XXXVI Convegno Nazionale della Divisione di Chimica Organica
Transcription
XXXVI Convegno Nazionale della Divisione di Chimica Organica
XXXVI Convegno Nazionale della Divisione di Chimica Organica Società Chimica Italiana Atti del Convegno BOLOGNA 13‐17 settembre 2015 Alma Mater Studiorum ‐ Università di Bologna Aule Complesso Belmeloro, via Belmeloro 14, Bologna La Società Chimica Italiana ringrazia le Aziende Sponsor del Convegno Pt SPONSOR Au SPONSOR SPONSOR SOSTENITORI XXXVI Convegno Nazionale della Divisione di Chimica Organica Comitato Scientifico Pietro Allegrini [email protected] Roberto Ballini [email protected] Anna Bernardi [email protected] Giorgio Cevasco [email protected] Valeria Conte [email protected] Marco D'Ischia [email protected] Gianluca Farinola [email protected] Paolo Scrimin [email protected] 4 Comitato Organizzatore Marco Bandini [email protected] Luca Bernardi [email protected] Carla Boga [email protected] Oscar Francesconi [email protected] Mauro Comes Franchini [email protected] Pier Giorgio Cozzi [email protected] Daria Giacomini [email protected] Luca Gentilucci [email protected] Marco Lombardo [email protected] Mauro Panunzio [email protected] Arianna Quintavalla [email protected] Paolo Righi [email protected] Letizia Sambri [email protected] Alessandra Tolomelli [email protected] Claudia Tomasini [email protected] Claudio Trombini [email protected] 5 Medaglie e Premi 6 MEDAGLIA ADOLFO QUILICO (M1) PROF. FRANCESCO NICOTRA UNIVERSITA’ DI MILANO-BICOCCA Per il suo rilevante contributo nel campo della sintesi di composti biologicamente attivi, in particolare di glicomimetici e di glicoconiugati, e nello studio delle loro proprietà biologiche e farmacologiche. Queste ricerche, all’interfaccia tra chimica, biochimica e medicina, costituiscono un importante patrimonio per la comunità scientifica nazionale ed internazionale. MEDAGLIA GIACOMO CIAMICIAN (M2) PROF. VITTORIO PACE UNIVERSITY OF WIEN Per i suoi contributi originali nella sintesi di composti farmacologicamente attivi. In particolare per lo sviluppo dell’uso di isocianati come precursori di aloimmidi e di metodi efficienti nell’impiego riproducibile di reazioni basate su carbenoidi e per lo studio della reattività di ammidi verso substrati organometallici. 7 MEDAGLIA PIERO PINO (M3) PROF. PIER GIORGIO COZZI UNIVERSITA’ DI BOLOGNA Per i suoi contributi di assoluto rilievo nel campo della catalisi, attraverso la progettazione e lo sviluppo di nuovi catalizzatori chirali e, in special modo, per lo sviluppo di catalizzatori organici ed organometallici in nuove strategie sintetiche fino ad oggi inesplorate. MEDAGLIA ANGELO MANGINI (M4) PROF. MICHELE MAGGINI UNIVERSITA’ DI PADOVA Per i suoi contributi allo sviluppo di architetture molecolari complesse basate su strutture carbon rich, e in particolare di diadi costituite da fullereni e unità con speciali proprietà spettroscopiche, redox, magnetiche e ottiche non lineari. I suoi studi l’hanno condotto ad esplorare materiali molecolari di nuova concezione per applicazioni che spaziano dal fotovoltaico di nuova generazione all’ottica non lineare, ed anche a sviluppare metodi sintetici di avanguardia, come quelli basati sull’uso di reattori in flusso continuo per la funzionalizzazione di fullereni e nanotubi di carbonio. 8 PREMIO ALLA RICERCA (P1) "CHIMICA ORGANICA NEI SUOI ASPETTI MECCANICISTICI E TEORICI" PROF. OLGA BORTOLINI UNIVERSITA’ DI FERRARA Per il suo rilevante contributo nell’utilizzo delle tecniche di Spettrometria di Massa, convenzionali ed avanzate, che ha permesso di ottenere fondamentali informazioni relative ad intermedi di reazione coinvolti in processi di organocatalisi e catalisi metallica. PREMIO ALLA RICERCA (P2) "CHIMICA ORGANICA NEI SUOI ASPETTI DI APPLICAZIONE INDUSTRIALE" DOTT. GABRIELE FONTANA INDENA SPA Per i suoi originali contributi alla sintesi organica applicata a sostanze naturali, sia nell’ambito dell’identificazione di analoghi di tassani e camptotecine che nella messa a punto di metodiche preparative industriali per la sintesi di prodotti naturali d’interesse farmaceutico. 9 PREMIO ALLA RICERCA (P3) "CHIMICA ORGANICA NEI SUOI ASPETTI DI DETERMINAZIONE STRUTTURALE E INTERAZIONI MOLECOLARI" PROF. ROBERTO CORRADINI UNIVERSITA’ DI PARMA Per i suoi importanti contributi allo studio delle interazioni intermolecolari per il riconoscimento di specie biologicamente attive e, in particolare, per la discriminazione di enantiomeri fino a ottenere il riconoscimento di acidi nucleici. PREMIO ALLA RICERCA (P4) "CHIMICA ORGANICA NEI SUOI ASPETTI SINTETICI (METODOLOGIE E PRODOTTI) " PROF. MICHELANGELO GRUTTADAURIA UNIVERSITA’ DI PALERMO Per gli importanti risultati ottenuti nel campo dei processi sintetici sostenibili mediante lo sviluppo di nuovi sistemi catalitici supportati su matrici organiche e per l’impiego di liquidi ionici e il riciclo del catalizzatore attraverso il processo Release and Catch. 10 Programma del Convegno 11 DOMENICA 13 settembre 2015 Registrazione Cerimonia di apertura R. Ballini, E. Ferrari, P. Bianchi 12:00-15:00 15:00 (Aula B) (chairperson C1: A. Evidente) 15:40 M1 Medaglia Quilico − F. NICOTRA 16:20 P1 "Premio Chimica organica nei suoi aspetti meccanicistici e teorici" O. BORTOLINI 16:50 Presentazione Bruker 17:10 coffee break (chairperson C2: M. Lucarini) Sessione parallela 17:35 17:55 18:15 18:35 18:55 Aula B Aula A Catalisi Bio-Medicina & Biotech (chairperson C3: O. De Lucchi) (chairperson C4: F. Gasparrini) OC 1 OC 2 OC 3 OC 4 OC 5 G. Licini K. Martina M. Stucchi F. Pesciaioli A. Rossetti Welcome Party 12 OC 6 S. Terracciano OC 7 P. Galletti OC 8 M. P. Verona OC 9 A. Manicardi OC 10 L. Valgimigli LUNEDI’ 14 settembre 2015 (chairperson C5: C. Chiappe) 9:00 (Aula B) Sessione parallela 9:45 10:15 10:35 PL1 H. Mayr Aula B Aula A Fine chemicals and APIs Enerchem (chairperson C6: P. Allegrini) (chairperson C7: A. Abbotto) KN 1 V. Farina OC 11 L. Lattuada OC 12 M. Tomassetti 10:55 11:20 (Aula B) KN 2 A. Pellegrino OC 18 L. Baldini OC 19 F. Sabuzi coffee break Tavola Rotonda (chairpersons C8: R. Ballini, C. Trombini) 13:00 Industria, giovani e accademia: futuro possibile D. Braga, V. Farina, C. Franco, M. Fumagalli Pausa pranzo 14:00 Sessione Poster 1 (PC1-PC62) 15:00 P2 "Premio Chimica organica nei suoi aspetti di applicazione industriale" − G. FONTANA 15:30 Comunicazioni Flash (CF1-CF6) V. Algieri, S. Crespi, P. Franchi, A. Mezzetta, A. Pelagalli, C. Petrucci (chairperson C9: V. Farina) Sessione parallela 16:00 16:20 (chairperson C10: V. Capriati) Aula B Aula B Fine chemicals and APIs Enerchem (chairperson C11: L. Lattuada) (chairperson C12: E. Licandro) OC 13 F. Fontana OC 14 E. Attolino OC 20 P. Galloni OC 21 V. Criscuolo 16:40 coffee break 17:10 17:30 17:50 18:10 OC 15 C. Cattaneo OC 22 A. Mucci OC 16 L. Carcone OC 23 G. Marzano OC 17 E. Cini OC 24 F. Parenti Sessione Poster 1 (PC1-PC62) 13 MARTEDI’ 15 settembre 2015 9:00 (Aula B) sessione parallela 9:45 10:15 10:35 (chairperson C13: R. Noto) M2 Medaglia Ciamician − V. PACE Aula B Aula A Organomet & Nanotech Green Chemistry (C14 chairperson A. Brandi) (C15 chairperson B. Floris) KN 3 A. Goti OC 25 L. Pasquato OC 26 E. Lubian 10:55 11:30 (Aula B) 12:00 KN 4 L. Vaccaro OC 27 A. Paternò OC 28 S. Rizzo coffee break (C16 chairperson M. Bietti) Comunicazioni Flash (CF7-CF12) L. Barbera, G. Lauro, S. Perrone, S. Rossi, S. Sattin, C. Vurchio (C17 chairperson O. Francesconi) Tavola Rotonda Gruppo Giovani Biocarburanti: una fonte energetica ecosostenibile? V. Balzani, G. Farinola, O. Francesconi, G. Venturi 13:00 Pausa pranzo 14:00 Sessione Poster 2 (PC63-PC122) (C18 chairperson C. Nativi) 15:15 (Aula B) sessione parallela 16:00 16:20 16:40 PL2 H. Suga Aula B Aula A Nanotech Bio-Medicina & Biotech (C19 chairperson B. Gabriele) (C20 chairperson E. Beccalli) OC 29 F. Sansone OC 30 R. Fiammengo OC 31 J. L. Y. Chen OC 35 A. Sganappa OC 36 A. Sartori OC 37 E. Petricci coffee break 17:00 sessione parallela 17:20 17:40 18:00 18:30 (Aula B) Aula B Aula A Nanotech Reazioni & Meccanismi (C21 chairperson S. Menichetti) (C22 chairperson G. Licini) OC 32 M. D’Onofrio OC 33 L. Degennaro OC 34 N. Zanna OC 38 L. Bagnoli OC 39 G. Bencivenni OC 40 A. Porta Assemblea soci SCI 14 MERCOLEDÌ 16 settembre 2015 (C23 chairperson E. Marcantoni) 9:00 (Aula B) PL3 N. Maulide (C24 chairperson F. De Angelis) 9:40 KN 5 G. Iacobellis sessione parallela 10:20 10:40 11:00 Aula B Aula A Bio-Medicina & Biotech Sintesi (C25 chairperson F. Formaggio) (C26 chairperson M. V. D’Auria) OC 41 S. Lepri OC 42 E. Moro OC 43 E. Masi OC 48 G. Petrillo OC 49 E. Beccalli OC 50 M. Caso 11:20 coffee break (C27 chairperson A. Zampella) 11:40 12:00 12:20 12:40 OC 44 OC 45 OC 46 OC 47 S. Pellegrino M. Dell’Acqua A. Trabocchi L. Sernissi 13:00 15:00 15:30 15:50 16:10 sessione parallela 17:20 17:40 18:00 OC 51 OC 52 OC 53 OC 54 N. Di Iorio A. Bochicchio G. Favi S. Gaspa Pausa pranzo (C29 chairperson M. Taddei) (C30 chairperson L. Lunazzi) KN 6 OC 55 OC 56 OC 57 KN 7 OC 58 OC 59 OC 60 L. Lay R. Mancuso R. De Marco R. Goracci M. Bonchio M. Lessi E. Occhiato P. Quagliotto coffee break 16:30 16:50 (Aula B) (C28 chairperson L. Pellacani) (C31 chairperson M. Bonchio) KN 8 Modena’s Lecture − J. T. Groves Aula B Aula A Meccanismi Bio-Medicina & Biotech (C31 chairperson M. Bonchio) (C32 chairperson M. Benaglia) OC 61 M. Bietti OC 62 O. Lanzalunga OC 63 C. Raviola OC 64 R. Romeo OC 65 L. Musso OC 66 O. Francesconi 20:30 Cena Sociale 15 GIOVEDÌ 17 settembre 2015 (C33 chairperson C. Trombini) 9:00 (Aula B) M3 Medaglia Pino − P. G. COZZI (C34 chairperson L. Mayol) 9:45 P3 "Premio Chimica organica nei suoi aspetti di determinazione strutturale e interazioni molecolari" − R. CORRADINI 10:15 Presentazione REAXYS 10:35 Premiazioni Flash poster, Poster e Premio Reaxys 11:00 coffee break 11:25 P4 "Premio chimica organica nei suoi aspetti sintetici" M. GRUTTADAURIA 11:55 M4 Medaglia Mangini − M. MAGGINI 12:45 Chiusura del Convegno (C35 chairperson M. Curini) (C36 chairperson G. Cruciani) 16 Programma dettagliato Domenica13 Settembre 2015 Aula 12:00‐15:00 Registrazione B 15:00 CerimoniadiApertura(R. Ballini, E. Ferrari, P. Bianchi) ChairedbyA.Evidente(C1) B 15:40 M1 F. Nicotra, L. Cipolla, B. La Ferla, C. Airoldi, M. Masserini, F. Re, S. Antimisiaris, G. Polzonetti, P. Couvreur Exploiting Organic Chemistry in Nanomedicine ChairedbyM.Lucarini(C2) B 16:20 P1 O.Bortolini Organic Reaction Mechanisms: The Electrospray Ionization Mass Spectrometry Approach 16:50 coffeebreak ChairedbyO.DeLucchi(C3)–Catalisi B 17:35 OC1 E.Amadio,E.Badetti,C.Zonta,G.Licini Selective Oxidations via Activation of H2O2 and O2 B 17:55 OC2 K. Martina, F. Baricco, M. Caporaso, G. Berlier, G. Cravotto Pd Nanoparticles Supported on Cyclodextrin Derivatized Silica: an Efficient and Versatile Catalyst for Ligand Free C-C Coupling and Hydrogenation Reaction B 18:15 OC3 M. Stuccchi, G. Lesma, G. Rainoldi, A. Sacchetti, A. Silvani Enantioselective Organocatalyzed Biginelli-like Reaction on Isatin: Synthesis of Enantioenriched Spiro[indoline- pyrimidine]-diones Derivatives B 18:35 OC4 L.Ratjen,M.vanGemmeren,F.Pesciaioli,B.List Towards High-Performance Lewis Acid Organocatalysis B 18:55 OC5 A.Rossetti,M.Bonfanti,G.Roda,A.Sacchetti Title Bio- and Organo-Catalyzed Reduction of Oxindole Based Olefins ChairedbyF.Gasparrini(C4)–BioMedicina&Biotech A 17:35 OC6 S. Terracciano, M. Strocchia, G. Lauro, F. Dal Piaz, 17 M. C. Vaccaro, M. G. Chini, R. Riccio, G. Bifulco, P. Filippakopoulos,I.Bruno Identification of Promising Drug Candidates Targeting Strategic Proteins Involved in Cancer Development A 17:55 OC7 P.Galletti,R.Soldati,F.Funiciello,D.Giacomini Selectivity in Alcohol and Amine Bio-oxidation Using Laccase-mediator System A 18:15 OC8 M. D. Verona, V. Verdolino, M. Parrinello, R. Corradini Pna:Rna Duplex Engineering: Computational Approach Using Molecular Dynamic And Metadynamics A 18:35 OC9 A.Manicardi,E.Gyssels,R.Corradini,A.Madder Crosslinking Peptide Nucleic Acids (Pnas) For Targeting Of DNA A 18:55 OC10 L. Valgimigli, R. Amorati, A. Baschieri, Derek, A. Pratt The Catalytic Antioxidant Behaviour of Nitroxides WelcomeParty Lunedì14 Settembre 2015 Aula ChairedbyC.Chiappe(C5) B 9:00 PL1 H. Mayr Mythology in Organic Chemistry: How Obsolete Concepts Survive ChairedbyP.Allegrini(C6)–FinechemicalsandAPIs B 9:45 KN1 V.Farina Synthesis of Anti-Diabetes Drug Canagliflozin and Related Substances by Non-Catalyzed Cross-Coupling of Arylzinc Derivatives with Bromosugars in Toluene/DBE Mixtures B 10:15 OC11 L.Lattuada Iodine/Iodic Acid: A Greener Iodination Methodology In The Synthesis of X-Ray Contrast Agents B 10:35 OC12 M. A. Ciufolini, E. Marcantoni, A. Aramini, G. Bianchini,M.Tomassetti Heterocyclic Five Member Rings As Structural Cores In 18 Drug Discovery ChairedbyA.Abbotto(C7)–Enerchem A 9:45 KN2 A. Pellegrino, R. Pò, A. Bernardi, G. Bianchi, C. Carbonera, A. Cominetti, F. Roberto, S. Fiorenza, A. Tacca Organic Chemistry Between Electronics and Photonics: a New Way Toward a More Sustainable Future A 10:15 OC18 I.Tosi,L.Baldini,F.Sansone,C.Sissa,F.Terenziani, M.DiDonato Simple Systems Based On Bichromophoric Calix[4]Arenes For The Study Of Energy Transfer A 10:35 OC19 F.Sabuzi,E.Gatto,V.Conte,B.Floris,M.Venanzi,P. Galloni KuQuinones As Dyes In Photoelectrochemical Devices 10:55 coffeebreak B 11:20 TavolaRotonda:Industria,giovanieaccademia:futuropossibile D.Braga,V.Farina,C.Franco,M.Fumagalli(ChairedbyR.Ballini andC.Trombini(C8)). 13:00 pausapranzo 14:00 SessionePoster1(PC1‐PC62) ChairedbyV.Farina(C9) B 15:00 P2 G.Fontana A Journey in the Industrial Natural Products World ChairedbyV.Capriati(C10) B 15:30 CF1‐CF6 Comunicazioniflash(CF1‐CF6) V. Algieri, , S. Crespi, P. Franchi, A. Mezzetta, A. Pelagalli,C.Petrucci) ChairedbyL.Lattuada(C11)–FinechemicalsandAPIs B 16:00 OC13 P. Stabile, E. Rossi, C. C. De Filippo, A. Leganza, F. Fontana Process Development and Scale Up of API Intermediates: A Case Study B 16:20 OC14 E.Attolino,A.Iuliano,P.Allegrini A Novel Efficient Total Synthesis Of Telaprevir ChairedbyE.Licandro(C11)–Enerchem 19 A 16:00 OC20 P.Galloni,A.Vecchi,B.Floris,V.Conte Electronic Communication In Tetraferrocenylporphrins A 16:20 OC21 V.Criscuolo,P.Manini,A.Pezzella,P.Maddalena,S. Aprano, M. G. Maglione, P. Tassini, C. Minarini, M. d’Ischia Synthesis And Photochemical Properties Of New MelaninInspired Electroluminescent Materials For OLED Applications 16:40 Coffeebreak B 17:10 OC15 L.Domenighini,A.Gambini,C.Cattaneo Cabaxitaxel: A Novel Second Generation Taxane B 17:30 OC16 G. Barreca, L. Carcone, R. Orru, E. Ruijter, M. Rasparini Development And Scale-Up Of An Innovative Synthesis To Generic Telaprevir B 17:50 OC17 V.R.Jumde,A.Porcheddu,G.I.Truglio,M.Vecchio, M.Taddei,E.Cini Metal-Catalyzed Tandem Hydrogen-Transfer Reactions for the Synthesis of Biologically Relevant Coumpounds A 17:10 OC22 F.Parenti,F.Tassinari,C.Fontanesi,L.Schenetti,P. Morvillo,R.Ricciardi,R.Diana,C.Minarini,M.Lanzi, A.Mucci Characterization of Conducting Polymers for Organic Solar Cells A 17:30 OC23 G. Marzano, D. Kotowski, F. Babudri, R. Musio, A. Pellegrino,S.Luzzati,R.Po,G.M.Farinola Ternary Direct (Hetero)Arylation vs Stille cross-coupling in the synthesis of a ternary copolymer for BHJ solar cells A 17:50 OC24 E. Libertini, P. Morvillo, A. Mucci, F. Tassinari, L. Schenetti,F.Parenti Synthesis Of Low Band-Gap Conjugated Polymers For Application In Solar Cells 18:10 Sessioneposter1(PC1‐PC62) 20 Martedì15 Settembre 2015 Aula ChairedbyR.Noto(C13) B 9:00 M2 V.Pace New Perspectives in Lithium Halocarbenoids Mediated Homologations ChairedbyA.Brandi(C14)–OrganometandNanotech B 9:45 KN3 F.Cardona,A. Goti Polar Organometallics and Carbohydrate Derived Nitrones: a Successful Partnership en Route to Iminosugars B 10:15 OC25 M.Vintila,M.Boccalon,P.Pengo L.Pasquato Self-Organization Of Binary Mixtures Of Fluorinated And Hydrogenated Alkyltiolates On The Surface Of Gold Nanoparticles B 10:35 OC26 E.Lubian,F.Mancin,PaoloScrimin Controlled Photo-Released Drug from Nanoparticles for PDT Applications ChairedbyB.Floris(C15)–GreenChemistry A 9:45 KN4 L.Vaccaro Developing new Synthetic Tools Towards Sustainability A 10:15 OC27 A. Paternò, G. Bocci, G. Cruciani, G. Musumarra, S. Scirè A QSPR Approach To Ionic Liquids Aquatic Toxicity By Volsurf Descriptors A 10:45 OC28 S.Rizzo, F.Sannicolò, V.Mihali, M.Pierini,R.Cirilli, P.Mussini,S.Arnaboldi,A.Gennaro,A.A.Isse Unconventional Inherently Chiral Ionic Liquids 10:55 Coffeebreak ChairedbyM.Bietti(C16) B 11:30 CF7‐CF12 Comunicazioniflash(CF7‐CF12) L.Barbera,G.Lauro,S.Perrone,S.Rossi,S.Sattin,C. Vurchio B 12:00 Tavola Rotonda Gruppo Giovani: Biocarburanti: una fonte di energia ecosostenibile? V. Balzani, G. Farinola, O. Francesconi, G. Venturi(ChairedbyO.Francesconi(C17)) 21 13:00 pranzo 14:00 SessionePoster2(PC63‐PC122) ChairedbyC.Nativi(C18) B 15:15 PL2 H.Suga A Rapid Way for the Discovery of Pseudo-natural Products ChairedbyB.Gabriele(C19)‐Nanotech B 16:00 OC29 M. Giuliani, S. Aleandri, G. Bozzuto, M. Condello, G. Mancini,A.Molinari,S.Avvakumova,L.Pandolfi,M. Colombo,D.Prosperi,F.Sansone,A.Casnati Liposomes And Gold Nanoparticles Decorated With Glycocalixarenes For Targeted Drug Delivery B 16:20 OC30 R.Fiammengo,H.Cai,F.Degliangeli,B.Palitzsch,B. Gerlitzki,E.Schmitt,U.Westerlind Glycopeptide-Functionalized Gold Nanoparticles For Antibody Induction Against The Tumor Associated Mucin-1 Glycoprotein B 16:40 OC31 J.L.Y.Chen,P.Scrimin,L.J.Prins Chiral Nanozymes: Transphosphorylation Gold-Nanoparticle-based Catalysts Capable of Enantiodifferentiation ChairedbyE.Beccalli(C20)–Bio‐Medicina&Biotech A 16:00 OC35 A.Sganappa,A.Volonterio,Y.Tor,E.Wexelblatt Biotin-PAMAM-Guanidinoneomycin Conjugates: Synthesis And Cellular Uptake A 16:20 OC36 A. Sartori, E. Portioli, L. Battistini, F. Bianchini, C. Curti,F.Zanardi Novel AmpRGD/Sunitinib Dual Conjugates as Potential Modulators of Tumor Angiogenesis A 16:40 OC37 A. Shibata, D. Moiani, A. Gabrielli, J. Tainer, E. Petricci Development of New Exo- And Endonucleasic Inhibitors of MRE11 as Versatile Tools for Chemical Biology 17:00 coffeebreak ChairedbyS.Menichetti(C21)‐Nanotech B 17:20 OC32 S.Zanzoni, A.Ceccon,M.Assfalg, M.D’Onofrio Biomolecular Recognition by Fullerenol 22 B 17:40 OC33 L.Degennaro,F. Fanelli,S. DeAngelis,D.Maggiulli, M.Delfine,R.Luisi Micro Flow Systems for Taming the Reactivity of Highly Unstable Intermediates B 18:00 OC34 N.Zanna,L.Milli,C.Tomasini Synthesis and Applications of New Peptide Based Hydrogelators ChairedbyG.Licini(C22)–Reazioni&Meccanismi A 17:20 OC38 M.Palomba,F.Marini,C.Santi, L. Bagnoli Effective Route to Fused-Indoles and Pyrroles Via a Domino Michael Addition/Cyclization From Vinyl Selenones A 17:40 OC39 N. Di Iorio, F. Eudier, P. Righi, A. Mazzanti, M. Mancinelli,A.Ciogli,G.Bencivenni Remote Control of Axial Chirality: Aminocatalytic Desymmetrization of N-Arylmaleimides A 18:00 OC40 A.Porta,S.Bugoni,V.Merlini,G.Zanoni,G.Vidari Competitive Gold-Promoted Meyer-Schuster and Oxy-Cope Rearrangements of 3-Acyloxy-1,3-Enynes B 18:30 AssembleasociSCI Mercoledì16 Settembre 2015 Aula ChairedbyE.Marcantoni(C23) B 9:00 PL3 N.Maulide Molecular Gymnastics: C-C bond formation with rearrangements ChairedbyF.DeAngelis(C24) B 9:40 KN5 G.Iacobellis Retrosynthetic Analysis and Forensic Science: the Organic Chemist’s Point of View ChairedbyF.Formaggio(C25)–BioMedicina&Biotech B 10:20 OC41 S.Lepri,L.Goracci,A.Valeri Modulation of Phospholipidosis Induction: the Case of Imipramine, its Metabolites and Synthetic Analogues 23 B 10:40 OC42 A.Feriani,P.Marchetti,E.Moro Stereochemical and Conformational Studies by NMR and Molecular Modelling: an Improved Approach. Application to New Tubulin Inhibitors B 11:00 OC43 E. Masi, S. E. Meyer, S. Clement, A. Cimmino, A. Evidente Phytotoxins Produced by Fungi With Potential Application for the Biocontrol of Cheatgrass (Bromus Tectorum) ChairedbyM.V.D’Auria(C26)–Sintesi A 10:20 OC48 L. Bianchi, M. Maccagno, G. Petrillo, C. Scapolla, C. Tavani Harvesting Heterocycles by Seeding Nitrothiophenes A 10:40 OC49 E.A.Beccalli,T.Borelli, A. Mazza Domino Inter/Intramolecular Copper(II)-Catalyzed Haloalkoxylation and Haloamination Reactions of Alkynes A 11:00 OC50 M. F.Caso,D.D’Alonzo,G.Palumbo,A.Guaragna The Iodine/Silane System: a Novel Exploitation in Nucleoside Synthesis 11:20 Coffeebreak ChairedbyA.Zampella(C27)–BioMedicina&Biotech B 11:40 OC44 S. Pellegrino, N. Tonali, J. Kaffy, A. Contini, M.‐L. Gelmi,S.Ongeri,E.Erba Flexible -Amyloid Synthetic Mimics Built on a PiperidinePyrrolidine Semi-Rigid Scaffold, Obtained Through a Click Cycloaddition Reaction B 12:00 OC45 G. Abbiati, M. Dell’Acqua, L. Ronda, R. Piano, Sara Pellegrino,E.Rossi,F.Clerici,A.Mozzarelli,M.Luisa Gelmi Mediachrom: Synthesis and Spectroscopical Evaluation of an Original Class of Pyrimidoindolone Based PolaritySensitive Dyes B 12:20 OC46 E.Lenci,G.Menchi,F.Bianchini, A.Trabocchi Skeletal Diversity from Carbohydrates: Diversity-Oriented Synthesis of Polyhydroxylated Compounds B 12:40 OC47 L. Sernissi, M. Petrović, D. Scarpi, A. Trabocchi, F. Bianchini,E.G.Occhiato 24 Cyclopropane Pipecolic Acids as Templates for Linear and Cyclic Peptidomimetics ChairedbyL.Pellacani(C28)–Sintesi A 11:40 OC51 N. Di Iorio, R.G. Margutta, P. Righi, S. Ranieri, A. Mazzanti,G.Bencivenni Controlling the Vinylogous Reactivity of Oxindoles Bearing Non Symmetric 3-Alkylidene Groups A 12:00 OC52 A. Bochicchio, L. Chiummiento, M. Funicello, P. Lupattelli,G.Hanquet,S.Choppi,F.Colobert [7,0]-Metacyclophanes from Biaryl Coupling/macro cyclisation A 12:20 OC53 G.Favi Synthesis of Novel Indole-Based Scaffolds by Different Assembly of Tryptamines, Azoenes, and Aldehydes A 12:40 OC54 S.Gaspa,A. Porcheddu, L. De Luca A One-Pot Two-Step Reaction to Prepare Esters Directly From Aldehydes and Alcohols 13:00 Pausapranzo ChairedbyM.Taddei(C29) B 15:00 KN6 L.Lay Carbohydrates Meet Immunology: Synthesis of neoGlycoconjugates for Vaccines Formulation B 15:30 OC55 R. Mancuso, D. S. Raut, N. Marino, G. De Luca, C. Giordano,S.Catalano,S.Andò,B.Gabriele A ζ-lactamization Carbonylative Approach to a New Class of Anti-Tumor Agents B 15:50 OC56 R. De Marco, S. Spampinato, A. Bedini, R. Artali, L. Gentilucci Lipophilicity Efficiency is a New Paradigm for Balancing Receptor Affinity and In Vivo Antinociceptive Efficacy of Opioid Peptides B 16:10 OC57 R. Goracci, S. Lepri, S. Massari, G. Nannetti, A. Loregian,G.Cruciani,R.Ruzziconi,O.Tabarrini Small Organic Molecules to Fight Influenza Virus: From Design to Optimization ChairedbyL.Lunazzi(C30) 25 A 15:00 KN7 M.Bonchio Light Activated Catalytic Manifolds for Artificial Photosynthesis A 15:30 OC58 F.Bellina,M.Lessi,L.Lodone Regioselective C2 Cross-Dehydrogenative Alkenylation of Azoles A 15:50 OC59 M.Petrović,D.Scarpi,B.Fiser,E.Gómez‐Bengoa,C. Prandi,E.Occhiato Gold(I)-Catalyzed Synthesis and Modification of NHeterocycles A 16:10 OC60 P.Quagliotto,C.Barolo,N.Barbero,R.Buscaino,E. Chiavazza,G.Viscardi Synthesis of Thiophene-Based Ligands in Micellar Solution 16:30 coffeebreak ChairedbyM.Bonchio(C31)‐Modena’sLecture B 16:50 KN8 J.T.Groves Manganese Catalyzed C-H Functionalization ChairedbyM.Bonchio(C31)–Meccanismi B 17:20 OC61 M.Salamone,M.Bietti Hydrogen Atom Transfer Reactions From Aliphatic CH Bonds to Alkoxyl Radicals. The Role of Structural and MediumEffectsonCHDeactivation B 17:40 OC62 O.Lanzalunga Role of Electron Transfer Processes in the N- demethylation of N,N-dimethylanilines and S-Oxidation of Aromatic Sulfides Promoted by the Nonheme Iron(IV)-Oxo Complex [FeIV(O)(N4Py)]2+ B 18:00 OC63 C.Raviola, D.Ravelli,S.Protti,M.Fagnoni,A.Albini Triplet Phenyl Cations as an Innovative Source Of Substituted ,N-Didehydrotoluenes. A Combined Computational And Experimental Investigation ChairedbyM.Benaglia(C32)Biomedicna&Biotech A 17:20 OC64 R.Romeo,S.V.Giofrè,R.Mancuso,B.Gabriele, G.Romeo,U.Chiacchio Microwave Assisted Heterocyclization Promoted by Lawesson’sReagent:SynthesisofBenzo[C]Thiophen‐ 26 1(3H)‐Onesand1H‐Isothiochromene‐1‐Ones A 17:40 OC65 R.Cincinelli,S.Dallavalle, L.Musso Intramolecular Reactions of 4-Quinolone-2- Carboxamides: A New Route to 4-Quinolone-Based Polycyclic Systems A 18:00 OC66 O. Francesconi, C. Nativi, G. Gabrielli, I. De Simone, S. Noppen, J. Balzarini, S. Liekens, S. Roelens Synthetic Aminopyrrolic Mannose Binding Agents Exert Anti-HIV Activity Targeting the Glycans of Viral Gp120 20:30 Cenasociale Giovedì17 Settembre 2015 ChairedbyC.Trombini(C33) B 9:00 M3 A.Gualandi,P. G.Cozzi Synergistic Stereoselective Organocatalysis: The Revenge of Metals ChairedbyL.Mayol(C34) B 9:45 P3 R.Corradini Expanding the Structure and Function of Peptide Nucleic Acids (PNAs) Through Design and Synthesis B 10:15 PresentazioneREAXYS B 10:35 PremiazioneFlashposter,PosterePremioREAXYS 11:00 Coffeebreak ChairedbyM.Curini(C35) B 11:25 P4 M.Gruttadauria Organocatalysts and Metal-based Catalysts: a Journey Toward the Development of New Catalytic Materials ChairedbyG.Cruciani(C36) B 11:45 M4 M.Maggini Sole e Molecole: Nuove Energie per il Nostro Futuro 12:45 ChiusuradelConvegno 27 Abstracts Plenary Lectures 28 PL1 Mythology in Organic Chemistry: How Obsolete Concepts Survive Herbert Mayr Department Chemie der Ludwig-Maximilians-Universität München Butenandtstr. 5-13, 81377 München, Germany, [email protected] Several concepts in organic chemistry persist, though their inconsistency has repeatedly been demonstrated in the past. This lecture will report on developments in the author’s laboratory on three different topics 1) Reactivity selectivity principle:1 Though the failure of the principle that an increase of reactivity is generally associated with a decrease in selectivity has been demonstrated to be obsolete by several authors in the 1970s, it is still considered as a general rule with some exceptions. It will be discussed, why this principle cannot hold generally. Its application is only justified, when reactions close to the diffusion limit are considered. In activation-controlled reactions, selectivity may decrease, increase, or remain constant as reactivity increases. 2) Kornblum’s rule and Salem-Klopman concept of charge and orbital controlled reactions:2 The ambident reactivities of the prototype nucleophiles, thiocyanate, cyanide, nitrite, cyanate, nitronate, phenylsulfinate, amide, and pyridone anions, do not follow these rules. Changes from kinetic to thermodynamic control, and from activation to diffusion limited reactivity has to be considered when interpreting ambident reactivities. Marcus theory provides a better approach to ambident reactivity. 3) α-Effect: According to IUPAC,3 the α-effect describes a positive deviation of an αnucleophile (a nucleophile bearing an unshared pair of electrons on an atom adjacent to the nucleophilic site) from a Brønsted-type plot of lg k vs. pKa constructed for a series of related normal nucleophiles. More generally, it is the influence of the atom bearing a lone pair of electrons on the reactivity at the adjacent site. Systematic kinetic investigations of the nucleophilic reactivities of a series of hydrazines in various solvents do not give evidence for unusual reactivities, i. e., reactivities which differ from those of ordinary alkylamines.4 The concept of the α-effect should, therefore, be reconsidered. 1) H. Mayr, A. R. Ofial, Angew. Chem. Int. Ed. Engl. 2006, 45, 1844-1854. 2) H. Mayr, M. Breugst, A. R. Ofial, Angew. Chem. Int. Ed. 2011, 50, 6470-6505. 3) P. Müller, Glossary of Terms used in Physical Organic Chemistry, Pure Appl. Chem. 1994, 66, 10771184. 4) T. A. Nigst, J. Ammer, H. Mayr, Angew. Chem. Int. Ed. 2012, 51, 1353-1356; T. A. Nigst, A. Antipova, H. Mayr, J. Org. Chem. 2012, 77, 8142-8155. 29 PL2 A Rapid way for the discovery of pseudo-natural products Hiroaki Suga1,2 1 Department of Chemistry, Graduate School of Science, The University of Tokyo 2 JST-CREST, Tokyo e-mail: [email protected] The genetic code is the law of translation, where genetic information encoded in RNA is translated to amino acid sequence. The code consists of tri-nucleotides, so-called codons, assigning to particular amino acids. In cells or in ordinary cell-free translation systems originating from prokaryotes, the usage of amino acids is generally restricted to 20 proteinogenic (standard) kinds, and thus the expressed peptides are composed of only such building blocks. To overcome this limitation, we recently devised a new means to reprogram the genetic code, which allows us to express non-standard peptides containing multiple non-proteinogenic amino acids in vitro. This lecture will describe the development in the genetic code reprogramming technology that enables us to express natural product-inspired non-standard peptides and pseudo-natural products. The technology involves (1) efficient macrocyclization of peptides, (2) incorporation of non-standard amino acids, such as N-methyl amino acids, and (3) reliable synthesis of libraries with the complexity of more than a trillion members. When the technology is coupled with an in vitro display system, referred to as RaPID (Random non-standard Peptide Integrated Discovery) system as a novel “molecular technology”, the libraries of natural product-inspired macrocycles with a variety ring sizes and building blocks can be screened (selected) against various drug targets inexpensively, less laboriously, and very rapidly. This lecture will discuss the most recent development of their technology and therapeutic applications toward drug discovery innovation. K. Ito; K. Sakai; Y. Suzuki; N. Ozawa; T. Hatta; T. Natsume; K. Matsumoto; H. Suga "Artificial human Met agonists based on macrocycle scaffolds" Nature Communications, 6, 6373 (2015) E.M. Novoa; O. Vargas-Rodriguez; S. Lange; Y. Goto; H. Suga; K. Musier-Forsyth; L. Ribas de Pouplana"Ancestral AlaX Editing Enzymes for Control of Genetic Code Fidelity are not tRNA Specific" The Journal of Biological Chemistry, in press. (2015) T. Morioka; N.D. Loik; C.J. Hipolito; Y. Goto; H. Suga "Selection-based discovery of macrocyclic peptides for the next generation therapeutics" Current Opinion in Chemical Biology, 26C, 34-41 (2015) T. Passioura; H. Suga* "Reprogramming the genetic code in vitro" Trends in Biochemical Sciences 39, 400-408 (2014). K. Torikai; H. Suga* "Ribosomal synthesis of an amphotericin-B inspired macrocycle" Journal of the American Chemical Society 136, 17359-17361 (2014). Y. Goto, Y. Ito, Y. Kato, S. Tsunoda, H. Suga* “One-pot synthesis of azoline-containing peptides in a cell-free translation system integrated with a posttranslational cyclodehydratase” Chemistry & Biology 21, 766–774 (2014). DOI: http://dx.doi.org/10.1016/j.chembiol.2014.04.008 Y. Tanaka, C.J. Hipolito, A.D. Maturana, K. Ito, T. Kuroda, T. Higuchi. T. Katoh, H.E. Kato, M. Hattori M, K. Kumazaki, T. Tsukazaki, R. Ishitani, H. Suga*, O. Nureki “Structural basis for the drug extrusion mechanism by a MATE multidrug transporter” Nature 496, 247-51 (2013). Y. Yamagishi, I. Shoji, S. Miyagawa, T. Kawakami, T. Katoh, Y. Goto, H. Suga* "Natural product-like macrocyclic N-methyl-peptide inhibitors against a ubiquitin ligase uncovered from a ribosome-expressed de novo library" Chemistry&Biology 18, 1562-1570 (2011). Y. Goto, T. Katoh, H. Suga “Flexizymes for genetic code reprogramming” Nature Protocols 6, 779-790 (2011) 30 PL3 Molecular Gymnastics: C-C bond formation with rearrangements Nuno Maulide1 1 University of Vienna, Institute of Organic Chemistry, Währinger Strasse 38, 1090 Vienna, Austria e-mail: [email protected] The turn of the century brought about a pressing need for new, efficient and clean strategies for the chemical synthesis of biorelevant compounds. Our group has studied the use of various molecular rearrangements and atom-economical transformations as particularly appealing means towards the streamlined synthesis of complex small molecule targets.1,2,3 In this lecture, we will present an overview of our research in these areas and how they provide efficient solutions for total synthesis as well as platforms for the discovery of unusual reactivity. 1) (a) Luparia, M.; Oliveira, M.T.; Audisio, D.; Frébault, F.; Maulide, N. Angew. Chem. Int. Ed. 2011, 50, 12631. (b) Audisio, D.; Luparia, M.; Oliveira, M.T.; Frébault, F.; Klütt, D.; Maulide, N. Angew. Chem. Int. Ed. 2012, 51, 7314. (c) Misale, A.; Niyomchon, S.; Luparia, M.; Maulide, N. Angew. Chem. Int. Ed. 2014, 53, 7068. 2) Huang, X.; Maulide, N. J. Am. Chem. Soc. 2013, 135, 7312. 3) Jurberg, I.D.; Peng, B.; Wöstefeld, E.; Wasserloos, M.; Maulide, N. Angew. Chem. Int. Ed. 2012, 51, 1950. 31 Abstracts Medaglie e Premi 32 M1 Exploiting Organic Chemistry in Nanomedicine Francesco Nicotra1, Laura Cipolla1, Barbara La Ferla1, Cristina Airoldi1, Massimo Masserini2, Francesca Re2, Sophia Antimisiaris3, Giovanni Polzonetti4, Patrick Couvreur5 1 Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, Milano. 2 Department of Experimental Medicine, University of Milano-Bicocca, 20052 Monza. 3 Laboratory of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece 4 Department of Sciences, INSTM, CNISM and CISDiC, University Roma Tre, Via della Vasca Navale 84, 00146 Rome, Italy 5 Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, University ParisSud, 5 rue Jean-Baptiste Clément, F-92296 Ch^atenay-Malabry, France, e-mail: [email protected] Organic compounds involved in recognition phenomena of biological relevance are invaluable tools to generate bio-responsive materials for nanomedicine applications such as drug delivery and regenerative medicine. As examples of drug delivery applications, our results on the generation of nanoparticles properly functionalized to interact wit Aβ-fibrils and cross the BBB will be described, and their in vivo activity against Alzheimer’s disease will be presented1,2. In the area of regenerative medicine, we developed biomaterials such as hydroxyapatite, PCL and collagen, chemoselectively functionalized with bioresponsive organic molecules, in particular carbohydrates3,4. Glycosylatedcollagens have been generated able to induce neuronal cell differentiation5, with consequent regeneration of the neuronal network, and to repair damaged cartilage in mice, restoring the walking capacity6. 1) Mourtas, S.; Canovi M.; Zona, C., Aurilia, D.; Niarakis, A.; La Ferla, B.; Salmona, M.; Nicotra, F.; Gobbi, M.; Antimisiaris, S; Biomaterials 2011, 32, 1635-1645 2) 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, 24, 5866-79 3) Russo, L.; Zanini, S.; Giannoni, P.; Landi, E.; Villa, A.; Sandri, M.; Riccardi, C.; Quarto, R.; Doglia, S.; Nicotra, F.; Cipolla, L. J. Mater. Sci.: Materials in Medicine, 2012, 23, 2727–2738 4) Russo, L.; Gloria, A.; Russo, T.; D’Amora, U.; Taraballi, F.; De Santis, R.; Ambrosio, L.; Nicotra, F.; Cipolla, L, RSC Advances 2013, 3, 6286 -6289 5) Russo, L.; Sgambato ,A.; Lecchi ,M.; Pastori, V.; Raspanti, M.; Natalello, A.; Doglia, S.; Nicotra F.; Cipolla L. ACS Chemical Neuroscience, 2014, 5, 261−265 6) Russo, L.; Battocchio, C.; Secchi, V.; Magnano, E.; Nappini, S.; Taraballi, Francesca; Gabrielli, Luca; Comelli, Francesca; Papagni, Antonio; Costa, B.; Polzonetti, G.; Nicotra, F.; Natalello, A.; Doglia, S.; Cipolla, L. Langmuir, 2014, 30, 1336-1342 33 M2 New Perspectives in Lithium Halocarbenoids Mediated Homologations Vittorio Pace Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Vienna (Austria). e-mail: [email protected] Organometallic compounds presenting a metal and at least one electronegative group (e.g. halogen, cyano) at the same carbon are referred as carbenoids.1 Their chemistry is characterized by the intrinsic ambiphilicity between nucleophilic and electrophilic behaviour, depending – inter alia – on the nature of the metal.2 Ongoing research in our group deals with the employment of nucleophilic lithium halocarbenoids in homologation processes: effectively, the rapid and effective introduction of an halomethylenic fragment into a given electrophile would guarantee further synthetic elaborations. However, despite the synthetic usefulness of these reagents, thoroughly applications in organic synthesis have been somewhat limited by their inherent thermal instability. The reactivity of carbenoids towards electrophiles such as Weinreb amides,3 heterocumulenes (e.g. isocyanates),4 unsaturated carbonyls5 and disulfides6 will be presented (Scheme 1) jointly with mechanistic rationale and discussion on the stability of the intermediates involved in the transformations. Scheme 1 1) 2) 3) 4) 5) 6) a) Boche, G.; Lohrenz, J. C. W. Chem. Rev. 2001, 101, 697-756. b) Pace, V. Aust. J. Chem. 2014, 67, 311-313. Capriati, V.; Florio, S. Chem. Eur. J. 2010, 16, 4152-4162. a) Pace, V.; Castoldi, L.; Holzer, W. J. Org. Chem. 2013, 78, 7764-7770. b) Pace, V.; Holzer, W.; Verniest, G.; Alcántara, A. R.; De Kimpe, N. Adv. Synth. Catal. 2013, 355, 919-926. a) Pace, V.; Castoldi, L.; Holzer, W. Chem. Commun. 2013, 49, 8383-8385. b) Pace, V.; Castoldi, L.; Mamuye, A. D.; Holzer, W. Synthesis 2014, 46, 2897-2909. Pace, V.; Castoldi, L.; Holzer, W. Adv. Synth. Catal. 2014, 356, 1761-1766. Pace, V.; Pelosi, A.; Rosati, O.; Curini, M.; Holzer, W. manuscript in preparation. 34 M3 Synergistic Stereoselective Organocatalysis: The Revenge of Metals Pier Giorgio Cozzi* and Andrea Gualandi ALMA MATER STUDIORUM, University of Bologna, Dipartimento di Chimica “G. Ciamician”, Via Selmi 2, 40126 Bologna, Italy. e-mail: [email protected] Synergistic catalysis is defined as “a synthetic strategy wherein both the nucleophile and the electrophile are simultaneously activated by two separate and distinct catalysts to afford a single chemical transformation”. Improved catalytic enantioselectivity transformations were realized by fruitful combination of different catalytic cycles. In combining stereoselective organocatalysis with indium salts we have described a simple access to allylic carbenium ions and their reactions with chiral enamines.1 In an alternate mechanistic picture, a new catalyst may induce formation of a reactive intermediate. By using a metal catalyst able to absorb visible light is possible to generate reactive radicals. This strategy was found essential for the success of stereoselective photoredox organocatalysis. However, rare and expensive ruthenium and iridium complexes are necessary for the reactions. We will illustrate new strategies based on the use of a cheap, abundant, and not toxic metals, that can open considerable new avenues in photocatalysis and in synergistic catalytic combinations.2 1) Gualandi, A; Mengozzi, L; Wilson, M. C; Cozzi, P. G. Synthesis 2014, 46, 1321-1328. 2) Gualandi, A; Marchini, M; Mengozzi, L; Natali, M.; Lucarini, M.; Ceroni, P; Cozzi, P.G. Submitted for publication. 35 M4 Sole e Molecole: Nuove Energie per il Nostro Futuro Michele Maggini Dipartimento di Scienze Chimiche, Università di Padova e-mail: [email protected] HELIOS è stato il nome di un progetto strategico dell’Università di Padova condotto in area chimica sui temi dell’interazione luce-materia, negli ambiti della fotosintesi artificiale e del fotovoltaico organico. Sarà preso a pretesto per raccontare l’approccio trans-disciplinare che ha guidato il progetto; un’esperienza meravigliosa in cui un gruppo di chimici hanno provato a guardare più lontano condividendo capacità e competenze complementari attraverso ipotesi, calcoli, esperimenti e lunghe discussioni, guidati dalla fantasia e dall’entusiasmo. 36 P1 Organic Reaction Mechanisms: The Electrospray Ionization Mass Spectrometry Approach Olga Bortolini Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 19, 44121 Ferrara Italy e-mail: [email protected] The success and rapid broad use of electrospray ionization mass spectrometry (ESI-MS) results mainly from its ability to transfer ions of many types, from solution into gas phase in a gentle and efficient way and to characterize these intact and isolated species according to their masses and connectivities. ESI-MS, for ion detection and mass determination, including isotopic pattern, as well as its tandem version ESI-MS/MS for structural investigation, are precious techniques to study mechanisms of organic reactions in solution. Working in both positive- and negative-ion modes, ESI-MS monitoring provides continuous snapshots of the changing ionic composition of reaction and hence facilitates the detection of key and often labile intermediates. ESI-MS has also provided access to gaseous metal-centered catalytic species, that are otherwise inaccessible or very difficult to study with other methodologies. Examples of the detection of metal-based peroxydic species, as active oxidation catalyst, will be discussed. The inherently blindness of mass spectrometry to neutrals, precluded the investigation of many organocatalyzed reactions mostly based on uncharged species as carbenes. This limitation has been elegantly overcome using the charge-tag strategy that entails the use of reagents, catalysts or ligands bearing a cationic or anionic unit located remotely from the reaction site, providing new insights in the study of reactions involving neutral catalysts and/or intermediates. Bortolini, O.; Giovannini, P. P.; Fantin, G.; Ferretti, V.; Fogagnolo, M.; Massi, A.; Pacifico, S.; Ragno D. Adv. Synth. Catal. 2013, 355, 3244-3252. Bortolini, O.; Chiappe, C.; Fogagnolo, M.; Giovannini, P. P.; Massi, A.; Pomelli, C. S.; Ragno, D. Chem Commun., 2014, 50, 2008-2011 37 P2 A Journey in the Industrial Natural Products World Gabriele Fontana INDENA SpA, R&D+Intelligence Department, viale Ortles 12, 20139 Milan, Italy e-mail: [email protected] The products of natural origin have played a fundamental role in the evolution of modern medicine. After more than 50 years from their discovery and 30 years from their registration, most of the drugs based on natural derivatives are still top-selling products and do represent irreplaceable weapons in the medicinal arsenale for lifethreatening pathologies. However complexity and unicity of their structure, that represent actually their intimate treasure, have often been (and are) holding back their sustainable development. Industrial natural product chemistry is of fundamental importance for successful product development, as about 80% of commercial drugs derived from natural products require synthetic efforts, either to enable economical access to bulk material, and/or to optimize drug properties through structural modifications. In this talk the author will present some case studies taken from his experience in the derivatives of paclitaxel (1), vinblastine (2), reserpine (3) and other natural products of industrial interest that are representative of the challenges that have to be addressed along the path from a lead to a viable drug: a) how can structural variations be performed in a time- and cost-efficient manner to modulate and optimize PD, PK and safety profile of the drug; b) how can a large-scale supply of drug substance in GMP (Good Manufacturing Practices)-quality be realized; c) how can organic chemists benefit from the interaction with the more recent technologies (like biotechnologies) and their industrial achievements. 2 1 3 38 P3 Expanding the structure and function of peptide nucleic acids (PNAs) through design and synthesis Roberto Corradini 1 Dipartimento di Chimica-Università di Parma, Parco Area delle Scienze 17/A 43124 Parma, Italy. e-mail: [email protected] Peptide nucleic acids (PNAs) are polyamide analogues of nucleic acids, very effective in terms of affinity and selectivity in DNA/RNA recognition. During the years, many drawbacks which hampered the full application of PNAs to diagnostic and therapeutics have been overcome by appropriate design of modified PNAs and of cellular carriers. In this context, this lecture will describe our recent work, focused on new applications of PNAs to treatment of diseases for which no effective therapy is available,1,2 on the epigenetic modulation of gene expression by targeting non coding microRNA,2,3 and on the development of new ultrasensitive diagnostic tools.4,5 To further improve the recognition properties of these compounds, we have during the years selected a series of chemical tools and strategies enabling to rationally create new PNA structures (Figure). Figure. a) General scheme of PNA structure showing modification points; b) scheme of functional group positioning based on available PNA:DNA structural data. Thus, we have obtained polyfunctional PNAs with improved cellular uptake, biostability and anti-miR activity.3 On the other hand, based on available structural data, we designed a series of nucleobase-modified PNAs which were found to be more selective in the recognition of single-point mutations.6 This approach has now been implemented using up-to date molecular modelling and molecular dynamics methods. Conjugation of PNAs to nano-zeolites as cargo systems for cellular delivery of PNA and small drug molecules is a suitable approach for combined personalised therapies;8 different types of nanomaterials are now under investigation for the same purposes using covalent and non-covalent bonds. The impact and perspectives of these new PNAbased structures in diagnostics and nano-biotechnology will be discussed. 1) Tonelli, R. et al. Clinical Cancer Res 2012, 18,796-807. 2) Brognara, E. et al. J. Neurooncol. 2014, 118, 19–28. 3) Manicardi, A. et al. ChemBiochem 2012, 13, 1327 – 1337. 4) Spoto, G., Corradini, R. Eds, Detection of non-amplified Genomic DNA. Springer, Dordrecht (NL) 2012. 5) Bertucci, A. et al. Biosens. Bioelectron 2015, 63, 248-254 6) Manicardi A, et al. Beilstein J. Org. Chem. 2014, 10, 1495-1503. 7) Bertucci, A. et al. Adv. Healthcare Mater. 2014, 3, 1812-1817. 39 P4 Organocatalysts and metal-based catalysts: a journey toward the development of new catalytic materials Michelangelo Gruttadauria Department of Biological, Chemical and Pharmaceutical Sciences and Technologies University of Palermo - Viale delle Scienze s/n Ed. 17, 90128 Palermo, Italy. e-mail: [email protected] Organocatalysis and metal-based catalysis represent two of the main pillars of catalytic reactions and have witnessed a huge interest in the last decade. Immobilization, recovery and reuse of these catalysts is of primary importance because of the high loading used especially in the case of organocatalysts. On the other hand, metal-based catalysts must be recovered even if used in low loading, in order to avoid contamination of the product. In this context, we started several years ago investigations on the use of supported ionic liquid phases for the asymmetric organocatalysis mediated by proline.1 This approach is an example of a “release and catch” catalytic system.2 Starting from this case, we describe the development of new catalytic materials based on the use of supported ionic liquid phase on several supports such as silica (Scheme 1a) and fullerene (scheme 1b), with the goal to obtain recyclable catalytic materials for C-C coupling reactions and alcohols oxidation.3 These studies have paved the way for the development of new hybrid materials such as silica-fullerenes-IL, hallosyte-IL, CNT-IL and POSS-IL. Scheme 1 1) Gruttadauria, M.; Riela, S.; Lo Meo, P.; D’Anna, F.; Noto, R. Tetrahedron Lett., 2004, 45, 61136116; b) Gruttadauria, M.; Riela, S.; Aprile, C.; Lo Meo, P.; D’Anna, F.; Noto, R. Adv. Synth. Catal., 2006, 348, 82-92. 2) Gruttadauria, M.; Giacalone, F.; Noto, R. Green Chem, 2013, 15, 2608-2618. 3) Recent examples: a) Campisciano, V.; La Parola, V.; Liotta, L.F.; Giacalone, F.; Gruttadauria, M. Chem. Eur. J. 2015, 21, 3327-3334; b) Beejapur, H.A.; Campisciano, V.; Giacalone, F.; Gruttadauria, M. Adv. Synth. Catal. 2015, 357, 51-58. 40 Abstracts Key Notes 41 KN1 Synthesis of Anti-Diabetes Drug Canagliflozin and Related Substances by Non-Catalyzed Cross-Coupling of Arylzinc Derivatives with Bromosugars in Toluene/DBE Mixtures Vittorio Farina Pharmaceutical Development and Manufacturing Sciences Janssen Pharmaceutica, Turnhoutseweg 30, B-2340 Beerse, Belgium e-mail: [email protected] The presentation will focus on the key step of the synthesis of approved anti-diabetes drug Canagliflozin (Scheme 1), i.e. the non-catalyzed direct coupling of an arylzinc reagent with a properly protected and activated glucose moiety. The paper will focus on the optimization of the reaction, its extension to related systems, and the mechanistic characterization of an unexpected side reaction (a cine-substitution process). Scheme 1: Simplified retrosynthetic analysis for Canagliflozin 42 KN2 Organic chemistry between electronics and photonics: a new way toward a more sustainable future Andrea Pellegrino, Riccardo Pò, Andrea Bernardi, Gabriele Bianchi, Chiara Carbonera, Alessandra Cominetti, Fusco Roberto, Simone Fiorenza, Alessandra Tacca Centro Ricerche per le Energie Rinnovabili e l’Ambiente, Via Fauser, 4 Novara. e-mail: [email protected] The need of efficient and sustainable technologies in the field of energy production and storage has pushed the scientific community to merge electronics, photonics, nanoscience and organic chemistry for producing new smarter device lighter and cheaper than existing ones [1]. Nevertheless at the moment there aren’t any commercial products based on these technologies because of several reasons: low efficiency, low lifetime of the devices and, in some cases, the fact that the most promising materials, in terms of efficiency, are often too complexes to be scaled-up in large amount [2], issues that can be solved only with further research. A material suitable for an efficient energy production has to satisfy several requirements in terms of light absorption, electronic levels, luminescence and redox properties; the tunability of the organic compounds and the powerful tools of the organic chemistry have allowed to synthesize thousands of new structures, opening the way to new technologies as, for instance, Organic Photovoltaics (OPV) [3] and Luminescent Solar Concentrators (LSC) [4]. Comparing the most efficient structures reported in literature some rules of design will be proposed. Moreover during the talk it will be demonstrated how for the organic chemist there is the possibility to play an important role not only in the production of energy but also in the storage (e.g. synthesizing new organic redox couples for batteries)[5]. The lecture will be concluded with a quantitative analysis of the scalability of some promising structures. 1) Søndergaard R.; Hosel M.; Angmo D.; Larsen-Olsen T.T.; Krebs F.C. Mater. Today. 2012, 15, 36-49. 2) Pò R.; Carbonera C.; Bianchi G.; Pellegrino A. Macromolecules. 2015, 48, 453-461 3) Kotowski D.; Luzzati S.; Bianchi G.; Calabrese A.; Pellegrino A.; Po R.; Schimperna G.; Tacca A. J. Mater. Chem. A. 2013, 1, 10736-10744. 4) Scudo P.F.; Abbondanza L.; Fusco R.;Caccianotti L. Solar Energy Materials and Solar Cells. 2010, 94, 1241-1246. 5) Huskinson B.; Marshak M.P.; Suh C.; Er S.; Gerhardt M.R.; Galvin C.J.; Chen X.; Guzik A.A.; Gordon R.G.; Aziz M.J. Nature. 2014, 505, 195-198. 43 KN3 Polar organometallics and carbohydrate derived nitrones: a successful partnership en route to iminosugars Francesca Cardona, Andrea Goti Dipartimento di Chimica "Ugo Schiff",Università di Firenze, via della Lastruccia 13, 50019 Sesto Fiorentino (FI) e-mail: [email protected] Nitrones are suitable electrophiles for addition reactions of main group metal organometallic derivatives to furnish nitrogen derivatives. Advantages in the use of nitrones with respect to the corresponding imines rest in their easy synthesis and manipulation and, at the same time, their increased reactivity. The addition gives hydroxylamines which are easily transformed into the corresponding amines by mild reduction but are also versatile intermediates susceptible of other transformations, such as oxidation to a new nitrone moiety. In the last decade, our research group has been strongly involved in this field with the use of carbohydrate derived nitrones, both of the cyclic (i.e., pyrroline N-oxides) and acyclic (i.e., N-glycosyl nitrones) type. Additions of appropriate Grignard reagents or organolithium derivatives to these highly hydroxylated chiral nitrones occurred with high stereoselectivity, affording intermediates which were elaborated into iminosugars of different structural classes through different strategies, which encompass cyclization, condensation, intramolecular cycloaddition, or alkene ring closing metathesis. Examples of synthesis of structurally differentiated iminosugars, including several natural products, belonging to the pyrrolidine (eg, radicamine B),1 nortropane,2 and pyrrolizidine (eg, hyacinthacine A2, australine, casuarine)3 classes will be given. Scheme 1 1) Merino, P.; Delso, I.; Tejero, T.; Cardona, F.; Marradi, M.; Faggi, E.; Parmeggiani, C.; Goti, A. Eur. J. Org. Chem. 2008, 2929-2947. 2) Delso, I.; Tejero, T.; Goti, A.; Merino, P. J. Org. Chem. 2011, 76, 4139-4143. 3) Parmeggiani, C.; Cardona, F.; Giusti, L.; Reissig, H.-U.; Goti, A. Chem. Eur. J. 2013, 19, 1059510604. 44 KN4 Developing new synthetic tools towards sustainability Luigi Vaccaro Laboratory of Green Synthetic Organic Chemistry, CEMIN, Università di Perugia, Via Elce di Sotto, 8 – Perugia; http://www.dcbb.unipg.it/greensoc. e-mail: [email protected] Our research program is mainly committed to the definition of waste-minimized synthetic procedures by combining the development of several crucial areas of investigation: i) use of safer reaction media (such water, azeotropes or bio-based reaction media) or solvent-free conditions (SolFC), ii) preparation and use of heterogeneous recoverable and reusable catalytic systems based on supports tailor-made for their use in greener reaction media or under SolFC; iii) definition of flow reactors able to allow the recovery of products with minimal waste production.1 We are currently paying attention toward several widely useful metal-catalyzed processes such as cross-couplings, hydrogen production from formic acid, hydroformylation and aromatic C-H activation Some examples from our laboratory concerning the design and preparation of novel polymeric supports, flow conditions and use of safer media for the definition of novel and efficient synthetic protocols for target will be presented this communication. 1) Some recent references: Green Chem. 2015, 17, 365-372; Green Chem. 2014, 16, 3680-3704; ACS Sus. Chem. Eng. 2014, 2, 2461-2464; J. Flow. Chem. 2014, 4, 40-43; J. Catal. 2014, 309, 260–267; Proven Green Syntheses, Volume 1, CRC Press. 110-119 and 191-202; Green Chem. 2013, 15, 2394– 2400; Adv. Synth. Catal., 2013, 355, 2007–2018. 45 KN5 Retrosynthetic analysis and forensic science: the Organic Chemist’s point of view Cap. inv.sc Giuliano Iacobellis1 Reparto Carabinieri Investigazioni Scientifiche, Parma [email protected] Retrosynthetic analysis is a technique for solving problems in the planning of organic syntheses. This is achieved by transforming a target molecule into simpler precursor structures without assumptions regarding starting materials. Each precursor material is examined using the same method. Retrosynthetic analysis may be considered as a tool in the Forensic Science especially when applied to precursor analysis in illicit drug manufacture form Clandestine Lab but also when new psychoactive substances have to be fully characterized. Clandestine methamphetamine labs are but one aspect of the larger set of problems related to illicit drugs manufacturing all over the world. Anyway, due to the easy synthetic route and the high availability of information and precursors, the synthesis of methamphetamine (Meth) in Clan Lab is nowadays becoming a growing problem in the U.S. In the same time in this communication, in spite of the few cases often related with very tiny quantities that have been reported in Italy, a brief overview on the retrosynthetic analysis approach applied to the possibility to differentiate between drug dealer and producers activity has been reported, starting our investigation from the analysis of precursor traces found on the illicit drug.3 From the analytical point of view Solid Phase Micro Extraction (SPME) methodology coupled to Gaschromatograpy/Mass Spectroscopy (GC/MS) on volatile precursors in the headspace originated by heating methamphetamine crystals in a closed vessel enables to investigate also very tiny amount of flavour ingredients originated by nail solvent found in the availability of the suspects. On the other hand, a brief overview on the retrosynthetic approach applied on the analysis of new psychoactive substances will be also accounted showing the power of organic chemistry knowledge in the Forensic Investigations. 1) E. J. Corey, X-M. Cheng (1995). The Logic of Chemical Synthesis. New York: Wiley. ISBN 0471-11594-0. 2) E. J. Corey (1988). "Retrosynthetic Thinking - Essentials and Examples". Chem. Soc. Rev. 17: 111–133. doi:10.1039/CS9881700111. 3) G. Iacobellis, G. Centonze, R. Calò, D. Marangoni, G.Furlan. "Methamphetamine Clan Lab detection by means of precursor identification" ; 7th European Accademy of Forensic Science Conference, Prague (6-11 September 2015). 46 KN6 Carbohydrates meet immunology: Synthesis of neo-glycoconjugates for vaccines formulation Luigi Lay Università degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, Milano (Italy) e-mail: [email protected] Glycoconjugate vaccines have been highly successful in preventing bacterial infectious diseases. Typically, these vaccines are obtained by isolation and purification of pathogen-associated polysaccharides, followed by chemical conjugation to an immunogenic carrier protein. In the conjugation process, the structural integrity of the polysaccharide has to be carefully assessed, as many bacterial polysaccharides raised severe issues of chemical stability during vaccine manufacture. Vaccines based on synthetic carbohydrate antigens feature important advantages, such as a well-defined and reproducible composition, and enable the introduction of chemical modifications during the optimization of the vaccine construct. These aspects will be discussed in relation to serotype A of Neisseria meningitidis (MenA), a major cause of bacterial meningitis worldwide, especially in the sub-Saharan region of Africa. The capsular polysaccharide (CPS) of MenA consists of (1→6)-linked 2-acetamido-2deoxy-α-D-mannopyranosyl phosphate repeating units, with 80% of O-acetylation at 3OH. This polysaccharide tends to hydrolyse significantly in water because of the intrinsic chemical lability of the phosphodiester linkages involving the anomeric position of each repeating unit. The scanty hydrolytic stability of MenA antigen represents a serious drawback for the development of efficient vaccines intended for the poorest countries, where the highest incidence of meningococcal disease occurs. Thus, we became interested in the design and synthesis of novel and hydrolytically stable analogues of MenA polysaccharide fragments, such as the phosphono-1 and carbaanalogues2 illustrated in Scheme 1. Scheme 1 Both kinds of analogues feature an enhanced chemical stability in water. We synthesized and conjugated to polyfunctional scaffolds, such as proteins and metal nanoparticles, carba-analogues and phosphonoester-linked oligomers of MenA CPS. The influence of the multivalent presentation of short chain synthetic oligosaccharides on their antigenicity and/or immunogenicity will be thoroughly analyzed. 1) L. Lay, G. Lombardi et al.,Chem. Eur. J. 2007, 13, 6623-6635. 2) Q. Gao, L. Lay et al., Org. Biomol. Chem. 2012, 10, 6673-6681. 47 KN7 Light Activated Catalytic Manifolds for Artificial Photosynthesis Marcella Bonchio University of Padova and ITM-CNR, Department of Chemical Sciences, via Marzolo 1, Padova I-35131, Italy e-mail: [email protected] Research in the field of artificial photosynthesis, for the conversion of water to solar fuels, has recently come to the awakening turning-point of what is a key issue: the design of efficient catalytic routines that can operate with energy and rates commensurate with the solar flux at ground level. In particular, water oxidation catalysis is the fundamental process of photosynthesis, providing a light-activated, electron and proton flux to feed the CO2 reduction terminal end.[1] An extraordinary research effort has been dedicated to elucidate the structural and mechanistic prerogatives of the natural oxygen evolving complex embedded within the photosystem II enzyme (PSII-OEC). The currently accepted model is a tetramanganesecalcium-oxo cluster (Mn4O5Ca), harbored within the PSII matrix, with a flexible and adaptive coordination environment provided by the protein residues. A recent breakthrough in the field of artificial photosynthesis is the discovery of synthetic multi-redox catalysts, as analogs of the PSII-OEC (Scheme 1), with a common functional-motif, i.e. a redox-active, tetranuclear {M4(O)4 core boosting H2O oxidation to O2 with unprecedented efficiency. Our vision points to a careful choice/design of the catalytic core, of its ligand set and of the surrounding nano-environment. We report herein a combined synthetic, spectroscopic and mechanistic study on the use multi-metal catalysts for water oxidation and their combined use with visible light sensitizers and carbon nanostructures (CNS). The outcome is a hybrid nanomaterial with unperturbed CNS electrical properties, enabling water splitting with high efficiency at low overpotentials. Scheme 1 1) Squarcina, A.; Fortunati, I.; Saoncella, O.; Galiano, F.; Ferrante, C.; Figoli, A.; Carraro, M.; Bonchio, M. Adv. Mater. Interfaces 2015, 2, DOI: 10.1002/admi.201500034. 2) Al-Oweini, R.; Sartorel, A.; Bassil, B. S.; Natali, M.; Berardi, S.; Scandola, F.; Kortz, U.; Bonchio, M. Angew. Chem. Int. Ed., 2014.,126, 11364-11367.; Piccinin, S.; Sartorel, A.; Aquilanti, G.; Goldoni, A.; Bonchio, M.; Fabris, S. PNAS 2013, 110, 4917-4922 3) Sartorel, A.; Bonchio, M.; Campagna, S.; Scandola, F. Chem. Soc. Rev. 2013, 42, 2262-2280. 4) Paolucci, F.; Prato, M.; Bonchio, M. et al. ACS Nano 2013, 7, 811; Nature Chem. 2010, 2, 826-831. 