7th - unioviedo.es · 7th spanish-italian symposium on organic chemistry 7th spanish italian...

7TH SPANISH-ITALIAN SYMPOSIUM ON ORGANIC CHEMISTRY

7th Spanish Italian Symposium on Organic Chemistry 1

WELCOME TO SISOC7

On behalf of the Organizing committee I have the pleasure to give our warmest welcome to Oviedo to all the participants in the 7th Spanish-Italian Symposium on Organic Chemistry.

SISOC7 forms part of a series of bilateral scientific meetings between Italy and Spain held alternatively in both countries every two years. Previous meetings took place at Valencia, Lecce, Málaga, Perugia, Santiago de Compostela and Taormina.

The Scientific Program includes 24 invited lectures (12 Italian and 12 Spanish), 18 short oral communications, as well as a number of poster presentations.

The series of Spanish – Italian meetings are aimed to provide opportunities for personal contacts and scientific exchanges, to provide useful interactions within Italian and Spanish scientists on various topics of Organic Chemistry, and to further enhance the relationships between Italian and Spanish Universities and Research Institutes. We hope that the participants will find an appropriate environment at SISOC7 to fulfill this expectations.

We wish you a fruithful work, friendly contacts and a pleasant stay in Oviedo and the Principado de Asturias.

Prof. José Barluenga Chairman of the Symposium

GENERAL INFORMATION


Secretariat The secretariat will be located in the Main Hall of Auditorio Palacio de Congresos

Príncipe Felipe de Oviedo. Plaza de la Gesta, s/n - 33007 Oviedo. SISOC7 documentation will be provided at the secretariat. Assembly Rooms

Lectures and discussions will take place at the Sala de Cámara of the Auditorio, located in the main floor. The posters session will take place at the Main Hall at the entrance of the Sala de Cámara. Posters

Poster demonstrators are kindly asked to fix their posters themselves on the boards that will be located at the Main Hall at the entrance of the Sala de Cámara. Please use the board with the same number as your Abstract and be present at your poster at the time indicated in the poster. Meals

Coffees breaks will be held at the times indicated in the program at the hall at the entrance of the Sala de Cámara of the Auditorio Príncipe Felipe.

Lunches are served in the Restaurants El Yantar de Campomanes and La Cuadra de Antón. Both restaurants are within a five minutes walk from the Auditorio Príncipe de Asturias. Please, do not forget your lunch ticket, which you will be asked to hand at the Restaurant.

Symposium dinner will take place at Palacio de la Zoreda. Buses will depart from Plaza de la Gesta (in front of the Aditorio) at 20.15.

GENERAL INFORMATION


SCIENTIFIC COMMITEE

Gregorio Asensio Universidad de Valencia

José Barluenga Universidad de Oviedo

Juan Bosch Universidad de Barcelona

Sandro Cacchi Università di Roma "La Sapienza"

Saverio Florio Università di Bari

Enrique Guitián Universidad de Santiago de Compostela

Jesús Jiménez-Barbero CSIC Madrid

Stefano Maiorana Università di Milano

Nazario Martín Universidad Complutense de Madrid

Víctor S. Martín Universidad de La Laguna

Luciano Mayol Università di Napoli

Giovanni Romeo Università di Messina

Paolo Scrimin Università di Padova

Rafael Suau Universidad de Málaga

Marcello Tiecco Università di Perugia

Achille Umani Ronchi Università di Bologna

General Information SISOC7

6 7th Spanish Italian Symposium on Organic Chemistry

ORGANIZING COMMITEE

José Barluenga

Chairman

Enrique Aguilar

Secretary

Vocals

Fernando Aznar

M. Paz Cabal

Francisco J. Fañanás

Josefa Flórez

Eduardo Rubio

Carlos Valdés

GENERAL INFORMATION


Patronage and Sponsors

SCIENTIFIC PROGRAMME


Sunday, September 7, 2008

16.00-20.00 Registration at Auditorio Palacio de Congresos Príncipe Felipe

17.30 Homage to Professor L. Castedo on the ocassion of his seventieth birthday

Chairperson: Rafael Suau

Juan R. Granja. Universidad de Santiago de Compostela Brief Sketch of the scientific and personal trayectory of Prof. Luis Castedo

18.00 Marcello Tiecco. Università di Perugia Organoselenium Chemistry for the Development of New Synthetic Methods

19.00 Enrique Guitián. Universidad de Santiago de Compostela Aryne Cycloadditions: From Natural Products to π-Functional Materials

20.00 SISOC7 Reception at Auditorio Príncipe de Asturias

Scientific Programme SISOC7


Monday, September 8, 2008 9.00-9.30 Symposium Opening

9.30 Morning session - Chairperson: Marcello Tiecco

9.30-10.00 Ernest GIRALT (Universidad de Barcelona - IRB Barcelona)

Molecular Recognition at Protein Surfaces

10.00-10.30 Andrea TEMPERINI (Università di Perugia) A New Stereoselective Approach to β3-Amino Acid Derivatives

10.30-11.00 Juan R. GRANJA (Universidad de Santiago de Compostela) From Structure to Application of α,γ-Cyclic Peptides

11.00-11.30 Coffee break

11.30 11.30-12.00

Afternoon session – Chairperson: Jesús Jiménez Barbero Bartolo GABRIELE (Università della Calabria) PdI2: an Efficient and Versatile Catalyst for the One-pot Synthesis of Functionalized Heterocycles

12.00-12.300 Juan Enrique OLTRÁ (Universidad de Granada) Water, an Unexpected Hydrogen Source in Free-radical Chemistry Mediated byTitanium(III)

12.30-13.00 Giancarlo FABRIZI (Università "La Sapienza", Roma) New Palladium-Catalyzed Routes to Substituted Indoles

13.00-15.00 Lunch

15.00-15.30 Posters Session

15.30-16.30 Oral communications 1-6 - Chairperson: Rafaelle Riccio

Ignacio Delso (Universidad de Zaragoza – CSIC) Nucleophilic Addition to Chiral Cyclic Nitrones: Efficiency and Versatility in Iminosugars Synthesis

Paolo Melchiorre (Universita di Bologna) Asymmetric Aminocatalysis: New Reactions and New Directions

M. Belén Cid (Universidad Autónoma de Madrid) Catalytic and Enantioselective Michael Addition of α-Substituted-α-Cyanosulfonyl Carbanions with Cinchona Alkaloids

Alessandro Degl’Innocenti, Antonella Capperucci (Universitá di Firenze) Stereoselective Synthesis of Polycyclic Sulfurated Heterocycles

Laura M. Monleón (Universidad de Salamanca) Stereoselectivity in the Synthesis of Isoprenyl-β-Lactams

Antonio Salomone (Universitá di Bari) Ortho-Lithiated Epoxides Based Synthesis of Tetrahydroindenofuranones


SISOC7 Scientific Programme


17.00 17.00-17.30

Evening session - Chairperson: Esther Domínguez Tomás MARTÍN (Instituto de Productos Naturales y Agrobiología (IPNA), CSIC, La Laguna) CH-π Interaction as Responsible for an Unprecedented Chiral Discrimination

17.30-18.00 Tiziana BENINCORI (Università dell´Insubria) Conventional and Non Conventional Stereogenic Elements in Designing Chiral Ligands for Asymmetric Catalysis

18.00-18.30 Concepció ROVIRA (Institut de Ciència de Materials de Barcelona (ICMAB), CSIC, Barcelona) Self-Assembly of Polychlorotriphenylmethyl Radicals on Surfaces

Tuesday, September 9, 2008 9.00 Morning session - Chairperson: Paolo Scrimin

9.00-9.30 Roberto CORRADINI (Università degli studi di Parma)

Peptide Nucleic Acids (PNAs) and Modified PNAs as Powerful Tools in Biomedical Applications

9.30-10.00 Rosario GONZÁLEZ (Lilly S. A., Madrid) From Peptides to Small Molecules: The Design and Synthesis of Efficacious BACE Inhibitors

10.00-10.30 Luca GENTILUCCI (Università di Bologna) Peptidomimetic Scaffolds for the Discovery of New Bioactive Compounds

10.30-11.00 Oral Communications 7-9 - Chairperson: Enrique Guitián

Aurelio Mateo-Alonso (Università degli Studi di Trieste) Fullerenes: Multitask Components in Molecular Machinery

Luis Álvarez de Cienfuegos (University of Granada) Bi-Functional Polymer-Attached Inhibitors of Influenza Viruses

Emanuela Licandro (University of Milan) Novel Functionalised Heterohelicenes: New Synthetic Routes and Applications

11.00-11.30 Coffee break 11.30

Afernoon session - Chairperson: Achille Umani-Ronchi

11.30-12.00 Roberto SANZ (Universidad de Burgos) Some New Catalytic Methodologies in Organic Synthesis. Oxo-transfer and Hydroxy-Substitution Reactions

12.00-12.30 Giovanni PETRILLO (Università di Genova) Nitrobutadienes in Synthesis and Pharmacology

12.30-13.00 Mikel OIARBIDE (Universidad del Pais Vasco, San Sebastián) Catalytic Enantioselective Transformations of Nitrocompounds

13.00-15.00 Lunch

15.00-15.30 Posters Session

Scientific Programme SISOC7


15.30

Oral Communications 10-15 - Chairperson: Gregorio Asensio

15.30-16.30 Daniela Iannazzo (Università di Messina) Direct RuO4-Catalyzed Oxidation of Isoxazolidines to 3-Isoxazolidones

Raul SanMartín (Euskal Herriko Unibertsitatea, Bilbao) Copper-Catalyzed N-Arylation of Ureas in Water: A Novel Entry to Benzimidazolones

Antonella Goggiamani (Università degli Studi ‘La Sapienza’, Roma) New Perspectives in Palladium-Catalyzed Reactions with Arenediazonuim salts

Rubén Vicente (Georg-August-Universität, Göttingen) Metal-Catalyzed Direct Arylations of 1,2,3-Triazoles: Complementary Regioselectivities and Mechanistic Insights

Alessandra Tolomelli (University of Bologna) Synthesis and Biological Evaluation of Nonpeptide αvβ3/α5β1 Integrin Dual Antagonists

Vittorio Pace (Universidad Complutense de Madrid) Effective Synthesis of α-Arylamino-α’-chloropropan-2-ones via Oxidative Isomerization Promoted by Calcium Hypochlorite


17.00 17.00-17.30

Evening session - Chairperson: Saverio Florio Antonella DALLA CORT (Università "La Sapienza", Roma) Uranyl-Salophen Complexes as Receptors and Supramolecular Catalysts

17.30-18.00 Francisco Javier CAÑADA (Centro de Investigaciones Biológicas, CSIC, Madrid) Molecular Recognition of Carbohydrates

18.00-18.30 Giuseppe BIFULCO (Università degli studi di Salerno) Structure Determination of Complex Molecules via NMR: Theory and Application

20.45- Symposium dinner Miércoles 10 de Septiembre de 2008 9.30-12.00 Morning session - Chairperson: Joan Bosch

9.30-10.00 José Luis SERRANO (Universidad de Zaragoza)

Ionic Liquid Crystal Dendrimers: New Materials for New Applications

10.00-10.30 Patricia CIMINIELLO (Università degli Studi di Napoli Federico II) Toxins from Mediterrenean Phytoplankton

10.30-11.00 Juan Alberto MARCO (Universidad de Valencia) Stereoselective Synthesis of Glycosidase Inhibitors from the Broussonetine Group

11.00-11.30 Oral Communications 16-18 - Chairperson: Stefano Maiorana

Begoña Checa (Universidad de Barcelona) Enantioselective Synthesis of Indole Alkaloids of the Ervatamine-Silicine Group

Paulina Lecińska (Department of Chemistry and Industrial Chemistry. Genova) A New Convergent Synthesis of 6-Membered Dihydrobenzoxazinones In Just 2 Steps Via Tandem Ugi and Cyclization Reactions

José Pérez Sestelo (Universidade A Coruña) Total Synthesis of (+)-Neomarinone

SISOC7 Scientific Programme


11.30-12.00

Coffee break

12.00-14.00 Afternoon session - Chairperson: Victor S. Martín

12.00-12.30 Maria Chiara AVERSA (Università degli Studi di Messina) Sulfenic Acids as Intermediates in the Synthesis of "Biorelevant" Products

12.30-13.00 Juan Carlos CARRETERO (Universidad Autónoma de Madrid) Coordinating Sulfonyl Substrates in Metal-Catalyzed Reactions

13.00-13.30 Pier Giorgio COZZI (Università di Bologna) New Ferrocenyl Ligands for Stereoselective Reactions

13.30-14.00 Concluding remarks

14.00- Lunch

COMMUNICATIONS INDEX


Invited Lectures

IL-1 Molecular Recognition at Protein Surfaces Ernest Giralt IL-2 A New Stereoselective Approach to β3-Amino Acid Derivatives Marcello Tiecco, Lorenzo Testaferri, Raffaella Terlizzi and Andrea Temperini IL-3 From Structure to Application of α,γ-Cyclic Peptides Roberto Brea, Cesar Reiriz, Manuel Amorín, Mª Jesús Pérez-Alvite, Luis Castedo and Juan R. Granja IL-4 PdI2: an Efficient and Versatile Catalyst for the One-pot Synthesis of Functionalized Heterocycles Bartolo Gabriele IL-5 Water, an Unexpected Hydrogen Source in Free-Radical Chemistry Mediated by Titanium(III) J. Enrique Oltra IL-6 New Palladium-Catalyzed Routes to Substituted Indoles Ilaria Ambrogio, Sandro Cacchi, Giancarlo Fabrizi and Alessandro Prastaro IL-7 CH/π Interaction Responsible for an Unprecedented Chiral Discrimination Romen Carrillo, Andrés Feher, Víctor S. Martín and Tomás Martín IL-8 Conventional and Non Conventional Stereogenic Elements in Designing Chiral Ligands for Homogeneous Stereoselective Catalysis Tiziana Benincori IL-9 Multifunctional Organic Radicals on Surfaces Núria Crivillers, Marta Mas-Torrent, José Vidal-Gancedo, Jaume Veciana,

Lourdes Basabe-Desmonts,

Bar

Jan Ravoo, Mercedes Crego-Calama, David Reinhoudt,

Concepció Rovira

IL-10 Peptide Nucleic Acids (PNAs) and Modified PNAs as Powerful Tools in Biomedical Applications Roberto Corradini, Andrea Faccini, Tullia Tedeschi, Stefano Sforza, Rosangela Marchelli IL-11 From Peptides to Small Molecules: The Design and Synthesis of Efficacious BACE Inhibitors Francisco Javier Agejas, David Bender, Leonard N. Boggs, Richard A. Brier, Howard Broughton, Ana Belén Bueno, Michael P. Clay, Cynthia L. Cwi, Robert Dally, Timothy B. Durham, Jon A. Erickson, Juan F. Espinosa, Patric J. Hahn, Jingdan Hu, Debra K. Laigle, Terry Lindstrom, Chin Liu, Alicia Marcos, Patrick C. May, James McCarthy, José Miguel Mínguez, Gema Ruano, Gema Sanz, Timothy Shepherd, David Timm, Paloma Vidal, Juan Ramón Rodríguez, Todd Kohn, Hsiu-Chiung Yang, and Rosario González

Communications Index SISOC7


IL-12 Cyclotetrapeptide Analogues Based on a 13-Membered, Partially Modified Retro-Inverso Structure. Applications to the synthesis of Cancer Cell Adhesion Inhibitors. Luca Gentilucci, Giuliana Cardillo, Santi Spampinato Alessandra Tolomelli, Federico Squassabia, Rossella De Marco, Monica Baiula IL-13 Some New Catalytic Methodologies in Organic Synthesis. Oxo-transfer and Hydroxy-Substitution Reactions Roberto Sanz IL-14 Nitrobutadienes in Synthesis and Pharmacology Giovanni Petrillo IL-15 Catalytic Enantioselective Transformations of Nitrocompounds Mikel Oiarbide IL-16 Uranyl-Salophen Complexes as Receptors and Supramolecular Catalysts Antonella Dalla Cort IL-17 Molecular Recognition of Carbohydrates F. Javier Cañada

IL-18 Structure Determination of Complex Molecules via NMR: Theory and Application Giuseppe Bifulco IL-19 Liquid Crystals Based on Novel V-Shaped Structures José Luis Serrano, Joaquín Barberá, Emma Cavero, Raquel Giménez, Nélida Gimeno, Ana Pérez, Pilar Romero, M. Blanca Ros, Teresa Sierra, Rosa Tejedor, Francisco Vera IL-20 Two-Decade Study on Toxic Outbreaks in the Mediterranean Sea Patrizia Ciminiello and Ernesto Fattorusso IL-21 Stereoselective Synthesis of Broussonetines J. Alberto Marco, Celia Ribes-Vidal, Eva Falomir, Miguel Carda, Juan Murga IL-22 Sulfenic Acids as Intermediates in the Synthesis of “Biorelevant” Products Maria Chiara Aversa IL-23 Coordinating Sulfonyl Substrates in Metal-Catalyzed Reactions Juan Carlos Carretero IL-24 New Ferrocenyl Ligands for Stereoselective Reactions Pier Giorgio Cozzi, Montse Guiteras Capdev-a, Antonio Zanotti-Gerosa, and Luca Zoli

SISOC7 Communications Index


Oral Communications

OC-1 Nucleophilic Addition to Chiral Cyclic Nitrones: Efficiency and versatility in iminosugars synthesis Pedro Merino, Tomás Tejero, Andrea Goti, and Ignacio Delso OC-2 Asymmetric Aminocatalysis: New Reactions and New Directions Giuseppe Bartoli, Marcella Bosco, Letizia Sambri, and Paolo Melchiorre OC-3 Catalytic and Enantioselective Michael Addition of α-Substituted-α-Cyanosulfonyl Carbanions with Cinchona Alkaloids Jesús López-Cantarero, Sara Duce, José Luis García Ruano and M. Belén Cid OC-4 Stereoselective Synthesis of Polycyclic Sulfurated Heterocycles Alessandro Degl’Innocenti, Antonella Capperucci OC-5 Stereoselectivity in the Synthesis of Isoprenyl-β-Lactams Josefa Anaya, Manuel Grande and Laura M. Monleón OC-6 Ortho-Lithiated Epoxides Based Synthesis of Tetrahydroindenofuranones Vito Capriati, Saverio Florio, Renzo Luisi and Antonio Salomone OC-7 Fullerenes: Multitask Components in Molecular Machinery Aurelio Mateo-Alonso, Dirk M. Guldi, Francesco Paolucci, Stelios Couris and Maurizio Prato

OC-8 Bi-Functional Polymer-Attached Inhibitors of Influenza Viruses Jayanta Haldar, Jianzhu Chen, Alexander M. Klibanov, Luis Álvarez de Cienfuegos OC-9 Novel Functionalised Heterohelicenes: New Synthetic Routes and Applications Emanuela Licandro, Alberto Bossi, Clara Rigamonti, Stefano Maiorana OC-10 Direct RuO4-Catalyzed Oxidation of Isoxazolidines to 3-Isoxazolidones Anna Piperno, Angelo Ferlazzo, Salvatore G. Giofrè, Roberto Romeo, Giovanni Romeo and Daniela Iannazzo OC-11 Copper-Catalyzed N-Arylation of Ureas in Water: A Novel Entry to Benzimidazolones Nekane Barbero, Raul SanMartin, Mónica Carril and Esther Domínguez



OC-12 New Perspectives in Palladium-Catalyzed Reactions with Arenediazonuim salts S. Cacchi, G. Fabrizi, D. Persiani, G. Bartoli and A. Goggiamani OC-13 Metal-Catalyzed Direct Arylations of 1,2,3-Triazoles: Complementary Regioselectivities and Mechanistic Insights Lutz Ackermann and Rubén Vicente OC-14 Synthesis and Biological Evaluation of Nonpeptide αvβ3/α5β1 Integrin Dual Antagonists Alessandra Tolomelli OC-15 Effective Synthesis of α-Arylamino-α’-chloropropan-2-ones via Oxidative Isomerization Promoted by Calcium Hypochlorite. V. Pace, F. Martínez, M. Fernandez, J. V. Sinisterra, A. R. Alcántara OC-16 Enantioselective Synthesis of Indole Alkaloids of the Ervatamine-Silicine Group Mercedes Amat, Núria Llor, Joan Bosch and Begoña Checa OC-17 A New Convergent Synthesis of 6-Membered Dihydrobenzoxazinones in just 2 Steps Via Tandem Ugi and Cyclization Reactions L. Banfi, G. Guanti, P. Lecińska, A. Basso, R. Riva OC-18 Total Synthesis of (+)-Neomarinone Miguel Peña-López, Monserrat Martínez, Luis A. Sarandeses and José Pérez Sestelo



Posters

PO-1 Enantioselective Organocatalysis: Synthesis of Isoquinuclidines. M-P. Cabal, F. Aznar, N. Quiñones. PO-2 Water-Compatible Iminium-Ion Activation C. Palomo, A. Mielgo, M. Oiarbide, A. Puente, S. Vera and A. Landa PO-3 New and Efficient Organocatalysts for the Michael Asymmetric Addition of Aldehydes to Nitroalkenes Claudio Palomo, Antonia Mielgo, Silvia Vera and Aitziber Lizarraga PO-4 Asymmetric Organocatalytic Aza-Henry Reaction Under Phase Transfer Catalysis: An Experimental and Theoretical Study Idoia Múgica Mendiola, Maitane Zalacain, Enrique Gómez Bengoa, Rosa López, Mikel Oiarbide and Claudio Palomo PO-5 Enantioselective Organocatalytic Intramolecular Aza-Michael Reaction Santos Fustero, Diego Jiménez, Javier Moscardó, Ana Vicedo, María Sánchez-Roselló and Carlos del Pozo PO-6 Novel Chiral Ureas and Thioureas as Organocatalysts: Enantio and diastereoselective Nitro-Michael Reaction Rubén Manzano, José María Andrés, M. Dolores Muruzábal and Rafael Pedrosa PO-7 Ruthenium-catalyzed Selective Hydration of Nitriles to Amides in Pure Aqueous Medium V. Cadierno, J. Gimeno, J. Francos PO-8 One-pot Three-component Catalytic Synthesis of Fully Substituted Pyrroles from Readily Available Propargylic Alcohols, 1,3-Dicarbonyl Compounds and Primary Amines V. Cadierno, J. Gimeno, N. Nebra PO-9 Water-Soluble Catalysts for Isomerization Processes Beatriz Lastra-Barreira and Pascale Crochet PO-10 Synthesis of Heteropolycyclic Compounds by “Formal” Ruthenium-Catalyzed [4+2+2] Cycloaddition of 1,6-Diynes to cis-Propenylheteroarenes S. García-Rubín, J. A. Varela, L. Castedo, C. Saá



PO-11 Cycloisomerization of α,ω- Alkynols and Alkynylamines via Catalytic Ru-vinylidenes: Formation of Benzofurans, Isochromenes, 3-Benzoxepines, Indoles and Isoquinolines A.Varela-Fernández, C. González-Rodríguez, J. A. Varela, L. Castedo, C. Saá PO-12 Platinum-Catalyzed Tandem Reactions Between Alkynols and N-Arylaldimines Francisco J. Fañanás, Félix Rodríguez and Abraham Mendoza PO-13 Gold-Catalyzed Reactions of ω-Alkynol Derivatives and Indoles Amadeo Fernández, Félix Rodríguez and Francisco J. Fañanás PO-14 Gold-Catalyzed Intermolecular Hetero-Dehydro-Diels-Alder Cycloaddition of Captodative Dienynes: regioselective access to Pyridines Patricia García-García, Enrique Aguilar and Manuel Ángel Fernández-Rodríguez PO-15 Transition-Metal Catalyzed Hetero-Dehydro-Diels-Alder Cycloaddition Between 1,3-Dien-5-ynes and Aldimines: Regio and Diasteroselective Synthesis of Dihydropyridin-2-ones Manuel Angel Fernández-Rodríguez, Enrique Aguilar and Jesús Manuel Fernández-García PO-16 Understanding the Behavior of Chelating Groups in Metal-Catalyzed Processes: 2-Pyridylsulfonyl and 8-Quinolylsulfonyl Moieties. Jorge Esquivias, Ramón Gómez Arrayás, Juan C. Carretero and Inés Alonso PO-17 N-Propargylic β-Enaminones: Common Intermediates for the Synthesis of Polysubstituted Pyrroles and Pyrydines Sandro Cacchi, Giancarlo Fabrizi, Eleonora Filisti PO-18 1.2-Disustituted 4-Quinolones via Copper-Catalyzed Cyclization of 1-(o-Bromophenyl)-3-enaminones Roberta Bernini, Sandro Cacchi, Giancarlo Fabrizi, and Alessio Sferrazza PO-19 Palladium-catalyzed [2+2+2] Cycloaddition Reactions of Tetraphenylnaphthalynes Alba E.Díaz-Álvarez, Diego Peña, Dolores Pérez, Enrique Guitián PO-20 Pd-Catalyzed Cross-Couplings Reactions with Carbonyls: Application in a Very Efficient Synthesis of 4-Aryltetrahydropyridines María Tomás-Gamasa and Patricia Moriel, Fernando Aznar, Carlos Valdés PO-21 Pd-Catalyzed Indole Synthesis from Phenols and Imines Agustín Jiménez-Aquino, Carlos Valdés, Fernando Aznar PO-22 Simple Indole Synthesis by One-Pot Sonogashira Coupling / NaOH-Mediated Cyclization Roberto Sanz, Delia Miguel, M. Pilar Castroviejo and Verónica Guilarte PO-23 From Aromatic Lithiation to Palladium-catalyzed Coupling Reactions. Synthesis of Substituted Quinolines from 2-Iodoanilines Oihane García-Calvo, Unai Martínez-Estíbalez, Esther Lete, and Nuria Sotomayor



PO-24 Palladium-catalyzed Intramolecular γ-Arylation of α-Nitroketones Giorgio Giorgi, Pilar López-Alvarado and J. Carlos Menéndez PO-25 Synthesis of 2,3-Substituted Maleimides by Chemoselective Palladium-Catalyzed Cross-Coupling Reactions of Indium Organometallics Latifa Bouissane, José Pérez Sestelo and Luis A. Sarandeses PO-26 Palladium-Catalyzed Cross-Coupling Reactions of Indium Organometallics with Pyrimidines. Synthesis of Hyrtinadine A Ángeles Mosquera, Ricardo Riveiros, José Pérez Sestelo and Luis A. Sarandeses PO-27 Transition Metal Catalysed Intramolecular [3+2+2] Cycloadditions of Alk-10-yn/en-5-ynylidenecyclopropanes: A novel Route to Azulene Derivatives Gaurav Bhargava, Beatriz Trillo, Fernando López, Luis Castedo and José L. Mascareñas PO-28 Divergent Titanium-Mediated Allylations via Modulation by Palladium or Nickel. Btissam Bazdi, Noelia Fuentes, Rafael Robles, Juan M. Cuerva, J. Enrique Oltra, Susana Porcel, Antonio M. Echavarren and Araceli G. Campaña PO-29 Enantioselective Barbier-Type Cyclizations Catalyzed by TiIII Rosa E. Estévez, José Justicia, Noelia Fuentes, Miguel Paradas, Rafael Robles, Juan M. Cuerva, and J. Enrique Oltra PO-30 Phosphine-Free Perfluoro-Tagged Palladium Nanoparticles Supported on Fluorous Reversed-Phase Silica Gel. Application for the C-C cross-coupling Reactions Roberta Bernini , Sandro Cacchi , Giancarlo Fabrizi , Giovanni Forte , Sandra Niembro , Francesco Petrucci , Roser Pleixats, Alessandro Prastaro , Rosa Maria Sebastian, Roger Soler, Mar Tristany, Adelina Vallribera

PO-31 A Mild Synthesis of 2-Arylquinolines Based on a CAN-catalyzed Four-Component Reaction Pascual Ribelles, Mª Teresa Ramos and J. Carlos Menéndez PO-32 Efficient Synthesis of Highly Substituted Pyrroles Through a CAN-Catalyzed Sequential Three-Component Reaction Verónica Estévez, Mercedes Villacampa and J. Carlos Menéndez PO-33 Synthesis of Areneciclobutane Derivatives Promoted by Aryne-Zirconocene Complexes Jonás Calleja, Félix Rodríguez and Francisco J. Fañanás PO-34 Understanding the Regioselectivity of Grignard Reagents Ana Alcalde, Julio Lloret , Gregorio Asensio, Agusti Lledos and Teresa Varea PO-35 Regioselective Vinylation of Anilides and Carbostyrils by Grignard Reagents Riccardo Egris, Mercedes Villacampa and J. Carlos Menéndez PO-36 Multicomponent Enantioselective Cyclization of Fischer Carbene Complexes, Lithium Enolates and Unsaturated Organometallic Reagents Marcos G. Suero and Josefa Flórez



PO-37 Multicomponent Cyclization of Fischer Carbene Complexes, Amide Lithium Enolates, and Allenyl Organometallics Leading to 2-Cyclopentenones Raquel de la Campa and Josefa Flórez PO-38 “One-Pot” Synthesis of the Indole Skeleton in a Consecutive [8+2] / [5+1] Cyclization Process of Fischer Enynylcarbenes and 8-Azaheptafulvenes Jaime García-Rodríguez, Ángel L. Suárez-Sobrino and Miguel Tomás PO-39 Synthesis of Cyclopentenones through EnynylFischer Carbene Complex Mediated Lithium Enolates Addition-pentannulation Sequence. Ana Álvarez-Fernández, Angel L. Suárez-Sobrino, Miguel Tomás PO-40 Cascade Reactions of Ortho-Aminophenyl Alkynyl Fischer Carbene Complexes Based on [1,5]-Hydride Transfer or C-H Insertion Processes Fernando Aznar and Martín Fañanás-Mastral PO-41 [2+2] Heterocyclization of Group 6 Non-Heteroatom-Stabilized Carbene Complexes with Imines. Synthesis of 2-Azetines Derivatives Aránzazu Gómez, Javier Santamaría and Miguel Tomás PO-42 New Approaches to the Synthesis of Taxanes Noel Sayar, Luis Castedo, Juan R. Granja* and María José Aldegunde PO-43 New Approach to the Synthesis of Natural Products Containing Cyclic Ethers: Tandem Nicholas Reaction-Ring Closing Metathesis Nuria Ortega, Tomás Martín and Víctor S. Martín PO-44 Synthesis of Novel Pyrimido[4,5-e][1,4]diazepines Synthesis of 9,9’-[Ethane-1,2-diylbis(oxymethanediyl)]bis(2-amino-1,9-dihydro-6H-purin-6-one). An Impurity of Acyclovir. R. M. Suárez, M. P. Matía, J. L. Novella, J. Alvarez-Builla PO-45 Fast Microwave Preparation of an Atorvastatin Intermediate. Synthesis and Scale-up. J. Hernando, M. P. Matía, J. L. Novella, J. Alvarez-Builla PO-46 Synthesis of Lissoclimide-type Diterpenes: Towards the Synthesis of Haterumaimide Q Damaris Romero-Torrejón, and Miguel A. González PO-47 Synthesis of Phosphonate Derivatives of 1,2-Disubstituted Carbocyclic Purine Nucleosides with a Cyclopentane Ring Pedro Besada, María J. González Moa, Marta Teijeira and Carmen Terán PO-48 A Short Synthesis of 6,7-Dideoxy-L-arabino-eptos-5-ulose Antonino Corsaro, Ugo Chiacchio, Venerando Pistarà, Elisa Vittorino PO-49 Stereoselective Generation of the Saframycin B Ring Using a Modified Pictet-Spengler Reaction Alberto López-Cobeñas, Pilar López-Alvarado, Carmen Avendaño, Mercedes Villacampa and J. Carlos Menéndez



PO-50 A Metabolite Produced By Aspergillus flavus With A Potential Antifungal Against Phytophthora spp Biancavaleria Punzo, Anna Andolfi, Gennaro Cristinzio, and Antonio Evidente PO-51 Chemo- and Diastereoselective Pictet-Spengler Reactions on 3-Arylmethyl-6-arylmethylene-2,5-piperazinediones. An Efficient Synthesis of Functionalized Derivatives of the Saframycin ABC Fragment Lucía Pérez Gómez-Cuétara, Alessandra Monaco, Alberto López-Cobeñas, Pilar López-Alvarado and J. Carlos Menéndez PO-52 Dehydroquinase Inhibitors for the Development of New Antimicrobial Agents Antonio Peón, Luis Castedo and Concepción González-Bello PO-53 Transformations of Gummiferolic Acid into Bioactive Compounds Josefa Anaya, Pablo M. Gago, Manuel Grande, and Isabel Navarro PO-54 New β-Lactam Peptidomimetics: Alosteric Modulators of D2 Dopamine Receptors Claudio Palomo , Jesús M. Aizpurua , Azucena Jiménez , Raluca M. Fratila , Ane M. Gabilondo , J. Javier Meana PO-55 Unexpected Highly Stable Ozonides Derived from (-)-Quinic Acid Sonia Paz, Lorena Tizón, Luis Castedo and Concepción González-Bello PO-56 Synthesis of Functionalized Phosphorylated Aziridines F. Palacios, A. M. Ochoa de Retana, J. M. Alonso and A. Vélez del Burgo PO-57 Synthesis and Reactivity of Heterocyclic Condensed Oxaziridines Luigino Troisi, Catia Granito, Francesca Rosato and Valeria Videtta PO-58 Synthesis of Pyrido[f]pyrrolo[1,2-a][1,4]diazepin-10-ones Domingo Domínguez and Loreto Legerén PO-59 Synthesis of Novel Pyrimido[4,5-e][1,4]diazepines M. Nogueras, J. M. de la Torre, J. Cobo PO-60 Multicomponent Synthesis of Spiroheterocyclic Systems from 3-tert-Butyl-N-aryl-1-phenyl-1H-pyrazol-5-amine and Cyclohexane-1,3-diones Jorge Trilleras, Jairo Quiroga, Rodrigo Abonía, Juan Carlos Castillo, Silvia Cruz, Manuel Nogueras, Justo Cobo PO-61 A Mild Method for the Chemoselective Deprotection of N-Pivaloylindoles and Carbazoles by Hydrolysis with Water-DBU Miriam Ruiz-Serrano, Pilar López-Alvarado and J. Carlos Menéndez PO-62 Olefination Reactions of Azecinone[5,4-b]indoles and Indolo[2,3-a]quinolizinones Domingo Domínguez, Mª del Carmen de la Fuente and Paula Estévez Santoro PO-63 C-N Bond forming Reactions in the Synthesis of Substituted 2-Aminoimidazole Derivatives Asier Gómez-San Juan, José Manuel Botija, Esther Lete, Almudena Méndez, and Nuria Sotomayor



PO-64 Microwave-Assisted Hydroformylation in the Synthesis of Spirotetrahydrofurans Maurizio Taddei, Jessica Salvadori and Giacomo Lonzi PO-65 Stereoselective Functionalizations of Imino Lactones: Synthesis of Fluorinated and non-Fluorinated Peptidomimetics Santos Fustero, Natalia Mateu, Laia Albert, Teresa Moscardó, Salvador Villanova, Juan F. Sanz-Cervera and José Luis Aceña PO-66 A Novel One-pot Synthesis of 1,4-Dihydropyridines Based on a Sequential Four-component Process Swarupananda Maiti and J. Carlos Menéndez PO-67 Synthesis of 4-Alkoxyindoles: Application to the Preparation of Indole Inhibitors of Phospholipase A2 Roberto Sanz, Verónica Guilarte, M. Pilar Castroviejo and Delia Miguel PO-68 Synthesis and Evaluation of Coumarin-Resveratrol Hybrid Derivatives as a New Class of Tyrosinase Inhibitors. G. Delogu, C. Picciau, G. Podda, M. Corda, M. B. Fadda, A. Fais, L. Santana, M. J. Matos and E. Quezada PO-69 Synthesis of New Coumarin Derivatives with Pharmacological Activity M. J. Matos, D. Viña, E. Quezada, C. Picciau, G. Delogu, P. Janeiro, L. Santana, E. Uriarte, G. Podda PO-70 Rhodium-Catalyzed Hydroformylation of 3-(Pyrrol-1-yl)Alk-1-enes: Two Examples of High 1,2- and 1,3-Substrate-Induced Diastereoselectivity Roberta Settambolo, Giuliano Alagona, Caterina Ghio, Raffaello Lazzaroni PO-71 Total Synthesis of (-)-Dysithiazolamide Jaime Rodríguez, Carlos Jiménez, Ana Ardá, M. Isabel Nieto, and Raquel G. Soengas PO-72 Stereoselective Synthesis of (R)- and (S)-3-Aminotetradecanoic Acid (Iturinic Acid) Raffaella Terlizzi, Andrea Temperini, Marcello Tiecco and Lorenzo Testaferri PO-73 An Unexpected Rearrangement of the β-Lactam Ring Under Basic Conditions Josefa Anaya, Manuel Grande and Ramón Martín PO-74 Efficient Synthesis of Heterocyclic Quinones by Oxidative Demethylation of Hydroquinone Methyl Ethers with the Koser’s Reagent Irene Ortín, Elena de la Cuesta and Carmen Avendaño PO-75 New Reactivity and Synthetic Applications of Hydroxyallyl Pyridines Donatella Giomi, Alberto Brandi and Renzo Alfini PO-76 Synthesis and Characterization of Polyamides Containing α-Aminoacids D . Kada and G. Tabak PO-77 Synthesis of Vinylogous Fluoroalkyl α-Aminonitriles and α-Amino acids F. Palacios, A. M. Ochoa de Retana, S. Pascual and G. Fernández de Trocóniz



PO-78 Uncatalyzed Strecker-type Reaction of N,N-Dialkylhydrazones in Pure Water Eugenia Marqués-López, Raquel P. Herrera, Rosario Fernández and José M. Lassaletta PO-79 A One-step Procedure for the γ -Functionalization of α-Nitroketones Based on an Anionic Domino Process Francisco José Arroyo, Giorgio Giorgi, Pilar López-Alvarado and J. Carlos Menéndez PO-80 Further Studies on a Novel Stereocontrolled Ring Closing Metathesis Mediated Synthesis of Polyhydroxylated Cyclopentane β-Amino Acids Fernando Fernández, Juan C. Estévez, Ramón J. Estévez and Begoña Pampín PO-81 Chiral (R)- and (S)-Allylic Alcohols via a one-pot Chemoenzymatic Synthesis Simona Sgalla, Giancarlo Fabrizi, Roberto Cirilli, Alberto Macone, Alessandra Bonamore, Alberto Boffi and Sandro Cacchi PO-82 Iodocarbocyclization Reaction of β-Ketoesters and Alkynes David Palomas, Eduardo Rubio , José M. González PO-83 Synthesis and Properties of a New Class of meso-Functionalized Calixpyrroles M. C. Aversa, A. Barattucci, P. Bonaccorsi, G. Cafeo, F. H. Kohnke and T. Papalia PO-84 Supramolecular Donor-Acceptor Systems Based on α,γ-Cyclic Peptides Mª Jesús Pérez, Michele Panciera, Luis Castedo, Juan R. Granja and Roberto J. Brea PO-85 Self-Assembling α,γ-Peptide with Functionalized Cavity Juan R. Granja, Luis F. Silva, César Reiriz and Arcadio Guerra PO-86 Cation Template Assisted Oligoethylene Glycol Desymmetrization Ezequiel Pérez-Inestrosa, Yolanda Vida, Rafael Suau and Antonio Jesús Ruiz-Sánchez PO-87 Conformational Studies on Significant Synthetic Sequences of Resilin A. M Tamburro, A. Pepe, B. Bochicchio and Simona Panariello PO-88 Human Heparanase: Structure and Catalytic Mechanism Sonsoles Martín-Santamaría, Beatriz de Pascual-Teresa, Primitiva Menéndez, Luis M. Quirós and Javier González PO-89 NMR Investigations of the 3D Structure of the Nodulation Factors María A. Morando, P. Groves, J. Cañada, J.M. Beau, B. Vauzeilles, J. Jiménez-Barbero PO-90 Synthesis and NMR/MD Evaluation of Saccharide/β-Lactam Hybrids for Lectin Inhibition. Claudio Palomo, Jesus M. Aizpurua, Eva Balentová, Itxaso Azcune, Iñaki Santos, José Ignacio Miranda, Jesús Jiménez-Barbero and Javier Cañada PO-91 DFT/NMR Integrated Approach: a Valid Support to the Total Synthesis of Chiral Molecules Maria Giovanna Chini, Raffaele Riccio, and Giuseppe Bifulco



PO-92 NMR Studies of Di- and Mononuclear Copper (I) Complexes Containing the (S, S)-iPr-Pybox Ligand M. P. Gamasa, J. Díez, M. Panera, E. Rubio, I. Merino PO-93 Synthesis and Characterization of Silica Nanoparticles as Carriers for PDT Iria Río Echevarría, Fabrizio Mancin and Umberto Tonellato

