceschin, Daniele Nocioni, Maria Luisa Scarpati,
Armandodoriano Bianco
Dipartimento di Chimica, “Sapienza” Università di Roma, Piazzale Aldo Moro5, 00185 Roma,Ital y
alessandro.altieri@uniroma1.it
G-quadruplexes are a family of nucleic acids secondary structures stabilized by G-tetrads, coplanar
quartets of guanines held together by a cyclic arrangement of eight unconventional hydrogen bonds.
There are many examples of molecules that have been shown to form non covalent adducts with
DNA G-quadruplexes in vitro.[1] These molecules are characterized by an aromatic core, which
favours stacking interactions with the G-tetrads, and by basic side chains, which interact with the
loops [2] and helix grooves.[3] Natural compounds such as berberine and telomestatin have also
been shown to stabilized G-quadruplex structures.
Here we report a new total synthesis of taspine, an alkaloid found in the sap of the Croton
MeO
N(Me)
Draconoides tree, which was used by
Jivaro Indians of Perù to promote
O
CO
OH
OMe
OC
O
MeO
wound healing and to treat various
MeO
O
O
diseases[4]. Taspine is characterized by
HO
MeOOCO
COOCH
OMe
a dilactonic core with a side chain that
Ferulic acid
Br
Taspine
ends with a tertiary amine. This
+
O
O
MeO
O
structure
corresponds
to
the
NR
O
O
characteristics, outlined above, to be a
Ph
O
HO
O
CO
Br
O
presumable ligand of G-quadruplex
OC
O
Isovanilline
RN
structures.
The
synthesis
was
OMe
summarized
in
the
figure,
starting
from
O
Similar symmetrical taspine structure
ferulic acid and isovanillin. The scheme
allowed to synthesize taspine as well as a symmetric analogue.
The affinity of this ligand at various concentrations towards different DNA structures, was
study by ESI-MS measurements.[5] This technique allows the transfer of non covalently bound
complexes into the gas phase without the disruption of the complex itself and therefore the
determination of the stoichiometry and, in particularly favourable cases, modes and energies of
interaction.[6] So we have shown the ability of this alkaloid to bind and stabilize G-quadruplex
DNA oligomers, with an average association constant K1 on the order of 4.9 on a logarithmic scale.
We are therefore considering the selectivity for G-quadruplex over duplex DNA. In fact, the
selectivity is surely a highly relevant topic and could be related to the specificity of the biological
activity of these compounds.
The symmetric analogue with two side chains, which are longer and more flexible than the
one of taspine, should improve the interactions with the grooves of the DNA G-quadruplex.
Preliminary studies show an ability to stabilize and bind to the oligomers with association constants
of the order of taspine itself.
2
3
(1) C. M. Incles, C. M. Schultes, S. Neidle, Curr. Opin. Investig.Drugs 2003, 4, 675–685
(2) S. Müller, G. D. Pantos¸, S. Balasubramanian,Chem. Commun. 2009, 80–82.
(3) S. M. Haider, G. N. Parkinson, S. Neidle, J. Mol. Biol. 2003, 326, 117–125
(4) G.F. Gonzales, L.G. Valerio Jr, Medicinal Chem. 2006 429-444
(5) V. Casagrande, A. Alvino, A. Bianco, M. Franceschin J. Mass Spectrom. 2009, 44, 530.
(6) Rosu F., Pirotte S., De Pauw E., Gabelica V. Journal of Mass Spectrom 2006; 253, 156
222
P99
A new flavonoid and other polar compounds from Galeopsis angustifolia Ehrh.
Alessandro Venditti, Anna Maria Serrilli, Armandodoriano Bianco.
Dipartimento di Chimica, Università di Roma “La Sapienza”, Piazzale Aldo Moro, 500185- Roma,
Italy.
Alessandro.venditti@uniroma1.it
Galeopsis angustifolia Ehrh. (Red Hemp Nettle) is a small herbaceous plant largely distributed on
stony soils of mountains and on coastal areas of Mediterranean[1]. The analysis of the polar fraction
of G.angustifolia. indicates that the main components are iridoids and flavonoids. Six compounds
were identified: a new flavonoid, 3’-hydroxy-isoscutellarein 7-O-[6’’’acetyl--D-glucopyranosyl(1→2)--D-glucopyranoside], (see figure); three iridoid glucosides (harpagide, acetyl harpagide
and for the first time in this specie, 8-epi-loganin (which is, in accordance with the biogenetic
pathway proposed by Jensen[2], the parent compound of the iridoids present in this species); two
known acetylated flavonoid glycosides: 3’-hydroxy-4’-O-methylisoscutellarein 7-O-[6’’’acetyl-D-allopyranosyl-(1→2)-6’’-acetyl--D-glucopyranoside], 3’-hydroxy-4’-O-methyl-isoscutellarein
7-O-[6’’’acetyl--D-allopyranosyl-(1→2)--D-glucopyranoside][3].