48 KN8 Manganese catalyzed C-H functionalization John T. Groves Department of Chemistry, Princeton University, Princeton, NJ, 08544 USA e-mail: [email protected] Despite the growing importance of fluorinated organic compounds in drug and agrochemical development, there have been no direct protocols for the fluorination of aliphatic C-H bonds using conveniently handled fluoride salts. We have recently discovered that manganese porphyrin and salen complexes catalyze alkyl C-H fluorination under mild conditions when used with stoichiometric O-atom transfer agents. Simple alkanes, terpenoids, more complex biomolecules and widelyused drugs have been selectively fluorinated in a single step at otherwise inaccessible sites in yields up to 70%. Several mechanistic probes have indicated that the C-H bond scission is mediated by a reactive oxomanganese(V) catalytic intermediate and that fluorine delivery is directed by an ususual manganese(IV) fluoride that has been isolated and structurally characterized. We also describe the first late-stage [18F] labeling chemistry for aliphatic C-H bonds with no-carrier added [18]F]fluoride. The approach has obvious application to PET imaging. The method uses simple, scalable Mn(salen) complexes as F-transfer catalysts and enables the facile labeling of a variety of bioactive molecules and building blocks with radio-chemical yields up to 72% within 10 minutes reaction time without the need for preactivation of the target molecule. Extensions of these methods now allow targeted fluorination of pendant carboxylyic acid functional groups via decarboxylation as well as a new C-H azidation reaction. These novel results and approaches to understanding the reaction mechanisms will be discussed. This work has been supported by the US Department of Energy and National Science Foundation. 1. 2. 3. 4. 5. 6. Wei Liu, Xiongyi Huang, Mu-Jeng Cheng, Robert J. Nielsen, William A. Goddard, III, John T. Groves, Science, 2012, 337, 1322-1325. Wei Liu and John T. Groves Angew. Chem. Int. Ed. 2013, 52, 6024-6027. Wei Liu, Xiongyi Huang and John T. Groves, Nature Protocols, 2013, 8, 2348-2354. Xiongyi Huang, Wei Liu, Hong Ren, Ramesh Neelamegam, Jacob M. Hooker and John T. Groves, J. Am. Chem. Soc. 2014, 136 (19), 6842–6845. Xiongyi Huang, Tova Bergsten and John T. Groves, J. Am. Chem. Soc. 2015, 137, 5300–5303. Wei Liu and John T. Groves, Acc. Chem. Res. 2015, 48, 1727–1735. 49 Abstracts Oral Communications 50 OC1 Selective Oxidations via activation of H2O2 and O2 Emanuele Amadio, Elena Badetti, Cristiano Zonta and Giulia Licini* Dipartimento Scienze Chimiche, Università di Padova, Via Marzolo 1, 35131, Padova, Italy e-mail: [email protected] Triphenolamines (TPA) 1 are highly symmetric, modular molecules that can be easily prepared on multigram scale from commercially available starting materials. They form stable metal complexes with a wide variety of transition and main group elements.1 Their application as catalysts is much more recent and the reports of the last 5 years shown how they are highly active in important reactions like polymerizations, olefin metathesis, CO2/epoxide cycloadditions, and oxygen transfer processes.1 In particular, from the results reported, it is evident how the perfect match between metal and ligand allows to tune the reactivity and selectivity in rather different types of reactions. Here we will report our latest results related to the TPA and related metal complexes in catalytic oxidations. Activation of hydroperoxides and in particular on W/VI) catalysed bromo and chloro peroxidations and the reactivity of V(V) TPA complexes for the catalytic aerobic carbon-carbon cleavage of vicinal diols and more complex lignin substructures will be presented. We acknowledge the Università di Padova for funding (PRAT-CPDA123307). The research has been carried out in the frame of COST Actions CM1003 and CM1205. 1) Mba, M.; Zonta, C.; Licini, G., Coordination chemistry and applications of nitrilotris(N– methylenephenoxy)–metal complexes, Patai Series, The Chemistry of Metal Phenolates (2014) (ISBN 978-0-470-97358-5J. Chmura, M. G. Davidson, C. J. Frankis, M. D. Jones and M. D. Lunn, Chem. Commun., 2008, 1293. 51 OC2 Pd nanoparticles supported on cyclodextrin derivatized silica: an efficient and versatile catalyst for ligand free C-C coupling and hydrogenation reaction Katia Martina1, Francesca Baricco1, Marina Caporaso1, Gloria Berlier2, Giancarlo Cravotto1 1 Dipartimento di Scienza e Tecnologia del Farmaco and NIS “Centre for Nanostructured interfaces and surfaces”, via Giuria 9, University of Turin, Italy 2 Department of Chemistry and NIS - Centre for Nanostructured interfaces and surfaces, University of Turin, Via P. Giuria 7, 10125 Turin, Italy. e-mail: [email protected] Supported palladium nanoparticles (PdNPs) have appeared as a valuable catalysts in green chemistry. Their high efficiency enable a wide applicability even at industrial scale.1 Examples of nanocatalysts includes colloidal suspension or solid supported nanoparticles. Silica is a versatile support capable to host metals enhancing stability and reactivity. Organic-inorganic hybrid materials have been widely used in this field and an efficient grafting of cyclodextrin into the inorganic silica framework has been recently object of our study.2 In the present work we report the preparation of a new PdNPs catalyst. With the aim to effectively immobilize and stabilize PdNPs, we exploited the features of an aminoalcohol branched spacer bound to a triazolyl-β-CD derivative. Both microwave irradiation in water, and solvent-free mechanochemical conditions afforded an efficient grafting. Being coupling reactions such as Suzuki, Heck and Sonogashira ranked amongst the most general transformation in organic synthesis together with hydrogenation, we design a catalyst with high versatility and activity. Selective heating of catalytically active metal species under microwave irradiation3 was exploited to successfully react activated and non-activated aryl bromide in ligand-less Suzuki and Heck reaction. The catalyst demonstrated high activity and selectivity in hydrogenation reaction. Pd Pd NN N N N Pd N Pd NN N N N N N NN N N N Pd Pd N NN Pd Scheme 1 1) 2) 3) Wu, Z.; Cherkasov,N.; Cravotto, G.; Borretto, E.; Ibhadon, A.O.; Medlock, J.; Bonrath, W.; ChemCatChem 2015, 7, 952 – 959 Martina, K.; Baricco, F. ; Berlier, G.; Caporaso, M.; Cravotto G.; ACS Sustainable Chem. Eng. 2014, 2 (11), 2595–2603. a) Calcio Gaudino, E.; Carnaroglio, D.; Martina, K.; Palmisano, G.; Penoni, A.; Cravotto, G. Org. Proc. Res. Dev., 2015, 19(4), 499-505 b) Caporaso, M.; Cravotto, G.; Georgakopoulos, S.; Heropoulos, G.e; Martina, K.; Tagliapietra, S. Beilstein. J. Org. Chem. 2014, 10, 1454-1461 52 OC3 Enantioselective organocatalyzed Biginelli-like reaction on isatin: synthesis of enantioenriched spiro[indoline-pyrimidine]-diones derivatives Mattia Stucchi1, Giordano Lesma1, Giulia Rainoldi1, Alessandro Sacchetti2, Alessandra Silvani1 1 Dipartimento di Chimica, Università di Milano, via Golgi 19, 20133, Milano, Italy. Dipartimento di Chimica, Materiali ed Ing.Chimica ‘Giulio Natta’, Politecnico di Milano, p.zza Leonardo da Vinci 32, 20133, Milano, Italy. 2 e-mail: [email protected] The multicomponent Biginelli reaction,1 discovered by the Italian chemist Pietro Biginelli in 1893, consists of the condensation between an aldehyde, (thio)urea and a βdicarbonyl compound to obtain 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) as major products. Although DHPMs are prominent pharmacologically active molecules and have found increasing applications,2 only few asymmetric versions of the Biginelli reaction have been reported,3 using different organocatalytic systems, including primary and secondary amines, chiral ionic liquids and BINOL-derived phosphoric acids.4 Going on with our interest in the asymmetric synthesis of 3,3’-disubstituted oxindole derivatives and related spiro-compounds,5 we looked at the potential application of BINOL-derived monophosphoric acids to the Biginelli-like reaction employing isatins as carbonyl components. We could obtain a small library of chiral spiro[indolinepyrimidine]-diones derivatives with good yields and moderate enantioselectivity. Postcondensation reactions have been performed, increasing the number of potentially useful compounds. The assignment of the configuration at the new oxindole C-3 stereocenter was assessed through quantum mechanical methods and NMR spectroscopy on diasteroisomeric derivatives.6 Computational studies in order to explain the enantioselectivity and the stereochemical outcome are currently underway. 1) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. 2) De Fatima, A.; Braga, T.C.; Da S. Neto, L.; Terra, B.S.; Oliveira, B.G.F.; Da Silva, D.L.; Modolo, L.V. J. Adv. Res. 2014, http://dx.doi.org/ 10.1016/j.jare.2014.10.006. 3) Heravi, M.M.; Asadi, S.; Lashkariani, B.M. Mol. Divers. 2013, 17, 389. 4) a) Chen, X.U.; Xu, X.Y.; Liu, H.; Cun, L.F.; Gong, L.Z. J. Am. Chem. Soc. 2006, 128, 14802. b) Li, N.; Chen, X.H.; Song, J.; Luo, S.W.; Fan, W.; Gong, L.Z. J. Am. Chem. Soc. 2009, 131, 15301. 5) Lesma G.; Meneghetti, F.; Sacchetti, A.; Stucchi, M.; Silvani, A. Belstein J. Org. Chem. 2014, 10, 1383. 6) Smith, S.G.; Goodman, J.M. J. Org. Chem. 2009, 74, 4597. 53 OC4 Towards High-Performance Lewis Acid Organocatalysis Lars Ratjen1, Manuel van Gemmeren2, Fabio Pesciaioli3, Benjamin List*4 1 Universidad Andrés Bello, Santiago, Chile 2 ICIQ, Tarragona, Spain 3 University of Pavia, Italy 4 Max-Planck-Institut für Kohlenforschung Muelheim an der Ruhr, Germany e-mail: [email protected] In the recent years chiral disulfonimides (DSIs) has been employed as a powerful tool in both Brønsted acid and Lewis acid catalysis. In fact DSIs are strong Brønsted acids which upon treatment with a silicon nucleophile become excellent Lewis acids able to catalyze a wide range of reactions.1 Here we report the synthesis and the evaluation of a new class of highly active chiral disulfonimide catalysts 3-4, based on the internal activation by alcohols as secondary interacting groups.2These catalysts can be achieved in only one step from the unsubstituted DSI backbone via directed ortho-metalation followed by alkytation with the corresponding ketone. As a first step of our evaluation we performed the Mukaiyama aldol reaction of benzophenone catalyzed by DSIs 1-4. This study showed that the intramolecular hydrogen-bond is responsible of the enhancement of the catalyst reactivity (Scheme 1). Scheme 1: Comparison of the catalysts activity Furthermore we employed the new catalysts 3 for performing an asymmetric Mukaiyama aldol reaction with 1,2-bis(trimethylsilyloxy)-cycloalkenes a class of silylnucleophiles never used in asymmetric organocatalysis as a consequence of its low reactivity. In summary we disclose a new motif for the design of high-performance Brønsted and Lewis acid catalysts that in future can be employed in both enantioselective and non asymmetric transformations. 1) van Gemmeren, M.; Lay, F.; List, B. Aldrichimica Acta 2014, 47, 3 – 13. 2) Ratjen, L.; van Gemmeren, M.; Pesciaioli, F.; List, B. Angew. Chem., Int. Ed. 2014, 53, 8765 –8769. 54 OC5 Title Bio- and Organo-catalyzed reduction of oxindole based olefins A. Rossetti1, M. Bonfanti1, G.Roda2, A. Sacchetti1 1 Dipartimento di Chimica, Materiali ed Ing. Chimica ‘Giulio Natta’, Politecnico di Milano, p.zza Leonardo da Vinci 32, Milan 20133, Italy. 2 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via L. Mangiagalli 25, Milan, 20133 Italy. e-mail: [email protected] 2-Oxindoles, especially 3-substituted, are found in a large number of natural and unnatural compounds with important biological activities, and are useful key intermediates for the synthesis of many kinds of drug candidates.1 Some derivatives act as non-peptide scaffolds1 in peptidomimetic chemistry, either as enzyme inhibitors or as ligands of G-protein-coupled receptors.1 Among the most interesting bioactivities displayed, we can cite a potent gastrin/CCK-B receptor antagonist, a vasopressin VIb receptor antagonist, a CRTH2 (DP2) receptor antagonist spirohydantoin, and a new antimalarial lead1. Due to the high reactivity of the C-3 prochiral carbonyl group, isatin can be easily transformed into 2-oxindole derivatives, mostly by nucleophilic additions or spiroannulation.1,2 As far as asymmetric synthesis of active products is concerned, and according to our experience in the field of enantioselective reduction of activated olefins,3,4 we have decided to focus on 2-oxindole derivatives. Starting from the commercially available isatin, we synthesized a library of 3-substituted 2-oxindoles. The olefins obtained have been submitted to two different reductive methods: a biocatalytic one, in which Beaker Yeast has been employed, and an organocatalytic approach, where Hantzsch ester and several organocatalysts were used (Scheme 1). Scheme 1: Library of reduced 3-substituted 2-oxindoles. 1) Lesma, G.; Meneghetti, F.; Sacchetti, A.; Stucchi, M.; Silvani, A. Beilstein J. Org. Chem. 2014, 10, 1383–1389. 2) Sacchetti, A.; Silvani, A.; Gatti, F.G.; Lesma, G.; Pilati, T.; Trucchi, B. Org. Biomol. Chem., 2011, 9, 5515–5522. 3) Brenna,E.; Gatti, F.G.; Monti, D.; Parmeggiani, F.; Sacchetti, A. Chem. Commun., 2012, 48, 79–81. 4) Brenna,E.; Gatti, F.G.; Malpezzi, L.; Monti, D.; Parmeggiani, F.; Sacchetti, A. J. Org. Chem., 2013, 78, 4811−4822. 55 OC6 Identification of promising drug candidates targeting strategic proteins involved in cancer development Stefania Terracciano1, Maria Strocchia1, Gianluigi Lauro1, Fabrizio Dal Piaz1, Maria Carmela Vaccaro1, Maria Giovanna Chini1, Raffaele Riccio1, Giuseppe Bifulco1, Panagis Filippakopoulos2, Ines Bruno1 1 Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy. 2 Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, U.K.. e-mail: [email protected] In the field of cancer research, proteins involved in the so called ‘epigenetic code’, have recently emerged as promising therapeutic targets for the development of potential antitumor agents. Bromodomains (BRDs), a branched protein family containing structurally conserved modules, act as readers of acetyl-lysine (Kac) residues on histone tails and are deeply implicated in several pathologies including cancer.1 Targeting this epigenetic readers by specific small molecule inhibitors would provide a novel exiting approach in cancer therapy.2 Heat shock protein 90 (Hsp90), an ATP-dependent molecular chaperone, is another very attractive target that has received great attention by the scientific community because of its crucial role in apoptosis and oncogenesis.3 The identification of innovative Hsp90 modulators represents a useful strategy for the development of attractive anticancer drug candidates. Based on these premises, we describe the design, the synthesis and biological effects of new molecular platforms able to interfere with the activity of these relevant biological targets.4,5 1) 2) 3) 4) 5) Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W. B.; Fedorov, O.; Morse, E. M.; Keates, T.; Hickman, T.T.; Felletar, I.; Philpott, M.; Munro, S.; McKeown, M. R.; Wang, Y.; Christie, A. L.; West, N.; Cameron, M. J.; Schwartz, B.; Heightman, T. D.; La Thangue, N.; French, C. A.; Wiest, O.; Kung, A. L.; Knapp, S.; Bradner. J. E. Nature 2010, 468, 1067–1073. Muller, S.; Filippakopoulos, P.; Knapp, S. Expert Rev. Mol. Med. 2011, 13:e29. Soga, S.; Akinaga, S.; Shiotsu, Y. Curr. Pharm. Des. 2013, 19, 366-76. Picaud, S.; Strocchia, M.; Terracciano, S.; Lauro, G.; Mendez, J.; Daniels, D. L.; Riccio, R.; Bifulco, G.; Bruno, I.; Filippakopoulos, P. J. Med. Chem. 2015, 58, 2718–2736. Strocchia, M.; Terracciano, S.; Chini, M. G.; Vassallo, A.; Vaccaro, M. C.; Dal Piaz, F.; Leone, A.; Riccio, R.; Bruno, I.; Bifulco, G. Chem. Commun. 2015, 51, 3850-3853. 56 OC7 Selectivity in alcohol and amine bio-oxidation using Laccase-mediator system Paola Galletti, Roberto Soldati, Federica Funiciello, Daria Giacomini Department of Chemistry “G. Ciamician”, University of Bologna, Via Selmi 2, 40126 Bologna, Italy e-mail: [email protected] Biocatalysis is emerging as a valuable tool to develop of more benign and selective redox processes. The use of enzymes as catalysts meets the need of modern chemistry for more selective and clean manufacturing technologies, reducing management of hazardous chemicals and waste, thus realizing more sustainable and environmental friendly processes. Bio-oxidations have the added value of high levels of selectivity (regio- chemo- and stereo-) reliable even to fine chemicals with complex structures and possessing oxidation sensitive functional groups. Laccases (EC 1.10.3.2) belong to the multi-copper family of oxidases. These enzymes contain four copper centers per protein molecule and catalyse the oxidation of electron rich aromatic substrates, usually phenols or aromatic amines using oxygen as the electron acceptor. Being water the only byproduct formed, in principle they are ideal catalysts for sustainable chemical and technological processes. Although the natural substrates of laccases are the phenolic residues of lignin, the inclusion of appropriate mediators in the so called laccasemediator system (LMS), makes accessible the oxidation of non-phenolic substrates. Commonly, laccases oxidize secondary alcohols to ketones and primary alcohols to the corresponding aldehydes whereas the overextended oxidation of primary alcohols to carboxylic acid is infrequent. Concerning the oxidation of amines, very few applications of Laccases were reported, mainly on anilines. Herein we report developments in the chemo-enzymatic oxidation by commercial Laccase from Trametes versicolor (TvL) of some primary alcohols and benzylamines. Primary alcohols were selectively converted to aldehydes or the carboxylic acids. The range of applicability of the bio-oxidation to carboxylic acids was widened applying the optimized protocol to the oxidation of 2arylpropanols (Profenols) to the corresponding 2-arylpropionic acids (Profens), in high yields and with complete retention of configuration.1 In the oxidation of benzylamines, we found that, depending on the reaction conditions, the bio-oxidation could be selectively driven to give the corresponding aldehydes or imines in good yields.2 Scheme 1 1) Galletti, P.; Pori, M., Funiciello, F.; Soldati, R., Ballardini, A.; Giacomini, D. ChemSusChem 2104, 7, 2684-2689. 2) Galletti, P.; Funiciello, F.; Soldati, R., Giacomini, D. Advances Synthesis & Catalysis 57 OC8 Pna:Rna Duplex Engineering: Computational Approach Using Molecular Dynamic And Metadynamics M. D. Verona1, V. Verdolino2, M. Parrinello2, R. Corradini1 1 a Chemistry Department - University of Parma - Parco Area delle Scienze 17/A I43124 Parma 2 Department of Chemistry and Applied Biosciences ETH Zurich, USI Campus, Via Giuseppe Buffi 13, CH-6900 Lugano). e-mail: [email protected] Peptide nucleic acids (PNAs) are powerful biotechnological tools for targeting DNA or RNA. Their chemical and biological stability combined with very high affinity and selectivity towards the target sequences identified PNAs as potential drugs, in particular as modulators of microRNA; 1,2 modifications of the PNA structure on the nucleobases or on the backbone are currently investigated to improve their properties in biological media. Synthesis of PNAs, in particular modified ones, is time and money demanding; computational chemistry could therefore be a useful tool for understanding duplex formation and design effective modifications. For these reasons, we studied the conformational properties of single strand PNA, PNA:RNA duplex (Fig. 1a), and the dynamic process of re-annealing of PNA:RNA distorted systems. The systems were solvated and Molecular Dynamics simulations were run for more than 200 ns using GROMACS. A PNA:RNA duplex (176D) was used to test the parameters used, by means of standard MD at 300K; simulated structural parameters were found in good agreement Figure 1. a) NMR structure 176D b) helix generated by with experimental ones. modified NAB c) dimeric bases to mimic triplex Standard MD on PNA single strand highlighted the multitude of conformers accessible at room temperature. In order to explore all the possible single strand conformations kinetically non-accessible, we used enhanced sampling reads Metadynamics3 (MDMT), thus exploring a much larger free energy landscape; the results show high conformational freedom and the absence of preorganization for unmodified PNA. Duplex PNA:RNA reannealing starting from different distorted geometries were studied by means of five different standard MD simulations. This study revealed the importance of central bases in the process of duplex formation. In order to overcome the lack of structures available in literature, we developed a tool for the generation of PNA:DNA (RNA) helixes, modifying NAB module of Amber Tools 14 (Fig. 1b). This allowed to rapidly generate a set of PNA:DNA duplexes with the sequences of interest and to introduce modifications on PNA in order to predict properties and behaviour of non-standard systems. We then considered the effects of the introduction of modified dimeric bases on PNA (Fig 1c). Several models were tested and results will be compared with experimental data on a first set of molecules; new monomers with theoretically improved properties are now being synthesized. 1) Manicardi, A. et al ChemBiochem 2012, 13, 1327-1337; 2) Cheng, C.J. et al. Nature 2015, 518, 107-110; 3) Barducci, A. et al. Review Letters 2008, 100 (2), 020603. 58 OC9 Crosslinking Peptide Nucleic Acids (PNAs) for targeting of DNA Alex Manicardi1, Ellen Gyssels1, Roberto Corradini2, Annemieke Madder1 1 Ghent University, Krijgslaan 281 S4, 9000 Ghent, Belgium. 2 Università degli Studi di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy. e-mail: [email protected] Covalent interstrand crosslinks (ICLs) are important in antigene therapy in the context of cancer treatment1. These ICLs are highly toxic DNA lesions that prevent transcription and replication of the DNA by inhibiting strand separation. Earlier, a new strategy for crosslinking duplex DNA was developed in the Madder group2. By modifying an oligonucleotide with an unnatural nucleoside containing a furan moiety, crosslinking can be achieved after selective oxidation of the furan moiety which reacts with a nucleophilic moiety present on the complementary base. Peptide nucleic acids (PNAs) are a class of DNA mimics, developed by Nielsen and coworker3, in which the phosphodiester backbone is substituted by a completely unnatural N-(2-aminoethyl)glycine backbone. Strategies for the synthesis of modified and multifunctional PNA were allready developed by our group, allowing to change probe properties, such as cellular internalizzation4, or introduce reporter molecules, such as aromatic moieties5. General scheme of PNA based ICL formation. We here present the synthesis of furan-modified PNAs and their use in oxidationcrosslinking strategy for targeting DNA. Exploiting the recognition abilities of the PNA, the furan moiety is positioned in close proximity to the reactive nucleophiles of the DNA nucleobases, and, once activated by oxidation, it can give highly sequencespecific ICL. Direct evidence of hybridisation and cross-linking to ss- and dsDNA will be presented. 1) 2) 3) 4) Deans, A. J.; West, S. C. Nat. Rev. Cancer 2011, 11, 467-80. Carrette, L. L. G.; Madder A. ChemBioChem 2014, 15, 103-107. Nielsen, P. E.; Egholm, M.; Berg, R. H.; Buchardt, O. Science 1991, 254, 1497-1500. Manicardi, A.; Fabbri, E.; Tedeschi, T.; Sforza, S.; Bianchi, N.; Brognara, E.; Gambari, R.; Marchelli, R.; Corradini, R. ChemBiochem 2012, 13, 1327-1337. 5) Manicardi, A.; Guidi, L.; Ghidini, A.; Corradini R. Beil. J. Org. Chem. 2014, 10, 1495-1503. 59 OC10 The Catalytic Antioxidant Behaviour of Nitroxides 1 Luca Valgimigli*1, Riccardo Amorati1, Andrea Baschieri1, Derek, A. Pratt2 University of Bologna Department of Chemistry “G. Ciamician”, Bologna, Italy. 2 University of Ottawa, Department of Chemistry, Ottawa, Ontario, Canada. e-mail: [email protected] 2,2,6,6-Tetramethylpiperidine-N-oxyl (TEMPO) is the best know nitroxyl radical. Being one electron away from hydroxylamines and oxoammonium ions, nitroxides have a privileged redox position that is responsible for their role as oxidation catalysts. The same chemistry is also the basis for the superoxide dismutase mimetic activity. Considerable interest has emerged in the biological activities of nitroxides, which have been ascribed to their antioxidant activity, but the mechanistic rationale behind it could be elucidated only recently.1 It is due to formal hydrogen-atom transfer from the protonated nitroxyl radical to oxidative chain-carrying peroxyl radicals, hence it requires acidic conditions. In the presence of strong pTSA (10 mM) kinh as high as 1.8×108 M-1s-1 was recorded at 30°C in acetonitrile, while with weak carboxylic acids kinh was up to 1.5×106 M-1s-1 outperforming -tocopherol.1 Importantly, when weak acids are used as the proton source, the TEMPO-inhibited autoxidations have apparently infinite inhibited period and the concentration of TEMPO shows nearly no decay during the reaction. This catalytic behavior implies that the oxidized TEMPOnium ion is recycled during the autoxidation, i.e. it is reduced back to the nitroxyl radical under oxidative conditions! Figure. Growth of the EPR signal of TEMPO during the autoxidation of cumene at 30°C in the presence of TEMPOnium ion. We will provide evidence that this reduction is performed at diffusion controlled rate (k ~ 1010M-1s-1) by alkyl radicals, which get oxidized to the corresponding carbocations. The reaction is sufficiently fast to outcompete the reaction of alkyl radicals with molecular oxygen to form the chain-carrying peroxyl radicals. 1) Amorati, R.; Pedulli, G. F.; Pratt, D.A.; Valgimigli, L. Chem. Commun., 2010, 46, 5139–5141. 60 OC11 Iodine/iodic acid: a greener iodination methodology in the synthesis of x-ray contrast agents Luciano Lattuada Bracco Imaging SpA, Centro Ricerche Bracco, Via Ribes 5, Colleretto Giacosa (TO) Italy e-mail: [email protected] Iodinated contrast agents, such as Iopamidol or Iomeprol (Scheme 1), are widely used in several different X-ray diagnostic procedures, providing images of paramount utility to radiologists.1 OH CONH CONH I OH I I I OH OH OH CONH HO CONH OH I OH CONH CON Me I Iopamidol OH OH Iomeprol Scheme 1 These molecules were patented more than thirty years ago but they still the most employed worldwide with a production of hundreds of tons per year. The current industrial manufacturing processes for these molecules involve the full iodination of intermediate aniline 1 or phenol 3 with a hydrochloric solution of iodine chloride.2 One of the main drawbacks of iodine chloride is related to its manufacturing process that requires the use of chlorine, a very poisonous gas.3 For this reason the production, transportation, storage and use of chlorine are strictly regulated. The couple iodine/iodic acid was identified as a safer and environmental friendly alternative to iodine chloride and new procedures were optimized and scaled-up to obtain the required triiodinated intermediates 2 and 4 with high quality and yields (Scheme 2). COOH I COOH I I2, HIO3 COOH H2N H2 O COOH H2N I 1 CONH OH I2, HIO3 OH HO CONH OH H2 O I 2 CONH I HO OH OH CONH I OH OH OH 4 3 Scheme 2 1) Lusic, H.; Grinstaff, M. W. Chem. Rev. 2013, 113, 1641-1666. 2) Anelli, P. L.; Brocchetta, M.; Lattuada, L. Uggeri, F. Pure Appl. Chem. 2012, 84, 485-491 3) Bommaraju, T. V.; Lüke, B.; O’Brien, T. F.; Blackburne, M. C. “Chlorine” in Kirk-Othmer Encyclopedia of Chemical Technology, John Wiley & Sons, Vol. 6, pp. 130-211, (2002). 61 OC12 Easy procedures for preparation of functionalized heterocyclic five member rings as structural cores in drug discovery Marco A. Ciufolini1, Enrico Marcantoni2, Andrea Aramini3, Gianluca Bianchini3, Mara Tomassetti2-3 1 Department of Chemistry, University of British Columbia, 2036 Main Mall,Vancouver 2 School of Science and Technology, Chemistry Division, University of Camerino, Via S. Agostino 1, 62032 Camerino; 3 Dompé s.p.a., Via Campo di Pile, 67100, L’Aquila, Italy; e-mail: [email protected] During our discovery programs, we have found a novel class of (R)-4(heteroaryl)phenylpropionic derivatives,1 showing strong selectivity and potency in C5aR inhibition. The C5a is a protein produced by the human immune system involved in the pathogenesis of inflammatory and neuropathic pain.2 We found that tetrazole moiety proved to be beneficial to the pharmacological profile (ADME and PK), maintaining potency and selectivity properties. Moreover the substituted 5-member ring seem to be also involved in the explanation of biological activity of 1 and 2. Necessity of discovery new, quick and scalable procedures for the preparation of 5member ring heterocyclic cores lead us to develop an easy procedures for preparation of such motifs based on α-chloro glycinate chemistry 3.3 1) Allegretti, M.; Cesta, M. C.; Bertini, R.; Mosca, M.; Colotta, F. 2-Phenylpropionic acid derivatives and pharmaceutical compositions containing them. U.S. Patent 8,293,788, Oct. 23, 2012. 2) Devulder, J.; Jacobs, A.; Richartz, U.; Wiggett, H. Br. J. Anaesth. 2009, 103, 576-585. 3) Zhang, J.; Coqueron, P. Y.; Vors, J. P.; Ciufolini, M. A. Org. Lett., 2010, 12, 3942-3945. 62 OC13 Process Development and Scale Up of API Intermediates: A Case Study Paolo Stabile, Emiliano Rossi, Christian Corrado De Filippo, Alessandro Leganza, Francesco Fontana F.I.S. - Fabbrica Italiana Sintetici S.p.A. Viale Milano, 26 - 36075 Montecchio Maggiore (Vicenza) Italy e-mail: [email protected] Chemical route scouting and process development targeting yields, impurity profile and cost benefits, are the main objectives of a contract development and manufacturing organization (CDMO). As such, FIS is involved in the development and optimization of chemical processes aimed to the commercial production of numerous APIs and pharmaceutical intermediates. In this context, a case study related to process development and preparation of three intermediates of the same API will be reported, detailing the steps performed from the proof of concept to the multi-kilogram scale production (Scheme 1).1 Br N N N O O N N H O Intermediate 1 Intermediate 2 90% 81% (over three steps) Br O N B API O CN Intermediate 3 64% (over three steps) Scheme 1 1) a) Fontana, F.; Stabile, P. EP2586777B. b) Fontana, F.; Leganza, A.; Stabile, P. IT1410390B c) Fontana, F.; Rossi, E.; De Filippo, C. WO2014/023576. 63 OC14 A novel efficient total synthesis of Telaprevir Emanuele Attolino,1 Anna Iuliano,2 Pietro Allegrini1¶ 1 Dipharma Francis srl, via Bissone 5, 20021 Baranzate (MI). 2DCCI, Università di Pisa, via Moruzzi 13, 56124, Pisa. e-mail: [email protected] Telaprevir (1) is a potent viral protease inhibitor used to treat hepatitis C infections. N O H N N N H O O O H N N H N O (1) O The preparation of Telaprevir,1 involves the assembly of the 6 structural units A-F (Figure 1) and subsequent oxidation of the hydroxy group of subunit E. 2Pyrazinylcarboxylic acid A, cyclopropylamine F, (S)-cyclohexylglycine B and (S)-tertleucine C are available in bulk on the market, while D and E are two synthetic amino acids with a more complex structure which must be prepared in view of the development of an industrial synthetic method for Telaprevir (1). O N H2N OH N OH OH OH H2N O N H B O OH O A OH H2N H2N O C D E F Figure 1 Several approaches reported in the literature will be analyzed2 and particular attention will be given to a novel and efficient 4 steps preparation of aminoacid D. The approach involves a first oxidative desymmetrization of bicyclic pyrrolidine (2), yielding imine (3) followed by a diastereoselective aza Henry reaction giving the nitro intermediate (4), which is finally converted into (5),3 precursor of racemic aminoacid D (Scheme 1). After resolution via diastereoisomeric salt formation, enantiopure D is isolated and its enantiomer can be recycled by conversion into starting amine (2). desymmetrization oxidation D N H N (2) (3) aza-Henry N O N boc NO2 (4) boc OH (5) Scheme 1 1) Babine, R.E. et al. US 7820671. 2) Köhler, V; Bailey, K. R.; Znabet, A.; Raftery, J.; Helliwell, M; Turner, N.J. Angew. Chem. Int. Ed. 2010, 49, 2182-2184 3) Iuliano, A.; Jumde, V.R.; Attolino, E.; Taddei, M. US 2014323689. 64 OC15 Cabaxitaxel: a novel second generation taxane Domenighini L1., Gambini A1., Cattaneo C.1 1 Indena S.p.A. R&D semisynthetic department (via don Minzoni 6, 20090 Settala (Mi)). e-mail: [email protected] Cabazitaxel (2) has been developed by Sanofi-Aventis for the treatment of patients with hormone-refractory metastatic prostate cancer (mHRPC)1 and shows a broad spectrum of antitumor activity in murine tumors, including prostate, colon, and mammary adenocarcinomas. It belongs to the taxane family and shows cytotoxic activity and toxicity profile similar to paclitaxel and docetaxel though it has demonstrated a superior penetration of the blood-brain barrier2 and activity on several taxane-resistant cell lines3. It acts as an antimitotic drug, binding to tubulin and promoting the assembly of tubulin into microtubules. It simultaneously inhibits their disassembly leading to mitotic block and apoptosis4. Starting material for the synthesis of cabazitaxel (2) is 10-deacethyl-baccatine III (10DAB-III) (1), a diterpenoid extracted from the European yew (Taxus baccata). 10-DABIII (1) is first converted into 7,10-dimethyl 10-DAB III (3) and then coupled with a protected side chain yielding eventually (2)(scheme 1). 10-DAB III (1) 7,10-dimethyl DAB III (3) Cabazitazel (2) Scheme 1 1 Tannock I, et al. , J. Clin. Oncol. 1989, 7, 590-597. Mita Ac, et. Al.; Clin. Cancer Res. 2009, 15(2), 723-730. 3 Sanofi-Aventis. Jevtana prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/201023lbl.pdf 4 Jordan MA, Wilson L., Nat. Rev. Cancer 2004, 4(4), 253-265. 2 65 Available from OC16 DEVELOPMENT AND SCALE-UP OF AN INNOVATIVE SYNTHESIS TO GENERIC TELAPREVIR Giuseppe Barreca1, Luca Carcone2, Romano Orru2, Eelco Ruijter2, Marcello Rasparini3 1 2 Chemessentia Srl (Via Bovio 6, 28100 Novara). VU University of Amsterdam (De Boelelaan 1083 , 1081 HV Amsterdam, The Netherlands). 3 Janssen Pharmaceutica (Turnhoutseweg 30, 2340 Beerse, Belgium). e-mail: [email protected] An improved, simpler and more economical route to Telaprevir, based on a previously published route1, is presented. Key modifications were to prepare an isocyanide 2 and to react it according to a multicomponent Ugi-Joulliè reaction. The ensuing para-nitro derivative 4 was subsequently converted into the corresponding aldehyde 5 and, finally, into a direct Telaprevir precursor by means of a Passerini reaction using an in-situ prepared cyclopropyl isocyanide. Scheme 1 1) R. Orru, N. Turner et al., Chem. Comm. 2010, 46, 7918-7920 66 OC17 Metal-Catalyzed Tandem Hydrogen-Transfer Reactions for the Synthesis of Biologically Relevant Coumpounds Varsha R. Jumde,1 Andrea Porcheddu,2 Giuseppina Ivana Truglio,1 Marialaura Vecchio,1 Maurizio Taddei,1 Elena Cini1 1 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A Moro, 53100 Siena 2 Dipartimento di Scienze Chimiche e Geologia, Università degli Studi di Cagliari, Cittadella Universitaria, I-09042, Cagliari e-mail: [email protected] The development of more efficient processes is one of the major goals of contemporary synthetic organic chemistry. Among the metal-catalysed reactions regularly used in organic synthesis, the redox process called “borrowing hydrogen” (or hydrogen autotransfer) has found several interesting applications especially in domino processes. Under Ir or Ru catalysis, alcohols are oxidized to aldehydes, which may undergo a nucleophilic addition and the condensation product can be further manipulated. With amines as nucleophiles, we present here the alkylation reaction applied to an industrial synthesis of the antipsychotic drug Cariprazine1 and a general synthesis of heterocyclic scaffolds as 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine2 or quinoline.3 When the nucleophile is a 1,3 diketone, the alcohol can be used for the sometimes difficult task of mono-alkylation in position 2. Using more functionalyzed alcohols, the intermediate can evolve to other multifunctional heterocyclic compounds. 1) Taddei, M.; Cini, E.; Rasparini, M. PCT Int. Appl. 2015, WO 2015056164 A1 2) Jumde, V. K.; Cini, E.; Porcheddu, A.; Taddei, M. Eur. J. Org. Chem. 2015, 1068-1074. 3) Mura M.G.; Rajamaki, S.; De Luca, L.; Cini, E.; Porcheddu, A. Adv. Synth. Catal. 2015, 357, 576582. 67 OC18 Simple systems based on bichromophoric calix[4]arenes for the study of energy transfer I. Tosi,1 L. Baldini,1 F. Sansone,1 Cristina Sissa,1 F. Terenziani,1 M. Di Donato2 1 Dipartimento di Chimica, Università degli Studi di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy. 2 LENS, European Laboratory for Non-linear Spectroscopy, Via N. Carrara 1, I-50019 Sesto Fiorentino, Firenze, Italy. e-mail: [email protected] Natural photosynthetic units are complex and well-organized structures, constituted by densely packed assemblies of chromophores, mainly chlorophylls and carotenoids, embedded in a protein matrix. In natural photosynthetic systems, sunlight is harvested by the antenna complexes and the excitation energy is funnelled to the reaction centre with extremely high efficiency. The synthesis of simplified light-harvesting complexes able to mimic the natural systems could allow the study of the factors that determine the efficiency of the natural systems in energy transfer and could result in the production of various optoelectronic devices and the development of solar concentrators. In this communication we present the synthesis of a simple and versatile bichromophoric system designed as a model for the study of the influence of different factors, such as the interchromophoric distance or the mutual orientation of the two dyes, on the excitation energy transfer (EET) process. The bichromophoric compounds (Scheme 1) were obtained by the introduction of two different dyes on a calix[4]arene macrocycle in cone (1 and 2) or partial cone structure (3a,b and 4a,b). The calix[4]arene was selected as scaffold because it easily allows the modification of the nature, the mutual orientation and the relative distances between the donor and acceptor chromophores also as a function of the medium. The dyes (i.e. the couples NBD - Nile Red and Coumarin 343 – NBD) were chosen according to their spectral properties, to ensure an extended overlap between the fluorescence spectrum of the donor and the absorption spectrum of the acceptor. Scheme 1 68 OC19 KuQuinones as dyes in photoelectrochemical devices Federica Sabuzi, Emanuela Gatto, Valeria Conte, Barbara Floris, Mariano Venanzi, Pierluca Galloni Università di Roma Tor Vergata, Via della Ricerca Scientifica, 00133, Roma, Italia e-mail: [email protected] KuQuinones belong to a new class of pentacyclic quinoid compounds, synthesized for the first time few years ago in our research group1. KuQuinones are characterized by a broad absorption spectrum in the visible region, due to the extended electronic conjugation over the five rings1; in particular, UV-vis spectrum shows two intense and broad absorption bands between 450 and 600 nm. This class of molecules is also characterized by a low reduction potential compared to simpler quinoid compounds: the first reduction process appears at −0.3 V vs. Ag/AgCl and it can be reasonably assigned to the formation of a radical monoanionic species, while the second, reversible, process (at -1,2 V) is a broad peak, probably due to two sequential reduction processes characterized by similar reduction potential values. This evidence suggested that the pentacyclic diquinoid compound might be an efficient electron acceptor molecule. In this regard, we are testing KuQuinone as dye in photoelectrochemical devices, in which photoinduced electron transfer processes occur. Preliminary studies on the efficiencies of the cells made by using KuQuinones as sensitive material have been carried out. Photocurrent generation mechanism will be proposed. Scheme 1: Left: KuQuinones general structure. Right: Absorption spectrum of 1EthylKuQuinone in CH2Cl2. Cyclic voltammetry of 1-EthylKuQuinone in CH2Cl2 0.1 M TBAP vs. Ag/AgCl. (Inset: Cyclic voltammetry of the first reduction process occurring at −0.26 V.) 1) Coletti, A.; Lentini, S.; Conte, V.; Floris, B.; Bortolini, O.; Sforza, F.; Grepioni, F.; Galloni, P. J. Org. Chem., 2012, 77, 6873-6879. 69 OC20 Electronic communication in tetraferrocenylporphrins* Pierluca Galloni, Andrea Vecchi, Barbara Floris, Valeria Conte Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, via ricerca scientifica snc, Roma e-mail: [email protected] *In Memory of Alessandro Bagno Metallocenyl porphyrins are of great interest for their electrochemical and photophysical properties and for possible application in different fields such as energy conversion, memory devices and electrochemical capacitors.1,2 In our group we studied the tetraferrocenylporphyrins showing interesting features in terms of electrochemical processes and photoelectrochemical catalysis.3 Figure 1 The easy accessibility to the monocationic porphyrin (TFcP+) is of particular interest because of the long-range electronic communication among ferrocenyl units, which gives rise to an intense inter-valence charge transfer (IVCT) band in the NIR region of the spectrum. This peculiar absorption can be used in the construction of redox-driven optical sensors and switches in the NIR. Mono-oxidized TFcPs free-base was prepared in good yields and characterized. Experimental data as well as theoretical calculations support the idea that the oxidation process involves a hydrogen atom abstraction, and the effects are very different between metallated and free base derivatives. 1) Vecchi, A.; Galloni, P.; Floris, B.; Dukin, S. V.; Nemykin, V. N. Coord. Chem. Rev. 2015, 291, 95171. 2) Bucher, C.; Devillers, C. H.; Moutet, J.-C.; Royal, G.; Saint-Aman, E. Coord. Chem. Rev. 2009, 253, 21-36. 3) Vecchi, A.; Gatto, E.; Floris, B.; Conte, V.; Venanzi, M.; Nemykin, V. N.; Galloni, P. Chem. Commun. 2012, 48, 5145-5147. 70 OC21 Synthesis and photochemical properties of new melanin-inspired electroluminescent materials for OLED applications Valeria Criscuolo1, Paola Manini1, Alessandro Pezzella1, Pasqualino Maddalena2, Salvatore Aprano3, Maria Grazia Maglione4, Paolo Tassini4, Carla Minarini4, Marco d’Ischia1 1 Dept. Chemical Sciences, Univ. Naples Federico II, Complesso Universitario Monte S. Angelo, via Cinthia 4, I-80126 Naples. 2 Dept. Physics, Univ. Naples Federico II, Complesso Universitario Monte S. Angelo, via Cinthia 4, I-80126 Naples. 3 4 SESMAT S.r.l., S.S.7 Appia 36, 82018, San Giorgio del Sannio (BN), Italy Lab. Nanomaterials and Devices, ENEA C. R. Portici, p.le E. Fermi 1, I-80055, Portici (NA). e-mail: [email protected] In recent years increasing interest has been devoted to the synthesis of electroluminescent organic materials for the development of efficient organic lightemitting diodes (OLEDs) or light-emitting electrochemical cells (LEECs) for displays and lighting applications.1 In the frame of a research line aimed at studying the potentiality of melanins in organic electronics,2,3 we report herein for the first time the synthesis of two different type of electroluminescent materials inspired to the melanin precursors 5,6-dihydroxyindole (DHI) and dopamine (DA). In particular, DHI has been used to prepare fluorescent asymmetric triazatruxenes (I) and DA has been involved in the synthesis of phosphorescent cyclometalated iridium(III) complexes (II) containing a novel set of 6,7-dihydroxy-3,4-dihydroisoquinoline ancillary ligands (DHQ) deriving from the catecholic neurotransmitter.4 Reported is also a survey of the optoelectronic properties of I and II, both in solution and as thin films, and the fabrication and characterization of the corresponding OLED/LEEC devices. References 1) De Cola, L. et al. Inorg. Chem. 2013, 52, 1812−1824 2) Manini, P. et al. ChemPlusChem 2015, 80, 898 3) Pezzella A. et al. Materials Horizons 2015, 2, 212-220 4) Manini, P. et al. Chem. Res. Toxicol. 2004, 17, 1190-1198 71 OC22 Characterization of Conducting Polymers for Organic Solar Cells F. Parenti1, F. Tassinari1, C. Fontanesi1, L. Schenetti2, P. Morvillo3, R. Ricciardi3, R. Diana3, C. Minarini,3 M. Lanzi4, A. Mucci1 1 2 Università di Modena e Reggio Emilia, Dipartimento di Scienze Chimiche e Geologiche, Via Campi 103, 41125 Modena (MO), Italy Università di Modena e Reggio Emilia, Dipartimento di Scienze della Vita, Via Campi 103, 41125 Modena (MO), Italy 3 4 ENEA, UTTP-NANO, Piazzale E. Fermi 1, 80055 C.R. Portici (NA), Italy Università di Bologna, Dipartimento di Chimica Industriale e dei Materiali, V.le del Risorgimento 4, 40136 Bologna, Italy e-mail: [email protected] Thiophene based copolymers are widely studied as the donor active layer in bulk hetero junction polymer solar cells (PSCs). These copolymers, in some cases formed by an alternating structure of donor/acceptor units, can be fine tuned in their electronic energy levels in order to achieve better power conversion efficiencies values.1 The characterization of organic polymers for application in PSCs, or organic electronics in general, is multidisciplinary in nature, for it requires expertise within different branches of chemistry and at the border among chemistry, physics and engineering.2 As organic chemists, we have to check the structure and properties of these polymers and this is not always trivial. This contribution will be mainly focussed on the NMR characterization of polymers in solution and to the problems arising when aggregation occurs. This is particularly observed when benzodithiophene and thienothiophene (that are among the most popular units) are present in the backbone. NMR findings appear to be strongly correlated to solvatochromism or morphological properties. Scheme 1 1) Beaujuge, P.M.; Amb, C.M.; Reynolds, J.R. Acc. Chem. Res., 2010, 43, 1396-1407. 2) Iarossi, D; Mucci, A.; Schenetti, L. ; Seeber, R.; Goldoni, F.; Affronte, M.; Nava, F. Macromolecules 1999, 32, 1390-1397; Morvillo, P.; Diana, R.; Fontanesi, C.; Ricciardi, R.; Lanzi, M.; Mucci, A.; Tassinari, F.; Schenetti, L.; Minarini, C.; Parenti, F. Polym. Chem., 2014, 5, 2391–2400. 72 OC23 Ternary Direct (Hetero)Arylation vs Stille cross-coupling in the synthesis of a ternary copolymer for BHJ solar cells G. Marzano1, D. Kotowski2, F. Babudri1, R. Musio1, A. Pellegrino3, S. Luzzati2, R. Po3, G.M. Farinola1* 1 Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, Bari, Italy. 2 Istituto per lo Studio delle Macromolecole, CNR-ISMAC, Milan, Italy. 3 Istituto Eni Donegani, Eni S.p.A.,Novara, Italy e-mail: [email protected] In the last few years, Direct (Hetero)Arylation polymerization (DHAP) has attracted growing interest in the community of the polymer chemists involved in the field of Organic Photovoltaics (OPVs). DHAP approach does not require the use of organometallic reagents (especially tin compounds) which strongly limits the possibility of industrial scale-up of the synthetic processes for the active materials.1 However, the formation of structural defects in the polymer backbone can occur, especially in the case of C-H bonds with similar heterolytic dissociation energy. We describe herein a comparative study (Stille vs DHAP) on the synthesis of a ternary random conjugated copolymer for application in BHJ solar cells (scheme 1). Threecomponent random copolymerization via direct arylation undoubtedly represents a promising approach for accessing to D-A polymeric structures starting from synthetically simple monomers. Our polymerization experiments are discussed in the light of Stille outcomes for the same polymer, not only from a methodological perspective but also in terms of performances in bulk heterojunction solar cell devices. The polymers synthesized via DHAP protocol have shown power conversion efficiencies around 3%. Moreover, a regiochemical study has been performed by isolation and full NMR characterization of the main coupling products formed during the early stage of the polycondensation process. Scheme 1 1) Marzano, G.; Ciasca, C.V.; Babudri, F.; Bianchi, G.; Pellegrino, A.; Po, R.; Farinola, G.M. Eur. J. Org. Chem 2014, 30, 6583-6614. 73 OC24 Synthesis of Low Band-Gap Conjugated Polymers for application in solar cells Emanuela Libertini1, Pasquale Morvillo3, Adele Mucci1, Francesco Tassinari1, Luisa Schenetti2, Francesca Parenti 1 1 Università di Modena e Reggio Emilia, Departimento di Scienze Chimiche e Geologiche, Via Campi 103, 41125 Modena (MO), Italy 2 Università di Modena e Reggio Emilia, Departimento di Scienze della Vita, Via Campi 103, 41125 Modena (MO), Italy 3 ENEA, UTTP-NANO, Piazzale E. Fermi 1, 80055 C.R. Portici (NA), Italy e-mail: [email protected] Polymer solar cells are a fascinating low cost alternative to silicon-based solar cells1 thanks to light weight, mechanical flexibility and processability. The polymers suitable for this purpose should possess good filming and absorption properties (absorption coefficients >105 cm-1 and UV–Vis spectrum ideally matching the solar spectrum)2, high hole mobility, and HOMO–LUMO energy levels suitable to be coupled with the acceptor species3. In this presentation the synthesis of three different low band gap copolymers (Scheme 1) is reported and discussed. The properties of these materials are compared in order to gain an insight on the molecular structure-performance relationship of the final device. Scheme 1 1) 2) 3) Günes, S.; Neugebauer H.; Sariciftci, N.S. Chemical Reviews 2007, 107, 1324–1338; Chidichino, G. and Filippelli, L. International Journal of Photoenergy, 2010, Vol 2010, Article ID 123534, 11 pages doi:10.1155/2010/123534 ; Li, G.; Zhu, R. and Yang Y. Nature Photonics, 2012, 6, 153-161; Xu, T.; Yu, L. Materials today, 17 (1), 11-15, 2014 Kroon, R.; Lenes, M. ; Hummelen, J.C. ; Blom, P.W.M. ; de Boer, B. Polymer Reviews, 2008, 48, 531–582. Gadisa, A.; Svensson, M. ; Andersson, M.R. ; Inganäs, O. Applied Physic Letters 2004, 84, 1609–1611; Morvillo, P. ; Bobeico, E. Solar Energy Materials and Solar Cells, 2008, 92,1192– 1198. 74 OC25 Self-organization of binary mixtures of fluorinated and hydrogenated alkyltiolates on the surface of gold nanoparticles Maria Vintila, Mariangela Boccalon, Paolo Pengo, Lucia Pasquato Department of Chemical and Pharmaceutical Sciences and INSTM Trieste Unit, University of Trieste, via L. Giorgieri 1, 34127 Trieste, Italy. e-mail: [email protected] The spontaneous organization of binary mixtures of dislike ligands on the surface of metal nanoparticles has been demonstrated to determine NPs properties such as their solubility, assembling and interactions with biological membranes.1 Such an organization can be exploited to enhance the performance of the nanoparticles, as for example, their catalytic efficiency, using ligands properly functionalized.2 In general, the organization of mixed-monolayers in domains of specific morphology triggered by the composition and the nature of the ligands opens to a variety of possible new materials which cannot be obtained by using classical approaches. Theoretical and experimental studies have disclosed the parameters determining the morphology of 3-D mixed self-assembled monolayers.3 However, several key issues still need to be clarified and more examples are needed in order to demonstrate what degree of control over the organization can be achieved and what is the role of specific parameters such as the Flory-Huggins parameter of the ligands in determining the shape and the size of the domains. Recent studies carried out on gold nanoparticles protected by mixtures of fluorinated- and hydrogenated amphiphilic thiolates have demonstrated that phase segregation is observed even when using less than 5% of fluorinated ligands.4 We aim to exploit the fluorophobicity of fluorinated thiolates to tune the morphology of 3-D mixed monolayers and to report, in this communication, our recent fundamental studies on simple model systems. To this end we have prepared series of gold NPs protected by mixtures of fluorinated and hydrogenated alkyl thiolates of different length and bulkiness, Scheme 1, and for each system we explored a variety of monolayer compositions. The NPs have been characterized with several techniques and among them of particular interest is the 19F NMR spectroscopy which gives clear information on the ligand shell organization. Scheme 1 1) Jackson, A. M.; Myerson, J. W.; Stellacci, F. Nature Mater. 2004, 3, 330-336. De Vries, G. A.; Brunnbauer, M.; Hu, Y.; Jackson, A. M.; Long, B.; Neltner, B. T.; Uzun, O.; Wunsh, B. H.; Stellacci, F. Science 2007, 315, 358-361. 2) Gosh, A.; Basak, S.; Wunsch, B. H.; Kumar, R.; Stellacci, F. Angew. Chem. Int. Ed. 2011, 50, 79007905. 3) Sing, C.; Ghorai, P. K.; Horsch, M. A.; Jackson, A. M.; Larson, R. G.; Stellacci, F.; Glotzer, S. C. Phys. Rev. Lett. 2007, 99, 226106. 4) Pengo, P.; Baltzer, L.; Pasquato, L.; Scrimin, P. Angew. Chem. Int. Ed. 2007, 45, 400-404. Posocco, P.; Gentilini, C.; Bidogia, S.; Pace, A.; Franchi, P.; Lucarini, M.; Fermeglia, M.; Pricl, S.; Pasquato, L. ACS Nano 2012, 6, 7243-7253. 75 OC26 Controlled Photo-Released Drug from Nanoparticles for PDT Applications Elisa Lubian,1 Fabrizio Mancin,1 Paolo Scrimin 1 1 Department of Chemical Science, University of Padova, Via Marzolo 1, 35131, Padova. e-mail: [email protected] Nanoparticle-based systems have been developed for nanomedicine applications, in order to improve the efficacy of a wide range of drugs, reducing the toxicity for the normal tissues and the long-term side-effects. As a matter of fact, “classic” approaches to nanomedicine based on simple or even targeted drug-loaded particles, are showing strong limitations and very few nanomedicine agents are currently used in healthcare. Likely, dealing with such a complex environment as a living organism requires complex tools, capable to adapt their behavior to the different situations they encounter. Chemists can substantially contribute to the development of such responsive systems, not only by producing new chemical entities or materials, but also by implementing in the nanosystems smart behaviors, based on externally triggered chemical reactions. Based on that, promising results will be accomplished in photodynamic therapy (PDT), a medical cancer treatment based on non-toxic photosensitizing drugs that become active producing cytotoxic reactive oxygen species (ROS, in particular singlet oxygen) by exposure to light. The major limitation of PDT is the lack of selectivity that cause the unfavorable accumulation of photosensitizer (PS) into healthy tissues, causing severe side effects. The introduction of the nanotechnology concept in the design of carriers for PDT may help in increasing the selectivity. Most important, the production of singlet oxygen combined with a photocleavable group offers a phototriggered mechanism that can be exploit in the design of photocontrolled behavior nanoparticles. Based on that, ORMOSIL (ORganically MOdified SILica)1 nanoparticles will be proposed as vehicle for molecules, such as PS, and an appropriate -enamino keton derivative that is shown to be cleaved after singlet oxygen exposure (Scheme 1).2 Preliminary data shown that after irradiation, a certain amount of PS is cleaved, and tends to increase by increasing the exposure time. In this way, the release of PS may be controlled by an external input, and the same concept should apply for releasing therapeutic molecules. The data reported in this work paved the way for the creation of smart nanoparticles for theranostic applications. Scheme 1 1) F. Selvestrel, D. Segat, E. Reddi, E. Papini, A.J. MacRobert, F. Mancin, Nanoscale. 2013, 5, 6106. 2) M. Bio, G. Nkepang, Y. You, Chem. Commun. 2012, 48, 6517. Acknowledgements: this work was funded by FIRB 2011 project “RINAME” 76 OC27 A QSPR approach to Ionic Liquids Aquatic Toxicity by VolSurf descriptors A. Paterno’1, G. Bocci2, G. Cruciani2, G. Musumarra1 and S. Scirè1 1 Dipartimento di Scienze Chimiche, Università di Catania, Viale A. Doria 6, I-95125 Catania, Italy 2 Laboratorio di Chemiometria e Chemioinformatica, Dipartimento di Chimica, Università di Perugia, Via Elce di Sotto 10, I-06123 Perugia, Italy e-mail: [email protected] VolSurf+ in silico physicochemical descriptors for both the cationic and the anionic counterparts of ionic liquids (ILs) are derived. These descriptors, suitable for molecular modelling of ILs structures which due to their amphiphilic nature interact strongly with biological matrices, can be related to aquatic toxicity by means of a partial least squares (PLS) statistical model. This model provides a better knowledge on the relationships between structural physicochemical properties and aquatic toxicity scores as well as a very satisfactory quantitative structure-property model allowing their prediction. 77 OC28 Unconventional Inherently Chiral Ionic Liquids Simona Rizzo,1 Francesco Sannicolò,2 Voichita Mihali,2 Marco Pierini,3 Roberto Cirilli,4 Patrizia Mussini,2 Serena Arnaboldi,2 Armando Gennaro,5 Abdirisak A. Isse5 1 Ist. di Scienze e Tecnologie Molecolari, CNR, via Golgi 19, Milano I-20133. Univ. degli Studi di Milano, Dip. di Chimica, via Golgi 19, Milano I-20133. 3 Univ. degli Studi di Roma La Sapienza, Dip. di Chimica e Tecnologie del Farmaco, Piazzale A. Moro 5, Roma I-00185. 4 Ist. Superiore di Sanità, Dip. del Farmaco, Viale Regina Elena 299, Roma I-00161. 5 Univ. degli Studi di Padova, Dip. Scienze Chimiche, Via Marzolo, 1, Padova I-35131 2 e-mail: [email protected] Ionic liquids have been recently recognized as highly versatile solvents and reagents thanks to their largely tunable features for various chemical tasks and their eco-friendly properties. Chiral ionic liquids (CILs), in particular, have attracted special attention since they can be successfully employed as mediators in asymmetric synthesis, as chiral phases for gas chromatography and as chiral shift reagents in NMR spectroscopy. The current design of CILs involves attachment of chiral substituents, generally provided by chiral pool and characterized by one or more stereocenters either on cationic or anionic moiety. In this work we illustrate a class of inherently chiral ILs where chirality is due to the presence of a stereogenic axis coincident with the fuctional units responsible for the IL properties of the material. This concept of inherent chirality has been recently applied for preparing electroactive materials with unprecedented enantiorecognition ability1 and some atropisomeric 1,1’-bibenzimidazoles exhibiting peculiar chromatographic2 and electrochemical3 properties. The CILs we are presenting here are based on bipiridinium and 2,2’-benzimidazolium scaffolds. Synthesis, evaluation of configurational stability, resolution of the racemates, DFT calculations and enantiorecognition experiments are discussed 1) Sannicolò, F.; Arnaboldi, S.; Benincori, T.; Bonometti, V.; Cirilli, R.; Dunsch, L.; Kutner, W.; Longhi, G.; Mussini, P. R.; Panigati, M.; Pierini, M.; Rizzo, S. Angew. Chem. Int. Ed. 2014, 53, 2623-2627. 2) Rizzo, S.; Menta, S.; Faggi, C.; Pierini, M.; Cirilli, R. Journal of Chromatography A, 2014, 1363, 128136. 3) Arnaboldi, S.; Cirilli, R.; Forni, A.; Gennaro, A.; Isse, A.; Mihali, V.; Mussini, P. R.; Pierini, M.; Rizzo, S.; Sannicolò, F. Electrochimica Acta, In Press, Available online 27 March 2015. Work supported by Fondazione Cariplo (reg. No 2011-1851) and C.N.R. (PM.P03.002.002). 78 OC29 Liposomes and gold nanoparticles decorated with glycocalixarenes for targeted drug delivery M. Giuliani1, S. Aleandri2, G. Bozzuto3,4, M. Condello3, G. Mancini2,4, A. Molinari3, S. Avvakumova5, L. Pandolfi5, M. Colombo5, D. Prosperi5, F. Sansone1, A. Casnati1 1 Dip.to di Chimica, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma. 2 Dip.to di Chimica, Università “La Sapienza”, P. le A. Moro 5, 00185 Roma. 3 Dip.to Tecnologie e Salute, Ist. Superiore Sanità, V.le Regina Elena 299, 00161 Roma. 4 CNR, Istituto di Metodologie Chimiche, P. le A. Moro 5, 00185 Roma. 5 Dip. Biotec. e Bioscienze, Università Milano-Bicocca, P.za Scienza 2, 20126 Milano e-mail: [email protected] The protein-carbohydrate recognition phenomena can conveniently be exploited for the targeted drug delivery, taking advantage from the numerous specific carbohydrate receptors present on the cell membrane.1 The recognition process between these receptors and their saccharide substrates are frequently characterized by the occurrence of a multivalency effect, or glycoside cluster effect, that determines highly efficient and specific interactions.1 For this reason, synthetic polyglycosylated systems are attracting great interest in nanomedicine as potential multivalent tools able to promote the targeting of specific cells and tissues. Calixarenes demonstrated in these years to be versatile scaffolds to build polyglycosylated derivatives,2 the glycocalixarenes, that are efficient and selective ligands for carbohydrate recognition protein (lectins) of medical relevance. Recently we planned to combine properly designed glycocalixarenes with liposomes3 and gold nanoparticles,4 two systems studied, proposed and used for drug delivery, to obtain new materials and systems with added advanced and innovative properties. Hybrid liposomes and gold nanoparticles decorated with -glucosylated and -mannosylated calixarenes (see figure), respectively, resulted to be able to interact with specific proteins and promote targeted delivery and cell uptake. 1) Gabius H.-J., Wiley-VCH, Weinheim, The Sugar Code. Fundamentals of glycosciences, ed. 2009. 2) Sansone, F.; Casnati, A. Chem. Soc. Rev. 2013, 42, 4623-4639. 3) Aleandri, S; Casnati, A.; Fantuzzi, L.; Rispoli, G.; Mancini, G.; Sansone, F. Org. Biomol. Chem. 2013, 11, 4811-4817. 4) Avvakumova, S.; Fezzardi, P.; Pandolfi, L.; Colombo, M.; Sansone, F.; Casnati, A.; Prosperi, D. Chem. Commun. 2014, 50, 11029-11032. 79 OC30 Glycopeptide-functionalized gold nanoparticles for antibody induction against the tumor associated Mucin-1 glycoprotein Roberto Fiammengo1, Hui Cai2, Federica Degliangeli1, Björn Palitzsch3, Bastian Gerlitzki4, Edgar Schmitt4, and Ulrika Westerlind2 1 Center for Biomolecular Nanotechnologies@UniLe – Istituto Italiano di Tecnologia (IIT), Via Barsanti, 73010 Arnesano (LE) Italy. 2ISAS - Leibniz Institute for Analytical Sciences, Otto-Hahn-Str. 6b, 44227 Dortmund, Germany. 3Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, 55128 Mainz, Germany. 4Institute of Immunology, University of Mainz, Langenbeckstr. 1, Geb. 708, 55101 Mainz, Germany. e-mail: [email protected] Mucin-1 (MUC1) has been identified as a top-priority cancer antigen for the development of therapeutic anticancer vaccines.1 To enhance the immunogenicity of synthetic MUC1-derived glycopeptides, aiming at effective vaccine candidates, these glycopeptides have been coupled to a carrier protein,2 to polymers3 or to selfassembling constructs4 resulting in multivalent antigen presentation. We have developed PEGylated gold nanoparticles (AuNPs) which can be easily functionalized with a controllable number of peptides5 and expect these to be ideally suited for the development of anticancer vaccines in view of their biocompatibility, simplicity of assembly and colloidal stability. In this contribution we describe the preparation and characterization of glycopeptide-functionalized AuNPs and we show that they induce specific antibodies directed against the tumor-associated form of MUC1. In particular, we immobilized chimeric peptides, consisting of a glycopeptide sequence derived from MUC1 and the T-cell epitope P30 sequence, on PEGylated AuNPs (Figure 1). Analysis of the antisera of immunized mice indicates a significant MHC-II mediated immune response. Furthermore, these antisera recognize their target antigen on human MCF-7 breast cancer cells. These results suggest that PEGylated AuNPs functionalized with MUC1-derived glycopeptides are very promising conjugates for the development of anticancer vaccines. Figure 1. Schematic structure of the immunized three-component AuNP-P30-MUC1 vaccine candidate. 