LIST OF PARTICIPANTS


Jose Luis Aceña [email protected] Centro Investigación Príncipe Felipe,

Valencia

Enrique Aguilar [email protected] Univ. Oviedo

Maria José Aldegunde [email protected] Univ. Santiago de Compostela

Renzo Alfini [email protected] Univ. Florence

Inés Alonso [email protected] Univ. Autónoma de Madrid

Luis Alvarez de Cienfuegos [email protected] Univ. Granada

Ana Belén Álvarez Fernández [email protected] Univ. Oviedo

Julieta Álvarez Gutiérrez [email protected] Univ. Burgos

Mercedes Amat Tusan [email protected] Univ. Barcelona

Josefa Anaya [email protected] Univ. Salamanca

Francisco José Arroyo [email protected] Univ. Complutense Madrid

Gregorio Asensio gregorio Univ. Valencia

Maria Chiara Aversa [email protected] Univ. di Messina

Fernando Aznar [email protected] Univ. Oviedo

Alfredo Ballesteros Gimeno [email protected] Univ. Oviedo

José Barluenga [email protected] Univ. Oviedo

Pablo Barrio [email protected] ETH Zurich

Giuseppe Bartoli [email protected] Univ. Bologna

Gaurav Bhargava [email protected] Univ. Santiago de Compostela

Giuseppe Bifulco [email protected] Univ. Salerno

Francesco Bonadies [email protected] Univ. "La Sapienza" di Roma

Joan Bosch Cartes [email protected] Univ. Barcelona

Marcella Bosco [email protected] Univ. Bologna

Roberto Brea Fernández [email protected] Univ. Santiago de Compostela

Mª Joao C.P.Carvalho de Matos [email protected] Univ. Santiago de Compostela

Paz Cabal [email protected] Univ. Oviedo

Sandro Cacchi [email protected] Univ. "La Sapienza" di Roma

Jonas Calleja Priede [email protected] Univ. Oviedo

Francisco Javier Cañada [email protected] Protein Science, CIB, Madrid

Juan Carlos Carretero [email protected] Univ. Autónoma de Madrid

Luis Castedo [email protected] Univ. Santiago de Compostela

Mª Pilar Castroviejo Fernández [email protected] Univ. Burgos

Begoña Checa Castaño [email protected] Univ. Barcelona

Maria Giovanna Chini [email protected] Univ. Salerno

Mª Belén Cid [email protected] Univ. Autónoma de Madrid

Patrizia Ciminiello [email protected] Univ. Napoli

Justo Cobo Domingo [email protected] Univ. Jaén

Roberto Corradini [email protected] Univ. Parma

Pier Giorgio Cozzi [email protected] Univ. Alma Mater Studiorum

Antonella Dalla Cort [email protected] Univ. "La Sapienza" di Roma

Raquel De la Campa Fernández [email protected] Univ. Oviedo

Jose Manuel de la Torre [email protected] Univ. Jaén

List of participants SISOC7


Lorenzo De Napoli [email protected] Univ. Di Napoli Federico II

AlessandroDegl´Innocenti [email protected] Univ. Firenze

Carlos del Pozo Losada [email protected] Univ. Valencia

Giovanna Delogu [email protected] Univ. Cagliari

Ignacio Delso [email protected] Univ. Zaragoza

Alba Estrella Díaz Álvarez [email protected] Univ. Santiago de Compostela

Esther Domínguez [email protected] Univ. País Vasco

Riccardo Egris [email protected] Univ. Complutense Madrid

Beatriz Escribano Arenales beatriz.escribano@sanofi_aventis.com Sanofi-Aventis

Verónica Estévez Closas [email protected] Univ. Complutense Madrid

Paula Estévez Santoro [email protected] Univ. Santiago de Compostela

Rosa Elena Estévez-Jiménez [email protected] Univ. Granada

Giancarlo Fabrizi [email protected] Univ. “La Sapienza” di Roma

Francisco JavierFañanás [email protected] Univ. Oviedo

Martín Fañanás Mastral [email protected] Univ. Oviedo

Guillermo Fernández de Trocóniz [email protected] Univ. Pais Vasco

Jesus Manuel Fernández García [email protected] U.de Oviedo

Amadeo Fernández Miranda [email protected] Univ. Oviedo

Manuel A. Fernández Rodríguez [email protected] CSIC-IIQAB-Barcelona

Eleonora Filisti [email protected] Univ. "La Sapienza" di Roma

Lucía Florentino Rico [email protected] Univ. Oviedo

Josefa Flórez González [email protected] Univ. Oviedo

Saverio Florio [email protected] Univ. Bari

Josep Font [email protected] Univ. Autónoma de Barcelona

Javier Francos Arias [email protected] Univ. Oviedo

Bartolo Gabriele [email protected] Univ. Calabria

María Pilar Gamasa [email protected] Univ. Oviedo

Oihane García Calvo [email protected] Univ. Pais Vasco

Jaime García Rodríguez [email protected] Univ. Oviedo

Silvia García Rubín [email protected] Univ. Santiago de Compostela

Marcos García Suero [email protected] Univ. Oviedo

Luca Gentilucci [email protected] Univ. Bologna

Giorgio Giorgi [email protected] Univ. Complutense Madrid

Antonella Goggiamani [email protected] Univ. "La Sapienza" di Roma

Aránzazu Gómez [email protected] Univ. Oviedo

Asier Gómez San Juan [email protected] Univ. Pais Vasco

Francisco Javier González [email protected] Univ. Oviedo

Jose Manuel González [email protected] Univ. Oviedo

Miguel A. González [email protected] Univ. Valencia

Rosario González [email protected] Lilly, Discovery Chemistry

Araceli González Campaña [email protected] Univ. Granada

Catia Granito [email protected] Univ. Salento

Juan Granja [email protected] Univ. Santiago de Compostela

SISOC7 List of Participants


Arcadio Guerra [email protected] Univ. Santiago de Compostela

Verónica Guilarte [email protected] Univ. Burgos

Juan Hernando García [email protected] Univ. Alcalá

Daniela Iannazzo [email protected] Univ. Messina

Azcune Itxaso [email protected] Univ. Pais Vasco

Azucena Jiménez [email protected] Univ. País Vasco

Agustín Jiménez Aquino [email protected] Univ. Oviedo

Aitor Landa Álvarez [email protected] Univ. Pais Vasco

Elena Lastra [email protected] Univ. Oviedo

Beatriz Lastra Barreira [email protected] Univ. Oviedo

Raffaello Lazzaroni [email protected] Univ. Pisa

Paulina Lecinska [email protected] Univ. Génova

Loreto Legerén Molina [email protected] Univ. Santiago de Compostela

Esther Lete [email protected] Univ. País Vasco

Emanuela Licandro [email protected] Univ. Milan

Aitziber Lizarraga [email protected] Univ. País Vasco

Giacomo Lonzi [email protected] Univ. Siena

Luis Ángel López [email protected] Univ. Oviedo

Salomé López [email protected] Univ. Oviedo

Alberto Enrique López Cobeñas [email protected] Univ. Complutense Madrid

Stefano Maiorana [email protected] Univ. Milan

Swarupananda Maiti [email protected] Univ. Complutense de Madrid

Juan Alberto Marco [email protected] Univ. Valencia

Laura Marcos [email protected] Univ. Salamanca

Tomás Martín [email protected] IPNA - CSIC, Tenerife

Víctor Martín [email protected] Univ. La Laguna

Ramón Martín [email protected] Univ. Salamanca

Unai Martínez Estibalez [email protected] Univ. Pais Vasco

Aurelio Mateo Alonso [email protected] Univ. degli Studi di Trieste

Mª Paz Matía Martín [email protected] Univ. Alcalá

Luciano Mayol [email protected] Univ. Di Napoli Federico II

Paolo Melchiorre [email protected] Univ. Bologna

Abraham Mendoza Valderey [email protected] Univ. Oviedo

Maria Isabel Merino Natal [email protected] Univ. Oviedo

Delia Miguel [email protected] Univ. Burgos

Alessandra Mónaco [email protected] Univ. Complutense de Madrid

Maria Agnese Morando [email protected] CIB-CSIC, Madrid

Patricia Moriel Blanco [email protected] Univ. Oviedo

Ángeles Mosquera Lamas [email protected] Univ. A Coruña

Idoia Mugica [email protected] Univ. País Vasco

Francesco Naso [email protected] Univ. Bari

Isabel Navarro [email protected] Univ. Salamanca

Noel Nebra Muñiz [email protected] Univ. Oviedo

List of participants SISOC7


M. Isabel Nieto Prieto [email protected] Univ. A Coruña

Manuel Nogueras [email protected] Univ. Jaén

Jose Luis Novella [email protected] Univ. Alcalá

Mikel Oiarbide [email protected] Univ. Pais Vasco

J. Enrique Oltra [email protected] Univ. Granada

Irene Ortín Remón [email protected] Univ. Complutense de Madrid

Vittorio Pace [email protected] Univ. Complutense Madrid

David Palomas [email protected] Univ. Oviedo

Claudio Palomo Nicolau [email protected] Univ. Pais Vasco

Begoña Pampín Casal [email protected] Univ. Santiago de Compostela

Simona Panariello [email protected] Univ. Basilicata

Teresa Papalia [email protected] Univ. Messina

Daniele Passarella [email protected] Univ. Milano

Rafael Pedrosa [email protected] Univ. Valladolid

Miguel Peña López [email protected] Univ. A Coruña

Antonio Peon Lopez [email protected] Univ. Santiago de Compostela

Raquel Pérez Herrera [email protected] ICMA, CSIC, Zaragoza

Dolores Pérez Meirás [email protected] Univ. Santiago de Compostela

José Pérez Sestelo [email protected] Univ. A Coruña

Giulio Petrillo [email protected] UNIGE, DCCI

Giovanni Petrillo [email protected] Univ. Genova

Luisa Petrillo [email protected] UNIGE-DCCI

Maria Carmen Picciau [email protected] Univ. Cagliari

Anna Piperno [email protected] Univ. Messina

Alessandro Prastaro [email protected] Univ. Tuscia, A.B.A.C.

Bianca Valeria Punzo [email protected] Univ. Federico II di Napoli

Noelia Quiñones Álvarez [email protected] Univ. Oviedo

Pascual Ribelles Torres [email protected] Univ. Complutense de Madrid

Raffaele Riccio [email protected] Univ. Salerno

Iria Río Echevarría [email protected] Univ. Padova

Felix Rodríguez [email protected] Univ. Oviedo

Giovanni Romeo [email protected] Univ. Messina

Víctor Rubio [email protected] FAES FARMA

Eduardo Rubio [email protected] Univ. Oviedo

Antonio Jesús Ruiz Sánchez [email protected] Univ. Málaga

Miriam Ruiz Serrano [email protected] Univ. Complutense Madrid

Antonio Salomone [email protected] Univ. Bari

María Sánchez Roselló [email protected] Univ. Valencia

Raul SanMartín [email protected] Univ. Pais Vasco

Javier Santamaría [email protected] Univ. Oviedo

Roberto Sanz [email protected] Univ. Burgos

Luis Sarandeses [email protected] Univ. A Coruña

Noel Sayar [email protected] Univ. Santiago de Compostela

SISOC7 List of Participants


Paolo Scrimin [email protected] Univ. Padova

José Luis Serrano [email protected] Univ. Zaragoza

Alessio Sferrazza [email protected] Univ. Tuscia

Simona Sgalla [email protected] Univ. "La Sapienza" di Roma

Luis Felipe Silva Oliveira [email protected] Univ. Santiago de Compostela

Antonio Simón [email protected] Univ. Valencia

Nuria Sotomayor [email protected] Univ. País Vasco

Samuel Suárez Pantiga [email protected] Univ. Oviedo

Ángel Luis Suárez Sobrino [email protected] Univ. Oviedo

Rafael Suau [email protected] Univ. Málaga

Ghezalla Tabak [email protected] USTHB-Fac. de Chimie

Andrea Temperini [email protected] Univ. Perugia

Carmen Terán [email protected] Univ. Vigo

Raffaella Giovanna Pia Terlizi [email protected] Univ. Perugia

Marcello Tiecco [email protected] Univ. Perugia

Lorena Tizón Valverde [email protected] Univ. Santiago de Compostela

Alessandra Tolomelli [email protected] Univ. Bologna

Miguel Tomás [email protected] Univ. Oviedo

Luigino Troisi [email protected] Univ. Salento

Achille Umani-Ronchi [email protected] Univ. Bologna

Carlos Valdés [email protected] Univ. Oviedo

M.Teresa Varea [email protected] Univ. Valencia

Alejandro Varela Fernández [email protected] Univ. Santiago de Compostela

Ander Vélez del Burgo Pérez [email protected] Univ. Pais Vasco

Silvia Vera [email protected] Univ. País Vasco

Rubén Vicente Arroyo [email protected] Georg-August-Universitat Göttingen

Valeria Videtta [email protected] Univ. Salento

Elisa Vittorino [email protected] Univ. Catania

Maitane Zalacain [email protected] Univ. País Vasco

INVITED LECTURES

Invited Lectures SISOC7


IL-1

Molecular Recognition at Protein Surfaces

Ernest Giralt

Institute for Biomedical Research, Barcelona Science Park, Barcelona, Spain and Department of Organic Chemistry, University of Barcelona, Spain

Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain http://www.pcb.ub.es/giralt http://www.pcb.ub.es/giralt

Both from a basic science perspective as well as from a drug design point of view there is no doubt that proteins can be considered as privileged targets for binding of small ligands. In this context the design of ligands able to disrupt protein-protein interactions is emerging as an even more relevant issue. However, the design of protein-surface binders and, specially, the design of ligands able to bind tightly and selectively to hydrophilic protein-surface patches is a very challenging task. In our laboratory, these last years we have been trying to get some insight in the principles that govern these molecular recognition processes using peptides as models for the entire protein receptors. Protein-protein interactions are usually mediated through large areas, ca. 600 square Å, that have complementary shape and charge. So, in our opinion, medium-size peptide compounds can be very appropriate candidates to modulate this kind of interactions. Of course, before a generalized use of peptides as therapeutic agents the metabolic stability and bioavailability issues must be solved, but there are very recent and spectacular advances in this area. The general methodology that is currently used in our laboratory for the design of new peptides able to recognize protein-surface patches is based on three consecutive steps: i) peptide-ligand design; ii) solid-phase synthesis of strongly focused peptide libraries; and iii) ligand screening. We report here on the different steps involved in such an approach including virtual screening using evolutionary algorithms and exhaustive use of NMR methods.

SISOC7 Invited Lectures


IL-2

A new Stereoselective Approach to β3-Amino Acid Derivatives

Marcello Tiecco, Lorenzo Testaferri, Raffaella Terlizzi and Andrea Temperini Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica

Università di Perugia via del Liceo 1, I 06123-Perugia

e-mail: [email protected]

In recent years β3-amino acids have increased enormously their importance1 for the preparation of peptides or peptidomimetics with enhanced in vivo activity. In addition, β3-amino acids are also component of several naturally occurring and biologically active peptides isolated from microorganisms or from plants. Given the significance of β3-amino acids, it is not surprising that the development of their synthesis in optically pure form has become an important challenge for organic chemists.2 We have now developed a new process for the conversion of chiral non-racemic propargylic alcohols 1 into the corresponding N-protected β3-amino acids 5 under simple and smooth conditions.

The key steps of the whole process are the stereospecific synthesis of the N-phthalimido propargylic amines 2 from 1 and the conversion of the alkynyl phenyl selenides 3 into the Se-phenyl selenocarboxylates 4 by treatment with p-toluenesulfonic acid.3 Compounds 4 can be easily transformed into β3-amino acid derivatives 5 by treatment with hydrogen peroxide or CuCl2 hydrate. Moreover, the Se-phenyl selenocarboxylates 4 are also very selective acyl transfer agents in reactions with protected β-amino acids to afford β-oligopeptides 6. Financial support from MIUR, National Projects COFIN2005, and Consorzio CINMPIS and University of Perugia is gratefully acknowledged.

1 S. Abele, D. Seebach, Eur. J. Org. Chem. 2000, 1-15. 2 M. Liu, M. P. Sibi, Tetrahedron 2002, 58, 7991-8035. 3 M. Tiecco, L. Testaferri, A. Temperini, L. Bagnoli, F. Marini, C. Santi, R. Terlizzi, Eur. J. Org. Chem. 2004, 3447-3458.

p-TsOHCH2Cl2/ 40 °C

1 3 4R

OH

R

PhthN

SePhR

PhthN O

SePh

R

PhthN O

OH

R

PhthN O

NH

5

2R

NPhth

4

R1

6

CO2R2



IL-3

From Structure to Application of α,γ-Cyclic Peptides

Roberto Brea, Cesar Reiriz, Manuel Amorín, Mª Jesús Pérez-Alvite, Luis Castedo and Juan R. Granja

Departamento de Química Orgánica Universidad de Santiago de Compostela 15782, Santiago de Compostela, Spain

[email protected] Recently there has been an increasing interest in the use of porous materials in technological fields such as the storage of gases and liquids, energy conversion, and catalysis.1 For these applications it is desirable to be able to tailor pore sizes and pore surfaces for each specific application. A class of porous materials built of a solid-state array of self-assembled peptide nanotubes (SPNs) where we can control easily the homo- and/or heterodimerization would be of great interest.2 Self-assembly processes in which individual components associate spontaneously in a predetermined fashion have emerged as one of the most powerful “bottom-up” techniques for the preparation of functional nanostructures.3 In the last few years we have been working with a new class of self-assembling cyclic peptides based on γ-Amino acids (α,γ-CPs) and our work was initially centered on structural properties based on α,γ-CPs that only form dimers to move later to the nanotubes and its applications. In this lecture we will present our most important results in this trip towards the nanotechnological application of the nanotubes.4,5

New Materials

Sensors

Molecular electronics

Ions Channels

Antimicrobial

SPN

α,γ−CP

N

N

NN

N

N

O

O

O

O

O

ORm

R1

R2

nn

n

H

R m

R

R

H

H

RR

R

R = Me

R = H

Applications

α,γ−CP

α,γ−Dimers

1 S. Kitagawa, R. Kitaura, S.-I. Noro, Angew. Chem. Int. Ed. 2004, 43, 2334; J. Mater. Chem. 2006, 16 (7), 623-698 (special issue). 2 R. J. Brea, J. R. Granja, Self-Assembly of Cyclic Peptides in Hydrogen-Bonded Nanotubes, in Dekker Encyclopedia of Nanoscience and Nanotechnology; J. A. Schwarz, C. I. Contescu, K. Putyera, Eds.; Marcel Dekker: New York, 2004, 3439; D. T. Bong, T. D. Clark, J. R. Granja, M. R. Ghadiri, Angew. Chem. Int. Ed. 2001, 40, 988. 3 S. Zhang, Nature Biotechnology 2003, 21, 1171; For recent reviews on supramolecular chemistry and self-assembly, see the special issues of Science (2002, 295, 2395–2421) and Proc. Natl. Acad. Sci. U.S.A. (2002, 99, 4762–5188). 4 a) M. Amorín, L. Castedo, J. R. Granja, J. Am. Chem. Soc. 2003, 125, 2844; b) M. Amorín, L. Castedo, J. R. Granja, Chem. Eur. J. 2005, 11, 6539; c) R. J. Brea, L. Castedo, J. R. Granja, Chem. Commun. 2007, 31, 3267. For donor-acceptor systems based on α,γ-CP heterodimers, see: R. J. Brea, M. A. Herranz, L. Sánchez, L. Castedo, W. Seitz, D. M. Guldi, N. Martín, J. R. Granja, Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 5291; R. J. Brea, M. E. Vázquez, M. Mosquera, L. Castedo, J. R. Granja, J. Am. Chem. Soc. 2007, 129, 1653. 5 This work was supported by the Spanish Ministry of Education and Science [SAF2004-01044 and SAF2007-61015, and Consolider Ingenio 2010 (CSD2007-00006)] and Xunta de Galicia (PGIDT04BTF209006PR, GRC2006/132 and R2006/124).



IL-4

PdI2: an Efficient and Versatile Catalyst for the One-pot Synthesis of Functionalized Heterocycles

Bartolo Gabriele Dipartimento di Scienze Farmaceutiche

Università della Calabria 87036 – Arcavacata di Rende (Cosenza), Italy

[email protected], www.unical.it

During the last years, the palladium-catalyzed heterocyclization of suitably functionalized acyclic precursors has become a powerful methodology for the direct, one-step synthesis of heterocycles under mild conditions.1

In this lecture, we will show that the use of a very simple catalytic system, based on PdI2 in the presence of iodide anions, is an efficient catalyst for the selective and atom-economical synthesis of different important heterocyclic derivatives, starting from very simple building blocks.2

acyclic precursorPdI2 cat

heterocycle Examples of selective syntheses of heterocycles by a simple cycloisomerization approach as well as by carbonylative cyclization reactions will be presented.

1 a) J. J. Li, G. W. Gribble, Palladium in Heterocyclic Chemistry, Pergamon, Oxford, 2000; b) G. Zeni, R. C. Larock, Chem. Rev. 2006, 106, 4644 – 4680; c) B. Gabriele, Curr. Org. Chem. 2006, 10, 1323 – 1323. 2 a) B. Gabriele, G. Salerno, PdI2, Electronic Encyclopedia of Reagents for Organic Synthesis, Wiley-Interscience, New York, 2006; b) B. Gabriele, G. Salerno, M. Costa, Synlett 2004, 2468 – 2483; c) B. Gabriele, G. Salerno, M. Costa, G. P. Chiusoli, Curr. Org. Chem. 2004, 8, 919 – 946; d) B. Gabriele, G. Salerno, M. Costa, G. P. Chiusoli, J. Organomet. Chem. 2003, 687, 219 – 228.



IL-5

Water, an Unexpected Hydrogen Source in Free-Radical Chemistry Mediated by Titanium(III)

J. Enrique Oltra Department of Organic Chemistry

University of Granada Faculty of Sciences, Campus Fuentenueva s/n, E-18071 Granada, Spain

[email protected] , www.ugr.es/local/fqm339

The reactivity of water with both carbanion and carbocation intermediates is well known, but until now it has generally been believed that water is inert towards free radicals.1 This hypothetical passivity has been attributed to the strong H-OH bond, which, with bond-dissociation energy of 118 kcal mol-1, would impede any potential hydrogen-atom transfer from water.2

Some years ago, however, we chanced to observe that tertiary radicals were effectively reduced in the presence of [Cp2TiIIICl] and water. This observation further facilitated the control of the final step in titanocene-catalyzed radical cyclizations useful for the synthesis of polycyclic terpenoids,3 and favoured the development of novel methods in synthesis.4 However, as, at the time, the idea of water acting as a hydrogen-atom source seemed to be counterintuitive, this phenomenon was rationalized by invoking the formation and subsequent hydrolysis of alkyl-TiIV complexes. Nevertheless, we now have solid evidence to show that water really can act as a hydrogen-atom source, presumably via acua-complex 1, for radical reductions mediated by TiIII.5 This unexpected reactivity can be advantageously exploited for the synthesis of anti-Markovnikov alcohols and deuterated derivatives,5 and even for the hydrogenation of alkenes and alkynes using water as hydrogen source.6

Cp2TiCl + H2O TiCp

Cp

Cl

OH

H

RR

H+ Ti

Cp

Cp

Cl

1OH

1 a) D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of Radical Reactions, VCH, Weinheim, 1996, p 4; b) D. P. Curran in Comprehensive Organic Synthesis, Vol. 4 (Eds.: B. M. Trost, I. Fleming, M. E. Semmelhack), Pergamon, Oxford, 1991, pp. 715-777. 2 B. Ruscic, A. F. Wagner, L. B. Harding, R. L. Asher, D. Feller, D. A. Dixon, K. A. Peterson, Y. Song, X. Qian, C.-Y. Ng, J. Liu, W. Chen, D. W. Schwenke, J. Phys. Chem. A 2002, 106, 2727-2747. 3 a) J. Justicia, A. G. Campaña, B. Bazdi, R. Robles, J. M. Cuerva, J. E. Oltra, Adv. Synth. Catal. 2008, 350, 571-576; b) J. Justicia, J. L. Oller-López, A. G. Campaña, J. E. Oltra, J. M. Cuerva, E. Buñuel, D. J. Cárdenas, J. Am. Chem. Soc. 2005, 127, 14911-14921; c) J. Justicia, J. E. Oltra, J. M. Cuerva, J. Org. Chem. 2005, 70, 8265-8272; d) J. Justicia, A. Rosales, E. Buñuel, J. L. Oller-López, M. Valdivia, A. Haïdour, J. E. Oltra, A. F. Barrero, D. J. Cárdenas, J. M. Cuerva, Chem. Eur. J. 2004, 10, 1778-1788. 4 a) R. E. Estévez, M. Paradas, A. Millán, T. Jiménez, R. Robles, J. M. Cuerva, J. E. Oltra, J. Org. Chem. 2008, 73, 1616-1619; b) R. E. Estévez, J. L. Oller-López, R. Robles, C. R. Melgarejo, A. Gansäuer, J. M. Cuerva, J. E. Oltra, Org. Lett. 2006, 8, 5433-5436. 5 J. M. Cuerva, A. G. Campaña, J. Justicia, A. Rosales, J. L. Oller-López, R. Robles, D. J. Cárdenas, E. Buñuel, J. E. Oltra, Angew. Chem. Int. Ed. 2006, 45, 5522-5526. 6 A. G. Campaña, R. E. Estévez, N. Fuentes, R. Robles, J. M. Cuerva, E. Buñuel, D. Cárdenas, J. E. Oltra, Org. Lett. 2007, 9, 2195-2198.



IL-6

New Palladium-Catalyzed Routes to Substituted Indoles

Ilaria Ambrogio, Sandro Cacchi, Giancarlo Fabrizi and Alessandro Prastaro Dipartimento di Chimica e Tecnologie del Farmaco

La Sapienza Università di Roma Piazzale Aldo Moro, 5 – 00185 Roma

[email protected]

Palladium chemistry is an important tool in the assembly of the indole nucleus through cyclization reactions from benzenoid precursors. In the last years our research activity in this area has been focused on the palladium-catalyzed construction of the functionalized pyrrole ring incorporated into the indole system via cyclization of o-aryl(alkyl)ethynyl-trifluoroacetanilide derivatives.1

More recently, we developed a new, straightforward approach to this class of compounds based on the palladium chemistry of propargylic systems.2

R3

EtO2CO R2

NHCOCF3

R1 NuHPd cat

NH R3

NuR2R1

The grounds of this new strategy, the search of the best reaction conditions, the obtained preparative results, the scope and the limitations of the process will be discussed at the meeting.

1 a) For some reviews, see: G. Battistuzzi, S. Cacchi, G. Fabrizi, Eur. J. Org. Chem, 2002, 5, 2671; b) S. Cacchi, G. Fabrizi, L. M. Parisi, Heterocycles, 2002, 667; c) S. Cacchi, G. Fabrizi, Chem Rew. 2005, 105, 2873. 2 a) I. Ambrogio, S. Cacchi, G. Fabrizi, Org. Lett. 2006, 8, 2083; b) I. Ambrogio, S. Cacchi, G. Fabrizi, Tetrahedron Lett. 2007, 48, 7721.



IL-7

CH/π Interaction Responsible for an Unprecedented Chiral Discrimination

Romen Carrillo,a Andrés Feher,b Víctor S. Martína and Tomás Martína,b aInstituto de Bio-Orgánica “Antonio González”, Universidad de La Laguna, Avda.

Astrofísico Francisco Sánchez, 38206, La Laguna, Tenerife, Spain bInstituto de Productos Naturales y Agrobiología, Consejo Superior de Investigaciones Científicas, Avda. Astrofísico Francisco Sánchez, 3, 38206, La Laguna, Tenerife, Spain

[email protected]

Non-covalent interactions play an important role in many areas of modern chemistry, ranging from molecular biology to material design. One of the weakest non-covanlent interactions is the attraction between the C-H bond and the π system and is called CH/π interaction.1 This interaction contributes significantly to the overall stability of protein structures,2 selective recognition and binding affinity between protein and ligands.3 On the other hand, chiral recognition is considered one of the most important phenomena in natural living systems. Therefore, the search for simple models that contribute to the molecular understanding of these phenomena is of particular relevance. In addition, chiral cation receptors have been used in enantioselective complexation, as sensors, in selective transport, in asymmetry catalysis, etc.

Within our program directed to the search of new structural units suitable for cation recognition phenomena, we focused our attention on the 2-alkyl-3-oxy-tetrahydropyran unit as a key motive for the design of new receptors.4 Herein, we present the design and synthesis of new C2-symmetry cyclic hosts showing excellent chiral discrimination ability towards chiral ammonium salts. In addition to the steric effects and structural rigidity, it appears that the CH/π interaction may be responsible for the enantiomeric recognition.

OOH

OH

O

O

OO

O

O

C2

spacer B

spacer A

2 3

O

O

O

O

OO

N

O

O O

RO

OCH3

NH3

Up to KD/KL = 33.8

A

1 M. Nishio, M. Hirota, Y. Umezawa, The CH/π interaction. Evidence, Nature, and Consequences; Wiley-VCH, Inc.: New York, 1998. 2 M. Harigai, M. Kataoka, Y. Imamoto, J. Am. Chem. Soc. 2006, 128, 10646-10647. 3 Y. Nakagawa, K. Irie, R. C. Yanagita, O. Hajime, K. Tsuda, J. Am. Chem. Soc. 2005, 127, 5746-5747. 4 R. Carrillo, V. S. Martín and T. Martín, Tetrahedron 2005, 61, 8177-8191; R. Carrillo, V. S. Martín and T. Martín, Tetrahedron Lett. 2004, 45, 5215-5219.



IL-8

Conventional and Non Conventional Stereogenic Elements in Designing Chiral Ligands for Homogeneous Stereoselective Catalysis

Tiziana Benincori

Dipartimento di Scienze Chimiche ed Ambientali dell’Università dell’Insubria, Via Valleggio, 11 –22100 – Como, Italy

A great variety of rigid stereogenic elements (center, axis, plane, helix) have been

employed in designing the chiral phosphine and diphosphine ligands to be employed as mediators in asymmetric catalysis. Several families of electronically and sterically tunable chiral diphosphines characterized by five-membered aromatic heterocyclic scaffolds and endowed with conventional stereogenic elemente have been prepared in our lab and their metal complexes successfully applied in an ample variety of reactions. Examples of industrially applied ligands based on stereogenic axis and centers are reported below.

SMe Me

P P

Me

MeMe

Me

UlluPHOS

NMe

P

NMe

P

Ph2

Ph2

N-Me-2-BINP

S

SP

P

Me

Me

Me

Me

Ph2

Ph2

tetraMe-BITIOP

Tris-arylphosphines and phosphine oxides bearing three identical aromatic or heteroaromatic rings are generally considered operationally achiral compounds, even though it is known that the preferred arrangement of the aryl rings is described by a three-bladed propeller in which the phosphorus atom is the hub. Chemists have always accepted their configurational instability as an unavoidable event due to the very easy helix reversal, which corresponds to an enantiomerization process, and rarely contemplated the possibility of taking profit of their inherent chirality.

The research demonstrates that, on the basis of an accurate structural design, it is possible to accede to C3 symmetric tris-arylphosphines and phosphine oxides 1, which are configurationally stable even at quite high temperature.1 Rotation of the rings is fast, but helix reversal is a disfavoured process.

zP

OROR

RO

R'

R'

R'

R = Me, Et R' = H Z = O, lone pairR, R' = CH2-CH2-O1

1 T. Benincori, T. Pilati, A. Ponti, S. Rizzo, F. Sannicolo’ Angew. Chem. Int. Ed., 2006, 45, 6193-6196.



IL-9

Multifunctional Organic Radicals on Surfaces

Núria Crivillers, a Marta Mas-Torrent,

a José Vidal-Gancedo,

a Jaume Veciana,

a

Lourdes Basabe-Desmonts, b

Bar Jan Ravoo,bMercedes Crego-Calama,

b David

Reinhoudt, b

Concepció Roviraa

a) Laboratory of Molecular Nanoscience and Organic Materials, Institut de Ciència de Materials de Barcelona (CSIC), Bellaterra, Campus de la UAB E-0183, Spain

b) Laboratory of Supramolecular Chemistry and Technology MESA+ Research Institute, University of Twente, P.O. Box 217, NL-7500 AE Enschede, The Netherlands

[email protected] http://www.icmab.es/nmmo/

The ultimate goal of molecular bottom up approaches is to employ functional building

blocks to construct nanometer scale devices addressed to specific applications. Furthermore, for practical device implementation the immobilisation of functional molecules on suitable surfaces is also often required.

Here, we describe the functionalisation of silicon oxide–based surfaces,1 and Au(111) surfaces,2 via covalent and noncovalent interactions, with appropriately functionalized polychorotriphenylmethyl (PTM) radicals.

We take advantage of the chemical and thermal stability of the family of PTM radicals that permits their functionalization and manipulation.3 These radicals are colored and also exhibit fluorescence in the red region of the spectra. More interestingly, PTM radicals are electroactive and can be easily and reversibly reduced (or oxidized) to their anionic (or cationic) species.44 The oxidised and reduced states show different absorption spectra than the radical and are in addition diamagnetic and non fluorescent. Consequently, the preparation of self-assembled monolayers (SAMs) functionalised with PTM radicals (PTM SAMs) on solid substrates results in multifunctional surfaces which are electrochemically, optically and magnetically active. We demonstrate that these SAMs can be used as chemical and electrochemical redox switches with optical (absorption and fluorescence) and magnetic responses. Therefore, the properties of PTM radicals in solution have been successfully transferred to the surfaces.

In addition, the fabrication of surface patterns of these radical molecules has also been achieved using microcontact printing and visualized by fluorescence microscopy and ToF-SIMS. The chemical flexibility and versatility of these molecules sheds lights on the huge potential of preparing surface self-assembled multifunctional molecular devices

1 N. Crivillers, M. Mas-Torrent, S. Perruchas, N. Roques, J. Vidal-Gancedo, J. Veciana, C. Rovira, L. Basabe-Desmonts, B-J. Ravoo, M. Crego-Calama, D. N. Reinhoudt, Angew. Chem. Int. Ed. 2007, 46 , 2215. 2 a) N. Crivillers, M. Mas-Torrent,, J. Vidal-Gancedo, J. Veciana, C. Rovira; J. Am. Chem. Soc. 2008, 130, 5499; b) O. Shekhah, N. Roques, V. Mugnaini, C. Munuera, C. Ocal, J. Veciana, C. Woll, Langmuir 2008, 24 in press 3 M. Ballester, J. Riera, J. Castañer, C. Badia, J. M. Monso. J. Am. Chem. Soc. 1973, 93, 2215 4 C. Sporer, I. Ratera, D. Ruiz-Molina, Y. Zhao, J. Vidal-Gancedo, K. Wurst, P. Jaitner, K. Clays, A. Persoons, C. Rovira, J. Veciana, Angew. Chem. Int. Ed. 2004, 43, 5266.



IL-10

Peptide Nucleic Acids (PNAs) and Modified PNAs as Powerful Tools in Biomedical Applications

Roberto Corradini, Andrea Faccini, Tullia Tedeschi, Stefano Sforza, Rosangela Marchelli

Dipartimento di Chimica Organica e Industriale-Università di Parma Viale G.P. Usberti 17/A 43100, Parma, Italy

e-mail: [email protected]

The synthesis of molecules which selectively bind DNA or RNA is one of the major challenges in Bioorganic Chemistry, which is providing new tools for diagnostics and therapeutics. Recently, our research has focused on peptide nucleic acid (PNA) and on synthetic strategies for improving their binding properties and selectivity. In particular, the introduction of one or more functional groups, together with the study of appropriate stereochemistry, has provided very efficient tools for the recognition of DNA sequences for diagnostics involving single-base discrimination,1,2 which has been applied to the detection of genetic diseases due to point mutations, such as cystic fibrosis.3,4

PNA can also be used as agents which block gene expression by a simple steric block mechanism.1 In the last years we have synthesized antisense5 and anti-gene6,7 peptide nucleic acids (PNAs) for the selective inhibition of the MYCN oncogene expression in pediatric tumors in which it is overexpressed, such as Neuroblastoma (NB) and other pediatric tumors. A very efficient approach turned out to be the use of a 16mer anti-gene PNA, conjugated with a nuclear localisation signal (NLS) peptide and directed against the non-coding strand of DNA. Specific reduction of MYCN mRNA and protein, followed by inhibition of cell proliferation up to 90% was observed.7 In this work we will present an overview of the biological properties of this and other related PNAs, together with the detailed study by UV and CD spectroscopy and mass spectrometry on the mechanism of action of this anticancer PNA. Evidences supporting the proposed anti-gene mechanism will also be presented.

Novel strategies for improving the efficiency of these potential drugs in terms of stability, cellular uptake, affinity and selectivity (backbone and base modifications) will also be discussed.

1 R. Corradini, S. Sforza, T. Tedeschi, F. Totsingan, R. Marchelli, R. Curr. Top. Med. Chem. 2007, 7, 681-694. 2 V. Menchise, G. De Simone, T. Tedeschi, R. Corradini, S. Sforza, R. Marchelli, D. Capasso, M. Saviano, C. Pedone, Proc Natl Acad Sci USA 2003, 100, 12021-12026. 3 R. Corradini, G. Feriotto, S. Sforza, R. Marchelli, R. Gambari, R. J. Mol. Rec. 2004, 17, 76-84. 4 M. Chiari, G. Galaverna, S. Sforza, M. Cretich, R. Corradini, R. Marchelli Electrophoresis 2005, 26, 4310–4316. 5 A. Pession, R. Tonelli, R. Fronza, E. Sciamanna, R. Corradini, S. Sforza, T. Tedeschi, R. Marchelli, L. Montanaro, C. Camerin, M. Franzoni, G. Paolucci, Int J Oncol. 2004, 24, 265-72 6 A. Pession, R. Tonelli, R. Fronza, S. Sforza, R. Marchelli, R. Corradini, PCT/IB2004/001297, 29-04-2004 7 R. Tonelli, R. Fronza, S. Purgato, C. Camerin, F. Bologna, S. Alberesi, M. Franzoni, R. Corradini, S. Sforza, A. Faccini, J. M. Shohet, R. Marchelli, A. Pession, Molecular Cancer Therapeutics, 2005, 4, 779-86.



IL-11

From Peptides to Small Molecules: The Design and Synthesis of Efficacious BACE Inhibitors

Francisco Javier Agejas,a David Bender,b Leonard N. Boggs,b Richard A. Brier,b Howard Broughton,a Ana Belén Bueno,a Michael P. Clay,b Cynthia L. Cwi,b Robert Dally,b Timothy B. Durham,b Jon A. Erickson,b Juan F. Espinosa,a Patric J. Hahn,b Jingdan Hu,b Debra K. Laigle,b Terry Lindstrom,b Chin Liu,b Alicia Marcos,a Patrick C. May,b James McCarthy,b José Miguel Mínguez,a Gema Ruano,a Gema Sanz,a Timothy Shepherd,b David Timm,b Paloma Vidal,a Juan Ramón Rodríguez,a Todd Kohn,b Hsiu-Chiung Yang, b and Rosario González.a

a Centro de Investigación Lilly, S.A. Avda. de la Industria, 30. 28108-Alcobendas. Madrid,

Spain. b Eli Lilly & Company, Lilly Research Laboratories, Lilly Corporate Center,

Indianapolis, IN 46285, USA

Email: [email protected] Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by a progressive loss of cognitive function, which affects almost 10% of the population over age 65, and 40% of the population over 85.1 In the search for a disease-modifying therapy, much interest has been focused on the amyloid cascade hypothesis. This hypothesis states that Aβ, a proteolytic derivative of the large transmembrane protein, amyloid precursor protein (APP), plays a crucial role in the clinical progression of AD.2 Since the discovery of BACE in 1999, the aspartic protease that generates the N-terminus of Aβ, there has been significant interest in the development of inhibitors of this enzyme.3 In this lecture, the design and synthesis of efficacious BACE inhibitors will be presented.

1 a) C. M. Clark, J. H. T. Karlawish, Annals of Internal Medicine 2003, 138, 400; b) B. V. Zlokovic, Adv. Drug Del. Rev. 2002, 54, 1533. 2 a) T. E. Golde, J. Clinical Invest. 2003, 111, 11; b) M. S. Wolfe, M. S. J. Med. Chem. 2001, 44, 2039. 3 a) T. B. Durham, T. A. Shepherd, Curr. Opin. Drug Discov. Devel. 2006, 9, 776; b) T. Guo, D. W. Hobbs, Curr. Med. Chem. 2006, 13, 1811; c) L. A. Thompson, J. J. Bronson, F. C. Zusi, Curr. Pharm. Design, 2005, 11, 3383; d) J. N. Cumming, U. Iserloh, M. Kennedy, M. Curr. Opin. Drug Discov. Devel. 2004, 7, 536; e) M. Citron, Trends Pharmacol. Sci. 2004, 25, 92; f) V. John, J. P. Beck, M. J. Bienkowski, S. Sinha, R. L. Heinrikson, R. L. J. Med. Chem. 2003, 46, 4625; g) R. Vassar, Adv. Drug. Del. Rev. 2002, 54, 1589; h) A. K. Ghosh, L. Hong, J. Tang, J. Curr. Med. Chem. 2002, 9, 1135.



IL-12

Cyclotetrapeptide Analogues Based on a 13-Membered, Partially Modified Retro-Inverso Structure. Applications to the synthesis of Cancer Cell

Adhesion Inhibitors.

Luca Gentilucci,*a Giuliana Cardillo, a Santi Spampinatob Alessandra Tolomelli,a Federico Squassabia,a Rossella De Marco,a Monica Baiulab

a Department of Chemistry “G. Ciamician”, Università degli Studi di Bologna, via Selmi 2, 40126 Bologna, Italy; b Dept. Of Pharmacology, Università degli Studi di Bologna, via

Irnerio 48, 40126 Bologna, Italy * e-mail: [email protected]; phone: +39 0512099462; fax: +39 0512099456

In recent years, we have been interested in cyclic peptides (CP) as restricted mimics of biologically active, naturally occurring peptides, and in particular, we pursued the synthesis of small, conformationally defined CPs or analogues that mimic β- or γ-turns.

Among the different members of the CP family, cyclotetrapeptides (CTP) are considered the smallest system which can reproduce all kinds of turns, but their potential utility is often diminished by difficult synthesis and poor conformational stability.

To overcame these limitations, we designed a novel family of CTP analogues, based on a 13-membered partially modified retro-inverso (PMRI) structure, built by introduction of a diamine (a β-amino acid mimetic) and a diacid, in different positions. The PMRI-CTPs give rise to a higher degree of chemical and spatial diversity respect to normal CTP, and can be utilized as scaffolds for applications in medicinal chemistry.

Figure. Schematic representation of the presumed disposition of 4 (white) and 5 (black) within α5β1 (black) and αvβ3 (grey) integrin binding site sketches. Unfavourable interactions are also shown. The PMRI-CTPs have been utilized to prepare a small library of RGD-mimetic compounds as αvβ3 and/or α5β1 integrin antagonists. In particular, compound 5 displayed a good activity in inhibiting the adhesion of fibronectin to αvβ3-integrin expressing human malignant melanoma cells, as well as to α5β1-integrin expressing human erythroleukemic cells. The diastereomeric compound 4 maintained a good efficacy in inhibiting the adhesion to α5β1-integrin expressing cells, while gaining a certain selectivity over αvβ3. The conformational analysis performed by 2D-ROESY and Molecular Dynamics revealed that the different pharmacological profile can be rationalized on the basis of the alternative display of the aromatic side-chain flanking Asp.



IL-13

Some New Catalytic Methodologies in Organic Synthesis. Oxo-transfer and Hydroxy-Substitution Reactions

Roberto Sanz Área de Química Orgánica. Departamento de Química. Facultad de Ciencias

Universidad de Burgos Pza. Misael Bañuelos s/n. 09001-Burgos. Spain

[email protected]; http://web.ubu.es/investig/grupos/cien_biotec/qo-3/index.html Catalysis plays a vital role in the synthesis of fine chemicals, and pharmaceuticals as well as providing the means for the development of greener processes. Both metal-based catalysis and organocatalysis are very important research fields in modern organic synthesis. Due to their relevance in biological processes, molybdenum-catalyzed oxygen-atom-transfer (OAT) reactions have attracted considerable interest. The OAT reactivity of dioxomolybdenum(VI) complexes, with the cis-[MoO2]2+ core that mimic oxotransferases, is by far the most characteristic behaviour pattern of these complexes, and our main contributions in this area will be presented (Scheme 1).

MoVIO2X2(L)2

Mo2VO3X4(L)4

MoIVOX2(L)2

PR3

O PR3SO

S

Scheme 1

The construction of C−C bonds is a fundamental process in organic synthesis and coupling reactions between reactive nucleophiles (NuM) and halides (RX) or related species are one of the most used strategies to achieve this end. However, the direct substitution of the hydroxy group in alcohols by nucleophiles could be considered as an ideal process because of the wide availability of the starting materials and the generation of H2O as the only side product. Until recent years, the main limitation of this strategy is that an excess of a Brønsted acid, or a stoichiometric amount of a Lewis acid were required, and so the range of possible nucleophiles is limited. Therefore, the development of catalytic versions of this reaction remains a major objective (Scheme 2). Although recent advances in this field are based on the use of transition metal complexes and different Lewis acids as catalysts, we have discovered that simple Brønsted acids are also efficient catalysts for this reaction. This metal-free methodology represents an enviromentally friendly, synthetically competitive, and cheap alternative to the established use of metal complexes. Our recent investigations in this field will be shown.