Both flavonoids and iridoids are present in high amount; respectively 16.7% and 4.5% of the crude
extract. The occurrence of 8-hydroxyflavone, as their monoacetylated and diacetylated derivatives,
has a chemosistematic importance because the occurrence is restricted to some genera of subfamily
Lamioideae (tribe Stachydeae), demonstrating the affinities among several Labiate species as
Pogostemon, Sideritis, Stachys and Galeopsis , as reported by Francisco et al.[4]. In addition
diacetylated flavones present higher antioxidant activity respect to the corresponding
monoacetylated ones and the presence of a methoxy group at 4’ makes the antioxidant reactivity kinetically fast. Methylation of OH in 4’ and monoacetylation result in acetylcholinesterasic inhibitory activity. In fact compound 5 was found to be neuroprotective in the Alzheimer disease in
a recent study by Uriate & Calvo[5].
References:
(1) Pignatti S., Flora d'Italia. 1982, Vol. II, Bologna, Edagricole, pag. 454
(2) Jensen S.R., Plant iridoids, their biosynthesis and distribution in angiosperms. 1991, In Proceedings of the
Phytochemical Society of Europe, 31 - Ecological Chemistry and Biochemistry of Plant Terpenoids. Eds. J.B. Harborne
and F.A. Tomas-Barberan. Oxford University Press, Oxford, 1991.
(3) Lenherr A., Mabry T.J., “Acetylated allose-containing flavonoid glucosides from Stachys anisochila.” Phytochemistry, 1997, 26(4), 1185-1188.
(4) Francisco A. Tomás-Barbera̋n, María I. Gil, Federico Ferreres, Francisco Tomás-Lorente. “Flavonoid pcoumaroylglucosides and 8-hydroxyflavone allosylglucosides in some Labiatae.” Phytochemistry, 1992, 31(9), 3097–
3102.
(5) Uriate-Pueyo I., Calvo M.I., “Structure-activity relationships of acetylated flavone glycosides from Galeopsis
ladanum L.(Lamiaceae).” Food Chemistry, 2010, 120, 697-683.
223
ELENCO DEI PARTECIPANTI
224
A
ABBOTTO
Al SAAD
ALBINI
ALLEGRINI
ALTIERI
AMICO
ATTANASI
ATTOLINO
AZZENA
Alessandro
Dalya
Angelo
Pietro
Alessandro
Vincenzo
Orazio
Emanuele
Ugo
Università di Milano Bicocca
Università di Pavia
Dipharma Francis s.r.l.
Università "La Sapienza" di Roma
Università di Catania
Università di Urbino
Dipharma Francis s.r.l.
Università di Sassari
Alessandro
Roberto
Luca
Margherita
Alessandro
Silvia
Angela
Benedetta
Lucia
Egle Maria
Emiliano
Gianluca
Francesca
Anna
Alice
Francesco
Arianna
Alessandro
Luca
Kahirnar
Lara
Massimo
Armandodoriano
Andrea
Elena
Bruno
Alberto
Gianluigi
Michele
Salvatore
Serena
Silvestre
Università di Padova
Università di Camerino
Università di Genova
Università di Torino
CBC-PROCOS S.p.A.
Università Statale di Milano
Università di Perugia
Università di Parma
Università di Napoli Federico II
Olon S.p.A.
Bruker Italia Srl
Università di Pisa
Politecnico di Milano
Università di Firenze
Università Tor Vergata di Roma
Università dell'Insubria
Invento srl
Università di Palermo
Diego
Marco
Università del Piemonte Orientale
B
BAGNO
BALLINI
BANFI
BARBERO
BAROZZA
BARTOCCI
BASSOLI
BATTISTELLI
BATTISTINI
BECCALLI
BEDINI
BELOGI
BENEVELLI
BERNARDI
BERNASCONI
BERTI
BERTOLANI
BERTUCCI
BEVERINA
BHUSHAN
BIANCHI
BIETTI
BIANCO
BONETTI
BORSINI
BOTTA
BRANDI
BROGGINI
BRUSCHINI
BUBICI
BUGONI
BUSCEMI
C
CAPRIOGLIO
CARICATO
225
CARRARO
CASAPULLO
CASINI
CASNATI
CASTELLUCCI
CAUTERUCCIO
CERULLI
CEVASCO
CHIAPPE
CHIUMMIENTO
CICCHI