1) Cheever, M. A.; Allison, J. P.; Ferris, A. S.; Finn, O. J.; Hastings, B. M.; Hecht, T. T.; Mellman, I.; Prindiville, S. A.; Viner, J. L.; Weiner, L. M.; Matrisian, L. M. Clin. Cancer. Res. 2009, 15, 5323. 2) Gaidzik, N.; Kaiser, A.; Kowalczyk, D.; Westerlind, U.; Gerlitzki, B.; Sinn, H. P.; Schmitt, E.; Kunz, H. Angew. Chem. Int. Ed. 2011, 50, 9977. 3) Nuhn, L.; Hartmann, S.; Palitzsch, B.; Gerlitzki, B.; Schmitt, E.; Zentel, R.; Kunz, H. Angew. Chem. Int. Ed. 2013, 52, 10652. 4) Huang, Z.-H.; Shi, L.; Ma, J.-W.; Sun, Z.-Y.; Cai, H.; Chen, Y.-X.; Zhao, Y.-F.; Li, Y.-M. J. Am. Chem. Soc. 2012, 134, 8730. 5) Maus, L.; Dick, O.; Bading, H.; Spatz, J. P.; Fiammengo, R. ACS Nano 2010, 4, 6617. 80 OC31 Chiral Nanozymes: Gold-Nanoparticle-based Transphosphorylation Catalysts Capable of Enantiodifferentiation Jack L. Y. Chen1, Paolo Scrimin, Leonard J. Prins1* 1 Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35121 Padova, Italy. e-mail: [email protected] Gold nanoparticles (Au NPs) with a monolayer of thiols terminating in Zn2+-bound triazacyclononane units have been found to cleave the phosphate bond of phosphodiesters in a model of a RNAse.1 The catalytic activity of these monolayer coated gold nanoparticles exhibit enzyme-like saturation kinetics that can be described by the Michaelis-Menten equation and has thus been coined ‘nanozymes.’ The classic model substrate that has been used to investigate this catalytic RNAase activity is 2hydroxypropyl p-nitrophenol phosphate (HPNPP; see Figure 1). Figure 1 Despite the large body of work on synthetic catalysts with RNAase activity, the activity of enantiomerically pure catalysts with enantiomerically pure substrates has never been investigated. Herein, we report the synthesis of two batches of gold nanoparticles, each covered with a monolayer of enantiomerically pure but opposite thiols containing the triazacyclononane headgroup [i.e. two batches of Au NPs, one with (+)-Headgroups, and the other with (-)-Headgroups]. We have found that the Au NPs possessing enantiomeric headgroups have different Michaelis-Menten profiles with enantiomerically pure (+)-HPNPP analogues (as an examples, see Figure 2). Excitingly, the difference between the two enantiomeric catalysts is not in KM but rather, in kcat, which indicates that the enantiomeric NPs form different energy transition states with the (+)Figure 2 HPNPP substrate. 1) Menea, F.; Houillon, F. B.; Pasquato, L.; Scrimin, P. Angew. Chem. Int. Ed. 2004, 43, 61656169. 81 OC32 Biomolecular recognition by fullerenol Serena Zanzoni1, Alberto Ceccon1, Michael Assfalg1, Mariapina D’Onofrio1 1 Dipartimento di Biotecnologie, Università di Verona, 37134 Verona, Italy e-mail: [email protected] The use of nanoparticles (NPs) offers outstanding potential for future biomedical applications. Thus, understanding the interaction of nanomaterials with biological systems becomes key for their safe and efficient application.1 NPs associating with biomacromolecules may interfere with protein–protein interactions and affect cellular communication pathways, however the impact of NPs on biomolecular recognition remains poorly characterized. In this respect, particularly relevant is the study of NPinduced functional perturbations of proteins implicated in the regulation of key biochemical pathways. In this study2 we focussed our attention on the interaction of polyhydroxylated [60]fullerene with monomeric ubiquitin (Ub) and a minimal polyubiquitin chain. Fullerenols are among the most important and promising fullerene derivatives with tunable properties by varying the number of hydroxyl groups introduced; their water solubility is an extremely important property for life science applications. Ubiquitin (Ub) is a prototypical protein post-translational modifier playing a central role in numerous essential biological processes (i.e. DNA repair, protein degradation via proteasome, translation). The adsorption of fullerenol on protein samples has been investigated in vitro at atomic resolution using mainly NMR technique. The specific interaction epitopes were identified, coincident with functional recognition sites in a monomeric and lysine48-linked dimeric Ub. Fullerenol appeared to target the open state of the dynamic structure of a dimeric Ub according to a conformational selection mechanism. Importantly, the biomolecule–NP association prevented the enzyme-catalyzed synthesis of polyubiquitin chains. Our findings provide an experiment-based insight into protein/fullerenol recognition, with possible nanotoxic consequences on cell homeostasis. Moreover, the specific inhibition of critical Ub/proteasome interactions represents a novel potential opportunity of therapeutic intervention in Ub-dependent cellular pathways. 1) Mahmoudi, M.; Lynch, I.; Reza Ejtehadi, M.; Monopoli, M.P.; Baldelli Bombelli, F.; Laurent, S. Chem. Rev. 2011, 111, 5610–5637. 2) Zanzoni, S.; Ceccon, A.; Assfalg, M.; Singh, R.K.; Fushman, D.; D'Onofrio, M.; Nanoscale 2015, 28, 7197-7205. 82 OC33 Micro Flow Systems for Taming the Reactivity of Highly Unstable Intermediates Leonardo Degennaro, Flavio Fanelli, Sonia De Angelis, Daniela Maggiulli, Manuela Delfine and Renzo Luisi Department of Pharmacy – Drug Sciences, University of Bari “A. Moro” Via E. Orabona 4, I-70125. FLAME-Lab Flow Chemistry and Microreactor Technology Laboratory e-mail: [email protected] Flow microreactor technology is bringing a revolutionary change in organic chemistry.1 As a consequence of the remarkable advances in microfabrication, microtechnology is becoming routinely employed in the development of sustainable synthetic processes and chemical synthesis in flow microreactors is receiving significant attention from both academia and industry. Our recent efforts in this field prompted us to investigate organometallic mediated transformations in integrated microflow systems.2 We focused our attention on the development of sustainable synthetic pathways employing highly reactive organometallic intermediates difficult to handle using traditional “flask-chemistry”. 1) a) Wirth, T. Microreactors in organic synthesis and catalysis, Wiley-VCH Verlag, Weinheim 2008. b) Hessel, V., Renken, A., Schouten, J. C., Yoshida, J. Micro process engineering, Wiley-VCH Verlag, Weinheim 2009. c) Watts, P., Wiles, C. Micro reaction technology in organic synthesis; CRC Press: New York 2011. 2) a) Degennaro, L., Fanelli, F., Giovine, A., Luisi, R., Adv. Synth. and Cat. 2015, 357, 21-27. b) Giovine, A., Musio, B., Degennaro, L., Falcicchio, A., Nagaki, A., Yoshida, J.-I., Luisi, R., Chem. - A Eur. J. 2013, 19, 1872-1876. c) Carroccia, L., Musio, B., Degennaro, L., Romanazzi, G., Luisi, R., J. Flow Chem. 2013, 29-33. 83 OC34 Synthesis and applications of new peptide based hydrogelators Nicola Zanna, Lorenzo Milli, Claudia Tomasini Dipartimento di Chimica “G.Ciamician” – Università di Bologna e-mail: [email protected] Hydrogels are solid like materials composed mainly by water, as they are formed by a water phase immobilized by a scaffold that results in a gel. Their applications range from the preparation of new materials, drug delivery, biomineralization, growth of cultured cells, mimicking the extracellular matrix, etc.1 Low molecular weight gelators (LMWGs) are small molecules able to gelate water and/or organic solvents by the formation of reversible supramolecular architectures governed by interactions such as π–π stacking, non-covalent interactions, hydrophobic and hydrogen bond, that favor the formation of layers that in turn get organized into fibers able to trap liquids. Recently, the gelation behavior of Fmoc-protected dipeptides has been studied and reported.2 Now we want to show here the gelation properties of some Fmoc-protected peptidomimetics, containing the L-Phe-D-Oxd unit (or the isosteric L-Phe-D-pGlu unit), that is a privileged scaffold for the preparation of supramolecular materials.3 Figure 1. Photographs of hydrogels (from left to right): water, Fmoc-L-Tyr-D-Oxd-OH, Fmoc-LTrp-D-Oxd-OH, Fmoc-L-Tyr-D-pGlu-OH, Fmoc-L-Trp-D-pGlu-OH, Fmoc-Phe-Phe-OH. 1) R. J. Wade, E. J. Bassin, W. M. Gramlich and J. A. Burdick, Adv. Mater., 2015, 27, 1356-1362 2) V. Jayawarna, M. Ali, T. A. Jowitt, A. E. Miller, A. Saiani, J. E. Gough and R. V. Ulijn, Adv. Mater., 2006, 18, 611–614 3) C. Tomasini, G. Angelici and N. Castellucci, Eur. J. Org. Chem., 2011, 3648-3669; G. Angelici, G. Falini, H.-J. Hofmann, D. Huster, M. Monari and C. Tomasini, Angew. Chem. Int. Ed., 2008, 47, 8075–8078. 84 OC35 Biotin-PAMAM-GuanidinoNeomycin Conjugates: Synthesis and Cellular Uptake Aurora Sganappa,a A. Volonterio,a Y. Tor,b E.Wexelblattb a b Department of Chemistry, Materials, and Chemical Engineering “G. Natta”, Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy Department of Chemistry and Biochemistry, University of California, San Diego 9500 Gilman Dr., La Jolla, California 92093, United States e-mail: [email protected] High molecular weight biomolecules such as certain proteins and nucleic acids display therapeutic potential. However, their limited cellular uptake hampers their utility and has prompted the development of diverse delivery technologies devoted to facilitate their cellular internalization. In this contest, the group of Prof. Tor has recently demonstrated that monomeric guanidinoglycosides, a family of synthetic carriers made by replacing all ammonium groups on aminoglycoside antibiotics with guanidinium groups, facilitate the cellular uptake of covalently linked high molecular weight cargos at nanomolar concentrations by binding to the cell surface heparan sulfate proteoglycans.1 In the frame of a project dealing with the synthesis of novel non-viral vectors for the gene delivery, we have tethered PAMAM dendrimers with aminoglycosydes through a suitable linker resulting in multifunctional conjugates with high transfection efficiency, good antibacterial activity, and negligible citoxicity.2 The same strategy has been applied for the preparation of PAMAM-guanidinoneomycin conjugates bearing a biotin molecule.3 The synthesis and the cellular uptake features of these multivalent carriers will be reported in this communication. 1) 2) 3) Y. Tor et al., ACS Chem. Biol. 2013, 8, 1383−1388. A. Sganappa et al., “Synthesis of Multifunctional PAMAM-Aminoglycoside Conjugates with Enhanced Transfection Efficiency”. Bioconj. Chem. 2013, 24, 1928-1936. A. Sganappa et al., Manuscript in preparation. 85 OC36 Novel AmpRGD/Sunitinib Dual Conjugates as Potential Modulators of Tumor Angiogenesis Andrea Sartori1, Elisabetta Portioli1, Lucia Battistini1, Francesca Bianchini2, Claudio Curti1, Franca Zanardi1 1 Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 17A, 43124, Parma, Italy 2 Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi di Firenze, Viale G.B. Morgagni 50, 50134, Firenze, Italy e-mail: [email protected] In recent past years an increasing interest has been observed in the role that cell surface receptors as integrins play in tumor genesis and progression. Some integrin subfamilies (αVβ3, αVβ5 and α5β1) are involved, even by close cooperation with other cell receptors (e.g. vascular endothelial growth factor receptors, VEGFRs) in tumor angiogenesis, which has a crucial role in tumor development and dissemination.1 The overexpression of several integrins in tumor related endothelial cells (ECs) and in various types of solid tumors makes them eligible targets for anti-angiogenesis intervention as well as useful biomarkers for tumor diagnosis and therapy. Recent studies clearly demonstrated a complex in vivo regulation of tumor angiogenesis events; in particular, the αVβ3 integrin receptor is physically and functionally correlated with the VEGFR2 receptor within ECs,2 suggesting that a dual specific agents capable of inhibiting them would have a great anti-angiogenesis potential. Our research group has recently introduced a new class of cyclic semipeptide ligands, cAmpRGD, containing the Arg-Gly-Asp (RGD) sequence and 4-aminoproline scaffolds. These ligands demonstrated to efficiently and selectively bind to the αVβ3 integrin and their binding capability is preserved even in the presence of covalently conjugated “bulky loads” (cytotoxic and chelating agents).3 We report here the synthesis of dual conjugates of type I, wherein the ligand cAmpRGD is covalently associated to a sunitinib derived moiety, a multikinase inhibitor approved worldwide as chemotherapeutic drug for treatment of RCC and GIST. Aim of the project is to investigate the anti-angiogenesis activity of these dual conjugates vis-à-vis the single components and related combinations. Preliminary in vitro biological results on endothelial and melanoma cell lines will also be reported. 1) C. J. Avraamides, B. Garmy-Susini, J. A. Varner, Nature Rev. Cancer 2008, 8, 604-617. 2) P. R. Somanath, N. L. Malinin, T. V. Byzova, Angiogenesis 2009, 12, 177-185. 3) L. Battistini, P. Burreddu et al. Org. Biomol. Chem. 2009, 7, 4924-4935. 86 OC37 Development of new exo- and endonucleasic inhibitors of MRE11 as versatile tools for chemical biology Atsushi Shibata,1 Davide Moiani,2 Annalisa Gabrielli,3 John Tainer,2 Elena Petricci3 1 Advanced Scientific Research Leaders Development Unit, Gunma University 3-39-22, Showa-machi, Maebashi, Gunma, Japan. 2 The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. 3 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. e-mail: [email protected] DNA repair complexes play a key role in the regulation of cell fate decisions, including programmed cell death (apoptosis) and senescence. MRE11, within the MRE11RAD50-NBS1 (MRN) complex, acts in DNA double strand breaks (DDSBs) repair, detection and signaling. MRN can be considered as an ATM effector involved in hereditary breast and ovarian cancer syndrome, ataxia-telangiectasia, and Nijmegen breakage syndrome.1 Resection is also particularly active in cancer stem cells inducing resistance to normal chemo- and radiotherapy. Consequently, development of MRE11 inhibitors has a great potential biological and clinical value in cancer therapy. We recently employed structure-based design to project and synthesize a focused library of specific inhibitors of MRE11. The first selective inhibitors of MRE11 exo- and endonuclease activities have been developed helping on elucidating its role on DDSBs repair by crystallization of the inhibitors with the protein (Scheme 1).2 Starting from our hit structures more drug-like compounds have been prepared showing interesting selectivity between the nuclease actions. Scheme 1 1) Srivastava, M.; Raghavan, S.C. Cell Biol. 2015, 22, 1-13. 2) Shibata, A.; Moiani, D.; Arvai, A.S.; Perry, J.; Harding, S.M.; Genois, M.M.; Maity, R.; Romoli, F.; Ismail, A.; Ismalaj, E.; Petricci, E.; Neale, M.J.; Bristow, R.G.; Masson, J.Y.; Wyman, C.; Jeggo, P.A.; Tainer, J.A. Mol Cell. 2014, 53, 7-18. 87 OC38 Effective route to fused-Indoles and Pyrroles via a domino Michael addition/cyclization from vinyl selenones Martina Palomba, Francesca Marini, Claudio Santi, Luana Bagnoli Department of Pharmaceutical Sciences, University of Perugia [email protected] Fused indoles are widely present as important structural units in diverse naturally alkaloids, pharmaceutical and agrochemicals. Despite their remarkable biological importance, a number of innovative methods for its efficient assembly have appeared in the literature.1 In term of reaction efficiency, cascade reactions have been considered as powerful tools for the rapid assembly of complex architectures. In this field vinyl selenones can be identified as valuable and versatile intermediates.2 As part of ongoing study herein we report a new domino process for the construction of highly functionalized N-fused indoles and pyrroles via Michael Initiated Ring Closure Reaction using vinyl selenones as bis electrophile and 2-substituted indole derivates in the presence of KOH as base. Oxazino, pyrano and pyrazino indoles or pyrroles were isolated in good to excellent yields. Starting materials availability, functional group tolerance and mild reaction conditions are relevant aspects of this simple procedure. Scheme 1 1) (a) An, J.; Chang, N.-J.; Song, L.-D.; Jin, Y.-Q.; Ma, Y.; Chen, J.-R.; Xiao, W.-J. Chem. Commun. 2011, 47, 1869-1871. (b) Trost, B. M.; Osipov, M.; Dong, G. J. Am. Chem. Soc. 2010, 132, 1580015807. (c) Bandini, M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi, A. Angew. Chem. Int. Ed. 2008, 47, 3238-3241. (d) Bandini, M.; Bottoni, A.; Eichholzer, A.; Miscione, G. P.; Stenta, M. Chem. Eur. J. 2010, 16, 12462-12473. 2) (a) Bagnoli, L.; Scarponi, C.; Rossi, M. G.; Testaferri, L.; Tiecco, M. Chem. Eur. J. 2011, 17, 993999. (b) Bagnoli, L.; Casini, S.; Marini, F.; Santi, C.; Testaferri, L. Tetrahedron 2013, 69, 481-486. (c) Sternativo, S; Calandriello A.; Costantino, F.; Testaferri, L.; Tiecco, M; Marini F. Angew. Chem. Int. Ed. 2011, 50, 9382-9385. (d) Sternativo, S.; Battistelli, B.; Bagnoli, L.; Santi, C.; Testaferri, L.; Marini, F. Tetrahedron Lett. 2013, 54, 6755-6757. 88 OC39 Remote Control of Axial Chirality: Aminocatalytic Desymmetrization of N-Arylmaleimides Nicola Di Iorio,1 Florine Eudier,1 Paolo Righi,1 Andrea Mazzanti,1 Michele Mancinelli,1 Alessia Ciogli2 and Giorgio Bencivenni*,1 1 Dept. of Industrial Chemistry, School of Science, University of Bologna, Viale del Risorgimento 4, 40136 Bologna, 2 Dept. of Chemistry and Drug Technology, "Sapienza" University of Rome, Viale Aldo Moro 5, 00185 Roma, e-mail: [email protected] N-(2-tert-butylphenyl)maleimides are a class of compounds having a hindered rotation of the CAr-N single bond.1 This implies the existence of a plane of symmetry which can be desymmetrized through nucleophilic addition at one of the two carbon atoms of the double bond, with the consequent generation of a stereogenic axis in the resulting succinimide (Scheme 1). Scheme 1 Herein we report two different organocatalytic startegies for the complete atroposelective desymmetrization of N-(2-tert-butylphenyl)maleimides based on a vinylogous Michael addition of cyclohexenones2 and on a formal Diels-Alder reaction of α,β-unsaturated ketones3 (Scheme 2). Scheme 2 The key feature of our methodologies is the ability of a cinchona alkaloid primary amine catalyst to transfer the stereochemical information to both prochiral centers several bonds away and a more distant prochiral axis thus realizing two simultaneous stereochemical events: the generation of two contiguous stereocenters and the remote control of an axial chirality. 1) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C.; J. Am. Chem. Soc. 1994, 116, 3131 2) Di Iorio, N.; Righi, P.; Mazzanti, A.; Mancinelli, M.; Ciogli, A.; Bencivenni, G.; J. Am. Chem. Soc., 2014, 136, 10250. 3) Eudier, F.; Righi, P.; Mazzanti, A.; Ciogli, A.; Bencivenni, G.; Org. Lett. 2015, 17, 1728. 89 OC40 Competitive gold-promoted Meyer-Schuster and oxy-Cope rearrangements of 3-acyloxy-1,3-enynes Alessio Porta, Serena Bugoni, Valentina Merlini, 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 (see scheme 1), this methodology was successfully employed by our research group for the total synthesis of α-ionone and important prostanoids like Latanoprost, Bimatoprost ans PGF2α.2,3. Scheme 1 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 oxy-Cope-like rearrangement (Scheme 2): O O [{Au(IPr)}2(µ-OH)][BF4] 2 mol % dry DCM, 30', rt OH H H + 65% Scheme 2 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 sigmatropiclike 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 (15%) drammatically influenced the success of the reaction. A rational explanation of this dual mechanism has been proposed with a complete methodological work using different propargylic alcohols containing an 1,5-enyne moiety. 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. References: 1. Nolan, S. P. Acc. Chem. Res. 2011, 44, 91. 2. Merlini, V.; Gaillard, S.; Porta, A.; Zanoni, G.; Vidari, G.; Nolan, S. P. Tetrahedron Letters 2011, 52, 1124. 3. Ramòn, R.S.; Gaillard, S.; Slawin M. Z. A.; Porta, A.; D’Alfonso, A.; Zanoni, G.; Nolan, S.P. Organometallics 2010, 29, 3665. 90 OC41 Modulation of phospholipidosis induction: the case of imipramine, its metabolites and synthetic analogues Susan Lepri, Laura Goracci, Aurora Valeri Chemistry, Biology and Biotechnology Department, University of Perugia (via Elce di sotto, 8, 06123 Perugia, Italy) e-mail: [email protected] Drug-induced phospholipidosis (PLD) is a lipid storage disorder in lysosomes, characterized by the formation of multilamellar inclusion bodies. More than 50 marketed drugs with various therapeutic use are known to induce PLD. Cationic amphiphilic drugs (CADs) represent the main class of PLD inducers. CADs are composed of a hydrophobic moiety, mainly aromatic, and a hydrophilic one, which is usually an amino group mainly protonated at physiological pH. Whether or not PLD has to be considered a toxic effect is still under debate, although examples of adverse events related to CADs treatment have been already reported.1 Recently, a great effort has been made to predict PLD induction risk, and a pharmacophoric model for CADs inducing PLD has been developed and validated.2 In addition, as for other xenobiotics, CADs are metabolized in the body, and their metabolites can or cannot be associated to the PLD risk.3 In the present study, imipramine was selected as a representative compound for CADs. A number of imipramine metabolites and analogues were designed and synthesized (Scheme 1) to explore the PLD effect by cellular in vitro assays. The obtained results proved to be useful to perform a structure-PLD induction relationship, to evaluate the pharmacophore model and to get insights about the effect of metabolism on PLD induction by imipramine. Scheme 1 The authors acknowledge MIUR “FIRB-Futuro in Ricerca 2010” (Project RBFR10X500) 1. Anderson, N.; Borlak, J. Drug-induced phospholipidosis. FEBS Lett 2006, 580, 5533-40. 2. Goracci, L.; Buratta, S.; Urbanelli, L.; Ferrara, G.; Di Guida, R.; Emiliani, C.; Cross, S. Evaluating the risk of phospholipidosis using a new multidisciplinary pipeline approach. Eur. J. Med. Chem. 2015, 92, 49-63. 3. Goracci, L.; Ceccarelli, M.; Bonelli, D.; Cruciani, G. Modeling Phospholipidosis Induction: Reliability and Warnings. J. Chem. Inf. Mod. 2013, 53, 1436-1446. 91 OC42 Stereochemical and conformational studies by NMR and molecular modelling: an improved approach. Application to new tubulin inhibitors. Aldo Feriani1, Paolo Marchetti2, Elisa Moro1 1 2 Aptuit Verona s.r.l (Via Fleming, 4-Verona) Department of Chemical and Pharmaceutical Sciences (University of Ferrara) e-mail: [email protected] Hemiasterlins are bioactive tripeptides derived from marine sponges that bind to the Vinca-peptide site in tubulin, disrupting normal microtubule dynamics: for this reason they act as potent tumor cell growth inhibitors.1 Taltobulin is a synthetic analogue of hemiasterlins showing more potent in vivo cytotoxicity and able to circumvent P-gp-mediated resistance in vitro and in vivo.2 Recently, a versatile enantioselective approach to synthesize novel Hemiasterlins modified at N-terminus has been proposed. Based on this new approach, the new derivative (R)(S)(S)-1 was synthesized and characterized as a potent tubulin inhibitor.3 Computational studies based on NMR data were performed to analyze the conformational behavior of Taltobulin (HTI-286) and its synthetic analogue. NMR spectroscopy has been used to characterize Taltobulin, (R)(S)(S)-1 and its diastereoisomer (S)(S)(S) -1, applying the same experimental conditions as reported in the literature 4 Interprotonic distances have been measured to determine the absolute configuration as well as solution conformations; both 1D and 2D measurements have been used and combined with PANIC5 approach for data analysis to improve accuracy. Results obtained with different approaches will be presented as well as advantages of PANIC approach in a non-rigid molecule. Finally the distances were used as constraints in conformational searches, run within MOE software, with the aim of characterizing the conformational behavior of Taltobulin and its synthetic analogues and eventually to identify structure activity relationships (SAR) useful to drive drug design. 1. 2. 3. 4. 5. Zask, J. Kaplan, S. Musto, F. Loganzo J. Am. Chem. Soc. 2005, 127, 17667-17671.3). F. Loganzo, C.M. Discafani, T. Annable, C. Beyer, S. Musto, M. Hari, X. Tan, C. Hardy, R. Hernandez, M. Baxter, T. Singanallore, G. Khafizova, M.S. Poruchynsky, T.; Fojo, J.A. Nieman, S.; Ayral-Kaloustian, A. Zask, R.J. Andersen, L.M Greenberger Cancer Research 63, 2003, 1838–1845. R. Rondanin, C. Rullo, P. Marchetti, et al Bioorg. Med. & Chem. Lett. 20, 2010, 3431-3435. C. Niu, D.M. Ho, A. Zask, S. Ayral-Kaloustian Bioorg. Med. & Chem. Lett 20, 2010, 1535-1538. H. Hu, K. Krishnamurthy J. of Magnetic Resonance, 2006, 173-177. 92 OC43 Phytotoxins produced by fungi with potential application for the biocontrol of cheatgrass (Bromus tectorum) Marco Masi1, Susan E. Meyer2, Suzette Clement2, Alessio Cimmino1, and Antonio Evidente1 1 2 Department of Chemical Sciences, University of Naples Federico II, Naples, Italy. USDA Forest Service, Rocky Mountain Research Station, Shrub Sciences Laboratory, Provo UT 84606 e-mail: [email protected] Bromus tectorum (cheatgrass, downy brome) is an exotic winter annual grass weed that causes serious losses in intensive agriculture, particularly in winter cereal crops, and is also a major problem on rangelands in the western U.S. A frequent but poorly understood phenomenon in these heavily invaded areas is periodic ‘die-off’ or complete stand failure of this weed. Cheatgrass stand failure is caused by a complex interaction among multiple soilborne fungal pathogens. Thus, some of these fungi, have been studied to evaluate their phytotoxin production. Pyrenophora semeniperda, a naturally occurring necrotrophic seed pathogen, has been proposed as a potential biocontrol agent for this weed.1 This fungus produced large quantities of cytotoxic cytochalasin B when grown in wheat and cheatgrass seed culture, along with smaller quantities of the related compounds cytochalasins A, F, and deoxaphomin.2 Three new phytotoxic sesquiterpenoid penta-2, 4-dienoic acids, named pyrenophoric acid and pyrenophoric acids B and C (Figure 1), were also isolated together with the known abscisic acid and characterized by spectroscopic methods (NMR and HR ESIMS).3,4 The phytotoxicity of these compounds was evaluated in cheatgrass seedling bioassays. All these compounds induced growth suppression of both radicles and coleoptiles, but only abscisic acid had an effect on germination per se. The compounds produced in PDB culture belonged to the spirocyclic lactam group, and included the new compound spirostaphylotrichin W. These latter had little effect on cheatgrass seedlings but caused necrosis in leaf puncture bioassays.5 In this communication the isolation and the chemical and biological characterization of phytotoxins produced by other fungi involved in the die off phenomenon will be illustrated as well as the role of these toxins in the symptoms induced on cheatgrass. Figure 1 1) 2) 3) 4) Meyer, S.E.; Clement, S.; Beckstead, J. Us Patent Application Number Us20130035231, 2013. Masi, M.; Evidente, A.; Meyer, S.; Nicholson, J.; Munoz, A. Biocontrol Sci. Techn.2014, 24, 53-64. Masi, M.; Meyer, S.; Cimmino, A.; Andolfi, A.; Evidente, A. J. Nat. Prod. 2014, 77, 925−930. Masi M., Meyer S., Cimmino A., Clement S., Black B., Evidente A. J. Agr. Food Chem., 2014, 62, 10304−10311. Masi, M.; Meyer, S.; Clement, S.; Andolfi, A.; Cimmino, A.; Evidente, A. Tetrahedron 2014, 70, 1497−1501. 93 OC44 Flexible β-amyloid synthetic mimics built on a piperidine-pyrrolidine semi-rigid scaffold, obtained through a click cycloaddition reaction. Sara Pellegrino1, Nicolo Tonali2, Julia Kaffy2, Alessandro Contini1, Maria-Luisa Gelmi1, Sandrine Ongeri2, Emanuela Erba1 1 DISFARM Sezione di Chimica Generale e Organica "A. Marchesini", Università degli Studi, via Venezian 21, 20133 Milano Italy 2 Molécules Fluorées et Chimie Médicinale, Université Paris Sud, BioCIS UMR-CNRS 8076, Châtenay-Malabry, France e-mail: [email protected] The cycloaddition of sulfonyl azides with enamines, followed by the in situ rearrangement of the dihydrotriazole cycloadducts, is a powerful click reaction yielding 2-alkyl-sulfonylamidines and to sulfonylformamidines depending on the nature of the starting carbonyl reactant. In particular, when cyclic ketones are employed the main obtained products are azacycloalkene monosulfonyl diamines that are interesting syntons for heterocycle synthesis.1 Here we present the preparation of flexible β-amyloid synthetic mimics built on the piperidinepyrrolidine semi-rigid scaffold 1 obtained through the above click cycloaddition reaction. Starting from commercially available and inexpensive reagents, i. e. N-benzyl piperidone, tosyl azide and proline methyl ester, the dipeptide mimetic 1 was prepared in multigram scale and in enantiopure form.2 This compound was found really effective in stabilizing β-turn conformation in model peptides and it was used in the design of supramolecular inhibitors of amyloid aggregation. The obtained constructs, containing sequences from neurotoxic Aβ1-42 peptide, are able to greatly delay the kinetic of aggregation process and represent promising compounds for future investigation on Alzheimer’s disease. 1) A. Contini, E. Erba RSC Advances, 2012, 2, 10652–10660. 2) S. Pellegrino, A. Contini, M. L. Gelmi, L. Lo Presti, R. Soave, E. Erba J. Org. Chem., 2014, 79, 3094-3102. 94 OC45 MediaChrom: synthesis and spectroscopical evaluation of an original class of pyrimidoindolone based polarity-sensitive dyes Giorgio Abbiati,1 Monica Dell’Acqua,1 Luca Ronda,2 Riccardo Piano,2 Sara Pellegrino,1 Elisabetta Rossi,1 Francesca Clerici,1 Andrea Mozzarelli,3 and Maria Luisa Gelmi1 1 Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Generale e Organica “A. Marchesini”, Università degli Studi di Milano, Via Venezian, 21, 20133 Milano, Italy. 2 Dipartimento di Neuroscienze, Università degli Studi di Parma, Parco Area delle Scienze, 23/A, 43124 Parma, Italy. 3 Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze, 23/A, 43124 Parma, Italy e-mail: [email protected] The modern biological research asks for a continuous development of new fluorescent dyes characterized by improved performances and suitable to be used as markers or probes.1 A particular class of dyes, called polarity-sensitive dyes2 have the unique features to display a different emission maximum as a function of the polarity of their molecular environment (media). This peculiarity makes polarity-sensitive dyes the ideal probes to monitor the local properties of particular cell districts as well as different type of biomolecular interactions. Several polarity-sensitive dyes have been developed, but most of them are far to meet simultaneously all the optimal spectroscopic requirements for biological applications. Since many years, we have been interested in the development of new strategies for the synthesis and the functionalization of indoles and polycyclic indole-based heterocycles. In this context, we reported a domino approach to pyrimidoindolones3 that displayed interesting fluorescence properties. Starting from these findings, a small library of original polarity-sensitive fluorescent dyes, nicknamed MediaChrom, has been prepared. This class of dyes is characterized by a pyrimidoindolone core fitted out with a conjugated push-pull system, and a linker for an easy coupling with biomolecules. The carefully planned and optimized synthetic strategy involves a highly chemo- and regioselective gold catalyzed cycloisomerization step. The photophysical properties of MediaChrom dyes have been evaluated, and some potential biological applications have been spottily investigated. 1) Lakowicz, J. R. Principles of Fluorescence Spectroscopy, 3rd ed.; Springer: New York, 2006. 2) Reichardt C. Chem. Rev. 1994, 94, 2319-2358. 3) Klymchenko, A. S.; Mely, Y. Fluorescent Environment-Sensitive Dyes as Reporters of Biomolecular Interactions, In: Progress in Molecular Biology and Translational Science, Morris, M.C. Editor(s), Academic Press, 2013, Vol. 113, Cap. 2, 35-58. 4) Facoetti, D.; Abbiati, G.; d’Avolio, L.; Ackermann, L.; Rossi E. Synlett 2009, 2273-2276. 95 OC46 Skeletal Diversity from Carbohydrates: Diversity-Oriented Synthesis of Polyhydroxylated Compounds ElenaLenci,1GloriaMenchi,1FrancescaBianchini2andAndreaTrabocchi1 1 Department of Chemistry “Ugo Schiff”, University of Florence, via della Lastruccia 13, I-50019 Sesto Fiorentino, Florence, Italy 2 Department of Clinical and Experimental Biomedical Science “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, Italy e-mail: [email protected] Diversity-Oriented Synthesis (DOS) was introduced by Schreiber in 2000 as a new paradigm for developing large collections of structurally diverse small molecules.1 DOS consists of developing synthetic pathways for the efficient production of small molecule collections having high degree of skeletal and stereochemical diversity, to investigate biological pathways and to provide a larger array of the chemical space in drug discovery issues.2 Carbohydrates are valuable molecular platforms for the generation of high-quality small molecule collections, taking advantage of their stereochemical diversity, structural bias, and polyfunctional opportunity, which have been exploited since the Nineties in traditional combinatorial chemistry. Figure 1 We developed a DOS strategy exploiting coupling and functional group-pairing approaches to integrate building blocks from D-mannose and glycine as a case study (Figure 1). The diversity of the obtained scaffolds was characterized in terms of shape and chemical properties using PMI (Figure 1) and PCA analysis and compared to a reference set of blockbuster drugs, demonstrating mannose as a powerful building block when applied to DOS chemistry. Preliminary evaluation of the anticancer potential of newly synthesized DOS scaffolds was studied by cell growth assays on selected metastatic melanoma (A375M) and breast carcinoma (MDA-MB-231) cells. 1) Schreiber, S. L. Science 2000, 287, 1964−1969. 2) Trabocchi, A., Ed. Diversity-Oriented Synthesis: Basics and Applications in Organic Synthesis, Drug Discovery, and Chemical Biology; John Wiley and Sons: Hoboken, NJ, 2013. 3) Lenci, E.; Menchi, G.; Guarna, A.; Trabocchi, A. J. Org. Chem. 2015, 80, 2182-2191. 96 OC47 Cyclopropane Pipecolic Acids as Templates for Linear and Cyclic Peptidomimetics Lorenzo Sernissi1, Martina Petrović1, Dina Scarpi1, Andrea Trabocchi1, Francesca Bianchini2, Ernesto G. Occhiato1 1 Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 13, 50019-Sesto Fiorentino (FI), Italy. 2 Department of Biomedical, Experimental and Clinical Sciences “Mario Serio” , University of Florence, Viale Morgagni 50, 50134-Florence, Italy. e-mail: [email protected] The synthesis of substituted cyclopropane pipecolic acids (CPA) as conformationally restricted templates for peptidomimetics is reported. A variety of differently substituted (poly)hydroxy- and amino-2-azabicyclo[4.1.0]heptane-1-carboxylic acids were prepared via the Pd-catalyzed methoxycarbonylation of suitably functionalized lactam-derived enol phosphates, followed by OH-directed cyclopropanations (Figure 1).1,2 R2 OH N R1 R2 OH N R1 CO2Me R2 CO2Me OH N R1 O R1 = CO2Me, CBz, Boc R2 = H, OH, NH2 Figure 1 Cyclopropane amino acids have been extensively exploited to reduce conformational mobility in peptidomimetics.3 However, to our knowledge there are no reports on CPAs embodied in peptides. Hence, we employed various substituted CPAs1,2 to build linear and cyclic peptidomimetics (Figure 2).2 CO2H O HO NH H HN H N N O NHBoc O CO2Bn CO2H O NH NH HN H O N R O O HN O NH N R O NH O NH R = CO2Me H 2N Figure 2 NH NH H 2N NH In particular, we synthesized two cyclic peptidomimetics bearing the RGD (ArginineGlycine-Aspartic Acid) sequence, which displayed nanomolar activity as antagonists for the v3 subfamily of integrins.2 This has received increasing attention as therapeutic target because of its critical role in tumor-induced angiogenesis and metastasis. Thus, CPAs appear suitable for the generation of novel peptidomimetics for drug discovery. 1) Occhiato, E. G.; Casini, A.; Guarna, A.; Scarpi, D. Eur. J. Org. Chem. 2011, 6544-6552. 2) Sernissi, L.; Petrović, M.; Scarpi, D.; Guarna, A.; Trabocchi, A.; Bianchini, F.; Occhiato, E. G. Chem. Eur. J. 2014, 20, 11187-11203. 3) Hanessian, S.; Auzzas, L. Acc. Chem. Res. 2008, 41, 1241-1251. 97 OC48 Harvesting heterocycles by seeding nitrothiophenes Lara Bianchi, Massimo Maccagno, Giovanni Petrillo, Carlo Scapolla and Cinzia Tavani Dipartimento di Chimica e Chimica Industriale, Università di Genova, Via Dodecaneso 31, I-16146 Genova, Italy [email protected] Nitrobutadienes 2-4 are versatile building-blocks which can be most effectively made available by means of the ring-opening of suitably substituted nitrothiophenes (1) with secondary amines, in different experimental conditions.1 On them, proper modifications of functionalities eventually enable ring-closing processes leading to a continuously expanding pool of heterocyclic derivatives.2 Recent, rather rewarding, achievements in the synthesis of N-heterocycles will be presented. 1) Guanti, G.; Dell’Erba, C.; Leandri, G.; Thea, S. J. Chem. Soc., Perkin Trans. 1 1974, 2357-2360. Dell’Erba, C.; Mele, A.; Novi, M.; Petrillo, G.; Stagnaro, P. Tetrahedron 1992, 48, 4407-4418. Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.; Cosimelli, B.; Spinelli, D. Tetrahedron 2001, 57, 8159-8165. 2) Bianchi, L.; Carloni-Garaventa Alessandro; Maccagno, M.; Pani, M.; Petrillo, G.; Scapolla, C.; Tavani, C. Tetrahedron submitted. Bianchi, L.; Maccagno, M.; Pani, M.; Petrillo, G.; Scapolla, C.; Tavani, C. Tetrahedron DOI: 10.1016/j.tet.2015.05.046. Bianchi, L.; Maccagno, M.; Petrillo, G.; Scapolla, C.; Tavani, C.; Tirocco, A. Eur. J. Org. Chem. 2014, 39-43. Bianchi, L.; Ghelfi, F.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Spinelli, D.; Stenta, M.; Tavani, C. Eur. J. Org. Chem. 2013, 62986309. Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Scapolla, C.; Tavani, C. Tetrahedron Lett. 2012, 53, 752-757. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Morganti, S.; Novi, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.; Spinelli, D.; Tavani, C. Tetrahedron 2004, 60, 4967-4973. 98 OC49 Domino inter/intramolecular copper(II)-catalyzed haloalkoxylation and haloamination reactions of alkynes Beccalli Egle Maria1, Borelli Tea2, Mazza Alberto1 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. e-mail: [email protected] Transition metal catalyzed reactions are versatile tools to prepare heterocycles. In particular, intramolecular amination and alkoxylation reactions of substrates containing unsaturated moiety are attractive routes to reach nitrogenated and oxygenated-ring systems.1 Our recent interests were focused on palladium(II)-catalyzed intra/intermolecular domino processes of alkenylureas.2 We report now the reactions of alkynes tethered to functional groups which could behave as nitrogen and oxygen nucleophiles under the catalysis of different transition metals. More in detail, we describe domino intra/intermolecular alkoxyhalogenation and aminohalogenation processes in the presence of copper(II) salts, the different paths depending on the substrates such as alkynyl-ureas, -amides and -carbamates. The convenient processes result in the construction in good yields of haloalkylidene-oxazole and 1,3-oxazine derivatives. Scheme 1 1) a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127-2198; b) Enthaler, S.; Company, A. Chem. Soc. Rev. 2011, 40, 4912; c) Chem. Rev. 2004, 104, 3079-3159. 2) a) Broggini, G.; Barbera, V.; Beccalli, E. M.; Cacchio, U.; Fasana, A.; Galli, S.; Gazzola, S. Adv. Synth. Catal. 2013, 355, 1640 – 1648; b) Beccalli, E. M.; Broggini, G.; Borelli, T.; Brusa, F.; Gazzola, S.; Mazza, A. Eur. J. Org. Chem. 2015, DOI: 10.1002/ejoc.201500386. 99 OC50 The Iodine/Silane system: a novel exploitation in nucleoside synthesis Maria Federica Caso, Daniele D’Alonzo, Giovanni Palumbo and Annalisa Guaragna Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, via Cintia 21, 80126 Napoli (Italy). e-mail: [email protected] Iodine/Silane (Et3SIH or PMHS, polymethylhydrosiloxane) system appears as a useful tool in a wide assortment of organic transformations as for example iodination,5 regioselective Bn group removal,6 O-glycosylation7 and rearrangement reactions.8 In the frame of our interest into new N-glycosidation methods,9 herein we describe its valuable use as promoter and substrate activator in the N-glycosylation process, which often represents the key step in the synthesis of nucleoside analogues, In particular the combined use of Iodine and silane has been exploited for the preparation of two well known bioactive oxathiolane nucleosides, Lamivudine (3TC) and Emtricitabine (FTC) (Figure 1). X NH 2 O HO S N N X = H Lamivudine (3TC) X = F Emtricitabine (FTC) O Figure 1 Silane/I2-mediated N-glycosidation was tested by reaction of acetylated 1 (an intermediate of the synthesis of Lamivudine and Emtricitabine)10 with cytosine and 5fluorocytosine (Scheme 1) The anhydrous HI led to the formation of 5-αiodooxathiolane, which gave the desired nucleoside in high yield and stereoselectivity.11 X O O O S 1. Silane/I2 DCM, 0°C, 1 h OAc 2. N4 -Protected cytosine or 5-fluorocytosine BSA, DCM, rt, 1 h NHPG O O O N S N O X = H, F PG = Ac, Bz -selectivity: up to >99% Scheme 1 Furthermore, nucleoside diastereoisomeric ratio has been considerably influenced by the nature of nucleobase protecting group ( selectivity up to >99%). Due to its low cost and efficiency, our synthetic route could reasonably considered as an effective alternative to the existing methodologies and reagents devoted to the same end. 5 Adinolfi, M., Iadonisi, A., Ravida`, A., Schiattarella, M. Tetrahedron Lett. 2003, 44, 7863-7866. Pastore, A., Valerio, S., Adinolfi, M., Iadonisi, A. Chem. Eur. J. 2011, 17, 5881-5889. 7 Adinolfi, M., Barone, G., Iadonisi, A., Schiattarella, M., Synlett 2002, 269-270. 8 Yadav, J.S., Reddy, S.B.V., Premalatha, K., Swamy, T. Tetrahedron Lett. 2005, 46, 2687-2690. 9 D’Alonzo, D.; Amato, J.; Schepers, G.; Froeyen, M.; Van Aerschot, A.; Herdewijn, P. Guaragna, A. Angew. Chem. Int. Ed. 2013, 52, 6662-6665. 10 Goodyear, M.D., Hill, M.L., West, J.P., Whitehead, A.J. Tetrahedron Lett. 2005, 46, 8535-8538. 11 Caso, M.F., D’Alonzo, D., D’Errico, S., Palumbo, G., Guaragna, A. Org. Lett. 2015, DOI: 10.1021/acs.orglett.5b00982 6 100 OC51 Controlling the vinylogous reactivity of oxindoles bearing non symmetric 3-alkylidene groups Nicola Di Iorio1, Riccardo G. Margutta1, Paolo Righi1, Silvia Ranieri1, Andrea Mazzanti1, Giorgio Bencivenni1* 1 Dipartimento di Chimica Industriale, Università di Bologna, Viale del Risorgimento 4, 40136 , Bologna, Italia e-mail: [email protected] In this work we present the organocatalytic asymmetric vinylogous Michael addition between 3-alkylideneoxindole and nitrostyrene derivatives.1 We observed that performing the reaction on alkylideneoxindoles bearing a non symmetrically-substituted double bond, would allow the formation of two distinguished active species (figure1). This way we were able to obtain products of high biological interest2,3 possessing not only two (or one) sterecenters far away from the active site, but also a double bond that, by virtue of its particular structure, introduced a high degree of stereochemical complexity and at the same time, unveiled the regiochemistry of the reaction. Using the proper conditions we found out that bifunctional catalysts bearing thiourea and tertiary amine moieties afford pure, stereochemically complex products in good yield and excellent optical purity. Figura 1: scheme of the reaction showing the active species and the resulting products 1. 2. 3. a) C. Curti, G. Rassu, V. Zambrano, L. Pinna, G. Pelosi, A. Sartori, L. Battistini, F. Zanardi, G. Casiraghi Angew. Chem. Int. 2012, 51, 6200-6204; b) Gloria Rassu, Vincenzo Zambrano, Luigi Pinna, Claudio Curti, Lucia Battistini, Andrea Sartori, Giorgio Pelosi, Franca Zanardi and Giovanni Casiraghi Adv. Syn, Catal. 2013 1881-1886. G.S. Singh, Z.Y. Desta Chem. Rev. 2012, 112, 6104-6155. K. Ding, Y. Lu, Z. Nikolovska-Coleska, G. Wang, S. Qiu, S. Shangary, W. Gao, D. Qin, J. Stukey, K. Krajewski, P.P. Roller, S.J. Wang J. Med. Chem. 2006, 49, 3432-3435 101 OC52 [7,0]-metacyclophanes from biaryl coupling/macrocyclisation Antonella Bochicchio1,2, Lucia Chiummiento1, Maria Funicello1, Paolo Lupattelli1, Gilles Hanquet2, Sabine Choppin2 and Françoise Colobert2 1 Dipartimento di Scienze, Università della Basilicata Via dell’Ateneo Lucano10, 85100 Potenza, Italia. 2 CNRS-Université de Strasbourg, UMR 7509, Equipe SynCat Rue Becquerel 25, 67087 Strasbourg Cedex 02, France. Email: [email protected] The biaryl structural motif is a predominant feature in many pharmaceutically relevant and biologically active compounds. As a result, for over a century organic chemists have sought to develop new and more efficient aryl-aryl bond-forming methods (1). Cyclophanic natural products comprise an intriguing class of structurally diverse compounds. As inherent for all cyclic compounds regardless of their origin, macrocyclization is naturally the most decisive step, which defines the overall efficiency of the synthetic pathway. Especially in small cyclophanic molecules, this key step constitutes an even greater challenge. Due to the strain imparted by the macrocyclic system, free rotation of the benzene ring(s) is often restricted depending on both the constitution of the tether and the aromatic portions (2). Among cyclophanic natural products, the diarylheptanoids are a structurally sub-class with their scaffold consisting of two benzene rings tethered by an oxygenated aliphatic heptyl chain. In this work we reported different metal catalysed approaches to obtain the biaryl motif of myricanol, a natural [7,0]-metacyclophane with very important and recently discovered biological activities (3),(4),(5),(6). (Figure 1) Figure 1 The desired product 1could be obtained from the functionalized linear diarylheptanoid 2 by Suzuki domino process (macrocyclisation by linkage of aryl moieties) or could be synthesized from ring closing metathesis of product 3 which derived from a biaryl coupling of fragments 4 and 5. 1) 2) 3) 4) 5) 6) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107 (1), 174–238. Gulder, T.; Baran, P. S. Nat. Prod. Rep. 2012, 29 (8), 899-934. Jones, J. R.; Lebar, M. D.; Jinwal, U. K.; Abisambra, J. F.; Koren, J.; 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 (1), 38–44. Martin, M. D.; Calcul, L.; Smith, C.; Jinwal, U. K.; Fontaine, S. N.; Darling, A.; Seeley, K.; Wojtas, L.; Narayan, M.; Gestwicki, J. E.; Smith, G. R.; Reitz, A. B.; Baker, B. J.; Dickey, C. A. ACS Chem. Biol. 2015, 10 (4), 1099–1109. Dai, G. H.; Meng, G. M.; Tong, Y. L.; Chen, X.; Ren, Z. M.; Wang, K.; Yang, F. Phytomedicine 2014, 21 (11), 1490– 1496. Dai, G.; Tong, Y.; Chen, X.; Ren, Z.; Ying, X.; Yang, F.; Chai, K. Int. J. Mol. Sci. 2015, 16 (2), 2717–2731. 102 OC53 Synthesis of novel indole-based scaffolds by different assembly of tryptamines, azoenes, and aldehydes Gianfranco Favi Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino (PU), Italy. e-mail: [email protected] High throughput screening (HTS) of chemical libraries against cells or classical biochemical targets is the mainstay of the pharmaceutical industry generating drug leads. Consequently, creative strategies to rapidly generate structurally and functionally diverse drug-like small molecules have appeared. Although substantial effort has been directed at the development of diversity oriented synthesis (DOS)1,2 platforms to fabricate heterocyclic compounds, a rational approach able to merge three different and independent components in such a way to obtain bis-heterocyclic compounds with skeletal diversity is very attractive. As a continuation of our work on the design of azaheterocycles3 via novel multicomponent reaction (MCR) pathways, we choose triptamines4 as the key privileged structure. The incorporation of these redundant frameworks in sequential MCR pathways represents therefore a valuable tool to explore new areas of chemical space.5 Here we describe a different assembly of novel indolebased compounds starting from tryptamines, azoenes and aldheydes. Exploiting the mutual reactivity of the reagents, this strategy provides selective access to classes of bisheterocyclic compounds, namely tetrahydro-β-carboline-pyrazolones 4 and N-imidazoyl tryptamines 5 simply by changing the addition order of the two electrophilic components (2 and 3) (Scheme 1). The scope and limitations of these reactions as well as the mechanistic considerations will be presented. Scheme 1 1) Garcia-Castro, M.; Kremer, L.; Reinkemeier, C. D.; Unkelbach, C.; Strohmann, C.; Ziegler, S.; Ostermann, C.; Kumar, K. Nat. Commun., 2015, 6, 6516-6529. 2) Burke, M. D.; Schreiber, S. L. Angew. Chem. Int. Ed., 2004, 43, 46-58. 3) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Perrulli, F. R.; Santeusanio, S.; Eur. J. Org. Chem., 2009, 3109-3127. 4) Lancianesi, S.; Palmieri, A.; Petrini, M. Chem. Rev. 2014, 114, 7108-7149. 5) Kim, J.; Kim, H.; Park, S. B. J. Am. Chem. Soc. 2014, 136, 14629-14638. 103 OC54 A one-pot two-step reaction to prepare esters directly from aldehydes and alcohols Silvia Gaspa1, Andrea Porcheddu2, Lidia De Luca1 1 Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari, Italia. 2 Dipartimento di Scienze Chimiche e Geologiche, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italia e-mail: [email protected] Esters are an important functional group in organic chemistry. They are present in many biologically active compounds with significant pharmacological properties, and are also important in chemical industry. The conventional syntheses of esters either couple an activated carboxylic acid derivative with the appropriate alcohol, or employ an equilibrium mediated esterification/transesterification protocol.1 These methods have many drawbacks such as the stoichiometric use of toxic coupling reagents2 and the formation of byproducts that can be difficult to remove during isolation. To overcome these problems we propose an eco-friendly alternative methodology where trichloroisocyanuric acid (TCCA) is used to convert aldehydes or alcohols in situ into acyl chlorides, that subsequently react with other alcohols to give a variety of esters in high yields. Trichloroisocyanuric acid is a stable, inexpensive and easily available reagent with low toxicity, low corrosive properties and low environmental impact. Scheme 1 Syntheses of esters from aldehydes or alcohols. 1) Otera, J.; Nishikido, J. Methods, Reactions, And Applications. Wiley-Vch; Weinheim 2010. 2) Neises, B.; Steglich, W. Angew. Chem. Int. Ed. Engl. 1978, 17, 522. 104 OC55 A ζ-lactamization Carbonylative Approach to a New Class of Anti-Tumor Agents Raffaella Mancuso, a,b Dnyaneshwar S. Raut,a Nadia Marino,a Giorgio De Luca,c Cinzia Giordano,d Stefania Catalano,d Sabastiano Andò,d Bartolo Gabrielea a Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Via Pietro Bucci, 12/C, 87036 Arcavacata di Rende (CS), Italy b Dipartimento di Ingegneria Meccanica, Energetica e Gestionale, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy c Istituto per la Tecnologia delle Membrane, Consiglio Nazionale delle Ricerche (ITM-CNR), 87036 Arcacavata di Rende (CS), Italy d Centro Sanitario e Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy [email protected] Medium sized ring-based scaffolds (7-11 membered, carbo- and heterocylic) are molecular framework of particular interest, owing to their biological activity1 and occurrence in many important natural products.2 Despite their significance, relatively few efficient synthetic methods for their preparation through cyclization of acyclic precursors are still known, compared to the quite abundant annulation protocols for the preparation of five- and six-membered rings. We have studied the reactivity of readily available 2-(2-ethynylphenoxy)anilines 1 under PdI2/KI-catalyzed oxidative carbonylation conditions (100 °C under 40 atm of a 4:1 mixture of CO/air in an alcohol as the solvent) for the synthesis of -lactams 3. O R2 PdI2 cat CO, ROH (R1=H) HN O 3 O R2 NH2 CO2R 1 R1 PdI2 cat CO, MeOH O R2 NH MeO2C 2 R1 Scheme 1 Although different reaction pathways could in principle be at work under these conditions, leading to different acyclic or cyclic carbonylated products, we have found that, in agreement to theoretical calculations, the process preferentially give acyclic carbamates 2 (scheme 1). On the other hand, as predicted by theoretical calculations, with R = H, the intramolecular 8-exo-dig triple bond insertion successfully competed with the attack by ROH, and carbonylated -lactam derivatives 3 were selectively obtained in satisfactory yields (53-75%) (scheme1). The formation of medium-sized heterocyclic derivatives 3 from simple substrates such as 1, represents a significant achievement, considering the importance of realizing a novel -lactamization process by a direct carbonylative approach, and the biological relevance of these compounds. In fact, biological tests showed that newly synthesized -lactams 3 exert antiproliferative effects in different breast cancer cell lines, highlighting their potential use as novel class of antitumor agents. 1) 2) a) Mallinson J.; Collins, I. Future Med. Chem. 2012, 4, 1409–1438. (b) Kitayama, T.; Saito, A.; Ohta, S. Tetrahedron-Asymmetry 2012, 23, 1490-1495. (c) Bauer, R. A.; Wenderski, T. A.; Tan, D. S. Nat. Chem. Biol. 2013, 9, 21-29. a) Alberta Marco, J.; Carda, M. Nat. Prod. Commun. 2011, 6, 505-514. (b) Su, X.; Thomas, G. L.; Galloway, W. R. J. D.; Surry, D. S.; Spandl, R. J.; Spring, D. R. Synthesis 2009, 3880-3896. 105 OC56 Lipophilicity Efficiency is a new paradigm for balancing receptor affinity and in vivo antinociceptive efficacy of opioid peptides Rossella De Marco1, Santi Spampinato2, Andrea Bedini2, Roberto Artali3, Luca Gentilucci1 1 Department of Chemistry “G. Ciamician”, University of Bologna, via Selmi 2, 40126 Bologna, Italy.2 Department of Pharmacy and Biotechnology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy. 3 Scientia Advice, 20832 Desio (MB), Italy. e-mail: [email protected] The lipophilicity efficiency indices LLE and LELP have been recently proposed to support balanced optimization of potency and ADMET profile. Ligand lipophilicity efficiency LLE represents the activity of a ligand without the contribution of its lipophilicity. LLE consents high potency while maintaining moderate lipophilicity. Ligand efficiency-dependent lipophilicity LELP has been recently proposed to combine lipophilicity, molecular size, and potency into one composite descriptor. In this respect, we compare for the first time the lipophilic efficiency indices to affinity and in vivo efficacy in the field of opioid compounds. We synthesizer a mini-library of lipophilic opioid peptides, carrying a Trp equipped with methyl, nitro, and halosubstituents at various positions of the indole ring. Substitution had a strong impact on experimental MOR affinities. We also observed that the different groups at Trp influenced stability and lipophilicity. Peptides with 5-nitro and 7-Br-2-Me Trp showed moderately faster analgesia as compared to the unsubstituted compounds in mouse tail flick assay. The antinociceptive efficacy profiles nicely correlated to the calculated LLE and LELP, suggesting that lipophilicity efficiency indices might represent a new and useful predictive tool for the design of centrally or peripherally acting analgesic compounds. Support by Fondazione Umberto Veronesi References. Gentilucci, L; De Marco, R; et al. ChemMedChem 2011, 6, 1640. De Marco, R.; Gentilucci, L.; Spampinato, S.; Bedini, A. J. Med. Chem. 2012, 55, 10292. De Marco, R.; Gentilucci, L.; Spampinato, S.; Bedini, A. J. Med. Chem. 2014, 57, 6861-6866. 106 OC57 Small organic molecules to fight influenza virus: from design to optimization Laura Goracci1, Susan Lepri1, Serena Massari2, Giulio Nannetti3, Arianna Loregian3, Gabriele Cruciani1, Renzo Ruzziconi1, Oriana Tabarrini2 1 Chemistry, Biology and Biotechnology Department, University of Perugia (via Elce di sotto, 8, 06123-Perugia, Italy) 2 3 Department of Pharmaceutical Sciences, University of Perugia (Via del Liceo, 1, 06123-Perugia, Italy) Department of Molecular Medicine, University of Padua (via A. Gabelli 63, 35121 Padua, Italy) e-mail: [email protected] Influenza is a highly contagious, acute, febrile, respiratory illness, characterized by high morbidity and significant mortality. Only two classes of drugs are currently available to treat influenza infections, i.e. M2 ion channel inhibitors and neuraminidase inhibitors. Unfortunately, their clinical use is limited by serious side effects, low efficacy, and the emergence of resistant virus variants. Clearly, new anti influenza virus (Flu) strategies based on alternative mechanisms of action are strongly needed. Recently, the viral RNA-dependent RNA polymerase (RdRP) appeared to be a valid antiviral target, being essential for virus replication. In addition, it is highly conserved among FluA, B, and C, and its mechanism of action significantly differs from that of the human RNA polymerases. In particular, the recent publication of two crystallographic structures of the PA-PB1 complex of the RNA polymerase prepared the way for the design and the synthesis of small molecules able to disrupt the PA-PB1 interaction. In the recent years, we were able to prove that the use of organic molecules having low molecular weight can be actually use as inhibitors of the PA-PB1 interaction. The first discovered inhibitors were obtained by a virtual screening campaign on commercial databases.1 Since then, a large number of compounds have been designed, synthesized and tested by us, to optimize the interaction with the target.2,3,4 As a result, we were able to discover a number of potent inhibitors endowed with a broad anti-Flu activity. A pharmacophore defining the common chemical features responsible for activity was also generated and used, in addition to a structure based drug design, for further optimization. 1. Muratore, G.; Goracci, L.; Mercorelli, B.; Foeglein, A.; Digard, P.; Cruciani, G.; Palù, G.; Loregian, A. PNAS, 2012, 109, 6247-6252. 2. Massari, S.; Nannetti, G.; Goracci, L.; Sancineto, L.; Muratore, G.; Sabatini, S.; Manfroni, G.; Mercorelli, B.; Cecchetti, V.; Facchini, M.; Palù, G.; Cruciani, G.; Loregian, A.; Tabarrini, O. J. Med. Chem. 2013, 56, 10118-10131. 3. Lepri, S.; Nannetti, G.; Muratore, G.; Cruciani, G.; Ruzziconi, R.; Mercorelli, B.; Palù, G.; Loregian, A.; Goracci, L. J. Med. Chem., 2014, 57, 4337-4350. 4. Massari, S.; Nannetti, G.; Desantis, J.; Muratore, G.; Sabatini, S.; Manfroni, G.; Mercorelli, B.; Cecchetti, V.; Palù, G.; Cruciani, G.; Loregian, A.; Goracci, L.; Tabarrini, O. J. Med. Chem., 2015, 58, 3830-3842. 107 OC58 Regioselective C2 cross-dehydrogenative alkenylation of azoles Bellina Fabio 1, Lessi Marco 1, Lodone Laura 1 1 Department of Chemistry and Industrial Chemistry, University of Pisa, Via Moruzzi 13, 56124 Pisa, Italy. e-mail: [email protected] Alkenylated heteroarenes represent a recurring structural motif found in bioactive natural products, pharmaceuticals, and organic materials. These compounds are of great importance either as building blocks or synthetic intermediates, and have become increasingly attractive for synthetic organic chemists. Since the discovery of the palladium-catalyzed olefination of benzene by Moritani and Fujiwara in 1967, significant progress has been made to improve the efficiency of this cross-dehydrogenative coupling (CDC) in order to prepare alkenylated (hetero)arenes with high chemo- and regioselectivity.1 In contrast with reactions involving simple arenes, which usually require the presence on the aromatic nuclei of directing groups to grant sufficient selectivity, the presence of the heteroatom(s) in heteroaromatic nuclei generally allows to discriminate among the diverse C-H bonds.2, 3, 4, 5 In this contest, we developed a novel protocol to prepare 2-alkenyl-substituted azoles through a palladiumcatalyzed ligandless cross-dehydrogenative regioselective C-2 alkenylation. In the presence of a catalytic amount Pd(OAc)2 and of Cu(OAc)2 as oxidant 1methylimidazole, 5-aryl-1-methyl-imidazoles, benzimidazole, 1-methylbenzimidazole, and benzoxazole were successfully reacted with functionalized styrenes at 120 °C in propionic acid, giving rise to the corresponding 2-alkenylated azoles in good chemical yields (Scheme 1). Scheme 1 The application of this protocol to the preparation of new alkenylimidazole-based fluorescent dyes to be used in functional materials will also show and discussed. 1) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170-1214. 2) Huang, Y.; Song, F.; Wang, Z.; Xi, P.; Wu, N.; Wang, Z.; Lan, J.; You, J. Chem. Comm., 2012, 48, 2864-2866. 3) Lee, W.; Wang, T-H.; Ong, T-G. Chem. Comm., 2014, 50, 3671-3673. 4) Rivara, S.; Piersanti, G.; Bartoccini, F.; Diamantini, G.; Pala, D.; Riccioni, T.; Stasi, M. A.; Cabri, W.; Borsini, F.; Mor, M.; Tarzia, G.; Minetti, P. J. Med. Chem., 2013, 56, 2147-1261. 5) Xin, W.; Yu, X.; Kaung, C. 2014, 16, 1798-1801. 108 OC59 Gold(I)-Catalyzed Synthesis and Modification of N-Heterocycles Martina Petrović,1 Dina Scarpi,1 Béla Fiser,2 Enrique Gómez-Bengoa,2 Cristina Prandi,3 Ernesto G. Occhiato1 1 Dipartimento di Chimica ”Ugo Schiff”, Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy. 2 Department of Organic Chemistry I, University of the Basque Country, Donostia, Spain. 