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Title of the abstract, centered, in bold face, using 14 pt Times New
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 ore 15.40 – Aula Magna PL1 – B. M. Trost The Alkyne Strategy For the Synthesis of Bioactive Targets ore 16.20 – Aula Magna 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 ore 17.30 – Aula Magna 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 ore 12.20 – Aula Magna 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 13.05 Fine Sessione ore 14.30 – Cortile Sforzesco Prima Sessione Poster: F1 – F9 e P01 – P48 Presiede: Alessandro Bagno ore 16.00 – Aula Magna 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. ore 16.40 Intervallo 8 Presiede: Ugo Azzena ore 17.10 – Aula Magna 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 CH 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. ore 18.50 Fine Sessione 9 Mercoledì 12 Settembre Presiede: Stefano Menichetti ore 9.00 – Aula Magna PL3 – E. Beccalli Pd-catalyzed reactions of indole derivatives Presiede: Gabriele Fontana ore 9.50 – Aula Magna 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 ore 9.50 – Aula del ‘400 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. ore 11.10 Intervallo 10 Presiede: Paolo Crotti ore 11.40 – Aula Magna 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 V3 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. Presiede: Andrea Goti ore 11.40 – Aula del ‘400 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 ore 12.30 – Aula del ‘400 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. ore 13.10 Fine Sessione 11 Presiede: Giorgio Cevasco ore 14.30 – Aula Magna PL4 – S. Garattini Open problems in drug discovery and development Presiede: Giovanni Petrillo ore 15.20 – Aula Magna 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 ore 15.20 – Aula del ‘400 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. ore 17.00 Intervallo Presiede: Marco Lucarini ore 17.30 – Aula Magna Conferenza del vincitore del premio per la ricerca in chimica organica 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 ore 19.30 Fine Sessione 12 Giovedì 13 Settembre Presiede: Pietro Allegrini ore 9.00 – Aula Magna Conferenza del vincitore del premio per la ricerca in chimica organica nei suoi aspetti di applicazione industriale PR3 – L. Lattuada Twenty years of research and development in Bracco Imaging Presiede: Agostino Casapullo ore 9.40 – Aula Magna 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 ore 9.40 – Aula del ‘400 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. ore 10.40 Intervallo Presiede: Rosa Lanzetta ore 11.10 – Aula Magna 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 ore 11.10 – Aula del ‘400 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 ore 12.20 – Aula Magna 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 13.10 Fine Sessione ore 14.40 – Cortile Sforzesco Seconda Sessione Poster: F10 – F17 e P49 – P97 Presiede: Francesco Nicotra ore 16.10 – Aula Magna 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 ore 16.10 – Aula del ‘400 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. ore 17.10 Intervallo 14 Presiede: Claudia Tommasini ore 17.40 – Aula Magna 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 ore 17.40 – Aula del ‘400 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 19.00 Fine Sessione ore 20.00 Cena Sociale presso il Collegio F.lli Cairoli 15 Venerdì 14 Settembre Presiede: Andrea Goti ore 9.20 – Aula Magna PL6 – G. Sartori, R. Maggi Fine chemical synthesis through heterogeneous catalysis under batch and continuous flow conditions ore 10.00 – Aula Magna Conferenza del vincitore del premio per la ricerca in chimica organica nei suoi aspetti meccanicistici e teorici PR4 – R. Noto Organic salts: from ionic liquids to gels ore 10.30 Intervallo Presiede: Michelangelo Gruttadauria ore 11.00 – Aula Magna 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) [email protected] 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. [email protected] 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 [email protected] 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) [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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. [email protected] 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) [email protected] 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. [email protected] 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. [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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. [email protected] 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 CH 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 [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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 [email protected] (-)-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 [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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 V3 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 [email protected] 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 V3 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 V3-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 V3 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 [email protected] 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. [email protected] 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) [email protected] 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) Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, 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. [email protected] 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 [email protected] 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 6and 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. [email protected] 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. [email protected] 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) [email protected] 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. [email protected] 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) [email protected] 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. [email protected] 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 [email protected] 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. [email protected] 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. [email protected] 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 [email protected] 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. [email protected] 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) [email protected] 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) [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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: [email protected] 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. [email protected] 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. [email protected] 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 [email protected] 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-(13)--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 [email protected] 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. [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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. [email protected] 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. [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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 [email protected] 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) [email protected] 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. [email protected] 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. [email protected] 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 [email protected] 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 PhotoGreen Lab, Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia - www.unipv.it/photochem [email protected] 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 [email protected] 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 Department of Biotechnology and Biosciences, University of Milano-Bicocca, 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 [email protected] 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: [email protected] 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. [email protected] 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. [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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: [email protected] 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. * Partecipazione con borsa di studio offerta da Dipharma. 