CIMARELLI
CIMMINO
CIPOLLA
CIRILLI
CITTI
CLERICI
COLETTI
COLOMBO
CONTE
CORDERO
CORRADINI
COSTA
CROTTI
Massimo
Agostino
Andrea
Alessandro
Nicola
Silvia
Valentina
Giorgio
Cinzia
Lucia
Stefano
Cristina
Alessio
Laura
Roberto
Cinzia
Francesca
Alessia
Lino
Valeria
Franca Maria
Roberto
Giosuè
Paolo
Università di Salerno
Università di Bologna
Bioindustria LIM SpA
Università di Pisa
Università della Basilicata
ISS
Università di Lecce
Università di Catanzaro
Università di Pisa
Antonella
Sabrina
Francesca
Francesco
Ottorino
Rossella
Ilse
Annamaria
Giovanni
Lorenzo
Valeria
Antonello
Simone
Marco
Filippo
Università dell'Aquila
Università di Venezia
MERCK SERONO SPA
Università di Pisa
Università di Pisa
Università di Chieti
Antonio
Pierangelo
Maurizio
D
DALLA CORT
DALLAVALLE
D'ANNA
DE ANGELIS
DE LUCCHI
DE MARCO
DE SALVE
DEAGOSTINO
DESIMONI
DI BARI
DI BUSSOLO
DI CRESCENZO
DI MICCO
D'ISCHIA
DORIA
E
EVIDENTE
F
FABBRIZZI
FAGNONI
226
FAITA
FARINOLA
FASANA
FASANI
FESTA
FIORANI
FIORILLO
FLORIO
FLORIS
FOCHI
FONTANA
FORMAGGIO
FRAU
FRECCERO
FRENNA
FRETTA
FRONGIA
FUNICELLO
FUSI
Giuseppe
Gianluca
Andrea
Elisa
Carmen
Giulia
Gaetano
Saverio
Barbara
Maria Francesca
Antonella
Fernando
Ileana
Mauro
Vincenzo
Roberta
Angelo
Maria
Stefania
Università di Bari
Università di Venezia
Naxospharma srl
Università di Bari
Università di Pisa
Bracco Imaging S.p.A.
Università di Cagliari
Università della Basilicata
Università di Siena
Bartolo
Raffaella
Luca
Aldo
Remo
Silvio
Francesco
Lara
Silvia
Maria Luisa
Luca
Giovanni
Assunta
Gianluca
Donatella
Andrea
Davide
Lucia
Arianna
Michelangelo
Università della Calabria
Istituto di Ricerche Farmacologiche Mario Negri
Università di Pisa
Barbara
Concetta
Stefano
Rosa
Alessandra
Luciano
Bracco Imaging S.p.A.
G
GABRIELE
GAGGERI
GAINO
GALEONE
GANDOLFI
GARATTINI
GASPARRINI
GAZZERA
GAZZOLA
GELMI
GERMANI
GHIGO
GHILARDUCCI
GILARDONI
GIOMI
GOTI
GOZZINI
GRAMIGNA
GRECO
GRUTTADAURIA
L
LA FERLA
LA ROSA
LANCIANESI
LANZETTA
LATTANZI
LATTUADA
227
LEGNANI
LENTINI
LEONELLI
LESSI
LICANDRO
LO MEO
LOMBARDO
LUCARINI
Laura
Sara
Francesca
Marco
Emanuela
Paolo
Marco
Marco
Università di Pisa
Massimo
Fabrizio
Stefano
Raffaella
Emanuela
Alex
Roberta
Enrico
Luigi
Luca
Alessandro
Andrea
Andrea
Lorenzo
Antonio
Mariella
Stefano
Valentina
Lucio
Federica
Pierangelo
Fabrizio
Alberto
Cosima
Luciano
Carlo F.
Iqbal
Loana
CNR Firenze
Università Politecnica delle Marche
Università di Ferrara
Aptuit Verona s.r.l.
Chemessentia Srl
Angelo
Monica
Francesco
Giammario
Renato
Università di Bari
Ernesto
M
MACCAGNO
MACHETTI
MAIORANA
MANCUSO
MANDIC'
MANICARDI
MANONI
MARCANTONI
MARGARUCCI
MASSACCESI
MASSI
MATTAREI
MAZZANTI
MEAZZA
MEGA
MELLA
MENICHETTI
MERLINI
MERLINI
MESSINA
METRANGOLO
MICHELI
MINASSI
MINELLI
MIOZZO
MORELLI
MULANI
MUSSO
N
NACCI
NARDI
NICOTRA
NIEDDU
NOTO
O
OCCHIATO
228
OLIVERIO
ORNANO
Manuela
Luigi
P
PACIFICO
Salvatore
PADOVAN
Pierluigi
PALUMBO PICCIONELLO Antonio
PANZELLA
Lucia
PARRILLI
Michelangelo
PASTORI
Nadia
PELLACANI
Lucio
PEPORI
Chiara
PERCIVALLE
Claudia
PERRONE
Serena
PETENZI
Michele
PETRILLO
Giovanni
PETRINI
Marino
PEVIANI
Elena Giulia
PIATEK
Anna
PIERINI
Marco
PIERSANTI
Giovanni
PINESCHI
Mauro
PIRAS
Pier Paolo
PIZZETTI
Marianna
PONTICELLI
Fabio
PORCHEDDU
Andrea
PORTA
Alessio
POZZOLI
Claudio
PROCOPIO
Antonio
PROTTI
Stefano
F.I.S. FABBRICA ITALIANA SINTETICI S.P.A.