3 Dipartimento di Chimica, Università di Torino, via P. Giuria 7, 10125 Torino, Italy e-mail: [email protected] Suitable enynes 1 and 2 obtained by Sonogashira coupling of lactam-derived enol triflates and phosphates are useful substrates for the synthesis of more complex Nheterocycles when reacted in the presence of a gold(I) catalyst. Depending on the position of an internal nucleophile, either exocyclic vinylogous amides 31 or annulated N-heterocycles 42 can be obtained in good to excellent yields. In the first case, the nucleophile is the carbonyl oxygen of the N-Boc protection. After oxyauration of the triple bond, hydrolysis of the cyclic intermediates provides vinylogous amides which are useful precursors in the synthesis of natural compounds. In the second case the nucleophile is an acetyloxy group on the alkynyl side chain and the gold-catalyzed propargylic ester [3,3] rearrangement generates a pentadienyl cation which cyclizes via a Nazarov reaction to form cyclopentannulated N-heterocycles whose structure is contained in many natural compounds. Both methodologies have been thoroughly studied, also by employing DFT calculations, to evaluate their scope and to understand reactivity, regio- and stereoselectivity of both processes. R2 R2 LAu + N O EWG t-Bu O 1 R1 O O O R3 R3 ( )n N R2 R1 O O R1 R1 ( )n + AuL N R2 2 AuL N N R ( )n R2 + OAc AuL N H O R1 3 Exocyclic vinylogous amides R1 R3 ( )n N R2 O 4 Cyclopenta-fused N-heterocycles Scheme 1 1) (a) Oppedisano, A.; Prandi, C.; Venturello, P.; Deagostino, A.; Goti, G.; Scarpi, D.; Occhiato, E. G. J. Org. Chem. 2013, 78, 11007-11016. (B) Scarpi, D.; Begliomini, S.; Prandi, C.; Oppedisano, A.; Deagostino, A.; Gómez-Bengoa, E.; Fiser, B.; Occhiato, E. G. Eur. J. Org. Chem. 2015, Doi: 10.1002/Ejoc.201500205. Petrović, M.; Scarpi, D.; Fiser, B.; Gómez-Bengoa, E.; Occhiato, E. G. Eur. J. Org. Chem. 2015, Accepted. 109 OC60 Synthesis of thiophene-based ligands in micellar solution P. Quagliotto, C. Barolo, N. Barbero, R. Buscaino, E. Chiavazza, G. Viscardi Dipartimento di Chimica and Interdepartmental “Nanostructured Surface and Interfaces” NIS Centre, Università di Torino, via P. Giuria 7, 10125 - Torino. e-mail: [email protected] Thienylpyridines and thienyloligopyridines can be used for several applications,1,2 including conductive polymers.3 The inclusion of thiophene-based N-ligands into polymers allows to obtain materials that can be responsive to the coordination of metals or alkylating reagents.4 The urge for synthetic procedures complying with Green Chemistry pushed us to explore the Suzuki reaction in a micellar environment, by combining thiopheneboronic acids with bromopyridines, with excellent yields.5 Now, we propose the preparation of thienylpyridines and thienylbispyridines with the Suzuki reaction using less reactive and cheaper chloropyridines in a system consisting of Pd(OAc)2 (2%) or PdCl2 (1-2%), an electron releasing phosphine, XPhos (1.25 eq. based on Pd), thiopheneboronic acids, CTAB and water. B(OH) 2 S X + Pd cat., CTAB, XPhos N N NaOH, H2 O 25°C S X= Br, Cl N N Scheme 1 The reactions were explored mainly at room temperature, obtaining good yields (54 to 80%) as a function of boronic acids and chloropyridines structure. The 4-chloropyridine reacted at higher temperature with respect to 2-chloropyridine, and gave a 54 % yield with 2-thiopheneboronic acid at 80°C. The 3-thiopheneboronic acid reactivity was lower than its 2- isomer and required longer times (24h) to give good yields. A strong base such as NaOH performed better than a weak base, K2CO3. A four-fold excess of base over the limiting reagent was found optimal. Using PdCl2 as catalyst, instead of Pd(OAc)2, slightly lower yields were obtained with chloropyridines. PdCl2 performed better with bromopyridines5 at 80°C. Its ability to give surfactant-stabilized Pd nanoparticles was demonstrated by TEM imaging. A trial reaction with the classical Pd(PPh3)4 catalyst was performed with 3-thiopheneboronic acid and 2-chloropyridine at 80°C for 30 min with the help of microwaves, giving substantially similar yields as those obtained with Pd(OAc)2 and XPhos at 25°C reacting for 24h. The Pd(OAc)2 / XPhos system can thus be exploited, using lower temperature and lower loading of phosphine compounds. A copolymer containing 3-hexylthiophene and a thiophene-based bispyridine ligand was also prepared and studied. 1) O’Regan, B.; Grätzel, M. Nature 1991, 353, 737-740. 2) Mishra, A.; Ma, C.; Bauerle, P. Chem.Rev. 2009, 109, 1141-1276. 3) Manca, P. Pilo, M.I.; Casu, G.; Gladiali, S.; Sanna, G.; Scanu, R.; Spano, N.; Zucca, A.; Zanardi, C.; Bagnis, D. Valentini, L. J. Polym Sci. 2011, 49, 3513-3523. 4) Gannot, Y.; Hertzog-Ronen, C.; Tessler, N.; Eichen, Y. Adv. Funct. Mater. 2010, 20, 105-110. 5) Quagliotto, P.; Barolo, C.; Carfora, P.; Prosperini, S., Viscardi G. submitted. 110 OC61 Hydrogen atom transfer reactions from aliphatic CH bonds to alkoxyl radicals. The role of structural and medium effects on CH deactivation Michela Salamone, Massimo Bietti Dipartimento di Scienze e Tecnologie Chimiche, Università "Tor Vergata", Via della Ricerca Scientifica, 1 00133 Roma e-mail: [email protected] Hydrogen atom transfer (HAT) reactions play a key role in a variety of important chemical and biological processes such as lipid peroxidation, the oxidative damage to biomolecules and polymers, the antioxidant activity of natural and synthetic radical scavenging antioxidants, the degradation of volatile organic compounds, as well as in an increasing number of synthetically useful C−H functionalization procedures. Among the radicals involved in these processes, alkoxyl radicals have received considerable attention, and cumyloxyl (PhC(CH3)2O, CumO) has emerged as a very convenient radical for the study of these reactions. CumO can be easily generated by photolysis of commercially available dicumyl peroxide and is characterized by an absorption band in the visible region of the spectrum and a lifetime that allow the direct measurement of rate constants for HAT from a large variety of substrates by means of the laser flash photolysis technique. In this framework, recent studies carried out in our research group have pointed towards the important role played by substrate structure, medium effects and polar effects on the reactivity and selectivity patterns observed in HAT reactions from aliphatic CH bonds to CumO.1 The influence of Brønsted and Lewis acids on HAT from the CH bonds of basic substrates and of ring-substitution on HAT from cyclic hydrocarbons will be discussed, emphasizing in particular the role played by acid-base interactions and torsional strain on CH bond deactivation. 1) (a) Salamone, M.; Ortega, V. B.; Bietti, M. J. Org. Chem. 2015, 80, 4710-4715. (b) Salamone, M.; Bietti, M. Synlett 2014, 25, 1803-1816. (c) Salamone, M.; Mangiacapra, L.; DiLabio, G. A.; Bietti, M. J. Am. Chem. Soc. 2013, 135, 415-423. (d) Salamone, M.; Giammarioli, I.; Bietti, M. Chem. Sci. 2013, 4, 3255-3262. 111 OC62 Role of Electron Transfer Processes in the N-demethylation of N,N-dimethylanilines and S-Oxidation of Aromatic Sulfides Promoted by the Nonheme Iron(IV)-Oxo Complex [FeIV(O)(N4Py)]2+ Osvaldo Lanzalunga Dipartimento di Chimica and Istituto CNR di Metodologie Chimiche-IMC, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy e-mail: [email protected] The role of electron transfer processes in the N-demethylation of N,N-dimethylanilines and the S-Oxidation of Aromatic Sulfides promoted by the nonheme iron(IV)-oxo complex [FeIV(O)(N4Py)]2+ has been investigated. In the oxidative N-demethylation of N,N-dimethylanilines, a mechanistic dichotomy between a direct hydrogen atom transfer and a sequential electron transfer/proton transfer mechanism (ET/PT) can be envisaged (Scheme 1).1 Scheme 1 The analysis of the kinetic isotope effects profiles in the N-demethylation of a series of 4-X-N,N-dimethylanilines promoted by [FeIV(O)(N4Py)]2+ supports the occurrence of an ET/PT mechanism with a rate determining deprotonation of the anilinium radical cation. The bell shaped profile of intramolecular kinetic deuterium isotope effect (KDIEintra) vs pKa anilinium radical cation allowed us to estimate the pKa value (9.7) of the iron(III)-hydroxo complex [FeIII(OH)(N4Py)]2+. The oxidation of aromatic sulfides to sulfoxides catalyzed by [FeIV(O)(N4Py)]2+ can occur either by a direct oxygen atom transfer mechanism (Scheme 2, path a) or by a sequential electron transfer/oxygen rebound mechanism (Scheme 2, paths b-c).2 Using aryl diphenylmethyl sulfides as substrates, sulfoxides are accompanied by diphenylmethanol, benzophenone and diaryl disulfides, i.e. products deriving from the C-S and C-H fragmentation of the sulfide radical cations (Scheme 2, path d) thus supporting the occurrence of the ET-oxygen rebound mechanism. Scheme 2 1) 2) Nam, W.; Lee, Y.-M.; Fukuzumi, S. Acc. Chem Res. 2014, 47, 1146–1154. Park, J.; Morimoto, Y.; Lee, Y.-M.; Nam, W. J. Am. Chem. Soc.2011,133, 5236–5239. 112 OC63 Triplet phenyl cations as an innovative source of substituted ,ndidehydrotoluenes. A combined computational and experimental investigation Carlotta Raviola, Davide Ravelli, Stefano Protti, Maurizio Fagnoni, Angelo Albini PhotoGreen Lab, Department of Chemistry, University of Pavia Viale Taramelli 12, 27100 Pavia, Italy e-mail:[email protected] Triplet phenyl cation (3Ar+is a useful and versatile species in organic chemistry.1Recently, we demonstrated that it can act as a source of further important intermediates, such as ,n-didehydrotoluene (,n-DHTs, n = 1-3) biradicals, with potential biological application as antitumoral agents.2 Unfortunately, up to now the only isomer accessible is the ,3-DHT that is obtained through the Myers-Saito cyclization of enyne-allenes.3 Our group has developed an alternative approach for the generation of all of the isomeric ,n-DHTs. In particular, the formation of a triplet (trimethylsilylmethyl)phenyl cation by irradiation of (n-chlorobenzyl)trimethylsilanes in protic media leads to the desired biradicals after detachment of the electrofugal group Me3Si+.4 In order to enlarge the scope of this method, we investigated the effect of a substituent on the aromatic ring on the photogeneration and reactivity of ,n-DHTs. The photoheterolysis of the aryl-chlorine bond to give a triplet phenyl cation (the key step in the generation of ,n-DHTs) is favored in the presence of strong electron-donating substituents, such as a methoxy group.5 Accordingly, we focused our attention on a set of (trimethylsilylmethyl)chloroanisole isomers (see Scheme). The photoreactivity of these substrates has been tested in protic media, including alcohols and alcohol/water mixtures. Likewise, a detailed computational analysis of the involved excited states and intermediates has been carried out.6 1) Dichiarante, V.; Fagnoni, M. Synlett 2008, 787-800. 2) Myers, A. G.; Parrish, C. A. Bioconjugate Chem. 1996, 7, 322-331. 3) Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am. Chem. Soc. 1992, 114, 9369-9386. 4) Protti, S.; Ravelli, D.; Mannucci, B.; Fagnoni, M.; Albini, A. Angew. Chem. Int. Ed. 2012, 51, 85778580. 5) Protti, S.; Mella, M.; Fagnoni, M.; Albini, A. J. Org. Chem. 2004, 69, 3465-3473. 6) Raviola, C.; Ravelli, D.; Protti, S.; Fagnoni, M. J. Am. Chem. Soc. 2014, 136, 13874-13881. Acknowledgement: We are grateful to the Fondazione Cariplo (grant 2011-1839) for support. 113 OC64 Microwave assisted heterocyclization promoted by Lawesson’s reagent: Synthesis of benzo[c]thiophen-1(3H)-ones and 1Hisothiochromene-1-ones. R. Romeo1, S.V. Giofrè1, R. Mancuso2, B. Gabriele2, G. Romeo1, U. Chiacchio3 1 2 Dipartimento SCIFAR, Università di Messina Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria 3 Dipartimento di Scienze del Farmaco, Università di Catania e-mail: [email protected] Intramolecular heterocyclization is a well exploited process for the preparation of a variety of heterocyclic systems. In this context, the cyclization of acetylenic compounds, promoted by the attack of a variety of nucleophiles in a close proximity to the triple bond, is a very efficient method to produce furans, pyrroles, thiazoles, indoles, imidazoles, indolizines, oxazoles, pyridines, quinolines, thiophenes1. In particular, the heterocyclization process of o-alkynylbenzoic acids, o-alkynylbenzamides and their derivatives have been of great significance in the formation of heterocyclic compounds such as isocoumarins, 3-alkylidenephthalides, 2H-isoquinolin-1-ones, 3aryl(alkyl)idene-isoindolones and 3-benzazepinones. Recently, we have reported the selective formation of functionalized isoindolinone and isobenzofuranimine through the oxidative carbonylation of 2-alkynylbenzamides, followed by the intramolecular nucleophilic attack to the conjugated triple bond.2 The recognition that thioacids are exploitable nucleophiles makes these compounds as interesting substrates for heterocyclization reactions, promoted by the intramolecular attack of the sulphur atom to the triple bond. In this work, starting from o-alkynyl benzoic acids, benzo[c]thiophen-1(3H)-ones or 1H-isothiochromene-1-ones have been synthesized in good yields by an intramolecular cyclization process performed by treatment with Lawesson’s reagent under microwave irradiation. Two alternative reaction routes are controlled by the nature of the substituent at the distal position of the carbon-carbon triple bond. 1) For recent reviews, see: (a) Mancuso, R.; Gabriele, B. Molecules 2014, 19, 15687-15719. (b) Gabriele, B.; Mancuso, R.; Larock, R. C. Curr. Org. Chem. 2014, 18, 341-358. (c) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1-35. (d) Alcaide, B.; Almendros, P. Acc. Chem. Res. 2014, 47, 939-952. (e) Gabriele, B.; Mancuso, R.; Salerno, G. Eur. J. Org. Chem. 2012, 68256839. (f) Wen, J. J.; Zhe, Y.; Zhan, Z.-P. Asian J. Org. Chem. 2012, 1, 108-129. 2) Mancuso, R., Ziccarelli, I., Armentano, D., Marino, N., Giofrè, S.V., Gabriele, B. J. Org. Chem. 2014, 79, 3506-3518. 114 OC65 Intramolecular reactions of 4-quinolone-2-carboxamides: a new route to 4-quinolone-based polycyclic systems Raffaella Cincinelli, Sabrina Dallavalle, Loana Musso Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, via Celoria 2, 20133 Milan, Italy e-mail: [email protected] Quinolones are relevant structural units in medicinal chemistry, due to the wide range of activities (e.g. anticancer, antimicrobial, antiviral and antimalarial activity) showed by compounds containing this heterocyclic scaffold. As an extension of our previous studies1 on acid-catalyzed intramolecular reactions of indole-2-carboxylic acid oxoamides, we devised to exploit this approach for the synthesis of new 4-quinolone fused heterocyclic rings from 4-quinolone-2carboxamides. Our results showed that the acid treatment of N-unsubstituted 4-quinolone-2-carboxylic acid--oxoamides furnished 3H-pyrazino[1,2-a]quinoline-4,6-diones, due to the nucleophilic attack of N-1 to the carbonyl group, whereas acid treatment of δ- and εoxoamides led to the formation of tetracyclic compounds by a tandem heteroannulation reaction. On the contrary, N-substituted 4-quinolone-2-carboxylic acid oxoamides underwent intramolecular Friedel-Crafts cyclization reactions. The described approach has been used for the synthesis of biologically active quinolone-containing natural compounds. 1) (a) Cincinelli, R.; Dallavalle, S.; Merlini, L.; Nannei, R.; Scaglioni, L. Tetrahedron 2009, 65, 3465-3472; (b) Cincinelli, R.; Dallavalle, S.; Merlini, L. Synlett 2008, 1309-1312; (c) Cincinelli, R.; Cassinelli, G.; Dallavalle, S.; Lanzi, C.; Merlini, L.; Botta, M.; Tuccinardi, T.; Martinelli, A.; Penco, S.; Zunino, F. J. Med. Chem. 2008, 51, 7777-7787. 115 OC66 Synthetic aminopyrrolic mannose binding agents exert anti-HIV activity targeting the glycans of viral gp120. Oscar Francesconi,1 Cristina Nativi,1 Gabriele Gabrielli,1 Irene De Simone,1 Sam Noppen,2 Jan Balzarini,2 Sandra Liekens2 and Stefano Roelens3 1 Dipartimento di Chimica, Università di Firenze Polo Scientifico e Tecnologico, 50019 Sesto Fiorentino, Firenze (Italy) 2 Rega Institute for Medical Research, KU Leuven, B-3000 Leuven (Belgium) 3 Istituto di Metodologie Chimiche (IMC) Consiglio Nazionale delle Ricerche (CNR), Dipartimento di Chimica Polo Scientifico e Tecnologico, 50019 Sesto Fiorentino, Firenze (Italy) e-mail: [email protected] The densely mannosylated N-glycans of the viral envelope of the human immunodeficiency virus (HIV) play a crucial role in viral transmission. Recently, they have been proposed as a potential target for new therapeutic strategies.1 Lectins capable of interacting with the highly-mannosilated glycoprotein gp120 of the HIV envelope were shown to effectively inhibit infection and transmission of HIV by blocking the virus entry process. Unfortunately, lectins present many drawbacks, which prevent their development as therapeutic agents. Therefore the development of small-size, nonpeptidic molecules as carbohydrate binding agents (CBAs) is recently emerging as a promising strategy for antiviral therapies and vaccines. In the last few years we have developed a family of structurally-related synthetic aminopyrrolic receptors for biomimetic recognition of mono- and disaccharides of biological interest.2 They were found to bind to mono- and dimannosides in competitive organic solvents with affinities in the low micromolar range by exploiting a combination of hydrogen bonding and van der Waals/CH-π interactions.3 Recently we have investigated their biological activity toward several strains of yeast and yeast-like microorganisms bearing mannoproteins on their cell surface, and found that they show antifungal activity and cytotoxicity comparable to commercial antifungal drugs.4 Moreover, localization studies on treated cells suggested that the interaction of these compounds with the surface glycans represents a key step in the internalization into the cell, where they exert their antibiotic activity. Because of the close similarity of the mannan portion of yeast cell wall with the HIV gp120 glycans, we carried out an investigation of their binding properties towards the highly mannosilated gp120 and gp41 glycoproteins of the HIV envelope together with an evaluation of the antiviral activity of this family of synthetic receptors.5 The cytostatic activities of the investigated compounds were also examined, and compared to their antiviral activities. In the present communication, we report the results of such a study and discuss the potential application as CBAs. 1) 2) 3) 4) 5) Balzarini, J. Nat. Rev. Microbiol. 2007, 5, 583–597. Cacciarini, M.; Nativi, C.; Norcini, M.; Staderini, S.; Francesconi, O.; Roelens, S. Org. Biomol. Chem. 2011, 9, 1085-1091. Francesconi, O.; Nativi, C.; Gabrielli, G.; Gentili, M.; Palchetti, M.; Bonora, B.; Roelens, S. Chem. Eur. J. 2013, 19, 1174211752. Nativi, C.; Francesconi, O.; Gabrielli, G.; De Simone, I.; Turchetti, B.; Mello, T.; Di Cesare Mannelli, L.; Ghelardini, C.; Buzzini, P.; Roelens, S. Chem. Eur. J. 2012, 18, 5064-5072. Francesconi, O.; Nativi, C.; Gabrielli, G.; De Simone, I.; Noppen, S.; Balzarini, J.; Liekens, S.; Roelens, S. Chem. Eur. J. 2015, DOI: 10.1002/chem.201501030. 116 Flash presentations CF1:"Solvent‐FreeSynthesisandCharacterizationofSpiro‐isoxazolidinesatPotentialBiological Activity",VincenzoAlgieri(DipartimentodiChimicaeTecnologieChimiche(CTC),Universitàdella Calabria,PonteBucciCubo12/C,87036Rende,Cosenza). CF2:"Tunablephotogenerationofreactiveintermediates fromchlorobenzylphosphonicacidsin aqueousmedia",StefanoCrespi(PhotoGreenLab,DepartmentofChemistry,UniversityofPavia, VialeTaramelli12,27100Pavia). CF3:"SOMO‐HOMOConversioninDistonicRadicalAnions:AnExperimentalTestinSolutionby EPRRadicalEquilibrationTechnique",PaolaFranchi(DepartmentofChemistry“G.Ciamician”‐ UniversityofBologna,ViaSanGiacomo11,I‐40126Bologna). CF4: "Biomass valorization using ionic liquids", Andrea Mezzetta (Dipartimento di Farmacia, UniversitàdiPisa,viaBonanno33,56126Pisa). CF5: "Synthesis of β‐Amino α‐Nitro β‐Trifluoromethyl Ketones by Nitro‐Mannich Reactions on Fluorinated Imines", Alessia Pelagalli (Dipartimento di Chimica, Università degli Studi di Roma “LaSapienza”,Roma). CF6: “Combining flow technology and microwave heating towards sustainable Metal‐catalyzed transformations”Chiara Petrucci (Laboratory of Green Synthetic Organic Chemistry, CEMIN, UniversitàdiPerugia,ViaElcediSotto,8,Perugia) CF7: "Self‐assembly of amphiphilic anionic calix[4]arene and encapsulation of poorly soluble naproxen and flurbiprofen", Luca Barbera (Dipartimento di Scienze Chimiche, Universita` di Messina,VialeF.Stagnod’Alcontres31,98166Messina). CF8: "Inverse Virtual Screening: A New Computational Approach For The Identification of The Interacting Targets of Bioactive Compounds", Gianluigi Lauro (Department of Pharmacy, UniversityofSalerno,Fisciano,Salerno). CF9:"MulticomponentSynthesisofUracilAnaloguesby Pd‐Catalyzed CarbonylativeCouplingof α‐Chloroketones, Isocyanates and Amines", Serena Perrone (Dipartimento di Scienze e TecnologieBiologicheedAmbientali,UniversitàdelSalento,Prov.leLecce‐Monteroni,Lecce). CF10: "Continuous‐flow stereoselective synthesis in 3D‐printed microreactors", Sergio Rossi (UniversitàdegliStudidiMilano,viaGolgi19,20133,Milano). CF11:"Activation ofHsp90 enzymaticactivity andconformational dynamics through rationally designed allosteric ligands", Sara Sattin (Università degli Studi di Milano, Dipartimento di Chimica,viaGolgi19,20133,Milano). CF12: "A new domino approach to lentiginosine and indolizine derivatives", Carolina Vurchio (UniversityofFlorence,DepartmentofChemistry“UgoSchiff”,viadellaLastruccia13,50019Sesto Fiorentino,Firenze). 117 Posters 118 Session Poster 1 (PC1-PC62): 1) Catalisi 2) Chimica Fisica Organica 3) Chimica Supramolecolare 4) Foldameri 5) Fotosica e Fotochimica 6) Green Chemistry 7) Sostanze Naturali Session Poster 2 (PC63-PC122): 1) Medicinal Chemistry – Chimica Bioorganica 2) Nanotecnologie 3) Sintesi Organica 119 A - Catalisi 120 PC1 Aerobic C-C Cleavage Catalyzed by Vanadium(V)-Amino Triphenolate Complexes Emanuele Amadio, Rosalia Di Lorenzo, Cristiano Zonta, Giulia Licini* Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131, Padova, Italy. e-mail: [email protected] Oxidative carbon-carbon bond cleavage of vicinal diols to carbonyl compounds is a fundamental and important reaction in fine chemical synthesis as well as in the renewable feedstock transformations such as in the oxidative valorization of lignin or cellulose.1 Since the earliest discovery in 1928,2 the cleavage of 1,2-diols has been traditionally performed with stoichiometric high-valent inorganic oxidants, like periodates or lead tetracarboxylates. However, most of these oxidants suffer from severe drawbacks in terms of toxicity and issues related to their storage, handling, cost and solubility. Therefore, one of the main goals in this area is the design of more efficient, environmentally benign and cleaner processes. Recently, the use of vanadium complexes as catalysts has emerged as a new effective method for the C-C oxidative bond cleavage using only air as final oxidant and with the corresponding formation of water as the only by-product (Scheme 1).1 Scheme 1. Aerobic C-C oxidative cleavage of diols to the corresponding carbonyl derivatives. Here we will show that vanadium(V)-amino triphenolate complexes3 are effective catalysts for this transformation. The correct tuning of the reaction conditions (catalyst, solvent, and temperature) allows the obtainment of carbonyl derivatives with high conversion and chemical yields with catalyst loading down to 0.2%. The methodology is effective with a large series of diols. The authors acknowledge the Università di Padova for funding [PRAT-CPDA123307, and Assegni Senior 2014, GRIC141OVJ. (E. A. fellowship)]. 1) 2) 3) Amadio, E.; Di Lorenzo, R.; Zonta, C.; Licini, G. Coord. Chem. Rev. 2015 and references there in. Malaprade, L.; Hebd, C. R.; Seances Acad. Sci. 1928, 186, 382. Mba, M., Pontini, M.; Lovat, S.; Zonta, C.; Bernardinelli, G; Kündig, E.P.; Licini, G. Inorg. Chem. 2008, 47, 8616-8618 121 PC2 Highly Enantioselective Mannich Reactions of Aldehydes with Quinoline-N,O-acetals by Synergistic Catalysis Francesco Berti1, Federico Malossi1, Fabio Marchetti2, Mauro Pineschi*1 1 Dipartimento di Farmacia, Sede di Chimica Bioorganica e Biofarmacia, Università di Pisa (Via Bonanno 33, 56126 Pisa, Italy). 2 Dipartimento di Chimica e Chimica Industriale, Università di Pisa (Via G. Moruzzi 3, 56124, Pisa, Italy). e-mail: [email protected] Enantioselective Mannich-type reactions represent a straightforward method for the synthesis of β-amino-carbonyl derivates. Recently, several organocatalytic approaches have been developed for an asymmetric functionalization of the key intermediate Nacyliminium ion exploiting mainly chiral Brønsted acids.1 On the other hand, the use of chiral enamine as nucleophile remains a challenging task due to the deactivation of the amine organocatalyst.2 We herein report an highly enantioselective functionalization of quinoline derivatives with the formation of two stereocenters with moderate to good diastereoselectivity. Scheme 1 The reaction exploits easily available N,O-acetals of type 1 (Scheme 1) activated in situ with Lewis or Brønsted acids in combination with Hayashi-Jørgensen catalyst L and aldehydes, according to a synergistic catalysis. The absolute configuration of compound 2 was determined by single crystal X-ray analysis indicating a lk (Si, Si) addition of the enamine to the intermediate quinolinium ion.3 Studies are ongoing in order to apply this simple and practical procedure to other challenging substrates. 1) Lee, Y. S.; Alam, M.M.; Keri, R. S. Chem. Asian J. 2013, 8, 2906. 2) For a solution to this problem, see: Mengozzi, L.; Gualandi, A.; Cozzi, P. G. Chem. Sci. 2014, 5, 3915 3) Manuscript under preparation. 122 PC3 The first enantioselective synthesis of 3-spiro--methylene-γbutyrolactoneoxindoles Lucia Cerisoli, Arianna Quintavalla, Marco Lombardo, Claudio Trombini Department of Chemistry ”G.Ciamician”, University of Bologna e-mail: [email protected] In recent years, spiro-fused oxindoles have been identified as potential bioactive compounds due to the fact that this skeleton is present in a huge amount of natural bioactive products, such as spirotryprostatins etc. For this reason the synthetic community started to investigate their chemical modification to obtain new biologically active classes of compounds.1 At the same time macrolides with -methylene-γbutyrolactone moiety have been recognized in different natural products, as sesquiterpene lactones, that presented biological activities as antitumour, phytotoxic and antibacterial compounds.2 Our purpose is the union of oxindole scaffold with the methylene-γ-butyrolactone fragment, to obtain a new class of promising highly functionalized spiro compounds.3Inspired by our previous works4 concerning the oxindoles reactivity, we investigated a new synthetic strategy for the first stereoselective synthesis of 3-spiro--methylene-γ-butyrolactoneoxindoles 4. 1) 2) 3) 4) (a) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104-6155. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748- 8758. (c) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209-2219. (a) Ogura, M.; Cordell, G. A.; Fransworth, N. R. Phytochemistry1978, 17, 957-961. (b) Kitson, R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem., Int. Ed.2009, 48, 9426-9451. (c) Bachelier, A.; Mayer, R.; Klein, C. D. Bioorg. Med. Chem. Lett. 2006, 16, 5605-5609. (a) Shanmugam, P.; Vaithiyanathan, V. Tetrahedron, 2008,64,3322-3330. (b)Shanmugam, P.; Viswambharan, B. Synlett, 2008, 2763-2768. (a) Quintavalla, A.; Lanza, F.; Montroni,E.; Lombardo, M.; Trombini, C. J. Org. Chem.2013, 78, 12049-12064. (b) Monari, M.; Montroni,E.; Nitti, A.; Lombardo, M.; Trombini, C.; Quintavalla, A.Chem. Eur. J.2015, 21, early view. 123 PC4 CeCl3 catalyzed imino Diels-Alder reactions: hydrated vs anhydrous Enrico Marcantoni1, Samuele Bordi1, Gabriele Lupidi1, Cristina Cimarelli1 1 School of Science and Technology - Chemistry division - University of Camerino e-mail: [email protected] Aza-Diels-Alder reaction is a straightforward way to synthesize useful nitrogen containing heterocyclic structures.1 In particular, the known reaction between imines and Danishefsky’s diene has proved to be an excellent way to obtain the 1,2-substituted2,3-dihydropyridinone scaffold, widely present in bioactive small molecules and versatile building block for the synthesis of more complex structures.2 The reaction of Danishefsky’s diene with aromatic imines has been widely studied in last years, anyway less examples of the same reaction involving imines derived from aliphatic amines or aldehydes are present. For this reason the possibility to extend the potentiality of this reaction performing it on a large variety of imines was studied, under the Lewis acid promoting system CeCl3.7H2O/CuI, previously applied with success3 in many other synthetic methodologies. Imines 3 were prepared by direct condensation of aliphatic or aromatic amines and aldehydes and then the diene was added together with the catalyst, obtaining dihydropyridinones 4 with good to excellent yields in short reaction times. To extend the scope of this work, also imines derived from aminoacids were tested as dienophiles. Scheme 1 1 R O CHO + H2N R* 1a-b 1a: R1 = Ph 1b: R1 = COOEt 2a-d MgSO4 CH3CN, r.t. N R* Danishefsky's diene CeCl3.7H2O/CuI 50% mol CH3CN, r.t. 1 R 3aa-ad R1 N R* 4aa-ad 2a: (R)-1-phenylethylamine 2b: (R)-phenylglycine methylester 2c: (L)-valine methylester 2d: (L)-tryptophan methylester The only moderate diastereoselectivity and the long time needed with some homochiral dienophiles prompted us to have a deeper insight into the mechanism, with the conclusion that the reaction proceed also through a slower competitive MannichMichael pathway, favoured by the presence of water in the catalyst. 1) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099-6138. 2) Cant, A. A.; Sutherland, A. Synthesis 2012, 44, 1935-1950. 3) Bartoli, G.; Marcantoni, E.; Marcolini, M.; Sambri, L. Chem. Rev. 2010, 110, 6104-6143. 124 PC5 Bioinspired Mn and Fe catalysed oxidations in Ionic media (ILs and DESs) Miquel Costas1, Marco Cianfanelli1,2, Barbara Floris2, Valeria Conte2 1 Departament de Quimica and Institute of Computational Chemistry and Catalysis (IQCC), University of Girona,Campus de Montilivi, Girona 17071 (Spain)). 2 Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, via della Ricerca Scientifica, snc, 00133 Roma, Italy. e-mail: [email protected] ILs with different physicochemical properties were used in epoxidation reaction of model alkenes with hydrogen peroxide, in particular cis-β-methylstyrene and 2cyclohexenone;1 with the ambition to recover the catalytic phase, to replace the molecular solvent and to improve the efficiency. The chiral catalyst employed were [Fe(CF3SO3)2-(S,S)-dMMPDP], [Fe(CF3SO3)2-(S,S)-dMMPDP] and [Mn(CF3SO3)2-(S,S)Me2N PDP].2 Fe catalyst provided results similar to those obtained in MeCN while, with Mn catalysts (2-3), an appreciable increase of the yield was obtained with respect to that observed in acetonitrile, accompanied by similar enantiomeric excesses. Using cis-β-methylstyrene with Mn and Fe catalysts, a more hydrophobic medium appears crucial. In recyclability experiments the yield decreased significantly after two cycles, however an improvement in the recycling procedure was obtained recharging the catalytic phase with a further amount of the catalyst. Deep eutectic solvents, a new class of “green” solvents,3 was also tested for the first time in epoxidation reactions with interesting results, even if Fe catalyst did not provide substrate conversion. Epoxide formation was observed with Mn catalyst with yields from moderate to good. The 1:2 mixture choline chloride/glycerol gave the best results in terms of yield and ee, (86% Y, 66% ee) with respect to the more viscous choline chloride/urea mixture, using cis-β-mehylstyrene as substrate. A preliminary substrates scope was performed with encouraging results. 1) The present work has been carried out within European Project COST Action: CM1003 “Biological oxidation reactions - mechanisms and design of new catalysts” between “Università di Roma Tor Vergata” and “Universitat de Girona”. 2) Cussò, O.; Garcia-Bosch, I.; Ribas, X.; Lloret-Fillol, J.; Costas, M. J. Am. Chem. Soc. 2013,135, 14871. 3) Abbott, A. P.; Capper, G.; Davies, D. L.; Rasheed, R. K.; Tambyrajah, V. Chem. Commun. 2003, 70. 125 PC6 Gold supported on silica catalyzes the aerobic oxidation of N,Ndisubstituted hydroxylamines to nitrones G. D’Adamio,1 F. Cardona,1 C. Parmeggiani,2 A. Goti1 1 Dipartimento di Chimica “Ugo Schiff”, Università degli Studi di Firenze, Via della Lastruccia 3-13, 50019 Sesto Fiorentino (FI), Italy. 2 CNR-INO and European Laboratory for Non-Linear Spectroscopy (LENS), University of Florence, Via N. Carrara 1, Sesto Fiorentino (FI), Italy. [email protected] Oxygen or air are ideal oxidants from a green chemistry point of view,1 since they are safe and inexpensive and produce only water as a co-product. The implementation of a transition metal catalyst in combination with oxygen for the oxidation of alcohols to the corresponding carbonyl compounds represents an emerging more sustainable alternative to the traditional procedures.2 The related oxidation of N,N-disubstituted hydroxylamines to nitrones is much less studied, despite the growing importance of these compounds as spin traps in biological studies and drugs for age-related diseases3,4 or as key intermediates for the synthesis of nitrogen containing biologically active compounds.5 Although bulk gold has being regarded for a long time as an inert catalyst, recently it has been recognized as surprisingly active in the form of nanoparticles.6 In this work we report our preliminary results on the oxidation of N,N-disubstituted hydroxylamines to nitrones catalyzed by a supported gold catalyst on silica previously described.7 N,N-dibenzylhydroxylamine (1) was selected as the model substrate in order to study the best conditions for the aerobic oxidation. After careful optimization of the reaction conditions, the reactivity of a series of both aliphatic and benzylic hydroxylamines, including cyclic and enantiopure ones, was examined. 1) Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437-1451; 2) Cardona, F.; Parmeggiani, C. “Transition Metal Catalysis in Aerobic Alcohol Oxidation” RSC Green Chemistry Book Series, Cambridge, 2015; 3) Dhainaut, A.; Tizot, A.; Raimbaud, E.; Lockhart, B.; Lestage, P.; Goldstein, S. J. Med. Chem. 2000, 43, 2165-2175; 4) Floyd, R. A.; Chandru, H. K.; He, T.; Towner, R. AntiCancer Agents Med. Chem. 2011, 11, 373-379; 5) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Eur. J., 2009, 15, 7808-7821; 6) Zhang, Y.; Cui, X.; Shi, F.; Deng, Y. Chem. Rev. 2012, 112, 2467-2505. 7) Biella, S; Rossi, M. Chem. Comm., 2003, 378-379. 126 PC7 Highly efficient Proline-catalysed enantioselective aldol reaction A. Tamburrini, A. Quintavalla, L. Cerisoli, M. Lombardo, C. Trombini, M. G. Emma Dipartimento di Chimica “G. Ciamician”, Università degli Studi di Bologna via Selmi 2, 40126, Bologna, Italy e-mail: [email protected] The first results obtained in the proline-catalysed direct aldol reaction represented a real breakthrough in the field of the asymmetric catalysis, paving the way to a strong development of this research area1. On the other hand, high catalyst loading, long reaction times and highly polar solvents have to be used in this reaction, mainly since proline is insoluble in commonly used organic solvents.2 In order to optimize the efficiency of this reaction, many efforts have been directed towards the design and synthesis of new more soluble and more reactive proline derivatives. Other strategies rely on the use of additives like inorganic salt, for example CoCl2,3 or organic molecules, for example thioureas,4 in order to complex proline increasing both selectivity and solubility. Unfortunately both strategies leads to an increase of the costs, because both proline-derivatives and additives are not as cheap as simple proline. In this communication, a new simple protocol for the highly efficient proline-catalysed aldol reaction will be presented, using only a certain amount of water and methanol, instead of other additives. While methanol allows proline to be dissolved in the reaction mixture, increasing the reactivity, water plays a key-role in the reaction mechanism, increasing the selectivity of the reaction. Scheme 1: Aldol reaction between cyclohexanone and aromatic aldehydes in the presence of water and methanol as additives. The new protocol has been applied first using cyclohexanone as donor, aromatic aldehydes as acceptors and only 10% of proline as the catalyst (Scheme 1). The results are very satisfactory with almost quantitative conversions, reaction time up to 4 hours and very good selectivities, with enantiomeric excess up to 99%. The scope of the reaction has been successfully expanded to different donors, like cyclopentanone and acetone, and also on less activated acceptors like aliphatic aldehydes. Since the aldol reaction is one of the most useful organic reaction in building a carboncarbon bond, this protocol may be a very useful both in scientific and in industrial applications. The reaction may be performed easily, with cheap reagents, low catalytic loadings and fast reaction times. 1) 2) 3) 4) B. List, R. A. Lerner, C. F. Barbas, J. Am. Chem. Soc. , 2000, 122, 2395. M. Bhanushali. C. Zhao, Synthesis (Stuttg). 2011, 12, 1815. A. Karmakar, T. Maji, S. Wittmann, O. Reiser, Chem. Eur. J., 2011, 17, 11024. N. El-Hamdouni, X. Company, R. Rios, A. Moyano, Chem. Eur. J., 2010, 16, 1142. 127 PC8 Enantioselective tools for the total synthesis of marine bioactive metabolites containing tetrahydrofuran moiety Mattia Fredditori, Alessio Porta, Giuseppe Zanoni and Giovanni Vidari Department of Chemistry, University of Pavia, Viale Taramelli, 10-27100, Italy [email protected] During the last years a large number of highly bioactive THF-containing macrolides has been isolated from algae and other marine invertebrates [1]. Our research group has developed an enantioselective stereodivergent methodology [2] to two key THF cores, named AC and ST compounds, starting from a single achiral precursor, the meso diol (1). The absolute configuration of the THF cores, was secured by a Pd-catalyzed asymmetric allylic alkylation using (S,S)-L1 and (R,R)-L2 ligands, respectively. Now, we are developing new catalysts in order to improve the stereoselectivity of this reaction and we are trying to extend the methodology to other meso diols bearing different substituents at C5, such as methyl, methylidene and hydroxymethyl groups. 1) A. Lorente, J. Lamariano-Merketegi, F. Albericio, and M. Álvarez, Chem. Rev., 113 (7), 2013, pp 4567–4610 . 2) M.Valli, P. Bruno, D. Sbarbada, A. Porta, G. Vidari, and G. Zanoni, JOC, 78, 2013, pp 5556-5567. 128 PC9 The mechanism of the aerobic Cu-catalysed oxidative cross-coupling of tertiary amines. An experimental and computational study. Giovanni Ghigo,1 Stefano Dughera,1 Pierpaolo Morgante1 1 Dipartimento di Chimica, Università di Torino, via P. Giuria 7-10125 Torino. e-mail: [email protected] Cross-Coupling reactions catalysed by transition metals are used since several years in the synthesis of organic molecules and applied to a wide spectrum of substrates.1 Among them, we focused our interest on the Aerobic Oxidative Cross-Coupling catalysed by copper and in particular, the reaction involving the tertiary amines.2 In this poster, we presents the preliminary results of a combined experimental and computational study of the mechanism of this reaction. Although the reaction has been extensively tested from the synthetic point of view2 the details of the reaction are still unknown. The mechanistic studies are still limited to a few experimental3 and computational4 works that have allowed only to verify the role as the oxidant of copper (Cu++) in the formation of the iminium as intermediate for the reaction with some nucleophilic reactant HNu (Scheme 1). Scheme 1 What is the real process leading to the iminium (Scheme 2), i.e. what is the specie that actually completes the oxidation through the hydrogen-abstraction (STEP 2 in Scheme 2) is still unknown. The ignorance of these details prevents an efficient application, extension and optimization of this reaction. For this reason we challenged to fill this gap with the combined use of computational and experimental methods. In particular, the roles of the counter-ion of Cu+/++ and of the molecular oxygen used as oxidant (a part from the oxidation of Cu+ to Cu++ regenerating the catalyser) are the subject of our study. The preliminary results indicate, in fact, that the commonly accepted mechanism is too naive and that it does not take in account a possible role for these species. Scheme 2 1) Yeung C. S., Dong V. M. Chem. Rev. 2011, 111, 1215–1292. 2) Zhang C., Tang C., Jiao N. Chem. Soc. Rev. 2012, 41, 3464–3484; Klussmann M., Jones. K. M. SYNLETT 2012, 23, 159–162. 3) (a) Boess, E.; Schmits, C.; Klussmann M. J. Am. Chem. Soc. 2012, 134, 5317–5325; (b) Scott, M.; Sud, A.; Boess, E.; Klussmann, M. J. Org. Chem. 2014, 79, 12033–12040. 4) Cheng, G. J.; Song, L. J.; Yang, Y. F.; Zhang, X.; Wiest, W.; Wu, Y.-D. ChemPlusChem 2013, 78, 943–951. 129 P10 Tuning of the electronic properties of armchair graphene nanoribbons by mild functionalization. Theoretical study of the 1∆g O2 border addition. Giovanni Ghigo,1 Andrea Maranzana,1 Glauco Tonachini1 1 Dipartimento di Chimica, Università di Torino, via P. Giuria 7-10125 Torino. e-mail: [email protected] Armchair graphene nanoribbons (a-GNRs) are finite strips of graphite sheets cut along a specific direction with a width < 10 nm and a length/width ratio > 10.1 They feature peculiar electronic and optical properties so they have been touted as a promising material for everything from solar cells to computers.2 The energies of their HOMOs and LUMOs, along with their difference (gap) are some of the most important parameters to be controlled in the design of organic electronic devices mechanisms.3 In this this work we propose a modification of their electronic properties through the oxidation of a-GNRs with 1∆g O2 in mild conditions.4 This process should bring about a decoration with vicinal dialdehydic groups (Figure 1) of the border of the a-GNRs via endoperoxide "1,2". Figure 1 The new material should present LUMO energies lowered by 0.3 – 0.5 eV with respect to the original material. As a consequence, the HOMO-LUMO gap should be reduced by almost the same amount, being the HOMO energy less sensitive to the oxidation. This method is intended to be alternative or complementary to the simple tuning of the a-GNRs size. 1) Duttaa, S.; Pati, S. K. J. Mater. Chem. 2010, 20, 8207–8223. 2) Novoselov, K. S.; Geim, A. K.; Morozov, S. V.; Jiang, D.; Zhang, Y.; Dubonos, S. V.; Grigorieva, I. V.; Firsov, A. A.. Science 2004, 306, 666–669. 3) Brabec, C. J.; Cravino, A.; Meissner, D.; Sariciftci, N. S.; Fromherz, T.; Rispens, M. T.; Snachez, L.; Hummelen, J. C. Adv. Funct. Mater. 2001, 11, 374–380. 4) Clennan, E. L. ; Pace, A. Tetrahedron 2005, 61, 6665–6691. 130 PC11 Multicomponent Cascade Synthesis of Biaryl-based Chalcones in Pure Water and in Aqueous Micellar Environment Nicola Armenise,[a] Danilo Malferrari,[b] Sara Ricciardulli,[a] Paola Galletti,[a,b] and Emilio Tagliavini[a,b] [a] Università di Bologna - Dipartimento di Chimica “G. Ciamician” - Via F. Selmi 2, 40126 Bologna (Italy) [b] Università di Bologna - Centro Interdipartimentale di Ricerca Industriale (CIRI) - Via S. Alberto 163, 48123 Ravenna (Italy) E-mail: [email protected] The goal of Green Chemistry is the design of chemical products and processes able to reduce or avoid the handling and emission of hazardous materials. In particular, the employment of solvents is highly concerning since it gives rise to toxicity, hazard and pollution issues. In this context the employment of water as solvent has attracted much interest in recent years. In fact, water offers many advantages because it is a cheap, readily available, non-toxic and non-flammable solvent, thus being very attractive from both an economical and an environmental point of view. Among the organic reactions that can be conducted in water, cross-coupling and aldol condensation reactions play an outstanding role; moreover, these kind of reactions can be coupled together with one-pot and sequential procedures. In particular, the one-pot synthesis of biarylchalcones in aqueous medium, through the sequential Suzuki–Miyaura coupling and aldol condensation reactions, is a challenging but attractive synthetic route. Unfortunately, the poor solubility of many substrates in water, the formation of β-arylated ketones as side product and other drawbacks still limit the exploitation of this strategy. Looking for the sustainability of the synthetic processes, we have developed an highly efficient protocol aimed to the multicomponent cascade synthesis of biaryl(hetero)chalcones and of their functionalized derivatives, in pure water or in aqueous micellar system, overcoming the existing drawbacks. The first step of our protocol is a simple Pd-catalyzed, ligand-free and aerobic Suzuki-Miyaura reaction in aqueous medium, which has proved to be extremely efficient for the coupling of aryl and heteroaryl bromides with different arylboronic acids. The second step consists of the addition of the third substrate (ketone or aldehyde) that undergoes in situ aldol condensation reaction. When the protocol was applied to highly lipophilic or less reactive reagents, micellar catalysis was required for achieving good performances. To this aim we successfully employed a new surfactant that we recently designed from renewable resources. Furthermore, thanks to this additive, the catalytic system could be repeatedly recycled without significant loss of activity. 131 PC12 The Osmium-Catalysed Tethered Aminohydroxylation of Glycals: A Stereodirected Access to 2- and 3-Aminosugars Stefania Mirabella1, Francesca Cardona1, Andrea Goti1 1 Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 3-13, Sesto Fiorentino (FI), Italy. [email protected] The aminohydroxylation reaction is an extremely useful method for the oxidation of alkenes to form 1,2-aminoalcohols. This moiety is present in important synthetic pharmaceutical targets like aminosugars, key constituents of a wide variety of natural substances.1 In 2001, Donohoe and co-workers introduced an innovative method to obtain vicinal aminoalcohols through an intramolecular aminohydroxylation of olefins, called “tethered aminohydroxylation”.2 This method is an adaptation of the Os-mediated Sharpless aminohydroxylation, but it guarantees a full regiocontrol by tethering the nitrogen source to the allylic alcohol. We describe herein the results of the application of this method on D-glucal and D-galctal and on their derivatives, in order to obtain 2amino and 3-aminosugars with different configurations at the stereogenic carbon atoms depending on the starting glycals.3 Glucals and galactals showed complementary reactivity in dependence of the stage at which the reaction was performed, i.e., directly or after double-bond shift consequent to a Ferrier rearrangement. This method allows access to both classes of 2-amino (compound 1-2) and 3-amino (compound 3) sugar derivatives (Scheme 1). The oxazolidinone moiety of the compound 3 was easily removed with a basic treatment to obtain the free 3-aminosugar with excellent yield. Scheme 1 1) Rai, R.; McAlexander, I.; Chang, C. T. Org. Prep. Proced. Int. 2005, 37, 337-375. 2) a. Donohoe, T. J.; Johnson, P. D.; Helliwell, M.; Keenan, M. Chem. Commun. 2001, 2078-2079. b. Donohoe, T. J.; Callens, C. K. A.; Lacy, A. R.; Winter, C. Eur. J. Org. Chem. 2012, 655-663. 3) Mirabella, S.; Cardona, F.; Goti, A. Org. Lett. 2015, 17, 728-731. 132 PC13 Synthesis of β-Amino -Nitro β-Trifluoromethyl Ketones by NitroMannich Reactions on Fluorinated Imines Stefania Fioravanti, Alessia Pelagalli, Lucio Pellacani Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza” e-mail: [email protected] Trifluoromethyl ketones are compounds of considerable interest due to their importance as synthetic intermediates of other trifluoromethyl-containing targets (1) as well as for biological activity (2). Of even greater importance and interest is the synthesis of nitrogenated trifluoromethyl carbonyl compounds and here we report our first results on the -nitro ketone (3) additions to trifluoromethyl N-protected aldimines (4) by nitro-Mannich reactions (5). The nitro-Mannich additions were performed under solvent-free conditions and without added catalyst and can be considered a good example of green chemistry. In fact, the reactions took place at room temperature, with very low environmental impact, no work-up was needed and they proceeded with total atom economy. Starting from optically pure primary amines, even the stereochemical reaction outcome was successfully studied. 1) 2) 3) 4) 5) (a) Zhang, P.; Wolf C. J. Org. Chem. 2012, 77, 8840–8844; (b) Gao, J.-R.; Xiang, H. Wu, B.; Yu, W.-B.; Han, L.; Jia Y.-X. J. Am. Chem. Soc. 2013, 135, 2983–2986. (a) Kelly, C. B.; Mercadante, M. A.; Leadbeater N. E. Chem. Commun. 2013, 49, 11133–11148; (b) Ilies, M.; Dowling, D. P.; Lombardi, P. M.; Christianson D. W. Bioorg. Med. Chem. Lett. 2011, 21, 5854–5858; (c) Kokotos, G.; Hsu, Y.-H.; Burke, J. E.; Baskakis, C.; Kokotos, C. G.; Magrioti, V.; Dennis E. A. J. Med. Chem. 2010, 53, 3602–3610. Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A. Tetrahedron 2005, 61, 8971–8993. Carroccia, L.; Fioravanti, S.; Pellacani, L.; Tardella, P. A. Synthesis 2010, 4096–4100. Nobel, A.; Anderson, J. C. Chem. Rev. 2013, 113, 2887–2939. 133 PC14 Combining flow technology and microwave heating towards sustainable Metal-catalyzed transformations Chiara Petrucci1, Elena Petricci2, Ferdinando Pizzo1, Luigi Vaccaro1 1 Laboratory of Green Synthetic Organic Chemistry, CEMIN, Università di Perugia, Via Elce di Sotto, 8 – Perugia; http://www.dcbb.unipg.it/greensoc. 2 Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via Aldo Moro, 2 – Siena e-mail: [email protected] In the development of new synthetic strategies towards interesting molecules the sustainability aspect cannot be neglected, i.e. the number of steps, the waste and the energy required should be minimized, while efficiency and selectivity must be enhanced. Our research activity aims at the development of sustainable synthetic processes, through the use of safer reaction media (water, azeotropes, biomass-derived) or SolFC, and the preparation of novel organic/inorganic supports for heterogeneous catalysis.1 The final optimization of the processes can be achieved with the flow technology, which enables us to exploit the features of the selected medium and catalyst.2 In this contribution, we present the results of the application of green synthetic strategies to several metal-catalyzed reactions, fundamental tools that enable the access to molecular moieties often found in the preparation of pharmaceutical targets and organic semiconductors. The use of heterogeneous catalysts in combination with the flow technology and microwave heating proved effective in minimizing waste, simplifying experimental procedures and in safety improvement. Moreover, with the use of flow reactors we were able to limit the effect related to the formation of hotspots during microwave heating. 1) Pavia, C.; Ballerini, E.; Bivona, L. A.; Giacalone, F.; Aprile, C.; Vaccaro, L.; Gruttadauria, M. Adv. Synth. Catal. 2013, 355, 2007; Petrucci, C.; Strappaveccia, G.; Giacalone, F.; Gruttadauria, M.; Pizzo, F.; Vaccaro, L. ACS Sustainable Chem. Eng.2014,2, 2813; Ismalaj, E.; Strappaveccia, G.; Ballerini, E.; Elisei, F.; Piermatti, O.; Gelman, D.; Vaccaro, L. ACS Sustainable Chem. Eng. 2014, 2, 2461; Strappaveccia, G.; Ismalaj, E.; Petrucci, C.; Lanari, D.; Marrocchi, A.; Drees, M.; Facchetti, A.; Vaccaro, L. Green Chem. 2015, 17, 365; Strappaveccia, G.; Luciani, L.; Bartollini, E.; Marrocchi, A.; Pizzo, F.; Vaccaro, L. Green Chem. 2015, 17, 1071; Petrucci, C.; Cappelletti, M.; Piermatti, O.; Nocchetti, M.; Pica, M.; Pizzo, F.; Vaccaro, L. J. Mol. Catal. A: Chem. 2015, 401, 27. 2) Vaccaro, L.; Lanari, D.; Marrocchi, A.; Strappaveccia, G. Green Chem. 2014, 16, 3680. 134 PC15 Exploiting Ethanolamines as Green and Sustainable Alkylating Agents in Iridium-Catalyzed Alkylation of C−H Bonds Using Borrowing Hydrogen Methodology Giovanni Di Gregorio, Silvia Bartolucci, Michele Mari, Giovannni Piersanti Department of Biomolecular Sciences, University of Urbino “Carlo Bo” e-mail: [email protected] Carbon−carbon bond formation reactions are fundamentally important transformations in organic synthesis.1 The formation of C−C bonds by the electrophilic alkylation of an alkyl halide/pseudohalide with a nucleophile results in the production of a stoichiometric amount of salt as well as the desired alkylation product. The use of alcohols as direct alkylating agents is generally limited due to the poor electrophilicity of most alcohols, although such a procedure is appealing since the only reaction byproduct is water.2 The use of the hydrogen autotransfer (or hydrogen borrowing) strategy overcomes the lack of reactivity by reversible changes in the oxidation state of the reacting partners. In essence, a catalyst (generally transition-metal such as Ir, Pd, Rh, Ru, etc.) alters the reactivity of a compound (tipically alcohols) by removing two hydrogen atoms in a formal oxidation of the substrate. This temporarily generates a highly reactive intermediate and permits bond formation to take place. Finally, the intermediate is reduced with the redelivery of two hydrogen atoms, giving a product without a net change in the overall oxidation state.3 Hydrogen borrowing represents already a promising alternative approach for the formation of C−C bonds of carbonyl compounds, as well as relatively unactivated substrates bearing fewer acidic αhydrogens, such as nitriles, esters, malonates using simple alcohols as the alkylating agent.4 However, the direct alkylation of nonacidic C−H bonds, such as aromatic or heteroaromatic C−H bonds, with alcohols has scarcely been reported.5 In addition, very little is know about the use of alcohols containing aminoethylene moieties although they could be suitable two-carbon nitrogen-containing electrophiles highly desiderable for C2N unit that is found in a number of drug and is a common motif in countless naturally occurring compounds. (Scheme 1) Scheme 1 1) Caine, D. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Patternden, G. Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 1. 2) The Functional group interconversion (FGI) of nonderivatized alcohols was recently voted as the second most desired reaction that pharmaceutical companies wanted a greener version of. See : Green Chem. 2007, 9, 411. 3) (a) Gunanathan, C.; Milstein, D. Science 2013, 341, 249. (b) Watson, A. J. A.; Williams, J. M. J. Science 2010, 329, 635. 4) (a) Obora, Y. ACS Catal. 2014, 4, 3972. (b) Pan, S.; Shibata, T. ACS Catal. 2013, 3, 704. 5) Bartolucci, S.; Mari, M.; Bedini, A.; Piersanti, G.; Spadoni G. J. Org. Chem. 2015, 80, 3217. 135 PC16 Enantioselective Organocatalyzed Vinylogous Mannich-Type Reaction Involving Isatin G. Rainoldi, G. Lesma, A. Silvani, M. Stucchi Dipartimento di Chimica, Università di Milano, via Golgi 19, 20133, Milano, Italy. e-mail: [email protected] The reactions at the C-3 carbonyl group of isatins, by nucleophilic addition or spiroannulation, transform them into 2-oxindole derivatives, featuring in a large number of natural and unnatural compounds with important biological activities.1 Going on with our interest in the asymmetric synthesis of 3,3-disubstituted oxindoles,2 we are developing a project aimed to explore the applicability of organocatalysis, particularly chiral Brønsted acid catalysis,3 to the enantioselective synthesis of quaternary 3-aminooxindole butenolides, through the vinylogous Mannich-type reaction of trimethylsilyloxyfuran and isatin-derived ketimines. The application of such reaction to ketimines remains to date largely unexplored,4 due to the steric challenge inherent in the stereocontrolled formation of a quaternary stereogenic center consecutive with a bulky tertiary one. Reaction of trimethylsilyloxyfurans with various preformed imines, derived from Nprotected isatins and benzhydrylamine, allowed us to access a small family of highly functionalized diastereoisomeric compounds, in high yields and enantiomeric eccesses. To demonstrate the synthetic utility of the Mannich-type adducts, transformation reactions are presently in progress, in order to increase the number of potentially useful compounds. The assignment of the absolute and syn/anti relative configuration through X-ray diffraction is currently underway on selected compounds, as well as computational studies aimed to explain the stereochemical outcome of this organocatalyzed process. 1) 1. Singh, G.S.; Desta, Z.Y. Chem. Rev. 2012, 112, 6104. 2) Lesma, G.; Meneghetti, F. Belstein J. Org. Chem. 2014, 10, 1383. 3) Mahalau, M.; List, B. Angew. Chem. Int. Ed. 2013, 52, 518. 4) Bhaskara Rao V.U., Jadhav P.A., Org. Lett., 2014, 16, 648; Hermange P., Dodd R.H., Org. Lett., 2009, 11, 4044; Wieland L.C., Hoveyda A.H., J. Am. Chem. Soc., 2009, 131, 570; Hayashi M., Nakamura S., Angew. Chem. Int. Ed., 2013, 52, 5557; Shy Y.H., Wang Z., Tetrahedron, 2012, 68, 3649. 136 PC17 V-catalyzed oxidation of thymol with hydrogen peroxide Federica Sabuzi, Paola Pesce, Valeria Conte, Pierluca Galloni, Barbara Floris Università di Roma Tor Vergata, Via della Ricerca Scientifica, 00133, Roma, Italia e-mail: [email protected] The reaction between Vanadium (V) derivatives and hydrogen peroxide or alkyl hydroperoxide leads to the formation of peroxocomplexes which are the effective oxidating species of organic and inorganic substrates in both, stoichiometric and catalytic conditions1. In this context, recently good results have been achieved in the oxidative bromination of thymol2, a monoterpenoid phenol compound, main component of the Thymus vulgaris essential oils. Bromination reaction proceeded with no organic solvents, in very mild conditions and using sustainable reactants. The process showed high substrate conversion and selectivity toward the formation of 4-bromothymol. Occasionally, among reaction products, the presence of the oxidation product, thymoquinone, has been detected. Considering the great importance of such quinoid compound in medical field3 and the lack of effective synthetic methods in the literature4, our interest has been focused on the possibility to oxidize thymol in water, using hydrogen peroxide as primary oxidant and a commercially available V-catalyst. OH O H2O2 NH4VO3 O Scheme 1: V-catalyzed oxidation of thymol The oxidative procedure has been explored and results will be reported. 1) Conte V.; Floris B. Dalton Trans., 2011, 40, 1419-1436; Conte V.; Coletti A.; Floris B.; Licini G.; Zonta C. Coord. Chem. Rev., 2011, 255, 2165-2177; Conte V.; Coletti A.; Mba M.; Zonta C.; Licini G. Coord. Chem. Rev., 2011, 255, 2345–2357. 2) Sabuzi F.; Churakova E.; Galloni P.; Wever R.; Hollmann F.; Floris B.; Conte V. Eur. J. Inorg. Chem., 2015, in press DOI:10.1002/ejic.201500086. 3) Guimarães A. G.; Quintans J. S. S.; Quintans-Júnior L. J. Phytother. Res., 2012, 27, 1-15; Vieira Sobral M.; Lira Xavier A.; Cardoso Lima T.; Pergentino de Sousa D. Scientific World J., 2014, 2014, 1-35; Razavi B. M.; Hosseinzadeh H. J. Endocrinol. Invest., 2014, 37, 1031–1040. 4) Henderson G. G.; Boy R. J. Chem. Soc. Trans., 1910, 97, 1659-1669; Dockal E. R.; Cass Q. B.; Brocksom T. J.; Brocksom U.; Correa A. G. Synth. Commun., 1985, 15, 1033-1036. 137 PC18 One-pot, four-step organocatalytic asymmetric synthesis of functionalized nitrocyclopropanes Anna Zaghi, Tatiana Bernardi, Valerio Bertolasi, Olga Bortolini, Alessandro Massi, Carmela De Risi Dipartimento di Scienze Chimiche e Farmaceutiche, Via Fossato di Mortara 17, 44121 Ferrara (Italy) e-mail: [email protected] Nitrocyclopropanes represent a special class of cyclopropane compounds,1 which are present in some natural products and used as precursors of pharmacologically relevant targets. In the last few decades, there has been a renewed interest in the stereoselective synthesis of nitrocyclopropanes, which is most frequently achieved through Michael initiated ring closure (MIRC) reactions between electrophilic alkenes and suitable nucleophiles bearing a good leaving group.2 Recently, it has been reported that racemic 2,5-dihydrothiophene-3-carbaldehydes 2, obtained by secondary amine-catalyzed domino sulfa-Michael/aldol condensations of 1,4-dithiane-2,5-diol 1 with ,-unsaturated aldehydes, are convenient substrates for diastereoselective cyclopropanations with bromonitromethane to give the bicyclic nitrocyclopropanes 3 via domino Michael/-alkylation reactions catalyzed by 3 DLproline. As a logical extension of this work, it has been investigated an asymmetric version of the above process by using a chiral proline surrogate as catalyst, with the aim at combining the two catalytic domino sequences to access the target nitrocyclopropane scaffolds by a challenging four reaction, one-pot process. Our studies led to disclose a one-pot, four-step method wherein chiral dihydrothiophenes 2, prepared by an organocatalytic domino sulfa-Michael/aldol condensation reaction, are treated in-situ with bromonitromethane anion to provide the target compounds 3 with good diastereo- and enantioselectivies (Scheme 1). This process is efficiently carried out by using (S)-diphenylprolinol TMS ether 4 as the only and one organocatalyst triggering both the domino sulfa-Michael/aldol condensation step and the following domino Michael/-alkylation reaction. Scheme 1 1) 2) 3) For reviews on synthesis and use of nitrocyclopropanes, see: a)E. B. Averina; N. V. Yashin; T. S. Kuznetsova; N. S. Zefirov Russ. Chem. Rev. 2009, 78, 887-902; b) R.Ballini;A.Palmieri;D. Fiorini,Arkivoc2007,vii,172‐194. G. Bartoli; G. Bencivenni; R. Dalpozzo Synthesis 2014, 46, 979-1029. De Risi, C.; Benetti, S.; Fogagnolo, M.; Bertolasi V. Tetrahedron Lett. 2013, 54, 283-286. 