Nu M + R X Nu R + M Xgeneralreaction

Nu H + R OH Nu R +ideal reaction

¿catalyst? H2O

product salt

Scheme 2



IL-14

Nitrobutadienes in Synthesis and Pharmacology

Giovanni Petrillo Dipartimento di Chimica e Chimica Industriale

Università di Genova Via Dodecaneso 31, I-16146 Genova

[email protected]

The versatile reactivity of the thiophene nucleus encompasses ring-opening processes triggered by the treatment of electron-poor derivatives with primary or secondary amines. Thus, nitrothiophenes 1-3 have proven to be the precursors of extremely appealing conjugated butadienes such as 4-6, respectively, although the overall picture is characterized by different reaction conditions and/or final outcomes.1

S NO2

1

R2NH, EtOH

(AgNO3)

R'Alg

R2N

NO2

SR'

4

S3

R2NH, EtOH

NO2O2N

R2N

6

NO2NR2

O2N

S2

AgNO3

R'Alg

XO2N

R2N

5

NO2SR'

X Y

R2NH, EtOH

Y

r.t.0 °Cr.t.

Compounds 4-6 actually represent a pool of polyfunctionalized molecules (containing e.g. nitroenamino, nitrovinyl, ketene dithioacetal groups) amenable to a number of applications both in organic synthesis and in pharmacology. An overview, together with some recent results in these fields will be presented.

1 a) L. Bianchi, L.; M. Maccagno, G. Petrillo, E. Rizzato, F. Sancassan, E. Severi, D. Spinelli, C. Tavani, M. Viale, Targets in Heterocyclic Systems: Chemistry and Properties 2007, 11, 1–20; b) L. Bianchi, M. Maccagno, G. Petrillo, F. Sancassan, D. Spinelli, C. Tavani, Targets in Heterocyclic Systems: Chemistry and Properties 2006, 10, 1–23. c) L. Bianchi, C. Dell’Erba, M. Maccagno, S. Morganti, G. Petrillo, E. Rizzato, F. Sancassan, E. Severi, D. Spinelli, C. Tavani, Arkivoc 2006, vii, 169-185. d) C. Dell'Erba, M. Novi, G. Petrillo, C. Tavani, Topics in Heterocyclic Systems: Synthesis, Reactions and Properties, 1996, 1, 1–12.



IL-15

Catalytic Enantioselective Transformations of Nitrocompounds

Mikel Oiarbide Departamento de Química Orgánica I

Universidad del País Vasco C/ Manuel Lardizabal 3, 20018 Donostia-San Sebastián

[email protected]

Three distinguished features of the nitro functional group (–NO2) are: (1) its strong electron withdrawing character, (2) its ability for coordination to Lewis acids and hydrogen donors, and (3) the wide range of transformations applicable to the C–NO2 moiety. These characteristics make nitrocompounds very attractive substrates for catalytic transformations.

In the context of the development of efficient, catalytic asymmetric methodologies carried out in our laboratories, we have worked out some new procedures that deal with nitrocompounds as the substrate materials. Thus an array of enantioselective C–C bond forming processes involving as reaction components either nitroalkenes, as Michael acceptors, or nitroalkanes, as (pro)nucleophiles, have been studied under catalytic conditions.1 Material for this talk has been selected as to cover distinct asymmetric catalysis strategies applied to these nitrocompounds: use of advanced achiral templates; chiral metal complexes as catalysts; chiral organocatalysts. Particular attention, based on experimental and computational studies, will be paid to the role played by the nitro group in these developments. Finally, some applications to the synthesis of relevant target molecules will be illustrated.

RNO2

O2N R

reactants / cat* RelevantTargets

EnantiomericallyPureNitro-Adducts

1 a) Angew. Chem. Int. Ed. 2005, 44, 3881-3884; b) Angew. Chem. Int. Ed. 2006, 45, 117-120; c) Adv. Synth. Catal 2006, 348, 1161-1164; d) Angew. Chem. Int. Ed. 2007, 46, 8431-8435; e) J. Am. Chem. Soc., in print.



IL-16

Uranyl-Salophen Complexes as Receptors and Supramolecular Catalysts

Antonella Dalla Cort Dipartimento di Chimica and IMC-CNR

Università La Sapienza, P.le A. Moro 5, 00185 Roma, Italy [email protected], http://www.chem.uniroma1.it/

Salophens are diimino tetradentate Schiff bases derived from the condensation of 1,2-phenylenediamine, or of its derivatives, with two equivalents of salicylaldehyde. They are one of the oldest and most popular class of ligands in coordination chemistry because of their versatility and easy synthetic availability.1 Among the metals that form strong complexes with these ligands there is the hexavalent uranyl ion, UO2

+2. This cation has a well known preference for pentagonal bipyramidal coordination, with the two oxygens in the apical positions. After accommodation of the four donor groups of the salophen ligand, a fifth equatorial site is still available to coordinate an additional group, see 1, such as anions or neutral molecules endowed with a donor site.2 This is one of the reasons why such electrically neutral receptors have found several applications in different fields. Here we will report about our most recent findings concerning their use as receptors for anions,3 ion pairs, 4, ketones and enones,5 and also as supramolecular catalysts for the conjugate addition of benzenethiol to cyclic enones,6 and for the Diels-Alder reaction.7 We will also present briefly how we established that nonsymmetrically substituted uranyl salophen complexes, 2-3, are inherently chiral and exist as a pair of enantiomers, thus providing new appealing opportunities for their applications.8

N N

O OUO2

GR'

1 2 3

R

N N

O OUO2

N N

O OUO2

O O

1 P. A. Vigato, S. Tamburini Coord. Chem. Rev., 2004, 248, 1717-2128. 2 G. Bandoli, D. A. Clemente J. Chem. Soc., Dalton Trans., 1975, 7, 612 3 M. Cametti, A. Dalla Cort, L. Mandolini, M. Nissinen, K. Rissanen New J. Chem, 2008, in press. 4 M. Cametti, M. Nissinen, A. Dalla Cort, L. Mandolini, Kari Rissanen J. Am Chem. Soc., 2007, 3641-3648. 5 V. van Axel Castelli, A. Dalla Cort, L. Mandolini, V. Pinto, D. N. Reinhoudt, F. Ribaudo, C. Sanna, L. Schiaffino, B. H. M. Snellink-Ruël Supramolecular Chem., 2002, 14, 211-219. 6 V. van Axel Castelli, A. Dalla Cort, L. Mandolini, V. Pinto, L. Schiaffino J. Org. Chem., 2007, 72, 5383-5386. 7 A. Dalla Cort, L. Mandolini, L. Schiaffino Chem. Commun., 2005, 3867-3869. 8 A. Dalla Cort, C. Pasquini, L. Schiaffino Supramolecular Chem., 2007, 19, 79-87.



IL-17

Molecular Recognition of Carbohydrates

F. Javier Cañada Department of Protein Science

Centro de Investigaciones Biológicas(CIB-CSIC) Ramiro de Maeztu 9, 28040 Madrid Spain

[email protected] Carbohydrates have been relegated to structural and metabolic roles, however nowadays it is becoming evident that carbohydrates play a central role in multitude of biological recognition processes at different stages, from atomic to organism and species level. Carbohydrates have huge possibilities to form different oligo- and polymeric structures compared to other biomolecules. This diversity, together with the particular geometrical properties of glycosidic bonds, confers to carbohydrates an enormous potential as selective and discriminating components in important molecular recognition processes. The polyhydroxylated nature of carbohydrates allows them to establish a network of hydrogen bonds with their receptor. However other types of interactions are essential in modulating the affinity and selectivity of carbohydrate recognition. The recurrent presence of aromatic aminoacids in the carbohydrate-binding sites of proteins highlights the importance of carbohydrate–aromatic stacking geometries with CH-Pi favourable interactions.

In our research group we are involved in the characterization, by NMR and other techniques, of the structural and thermodynamic parameters of binding of carbohydrates by glycosidases and lectins. In this context of these molecular recognition processes, we have confirmed the importance of the CH-Pi interactions between pyranose rings of carbohydrates and aromatic side chains of aminoacids.1

Acknowledgements: Financial support from “Ministerio de Ciencia e Innovación” (BQU2006-10874-C02-01), European Union and “Comunidad de Madrid”.

1 a) M. C. Fernandez-Alonso, F. J. Cañada, J. Jimenez-Barbero, G. Cuevas, J. Am. Chem. Soc. 2005, 127, 7379. b) M. I. Chavez, C. Andreu, P. Vidal, N. Aboitiz, F. Freire, P. Groves, J. L. Asensio, G. Asensio, M. Muraki, F. J. Cañada, J. Jimenez-Barbero, Chem. Eur. J 2005, 11, 7060. c) S. Vandenbussche, D. Diaz, M. C. Fernandez-Alonso, W. Pan, S. P. Vincent, G. Cuevas, F. J. Cañada, J. Jimenez-Barbero, K. Bartik, Chem. Eur. J, 2008.

Chitin binding protein PDB: 1T0W

Glucosidase PDB: 1E4I



IL-18

Structure Determination of Complex Molecules via NMR: Theory and Application

Giuseppe Bifulco Dipartimento di Scienze Farmaceutiche, Università di Salerno

Via Ponte Don Melillo, 84084 Fisciano (SA) ITALY [email protected] , http://www.unisa.it/Facolta/Farmacia/bifulco.php

The recent progress in both the field of NMR and of the quantum chemistry have contributed to a great acceleration in the structural determination of complex organic molecules. Indeed, the NMR techniques have had an exponential development in the last two decades, and their applications have been extended to the study of biopolymers such as proteins or nucleic acids. In analogy, the enormous increase of the computer performances in the last ten years has allowed the conformational studies of molecules with always increasing dimension by means of molecular mechanics and dynamics calculations using empirical force fields. Also, very recently, the substantial potentialities offered even from the common personal computers has made possible the use of ab initio methods in the optimizations of the geometries of medium and high molecular weight, a task which was unconceivable until few years ago. In these circumstances, our research group has shown its interest in the structural study of organic compounds, with particular regard to the natural products and to the determination of their relative configuration. An NMR J-coupling approach, based on the 1H-1H and 1H-13C spin spin coupling constants, and its variations proposed by our group, has been used to accomplish the knowledge of the relative configuration of several compounds of natural origin showing diverse biological and/or pharmacological activity.1 Moreover, NMR chemical shift calculation by quantum mechanical methods, a field which has attracted the interest not only of the theoretical chemists, but also of the experimental NMR spectroscopists, has been investigated by our group of research in order to assess its possible contribution to the structure elucidation of natural products. Indeed, we have recently presented two original methodologies: the first one is based on GIAO (gauge including atomic orbitals) quantum-mechanical 13C chemical shift calculations, that may be efficiently employed as a support in the analysis of the NMR data of organic molecules, and the second one concerns the quantum chemical calculation of J-couplings in the determination of the stereostructure of complex molecules.1

NH

NMe

NH

HNNH

HN

NH

O

MeN OO

OO

OO

O

O

O

NH

HN

NH

H2NO

O

OH

NH2O

OH

OH

MeO

OH

NH2

O

NH

NH2

NH

OHNH AGDHE

D-aThr1

D-aThr2

β−OMeTyr

Revised Structure of Callipeltin A

1 G. Bifulco, P. Dambruoso, L. Gomez-Paloma, R. Riccio Chem. Rev. 2007, 107, 3744-3779.



IL-19

Liquid Crystals Based on Novel V-Shaped Structures José Luis Serrano, Joaquín Barberá, Emma Cavero, Raquel Giménez, Nélida Gimeno, Ana Pérez, Pilar Romero, M. Blanca Ros, Teresa Sierra, Rosa Tejedor, Francisco Vera

Dept. Química Orgánica - Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza – CSIC, 50009 Zaragoza, SPAIN, e-mail: [email protected]

V-shaped structures allow the appearance of a rich phenomenology in the field of liquid crystals as consequence of their molecular shape and polarity. Here we show several approaches, which have been followed in our group towards the design of novel liquid crystals. In all of them, the V-shaped moiety is responsible for their supramolecular organizations, leading to new soft materials. In a first place, H-bond has been studied as a tool to obtain novel banana-shaped liquid crystals. A versatile and straightforward approach to the design and development of structure-activity investigations into bent-core liquid crystals has been carried out. Through a broad selection of carboxylic acids linked to H-acceptors using H-bonds, structural modifications concerning length, chirality or the introduction of a bulky group have been carried out.1

Moreover, comparisons with analogue covalent compounds highlight the usefulness of this approach. Secondly, the V-shaped units have been used for endowing columnar liquid crystals with special functions. Well-organized helical structures have been obtained, as the expression of supramolecular chirality, which can be controlled and switched by molecular as well as external chiral factors. Chiral columnar mesophases are attained from H-bonded tetrameric complexes of a melamine derivative and non-mesomorphic V-shaped acids. This unusual mesogenic core, interpreted as a propeller-like structure, promotes the appearance of columnar mesomorphism.2 Chiral information of Circularly Polarized Light (CPL) is transferred to the Columnar Organization through photoaddressable azobenzene groups. This process enables switching of the supramolecular chirality of the columnar arrangement in a reversible manner. Furthermore, achiral columnar systems can be biased towards a chiral supramolecular organization upon illumination with the corresponding CPL. Thirdly, liquid crystalline compounds with a “two-point bend” in their central part have been prepared as an innovative approach to the described “in-plane angle” of bent-core liquid crystals. The molecules posses a pyrazabole ring at the core, substituted with rod-like moieties of different length. Nematic and intercalated lamellar mesophases have been observed, including a novel transition from a tilted to a non-tilted lamellar mesophase. The nematic mesophase exhibits interesting electrooptic behavior.3 Acknowledgment. This work was supported by the project MAT2006-13571-C02 (CICYT-FEDER) from Spain-EU, the “Ramón y Cajal” program and by the Gobierno de Aragón (Spain).

1 a) N. Gimeno, M. B. Ros, J. L. Serrano, M. R. de la Fuente, Angew. Chem. Int. Ed. 2004, 43, 5235; b) J. Barberá, N. Gimeno, I. Pintre, M. B. Ros, J. L. Serrano, Chem. Commun. 2006, 1212. 2 a) J. Barberá, L. Puig, P. Romero, J. L. Serrano, T. Sierra, J. Am. Chem. Soc. 2006, 128, 4487; b) F. Vera, R. M. Tejedor, P. Romero, J. Barberá, M. B. Ros, J. L. Serrano, T. Sierra, Angew. Chem. Int. Ed. 2007, 46, 1873. 3 a) E. Cavero, D. P. Lydon, S. Uriel, R. M. de la Fuente, J. L. Serrano, R. Giménez, Angew. Chem. Int. Ed. 2007, 46, 5175; b) E. Cavero, R. M. de la Fuente, E. Beltrán, P. Romero, J. L. Serrano, R. Giménez, Chem. Mater. 2007, 19, 6230.



IL-20

Two-Decade Study on Toxic Outbreaks in the Mediterranean Sea

Patrizia Ciminiello and Ernesto Fattorusso Dipartimento di Chimica delle Sostanze Naturali- University of Naples “Federico II”,

Via D. Montesano, 49 – 80131 Napoli, ITALY 0039 081 678507 - [email protected]

Across the Mediterranean basin, toxic outbreaks due to harmful algal blooms have been spreading with an ever increasing incidence over the past decades. Such toxic events have been particularly monitored and studied across the Northern Adriatic Sea, where mollusk consumers have experienced recurring sanitary problems, and shellfish farmers suffered heavy economic losses. Our study, carried out over the past 20 years, has afforded significant insights into the problem of marine biotoxins infesting the Adriatic Sea, that shows a pretty unique, complex, and continuously changing toxin profile.1 In the late ‘80s we afforded the first experimental evidence over the occurrence of a marine biotoxin in the Adriatic Sea, by isolating and characterizing okadaic acid (OA). Since then through the mid ‘90s, OA and some of its analogues have been the main Adriatic marine biotoxins. From 1995 on yessotoxin (YTX) and its analogues have played a dominant role in Adriatic mussel poisoning, while OA has slowly subsided until virtually disappearing around the turn of the new millennium. A number of new YTX analogues have been isolated from Adriatic mussels and chemically characterized by our research group.1 In particular, around the beginning of the 3rd millennium, desulfocarboxyYTXs have proven the most abundant toxic compounds detected in Adriatic mollusks.2 Because of the strong difference in harmfulness between OA (a potent tumor promoter) and YTXs (with no significant oral toxicity), the EU set up a new protocol for separating these toxins in two distinct layers. However, detection of the new desulfocarboxyYTXs, co-extracted in the same layer as OA, requires an urgent revision of the official protocol. In addition, over the last years spirolides have become the main Adriatic toxins posing serious health risks to seafood consumers. To make the picture even more complex, also domoic acid has recently entered the Adriatic toxin profile. Even though detected so far at concentrations lying below its regulatory limit, this latter toxin must be attentively monitored as it could any time be rising at alarming levels. Besides all of the above hazards, over the past years another most dangerous threat has been impending over the Mediterranean Sea: the spreading of the tropical alga O. ovata, responsible of a human intoxication characterized by respiratory distress and conjunctivitis. Our investigation on Mediterranean O. ovata has brought to light the presence of a new palytoxin-like compound, we named ovatoxin-a, alongside minor amounts of a putative palytoxin;3,1 both toxins can be considered responsible for human intoxications.

1 P. Ciminiello and E. Fattorusso, In Progress in Molecular and Subcellular Biology - Subseries Marine Molecular Biotechnology, G. Cimino, M. Gavagnin (Eds.): Molluscs, Springer-Verlag Berlin, Heidelberg, 2006, 53-82. 2 P. Ciminiello, C. Dell’Aversano, E. Fattorusso, M. Forino, L. Grauso, S. G. Magno, R. Poletti, L. Tartaglione, Chem. Res. Toxicol. 2007, 20, 95-98. 3 P. Ciminiello, C. Dell’Aversano, E. Fattorusso, M. Forino, L. Tartaglione, C. Grillo, and N. Melchiorre, J. Am. Soc. Mass Spectrom., 2008, 19, 111–120.



IL-21

Stereoselective Synthesis of Broussonetines

J. Alberto Marco,a Celia Ribes-Vidal,b Eva Falomir,b Miguel Carda,b Juan Murgab

aDepart. de Quím. Orgánica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain; bDepart. de Quím. Inorgánica y Orgánica, Univ. Jaume I, E-12080 Castellón, Spain

The broussonetines constitute a group of polyhydroxylated lipophilic alkaloids isolated in recent years by Kusano et al. from species of the genus Broussonetia (Moraceae).2

Compounds of this group have been found to exhibit inhibitory activity on several glycosidases and related glycoenzymes. The frequent association of this type of biological property with useful pharmacological applications has led to the development of an ample synthetic effort for members of this compound class.

N

HO OH

HO

HBroussonetines C-I, K-M, O, P, R-T, W

(general structure)

1 13

various funct ions

OHO

OH

OH

OH

O

C

D

M

P

OH

O

Among all reported broussonetines (ca. 30),1 about the half have the general structure depicted above. Only broussonetines C and G have yielded until now to total syntheses.32 Our own synthesis of members of this compound class, represented below, provides broussonetines C, D, M and P in a convergent way from Garner´s aldehyde 1 as the chiral starting material. Compound 1 was first converted into oxazolidinone 2, which represents a branching point for the synthesis of broussonetines having the aforementioned general structure. Cross metathesis of 2 (Grubbs second-generation ruthenium catalyst) with the appropriate side-chain fragments, represented below as terminal olefins RCH=CH2, provided compounds 3 having the complete carbon framework of the target compounds. Application of suitable deprotection prot4ocols finally afforded the desired broussonetines (R´ = side chain).

O HNBoc

O

1

8 steps

NH

OHHO

R´OH

2

N

OBnBnO

OO

R

Grubbs II

3

N

OBnBnO

OO Broussonetines

R

1 P. Ciminiello, C. Dell’Aversano, E. Fattorusso, M. Forino, G. S. Magno, L. Tartaglione, C. Grillo, N. Melchiorre, Analytical Chemistry 2006, 78, 6153-6159. 2 a) M. Shibano, D. Tsukamoto, G. Kusano, G., Heterocycles 2002, 57, 1539. b) D. Lee, A. D. Kinghorn, in Studies in Natural Products Chemistry (Atta-ur-Rahman, Ed.), Elsevier Science, 2003, vol. 28, pp. 3-33. 3 a) H. Yoda, T. Shimojo, K. Takabe, K., Tetrahedron Lett. 1999, 40, 1335; b) P. Perlmutter, F. Vounatsos, J. Carbohydr. Chem. 2003, 22, 719. c) B. M. Trost, D. B. Horne, M. J. Woltering, Chem. Eur. J. 2006, 12, 6607.



IL-22

Sulfenic Acids as Intermediates in the Synthesis of “Biorelevant” Products

Maria Chiara Aversa Dipartimento di Chimica organica e biologica

Università degli Studi di Messina Salita Sperone 31 (vill. S. Agata), 98166 Messina, Italy

[email protected] The generation of transient sulfenic acids from suitable precursors in the presence of double or triple carbon-carbon bonds allows the easy introduction into the unsaturated substrates of a sulfoxide group by means of a syn-addition. It represents also a source of relevant chemical and stereochemical peculiarities that are produced in the acceptors. First of all, the formation of a C-S bond has a synthetic relevance from a biological point of view if one considers its similarity/diversity with respect to a C-O bond and its presence in many naturally occurring compounds. The sulfoxide moiety can be easily manipulated to give derivatives having different sulphur oxidation states. It also introduces chirality into the molecule, and its optical stability up to 300°C guarantees useful properties in biological investigations. Moreover, the sulfenic acid / double bond syn-addition is a stereospecific reaction that allows the complete stereocontrol of the configuration of the newly formed stereogenic carbons. This lecture will focus on the main features of the syn-addition of transient and, in some cases, enantiomerically pure sulfenic acids to double or triple bonds, and the use of this reaction for introducing “bio-relevant” residues such as carbohydrate or amino acid moieties into unsaturated skeletons as key-step in the synthesis of uncommon sulfoxides (scheme).1

OO

SO

OAc

AcOAcO OAc Spacer S

OO O

AcOOAc

OAcOAc

sulfenic acids

OO

S

OAc

AcOAcO OAc AcO O OAc

OAc

AcO

O2

NPh

O

OMeO

Sisoborneol

O

CO2Me

CO2Me

OOAc

AcOAcO AcO

SO

MeO2CS

R1

R2

BocNH O

1 a) M. C. Aversa, A. Barattucci, P. Bonaccorsi, G. Bruno, F. Caruso, P. Giannetto, Tetrahedron: Asymmetry 2001, 12, 2901-2908; b) V. Aucagne, M. C. Aversa, A. Barattucci, P. Bonaccorsi, P. Giannetto, P. Rollin, A. Tatibouët, J. Org. Chem. 2002, 67, 6925-6930. c) M. C. Aversa, A. Barattucci, P. Bonaccorsi, P. Giannetto, J. Org. Chem. 2005, 70, 1986-1992. d) M. C. Aversa, A. Barattucci, M. C. Bilardo, P. Bonaccorsi, P. Giannetto, P. Rollin, A. Tatibouët, J. Org. Chem. 2005, 70, 7389-7396. e) M. C. Aversa, A. Barattucci, P. Bonaccorsi, P. Giannetto, Curr. Org. Chem. 2007, 11, 1034-1052.



IL-23

Coordinating Sulfonyl Substrates in Metal-Catalyzed Reactions

Juan Carlos Carretero Departamento de Química Orgánica

Facultad de Ciencias. Universidad Autónoma de Madrid. 28049 Madrid [email protected]; http://www.uam.es/catalisisasimetrica

The development of truly efficient catalytic processes for an ever broadening range of organic reactions continues to be a major goal in current organic synthesis. An useful strategy to control the stereoselectivity of Lewis acid-catalyzed reactions is the use of substrates containing two binding sites for its coordination with the transition metal, which provide well ordered intermediates very suitable for inducing asymmetric induction by chiral Lewis-acids.1

In the last few years our group has been engaged in the development of novel metal-mediated catalyzed processes based on the use of substrates having a coordinating sulfonyl moiety as the key controlling group of the process. For instance, the 2-pyridylsulfonyl and the quinolylsulfonyl groups have been found to provide exceptional levels of reactivity (and/or stereoselectivity) in a variety of transformations, compared to related substrates bearing the classical tosyl group. As examples of the potential of these coordinating sulfonyl groups in metal-catalyzed reactions, in this lecture we will present our recent results on the Rh-catalyzed asymmetric addition of boronic acids and Cu-catalyzed asymmetric reduction of α,β-unsaturated 2-pyridyl sulfones,2 the Cu-catalyzed addition of organozinc reagents and Friedel-Crafts reaction of N-(2-pyridyl)sulfonyl imines,3 and the Ni-catalyzed asymmetric aza Diels-Alder reaction of N-quinolylsulfonyl vinyl imines4 (see scheme).

R3-B(OH)2

Aza Friedel-Crafts reaction

R1 Rh(acac)C2H4Chiraphos

R1 SO2Py

R2

ee = 80-99%

Alkylation of imines with alkylzinc halides

Ar1 H

NS

O O

N

Ar2-HCu(OTf)2

-

(10 mol%) Ar1 Ar2

NHSO2PyAr3-H

Ar1 Ar2

Ar3

Binap

Cu(OTf)2

R2 R3

+OR Ni(ClO4)2·6H2OR1

R2

NS

OO

N

N

SO2(8-Quin)

OR

R2

R1

DBFOX-Ph

ee = 84-92%

Ar H

NS

O O

N

Cu(OTf)2 Ar R

NHSO2PyR-ZnBr

Asymmetric Aza Diels-Alder reactionAsymmetric conjugate addition to vinyl sulfones

S OO

NPhSiH3

CuI-Binapee = 90->99%

R1 SO2Py

R2H

1 Catalytic Asymmetric Synthesis, 2nd Ed.; I. Ojima, Ed.; VCH, New York, 2000. 2 P. Mauleón, I. Alonso, M. Rodríguez Rivero, J. C. Carretero, J. Org. Chem. 2007, 72, 9924. T. Llamas, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2007, 46, 3329. 3 J. Esquivias, R. Gómez Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2006, 45, 626 and 2007, 46, 9257. 4 J. Esquivias, R. Gómez Arrayás, J. C. Carretero, J. Am. Chem. Soc. 2007, 129, 1480.



IL-24

New Ferrocenyl Ligands for Stereoselective Reactions

Pier Giorgio Cozzi,* Montse Guiteras Capdev-a, Antonio Zanotti-Gerosa, and Luca Zoli Dipartimento di Chimica “G. Ciamician”, Institution

Via Selmi 2, 40126 Bologna, [email protected]: www.chimica.unibo.it

In the 2005, the ACS Green Chemistry Institute and the global pharmaceutical corporations developed the ACS GCI Pharmaceutical Roundtable to encourage the integration of green chemistry into Pharmaceutical industry. The substitution of activated alcohols is a frequently used approach for the production of active pharmaceutical ingredients. The OH activation for nucleophilic substitution is consider a central issue. Unfortunately, hydroxide ion is a poor leaving group usually requiring activation. Direct activation of benzylic and allylic alcohols may be achieved via SN1 reaction. Recently, a number of interesting catalytic activation of allylic and benzylic alcohols has been demonstrated by the use of a Brønsted acid (4-toluensolfonic acid) or by Lewis acids such as InBr3, In(OTf)3, Bi(OTf)3, FeCl3, and many others. Using chiral ferrocene alcohols as starting materials we have prepared several new ferrocenyl derivatives,11 building blocks for the preparation of electron active materials and new chiral ligands. In addition, we have recently described a direct nucleophilic substitution of ferrocenyl alcohols “on water”,2,33 without the addition of additive, co-solvents, surfactants, Lewis or Brønsted acids. The concept of reaction “on water” was introduced by Sharpless in 2005, and successfully used by Pirrung, Li, and Tour in interesting multicomponent, Michael reaction, and Friedel-Crafts chemistry. Ferrocenyl alcohols can be directly reacted with Me3SiN3 “on water”, and the corresponding. Ferrocenyl azides used in “Click chemistry”, through consecutive reactions performed in the presence of water. The mild reaction conditions (water at 80 °C) and the absence of Lewis or Brønsted acids, as well as other additives and co-solvents, makes our finding useful for the direct functionalyzation of complex biological molecules with ferrocenes, allowing interesting multidisciplinary researches.

OH

RFe

waterNu

Nu

RFe

Ligands

Chiral building blocks

New enantioselective reactions

1 P. Vicennati, P. G. Cozzi, Eur. J. Org. Chem. 2007, 2248-2251. 2 P. G. Cozzi, L. Zoli, Green Chem. 2007, 1292-1295. 3 P. G. Cozzi, L. Zoli, Angew. Chem. Int. Ed. 2008, 47, 4162-4166.

ORAL COMMUNICATIONS

Oral Communications SISOC7


OC-1

Nucleophilic Addition to Chiral Cyclic Nitrones: Efficiency and Versatility in Iminosugars Synthesis

Pedro Merino,a Tomás Tejero,a Andrea Gotib, and Ignacio Delsoa,b a Laboratorio de Síntesis Asimétrica. Instituto de Ciencia de Materiales de Aragón.

Universidad de Zaragoza - CSIC. Pza. San Francisco, s/n. E-50009 Zaragoza, Spain b Dipartimento di Chimica Organica “Ugo Schiff”. Università Degli Studi di Firenze. Via

della Lastruccia,13 I-50019 Sesto Fiorentino (FI) Italia [email protected], www.bioorganica.es

Iminosugars and polyhydroxylated pyrrolidines are interesting biologically active compounds showing a remarkable and selective inhibitory activity towards several glycosidase enzymes. Since first iminosugars were discovered, many efforts have been made both to obtain new unnatural derivatives and to assay their biological activity, in order to find new therapies and improve those already known.1

NO

(OR)n

NH

∗

(OH)n

NH

∗

(OH)n

NH

∗

(OH)n

NH

∗

(OH)n

∗

N

(OH)n

∗

N

(OH)n

n(HO)

Ar

OH

NH2

OHOH

n

In this communication it will be shown the application of nucleophilic additions to cyclic chiral nitrones and further elaborations as an efficient and reliable methodology to prepare a wide variety of new and known structures, all of them containing a pyrrolidine moiety.2

1 P. Compain, O. R. Martin, Iminosugars. From synthesis to therapeutic applications; Wiley: West Sussex, 2007; Stütz, A. E. Iminosugars as Glycosidase inhibitors: Nojirimycin and beyond; Wiley-VCH: Weinheim, 1999 2 P. Merino, I. Delso, T. Tejero, F. Cardona, M. Marradi, E. Faggi, C. Parmeggiani, A. Goti, Eur. J. Org. Chem. 2008, available on line

SISOC7 Oral Communications


OC-2

Asymmetric Aminocatalysis: New Reactions and New Directions

Giuseppe Bartoli, Marcella Bosco, Letizia Sambri, and Paolo Melchiorre Department of Organic Chemistry “A. Mangini” Alma Mater Studiorum - Università di Bologna

Viale Risorgimento, 4 – Bologna (Italia) [email protected]

The use of chiral secondary amine catalysis (Asymmetric Aminocatalysis)1 has become a well-established and powerful synthetic tool for the chemo and enantioselective functionalization of carbonyl compounds. In the last eight years alone, this field has grown at such an extraordinary pace that it is now recognized as a fundamental and reliable discipline in asymmetric synthesis. Today, aminocatalysis is going to face problems of increasing complexity and diversity, and the rational design of new catalysts and new reactions represents a critical goal for the continued expansion of aminocatalysis.

Herein we describe our efforts to expand the scope of asymmetric aminocatalysis by developing the highly enantioselective (ee’s ranging from 95 to 99%) α-selenenylation of aldehydes2 and the first organocatalytic asymmetric β-functionalization of aldehydes with a P-centered nucleophile providing a direct access to highly enantioenriched β-phosphine aldehydes.3 Moreover, a recently disclosed organocatalytic triple cascade will be described.4 This bio-inspired strategy, based upon the combination of multiple asymmetric transformations in a cascade sequence, provids rapid access to complex molecules containing multiple stereocenters in enantiomerically pure form (ee = 99%) from simple precursors and in a single operation. All these strategies employ the simple chiral secondary amine A, which has emerged recently as potentially general enamine and iminium activator suitable for a broad range of highly selective functionalization of aldehydes.

Finally, our latest results on the exploitation of asymmetric counteranion directed catalysis (ACDC) will be presented: central to these studies has been the identification of a new catalytic amine salt B, in which both the cation and the anion are chiral, that exhibits high reactivity and selectivity for iminium ion catalysis with unsaturated enones.5

N

N

OMe

NH3

Boc-HNCOO

Ph

catalytic salt B

H

2

NH

OTMS

CF3

CF3

F3C CF3

A

1 a) B. List, Chem. Commun. 2006, 819; b) G. Lelais, D. W. C. MacMillan, Aldrichimica Acta 2006, 39, 79. 2 M. Tiecco, A. Carlone, S. Sternativo, F. Marini, G. Bartoli, P. Melchiorre, Angew. Chem. Int. Ed. 2007, 46, 6882–6885. 3 A. Carlone, G. Bartoli, M. Bosco, L. Sambri, P. Melchiorre, Angew. Chem. Int. Ed. 2007, 46, 4504–4506. 4 O. Penon, A. Carlone, A. Mazzanti, M. Locatelli, L. Sambri, G. Bartoli, P. Melchiorre, Chem. Eur. J. 2008, 14, 4788–4791. 5 G. Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, L. Sambri, P. Melchiorre, Org. Lett. 2007, 9, 1403–1405.



OC-3

Catalytic and Enantioselective Michael Addition of α-Substituted-α-Cyanosulfonyl Carbanions with Cinchona Alkaloids

Jesús López-Cantarero, Sara Duce, José Luis García Ruano and M. Belén Cid Departamento de Química Orgánica, Universidad Autónoma de Madrid,

Cantoblanco, 28049-Madrid, Spain [email protected]

Sulfones are considered mimic of the carbonyl moiety in the transition state and therefore are gaining an increasing importance in medicinal chemistry. Chiral sulfonyl compounds have shown interesting activities in diseases such as glaucoma1 or Alzheimer.2 In spite of the significant amount of tertiary sulfones76 and particularly cianosulfones3 with biological activity, no enantioselective method to prepare this kind of compounds has been described.

During the past few years asymmetric organocatalysis has emerged as a powerful strategy in organic synthesis. Different reactions and transformations have been achieved using this approach, giving multiple complex structures with high levels of stereoselectivity.4 In this sense, Michael addition has been extensively studied as one of the most versatile strategies in C-C bond formation.5 In order to increase the scope of this strategy and give access to an enantioselective route to tertiary sulfones, we have studied the reaction of α-cyano-α-substituted sulfonyl carbanions as nucleophiles in Michael addition to α,β-unsaturated ketones by using cinchona alkaloids as chiral bases.

The conditions have been optimised using methyl vinyl ketone (MVK) as Michael acceptor. The best results were obtained using 1 (1 mol %) as catalyst, R= CF3-C6H4- as substituent and toluene as solvent at -40 ºC. Being the conditions general for a variety of α-substituents (R’) to afford the Michael adducts in high yields and enantiomeric ratios up to 89:11 (>99:<1 after crystallization).

This method is also applicable to cyclic α,β-unsaturated ketones to afford the 1,4-adducts in high yields and good diastereo and enantioselectivities.

Ph SO2C6H4-pCF3

CN

n OToluene, -40ºC1 (1-10mol%)

+ Ph

NC SO2C6H4-pCF3

nn=0,1,2

yield= 70-80%dr= 80:20er up to 90:10

O

1M. F. Surgrue, A. Harris, I. Adamsoms, I. Drugs Today 1997, 33, 283-298. 2 J. P. Scott, D. R. Lieberman, O. M. Beureux, K. M. J. Brands, A. J. Davies, A. W. Gibson, D. C. Hammond, C. J. McWilliams, G. W. Stewart, R. D. Wilson, U-H.Dolling, J. Org. Chem. 2007, 72, 4149 and referentes cited therein. 3 H. Miyazaki, PCT Int. Appl. WO 2007060839 (2007). 4 Thematic Issue on Organocatalysis : Chem. Rev. December (Volume 107, Issue 12). 5 D. Almasi, D. A. Alonso, C. Nájera, C.; Tetrahedron: Asymmetry 2007, 18, 299.

R' SO2R

CNO

Toluene, -40ºC

1 (1-10mol%)+ R'

NC SO2R

yield= 85-98%er up to 89:11

ON

HO

NPh3Si 1R=p-CF3-C6H4, p-Tol, Me, p-MeO-C6H4, Bn, PyR'= Ph, p-MeO-C6H4, p-Cl-C6H4, o-Cl-C6H4



OC-4

Stereoselective Synthesis of Polycyclic Sulfurated Heterocycles

Alessandro Degl’Innocenti, Antonella Capperucci Department of Organic Chemistry

Università di Firenze Via della Lastruccia, 13 Sesto Fiorentino, Italy

[email protected]

Sulfur containing organosilanes are interesting key intermediates in synthetic organic chemistry as building blocks for the synthesis of more complex molecules. Our recently developed methodology for silyl-1,3-dithiolanes and silyl-1,3-thiazolidines1 functionalization opened new perspectives in the chemistry of such sulfurated heterocycles. In this communication we want to give a general overview of our research in the investigation of such methodology, that has led to the development of a general protocol, through a fine tuning of the reaction conditions, for their selective functionalization leading to different heterocyclic systems.

We found that the reactivity of silyl thiazolidines is strictly dependent on the nature of the protecting group present on the nitrogen atom and the substituents on the heterocyclic ring, as well as the reaction conditions and the nature of the electrophile, thus leading to the selective formation of α-hydroxy thiazolidines or fused oxazolidinones. (Scheme 1)

When N,N-diprotected natural aminoacid derivatives were used as protecting groups of thiazolidines, a stereocontrolled entry to interesting pyrazine derivatives was obtained.

1 A. Degl’Innocenti, S. Pollicino, A. Capperucci, A. Chem. Commun., 2006, 4881 – 4893.

R'R''

N N

S

OR O

OH

N S

SiMe3O

RR'

R''

TBAF

THF

R = CH3, CH(CH3)2, CH2CH(CH3)2, CH2Ph R' =R'' = H, R', R'' = Ph

O

O

Scheme 2

S N-Pg

SiMe3

RS N-Boc

R

Ph OH

S N-Boc

R

Ph OH

>S N

R

OPh

O

S N

R

OPh

O

S N-Cbz

R

Ph OH

>S N

R

OPh

O

Pg=Boc

PhCHOF-

Pg=Cbz

R=H R=H

R H R H

Scheme 1

PhCHOF-



OC-5

Stereoselectivity in the Synthesis of Isoprenyl-β-Lactams

Josefa Anaya, Manuel Grande and Laura M. Monleón Departamento de Química Orgánica

Universidad de Salamanca. Facultad de Ciencias Plaza de los Caídos, 1-5. 37.008-Salamanca. España.

[email protected]

Several tandem radical cyclizations of polycyclic natural products mediated by titanocene trichloride have been recently published.1 Because of our interest in the synthesis of new β-lactam derivatives, we tried to synthesize tribactams T following the same methodology.2

Staudinger reaction between methoxyacetic ketene and different imines formed from citral, afforded the epoxymonolactams A, B and C, the precursors of tribactams T. Under several reaction conditions, the expected tribactams were not obtained, as the allylic alcohols D were the main or the exclusive reaction products. The particular behavior observed for the isoprenoid side chain in the Staudinger reaction and in the epoxidation processes as well as the reaction with Cp2TiCl will be discussed.

R X

CO2MeCO2R0

CN

N

MeO

CO2R0

OH

N

MeOOH

T

A

B

O

OC

65

N

MeO

RX

9 10

O

O

43

N

MeO

R3

R2R1O

H2NOH

H2N

CO2R0H

O

Cp2TiCl

D

RX

R X

CO2MeCO2R0

CN

1

2

4 CHO

3

TGF

Acknowledgements: We gratefully acknowledge the Ministerio de Educación y Ciencia of Spain (CTQ2005-05026/BQU) for financial support.

1 a) A. F. Barrero, J. M. Cuerva, M. M. Herrador, M. V. Valdivia, J. Org. Chem. 2001, 66, 4074; b) J. Justicia, E. Oltra, J. M. Cuerva ibid. 2005, 70, 8265; c) A. F. Barrero, J.F. Quílez del Moral, E. M. Sánchez, J. F. Arteaga, Eur. J. Org. Chem. 2006, 1627. 2 a) W. A. Nugent, T.V. RajanBabu, J. Am. Chem. Soc. 1994, 116, 986; b) A. Gansäuer, T. Lauterbach, S. Narayan, Angew. Chem. Int. Ed. Engl. 2003, 42, 3687; c) A. Fernández Mateos, P. Herrero Teijón, R. Rabanedo Clemente, R. Rubio González, F. Sanz González, Synlett 2007, 2718; d) L. M. Monleón, M. Grande, J. Anaya, Tetrahedron 2007, 63, 3017; e) Ibid., Synlett 2007, 1243.



OC-6

Ortho-Lithiated Epoxides Based Synthesis of Tetrahydroindenofuranones

Vito Capriati, Saverio Florio, Renzo Luisi and Antonio Salomone Department of Pharmaceutical Chemistry

University of Bari Via Orabona, 4 – 70125 Bari (Italy)

[email protected]

We have found recently that ortho-bromoaryloxiranes, when treated with alkyl- and aryllithiums, can be easily transformed in the corresponding ortho-lithiated aryloxiranes, a useful class of reactive intermediates employed in the enantioselective synthesis of tetrahydronaphthols1 and phthalans.2

OLi

R1R2

R3

OHR2

COOEt

R1O

R3 R4

OHR1

R2

Tetrahydronaphthols Phthalans In this communication we report a simple and efficient method of synthesis of tetrahydroindenofuranones from ortho-lithiated aryloxiranes and α,β-unsaturated malonates.3

The reaction is a domino process that initiates with the conjugate addition of 1−Li to 2 to give intermediates 3−Li which then cyclize on the oxirane ring via a stereospecific intramolecular SN2 (5-exo-tet mode); successive lactonization furnishes the tetrahydroindenofuranones 4.