Chemessentia Srl
Università di Urbino
Università di Pisa
Farmabios (Zellbios Group)
Q
QUADRELLI
Paolo
Marcello
Federico
Davide
Carlotta
Raffaele
Serena
PierPaolo
Sergio
Simona
Ornelio
Chemessentia Srl
CNR Milano
R
RASPARINI
RASTRELLI
RAVELLI
RAVIOLA
RICCIO
RIELA
RIGHETTI
RIVA
RIZZO
ROSATI
229
S
SACCHETTI
SACCONE
SAIELLI
SAMORI'
SANNICOLO'
SANSONE
SANTI
SARTORI
SASSI
SBARBADA
SCAMPORRINO
SCRIMIN
SECCI
SEPE
SERRA
SERRA
SILIPO
SOLDATI
SORANA
SPADA
SPATAFORA
SPERANZA
SPINELLI
STANOVNIK
STIVANELLO
STRAPPAVECCIA
STROCCHIA
STURINI
Alessandro
Marco
Giacomo
Chiara
Francesco
Francesco
Claudio
Giovanni
Mauro
Davide
Emilio
Paolo
Francesco
Valentina
Stefano
Massimo
Alba
Roberto
Federico
Gian Piero
Carmela
Giovanna
Domenico
Branko
Mariano
Giacomo
Maria
Michela
CNR Padova
CNR-ICRM
Università di Lubjana
Lundbeck Pharmaceuticals Italy SpA
Maurizio
Emilio
Carmen
Cinzia
Tullia
Lucio
Claudia
Antonio
Claudio
Corrado
Ciro
Luigino
Andrea
Barry M.
Beatrice
Università di Stanford
T
TADDEI
TAGLIAVINI
TALOTTA
TAVANI
TEDESCHI
TOMA
TOMASINI
TOPPINO
TRAPELLA
TRINGALI
TROISE
TROISI
TROMBETTA
TROST
TRUCCHI
230
V
VALLI
VENDITTI
VIDARI
VILLA
VISCARDI
VITA FINZI
VOLONTERIO
VURCHIO
Matteo
Alessandro
Giovanni
Davide Carlo
Guido
Paola
Alessandro
Carolina
Angela
Giuseppe
Romina
Armando
Alberto
Cristiano
Z
ZAMPELLA
ZANONI
ZAPPACOSTA
ZARRELLI
ZEFFIRO
ZONA
231
ELENCO DEGLI AUTORI
232
A
Abdullah F. O.
P9
Aime S.
O34, P24
Aimi F.
P70
Airoldi C.
F6, P86, P87
Alberti D.
O34, P24
Albertini A. M.
O60
Albini A.
O2, F4, P14, P47, P48, P83
Alcaro S.
O35
Aleandria S.
P73
Alfini R.
P71
Allegrini P.
O36
Al-Saad D.
P67
Alvino A.
P98
Amin H. I. M.
P9
Amorati R.
O54
Andolfi A.
O22, F10
Andrea Motta A.
F10
Angioni S.
F11, P84
Antimisiaris S.G.
F6
Antonio Evidente A.
F10
Appendino G.
P96
Armuzza V.
O14
Artali R.
P59
Artese A.
O35
Attolino E.
O36
Avanzini A.
O21
Avato P.
P97
Azzena U.
P77
Azzolini M.
P52, P53
B
Bagno A.
Bagnoli L.
Baiula M.
Ballero M.
Ballini R.
Banfi L.
Barbero M.
Barbero N.
Barolo C.
Barondi S.
Barozza A.
Barreca G.
Barresi V.
Bartali L.
Bartik K.
Bartocci S.
Bartoccini F.
O5
O58, P18
P82
P95
P14
O46
P5, P62
P49
P49
O16
O24
O31
O48
O19
P23
P23
O20
Bartoli G.
F9
Bassanini M.
O39
Basso A.
O46
Bassoli A.
O23
Battistelli B.
P18
Battistini L.
O27
Bavaro T.
P12, P61
Beccalli E. M.
PL3, P29, P33
Bedini E.
O53
Bella M.
O46
Bellina F.
O16
Bellucci M. C.
O38
Belogi G.
O30
Benevelli F.
NT1
Benotti M.
O39
Berestetskiy A.
F10
Bernasconi A.
P29
Berti F.
F5, P51
Bertolani A.
F15
Bertucci A.
F12, P42
Beverina L.
O6,F8
Bhusainahalli V.
O48
Bianchi L.
P89, P90, P91
Bianchi N.
P70
Bianco A.
P95, P98, P99
Biasutto L.
P52, P53
Biazzi E.
P97
Bietti M.
O10
Bifulco G. O42, O48, P3, P7, P8, P25, P31
Bigi F.