138 B – Chimica Fisica Organica 139 PC19 Stable diarylmethylium salts as reagents and catalysts Margherita Barbero1, Silvano Cadamuro1, Stefano Dughera1, Giovanni Ghigo1, Domenica Marabello2 1 Dipartimento di Chimica (Università di Torino, Via P. Giuria 7, 10125 Torino) 2Dipartimento di Chimica e CrisDi (Università di Torino, Via P. Giuria 7, 10125 Torino) e-mail: [email protected] We have recently reported the synthesis of a representative number of bench-stable and ready to use non-symmetric diarylcarbenium tetrafluoroborates via the direct coupling of aryl (or heteroaryl) aldehydes and N-heteroarenes (Scheme 1).1 Some of them have been previously isolated as long shelf life o-benzenedisulfonimides,2 which have been recently employed in a direct organocatalyzed asymmetric alkylation of aldehydes.3 The presence of the azole moiety (whether isolated or benzene-fused) is the crucial framework for the high stability of these diarylcarbenium ions due to the vinylogous iminium (alkylideneindoleninium) substructure stabilization. Scheme 1 The easy preparation procedure, ready to use availability, high stability and structure variety of these normally highly reactive intermediates, along with the commercial availability of the tetrafluoroborate anion, make them a tool of great synthetic relevance in organic chemistry for the synthesis of more complex structures. On the other hand, carbocations represent an hitherto almost completely neglected but very versatile Lewis acid class.4 Researches are currently under way on our laboratory on suitable reactions of these reactive species as electrophilic reagents in reactions with nucleophiles such as activated aromatics and cyclic silyl enol ethers, where good yields and diastereomeric ratio are observed. Meanwhile, they are tested in catalytic amounts in Lewis acid catalyzed organic reactions (e.g. Michael additions, dehydrative coupling). 1) Barbero, M.; Buscaino, R.; Cadamuro, S.; Dughera, S.; Gualandi, A.; Marabello, D.; Cozzi, P. G. J. Org. Chem. 2015, 80, 47914796. 2) Barbero, M.; Cadamuro, S.; Cauda, F.; Dughera, S.; Gervasio, G.; Venturello, P. J. Org. Chem. 2012, 77, 427887. 3) Armenise, N.; Dughera, S.; Gualandi, A.; Mengozzi, L.; Barbero, M.; Cozzi, P. G. Asian J. Org. Chem. 2015, 4, 337345. 4) Bah, J; Naidu, V. R.; Teske, J.; Franzen, J. Adv. Synth. Catal. 2015, 357, 148158. 140 PC20 Peptide-based Low Molecular Weight Gelators: their versatility and applications S. Bartocci1, M. Mba1 1 Department of Chemical Sciences, University of Padova Via Marzolo 1, 35131 Padova, Italy e-mail: [email protected] Supramolecular gels derived from low molecular weight gelators (LMWGs)1 received great attention in recent years and it is possible to design many different gelators with very different structures but, despite the structural variety, the self-assembly into fibrous networks is always driven by non-covalent interactions like van der Waals interactions, π-interactions, hydrogen bonding and so on. The reason of such an interest is not only to study and understand the fundamental aggregates structures but also to explore their technological applications. Indeed, a clever incorporation of sensitive units as part of the gelator molecule lead to obtain stimuli-responsive gels that respond to the change in their surroundings such as solvent, temperature, pH, light, ultrasound etc. that can be exploited as smart materials which have sensor, processor and actuator functions. Among the different small organic compounds able to form supramolecular gels, peptides are really good low molecular weight gelators since they give secondary structures through hydrogen bond formation moreover the synthetic protocol is well established and is possible to choose in a pool of 20 natural amino acids. In this work we report our last achievements in this field showing the ease of synthesis of these systems and their versatility2, 3. Scheme 1 1) Abdallah, J.; Weiss, R. G. Adv. Mater. 2000, 17, 1237-1247. 2) Bartocci, S.; Mazzier, D.; Moretto, A.; Mba, M. Org. Biomol. Chem. 2015, 13, 348-352. 3) Morbioli, I.; Bartocci, S.; Maggini, M.; Mba, M. J. Pept. Sci. submitted 141 PC21 Predictions of the nucleofugality of carbanionic leaving groups based upon NMR chemical shifts in the enantioselective synthesis of sulfoxides Maria Annunziata M. Capozzi1, Cosimo Cardellicchio2 1 2 Dipartimento di Chimica, Università di Bari, via Orabona 4, Italy. CNR ICCOM; Dipartimento di Chimica, Università di Bari, via Orabona 4, Italy.. e-mail: [email protected] Our sequential coupling of Grignard reagents with suitable sulfinyl compounds involving the displacement of carbanionic leaving groups is now a well established procedure1 for the synthesis of enantiopure sulfoxides. Scheme 1 After our synthetic and mechanistic investigation on the straightforward synthesis of selected sulfinyl precursors through a highly enantioselective oxidation of the sulfides with hydroperoxide in the presence of a complex between titanium and hydrobenzoin, more than 40 enantiopure aryl benzyl sulfoxides are now easily available as starting materials.2 Thus, we decided to give a deep insight into the reaction of organometallic reagents with the enantiopure items of this chemical library. We found that the nucleofugality of the leaving groups, and the order in the sequence of substitution, can be tuned by choosing the aryl benzyl sulfoxide that bears appropriate substituents on both the phenyl groups. We report now that the nucleofugality of the carbanionic leaving groups can be predicted by comparing analogous NMR chemical shifts of signals of the starting sulfoxides. The agreement between the experimental results and the expectations will be briefly surveyed. (1) Wojaczyńska, E.; Wojaczyński, J. Chem. Rev. 2010, 110, 4303-4356. O’ Mahony, G. E.; Kelly, P.; Lawrence, S. E.; Maguire, A. R. ARKIVOC 2011, 1-110. (2) Naso, F., Capozzi, M.A.M.; Bottoni, A.; Calvaresi, M.; Bertolasi, V.; Capitelli, F. Chem. Eur. J. 2009, 10, 13417-13426. Capozzi, M.A.M.; Centrone, C.; Fracchiolla, G.; Naso, F.; Cardellicchio, C. Eur. J. Org. Chem. 2011, 4327-4334. Capozzi, M.A.M.; Capitelli, F.; Bottoni, A.; Calvaresi, M.; Cardellicchio, C. ChemCatChem 2013, 5, 210-219. Capozzi, M.A.M.; Terraneo, G.; Cavallo, G.; Cardellicchio, C. Tetrahedron, 2015, 4810-4816 and references therein. 142 PC22 Stability study of synthetic organic pigments and dyes used in contemporary paintings Alessandro Ciccola1, Marcella Guiso1, Armandodoriano Bianco1 1 Dipartimento di Chimica, “Sapienza” Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, e-mail: [email protected] Industrial revolution represented a threshold of complete change also in artistic field: the synthesis of new colouring molecules offered new colours to the artists, who could obtain new painting materials, less expensive and easy to use.1 These compounds, like azopigments, quinacridones, anthraquinones and pthalocyanines, are typically organic and they have replaced the inorganic historical pigments. However, because of their industrial and recent origin, their stability in a pictorial film is unknown. After all, it is plausible that the organic nature of these molecules could be responsible of their susceptibility to chemical degradation.2 Figure 1: examples of structures of common synthetic pigments. In this study, part of a PhD project, we monitor and characterize the degradation products of some selected organic pigments. Starting from the preparation of standard samples of pictorial films, combining the pigments with organic binders used in contemporary art (oil, acrylic, etc.), we monitor their accelerated aging process, using UVA and UVB lamps. This process causes the formation of degradation products, which would be characterized with mass spectrometry and NMR techniques. The identification of their structures could result useful to understand reactions involved in pictorial film alteration and to identify optimal conditions for conservation of contemporary artworks. Besides, these samples will be analysed with several analytical techniques used in cultural heritage, as Raman spectroscopy3 and chromatography.4 Synergy among all these techniques would supply useful information for the analysis of art objects. 1) Herbst W., Hunger K., Industrial Organic Pigments, WILEY-VCH Verlag GmbH & Co. KGaA, 2004 2) Papliaka Z. E., Andrikopoulos K. S., Varella E. A., Study of the stability of a series of synthetic colorants applied with styrene-acrylic copolymer, widely used in contemporary paintings,concerning the effects of accelerated ageing, Journal of Cultural Heritage 2010, 11 () 381–391 3) Schulte F., Brzezinka K., Lutzenberger K., Stege H., Panne U., Raman spectroscopy of synthetic organic pigments used in 20th century works of art, J. Raman Spectrosc. 2008; 39, 1455–1463 4) Brosseau C. L., Gambardella A., Casadio F., Grzywacz C. M., Wouters J., Van Duyne R. P., Ad-hoc Surface-Enhanced Raman Spectroscopy Methodologies for the Detection of Artist Dyestuffs: Thin Layer Chromatography-Surface Enhanced Raman Spectroscopy and in Situ On the Fiber Analysis, Anal. Chem., 2009, 81, 3056–3062 143 PC23 SOMO-HOMO Conversion in Distonic Radical Anions: An Experimental Test in Solution by EPR Radical Equilibration Technique Marco Lucarini1, Elisabetta Mezzina1, Paola Franchi1 1 Department of Chemistry “G. Ciamician” (University of Bologna, Via San Giacomo 11, I-40126 Bologna, Italy)). e-mail: [email protected] Knowledge of the energy required to break bonds and energy released on making bonds are basic to our understanding of chemical reactivity. This is definitely true for reactions involving free radical intermediates. For these reactions, knowledge of the dissociation energies (BDEs) of the bonds that are being broken and made is generally sufficient to predict their thermochemistry and thus their feasibility. In this context it is of great relevance the recent report of Coote and co-authors who predicted by theoretical calculations an unexpected radical stabilization in distonic radical anions where a truly remote negative charge (such as carboxylate, sulfate or phosphate) and a stable radical center (aminoxyl, peroxyl or aminyl) are separated by more than 5 Å and are not πconjugated.1-2 This effect was ascribed to an inversion of SOMO and HOMO energy levels of the radical.1-2 In order to verify under real conditions (i.e. in solution) Coote’s computational predictions, we decided to measure the BDEs of O-H bonds in hydroxylamines deriving from neutral and deprotonated forms of 4-carboxy-TEMPO in solution (acetonitrile and dimethylsulfoxide) by using the EPR radical equilibration technique (see Scheme 1).3 Scheme 1 The experimental results indicated that the stabilizing interaction between a remote negative charge and a stable radical center, predicted in gas phase, is completely lost in polar solvents.4 1) 2) 3) 4) Grin’ova, G.; Marshall, D. L.; Blanskby, S. J.; Coote, M. L. Nat. Chem. 2013, 5, 474. Grin’ova, G.; Coote, M. L. J. Am. Chem. Soc. 2013, 135, 15392. Lucarini, M.; Pedulli, G.F. Chem. Soc. Rev. 2010, 39, 2106. Franchi, P.; Lucarini, M.; Mezzina, E. J. Am. Chem. Soc. 2014, 136, 1250. 144 PC24 Characterization of compounds present in the ammonia extract of Madder lake, using NMR, ESI-MS and HPTLC-SERS L. Lombardi1,2, C. Fasolato3, I. Serafini1,2, M. Guiso1, F. Sciubba1, P. Postorino3, A. Bianco1 1 Dipartimento di Chimica, 2Dipartimento di Scienze della Terra,3Dipartimento di Fisica Università di Roma “La Sapienza” , Piazzale A. Moro 5, Roma ( Italy) <[email protected]> Until the introduction of synthetic dyes in the XIX century, artworks were realized using lakes prepared from natural raw materials. The precipitation of lake pigments occurs due to the formation of a complex with different cations. The complexes thus obtained are particularly stable and therefore insoluble in water or common organic solvents. This work was aimed at the identification of compounds present in the ammonia extract of Madder lake. To perform the analysis, it is necessary the breakdown of the complex and then extract the compounds. The most common method used until now had been a mixture of organic solvent with strong acid as HCl or H2SO4 [1]. This method ensured high yield of extraction producing, however, hydrolysis, alteration of original compounds in the sample and allowing only the identification of the main aglycones. Our new extraction method [2], was developed in order to preserve the glycoside compounds present and then to get closer to the real molecule pattern involved in lake precipitation. In fact, understanding the chemical nature of the compounds is very important in order to adequately respond to questions regarding for example the proper storage conditions, the dating or the provenance of an artwork. The first step of the research was the preparation of samples of Madder lake from Rubia tinctorum L., following the recipes contained in the ancient and medieval recipes [3,4]. Then a chromatographic separation of ammonia extract was performed. In order to identify the isolated compounds, NMR, ESIMS and HPTLC-SERS (Surface Enhanced Raman Spectroscopy) analysis were carried out (example in Fig.1). Fig. 1 – Example of HPTLC-SERS results To identify these compounds in artworks, it is very important to apply a technique that allow a rapid, minimally invasive and highly sensitive identification of these natural organic dyes. We developed a new analytical protocol, the micro-sampling with Ag-gel matrix associated with SERS analysis [4] that presents these characteristics and, for this reason, could be very useful in the field of diagnostic for Cultural Heritage. To interpret the SERS spectra of micro-samples on Ag-gel matrix, we use as reference spectra those obtained from HPTLC-SERS analyses. 1) Wouters J. Stud. Conservation. 1985, 30, 119-128. 2) Lombardi L. ; Serafini I. ;Guiso M. ; Sciubba F. ; Bianco A. , 2015, Tetrahedron Letters, submitted to 3) Merrifield M. P., London 1849 4) Lombardi L. , Guiso M., Santamaria U. , Bianco A. , Book of abstracts TECHNART 2015 145 PC25 Stereochemical lability of 2,5-diphenyl-1,3,4 oxadiazoline and -1,3,4 thiadiazoline chiral derivatives: effects of solvent and substituent groups. Roberto Cirilli1, Simona Distinto2, Maria L. Sanna2, Elias Maccioni2, Sergio Menta3, Marco Pierini3 1 Dipartimento del Farmaco (Istituto Superiore di Sanità, V.le Regina Elena, 299, 00161 Rome, Italy). 2 Dipartimento Farmaco Chimico Tecnologico (Università di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy). 3 Dipartimento di Chimica e Tecnologie del Farmaco (Sapienza, University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy). e-mail: [email protected] The 1,3,4 oxadiazole and 1,3,4-thiadiazole rings, two five-membered heterocycles, as well as their totally or partially reduced forms (i.e. the -diazolidine or -diazoline cycles), characterize molecules endowed with a wide spectrum of pharmacological activities1,2 (e.g. antimicrobial, fungicidal, anticancer, antiviral, analgesic and anti-inflammatory activity, etc.). Accordingly, these peculiar structural frameworks can be observed in a variety of medicinal agents, thus that their insertion within suitable molecular structures can constitute a successful strategy for the synthetic development of new drugs. With attention to the particular cases of the 1,3,4 oxadiazoline and 1,3,4 thiadiazoline rings as pharmacologically significant scaffolds, we performed a study concerning the stereochemical lability expressed by 2,5-diphenyl-substituted chiral derivatives of these heterocycles (Scheme 1). The tendency to lose the stereo-integrity at the asymmetric carbon C2 has been experimentally investigated on compound 1 by determining the relevant enantiomerization rate constant within eleven solvents endowed with very different polarities and proticities. The obtained findings have been rationalized by resorting to extensive LSER analyses and molecular modelling investigation. Through DFT calculations, information have also been achieved about the effects exercised on the enantiomerization barrier by electron-donor and -withdrawing groups substituting the 2-phenyl ring and/or the 3-nitrogen atom of both the oxadiazoline and thiadiazoline structures. The overall results have been discussed in the perspective to make rational the design of new chiral pharmacological agents based on these heterocycles which are endowed with high configurational stability. R3 R1 N N X R4 Br X=O 1,3,4 oxadiazoline derivative X=S 1,3,4 thiadiazoline derivative X=O R1 = R2 Compound 1: Scheme 1 R2 = R3 = R4 = R1 O R2 = R 3 O Cl CN O R4 H Cl O H CH3 NO2 OCH3 NH2 1) Abu-Zaied, M.A.Z.; Nawwar, G.A.M.; Swellem1, R.H.; El-Sayed, S.H. Pharmacology & Pharmacy, 2012, 3, 254-261. 2) Asif M. American Journal of Current Organic Chemistry 2014, 1, 17-36 146 PC26 Acid-base equilibria in ionic liquids Gabriella Siani, Romina Zappacosta, Antonello Di Crescenzo, Antonella Fontana Dipartimento di Farmacia, Università “G. d’Annunzio” via dei Vestini, 31- 66100 Chieti. e-mail: [email protected] Ionic liquids (ILs) are low temperature molten organic salts, with melting points lying often below room temperature. Due to their peculiar properties, such as low volatility, low flammability and high stability, they have been widely used in the last two decades as alternative reaction media to conventional organic solvents for many organic reactions.1 Aliphatic amines2,3 and pyridines4 have been used as nucleophiles or bases in organic reactions performed in ILs. In some cases, rate constants are higher than those expected on the basis of the pKa values in water, suggesting a higher nucleophilicity/basicity of amines in ILs than in conventional organic solvents. It is well known that the acid-base strength depends on the solvent and it is reasonable to expect that acids and bases can differently interact with a molecular solvent and an ionic solvent. Hence, particular caution is necessary if pKa values determined in water are used to rationalize quantitative results obtained in ILs. In a previous work5 we have determined the equilibrium constants for ion pair formation, Kip, of some pyridines with trifluoroacetic acid in different ionic liquids. It turned out that the basicity order is the same in ionic liquids and in water and pyridine basicity is less sensitive to the substituent effect in ionic liquids than in water. In the present work we have determined the ion-pair basicity in ILs of various substituted anilines and other bases as a further extension of the earlier established basicity scale for pyridines. The ion-pair basicity has been estimated quantitatively from the aptitude of the base to take a proton from trifluoroacetic acid. The values of Kip have been measured in ILs, obtained from the combination of different cations and anions, by spectrophotometric titration, adding increasing amounts of TFA to a solution of the base. The effects of the different ILs cation/anion compositions on the ion-pair basicities have been discussed. To compare more rigorously the basicities in ILs and in water, the experimental Kip values have been corrected for ion-pairing using the Fuoss equation to obtain relative ionic basicities, Ka 1) Chiappe, C.; Pieraccini, D. Eur. J. Org. Chem. 2002, 2831-2837. 2) D’anna, F.; Noto, R. Tetrahedron. 2007, 63, 11681-11685. 3) D’anna, F.; Frenna, V.; La Marca, S.; Noto, R.; Pace, V.; Spinelli, D. Tetrahedron. 2008, 64, 672680. 4) Angelini, G.; De Maria, P.; Chiappe, C.; Fontana, A.; Gasbarri, C.; Siani, G. J. Org. Chem. 2009, 74, 6572-6576. 5) Angelini, G.; De Maria, P.; Chiappe, C.; Fontana, A.; Pierini, M.; Siani, G. J. Org. Chem. 2010, 75, 3912-3915. 147 C – Chimica Supramolecolare 148 PC27 Reversible Mechanical Switching of Magnetic Interactions in a Molecular Shuttle Valentina Bleve, Christian Schäfer, Paola Franchi, Serena Silvi, Elisabetta Mezzina, Alberto Credi, Marco Lucarini Dipartimento di Chimica “G. Ciamician” Università di Bologna Via Selmi 2, 40126, Bologna (Italy). e-mail: [email protected] An acid-base switchable molecular shuttle based on a [2]rotaxane incorporating stable radical units in both the ring and dumbbell components is reported. The [2]rotaxane comprises a dibenzo[24]crown-8 ring (DB24C8) interlocked with a dumbbell component that possesses a dialkylammonium and a 4,4’-bipyridinium (Bpym2+) recognition sites. In the rotaxane deprotonation of the NH2+ centre of the guest effects a quantitative displacement of the DB24C8 macroring to the Bpym2+ recognition site, a process that can be reversed by acid treatment. Interaction between stable 2,2,6,6tetramethylpiperidine-1-oxyl (TEMPO) radicals connected to the ring and dumbbell components could be switched between noncoupled (three-line EPR spectrum) and coupled (five-line EPR spectrum) upon displacement of the spin-labelled DB24C8 macroring.1 A system of this kind can represent a first step towards a new generation of nanoscale magnetic switches that may be of interest for ICT applications.2 Spin labelling in molecular machines is also interesting because correlations between radical pairs, monitored by pulsed EPR methods, enable detailed conformational analyses, dynamics studies and precise measurements of nanoscale distances.3 Scheme 1) Bleve, V.; Schäfer, C.; Franchi, P.; Silvi, S.; Mezzina, E.; Credi, A.; Lucarini, M. ChemistryOpen 2015, 4, 18-21. 2) Sato, O.; Tao, J.; Zhang, Y. Angew. Chem. Int. Ed. 2007, 46, 2152-2187, and references therein. 3) Pievo, R.; Casati, C.; Franchi, P.; Mezzina, E.; Bennati, M.; Lucarini, M. ChemPhysChem, 2012, 13, 2659-2661; Mezzina, E.; Manoni, R.; Romano, F.; Lucarini M. Asian J. Org. Chem, 2015, 4, 296-310. 149 PC28 Solvent molding of organic morphologies made of supramolecular chiral polymers Luka Đorđević,1 Tomas Marangoni,1 Tanja Miletić,1 Jenifer Rubio-Magnieto,2 Mathieu Surin2,* and Davide Bonifazi1,3* 1Department of Chemical and Pharmaceutical Sciences, INSTM UdR Trieste, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy 2Laboratory for Chemistry of Novel Materials, Center for Innovation in Materials and Polymers, University of Mons – UMONS, 20 Place du Parc, B-7000 Mons, Belgium 3Namur Research College (NARC) and Department of Chemistry, University of Namur (UNamur) Rue de Bruxelles 61, 5000 Namur, Belgium e-mail: [email protected] The self-assembly and self-organization behavior of uracil-conjugated enantiopure (R) or (S) 1,1’-binaphthyl-2,2’-diol (BINOLs) and an hydrophobic oligo(para-phenylene ethynylene) (OPE) chromophore exposing 2,6-di(acetylamino)pyridine termini are reported.1 Systematic spectroscopic (UV-Vis, CD, fluorescence, NMR and SAXS) and microscopic studies (TEM and AFM) showed that BINOL and OPE compounds undergo triple H-bonding recognition generating different organic nanostructures in solution. Depending on the solvophobic properties of the liquid media (Toluene, CHCl3, CHCl3/CHX and CHX/THF), spherical, rod-like, fibrous and helical morphologies were obtained, with the latter being the only nanostructures expressing chirality at the microscopic level. SAXS analysis combined with molecular modeling simulations showed that the formation of the helical superstructures is composed of dimeric doublecable tape-like structures that, in turn, are supercoiled at the microscale. This behavior is interpreted as a consequence of an interplay between the degree of association of the Hbonded recognition, the vapour pressure of the solvent and the solvophobic/solvophilic character of the supramolecular adducts in the different solutions under static and dynamic conditions, namely during solvent evaporation conditions at room temperature. 1) L. Đorđević, T. Marangoni, T. Miletić, J. Rubio-Magnieto, J. Mohanraj, H. Amenitsch, D. Pasini, N. Liaros, S. Couris, N. Armaroli, et al., J. Am. Chem. Soc. 2015, doi: 10.1021/jacs.5b02448. 150 PC29 New Chiral Rotaxanes for Asymmetric Catalysis Andrea Gualandi1, Elisabetta Manoni1, Serena Silvi1, Alberto Credi1, Pier Giorgio Cozzi1 1 ALMA MATER STUDIORUM-Università di Bologna, Dipartimento di chimica “G. Ciamician”, Bologna, Italy. e-mail: [email protected] Nowadays, rotaxanes incorporating catalytic centers are emerging as new catalysts in catalytic transformations. Inspired by nature, where external stimuli are able to control the enzymatic processes, numerous synthetic systems have been developed. In these systems a stimulus (e.g. pH, light) can be used to turn a catalyst's activity 'on' or 'off'.1 In particular, switchable rotaxane-based organocatalysts have been synthesized, where the catalytic activity can be switched by addition of acid or base, which acts to move the rotaxane ring to either conceal or reveal the catalytic site.2 The rotaxane systems is also suitable for the addition of multiple catalytic active sites in the various components of rotaxane, thus creating multi-functional catalyst. The two or more active sites can work cooperatively or individually, through an external stimulus that controls the activity. Furthermore, the high structural flexibility of rotaxanes allows to the different groups, taking part in the catalytic process, to spatially arranged in the best way, thus increasing the efficiency of process. Furthermore, the possibility to insert in a rotaxane two or more sites capable to coordinate transition metals, open the way to the use of these structures in asymmetric metal-catalysed reaction.3 Here we report the synthesis of new chiral catalysts based on rotaxane architectures able to act as switchable catalysts or ligands for transition metals in asymmetric transformations. Acknowledgments: This work was financially supported by ALMA MATER STUDIORUM-Università di Bologna through the SLAMM FARB project. 1) For an highlight see: Angew. Chem. Int. Ed. 2012, 51, 8163. For some selected examples: Science 2011, 331, 1429; ACS Catal. 2013, 3, 1874; Chem. Commun. 2013, 49, 5453; Chem. Commun. 2012, 48, 11730. 2) Angew. Chem. Int. Ed. 2012, 51, 5166; J. Am. Chem. Soc. 2014, 136, 4905. 3) J. Am. Chem. Soc. 2007, 129, 12930. 151 PC30 Supramolecular Control of Spin Exchange in Spin Labelled [2]Rotaxane Incorporating a Tetrathiafulvalene Unit Lorenzo Gualandi, Francesco Romano, Roberta Manoni, Valentina Bleve, Paola Franchi, Elisabetta Mezzina and Marco Lucarini Department of Chemistry “G. Ciamician”University of Bologna, Via S. Giacomo 11, 40126, Bologna, Italy e-mail: [email protected] Exchange-coupled oligoradicals are of great importance and interest in many fields of chemistry and related sciences.1 An essential parameter in such structures is represented by the magnitude and sign of the spin−spin coupling interaction (J). This interaction can be through-bond and/or through-space, and its value depends on the extent of electronic communication which is sensitive to their relative orientation between molecules. In this contest, mechanically interlocked molecules (MIMs), such as catenanes and rotaxanes, containing paramagnetic species provided stimulating framework in consideration of their capacity to vary the relative positions of the dumbbell and ring components in response to external stimuli.2 Very recently, we prepared a [2]rotaxane, where spin exchange between two nitroxide units located both at the ring and the dumbbell could be switched on/off by changing the pH.3 In the present communication, differently from the previous paramagnetic MIM,3 we report novel examples of nitroxide-spin-labelled bistable rotaxanes containing both tetrathiafulvalene (TTF) and 1,5-dioxynaphthalene (DNP) units, and cyclobis(paraquatp-phenylene) ring (CBPQT4+) in which the paramagnetic centers are directly involved in the shuttling process. In this case the movement of the ring induced by single electron oxidation of the TTF station provides important differences in the electronic communication between TTF+ radical cation and a spin label introduced “ad hoc” as a stopper in the dumbbell, highlighting the effect of rotaxanation on through-space magnetic interactions between radical fragments.4 Introduction of a spin label also on the CBPQT4+ ring in the rotaxane structure will also be discussed. Scheme 1 1) Abe, M. Chem. Rev. 2013, 113, 7011-7088. 2) Bleve, V.; Schäfer, C.; Franchi, P.; Silvi, S.; Mezzina, E.; Credi, A.; Lucarini, L. ChemistryOpen 2015; 4, 18-21. 3) Coskun, A.; Spruell, J. M.; Barin, G.; Dichtel, W. R.; Flood, A. H.; Botrosghi, Y. Y.; Stoddart, J. F. Chem. Soc. Rev. 2012, 41, 4827-4859. 4) Romano, F.; Manoni, R.; Franchi, P.; Mezzina, E.; Lucarini, M. Chem. Eur. J. 2015; 21, 2775-2779. 152 PC31 Unique binding behavior of water-soluble polycationic oxacalix[4]arene tweezers towards the paraquat dication G. Gattuso,a G. Lando,a N. Manganaro,a A. Notti,a S. Pappalardo,b M. F. Parisia and I. Pisagattia a b Dipartimento di Scienze Chimiche, Università di Messina, 98166 Messina, Italy. Dipartimento di Scienze Chimiche, Università di Catania, 95125 Catania, Italy. E-mail: [email protected] After four decades of oblivion, oxacalix[4]arenes1 are finally emerging as a promising class of macrocyclic receptors.2 As part of our studies on these old yet new macrocycles,3 in this communication, we report on a unique water-soluble oxacalix[4]arene, the tetraammonium derivative 14HCl (Figure 1), able to recognize and bind the methyl viologen dication under acidic conditions. A combined UV-Vis and 1H NMR study demonstrates that the tri- (13H+) and tetra protonated (14H+) forms predominate at pH < 2, but only 13H+ is able to efficiently bind the paraquat dication (Ka = 253 ± 50 M–1), overcoming the repulsion between the positive charges on both host and guest. 2D ROESY spectra reveal that the guest is nestled within the -rich cleft generated by the two resorcinol moieties. Moreover, DFT calculations show that protonation preorganizes the oxacalixarene tweezers: the increasing repulsion between the ammonium groups (on the facing amino-bearing aromatic rings) results in a narrowing of the resorcinol-resorcinol interplanar angle, thus making this saddle-shaped oxacalixarene a good receptor for aromatic guest molecules. + Figure 1. Tricationic oxacalix[4]arene 13H acts as molecular tweezers for the paraquat dication. 1) Sommer, N.; Staab, H. A. Tetrahedron Lett. 1966, 7, 2837–2841. 2) a) Maes, W.; Dehaen, W. Chem. Soc. Rev. 2008, 37, 2393–2402; b) Wang, M.-X. Acc. Chem. Res. 2012, 45, 182–195. 3) a) Capici, C.; Garozzo, D.; Gattuso, G.; Messina, A.; Notti, A.; Parisi, M. F.; Pisagatti, I.; Pappalardo, S. Arkivoc 2009, (viii), 199–211; b) Capici, C.; Gattuso, G.; Notti, A.; Parisi, M. F.; Bruno, G.; Nicolò, F.; Pappalardo, S. Tetrahedron Lett. 2011, 52, 1351–1353; c) Gargiulli, C.; Gattuso, G.; Notti, A.; Pappalardo, S.; Parisi, M. F.; Puntoriero, F. Tetrahedron Lett. 2012, 53, 616–619. 153 D – Foldameri 154 PC32 A new synthetic route towards the fully-extended conformation and its employment as peptide spring Marta De Zotti1, Jonathan Clayden2 1 ICB CNR, Padova Unit, Department of Chemistry, University of Padova, via Marzolo 1, 35131 Padova, Italy 2 School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K. e-mail: [email protected] Peptides consisting of Cα-tetrasubstituted α-amino acids1 can adopt stable and well defined helical conformations even with very short sequences (4-6 residues). Homopeptides made of diethylglycine (Deg) residues undergo reversible spring-like conformational transitions between a 2.05 (fully extended) and a 310-helix upon changing a single environmental paramater.2 The 2.05-helix has an axial translation per residue of about 3.7 Å, the longest possible for a single α-amino acid (for the 310-helix, this translation is only 1.9 Å). Poly-Deg peptide springs are however difficult to synthesize, owing to the very poor reactivity of Deg. In this contribution, we describe a novel strategy that employs more reactive 4-amino-tetrahydrothiopyran-4-carboxylic acid (Thp)3 residues as Deg precursors. After synthesis of the Thp homopeptides, hydrogenolysis of the C–S bonds with hydrogen and Raney-Ni provides, quantitatively, the corresponding Deg homopeptides. S S Ac N H O H N N H O S O H N 1) Raney-Ni, H2 O 2) reflux o.n., quant. O Ac N H H N O O N H H N O O O S A comprehensive conformational analysis of our systems will also be discussed. 1) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Biopolymers (pept. Sci.) 2001, 60, 396-419. 2) Peggion, C.; Crisma, M.; Toniolo, C.; Formaggio, F. Tetrahedron 2012, 68, 4429-4433. 3) Lewis, N.J.; Inloes, R. L.; Hes, J.; Matthews, R.H.; Milo, G. J. Med. Chem. 1978, 21, 1070-1073. 155 PC33 Synthesis , Conformational Analysis And Biological Evaluation Of Pseudopeptide Foldamers Benedetta Del Secco , Lorenzo Milli, Nicola Zanna, Claudia Tomasini Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum Università di Bologna, - Via Selmi 2, 40126, Bologna, Italia e-mail: [email protected] The aim of this work is the synthesis, the conformational analysis and the biological evaluation of a series of foldamers all containing the D-Oxd unit (5-carboxy-4-methyloxazolidin-2-one) alternating with a valine or a lysine unit. These compounds may used to prepare nanoparticles ready available for the human body (Figure 1). Figure 2 Schematic rapresentation of the synthesis of decored nanoparticles The introduction of the Oxd moiety is very useful in the preparation of organized oligomers because it imparts rigidity to the pseudopeptide chain,1 as we could demonstrate by X-Ray analysis of a Boc-L-LeuD-Oxd-OBn unit (Figure 2). By peptide coupling reactions we have obtained BocL-Val-D-Oxd-L-Lys(2Cl-Z)-D-Oxd-OBn, Boc-(-LVal-D-Oxd-L-Lys(2Cl-Z)-D-Oxd-)2-OBn and Boc-(L-Val-D-Oxd-L-Lys(2Cl-Z)-D-Oxd-)3-OBn that have been analyzed by IR, NMR and ECD. Figure 3 X-Ray structure of Boc-L-Leu-D-Oxd-OBn These compounds have been fully deprotected for biological evaluation, that was performed on HeLa cells and proved the effective non-toxicity of all three compounds. 1) Tomasini, C.; Castellucci, N. et al., Eur. J. Org. Chem., 2013, 3567 – 3573 156 PC34 Synthesis and conformation of a peptide with two pendant nitronyl nitroxide free radical units Karen Wright1, Edouard d’Aboville1, Antonio Toffoletti2, Marta De Zotti2, Fernando Formaggio2, Claudio Toniolo2 1 Institute Lavoisier de Versailles, UMR 8180, University of Versailles St-Quentin en Yvelines, 78035 Versailles, France 2 ICB, Padova Unit, CNR, Department of Chemistry, University of Padova, 35131 Padova, Italy e-mail: [email protected] The blue-colored Ullman imidazolinyl nitronyl nitroxide (NN) monoradicals1 have been extensively investigated, in particular as spin probes and organic magnetic materials. Recently, we reported synthesis, configurational and conformational assignments, and physico-chemical properties of a tripeptide with a central (R)-Aic(NN), where Aic(NN) is the helicogenic 2-amino-5-nitronylnitroxideindan-2-carboxylic acid.2 Here, we discuss the synthesis and spectroscopic/conformational properties of the hexapeptide Boc-[Ala-(R)-Aic(NN)-Ala]2-OMe (Figure 1), with the spin labels at positions i and i+3. Figure 1. Molecular structure of the hexapeptide Boc-[Ala-(R)-Aic(NN)-Ala]2-OMe The preparation of this peptide was performed from the precursor with two Aic(CN) units, which in turn was synthesized by N-to-C chain elongation in solution. Reduction of the two cyano groups to aldehydes, followed by condensation with 2,3-diamino-2,3dimethylbutane, afforded the bis-tetramethyl-imidazoline hexapeptide. Oxidation gave the target bis-nitronyl nitroxide compound. The results of our solution conformational analysis, carried out by use of the UV-Vis absorption, CD, FT-IR absorption, fluorescence, NMR, and EPR spectroscopic techniques, will also be described. 1) Osiecki, J.H.; Ullman, E.F. J. Am. Chem. Soc. 1968, 90, 1078-1079. 2) Wright, K.; d’Aboville, E.; Scola, J.; Margola, T.; Toffoletti, A.; De Zotti, M.; Crisma, M.; Formaggio, F.; Toniolo, C. Eur. J. Org. Chem. 2014, 1741-1752. 157 PC35 Spherical shape supramolecular structure of serum stable selfassembled pentapeptides containing the constrained norbornene amino acid Marco Zuccoloa, Alessandro Ruffonia, Maria Vittoria Cavannab, Simona Argentiereb, Francesca Clericia a DISFARM, Sez. di Chimica Generale e Organica “A. Marchesini”, Università degli Studi di Milano, V. Venezian 21, Milano; b Fondazione Filarete, V. Ortles 22, Milano e-mail: [email protected] Self-assembly is a spontaneous process by which unordered systems of monomers organize into ordered structures as the result of non-covalent interactions and lies behind a number of biological nanostructures. The concept of self-assembly has also been used in many disciplines for constructing useful materials. Supramolecular spontaneous assembly of high molecular weight peptides or peptides conjugated with non-peptidic molecules has been reported. Less is known on the self-assembly of short peptides alone which self-organize predominantly into nanotubes and nanofibers. Spherical (micellar and vesicle-like) architectures are rarely described although they appear very attractive, due to promising applications in biomedicine and nanotechnology.1 Besides the numerous advantages of using peptides containing natural amino acids for nanostructures, they present some limitations such as low bio-stability and unstable conformation especially when they are short or medium-sized. The insertion of unnatural amino acids in the peptide sequences is a well-known tool to overcome these problems.2 Here we report on the preparation and self-assembly of short hydrophobic peptides able to stabilize the formation of supramolecular spherical shape assemblies in water. Two diastereoisomeric pentapeptides AcAla-NRB-Ala-AibAlaNH2 1 and 2, containing the unnatural constrained norbornene amino acid (NRB) 3, were prepared. Interestingly, peptides 1 and 2 are insoluble in organic solvent but completely soluble in water despite the presence of hydrophobic non polar norbornene scaffold. Me H N AcHN O Me O N H H N O Me Me O Me N H Me NH2 O H N AcHN O O Me N H 2 1 H N O Me O Me Me N H R* COOH R* NH2 NH2 R* O 3 The formation of a supramolecular assembly in water was assessed by DLS analyses for both 1 and 2 either as pure compounds or as a mixture. In all cases, the obtained assemblies showed almost monomodal distributions in the size range of 320-370 nm with low polidispersity. To assess their stability in conditions mimicking the in vivo environment, they were suspended in fetal bovine serum. Interestingly, peptide assemblies were found to keep their size and shape. An interesting feature of these peptides is also the presence of the C-C double bond in the norbornene scaffold, which could allow the easy labeling of the system introducing a variety of useful biotag. 1. Panda, J. J.; Chauhan, V. S. Polym. Chem. 2014, 5, 4418 2. Ruffoni, A. et al. RSC Adv., 2015, 5, 32643-32656 158 E – Fotofisica e Fotochimica 159 PC36 Influence of structural variations over the synthesis and fluorescent properties of new thermochemiluminescent labels Luca Alfio Andronico1, Massimo Di Fusco1,2, Arianna Quintavalla1, Marco Lombardo1, Massimo Guardigli1, Mara Mirasoli1,2, Claudio Trombini1, Aldo Roda1 1 2 Department of Chemistry ‘‘G. Ciamician’’, Alma Mater Studiorum, University of Bologna, Via Francesco Selmi 2, 40126 Bologna, CIRI-MAM, Alma Mater Studiorum, University of Bologna, Viale Risorgimento 2, 40136 Bologna e-mail: [email protected] Thermochemiluminescence (TCL) is the process by which a thermolabile molecule generates a light emission after heating above a threshold temperature. It was proposed in the late 1980s as an innovative reagentless detection technique for immunoassays. However, it was quickly abandoned owing to the high decomposition temperatures (200-250 °C) and poor detectability of early employed substrates. Recently, we synthesized new 1,2-dioxethane derivatives, characterized by remarkably TCL properties in terms of lower triggering temperature and high fluorescence efficiency1-3. The synthesis of these new TCL-labels consists of two steps, as shown in Scheme 1a. After heating, these substrates decompose giving two carbonyl fragments, one of which in its singlet excited state. Consequently, the excited fragment relaxes to its ground state generating light emission (Scheme 1b). a) b) Scheme 1. a) Scheme of the synthesis of 1,2-dioxethane derivatives; b) Schematic representation for a typical TCL process. We will present the impact of structural modifications both on the photo-oxygenation step and on TCL properties of a small library of dioxetanes, and preliminary results on the employment of these molecules for TCL-based immunoassay. 1. 2. 3. A. Roda, M. Di Fusco, A. Quintavalla, M. Guardigli, M. Mirasoli, M. Lombardo, C. Trombini Anal. Chem. 2012, 84, 9913−9919. M. Di Fusco, A. Quintavalla, C. Trombini, M. Lombardo, A. Roda, M. Guardigli, M. Mirasoli J. Org. Chem. 2013, 78, 11238-11246. M. Di Fusco, M. Guardigli, M. Lombardo, M. Mirasoli, A. Quintavalla, A. Roda, C. Trombini Patent WO2014024106 A1 (2014). 160 PC37 Benzodithiophene Based Organic Dyes for DSSC: Effect of Alkyl Chain Substitution on Dye Efficiency Clara Baldoli,1 Stefania Bertuolo,2 Ivan Andreosso,3 Emanuela Licandro,2 Gabriele Marotta,4 Paolo Salvatori,4,5 Filippo De Angelis,4 Paola Manca,4 Norberto Manfredi,6 Alessandro Abbotto6 1 2 CNR - Istituto di Scienze e Tecnologie Molecolari (ISTM). Via C. Golgi 19. 20133 Milano Dipartimento di Chimica. Università degli Studi di Milano. Via C. Golgi 19. 20133 Milano 3 SmartMatLab Centre - Dipartimento di Chimica. Via C. Golgi 19. 20133 Milano 4 Computational Laboratory for Hybrid Organic Photovoltaics (CLHYO)-CNR-ISTM. Via Elce di Sotto 8. 06123 Perugia 5 D3-Computation, Istituto Italiano di Tecnologia. Via Morego 30. 16163 Genova 6 Dipartimento di Scienze dei Materiali and Solar Energy Research Center MIB-SOLAR; INSTM MilanoBicocca Unit. Università di Milano-Bicocca. Via Cozzi 55. 20125 Milano e-mail: [email protected]. A series of push-pull triarylamine organic dyes containing the benzo[1,2-b:4,5b’]dithiophene unit as a spacer and bearing alkyl chains in different positions of the molecule were synthesized. The new dyes 1-4 were characterized by optical and electrochemical measurements and density functional theory calculations and tested as sensitizers in liquid dye-sensitized solar cells (DSSC). The effect of the alkyl chain position on the dye properties and their photovoltaic performance were investigated. The best PCE was recorded for dye 1 (6.6% at 0.5 sun), this value was only ~20% less than the benchmark dye N719 (8.1%) under the same fabrication conditions. The best LHE profile, in agreement with optical properties, and the APCE values, greater than 80%, suggested that the efficiency of 1 originates from high light harvesting and charge formation and collection efficiency. In addition, it was found that photovoltaic performance were dramatically dependent on the choice of the solvent used for the dye-sensitizing bath. The results were correlated, through extensive optical studies in different solvents and acid/base additives, with protonation equilibrium of COOH/COO- group of dyes. This study clearly demonstrated the strategic importance of selecting an appropriate solvent for dye absorption in the DSSC fabrication, even in the case of performing sensitizers. 1 Baldoli, C.; Abbotto, A.; Licandro, E.; De Angelis, F.; et al. Dyes and Pigments 2015, 121, 351-362 Acknowledgements: CNR and Accordo Quadro Regione Lombardia-CNR (Times Project). Regione Lombardia-Fondazione CARIPLO "SmartMatLab Centre" project. 161 PC38 Versatile dibenzofulvene structures as dyes for efficient DSSCs and HTM perovskite solar cells A.-L. Capodilupo,1 G. Gigli,1,2 and G. Ciccarella1,3 1 2 3 CNR NANOTEC - Istituto di Nanotecnologia, Polo di Nanotecnologia c/o Campus Ecotekne, via Monteroni - 73100 Lecce Dipartimento di Matematica e Fisica “Ennio De Giorgi”, Università del Salento, Via Monteroni, 73100, Lecce, Italy. Dipartimento di Ingegneria dell'Innovazione, Università del Salento, Via Monteroni, 73100, Lecce, Italy. e-mail: [email protected] DSSCs and perovskite solar cells (PSCs) represent the most promising photovoltaic devices. They have been attracting a great interest thanks to high performance and low-cost production. In these devices the organic component play a key role: is the lightharvesting antenna in the DSSCs and the hole transporting material in the PSCs. Design and synthesize new organic molecules with improved performance is demanding in order to increase cell efficiency. Moreover, easy, versatile and low cost synthetic strategies are necessary to ensure an effective low cost production of final devices. Here we present the results of our study of a new class of organic molecules for solar cells based on the dibenzofulvene structure. The main aspects of the work lie in the versatility of the molecular structure, that allows, by a proper functionalization, to obtain different derivatives which have been successfully used in DSSCs and PSCs devices. Scheme 1 We have prepared dyes for DSSCs with power conversion efficiency of 7.45% and hole transporting materials for PCEs with power conversion efficiency of 10.9%. References 1. A.-L. Capodilupo, L. De Marco, E. Fabiano, R. Giannuzzi, A. Scrascia, C. Clarlucci, G. A. Corrente, M. P. Cipolla, G. Gigli and G. Ciccarella J. Mater. Chem. A 2, 14181 (2014). 162 PC39 Tunable photogeneration of reactive intermediates from chlorobenzylphosphonic acids in aqueous media. Stefano Crespi, Stefano Protti, Davide Ravelli and Maurizio Fagnoni PhotoGreen Lab, Department of Chemistry, University of Pavia Viale Taramelli 12, 27100 Pavia, Italy. e-mail: [email protected] The photoreactivity of the three isomeric chlorobenzylphosphonic acids (I) has been investigated and found to be tunable by modifying the pH of the reaction medium. Thus, irradiation of I in aqueous/organic solvent mixtures at pH = 2.5 results in the formation of a highly electrophilic triplet aryl cation (3II) after chloride anion detachment (path a).1 Two main competing pathways departing from 3II are observed, viz. the reduction upon hydrogen abstraction from the solvent (path b) and Intersystem Crossing (ISC) to singlet phenyl cation (1II) and the subsequent solvolysis to phenol (path c). In contrast, when moving to basic pH (pH = 11) formation of 3II from the corresponding phosphonate is followed by detachment of a phosphate ion, with the subsequent generation of a ,n didehydrotoluene diradical (,n DHTs, path d).2 At physiological pH (pH = 7.2) a competition between the aforementioned pathways has been observed. In the aim of fully characterize the nature and the role of the involved intermediates, different factors including the polarity of the solvent and the presence of triplet sensitizer (acetone) have been considered, and the experimental data have been supported by computational analyses. 1) Raviola, C.; Ravelli, D.; Protti, S.; Albini, A.; Fagnoni, M. Synlett 2015, 26, 471-478. 2) Protti, S.; Ravelli, D.; Mannucci, B.; Fagnoni, M.; Albini, A. Angew. Chem. Int. Ed. 2012, 51, 8577-8580; Crespi, S.; Ravelli, D.; Protti, S.; Albini, A.; Fagnoni, M. Chem. Eur. J. 2014, 20, 17572-17578. Acknowledgement: We are grateful to the Fondazione Cariplo (grant 2011-1839) for support. 163 PC40 Photogeneration of methanesulfonic acid from aromatic bis(methanesulfonylimides): Application in cationic photopolymerization Maurizio Fagnoni,1 Edoardo Torti,1 Stefano Protti,1 Daniele Merli,1 Gioia Della Giustina,2 Giovanna Brusatin.2 1 PhotoGreen Lab, Department of Chemistry, University of Pavia, Italy. 2 Department of Industrial Engineering, University of Padova, Italy e-mail: [email protected] Mild generation of strong acids is a crucial issue for material chemistry. Compounds able to release acid upon light absorption (photoacid generators, PAGs) find wide application in photoresists and other similar devices.1 Thus, the study of innovative PAGs is a prominent challenge in microelectronic field. In the last few years our group demonstrated that aryl sulfonates such as mesylates, tryflates and tosylates are able to release the corresponding sulfonic acid under UV irradiation.2,3 Aryl tosylates have been exploited as PAGs in epoxy based hybrid organic-inorganic materials.3 We present herein a detailed photochemical investigation of N-aryl bis(methanesulfonylimides (1). Irradiation of 1 in N2 saturated acetonitrile resulted in the formation of different photoproducts (including N-aryl methanesulfonamides, anilines and thia-Fries rearrangement products) along with methanesulfinic acid (0-116%). In O2 saturated media, methanesulfonic acid was released in high yields (up to 2 equiv for one equiv of 1). The photochemical behaviour is consistent with a homolytic cleavage of the ArNS bond with the formation of a radical pair (2); trapping of the methanesulfonyl radical by O2 leads then to strong CH3SO3H. Compounds 1 were tested as photoinitiators for cationic polymerization and incorporated in an epoxy based hybrid organic-inorganic material obtained from 3-glycidoxypropyltrimethoxysilane (GPTMS) and germanium tetraethoxide (TEOG).4 The devices were exposed to UV light and the structural modifications induced were quantified by FT-IR spectroscopy. The results obtained show that 1 are able to induce polymerization of the epoxy groups, making these compounds good candidates as PAGs for hybrid organic-inorganic photoresists. This work has been supported by the Fondazione Cariplo (grant no. 2012-0186). 1) Moon, S. Y.; Kim, J. M. J. Photoch. Photobio. C, 2007, 8, 157-173. 2) Terpolilli, M.; Merli, D.; Protti, S.; Dichiarante, V.; Fagnoni, M.; Albini, A. Photochem. Photobiol. Sci., 2011, 10, 123-127. 3) Torti, E.; Della Giustina, G.; Protti, S.; Merli, D.; Brusatin, G.; Fagnoni, M.RSC Adv.,2015,5, 3323933248. 4) Brusatin, G.; Della Giustina, G. J. Sol-Gel Sci. Technol., 2011, 60, 299-314. 164 PC41 Photoresponsive supramolecular architecture based on α-cyclodextrine functionalized with azobenene M. Stefania Ferrito1, Stefano Masiero1, Yoshinori Takashima2, Akihito Hashidzume2, Akira Harada2 1 Department of Chemistry «Giacomo Ciamician» Via S. Giacomo, 11, 40127 Bologna Italy; Department of Macromolecular Science, Graduated School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan 2 Email: [email protected] Abstract Photoresponsive assembling/disassembling behavior of a supramolecular architecture in aqueous solution based on α-cyclodextrine functionalized with an azobenzene (Azo) moiety (2AzoH-αCD) has been studied. A model system consisting of azobenzene sodium carboxylate and α-CD has been studied(1,2). CDs can form inclusion complexes with organic compounds improving the host solubility, and their binding abilities have been shown to be changed by light when an azobenezene moiety is incorporated (3,6). In this project we have focused on the use of supramolecular system based on azobenezene-CD interactions as photoresponsive host-guest assembling. Two-dimensional NMR, diffusion coefficient, ESI-MS and circular dichroism indicated that the trans-isomer of 2-AzoH-αCD formed a supramolecular oligomer in aqueous solution even at lower concentrations (< 1 mM). On the contrary the cis-Azo moiety was excluded from the cavity of αCD. Reference 1) Pietro Bortulus, Sandra Monti J.Phys.Che. 1987, 91, 5046-5050 2) Di Motta, Avellini, Silvi, Venturi, Ma, Tian, Credi and Negri, Chem. Eur. J. 2013, 19, 3131-3138 3) Shinkai,S.;Shigematsu,K.; Sato,M; Manabe, O.J. Chem. Soc., Perkin trans. 1 1982, 2735-2745 4) Shiki Yagai, Akihide Kitamura, Chem.Soc.Rev. 2008, 37, 1520–1529 5) A. Harada, Y. Takashima, and M. Nakahata, Acc. Chem. Res., 2014, 47 (7), 2128–2140. 6) Yamaguchi, H.;Kobayashi, Y.; Kobayashi, R.; Takashima,Y.; Hashidzume, A.; Harada, A. Nature Communications 2012, 3, 603. 165 PC42 A Multipurpose Catechol-Based Fluorescence Turn-On System for Sensing and Coating Mariagrazia Iacomino, Orlando Crescenzi, Alessandra Napolitano, Marco d’Ischia. Department of Chemical Sciences, University of Naples Federico II, Via Cintia 4, I-80126, Naples, Italy. e-mail: [email protected] The advancing developments in fluorescence-based analytical, imaging and functionalization techniques have spurred increasing efforts toward the design of highly efficient, robust, versatile and biocompatible chromophores and complexes which respond to specific stimuli with a strong emission (the “turn-on” modality). Capitalizing on the previously reported oxidative reaction of catecholamines with resorcin derivatives, leading to strongly emitting 1,2 methanobenzofuroazocinone scaffolds, we report herein the prototype of robust multipurpose turn-on fluorescence systems based on a 1:1 mixture of dopamine and a resorcin derivative. The system can be activated under oxidative conditions at pH 7.4 or by autoxidation at pH 8.5 and the resulting emission can be reversibly quenched by acids. The versatility of the system is exemplified by some preliminary applications reported herein, including: a) sensing of oxidizing systems (e.g. hydrogen peroxide) at pH 7.4; b) detection of gaseous ammonia; c) surface coating with highly adhesive fluorescent thin films at pH 8.5 using a symmetric bifunctional derivative (Bis-Res) as the resorcin component. Figure 1: Oxidative coupling of dopamine with resorcin leading to the fluorescent methanobenzofuroazocinone scaffold and turn-on response of alginate hydrogel beads containing the dopamine/resorcin system to ammonia vapors. Figure 2. Quartz surface functionalized by dip-coating with dopamine/Bis-Res at pH 8.5 (right, functionalized quartz, left, uncoated quartz ) and emission spectrum of the thin film (exc. 420 nm). A detailed reexamination of the fluorophore, including its behavior to acids, using DFT calculations, is also reported. References 1. Crescenzi,O.; Napolitano, A.; Prota , G., Tetrahedron 1991, 47, 6243-6250. 2. Acuña, A.U.; Alvarez-Perez, M.; Liras, M.; Coto, P.B.; Amat-Guerriz, F., Phys. Chem. Chem. Phys., 2013, 15, 16704-16712. 166 PC43 Blue emitting nanostructured silica by in vivo functionalization of diatom algae shells with an aryleneethynylene fluorophore M. Lo Presti,a R. Ragni,a D. Vona,a S. R. Cicco,a O Hassan Omar,b G. M. Farinola*a a Dipartimento di Chimica, Università degli Studi di Bari “Aldo Moro”, via Orabona 4, 70126 Bari (Italy) b CNR-ICCOM, Dipartimento di Chimica, Università degli Studi di Bari“Aldo Moro”, via Orabona 4, 70126 Bari (Italy). e-mail: [email protected] Hybrid systems in which organic luminescent molecules are covalently bound or embedded into mesoporous nanostructured silica have recently attracted scientific and technological interest as versatile multifunctional materials with applications in photonics, sensing and bioimaging.[1] Diatoms are a class of single cell photosynthetic algae bearing a three-dimensional silica skeleton (frustule) whose size and morphology is strictly dependent on the algal species: these microorganisms are a natural and low cost source of biosilica with highly hierarchically ordered nanostructure behaving as natural photonic crystal. Hence, the integration of organic fluorophores into diatom frustules represents a very promising strategy to afford new bio-hybrid luminescent materials for laser technology or light emission modulation. In the frame of our studies on new functional bioorganic materials,[2] here we present the synthesis of a new blue emitting arylenethynylene fluorophore (Figure 1a) properly designed to be a model compound with sterically unhindered structure and a triethoxysilyl group allowing its in vivo incorporation into frustules of the Thalassiosira weissflogii centric diatom (figure 1b). Figure 1 Our results demonstrate the possibility to in vivo convey the dye into the biosilica and to isolate, by proper oxidative treatment, new hybrid luminescent materials with the natural frustules retained morphology (Figure 1c). This approach discloses intriguing possibilities in the massive biotechnological production of photoactive nanostructured materials, whose properties can be finely tailored by chemical design of the light emitting molecule and by selecting and modifying the characteristics of the microorganism used. 1) Wenrong Yang, et Al; “Diatoms: Self assembled silica nanostructures, and templates for bio/chemical sensors and biomimetic membranes” ; Analyst, 2011, 136, 42 2) Stefania R. Cicco, Gianluca M. Farinola et Al; ”Chemically Modified Diatoms Biosilica for Bone Cell Growth with Combined Drug-Delivery and Antioxidant Properties” ; ChemPlusChem, 2015. 167 PC44 SiC/SiO2 NWs conjugated with porphyrins for Photodynamic therapy Elena Bedogni1, Cecilia Loffi1, Marco Negri2, Giovanni Attolini2, Giovanna Benecchi3, Tiziano Rimoldi4, Luigi Cristofolini4, Silvana Pinelli5, Rossella Alinovi5, Francesca Rossi4, Giancarlo Salviati4 and Franca Bigi1 1 2 Chemistry Department (Parma University) IMEM-CNR (Parco Area delle Scienze 37/A, Parma). 3 4 5 Health Physics (Parma Hospital) Department of Physics and Heart Science (Parma University) Unit of Experimental Oncology, (Parma University and CERT) e-mail: [email protected] In recent years, increasing attention has been devoting in the literature to the preparation of nanosystems for biomedical applications, such as drug delivery, bio-separation, immunoassays, and in particular for alternative approaches in cancer treatment, such as photodynamic therapy (PDT). In this communication we report the preparation of a novel nanosystem obtained by functionalization of core-shell SiC@SiO2 nanowires with porphyrins for application in nanomedicine. Due to its high biocompatibility, cubic SiC is a promising material for biomedical applications and recently we evidenced that SiC/SiO2 NWs can easily penetrate the cell membrane and that they are cytocompatible.1 Porphyrins are an important class of photosensitizers largely employed in PDT, absorbing light and producing singlet oxygen. We decided to conjugate porphyrins to the SiC/SiO2 NWs to obtain nanosystem able to promote Xray-excited PDT for deep tumor treatment.2 Here we present a conjugation strategy based on the formation of amidic bonds. The efficient anchorage of tetracarboxyphenylporphyrin (H2TCPP) to the nanowires surface was performed through covalent amidic bonds by reacting the porphyrin with the nanowires previously functionalized with amino groups. To increase the dispersion of the nanosystem in aqueous medium short PEG chains were linked to the porphyrins. The hybrid nanosystem was characterized by fluorescence spectroscopy, that confirmed the successful porphyrin conjugation. In vitro studies on tumor cell lines are in progress and will be presented. 1) Cacchioli, A.; Ravanetti, F.; Alinovi, R.; Pinelli, S., Rossi, F.; Negri, M.; Bedogni, E.; Campanini, M.; Galetti, M.; Goldoni, M.; Lagonegro, P.; Alfieri, R.; Bigi, F.; and G. Salviati, Nano Lett., 2014, 14 (8), 4368–4375. 2) Rossi, F.; Bedogni, E.; Bigi, F., Rimoldi, T.; Cristofolini, L.; Pinelli, S.; Alinovi, R.; Negri, M.; Dhanabalan, S.C.; Attolini, G.; Fabbri, F. M. Goldoni, A. Mutti, G. Benecchi, C. Ghetti, S. Iannotta and G. Salviati Scientific Reports 2015, 5:7606. 168 PC45 Synthesis and optical properties of novel azole-based fluorophores F. Bellina,1 M. Lessi,1 G. Marianetti,2 P. Minei,2 L. A. Perego,2 C. Pezzetta,2 A. Pucci1, Chiara Manzini1 1 Dipartimento di Chimica e Chimica Industriale, Università di Pisa, via Moruzzi 3, 56124, Pisa, Italy. 2 Scuola Normale Superiore, Università di Pisa, Piazza dei Cavalieri 7, 56126, Pisa, Italy. e-mail: [email protected] Heteroaromatic fluorophores with electron-donor and –acceptor architectures have attracted growing interest for both the understanding of fundamental chemistry and physics and promising applications in diverse fields, ranging from solar energy conversion1 to optoelectronic devices2 and chromogenic materials.3 These fluorophores show interesting intramolecular charge-transfer (ICT) properties and the presence in their structure of azole rings, such as imidazole and thiazole, confers them chemical and thermal robustness, as well as good solubility in common organic solvents. Furthermore, heteroatoms can enhance the donor/acceptor character of the groups and improve the overall polarizability of the chromophore. In continuation of our studies on the synthesis of new classes of organic fluorophores,4 we recently focused our attention on the design of azole-based fluorescent molecules to be used in luminescent solar concentrator (LSC) devices. In this communication we will describe the synthesis of novel fluorophores of general formula 1-3 (Figure 1),4a,5 obtained through an innovative and operationally simple reaction protocol consisting in two sequential Pd-catalyzed direct arylation reactions.6 N N N Me N Me Y N N N Me S R Z 1 N N S S 2 Y = -Me, -MeO, -CN Z = -Me, -MeO, -CN, -O(2-ethyl)hexyl R = H, -CH=C(CN)2 Z 3 Figure 1: General structure of organic fluorophores. The optical properties of these new interesting classes heteroaromatic fluorophores will be also shown and discussed in details. 1) 2) 3) 4) A. Hagfeldt, G. Boschloo, L. Sun, L. Kloo, H. Pettersson, Chem. Rev., 2010, 110, 6595-6663. G. S. He, L.-S. Tan, Q. Zheng, P. N. Prasad, Chem. Rev., 2008, 108, 1245-1330. F. Ciardelli, G. Ruggeri, A. Pucci, Chem. Soc. Rev., 2013, 42, 857-870. a) M. Lessi, C. Manzini, P. Minei, L. A. Perego, J. Bloino, F. Egidi, V. Barone, A. Pucci, F. Bellina, ChemPlusChem, 2014, 79, 366-370; b) G. Prampolini, F. Bellina, M. Biczysko, C. Cappelli, L. Carta, M. Lessi, A. Pucci, G. Ruggeri, V. Barone, Chem. Eur. J., 2013, 19, 1996-2004; c) I. Platonova. A. Branchi, M. Lessi, G. Ruggeri, F. Bellina, A. Pucci, Dyes and Pigments, 2014, 110, 249-255. 5) C. Manzini, PhD Thesis, 2015, Università di Pisa. 6) F. Bellina, M. Lessi, C. Manzini, Eur. J. Org. Chem., 2013, 5621-5630. 169 PC46 2,5-Diaryl substituted azoles as promising organic fluorescent dyes for luminescent solar concentrators. V. Barone,a F. Bellina,b M. Lessi,b P. Minei,a A. Pucci,b G. Marianettia a b Scuola Normale Superiore. Piazza dei Cavalieri 7, 56126 Pisa, Italy Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Moruzzi 3, 56124 Pisa, Italy In the past two decades lot of research has focused on Luminescent Solar Concentrators (LSCs) as a way to decrease the cost of solar photovoltaics.1 LSC devices usually consist in a thin slab of transparent material (glass or polymer) doped with a fluorescent dye. Upon solar irradiation, a fraction of the luminescence emitted by the dye remains trapped inside the slab though means of internal reflection and is collected at the edges of the device by photovoltaic cells. Compared to traditional concentrators, which make use of mirrors and lenses, this kind of devices show numerous advantages, such as theoretical higher concentration factors, the ability to work with both diffuse and incident light and no need for tracking devices or cooling apparatuses.1,2 Moreover, the simplicity and the low cost of this devices make them particularly appealing. In this insight, efforts can be directed towards the synthesis of novel organic dyes which not only display interesting optical features, but are also attainable through cheap and scalable procedures. Organic fluorescent dyes bearing -conjugated electron-donor and -acceptor moieties exhibit intramolecular charge-transfer (ICT) properties,3 and can therefore show the optical properties required by LSCs such as high quantum yield and high Stokes shift. On account of this, in the present communication it will be discussed the synthesis and UV-Vis characterization of a set of novel symmetrical push-pull azole-based dyes of general structure 1. These compounds are characterized by a central 1,3-azole core substituted at its 2 and 5 positions with two aromatic rings bearing typical electron withdrawing (EWG) functional groups. Remarkably, the heteroatoms have a positive impact on the overall polarizability properties, and the introduction of a -heteroaromatic ring usually improves the thermal and chemical stability required for fabrication processes of the final device. The 2,5-diaryl substituted azoles 1 were prepared through a robust synthetic pathway involving a palladium-catalyzed direct arylation reaction as key step. In order to rationalize the experimental results we carried out TD-DFT studies is solution and in a polymeric matrix, with the aim of selecting the best candidate to be employed in LSC devices. References 1. Van Sark, W. et al. Optics Express 2008, 16 (26), 21773-21792. 