R3

O

OCOOEt

R2 R1

O

R1R2

X

O

R1R2

R3COOEt

COOEt

Li

R3 COOEt

COOEt

1 (X=Br)

1-Li (X=Li)RLi−78 °C

THF

2

3-Li4

Yield 50-75%dr: 50/50 ÷ ≥ 98/2

er: ≥ 97/3 This methodology has also been developed in an asymmetric version: starting from optically enriched ortho-bromoarylepoxides, it was possible to obtain tetrahydroindenofuranones 4 in almost enantiopure form (er ≥ 97/3). It is noteworthy that compounds 4 can undergo selectively hydrolysis and decarboxylation of the ester moiety leading to structural analogues of the natural antitumor agents Epipodophyllotoxins.4

1 V. Capriati, S. Florio, R. Luisi, F. M. Perna, A. Salomone, F. Gasparrini, Org. Lett. 2005, 7, 4895. 2 V. Capriati, S. Florio, R. Luisi, F. M. Perna, A. Salomone, J. Org. Chem. 2006, 71, 3984. 3 A. Salomone, V. Capriati, S. Florio, R. Luisi, F. M. Perna, Org. Lett. 2008, 10, 1947. 4 L. Klein, C. Yeung, D. Chu, E. McDonald, J. Clement, J. Plattner, J. Med. Chem. 1991, 34, 984.



OC-7

Fullerenes: Multitask Components in Molecular Machinery

Aurelio Mateo-Alonso,a Dirk M. Guldi,b Francesco Paolucci,c Stelios Courisd and Maurizio Pratoa

aDipartimento di Scienze Farmaceutiche, Università degli Studi di Trieste, Piazzale Europa 1, 34127 Trieste, Italy. bLehrstuhl für Physikalische Chemie I, Universität Erlangen-Nürnberg, Egerlandstraße 3, D-91058 Erlangen, Germany. cDipartimento di Chimica "G. Ciamician", Università di Bologna, v. Selmi 2, 40126 Bologna, Italy. dInstitute of Chemical Engineering

and High Temperature Chemical Processes, Foundation for Research and Technology–Hellas, P.O. Box 1414, 26504 Patras, Greece

Molecular machines are molecular-scale devices that carry out predetermined tasks derived from molecular motion. A versatile prototype of such nanomachines displays an analogous structure to that of an abacus, in which the ring component can be placed in different positions under controlled conditions. These systems have been named molecular shuttles and are basic components in molecular machinery. The preparation and behaviour of molecular shuttles stoppered with fullerenes will be discussed in detail, focusing on how fullerenes can be applied to monitor and to induce molecular motion.1 Also, it will be illustrated how such motion can be employed to modulate the physicochemical properties of molecules such as light-driven electron transfer events,2 non-linear optical properties,3 fluorescence,2,4 electrochemical potential4,5 and chemical stability.6

1 A. Mateo-Alonso, D. M. Guldi, F. Paolucci, M. Prato, M. Angew. Chem. Int. Ed. 2007, 46, 8120-8126. 2 A. Mateo-Alonso, C. Ehli, G. M. A. Rahman, D. M. Guldi, G. Fioravanti, M. Marcaccio, F. Paolucci, M. Prato, M. Angew. Chem. Int. Ed. 2007, 46, 3521-3525. 3 A. Mateo-Alonso, K. Iliopoulos, S. Couris, M. Prato, M. J. Am. Chem. Soc. 2008, 130, 1534-1535. 4 A. Mateo-Alonso, G. Fioravanti, M. Marcaccio, F. Paolucci, G. M. A. Rahman, C. Ehli, D. M. Guldi, M. Prato, Chem. Comm. 2007, 1945-1947. 5 A. Mateo-Alonso, G. Fioravanti, M. Marcaccio, F. Paolucci, D. C. Jagesar, A. M. Brouwer, M. Prato, Org. Lett. 2006, 8, 5173-5176. 6 A. Mateo-Alonso, P. Brough, M. Prato, M. Chem. Comm. 2007, 1412-1414.



OC-8

Bi-Functional Polymer-Attached Inhibitors of Influenza Viruses Jayanta Haldar†, Jianzhu Chen‡, Alexander M. Klibanov†§, Luis Álvarez de Cienfuegos∗

Department of †Chemistry, ‡Biology and §Biological Engineering Massachusetts Institute of Technology

Cambridge, MA 02139, USA ∗Department of Organic Chemistry

Faculty of Sciences. University of Granada Campus Fuentenueva s/n 18071

[email protected]

Influenza virus causes one of the most prevalent human infections:1 in a typical year ≈15% of the U.S. population is infected, resulting in up to 40,000 deaths and 200,000 hospitalizations (www.cdc.gov / flu). Influenza A and B viruses have two major membrane-associated surface glycoproteins, hemagglutinin (HA, about 600 units) and neuraminidase (NA, about 50 units), which are both essential for infectivity. Therefore, both HA and NA are attractive potential targets in the search for anti-influenza drugs2. In this communication we will present the advance in the synthesis and virucidal activity of polymeric structures that can attach to both HA and NA proteins increasing the activity by a polyvalent interaction versus the monomers precursors.

1 J. Haldar, D. An,, L. Álvarez de Cienfuegos, J. Chen, A. M. Klibanov. Proc. Natl. Acad. Sci. 2006, 103, 17667-17671. 2 M. Matrosovich, H.-D. Klenk, Rev. Med. Virol. 2003; 13, 85–97.

SA

ZAx

y

SA = sialic acidZA = zanamivir



OC-9

Novel Functionalised Heterohelicenes: New Synthetic Routes and Applications

Emanuela Licandro, Alberto Bossi, Clara Rigamonti, Stefano Maiorana Department of Organic and Industrial Chemistry, University of Milan

Via C. Golgi 19, I-20133 Milan (Italy) [email protected]; http://www.dipcorind.unimi.it/pc/p_docente.htm;

Organic materials with non-linear optical (NLO) properties play a key role in the development of new ultra-fast, large-scale optical data processing devices. Chiral systems in particular are promising candidates for such applications. The NLO properties of many carbohelicenes, such as [7]-helicene and [6]-helicenebisquinones, have already been investigated but, to the best of our knowledge, little has been done on the corresponding heterohelicenes, although some of them were synthesised in the late 1960s. We focused our attention on the chiral helical tetrathia-[7]-helicene, [7]-TH, 1, because its functionalisation should, in principle, be easier than in the case of the corresponding carbohelicenes and could therefore provide new derivatives to investigate then optical properties in view of applications in optoelectronics.

Within a research project on the above topic, we have set up appropriate methodologies1 for the synthesis of novel functionalised derivatives of type 1, 5 and 6, following two strategies: 1) functionalization of [7]-TH 1, or 2) photocyclization of functionalized alkene precursors 2-4 [Scheme 1]

SS

S S

SS

SS

I2, C6H6

hν

RR

R

R

2, R = H 3, R = SiR3

1, R = R' = H5, R = SiR3, R'= H6, R = H, R' = alkyl, aryl, alkoxycarbonyl, CF3 R = COCF3, R' = H

R'

SS SS

4, R = H, COCF3, R = H, R' = alkyl, aryl, alkoxycarbonyl, CF3

R' R'R'

RR

1 a) S. Maiorana, E. Licandro, K. Clays, A. Persoons, et al. Tetrahedron, 2003, 59, 6481; b) A. Bossi, E. Licandro, S. Maiorana et al. Synlett, 2005, 1137; c) E. Licandro, C. Rigamonti, S. Maiorana et al. Synthesis, 2006, 21, 3670; d) A. Bossi, S. Maiorana, E. Licandro et al. Eur. J. Org. Chem., 2007, 27, 4499



OC-10

Direct RuO4-Catalyzed Oxidation of Isoxazolidines to 3-Isoxazolidones

Anna Piperno, Angelo Ferlazzo, Salvatore G. Giofrè, Roberto Romeo, Giovanni Romeo,

and Daniela Iannazzo Dipartimento Farmaco-chimico

Università di Messina Viale S.S. Annunziata, 98168 Messina

[email protected]

Ruthenium tetraoxide (RuO4) is a powerful oxidant which has a widespread application in organic transformations as attested by recent examples, such as the oxidation of saturated hydrocarbons, the oxidative cleavage of alkenes, the α-ketohydroxylation of alkenes, the cis-dihydroxylation of alkenes, and the oxidative polycyclization of polyenes.1

Recently, we have reported the first example of a direct oxidation of the isoxazolidine nucleus to the 3-isoxazolidone system by the use of RuO2/NaIO4, under ethyl acetate/water biphasic conditions.2 The oxidation reaction of the isoxazolidine nucleus is uncommon because of the sensitivity of the N,O-bond toward the usual oxidizing agents. This synthetic method can be exploited on either racemic or enantiopure isoxazolidines and allows the preparation of 3-isoxazolidones not easily accessible by conventional methods reported in literature.

Further advances in this research area have been reached by exploring the reactivity of differently substituted isoxazolidines. In this context, the obtained 3-isoxazolidones have been exploited as useful synthons for the preparation of a new series of N,O-nucleosides3 which possess the nucleobase at the C-3 position.

1 H. M. C. Ferraz, L.S. Longo, J. Org. Chem., 2006, 72, 2945-2950. 2 A. Piperno, U. Chiacchio, D. Iannazzo, S.V. Giofrè, G. Romeo, R. Romeo, J. Org. Chem., 2007, 72, 3598-3600 3 U. Chiacchio, A. Rescifina, D. Iannazzo, A. Piperno, R. Romeo, M. T. Sciortino, E. Balestrieri, B. Macchi, A. Mastino, G. Romeo, J. Org. Chem., 2007, 50, 3747-3750.



OC-11

Copper-Catalyzed N-Arylation of Ureas in Water: A Novel Entry to Benzimidazolones

Nekane Barbero, Raul SanMartin,* Mónica Carril and Esther Domínguez* Kimika Organikoa II Saila

Zientzia eta Teknologia Fakultatea, Euskal Herriko Unibertsitatea PO Box 644, 48080 Bilbao, Spain

[email protected]

In the plethora of metal-catalyzed cross-couplings of the last decades, copper-catalyzed N-arylations in water stand out as a most promising area which combines catalytic amounts of such a safer, non-expensive metal with all the advantages in terms of economy, safety and environmental issues associated to the use of water as the solvent of a fundamental transformation in synthetic chemistry.1 Although aqueous mixtures with organic solvents (ethylene glycol, DMSO, iPrOH, DMF, N,N-dimethylethanolamine), or microwave activation are relatively well documented in this field, the use of neat water under classical thermal reaction conditions remains almost intact, on account of the scarcity of examples reported so far.2 In this context, the copper-catalyzed arylation of nitrogen compounds other than amines and amides, such as urea derivatives, is a barely explored field even when using standard reaction media,3 and unexplored in water.

Considering the relevance in the pharmaceutical industry of benzimidazolones, which constitute the core of a number of biologically relevant structures, including non-nucleoside reverse transcriptase inhibitors of potent antiretroviral activity against HIV strains, potassium channel regulators, and orally bioavailable inhibitors of respiratory syncytial virus fusion, inter alia,4 we envisaged a short, more sustainable synthetic pathway from commercially available substrates. We wish to present the latter approach to benzimidazolones by an straightforward sequence based on a copper-catalyzed intramolecular N-arylation of 2-bromoarylureas in water. In addition to experimental details, the scope of this key transformation and some mechanistic considerations will be also discussed.

N

HN

O

R'

R

Br

NR'

NH2

OR [Cu], H2O

1,2-diamine

R' = Alkyl, ArylR= H, Me, F, NO2, CF3, OMe

NH2

RBr

Acknowledgements: This research was supported by Regional Government of Biscay/Basque Government/University of the Basque Country (Projects DIPE 06/10, UNESCO07/08 and GIC07/IT-349-07) and the Spanish Ministry of Education and Science (MEC CTQ2007-64501). N.B. thanks the Ministry of Education and Science (MEC) for a predoctoral scholarship.

1 M. Carril, R. SanMartin, E. Domínguez Chem. Soc. Rev. 2008, 37, 639. 2 M. Carril, R. SanMartin, E. Domínguez and I. Tellitu, Chem. Eur. J. 2007, 13, 5100. 3 R. Hosseinzadeh, Y. Sarrafi, M. Mohadjerani and F. Mohammadpourmir, Tetrahedron Lett. 2008, 49, 840. 4 M. L. Barreca, A. Rao, L. De Luca, N. Iraci, A.-M. Monforte, G. Maga, E. De Clercq, C. Pannecouque, J. Balzarini and A. Chimirri, Bioorg. Med. Chem. Lett. 2007, 17, 1956.



OC-12

New Perspectives in Palladium-Catalyzed Reactions with Arenediazonuim salts

S. Cacchi, G. Fabrizi, D. Persiani, G. Bartoli and A. Goggiamani Dipartimento di Studi di Chimica e Tecnologie del Farmaco

Università degli Studi ‘La Sapienza’ P.le A. Moro 5, 00185 Rome, Italy

[email protected]

Because of their higher reactivity, their availability from inexpensive anilines, the utilization of mild conditions and the absence of added bases in several applications, arenediazonium salts represent an attractive alternative to aryl halides or triflates in palladium-catalyzed reactions. They have been widely utilized in Mizoroki-Heck reactions, Suzuki-Miyaura and Stille cross-couplings as well as carbonylation reactions, synthesis of sulfinic acids and boronic esters. However, a number of applications still remain a challenging target.

Recently we have described the first synthetically useful palladium-catalyzed alkyne-based reaction of arenediazonium tetrafluoroborates1. In particular, we have shown that arenediazonium tetrafluoroborates can be used as aryl partners in the hydroarylation of internal alkynes (Scheme 1). Hydroarylation products have been isolated in good to high yields under mild conditions with very high stereoselectivity and, with asymmetrically disubstituted alkyne, the regioselectivity was found to be comparable to that observed with aryl iodides.

R RR R

Ar HArN2 BF4

Pd(OAc)2Ph3SiH

THF, rt

Scheme 1

On the basis of these results, we decided to study the feasibility of a hydroarylation process involving hindered olefinic systems such as norbornenes and analogues (Scheme 2)2.

X

RR

+ ArN2 BF4

X

RR

Ar

Pd(OAc)2iPr3SiH

THF, 5°C-rt

Scheme 2

The hydroarylation of norbornenes with arenediazonium tetrafluoroborates has proved to be an effective method for the synthesis of bicyclo[2.2.1]heptanes and related compounds with an aryl substituent in the exo position.

Both procedures tolerate a variety of substituents including keto, ester, cyano, and nitro groups and can be performed as a one-pot synthesis generating the arenediazonium salt in situ.

1 S. Cacchi, G. Fabrizi, A. Goggiamani, D. Persiani Org. Lett. 2008, 10, 1597. 2 G. Bartoli, S. Cacchi, G. Fabrizi, A. Goggiamani Adv. Synth. Cat. submitted.



OC-13

Metal-Catalyzed Direct Arylations of 1,2,3-Triazoles: Complementary Regioselectivities and Mechanistic Insights

Lutz Ackermann and Rubén Vicente

Institute für Organische und Biomolekulare Chemie, Georg-August-Universität, Göttingen Tammanstr. 2, 37077-Göttingen, Germany

[email protected] (http://www.org.chemie.uni-goettingen.de/ackermann/)

1,2,3-Triazoles are substructures of various valuable compounds in organic syntheses, biology or material sciences. Consequently, the development of methodologies for their regioselective arylation highly is desirable. Moreover, direct arylations through C–H bond activation represent an interesting approach for economically efficient and environmental friendly functionalization reactions.1

Herein, we present methodologies for the metal-catalyzed direct arylations of 1,2,3-triazoles with chloroarenes as electrophiles. Thus, palladium-catalyzed direct arylations take place on the electron-rich heterocycle,2,3 whereas ruthenium-catalyzed reactions occur with complementary selectivity on the arene (1).4

NN

N

R1

R2

+ ArClcat. [Ru] cat. [Pd]

NN

N

R1

R2

Ar

NN

N

R1

R2

(1)Ar

H

H H

H

Interestingly, we found that ruthenium-catalyzed direct arylations of 1,2,3-triazoles can be efficiently accomplished in apolar solvents using carboxylic acids as co-catalysts (2). A cooperative metalation-deprotonation mechanism accounts for these observations.5

NN

N

R1

R2

+ ArBrcat. [Ru]

cat. MesCO2H

NN

N

R1

R2

ArN

NN

R1

H

[Ru] O

O

R2

Mes(2)

Acknowledgments. Ministerio de Educación y Ciencia, Alexander von Humboldt foundation (fellowships to R.V.), DFG and the Fonds der Chemischen Industrie are gratefully acknowledged.

1 L. Ackermann, R. Vicente, S. I. Kozhushkov, “Metal-Catalyzed Direct Arylations” in Modern Arylation Methods Ed.: L. Ackermann, Wiley-VCH, Weinheim, 2008, in press. 2 L. Ackermann, R. Vicente, R. Born. Adv. Synth. Catal. 2008, 350, 741–748. 3 Direct arylations of 1,2,3-triazoles with CuI proceed with the same regioselectivity, however, aryl iodides are required, L. Ackermann, H. K. Potukuchi, D. Landsberg, R. Vicente, 2008, submitted. 4 L. Ackermann, R. Vicente, R. Born. Manuscript in preparation. 5 L. Ackermann, R. Vicente, A. Althammer. Org. Lett. 2008, 10, doi: 10.1021/ol800773x.



OC-14

Synthesis and Biological Evaluation of Nonpeptide αvβ3/α5β1 Integrin Dual Antagonists

Alessandra Tolomelli D epartment of Chemistry "G. Ciamician"

University of Bologn, Via Selmi 2, 40126 Bologna, Italy

[email protected] http://www.ciam.unibo.it/index2.html

Integrins are a large family of heterodimeric transmembrane glycoproteins involved in the attachment of a cell to the extracellular matrix (ECM).1 Alterations or aberrations in integrin-mediated cell adhesion have been connected with the pathogenesis of several diseases. In particular, αVβ3 integrins, which are involved in many processes such as tumour proliferation and metastasis, bind to a wide number of ECM components through recognition of the Arg-Gly-Asp (RGD) tripeptidic sequence. This sequence is also essential for the binding of α5β1 integrin to fibronectin, which has been unambiguously recognized as proangiogenic receptor. Therefore, antagonists of both integrins, block the pathway of angiogenesis.2 The need for antagonists with high bioavailability and low molecular weight has prompted several research groups to develop small constrained non-peptidic molecules mimicking the RGD motif. Most of the structures proposed so far share a common pattern, consisting of a polyfunctionalized rigid core, linked to appendages corresponding to arginine and aspartic acid side chains. Recently the design and application of novel synthetic pathways leading to constrained non-peptidic RGD mimetics, containing heterocyclic scaffolds or unusual β-aminoacids, has been developed.3 Modifications have been addressed to the nature and length of the arginine and aspartate mimicking branches. Moreover, the blockade of fibronectin-mediated cell adhesion of these novel αvβ3/α5β1 integrin dual antagonists has been tested, to verify if their activity could be synergistically effective in preventing angiogenesis. Some derivatives showed a promising binding affinity and could represent lead compounds for drug development.

1 K.-E. Gottschalk, H. Kessler, Angew. Chem. Int. Ed., 2002, 41, 3767-3773. 2 S. Kim, M. Harris, J. A. Varner, J Biol Chem. 2000, 275, 33920-33928. 3 a) F. Benfatti, G. Cardillo, S. Fabbroni, P. Galzerano, L. Gentilucci, R. Juris, A. Tolomelli, M. Baiula, A. Spartà, S. Spampinato, Bioorg. Med. Chem. 2007, 15, 7380-7390; b) F. Benfatti, G. Cardillo, S. Fabbroni, P. Galzerano, L. Gentilucci, R. Perciaccante. A. Tolomelli, M. Baiula, S. Spampinato, S. Tetrahedron: Asymmetry, 2006, 17, 167-170



OC-15

Effective Synthesis of α-Arylamino-α’-chloropropan-2-ones via Oxidative Isomerization Promoted by Calcium Hypochlorite.

V. Pace, F. Martínez, M. Fernandez, J. V. Sinisterra, A. R. Alcántara. Departamento de Química Orgánica y Farmacéutica. Facultad de Farmacia. Universidad

Complutense de Madrid. [email protected]; www.biotransformaciones.com

Although α-arylamino-α’-chloropropan-2-ones show a high degree of structural simplicity, they have not been described in literature; analogously, neither corresponding α-alkylamino-α’-chloropropan-2-ones have been synthesized. The use of vinyl halide moiety as a latent carbonyl function has been previously reported: in particular due to the high degree of hydrolytic stability, it is possible their conversion in α-haloketones by employing an oxidative isomerization promoted by N-halosuccinimide1a,b or by hypochlorite anion1c in acidic media. Treatment of vinyl chloride, readily prepared as we previously reported,2 containing an activated phenyl ring with NaClO/AcOH according to VanBrunt protocol1c did not isomerize the vinyl chloride moiety, but exclusively chlorinated aromatic ring in the o, p-positions; excess of hypochlorite does not modify the pattern. Analogous aromatic chlorination takes place if phenyl ring is desactivated by the introduction of strong EWG (e.g. NO2). It must be stressed that by changing temperature, solvent and stoichiometric ratio it is not possible to achieve the desired α-chloroketone. So, reduction of the activator effect of the amine by N-protection as carbamate (Boc) or amide (acetyl and trifluoroacteyl) represents the only possible strategy to direct the action of hypochlorite on vinyl chloride moiety. Trifluoroacetyl amide permits an effective isomerization even if aromatic ring does not present other desactivating groups and may be easily introduced [Cu(OTf)2 catalysis3] and removed in both acidic or basic conditions: although basic hydrolisis is more rapid (2h), Favorskii rearrangement products are present in the crude reaction, so removal of trifluoroacetamide group was effectively achieved in the presence of HCl-MeOH, affording in 12 h α-chloroketone nearly quantitavely. Isomerization reaction is very fast, reaching within 1 hour a quantitative conversion in the desired products. To the best of our knowledgement, it is the first example of an oxidative isomerization in the presence of activated phenyl rings. Calcium hypochlorite presents a series of advantages on sodium one, among them, an increased stability as solid that allows solution preparation just in the moment of perform the reaction.

NH Cl

TFAA, Cu(OTf)2

CH2Cl2, 1h, 100%N

ClCF3O

Ca(ClO)2 (2 eq.)AcOH, H2OMe2CO, 1h, 100%

NH

ClOHCl-MeOH

12h, 98%

R R

R = H, Me, Cl, NO2

R

1 a) H. E. Morton, M. R. Leanna, Tetrahedron Lett. 1993, 34, 4481-4484; Tetrahedron Lett. 1993, 34, 4485-4488; b) R. Duncan, D. G. Drueckhammer Tetrahedron Lett. 1993, 34, 1733-1736; c) M. P. VanBrunt, R. O. Ambenge, S. M. Weinreb, J. Org. Chem. 2003, 68, 3323-3326. 2 V. Pace, F. Martínez, M. Fernández, J. V. Sinisterra, A. R. Alcántara, Org. Lett. 2007, 9, 2261-2264. 3 P. Saravanan, V. K. Singh, Tetrahedron Lett. 1999, 40, 2611-2614.



OC-16

Enantioselective Synthesis of Indole Alkaloids of the Ervatamine-Silicine Group

Mercedes Amat, Núria Llor, Joan Bosch and Begoña Checa Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine

(IBUB), University of Barcelona

Av. Joan XXIII s/n, 08028-Barcelona e-mail: [email protected] ; web site: http://www.ub.edu/farmaco/grupos/amatbosch/indice.htm

The ervitsine-ervatamine alkaloids constitute a group of 2-acylindole alkaloids of the Corynanthean type with an unusual skeleton in which the carbon atoms of the tryptamine fragment (C5-C6) are in a rearranged situation, forming C5-C16 and C-6-C16 bonds. No enantioselective synthesis for these alkaloids has been reported so far.

1620

N

N

OH

Me

H

H

H20

Silicine 16-β-H; 20-β-H16-Episilicine 16-α-H; 20-β-H20-Episilicine 16-β-H; 20-α-H16,20-Episilicine 16-α-H; 20-α-H

Ervatamine 20-α-H20-Epiervatamine 20-β-H

16

5

6

N

N

O

Me

H

MeO2C

H

H

In the context of our studies1 on the use of phenylglycinol-derived oxazolopiperidone lactams for the enantioselective synthesis of piperidine-containing natural and bioactive products, we will be presenting an enantioselective synthetic route to alkaloids of the ervatamine-silicine group. The key steps are a stereoselective conjugate addition to an unsaturated lactam, a stereoselective alkylation at the α-position of the lactam carbonyl, and a ring closing metathesis reaction.

16- Episilicine

16

NO O

C6H5

NO O

C6H5

t-BuO2C

NO O

C6H5

t-BuO2C N

NO

O

C6H5

t-BuO2CO

PG

N

NO

C6H5O

PGN

NMe

H O

N

Br

OPG

H

H

H

H

1 For a revision, see: M. Amat, C. Escolano, J. Bosch, J. Chem. Eur. J. 2006, 12, 8198.



OC-17

A New Convergent Synthesis of 6- Membered Dihydrobenzoxazinones in Just 2 Steps Via Tandem Ugi And Cyclization Reactions

L. Banfi, G. Guanti, P. Lecińska, A. Basso, R. Riva Department of Chemistry and Industrial Chemistry, via Dodecaneso 31, 16146, Genova, Italy

E-mail: [email protected]

Multicomponent reactions1 are, by definition, processes where more than three substrates are combined together in one step to give a product which contains essential parts of all used components. MCRs are a convergent way for generating new collections of structurally complex molecules, introducing three or more points of diversity in only one step. The classical versions of the Ugi2 and Passerini3 isocyanide-based reactions lead to acyclic adducts. On the other hand, through application of various post-condensation reactions we are able to obtain very interesting drug- like heterocyclic scaffolds.

In this communication we would like to introduce a new convergent and short (2-steps) pathway to obtain 6-membered: dihydrobenzo[e] [1, 3] oxazin-4-ones decorated with three points of diversity. Similar compounds were already reported to be endowed with biological activity. by Shaffer in 1970.4

To synthesize the above mentioned products we always used as starting materials: glycolaldehyde dimmer, salicylic acids (substituted or not), various amines and isocyanides.

The proposed strategy implied two bifunctionalized compounds (glycolaldehyde and the salicylic acids) in order to perform, after the Ugi condensation, a following ring closing nucleophilic substitution.5 As anticipated by Kim,6 we found out that glycolaldehyde dimmer is a good substrate for the Ugi reaction.

The following cyclization, carried out under Mitsunobu or Mitsunobu-type conditions, had an unexpected outcome: instead of a benzoxazepinones, deriving from a direct substitution of the hydroxy group by the phenol, a benzoxazinones, resulting from a cine-substitution, was obtained. A mechanism of elimination-addition was demonstrated to be operating. The best conditions were found to be the use of PPh3 and CCl4. Alternatively, classical Mitsunobu conditions (DEAD, PPh3), followed by treatment with an acid (CSA) were followed. A small library of diverse dihydrobenzoxazinones was synthesized in good yields.

N

OH HN R3

O

O R2R1

HHO

R3 NC

R2 NH2

OH

CO2HR1

N

ONH

R3

OR2

O

R1

UGI

PPh3, CCl4, Et3N excessMeCN, reflux 3h

or

1) DEAD, PPh3, 3h2) Camphorsulphonic acid, 3h O

OOHHO

1 J. Zhu, H. Bienayme, Multicomponent Reaction, Wiley-VCH, Weinheim, 2005 2 A. Dömling, I. Ugi, Angev. Chem, Int. Ed., 2000, 39, 3169-3210. 3 L. Banfi, R. Riva, Org. React., 2005, 65, 1-140. 4 N. D. Heindel, L. A. Schaeffer, J. Med. Chem., 1970, 13, 981-983. 5 L. Banfi, A. Basso, G. Guanti, P. Lecińska, R. Riva, Org. Biomol. Chem., 2006, 4, 4236-4240. 6 Kim, Y. B.; Choi, E. H.; Keum, G.; Kang, S. B.; Lee, D. H.; Koh, H. Y.; Kim, Y. S., Org. Lett. 2001, 3, 4149-4152.



OC-18

Total Synthesis of (+)-Neomarinone

Miguel Peña-López, Monserrat Martínez, Luis A. Sarandeses and José Pérez Sestelo Departamento de Química Fundamental, Facultad de Ciencias, Campus A Zapateira s/n,

Universidade da Coruña, A Coruña (Spain) [email protected]

Neomarinone (1) is a marine natural product isolated from the fermentation broth of actinomycetes strain (#CNH-099) by Fenical et al. in 2000,1 which displays in vitro cytotoxicity (IC50 = 8 mg/mL) against HCT-116 colon carcinoma and antibiotic activity. Structurally, neomarinone has a furanonaphthoquinone unit linked to a ramified sesquiterpenoid side chain with four stereogenic centers, two of them quaternary. In 2003, the structure of neomarinone was revised but the absolute configuration is still unknown.2

In this communication we report the first total synthesis of neomarinone. The synthesis was achieved following the retrosynthetic analysis depicted in the scheme. The synthetic strategy is based in the construction of the furanonaphtoquinone core by regioselective Diels-Alder reaction between the 1,3-bis(trimethylsilyloxy)-1,3-diene 2 and the bromoquinone 1.3 The diene precursor, the 1,3-dicarbonylic compound 3, was prepared by diastereoselective conjugate addition reaction of the cuprate derived from iodide 4 to the enantiomerically pure lactone 5. The lactone 5 was synthesized from the commercially available (R)-methyl lactate and the enantiomerically pure iodide 4 prepared from (R)-3-methylcyclohexanone.

O

O

O

OH

Me

HO

O

O

O

RI

O

O

Me

MeO

Br O

OTMS

TMSO

O

O

O

Neomarinone

+

+

1 2

345

Acknowledgements: We are grateful to Xunta de Galicia (PGIDIT05BTF10301PR) for financial support. M.P.L. and M.M.M. thank Xunta de Galicia for a predoctoral fellowship (María Barbeito program) and a postdoctoral contract (Isidro Parga Pondal program), respectively.

1 I. H. Hardt, P. R. Jensen, W. Fenical, Tetrahedron Lett. 2000, 41, 2073. 2 J. A. Kalaitzis, Y. Hamano, G. Nilsen, B. S. Moore, Org. Lett. 2003, 5, 4449. 3 a) A. B. Smith, J. Pérez Sestelo, P. G. Dormer J. Am. Chem. Soc. 1995, 117, 10755; b) J. Pérez Sestelo, M. M. Real, L. A. Sarandeses, J. Org. Chem. 2001, 66, 1395.

POSTERS

Posters SISOC7


PO-1

Enantioselective Organocatalysis: Synthesis of Isoquinuclidines.

M-P. Cabal, F. Aznar, N. Quiñones. Instituto Universitario de Química Organometálica “Enrique Moles”. Unidad Asociada al

CSIC. Universidad de Oviedo. Julián Clavería, 8. Oviedo 33006. España

[email protected]

Asymmetric organic synthesis using metal-free low-molecular-weight organic molecules as catalysts (organocatalysis) is one of the most rapidly growing research areas in the past few years.1 Among the organocatalysts commonly used, proline and its derivatives stand out because of their numerous advantages: low cost, availability of both enantiomerically-pure forms, non-toxicity, stability and easy use. In this context, our research group have recently developed a synthesis of meso- and cis-2,6-diaril-4-piperidones by reaction of acyclic α,β-unsaturated ketones and imines in the presence of (L)-proline as catalyst2. We have also shown that the same reaction can be done in one-pot, three component, aza-Diels-Alder reaction.3 Based on these results, we have developed a similar process using cyclic α,β-unsaturated ketones, aromatic aldehydes and aromatic and aliphatic amines, to afford the synthesis of isoquinuclidine derivatives, which represent the structural framework of several natural products having interesting biological properties. Other related methods described in the literature have the limitation of using exclusively formaldehyde4 as carbonyl component and aromatic amines.5

O

n

NR

Ar

L-proline(30 mol%)

MeOH, rt, 7d∗ ∗

N∗R

O Ar

nL-proline(30 mol%)

MeOH, rt, 7d

O

Ar

RNH2

O

n

30-85%dr=99:1 (exo:endo)

ee=10-70%

1

In this way, we were able to synthesized N-substituted-3-aryl-2-azabicyclo[2.2.2]octan-5-one 1 derivatives, having three new chiral centres, with very high exo diastereoselectivity and moderately good enantioselectivity. The compounds obtained can be further derivatized to NH free systems, opening new synthetic routes to a wide variety of alkaloids.

1 Reviews on organocatalysis: a) B. List, Synlett. 2001, 1675-1686; b) B. List, Tetrahedron. 2002, 58, 5573-5590; c) W. Notz, F. Tanaka, C. F. Barbas III, Acc. Chem. Res. 2004, 37, 580-591; d) G. Lelais, D. W. C. McMillan, Aldrich. Acta. 2006, 39, 79-87. 2 F. Aznar, A-B. García, M-P. Cabal, Adv. Synth. Catal. 2006, 348, 2443-2448. 3 F. Aznar, A-B. García, N. Quiñones, M-P. Cabal, Synthesis, 2008, 479. 4 H. Sundén, I. Ibrahem, L. Ericsson, A. Córdova, Angew. Chem. Int. Ed., 2005, 44, 4877-4880. 5 a) H. Liu, L-F. Cun, A-Q. Mi, Y-Z. Jiang, L-Z. Gong, Org.. Lett. 2006, 8, 6023; b) M. Rueping, C. Azap, Angew. Chem. Int. Ed., 2006, 45, 7832-7835; c) G. Babu, P. T. Perumal, Tetrahedron. 1998, 54, 1627.

SISOC7 Posters


PO-2

Water-Compatible Iminium-Ion Activation

C. Palomo, A. Mielgo, M. Oiarbide, A. Puente, S. Vera and A. Landa

Department of Organic Chemistry University of the Basque Country. Manuel de Lardizabal, 3, 20018

[email protected]

The ultimate challenge in organic synthesis is the identification of new chemical strategies that allow, in an efficient and elegant manner, to create complex molecules minimizing the number of manual operations and purifications. One step in that direction is the recent development of asymmetric reactions catalyzed by metal-free components (organocatalysis) in the presence of water.1 Asymmetric catalysis of carbonyl transformations using chiral secondary amines or ammonium salts, based in enamine or iminium ion catalysis, respectively, have been intensively investigated in the last five years. Nevertheless, until now just a few general catalytic systems have been reported fully water-compatible.2 In this communication, a procedure for the synthesis of a new water compatible catalysts family is presented.

1

NH OSiPh3

5

5N

hydrophobicalkyl chains

bulky group(directs E geometry)R

This family of catalysts in aqueous environment was tested for the yet unprecedented enantioselective conjugate addition of nitromethane to enals.3

H2O

O

H

R

N

R1

R

O

H

R *NO

O

+ NO2NO2

1

NH OSiPh3

5

5

OSiPh3

5

5

1 C. J. Li, Chem.Rev, 2005, 105, 3095. 2 For aqueous enamine activation, see: a) A. P. Brogan, T. J. Dikerson, K. D. Janda, Angew. Chem. Int. Ed. 2006, 45, 8100. b) Y. Hayashi, Angew. Chem. Int. Ed. 2006, 45, 8103 and references therein. For aqueous iminium-ion activation, see: c) A. Carlone, M. Marigo, C. North, A. Landa, K. A. Jørgensen, Chem. Commun. 2006, 4928. 3 C. Palomo, A. Landa, A. Mielgo, M. Oiarbide, A. Puente, S. Vera, Angew. Chem. Int. Ed. 2007, 46, 8431.

Posters SISOC7


PO-3

New and Efficient Organocatalysts for the Michael Asymmetric Addition of Aldehydes to Nitroalkenes

Claudio Palomo*, Antonia Mielgo, Silvia Vera and Aitziber Lizarraga Departamento de Química Orgánica I

Facultad de Química Universidad del País Vasco. Apdo. 10072. 20080 San Sebastián. Spain.

Fax: (+)34-943015270 e-mail: [email protected]; [email protected]

web-site: : www.sc.ehu.es/qpwaiipj/organica.html Inspired by nature, where enantioselective reactions are efficiently performed by enzymes, synthetic chemists have developed new strategies to enantioselectively synthesize chiral compounds. In this context, enantioselective organocatalytic processes have reached maturity in recent years with an impressive number of applications now available. In this incipient research area, however, there are still some unsolved problems related to chemical efficiency, stereocontrol, substrate scope, and catalyst loading and recovery.

The Michael addition of aldehydes to nitroalkenes is an important benchmark for the construction of C-C bonds because of the possibility of simulta-neously generate up to three stereogenic centers and because of the pivotal importance of the nitro group as precursor of many functionalities. Here we present the design of type I1 and II2 catalysts, which have provided a solution to some of the problems pertaining to this kind of transformations in both organic solvents and water.

1 C. Palomo, S. Vera, A. Mielgo, E. Gómez-Bengoa, Angew. Chem. Int. Ed. 2006, 45, 5984-5987. 2 C. Palomo, A. Landa, A. Mielgo, M. Oiarbide, A. Puente, S. Vera, Angew. Chem. Int. Ed 2007, 46, 8431-8435.

NH OSiR3

n

n

II

Nhydrophobic alkyl chains

bulky group(directs E geometry)R

cat I (5 mol%)

CH2Cl2, 0ºC syn:anti to 99:1ee (syn) to 99%

H

O

R

+ R1 NO2H

NO2

O

R

R1

NH

HOO

N

PhPhI ACIE 2006, 45, 5984

(1-2 equiv.) R1: Aryl, alkyl

A DESING: Catalyst I

Activates the acceptor and directs its approach from theless hindered enamina fase

Activates the acceptor

Controls the eqilibriumbetween enamine conformers and blocksone enamine face

B DESING: Catalyst II

Solvent Cat. t (h) T(ºC) Conv.(%) syn/anti ee

CH2Cl2H2OH2O

202015

00rt. >99

80>99 99:1

96:4>99:1

>997597

I

IIaI

n = 0,2,5,8,11(best resultsn = 5)

n=5, R=Me Cat. IIa

THE MICHAEL ADDITION REACTION

ACIE 2007, 46, 8431

SISOC7 Posters


PO-4

Asymmetric Organocatalytic Aza-Henry Reaction Under Phase Transfer Catalysis: An Experimental and Theoretical Study

Idoia Múgica Mendiola, Maitane Zalacain, Enrique Gómez Bengoa, Rosa López, Mikel Oiarbide and Claudio Palomo

Depto. Química Orgánica /UPV-EHU Ibaeta, Paseo Manuel Lardizabal 3, 20018 Donostia-San Sebastián

[email protected], [email protected]

The reaction between nitroalkanes and azomethines to give β-amino nitrocompounds

(the aza-Henry reaction) is one of the fundamental C-C bond forming reactions and represents one of the most powerful tools for the asymmetric synthesis of 1,2-diamines. Although several catalytic asymmetric protocols have been reported, some general restrictions still remain. The vast majority of the methods just allow the reaction of imines derived from non-enolizable aldehydes and are restricted to the use of nitromethane. A recent contribution from our laboratory1 has shown that α-amido sulfones upon reaction with nitromethane in the presence of CsOH.H20 using cinchona derived ammonium salts as catalysts could provide a good solution to the afore mentioned problems. In this communication we present the results obtained by the employment of optimized reaction conditions in the reaction of enolizable and non-enolizable aldehyde-derived α-amido sulfones with a variety of nitroalkanes. High yields and high levels of diastereo- and enantioselectivities were achieved for the α,β-disubstituted β-nitroamines revealing the scope of the approach. The utility of this methodology has been further demonstrated for the synthesis of a variety of highly functionalized 1,2-diamines in good yields without lost of diastereo and enantioselectivity and for the production of γ-vinologous aminoacids.2

We will also show a theoretical investigation (computational calculations at B3LYP/6-31G* level) of the reaction mechanism, which revealed a rather unusual hydrogen bonding pattern of the TS for the catalytic reaction with potential implications in a more general context.

1 Palomo, C.; Oiarbide, M.; Laso, A.; López, R. J. Am. Chem. Soc. 2005, 127, 17622-17623. Also, see Fini, F.; Sgarzani,V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci, A. Angewandte. Chem. Int. Ed. 2005, 44, 7975-7978. 2 Palomo, C.; Oiarbide, M.; Gómez-Bengoa E.; López R.; Linden A.; Múgica-Mendiola I. J. Am. Chem. Soc., ASAP Article, 10.1021/ja800253z Web Release Date: May 30, 2008.

R1 SO2Tol-p

NHBoc

R1NO2

NHBoc

+CsOH.H2O (130 mol%)Toluene, -50º C, 44 h R2

N

N

OHOMe

Ph

Cl

(12 mol%)

R1NH2

NH2

R2

R1= Aromatic, Aliphatic R1

NHBoc

CO2EtUp to 19:1 d.r.Up to 98% ee

Up to 94% ee

Up to 95% eeNO2

R2

Posters SISOC7


PO-5

Enantioselective Organocatalytic Intramolecular Aza-Michael Reaction

Santos Fustero,a,b Diego Jiménez,a Javier Moscardó,a Ana Vicedo,a María Sánchez-Rosellóa and Carlos del Pozoa

aDepartamento de Química Orgánica, Facultad de Farmacia, Universidad de Valencia E-46100-Burjassot (Valencia), Spain. bLaboratorio de Moléculas Orgánicas, Centro de

Investigación Principe Felipe, E-46013-Valencia, Spain e-mail: [email protected]

In the past decade, organocatalysis has emerged as a powerful synthetic tool in asymmetric synthesis. The use of metal free low molecular weight organic molecules as catalysts, despite the ignorance suffered for three decades, is now reaching its adolescence, as it was recently stated in an extensive review appeared in the literature.1 A variety of asymmetric carbon-carbon and carbon-heteroatom bond-forming reactions can be accomplished by using this methodology.

On the other hand, aza-Michael reaction is regarded as one of the most powerful tools for the formation of C-N bonds, giving rise to the formation of β-amino carbonyl derivatives.2 The enantioselective version of this reaction remained elusive, and only recently, several organocatalyzed nucleophilic nitrogen addition to α,β-unsaturated carbons have been devised.3

We have developed a very high enantioselective organocatalytic intramolecular aza-Michael addition of carbamates containing pendant conjugated aldehydes.4 This process, efficiently catalyzed by a prolinol derivative, is useful for the enantioselective preparation of several five- and six-membered ring heterocycles. It is noteworthy that the organocatalytic intramolecular version of the aza-Michael reaction has not been described before.

PGHN X CHO( )n

1) PhCO2H, CHCl3Catalyst IV

2) NaBH4, MeOH

IV:NH

Ar

ArOTMS

X

NPG

OH( )n

up to 99% eeX = CH2, NCbz, O, Sn = 1, 2Ar = 3,5-(CF3)2C6H3

1 (a) A. Dondoni, A. Massi, Angew. Chem. Int. Ed. 2008, early view. (b) P. I. Dalko, Enantioselective Organocatalysis, Wiley-VCH, Weinheim, Germany, 2007. 2 (a) J. L. Vicario, D. Badia, L. Carrillo, Synthesis 2007, 2065. (b) L.-W. Xu, C.-G. Xia, Eur. J. Org. Chem. 2005, 633. 3 (a) Y. K. Chen, M. Yoshida, D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128, 9328. (b) Vesely, J., Ibrahem, I.; Ríos, R.; Zhao, G.-L.; Xu, Y.; Córdova, A. Tetrahedron Lett. 2007, 48, 2193. 4 S. Fustero, D. Jiménez, J. Moscardó, S. Catalán, C. del Pozo, Org. Lett 2007, 9, 5283.