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. [email protected] 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 Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100, Siena, Italy [email protected] 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 [email protected] 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: [email protected] 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 [email protected] 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 [email protected] 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 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 Dipertimento di Farmacologia Sperimentale Università di Napoli “Federico II”, via D. Montesano 49, 80131 Napoli, Italy; 4 Institut de Richerche puor Developpement (IRD), Polynesian Reaserch Center on the Island Biodiversity, BP529, 98713 Papeete, Tahiti, French Polynesia. [email protected] 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. [email protected] 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. [email protected] 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 Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli “Federico II”, 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 [email protected] 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 Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli “Federico II”, via D. Montesano 49, 80131 Napoli, Italy 3 Dipartimento di Scienze Farmaceutiche e Biomediche, Università di Salerno, via Ponte don Melillo, Fisciano, Salerno, 84084 Italy [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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 [email protected] 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 PhotoGreen Lab, Department of Chemistry, University of Pavia, 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 [email protected] 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 [email protected] -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) [email protected] 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 [email protected] 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 [email protected] 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: [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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. * Partecipazione con borsa di studio offerta da Dipharma. 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. [email protected] 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. [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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) [email protected] 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 [email protected] 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 [email protected] 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). * Partecipazione con borsa di studio offerta da Dipharma. 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 Dipartimento di Scienze Farmaceutiche e Biomediche, Università di Salerno, via Ponte don Melillo, 84084 Fisciano (SA), Italy. 2 Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli “Federico II”, via D. Montesano 49, 80131 Napoli, Italy. 3 Department of Chemistry, University of Bristol, Cantocks Close, BS8 1TS Bristol, United Kingdom. [email protected] 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). [email protected] 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. [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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” [email protected] 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 ([email protected]) 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 [email protected] 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 [email protected] 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 Dipartimento di Chimica Organica e Industriale, Università di Parma, 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 [email protected] 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. [email protected] 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. [email protected] 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 [email protected] 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) [email protected] 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 [email protected] 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) [email protected] 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. [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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. * Partecipazione con borsa di studio offerta da Dipharma. 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). [email protected] 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. [email protected] 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 [email protected] 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 [email protected] 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 Dipartimento di Scienze Farmaceutiche e Biomediche, Università di Salerno, via Ponte don Melillo, 84084, Fisciano, Italy [email protected] 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) [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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) [email protected] 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. [email protected] 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). [email protected] 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 Dipartimento di Chimica Organica e Industriale, Università di Parma, 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 [email protected] 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. [email protected] 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. [email protected] 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) [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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. [email protected] 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 [email protected] 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 [email protected] ,n-Didehydrotoluenes (,n-DHTs) are hetero-symmetric diradical species (51) 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) [email protected] 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) [email protected] 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 [email protected] 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 Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.zza della Scienza 2, 20126 Milano-Italy. [email protected] 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. [email protected] 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 Dipartimento di Chimica e Chimica Industriale, Università di Genova, Via Dodecaneso 31, 16146 Genova [email protected] 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 [email protected] 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. (2) 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. 