2. Reisfeld, R.; Jørgensen, K. C. Solar Energy Materials 1982, 49, 1-36. 3. Hagfeldt, A.; Boschloo, G.; Sun, L.; Kloo, L.; Pettersson, H. Chem. Rev. 2010, 110, 6595-6663. 170 F – Green Chemistry 171 PC47 Solvent-Free Synthesis and Characterization of Spiro-isoxazolidines at Potential Biological Activity. Vincenzo Algieri1, Antonio De Nino1, Loredana Maiuolo1, Monica Nardi, Beatrice Russo1. 1 Dipartimento di Chimica e Tecnologie Chimiche (CTC), Università della Calabria, Ponte Bucci Cubo 12/C, 87036 Rende (CS), IT. e-mail: [email protected] The discovery of new pharmacological agents is one of the biggest challenges for chemists. One of these is the synthesis of spiro-isoxazolidines pharmacologically active. In recent years it has been developed the synthesis of spiro compounds by 1,3-dipolar cycloaddition reactions, in which the isoxazolidinic core product is an interesting pharmacophore that could be the future in biology and pharmacology fields. Isoxazolidines are cyclic molecules that mimic natural nucleosides exerting antiviral activity; for example, the furanopirimidine N,O-nucleosides inhibit the replication of DNA and RNA of poliovirus 1. The presence of a nucleobase on the oxazolidine ring leads to the formation of modified N,O-nucleosides which greatly increase the cytotoxicity of these molecules making them excellent candidates as antitumor agents1,2. In addition, the asymmetric character of the molecules that have one or more spiro carbon is one of the most important factors that determine the biological activities3,4. The indole compounds are further relevant since their spiro derivatives are excellent anti-cancer agents, antibiotics, inhibitors of the receptor NK-15 and inhibitors of p53MDM2 interaction. In this context, the object of this work is the synthesis of a new class of indolyl spiro-isoxazolidine N,O-nucleosides variously functionalized that can enclose all the pharmacological properties of each class of molecules above described. The synthesis of these chiral compounds is carried out with simple and "Solvent-free" methodologies, by diastereoselective and microwave assisted 1,3-dipolar cycloaddition reaction between a chetonitrone derived from 1-indanone and a vinylnucleobase (Scheme 1). The synthetic methodology is innovative in that the two precursors are reacted in the solid phase and without solvent. Scheme 1 The reaction products were obtained with high reaction yields and excellent diasteroisomeric ratio. Moreover, all products are been subjected to a subsequent test phase to evaluate the pharmacological activity. 1) O. Bortolini, M. D’agostino, A. De Nino, L. Maiuolo, M. Nardi, G. Sindona. Tetrahedron, 2008, 64, 8078-8081. 2) R. Romeo, S. V. Giofrè, A. Garozzo, B. Bisignano, A. Corsaro, M. A. Chiacchio. Biorganic & Medicinal Chemistry, 2013, 21, 5688-5693. 3) P. Das, A. O. Omollo, L. J. Sitole, E. McClendon, E. J. Valente, D. Raucher, L. R. Walcher, A. T. Hamme II. Tetrahedron Letters, 2015, 56, 1794-1797. 4) M. Mehrdad, L. Rafaji, K. Jadidi, P. Eslami, H. Sureni. Monaths Chem, 2011, 142, 917-921. 5) T. Okita, M. Isobe, Tetrahedron, 1994, 50, 11143-11152. 172 PC48 Task-specific dicationic ionic liquids used as reaction media for Michael addition. Carla Rizzo1, Francesca D’Anna1, Salvatore Marullo1, Paola Vitale1, Renato Noto1 1 Dipartimento STEBICEF, Sezione di Chimica, Viale delle Scienze-Parco d’Orleans II, 90128 Palermo, Italy. e-mail: [email protected] Nowadays one of the main goals in organic chemistry is the research of increasing efficiency in chemical processes taking care of the environmental impact. In this context the choice of the right catalysts and solvents for organic reactions becomes crucial. For this reason in the last decades, ionic liquids have been applied as alternative solvents thanks to their low flammability, vapor pressure and high structural organization.1 If a catalyst is tethered in the cation or in the anion of the ionic liquids, they are called “task-specific ionic liquids”. The ensemble of catalyst and solvent in one compound increases the kinetic mobility and allows a large operational surface area.2 We have recently studied the properties and the catalytic ability of novel diimidazolium ionic liquids bearing an imidazole as basic functionality.3 Properties of these ionic liquids, such as thermal stability, catalytic ability and recyclability are strongly dependent on the nature of the anion used. With this in mind, we are now interested in the study of Michael addition of malonitrile to trans-calchone (Scheme 1), a base catalyzed reaction that leads to a key precursor for the synthesis of some biological and pharmaceutical products. In addition to the basic functionality present on the cationic unit, chiral anions such as tartrate, proline, phenilalanine, (R)-(-)-1,1’binaphtyl-2,2’diyl-phosphate, have been used in order to analyze stereochemical aspects of the reaction, studying their effects on reaction time, percentage yields and enantiomeric excess. Scheme 1 Task-specific ionic liquids used for the study of Michael addition. References: 1. Dupont, J.; Acc. Chem. Res. 2011, 44, 1223. 2. a) Lee, S.-G.; Chem. Commun. 2006, 1049. b) Sawant, A. D.; Raut, D. G.; Darvatkar, N. B.; Salunkhe, M. M.; Green Chem. Lett. Rev. 2011, 4, 41. 3. a) D’Anna, F.; Gunaratne, N. H. Q.; Lazzara, G.; Noto, R.; Rizzo, C.; Seddon, K. R.; Org. Biomol. Chem. 2013, 11, 5836. b) Rizzo, C.; D’Anna, F.; Marullo, S.; Noto, R.; J. Org. Chem. 2014, 79, 8678. 173 PC49 Catalytic Hunsdiecker Reaction in Continuous-Flow Graziano Fusinia, Adriano Carpitaa, Federico Galloa, Cosimo Boldrinia a Department of Chemistry and Industrial Chemistry, University of Pisa, Via G.Moruzzi, 13, 56124 Pisa, Italy e-mail: [email protected] The decarboxylative halogenation of carboxylic acids is a synthetically useful route to various organic halides. Various modifications of the classical Hunsdiecker1 reaction are testimony to the unabated interest of organic chemists in this reaction.2 Currently, simple strategy to employ a catalytic metal or ammonium salt pool, mediating an catalytic Hunsdiecker for the synthesis of β-halo styrenes from corresponding α,β-unsaturated aromatic carboxylic acids using N-halosuccinimides.3 However, until recently, despite the fact that a large number of publications describing the Catalytic Hunsdiecker reaction are available, the reaction has major limitations of safety and cost in the industrial application, due release of a variable amount of CO2 depending on the reaction conditions. Therefore, the use of continuous-flow tecnology can make such application much simple, safe and cheap.4 Herein we wish to report our recent results in the Catalytic Hunsdiecker reaction under continuous-flow conditions, compared to results obtained in batch mode, by using NBS as brominating agent and LiOAc as catalyst in mild homogeneous conditions. In a first approach, the experiments were performed in the batch mode with homogeneous condition using the LiOAc when catalyst at 70°C. Then, an effective continuous mini-reactor was developed, by filling pieces of Teflon tubing (2-4 mm internal diameter) with appropriate inert material to allow an efficient mixing. The resulting device was employed for carrying out the reactions in the flow mode, with pneumatic pumping. R1 R 1 O NX 2 COOH R1 LiOAc (cat.) - CO2 CH3CN/H2O (7:1) 70°C X R 3 O R = H, 4-Me, 2-OMe, 4-NO2, 4-Cl, 4-OH, 4-TBDMSO R1 = H, Me X = I, Br The efficiency of this reaction in continuous mode will be compared with those in classical bath mode in terms of reaction time, productivity and Space Time Yield. 1) (a) Borodin, B. Liebigs Ann. 1861, 119, 121. (b) Hunsdiecker, H. C. Chem. Ber. 1942, 75, 291. 2) (a) Sheldon, R. A.; Kochi, J. K. Org. React. (NY) 1972, 19, 326. (b) Zerong Wang Comprehensive Organic Name Reactions and Reagents; 2010, 338, 1511. (c) Chrich, D. In Comprehensive Organic Synthesis; Trost, B. M., Steven, V. L. Eds.; Pergamon: Oxford, 1991; Vol. 7, pp. 723–734. (d) Hassner, A.; Stumer, C. Organic Synthesis based on Name Reactions and Unnamed Reactions; Pergamon: Oxford, 1994; p 183. (e) Camps, P.; Lukach, A. E.; Pujol, X.; Vazquez, S. Tetrahedron 2000, 56, 2703. 3) (a) Das J. P.; Roy S. J. Org. Chem. 2002, 67, 7861. (b) Chowdhury S.; Roy S. J. Org. Chem. 1997, 62, 199. (c) Kuang C. X.; Senboku H.; Tokuda M. Synthesis 2005, 1319. (d) Graven, A.; Jorgensen, K. A.; Dahl, S.; Stanczak, A. J. Org. Chem. 1994, 59, 3543. (e) Naskar, D.; Roy, S. Tetrahedron 2000, 56, 1369. (f) Rajanna K. C.; Reddy N. M.; Reddy M. R. J. Disp. Sci. Techn. 2007, 28, 613 4) (a) Wiles C.; Watts P. Micro Reaction Technology in Organic Synthesis, 2011, CRC Press: Boca Raton. (b) B. Ahmed-Omer, J. C. Brandt, T. Wirth, Org. Biomol. Chem. 2007, 5, 733 (c) D. M. Roberge, L. Ducry, N. Bieler, P. Cretton, B. Zimmermann, Chem. Eng. Techn., 2005, 28, 318. (d) Wegner J.; Ceylan S.; Kirschning A. Adv. Synth. Catal. 2012, 354, 17 174 PC50 Room Temperature Ionic Liquids as Reaction Media for the Isomerization of Azobenzene Derivatives Guido Angelini1, Nadia Canilho2, Mélanie Emo3, Molly Kingsley4, Carla Gasbarri1 1 Department of Pharmacy, University “G. d’Annunzio” of Chieti – Pescara, Italy 2 University of Lorraine, Vandœuvre-lès-Nancy Cedex, France 3 Institut J. Barriol, University of Lorraine, Vandœuvre-lès-Nancy Cedex, France 4 University of Colorado Denver, Anschutz Medical Campus, USA e-mail: [email protected] Room temperature ionic liquids (RTILs) have attracted much attention in the last years for their unique properties and their potential high recyclability1. The effect of a para substituent (OtBu, OCH3, F and Br) on the azobenzene isomerization has been investigated by using BMIM+ / Tf2N- based RTILs as reaction media2. Typical V-shape Hammett plots for the cis – trans isomerization have been obtained in EMIM Tf2N, BMIM Tf2N and HMIM Tf2N, showing that both the rotation and the inversion mechanisms occur, according to the electronic nature of the substituent, but only rotation takes place in BMIM BF4, BMIM PF6 and BM2IM Tf2N. Small-wide angle X-ray scattering (SWAXS) has been performed before and after UV irradiation to determine the effect of the azobenzene isomers on the structural network formed by cations and anions in the RTILs. Finally, the cis population in the photostationary state and the hardness parameter of the trans isomer have been calculated to compare the reactivity of the investigated azobenzene derivatives in the trans – cis isomerization. Hammett plot for the cis – trans isomerization of the azobenzene derivatives 1) Seddon, K.R. J. Chem. Technol. Biotechnol. 1997, 68, 351-356. 2) Angelini, G.; Canilho, N.; Emo, M.; Kingsley, M.; Gasbarri, C. submitted 2015. 175 PC51 Synthesis of (-)-oseltamivir by the use of supported organocatalysts Luca Mengozzi1, Carles Rodriguez2, Pier Giorgio Cozzi1, Miquel A. Pericàs2,3 1 Dipartmento di Chimica “G. Ciamician”ALMA MATER STUDIORUM Università di Bologna, Via Selmi 2, 40126, Bologna, Italy 2 Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain 3 Departament de Química Orgànica, Universitat de Barcelona (UB), 08028 Barcelona, Spain e-mail: [email protected] The use of immobilized catalyst and the development of continuous flow processes that allow either for the catalyst recovery and re-use have emerged as a powerful strategy to develop sustainable chemical processes.1 Six membered cyclohexenes bearing several stereocenters with a high density of functional groups can be retrieved in the core of important pharmaceutical compounds such as (-)-oseltamivir2,3 zanamivir and laninamivir.4 The synthesis of key intermediate 4, a direct precursor of (-)-oseltamivir, through a nitro Michael reaction promoted by supported proline derived catalyst 35 will be presented. Scheme 1. Synthesis of (-)-oseltamir using supported organocatalysts. Acknowledgements: Bologna University through a Marco Polo fellowship and ICIQ, Institut Català d’Investigatiò Quimica are acknowledged for financial support. 1) 2) 3) 4) 5) Brzozowski, M.; O’Brien, M.; Ley, S.V.; Polyzos, A. Acc. Chem. Res. 2015, 48, 349-362 Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem. Int. Ed. 2009, 49, 1330-1333. Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem. Int. Ed. 2010, 53, 4656-4660. Tian, J.; Zhong, J.; Li, Y.; Ma, D. Angew. Chem. Int. Ed. 2014, 53, 13885-13888. Alza, E.; Pericas, M. A. Adv. Synth. Cat. 2009, 351, 3051-3056. 176 PC52 Biomass valorization using ionic liquids Cinzia Chiappe1, Maria Jesus Rodriguez-Douton1, Barbara Masciocchi2, Alessio Gentile2, Andrea Mezzetta1 1 Dipartimento di Farmacia, Università di Pisa, via Bonanno 33, 56126 Pisa, Italy. 2 Processi Innovativi Srl, Via Guido Polidoro 1,67100 L’Aquila, Italy. e-mail: [email protected] Nowadays, conversion of biomass into bio-fuels or value-added compounds is one of the most possible alternatives to alleviate the environmental and economic burdens associated with the depletion and consumption of fossil-based resources 1. Ionic liquids (ILs) are not only able to dissolve important biomacromolecules such as cellulose and chitin but, due to their negligible vapor pressure and thermal stability, they have been considered as “greener” alternative media to use as solvents and/or catalysts in several fields, including also the industrial processes for generating fuels from renewable feedstock. Herein, we report some selected examples showing the efficacy of ILs to affect the dissolution and transformation of biomass (based on cellulose or other biopolymers) and the possibility to develop new industrial processes. In particular, we discuss the extraction of fatty acids from micro-algae for biodiesel production and the conversion of cellulose (present in the biomass) into sugars and subsequently into their degradation compounds, such as 5-hydroxymethylfurfural (5-HMF), levulinic acid and formic acid. 1) Baliban, R, C.; Elia, J. A. Y.; Floudas, C, A. Energy Environ. Sci. 2013, 6, 267-287 177 PC53 Microwave assisted synthesis of lipophilic hydroxytyrosol fatty esters Emanuela Vitale1, Manuela Oliverio1, Luca Cariati1, Monica Nardi2, Antonio Procopio1. 1 Università Magna Græcia di Catanzaro, Campus Salvatore Venuta, 88100 Germaneto (CZ) 2 Università della Calabria, Ponte Bucci, cubo 12C, 87036 Arcavacata di Rende (CS) e-mail: [email protected] Natural products display various biological activities and, therefore, constitute important targets for drug synthesis. Hydroxytyrosol is natural antioxidant largely investigated owing to his safety and his usefulness in food, cosmetic and pharmaceuticals. Hydroxytyrosol fatty esters, compared with hydroxytyrosol, show a better skin permeability [1] and have a greater antioxidant activity in biological models [2]. In a previous report, we developed a mild method for the synthesis of lipophilic hydroxytyrosol esters at room temperature using THF dry and Er(OTf)3 as a catalyst [1]. In this report, instead, we explain a new green protocol developed for the synthesis of these compounds. This new method expect the use of fatty chlorides and hydroxytyrosol acetonide, a protected form of hydroxytyrosol where the oxidation during the storage is avoided, reacted by a microwave assisted one-pot synthesis. [3] In particular, because of the acetonide can be removed from hydroxytyrosol in acid environment, we thought that the hydroxytyrosol fatty ester synthesis and the hydroxytyrosol deprotection may occur simultaneously thanks to the HCl formed in the first reaction step. This new economic and eco-friendly protocol allows to synthetize hydroxytyrosol fatty esters not using any catalyst and toxic organic solvent. It is critical to note that neither the reagents nor the products are soluble in water, thus creating an oil/water interface where the reaction could take place allowing eater to play a pivotal role in accelerating the reaction thanks to the so-called “on-water effect”. This compounds are synthetized by one-pot reaction with a slightly molar excess of acyl chloride with a yield higher than the 60%. 1) 2) 3) Procopio A., Celia C., Nardi M., Oliverio M., Paolino D., and Sindona G., J Nat. Prod., 2011, 74, 2377-2381. rujillo M., Meteos R., Collantes de Teran L., Espartero J. L., Cert R., Jover M., Alcudia F., Bautista J, Cert A. and Parrado J., J. Agric. Food. Chem., 2006, 54, 3779-3785. orres de Pinedo A., Peñalver P., Rondón D. and Morales J. C., Tetrahedron, 2005, 61, 7654-7 660. 178 G – Sostanze Naturali 179 PC54 Phytotoxins by Phoma chenopodicola as potential herbicides to biological control of Chenopodium album Marco Evidentea, Maria Chiara Zonnob, Alessio Cimminoa, Marco Masia, Maurizio Vurrob, Alexander Berestetskiyc, Antonio Evidentea a Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, Via Cintia 4, 80126 Napoli; bIstituto di Scienze delle Produzioni Alimentari, Consiglio Nazionale delle Ricerche, Via Amendola 122/O, 70125 Bari, Italy; cAll-Russian Institute of Plant Protection, Russian Academy of Agricultural Sciences, Pushkin, Saint-Petersburg 196608, Russia [email protected] Chenopodium album, also known as common lambsquarters or fat hen, is a worldwide weed of arable crops such as sugar beet and maize (1). The difficulties in managing this weed have increased the interest in the use of fungal pathogens as a suitable option for its biological control. The first mycoherbicide proposed for the control of C. album was Ascochyta caulina (2, 3). More recently, another pathogenic Sphaeropsidales, Phoma chenopodicola, was proposed as a potential mycoherbicide for the control of the same weed. Taking into account that leaf and stem pathogenic Sphaeropsidales are well known as toxin producers, it was considered to be worthwhile studying the production of toxic metabolites by culture filtrates of P. chenopodicola. This study led to the isolation and the chemical and biological characterization of the main toxin, a new unrearranged ent-pimaradiene diterpene, named chenopodolin (4). This compound showed to have phytotoxic activity, causing necrotic lesions to leaves of different weeds, namely Mercurialis annua, Cirsium arvense and Setaria viridis. In order to figure out the structural features responsible for the activity, a structure-activity relationship study was carried out by using five derivatives obtained by chemical modification of the main functional groups of the toxin (4). Moreover, a successive investigation of the organic extract allowed to isolate three new tetrasubstituted furopyrans, named chenopodolans A, B and C, together with the well known fungal metabolite (-)-(R)-6-hydroxymellein (5). Considering that the organic extract obtained from the culture filtrates showed a phytotoxicity higher than the expected by chenopodolin and chenopodolans A-C content, a further analysis of the organic extracts of the fungus allowed to ascertain the presence of further bioactive metabolites, whose isolation, and chemical and biological characterization will be discussed in this communication. 1) 2) 3) 4) 5) L. G. Holm, D. L. Pluckett, J. V. Pancho, J. P. Herberger, The World’s Worst Weeds (Distribution and Biology); University Press of Hawaii: Honoloulou, HI, 1977; pp 84−91. C. Kempenaar, Studies on the Biological Control of Chenopodium album by Ascochyta caulina. Doctoral Thesis, University of Wageningen, The Netherlands, 1995. C. Kempenaar, P. J. F. M. Horsten, P. C. Scheepens, Eur. J. Plant Pathol., 1996, 102, 143−153. A. Cimmino, A. Andolfi, M.C. Zonno, F. Avolio, A. Santini, A. Tuzi, A. Berestetskiy, M. Vurro & A. Evidente, J. Nat. Prod., 2013, 76, 1291-1297. A. Cimmino, A. Andolfi, M.C. Zonno, F. Avolio, A. Berestetskiy, M. Vurro & A. Evidente, Phytochemistry, 2013, 96, 208-213. 180 PC55 Secondary metabolites from Scrophularia canina L. A. Vendittia,b, C. Frezzab*, M. Nicolettib , A. Biancoa, M. Serafinib a) Università di Roma “La Sapienza”, Dipartimento di Chimica, Piazzale Aldo Moro, 5 00185 Roma (Italia) b) Università di Roma “La Sapienza”, Dipartimento di Biologia Ambientale, Piazzale Aldo Moro, 5 00185 Roma (Italy) *e-mail: [email protected] Scrophularia canina L. is a herbaceous perennial plant belonging to Scrophulariaceae and growing abundantly in Italy1. In this work we report the composition of the polar fraction of the ethanolic extract of S. canina harvested in the pre-park area of National Park of Abruzzo, Lazio and Molise (Central Italy). This study allowed the isolation and the identification of a total of six compounds: one phenyl-propanoid, verbascoside2; one acyclic diterpenic alcohol called phytol3; four iridoid glucosides namely aucubin4, harpagide5, 8-O-acetyl-harpagide5 and 8-epiloganic acid6. Verbascoside is a quite common compound which is often identified as a constituent of species of the Asterideae subclass and has a taxonomic relevance when evidenced together with iridoids7. Also phytol is a widespread compound since it’s part of the chlorophyll structure. Aucubin, harpagide and 8-O-acetyl-harpagide have already been evidenced in this species8 while the other three compounds were recognized for the first time in this study. From a biosynthetic point of view, it’s important to underline the presence of 8epiloganic acid since it is considered the biogenetic precursor of a wide series of substances owning an iridoidic skeleton which are generally found in Scrophulariaceae and in other families of the Lamiales order and for this reason they are considered of chemotaxonomical relevance. 1) Pignatti, S. Flora d’Italia, 1982, 2, 590-596. 2) Venditti, A.; Bianco, A.; Nicoletti, M.; Quassinti, L.; Bramucci, M.; Lupidi, G.; Vitali, L.A.; Papa, F.; Vittori, S.; Petrelli, D.; Maleci Bini, L.; Giuliani, C And Maggi, F. Chemistry & Biodiversity, 2014, 11, 245-261. 3) Li, G.; Dumaa, M.; Xiang, P.; Jinhai, Y.; Guolin, Z.; Yinggang, L. Chin. J. Appl. Environ. Biol. 2012, 18(6), 924-927. 4) Paris, Mm.R. And Chaslot, M. Ann. Pharm. Franc., 1955, 13, 648. 5) Scarpati, M.L.; Guiso, M.; Panizzi, L. Tethraedron Lett., 1965, 39, 3439. 6) Coscia, C.J. And Guarnaccia, R. Chem Comm., 1968, 138. 7) Jensen, S.R. Annales Of The Missouri Botanical Garden Press, 1992, 79(2), 284-302. 8) Berdini, R.; Bianco, A.; Guiso, M.; Marini, E.; Nicoletti, M.; Passacantilli, P.; Righi, G. Journal of Natural Products. 1991, 54(5), 1400-1403. 181 PC56 Secondary metabolites content of two Stachys species: S. germanica subsp germanica and S. annua subsp. annua A. Vendittia,b, C. Frezzab*, F. Maggic, K. Cianfaglioned, A. Biancoa, M. Serafinib a) Università di Roma “La Sapienza”, Dipartimento di Chimica, Piazzale Aldo Moro, 5 00185 Roma (Italia) b) Università di Roma “La Sapienza”, Dipartimento di Biologia Ambientale, Piazzale Aldo Moro, 5 00185 Roma (Italy) c) Scuola di Farmacia, Università di Camerino, Camerino, Italia d) Scuola di Bioscienze e Medicina Veterinaria, Università di Camerino, Camerino, Italia *e-mail: [email protected] Stachys is an important and large genus belonging to the Lamiaceae family comprising 31 species in Italy out of 450 with characteristics not common and specific among themselves1. In this work we report the contents of the polar fractions of Stachys germanica L. subsp. germanica and S. annua L. subsp. annua. The study of the ethanolic extract of the former allowed the isolation and identification of two flavonoids, isoscutellarein derivates2,3, a phenyl-propanoid, stachysoside3, a caffeoylquinic derivative, clorogenic acid3 and lastly one iridoid, harpagide4. They all have been already evidenced in this genus5 and some are considered chemotaxonomic markers. On the other hand, the study of the latter led to the isolation and identification of two flavonoids, again isoscutellarein derivates2,3. These last compounds containing allose have been often evidenced in several genera of the Lamiaceae family such as Sideritis and even Stachys itself6,7, thus confirming their own chemotaxonomic proximity. Making a comparison between the two studied plants it can be noted that only a compound, one of the isoscutellarein derivates, was found in both species: in particular the observed composition of S. germanica resulted in accordance with those reported for several Stachys species5,6, while S. annua showed only the presence of flavonoids, instead. Such fact might be a starting basis for a reconsideration of the systematic collocation of this species. 1) Tomás-Barberan, F.A.; Gil, M.I.; Ferreres, F.; Tomás-Lorente, F. Phytochemistry. 1992, 31(9), 30973102. 2) Lenherr, A. And Mabry, T.J. Phytochemistry, 1987, 26, 1185. 3) Venditti, A.; Bianco, A.; Nicoletti, M.; Quassinti, L.; Bramucci, M.; Lupidi, G.; Vitali, L.A.; Papa, F.; Vittori, S.; Petrelli, D.; Maleci Bini, L.; Giuliani, C And Maggi, F. Chemistry & Biodiversity, 2014, 11, 245-261. 4) Scarpati, M.L.; Guiso, M.; Panizzi, L. Tethraedron Lett., 1965, 39, 3439. 5) Venditti, A.; Bianco, A.; Maggi, F.; Nicoletti, M. Natural Product Research, 2013, 27(15), 14081412. 6) Venditti, A.; Bianco, A.; Nicoletti, M.; Quassinti, L.; Bramucci, M.; Lupidi, G.; Vitali, L.A.; Papa, F.; Vittori, S. Et Al. Fitoterapia, 2013, 90, 94-103. 7) Serrilli, A.M.; Ramunno, A.; Piccioni, F.; Serafini, M.; Ballero, M.; Bianco, A. Natural Product Research, 2006, 20(6), 648-652. 182 PC57 Bioactive metabolites produced by Diplodia species pathogens of forest plants Wanda D’Amico,1 Marco Masi,1 Benedetto T. Linaldeddu,2 Marco Evidente,1 Lucia Maddau,2 Alessio Cimmino,1 Antonio Evidente1 1 Dipartimento di Scienze Chimiche, Universita’ di Napoli Federico II, Complesso Universitario Monte S. Angelo, Via Cintia 4, 80126 Napoli 2 Dipartimento di Agraria, Sezione di Patologia vegetale ed Entomologia, Università degli Studi di Sassari, Viale Italia 39, 07100 Sassari, Italy e-mail: [email protected] Several studies have pointed out the important role of fungi belonging to Diplodia genus in the aetiology of serious disease affecting forest trees worldwide. Among them, the infections of D. cupressi, D. africana D. quercivora, and D. corticola have a heavy impact on forest ecosystems, compromising both vitality and productivity of trees. Several Diplodia species are well-known for their ability to produce in vitro a wide range of secondary metabolites, exhibiting a variety of biological activities such as phytotoxic, cytotoxic, and antimicrobial which have drawn the attention in application studies. Sphaeropsidin A, an ent-pimarane isolated from D. cupressi, has been studied as a novel therapeutic strategy to combat drug-resistant cancers.1 Two new phytotoxic dihydrofuropyran-2-ones, named afritoxinones A and B, and oxysporone were isolated from Diplodia africana, a pathogen directly involved in the aetiology of juniper die-back in Italy.2 A new phytotoxic nor-ent-pimarane, namely diplopimarane, was isolated together with sphaeropsidin A and epi-epoformin from D. quercivora, a pathogen recently found on declining Quercus canariensis trees in Tunisia.3 Diplodia corticola, an aggressive cork oak pathogen, produced in liquid culture monocyclic and bicyclic substituted furanones and a new phytotoxic tetrahydropyranpyran-2-one, namely diplopyrone as well as the sphaeropsidin A.4 A re-investigation of the culture filtrates of D. corticola allowed us to isolate new metabolites, which appear, from preliminary spectroscopic investigations, to be closely related to sphaeropsidins and furanones. In addition, for the first time bioactive secondary metabolites were isolated from two other pathogenic Diplodia species, namely Diplodia olivarum and Diplodia fraxini. Their organic extracts showed phytotoxicity. The results will be illustrated in this communication. 1) Mathieu, V.; Chantome, A.; Lefranc, L.; Mohr, T.; Maddau, L.; Berger, W.; Evidente, A.; Vandier, C.; Delpire, E.; Kiss, R. Cmls 2015, In Press. 2) Evidente, A.; Masi, M.; Linaldeddu, B.T.; Franceschini, A.; Scanu, B.; Cimmino, A.; Andolfi, A., Motta, A.; Maddau, L. Phytochemistry, 2012, 77, 245-250. 3) Andolfi, A.; Maddau, L.; Basso, S.; Linaldeddu, B.T.; Cimmino, A.; Scanu, B.; Deidda, A.; Tuzi, A.; Evidente, A. J. Nat. Prod., 2014, 77, 2352-2360. 4) Evidente, A.; Andolfi, A.; Fiore, M.; Spanu, E.; Maddau, L.; Franceschini, A., Marras, F.; Motta, A. J. Nat. Prod., 2006, 69, 671-674. 183 PC58 Natural dyes from Rubia tinctorum L., used in tapestries Ilaria Serafini1,2, Livia Lombardi1,2, Fabio Sciubba1, Marcella Guiso1, Armandodoriano Bianco1 1 Dipartimento di Chimica, 2Dipartimento di Scienze della Terra, Università di Roma “La Sapienza”, Piazzale Aldo Moro 5, 00185 Roma. e-mail: [email protected] Plants and insects had been used for a long time in the ancient period as source for dyes for art materials. On many tapestries, there is a widespread state of decay in charge of the colour of many yarns. This phenomenon may be due to presence of alteration products or total destruction of dye molecules. If we consider madder root, for example, contains a large number of compounds characterized by anthraquinone structures, thought as the main chromophores [1]. However, it is worth to notice that the analyses of madder’s extract, obtained in the same condition of dyeing bath [2], reveal also the presence of other types of molecules (not necessarily anthraquinones), present in the matrix. Some of them can be fixed on the yarn and, probably, these are involved in the degradation processes. During this work, it has carried out extraction of dyes from R.tinctorum L. and analysed by HPTLC (Fig. 1), 1H-NMR (Fig. 2). and ESI-MS With ESI-MS/MS, in both positive and negative mode, it has been possible to draw a structural profile of the compounds. These compounds are compared to those extracted by yarns [3] [4], dyed following the ancient recipes [2], in order to evaluate which molecules are fixed on the textile . Fig.1 Chromatographic separation of madder extract Fig.2 1H-NMR of madder yarn extract . 1) G. C. H. Derksen, H.A.G. Niederländer, T.A. Van Beek, J. Chromatogr, 2002, 978, 119–127. 2) D. Cardon, Natural Dyes: Sources, Tradition, Technology and Science, 2007, Archetype Publications Ltd, London. 3) Lombardi L., Serafini I., Guiso M., Sciubba F, Bianco A., Tetrahedron Letters, Submitted, 2015. 4) Valaniou, L., Karapanagiotis I., Chryssoulakis, Anal Bioanal Chem, 2007, 395, 2175 -2189. 184 PC59 Anthemis cretica subsp. petraea (Ten.) Oberpr. & Greuter from Majella National Park. Alessandro Venditti1,2, Mirella Di Cecco3, Giampiero Ciaschetti3, Armandodoriano Bianco1 1 2 3 Dipartimento di Chimica Sapienza Università di Roma (P.le A. Moro 5, 00185 Roma). Dipartimento di Biologia Ambientale Università di Roma (P.le A. Moro 5, 00185 Roma). Ente Parco Nazionale della Majella, Via Occidentale 6, 66016 Guardiagrele (CH),(Italy) e-mail: [email protected] Anthemis cretica subsp. petraea (Ten.) Oberpr. & Greuter (Asteraceae) is an endemic species of central Italy which grows between 110 and 2600 m a.s.l.. In Italy it is present only in Abruzzo and Molise regions. We studied a sample collected from the Majella National Park, where this species represent a rare entity. The preliminary study of the ethanolic fraction led to the identification of partenolide (1) already evidenced in Anthemis melampodina Delile2 and in other Asteraceae, kaempferol (2), a common flavonoid in Anthemideae and Cichorideae3,4,5 and a cycloexenetetraol named leucanthemitol (3) previously evidenced in Anthemis nobilis L. and in Chrysanthemum leucanthemum L., together with several other compounds under study. Compound (3) is a quite rare compound and represent a molecular evidence of the botanical proximity among these correlated genera of Asteraceae. 1) Conti, F.; Abbate, G.; Alessandrini, A.; Blasi, C., An Annotated Checklist of the Italian Vascular Flora. 2005, Palombi Press: Rome. 2) Sarg, T.; El-Dahmy, S.; Salem, S., Scientia Pharmaceutica, 1990, 58(1), 33-35. 3) Wollenweber, E.; Dorr, M.; Fritz, H.; Valant-Vetschera, K.M., Z Naturforsch C, 1997, 52(3/4), 137143. 4) Valant-Vetschera, K.M.; Wollenweber, E.; Faure, R.; Gaydou, E., Biochem Syst Ecol, 2003, 31(5), 545-548. 5) Guimaraes, R.; Barros, L.; Duenas, M.; Calhelha, R.C.; Carvalho, A.M.; Santos-Buelga, C.; Queiroz, M.J.R.P.; Ferreira, I.C.F.R., Food Chem., 2013, 136(2), 718-725. 6) Plouvier, V., Compt. Rend., 1962, 255, 360-362. 185 PC60 Secondary metabolites from flowers of Genista cilentina Vals. Alessandro Venditti1,2, Mauro Serafini2, Claudio Frezza2, Armandodoriano Bianco1 1 2 Dipartimento di Chimica Sapienza Università di Roma (P.le A. Moro 5, 00185 Roma). Dipartimento di Biologia Ambientale Università di Roma (P.le A. Moro 5, 00185 Roma). e-mail: [email protected] Genista cilentina Vals. is an Italian endemic species belonging to Fabaceae which is characteristic of Cilento, a territory of Campania region overlooking the Tyrrhenian Sea1. The phytochemical analysis of the ethanolic extract from the flowers revealed the presence of several flavonoid and isoflavonoid yet evidenced in this genus, and resulted in accordance with the flavonoidic pattern reported by Harborne for Genisteae tribe2. In particular were identified genistein (1) the main isoflavonoid, biochanin A (2), luteolin (3) and apigenin (4) as aglycones, while several glycosidated derivatives are currently under study. Is worth of mention the conspicuous presence of liquiritigenin (5) a chalcone evidenced as the only synthesized compound in Genista tinctoria hairy root cultures3 treated with abscissic acid. Compound (5) is also endowed with interesting biological activities, i.e. gastroprotective4, antiviral5 and counteracting the Alzheimer disease progression6. 1) Conti, F.; Abbate, G.; Alessandrini, A.; Blasi, C., An Annotated Checklist of the Italian Vascular Flora. 2005, Palombi Press: Rome. 2) Harborne, J.B., Phytochemistry, 1969, 8(8), 1449-1456. 3) Luczkiewicz, M.; Kokotkiewicz, A., Z Naturforsch. C, 2005, 60(11/12), 867-875 4) Choi, Y.H.; Kim, Y-J.; Chae, H-S.; Chin, Y-W., Planta Med. 2015, 81(7), 586-593. 5) Li, Z.; Zhao, Y.; Lin, W.; Ye, M.; Ling, X., J Pharmaceut Biomed., 2015, 111, 28-35. 6) Link, P.; Wetterauer, B.; Fu, Y.; Wink, M., Planta Med., 2015, 81(5), 357-362. 186 PC61 Anti-inflammatory effects of dihydroasparagusic acid in lipopolysaccharide-activated microglial cells Adele Salemme1,Anna Rita Togna1,Vittoria Cammisotto1, Armandodoriano Bianco2, Alessandro Venditti2,3 1 Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy 2 Department of Chemistry, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy 3 Department of Environmental Biology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy [email protected] The activation of microglia and resulting elevated levels of pro-inflammatory and neurotoxic mediators, is crucially associated with neurodegenerative diseases, including Alzheimer and Parkinson diseases and multiple sclerosis1,2. Dihydroasparagusic acid (DHAA) is a natural dimercaptanic acid, a sulfur-containing flavor component produced by Asparagus plants. It has two thiolic functions able to coordinate metal ions, and a carboxylic moiety, which may enhance excretion of the complexes. Indeed a protective effect of DHAA toward Hg2+ poisoning has been demonstrated in an in vitro study4. Thiol functions are also present in several biomolecules with important physiological antioxidant role as glutathione. DHAA has been recently reported to exert several interesting biological activities, including radical scavenging and antioxidant activities and an inhibitory action on mushroom tyrosinase3. The aim of this study was to investigate the in vitro anti-inflammatory potential of DHAA on LPS-activated primary rat microglia cultures. LPS was used as a stimulus, being capable of causing a wide variety of pathophysiological effects, i.e. release of proinflammatory cytokines and mediators, increased ROS production, which cause oxidative stress5. Our results suggest that DHAA significantly prevented LPS-induced production of proinflammatory and neurotoxic mediators such as NO, TNF-α, PGE2, as well as iNOS and COX-2 protein expression and LOX activity in microglia cells, suggesting that DHAA can effectively inhibit inflammation and oxidative processes that are typical of activated microglia. So it can be a valuable source for further development of agents designed for prevention or treatment of neuroinflammation, an important part of the etiopathogenesis of neurodegenerative diseases. 1) Block, M.L., Zecca, L., Hong, J.S. Nat. Rev. Neurosci. 2007, 8, 57-69. 2) Kim, E.A., Han, A.R., Choi, J., Ahn, J.Y., Choi, S.Y., Cho, S.W. Int. Immunopharmacol. 2014, 22, 73-83 3) Venditti, A., Mandrone, M., Serrilli, A.M., Bianco, A., Iannello, C., Poli, F., Antognoni F. J. Agric. Food Chem. 2013, 61, 6848-6855 4) Bianco, A., Bottari, E., Festa, M.R., Gentile, L., Serrilli, A.M., Venditti, A. Monatsh Chem., 2013, 144, 1767-1773 5) Hou, X., Zhang, J., Ahmad, H., Zhang, H., Hu, Z., Wang, T. PLoS One, 2014, 9(9):e108314. doi: 10.1371/journal.pone.0108314 187 PC62 Molecular traits of hemiparasitism in Odontites lutea (L.) Clairv. Alessandro Venditti1,2, Mauro Serafini2, Marcello Nicoletti2, Sebastiano Foddai2, Armandodoriano Bianco1 1 2 Dipartimento di Chimica Sapienza Università di Roma (P.le A. Moro 5, 00185 Roma). Dipartimento di Biologia Ambientale Università di Roma (P.le A. Moro 5, 00185 Roma). e-mail: [email protected] Odontites lutea (L.) Clairv. is an erect hemiparasitic plant traditionally comprised in Scrophulariaceae which was recently moved in Orobanchaceae1. In this study we reported the analysis of the monoterpene glycoside fraction obtained following the procedure of an our recent patent2. The studied sample was collected from a spontaneous population growing in a cultivated olive field (Olea europaea, Oleaceae) bordering a Mediterranean forest represented mainly by Arbutus unedo (Ericaceae), to verify the influence of the environmental conditions on the secondary metabolite content. After repeated chromatographic purification fourteen iridoidic compounds were isolated and identified. Besides iridoids already evidenced in Odontites as melampyroside (1), bartsioside (2), aucubin (3), 6-O-glucosyl-aucubin (4) and aucubigenin-1-O-cellobioside (5), shanzhiside methyl ester (6), mussaenoside (7), 8-epiloganin (8) and adoxosidic acid (9), and currently considered chemotaxonomical markers for the Scrophulariaceae family since recognized in many genus belonging to this family3,4,5,6,7,8, were also evidenced compounds peculiar of different families which were not reported before as constituents of Scrophulariaceae or Orobanchaceae. In particular were recognized: monotropein (10) and 6,7-dihydromonotropein (11) which are characteristic of Ericaceae9,10; agnuside (12), previously found in Verbenaceae11; methyl oleoside (13) and methyl gluco-oleoside (14)11, two secoiridoids usually found in Oleaceae12,13. The occurrence of these unusual compounds (10-14) in the studied species is a molecular evidence of the parasitic behaviour of O. lutea, which demonstrates a host-guest metabolites exchange. 1) APG II. The Angiosperm Phylogeny Group.: APG II. Bot. J. Linn. Soc., 2003; 141: 399–436. 2) Ballero, M.; Bianco A.; Serrilli A. M., Italian Patent, 2009, MI2009A000720 3) Bianco, A.; Francesconi, A; Passacantilli, P., Phytochemistry 1981, 20(6), 1421-1422. 4) Bianco, A.; Bolli, D.; Passacantilli, P., Gazz. Chim. Ital. 1981, 111(3-4), 91-94. 5) Bianco, A.; Bolli, D.; Passacantilli, P., 6 Planta Med. 1982, 44(2), 97-99. 6) Venditti, A.; Serrilli, A.M.; Bianco, A., Nat. Prod. Res., 2013, 27(15), 1413-1416. 7) Venditti, A.; Ballero, M.; Serafini, M.; Bianco, A., Nat. Prod. Res. 2015, 29(7), 602-606. 8) Mead, E.W.; Stermitz, F.R., Phytochemistry 1993, 32(5), 1155-1158. 9) Karikas, G.A.; Euerby, M.R.; Waigh, R.D., Planta Med. 1987, 53(2), 223-224. 10) Jensen, H.D.; Krogfelt, K.A.; Cornett, C.; Hansen, S.H.; Christensen, S.B., J. Agr. Food Chem., 2002, 50(23), 6871-6874. 11) Sridhar, C.; Subbaraju, G.V.; Venkateswarlu, Y.; Venugopal, R.T., J. Nat. Prod., 2004, 67(12), 20122016. 12) Bianco, A.; Buiarelli, F.; Cartoni, G.; Coccioli, F.; Muzzalupo, I.; Polidori, A.; Uccella, N. Anal. Lett, 2001, 34(6), 1033-1051. 13) Takenaka, Y.; Tanahashi, T.; Shintaku, M.; Sakai, T.; Parida N.N., Phytochemistry 2000, 55(3), 275284. 188 H – Medicinal Chemistry e Chimica BioOrganica 189 PC63 Self-assembly of amphiphilic anionic calix[4]arene and encapsulation of poorly soluble naproxen and flurbiprofen. L. Barbera,a G. Gattuso,a F.H. Kohnke,a A. Notti,a M. F. Parisi,a I. Pisagatti,a S. Pappalardo,b S. Patanè,c N. Micali,d and V. Villarid a Dipartimento di Scienze Chimiche, Universita` di Messina, Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy. b Dipartimento di Scienze Chimiche, Universita` di Catania, Viale A. Doria 6, 95125 Catania, Italy. c Dipartimento di Fisica e di Scienze della Terra, Universita` di Messina, Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy. d CNR-IPCF Istituto per i Processi Chimico-Fisici, Viale F. Stagno d’Alcontres 37, 98158 Messina, Italy. E-mail: [email protected] Calixarenes-based surfactants represent a new class of amphiphiles with unique and intriguing properties assigned by the presence of an aromatic cavity, which may offer, together with the other hydrophobic and hydrophilic characteristics, additional interactions.1 The present work describes the synthesis of a water-soluble calix[4]arere 1 bearing 4-butylsulfonato pendant groups at the lower rim and the analysis of its selfassembling properties by a combination of NMR, DLS and AFM techniques, thus revealing their complementarity in the study of amphiphilic systems. Surfactant formulations are finding growing applications as drug delivery systems in pharmaceutical and clinical fields, owing to their ability to encapsulate and transport a hydrophobic pharmaceutically active drug to its therapeutic target. In this context the ability of the micellar aggregates of calixarene 1 to encapsulate the non steroidal antiinflammatory naproxen 2 and flurbiprofen 3 in their environment was investigated, and the results showed that calixarene-type surfactants might be employed in the design of novel drug delivery systems. 1) a) Shinkai S.; Mori S.; T. Tsubaki; Sone T.; Manabe O. Tetrahedron Letters 1984, 25, 5315; b) Shinkai S. Pure Appl. Chem 1986, 58, 1523. 190 PC64 Synthesis and Preclinical Evaluation of a Novel, Selective 111In-labelled Aminoproline-RGD-peptide For Non-invasive Tumor Imaging Andrea Sartori,1 Francesca Bianchini,2 Paola Burreddu,3 Claudio Curti,1 Franca Zanardi,1 Lucia Battistini1 1 2 Dipartimento di Farmacia, Università degli Studi di Parma, Parma 43124, Italy Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, “Mario Serio” Università degli Studi di Firenze, Firenze 50134, Italy 3 Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Li Punti Sassari 07100, Italy e-mail: [email protected] In recent years, many efforts have been addressed to develop new techniques enabling the early diagnosis and non-invasive monitoring in primary tumors and metastasis. Integrins V3 and 51 have been characterized as prototypic molecules of angiogenic tumor associated-endothelial cells and their overexpression in tumor cells has been correlated to different stages of progression in various tumor types.1,2 The chemical and radiochemical synthesis, characterization and preclinical evaluation of a 111In-labelled DOTA conjugate embodying a cyclic aminoproline-RGD semipeptide [c(AmpRGD)] as a competent dual V3/51 integrin ligand will be reported.3 Evaluation of the 111In-labelled bioconjugate as SPECT tracer in a xenograft model of human melanoma will be described, as well as displacement experiments assessing the V3/51 integrin specificity of tumor uptake. The 111In-labelled c(AmpRGD)-DOTA conjugate holds promise as SPECT-imaging small-molecular probe for non-invasive visualization of human melanoma and other V3/51-positive tumors. 1) Zhou, Y.; Chakraborty, S.; Liu, S. Theranostics. 2011, 1, 58-82. 2) Auzzas, L.; Zanardi, F.; Battistini, L.; Burreddu, P.; Carta, P.; Rassu, G.; Curti, C.; Casiraghi, G. Curr. Med. Chem. 2010, 17, 1255-1299. 3) Battistini, L.; Burreddu, P.; Carta, P.; Rassu, G.; Auzzas, L.; Curti, C.; Zanardi, F.; Manzoni, L.; Araldi, E.M.V.; Scolastico, C.; Casiraghi, G. Org. Biomol. Chem. 2009, 7, 4924-4935. 191 PC65 Design, synthesis and characterization of helical oligopeptides inhibiting the VEGF/VEGFR protein-protein interaction Laura Belvisi1, Gianfranco Bocchinfuso2, Stefano Raniolo2, Antonio Palleschi2, Marta De Zotti3, Giacomo Panighel3, Fernando Formaggio3, Daniela Arosio4, Umberto Piarulli5, Simone Zanella1, Luca Pignataro1, Cesare Gennari1, Lorenzo Stella2 1 2 Department of Chemistry, University of Milan, 20133 Milan, Italy Department of Chemical Sciences and Technologies, University of Rome ‘Tor Vergata’, 00133 Rome, Italy 3 Department of Chemistry, University of Padova, 35131 Padova, Italy 4 5 ISTM CNR, 20133 Milan, Italy Department of Science and High Technology, 22100 Como, Italy e-mail: [email protected] Protein-protein interactions modulate most biological processes, but their inhibition by small organic molecules is challenging, due to the large interacting protein interfaces. One example is provided by the association between vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). It is crucial in regulating angiogenesis and therefore constitutes a key target in cancer therapy. Oligopeptides mimicking a VEGF interface helix represent a promising strategy to inhibit this interaction.1 Receptor (VEGFR, D2 VEGF (dimer) Here we report in silico design, synthesis, structural and functional characterization of several short peptides (9-15 residues) targeting VEGFRs. In particular, we exploited the known helix-inducing capabilities of Cα-tetrasubstituted α-amino acids to stabilize the secondary structure of our peptides.2 We gratefully acknowledge MIUR for financial support (PRIN project 2010NRREPL: Synthesis and biomedical applications of tumor-targeting peptidomimetics). 1) Basile, A.; Del Gatto, A.; Diana, D.; Di Stasi, R.; Falco, A.; Festa, M.; Rosati, A.; Barbieri, A.; Franco, R.; Arra, C.; Pedone, C.; Fattorusso, R.; Turco, M. C.; D'Andrea, L. D. J. Med. Chem. 2011, 54, 1391-1400. 2) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Biopolymers 2002, 60, 396-419. 192 PC66 Stereoselective synthesis of carba analogs of Manα1-2Man as potential DC-SIGN ligands Vittorio Bordoni,1 Alessia Nocciolini,1 Lucilla Favero,1 Paolo Crotti,1 Anna Bernardi,2 Franck Fieschi3, Valeria Di Bussolo1 1 2 Dipartimento di Farmacia, Università di Pisa, via Bonanno 33, 56126 Pisa Dipartimento di Chimica, Università degli studi di Milano, via Golgi 19, 20133 Milano 3 Institut de Biologie Structurale, 41 rue Jules Horowitz, 38027 Grenoble (France) e-mail: [email protected] DC-SIGN is a novel DC-specific adhesion receptor on human Dendritic cells, which is essential in binding antigens and in transfecting the infection to T cells. DC-SIGN binds ligand motifs through a terminal carbohydrate recognition domain (CRD).1 The main carbohydrate ligand recognized by DC-SIGN is the high mannose glycan (Man)9(GlcNAC)2, in which the terminal disaccharide portion Manα1-2Man binds DCSIGN almost as efficiently as the entire high mannose glycan (Man)9(GlcNAC)2. This suggests an important role of the nonreducing end Manα1-2Man fragment of Man9 in DC-SIGN recognition.2 Recently, Bernardi’s group synthesized pseudodisaccharide 1 having a threedimensional structure and a conformational behavior corresponding to that of the natural disaccharide Manα1-2Man. It also showed a significant anti-viral activity.3 a,b,c On the basis of this result, we achieved the synthesis of the new pseudomannobiosides 2 and 3, mimics of the natural Manα1-2Man, with an amino and an azido functionality at the end, respectively. These compounds are conceptually corresponding to the previously pseudodisaccharide 1, but with the important difference of the presence of a real D-carbamannose unit instead of a simplified mimic structure. The synthetic project proceeds through the obtainment of the (+)-6-O-benzyl-5a-carba-D-glucal (4), as a key intermediate, which was subjected to two different type of elaborations to afford the carbaglycosylating agents (+)-tri-O-benzyl-β-epoxide (5), and the (+)-tri-O-acetyl-βepoxide (6), precursors of the pseudomannobiosides 2 and 3, respectively. 1) Gejtenbeek, T. B. H.; Engering, A.; van Kooyk, Y. J. J. Leuk. Bio. 2002, 921-931. 2) Engering, A.; Gejtenbeek, T. B. H. J. Immunol. 2002, 168: 2118-2126. 3) (a) Bernardi, A.; Arosio, D.; Dellavecchia, D.; Micheli, F. Tetrahedron: Asymmetry 1999, 10, 34033407. (b) Reina, J. J.; Sattin, S.; Invernizzi, D.; Mari, S.; Mart nez-Prats, L.; Tabarani, G.; Fieschi, F.; Delgado, R.; Nieto, P. M.; Rojo J.; Bernardi, A. ChemMedChem 2007, 2, 1030-1036. (c) Thépaut, M.; Guzzi, C.; Sutkeviciute, I.; Sattin, S.; Ribeiro-Viana, R.; Varga, N.; Chabrol, E.; Rojo, J.; Bernardi, A.; Angulo, J.; Nieto, P. M.; Fieschi, F. J. Am. Chem. Soc. 2013, 135, 2518-2529. 193 PC67 Guanosine-based hydrogen-bonded Scaffolds: G-ribbons and Gquartets Formed in the Absence of a Templating Metal Cation Mohamed El Garah,[a] Rosaria C. Perone,[b] Alejandro Santana Bonilla,[c,d] Sébastien Haar,[a] Marilena Campitiello,[b] Rafael Gutierrez,[c] Gianaurelio Cuniberti,*[c,e] Stefano Masiero,*[b] Artur Ciesielski*[a] and Paolo Samorì*[a] [a] [b] ISIS & icFRC, Université de Strasbourg & CNRS, Strasbourg (France) Alma Mater Studiorum - Università di Bologna Dipartimento di Chimica “G. Ciamician”, Bologna (Italy) [c] Institute for Materials Science and Max Bergmann Center of Biomaterials Dresden University of Technology (Germany) [d] Max Planck Institute for the Physics of Complex Systems (Germany) [e] Dresden University of Technology (Germany) e-mail: [email protected] Here we describe the design and synthesis of novel alkyl substituted guanosine derivatives equipped with a ferrocene1 moiety on the C(5’) position of the sugar, and their self-assembly at the solid/liquid interface on highly oriented pyrolitic graphite (HOPG). Scanning Tunneling Microscopy imaging at the graphite/solution interface revealed that the functionalization of the C(8) position of the guanine core rules the type of 2D pattern at surfaces.2 In particular, when the C(8) position of the guanine core is exposing either a proton or a Br atom, the molecule was found to form different 1D supramolecular nanoribbons on graphite.3 On the other hand, upon functionalization of the C(8) with a sterically demanding substituent like a phenol group, cyclic G-quartet motifs were formed.4 This result represents the first example of the formation and visualization at the solid/liquid interface of metal-free G-quartets, a structure of biological significance, in the frame of nucleic acid telomerase. The tunability of the structural motif of the guanosine based assembly via simple substitution in the C(8) position also opens perspectives towards the use of ferrocene based ordered architectures for applications in (opto)elecronics. 1) 2) 3) 4) D. Astruc, C. Ornelas, J. Ruiz, Acc. Chem. Res. 2008, 41, 841-856 a) G. P. Spada, S. Lena, S. Masiero, S. Pieraccini, M. Surin, P. Samorì, Adv. Mater. 2008, 20, 2433-2438; b) T. F. A. Greef, E. W. Meijer, Nature 2008, 453, 171-173. S. Masiero, S. Pieraccini, G. P. Spada, in Guanine Quartets: Structure and Application, The Royal Society of Chemistry, 2013, pp. 28-39 V. Andrisano, G. Gottarelli, S. Masiero, E. H. Heijne, S. Pieraccini, G. P. Spada, Angew. Chem. Int. Ed. 1999, 38, 2386-2388. 194 PC68 Discovery of gymnemic acids as a new class of liver X receptor antagonists Carmen Festa1, Barbara Renga2, Simona De Marino1, Simone Di Micco3, Maria Valeria D’Auria1, Giuseppe Bifulco3, Stefano Fiorucci2, Angela Zampella1 1 Department of Pharmacy (University of Naples “Federico II”, Via D. Montesano 49, I-80131 Naples, Italy). 2Department of Surgery and Biomedical Sciences (Nuova Facoltà di Medicina, P.zza L. Severi, I06132 Perugia, Italy). 3Department of Pharmacy (University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, Italy) e-mail: [email protected] Liver X receptor- and - are ligand-activated transcription factors belonging to the nuclear receptor superfamily that controls biological responses by coordinating regulation of gene transcription. These receptors are critical modulators of lipid and glucose metabolism, inflammatory responses and innate immunity.1-3 Within our interest in nuclear receptor modulators from natural sources,4,5 we proceeded in the isolation and pharmacological decodification of gymnemic acids from a commercial available preparation of Gymnema sylvestre extracts. Gymnema sylvestre is considered a relevant medicinal plant, especially for its antidiabetic properties, but also for the treatment of a broad range of ailments including asthma, eye complaints, family planning, colic pain, cardiopathy, constipation, dyspepsia, hemorrhoids, and hyperlipidemic conditions.6-9 We demonstrated for the first time that individual gymnemic acids are potent and selective antagonists for the isoform of LXR. Deep pharmacological investigation Gymnestrogenin demonstrated that gymnestrogenin, reducing the expression of SREBP1c and ABCA1 in vitro, is able to decrease lipid accumulation in HepG2 cells. The results of this study substantiate the use of Gymnema sylvestre extract in LXR-mediated dislypidemic diseases. 1) Kalaany, N.Y.; Mangelsdorf, D.J. Annu Rev Physiol 2006; 68; 159-91. 2) Tontonoz, P.; Mangelsdorf, D.J. Mol Endocrinol 2003;17;985-93. 3) Swanson, H.I.; Wada, T.; Xie, W.; Renga, B.; Zampella, A. et al. Drug Metab Dispos 2013;41;1–11. 4) D'Auria, M.V.; Sepe, V.; Zampella, A. Curr Top Med Chem 2012;12;637–69. 5) Fiorucci, S.; Distrutti, E.; Bifulco, G.; D'Auria, M.V.; Zampella, A. Trends Pharmacol Sci 2012;33;591–601. 6) Kanetkar, P.; Singhal, R.; Kamat, M. J Clin Biochem Nutr 2005;1;77–81. 7) Saneja, A.; Sharma, C.; Aneja, K.R.; Pahwa, R. Der Pharmacia Lettre 2010;2;275–84. 8) Porchezhian, E.; Dobriyal, R.M. Pharmazie 2003;58;5–12. 9)Shigematsu N, Asano R, Shimosaka M, Okazaki M. Biol Pharm Bull 2001;24;713–17. 195 PC69 Targeting Microsomal Prostaglandin E2 Synthase 1 For The Development Of New Potential Anti-inflammatory Drugs. Antonio Foglia, Stefania Terracciano,Gianluigi Lauro, Carmela Saturnino, Raffaele Riccio, Ines Bruno, Giuseppe Bifulco.1 1 Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, Italy e-mail: [email protected] Arachidonic acid metabolism is a critical process mediated by several enzymes, which lead to the formation of different classes of eicosanoids.1 Prostaglandin E2 (PGE2) is the most prominent prostanoid and it elicites a wide range of biological effects associated with inflammation, pain, fever and cancer.2 The synthesis of this bioactive lipid is mediated by three terminal Prostaglandin E2 synthases (PGES): a cytosolic isoform (cPGES) and two microsomal isomerases (mPGES-1 and mPGES-2).3 In contrast to mPGES-2 and cPGES, the expression of mPGES-1 is inducible and therefore responsible for enhanced PGE2 levels during inflammation processes. Therefore, mPGES-1 has emerged as a promising target for therapeutic application in light of the possibility of overcoming the classical side effects commonly associated with use of traditional anti-inflammatory drugs (NSAIDs and Coxibs).5 This membrane protein is structurally a homotrimer and the active site is located at the interfaces of the three asymmetric monomers, which are formed by four α-helices and are partially occupied by the glutathione (GSH) cofactor.4 Although many structurally different compounds able to efficiently inhibit mPGES-1 have been developed, the discovery of new and more potent mPGES-1 inhibitors is strongly required. With the aim of discovering a new potential class of mPGES-1 inhibitors, we have accomplished a virtual screening on a huge number of synthetically accessible molecules in order to select the best candidates for the subsequential steps of chemical synthesis and biological evaluation. Computational calculations were performed by using the X-ray crystallographic structure of mPGES-1 solved in 20146 and results will enable the selection of scaffolds displaying the most promising binding affinity toward the target protein. 1) 2) 3) 4) 5) 6) Smith, W. L.; Urade, Y.; Jakobsson, P.-J.; Chemical Reviews, 2011, 111, 5821-5865 Park, JY.; Pillinger, MH.; Abramson, SB. Clinical Immunology, 2006, 119, 3, 229-240. Nakanishia, M.; Gokhaleb, V.; Meuilletc, E.J.; Rosenberg D.W. Biochimie, 2010, 92, 660-664. Chang, H.; Meuillet, E.J.; Future Med Chem, 2011, 3, 1909–1934. T. Sjögren, J. Nord, M. Ek, P. Johansson, G. Liu, S. Geschwindner Proc. Natl. Acad. Sci. U.S.A., 2013, 110, 3806-3811. Li, D.; Howe, N.; Dukkipati, A.; Shah, S. T.; Bax, B. D.; Edge, C.; Bridges, A.; Hardwicke, P.; Singh, O. M.; Giblin, G.; Pautsch, A.; Pfau, R.; Schnapp, G.; Wang, M.; Olieric, V.; Caffrey, M. Cryst Growth Des 2014, 14, 2034-2047. 196 PC70 Targeting integrins with new beta-lactam derivatives Paola Galletti,1 Giulia Martelli,1 Monica Baiula,2 Samantha Deianira Dattoli,2 Santi Spampinato,2 Daria Giacomini.1 1 Department of Chemistry “G. Ciamician”, University of Bologna, Via Selmi 2, 40126 Bologna, Italy Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy b [email protected] -Lactam compounds are really evergreen molecules. Because of the unique properties of the azetidinone ring, which is particularly strained and activated towards nucleophilic acyl substitution, the β-lactam structure is a versatile building block in the synthesis of several biologically active compounds. Notably, in the last decades monocyclic βlactams gained importance as effective enzymatic inhibitors; among them there are only few examples of azetidinones that demonstrated activity against integrins.1 Integrins are heterodimeric α/β transmembrane receptors that mediate dynamic adhesive cell-cell and cell-matrix interactions. Because of their important roles in intracellular signalling, immune responses, leukocyte traffic, haemostasis and cancer, their potential as a therapeutic target is now widely recognized. We have actively contributed to this field with the design and synthesis of new monocyclic β-lactams specifically designed to target integrins, thus acting like mimetics of the RGD (Arg-Gly-Asp) peptide sequence, the key portion for the recognition of ligands. The new molecules contain the azetidinone as the only cyclic framework armed with carboxylic acid and amine terminals spaced from 9 to 14 atoms to switch on recognition by integrins. We recently reported the synthesis of some biologically active derivatives which showed good affinity and specificity towards αvβ3 and α5β1 integrin classes. All tested molecules showed a concentration-dependent enhancement in fibronectin-mediated adhesion of K562 and SK-MEL-24 cells.2 After first biological data, a library of new beta-lactams derivatives with a wider structural variability was developed. The biological activity, indeed, is always related to the residues present on the β-lactam scaffolds. New compounds were designed especially to deepen a preliminary SAR study on their agonist or antagonist activities and to develop new promising active molecules that can be selective towards different integrin isoforms. Moreover, we also evaluated some structural parameters in selected compounds such as the formation of intramolecular Hbonds through VT NMR studies. O H N COOH H N N O O NH3 N O NH COOH COOH O O H N N O NH3 CF3COO CF3COO NH3 CF3COO 1) 2) Aizpurua, J.M.; Ganboa, J.I.; Palomo, C.; Loinaz, I.; Oyarbide, J.; Fernandez, X.; Balentova, E.; Fratila, R.M.; Jimenez, A.; Miranda, J.I.; Laso, A.; Avila, S.; Castrillo, J.L.; ChemBioChem, 2011, 12, 401- 405. Aizpurua, J.M.; Oyarbide, J.; Fernandez, X.; Miranda, J.I.; Ganboa, J.I.; Avila, S.; Castrillo, J.L.; Eur. Pat. Appl., 2012, EP 2407478 A1 20120118. Aizpurua, J.M.; Ganboa, J.I.; Palomo, C.; Loinaz, I.; Miranda, J.I.; PCT Int. Appl., 2006, WO 2006048473 A1 20060511 Galletti, P.; Soldati, R.; Pori, M.; Durso, M.; Tolomelli, A.; Gentilucci, L.; Dattoli, S.D.; Baiula, M.; Spampinato, S.; Giacomini, D.; Eur.J. Med. Chem., 2014, 83, 284-293 197 PC71 Scaffold optimisation and activity evaluation of multimeric MBL antagonists G. Goti1, A. Palmioli1, M. Stravalaci2, M. Gobbi2, A. Bernardi1 1 Università degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133 Milano, Italy. 2 Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, 20156 Milano, Italy. e-mail: [email protected] Mannose Binding Lectin (MBL) is a circulating multimeric calcium dependent (Clectin) protein that acts as a first-line host defence by selectively recognizing and binding to polyglycosylated surfaces of invading pathogens or damaged self cells.1 MBL is also able to modulate inflammation and it is likely involved in reperfusion damage in acute stroke,2 therefore representing an attractive target for the development of new drugs against this disease. Our groups have already reported that pseudoglycosylated tetravalent dendrons based on a polyester scaffold such as 1a,b are good antagonists of MBL, with kd values in the low micromolar range. They were shown to supply a protective effect in a mouse model of brain stroke, reducing the reperfusion damage with a surprisingly wide therapeutic window.3 Unfortunately, these constructs proved to be rather chemically unstable: the polyester scaffold does not survive silica gel chromatography in either direct or reverse phase and slowly hydrolyses in water solution at physiological pH (27% hydrolysis in 6h). Here we present the synthesis of two new dendrons characterised by an optimised scaffold that allows to obtain still water soluble compounds with an improved chemical stability. Preliminary results of in vitro SPR binding assays of the new dendrons to MBL will also be discussed. Figure 1. - Polyester tetravalent dendrons 1a,b and monovalent ligands 2, 3 employed as MBL antagonists. 