SISOC7 Posters


PO-6

Novel Chiral Ureas and Thioureas as Organocatalysts: Enantio and diastereoselective Nitro-Michael Reaction

Rubén Manzano, José María Andrés, M. Dolores Muruzábal and Rafael Pedrosa* Centro de Innovación en Química y Materiales Avanzados (CINQUIMA) y

Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid Dr. Mergelina s/n, 47011 Valladolid. Spain

[email protected]

Chiral ureas and thioureas are important organocatalysts for enantioselective transformations.1 We will present a modular synthesis that allows the preparation of these derivatives from natural and unnatural α-amino acids. Our method is versatile and modular because it is possible to prepare different ureas and thioureas changing the substituent at the stereocenter, and their stereochemistry by the election of the starting amino acid. The nature of the urea or thiourea moiety can also be changed depending on the isocyanate or isothiocyante used in the final step (Scheme 1).

ROH

NHBoc

OR

NNH2

RN

HN

HN

X

Ar4a: R = i-Pr, X = S, R1 = R2 = Me, Ar = 3,5-(CF3)2C6H34b: R = (S)-sec-butyl, X = S, R1 = R2 = Me, Ar = 3,5-(CF3)2C6H34c: R = PhCH2, X = S, R1 = R2 = Me, Ar = 3,5-(CF3)2C6H34d: R = t-Bu, X = S, R1 = R2 = Me, Ar = 3,5-(CF3)2C6H34e: R = i-Pr, X = O, R1 = R2 = Me, Ar = 3,5-(CF3)2C6H34f: R = i-Pr, X = S, R1 = R2 = PhCH2, Ar = 3,5-(CF3)2C6H34g: R = i-Pr, X = S, R1 = Me, R2 = i-Pr, Ar = 3,5-(CF3)2C6H34h: R = i-Pr, X = S, R1 = R2 = Me, Ar = Ph4i: R = CH2CH2OH, X = S, R1 = R2 = Me, Ar = 3,5-(CF3)2C6H34j: R = CH2CH2CH2OH, X = S, R1 = R2 = Me, Ar = 3,5-(CF3)2C6H3

R1

R2

R1

R2

Scheme 1 These compounds have been used as organocatalysts in the nitro-Michael reaction2 with different malonates and β-diketones yielding the addition products with excellent chemical yields and enantio- and diastereoselectivity (Scheme 2).

RNO2

R NHN

HNX

Ar

R1

R2

R1OC COR1

(2-10 mol%)solvent

RNO2

R1OC COR1R2

R2

+up to 99 % yieldup to 99% eeup to 97% dr

1 Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520-1543. 2 a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119-125; b) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170-7171.

Posters SISOC7


PO-7

Ruthenium-catalyzed Selective Hydration of Nitriles to Amides in Pure Aqueous Medium

V. Cadierno,* J. Gimeno,* J. Francos Departamento de Química Orgánica e Inorgánica (IUQOEM), Universidad de Oviedo, Julián

Clavería 8, E-33006 Oviedo (Spain) [email protected] (V.C.); [email protected] (J.G.)

Selective hydration of nitriles to amides is an important transformation from both academic and industrial points of view, a variety of transition-metal catalysts being presently available to promote efficiently this transformation in organic media.1 In contrast, despite the current interest in using water as solvent for organic synthesis,2 efforts directed to design metal-catalysts active in aqueous media have been scarce. In this contribution, we would like to communicate that the selective hydration of nitriles to amides can be efficiently performed in pure aqueous media by using water-soluble ruthenium(II) catalysts. Among them, the half-sandwich derivative [RuCl2(η6-C6Me6)(PTA•Bn)] (PTA•Bn = benzylated form of the 1,3,5-triaza-7-phosphaadamantane ligand PTA) has shown to be by far the most active (see Scheme).

H2O / 100 °C / 1-8 h(>90% GC yield)

[Ru] (5 mol%)C NR C

R

O

NH2

R = Alkyl, aryl, alkenyl (more than 40 examples) N N

NP

PhRuCl

Cl Cl

Scheme. Ruthenium-catalyzed nitrile hydration in water

1 For a review, see: V.Y. Kukushkin, A.J.L. Pombeiro, Inorg. Chim. Acta, 2005, 358, 1. 2 (a) Organic Reactions in Water: Principles, Strategies and Applications; Lindström, U. M., Ed.; Blackwell Publishing: Oxford, 2007. (b) Aqueous Organometallic Catalysis; Horváth, I. T., Joó, F., Eds.; Kluwer: Dodrecht, 2001.

SISOC7 Posters


PO-8

One-pot Three-component Catalytic Synthesis of Fully Substituted Pyrroles from Readily Available Propargylic Alcohols, 1,3-Dicarbonyl Compounds

and Primary Amines

V. Cadierno,* J. Gimeno,* N. Nebra Departamento de Química Orgánica e Inorgánica (IUQOEM), Universidad de Oviedo,

Julián Clavería 8, E-33006 Oviedo (Spain) [email protected] (V.C.); [email protected] (J.G.)

The pyrrole ring is not only a key structural attribute of many bioactive natural products, pharmaceutical substances and organic conducting materials, but also a useful and versatile building block in organic synthesis. Consequently, the search of efficient synthetic routes to this class of heterocycles constitutes an active research field.1 Herein, we describe a novel method for the preparation of fully substituted pyrroles, through an one-pot three-component coupling reaction, in which easily accessible terminal secondary propargylic alcohols, commercially available 1,3-dicarbonyl compounds and primary amines are used as starting materials (see Scheme).2 This process allows the direct introduction of carbonyl functionalities in the pyrrolic skeleton and tolerates the presence of several functional groups in the starting materials.

CF3CO2H (50 mol%)[Ru] (5 mol%)

HHO

R1

O

R2

O

R3+- 2 H2O

N

R3

O

R2

R1

+ R4-NH2

R4

[Ru] = [Ru(η3-2-C3H4Me)(CO)(dppf)][SbF6] 36 examples56-95% yield

Scheme. Ruthenium/TFA-catalyzed synthesis of pyrroles.

1 For recent reviews and highlights on pyrrole syntheses, see: G. Balme, Angew. Chem. Int. Ed., 2004, 43, 6238; N.T. Patil, Y. Yamamoto, Arkivoc, 2007, 10, 121; D.M. D´Souza, T.J.J. Müller, Chem. Soc. Rev., 2007, 36, 1095. 2 V. Cadierno, J. Gimeno, N. Nebra, Chem. Eur. J., 2007, 13, 9973.

Posters SISOC7


PO-9

Water-Soluble Catalysts for Isomerization Processes

Beatriz Lastra-Barreira and Pascale Crochet* Departamento de Química Orgánica e Inorgánica

Universidad de Oviedo Facultad de Química, C/ Julian Clavería s/n, 33071 Oviedo, Spain [email protected] (B. L.-B.), [email protected] (P. C.)

Metal-catalyzed organic reactions in aqueous medium have received a great attention in recent years since water is a safe, non-toxic and cheap solvent.1 In this context, we have developed new efficient organometallic catalysts for several organic transformations.2 Herein we present the synthesis of novel water-soluble arene-ruthenium(II) complexes of type A (Figure 1) and their application in the catalytic isomerization of allylic substrates (see examples in Schemes 1 and 2). For all the processes studied, high activities and selectivities have been attained.

: hydro-solubilizing groupRuCl Cl L

(A)L : P-donor ligand

Figure 1: Structure of water-soluble catalysts

[Ru]OH

OMe

OH

OMe

Eugenol Isoeugenol

Scheme 1: Isomerization of aromatic allylic substrates.

[Ru]OH

R2R1

O

R2R1

Scheme 2: Isomerization of allylic alcohols to carbonylic compounds.

1 See for example: Multiphase Homogeneous Catalysis, B.Cornils, W. A. Hermann, I. T. Horváth, W. Leitneir, S. Mecking, H. Oliver-Bourbigou, D. Vogt (Eds.), Wiley-VCH, Weinheim, 2005. 2 a) V. Cadierno, P. Crochet, S. E. García-Garrido, J. Gimeno, Dalton Trans. 2004, 3635. b) P. Crochet, J. Díez, M. A. Fernández-Zúmel, J. Gimeno, Adv. Synth. Catal. 2006, 348, 93. c) A. E. Díaz-Álvarez, P. Crochet, M. Zablocka, C. Duhayon, V. Cadierno, J. Gimeno, J. P. Majoral, Adv. Synth. Catal. 2006, 348, 1671. d) A. E. Díaz-Álvarez, P. Crochet, M. Zablocka, C. Duhayon, V. Cadierno, J. P. Majoral, Eur. J. Inorg. Chem. 2008, 786.

SISOC7 Posters


PO-10

Synthesis of Heteropolycyclic Compounds by “Formal” Ruthenium-Catalyzed [4+2+2] Cycloaddition of 1,6-Diynes to cis-Propenylheteroarenes

S. García-Rubín, J. A. Varela, L. Castedo, C. Saá Departamento de Química Orgánica, Facultad de Química

Universidad de Santiago de Compostela Avda. das Ciencias s/n, 15782, Santiago de Compostela, Spain

[email protected] Heteropolycyclic natural products containing eight-membered rings are interesting synthetic targets due to their important biological activity.1 Recently, in our research group, we have developed a new “formal” ruthenium-catalyzed [4+2+2] cycloaddition of 1,6-diynes to 1,3-dienes to give conjugated 1,3,5-cyclooctatrienes. 2 When cis-propenylheteroarenes (heteroaryl-1,3-dienes) were used, heterofused cyclooctatrienes 4 were obtained in good yields. These compounds arise from a “formal” ruthenium-catalyzed [4+2+2] cycloaddition of diynes 1 and heteroaryldienes 2 to give 1,3,5-cyclooctatrienes 3, followed by [1,5]-hydrogen shift.

X +Z

Me10% [Cp*Ru(CH3CN)3]PF6

10% Et4NCl

DMF, 80ºC

XZ

Me

XZ

Me

[1,5]-H

X= C(CO2Me)2, OZ= N-Boc, O

40-72%

1 2 3 4

Acknowledgement: This work was supported by the M.E.C. (CTQ2005-08613), Consolider Ingenio 2010 (CSD2007-00006) and the Xunta de Galicia (2007/XA084 and PGIDIT06PXIC209041PN). S. G-R. and. J.A.V. also thank the M.E.C. for a FPU fellowship and a Ramón y Cajal research contract, respectively.

1 G. Metha, V. Singh, Chem. Rew. 1999, 99, 881-930. 2 J. A. Varela, L. Castedo, C. Saá, Org. Lett. 2003, 5, 2841-2844.

Posters SISOC7


PO-11

Cycloisomerization of α,ω- Alkynols and Alkynylamines via Catalytic Ru-vinylidenes: Formation of Benzofurans,

Isochromenes, 3-Benzoxepines, Indoles and Isoquinolines

A. Varela-Fernández, C. González-Rodríguez, J. A. Varela, L. Castedo, C. Saá* Departamento de Química Orgánica, Facultad de Química

Universidad de Santiago de Compostela Avda. das Ciencias, s/n. 15782 Santiago de Compostela. España

[email protected] Heterocyclic compounds are widely spread in nature. The development of new metal-catalyzed cyclizations can offer powerful means to synthesize these compounds.1 An attractive approach to this end, under the basis of atom economy,2 is the involvement of catalytic metal vinylidenes.3 Herein we present new 5-, 6-, and 7-endo cyclizations of aromatic α,ω- alkynols and alkynylamines 1 to give 5-, 6- and 7-membered heterocyclic compounds 2 in good to excellent yields. A plausible mechanism for this transformation involves an endo nucleophilic trapping of a Ru-vinylidene species (Scheme 1).4

XHR R

X

CpRuCl(PPh3)2amine, ∆( )n ( )n

X = O, Nn = 0, 1, 2

1 2

XR

( )n

Ru

X = O, n = 1 Benzofuransn = 2 Isochromenesn = 3 3-Benzoxepines

X = N, n = 1 Indolesn = 2 Isoquinolines

-

Scheme 1 Acknowlegment: We thank the M.E.C. (Spain) and FEDER (CTQ2005-08613), Consolider Ingenio 2010 (CSD2007-00006) and the Xunta de Galicia (2007/XA084 and PGIDIT06PXIC209041PN) for funding. A. V.-F. and C. G.-R. thank the XUGA and M.E.C, respectively, for predoctoral grants, and J. A. V. thanks the M.E.C. for a Ramón y Cajal research contract. 1 D. M. P. Mingos, R. H. Crabtree, Eds. Comprehensive Organometallic Chemistry III; Elsevier: Kyoto, 2007; Vol. 11. 2 a) B. M. Trost, Science 1991, 254, 1471-1477; b) B. M. Trost, Angew. Chem. Int. Ed. Engl. 1995, 34, 259-281. 3 a) F. E. McDonald, K. S. Reddy, Y. Diaz, J. Am. Chem. Soc. 2000, 122, 4304-4309. b) B. M. Trost, Y. H. Rhee, J. Am. Chem. Soc. 2002, 124, 2528-2533. c) B. M. Trost, Y. H. Rhee, J. Am. Chem. Soc. 2003, 125, 7482-7483. d) B. M. Trost, Angew. Chem. Int. Ed. 2007, 46, 2074-2077. 4 a) S.-I. Murahashi, Ed. Ruthenium in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2004. b) C. Bruneau, P. H. Dixneuf, Eds. Topics in Organometallic Chemistry; Springer: Berlin, 2004; Vol. 11.

SISOC7 Posters


PO-12

Platinum-Catalyzed Tandem Reactions Between Alkynols and N-Arylaldimines

Francisco J. Fañanás, Félix Rodríguez and Abraham Mendoza Instituto Universitario de Quimica Organometálica “Enrique Moles”

Universidad de Oviedo C/ Julián Clavería, 8 – 33006 Oviedo, Spain

[email protected] The development of tandem reactions is an important challenge in organic synthesis as these processes allow the access to structurally complex molecules in a single synthetic step. In this context, we have developed some tandem catalytic processes based on alkoxycyclization reactions as key reactions.1c These new reactions suppose a straightforward route to medium-size ring carbo- and heterocycles.1a,b

On the other hand the reaction of N-arylaldimines with an activated olefin in a [4+2] fashion is known as the Povarov reaction. This process can be catalyzed by Brönsted or Lewis acids.2

So, we envisioned a new catalytic tandem reaction in which the first step would be an alkoxycyclization of a ω-alkynol to yield an exocyclic enol ether. This intermediate species would react in a second step with the N-arylaldimine in a Povarov fashion to furnish interesting furoquinoline derivatives. The main challenge in developing this transformation would be to find an appropriate metal complex that catalyzes the two steps of the tandem process. Recent progresses on this area are presented in this communication (see scheme below).

1 a) Barluenga, J.; Fernández, A.; Rodríguez, F.; Fañanás, F. J. Angew. Chem. Int. Ed. 2006, 45, 2091. b) Barluenga, J.; Diéguez, A.; Rodríguez, F.; Fañanás, F. J. Angew. Chem. Int. Ed. 2005, 44, 126. c) Sordo, T.; Campomanes, P.; Diéguez, A.; Rodríguez, F.; Fañanás, F. J. J. Am. Chem. Soc. 2005, 127, 944 2 Xing, X.; Wu, J.; Dai W.-M. Tetrahedron 2006, 62, 11200 and references cited therein.

Posters SISOC7


PO-13

Gold-Catalyzed Reactions of ω-Alkynol Derivatives and Indoles

Amadeo Fernández, Félix Rodríguez and Francisco J. Fañanás Instituto Universitario de Química Organometálica “Enrique Moles”

Universidad de Oviedo C/ Julián Clavería Nº 8, 33006, Oviedo, Asturias, Spain

[email protected] Since the beginning of the 20th century, when the first domino reaction for the synthesis of a natural product was performed by Schöpf and Robinson, this type of processes have become powerful tools to accomplish the demands of modern organic chemistry (efficiency, low production costs, etc)1. These reactions offer the opportunity of building up complex molecules, frequently with high stereoselectivity, from simple and easily available substrates2. In particular, metal-catalyzed intramolecular addition of heteroatoms to alkynes provides a rapid and efficient access to a variety of heterocyclic compounds for a great range of synthetic applications3.

In this context, we have recently discovered a variety of catalytic domino processes for the diastereoselective synthesis of interesting carbo- and heterocycles from ω-alkynol derivatives in a very straight-forward way using wolframium, gold and platinum metallic complexes4.

In the present communication, we report a new type of gold catalyzed domino process involving the reactions of ω-alkynol derivatives and indoles. Different reaction products are obtained depending on the structure of the alkynol derivative.

OH+

N

[Au]

R1

O

N

R2

R2

n

OH

n = 3

n = 1

N

N

R1

R1

1 a) Robinson, R. J. Chem. Soc. 1917, 111, 762 and J. Chem. Soc. 1917, 111, 876. b) Schöpf, C.; Lehmann, G.; Arnold, W. Angew. Chem. 1937, 50, 779. 2 a) Tietze, L. F.; Chem. Rev. 1996, 96, 115. b) Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. Engl. 1993, 32, 131. 3 Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079. 4 a) Barluenga, J.; Diéguez, A.; Rodríguez, F.; Fañanás, F. J. Angew. Chem. Int. Ed. 2005, 44, 126; b) Barluenga, J.; Diéguez, A.; Fernández, A.; Rodríguez, F.; Fañanás, F. J. Angew. Chem. Int. Ed. 2006, 45, 2091. c) Barluenga, J.; Fernández, A.; Satrústegui, A.; Rodríguez, F.; Fañanás, F. J. Chem. Eur. J. 2008, 14, 4153.

SISOC7 Posters


PO-14

Gold-Catalyzed Intermolecular Hetero-Dehydro-Diels-Alder Cycloaddition of Captodative Dienynes: regioselective access to Pyridines

Patricia García-García, Enrique Aguilar and Manuel Ángel Fernández-Rodríguez Instituto de Investigaciones Químicas y Ambientales de Barcelona (IIQAB)-CSIC, Jordi

Girona 18-26, 08034-Barcelona, Spain and Instituto Universitario de Química Organometálica “Enrique Moles”, Unidad asociada al CSIC, Universidad de Oviedo, Julián

Clavería 8, 33006-Oviedo, Spain. [email protected]

The Diels-Alder reaction is undoubtedly the most powerful synthetic tool for the formation of six-membered cyclic structures. However, parallel studies to develop the closely related dehydro-Diels-Alder reaction (DDAR) have been less fruitful. Therefore, the state of the art for DDAR is mainly confined to intramolecular versions,1 while intermolecular approaches are limited to the employment of highly reactive intermediates such as benzyne or to photochemical activation. On the other hand, metal complexes derived from copper, platinum, silver and, especially, gold have recently shown a significant relevance as catalysts in the activation of carbon-carbon multiple bonds.2 These complexes act as soft carbophilic Lewis acids promoting the addition of soft nucleophiles in carbon-carbon and carbon-heteroatom bond forming reactions. Among this class of transformations, cycloisomerization reactions have been extensively studied; however, catalytic intermolecular cycloadditions have been scarcely developed although they are more synthetically attractive.

We present here the first example of a catalyzed intermolecular hetero-dehydro-Diels-Alder cycloaddition which occurs between push-pull 1,3-dien-5-ynes (easily obtained from commercially available 2-methoxyfurane and Fischer alkynyl carbene complexes) and nonactivated nitriles. The sequence is promoted by both gold (I) and gold (III) catalysts and lead to the regioselective formation of tetrasubstituted pyridines in good yields and with broad scope (Scheme 1).

N

R

OMeMeO2C

R1

R1-CN+

R

OMe

MeO2C Au (5 mol%)

DCE / 85 ºC

55-75%

Scheme 1

1 Recent references: (a) M. F. Martínez-Esperón, D. Rodríguez, L. Castedo, C. Saá Tetrahedron 2006, 62, 3843-3855. (b) E. González-Cantalapiedra, O. de Frutos, C. Atienza, C. Mateo, A. M. Echavarren Eur. J. Org.Chem. 2006, 3, 1430-1443. 2 Selected recent reviews: (a) D. J. Gorin, F. D. Toste Nature 2007, 446, 395-403. (b) A. S. K. Hashmi Chem. Rev. 2007, 107, 3180-3211. (c) N. T. Patil, Y. Yamamoto Arkivoc 2007, V, 6-19. (d) C. Bruneau Angew.Chem., Int. Ed. 2005, 44, 2328-2334. (e) A. M. Echavarren, C. Nevado Chem. Soc. Rev. 2004, 33, 431-436.

Posters SISOC7


PO-15

Transition-Metal Catalyzed Hetero-Dehydro-Diels-Alder Cycloaddition Between 1,3-Dien-5-ynes and Aldimines: Regio and Diasteroselective

Synthesis of Dihydropyridin-2-ones

Manuel Angel Fernández-Rodríguez, Enrique Aguilar and Jesús Manuel Fernández-García

Instituto Universitario de Química Organométalica “Enrique Moles”, Unidad Asociada al CSIC, Universidad de Oviedo, Julian Clavería 8, 33006-Oviedo, Spain

[email protected]

The transition metal-catalyzed enyne cycloisomerization is among the most important strategies for the synthesis of functionalized cyclic structures;1 however, cycloaddition reactions of these systems are not reported in a big extension.

We have recently described a gold-catalyzed cycloaddition of push-pull enynes with nitriles to yield pyridines,2 being this the first example of a catalyzed intermolecular hetero-dehydro-Diels-Alder cycloaddition. Herein we report the gold-catalyzed cycloaddition of captodative dienynes with other dienophiles, such as aldimines, to afford dihydropyridin-2-ones in moderate to good yields (Scheme 1). Moreover, this reaction is catalyzed by economically more affordable transition metals complexes derived from silver or copper, leading to the regio- and trans-stereoselective formation of tetrasubstituted dihydropyridin-2-ones with broad scope.

+MeO2C

R

OMe

N

R1

R2M (5-10 mol%)

50ºC - 85ºCN

R

OR1

R2

MeO2C

M = Au, Ag, Cu

Scheme 1

1 L. Zhang, J. Sun, and S. A. Kozmin Adv. Synth. Catal. 2006, 348, 2271-2296 and cited references. 2 J. Barluenga, M. A. Fernández-Rodríguez, P. García-García, E. Aguilar J. Am. Chem. Soc. 2008, 130, 2764-2765.

SISOC7 Posters


PO-16

Understanding the Behavior of Chelating Groups in Metal-Catalyzed Processes: 2-Pyridylsulfonyl and 8-Quinolylsulfonyl Moieties.

Jorge Esquivias, Ramón Gómez Arrayás, Juan C. Carretero and Inés Alonso Departamento de Química Orgánica

Universidad Autónoma de Madrid. Cantoblanco, 28049-Madrid, Spain [email protected], www.uam.es/catalisisasimetrica

Differences in reactivity and/or selectivity during a given metal-catalyzed process can often be observed by the introduction of chelating groups into the substrate. Despite its difficulty, a full understanding of the mechanism by which these groups work would be interesting for further applications. Theoretical calculations constitute a helpful tool to ascertain the origin of these effects.

The Lewis acid-promoted aza Friedel-Crafts reaction (AFCR) between electron-rich aromatic compounds and imines constitutes a powerful tool for the preparation of benzylic amines but, with less activated substrates, side products, especially triarylmethanes, are formed. Within this context, we have found a different behavior of N-tosyl imines and N-(2-pyridyl)sulfonyl imines.1 DFT theoretical calculations on the mode of coordination of the copper atom to both types of substrates allow understanding this different reactivity.2

N

Ph H

SO2-Ar NMe

Ph

NMe

NMe

CH2Cl2, rt, 5-15 min.

NHSO2Ar

PhNMe

Cu(OTf)2/(±)-BINAP(10 mol%)

Ar = 4-Tol

Ar = 2-Py

NH

Ar'Ph

SO2TolCu2+

Ar'Ph

HNS

OO N

Cu2+ (Ar'-H)

Herein we also present a preliminary study carried out to explain the enantioselectivity observed in the aza Diels-Alder reaction (ADAR) of N-sulfonyl-1-aza-1,3 dienes with vinyl ethers.3 In this case both pyridylsulfonyl and quinolylsulfonyl groups provided an adequate reactivity but better enantioselectivities were obtained with quinoline derivative.

Ph Ph

NS

Ar

O O

OEtNi(ClO4)2.6H2O

DBFOX-Ph

CH2Cl2, rt, 72 h(10 mol%)

NPhSO2Ar

Ph

OEt

(5 equiv)

Ar= 2-pyridyl, 42% eeAr= 8-quinolyl, 88% ee

O

NOO

N

PhPhDBFOX-Ph

1 J. Esquivias, R. Goméz-Arrayás, J. C. Carretero, Angew. Chem. Int. Ed. 2006, 45, 629-633. 2 I. Alonso, J. Esquivias, R. Goméz-Arrayás, J. C. Carretero, J. Org. Chem. 2008, (submitted). 3 J. Esquivias, R. Goméz-Arrayás, J. C. Carretero, J. Am. Chem. Soc. 2007, 129, 1480-1481.

Posters SISOC7


PO-17

N-Propargylic β-Enaminones: Common Intermediates for the Synthesis of Polysubstituted Pyrroles and Pyrydines

Sandro Cacchi,* Giancarlo Fabrizi,* Eleonora Filisti

Dipartimento di Studi di Chimica e Tecnologie del Farmaco Università degli Studi “La Sapienza”

P.le A. Moro 5, 00185, Rome, Italy [email protected]

N-propargylic β-enaminones have been used as common intermediates for the synthesis of pyrroles and pyridines containing a variety of neutral, electron-donating and electron-withdrawing substituents (Scheme 1).1

N

R3

R1

R2

O CuBrDMSO60-80 °C O

R2

NHR1

R3

Cs2CO3DMSOrt

NH

R3

OR2

R1

Scheme 1

Best results have been obtained using anhydrous DMSO as solvent. In presence of Cs2CO3, N-propargylic β-enaminones are cyclized in good to high yields to NH free pyrroles through a 5-exo-dig carbocyclization (Figure 1a).2 The use of recrystallized CuBr omitting bases, ligands and additives leads to the selective formation of pyridines through a 6-endo-dig cyclization which is favored by the coordination of the C-C triple bond to the transition metal (Figure 1b; M = transition metal).2

NR1

R2CO

R3

NH

R1

R2CO

MR3

a b Figure 1

In conclusion, a new and efficient approach to pyrroles and pyridines from readily available N-propargylic β-enaminones has been developed. The method tolerates different functional moieties and needs only inexpensive reagents such as Cs2CO3 and CuBr.

1 Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. In press. 2 (a) Baldwin, J. E.; J. Chem. Soc., Chem. Commun. 1976, 738. (b) Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42, 3846.

SISOC7 Posters


PO-18

1.2-Disustituted 4-Quinolones via Copper-Catalyzed Cyclization of 1-(o-Bromophenyl)-3-enaminones

Roberta Bernini,a Sandro Cacchi,b Giancarlo Fabrizi,b and Alessio Sferrazzaa a Dipartimento A.B.A.C.

Università della Tuscia e Consorzio Universitario “La Chimica per l’Ambiente” Via S. Camillo De Lellis, 01100 Viterbo, Italy

b Dipartimento di Chimica e Tecnologie del Farmaco Università degli Studi “La Sapienza”

P.le A. Moro 5, 00185, Rome, Italy [email protected]

We report a simple approach to the preparation of 1,2-disubstituted 4-quinolones 2 that is based on the copper-catalyzed cyclization of readily available 1-(o-Bromophenyl)-3-enaminones 1 (Scheme 1).

OBr

HN R1

R2

1

N

O

R2R1

2

"Cu"

Scheme 1

1-(o-Bromophenyl)-3-enaminones 1 were prepared via Sonogashira cross-coupling of terminal alkynes with commercially available o-bromobenzoyl chloride, followed by the conjugate addition of a primary amine with the resultant α,β-enones 3 (Scheme 2).

R1O

Cl

Br

R1

OPdCl2(PPh3)2, CuI

80-95%

O

Br

Br

HN R1

NEt3,THF, rt, 1 h

R2NH2, MeOH

60 °C, 4 hR280-95%

3

1 Scheme 2

After an initial screen of bases, solvents, ligands and reaction temperatures, we found that the use of 5 % of CuI and 5 % of TMEDA in anhydrous DMSO at 80 °C with 2 equivalents of K2CO3 with our model system (R1 = R2 = Ph) produced the corresponding quinolone after 2 h in 93% yield. Using these conditions, a variety of 1,2-disubstituted 4-quinolones (20 examples) containing neutral, electron-donating and electron-withdrawing substituents were isolated in good to high yields.

Posters SISOC7


PO-19

Palladium-catalyzed [2+2+2] Cycloaddition Reactions of Tetraphenylnaphthalynes

Alba E. Díaz-Álvarez, Diego Peña, Dolores Pérez, Enrique Guitián. Departamento de Química Orgánica

Universidad de Santiago de Compostela 15782 Santiago de Compostela, Spain

[email protected]

Polycyclic aromatic hydrocarbons (PAHs) have recently received increased attention because of their electronic and optoelectronic properties.1 In the last years, we have developed methods for the preparation of PAHs based on the palladium-catalyzed cyclotrimerization of arynes2, allowing us to obtain large polycyclic arenes under mild conditions.

In this communication we describe our efforts to synthesize compounds 3-5 by Pd-catalyzed [2+2+2] cycloaddition reactions of tetraphenylnaphthalyne 2, which is generated in situ by fluoride-induced decomposition of triflate 1.

PhPh

PhPh

OTf

TMS

CsF

PhPh

PhPh

[2+2+2]

PhPh

PhPh

PhPh

Ph

Ph

Ph

PhPh

Ph

[Pd2(dba)3]

DMAD

[Pd(PPh3)4]

DMAD

CO2Me

CO2Me

CO2Me

CO2Me

CO2MeCO2Me

1 2 3

5 4

CO2MeMeO2CPh

Ph

PhPh

PhPh

PhPh

PhPh

Ph

Ph

DMAD

[Pd]

1 J. Wu, W. Pisula, K. Müllen, Chem. Rev. 2007, 107, 718-747. 2 (a) D. Peña, S. Escudero, D. Pérez, E. Guitián, L. Castedo, Angew. Chem. Int. Ed. 1998, 37, 2659-2661. (b) D. Peña, D. Pérez, E. Guitián, L. Castedo, J. Am. Chem. Soc. 1999, 121, 5827-5828. (c) C. Romero, D. Peña, D. Pérez, E. Guitián, Chem. Eur. J. 2006, 22, 5677-5684. (d) J. Caeiro, D. Peña, A. Cobas, D. Pérez, E. Guitián, Adv. Synth. Catal. 2006, 348, 2466-2474.

SISOC7 Posters


PO-20

Pd-Catalyzed Cross-Couplings Reactions with Carbonyls: Application in a Very Efficient Synthesis of 4-Aryltetrahydropyridines1

María Tomás-Gamasa, Patricia Moriel, Fernando Aznar, Carlos Valdés Instituto Universitario de Química Organometálica “Enrique Moles”

Universidad de Oviedo Julián Clavería, 8. 33071. Oviedo, Spain

Palladium-catalyzed coupling reactions can be considered nowadays to be some of the most reliable methodologies for the formation of C-C linkages.2 Recently, we have uncovered a new Pd-catalyzed C-C bond-forming reaction that employs N-tosylhydrazones as nucleophilic partner, eliminating the need of a stoichiometric amount of an organometallic reagent.3 Since then, we have initiated a research program to evaluate the synthetic potential of this novel reaction. In this context, we found 4-aryltetrahydropyridines as ideal synthetic targets for our methodology. The 4-arylpiperidine scaffold is an important structure for medicinal chemistry, which is present in a vast number of biologically active and therapeutically useful molecules, and is continuously employed in drug discovery programs.4

N

O

R

(Het)Ar-X

Tos-NHNH21-2 mol% Pd2(dba)3 / XPHOS

LiOtBu, Dioxane, 110ºC

R = Et, Bn, H; X = Br, Cl

N

(Het)Ar

R

70-99%16 examples

The exhibited reaction constituted an extremely efficient methodology for the preparation of 4-arylpiperidines in very high yields by a novel Pd-catalyzed cross-coupling reaction that employs a tosylhydrazone as the nucleophilic coupling partner, with no stoichiometric organometallic reagent added. Importantly, the tosylhydrazone can be generated in situ, without being observed products derived from undesired side reactions, such as ketone α-arylation or tosylhydrazine N-arylation. Moreover, N-H unprotected 4-piperidones afforded excellent results, and the use of dry solvents or an inert atmosphere is not required for the coupling reaction. From a practical point of view, in this transformation a ketone is employed as a nucleophilic cross-coupling reagent, with no previous synthetic modification, only the addition of tosylhydrazine to the reaction medium. Acknowledgements: Financial support of this work by the DGI of Spain. FPU predoctoral fellowships to M. T.-G. and P. M. are gratefully acknowledged.

1 J. Barluenga, M. Tomás-Gamasa, P. Moriel, F. Aznar, C. Valdés Chem. Eur. J. D.O.I.: 10.1002/chem.200800390. 2 a) Handbook of Organopalladium Chemistry for Organic Synthesis (Ed.: E. Negishi), Wiley, New York, 2002; b) Metal-Catalyzed Cross-Coupling Reactions (Eds.: A. de Meijere, F. Diederich), Wiley-VCH, Weinheim, 2004. 3 J. Barluenga, P. Moriel, C. Valdés, F. Aznar Angew. Chem. Int. Ed. 2007, 46, 5587. 4 A simple Scifinder Scholar search of the 4-arylpiperidine concept between 1997 and 2007 gave over 50 entries of patents that referred to the synthesis and/or clinical applications of molecules containing this moiety.

Posters SISOC7


PO-21

Pd-Catalyzed Indole Synthesis from Phenols and Imines

Agustín Jiménez-Aquino, Carlos Valdés, Fernando Aznar Instituto Universitario de Química Organometálica “Enrique Moles” Unidad Asociada al

CSIC. Universidad de Oviedo

Julián Clavería 8, 33006 Oviedo, Spain [email protected]

We have recently developed a novel cascade synthesis of indoles from o-dihalobenzene derivatives and imines 1. The process involves the α−arylation of the imine followed by an intramolecular C-N bond forming reaction.1

To expand the applicability of this synthesis of indoles, we studied the reaction employing o-halobenzene sulfonates 2 as starting materials. The o-halobenzene sulfonates 2 are readily available from o-chlorophenols 3, which are very abundant commercially, or otherwise easily prepared from phenols 4 (Scheme 1).

Scheme 1

The potencial of this method is also illustrated by the regioselective preparation of unusual 4,6-disubstituted indoles. The 4-methoxy-6-allylindole derivative 5, was synthesized from imine 1a and the chlorononaflate 2a. The latter was easily prepared in two steps from anethole 4a, a naturally occuring phenol (Scheme 2).

Scheme 2

1 Barluenga, J.; Jiménez-Aquino, A.; Valdés, C.; Aznar, F. Angew. Chem. Int. Ed. 2007, 46, 1529 –1532.

SISOC7 Posters


PO-22

Simple Indole Synthesis by One-Pot Sonogashira Coupling / NaOH-Mediated Cyclization

Roberto Sanz, Delia Miguel, M. Pilar Castroviejo and Verónica Guilarte Área de Química Orgánica. Departamento de Química. Facultad de Ciencias


[email protected]; http://web.ubu.es/investig/grupos/cien_biotec/qo-3/index.html The synthesis of functionalized indoles remains a major challenge for synthetic organic chemists, and numerous methods for their preparation have been developed.1 Among the many methods for indole ring synthesis, an interesting access to 2-substituted indoles makes use of a metal alkoxide-mediated cyclization of 2-alkynylaniline derivatives and several examples of this methodology have been reported.2 Most of these methods suffer from drawbacks like the use of air-sensitive bases. Herein, we report a new method for the one-pot synthesis of 2-substituted indoles from o-iodoanilines using a NaOH-mediated 5-endo-dig cyclization of o-alkynylanilines as the key step. This base-mediated cyclization takes place under conventional heating, or more conveniently, under microwave irradiation (Scheme 1).

R

NH2NH

R

R = Alk, Ar, HetAr,...

NaOH (3 equiv), DMF, 140 ºC, 2−9 hor

NaOH (1.5 equiv), DMA,µW (170 ºC), 7−40 min

(72-91%)

Scheme 1 Although the starting o-alkynylanilines were easily synthesized by the Sonogashira cross-coupling of o-iodoanilines with 1-alkynes, we found that the targeted 2-substituted indoles could be prepared by a one-pot procedure from o-iodoanilines. (Scheme 2). This process is compatible with the presence of several important functional groups onto the benzenoid moiety, and also it does work with N-unsubstituted anilines as well as with substituted ones. Moreover, an arylthio group can also be selectively introduced at the C-3 position without isolation of any intermediate.

I

NH NR2

G = Hal, CN, NO2R1 = H, Ac, Alk

1. PdCl2(PPh3)2 (3 mol%), CuI (5 mol%) Et2NH (1.5 equiv), DMF or DMA, rt, 1−2 h or µW (70 ºC), 10 min2. NaOH (10 equiv), 140 ºC, 2−20 h, or NaOH (1.5 equiv), µW (180 ºC), 20−40 min

(61-89%)

G

R1

R2 G

R1

+

Scheme 2

1 a) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 28732920; b) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 28752911. 2 a) Y. Kondo, S. Kojima, T. Sakamoto, J. Org. Chem. 1997, 62, 65076511; b) A. L. Rodríguez, C. Koradin, W. Dohle, P. Knochel, Angew. Chem. Int. Ed. 2000, 39, 24882490.

Posters SISOC7


PO-23

From Aromatic Lithiation to Palladium-catalyzed Coupling Reactions. Synthesis of Substituted Quinolines from 2-Iodoanilines

Oihane García-Calvo, Unai Martínez-Estíbalez, Esther Lete, and Nuria Sotomayor Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología

Universidad del País Vasco/EHU Apdo. 644, 48080 Bilbao (Spain)

[email protected]

During the last years our group has been involved in a research program oriented to the development of the new methods for asymmetric synthesis of heterocycles, using organolithium intermediates in the stereocontrolled formation of carbon-carbon bonds. Thus, fused indolizidine and quinolizidine systems have been accessed using Parham-type cyclizations, using imides and amides as internal electrophiles. We have demonstrated that these cyclizations proceed with high diastereoslectivity due to the steric control by the substituents in the position to the carbonyl group or the nitrogen atom. We have developed the enantioselective synthesis of pyrroloisoquinolines by the introduction of a chiral auxiliary on the imide precurors.1

In this context, we have also explored these Parham cyclizations in the synthesis of tetrahydroquinoline systems using alkenes as internal electrophiles. Therefore, we have studied the intramolecular carbolithiation reaction of unsaturated aryllithium compounds for the construction of six-membered rings through a 6-exo-trig cyclization process. On the other hand, since intramolecular Pd(0)-catalyzed Heck reaction can also be performed on aryl halides bearing an alkene unit, we decided to carry out a comparative study of intramolecular carbolithiation and Heck reactions. We have found the combination of catalytic systems and experimental conditions to achieve the regioselective preparation of substituted quinolines starting from adequately functionalized 2-haloaniline derivatives. The scope and limitations of both procedures will be discussed.

Pd(0)

and/or

N R1

R2

X

N R1 N R1

catalyst

X = I, BrR1 = H, Ph, OCH2Bn, CO2EtR2 = H, CONEt2, CONMeOMe

N R1

CONR2

R2 = H

R2 = CONR2

1 For reviews on our work on this area, see: (a) N. Sotomayor, E. Lete Curr. Org. Chem. 2003, 7, 275. (b) S. Arrasate, N. Sotomayor, E. Lete Trends Org. Chem.(New Methods for the Asymmetric Synthesis of Nitrogen Heterocycles), 2005, 223..

SISOC7 Posters


PO-24

Palladium-catalyzed Intramolecular γ-Arylation of α-Nitroketones

Giorgio Giorgi, Pilar López-Alvarado and J. Carlos Menéndez Departamento de Química Orgánica y Farmacéutica

Facultad de Farmacia, Universidad Complutense Plaza de Ramón y Cajal, s.n., 28040 Madrid, Spain

[email protected]

Areno-fused derivatives of bicyclo[n.3.1]decane systems are present in several bioactive natural products, including the MDR reversor N-methylwelwitindolinone C isothiocyanate1 and the acetylcholinesterase inhibitor huperzine A.2 Synthetic derivatives of this framework have also shown potent pharmacological activities (e.g. the analgesic activity of compound 1).

NO

CH3

CH3

CH3SCN O

HH3C

H2CCl

H

N-Methylwelwitindolinone C isothiocyanate (welwistatin)

N

NH2H3C

CH3

OH

Huperzine A

H2N

CH3OH

1

We describe in this communication a very concise synthetic pathway that allows the preparation of highly functionalized benzo-fused bicyclo[n.3.1] systems (n = 1-3). Thus, treatment of α-nitroketones 2 with benzylic halides 3 in the presence of DBU gave the C-alkylation derivatives 4. The final cyclization to bicyclic systems 5 was achieved by an intramolecular Pd-catalyzed carbon-carbon formation reaction,3 which proceeded in 50-92% yield with no interference from the nitro group:

O2N

O

( )nOO2N

Br

X

O

O2N

Br

+( )n

n = 1, 2, 32X = Br, I

DBU

THF, r. t.

R = H; Cl; CH3

PdCl2(Ph3P)2, CsCO3, toluene,

reflux

5

R

3 4

R

( )n

R

1 (a) Avendaño C.; Menéndez J.C. Curr. Org. Synth. 2004, 1, 65. (b) Menéndez, J. C. Topics Heterocycl. Chem.

2007, 11, 63 2 Bai, D. L.; Tang, X. C.; He, X. C. Curr. Med. Chem. 2000, 7, 355. 3 Hideaki M.; Mitsutaka N.; Hiroshi N. Tetrahedron 2004, 60, 11783.

Posters SISOC7


PO-25

Synthesis of 2,3-Substituted Maleimides by Chemoselective Palladium-Catalyzed Cross-Coupling Reactions of Indium Organometallics

Latifa Bouissane, José Pérez Sestelo and Luis A. Sarandeses Departamento de Química Fundamental

Universidade da Coruña Facultade de Ciencias, Campus A Zapateira, s/n, E-15071 A Coruña, Spain

[email protected]

2,3-Disubstituted maleimides such as bisindolylmaleimides, indolylarylmaleimides and indolocarbazoles are a valuable family of compounds with pharmacological properties such as antitumoral and antibiotic activity and PKC inhibitors.1 Although many substituted maleimides have been synthesized and biologically evaluated, only few methods are available for the synthesis of these compounds, which generally involves the generation of the maleimide ring from expensive precursors. The high chemo- and regioselectivity showed by the indium reagents in cross-coupling reactions led us to explore their reactivity towards halomaleimides.2 In this communication, we present the synthesis of 2,3-disubstituted maleimides by selective palladium-catalyzed cross-coupling reactions of indium organometallics.