P65
Bini D.
P87
Biondi B.
P94
Blanco Jaimes M. C.
P50
Bochicchio A.
O49
Bonacci S.
P56
Bonanno P.
P16
Bonchio M.
O65
Bonetti A.
O15
Bonnassieux Y.
O8
Borgonovo G.
O23
Borin F.
O33
Borsini E.
P33
Bortolini O.
O69
Bortolini O.
F1, P92
Botta B.
PL2
Botta M.
P39
Bottoncetti A.
O41
Bovicelli P.
P88
Bradaschia A.
P53
Brandi A.
M1, O26, P16, P17, P71
Bravo L.
O54
Broggini G.
P20, P33
2
Brognara E.
Bruno I.
Bruschini M.
Brusotti G.
Bubici S.
Bucci M.
Buonocore D.
Burreddu P.
Buscaino R.
Buscemi S.
Buttafava A.
Butts C. P.
Buzzetti F.
Bugoni S.
P70
P25
O12
P9
NT2
P4
P9
O27
P49
O52
P48, P84, P85
P31
P43
F7
C
Cadamuro S.
Cagnina S.
Calcaterra A.
Cambianica I.
Cametti M.
Campitiello M.
Candiani A.
Cannazza G.
Canovi M.
Capitoli A.
Caprioglio D.
Carbone M.
Carcone L.
Cardani D.
Carloni-Garaventa A.
Carradori S.
Carraro M.
Carrozzo M. M.
Carta P.
Casapullo A.
Casati C.
Cascio F.
Casella G.
Casini A.
Casiraghi G.
Casnati A.
Cassano G.
Cassiano C.
Castellucci N.
Causin V.
Cauteruccio S.
Cavallaro G.
Cavallo G.
Cavatorta E.
Cavazzini A.
P5, P62
P6
PL2
F6
F14
O18
P42
F3
F6
P87
P96
P36
O31
P86
P89
P41, P66
O65, P52, P53
F3
O27
O61, P58
P22
P1
O65
O19, P34
O27
PR2, P73
P51
O61
O45
O65
P50
P46
O1, F15
P42
O69
Ceccacci F.
Chicca A.
Chiesa F.
Chini M. G.
Chiummiento L.
Choi J.-W.
Choppin S.
Ciao R.
Cicchi S.
Ciesielski A.
Cimarelli C.
Ciminale F.
Cimmino A.
Cincinelli R.
Cini E.
Cioffi N.
Cipolla L.
Cipolletti R.
Cipriani S.
Cirilli R.
Citti C.
Clerici A.
Clericuzio M.
Coletti A.
Collina S.
Colobert F.
Colombo D.
Colombo Lino
Colombo Luca
Compostella F.
Condorelli D.
Conte V.
Cordero F. M.
Corradini R.
Costa G.
Costanzo P.
Cotugno P.
Crisma M.
Crotti P.,P51,P57
Cucinotta A.,P42
Curini M.,O63
Curti C.,O27
F9
P96
P78
P7, P8, P25
O49, P79
O8
O49
O13
O26
P28
O44
O57
O22 ,F10
P59, P64
O31
O57
O7
O29
P8
P41, P66
F3
P81
P76
F13
O21
O49
O4
P75
P55
P93
O48
O14, P36
P16, P17
O25, F12, P42, P70
O35
P56, P63
O57
P94
D
D’Acquarica I.
D’Alfonso A.
D’Amore C.
D’Angelo A.
D’Anna F.
D’Auria M. V.
d’Ischia M.
PL2
P1
P3, P7, P8
F13
P44, P45
O42, P3, P4, P7, P8
O54
3
D’Orazio G.
Dal Piaz F.
Dalla Cort A.
Dallavalle S.
Dattilo S.
Dattoli S.
De Castro C.
De Faveri C.
De Fusco C.
De Luca G.
De Marco R.
De Marino S.
De Nino A.
De Petrocellis L.
De Rosa M.
De Sarlo F.
De Zotti M.
Deagostino A.
Debitus C.
Degennaro L.
dei Cicchi S.
Del Canto E.
Dell’Anna G.
DellaGreca M.
Di Antonio M.
Di Bari L.
Di Bussolo V.
Di Crescenzo A.
Di Labio G. A.
Di Marzo V.
Di Micco S.
Di Nicola M.
Di Nola A.
Dichiarante V.
Diomedi S.
Distinto S.
Divincenzo M. V.
Donati D.
Dondi D.
Doria F.
Dossena A.
Dova D.
Dughera S.
P86
P25
O12, P23
P59, P64
P35
P82
O53
O33
O56
P56
O18, P82
O42, P3, P4
F1
O23
O53
O9
P94
O34, P24
P4
P77
P66
P27, P30
O36
O59
P40
O67
F5, P57
P27, P30
O10
O23
O48, P31
O29
O53
P47
O29
O35
O57
O17
P48, P84, P85
O43, P40, P68, P69
O25
P50
P5, P62
E
Etgar L.