1) Weis, W. I.; Drickamer, K.; Hendrickson, W. A. Nature 1992, 360, 127-134. 2) Osthoff, M.; Katan, M.; Fluri, F. et al. PLoS One 2011, 6, e21338. 3) Orsini, F.; Villa, P.; Parrella, S. et al. Circulation 2012, 126, 1484-1494. 198 PC72 New Silibinin glyco conjugates: synthesis, characterization and preliminary evaluation of antioxidant properties Raffaele Gravante1, Valeria Romanucci1,Valeria Sgambati2, Elio Pizzo2, Daniele D’Alonzo1, Annalisa Guaragna1, Armando Zarrelli1 and Giovanni Di Fabio1. 1 Department of Chemical Sciences; 2Department of Biology, University of Naples "Federico II", Via Cintia 4, I-80126, Napoli, Italy e-mail: [email protected] Medicinal nutrients derived from plants have been used for health maintenance and disease management since the dawn of history. Today, natural products still represent a precious building blocks and an inspiration for the synthesis of medicinal drugs. In this way, an interesting plant is the milk thistle (Silybum. marianum L. Gaertn., Asteraceae); in particular its main component: the Silibinin1. Silibinin is a diastereoisomeric mixture of two flavonolignans, Silybin A and B, extracted from the seeds of the milk thistle. This metabolite presents multiple biological activities operating at various cell levels, however its therapeutic efficiency is rather limited by its low water solubility2. In order to improve its solubility, and therefore bioavailability and permeability to cell membranes, we present here the preliminary results of an efficient synthetic procedure to obtain new 9''-phosphodiester Silibinin conjugates with different mono- and disaccharide labels. The introduction of the phosphate group is generally used to bring great pharmaceutical and pharmacokinetic benefits. In our approach 9''-phosphoramidite (I)3 have been used as Silibinin substrate and fully protected 6-OH mono- and disaccharide derivatives (Glucose, Galactose, Mannose, Lactose, Glucosamine, Trehalose) chosen as sugar starting materials. All derivatives were obtained as a mixture of diastereoisomers and as expected they showed a water solubility well above that of Silibinin. All compounds were obtained in good yields after RP-18 HPLC purification, and characterized by NMR and ESI-MS analysis. All conjugates were subjected to several biological assays to evaluate their cytotoxicity and antioxidative properties. 1) Gažák, R.; Walterová, D.; Křen, V. Curr. Med. Chem. 2007, 14, 315. 2) Zhan, T.; Digel, M.; Küch, E.-M. J. Cell. Biochem. 2011, 112, 849 and references therein. 3) Zarrelli, A.; Romanucci, V.; Tuccillo, C.; Federico, A.; Loguercio, C.; Gravante, R.; Di Fabio, G. Bioorg. Med. Chem. Lett. 2014, 24, 5147. 199 PC73 GEM-DCA: synthesis of a novel codrug Raffaele Gravante1, Daniele D’Alonzo1, Valeria Romanucci1, Armando Zarrelli1, Giovanni Di Fabio1, Giovanni Palumbo1 and Annalisa Guaragna1 1 Department of Chemical Sciences, Università di Napoli "Federico II", Via Cintia 21, I-80126, Napoli, Italy e-mail: [email protected] One of the most efficient approaches in the field of prodrug antitumor therapy is the use of codrugs or mutual drugs.1 They consist of two or more pharmacologically active agents coupled together via a covalent chemical linkage, generating prodrugs in which drugs and promoieties are both pharmacophores. The resulting molecules will be inactive until methabolic processes will enable their chemical conversion to the active forms. Codrug approach is usually used to improve physicochemical, biopharmaceutical and drug delivery properties of therapeutic agents. In the frame of our interest of nucleoside analogues,2 herein we reported the synthesis of a novel codrug consisting of Gemcitabine (GEM)-Dichloroacetate (DCA) moieties in 1:1, 1:2, 1:3 ratio (Figure 1). O O NH 2 DCA Cl N Cl O Cl O N O Cl O GEM N NH Cl N Cl N Cl O F 1 NH Cl O F OH Cl O O F OH F 2 N O Cl O O O F Cl O Cl O F 3 Figure 1. GEM-DCA codrugs. Gemcitabine (2′,2′-difluorodeoxycytidine) is an established and highly potent cytotoxic drug with a broad spectrum of cancer targets.3 The main disadvantage in its use is its rapid inactivation due to the conversion, by cytidine deaminase, to its inactive metabolite 2,2′-difluorodeoxyuridine. Furthermore, the prolonged use of GEM typically results in the onset of different forms of drug resistance after initial tumor regression.3 DCA is an orphan drug,4 a small molecule already used in humans for the treatment of lactic acidosis, which has been shown to shift cancer cell metabolism from glycolysis to glucose oxidation, inducing apoptosis leading to a decrease in proliferation, and inhibiting tumor growth, without affecting healthy cells. Taking into account of some recent results on the anticancer activity of a DCA codrug,4 we are expected to obtain a complementary synergistic and selective capability to stall malignant cells. 1) Das, N.; Dhanawat, M.; Dash, B.; Nagarwal, R. C.; Shrivastava, S. K. Eur. J. Pharm. Sci. 2010, 41, 571–588. 2) Caso, M. F.; D'Alonzo, D.; D'Errico, S.; Palumbo, G.; Guaragna, A. Org. Lett. 2015, 17, 2626-2629. 3) Bergmann, A. M.; Peters, G. J. In Deoxynucleosides in Cancer Therapy; Peters, G. J. Ed.; Humana Press: Totowa, NJ, 2006. 4) Saha, S.; Ghosh, M.; Dutta, S. K. Sci. Rep. 2015, 5, 7762-7772. 200 PC74 Cellulose Nanocrystals: Novel Nanotools Targeting Bone Tissue Barbara La Ferla1, Luca Zoia2, Laura Colombo3, Francesco Nicotra1, Marco Orlandi2, Mario Salmona3, Paolo Bigini3 1 University of Milano-Bicocca, Dep. Biotechnology and Bioscience, Piazza della Scienza 2, Milan, ZIP 20126, ITALY 2 University of Milano-Bicocca, Dep. Earth and Environmental Science, Piazza della Scienza 1, ZIP 20126 Milan, ITALY; 3 IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri”, via La Masa 19, ZIP 20156, Milan, ITALY. e-mail: [email protected] The physico-chemical properties and its relative inexpensive costs, make Cellulose Nano-Crystals (CNCs) as a potential target for a future large-scale production in many fields, including nanomedicine. These CNCs, along with the dimensions in the nanometer range [1], possess a typical rod-shape that, from a pharmacokinetic point of view, has been observed to present a reduced risk of NP uptake by monocytes and also an enhanced extravasation [2,3]. However, robust and reliable data concerning their safety and biocompatibility and their tissue distribution should be provided prior to a sustained and responsible development as theranostic agents. In the present study the interaction between CNCs, extracted from Whatman filters and functionalized with a fluorescent dye, and living organisms has been deeply assessed. Our experimental evidence demonstrated that CNCs: 1) are well tolerated by healthy mice after systemic injection; 2) are rapidly up taken by excretory organs and progressively cleared thus avoiding bioaccumulation; 3) are able to penetrate in the cytoplasm of cells without detrimental effects in terms of survival; 4) show a peculiar localization in bones. The tropism to the bones is likely due to the chemical interaction between the Ca2+ of the bone matrix and the active surface of CNCs. These properties could be exploited for the development of new nanodevices for theranostics purposes, mainly in the field of bone diseases[4]. Figure 1 1) 2) 3) 4) Y. Habibi, L.A. Lucia, O.J. Rojas, Chem Rev, 2010, 110(6),3479-500 J.S. Ananta, B. Godin, R. Sethi, L. Moriggi, X. Liu, R.E. Serda, R. Krishnamurthy, R. Muthupillai, R.D. Bolskar, L. Helm, M. Ferrari, L.J. Wilson, P. Decuzzi. Nat Nanotechnol, 2010, 5(11), 815-21. J. Key, S. Aryal, F. Gentile, J.S. Ananta, M. Zhong, M.D. Landis, P. Decuzzi. Biomaterials. 2013, 34(21), 5402-10. Manuscript submitted 201 PC75 Inverse Virtual Screening: A New Computational Approach For The Identification of The Interacting Targets of Bioactive Compounds Gianluigi Lauro, Raffaele Riccio, Giuseppe Bifulco Department of Pharmacy, University of Salerno, Fisciano (SA), Italy e-mail: [email protected] Inverse Virtual Screening approach represents a new and fast computational method allowing the analysis of different binding hypotheses between a single ligand and a high number of targets by means of molecular docking experiments.1 It represents a fast and inexpensive tool for the identification and selection of possible ligand-receptor favorite complexes among a set of numerous other theoretical possibilities. It has been applied to several natural bioactive molecules to screen their efficacy on proteins involved in cancer processes successfully directing subsequent experimental assays. New insights and applications of Inverse Virtual Screening are here reported.2,3,4,5 1) Lauro, G.; Romano, A.; Riccio, R.; Bifulco, G. J. Nat. Prod. 2011, 74, 1401-1407. 2) Lauro, G.; Masullo, M.; Piacente, S.; Riccio, R.; Bifulco, G. Bioorg. Med. Chem. 2012, 20, 3596-3602. 3) Cheruku, P.; Plaza, A.; Lauro, G.; Keffer, J.; Lloyd, J. R.; Bifulco, G.; Bewley, C. A. J. Med. Chem. 2012, 55, 735-742. 4) Scrima, M.; Lauro, G.; Grimaldi, M.; Di Marino, S.; Tosco, A.; Picardi, P.; Gazzerro, P.; Riccio, R.; Novellino, E.; Bifulco, M.; Bifulco, G.; D’Ursi, A. M. J. Med. Chem. 2014, 57, 7798-7803. 5) Gong, J.; Sun, P.; Jiang, N.; Riccio, R.; Lauro, G.; Bifulco, G.; Li, T.-J.; Gerwick, W.; Zhang, W. Org. Lett. 2014, 16, 2224-2227. 202 PC76 Hydrosoluble Oligo-Heteroaromatic Ligands Targeting G-Quadruplex Folded Nucleic Acids Alberto Lena, Filippo Doria, Vincenzo Grande and Mauro Freccero Dipartimento di Chimica, Università di Pavia, V.le Tramelli 10, 27100 Pavia, Italy [email protected] G-quadruplexes are secondary structures adopted by guanine-rich DNA oligonucleotides containing short G tracts 1. Many guanine-rich sequences capable of G4 formation have been found concentrating in areas of human genome involved in regulational processes, such as gene expression, transcription and cell immortality 2 . The significant biological role of G4 gives rise to the developement of many ligands targeting G4 as anticancer drugs 3. Among these, the polyoxazole-based natural product telomestatin has played a major role, since it first showed potent telomerase inhibitory activity through stabilization of G4 structures in telomeres and great selectivity over duplex DNA 4. With the aim to design telomestatine-like synthetic analogues, a small library of new hydrosoluble oligo-heteroaromatic class of G4 selective ligands has been synthesized, focusing on the development of an efficient and versatile synthetic pathway. Particular efforts have been devoted to optimize the critical steps of amidoxime acylation (a) and the subsequent cyclization of the resulting O-acyloxime (b). Qualitative in vitro affinity for G4 structures has been inferred by FRET-melting assay. This preliminary data are consistent with the assignment of exceptionally good binding properties towards G4 for the new scaffold, revealing a much higher stabilization in comparation to related nonhydrosoluble compounds.5 We demonstrated for the first time that individual gymnemic acids are potent and selective antagonists for the isoform of LXR. Deep pharmacological investigation demonstrated that gymnestrogenin, reducing the expression of SREBP1c and ABCA1 in vitro, is able to decrease lipid accumulation in HepG2 cells. The results of this study substantiate the use of Gymnema sylvestre extract in LXR-mediated dislypidemic diseases. 1. S. Neidle, Curr. Opin. Struct. Biol., 2009, 19, 239. 2. G. W. Collie and G. N. Parkinson, Chem. Soc. Rev., 2011, 40, 5867. 3. S. Balasubramanian, L. H. Hurley and S. Neidle, Nat. Rev. Drug Discov., 2011, 10, 261. 4. M. Y. Kim et al., J. Am. Chem. Soc., 2002, 124, 2098. 5. F. Hamon et al., Angew. Chem. Int. Ed., 2011, 50, 8745. 203 PC77 Bile acids derivatives in the selective modulation of FXR and GPBAR1 Dario Masullo,a Claudia Finamore,a Valentina Sepe,a Claudio D’Amore,b Carmen Festa,a Barbara Renga,b Simona De Marino,a Angela Zampella,a Stefano Fioruccib a Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano, 49, I-80131 Napoli, Italy; b Department Experimental and Clinical Medicine, University of Perugia, Via Gambuli 1, S. Andrea delle Fratte, 06132 Perugia, Italy; [email protected] Farnesoid-X-receptor (FXR) and GP-BAR1 are bile acids receptors mainly expressed in entero-hepatic tissues that regulates some metabolic and non-metabolic functions [1]. In the last ten years, this two receptors gained an increasing importance because they are involved in many physiological and physio-pathological human conditions. One of the main problem of these receptors is that bile acids are promiscuous ligand for both receptors. Even if the dual activation could be a promising pharmacological opportunity for several metabolic deseases, often it is associated to several side effects. Starting from the results obtained in several our previous works, [2, 3] in this contest, we decide to manipulate bile acids scaffold in order to produce new selective FXR and GP-BAR1 modulators. 1) Fiorucci, S.; Cipriani, S.; Mencarelli, A.; Baldelli, F.; Bifulco, G.; Zampella A. Farnesoid, Mini Rev. Med. Chem. 2011, 11, 753–762 2) Sepe, V.; Renga, B.; Festa, C.; D’Amore, C.; Masullo, D.; Cipriani, S.; Di Leva, F. S.; Monti, M.C.; Novellino, E.; Limongelli, V.; Zampella, A. and Fiorucci, S. J. Med. Chem 2014, 57 (18), pp 7687– 7701 3) Festa, C.; Renga, B.; D’Amore, C.; Sepe, V.; Finamore, C.; De Marino, S.; Carino, A.; Monti, M. C.; Zampella, A. Fiorucci, S. J Med Chem. 2014, 57 (20), pp 8477-95 204 PC78 Amphiphilic calix[4]arenes for the modulation of TLR4 activity I. Morbioli1, S. Sestito2, F. Sansone1, A. Casnati1, F. Peri2 1 2 Department of Chemistry, University of Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy. Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy. e-mail: [email protected] Toll-like receptor 4 (TLR4) is a transmembrane protein that selectively recognizes bacterial lypopolysaccharides (LPS) and their portions like lipid A and immediately induces the innate immune response in the organism.1 It is a significant biological and pharmacological target because the modulation of the receptor activation pathway allows the control of the inflammatory response. Therefore, on one hand molecules able to activate the receptor have interest as vaccines or immunotherapeutics, on the other hand molecules that inhibit the receptor acting as antagonists can work as antisepsis and anti-inflammatory agents.2 Different natural and synthetic molecules are known to act as agonists or antagonists in the TLR4 activation process and they present generally an amphiphilic structure with the hydrophilic domain that can bear both positively and negatively charged groups.3 The aggregation ability of the compound can also have a significant role in determining its biological activity. Starting from this point, we have synthesized different calix[4]arenes bearing at the lower rim alkyl chains of different length and at the upper rim guanidinium or carboxylic moieties (Figure 1). The tendency of these molecules to self-assemble has been investigated by NMR, Dynamic Light Scattering and Fluorescence Spectroscopy. At the same time, biological tests aimed at studying their activity in TLR4 modulation have been performed evaluating the effects of the compounds on the receptor activity stimulated through administration of LPS doses to properly modified HEK-Blue cells. Micro and submicromolar IC50 values have been found for some of the calixarenes closely related to nature of charge and chain length (Figure 1). The first results regarding the self-assembling properties and the biological activity of the amphiphillic calix[4]arenes will be shown. Figure 1. Calix[4]arenes synthesized for this work and inhibition curve relative to 1a. 1) Beutler, B. Curr. Top. Microbiol. Immunol. 2002, 270, 109-120. 2) Peri, F.; Piazza, M. Biotechnol Adv. 2012, 30, 251-260. 3) Peri, F.; Calabrese, V. J. Med. Chem 2014, 57, 3612-3622. 205 PC79 Extraction, fractionation and HPLC-MS-MS analysis of the main antioxidative constituents from an oak wood (Quercus robur) commercial tannin Vera Muccilli, Nunzio Cardullo, Carmela Spatafora, Vincenzo Cunsolo, Corrado Tringali Department of Chemical Science, University of Catania, V.le A. Doria 6, 95125 Catania e-mail: [email protected] Nowadays there is a growing interest in plant polyphenols and in their exploitation in the fields of agro-food, cosmetic and over-the-counter (OTC) drug industry.1 Polyphenols were originally considered equivalent to ‘vegetable tannins’. The two main groups of vegetable tannins are generally known as ‘condensed tannins’ (oligomers of the structural unit of flavan-3-ols) and ‘hydrolyzable tannins’ (‘gallotannins’ and ‘ellagitannins’). Both hydrolyzable and condensed tannins have promising antioxidative and other healthy properties; some ellagitannins have been recently cited for their chemopreventive or antitumor properties. Commercial tannins are widely used in enology, tanning and other industrial sectors. Thus, we planned to examine some commercial tannins widely exploited for commercial purposes. As first sample for this study, we selected a commercial hydrolizable tannin obtained from roasted oak wood, because Quercus spp. and Quercus robur in particular are widely reported as a source of bioactive polyphenols. In this study we privileged a fractionation guided by DPPH radical scavenging activity, in view of both the known antioxidant properties of plant polyphenols, and the well-known relationship between antioxidant activity and chemoprevention of degenerative diseases. Extraction followed by DPPH-guided chromatographic fractionation, afforded sub-fractions showing enhanced antioxidant activity. The main polyphenols in the extract/fractions were identified by means of HPLC-ESI/MSMS in order to establish a possible relationship between composition and antioxidant activity. 1. Quideau, S.; Deffieux, D.; Douat-Casassus, C.; Pouységu, L. Angew. Chem. Int. Ed. 2011, 50, 586–621 206 PC80 High resolution mass spectrometry in the analysis of site-specific donkey milk lactoferrin glycosylation Serafina Gallina1,Rosaria Saletti1, Vincenzo Cunsolo1, Vera Muccilli1 Antonella Di Francesco1, Salvatore Foti1, Peter Roepstorff2 1DepartmentofChemicalSciences,UniversityofCatania,V.leA.Doria6, IT‐95123,Catania,Italy 2ProteinResearchGroup,DepartmentofBiochemistryandMolecularBiology,UniversityofSouthern Denmark,Campusvej55,DK‐5230OdenseM,Denmark e-mail: [email protected] Donkey milk is considered the best mother milk substitutes for allergic newborns for its reduced or absent allergenic properties, coupled to excellent palatability and nutritional value. Lactoferrin (LF) is one of the most important milk glycoproteins, member of the transferrin family, present in the whey protein fraction. It shows an array of biological properties, including antibacterial, antiviral, antioxidant activities, iron-binding and immunomodulation. Glycosylation, one of the most common post-translational modifications, can modify the structural conformation of the protein and consequently its biological activity. Within the frame of our research line aimed at the systematic investigation of donkey milk protein composition,1-4 we isolated LF from the milk of an individual donkey belonging to the Ragusano breed and investigated by nanoflow liquid chromatography/mass spectrometry (Nano-LC-MS/MS) in order to identify a comprehensive glycosylation profile. The protein isolated by ion exchange high performance liquid chromatography (IEC-HPLC), was digested by chymotrypsin and the glycopeptides were enriched by TiO2,5 in order to enrich acid glycopeptides, and by Hydrophilic Interaction Liquid Chromatography (HILIC),6 in order to enrich neutral glycopeptides. Analysis by nano-reversed phase high performance liquid chromatography (nRP-HPLC) coupled on-line with a hybrid ESI-MS LTQ/Orbitrap mass spectrometrer (Q-Exactive Plus), identified at least 29 different glycan compositions at three N-glycosylation sites on donkey LF. To identify the glycopeptides, mass spectral data were processed by an in-house developed software (MassAI Bioinformatics)7. All identified glycopeptides were manually validated. Preliminary results indicate that N-glycolylneuraminic acid, which is absent in human LF and is considered a potential allergen, is less abundant in the donkey milk glycans in comparison with other animal species. 1) Cunsolo, V.; Muccilli, V.; Fasoli, E,; Saletti, R.; Righetti, P.G.; Foti, S. J. Proteomics 2011, 74, 20832099 2) Cunsolo, V.; Muccilli, V.; Saletti, R.; Foti, S. Eur. J. Mass Spectrom. 2011, 17, 305-320 3) Cunsolo, V.; Costa, A.; Saletti, R.; Muccilli, V.; Foti, S. Rapid Commun. Mass Spectrom. 2007, 21, 1438-1446 4) Cunsolo, V.; Muccilli, V.; Saletti, R.; Foti, S. J. Mass Spectrom. 2007, 42, 1162-1174 5) Larsen, M.R.; Jensen, S.S.; Jakobsen, L.A.; Heegaard, N.H. Mol. Cell. Proteomics. 2007,6, 1778-1787 6) Hägglund, P.; Bunkenborg, J.; Elortza, F.; Jensen, O.N.; Roepstorff, P. J. Proteome Res. 2004, 3, 556-566 7) Mass AI-Bioinformatics. MassAI. At <http://massai.dk/index.html> 207 PC81 Integrated bottom-up/top-down ms-based approach for sequence determination of a donkey’ CSN1S2 duplicate gene products Vincenzo Cunsolo, Vera Muccilli, Rosaria Saletti, Serafina Gallina, Antonella Di Francesco, Salvatore Foti Department of Chemical Sciences, University of Catania, V.le A. Doria 6, IT-95123 Catania, Italy e-mail: [email protected] Cow’s milk represents the main source of allergens in early childhood, affecting about 3% of infants, and therefore constitutes a problem of social relevance. In the last few years, milk from different mammalian species (goat, donkey, mare, camel) have been studied to identify the best natural substitute for human milk. On this respect, several clinical trials indicate the positive effects of donkey milk in nutrition of infants allergic to cow’s milk proteins (CMPs).1 However, although composition, physico-chemical and nutritional properties of donkey’s milk are well known, the information available for its proteins and their polymorphism are still scant,2 and the data available for the casein (CN) fraction, constituted by αs1-, αs2-, - and κ-CN, are at a relatively early stage of progress.3-5 In this study, a casein component with experimentally high resolution measured Mr 16316.175 was detected by capillary reversed-phase high-performance liquid chromatography (RP-HPLC) coupled on-line with an hybrid ESI-MS LTQ/Orbitrap mass spectrometry in the dephosphorylated casein fraction of a milk sample collected from an individual donkey belonging to the Ragusano breed. By coupling both top-down and bottom-up approaches, the unknown casein component was identified as a gene product of the duplicate gene CSN1S2 II. Primary structure of this protein was characterized using the m-RNA derived amino acid sequence of the donkey’s s2-CN variant B as reference (GenBank Acc. No. CAX65660.2), which should be encoded at CSN1S2 II locus. The MS data derived sequence revealed that the investigated protein differs from the GenBank reported sequence for amminoacid point substitution, insertion and absence of short peptides. 1) Vita, D.; Passalacqua, G.; Di Pasquale, G.; Caminiti, L.; Crisafulli, G.; Rulli, I.; Pajno, G.B. Pediatr. Allerg. Immunol. 2007, 18, 594. 2) Criscione, A.; Cunsolo, V.; Bordonaro, S.; Guastella, A.M.; Saletti, R.; Zuccaro, A.; D’Urso, G., Marletta, D. Int. Dairy J. 2009, 19, 190. 3) Cunsolo, V.; Cairone, E.; Muccilli, V.; Saletti, R.; Foti, S. Rapid Commun. Mass Spectrom.2009, 23, 1907. 4) Cunsolo, V.; Cairone, Fontanini, D.; Criscione, A.; Muccilli, V.; Saletti, R.; Foti, S. J. Mass Spectrom. 2009, 44, 1742. 5) Saletti, R.; Muccilli, V.; Cunsolo, V.; Fontanini, D.; Capocchi, A.; Foti, S. J. Mass Spectrom. 2012, 47, 1150 208 PC82 Parallel Synthesis of Analogs of Permethylated Anigopreissin A Palmina Nigro, Eugenio D’Amato, Maria Funicello, Paolo Lupattelli, Lucia Chiummiento Dipartimento di Chimica, Università della Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy [email protected] Permethylated Anigopreissin A (PAA)1 is a protected form of naturally occurring Anigopreissin A2 which belongs to the class of oligomeric stilbenes containing a benzofuran ring system. PAA kills different types of human cancer cells without affecting non-tumorigenic cells; particularly, hepatic cancer cell line show the highest sensitivity to it (IC50=0.24± 0.05 μM)3. Biological activity of PPA and its pharmacological potential has generated extensive efforts toward the syntheses of its analogs in order to evaluate structure-activity relationship. We planned to synthesize two classes of analogs with single modifications to aryl group on C3 (series A analogs) and to styryl moiety on C6 (series B analogs). The key retrosynthetic steps are outlined below. To insert the aryl groups on C3 of the benzo[b]furan ring we perform Suzuki crosscoupling reactions between A and different phenylboronic acids, whilst the styryl groups are introduced via Wittig olefinations between aldehyde B and different phosphonium salts; synthon C would be constructed through the 5-endo-dig cyclization of the corresponding diaryl alkyne, which could, in turn, arise from the Sonogashira reaction. 1) Chiummiento, L.; Funicello, M.; Lopardo, M. T.; Lupattelli, P.; Choppin, S.; Colobert, F. Eur. J. Org. Chem. 2012, 188-192. 2) a) Holsche, D.; Schneider, B. Phytochemistry 1996, 44, 471– 473; b) Schneider, B. Phytochemistry 2003, 64, 459– 462. 192 3) Convertini, P.; Tramutola, F.; Iacobazzi, V.; Lupattelli, P.; Chiummiento, L.; Infantino, V. Submitted Manuscript. 209 PC83 “Two is better than one”: probes for dual-modality molecular imaging approach. Design, synthesis and characterization of a mini-library of NOTA derivatives Claudia Riccardi, Domenica Musumeci, Daniela Montesarchio Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Via Cintia 21, I-80126, Napoli, Italy [email protected] The increasing incidence of cancer pathologies more and more requires an early diagnosis of the disease to achieve effective therapeutic results. The use of a single diagnostic technique is often insufficient, not being able to provide complete structural and functional information. Thus different imaging modalities such as PET-CT, PET-MRI or PET-fluorescence can be used in combination to overcome the inherent disadvantages of each single methodology and to obtain a timely detection of neoplastic cells1. The interest in this field is strongly growing and many new, more efficient radio-pharmaceuticals have been recently proposed to improve tumour identification and localization2-3. In this context, we here describe the synthesis and characterization of a mini-library of lipophilic derivatives of NOTA - which is a well-known 68 Ga chelator used for PET analyses - differing for the functional tails, i.e. an oleic acid, a lipoic acid and a biotin moiety (NOTA-OL, NOTA-Lip and NOTA-Bio, respectively, Figure 1). These functionalizations have been designed to allow the subsequent immobilization of NOTA onto different nanoplatforms, each carrying a suitable coating, so to perform bimodal “two-in-one” imaging investigations4-6. In our future studies, these derivatives will be anchored on nanoparticles (NPs) intrinsically sensitive to MRI, fluorescence or other sensitive imaging techniques (as iron oxide or zinc oxide-based NPs). Oleic acid has a 18-carbon atoms chain which allows its immobilization onto lipid-functionalized NPs through hydrophobic interactions. The disulfide bond of lipoic acid, thanks to its high affinity for metals, provides covalent bonds with metal or metal-oxide NPs. Finally, biotin is useful to functionalize avidin or streptavidin-coated NPs exploiting the high affinity of these proteins for biotin molecules. Furthermore, upon insertion on the NPs’ surface also of suitable therapeutic agents, exploiting different recognition schemes (hydrophobic interactions, covalent bonds or specific recognition), multi-functional tools7 can be easily obtained in a modular or one-step approach. This design will open the way to a variety of theranostic agents, concomitantly able to provide early diagnosis and therapy of a disease. 1. Velikyan, I. Theranostics. 2014, 4, 47-80. 2. Chong, H. S. et al. Bioorg. Med. Chem. 2015, 23, 1169–1178. 3. Frigell, J.et al. J. Am. Chem. Soc. 2014, 136, 449−457. 4. Paeng, J. C. et al. The Open Nuclear Medicine Journal 2010, 2, 145-152.Open Access 5. Louie, A. Chem. Rev. 2010, 110, 3146–3195. 6. Schober, O. et al. Eur J Nucl Med Mol Imaging. 2009 36, 302–314. 7. Cheon, J. et al. Acc Chem Res. 2008, 41, 1630-1640. Open Access 210 PC84 Discovery of potential modulators of Macrodomain proteins MacroD1 and MacroD2 Alessandra Russo, Stefania Terracciano, Gianluigi Lauro, Giuseppe Bifulco, Raffaele Riccio, Ines Bruno Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084, Fisciano, Salerno e-mail: [email protected] Macrodomains are a family of evolutionarily conserved protein structural domains (130-190 a.a.) which bind several NAD+ products, such as mono-ADP-ribose, polyADP-ribose and O-acetyl-ADP-ribose (OAADPr).1 ADP-ribosylation is an important, reversibile, protein post-translational modification that regulates different biological processes, catalyzed by a variety of enzymes, implicated in important cellular functions including transcription, DNA repair, chromatin remodeling and apoptosis.2 Recent studies demonstrated that a family of Macrodomains enzymes, such as: MacroD1, MacroD2 and C6orf130, act as mono ADP hydrolases capable of removing from proteins the last glutamate-linked ADPr releasing ADPr and the unmodified aminoacidic product that is readily available for the next cycle of ADP-ribosylation.2 Consequently,it has been demonstrated that the dysregulation of Macrodomain function can affect both reversible cellular mono-ADP-ribosylation and OAADPr homeostasis. In fact, human MacroD1 and MacroD2 cellular levels are, also, overexpressed in a range of tumors such as endometrial carcinoma, gastric carcinoma, colorectal carcinoma and breast carcinoma.3 In this context, our project is focused on the identification of potential Macrodomains modulators as new promising anticancer agents. With this aim we performed a preliminary virtual screening, through molecular docking calculations using the recently crystallized structure of MacroD and the X-ray crystallographic structure of MacroD2 in complex with ADP-ribose.4 This screening started from libraries of syntetically accessible molecules that will allow us to identify different scaffolds that display a high binding affinity for the target enzymes. The subsequent step will consist in the biological evaluation of synthetized compounds in order to obtain the key structural information for the binding with the catalytic site of the protein. References: 1) Rosenthal F. et al Nature Structural & Molecular Biology, 2013, 20, (4) 2) Li N., Chen J., Mol. Cells. 2014, 37, 9-16 3) Weidong H. et al, Review, Mutation Research, 2011, 727 , 86-103 4) Chen D., et al J.Biol.Chem. , 2011, 286, 13621-13271 211 PC85 Activation of Hsp90 enzymatic activity and conformational dynamics through rationally designed allosteric ligands Sara Sattin,1 Jiahui Tao,2 Gerolamo Vettoretti,3 Laura Morelli,1 Matteo Panza,1 Elisabetta Moroni,3 David A. Agard,2 Giorgio Colombo,3 Anna Bernardi1 1 2 Università degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133 Milano, Italy Howard Hughes Medical Institute and Dept. of Biochemistry & Biophysics, University of California, San Francisco, 94158 USA) 3 Istituto di Chimica del Riconoscimento Molecolare - CNR, Via Mario Bianco, 9, 20131 Milan, Italy e-mail: [email protected] Hsp90 is a chaperone that mediates the folding and activation of diverse client proteins essential for a variety of signal-transduction pathways1 and an established anti-apoptotic target in cancer therapy.2 Instead of targeting the Hsp90 N-terminal domain inhibiting its ATPase activity,3 we aim to target the protein C-terminal domain (CTD) through the allosteric modulation of its chaperone activity, hopefully avoiding important secondary effects. Eupomatenoid-2 (1, Figure 1) has been identified as a potential lead targeting a CTD allosteric pocket that control interdomain communication.4 (Glyco)diversification of the benzofuran core5 at R’’ and preliminary work on the chemical expansion at R’ allowed to obtain about 40 derivatives that are mostly activators of the chaperone ATPase activity. The peculiarity of these compounds is that, in selected cancer cell lines, they retain the cytotoxic activity showed by small molecule ATPase inhibitors. Synthetic approaches to the benzofuran derivatives will be presented along with biochemical and biological data of their effects on the Hsp90 chaperone machinery. Figure 4: Lead compound 1 (Eupomatenoid-2). 1) 2) 3) 4) 5) Jackson, S. E. In Molecular Chaperones; Jackson, S., Ed.; Springer Berlin Heidelberg: 2013; Vol. 328, p 155-240. Trepel, J.; Mollapour, M.; Giaccone, G. and Neckers, L., Nat Rev Cancer 2010, 10, 537-549. Kitson, R. R. A. and Moody, C. J., J. Org. Chem. 2013, 78, 5117-5141. Morra, G.; Neves, M. A. C.; Plescia, C. J.; Tsustsumi, S.; Neckers, L.; Verkhivker, G.; Altieri, D. C. and Colombo, G., J. Chem. Theory Comput. 2010, 6, 2978-2989. Morelli, L.; Bernardi, A. and Sattin, S., Carbohydr. Res. 2014, 390, 33-41. 212 PC86 9H-Purine Derivatives as New Modulators of non-BET Human Bromodomains Maria Strocchia1, Stefania Terracciano1, Gianluigi Lauro1, Sarah Picaud2, Jacqui Mendez3, Danette Daniels3, Raffaele Riccio1, Giuseppe Bifulco1, Panagis Filippakopoulos2, Ines Bruno1 1 Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy. 2 Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, U.K. 3 Promega Corporation, 2800 Woods Hollow Road, Madison, Wisconsin 53711, USA. e-mail: [email protected] Bromodomains (BRDs) are structurally conserved modules which act as readers of acetyl-lysine residues on histone tails.1 The involvement of BRD containing proteins in a variety of human diseases has recently emerged.2 Here we report the design and synthesis of some 9Hpurine-based derivatives which showed nanomolar affinity towards the BRD9 bromodomain and only weak residual micromolar affinity for BRD4. High-resolution X-ray crystal structure of our molecules in complex with BRD9 revealed extensively structural re-arrangements of the Kac binding cavity of BRD9, resulting in an unprecedented cavity shape arrangement.3 Finally, we assessed the ability of these compounds to competitively displace the BRD9 bromodomain from the chromatin in cellular environment through bioluminescence proximity assays.3 1) 2) 3) Filippakopoulos, P.; Knapp, S. FEBS Letters 2012, 586, 2692-2704. Filippakopoulos, P.; Knapp, S. Nat Rev Drug Discov 2014, 13, 337-56. Picaud, S.; Strocchia, M.; Terracciano, S.; Lauro, G.; Mendez, J.; Daniels, D. L.; Riccio, R.; Bifulco, G.; Bruno, I.; Filippakopoulos, P. J. Med. Chem. 2015, 58, 2718–2736. 213 PC87 Discovery of innovative Hsp90 C-terminal modulators: synthesis and biological evaluation of 3,4- dihydropyrimidinone derivatives Stefania Terracciano, Maria Strocchia, Fabrizio Dal Piaz, Maria Carmela Vaccaro, Antonio Foglia, Maria Giovanna Chini, Antonietta Leone, Raffaele Riccio, Giuseppe Bifulco, Ines Bruno Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy. e-mail: [email protected] Heat shock protein 90 (Hsp90) is a molecular chaperone that controls the folding of key proteins in multiple cancer signaling networks. Its pivotal role in human tumor development and progression has attracted much interest in order to identify new potent inhibitors of this protein.1 Traditional inhibitors of Hsp90 target the N-terminal domain, however this type of modulation induces undesiderable side effects and the deleterious pro-survival heat shock response (HRS).2 Although less explored, C-terminal inhibition of Hsp90 is a very promising approach for developing new potential anti-cancer drugs lacking the known drawbacks of the Nterminal ligands.3 Recently, our research group focused the attention on the chemically accessible dihydropyrimidinone (DHPM) scaffold, as a new template for the discovery of innovative Hsp90 C-terminal inhibitors.4 In the course of our study we identified a new promising hit showed antiproliferative activity in two different cancer cell lines, without any apparent cytotoxic effect in non-tumor cells.4 On the basis of these encouraging findings, we decided to expand our collection of DHPM derivatives in order to get further structural information and to identify more powerful and safer Hsp90 inhibitors. 1) Miyata, Y.; Nakamoto, H.; Neckers, L. Curr. Pharm. Des. 2013, 19, 347-365. 2) Kim, Y. S.; Alarcon, S. V.; Lee, S.; Lee, M. J.; Giaccone, G.; Neckers, L.; Trepel, J. B. Curr. Top Med. Chem. 2009, 9, 1479-1492; Bhat, R.; Tummalapalli, S. R.; Rotella, D. P. J. Med. Chem. 2014, 57, 8718-8728; Neckers, L.; Workman, P. Clin. Cancer Res. 2012, 18, 64-76. 3) Conde, R.; Belak, Z. R.; Nair, M.; O'Carroll R. F.; Ovsenek, N. Biochem. Cell Biol. 2009, 87, 845851; Wang Y.; McAlpine, S. R. Chem. Commun. 2015, 51, 1410-1413. 4) Strocchia, M.; Terracciano, S.; Chini, M. G.; Vassallo, A.; Vaccaro, M. C.; Dal Piaz, F.; Leone, A.; Riccio, R.; Bruno, I.; Bifulco, G. Chem. Commun. 2015, 51, 3850-3853. 214 PC88 Design and synthesis of integrin ligands as “Molecular Shuttles” for drug and fluorescent molecules delivery Alessandra Tolomelli, Lucia Ferrazzano, Angelo Viola Alma Mater Studiorum - University of Bologna, Department of Chemistry “G. Ciamician” (Via Selmi 2, 40138 Bologna, Italy) e-mail: [email protected] In the field of cancer theranostic, one of the main goal of medicinal chemistry is the development of systems for selective and targeted delivery of drugs and diagnostic molecules towards the pharmacologic target, for the reduction of side effects associated to an uncontrolled distribution of drugs during treatments and the localization of tumours, using fluorescent molecules and nanoparticles. This is possible through overexpression on cancer cells of several receptors, which became the anchoring points of cancer therapy. Among them, integrins are receptors involved in cell signalling, cell adhesion and cell motility, three of the upregulated phenomena in cancer cells.1 Since integrins recognize RGD sequence, our purpose is to develop an RGD peptidomimetic functionalized with drugs, fluorescent molecules and nanoparticles.2 The RGD mimetic have been designed to have an alkyne side chain to link amino-, acidic- and PEG-azides but also selected dipeptides by Click chemistry. 1) K. Chenr, X. Chen, Theranostics, 2011, 1, 189–200. 2) F. Danhier, A. Le Breton, V. Préat, Mol. Pharmaceutics, 2013, 9, 2961-2973. 215 PC89 Red-NIR G-quadruplex sensing harvesting blue light by a coumarinnaphthalene diimide dyad Michela Zuffo1, Filippo Doria1, Vincenzo Spalluto1, Sylvain Ladame2 and Mauro Freccero1 1 2 Dipartimento di Chimica, Università di Pavia. V.le Taramelli 10, 27100 Pavia, Italy Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K. [email protected] G-quadruplex (G-4) are non-canonical structures formed by guanine rich nucleic acids strands1, located in genomic regions relevant for a number of pathologies2. After their validation as suitable therapeutic targets3, the need of selective methodologies for their sensing became urgent. In this perspective, fluorescence light-up chemosensors represent a valuable tool4. A conceptually new light-up fluorescent probe will be presented. Two moieties, a coumarin (C) and a naphthalene diimide (NDI), have been conjugated through a flexible alkyl spacer. The dyad exhibits a single wavelength emission at 494 nm when free in solution, due to the complete quenching of the NDI emission via an electron transfer (eT) process. The same molecule, when bound to a G4, exhibits an additional red-NIR emission upon excitation of the coumarin moiety. The emission centred at 666 nm is due to an energy transfer (ET) process from the coumarin to the NDI. This light up response is highly specific for quadruplex DNA when compared to duplex DNA or to RNA quadruplexes. N O O O H N H N O N H O 1. 2. 3. 4. (CH 2) 3NMe2 N O R N O (CH 2) 3NMe2 S. Neidle, Curr. Opin. Struct. Biol., 2009, 19, 239. (a) A.T. Phan, FEBS J., 2010, 277, 1107; (b) R. Rodriguez and K. M. Miller, Nat. Rev. Genet., 2014, 15, 783. S. Balasubramanian, L.H. Hurley and S. Neidle, Nat. Rev. Drug. Discov., 2011, 10, 261. (a) D.-L. Ma, H.-Z. He, K.-H. Leung, H.-J. Zhong, D. S.-H. Chan and C.-H. Leung, Chem. Soc. Rev., 2013, 42, 3427; (b)L.D. Lavis and R.T. Raines, ACS Chem. Biol., 2008, 3, 142. 216 I – Nanotecnologia 217 PC90 Single-walled carbon nanotubes dispersions in high viscous solvents Carla Gasbarri, Fausto Croce, Ida Meschini, Guido Angelini Department of Pharmacy, University “G. d’Annunzio” of Chieti – Pescara, Italy e-mail: [email protected] The properties induced by single-walled carbon nanotubes (SWNTs) in three high viscous solvents, as BMIM BF4, Pluronic L121 and Triton X-100 have been studied by using UV-Vis-NIR spectroscopy, electrochemical impedance spectroscopy and optical microscopy. The size of the SWNTs aggregates and the dispersion degree in the three systems depend on the sonication time as highlighted by optical microscopy (Fig. 1) and UvVis-NIR spectra. A non-linear increasing in electronic conductivity as a function of the nanotubes concentration can be observed by electrochemical impedance spectroscopy measurements. Moreover, in the case of SWNTs-BMIM BF4 dispersions ionic conductivity has also been observed. A critical percolation threshold has been determined by using a classical percolation power-law1, suggesting the generation of a three-dimensional network of SWNTs in the investigated systems. (a) (b) Fig. 1 Micrographs of SWNTs-L121 dispersion (5 mg/mL) before sonication (a) and after 5 hours of sonication (b). The obtained results show that Triton-X100 is the best dispersing solvent in comparison to L121 and BMIM BF4, because of the presence of an aromatic hydrophobic moiety and an hydrophilic polyoxyethylene chain. 1) Martins J.N.; Bassani, T. S.; Barra, G. M. O.; Oliveira, R. V. B., Polym. Int. 2011, 60, 430-435. 218 PC91 Carbon nanotubes-polymer electrospun nanofibers as biocompatible scaffolds for neuronal cells differentiation Nicola Vicentini1, Teresa Gatti1, Patrizio Salice1, Giorgia Scapin2, Carla Marega1, Francesco Filippini2, Enzo Menna1 1 Dipartimento di Scienze Chimiche (Università di Padova). 2 Dipartimento di Biologia (Università di Padova). e-mail: [email protected] Carbon nanotubes (CNTs) are attractive candidates for the development of scaffolds able to support neuronal growth and development thanks to their ability to conduct electrical stimuli, to interface with cells and to mimic the neural environment. We recently proposed for tissue engineering purposes a freestanding nanocomposite scaffold that combines the conductive and topographical features of 4-methoxyphenyl functionalized multi-walled carbon nanotubes (MWCNT-PhOMe) with the biocompatible and mechanical properties of a poly(L-lactic acid) matrix (PLLA).1 The functionalization of MWCNTs, necessary for their proper compatibilization into the polymeric matrix, has been achived through the addition of diazonium salts. We will present here a novel morphology for the polymeric nanocomposite scaffold, based on electrospun nanofibers. This particular morphology is characterized by an extremely high surface to volume ratio and its porosity allows better mimicking of the extracellular matrix in which neurons normally grow in physiological conditions. Details on the preparation and characterization of such nanofibers will be given, together with preliminary evidences of polarized neurite outgrowth along the scaffold nanofibrous topography and peripheral blood stem cells selective differentiation into neurons.2 a) b) Figure 1. a) TEM image of PLLA electrospun nanofibers containing MWCNT-PhOMe aligned along the fiber axis. b) Fluorescence microscopy images of SH-SY5Y cells stained with Calcein-AM. White arrows indicate neurites following the scaffold fibers orientation. 1) Scapin, G.; Salice, P. et al. Nanomed. Nanotechnol. Biol. Med. 2015, 11, 621-632. 2) Submitted 219 J – Sintesi Organica 220 PC92 From nutraceutical to materials: effects of natural hydroxytyrosol on the performances of PVA-based films for food packaging applications Roberta Bernini,1 Elena Fortunati,2 Francesca Luzi,2 Luca Santi,1 Chiara Fanali,3 Laura Dugo,3 Giorgio M. Balestra,1 Josè M. Kenny,2 Luigi Torre 2 1 University of Tuscia, Department of Agriculture, Nature, Forests and Energy, Via S. Camillo De Lellis, 01100 Viterbo 2 University of Perugia, Civil and Environmental Engineering Department, Strada di Pentima 4, 05100, Terni 3 University Campus Bio-Medico, Center of Integrated Research (CIR), Via Alvaro del Portillo 21, 00128 Roma e-mail: [email protected] Hydroxytyrosol (3,4-dihydroxyphenylethanol, HTyr) is a phenolic compound found in olive leaves and fruits and extra-virgin olive oil, well-known for its strong antioxidant, and radical-scavenging properties.1 Pure samples of HTyr were obtained in high yield in our laboratory by a three-steps procedure using commercial available tyrosol as starting material, according to the following Scheme.2 Poly(vinyl alcohol) (PVA) is an industrially relevant polymer widely used also for the production of environment-friendly materials due its excellent chemical and physical properties, easy processing technique and low cytotoxicity.3 In search of natural antioxidants to be used in alternative to those synthetic, the potential use of HTyr in PVA films for food packaging applications was evaluated and described in this communication. PVA/HTyr-based films were produced by solvent casting in water; their morphological, thermal, mechanical and swelling in water properties were tested; the antioxidant and migration properties were also investigated taking into account their potential application for food packaging. 1) Bernini, R.; Merendino, N.; Romani, A.; Velotti, F. Curr. Med. Chem. 2013, 20, 655-670. 2) Bernini, R.; Mincione, E.; Barontini, M.; Crisante. F. J. Agric. Food Chem. 2008, 56, 8897-8904. 3) Fortunati, E.; Puglia, D.; Luzi, F.; Santulli, C.; Kenny, J. M.; Torre, L. Carbohyd. Polym. 2013, 97, 825-836. 221 PC93 Aerobic oxidation of 1-aryl-isochromans isochromans catalyzed by the Trametes villosa laccase/1-hydroxybenzotriazole system Roberta Bernini,1 Fernanda Crisante,1 Patrizia Gentili,2 Emanuele Ussia,2 R. Vadalà 2 1 University of Tuscia, Department of Agriculture, Nature, Forests and Energy, Via S. Camillo De Lellis, 01100 Viterbo 2 Sapienza, University of Roma, Department of Chemistry, P.le A. Moro, 00185 Roma e-mail: [email protected] Isochromans or 3,4-dihydro-1H-benzo[c]pyran derivatives are a rare class of natural products and structural motif of several drugs, agrochemicals and fragances. The presence of the benzyl carbon at C-4 and benzyl ethereal carbon at C-1 in these compounds has led us to investigate the potentiality of the Trametes villosa laccase in the presence of 1-hydroxybenzotriazole (HBT) as mediator on the aerobic oxidation already studied by us on catechin derivatives.2,3 As known, mediators enable laccases to oxidize substrates with a redox potential above 1.3 V by means of an indirect way where the active species is the oxidized form of the mediator (Scheme 1). Scheme 1 Then, we synthetized several 1-aryl-dihydroxyisocromans by the oxa-Pictet-Spengler reaction.1 After the protection of the phenolic groups by acetylation reaction, the corresponding 1-aryl-isochromans were oxidized with oxygen in the presence of the Trametes villosa laccase/1-hydroxybenzotriazole system. The reaction proceeded selectively at the C-1 position affording novel phenolic compounds (Scheme 2). Scheme 2 1) Bernini, R.; Crisante, F.; Fabrizi, G.; Gentili, P. Curr. Org. Chem. 2012, 16, 1051-1057 2) Bernini, R.; Crisante, F.; Gentili, P.; Morana, F.; Pierini, M. J. Org. Chem. 2011, 76, 820-832. 3) Bernini, R.; Crisante, F.; Gentili, P.; Menta, F.; Morana, F.; Pierini, M. RSC Adv. 2014, 4, 8183-8190. 222 PC94 Chiral non-racemic aryl-substituted oxetanes: stereoselective chemoenzymatic synthesis and regioselective functionalization by metallation Paola Vitale, Ruggiero Rizzi, Filippo Maria Perna, Antonio Salomone, Vito Capriati Dipartimento di Farmacia – Scienze del Farmaco, Università di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy e-mail: [email protected] Oxetanes are important four-membered cyclic ethers whose ring was found in many natural products that exhibit a range of biological activities.1a They find extensive use in polymer chemistry,1b as versatile building blocks in preparative chemistry for the synthesis of drugs, materials, and agrochemicals, and also act as interesting intermediates in ring-opening and rearrangements reactions.1c-f Recently, the reactivity of 2-aryloxetanes toward organolithium reagents was investigated by our group and successfully exploited for the regioselective preparation of both - and orthofunctionalized derivatives.2 In this communication, we report the first diastero- and enantioselective chemo-enzymatic synthesis of chiral 2,4-disubstituted oxetanes 4 and their regioselective functionalization by lithiation/electrophilic interception to afford the corresponding 2,2,4-trisubstituted derivatives 5. Optically active 2,4-disubstituted oxetanes 4 have been synthesized by stereospecific cyclization of optically active 1,3diols 3, in turn prepared by reduction with high stereo-preference of 3-hydroxy-1arylpropan-1-ones 2, obtainable by subjecting to stereoselective reduction 1,3-diketones 1 with different and cheap yeast strains in water at RT, and thus under “green” conditions (Scheme 1). Stereochemical aspects concerning both the chemo-enzymatic reductions and the lithiation process, as well as stereospecific ring-opening reactions, will be discussed as well. O yeast strains O R Ar 1 H2O, RT O OH Ar CH3CN/CH3COOH R -40 °C 2 4 R Ar 1) (OCH3)3CHCH3, PPTS/CH2Cl2 solvent Ar Li E+ O Ar O E R 5 Ar 2) AcBr 3) NaH/THF R 90–98% yield dr from 87:13 to 98:2 ees=30–80% RLi O OH 3 65–98% yield ees=60–90% Ar OH (CH3)4BH(OAc)3 O 4 R 69–87% overall yield (dr from 66:33 to > 95:5) Stereospecific ring-opening reactions R Scheme 1 1) (a) Hailes, H. C.; Behrendt, J. M. in Comprehensive Heterocyclic Chemistry III. Oxetanes and Oxetenes: Monocyclic, Katritzky, A. R. Ed., Pergamon, Oxford, 2008, vol. 2, ch. 2.05, p. 321; (b) Ghosh, B.; Urban, M. W. Science 2009, 323, 1458–1460; (c) Bukhard, J. A.; Wuitschik, G.; RogersEvans, M.; Müller, K.; Carreira, E. M. Angew. Chem. Int. Ed. 2010, 49, 9052–9067; (d) Guo, B.; Schwarzwalder, G.; Njardarson, J. T. Angew. Chem. Int. Ed. 2012, 51, 5675–5678; (e) Wang, Z.; Chen, Z.; Sun, J. Angew. Chem. Int. Ed. 2013, 52, 6685–6688; (f) Davis, O.A.; Bull, J. A. Synlett, 2015, DOI: 10.1055/s-0034-1380412. 2) (a) Coppi, D. I.; Salomone, A.; Perna, F. M.; Capriati, V. Chem. Comm. 2011, 47, 9918–9920; (b) Coppi, D. I.; Salomone, A.; Perna, F. M.; Capriati, V. Angew. Chem. Int. Ed. 2012, 51, 7532–7536. 223 PC95 Diastereoselective Ugi Reaction Followed By Intramolecular Nucleophilic Substitutions: Convergent Multicomponent Synthesis of Diverse Heterocyclic Scaffolds. Samantha Caputo, Luca Banfi, Andrea Basso and Renata Riva University of Genova, Department of Chemistry and Industrial Chemistry, Via Dodecaneso 31, 16146, Genova, Italy e-mail: [email protected] Multicomponent reactions exhibit many advantages over traditional approaches, allowing the synthesis of large libraries in highly convergent fashion. A high level of structural diversity can be achieved with this synthetic approach, providing a platform for the production of functionalized building blocks for novel bioactive molecules. However, in some cases, this metod appears to be limited to the smaller availability of functionalized and chiral substrates; another problem is poor stereochemical control. In particular, the aim of this project was to explore diastereoselective Ugi reactions to afford adducts bearing a variety of functional groups that may be employed in subsequent cyclization reactions for the rapid synthesis of diverse heterocyclic scaffolds. Starting from chiral β-amino alcohols (1), it was possible to check the best combination of solvent, temperature, potential Lewis acids, stereochemistry of the amino alcohol and the influence of R1 and R2 groups, to optimize yeld and diastereoselectivity of the reaction. Chiral β-amino alcohol precursors for the Ugi reaction are prepared via proline-catalyzed Mannich reaction of aldehydes with Boc-imines, which gives syn-products in high e.e.s.1 After optimization of the Ugi reaction conditions, these adducts (2) have been employed as substrates in the synthesis of diverse heterocyclic compounds, through secondary transformations. For example, without employing any additional functional group, complex bicyclic system (3) was obtained.2 Other possibilities may be envisaged by adding additional functional groups, beside the alcohol. Thus, chromanes (4) could be obtained by employing the alcoholic functional group as electrophilic substrate in a nucleophilic substitution by an additional phenol, under Mitsunobu conditions.3 Finally, the use, as nucleophile, of the secondary amide derived from isocyanide, and of an additional alkyl chloride, leads to the diketopiperazine scaffold (5).4 1) 2) 3) 4) Yang, J. W.; Stadler, M.; List, B., Angewandte Chemie-International Edition, 2007, 46, 609611. Banfi; Basso, A.; Guanti, G.; Kielland, N.; Repetto, C.; L.; Riva, R.; Journal of Organic Chemistry, 2007, 72, 2151-2160. Morana, F.; Basso, A.; Riva, R.; Rocca, V.; Banfi, L., Chemistry-a European Journal, 2013, 19, 4563-4569. Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.; Garcıa-Lo´pez, M. T.; GonzalezMuniz,R.; Journal of Organic Chemistry, 2001, 66, 3538-3547 224 PC96 Comparing the Chemo- and Stereoselectivity of Addition Reactions of Organolithiums and Grignard Reagents to Carbonyl Compounds in Deep Eutectic Solvents and in the Water: Synthesis of Tetrahydrofurans Luciana Cicco, Rosmara Mansueto, Francesca Claudia Sassone, Antonio Salomone, Filippo Maria Perna, Vito Capriati Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S Via E. Orabona 4, I-70125 Bari, Italy e-mail: [email protected] In many chemical reactions an organic solvent is often required to favour a better contact between reactants and to guarantee a convenient separation of products, and those with a low boiling point are generally preferred because of their easy recovery and recycling. However, most organic solvents still used in chemistry are volatile, flammable, and hazardous to humans and to the environment. Among unconventional, more eco-friendly reaction media, the so-called Deep Eutectic Solvents (DESs) are worth mentioning. DESs are usually formed by the combination of two or three inexpensive components which are able to engage in hydrogenbond interactions with each other, to form an eutectic mixture with a melting point lower than either of the individual components. Thanks to their low ecological footprint and attractive low price, DESs have now become of growing interest both at academic and industrial levels especially for their unusual solvent properties.1 Recent independent contribution from Hevia and García-Álvarez groups,2 and our group3 have shown that reactions of simple/functionalized organolithium compounds can be smoothly performed in DES mixtures at room temperature, under air, and competitively with protonolysis. Building on these findings, we have started a systematic investigation of the addition reactions of highly polarized organometallic compounds to carbonyl derivatives in unconventional solvents. In this communication, the chemo- and stereoselectivity of the addition reactions of organolithiums and Grignard reagents to γchloroketones (1) aimed at synthesizing tetrahydrofurans (2), which are important structural components of several natural compounds,4 will be compared and discussed for reactions run both in DESs and in water, and in the presence of a chiral non racemic ligand (L*). The results obtained will help pave the way towards a sustainable polar organometallic chemistry, which is one of the main challenges that chemists must address to face environmental issues. 1) For recent reviews, see: (a) M. Francisco, A. van den Bruinhorst, M. C. Kroon, Angew. Chem. Int. Ed. 2013, 52, 3074; (b) E. Smith, A. P. Abbott, K. S. Ryder, Chem. Rev. 2014, 114, 11060. 2) C. Vidal, J. Garcìa-Álvarez, A. Hernan-Gòmez, A. R. Kennedy, E. Hevia, Angew. Chem, Int. Ed., 2014, 53, 5969. 3) (a) V. Mallardo, R. Rizzi, F. Sassone, R. Mansueto, F. M. Perna, A. Salomone, V. Capriati. Chem Comm. 2014, 50, 8655; (b) F. C. Sassone, F. M. Perna, A. Salomone, S. Florio, V. Capriati, Chem. Comm., 2015, DOI: 10.1039/C5CC02884a. 4) A. Lorente, J. Lamariano-Merketegi, F. Albericio, M. Alvarez, Chem. Rev. 2013, 113, 4567. Acknowledgements: This work was finantially supported by Interuniversities Consortium C.I.N.M.P.I.S, and by the University of Bary. 225 PC97 Chemodivergent entry to enantioenriched (poly)phenolvalerolactone metabolites and their -lactone analogues 1 Claudio Curti,1 Nicoletta Brindani,1,2 Daniele Del Rio,2 Andrea Sartori,1 Lucia Battistini,1 Franca Zanardi1 Dipartimento di Farmacia, Università degli Studi di Parma, Via Parco Area delle Scienze 27/A, 43124, Parma, Italy 2 Dipartimento di Scienze degli Alimenti, Università degli Studi di Parma, Via Parco Area delle Scienze 59/A, 43124, Parma, Italy e-mail: [email protected] Polyphenols and related compounds are a group of plant-derived secondary metabolites which epidemiology indicates playing an important role in the protective effects of a fruit and vegetable-based diet. In particular, flavan-3-ols such as those belonging to the family of catechins, have attracted considerable attention for the role they seem to play in the prevention of chronic diseases such as cardiovascular- and diabetes-related pathologies, as well as neurodegenerative disorders.1 The scientific evidence accumulated during the last decade though, indicates that the beneficial effect of flavan3-ols in the human organism, could be mainly attributed not to the parent set of compounds, but rather to the corresponding enteric metabolites, of which chiral hydroxyphenyl -valerolactone derivatives 1 represents the most significant part. As part of our ongoing studies on the development of new, catalytic, enantioselective vinylogous aldol reactions (VMAR) for the construction of functionalized chiral nonracemic butenolide-type frameworks,2 we report here the implementation of an expedient and general asymmetric route to valuable -valerolactone metabolites.3 Also, while conducting these studies, TMSCl/NaI couple was found to promote an unprecedented, reductive ring-expansion of butanolide A, yielding several valerolactone analogues. The results of our endeavour in understanding the latter reaction mechanism and substrate viability will be also outlined. 1) Del Rio, D.; Rodriguez-Mateos, A.; Spencer, J.P.E.; Tognolini, M.; Borges, G.; Crozier, A. Antioxid. Redox Signal. 2013, 1818–1892. 2) Curti, C.; Ranieri, B.; Battistini, L.; Rassu, G.; Zambrano, V.; Pelosi, G.; Casiraghi, G.; Zanardi, F. Adv. Synth. Catal. 2010, 352, 2011-2022. 3) Curti, C.; Brindani, N.; Zanardi, F.; et al. Manuscript in preparation 226 PC98 Synthesis of pyrimidin-2-one derivatives via thermal decomposition of uracil-analogues W (0) Fischer carbene complexes Mariantonietta D’Acunto1, Antonella Carabellese1, Susagna Ricart2, Aldo Spinella1. 1 2 University of Salerno, Department of Chemistry and Biology, Via Giovanni Paolo II, 132, Fisciano (Salerno). Laboratorio de Catalisi Homogenea. Institut de Ciencia de Materials de Barcelona (CSIC). Campus de la UAB. E-08193-Bellaterra. Spain e-mail: [email protected] Pyrimidin-2-one substructure is a part of many compounds showing several biological activities ranging from pharmaceutical to agricultural fields and its preparation has attracted an increasing research interest. Starting from carbene complex 1 and substituted ureas, Fischer carbene uracilanalogues 2 and 3 can be easily prepared1, 2 and, subsequently, they can be oxidized affording uracil derivatives 4 and 5 (Scheme 1). 3 In the course of our study on the reactivity of W(0) alkynyl alkoxy carbene complexes, the synthesis of pyrimidin-2-one derivatives 6 and 7 has been achieved via base mediated decomposition of uracil analogues 2 and 3. 4 In this communication, pyrimidin-2-one derivatives 6 and 7 are synthetized from Fischer carbene uracil-analogues 2 and 3 through thermal elimination under microwave irradiation. Scheme1-General preparation of uracil derivatives and pyrimidin-2-one derivatives starting from alkynyl alkoxy carbene metal complexes 1) Spinella, A.; Caruso, T.; Pastore, U.; Ricart, S. J. Organomet. Chem. 2003, 684, 266-268. 2) Artillo, A.; Della Sala, G.; De Santis, G.; M., Llordes, A.; Ricart, S.; Spinella, A. J. Organomet. Chem. 2007, 692, 1277-1284. 3) Della Sala, G.; Artillo, A; Ricart, S.; Spinella, A. J. Organomet. Chem. 2007, 692, 1623-1627. 4) C. Bocchino, A. Carabellese, T. Caruso, G. Della Sala, S. Ricart, A. Spinella, J. Organomet. Chem., 2014, 749, 47-50. 227 PC99 Structural Features of Functionalized Sulphur-Bearing Four Membered Heterocycles a Flavio Fanelli,a,b Laura Carroccia,a Giovanna Parisi,a Marina Zenzola,a Angela Altomare,b Leonardo Degennaro,a Renzo Luisia Dipartimento di Farmacia, Università degli Studi di Bari “A. Moro” Via E. Orabona 4, I-70125 Bari b Istituto di Cristallografia – CNR, Via G. Amendola 122/O, I-70126 Bari [email protected] Four-membered heterocycles (4-MH) with one or two heteroatoms are of great importance in medicinal chemistry and synthetic organic chemistry.1 This kind of scaffolds shows peculiar structural features and biological properties. Our recent research efforts have been focused on the stereoselective synthesis and functionalization of some almost unexplored 4-MH such as azetidines2 and thietanes. Our interest on this kind of heterocycles comes from the evidence that effective methodologies for their direct functionalization are scarce. In this communication, we report some recent findings concerning the direct regio- and stereoselective functionalization of thietane 1oxides.3 Strategies for the generation of the corresponding polar organometallic intermediates as well as structural and stereochemical aspects will be highlighted. 