The palladium-catalyzed cross-coupling reaction of different triorganoindium reagents (2- and 3-indolyl, aryl, heteroaryl, alkynyl, alkyl, 40 mol%,) with a N-protected 2,3-dichloro- or dibromomaleimide (1) afforded chemoselectively the monosubstitution products (2) in good yields (67–81%). The resulting 2-halomaleimides 2 are suitable substrates for a new coupling reaction with different R3In reagents, obtaining a variety of disubstituted maleimides (3) in good yields (80–90%). Interestingly, the two-step coupling sequence can be also performed in an one pot procedure. In this way, the sequential addition of two different organoindium reagents to a N-protected-2,3-dibromomaleimide afforded, in the presence of a palladium catalyst, the corresponding 2,3-disubstituted maleimides (4) in good yields (68–89%). Further applications of this methodology to the synthesis of maleimides and indolocarbazoles will be presented.

NO O

PG

X X

NO O

PG

R1 X

NO O

PG

R1 R2

1 2 3

R13In

Pd cat.

X = Cl, BrPG = protecting groupR1, R2 = 2- and 3-indolyl, aryl, heteroaryl, alkynyl, alkyl

R23In

Pd cat.

1) R13In, Pd cat.

2) R23In

Acknowledgements: This research was supported by the Ministerio de Educación y Ciencia (Spain, CTQ2006-06166) and Xunta de Galicia (PGIDIT05BTF10301PR). 1 S. Roy, S. Roy, G. W. Gribble, Org. Lett. 2006, 8, 4975–4977, and references therein. 2 R. Riveiros, L. Saya, J. Pérez Sestelo, L. A. Sarandeses, Eur. J. Org. Chem. 2008, 1959–1966

SISOC7 Posters


PO-26

Palladium-Catalyzed Cross-Coupling Reactions of Indium Organometallics with Pyrimidines. Synthesis of Hyrtinadine A

Ángeles Mosquera, Ricardo Riveiros, José Pérez Sestelo and Luis A. Sarandeses Departamento de Química Fundamental

Universidade da Coruña Facultade de Ciencias, Campus A Zapateira, s/n, E-15071 A Coruña, Spain

[email protected] The palladium-catalyzed cross-coupling reaction of indium organometallics with organic electrophiles is an useful reaction in organic synthesis.1 This reaction proceeds with high efficiency, versatility and chemoselectivity, where all the three organic groups attached to the metal are efficiently transferred to the electrophile. In this communication, we present the reactivity of R3In in Pd-catalyzed cross-coupling reactions with halopyrimidines and the first synthesis of the alkaloid hyrtinadine A.

Hyrtinadine A (1) is a novel indole alkaloid recently isolated from an Okinawan marine sponge of the Hyrtios genus with in vitro cytotoxic activity against some tumoral lines.2 Structurally, hyrtinadine A is the first example of a natural bis-indole alkaloid with a 2,5-disubstituted pyrimidine nucleus. The synthesis of hyrtinadine A was accomplished through a two-fold palladium-catalyzed cross-coupling reaction between a 3-indolylindium reagent and 5-bromo-2-chloropyrimidine (2).

Br

N N

ClNH

N

NHN

OH HO

Hyrtinadine A (1)

R1

N N

Cl

R1

N N

R1

R1

N N

R2

; ;

R13In

R23In

2

R3In

Pd cat. Pd cat.

3 4 5

2,5-Disubstituted pyrimidines are attractive compounds that present particular photophysical properties with interest in materials science, or as intermediates in the synthesis of pharmaceuticals. The Pd-catalyzed cross-coupling reactions of R3In with 2 is chemoselective and has allowed the possibility to perform selective coupling reactions in the more reactive bromine atom (3), dicoupling reactions (4), and sequential cross-coupling reactions (5). Acknowledgements: We are grateful to the Ministerio de Educación y Ciencia (Spain, CTQ2006-06166) and Universidade da Coruña for financial support. A.M. thanks the Ministerio de Educación y Ciencia of Spain for a predoctoral fellowship (FPI) and R.R. thanks the Xunta de Galicia for a postdoctoral contract (“Isidro Parga Pondal” program)

1 a) M. A. Pena, J. Pérez Sestelo, L. A. Sarandeses, J. Org. Chem. 2007, 72, 1271–1275. b) J. Caeiro, J. Pérez Sestelo, L. A. Sarandeses, Chem. Eur. J. 2008, 14, 741–746; and references therein. 2 T. Endo, M. Tsuda, J. Fromont, J. Kobayashi, J. Nat. Prod. 2007, 70, 423–424.

Posters SISOC7


PO-27

Transition Metal Catalysed Intramolecular [3+2+2] Cycloadditions of Alk-10-yn/en-5-ynylidenecyclopropanes: A novel Route to Azulene Derivatives

Gaurav Bhargava, Beatriz Trillo, Fernando López, Luis Castedo and José L. Mascareñas

Departamento de Química Orgánica Universidade de Santiago

15782, Santiago de Compostela SPAIN

[email protected]

In this communication we will present our preliminary results on metal-catalyzed

intramolecular [3+2+2] cycloadditions of alkynylidenecyclopropanes of type 1 to give

interesting cyclopenta[e]azulene frameworks.11 The reactivity outcome, in particularly the

selectivity between the seven- and the five-membered products, is quite dependent on the

transition metal and ligand employed, as well as on other reaction parameters such as solvent

and temperature. Fine tuning of the conditions allowed to obtain the desired [3+2+2] adduct

(2) as the major or unique product of this process. The effect of various substituents at

terminal alkene/-yne position, as well as a mechanistic hypothesis, will be also discussed.

X

X

X= O, N, C(CO2Et)2 R= CH3, CO2Et

"Pd" or "Ni"

X

X

2

X

3

+

X

RR

1

R

ligands

1 Pd-catalyzed [3+2] and [3+4] processes have been previously described by our group: our references: (a) Delgado, A.; Rodrıguez, J. R.; Castedo, L.; Mascarenas, J. L. J. Am. Chem. Soc. 2003, 125, 9282-9283. (b) Duran, J.; Gulıas, M.; Castedo, L.; Mascarenas, J. L. Org. Lett. 2005, 7, 5693-5696. (c) Gulıas, M.; Garcıa, R.; Delgado, A.; Castedo, L.; Mascarenas, J. L. J. Am. Chem. Soc. 2006, 128, 384-385. (b). Gulias M.; Duran, J.; Lopez, F.; Castedo, L.; Mascarenas J. L. J. Am. Chem. Soc. 2007, 129, 11026-11027

SISOC7 Posters


PO-28

Divergent Titanium-Mediated Allylations via Modulation by Palladium or Nickel.

Btissam Bazdi, Noelia Fuentes, Rafael Robles, Juan M. Cuerva, J. Enrique Oltra, Susana Porcel, Antonio M. Echavarren and Araceli G. Campaña

Department of Organic Chemistry University of Granada

Faculty of Sciences. E-18071. Granada (Spain) [email protected], www.ugr.es/~fqm339

Allylation reactions are basic synthetic methods among the most useful C-C bond forming processes.1 Nevertheless, the vast majority of allylation protocols, including TiIII-mediated radical generation, requires reactive substrates like allylic halides.2

A more attractive approach involves the use of allyl carboxylates as excellent allyl donors, with the benefits of easy handling and low cost. However, allylic carboxylates are inert against titanocene(III) complexes.

The combination of late transition metals with titanocene(III) complexes might facilitate the development of novel allylation processes using accessible allyl carbonates as allylic reagents.

[M] = Pd. Cp2TiCl

[Ti]MOCOR [M] = Ni

OCOR

[M]

TiCp2Cl Cp2TiCl

E+

E

.

TiCp2Cl

Cp2TiCl

Cp2TiCl

In the present communication, we will report our results using multimetallic systems based on TiIII and late transition metals, such as Pd and Ni, lead to develop carbon-carbon bond forming processes under mild reaction conditions with complete selectivity.

Acknowledgment. We thank the Spanish MEC for the financial support (Project CTQ2005-08402).

1 Comprehensive Organic Synthesis, B. M. Trost and I. Fleming (Eds), Pergamon Press, Oxford, 1991, vol. 1 and 2. 2 A. Rosales, J. L. Oller-López, J. Justicia, A. Gansaüer, J. E. Oltra, J. M. Cuerva. Chem. Commun. 2004, 2628-2629.

Posters SISOC7


PO-29

Enantioselective Barbier-Type Cyclizations Catalyzed by TiIII

Rosa E. Estévez, José Justicia, Noelia Fuentes, Miguel Paradas, Rafael Robles, Juan M. Cuerva, and J. Enrique Oltra.

Department of Organic Chemistry, Faculty of Sciences, University of Granada, E-18071 Granada, Spain.

Email: [email protected], [email protected], [email protected].

As early as 1899, P. Barbier reported the coupling reaction between a ketone and an alkyl halide in the presence of a stoichiometric quantity of magnesium metal,1 thus establishing the basis for the one step C-C bond-forming process currently known as the Barbier reaction. In many occasions, the one-step strategy of this reaction can be more convenient than the two-step one (preparation of the organometallic reagent and subsequent coupling with the carbonyl derivative) characteristic of Grignard-type processes. Due to the considerable synthetic utility of allylation reactions, in the last decades different transition metals have been applied for promoting Barbier-type allylations.2 Nevertheless, methods described for Barbier-type intramolecular crotylations (cyclizations) are scarce. Based on our precendent report on Ti-catalyzed intermolecular Barbier-type allylations,3 we have recently developed a novel procedure for stereoselective Barbier-type cyclizations (see scheme below).

ZBr

O

Z

O

Z

OH

Cp2TiCl2(0.4 equiv)

TMSCl/collidineMn,

Br

(80-90%) This stereoconvergent reaction takes place at room temperature, under mild conditions compatible with many functional groups, provides high yields of cyclic homoallylic alcohols, including piperidine derivatives, and can be conducted in an enantioselective manner. In this communication, we will present our recent results in this field. 1 Barbier, P. Compt. Rend. 1899, 128, 110-111. 2 Larock, R. C. Comprehensive Organic Transformations,2nd ed.; Wiley-VCH: New York, 1999; pp 1126-1133. 3 Rosales, A.; Oller-López, J. L.; Justicia, J.; Gansäuer, A.; Oltra, J. E.; Cuerva, J. M. Chem. Commun. 2004, 2628-2629.

SISOC7 Posters


PO-30

Phosphine-Free Perfluoro-Tagged Palladium Nanoparticles Supported on Fluorous Reversed-Phase Silica Gel. Application for the C-C cross-coupling

Reactions

Roberta Bernini,1 Sandro Cacchi,2 Giancarlo Fabrizi,2 Giovanni Forte,3 Sandra

Niembro,4 Francesco Petrucci,3 Roser Pleixats,4 Alessandro Prastaro,1 Rosa Maria Sebastian,4 Roger Soler,4 Mar Tristany,4 Adelina Vallribera4

1 Dipartimento A.B.A.C., Università della Tuscia e Consorzio Universitario “La Chimica per l’Ambiente”, Via S. Camillo De Lellis, 01100 Viterbo, Italy

2 Dipartimento di Studi di Chimica e Tecnologia delle Sostanze BiologicamenteAttive Università degli Studi “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy 3 Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy

4 Department of Chemistry, Universitat Autònoma de Barcelona, Cerdanyola 08193, Spain. [email protected]

Solid-supported palladium-catalyzed reactions have become valuable tools for facilitating the recovery and reutilization of palladium and reducing the palladium contamination of the isolated products, a significant problem for the pharmaceutical industry. Activated carbon is the most commonly used insoluble support for palladium. Silica has also been used as an inert surface to adsorb palladium. A different approach to supported palladium catalysts involves the coordination of palladium to a ligand covalently bound to a polymer backbone. More recently, micro encapsulation of palladium in polymeric coating has been shown to be an efficient and cost effective technique to legate and retain palladium species and, in the same direction, aerogels, a new class of porous solids obtained via sol-gel processes coupled with supercritical drying of wet gels, have also been shown to exhibit a great potential for the preparation of heterogeneous catalysts. In this context, we investigated the immobilization of phosphine-free perfluoro-tagged palladium nanoparticles - prepared by reduction of Pd(II) chloride in the presence of 1, a stabilizing agents featuring long perfluorinated chains - on fluorous reversed-phase silica gel (FRPSG; 2) and their utilization in the cross-coupling reactions. Previous examples of utilization of FRPSG for immobilizing palladium catalysts entail palladium complexes containing perfluoro-tagged phosphine ligands.1

N

N

N

SCH2CH2C8F17

SCH2CH2C8F17C8F17H2CH2CS

1

OO

OSi

C6F13

2

________________________________ 1 (a) Tzschucke C. C.; Markert C.; Glatz, H.; Bannwarth W. Angew. Chem. Int. Ed. 2002, 41, 4500. (b) Tzschucke C. C.; Bannwarth W. Helv. Chim. Acta 2004, 87, 2882. 2 R. Bernini, S. Cacchi, G. Fabrizi, G. Forte, S. Niembo, F. Petrucci, R. Pleixats, A. Prastaro, R. M. Sebastiàn, R. Soles, M. Tristany, A. Vallribera., Org. Lett. 2008, 10, 561-564.

Posters SISOC7


PO-31

A Mild Synthesis of 2-Arylquinolines Based on a CAN-catalyzed Four-Component Reaction

Pascual Ribelles, Mª Teresa Ramos and J. Carlos Menéndez Departamento de Química Orgánica y Farmacéutica


[email protected]

2-Arylquinolines are essential structural fragments in compounds with a variety of interesting pharmacological properties, including inhibition of hepatitis C proteases,1 antagonism of P-selectin2 and binding to heat-shock protein 90.3 Literature methods for the construction of this structural motif are relatively scarce and normally involve multi-step sequences.

We report in this communication a new procedure for the synthesis of 2-arylquinolines, based on a CAN-catalyzed four-component reaction4 starting from anilines, aromatic aldehydes and vinyl ethers, followed by in situ aromatization in the presence of iron trichloride.5 Besides using very simple starting materials and unexpensive and non-toxic catalysts, the method proceeds in good to excellent yields.

NH2

Ar

O

HNH2

OEt

+

CAN (10%), CH3CN, r.t., 3h

NH

Ar

HNR3

R3

R1

RR1

R

1

N ArR1

R

2

FeCl3.6H2O, MeOH, r.t., 3h

1 Liverton, N. J.; Holloway, M. K.; McCauley, J. A.; Rudd, M. T.; Butcher, J. W.; Carroll, S. S.; DiMuzio, J.;

Fandozzi, C.; Gilbert, K. F.; Mao, S. S.; McIntyre, C. J.; Nguyen, K. T.; Romano, J. J.; Stahlhut, M.; Wan, B.-L.; Olsen, D. B.; Vacca, J. P. J. Am. Chem. Soc. 2008, 130, 4607.

2 Kaila, N.; Janz, K.; DeBernardo, S.; Bedard, P. W.; Camphausen, R. T.; Tam, S.; Tsao, D. H. H.; Keith, J. C.; Nickerson-Nutter, C.; Shilling, A.; Young-Sciame, R.; Wang, Q. J. Med. Chem. 2007, 50, 21.

3 Hargreaves, R.; David, C. L.; Whitesell, L.; Skibo, E. B. Bioorg. Med. Chem. Lett. 2003, 13, 3075. 4 Zhu, J.; Bienaymé, H. (eds.), Multicomponent Reactions. Wiley-VCH, Weinheim, 2005. 5 Hermanth, K.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2004, 45, 7903.

SISOC7 Posters


PO-32

Efficient Synthesis of Highly Substituted Pyrroles Through a CAN-Catalyzed Sequential Three-Component Reaction

Verónica Estévez, Mercedes Villacampa and J. Carlos Menéndez Departamento de Química Orgánica y Farmacéutica


[email protected] The pyrrole nucleus is widespread in nature and can be found in a large number of pigments and bioactive natural products. It is also a structural fragment of many compounds with varied pharmacological properties, including inhibition of HIV fusion,1 antimycobacterial2 and hepatoprotective3 activities, among many others, and it is also very important in materials science. Although a variety of approaches to substituted pyrroles exists, their synthesis remains challenging. In particular, the development of mild and efficient methods that allow the synthesis of polysubstituted pyrroles is a difficult problem that remains largely unsolved.4

We report in this communication a new procedure for the synthesis of pyrroles bearing up to five different substituents, based on a sequential three-component reaction5 between primary amines, β-ketoesters and α-iodoketones in the presence of CAN, a non-toxic and unexpensive catalyst. Our method is related to the traditional Hantzsch pyrrole synthesis, but has the advantage of affording good to excellent yields and allowing a much broader substitution pattern, including the preparation of N-substituted pyrroles.

HN R2

CO2R3

R1R2

CO2R3

O

NH2

R1+

(NH4)2Ce(NO3)6 (5%)

O

R5R4

I

AgNO3

HN R2

CO2R3

R1

R4

O

R5

NR1

R5 R2

CO2R3R4

NR1

R5

R2

CO2R3R4

HO

CH3OH, r.t.

- H2O

1 2 3

45

1 Teixeira, C.; Barbault, F.; Rebehmed, J.; Liu, K.; Xie, L.; Lu, H.; Jiang, S.; Fan, B.; Maurel, F. Bioorg. Med.

Chem. 2008, 16, 3039. 2 Biava, M.; Porretta, G. C.; Deidda, D.; Pompei, R.; Tafic, A.; Manettic, F. Bioorg. Med. Chem. 2004, 12,1453. 3 Chin, Y. W.; Lim, S. W.; Kim, S.-H.; Shin, D.-Y.; Suh, Y.-G.; Kim, Y.-B.; Kim, Y. C.; Kim, J. Bioorg. Med.

Chem. Lett. 2003, 13, 79. 4 Schmuck, C.; Rupprecht, D. Synthesis 2007, 3095. 5 Multicomponent Reactions, Zhu, J.; Bienaymé, H. (Eds.). Wiley-VCH, Weinheim, 2005.

Posters SISOC7


PO-33

Synthesis of Areneciclobutane Derivatives Promoted by Aryne-Zirconocene Complexes

Jonás Calleja, Félix Rodríguez and Francisco J. Fañanás.* Instituto Universitario de Química Organometálica “Enrique Moles”, Universidad de

Oviedo, Julián Clavería 8, 33006, Oviedo, Spain. [email protected]

The growing interest of zirconium organometallic complexes in organic synthesis is due to the ability of these type of complexes to promote unusual transformations.1 One of the most interesting applications of those organozirconium complexes is the co-cyclization of alkenes and/or alkynes. In spite of the enormous effort performed by several groups in this field, the reaction of heterosubstituted alkenes with zirconocene complexes has not yet studied in detail.2 For this reason, we have recently started a new project aimed to the study of coupling reactions between zirconocene complexes and alkenyl bromides or enol ethers.3 Recent results related to the coupling reactions between aryne-zirconocene complexes and alkenyl bromides are presented in this communication. Thus, the simple treatment of an aryllithium compound with zirconocene methyl chloride followed by addition of an alkenyl bromide leads, after a final treatment with an electrophile, to the corresponding aryneciclobutane derivative in high yield and as a single diastereoisomer (Scheme).

R1

R2 LiR1

R2 E

R3

1. Cl(Me)ZrCp2

2. R3 Br

3. E+

Scheme

Noteworthy, this process supposes an easy functionalization of two adjacent positions of the initial aromatic ring and both sp2-carbons of the alkenyl bromide. Non conventional reactions are involved in this transformation: functionalization of an aromatic C-H bond, substitution of a bromine atom in an alkenyl bromide and a formal and net [2+2] cycloaddition reaction between an aryllithium reagent and an alkenyl bromide. 1 a) New Aspects of Zirconium Containing Organic Compounds, Topics in Organomet. Chem., Vol 10; Marek I., (Vol Ed.); Springer: Berlin, 2005; b) Titanium and Zirconium in Organic Synthesis; Marek, I., (Ed.); Willey-VCH: Weinheim, 2002. 2 Barluenga, J.; Rodríguez, F.; Álvarez-Rodrigo, L.; Fañanás, F. J. Chem. Soc. Rev. 2005, 34, 762. 3 a) Barluenga, J.; Rodríguez, F.; Álvarez-Rodrigo, L.; Fañanás, F. J. Chem. Eur. J. 2004, 10, 101; b) Barluenga, J.; Rodríguez, F.; Álvarez-Rodrigo, L.; Zapico, J. M.; Fañanás, F. J. Chem. Eur. J. 2004, 10, 109; c) Barluenga, J.; Álvarez-Rodrigo, L.; Rodríguez, F.; Fañanás, F. J. Angew. Chem. Int. Ed. 2004, 43, 3932; d) Barluenga, J.; Fernández, A.; Álvarez-Rodrigo, L.; Rodríguez, F.; Fañanás, F. J. Synlett 2005, 2513; e) Barluenga, J.; Álvarez-Rodrigo, L.; Rodríguez, F.; Fañanás, F. J. Angew. Chem. Int. Ed. 2006, 45, 6362; f) Barluenga, J.; Álvarez-Rodrigo, L.; Rodríguez, F.; Fañanás, F. J.; Sordo, T. L.; Campomanes, P. Angew. Chem. Int. Ed. 2007, 46, 2607.

SISOC7 Posters


PO-34

Understanding the Regioselectivity of Grignard Reagents

Ana Alcalde,ŧ Julio Lloret,ŧ Gregorio Asensio,ŧ Agusti Lledos,§ and Teresa Vareaŧ ŧDepartamento de Química Orgánica,

Universidad de Valencia, Avda. V.A. Estellés s/n 46100-Burjassot, Spain

§Departament de Química, Edifici Cn, Universitat Autónoma de Barcelona,

08193 Bellaterra, Spain [email protected]

Compounds 1 obtained in the mono addition of vinylmagnesium bromide to a carbonyl group of a squarate are attractive structural models to determine the influence of complexation between magnesium (II) and the alkoxide group on the regioselectivity of the 1,2- versus 1,4-addition organomagnesium by complex induced proximity effects (CIPE).1 The 1,4-addition is observed almost exclusively in the case of vinyl magnesium in THF solution with formation of hydroxyketones type 2 which are always side or minor products in the known reaction of alkenyl lithium derivatives.2 The high regioselectivitity observed in the 1,4-addition of vinylmagnesium bromide is fully understood by computational studies of compounds 1 at DFT level with the density functional B3LYP. Simplified models do not suggest any regioselectivity in the addition of vinylmagnesium bromide to the α,β-unsaturated moiety since alkoxide coordinated Mg(II), is placed at a similar distance to both electrophilic centers. Calculation of LUMO coefficients and NPA charges of the magnesium alkoxide does not allow expecting any regioselectivity in the addition of the second vinylmagnesium equivalent since LUMO coefficients and NPA charges in C-2 and C-4 show very similar values. B3LYP/6-31++G** calculations including solvent effects show the existence of a lower energy transition state leading to the 1,4-addition product from an intermediate involving the coordination of the second vinyl magnesium bromide unity by interacting tetracoordinated Mg(II) with the negatively charged alkoxy oxygen atom.

R1O

R1O O

1,4-additionO

R1O

R1O

OH

R1O

R1O

OH

THF, -78ºC

(isomers ratio >9:1)

OMgBrMgBr

1,2-addition

O

1

2

3 (Financial support by the Project Consolider Ingenio 2010 CSD2007-00006 is gratefully acknowledged)

1 Beak, P.; Meyers, A.I. Acc. Chem. Res. 1986, 19, 356. 2 Paquette, L. A. Eur. J. Org. Chem., 1998, 1709 and references cited therein.

C(4)

C(2)

C(7) Mg(2)

Br(2)

Br(1)

Mg(1)

Posters SISOC7


PO-35

Regioselective Vinylation of Anilides and Carbostyrils by Grignard Reagents

Riccardo Egris, Mercedes Villacampa and J. Carlos Menéndez Departamento de Química Orgánica y Farmacéutica

Facultad de Farmacia, Universidad Complutense 28040 Madrid, Spain [email protected]

The reaction between vinyl Grignard compounds and nitroarenes is the basis of a well-known method for indole synthesis, known as the Bartoli reaction.1 Its mechanism involves two consecutive additions of a vinyl Grignard reagent to the oxygen atom in the N=O bond of nitro and nitroso groups. We describe here that the conjugation of the nitro group with electron-releasing substituents allows deviating the course of the reaction to aromatic vinylation through a mechanism involving conjugate addition-elimination onto an o-methoxynitroarene system. This reaction has allowed the vinylation, normally in excellent yield, of hindered positions in anilides 1 to give compounds 2. The same conditions could also be applied to the vinylation of carbostyril systems 3, which were transformed into compounds 4.

OMe

MeO

N+O–

O

N

Me

MeO

MgX

+

MeO

N+O–

O

N

Me

MeO

R1

3 4

OMeN+O–

O

N

Me

MeOR

1

R1

MgX

+R1

N+O–

O

N

Me

MeO

2

R1

R

1 For a review, see: Dalpozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163-178.

SISOC7 Posters


PO-36

Multicomponent Enantioselective Cyclization of Fischer Carbene Complexes, Lithium Enolates and Unsaturated Organometallic Reagents

Marcos G. Suero and Josefa Flórez∗ Instituto Universitario de Química Organometálica Enrique Moles, Universidad de Oviedo

c/ Julián Clavería, 8, 33006 Oviedo, Spain [email protected], http://www.uniovi.es/emoles/barluenga/indice.htm

Fischer carbene complexes (FCCs) are able to participate in different multicomponent reactions allowing the construction of a large variety of highly functionalized structures.1 Recently, we have described a novel selective synthesis of highly substituted cyclopentanols and 1,4-cyclohexanediols by a multicomponent sequential coupling reaction of a FCC, a ketone or ester lithium enolate, and allylmagnesium bromide.2 Subsequently, we explore the behaviour of other unsaturated organometallic reagents and the feasibility of an asymmetric synthesis of these cyclic derivatives. The following Scheme summarizes the selective preparation of 4-hydroxy-2-cyclohexenones 3, bicyclic butenolides 4 and 1,4-cyclohexanediols 5, which were obtained as highly enantiomerically pure compounds by one-pot five/six-component coupling of a carbene complex 1, a chiral imide lithium enolate 2,3 and an organomagnesium/organocerium reagent (up to six new bonds and up to three new stereogenic centers are efficiently formed).

(CO)5Cr R1

OMe

ON

OOLi

R2

+

MgBr

OHOMe

R1

HO

77-82 %, 97-99% ee

OOMeR1

HOR3

R3

69-84 %, 97-99% ee

3

OO

R1

HOR3

R3

70-88%98-99% ee

R3CeCl2

1

24

5

R3MgBr

Addition of enolate 2 to the carbene carbon atom of complex 1 followed by organometallic addition to the imide carbonyl group led to functionalized alkylpentacarbonylchromate intermediates which further evolved through different intramolecular insertion processes.

1 J. Barluenga, M.A. Fernández-Rodríguez, E. Aguilar, J. Organomet. Chem. 2005, 690, 539-587. 2 a) J. Barluenga, I. Pérez-Sánchez, E. Rubio, J. Flórez, Angew. Chem., Int. Ed. 2003, 42, 5860-5863. b) J. Barluenga, I. Pérez-Sánchez, M. G. Suero, E. Rubio, J. Flórez, Chem. Eur. J. 2006, 12, 7225-7235. 3 a) D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981, 103, 2127-2129. b) D. J. Ager, I. Prakash, D. R. Schaad, Chem. Rev. 1996, 96, 835-876.

Posters SISOC7


PO-37

Multicomponent Cyclization of Fischer Carbene Complexes, Amide Lithium Enolates, and Allenyl Organometallics Leading to 2-

Cyclopentenones

Raquel de la Campa and Josefa Flórez* Instituto Universitario de Química Organometálica “Enrique Moles”, Universidad de

Oviedo, Julián Clavería 8, 33006 Oviedo (Spain). [email protected]

Heteroatom stabilized Fischer carbene complexes (FCCs) are valuable reagents in synthetic organic chemistry that present the ability to participate in multicomponent reactions allowing the construction of a large variety of higly functionalized structures through several patterns of reactivity.1 A multicomponent strategy for the selective synthesis of pentasubstituted cyclopentanols and tretrasubstituted 1,4-cyclohexanediols, which involves the reaction of an alkoxycarbene complex of chromium, a ketone or ester lithium enolate, and allylmagnesium bromide, has been reported recently.2 In this context, we have developed a new multicomponent cyclization reaction, which allows the synthesis of substituted 2-cyclopentenones by sequential coupling of a FCC, an amide lithium enolate, an allenyl organometallic reagent and an electrophile (see Scheme).

(OC)5Cr R1

OR2

N

OLiR3

Me

+•

R4

M1.

2. D2O3. NH4Cl/H2O

O

R4

OR2R1

D

M= MgBr, Li The cyclopentenone ring skeleton combines the carbene ligand, the enolate framework, and one unit of the allenyl reagent in a process where three new carbon-carbon bonds are formed. The cyclization reaction finally provides a new alkylpentacarbonylchromate intermediate A which can be trapped by addition of an electrophile.

[Cr]

N OM

OR2R1

R3

Me

•

Li

N OM

[Cr]

R4R4

R3

Me

OR2R1

Li[Cr]= Cr(CO)5A

1 (a) Metal Carbenes in Organic Síntesis, Top. Organomet. Chem. Vol. 13, Ed.: K. H. Dötz, Springer-Verlag, Berlin, 2004. (b) J. Barluenga, M. A. Fernández Rodríguez, E. Aguilar, J. Organomet. Chem. 2005, 690, 539-587. 2 (a) J. Barluenga, I. Pérez-Sanchez, E. Rubio, J. Flórez, Angew. Chem. Int. Ed. 2003, 42, 5860-5863. (b) J. Barluenga, I. Pérez-Sanchez, M. G. Suero, E. Rubio, J. Flórez, Chem. Eur. J. 2006, 12, 7225-7235.

SISOC7 Posters


PO-38

“One-Pot” Synthesis of the Indole Skeleton in a Consecutive [8+2] / [5+1] Cyclization Process of Fischer Enynylcarbenes and 8-Azaheptafulvenes

Jaime García-Rodríguez, Ángel L. Suárez-Sobrino and Miguel Tomás Instituto Universitario de Química Organometálica “Enrique Moles”

Unidad Asociada al CSIC, Universidad de Oviedo Julián Clavería, 8, E-3306 Oviedo, Spain

[email protected], Phone: 985103447

Heteroatom-stabilized Fischer carbene complexes have been shown to be useful reagents in a number of cyclization reactions, allowing the preparation of a plethora of three- to eight-membered carbocyclic rings and acyclic compounds.1 Despite the intensive work on carbocyclization reactions, the reactivity of metal–carbene complexes toward substrates containing heteroatoms has been much less studied. In this context the reactivity of Fischer alkenyl carbenes toward 8-azaheptafulvenes was recently described.2

Alkynyl carbenes react with 8-azaheptafulvenes with complete regioselectivity through a formal [8+2] heterocyclization reaction to afford a new carbene complex that can undergo a consecutive isonitrile or CO insertion in a benzannulation process. All these “one-pot” reactions provide polycyclic compounds containing a polysubstituted indole skeleton, present in many biologically active compounds.

N

R1 (CO)5Cr OMe

N

Cr(CO)5

OMe

R1

[8+2]

N

R3R2

OMe

NH

R1

N

R3R2

OMe

OH

R1

t-BuNC

COR2

R3

R2 R3

1Recent reviews: a) W. D. Wulff, in Comprehensive Organometallic Chemistry II, Vol. 12, (Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson), Pergamon, New York, 1995, pp. 469-547; b) J. W. Herndon, Tetrahedron 2000, 56, 1257 –1280; c) D. F. Harvey, D. M. Sigano, Chem. Rev. 1996, 96, 271–288; d) J. Barluenga, F. J. Fañanás, Tetrahedron 2000, 56, 4597 –4628; e) M. A. Sierra, Chem. Rev. 2000, 100, 3591 – 3637; f) A. de Meijere, H. Schirmer, M. Duetsch, Angew. Chem. 2000, 112, 4124 – 4162; g) A. de Meijere, Y.-T. Wu, Top. Organomet. Chem. 2004, 13, 21 –57; h) J. Barluenga, F. Rodríguez, F. J. Fañanás, J. Flórez, Top. Organomet. Chem. 2004, 13, 59– 121; i) J. Barluenga, M. Fernández-Rodríguez, E. Aguilar, J. Organomet. Chem. 2005, 690, 539 – 587; j) J. W. Herndon, Coord. Chem. Rev. 2005, 249, 999 –1083. 2 J. Barluenga., J. García-Rodríguez, S. Martinez, A. L. Suárez-Sobrino, M. Tomás, Chem. Asian J., 2008, 3, 767-775.

Posters SISOC7


PO-39

Synthesis of Cyclopentenones through EnynylFischer Carbene Complex Mediated Lithium Enolates Addition-pentannulation Sequence.

Ana Álvarez-Fernández, Angel L. Suárez-Sobrino, Miguel Tomás Instituto Universitario de Química Organometálica “Enrique Moles”

Universidad de Oviedo Julián Clavería 8, 33006 Oviedo (Spain).

[email protected]

Fischer carbene complexes have attracted a broad and increasing interest in organic synthesis,1 consequently they have been extensively used in the preparation of different size carbocycles.2

In the past years our research group has been interested in the study of the reactivity of these complexes with a variety of lithium enolates.3 However, despite the enormous effort made in this field, the reaction of α,β,γ,δ-unsaturated carbene complexes and lithium enolates had not yet investigated.

The reactivity of lithium enolates toward enynylFischer carbenes to furnish five members carbocycles is described. The process takes place through a selective 1,4-addition of the lithium enolates to the carbene complex, followed by a pentannulation reaction of the complex intermediate.

This reaction represents a simple and effective method to prepare functionalized cyclopentenones.

1

1 Wulff W. D., in Comprehensive Organometallic Chemistry II, vol. 12, Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds., Pergamon, Oxford, 1995, p. 469. 2 Barluenga J.; Rodríguez F.; Fañanás F. J; Flórez J., Topics Organomet. Chem., 2004, 13, 59-121. 3 (a) Barluenga, J.; Alonso, J.; Fañanás, F. J. Chem. Eur. J. 2005, 11, 4995. (b) Barluenga, J.; Alonso, J.; Fañanás, F. J.; Borge, J.; García-Granda, S. Angew. Chem. Int. Ed. 2004, 43, 5510. (c) Barluenga, J.; Alonso, J.; Fañanás, F. J. J. Am. Chem. Soc. 2003, 125, 2610. (d) Barluenga, J.; Alonso, J.; Rodríguez, F.; Fañanás, F. J. Angew. Chem. Int. Ed. 2000, 39, 2460 (e) Barluenga, J.; Diéguez, A.; Rodríguez, F.; Fañanás, F. J. J. Am. Chem. Soc. 2002, 124, 9056. (f) Barluenga, J.; Montserrat, J. M.; Flórez, J.; García-Granda, S.; Martín, E. Chem. Eur. J. 1995, 1, 236.

SISOC7 Posters


PO-40

Cascade Reactions of Ortho-Aminophenyl Alkynyl Fischer Carbene Complexes Based on [1,5]-Hydride Transfer or C-H Insertion Processes

Fernando Aznar and Martín Fañanás-Mastral Instituto Universitario de Química Organometálica “Enrique Moles”

Universidad de Oviedo Julián Clavería 8, 33006, Oviedo, Spain

[email protected] Fischer carbene complexes have shown to be very useful building blocks for the construction of heterocyclic systems.1 A particularly interesting feature of the chemistry of Fischer carbene complexes is their ability to provide complex policyclic structures from simple starting materials in cascade processes that usually involve the formation of several C-C bonds.2 Herein we present some novel cascade reactions of ortho-aminophenyl alkynyl Fischer carbene complexes that lead to the formation of different polycyclic heterocyclic systems. When a solution of alkynyl carbene complex 1 was heated at 90ºC, the new 1,2-dihydroquinolinyl carbene complex 2 was isolated. The key step of this transformation is an unprecedented [1,5]-hydride transfer/cyclization cascade. When the reaction is carried out under the same conditions and in the presence of an alkyne, 5,6-dihydrophenantridine derivatives 3 are obtained.

[Cr]OMe

N

R1

R3

R2

THF90ºC

THF, 90ºCN

R1

R3

HO

R4

OMe

R2

R5

N

R1[Cr]OMe

R3H

HR2

1

2

3

ON

R1

R2H

OMe

R3

N

R1

R2H

OMe

R3

O

[Cr] = Cr(CO)5

R4

R5

1. RT2. 90ºC

1. RT2. 90ºC

4

5 In addition, when these alkynyl Fischer carbene complexes are treated with 2,3-dihydrofuran or cyclopentadiene at room temperature and then the mixture is heated at 90ºC, the reaction leads to the formation of benzazepine derivatives 4 or 5, respectively, through a sequential [n+2] cyclization/intramolecular C-H carbene insertion reaction.

1 a) J. Barluenga, Pure Appl. Chem. 2002, 74, 1317-1325. b) J. Barluenga, J. Santamaría, M. Tomás, Chem. Rev. 2004, 104, 2259-2284. 2 a) A. De Meijere, H. Schrimer, M. Duetsch, Angew. Chem. Int. Ed. 2000, 39, 3964-4002. b) J. Barluenga, M. Fañanás-Mastral, M. A. Palomero, F. Aznar C. Valdés, Chem. Eur. J. 2007, 13, 7682-7700; and references cited therein.

Posters SISOC7


PO-41

[2+2] Heterocyclization of Group 6 Non-Heteroatom-Stabilized Carbene Complexes with Imines. Synthesis of 2-Azetines Derivatives

Aránzazu Gómez, Javier Santamaría and Miguel Tomás Instituto Universitario de Química Organometálica “Enrique Moles”

Unidad Asociada al CSIC Universidad de Oviedo, Julián Clavería, 8, E-33006 Oviedo, Spain

[email protected], Phone: 985103459

During last decades, group 6 Fischer carbene complexes have been developed as important tools in organic synthesis due to their high versatility.1 However, non-heteroatom-stabilized carbene complexes have found less applicability than Fischer carbene complexes in order to their lower stability.2

In this work, it is shown the synthesis of 2-azetine derivatives 4 by a [2+2] heterocyclization reaction of non-heteroatom-stabilized carbene complexes 2 and imines 3. Non-heteroatom-stabilized carbene complexes 2, generated “in situ” from the corresponding alkoxycarbene complexes 1,3 smoothly react with imines 3 to produce new 2-azetine carbene complexes 4.

The work presented here consists in the first example reported to date of [2+2]-heterocyclization of either heteroatom stabilized or non-stabilized group 6 carbene complexes. On the other hand, the presence of the carbene function increases the stability of the 2-azetine heterocycle.

These new systems 4 react with other organic molecules such as acetylenes leading to the formation of more complex structures.

NBu

R3

-80ºC a 0ºC

(CO)5MR1

R3

NBuR2

M(CO)5= Cr(CO)5, W(CO)5

(CO)5MR1

R2

TMSOTf(CO)5M

R1

OMeR2Li

R1= Ph, Ph, FcR2= Ph, Bu, cPr, FcR3= Ph, Fu, C7H15

Rto(%)= 52-72

THF, -80ºC1.

2.1 2

3

4

THF

1 a) A. de Meijere, H. Schirmer, M. Duesch, Angew. Chem. Int. Ed. 2000, 39, 3964; b) J. Barluenga, J. Santamaría, M. Tomás, Chem. Rev. 2004, 104, 2259. 2 J. Barluenga, P. García-García, D. de Saá, M. A. Fernández-Rodríguez, R. Bernardo de la Rúa, A. Ballesteros, J. Santamaría, E. Aguilar, M. Tomás, Angew. Chem. Int. Ed. 2007, 46, 2610. 3 J. Barluenga, A. Ballesteros, R. Bernardo de la Rúa, J. Santamaría, E. Rubio, M. Tomás, J. Am. Chem. Soc. 2003, 125, 1834.

SISOC7 Posters


PO-42

New Approaches to the Synthesis of Taxanes

Noel Sayar, Luis Castedo, Juan R. Granja* and María José Aldegunde. Departamento de Química Orgánica

Facultad de Química, Universidad de Santiago de Compostela Avda das Ciencias s/n, 15782 Santiago de Compostela, Spain

*[email protected] During the last decades, taxanes have considerably attracted synthetic chemists’ attention and have been the focus of numerous investigations, mainly due to the fact that paclitaxel (taxol®, 1) and docetaxel (taxotere®, 2), progenitors of this family, exhibit an excellent clinical activity against several types of human cancer.1 Nevertheless, their utilization in chemotherapy treatments often results in a number of undesirable side effects, as well as multidrug resistance (MDR),2 which make it essential to develop new effective and less toxic paclitaxel analogues. To date, several second generation analogues have been prepared, mostly by modification of nature occurring taxanes, which constitutes a serious limitation for the manipulation of certain positions in the molecule. Hence the necessity of developing new efficient and practical synthetical methods for preparing improved taxol structural analogues. In our research group, we have proposed the utilization of a highly atom-economical ring closing dyenine methatesis reaction (RCDEYM) to build, in only one step, the framework of taxanes. The posterior functionalization of the skeleton, using a low number of chemical transformations, furnished a new type of analogues through one of the shortest synthesis hitherto reported.

OH R1O

OOHBzO

HAcO

O

O

O

OH

NHR2

Ph

1: R1= Ac, R2= Bz2: R1= H, R2= Piv

OP OBziPrH

H

POBzO H

H

H

OAc

Sch

RCDEYM

Sch= Taxol Side Chain

1 For recent reviews on the clinical use of taxol and taxotere see: (a) Rowinsky, E. K. Annu. Rev. Med. 1997, 48, 353-374. (b) Von Hoff, D. D. Semin. Oncol. 1997, 24, 3-10. (c) DeFuria, M. D. Phytomedicine 1997, 4, 273-282. (d) Eisenhauer, E. A.; Vermorken, J. B. Drugs 1998, 55, 5-30. (e) Crown, J.; O’Leary, M. Lancet 2000, 335, 1176. 2 (a) Verweij, J.; Clavel, M.; Chevalier, B. Ann. Oncol. 1994, 5, 495-505. (b) Casazza, A. M.; Fairchild, C. R. In Drug Resistance Cancer Treatment and Research; Freidreich, E. J., Series Ed.; Hait, W. N., Ed.; Kluwer Academic Publishers: New York, 1996; Chapter 6, pp 149-171. (c) Horwitz, S. B. Taxol: Mechanism of Action and Resistance. In Stony Brook Symposium on Taxol and Taxotere; May 14-15, 1993; The State University of New York at Stony Brook: Stony Brook, NY, 1993; Abstracts 23-24. (d) Gottesmann, M. M.; Pastan, I. Annu. Rev. Biochem. 1993, 62, 385-427. (e) Rose, W. C.; Clark, J. L.; Lee, F. Y.; Casazza, A. M. Cancer Chemother. Pharmacol. 1997, 39, 446. (d) Georg, G. I.; Boge, T. C.; Cheruvallath, Z. S.; Clowers, J. S.; Harriman, G. C. B.; Hepperle, M.; Park, H. In Taxol: Science and Applications; CRC Press: New York, 1995; p 317.