Evidente A.
P49
O22
F
Fabbri E.
Fabbrizzi P.
Faggi C.
Fagnoni M.
Falcicchio A.
Fantuzzi L.
Fasana A.
Fasanella F.
Fasani E.
Faucitano A.
Ferrante G.
Ferretti R.
Festa C.
Fiorani G.
Fioravanti S.
Fiorillo G.
Fiorucci S.
Floris B.
Fogliato G.
Fontana A.
Formaggio F.
Foster J. A.
Francescato P.
Franceschin M.
Franchi P.
Fratoni D.
Frau I.
Freccero M.
Fretta R. ,
Frongia A.
Fucke K.
Funicello M.
Fusi S.
P70
O41
P41
O2, F4, P14, P83
F3
P73
P20
P12, P61
P47
P84, P85
NT2
P41, P66
P3, P4
P21
P38
P43
O42, P3, P7, P8
O14, P36
O39
P26, P27, P30
P94
O66
P12
P98
P22
O44
P57
O39, O43, P40, P68, P69
O40
O28, P54
O66
O49, P79
O17, P13
G
Gabriele B.
Gabrielli L.
Gaeta C.
Gaggeri R.
Gaino L.
Gale P. A.
Galeazzi R.
Galletti P.
Galloni P.
Gambari. R.
Gandini A.
O37
P87
O13
O21
P39
O12
P60
F17, P15
O14
P70
P78
4
Garattini S.
Garbisa S.
Garlaschelli L.
Garzia R.
Gasparrini F.
Gatti F.
Gatto E.
Gazzera L.
Gazzola S.
Geffroy B.
Gelmi M. L.
Geninatti S.
Gentilucci L.
Germani L.
Gertsch J.
Ghigo G.
Ghirga F.
Giacomelli G.
Giacomini D.
Giambastiani G.
Gil J. F.
Gilardoni G.
Giomi D.
Giordani S.
Giovannini R.
Gironda R.
Gobbi M.
Goya L.
Gozzini D.
Graetzel M.
Gramigna L.
Granito C.
Greco A.
Gregori M.
Gruttadauria M.
Guamán Ortiz L. M.
Guanci C.
Guarcello A.
Guarino G.
Guarna A.
Guerrini R.
Gugliotta G.
Guideri L.
Guidetti G.
PL4
P53
F11
P85
P66
O64
O14
F14
P20
O8
O15
O34, P24
O18, P82
O43, P68
P96
P5, P6
PL2
F2
P15
O26
P2
O21, P9, P10, P76
P71
P27 ,P30
O29
O8
F6
O54
P9, P10, P76
P49
P28
P37
O18, P82
F6
P44, P46
P43
P80
O52
O5
O41, P34
O11
P39
O9
P92
H
Hamprecht D.
Hashmi A. S. K.
Hiscock J. R.
Huber F. A. M.
Hussain F. H. S.
O29
P50
O12
O33
P9
I
Iacovelli O.
Iesce M. R.
Incipini L.
O57
O59
O58
J
Jadhav M. S.
O29
K
Keymuelen F.
Khairnar B. B.
Kopf I.
P23
P16, P17
P27, P30
L
La Bella A.
La Corte D.
La Ferla B.
Lamba D.
Lanari D.
Lancianesi S.
Lascialfari L.
Latini V.
Lattanzi A.
Lattuada L.
Lauro G.
Lazzara G.
Legnani L.
Lentini S.
Leonelli F.
Lessi M.
Licandro E.
Lo Meo P.
Lombardi P.
Lombardo M.
Lozito, F.
Lucarini M.
Luconi L.
Luisi R.
Lupattelli P.
F9
P44
F6, P86
F9
O50
P19
O26
F9
O56
PR3
P3
P46
O4, P72, P93
O14
F9
O16
P50
P44
P43
O3
O57
P22
O26
P77
O49, P79
M
Maccagno M.
Machetti F.
P89, P90, P91
O9
5
Maggi F.
Maggi R.
Mahmood K.
Maiorana S.
Maiuolo L.
Malagòn O.
Manca A.
Mancin F.
Mancini G.
Mancuso R.
Mandic’ E.
Mangiacapra L.
Manica M.
Manicardi A.
Mannucci B.
Manoni R.
Mansueto R.
Maraschi F.
Marcantoni E.
Marchelli R.
Marco Valerio A.
Marcotullio M. C.
Margarucci L.
Mari C. M.
Mari M.
Marini Bettolo R.
Marini F.
Marini M.
Marinone Albini F.
Marotta E.
Marras G.
Marsili L.
Martín M. A.
Martinelli A.
Martí-Rujas J.
Martorana A.
Marucci C.
Marullo S.
Masiero S.
Massaccesi L.
Massaro M.
Masserini M.
Massi A.
Mattarei A.