1) 2) 3) a) Rousseau, G.; Robin, S. Four-Membered Heterocycles: Structure and Reactivity, in Modern Heterocyclic Chemistry, Ed. J. Alvarez-Builla, J. J. Vaquero and J. Barluenga, Wiley-VCH, ch. 3, 2011, pp. 163–268; b) Four-membered Heterocycles together with all Fused Systems containing a Four-membered Heterocyclic Ring in Comprehensive Heterocyclic Chemistry III, Ed. A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Elsevier Ltd, 2008, vol. 2, pp. 1–989. c) Couty, F.; Drouillat, B.; Evano, G.; David, O. EurJOC 2013, 11, 2045-2056. d) Guérot, C.; Tchitchanov, B.H.; Knust, H.; Carreira, E.M. Org.Lett. 2011, 13, 780-783. e) Brandi, A.; Cicchi, S.; Cordero, F.M. Chemical Reviews 2008, 108, 3988-4035. a) Luisi, R.; Degennaro, L.; Zenzola, M.; Trinchera, P.; Carroccia, L.; Giovine, A.; Romanazzi, G.; Falcicchio, A. Chem.Commun., 2014, 50, 1698-1700. b) Zenzola, M.; Degennaro, L.; Trinchera, P.; Carroccia, L.; Giovine, A.; Romanazzi, G.; Mastrorilli, P.; Rizzi, R.; Pisano, L.; Luisi, R. Chem. Eur. J. 2014, 20, 12190. Carroccia, L.; Degennaro, L.; Romanazzi, G.; Cuocci, C.; Pisano, L.; Luisi, R. Org. Biomol. Chem. 2014, 12, 2180. 228 PC100 Enantioselective enzymatic synthesis of tertiary -hydroxyketones O. Bortolini1, A. Massi1, G. Di Carmine1,Morena De Bastiani2, P.P. Giovannini1 1 University of Ferrara, Department of Chemistry and Pharmaceutical Science Via L. Borsari 46, 4412, Ferrara, Italy. 2 University of Ferrara, Department of Life Science and Biotechnology, Via L. Borsari 46, 4412, Ferrara, Italy. e-mail: [email protected] Thiamine diphosphate (ThDP)-dependent enzymes are well-established biocatalysts for the stereoselective formation of C–C bonds. The members of this enzyme family have been successfully applied in various carboligation processes like benzoin condensations and intermolecular Stetter reactions.1 Aldehyde–ketone cross-coupling is another type of enzymatic reaction that has been recently studied in order to access optically active tertiary -hydroxy ketones. Only few ThDP-dependent enzyme catalyzed asymmetric intermolecular aldehyde–ketone cross-carboligations have been reported and the use of the acetoin dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR), also called acetylacetoin synthase (AAS), has been recently introduced by our group. This enzyme has been successfully applied for the enantioselective synthesis of tertiary -hydroxy ketones through the homo- and cross-coupling of -diketones, either in batch or in flow-mode.2 In order to extend the catalytic scope of this enzyme, the use of alternative acyl anion donors was recently explored with a pure recombinant Ao:DCPIP OR. Inspired by the physiological role of the enzyme, the unprecedented use of methylacetoin was highlighted.3 The new synthetic strategy has shown a complete chemoselectivity allowing to prepare in an enantioselective way a broad range of tertiary -hydroxy ketones, some of which never obtained before through enzymatic synthesis. Furthermore, some of the products showed the opposite absolute configuration respect that of the same products obtained with other ThDP-enzymes. Scheme 1: Ao:DCPIP OR catalysed cross-coupling carboligation reaction 1) Müller, M.; Sprenger, G. A.; Pohl, M. Curr. Opin. Chem. Biol. 2013, 17, 261-270. 2) Giovannini, P. P.; Bortolini, O.; Cavazzini, A.; Greco, R.; Fantin, G.; Massi, A. Green Chem. 2014, 16, 3904-3915. 3) G. Bernacchia, O. Bortolini, M. De Bastiani, L. A. Lerin, S. Loschonsky, A. Massi, M. Müller, P. P. Giovannini, Angew. Chem. Int. Ed. DOI: 10.1002/anie.201502102R1. 229 PC101 Diversity-Oriented Synthesis of nitrogen-containing heterocycles through morpholine acetal rearrangement Elena Lenci, Riccardo Innocenti, Gloria Menchi, Andrea Trabocchi Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 13, 50019, Sesto Fiorentino (FI), Italy e-mail: [email protected] Modern chemical biology requires efficient synthetic processes, able to produce highquality small-molecule collections, as probes to investigate biological pathways.1 Our efforts in this field are focused on the Diversity-Oriented Synthesis2 of peptidomimetic molecules, taking advantage of amino acid- and sugar-derived building blocks. During last years, we reported the successful generation of the bicyclic diketopiperazine scaffold A and the 2-oxopiperazine ring C, starting from threonine-derived morpholines and suitable Fmoc-amino acid chlorides (Scheme 1). The skeletal diversity was obtained tuning the acid-base three-step process, from stepwise to sequential one-pot, achieving the modulation of the ring rearrangement mechanism.3 Recently, we found that the one-pot synthesis involving serine-derived morpholine acetals leads to the uncommon dihydropyrazinone heterocycle D. These new compounds are potential Xaa-Ser dipeptide isosteres, thus they can be applied in the generation of peptidomimetic libraries for medicinal chemistry.4 Finally, the biological activity of these morpholine-derived scaffolds was evaluated on yeast deletant strains, using cell growth as a phenotypic screening, in order to identify novel hit compounds as antifungal and anticancer agents, and to dissect their mode of action. Scheme 1 1) Lenci, E.; Guarna, A.; Trabocchi, A. Molecules. 2014, 19, 16506-16528. 2) (a) Schreiber, S. L. Science 2000, 17, 1964-1969; (b) “Diversity-Oriented Synthesis – Basics and Applications in Organic Synthesis, Drug Discovery, Chemical Biology”, Trabocchi, A.; Wiley, 2013. 3) Ciofi, L.; Trabocchi, A; et al. Tetrahedron Lett. 2010, 51, 6282-6285. 4) Lenci, E.; et al. Org. Biomol. Chem. 2015, 10.1039/C5OB00783F. 230 PC102 Molecular Design and Synthesis of Acetylsalycilic Esters for Transdermal Delivery Raffaella Mancuso,a,b Giorgio De Luca c, Elisabetta Conforti,a,c, Bartolo Gabrielea a Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Via Pietro Bucci, 12/C, 87036 Arcavacata di Rende (CS), Italy b Dipartimento di Ingegneria Meccanica, Energetica e Gestionale, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy c Istituto per la Tecnologia delle Membrane, Consiglio Nazionale delle Ricerche (ITM-CNR), 87036 Arcavacata di Rende (CS), Italy [email protected] Aspirin (acetylsalycilic acid, ASA) is a widely known non-steroidal anti-inflammaatory drug. A major problem associated with the oral administration of aspirin regards the gastrointestinal side effects, which may appear even at low doses. Transdermal delivery of this drug could offer a valid alternative route, more convenient and safer during long-tem use. Animal and human studies suggest that skin is moderately permeable to aspirin and its metabolite, salycilic acid.1 With the aim of developing a novel ASA-like hybrid molecule2 with increased skin permeability, we have computationally studied, designed then synthesized some alkyl esters of aspirin with different chain lengths, as shown in Scheme 1. OH OH O 1 HO CH3 n DCC n=4,5,9,13 OH O H3C CH3 O O Cl O CH3 n O O O 2 3 CH3 n Scheme 1 The molecular design was carried out analyzing the kinetic diameter of several esters, according to Samir Mitragotri.3 This molecular descriptor dramatically controls the transport molecules with low weight through the stratum corneum. A careful conformational analysis of 10 hybrids, with a different number of methylene groups, was performed using a in house code.4 In particular, the distribution of the kinetic diameters was analyzed in addition to the LogP of the target molecules, predicting the hybrids which best optimizes the considered molecular descriptors regulating the molecular transport through the skin. 1) Keimowitz, R.M.; Pulvermacher, G.; Mayo, G.; Fitzgerald, D., Circulation, 1993, 88, 556-561 2) Wach, J.; Bonazzi, S.; Gademann, K., Angew. Chem. Int. Ed., 2008, 47, 7123 -7126 3) Mitragroti, S., J. Contr. Rel., 2003, 86, 69-92. 4) Buekenhoudt, A; Bisignano F.; De Luca, G.; Vandezande, P.; Wouters, M;, Verhulst K., J. Membr. Sci. 2013, 439, 36–47. 231 PC103 Coumarin as Backbone for the Production of New Natural-Like Herbicides Raffaella Mancuso,a,b Fabrizio Araniti,c Francesco Sunseri,c Maria Rosa Abenavoli,c Bartolo Gabrielea a Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Via Pietro Bucci, 12/C, 87036 Arcavacata di Rende (CS), Italy b Dipartimento di Ingegneria Meccanica, Energetica e Gestionale, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy c Dipartimento di Agraria, Università Mediterranea di Reggio Calabria, 89124 Reggio Calabria, Italy [email protected] In the search of new compounds with herbicidal activity the natural compound coumarin, known for its phytotoxic potential,1 was used as backbone for the synthesis of new coumarin derivatives. 3-[(alkoxycarbonyl)methyl]coumarins 2 have been assayed in-vitro on germination and root growth of the two noxious weeds Amaranthus retroflexus and Echinochloa crusgalli. Moreover, in order to identify the possible physiological targets affected, synthetic coumarins 2 were assayed in-vitro on seedlings growth of the model species Arabidopsis thaliana. 3-[(alkoxycarbonyl)methyl]coumarins 2 was prepared in good yields starting from readily available 2-(1-hydroxyprop-2-ynyl)phenols 1 by palladium-catalyzed dicarbonylation process, in methanol such as solvent and at 25 °C (eq.1).2 R1 R1 OH R3 PdI2 cat OH R3 O R2 1 CO2Me CO, MeOH R2 O (1) 2 R1=R2=H, R3=OMe (70%) R1=H, R2=OMe, R3=H (81%) R1=Me, R2=R3=H (87%) All the assayed molecules strongly affected germination and root growth processes of both weeds. Interestingly, the effects exerted by the three molecules on weed germination were higher than that observed in bibliography with the natural coumarin pointing out ED50 values ranging from 50 to 115 µM. Moreover, all the assayed molecules showed a strong phytotoxic activity on both Arabidopsis shoot and root growth. In fact, seedlings treated with synthetic coumarins 2 pointed out a strong reduction in shoot fresh weight (ED50 values ≤ 60 µM), accompanied by a reduction of leaf development and pigment content, and a strong alteration of root growth (ED50 values ≤ 170 µM) and morphology with evident alterations of root anatomy (not aligned cells, gravitropism loss, inhibition of lateral roots and root hairs). Taken together the results highlight the promising potential herbicidal activity of these new natural-like molecules. 1) (a) Lupini, A.; Araniti, F.; Sunseri, F.; Abenavoli, M. R.;Plant Growth Regulation, 2014, 74, 23-31. (b) Abenavoli, M. R.; Lupini, A.; Oliva, S.; Sorgonà, A. Biologia Plantarum, 2010, 54, 149-153. 2) Gabriele, B.; Mancuso R.; Salerno, G; Plastina, P., J. Org. Chem, 2008, 73, 756-759. 232 PC104 A Recyclable Method for the Synthesis of Thiophenes in DES Raffaella Mancuso, a,b Asif Maner,a Vito Capriati,c Bartolo Gabrielea a Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Via Pietro Bucci, 12/C, 87036 Arcavacata di Rende (CS), Italy b Dipartimento di Ingegneria Meccanica, Energetica e Gestionale, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy c Istituto Dipartimento di Farmacia-Scienze Del Farmaco, Università di Bari Aldo Moro, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, Bari, Italy [email protected] Deep eutectic solvents (DESs), which can be defined as molecular complexes typically formed between a simple halide salt (i.e. choline chloride) and a hydrogen bond donor, have found a wide variety of applications in different fields of modern chemistry, including organic synthesis, biocatalytic reactions, dissolution of metal oxides, electrodeposition of metals, and materials chemistry. However the number of studies reporting the ability of DESs to serve as green and biorenewable reaction media in metal-catalysed organic reactions is still scarce and no examples of iodocyclization reactions in DESs are reported in literature. We report here the first example of iodocyclisation reaction in DES. Readily available 1-mercapto-3-yn-2-ols 1 are converted into the corresponding 3-iodothiophenes 2 under base-free conditions, at room temperature and in Choline Chloride/Glycerol (1ChCl/2Gly) such as solvent (eq.1). Products 2 are obtained in good yields (50-85%) and the DES can be recycled different times without lost of activity. 2 R1 R OH HS R2 I2 DES, 25 °C 1 I (1) R1 R3 S 2 R3 Starting from 1-mercapto-3-yn-2-ols 1 we have also obtained thiophenes 3 by PdI2catalyzed heterocyclization reaction (eq. 2). The reaction is carried out under air, at room temperature and in 1ChCl/2Gly such as solvent. Thiophenes 3 are formed in good to high yields (50-85%) and with the possibility to recycle DES-catalyst system several times without affecting the reaction. 2 R1 R OH PdI2/KI HS 1 DES, 25 °C R R2 3 233 (2) R 1 S 3 R3 PC105 Design and synthesis of polycyclic aromatic hydrocarbons-based hetero-doped molecular modules Domenico Milano1, Tanja Miletić1 and Davide Bonifazi1,2 1 Department of Chemical and Pharmaceutical Sciences, University of Trieste, Piazzale Europa 1, 34127, Trieste, Italy. 2 Namur Research College (NARC) and Department of Chemistry, University of Namur (UNamur), Rue de Bruxelles 61, 5000 Namur, Belgium. e-mail: [email protected] The design and synthesis of polycyclic aromatic compounds are of great interest owing to their potential applications as organic semiconductors for electronic devices, such as organic field-effect transistors (OFETs),1 light emitting diodes (LEDs),2 and photovoltaic cells.3 In this context peri-Xanthenoxanthene (PXX) derivative, investigated by Merck and Sony as organic semiconductor, is stable under oxygen, moisture, light and heat exposure and has an excellent carrier transport capacity.4 The large π-conjugated system in PXX derivatives is expected to enhance the overlap of molecular orbitals and the introduction of heteroatoms like oxygens into the π-system, stabilizing the reactive sites against oxidation, can improve its environmental stability4,5. From the synthetic chemistry viewpoint, efficient synthetic strategies for conjugated hexacyclic heteroaromatic compounds containing chalcogens are limited. In the design of new classes of naphtol-based PXX derivatives, an O-ring closure through metal-catalyzed C-H activation of binaphthol derivatives has been developed in our group for the preparation of such new library of PXX derivatives. Here is presented the design and synthesis of new PAH-based PXX derivatives, in particular pyrenolbased ones, for application as organic emitting systems (Scheme 1). Scheme 1. Example of a synthethic route to pyrenol-based PXX derivatives. 1) Wang, C.; Dong, H.; Hu, W.; Liu, Y.; Zhu, D. Chem. Rev. 2012, 112, 2208–2267. 2) Tao, Y.; Yang, C.; Qin, J. Chem. Soc. Rev. 2011, 40, 2943–2970. 3) Liu, J.; Walker, B.; Tamayo, A.; Zhang, Y.; Nguyen, T.-Q. Adv. Funct. Mater. 2013, 23, 47–56. 4) Kobayashi, N.; Sasaki, M.; Nomoto, K. Chem. Mater. 2009, 21, 552-556. 5) Lv, N.; Xie, M.; Gu, W.; Ruan, H.; Qiu, S.; Zhou, C.; Cui, Z. Org. Lett. 2013, 15, 2382–2385. 234 PC106 An easy route to enantiomerically pure 7- and 8-HSA by an olefin metathesis-based approach Carla Boga,1 Sara Drioli,2 Cristina Forzato,2 Gabriele Micheletti,1 Patrizia Nitti,2 Fabio Prati3 1 Dipartimento di Chimica Industriale «Toso Montanari», Università di Bologna, Viale Risorgimento 4, I40136 Bologna Italy. 2 Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, via Licio Giorgieri 1, I-34127 Trieste, Italy. 3 Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, via Giuseppe Campi 183, I41125 – Modena, Italy e-mail: [email protected] Synthesis of enantiomerically pure 7- and 8-hydroxystearic acids1 (7- and 8-HSA) has been accomplished starting from chiral non racemic 1-pentadecen-4-ol 1a and 1tetradecen-4-ol 1b respectively, in accordance with the retrosynthetic procedure depicted in the Scheme. Access to enantiomerically pure homoallylic alcohols 1a,b was possible via kinetic resolution of the corresponding racemic acetates, catalyzed by Novozym 435 (Lipase B from Candida antarctica). Yamaguchi esterification2 of 1a,b with 4-pentenoic and 5-hexenoic acids 2a,b respectively afforded the suitable dienic esters 3a,b which were submitted to RingClosing Metathesis Reaction (RCM).3 Hydrogenation of the resulting complex reaction mixtures followed by hydrolysis under basic conditions afforded the expected chiral non racemic 7- and 8-HSA in about 40% total yield. Scheme 1) Ebert, C.; Felluga, F.; Forzato, C.; Foscato, M.; Gardossi, L.; Nitti, P.; Pitacco, G.; Boga, C.; Caruana, P.; Micheletti, G.; Calonghi, N.; Masotti, L. J. Mol. Catal. B- Enzym. 2012, 83, 38-45. 2) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 19891993. 3) Monfette, S.; Fogg,D. E. Chem. Rev. 2009, 109, 3783-3816. 235 PC107 Metal-Free Reduction of Nitro-Group: a SiCl2-mediated Transformation of Wide General Applicability Manuel Orlandi1, Maurizio Benaglia1, Davide Brenna1 1 Università degli Studi di Milano, Via Golgi, 19, Milan e-mail: [email protected]. Reduction of nitro-group is one of the most straightforward method for the synthesis of aliphatic or aromatic amines. A great number of methodologies for the promotion of this reaction exists. Classical protocols use Pd/C, PtO2, Nickel-Raney or other homogenous metal catalysts under H2 atmosphere or under transfer hydrogenation conditions. Also SnCl2 or metal dissolving reductions involving Zn, Fe, In or Sm, have been widely employed as nitro reducing species. However, these synthetic methods suffer from several drawbacks. For example, the use of high pressure equipment, flammable hydrogen gas, hazardous reagents (e.g. hydrazine in transfer hydrogenation reactions), or the presence of potentially toxic transition metal complexes. Moreover, these protocols lack of functional group compatibility. Thus, great efforts have been made in order to develop new metal-free methodologies for the reduction of nitro group.1 Here, a new efficient and green HSiCl3-mediated methodology for the reduction of aromatic and aliphatic nitrogroups is presented (Figure). This new reaction is highly compatible with a plethora of functional groups providing a new powerful synthetic tool. The ability of HSiCl3 to generate SiCl2 in the presence of a tertiary amine was already reported.2,3 Indeed, mechanistic studies and quantum mechanical calculations shed light on the reaction mechanism evidencing the involvement of SiCl2 as the active reducing agent. 1) Sharma, S.; Kumar, M.; Kumar, V.; Kumar, N. J. Org. Chem. 2014, 79, 9433-9439 and references herein reported. 2) Karsch, H. H.; Schlüter, P. A.; Bienlein, F.; Herker, M.; Witt, E.; Sladek, A.; Heckel, M. Z. anorg. allg. Chem. 1998, 295-309. 3) Bernstein, S.C., J. Am. Chem. Soc. 1969, 91, 699-700. 236 PC108 A New Flow Chemical Synthesis of 6-Nitroindoles Roberto Ballini, Serena Gabrielli, Susanna Sampaolesi Marino Petrini, Alessandro Palmieri ”Green Chemistry Group”, School of Science and Technology, Chemistry Division, University of Camerino, via S. Agostino 1, 62032 Camerino (MC), Italy e-mail: [email protected] The indole ring constitutes a privileged framework in medicinal and in organic chemistry, due to its presence in many synthetic and naturally occurring biologically active molecules.1 In this context, over the years, several new methodologies for their preparation and derivatization have been proposed in literature,2 and in this sense, our research group has disclosed fruitful contributions to this field (Figure 1).3 Figure 1 Following these studies, we have now developed a new flow chemical synthesis of 6nitroindoles, which have been demonstrated to be useful precursors of dyeing keratinous fibers (Figure 2).4 Our method exploits the reactivity of substituted pyrrole2-carboxaldehydes 1 in combination with protected β-nitroketones 2 under basic condition. Using this procedure it has been possible to prepare a wide range of polysubstituted indoles 3 in good overall yields. It is important to note, that the same results cannot be obtained by the classic batch approach, due to the instability of the starting materials under the adopted reaction conditions. Figure 2 References 1) (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-48. (b) Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998. (c) Sundberg, R. J. In Indoles; Academic Press: New York, 1997. (d) Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559-590. 2) (a) Gribble, G. W. Contemp. Org. Synth. 1994, 145-172. (b) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075. c) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875-2911. 3) (a) Palmieri, A.; Petrini, M.; Shaikh R. R. Org. Biomol. Chem. 2010, 8, 1259-1270; (b) Palmieri, A.; Gabrielli, S.; Lanari, D.; Vaccaro, L.; Ballini, R. Adv. Synth. Catal. 2011, 353, 1425-1428. (c) Palmieri, A.; Gabrielli, S.; Maggi, R.; Ballini, R. Synlett 2014, 25, 128-132. 4) (a) Patent: US5180400 A1. 1993. (b) Patent: US5752982 A1. 1998. (c) Patent: US5938792 A1, 1999. 237 PC109 A Selenone Mediated Domino Strategy for the Construction of Variously Functionalized Spirocyclopropyl Oxindoles Martina Palomba, Luca Rossi, Luca Sancineto, Luana Bagnoli, Claudio Santi, Francesca Marini Department of Pharmaceutical Sciences (University of Perugia) e-mail: [email protected] Multi bond forming reactions, such as domino and multi component processes, creating several bonds in a single operation are effective strategies for the concise assembly of bioactive molecules.1 Herein we report a domino Michael addition/cyclization process for the construction of spirocyclopropyl oxindoles with different substitution patterns. Spirocyclopropyl oxindoles were prepared in high yields and good diastereoselectivities (up to 98% for R=Aryl) using commercially or readily available N-substituted or Nunsubstituted 2-oxindoles and vinyl selenones as bis electrophiles2 by simple treatment with aqueous NaOH. Spirooxindole ring is a privileged skeleton in several natural products and drug candidates and our method can provide a facile and effective route to compounds with promising anti-HIV activity.3 Scheme 1 1) (a) Multibond Forming Reactions: A New Frontier in the Synthesis of Heterocycles. Special Issue. Curr. Org. Chem. 2013, 17, No 18. Ed Menendez J. C.; (b) Stereoselective Multiple Bond-Forming Transformations in Organic Synthesis (Eds Rodriguez J., Bonne D.) Wiley & Sons, New Jersey, 2015. 2) (a) Sternativo, S.; Calandriello, A.; Costantino, F; Testaferri, L.; Tiecco, M.; Marini, F. Angew. Chem. Int. Ed. 2011, 50, 9382-9385; (b) Bagnoli, L.; Scarponi, C.; Rossi, M. G.; Testaferri, L.; Tiecco, M. Chem. Eur. J. 2011, 17, 993-999; (c) Sternativo, S.; Battistelli, B.; Bagnoli, B.; Santi, C.; Testaferri, L.; Marini, F. Tetrahedron Lett. 2013, 54, 6755-6757. 3) (a) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Wu, T. Y.-H.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16, 2105-2108; (b) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza J.; Caldwell, J.; Bursulaya, B.; Tuntland, T, Zhang, K.; Karanewsky, D.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16, 2109-2112; (c) Kumari, G.; Nutan, Modi, M.; Gupta, S. K.; Singh, R. K. Eur. J. Med. Chem. 2011, 46, 1181-1188. 238 PC110 Mechanochemical Oxidation Of Perfluoro Anilines To Perfluoro Azobenzenes Luca Vaghi1, Giancarlo Cravotto2 and Antonio Papagni*1 1 2 Department of Materials Science, University of Milano-Bicocca, Via Cozzi 55, 20125 Milano, Italy Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, via Giuria 9, Torino 10125, Italy e-mail:[email protected] Aromatic azo compounds have been extensively used in industrial applications mainly as organic dyes and pigments, but also as food additives, indicators, and therapeutic agents.1 Moreover, exploiting their peculiar photochemical response, the applications of azo compounds have been recently extended to a broad range of light-responsive functional materials, such as liquid crystals, molecular switches, smart polymers and photochromic ligands.2 A multitude of synthetic methods to affording symmetric azo compounds are known,3 the most used involve the oxidative coupling of aromatic amines and the reductive homodimerization of nitroarenes. In the case of anilines omocoupling the stoichiometric use of toxic and environmentally unfriendly transitionmetal based oxidants, like mercury, lead and manganese derivatives, is often needed to achieve satisfactory yields, especially with electron-poor aromatic amines. One of our research efforts entail the synthesis of polifluorinated aromatic compounds as possible candidates to be used in material science applications.4,5 On the route to target perfluorinated molecules we needed an efficient method to gain perfluoro azobenzenes, we focused our attention on the mechanochemical approach.6 Gratifying the use of environmental friendly oxidants in a zirconia mill, without the aid of milling auxiliaries, afforded the desired products in satisfactory yields. In addition polyfluoroazobenzenes undergo regiocontrolled aromatic nucleophilic substitutions in reaction with anilines simply acting on the reaction solvent polarity. Ortho-anilino substituted derivatives had be proved to be suitable starting material for the synthesis of polyfluoro phenazines. [1] K. Hunger, P. Mischke, W. Rieper, R. Raue, K. Kunde, A. Engel "Azo Dyes" in Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2005. [2] H. M. D. Bandarab, S. C. Burdette, Chem. Soc. Rev. 2012, 41, 1809-1825. [3] E. Merino, Chem. Soc. Rev. 2011, 40, 3835-3853. [4] A Papagni, P. Del Buttero, M. Moret, A. Sassella, L. Miozzo, G. Ridolfi, Chem. Mater. 2003, 15, 5010-5018. [5] P. Del Buttero, R. Gironda, M. Moret, A. Papagni, M. Parravicini, S. Rizzato, L. Miozzo, Eur. J. Org. Chem. 2011, 2265–2271. [6] R. Thorwirth, F. Bernhardt, A. Stolle, B. Ondruschka, J. Asghari, Chem. Eur. J. 2010, 16, 1323613242. 239 PC111 Thermally Triggered Self-mending in Novel Polyurethanes (PUs) Antonello Pastore1, Stefania Dello Iacono1, Maddalena Giordano1, Alfonso Iadonisi2, and Eugenio Amendola1, 3 1 National Research Council (CNR), Institute for Polymers, Composites and Biomaterials (IPCB), P.le E. Fermi 1 I-80055 Portici (NA) Italy. 2Department of Chemical Sciences, University of Naples “Federico II”, Via Cintia, I-80126 Napoli, Italy. 3IMAST - Technological District on Engineering of polymeric and composite Materials and Structures, P.zza Bovio 22, I-80133 Napoli, Italy. e-mail: [email protected] Material intrinsic healing is related to the presence of furan and maleimide moieties, insitu generated during damage or by heating above the r-DA reaction temperature; this mechanism was established for epoxies 1 and polyurethanes.2 In order to ensure flexibility and mobility of polymeric backbone, semi-flexible structures are required. Herein 2Ph2Isocyan Diels-Alder adduct (1) was thermally assembled starting from furfuryl isocyanate and 1,1′-(Methylenedi-4,1-phenylene)bismaleimide (Scheme 1). Scheme 1 Synthesis of monomer (1). Compound (1) was subsequently characterized by NMR spectroscopy and its thermal properties were preliminarily investigated. Metal catalyzed step-growth polymerization of monomer (1), in the presence of flexible and mobile poly(ethylene glycol) species, afforded polyurethanes (PUs) films amenable to recover from scratches (Figure 1). An integrated approach based on solution NMR spectroscopy, Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TGA), micromechanical analysis and optical microscopy allowed a deep characterization of the novel synthesized PUs in terms of structure, thermo-mechanical properties and morphology. These PUs satisfactory recover morphological scratch damages, between reaction temperatures of DA and r-DA processes, and they could promisingly be applied in the field of adhesives, spray painting and surface coatings. Figure 1 Scratched PU surface and same location after thermal healing. 1) Peterson, A. M.; Jensen, R. E.; Palmese, G. R. Appl. Mat. & Int. 2010, 2, 1141-1149. 2) Heo, Y.; Sodano, H. A. Adv. Funct. Mater. 2014, 24, 5261-5268. Acknowledgemets: The activities were performed in the frame of the projects “PRADE - PON02_00029_3205863” granted to IMAST S.c.a.r.l. and funded by the MIUR and “ALAMSA FP7 Grant Agreement 314768”. 240 PC112 Multicomponent Synthesis of Uracil Analogues by Pd-Catalyzed Carbonylative Coupling of α-Chloroketones, Isocyanates and Amines S. Perrone,1 M. Capua,1 C. Granito,1 A. Salomone,1 L. Troisi1 1 Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Prov.le LecceMonteroni, Lecce 73100, Italy e-mail: [email protected] Multicomponent reactions (MCRs) are a very powerful synthetic tool characterized by efficiency, selectivity, molecular diversity and, in particular, atom-economy. Recently we have studied the Pd-catalyzed carbonylation of unsaturated halides such as allyl-, benzyl-halides, and α-chloroketones. Particularly, these last ones constitute an efficient method to generate valuable β-dicarbonylpalladium chloride intermediates (B, Scheme 1). These palladium species, when generated in the presence of triethylamine, can convert into ketenes (C) that are very useful reagents in cycloaddition reactions. In fact, the postulated intermediate C was successfully employed in the synthesis of 3acyl-4-hydroxy-2-pyranones (path a) via a dimerizative [4+2] cycloaddition and also coupled with aromatic imines, to yield, in a [2+2] cycloaddition, (Z)-configured αalkylidene-β-oxoamides (path b) in a high stereoselectivity (Scheme 1).1-2 O R 1 Cl O Pd(AcO)2, Ph3P Et3N, CO (27 atm) THF,110 °C 1 R = Alkyl, Aryl R O 1 path a O PdCl - HPdCl R C 1 R1 O R 1 OH O O [2+2] C B O O [4+2] dimerization R2 N path b O R1 R 3 NHR3 R (Z) 2 Scheme 1 In this contribution we report a study about the reactivity of the -dicarbonyl palladium species (B) towards isocyanates as potential partners for the cycloaddition reactions with in-situ generated ketenes (C). The results obtained are very interesting because uracil analogues, that exhibit remarkable biological activities, were obtained in high yields by a multicomponent synthesis (four component reaction, chloroketone, isocyanate, CO, primary amine, Scheme 2). In addition, a reaction mechanism has been proposed.3 Scheme 2 1) S. Perrone, A. Salomone, A. Caroli, A. Falcicchio, C. Citti, G. Cannazza, L.Troisi Eur. J. Org. Chem., 2014, 27, 5932-5938. 2) S. Perrone, A. Caroli, G. Cannazza, C. Granito, A. Salomone, L. Troisi Tetrahedron Lett., 2015, 56, 2773-2776. 3) S. Perrone, M. Capua , A. Salomone, L. Troisi J. Org. Chem. 2015, submitted. 241 PC113 Synthesis and Reductive Elaborations of Piperidinyl Enamides and Enecarbamates Francesco Berti, Andrea Menichetti, and Mauro Pineschi* Dipartimento di Farmacia, Sede di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno 33, 56126, Italy. [email protected] Functionalized piperidines are very popular compounds widespread in a number of biologically active molecules. Therefore, the exploration of new methods to obtain these scaffolds is an intensive area of research. We recently reported the synthesis and the elaborations of substituted 1,2-dihydropyridines 1 by means of arylnitroso Diels-Alder reactions.1,2 We herein report the study of a metal-catalyzed hetero-Cope rearrangement reaction of acylnitroso Diels-Alder cycloadducts with 1,2-dihydropyridines to give synthetically valuable six-membered amine activated olefins such as 2 and others not shown here. Piperidinyl enamides and enecarbamates play an important role as intermediates in a variety of organic transformations and significant efforts have been devoted to their synthesis.3 Interestingly, during the elaboration of compound of type 2 in reductive reaction conditions (H2/Pd(C) or PdCl2(PPh3)2/LiEt3BH), the formation of 3-hydroxypiperidine derivatives and of a novel [3.3.1]-heterobicyclic structure, respectively, was observed. (1) Crotti, S.; Berti, F.; Pineschi, M. Org. Lett. 2011, 13, 5152. (2) Berti, F.; Di Bussolo, V.; Pineschi, M. J. Org. Chem. 2013, 78, 7324. (3) For typical preparations, see: (a) Gigant, N.; Dequirez, G.; Retailleau, P.; Gillaizeau, I.; Dauban, P. Chem. Eur. J. 2012, 18, 90. (b) Moriyama, N.; Matsumura, Y.; Kuriyama, M.; Onomura, O. Tetrahedron: Asymmetry 2009, 20, 2677. 242 PC114 Synthesis of 1,2,3,4-tetrahydro-β-carboline and 1,2,3,4tetrahydroisoquinoline based diketopiperazines by a post Ugi-3CR cyclization strategy A. Rossetti1, M. Gatti1, A. Sacchetti1 1 Dipartimento di Chimica, Materiali ed Ing. Chimica ‘Giulio Natta’, Politecnico di Milano, p.zza Leonardo da Vinci 32, Milan 20133, Italy. e-mail: [email protected] Multicomponent reactions (MCRs) are defined as one-pot synthesis reactions, where more than two starting materials interact to form a product. On the contrary to the classical assembly line of complex organic molecules, MCRs are convergent reactions, where the main standard operations, such as reaction set up, work-up, purification and analyses have to be performed just once. First examples of MCRs appeared in the last 19th century, although a revolution in this field was given in 1921 by the Italian chemist Passerini, who first reported a reaction based on isocyanide. In 1959 Ivar Ugi discovered the most useful isonitrile-mediated MCR,1 which can be classified in two main variations.2 Following our interest in the use of multicomponent reactions3 along with the study of isoquinoline and carboline based peptidomimetics,4 in this work we describe a straightforward approach for the synthesis of complex diketopiperazines through a two steps sequence (Scheme 1). Starting from a 3,4-dihydroisoquinoline or a β-carboline precursor, a three-component Ugi reaction was performed with chloroacetic acid and different types of isonitriles. The obtained intermediate was then submitted to cyclization to form the desired diketopiperazine. Studies on the possibility to achieve the products in a one-pot sequence were also performed. R1 R1 Ugi-3CR N O R1 N H N R1 N O NH R2 Cl N cyclization O N R2 O R1 = H, COOR R1 R1 Ugi-3CR N H O N O NH R2 Cl cyclization N N H O O N R2 Scheme 1: Post Ugi-3CR cyclization synthetic scheme. 1) Ramon, D.J.; Yus, M. Angew. Chem. Int. Ed. 2005, 44, 1602-1634. 2) Chèron,N.; Ramozzi, R.; El Kaїm, L. et al. J. Org. Chem. 2012, 77, 1361-1366. 3) Lesma, G.; Cecchi, R.; Crippa, S.; Giovanelli, P.; Meneghetti, F.; Musolino, M.; Sacchetti, A.; Silvani, A. Org. Biomol. Chem. 2012, 10, 9004–9012. 4) Airaghi, F.; Fiorati, A.; Lesma, G.; Musolino, M.; Sacchetti, A.; Silvani, A.. Beilstein J. Org. Chem. 2013, 9, 147–154 243 PC115 Continuous-flow stereoselective synthesis in 3D-printed microreactors Sergio Rossi, Riccardo Porta, Davide Brenna, Maurizio Benaglia Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy e-mail: [email protected] Continuous-flow systems1 have recently emerged as a powerful technology for performing chemical transformations, since they ensure some advantages over traditional batch procedures, such as faster reactions, cleaner products, safer reactions, quick reaction optimization, easy scale-up. On the other hand, 3D-printing technology allows chemists to build devices with high precision and well-defined architecture.2 Among the many different 3D-printing techniques developed in the industrial field, the most known is the Fused Deposition Modeling (FDM), where a plastic filament is unwound from a coil, heated to a melt, and fed through a nozzle that can be moved in three-directions to produce objects, according to the virtual design. The combination of these two only partially explored technologies in organic synthesis opens new and intriguing possibilities; the fabrication of ad hoc designed reactors and other devices, to perform at best different reactions becomes now feasible. In this work, an in-house designed and 3D-printed reactionware device was realised and employed for the organocatalytic synthesis of Active Pharmaceutical Ingredients (APIs) such as (1R,2S)-meta-hydroxyphenylpropanoalmine (MHPA), a potent vasopressor known under the trade name of Metaraminol. The 3D printed microreactor was fed with methanol solutions of 3-(benzyloxy)benzaldehyde, nitroethane and a chiral copper catalyst, leading to the formation of the corresponding nitro-aldol product in high yield and good diastereo and enantioselectivity (scheme 1). Scheme 1 References 1) A. Puglisi, M. Benaglia, R. Porta, F. Coccia, Current Organocatalysis, 2015, DOI: 0.2174/2213337202666150513002701 2) a) P. J. Kitson, M. H. Rosnes, V. Sans, V. Dragone, L. Cronin, Lab on a chip 2012, 12, 3267-3271; b) V. Dragone, V. Sans, M. H. Rosnes, P. J. Kitson, L. Cronin, Beilstein Journal of Organic Chemistry 2013, 9, 951-959. 244 PC116 Synthesis of Novel Neomycin-Sugar Conjugate Antibiotics by a Domino Multicomponent Process Aurora Sganappa a, A. Volonterio a, Y. Torb a Department of Chemistry, Materials, and Chemical Engineering “G. Natta”, Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy b Department of Chemistry and Biochemistry, University of California, San Diego 9500 Gilman Dr., La Jolla, California 92093, United States e-mail: [email protected] The excessive and often unnecessary use of antibiotics has helped the development of increasingly resistant bacteria. Unfortunately, beside to the constant increase in the appearance of these resistant strains, there is not a correspondece with the introduction of new effective drugs. In this scenario, aminoglycoside antibiotics have been identified and used as scaffolds for the synthesis of different derivatives with a prospective antibacterial activity. Recently, we have developed an interesting multicompontent domino process to sythesize multivalent glycomimetics in high yield and mild condiction.1,2 This straigthforward process has been also exploited to synthesize a little library of aminoglycoside-sugar conjugates, in particular neomycine derivatives, as potetntial novel antibiotics.3 The synthetic pathway as well the results of minimum inhibitory concentration evaluations will be reported. 1) A. Sganappa et al., ACS Comb. Sci. 2014, 16, 711-720. 2) A. Sganappa et al., Manuscript submitted. 3) A. Sganappa et al., Manuscript in preparation. 245 PC117 Synthesis of Complex Heterocyclic Scaffolds through Cascade Processes Based on Multicomponent Reactions Followed by Palladium Mediated SN2' and Ring Closing Metathesis Cyclizations Martina Spallarossa a, Luca Banfi a, Andrea Basso a, Renata Riva a a University of Genova, Department of Chemistry and Industrial Chemistry, Genova e-mail: [email protected] The strategy that combines classical isocyanide-based multicomponent reactions followed by subsequent cyclizations has proved to be one the most effective methods for the diversity oriented obtainment in few steps (typically 1-3) of a variety of druglike or natural product-like heterocyclic scaffolds.1,2 We envisioned that a 2-step protocol involving an Ugi reaction followed by a Pd(0) mediated SN2' cyclization could have a great potential: this latter reaction leaves a terminal double bond that can be involved in a third organometal catalysed step leading to complex polycyclic heterocycles. We already previously demonstrated this principle using a custom-made isocyanide containing an allyl carbonate.3 Now we have decided to access a different type of alkaloid-like systems, by incorporating the allyl carbonate in the aldehyde component instead. We have carried out a series of Passerini and Ugi reactions followed by the SN2' cyclization, where the isocyanide derived NH group acts as nucleophile. Finally different scaffolds have been prepared exploiting the terminal bond in a Ring Closing Metathesis based cyclization. OCO2Me 1) Ugi or Passerini reactions R2NC R3CO2H O R1 R4NH 2) Pd(0) cat. SN2' * R1 2 N * R2 O Y O Y= O or NR4 R3 * R1 * N * O Y O R3 R1 R5 N * O Y Further cyclizations (depending on R 2) RCM O R3 (1) Banfi, L.; Basso, A.; Riva, R. Top. Heterocycl. Chem. 2010, 23, 1. (2) Banfi, L.; Riva, R.; Basso, A. Synlett 2010, 23. (3) Riva, R.; Banfi, L.; Basso, A.; Cerulli, V.; Guanti, G.; Pani, M. J. Org. Chem. 2010, 75, 5134. 246 PC118 Helical shaped quinolines through the Povarov reaction Caterina Viglianisi, Chiara Biagioli, Stefano Menichetti, Lorenzo Tofani Department of Chemistry “U. Schiff”, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy. e-mail: [email protected] The formal [4+2] cycloaddition reaction of N–aryl imines with electron-rich dienophiles is known as Povarov reaction and represents one of the most convenient methods for the preparation of tetrahydroquinolines and quinolines.1 On the other hand, [4+2] cycloadditions represent one of the most commonly used methodology for the preparation of helical frameworks and several carba- and heterohelicenes have been synthesized using a Diels-Alder reaction.2 To the best of our knowledge, however, no report is available describing the preparation of azaheterohelicenes exploiting the Povarov reaction. In this communication we report a preliminary study on the synthesis of properly substituted electron-rich alkenes and N-arylimines able to react to give helical shaped quinolines. The optimization of the synthetic procedure as well as the structural features of the tetrahydroquinolines and quinolines so far obtained will be discussed. 1) a) Tetrahedron. 2009, 65, 2721-2750; b) Synthesis 2014, 46, 135-157. 2) Chem. Rev. 2012, 112, 1463-1535. 247 PC119 One-step fast protocol for identification and quantification of Nheterocyclic compounds in corals Chiara Samorì,1 Federica Costantini,2 Marco Abbiati,2 Paola Galletti,1,3 Emilio Tagliavini.1,3 1 2 Centro Interdipartimentale di Ricerca Industriale (CIRI), Università di Bologna Dipartimento di Scienze Biologiche, Geologiche e Ambientali, Università di Bologna 3 Dipartimento di Chimica ”Giacomo Ciamician”, Università di Bologna [email protected] Soft corals (Alcyonacea) are a rich source of structurally diverse and pharmacologically active natural products, including a variety of nitrogen-based metabolites with cytotoxic, antibacterial and insecticidal activities.1 The typical protocol for isolation and identification of these metabolites requires the extraction with organic solvents (e.g. haloalkanes and/or alcohols) followed by the fractionation of the extract by chromatography and by the identification through NMR and hyphenated techniques (mainly GC-MS and LC-MS). The major limitation of this approach is probably the relatively large amount of material required for isolating pure components from the complex mixture of the crude extract and for performing spectroscopic investigation.2 In fact, since the quantity of secondary metabolites produced by the organisms is often scarce, a considerable amount of living tissue is needed to get enough material to accomplish a satisfactory characterization. The present study aims at developing a novel onestep protocol for a fast and simple identification and quantification of N-heterocyclic compounds from the most common Mediterranean octocorals, applicable to small-size samples (tens of milligrams) without using concerning or hazardous chemical compounds (e.g. halogenated solvents). The first qualitative and quantitative analysis of N-heterocyclic compounds produced by the octocorals Eunicella cavolinii, E. verrucosa, E. singularis, Paramuricea clavata, Leptogorgia sarmentosa and Corallium rubrum has been provided (Figure 1). Moreover, an investigation of intraspecific patterns of variability in the amount and distribution of these compounds by analyzing samples collected in different sites along the Mediterranean coasts has been performed. Finally, the effectiveness and appropriateness of the analytical approach here proposed in species identification has been evaluated. Figure 1. Main N-heterocyclic compounds identified in the Mediterranean octocoral samples analyzed. Hypoxanthine Guanine 7-Methylguanine 3,7-Dimethylguanine Creatinine 1,3,7-Trimethylguanine Psilocin Adenosine 1) 2) J. W. Blunt, B. R. Copp, M. H. G. Munro, P. T. Northcote, M. R. Prinsep. Nat. Prod. Rep., 2011, 28, 196–268 N. Penez, G. Culioli, T. Perez, J. F. Briand, O. P. Thomas, Y. Blache. J. Nat. Prod. 2011, 74, 2304–2308 248 PC120 One more substituent makes the difference! Lara Bianchi, Massimo Maccagno, Giovanni Petrillo, Carlo Scapolla and Cinzia Tavani Dipartimento di Chimica e Chimica Industriale, Università di Genova, Via Dodecaneso 31, I-16146 Genova, Italy [email protected], [email protected] Among the nitrothiophenes which candidate themselves as substrates for ring-opening by reaction with amines, the polysubstituted -nitroderivative 1 is surely most synthetically useful as far as X and Y can be varied within a wide range of functional groups.1 Thus, the nitrobutadiene 2, which can be obtained by proper modification of the initial ring-opened product from 1 (X = SO2Ph, Y = H or COOMe), enjoys a versatile reactivity which can be quite rewardingly driven towards structurally different targets (either open-chain building-blocks or N-heterocycles) by simply varying Y and/or the reacting amine. Recent results on the system will be presented. 1) Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.; Cosimelli, B.; Spinelli, D. Tetrahedron 2001, 57, 8159-8165. 249 PC121 A new domino approach to lentiginosine and indolizine derivatives Carolina Vurchio, Franca M. Cordero, Alberto Brandi. University of Florence, Department of Chemistry “Ugo Schiff”, via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy. [email protected] (+)-Lentiginosine 1 is a natural iminosugar with important inhibitory activity towards amyloglucosidases and Hsp90 (Heat Shock Protein 90).1 Interestingly, it has been proven that the non natural enantiomer (–)-lentiginosine 2 and its 7-hydroxy derivative 3 display a potent proapoptotic activity against different cancer cell lines with a low toxicity towards healthy cells.2 Other 7-substituted (–)-lentiginosines such as 4 are able to induce apoptosis (Figure 1).3 Figure 1. The enantiopure dihydroxylated pyrroline N-oxides 5 have been used as building block in original highly stereoselective syntheses of hydroxyindolizidines such as lentiginosine and 7,8-disubstituted derivatives. The synthetic strategy is based either on nitrone alkylation and 1,3-dipolar cycloaddition with different dipolarophiles followed by suitable elaboration of the adducts (Scheme 1). OR R'O OR' HO N H OR D-tartaric acid H OR Z OR O N OR N O 5 OR N EtO2C RO OR H OH HO 7 MeO2C HO H O N 8 N OR OH OR Scheme 1. In this communication synthetic aspects and peculiar reactivities of some intermediates towards these interesting indolizine derivatives will be discussed. 1) 2) 3) Dal Piaz, F.; Vassallo, A.; Chini, M. G.; Cordero, F. M.; Cardona, F.; Pisano, C.; Bifulco, G.; De Tommasi, N.; Brandi, A. PLoS One 2012, 7, e43316. a) Macchi, B.; Minutolo, A.; Grelli, S.; Cardona, F.; Cordero, F. M.; Mastino, A.; Brandi A. Glycobiology 2010, 20, 500-506. b) Minutolo, A.; Grelli, S.; Marino-Merlo, F.; Cordero, F. M.; Brandi, A.; Macchi, B.; Mastino, A. Cell Death. Dis. 2012, 3, e358. c) Cordero, F. M.; Bonanno, P.; Khairnar, B.; Cardona, F.; Brandi, A.; Macchi, B.; Minutolo, A.; Grelli, S.; Mastino, A. Chem Plus Chem, 2012, 77, 224-233. a) Cordero, F. M.; Vurchio, C.; Macchi, B.; Minutolo, A.; Brandi A. ARKIVOC, 2014, 3, 215227. b) Vurchio, C.; Cordero, F. M.; Faggi, C.; Macchi, B.; Frezza, C.; Grelli, S.; Brandi A. Tetrahedron, 2015, http://dx.doi.org/10.1016/j.tet.2015.03.108. 250 PC122 Phenyl(2-quinolyl)methanol: a New Reagent for Metal-free Reduction of Nitro Aromatic Compounds Donatella Giomi, Renzo Alfini, Marino Malavolti, Antonella Salvini, Alberto Brandi Dipartimento di Chimica ‘Ugo Schiff’, Università di Firenze, Polo Scientifico e Tecnologico, Via della Lastruccia 3-13, I-50019 Sesto Fiorentino, Italy e-mail: [email protected] 1-(2-Pyridyl)-2-propen-1-ol (1) showed a peculiar behaviour as C-1, C-2, or C-3 carbon nucleophile, likely associated to the weak acidity of the ‘picoline type’ hydrogen atom.1 This characteristic also allowed alcohol 1 to react with nitro-aromatic/heteroaromatic compounds as Hantzsch ester (HEH) 1,4-dihydropyridine mimic, performing the metalfree reduction of nitro compounds to the corresponding amino derivatives.1 The multifacet reactivity of allyl alcohol 1 was responsible for competitive reaction pathways leading to mixtures of products with low selectivities. This problem was resolved exploiting phenyl(2-pyridyl)methanol (2)2 and phenyl(2-quinolyl)methanol (3) as new reagents for the metal-free reduction of nitro-aromatic/heteroaromatic systems. They were applied to the synthesis of -amino esters via domino nitro group reduction and aza-Michael conjugate addition to methyl acrylate, but the quinolyl carbinol 3 was also efficient in the reductive amination of suitably activated aldehydes and ketones as well as in new metal-free Friedländer quinoline and Reissert indole syntheses. Mechanistic aspects as well as applications and limits of these new HEH mimics will be properly presented. 1) Giomi, D.; Piacenti, M.; Alfini, R.; Brandi, A. Tetrahedron 2009, 65, 7048-7055. 2) Giomi, D.; Alfini, R.; Brandi, A. Tetrahedron 2011, 67, 167-172. 251 Lista dei partecipanti 252 A ABBIATI G: Università di Milano [email protected] ABBOTTO A. Università di Milano-Bicocca [email protected] ALGIERI V. Università della Calabria [email protected] ALLEGRINI P. Indena Spa [email protected] AMADIO E. Università di Padova [email protected] ANDRONICO L.A. Università di Bologna [email protected] ANGELINI G. Università "G. D'annunzio" di Chieti - [email protected] Pescara ATTANASI O. Università di Urbino [email protected] ATTOLINO E. Dipharma Francis Srl [email protected] BAGNOLI L. Università di Perugia [email protected] BALDINI L. Università di Parma [email protected] BALLINI R. Università di Camerino [email protected] BALZANI V. Università di Bologna [email protected] BANDINI E. Isof-Cnr Bologna [email protected] BANDINI M. Università di Bologna [email protected] BARBERA L. Università di Messina [email protected] BARBERO M. Università di Torino [email protected] BARTOCCI S. Università di Padova [email protected] BATTISTINI L. Università di Parma [email protected] BECCALLI E. Università di Milano [email protected] BELVISI L. Università di Milano [email protected] BENAGLIA M. Università di Milano [email protected] BENCIVENNI G. Università di Bologna [email protected] BERNARDI L. Università di Bologna [email protected] BERNARDI A. Università di Milano [email protected] BERNINI R. Università della Tuscia [email protected] BERTI F. Università di Pisa [email protected] BIETTI M. Università Roma "Tor Vergata" [email protected] BLEVE V. Università di Bologna [email protected] BOCHICCHIO A. Università della Basilicata [email protected] BOGA C. Università di Bologna [email protected] BONCHIO M. ITM-Cnr, Università di Padova [email protected] B 253 BORDONI V. Università di Pisa [email protected] BORTOLINI O. Università di Ferrara [email protected] BRAGA D. Università di Bologna [email protected] BRANDI A. Università di Firenze [email protected] BRINDANI N. Università di Parma [email protected] BRUNO I. Università di Salerno [email protected] CAMPITIELLO M. Università di Bologna [email protected] CAPRIATI V. Università di Bari "Aldo Moro" [email protected] CAPUTO S. Università di Genova [email protected] CARCONE L. Chemessentia S.R.L. [email protected] CARDELLICCHIO C. ICCOM - Cnr Bari [email protected] CASNATI A. Università di Parma [email protected] CASO M.F. Università di Napoli [email protected] CATTANEO C. Indena Spa [email protected] CECCONI B. Università di Milano Bicocca [email protected] CERISOLI L. Università di Bologna [email protected] CEVASCO G. Università di Genova [email protected] CHEN J. Università di Padova [email protected] CHIAPPE C. Università di Pisa [email protected] CICCO L. Università di Bari "Aldo Moro" [email protected] CICCOLA A. Università Roma La Sapienza [email protected] CIMARELLI C. Università di Camerino [email protected] CINI E. Università di Siena [email protected] CLERICI F. Università di Milano [email protected] C COMES FRANCHINI M. Università di Bologna [email protected] CONTE V. Università di Roma Tor Vergata [email protected] CORRADINI R. Università di Parma [email protected] COSTANTINO V. Università di Napoli Federico II [email protected] COZZI P.G. Università di Bologna [email protected] CRESPI S. Università di Pavia [email protected] CRISCUOLO V. Università di Napoli Federico II [email protected] CRUCIANI G. Università di Perugia [email protected] CURINI M. Università di Perugia [email protected] CURTI C. Università di Parma [email protected] 254 D D'ACUNTO M. Università di Salerno [email protected] D'ADAMIO G. Università di Firenze [email protected] D'ANNA F. Università di Palermo [email protected] D'AURIA V. Università di Napoli [email protected] DE ANGELIS F. Università dell'Aquila [email protected] DE LUCCHI O. Università Cà Foscari Venezia [email protected] DE MARCO R. Università di Bologna [email protected] DE NAPOLI L. Università di Napoli Federico II [email protected] DE ZOTTI M. Università di Padova [email protected] DEGENNARO L. Università di Bari Aldo Moro [email protected] DEL SECCO B. Università di Bologna [email protected] DELL'ACQUA M. Università di Milano [email protected] DI BARI L. Università di Pisa [email protected] DI IORIO N. Università di Bologna [email protected] D'ISCHIA M. Università di Napoli Federico II [email protected] D'ONOFRIO M. Università di Verona [email protected] DORDEVIC L. Università di Trieste [email protected] DOSSENA A. Università diParma [email protected] EMMA M.G. Università di Bologna [email protected] EVIDENTE M. Università di Napoli Federico II [email protected] FAGNONI M. Università di Pavia [email protected] FANELLI F. Università di Bari "Aldo Moro" [email protected] FARINA V. Janssen Pharmaceutica, Belgium [email protected] FARINOLA G.M. Università di Bari [email protected] FAVI G. Università di Urbino [email protected] FESTA C. Università di Napoli Federico II [email protected] FIAMMENGO R. Istituto Italiano di Tecnologia (IIT) [email protected] FLORIS B. Università Roma Tor Vergata [email protected] FOGLIA A. Università Di Salerno [email protected] FONTANA G. Indena Spa [email protected] E F 255 FONTANA F. F.I.S.-Fabbrica Italiana Sintetici Spa [email protected] FORMAGGIO F. Università di Padova [email protected] FRANCESCONI O. Università di Firenze [email protected] FRANCHI P. Università di Bologna [email protected] FRANCO C. Endura [email protected] FREDDITORI M. Università di Pavia [email protected] FREZZA C. Università di Roma La Sapienza [email protected] FUMAGALLI M. Chemical Pharmaceutical Generic Ass. [email protected] FUSINI G. Università di Pisa [email protected] GABRIELE B. Università della Calabria [email protected] GALLETTI P. Università di Bologna [email protected] GALLONI P. Università Roma Tor Vergata [email protected] GASBARRI C. Università "G. D'annunzio" di Chieti- [email protected] G Pescara GASPA S. Università di Sassari [email protected] GASPARRINI F. Università Roma La Sapienza [email protected] GATTI T. Università di Padova [email protected] GENTILUCCI L. Università di Bologna [email protected] GHIGO G. Università di Torino [email protected] GIACOMINI D. Università di Bologna [email protected] GIOVANNINI P.P. Università di Ferrara [email protected] GORACCI L. Università di Perugia [email protected] GOTI G. Università di Milano [email protected] GOTI A. Università di Firenze [email protected] GRAVANTE R. Università di Napoli [email protected] GROVES J. T. Princeton University [email protected] GRUTTADAURIA M. Università di Palermo [email protected] GUALANDI L. Università di Bologna [email protected] GUALANDI A. Università di Bologna [email protected] IACOBELLIS G. RIS – Parma [email protected] IACOMINO M. Università di Napoli Federico II [email protected] I 256 L LA FERLA B. Università Milano-Bicocca [email protected] LANZALUNGA O. Università di Roma "La Sapienza" [email protected] LATTUADA L. Bracco Imaging Spa [email protected] LAURO G. Università di Salerno [email protected] LAY L. Università di Milano [email protected] LENA A. Università di Pavia [email protected] LENCI E. Università di Firenze [email protected] LEPRI S. Università di Perugia [email protected] LESSI M. Università di Pisa [email protected] LICANDRO E. Università di Milano [email protected] LICINI G. Università di Padova [email protected] LO PRESTI M. Università di Bari [email protected] LOFFI C. Università di Parma [email protected] LOMBARDO M. Università di Bologna [email protected] LUBIAN E. Università di Padova [email protected] LUCARINI M. Università di Bologna [email protected] LUISI R. Università di Bari [email protected] LUNAZZI L. Università di Bologna [email protected] MAESTRI G. Università di Parma [email protected] MAGGINI M. Università di Padova [email protected] MANCUSO R. Università della Calabria [email protected] MANGANARO N. Università di Messina [email protected] MANICARDI A. Università di Parma [email protected] MANZINI C. Università di Pisa [email protected] MARCANTONI E. Università di Camerino [email protected] MARTINA K. Università di Torino [email protected] MARZANO G. Università di Bari [email protected] MASI M. Università di Napoli Federico II [email protected] MASIERO S. Università di Bologna [email protected] MASULLO D. Università di Napoli Federico II [email protected] MAULIDE N. University of Vienna [email protected] MAYOL L. Università di Napoli Federico II [email protected] MAYR H. Ludwig-Maximilian University, [email protected] M 257 Münich MAZZANTI A. Università di Bologna [email protected] MENCHI G. Università di Firenze [email protected] MENGOZZI L. Università di Bologna [email protected] MENICHETTI S. Università di Firenze [email protected] MENNA E. Università di Padova [email protected] MEZZETTA A. Università di Pisa [email protected] MEZZINA E. Università di Bologna [email protected] MILANO D. Università di Trieste [email protected] MIRABELLA S. Università di Firenze [email protected] MONTESARCHIO D. Università di Napoli Federico II [email protected] MORBIOLI I. Università di Parma [email protected] MORO E. Aptuit [email protected] MUCCI A. Università di Modena e Reggio Emilia [email protected] MUCCILLI V. Università di Catania [email protected] MUSSO L. Università di Milano [email protected] NICOTRA F. Università di Milano-Bicocca [email protected] NIGRO P. Università della Basilicata [email protected] NITTI P. Università di Trieste [email protected] NOTO R. Università di Palermo [email protected] OCCHIATO E. Università di Firenze [email protected] OLIVIERO G. Università di Napoli Federico II [email protected] ORLANDI M. Università di Milano [email protected] PACE V. University of Vienna [email protected] PALMIERI A. Università di Camerino [email protected] PALOMBA M. Università di Perugia [email protected] PANUNZIO M. ISOF-Cnr Bologna [email protected] PAPAGNI A. Università Milano-Bicocca [email protected] PARENTI F. Università di Modena e Reggio Emilia [email protected] N O P 258 PASQUATO L. Università di Trieste [email protected] PASTORE A. IPCB– Cnr, Napoli [email protected] PATERNO' A. Università di Catania [email protected] PELAGALLI A. Università Roma La Sapienza [email protected] PELLACANI L. Università di Roma La Sapienza [email protected] PELLEGRINO A. Centro Ricerche per le Energie [email protected] Rinnovabili e l’Ambiente – ENI PELLEGRINO S. Università di Milano [email protected] PERRONE S. Università del Salento [email protected] PESCIAIOLI F. Università di Pavia [email protected] PETRICCI E. Università di Siena [email protected] PETRILLO G. Università di Genova [email protected] PETRINI M. Università di Camerino [email protected] PETRUCCI C. Università di Perugia [email protected] PEZZELLA A. Università di Napoli "Federico II [email protected] PICCIALLI G. Università di Napoli Federico II [email protected] PICCIALLI V. Università di Napoli Federico II [email protected] PIERINI M. Università Roma La Sapienza [email protected] PIERSANTI G. Università di Urbino Carlo Bo [email protected] PINESCHI M. Università di Pisa [email protected] PIZZUTO L. Bracco Imaging Spa [email protected] PORTA A. Università di Pavia [email protected] POZZOLI C.G. Pharmabios [email protected] QUAGLIOTTO P. Università di Torino [email protected] QUINTAVALLA A. Università di Bologna [email protected] RAINOLDI G. Università di Milano [email protected] RAVIOLA C. Università di Pavia [email protected] RICCARDI C. Università di Napoli Federico II [email protected] RICCIO R. Università di Salerno [email protected] RIGHI P. Università di Bologna [email protected] RIZZO S. CNR Milano [email protected] ROMEO R. Università di Messina [email protected] Q R 259 ROSSETTI A. Politecnico di Milano [email protected] ROSSI S. Università di Milano [email protected] RUSSO A. Università di Salerno [email protected] SABUZI F. Università di Roma Tor Vergata [email protected] SAMBRI L. Università di Bologna [email protected] SANNICOLÒ F. Alchemia s.r.l. [email protected] SANSONE F. Università di Parma [email protected] SARTORI A. Università Di Parma [email protected] SATTIN S. Università di Milano [email protected] SCAMPORRINO E. Università di Catania [email protected] SCRIMIN P. Università di Padova [email protected] SERAFINI I. Università di Roma La Sapienza [email protected] SERNISSI L. Università di Firenze [email protected] SGANAPPA A. Politecnico di Milano [email protected] SIANI G. Università "G. D'annunzio" Chieti- [email protected] S Pescara SPALLAROSSA M. Università di Genova [email protected] SPINELLI D. Università di Bologna [email protected] STUCCHI M. Università di Milano [email protected] SUGA H. University of Tokyo T TADDEI M. Università di Siena [email protected] TAGLIAVINI E. Università di Bologna [email protected] TERRACCIANO S. Università di Salerno [email protected] TOLOMELLI A. Università di Bologna [email protected] TOMASINI C. Università di Bologna [email protected] TOMASSETTI M. Università di Camerino [email protected] TRABOCCHI A. Università di Firenze [email protected] TROISI L. Università del Salento [email protected] TROMBINI C. Università di Bologna [email protected] TRUSSO G. Università di Catania [email protected] 260 V VACCARO L. Università di Perugia [email protected] VALGIMIGLI L. Università di Bologna [email protected] VENTURI G. Università di Bologna [email protected] VERONA M.D. Università di Parma [email protected] VIOLA A. Università di Bologna [email protected] VITALE E. Università Magna Græcia di Catanzaro [email protected] VURCHIO C. Università di Firenze [email protected] ZAGHI A. Università di Ferrara [email protected] ZAMPELLA A. Università di Napoli Federico II [email protected] ZANARDI F. Università di Parma [email protected] ZANNA N. Università di Bologna [email protected] ZUCCOLO M. Università di Milano [email protected] ZUFFO M. Università di Pavia [email protected] Z 261 NOTE 262 NOTE 263 NOTE 264 NOTE NOTE 265 NOTE 266 NOTE 267 268