Posters SISOC7


PO-43

New Approach to the Synthesis of Natural Products Containing Cyclic Ethers: Tandem Nicholas Reaction-Ring Closing Metathesis

Nuria Ortega,a Tomás Martína,b and Víctor S. Martína

aInstituto de Bio-Orgánica “Antonio González”, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez, 38206, La Laguna, Tenerife, Spain

bInstituto de Productos Naturales y Agrobiología, Consejo Superior de Investigaciones Científicas, Avda. Astrofísico Francisco Sánchez, 3, 38206, La Laguna, Tenerife, Spain

[email protected] Red algae of the genus Laurencia produce a large number of unique compounds, such as series of nonterpenoid C15 metabolites named lauroxanes. These molecules exhibit a large number of biological properties including antitumor, antimicrobial, immunosuppressant, antifeedant, pesticide activity, etc.1 These natural products present polysubstituted cyclic ethers with a defined stereochemistry in the substituents and a ring size changing from five to nine members.

(+)-Isolaurepinnacin

OH H

Br Cl

O

O

BrC

HBr

H

(−)-Isolaurallene

H HO HH

(+)-Laurencin

BrOAc

In this contribution, we report on a new methodology for the synthesis of highly substituted medium sized cyclic ethers. Our strategy is based on an intermolecular Nicholas reaction between a propargylic-Co2(CO)6 cation and a secondary alcohol as nucleophile to form a linear ether, followed by a ring closing metathesis to obtain the cyclic ether, and finally, an isomerization promoted by Montmorillonite K-10 in order to obtain the cis stereochemistry founded in most of the lauroxanes.2

OH

R

OH

O RCo2(CO)6

Ring Closing

metathesis

Montmorillonite-K10

isomerisationOR

OR

Nicholasreaction

( )n ( )n

( )n ( )n

(OC)6Co2

Co2(CO)6 Co2(CO)6

1 a) Yasumoto, T.; Murata, M. Chem Rev. 1993, 93, 1987-1909. b) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-48 2 Ortega, N.; Martín, T.; Martín, V. S. Org. Lett. 2006, 8, 871-873.

SISOC7 Posters


PO-44

Synthesis of Novel Pyrimido[4,5-e][1,4]diazepines Synthesis of 9,9’-[Ethane-1,2-diylbis(oxymethanediyl)]bis(2-amino-1,9-

dihydro-6H-purin-6-one). An Impurity of Acyclovir.

R. M. Suárez, M. P. Matía, J. L. Novella, J. Alvarez-Builla* Planta Piloto de Química Fina. Universidad de Alcalá. Ctra. Madrid-Barcelona Km. 33,600.

28871 Alcalá de Henares. Madrid. España.

Acyclovir1, is a guanosine analogue antiviral drug, marketed under trade names such as Zovirax and Zovir (GSK). One of the most commonly-used antiviral drugs, it is primarily used for the treatment of herpes simplex virus infections, as well as in the treatment of herpes zoster (shingles). Acyclovir was seen as the start of a new era in antiviral therapy, because it is extremely selective and of low cytotoxicity.

NH

N N

N

O

NH2O

OH

In the present work, we have prepared one of the impurities of Acyclovir. The method is indicated in scheme 12,3. The guanine derivative 4 is an intermediate used in the synthesis of Acyclovir.4,5,6

OHOH

OO

ClCl

OO

OO CH3

O

CH3

O

NH

N N

N

O

NH

O

CH3

OCH3

NH

NN

N

O

NH

O

CH3

NH

N N

N

O

NH

O

CH3

O

O

NH

NN

N

O

NH2

NH

N N

N

O

NH2

O

O

OHNH2

(CH2O)n

HCl (g)

NaOAc

1 2 3

4

5

6

p-TSATBABDowterm Q

1 USP 4 544 634 2 T. Shimamura, Y. Yamashita; Kogyo Kagaku Zasshi, 1957, 60, 575. 3 F. Walter; Plastic Products, 1933, 9, 187. 4 DE 2 539 963 5 US 4 199 574 6 GB 1 523 865

Acyclovir

Posters SISOC7


PO-45

Fast Microwave Preparation of an Atorvastatin Intermediate. Synthesis and Scale-up.

J. Hernando, M. P. Matía, J. L. Novella, J. Alvarez-Builla* Planta Piloto de Química Fina. Universidad de Alcalá. Ctra. Madrid-Barcelona Km. 33,600.

28871 Alcalá de Henares. Madrid. España.

Atorvastatin, usually marketed under the trade name Lipitor, is a member of the drug class known as statins, used for lowering cholesterol synthesis1. Atorvastatin inhibits the rate-determining step of the enzyme located in hepatic tissue that produces mevalonate, a small molecule used in the synthesis of cholesterol and other related derivatives. This lowers the amount of cholesterol produced, which in turn lowers the total amount of cholesterol. Figure 1 Atorvastatin is commercially available as a calcium salt2. We have prepared a precursor of atorvastatin3,4 (Comp. 3) using microwave irradiation. Normally, in the Paal-Knorr condensation is necessary a long reaction time. Thus, we have reduced the reaction times with the same yields.

This procedure was optimized in an explorer microwave (CEM) and was scaled up using the voyager system in the best conditions obtained in the small scale. 1 B. D, Rorh et al. J. Med, Chem. 1991, 34, 357. 2 WO 02 057 229 3 K. L. Baumann et al. Tetrahedron Lett. 1992, 17, 2283. 4 WO 06 097 909

NH

O

O

F

O

O

O OO

NH2

+solvent

catalyst

N O

O O O

F

ONH 31 2

N

OH OH O

F

ONH

OH

Atorvastatin

Scheme 1

SISOC7 Posters


PO-46

Synthesis of Lissoclimide-type Diterpenes: Towards the Synthesis of Haterumaimide Q

Damaris Romero-Torrejón, and Miguel A. González Departamento de Química Orgánica, Universidad de Valencia

Dr. Moliner 50, Burjassot, Valencia, Spain [email protected]

These compounds are alkaloids which have been isolated from tunicates, organisms of the genus Lissoclinum sp., hence their name, and have attracted considerable interest because of their potential use as protein synthesis inhibitors, as antitumor drugs, and due to their unusual structural features. They are potent cytotoxic agents at very low concentrations (IC50 = 1 ng/mL mouse lymphocytic leukemia cells P388). The first member of the family, dichlorolissoclimide (1), was isolated in 1991 by a French research team and its chemical structure was deduced by spectroscopic means and confirmed by X-ray analysis which corrected an initial misassignment.1

This family of compounds is characterized by the labdane carbon framework, which presents one or two chlorine atoms in one of the rings and a succinimide moiety, which is extremely rare in natural products. In 1994, it was reported the isolation of chlorolissoclimide (2) by the same team and years later (2001-2002) a Japanese research group described the isolation of 11 related compounds from Lissoclinum sp., haterumaimides A-K, thus called because the tunicates were collected in the Japanese island hateruma.2 The same authors have described recently until 4 additional structures, haterumaimides N-Q. In their report, the biological activity against P388 cells and structure-activity relationships were studied. Also recently, an American group has described 3 new structures of which two are renamed as haterumaimides L y M and their biological activity has not been investigated.

In this communication, we present a synthetic approach leading to lissoclimide-type diterpenes with the complete carbon skeleton. In the synthesis we used as starting material (+)-sclareolide (1), which after three steps is converted into γ-bicyclohomofarnesal (2). This aldehyde reacted with the dianion of succinimide to afford the simplest lissoclimide alkaloid, , which was functionalized to give 7-epihaterumaimide Q, compound 3.

1 a) Malochet-Grivois, C.; Cotelle, P.; Biard, J. F.; Hénichart, J. P.; Debitus, C.; Roussakis, C.; Verbist, J. F. Tetrahedron Lett. 1991, 32, 6701-6702; b) Toupet, L.; Biard, J. F.; Verbist, J. F. J. Nat. Prod. 1996, 59, 1203-1204. 2 a) Uddin, M. J.; Kokubo, S.; Suenaga, K.; Ueda, K.; Uemura, D. Heterocycles 2001, 54, 1039-1047; b) Uddin, M. J.; Kokubo, S.; Suenaga, K.; Ueda, K.; Uemura, D. J. Nat. Prod. 2001, 64, 1169-1173; c) Uddin, M. J.; Kokubo, S.; Suenaga, K.; Ueda, K.; Uemura, D. Chem. Lett. 2002, 10, 1028-1029.

Posters SISOC7


PO-47

Synthesis of Phosphonate Derivatives of 1,2-Disubstituted Carbocyclic Purine Nucleosides with a Cyclopentane Ring

Pedro Besada, María J. González Moa, Marta Teijeira and Carmen Terán Department of Organic Chemistry, Faculty of Chemistry

Vigo University 36310 Vigo, Spain

e-mail, [email protected] and web site, http://webs.uvigo.es/qo/default.htm

Nucleoside phosphonates have received great attention in last years due to their therapeutic potential. Thus, acyclic nucleoside phosphonates, such as cidofovir, adefovir and tenofovir, are becoming widely used for treatment of viral diseases.1 In addition, chemotherapeutic properties were found in several phosphonate derivatives of furanose,2 whose carbocyclic analogues were also described.3

As part of our ongoing program on the synthesis of 1,2-disubstituted carbonucleosides (OTCs)4 we decided to prepare a representative phosphonate derivative of OTCs, a cis hypoxantine analogue with a cyclopentane ring (1). The synthesis of phosphonate 1 was carried out according to a convergent methodology, starting from the 1,2-trans-diol 2,4a and following two different strategies: inclusion of the phosphonomethyl group before or after coupling of the carbocyclic moiety with the heterocyclic base. In both strategies, the diethyl[(trifluoromethylsulfonyl)oxy]methanephosphonate 3 was the key phosphonylating agent.5 The first strategy is more direct and interesting in order to synthesize different phosphonate derivatives from a common synthon.

HO

OHEtO

P OSO2CF3

O

OEt

O

N

PHO

O

OH

HO

N

N

N

N

Cl

EtOP OSO2CF3

O

OEt

+

+

N

N

N

OH

1

2 3

3 Acknowledgment: we are grateful to the Xunta de Galicia (PGIDT04BTF301031PR and PGIDIT07PXIB) and University of Vigo for financial support. P.B. thanks the Xunta de Galicia for an Isidro Parga Pondal contract. 1 De Clercq, E.; Holý, A. Nat. Rev. Drug Discov. 2005, 4, 928. 2 Kim, C. U.; Luh, B. Y.; Misco, P. F.; Martín, J.C. Nucleosides & Nucleotides 1991, 10, 371. 3 Jähne, G.; Müller, A.; Kroha, H.; Rösner, M.; Holzhäuser, O.; Meischsner, C.; Helsberg, M.; Winkler, I.; Riess, G. Tetrahedron Lett. 1992, 33, 5335. 4 (a) Santana, L.; Teijeira, M.; Terán, M.; Uriarte, E.; Viña, D. Synthesis 2001, 1532. (b) Besada, P.; González-Moa, M. J.; Terán, C.; Santana, L.; Uriarte, E. Synthesis 2002, 2445. (c) Viña, D.; Santana, L.; Uriarte, E.; Terán, C. Tetrahedron 2005, 61, 473. 5 Phillion, D. P.; Andrew, S. S. Tetrahedron Lett. 1986, 27, 1477.

SISOC7 Posters


PO-48

A Short Synthesis of 6,7-Dideoxy-L-arabino-eptos-5-ulose

Antonino Corsaro, Ugo Chiacchio, Venerando Pistarà, Elisa Vittorino Dipartimento di Scienze Chimiche

Università di Catania viale A. Doria 6, I-95125 Catania

[email protected]

Within our researches on the elaboration of unsaturated derivatives of lactose,1 α- and β-galactopyranosides, as useful intermediates for the synthesis of new 1,5-dicarbonyl compounds, recently we have described2 the synthesis of a carba-L-fucose analogue thorough the catalytic reduction of the unknown epi-gabosine A, in turn obtained from the electrophilic ring opening of the 4,5-cyclopropanated galactopyranoside by methoxymercuria-tion/demercuriation followed by acidic hydrolysis of the obtained bis-glycoside.

As extension of these studies, we have also studied the cyclopropanation reactions of 5-exo-glycals to obtain the corresponding spirocyclopropil sugars such as 1;3 here, we describe the preliminary results obtained from the nucleophilic cyclopropane ring-opening of the spirocyclopropyl-sugars.

OOCH3

O

OBnO

OOCH3

O

OBnO

ClHg

OMeO

OCH3

O

OBnO

OMe

O

H

HO

HOBnO

O

1 2a, b 3a, b

4

2a, 3a

2b, 3b

OMeC5

OMeC5

The cyclopropyl adduct 1, obtained in a near quantitative yield in the Simmons-Smith reaction of 5-exo-pyranoside,3 was treated with mercuric trifluoroacetate to give an anomeric mixture of the two organomercuric chlorides 2a,b with good yield. These latter after reductive demercuration with hydride, afford the corresponding 6,7-dideoxy-1,5-bis-glycosides 3a and 3b, masked form of the 1,5-dicarbonyl eptose 4.

To our best knowledge this is the first example about the synthesis of a 6,7-dideoxy-δ-eptulose from a spiro-galactose reported in literature.

1 G. Catelani, A. Corsaro, F. D’Andrea, M. Mariani, V. Pistarà, E. Vittorino, Carbohydr. Res. 2003, 338/22, 2349. 2 A. Corsaro, V. Pistarà, G. Catelani, F. D’Andrea, R. Adamo, M.A. Chiacchio, Tetrahedron Lett. 2006, 47, 6591. 3 A. Corsaro, M.A. Chiacchio, V. Pistarà, A. Rescifina, E. Vittorino, Tetrahedron, submitted.

Posters SISOC7


PO-49

Stereoselective Generation of the Saframycin B Ring Using a Modified Pictet-Spengler Reaction

Alberto López-Cobeñas, Pilar López-Alvarado, Carmen Avendaño, Mercedes Villacampa and J. Carlos Menéndez

Departamento de Química Orgánica y Farmacéutica Facultad de Farmacia, Universidad Complutense

Plaza de Ramón y Cajal, s.n., 28040 Madrid, Spain [email protected]

The saframycin-ecteinascidin1 family of tetrahydroisoquinoline alkaloids includes a large number of bioactive compounds, many of which show potent antitumour activities. We are currently developing a symmetry-based approach to the pentacyclic framework present in many of these natural products, based on the generation of ring B at a very late stage. We describe in this communication that the desired transformation can be achieved under very mild conditions by activation of compounds 1 as trimethylsilyl lactim ethers followed by addition of acetals and trimethylsilyl triflate as a catalyst. In the case of aromatic acetals, the reaction was completely diastereoselective and afforded compouds 3, with the same relative configuration found in the natural products. This result is in contrast with previous literature observations on the stereochemistry of the Pictet-Spengler reaction and can be attributed to stabilization of transition state 2 by π-stacking interactions.

HNN

O

H

H

H

NN

O

H

H

H

CH3

O

1. TMSCl, Et3N, r.t.2. PhCH(OMe)2,

1

NN

HO

HHAc

H

R

R

3

2

CH3

O

TfOTMS, r.t.R

R

R

R

1 For a review, see: Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.

SISOC7 Posters


PO-50

A Metabolite Produced By Aspergillus flavus With A Potential Antifungal Against Phytophthora spp

Biancavaleria Punzo,a Anna Andolfi,a Gennaro Cristinzio,b and Antonio Evidentea aDipartimento di Scienze del Suolo, della Pianta dell’Ambiente e delle Produzioni Animali e

bDipartimento di Arboricoltura, Botanica e Patologia Vegetale, Università di Napoli Federico II, Via Università 100, 80055 Portici Italy

E-mail: [email protected] In the last 50 years, beside the traditional agrarian practises, the most diffused methods

in controlling pests are the use of pesticides, herbicides and insecticides which are responsible for major environmental pollution with human and animal health risks. Therefore, numerous studies have been carried out to develop biological control.

Fungi are a well-known source of bioactive compounds, and the research for isolation of novel fungal antibiotics and agrochemicals that blossomed more than forty years ago is still very active today. In addition to their potential use as agrochemicals or chemotherapeutics, bioactive compounds are also useful as lead molecules, by serving as structural models for the design of new synthetic compounds with higher activity or stability. In particular, these compounds may disclose novel mechanisms of action capable of overcoming the acquired resistance of plant pathogens to known antibiotics. Moreover, the combined use of bioactive natural compounds with biocontrol agents, e. g. antagonistic yeasts, has been proposed as a profitable approach to achieve additive and/or synergistic effects and provide greater consistency and efficacy of disease control.1

A soil born strain of Aspergillus flavus was isolated from a compost picked up and created in Chestnut orchard, not only as possible substratum to use as fertilizer, but also as possible substratum from which pick up fungi from his inside, to use as antagonists against several illnesses of the chestnut.

Phytophthora cinnamomi is the causal agent of “ink disease” of Chestnut, one of the most dangerous parasite for this plant. The A. flavus strain (ECO-6) culture filtrates showed a strong inhibitory activity against this pathogen as well as towards P. cactorum and P. nicotianae, which are pathogen of strawberry, tomato, tobacco and many other plants.

This communications will describe the results of the chemical and biological characterization of the main antifungal metabolite, named asperfuran, produced in vitro by A. flavus. Furthermore the results of a structure-activity relationships study, carried out testing the antifungal activity of asperfuran and some its derivatives, prepared by chemical modifications, against the three Phytophthora spp., will be illustrated.

1 El-Ghaouth, A., Smilanick, J.L., Brown, G.E., Ippolito, A., Wisniewski, M., and Wilson, C.L. (2000). Application of Candida saitoana and glycolchitosan for the control of postharvest diseases of apple and citrus fruit under semi-commercial conditions. Plant Disease, 84: 243-248.

Posters SISOC7


PO-51

Chemo- and Diastereoselective Pictet-Spengler Reactions on 3-Arylmethyl-6-arylmethylene-2,5-piperazinediones. An Efficient Synthesis of

Functionalized Derivatives of the Saframycin ABC Fragment

Lucía Pérez Gómez-Cuétara, Alessandra Monaco, Alberto López-Cobeñas, Pilar López-Alvarado and J. Carlos Menéndez



Many alkaloids belonging to the saframycin-ecteinascidin family1 show potent antitumour activities. The pentacyclic framework shared by most of these compounds can be accessed from arylmethylene derivatives of a tricyclic system comprising the ABC fragment.2 We describe in this communication a symmetry-based, improved synthesis of these starting materials having as the key step a chemo- and diastereoselective Pictet Spengler reaction of 3-arylmethyl-6-arylmethylene-2,5-piperazinediones 1.

R-CHO,CF3CO2H-CH3CO2H

1 2

NHHN

O

OH

100 ºC, 2-5 hAr Ar NHN

O

OH

Ar Ar

R

Ar R=NR

,

O

NN

H

Z

O

O

H3COCH3

CH3

OH3C

H3CO

NH

OCH3

O

A B CZ = CN Saframycin AZ = OH Saframycin SZ = H Saframycin B

EH

H

1 For a review, see: Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669. 2 González, J. F.; de la Cuesta, E.; Avendaño, C. Tetrahedron 2004, 60, 6319.

SISOC7 Posters


PO-52

Dehydroquinase Inhibitors for the Development of New Antimicrobial Agents

Antonio Peón, Luis Castedo and Concepción González-Bello* Departamento de Química Orgánica, Facultad de Química

Universidad de Santiago de Compostela, Avenida de las Ciencias s/n, 15782 Santiago de Compostela, Spain

[email protected] Although effective chemotherapeutic agents have been developed, the synergy between the AIDS epidemic and increasing surge of multidrug-resistant isolates to antibiotics leads to the alarming conclusion that antibiotics are loosing their effectiveness. It is therefore necessary to discover new, safe, selective and more efficient antibiotics. Selectivity can sometimes be achieved by using compounds that inhibit one of the biosynthetic pathways present in bacteria. Our research groups have been focused on the inhibition of the shikimic acid pathway, through which the biosynthesis of nearly all aromatic compounds in nature must pass.1 The absence of this pathway in mammals, combined with its essential nature in certain micro-organisms, makes it an attractive target for the development of new antibiotics. We are focused on the inhibition of important bacterial pathogens of therapeutic interest, particularly, Mycobacterium tuberculosis that causes tuberculosis, the greatest single infectious cause of mortality worldwide, and Helicobacter pylori, bacterium that has been identified as the casual agent of gastric and duodenal ulcers and it has also been classified as type I carcinogen.

The important observation that compounds 1 with a double bound between C2-C3 and containing aryl groups or small heterocycles at C3 are very potent competitive inhibitors against M. tuberculosis and H. pylori dehydroquinase enzymes, have encouraged us to study, with derivatives 2, the effect of the incorporation of different substituents at the position 2.2 In this communication we will present our recent progress made on this aim.

2OH

OH

HO CO2H

Ar

Ar = XOH

OH

HO CO2HR

1

Z

Z = NO2, F, CF3 X = O, S

Acknowledgements: Financial support from the Xunta de Galicia (P PGIDT07PXIB209080PR and GRC2006/132) and the Spanish Ministry of Education and Culture (SAF2007-63533) are gratefully acknowledged. AP thanks the Spanish Ministry of Education for a FPU scholarship.

1 C. González-Bello, L. Castedo, Med. Res. Rev. 2007, 27, 177. 2 a) C. Sánchez-Sixto, V. F. V. Prazeres, L. Castedo, H. Lamb, A. R. Hawkins, C. González-Bello, J. Med. Chem. 2005, 46, 5735. b) V. F. V. Prazeres, C. Sánchez-Sixto, L. Castedo, H. Lamb, A. R. Hawkins, A. Riboldi-Tunnicliffe, J. R. Coggins, A. J. Lapthorn, C. González-Bello, ChemMedChem 2007, 2, 194. c) C. Sánchez-Sixto, V. F. V. Prazeres, L. Castedo, S. W. Suh, H. Lamb, A. R. Hawkins, F. J. Cañada, J. Jiménez-Barbero, C. González-Bello, ChemMedChem 2008, 3, 756.

Posters SISOC7


PO-53

Transformations of Gummiferolic Acid into Bioactive Compounds

Josefa Anaya, Pablo M. Gago, Manuel Grande, and Isabel Navarro Departamento de Química Orgánica

Universidad de Salamanca. Facultad de Ciencias Químicas Plaza de los caídos, 1-5. 37008-Salamanca. España

[email protected]

We have recently reported the preparation of 6-formyl atisagiberellins from the gummiferolic acid.1 The key step in this transformation was the ring contraction of 6,7-dihydroxy derivatives obtained from the ketone 1. Oxidation of this ketone with O2 at –40ºC gave a 1:1 mixture the compounds 2 and 3 in 86% yield.

CO2H

OAngH

A B

CO2MeCO2MeH

1 3 (45%)

OH CHO

67 6

CO2Me

OOH

+

CO2Me

OOHH

atisagiberellinsgummiferolic acid 2 (41%)

80%---48% 35%

CO2Me

OOH

OH

4 (11%)

CO2Me

OO

O

a)

b)

5 (50%)

a) 1: KMHDS, -70¼C, 1h. 2: O2 , -70¼C, 1h 3: rt, 2hb) 1: KMHDS, -70¼C, 1h. 2: dry O2 , -70¼C, 1h 3: (EtO)3P, -70¼C to -50¼C, 2h

In order to increase the yields and modify the chemoselectivity of this transformation, we carried out the α-oxidation with O2 under different reaction conditions. If the reaction product is stirred at room temperature for 1-3h after oxygen treatment, the yields of 3 increases (~80%), but when the same reaction mixture is treated with triethylphosphite at –70ºC and kept at low temperature for two hours, the 6β-hydroxyketone 2 was isolated as the major constituent together with the compounds 3 and 4.

Further oxidation of diosphenol 3 let us isolate in 50% yield the oxetane 5, structurally related to natural diterpenoids that have been reported as cytotoxic substances against KB cells.2


1 J. Anaya, J. J. Fernández, M. Grande, J. Martiañez, and P. Torres. Nat. Prod. Común. 2008, 3, 483. 2 C. Li, D. Lee, T. N. Graf, S. S. Phifer et al. Org. Lett. 2005, 7, 5709.

SISOC7 Posters


PO-54

New β-Lactam Peptidomimetics: Alosteric Modulators of D2 Dopamine Receptors

Claudio Palomo,a Jesús M. Aizpurua,a Azucena Jiménez,a Raluca M. Fratila,a Ane M.

Gabilondo,b J. Javier Meanab

a Dpto.Química Orgánica-I, Universidad del País Vasco, Joxe Mari Korta R&D Center Avda. Tolosa-72. 20018 San Sebastián. Spain

[email protected] b Dpto. Farmacología, Universidad del País Vasco, CIBERSAM

48940 Leioa. Spain [email protected]

The neuropeptide prolyl-leucyl-glycinamide (PLG) has been shown to modulate dopaminergic neurotransmission by increasing the binding affinity of agonists to D2 receptors. It is generally assumed that PLG adopts a bioactive conformation of type II β-turn1. Investigations in our laboratory aimed to prepare β-lactam peptidomimetics with stabilized β-turn conformations2 have resulted in the development of a general methodology to synthesize enantiopure β-lactam scaffolds through aziridine intermediates3. We now report the application of such methodology to prepare the PLG peptidomimetics 1, starting from the handy α-substituted serinates 2.

NH

HN

NH2NH

O

O

O

PLG

NO

HN

NH

H

ONH2

O

R1

R2 R2HO

CO2MeH2NR1

*

1 (R1= iBu, Bn, CH2-CH=CH2); (R2= H, Me) 2

*

The novel β-lactam/PLG analogues 1 were tested in competition assays between the D2 dopamine receptors selective antagonist [3H]-spiperone and the agonist N-propylnorapomorphine [(-) NPA] in human caudate membranes. It was found that both the natural tripeptide PLG and some of the new mimetics increased the affinity of the agonist for the high affinity state of the receptor. These results show that new peptidomimetics have greater ability to modulate agonist-D2 binding than PLG. Among them, compound 1-(*R), [R1= i Bu; R2= Me] exhibited the higher effect.

1 E. M. Khalil, W. H. Ojala, A. Pradham, V. D. Fair, W. B. Gleason, R. K. Mishra, R. L. Johnson, J. Med. Chem

1999, 42, 628-37. 2 C. Palomo, J. M. Aizpurua, A. Benito, J. I. Miranda, R. M. Fratila, C. Matute, M. Domercq, F. Gago, S.

Martin-Santamaría, A. Linden, J. Am. Chem. Soc. 2003, 125, 16243-16260. 3 C. Palomo, J. M. Aizpurua, E. Balentova, A. Jiménez, J. Oyarbide, R. M. Fratila, J. I. Miranda, Org. Lett.

2007, 9, 101-104.

Posters SISOC7


PO-55

Unexpected Highly Stable Ozonides Derived from (-)-Quinic Acid

Sonia Paz, Lorena Tizón, Luis Castedo and Concepción González-Bello* Departamento de Química Orgánica, Facultad de Química

Universidad de Santiago de Compostela, Avenida de las Ciencias s/n, 15782 Santiago de Compostela, Spain

[email protected] In the course of our research towards the synthesis of conformationally restricted analogues of (-)-quinic acid, we unexpectedly found that ozonolysis of alkene 1 (R = Me) afforded an enantiomerically pure and highly stable intramolecular cross-ozonide 2.

OTBS

TBSO

O

O

O

R O3

OTBS

TBSO

O

O

OO

O

1 2

R = Me

OTBS

TBSO

O

O

OO

3

O

O

O3

R = H

In this communication, the synthesis of ozonides 2 and 3 will be discussed. Acknowledgements: Financial support from the Xunta de Galicia (PGIDT07PXIB209080PR and GRC2006/132) and the Spanish Ministry of Education and Culture (SAF2007-63533) are gratefully acknowledged. SP and LT thank the Xunta de Galicia for a contract and a scholarship, respectively.

SISOC7 Posters


PO-56

Synthesis of Functionalized Phosphorylated Aziridines

F. Palacios, A. M. Ochoa de Retana, J. M. Alonso and A. Vélez del Burgo Dpto. Química Orgánica I, Fac. Farmacia, Universidad del País Vasco UPV/EHU

Apdo. 450, 01080 Vitoria-Gasteiz, Spain [email protected]

2H-Azirine ring systems represent an important class of compounds because of their high reactivity.1 They can be used as key intermediates in organic synthesis in the preparation of heterocycles and acyclic functionalized amino derivatives. Continuing with our interest in the chemistry of small strained nitrogen heterocycles,2 we report here the addition of phosphorylated reagents to 2H-azirines derived from phosphine oxides, phosphonates and carboxylates.

2H-Azirines 2 and 5 were obtained from p-tolylsulfonyl oximes 1 and 4. In this study, we reported the synthesis of functionalized phosphorylated aziridines 3 through simple addition of sodium diethylphosphonate to 2H-azirine-diphenylphosphine oxide 2 (R= Ph) and -diethyl phosphonate 2 (R= OEt). In a similar way, the reaction of carboxylated 2H-azirine derivatives 5 with sodium diethylphosphonate gave phosphorylated aziridines 6 (Figure 1).

R1

N

PR2R1

HN

PR2

HN

R1 PR2

TsO

2 3 R= Ph, OEt1

(EtO)2PONa

R1

N

CO2R R1

HN

CO2R

HN

R1 CO2R

TsO

5 64

(R2O)2PONa

(EtO)2P

(R2O)2P

Figure 1

O

O

O

O

Acknowledgements: The present work has been supported by the Dirección General de Investigación del Ministerio de Ciencia y Tecnología (MCYT, Madrid, DGI, CTQ2006-09323) and by the University of the Basque Country (UPV, GIU 06/51). A. Vélez del Burgo thanks the Ministerio de Educación y Cultura (Madrid) for predoctoral fellowships.

1 a) Palacios, F.; Ochoa de Retana, A. M.; Martínez de Marigorta, E.; De los Santos, J. M., Org. Prep. Proc. Int. 2002, 34, 219-269. b) Palacios, F.; Ochoa de Retana, A. M.; Martínez de Marigorta, E.; De los Santos, J. M., Eur. J. Org. Chem. 2001, 2401-2414. 2 a) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Alonso, J. M., Tetrahedron 2004, 60, 8937-8947. b) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M., J. Org. Chem. 2005, 70, 8895-8901. c) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M., J. Org. Chem. 2006, 71, 6141-6148.

Posters SISOC7


PO-57

Synthesis and Reactivity of Heterocyclic Condensed Oxaziridines

Luigino Troisi, Catia Granito, Francesca Rosato and Valeria Videtta Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali

University of Salento Via Prov-le Lecce-Monteroni, 73100 – Lecce, Italy

[email protected] The high levels of asymmetric induction that have been observed in the reaction of chiral dioxiranes1 and oxaziridium salts2 with alkenes suggest that the closely related oxaziridines may also have considerable potential for asymmetric reactions in the organic chemistry field.

Consequently, we have recently performed the [3+2] cycloaddition reaction of non chiral oxaziridines with alkenes3 and alkynes4 in order to obtain isoxazolidines and isoxazolines, respectively.

Subsequently, using chiral oxaziridines as subtrates in an analogous [3+2] cycloaddition reaction with alkenes, we could isolate with good stereoselectivity chiral isoxazolines.

ON

ArPh*

**

+ Ar'toluene

110 °C, 24 - 48h N

OAr'Ar

Ph

**

* More recently, we are investigating the synthesis of new chiral and non chiral condensed oxaziridines in order to increase the reactivity and the stereoselectivity of some reactions to which they can undergo.

NOx

O

N

R

R1 R2

SR R'

1 a) Y. Shi, Acc. Chem. Res., 2004, 37, 488-496; b) D. Yang, Acc. Chem. Res., 2004, 37, 497-505; c) A. Armstrong, Angew. Chem. Int. Ed., 2004, 43, 1460-1462. 2 P. C. Bulman Page, B. R. Buckley, A. J. Blaker, Org. Lett., 2004, 6, 1543-1546. 3 M. Fabio, L. Ronzini, L. Troisi, Tetrahedron, 2007, 63, 12896-12902. 4 M. Fabio, L. Ronzini, L. Troisi, Tetrahedron, 2008, 64, 4979-4984.

SISOC7 Posters


PO-58

Synthesis of Pyrido[f]pyrrolo[1,2-a][1,4]diazepin-10-ones

Domingo Domínguez and Loreto Legerén

Departamento de Química Orgánica

Facultad de Química, Universidad de Santiago de Compostela

Avenida de las ciencias s/n, 15782, Spain

[email protected]

The pyrrolo[1,4]benzodiazepine skeleton is one of medicinal chemistry´s most relevant motifs. Herein, we present an efficient synthesis of pyridopirrolodiazepinones (1-3), a new pharmacophore resulting from the fusion of the pyrrolo[1,2-a][1,4]diazepine1 to a pyridine ring. The synthesis relies on the use of halopyridines and L-proline as building bloks.

The starting halopyridines were formylated with LDA and DMF to provide the correspondent halopyridine carbaldehydes. Reductive amination and condensation with L-Boc-proline gave the amides 5. After deprotection, the final ring-closure was performed through a base induced cyclization or by palladium catalyzed N-arylation.

Several isomers (1-3) with high pharmacologic potential were prepared in good overall yields.

N(Cl,Br) Y

Z

X

N

NO

HL-Boc-ProYZ

X (Cl,Br)HN

YZ

X (Cl,Br)

4

5X=N; Y=Z=CX=Z=C; Y=NX=Y=C; Z=N

N O

BocNH

1-3

Acknowledgment. Support of this work by the Spanish Ministry of Education and Science (Project CTQ2005-02338), in collaboration with ERDF, and by Xunta de Galicia (Projects PGIDITO6PXIC209067PN and 2007/XA084, and pre-Doctoral grant to L. L.) is gratefully acknowledged.

1 Meerpoel, L.; Van Gestel, J.; Van Gerven, F.; Woestenb.; Terence, G.; Nash, R.; Corens, D.: Richards,R.D. Bioorg. Med. Chem. Lett.2005, 15, 3453-3458.

Posters SISOC7


PO-59

Synthesis of Novel Pyrimido[4,5-e][1,4]diazepines

M. Nogueras, J. M. de la Torre, J. Cobo. Departamento de Química Inorgánica y Orgánica

Facultad de Ciencias Experimentales. Universidad de Jaén Campus Las Lagunillas s/n. Jaén (Spain.)

[email protected]

It is well known the biological activity of pyrimidine nucleus in a lot of important natural occurring products such as nucleic acids, showing their analogues a wide range of pharmaceutical and agrochemical properties, i.e. antibiotic, antitumoral or antifungal. 1

We have focused our work in the synthesis of new pyrimido-diazepines systems. Many studies have been done about pyrimido[4,5-b][1,4]diazepines,2 but not much on their isomeric pyrimido[4,5-e][1,4]diazepine derivatives, which have also displayed interesting biological activity such as anticonvulsants, tyrosine kinase inhibitors, etc.

Here we report an efficient method for the synthesis of pyrimido[4,5-e][1,4]diazepin-4,7-diones (4) starting from 6-aminopyrimidin-4(3H)-one.

The key step in order to get these compounds is the preparation of appropriated intermediates, such 5-aminomethylenepyrimidine derivatives (2).3 Once these intermediates have been prepared, a simple sequence consisting in Acylation-Nucleophilic Substitution yields the desired molecules.

X-Ray diffraction analysis corroborates the structure of the final products.

1 D. J. Brown, R. F. Evans, W. B. Cowden and M. D. Fenn, The Pyrimidines, Wiley, New York, 1994. 2 (a) R. M. Freidinger, B. E. Evans, M. G. Bock, Eur. Pat. Appl.: EP 92-305501 19920616, 1992; Chem. Abstr. 1993, 118, 139861. (b) M .Di Braccio, G. Grossi, G. Roma, L. Vargiu, M. Mura, M. E. Marongiu, Eur. J. Med. Chem. 2001, 36(11-12), 935-49. (c) H. Schaefer, R. Riedel, K. Klemm, J. Senn-Bilfinger, M. Eltze, Eur. Pat. Appl. EP 80-104589 19800804, 1981; Chem. Abstr. 1981, 95, 132969. 3 J. M. de la Torre, M. Nogueras, J. Cobo, J. N. Low, 4º Spanish Portuguese Japanese Organic Chemistry Symposium. Book of Abstracts, pag. 85 (2006).

N

N

O

H3CX

H3C

NH2

NH

R1

R2Cl

O

Cl N

N

O

H3CX

H3C

NH2

NR1

O

R2

Cl

N

N NH

NO

H3C

H3CXO

R1

R2

N

N

OH3C

H3CX NH2

CHO

R1NH2

NaBH(OAc)3

(1)

(2) (3)

(4)

SISOC7 Posters


NN N

HAr

CH3

H3C CH3

H H

OO

OR

R NN

N

R

RO

O

Ar

H3CCH3

H3C

+

1 2 3 4

+

PO-60

Multicomponent Synthesis of Spiroheterocyclic Systems from 3-tert-Butyl-N-aryl-1-phenyl-1H-pyrazol-5-amine and Cyclohexane-1,3-diones

Jorge Trilleras,1 Jairo Quiroga,1 Rodrigo Abonía,1 Juan Carlos Castillo,1 Silvia Cruz,2 Manuel Nogueras,3 Justo Cobo3

1Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A. A. 25360 Cali, Colombia

2Departamento de Química, Universidad de Nariño, A.A. 1175 Pasto, Colombia. 3Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén,

España. e-mail: [email protected]

Multi-component reactions are one-pot processes with at least three components to form a single product, which incorporates most or even all of the starting materials.1 Hence, most of the scientific efforts have been focused on the development of multi-component procedures to prepare diverse heterocyclic compound libraries.1b Parallely, the application of microwave technology in organic synthesis,2 and particularly under free-solvent conditions, is increasing because of its simplicity, lesser environmental impact and reduced reaction times, providing a rapid access to large libraries of diverse molecules. We have concentrated much of our recent work in the preparation of bioactive nitrogen-containing spiro-heterocyclic analogs by combination of both strategies.3

Here, we communicate a facile three-component one-pot cyclocondensation to prepare pyrazolo[3,4-b]pyridin-5-spirocyclohexanediones 4 under microwave irradiation induction of a multicomponent reaction between 5-(benzylamino)-3-tert-butyl-1-phenylpyrazole 1, cyclohexane-1,3-diones 2 and a large excess paraformaldehyde 3, which rendered good yields (70-85 %). We have to remark that the reaction under conventional heating, using ethanol as solvent, proceeded rather similarly rendering products 4 in equal yields. The main difference between those methods is the shorter reaction times for microwave irradiation vs conventional heating, 20 min. vs 24 h, respectively.

1 (a) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51-80; (b) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471-1499; (c) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3220. 2 (a) Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J.-L.; Petit, A. Tetrahedron 1999, 55, 10870-10951; (b) Cossy, J.; Willis, C.; Bellosta, V.; Jalmes, L. S. Synthesis 2002, 951-957. 3 Quiroga, J.; Cruz, S.; Insuasty, B.; Abonía, R.; Nogueras, M., Cobo, J. Tetrahedron Lett. 2006, 47, 27-30.

Posters SISOC7


PO-61

A Mild Method for the Chemoselective Deprotection of N-Pivaloylindoles and Carbazoles by Hydrolysis with Water-DBU

Miriam Ruiz-Serrano, Pilar López-Alvarado and J. Carlos Menéndez Departamento de Química Orgánica y Farmacéutica

Facultad de Farmacia Universidad Complutense, 28040 Madrid. Spain

[email protected]

N-Protection is a very important aspect of indole chemistry because of the poor stability of indole under a variety of conditions. For this reason, a large number of indole N-protecting groups such as carbamates, arylsufonyl derivatives, alkyl groups and N,O- acetals are known.1 On the other hand, protecting groups for the indole C2-C3 bond are almost unknown.2 The pivaloyl group would be a very interesting protecting group for indole because, due to steric reasons, it protects both the N-1 and C-2 indole positions; however, pivaloyl is normally considered to be difficult to remove, which has prevented its widespread use. Deprotection of pivaloylindoles has occasionally been achieved by use of alkoxides and by hydride transfer from LDA.3 These methods need strongly basic conditions that are not compatible with many functional groups.

We present in this communication an efficient N-deprotection method based on the use of DBU and water-THF (Scheme 1), that allows the deprotection of a large variety of N-pivaloylindoles and can also be extended to N-pivaloylcarbazoles with excellent yields and under mildly basic conditions. Importantly, these conditions were tolerated by a variety of other groups present in our starting materials, including alkyl halide, aldehyde, ketone, ester and carboxylic acid functions.

N

R3

R2R5

R7 C(CH3)3O

NH

R3

R2R5

R7

DBU, H2O-THF

Scheme 1

1 a) Kocienski, P.J. Protecting groups (3rd Ed.). Georg Thieme Verlag, 2004. b) Greene, T. W.; Wuts, P. G. M.

Protective groups in Organic Synthesis (4th Ed.), pp. 872-888. Wiley-Interscience, 2007. 2 Baran, P.S.; Guerrero, C. A.; Corey, E. J. Org. Lett. 2003, 5, 1999. 3 Avendaño C.; Sánchez, J. D.; Menéndez, J. C. Synlett 2005, 1, 107.

SISOC7 Posters


PO-62

Olefination Reactions of Azecinone[5,4-b]indoles and Indolo[2,3-a]quinolizinones

Domingo Domínguez, Mª del Carmen de la Fuente and Paula Estévez Santoro Departamento de Química Orgánica, Facultad de Química

Universidad de Santiago de Compostela Avda. de las Ciencias s/n 15782, Santiago de Compostela, España

[email protected]

Akuammiline (1) and echitamine (2) are pentacyclic monoterpenoid indole alkaloids with a characteristic C7-C16 bond,1 which exhibit antitumor and antimalarial effects.2

Within a project directed to the synthesis of the characteristic pentacyclic structures of these alkaloids, we consider an approach based on the C7-C16 bond formation by a nucleophilic addition of an enolate to the C3 position of an electron-deficient indole, having a leaving group at the Nitrogen atom, as in the azecinone 3.

Here we report preliminary studies directed to the preparation of the required key precursor 3 from the quinolizinone 4.3 In a first attempt, we succeeded in the ring opening of the quinolizinone 4 to give the azecinones 5a,b; however, repeated attempts to olefinate their carbonyl either by Knoevenagel or Horner-Emmons methods meet with failure. Alternatively, a tandem Knoevenagel/hydrogenation reaction provided an excellent yield of the alkylated quinolizine 7a, which was subsequently opened under acylating conditions in basic media to give the alkylated azecine 8.

N

N

O

-O CO2Me

CO2R

L

MeO

NH

N

HOH

Cl

CO2MeMeO2C

16

7

32

N

N

HH

CO2MeHOH2C

16

7

1

NH

N

ONH

N

NCCN

O

O

O

O

O

84

NR

N

NH

N

RO

O

O

5a, R= H5b, R=TBDMS

O(for 7a)

7a, R= H7b, R=Ts

NCCN

NH

N

RO

O

O

R1

R2

6(R1,R2 =CN, CO2R, H)

Acknowledgment. Support of this work by the Spanish Ministry of Education and Science (Project CTQ2005-02338), in collaboration with ERDF, and by Xunta de Galicia (Projects PGIDITO6PXIC209067PN and 2007/XA084) is gratefully acknowledged.