Mattia E.
Meazza L.
Meazza M.
Mega A.
Mella M.
Melucci M.
Mencarelli A.
Menchi G.
P95
PL6
O21
P50
F1
P10
O39
O5
P73
O37
P88
O10
O57
F12, P42, P70
O2
P22
F3
P48
O29
O25, F12, P70
F13
O63
O61, P58
O6
O20
F9
O58, P18
P60
P93
P53
O31
O29
O54
P17
P55
O52
P88
P45
P27, P28, P30
P60
P46
F6
O69, P92
P52, P53
O62
O66
P29
P65
P69, P97
O26
P3, P8
O41
Meneghetti F.
Menta S.
Mercuri F.
Merli D.
Merlini V.
Merlo S.
Mesiano L.
Messina F.
Metrangolo P.
Mezzina E.
Micheli F.
Migneco L. M.
Milan M.
Milioto S.
Minassi A.,
Minei P.
Mineo P.
Miozzo L.
Mobbili G.
Mocci S.
Moni L.
Monopoli A.
Montanaro S.
Monti M. C.
Montroni E.
Moraca F.
Morana F.
Morelli C. F.
Moretti M.
Moretto A.
Morini G.
Morocho V.
Mourtas S.
Mulani I.
Mura M. G.
Musio B.
Musso L.
Musso N.
O4
P41, P66
O26
F4
O62, F7, P80
P87
P32
O63
O1, O66, F14, F15, P55
P22
O47
F9
O10
P46
P96
O16
P35
O8
P60
P77
O46
O57
,F4
O61, P4, P8, P58
O3
O35
O46
O60, P12, P61
O64
P94
O23
P10
F6
F1
F11
P77
P59, P64
O48
N
Nacci A.
Nadai M.
Napolitano A.
Naponiello G. C. M.
Nardi M.
Nasini G.
Nazeeruddin M.
Neri P.
Niarakis A.
Nicotra F.
Nieddu G.
O57
P68
O54
P88
P56, P63
P64
P49
O13
F6
F6, P86, P87
F2
6
Noto R.
Nocioni D.
PR4, P44, P45, P46
P98
O
Occhiato E. G.
Oliverio M.
Ornano L.
Ortuso F.
Orzi F.
O19, P34
P56, P63
P95
O35
P43
P
Pace A.
Pacifico S.
Pagani G. A.
Paissoni P.
Palleschi G.
Palmieri A.
Palmieri G.
Palumbo Piccionello A.
Panzella L.
Papagni A.
Paradisi C.
Park J.
Parks M.
Parrilli M.
Parrotta L.
Pastori N.
Peggion C.
Pelà M.
Pelagalli A.
Pellacani L.
Pellegrino S.
Pennè U.
Pepori C.
Percivalle C.
Perego L.
Perosa A.
Perrone S.
Petek S.
Petenzi M.
Petricci E.
Petrillo G.
Petrini M.
Peviani E. G.
Pieraccini S.
Pierini M.
Piersanti G.
Pilati T.,O1
Pineschi M.
O52
P92
O6
O24
P36
P14, P19
O44
O52
O54
O8
P52, P53
P49
P43
O53
O35
P81
P94
O11
P38
P38
O15
P2
P84
O43, P40, P68
O16
P21
P37
P3
O43, P69
F16
P89, P90, P91
P14, P19
P75
P27, P30
P41, P66
O20
P55
F5, P51, P57
Piras P. P.
Pisani M.
Pisano L.
Pittalis M.
Pizzetti M.
Pizzo F.
Ponticelli F.
Porcheddu A.
Pori M.
Porta A.
Possanza F.
Pozzoli C.
Pretali L.
Previtera L.
Procopio A.
Profumo A.
Properzi R.
Protti S.
Pucci A.
Punta C.
Pupi A.
O28,P54
P60
P77
P77
F16
O50
O17,P13
O51,P11
P15
O62, F7, P1, P2,P72,
P74 , P78, P80
P36
O32
P47
O59
P56, P63
P48
O29
O2, P14, P83
O16
P81
O41
Q
Quadrelli P.
Quagliotto P.
Quaroni M.
Quintavalla A.
P67
P49
P2
O3
R
Ragno D.
Ramos S.
Raspanti S.
Rasparini M.
Rassu G.
Rastrelli F.
Ravelli D.
Raviola C.
Re F.
Renga B.
Resnati G.
Riccio R.
Richter S. N.
Riela S.
Righetti P. P.
Righi G.
Rispoli G.
Riva R.
Riva S.
P92
O54
O41
O31
O27
O5, O65
O2, F4, P83
P83
F6
O42, P3 ,P7, P8
O1, O66, F14, F15, P55
O48, O61, P25, P31, P58
O43, P68
P44, P46
F11, P84
P88
P73
O46
O68
7
Rizzo C.
Roletto J.
Rosati O.
Rosato F.
Rosciano F.