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 Dipartimento di Chimica e Chimica Industriale, Università di Genova, via Dodecaneso 31, I-16146 Genova, Italy [email protected] 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. (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) 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 [email protected] 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 [email protected] 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 [email protected] 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. [email protected] 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. [email protected] 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. [email protected] 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 [email protected] 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. [email protected] 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 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 "La Sapienza" di Roma Università Statale di Milano Università di Perugia Università di Parma Università Statale di Milano Università di Napoli Federico II Olon S.p.A. Bruker Italia Srl Università Statale di Milano Università Statale di Milano Università di Pisa Politecnico di Milano Università di Parma Università di Milano Bicocca Università di Firenze Università di Genova Università Tor Vergata di Roma Università "La Sapienza" di Roma Università Statale di Milano Università Statale di Milano Università "La Sapienza" di Roma Università di Firenze Università dell'Insubria Università "La Sapienza" di Roma Invento srl Università di Pavia Università di Palermo Diego Marco Università del Piemonte Orientale Università di Pavia 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 Padova Università di Salerno Università di Firenze Università di Parma Università di Bologna Università Statale di Milano Bioindustria LIM SpA Università di Genova Università di Pisa Università della Basilicata Università di Firenze Università di Camerino Università di Napoli Federico II Università di Milano Bicocca ISS Università di Lecce Università Statale di Milano Politecnico di Milano Università di Pavia Università Tor Vergata di Roma Università di Firenze Università di Parma Università di Catanzaro Università di Pisa Antonella Sabrina Francesca Francesco Ottorino Rossella Ilse Annamaria Giovanni Lorenzo Valeria Antonello Simone Marco Filippo Università "La Sapienza" di Roma Università Statale di Milano Università di Palermo Università dell'Aquila Università di Venezia Università di Bologna MERCK SERONO SPA Università di Torino Università di Pavia Università di Pisa Università di Pisa Università di Chieti Università di Salerno Università di Napoli Federico II Università di Pavia Antonio Università di Napoli Federico II Pierangelo Maurizio Università di Firenze Università di Pavia 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 Pavia Università di Bari Università dell'Insubria Università di Pavia Università di Napoli Federico II Università di Venezia Naxospharma srl Università di Bari Università Tor Vergata di Roma Università di Bologna Università di Chieti Università di Padova Università di Pisa Università di Pavia Università di Palermo 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 Università di Pavia Università del Piemonte Orientale Università di Napoli Federico II Università di Pavia Istituto di Ricerche Farmacologiche Mario Negri Università "La Sapienza" di Roma Politecnico di Milano Università dell'Insubria Università Statale di Milano Università di Pavia Università di Torino Università di Pisa Università di Pavia Università di Firenze Università di Firenze Università di Pavia Università di Bologna Università di Bologna Università di Palermo Barbara Concetta Stefano Rosa Alessandra Luciano Università di Milano Bicocca Università Statale di Milano Università di Camerino Università di Napoli Federico II Università di Salerno 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 Pavia Università Tor Vergata di Roma Università "La Sapienza" di Roma Università di Pisa Università Statale di Milano Università di Palermo Università di Bologna Università di Bologna 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 Università di Genova CNR Firenze Università Statale di Milano Università della Calabria Università "La Sapienza" di Roma Università di Parma Università di Bologna Università di Camerino Università di Salerno Università Politecnica delle Marche Università di Ferrara Università di Padova Università di Bologna Politecnico di Milano Università di Parma Università di Pavia Università di Firenze Università di Pavia Università Statale di Milano Università di Perugia Politecnico di Milano Aptuit Verona s.r.l. Università del Piemonte Orientale Chemessentia Srl Università di Milano Bicocca Università Statale di Milano Università della Calabria Università Statale di Milano Angelo Monica Francesco Giammario Renato Università di Bari Università della Calabria Università di Milano Bicocca Università di Sassari Università di Palermo Ernesto Università di Firenze 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 Università di Catanzaro Università "La Sapienza" di Roma 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 Università di Ferrara F.I.S. FABBRICA ITALIANA SINTETICI S.P.A. Università di Palermo Università di Napoli Federico II Università di Napoli Federico II Politecnico di Milano Università "La Sapienza" di Roma Università di Pavia Università di Pavia Università di Lecce Università di Pavia Università di Genova Università di Camerino Università di Pavia Chemessentia Srl Università "La Sapienza" di Roma Università di Urbino Università di Pisa Università di Cagliari Università di Siena Università di Siena Università di Sassari Università di Pavia Farmabios (Zellbios Group) Università di Catanzaro Università di Pavia Q QUADRELLI Paolo Università di Pavia Marcello Federico Davide Carlotta Raffaele Serena PierPaolo Sergio Simona Ornelio Chemessentia Srl Università di Padova Università di Pavia Università di Pavia Università di Salerno Università di Palermo Università di Pavia CNR Milano Università Statale di Milano Università di Perugia 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 Politecnico di Milano Politecnico di Milano CNR Padova Università di Bologna Università Statale di Milano Università di Parma Università di Perugia Università di Parma Università di Milano Bicocca Università di Pavia Università di Catania Università di Padova Università di Cagliari Università di Napoli Federico II CNR-ICRM Università di Pavia Università di Napoli Federico II Università di Bologna Università di Camerino Università di Bologna Università di Catania Università Statale di Milano Università di Bologna Università di Lubjana Lundbeck Pharmaceuticals Italy SpA Università di Perugia Università di Salerno Università di Pavia Maurizio Emilio Carmen Cinzia Tullia Lucio Claudia Antonio Claudio Corrado Ciro Luigino Andrea Barry M. Beatrice Università di Siena Università di Bologna Università di Salerno Università di Genova Università di Parma Università di Pavia Università di Bologna Università di Torino Università di Ferrara Università di Catania Università di Napoli Federico II Università di Lecce Università "La Sapienza" di Roma Università di Stanford Università Statale di Milano 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 Università di Pavia Università "La Sapienza" di Roma Università di Pavia Università di Pavia Università di Torino Università di Pavia Politecnico di Milano Università di Firenze Angela Giuseppe Romina Armando Alberto Cristiano Università di Napoli Federico II Università di Pavia Università di Chieti Università di Napoli Federico II Università di Pavia Università di Milano Bicocca 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