Roscioli D.
Rossi B.
Rossi D.
Rossin A.
Rubini P.
Ruffo R.
Ruggeri G.
Rumio C.
Rupiani S.
Russo A.
Russo B.
Russo M.
P45
O24
O63
F3, P37
F8
P36
P81
O21
O26
O18
O6,F8
O16
P86
O18
O31, O56
F1
P44
S
Sacchetti A.
Saccone M.
Saielli G.
Salamone M.
Salamone M. M.
Salerno G.
Salvadori S.
Samorì C.
Samorì P.
Sandri C.
Sanna C.
Sansone F.
Santi C.
Sartori A.
Sartori G.
Sassi M.
Sbarbada D.
Scalera C.
Scamporrino E.
Scapolla C.
Scarpati M.L.
Scarpi D.
Schiano Moriello A.
Schiraldi C.
Scialdone O.
Scopini J.
Scovassi A. I.
Secci D.
Secci F.
Selleri S.
Selva M.
Sepe V.
O64
O1
O65
O10, F8
O6
O37
O11
F17
P28
P86
P95
P73
O58, P18
O27
PL6
O6, F8
P74
O58
P35
P89, P90
P98
O19, P34
O23
O53
F13
P87
P43
P41, P66
O28, P54
P42
P21
O42, P7, P8
Serra A.
Serra C. D.
Serra I.
Serra M.
Serra S.
Serrilli A. M.
Sesana S.
Sferrazza A.
Sforza S.
Sforza S.
Sgambato A.
Silipo A.
Silvani A.
Sindona G.
Sironi E.
Sisto A.
Soldati R.
Sorana F.
Sozzi M.
Spada G. P.
Spampinato S.
Spatafora C.
Speltini A.
Speranza G.
Spina E.
Spitaleri F.
Stabile G.
Stanovnik B.
Steed J. W.
Steele R.
Sternativo S.
Stivanello M.
Strappaveccia G.
Strocchia M.
Sturini M.
P48
O60
O60, P61
P75
O55
P95, P99
F6
F9
O25
P70
P87
M2
O64
P63
F6
P88
P15
O29
P42
M3, P27, P28, P30
P82
O48
P48
O60,P12, P61
P35
P35
F1
PL5
O66
NT2
P18
O33
O50
P25
P48
T
Taddei M.
Taglialatela-Scafati O.
Tagliavini E.
Talotta C.
Tatulli G.
Tava A.
Tavani C.
Tedeschi T.
Tei L.
Temporini C.
Tengattini S.
Terracciano S.
Terraneo G.
Terreni M.,P12,P61
PR1, O31, F16
P96
F17
O13
O57
P97
P89, P90, P91
O25, P70
P39
P61
P61
P25
P55
8
Tessari F.
Testaferri L.
Teulade-Fichou M.-P.
Tidei C.
Tillhon M.
Tirocco A.
Tolomelli A.
Toma L.
Tomasini C.
Tomei M.
Tondelier D.
Tonelli A.
Toniolo C.
Toppino A.
Toscano S.
Tosco A.
Tosi S.
Trabocchi A.
Tramutola F.
Trapella C.
Tringali C.
Troise C.
Troisi L.
Trombetta A.
Trombini C.
Trost B. M.
Trucchi B.
O33
O58, P18
P69
O58
P43
P90
O18, P82
O4, P72, P93
O45
P88
O8
O25
P94
O34, P24
PL2
P58
P9
O41
P79
O11
O48
F10
F3, P37
F9
O3
PL1
P32
U
Ubiali D.
Ummarino R.
O60
O42, P7
Viscardi G.
Vismara E.
Vita Finzi P.
Vitale P.
Vitalini D.
Volonterio A.
Vurchio C.
Vurro M.
P49
F13
P9, P10
P45
P35
O38
P16
F10
Y
Yafteh Mihan F.
Yassar A.
Yum J.
P23
O8
P49
Z
Zampella A.
Zanardi F.
Zanoni G.
O42, P3, P4, P7, P8, P31
O27
O62, F7, P1, P2
P72, P74, P78, P80
Zanotti-Gerosa A.
O31
Zappacosta R.
P26
Zarrelli A.
O59
Zeffiro A.
P84, P85
Ziccarelli I.
O37
Zona C.
F6
Zonno M. C.
F10
Zoratti M.
P52, P53
Zuppolini S.
O59
V
Vaccaro L.
Valentini F.
Valgimigli L.
Valli M.
Vellecco V.
Venanzi M.
Venditti A.
Venturello P.
Vergari M. C.
Verotta L.
Vidari G.
Villa D. C.
Villa S.
Villani C.
Viola A.
O50
P36
O54
P1 ,P74, P78
P4
O14
P95
O34, P24, P62
P38
O54,P32
O62,F7,P1,P2,P9,
P10,P72,P74,P76,P78,P80
F11
O4
P66
P82
9

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