1 Ramírez, A.; García- Rubio, S. Current Medicinal Chemistry 2003, 10(18), 1891-1915. 2 Salim, A. S.; Garson, M. J.; Cralk, D. J. J. Nat. Prod. 2004, 67, 1591-1594. 3 Kuehne, M. E.; Muth, R. S. J. Org. Chem. 1991, 56, 2707.

Posters SISOC7


PO-63

C-N Bond forming Reactions in the Synthesis of Substituted 2-Aminoimidazole Derivatives

Asier Gómez-San Juan,a José Manuel Botija,b Esther Lete,a Almudena Méndez,b and Nuria Sotomayora

aDepartamento de Química Orgánica II, Facultad de Ciencia y Tecnología Universidad del País Vasco/EHU, Apdo. 644, 48080 Bilbao (Spain), [email protected]

bDepartamento de I+D MaxamEurope, 48960 Galdácano, Vizcaya (Spain)

The 2-aminoimidazoles represents a significant class of alkaloids of broad pharmacological activity.1 However, to date the synthesis of substituted 2-aminoimidazole key structural unit continues to be a challenge for synthetic organic chemists.2

As part of our program to develop new procedures for the synthesis of heterocyclic systems, in this communication we disclose our preliminary results on the several carbon-nitrogen bond forming reactions oriented to the synthesis of 2-aminoimidazole derivatives. Thus, we have carried out a comparative study on amination of imidazolidin-ones via the corresponding 2-halodihydroimidazles, reaction of 2-methylsulfanylhydroimidazoles, and palladium catalyzed reactions of 2-haloimidazoles and amines. These procedures are illustrated in the respresentative examples shown below. Details of these transformations will be discussed.

N NH

SCH3

p-anisidina

HN NH

ONH

HN

NBn

NH

NN

Bn

NH

N

N N

OSCH3

N N

Br

Pd2(dba)3, BINAP

p-anisidina

Ac2O

1. PCl5

2. BnNH2

and/or

HN N

ONPMP

N N

NHPMP

1 S. E. Webber, T. L. Little, J. Org. Chem. 1994, 59, 7299. 2 See, for instance: R. Abou-Jneid, S. Ghoulami, M. T. Martin, E. Tran Huu Dau, N. Travert, A. Al-Mourabit Org. Lett. 2004, 6, 3933.

SISOC7 Posters


PO-64

Microwave-Assisted Hydroformylation in the Synthesis of Spirotetrahydrofurans

Maurizio Taddei, Jessica Salvadori and Giacomo Lonzi Dipartimento Farmaco Chimico Tecnologico

Università degli Studi di Siena Via A. Moro, 53100 Siena, Italy

[email protected]

Recently we developed a new procedure to carry out microwave-assisted hydroformylation at lower temperature and pressure compared with the standard procedure1.

This reaction is particularly useful for the application of hydroformylation followed by intramolecular reactions using different functional groups present in the molecule. With the goal of preparing the spiro-furan piperidine present in the right part of Cyclopamine (1) (and several other Jervine alkaloids), we explored the possibility of use this reaction in a key step. Thus, different isopropenylcylohexanols were submitted to the hydroformylation-cyclization tandem procedure and we found that better results were achieved using THF / H2O as the solvent, allowing the preparation of the corresponding spirotetrahydrofurans with good yields.

O

HNH

H

H

H

HOH

1

O

OHCO/H2, Xantphos,(PPh3)3RhCO(H),

THF:H2O 10:1

MW, 3x30 min110 °C, 120 psi

RR R

R

OH

a: R=H; b: R=CH3

2a,b 3a,b

Starting from this product we developed different synthetic approaches in order to obtain the furan-piperidine moiety with good control of the stereochemistry. From hemiacetal (3a) it is possible to prepare the corresponding dihydrofuran (4) that undergoes photochemical addition of CbzN3 in MeOH to give compound (5) that can be considered an interesting precursor of polyfunctionalized amino acids.

OMsCl, Et3N,

THF

-78 °C to r.t.MW, 10 min 60 °C

O

OH

3a 4

hv 254 nm,r.t., 7 h

CbzN3, MeOH,CH3CN O

5

OCH3CbzHN

1 a) Petricci, E.; Mann, A.; Schoenfelder, A.; Rota, A.; Taddei, M. Org. Lett. 2006, 8, 3725-3727. b) Petricci, E.; Mann, A.; Salvadori, J.; Taddei, M. Tetrahedron Lett. 2007, 48, 8501-8504.

Posters SISOC7


PO-65

Stereoselective Functionalizations of Imino Lactones: Synthesis of Fluorinated and non-Fluorinated Peptidomimetics

Santos Fustero,a,b Natalia Mateu,a,b Laia Albert,a,b Teresa Moscardó,b Salvador Villanova,b Juan F. Sanz-Cerveraa,b and José Luis Aceñaa

aLaboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46013 Valencia

bDepartamento de Química Orgánica, Universidad de Valencia, Burjassot, 46100 Valencia E-mail: [email protected]

Optically active imino lactones 1, readily available from α-keto esters and (R)-phenylglycinol1 or by rearrangement of the parent oxazolines,2 are a valuable class of chiral building blocks for the preparation of a variety of synthetic targets. For instance, alkylation with Grignard reagents in the presence of BF3·OEt2 takes place at the iminic carbon with complete chemo- and stereoselectivity.1 When unsaturated Grignards are used, the resulting compounds 2 can be further elaborated into cyclic structures of different ring sizes by means of ring-closing metathesis reactions. We have used this strategy for the preparation of mimetics of peptidic molecules.

In contrast, reaction of lactones 1 with TMSCF3 in the presence of a catalytic fluoride source such as TBAF3 leads to trifluoromethyl lactols 3. These compounds serve as precursors for the stereoselective synthesis of trifluoromethylated amino alcohols and amino acids.4

NO

Ph

OR

TMSCF3

cat. F

NO

Ph

OHR

F3C

HNO

Ph

OR

n

nMgBr

BF3·OEt2

12 3

cyclic peptidomimetics fluorinated amino alcoholsand amino acids

1 L. M. Harwood, K. J. Vines, M. G. B. Drew, Synlett 1996, 1051. 2 C. M. Shafer, T. F. Molinski, J. Org. Chem. 1996, 61, 2044. 3 G. K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757. 4 S. Fustero, L. Albert, J. L. Aceña, J. F. Sanz-Cervera, A. Asensio, Org. Lett. 2008, 10, 605.

SISOC7 Posters


PO-66

A Novel One-pot Synthesis of 1,4-Dihydropyridines Based on a Sequential Four-component Process

Swarupananda Maiti and J. Carlos Menéndez Departamento de Química Orgánica y Farmacéutica


[email protected]

Multicomponent reactions have emerged as a powerful tool in organic synthesis1 and have found widespread applications in the preparation of bioactive compounds.2 The 1,4-dihydropyridine nucleus can be considered as a privileged scaffold that can interact at diverse receptors and ion channels,3 and indeed 1,4-dihydropyridines are among the most widely used drugs for the management of cardiovascular disease and have a broad range of other pharmacological activities.

We report in this communication a new one-pot procedure for the synthesis of 1,2,3,4-tetrasubstituted 1,4-dihydropyridines, which are unaccesible using traditional methods, based on a Lewis acid-catalyzed, sequential four-component process that leads to dihydropyridines 7 starting from very simple starting materials, namely amines, β-ketoesters, α,β-unsaturated aldehydes and ethanol, followed by a subsequent reflux in the presence of neutral alumina afforded the target compounds 7 in good to excellent yields. As proof of the proposed mechanism, intermediates 3, 5 and 6 have been isolated.

R1 NH2 +H3C OR2

O O

H3C OR2

ONHR1

N

R3

CH3

R1

HO

OR2

O

Lewis acid (5 mol%)CH3CN, rt, 30 min

N

R3

CH3

R1

OR2

O

2 3

5

Al2O3, reflux

OR3 4

EtOH (3 eq), rt, 1h

N

R3

CH3

R1

EtO

OR2

O

67

Lewis acids: (NH4)2Ce(NO3)6, InCl3

1

1 Zhu, J.; Bienaymé, H. (eds.), Multicomponent Reactions. Wiley-VCH, Weinheim, 2005. 2 Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51. 3 Triggle, D. J. Cell. Mol. Neurobiol. 2003, 23, 293.

Posters SISOC7


PO-67

Synthesis of 4-Alkoxyindoles: Application to the Preparation of Indole Inhibitors of Phospholipase A2

Roberto Sanz, Verónica Guilarte, M. Pilar Castroviejo and Delia Miguel Área de Química Orgánica. Departamento de Química. Facultad de Ciencias


[email protected]; http://web.ubu.es/investig/grupos/cien_biotec/qo-3/index.html Indole derivatives with oxygen-bearing substituents at the benzo moiety are important compounds and many of these are known to be synthetic medicines and physiologically active substances (serotonin, melatonin, psilocin,..).1 In this field, we have recently reported an easy preparation of indole derivatives, oxygen-functionalized at the C-4 or C-7 position,2 by using a directed ortho-metallation reaction to achieve 2,3-dihalophenol derivatives, and a selective Sonogashira monoalkynylation, followed by a one-pot Pd-catalyzed amination and subsequent cyclization. Among the reported inhibitors of secreted phospholipases A2 (sPLA2),3 indole 3-glioxamides with additional oxygenated functionalities at the benzenoid ring appear to be the most potent inhibitors of sPLA2. Herein, we want to show the application of our reported strategy to the synthesis of a series of inhibitors of phospholipase A2 (Scheme 1).

OMe

Cl

OMe

Cl

IOMe

Cl

R

NR

O

Bn

NH2O

O

O OH

R = Et (LY315920) Pr Bu Ph

NR

OMe

Bn

1. t-Bu2Zn(TMP)Li2. I2

(86%)

R

PdCl2(PPh3)2 (cat.)TBAF·3H2O

BnNH2

Pd(OAc)2 (cat.)HIPrCl (cat.), t-BuOK

(68-92%)R = Et, Pr, Bu, Ph

(57-84%)

overall yields

1. BBr32. NaH, BrCH2CO2t-Bu

3. (COCl)24. HDMS5. TFA

19%20%21%29%

Scheme 1

Starting from cheap and commercially available 3-chloroanisole, four different 3-glioxamide indole derivatives have been synthesized in good overall yields. This methodology favorably competes with other reported sequences, which make use of expensive starting materials or require several steps. 1 O. Shirota, W. Hakamata, Y. Goda, J. Nat. Prod. 2003, 66, 885-887. 2 R. Sanz, M. P. Castroviejo, V. Guilarte, A. Pérez, F. J. Fañanás, J. Org. Chem. 2007, 72, 51135118. 3 R. C. Reid, Curr. Med. Chem. 2005, 12, 30113026.

SISOC7 Posters


PO-68

Synthesis and Evaluation of Coumarin-Resveratrol Hybrid Derivatives as a New Class of Tyrosinase Inhibitors.

G. Delogu,a C. Picciau,a G. Podda,a M. Corda,b M. B. Fadda,b A. Fais,b L. Santana,c M. J. Matosa,c and E. Quezadaa,c

a) Dipartimento Farmaco Chimico Tecnologico-Via Ospedale 72,09124 Cagliari-Italy [email protected]

b) Dipartimento di Scienze Applicate ai Biosistemi, Cittadella Universitaria di Monserrato, 09042 Monserrato, CA, Italy

c) Department of Organic Chemistry, University of Santiago de Compostela, Santiago de Compostela, Spain.

Trans-Resveratrol (3,5,4’-trihydroxystilbene) is a stilbenic phytoalexin produced by plants via metabolic sequence induced in response to biotic or abiotic stress factor. It has been found in a multitude of dietary plants, such as pines, legumes and grapevines: thus, relatively high concentrations of this compound are present in grape juice and in red wine. Resveratrol in one of the phenolic compounds present in wine that could be responsible for the decrease in coronary heart disease observed among wine drinkers (French paradox). This natural compound has shown a number of biological activities including antiinflammatory and anticancer properties. On the other hand, coumarins are a large group of compounds that have been reported to possess a wide range of biological activities, including cardiovascular properties.1 In this work we have synthesized the coumarin-resveratrol hybrids 3,4 and its methoxy derivatives 1,2 by a very direct synthetic route involving a Perkin procedure that fixes the trans disposition of the trans-resveratrol-type double bond.

O

OH

O ODCC/DMSO 110°C

R'

R

OH

H

OOCH3

H3CO

OCH3OCH3R

R' O O

OHOH

R

R'

1 R= H; R'= OCH3 2 R= OCH3; R'= OCH3

MW

pyridine HCl

3 R= H; R'= OH 4 R= OH; R'= OH

In addition, we have evaluated the potential inhibitory activity against tyrosinase. Tyrosinase, is a copper-containing enzyme that catalyzes two different reactions: a) hydroxylation of monophenols to o-diphenols (monophenolase activity) and an oxidation of o-diphenols to o-quinones (diphenolase activity), both using molecular oxygen. It is well know that tyrosinase is a key enzyme for melanin biosynthesis in plants and animals.2

1 S. Vilar, E. Quezada, L. Santana, E. Uriarte, M. Yanez, N. Fraiz, C. Alcaide, E. Cano, P. Orallo, Bioorg. Med. Chem. Lett. 2006, 16, 257-261. 2 H. Gao, J. Nishida, S. Saito, J .Kawabata, Molecules 2007, 12, 86-97.

Posters SISOC7


PO-69

Synthesis of New Coumarin Derivatives with Pharmacological Activity

M. J. Matos,1,2 D. Viña,3 E. Quezada,1,2 C. Picciau,1,2 G. Delogu,2 P. Janeiro,1 L. Santana,1 E. Uriarte,1 G. Podda2

1Departamento de Química Farmacéutica, Facultad de Farmacia, 15782, Santiago de Compostela, Spain

2Dipartimento Farmaco Chimico Tecnologico, Facoltà di Farmacia, 09124, Cagliari, Italy 3Departamento de Farmacología, Facultad de Farmacia, 15782, Santiago de Compostela,

Spain [email protected]

Coumarins are a class of compounds of natural and synthetic origin with a variety of pharmacological properties depending on their substitution pattern.1 Recently, we are studding this structural moiety and their pharmacological properties, with special attention to the vasodilatory, hypotensive and monoamino oxidase (MAO) inhibitory activity.2,3 On the basis of the above information and with the aim to establish the structure-activity relationships (SAR) in the coumarin scaffold, in the present communication we have designed a new series of derivatives. The substituents on the coumarin have been chosen taking in account their lipophilic, steric and/or electronic properties, and were introduced either in the 3 and 4 positions of the pyrone ring and in the 7 and/or 8 positions of the coumarin moiety. The new compounds have been prepared starting from the resorcinol and the corresponding ketoester derivative, by condensation via Pechmann. The subsequent reaction of 7-hydroxycoumarins with the haloketone derivatives gave the corresponding ethers that were finally oxidized to give the 3,4-benzocoumarin derivatives.

R

OHHOOO O

R

R´ Z

OHO OR

Cn

OO O

CnR´ Z

R

The synthesis, structural requirements, SAR analysis and MAO inhibitory activity of the synthesized compounds will be presented.

1Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Current Medicinal Chemistry, 2005, 12, 887-916. 2Santana, L.; Uriarte, E.; González-Díaz, H.; Zagotto, G.; Soto-Otero, R.; Méndez-Álvarez, E. Journal of Medicinal Chemistry, 2006, 43, 1149-1156. 3Vilar, S.; Quezada, E.; Santana, L.; Uriarte, E.; Yánez, M.; Fraiz, N.; Alcaide, C.; Cano, E.; Orallo, F. Bioorganic & Medicinal Chemistry Letters, 2006, 16, 257-261

SISOC7 Posters


PO-70

Rhodium-Catalyzed Hydroformylation of 3-(Pyrrol-1-yl)Alk-1-enes: Two Examples of High 1,2- and 1,3-Substrate-Induced Diastereoselectivity

Roberta Settambolo,1 Giuliano Alagona,2 Caterina Ghio,2 Raffaello Lazzaroni3 1ICCOM-CNR (Pisa Section), Via Risorgimento 35, 56126 Pisa, 2IPCF-CNR, MML, Via

Moruzzi 1, 56124 Pisa, 3DCCI, University of Pisa, Via Risorgimento 35, 56126 Pisa E-mail: [email protected]

The generation of a new stereocenter, either with the aid of a chiral catalyst or by substrate-based asymmetric induction, is a topic of great interest in transition metal catalyzed reactions, especially if the involved processes are in accord with the criteria of atom economy. We observed, and report here, high values of both 1,2- and 1,3-asymmetric induction (d.e. up to 99%) under N-allylpyrroles1 rhodium-catalyzed hydroformylation conditions (Scheme 1). Scheme 1

N

R'

R''

R

N

NO

N

OCO/H2

Rh4(CO)12

25 °C, 100 atmR=R''=H R'=CH(CH3)2

100 °C, 100 atmR= COCH3R'=HR''=CH3

1,2-asymmetric induction

1,3-asymmetric induction

12

13

1

2

OH

OH

O

The former example regards the formation of 4-methyl-3-(pyrrol-1-yl)pentanal (1) from the corresponding chiral N-allylpyrrole: due to a 1,2-asymmetric induction of the chiral center into the starting olefin, 1 was obtained with a d.e. value 80%.2 In the latter a complete asymmetric induction was exerted by the new chiral center (1 carbon atom) of the formed pyrrolylbutanal intermediate on the carbon atom in position three during a one-pot intramolecolar cyclization to tricycle 2 (d.e. 99/1). In both cases the diastereomer having the same configuration at both chiral centers was selectively formed. R,R Is the only diastereomer depicted into Scheme 1. Interestingly, regio-selectivity (> 85/15) and diastereo-selectivity as well as the absolute configuration of the prevailing diastereomer, evaluated from computational investigations,3

correspond to those experimentally determined. The selectivity of the result together with the interest of these products on fine chemistry, make the oxo process of pyrrolylolefins a valid synthetic instrument.

1 R. Settambolo, G. Guazzelli, L. Mengali, A. Mandoli, R. Lazzaroni, Tetrahedron: Asymmetry 2003, 14, 2491. 2 R. Settambolo, S. Rocchiccioli, G. Uccello-Barretta, R. Lazzaroni, Letters in Organic Chemistry 2007, 4, 388. 3 G. Alagona, C. Ghio, S. Rocchiccioli, J. Mol. Model. 2007, 13, 823.

Posters SISOC7


PO-71

Total Synthesis of (-)-Dysithiazolamide

Jaime Rodríguez, Carlos Jiménez, Ana Ardá, M. Isabel Nieto, and Raquel G. Soengas Departamento de Química Fundamental

Universidade da Coruña Facultade de Ciencias, s/n, 15071. A Coruña, Spain

[email protected] More than 4500 natural products of both marine and terrestrial origin have in common some biohalogenation processes. Very recently, Walsh and co-workers described a novel class of halogenating enzymes capable of carrying out halogenations at aliphatic carbon centers of peptidyl carrier protein-linked amino acid residues such as L-leucines.1 This mechanism of chlorination was first proposed by Gerwick et al. in the biosynthetic studies of barbamide,2 a mixed polypeptide-polyketide natural product that contains a trichloromethyl group and whose biosynthetic gene cluster was isolated and characterized.

Recently, we reported the structure of a new member of this class of compounds, the tetrachlorinated dipeptide dysithiazolamide (1), the relative configuration of which was deduced through configurational analysis using proton-proton and proton-carbon coupling constants.3 Furthermore, the absolute configuration was proposed by comparison with previous compounds isolated from Dysidea species.

A practical and reasonably efficient síntesis of dysithiazolamide (1) has been developed from L-glutamic acid, confirming the initially proposed (2S,4S,6S,8S) absolute stereochemistry.

ClN

Cl

SN

ONH

O

Cl ClClNH

Cl

SN

O

HNOCl

Cl

HO

1

HO OMe

O

NHBoc +

Acknowledgements: This work was financially supported by a Grant of the Ministerio de Educación y Ciencia (CQT2005-00793) and Xunta de Galicia (PGI-DIT03PXIC10302PN). R. G. S. and M. I. N. also thank Xunta de Galicia for IPP program. 1. Galonic, D. P.; Vaillancourt, F. H.; Walsh, C. T. J. Am. Chem. Soc. 2006, 128, 3900–3901. 2. a) Sitachitta, N.; Rossi, J.; Roberts, M. A.; Gerwick, W. H.; Fletcher, M. D.; Willis, C. L. J. Am. Chem. Soc. 1998, 120., 7131–7132. b) Sitachitta, N.; Márquez, B. L.; Williamson, R. T.; Rossi, J.; Roberts, M. A.; Gerwick, W. H.; Nguyen, V.-A.; Willis, C. L Tetrahedron 2000, 55, 9103–9113. 3. Ardá, A.; Rodríguez, J.; Nieto, R.; Bassarello, C.; Gomez-Paloma, L.; Bifulco, G.; Jiménez, C. Tetrahedron 2005, 61, 10093–10098.

SISOC7 Posters


PO-72

Stereoselective Synthesis of (R)- and (S)- 3-Aminotetradecanoic Acid (Iturinic Acid)

Raffaella Terlizzi, Andrea Temperini, Marcello Tiecco and Lorenzo Testaferri Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica,

Università di Perugia, via del Liceo 1, I 06123-Perugia. Italy [email protected]

In recent years β3-amino acids have increased enormously their importance1 for the preparation of peptides with enhanced in vivo stability as well as for the synthesis of beta-lactam antibiotics. In addition, β3-amino acids are also component of several naturally occurring and biologically active peptides isolated from marine organisms or from plants. Given the significance of β3-amino acids, it is not surprising that the development of their synthesis in optically pure form has become an important challenge for organic chemists.2 We have now developed a new process for the conversion of ynone 1 into the corresponding β3-amino acid 4 under simple and smooth conditions.

p-TsOHCH2Cl2

R= nC11H23

1 2 3

R

O

R

PhthN

SePhR

PhthN O

SePh R

H2N O

OH4

(R)-iturinic acid

The key step of the whole conversion is represented by the synthesis of the corresponding alkynyl phenyl selenide 2 which, in the presence of p-toluenesulfonic acid, give the Se-phenyl selenocarboxylate 3 in good yield.3 Compound 3 can be then easily transformed into the (R)-iturinic acid 4. Moreover, the Se-phenyl selenocarboxylate 3 is also a very selective acyl transfer agent in its reactions with amines or amino acids to afford the corresponding amides. Acknowledgement: Financial support from MIUR, National Projects COFIN2005, and Consorzio CINMPIS and University of Perugia is gratefully acknowledged.

1 Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1. 2 Liu, M; Sibi, M. P. Tetrahedron 2002, 58, 7991. 3 Tiecco, M.; Testaferri, L.; Temperini, A.; Bagnoli L.; Marini, F.; Santi, C.; Terlizzi, R. Eur. J. Org. Chem. 2004, 3447.

Posters SISOC7


PO-73

An Unexpected Rearrangement of the β-Lactam Ring Under Basic Conditions

Josefa Anaya, Manuel Grande and Ramón Martín Departamento de Química Orgánica

Universidad de Salamanca. Facultad de Ciencias Químicas Plaza de los caídos, 1-5. 37008-Salamanca. España

[email protected]

We have recently reported the preparation of polycyclic β-lactams by 5- and 6-exo-radical cyclisation from N-alkenyl-4-epoxyalkylmonolactams, using Cp2TiCl as radical inductor.1 In this line, we are now investigating the 6-endo-trigonal process in epoxides 1 and 2 in order to prepare new carbacephem compounds as potential inhibitors of human leucocyte elastase (HLE), as exhibit the precursor 1.2

43 65

N

MeO Ph

Ro

HMeO2C

3: R0 = Me

O

4: R0 = Pr

43

N

MeO Ph

Ro

SePhMeO2CO

43

N

MeO Ph

1: R1 = H

O

2: R1 = Et

N

MeO

O

Ph

CO2Me

OO

B

O

CO2MeR1 R1

NH

MeO Ph

O 5MeO Pr

HN

Ph

O

O

6

2

Throughout our studies we have found that to get good results in the synthesis of the epoxides 1 and 2 it is necessary to do firstly the epoxidation of 3 or 4 and then the β-elimination of the selenyl derivatives B through the selenoxide intermediate. If the β-elimination is carried out before the epoxidation, then the yields of the epoxyalkenes decreases. In this case the main component is the unsaturated monolactam 5 that was also accompanied by the bicyclic γ-lactam 6 when started from 4.

The structure of the bicyclic pyrrolidinedione 6 was established by NMR and confirmed by X-ray crystallography.


1 a) J. Anaya, A. Fernández-Mateos, M. Grande, J. Martiáñez, G. Ruano and Ma. R. Rubio-González. Tetrahedron, 2003, 59, 241. b) G. Ruano, M. Grande, and J. Anaya, J. Org. Chem. 2002, 67, 8243. c) G. Ruano, J. Martiáñez, M. Grande, and J. Anaya, J. Org. Chem. 2003, 68, 2024. 2 R. Martín, Grado de Salamanca, Universidad de Salamanca, 2007. (Unpublished results).

SISOC7 Posters


PO-74

Efficient Synthesis of Heterocyclic Quinones by Oxidative Demethylation of Hydroquinone Methyl Ethers with the Koser’s Reagent

Irene Ortín, Elena de la Cuesta and Carmen Avendaño Departamento de Química Orgánica y Farmacéutica


[email protected]

HTIB ([hydroxy(tosyloxy)iodo]benzene) has been used in the tosyloxylation of glycine templates,1 but in the case of compounds 1 oxidative demethylation to quinones 2 takes place instead. This unprecedent reaction2 has been studied and compared to the CAN-mediated reaction.

NN

O

O

R2

O

O

H

HTIB (4 equiv)

CH3CN, 90 ºC, 1 h98%

2

NN

O

O

CH3O

CH3O

H

R6

R3

R2

R

1

R6

R3

R

In conclusion, we have developed a practical oxidative non-hydrolytic protocol that provides a general route to heterocyclic quinones from accessible 1,4-hydroquinone methyl ethers and the relatively benign oxidant HTIB. The reaction may be carried out under conventional heating or microwave irradiation without affecting catechol methyl ethers and other functionalities. This work expands the current interest and research activity in the development of synthetic methods based on the organic chemistry of hypervalent iodine reagents.

1 See the use of Koser’s reagent in the tosyloxylation of glycine templates in: Sánchez, J. D.; Ramos, M. T. Avendaño, C. J. Org. Chem. 2001, 66, 5731. 2 (a) Tohma, H.; Mariota, H.; Harayama, Y.; Hashizume, M.; Kita, Y. Tetrahedron Lett. 2001, 42, 6899. (b) For a recent use of PIFA to obtain 1-benzyl-1H-indole-4,7-dione and to oxidize aromatic amines to quinones see: Marminon, Ch.; Gentili, J.; Barret, R.; Nebois, P. Tetrahedron, 2007, 63, 735-739.

Posters SISOC7


PO-75

3-Amino-2(5H)furanones: a New Class of Antiviral Agents

Elisa Brunaccini, Caterina Carnovale, Maria Gabriella Chindamo,

Daniela Iannazzo, and Rossella Caminiti, Dipartimento Farmaco-chimico

Università di Messina Viale S.S. Annunziata, 98168 Messina

[email protected]

Hepatitis C Virus (HCV) infection constitutes a global health problem, which affects more than 170 million individuals.1,2 The NS5B RNA-dependent RNA polymerase (NS5B RdRp) has shown to be the catalytic core of the HCV replication machinery.3 Different classes of NS5B inhibitors have been disclosed and they can be divided by their mechanism of action into three major classes: non-nucleoside inhibitors acting at allosteric binding sites, nucleoside analogues, and pyrophosphate analogues. In these last years, we have developed an efficient synthetic procedure towards the construction of 3-amino-2(5H)furanones by basic treatment of 3-alkoxycarbonyl substituted isoxazolidines.4 We have assumed that the introduction of a carbonyl group at the C4 position of the 3-amino-2(5H)furanone skeleton, could produce potential inhibitors of pyrophosphate site. In fact, 3-amino-2(5H)furanones 4 may be regarded as DKA cyclic analogues: the 1,3-diketonic functionality is replaced by the 1-keto-3-imino group, enolized into the corresponding 1-keto-enamino functionality, while the acid moiety is masked in the furanose structure. Some of the newly described compounds have shown a good inhibitory activity in a cell-based subgenomic HCV replication assay.5

1 Wasley, A.; Alter, M.J., Semin. Liver Dis., 2000, 20, 1–16. 2 Lauer, G. M.; Walker, B. D., N. Engl. J. Med. 2001, 345, 41–52. 3 Penin, F.; Dubuisson, J.; Rey, F. A.; Moradpour, D.; Pawlotsky, J.-M., Hepatology, 2004, 39, 5–19. 4 Casuscelli, F.; Chiacchio, U.; Di Bella M. R.; Rescifina, A.; Romeo, G.; Romeo, R.; Uccella, N., Tetrahedron, 1995, 31, 8605–8612. 5 D. Iannazzo, A. Piperno, G. Romeo, R. Romeo, U. Chiacchio, A. Rescifina, E. Balestrieri, B. Macchi, A. Mastino, R. Cortese. Biorg. Med. Chem., 2008, in press.

SISOC7 Posters


PO-76 Synthesis and Characterization of Polyamides Containing α-Aminoacids

D . Kadaa and G. Tabakb a, b Laboratoire de Synthèse Macromoléculaire et Thio-organique Macromoléculaire,

faculté de chimie U.S.T.H.B , B.P 32 El-Alia Bab Ezzouar 16111 Alger. [email protected], [email protected].

Polyamides are useful biomaterials owing to their biodegradability and good mechanical strength.1 The interest for developing new biodegradable and/or biocompatible polymers specially polyesters and polyamides has largely encouraged the use of natural monomers such as α– aminoacids. Poly(α–aminoacid)s and synthetic copolymers of α–aminoacids (synthetic polypeptides) were intensively studied as model of natural polypeptides and proteins.2,3 These polymers can be prepared by polycondensation of amino acids or by ring opening polymerization of α -aminoacid NCAs.4,5,6 In this work we describe the synthesis and characterisation of a set of polyamides prepared from α–aminoacids and 6 amino hexanoic acid. The polyalanine obtained by polycondensation of L-alanine is an oligopolymer, the DPn determined by RMN1H is = 5. We have prepared with yield going from 39 to 62% novel linear copolyamides by polycondensation in aqueous solution of α-aminoacids such as L-alanine, phenyl alanine, phenylglycine, leucine and 6-amino hexanoic acid. These water-soluble polymers present a polyelectrolyte effect at concentration lower than 0.3 g.dL-1 and an intrinsic viscosity varying from 0.19 to1 dL.g-1. These copolyamides synthesized have high melting points and are thermically stable. The potential as water soluble polyelectrolyte drug carriers may be investigated. The thionation of finely derived copolyamides by Davy reagent7 has been used for synthesis of copolythioamides. All the polymers were characterized by IR, UV, NMR1H and NMR13C.

1 Fan Y., Kobayashi M., Kise H., Polymer Sci Part A: Polym Chem, 2001, 39,1318-1328 2 Stahmann M.A., “polyamino Acids, Polypeptides and Proteins”, Ed., The University of Wisconsin Press Madison, WI, USA, 1962. 3 Walton A.G., Blackwell J., Biopolymers, Academic, Boston,MA, London, 1973. 4 Kricheldorf H. R., ”α –Amino Acid -N- Carboxyanhydrides and Related Heterocycles”, Springer, Berlin, New York 1987. 5 Kricheldorf H. R., Models of Biopolymers by Ring Opening polymerization, S. Penczek, Ed., CRC Press Inc., Boca Raton, FL, 1990, chapter 1. 6 Kricheldorf H. R., Colin Von LossOW, Schwartz G., Macromol. Chem. Phys. 2004, 205, 918-924 7 Davy H., Mertzner P., Chemistry and Industry, 16 December 1985.

Posters SISOC7


PO-77 Synthesis of Vinylogous Fluoroalkyl α-Aminonitriles and α-Amino acids

F. Palacios a, A. M. Ochoa de Retana, S. Pascual and G. Fernández de Trocóniz. aDpto. Química Orgánica I, Fac. Farmacia, Universidad del País Vasco UPV/EHU

Apdo. 450, 01080 Vitoria-Gasteiz, Spain E-mail: [email protected]

The development of efficient and mild methods for organofluorine compound synthesis represents a broad area of organic chemistry since the incorporation of a fluorine-containing group into an organic molecule dramatically alters its physical, chemical and biological properties.1 These changes in properties make them suitable for diverse applications in synthetic, agricultural, and medicinal chemistry as well as in materials science.2 In this way, we disclosed recently the synthesis of fluoroalkylated unsaturated imines3 as well as of β- fluoroalkylated aminofosfonates and pyridines4 from primary β-enaminophosphonates 1.

Continuing with our interest in the design of new fluoroalkyl substituted building blocks, we report here an easy and efficient synthesis of vinylogous fluoroalkyl α-aminonitriles and α-amino acids derivatives 3 and 4. Olefination reaction of primary β-enaminophosphonates 1 with aldehydes gave α,β-unsaturated imines 2. Addition of TMSCN to imines 2 led to the formation of vinylogous fluorinated α-aminonitriles 3. The hydrolysis of these new fluorinated α-aminonitriles 3 afforded new α,β-unsaturated fluoroalkyl α-amino acids 4.

(EtO)2PRF

NH2

R1

O 1.BuLi

2.R2CHO3.TMSCN

R2 RFR1

H2N CN NaOHR2 RF

R1

H2N COOH

1

2

3 4

RF

NH

R2TMSCN1.BuLi

2.R2CHO R1

RF = CF3,CHF2, CH2F, C2F5

Acknowledgements: The present work has been supported by the Dirección General de Investigación del Ministerio de Ciencia y Tecnología (MCYT, Madrid, DGI, CTQ2006-09323) and by the University of the Basque Country (UPV, GIU 06/51)

1 Selective Fluorination in Organic and Bioorganic Chemistry, Welch, J.T., Ed.; American Chemical Society: Washington D.C., 1991 2 Chambers, R.D. Fluorine in Organic Chemistry. 2nd Ed. Blackwell, London 2004 3 Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J.; Pascual, S., J. Org. Chem., 2004, 69, 8767-8774. 4 Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J.; Pascual, S.; Férnandez de Trocóniz, G., J. Org. Chem., 2008.

SISOC7 Posters


PO-78

Uncatalyzed Strecker-type Reaction of N,N-Dialkylhydrazones in Pure Water

Eugenia Marqués-López,[a] Raquel P. Herrera,[b] Rosario Fernández*[c] and José M. Lassaletta*[d]

[a] Organische Chemie, Technische Universität Dortmund. Otto-Hahn-Str. 6. 44227 Dortmund, Germany.

[b] Laboratorio de Síntesis Asimétrica, Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC. E-50009 Zaragoza, Spain.

[c] Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla. Apdo. de Correos Nº 553, E-41071 Seville, Spain.

[d] Instituto de Investigaciones Químicas, CSIC-USe. c/ Américo Vespucio 49, Isla de la Cartuja. 41092 Seville, Spain.

[email protected] and http://www.bioorganica.es

α-Amino nitriles have occupied an important position in organic chemistry ever since Strecker’s original report in 1850 on the three component reaction, between aldehydes, ammonia and hydrogen cyanide.1 These bifunctional compounds are versatile intermediates in a number of synthetic applications such as the synthesis of non-proteinogenic α-amino acids, of importance in the pharmaceutical and biological fields.2 They are also precursors of natural products and heterocycles.3 Although the Strecker-type reaction has been widely reported using imines, there is only one organocatalytic non enantioselective precedent with N-acylhydrazones as imines surrogates.4 These precedents and the demonstrated greater stability of hydrazones against imines, mainly aliphatic and formaldehyde derivatives, prompted us to study a new version of this reaction using N,N-dialkylhydrazones.

Aldehyde and ketone N,N-dialkylhydrazones exhibit a unique reactivity in the Strecker reaction with in situ generated HCN, that proceeds in pure water in the absence of co-solvents, catalysts or promoters. Experimental evidence suggests that the reaction proceeds assisted by an intramolecular activation of HCN by the N,N-dialkyl amino lone pair.5

N

R2R1

NR2 HN

CNR1

NR2

R2

71-94%

TMSCN or KCN/AcOH

H2O, r.t.

TMSCN or KCN/AcOH

H2O, r.t.

O

R2R1H2NNR2

R1, R2 = Alkyl, aryl; NR2 = piperidin-1-yl, NMe2

+

The use of hydrazones as substrates in this reaction is of particular interest for the synthesis of α-hydrazino acids, valuable precursors of peptidomimetics.6

1 A. Strecker, Ann. Chem. Pharm. 1850, 75, 27. 2 M. J. O’Donnell Ed. Tetrahedron Simposia in Print 1988, 44, 5253. 3 Y. M. Shafran, V. A. Bakulev, V. S. Mokrushin, Russ. Chem. Rev. 1989, 58, 148. 4 T. Chiba, M. Okimoto, Synthesis 1990, 209. 5 E. Marqués-López, R. P. Herrera, R. Fernández, J. M. Lassaletta, Eur. J. Org. Chem. 2008 in press. 6 M. Marraud, R. Vanderesse, Peptides Containing C/N/O Amide Bond Replacements. In Houben-Weyl: Synthesis of Peptides and Peptidomimetics, Vol. E22c (Ed.: M. Goodman, A. Felix, L. Moroder, C. Toniolo), Georg Thieme Verlag, Stuttgart, 2003, pp. 423–457.

Posters SISOC7


PO-79

A One-step Procedure for the γ-Functionalization of α-Nitroketones Based on an Anionic Domino Process Francisco José Arroyo, Giorgio Giorgi, Pilar López-Alvarado and J. Carlos Menéndez



Multifunctional reagents are very valuable synthetic tools, specially if they contain simultaneously electrophilic and nucleophilic centers. In the case of β-dicarbonyl compounds, while γ-alkylation is a well-established procedure, other types of functionalization, like γ-alkenylidenation, are a challenging problem that has been addressed only recently.1 On the other hand, α-nitro ketones are an emerging class of synthetic building blocks that exhibit peculiar and often intriguing reactivity patterns.2 We describe in this communication the first example of a one-step γ-alkenylidenation of α-nitro ketones. Thus, treatment of cyclic α-nitro ketones 1 with phthalaldehyde derivatives 2 provides compounds 5, presumably through an anionic domino mechanism that involves four individual reactions and has species 3 and 4 as intermediates.

O

NO2

OHC CHO

O

NO2

OHO

OH

NO2

CHO

+

DBU, THF, r.t., 24 h

5

O

NO2

CHO OH

1 2 34

- OH-

1 (a) Charonnet, E.; Filippini, M. H.; Rodriguez, J. Synthesis 2001, 788. (b) Habib-Zahmani, H.; Hacini, S.;

Charonnet, E.; Rodriguez, J. Synlett 2002, 1827. 2 For a review, see: Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A. Tetrahedron 2005, 61, 8971.

SISOC7 Posters


PO-80

Further Studies on a Novel Stereocontrolled Ring Closing Metathesis Mediated Synthesis of Polyhydroxylated Cyclopentane β-Amino Acids

Fernando Fernández, Juan C. Estévez,* Ramón J. Estévez* and Begoña Pampín Departement of Organic Chemistry

University of Santiago de Compostla Faculty of Chemistry. 15782 Santiago de Compostela (SPAIN)

[email protected]

An area of continuous increasing interest is the area of peptidomimetics, where intense work has been carried out in recent years aimed at the synthesis of nonnatural amino acids as the first step to introduce elements of diversity for the development of peptidomimetics with high diversity level and capability to generate high-ordered structures that may improve recognition and catalytic properties of natural peptides, so, may acts as new drugs that overcome their pharmacological limitations.

The peptidomimetics most extensively studied are oligomers of β-amino acids, which have been shown to adopt a range of stable secondary structures such as α-helices, β-turn, and β-sheets, which facilitates its interaction with receptors and enzymes and prevent its peptidase degradation.1 Within this field, cyclopentyl and cyclohexyl β-amino acids are of considerable current interest as stabilizers of peptide conformations due to their promote folding of β-peptides, as it can be ilustrated by high tendeny of their homopolymers to folds in rigid secondary structures in short peptide sequences. 2

As a continuation of our recent contributions in this field,3 we present here preliminary results on a new stereocontrolled synthesis of polyhydroxylated cyclopentane β amino acids, which includes two key steps: a ring Closing Metathesis of the diene carbohydrate derivative 1 (obtained from D-manosa) followed by an addition of benzylamine to the resulting cyclopentane 2, which leads finally to the protected β-aminoacid 3 required.

OH

OO

TBDPSO

MeO

MeO

O

MeO

MeO

ONHBoc

D-Mannose

1 23

OO

OO

Incorporation of the β-amino acid 3 into peptides and modeling studies on homopolymers of these β-amino acids are now in progress.

[1] Venkatraman, J.; Shankaramma, S.C.; Balaram, P. Chem. Rev. 2001, 101, 3131. Cheng, R.P.; Gellman, S.H.; DeGrado, W. Chem. Rev. 2001. [2] Gruner, S.A.W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491. [3] a) Soengas, R.G.; Estévez, J.C.; Estévez, R.J. Org. Lett. 2003, 5, 1423. b) Soengas, R.G.; Pampín, M.B.; Estévez, J.C.; Estévez, R.J. Tetrahedron: Asymm. 2005, 16, 205. c) Fernando Fernández, José M. Otero, Juan C. Estévez and Ramón J. Estévez Tetrahedron: Asymm. 2006, 17,3063

Posters SISOC7


PO-81

Chiral (R)- and (S)-Allylic Alcohols via a one-pot Chemoenzymatic Synthesis

Simona Sgalla,a Giancarlo Fabrizi,a Roberto Cirilli,b Alberto Macone,c Alessandra Bonamore,c Alberto Boffic and Sandro Cacchia

aDipartimento di Studi di Chimica e Tecnologie del Farmaco

Università degli Studi ‘La Sapienza’ P.le A. Moro 5, 00185 Rome, Italy

bIstituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy cDipartimento di Scienze Biochimiche, Università degli Studi ‘La Sapienza’,

P.le A. Moro 5, 00185 Rome, Italy [email protected]

Chiral (R)- and (S)-allylic alcohols with an enantiomeric excess exceeding 99% have been prepared in good to high overall isolated yields through a two-step one-pot chemoenzymatic process based on the palladium-catalyzed Heck reaction of aryl iodides with butenone followed by an enzymatic reduction of the resultant vinylic substitution products. Alcohol dehydrogenases from Lactobacillus brevis (LB-ADH) and Thermoanaerobacter species (T-ADH) were used to attain (R)- and (S)-stereoselectivity, respectively (Scheme 1).1

Pd (OAc),ttmppI

R

+

O

proton sponge

O

R80 °C

T-ADHLB-ADH

R R

H OH H OH

R S

Scheme 1

Our results set the basis for a novel chemoenzymatic synthesis of chiral allylic alcohols. The method proves to be superior in product yield and enantioselectivity to conventional dynamic kinetic resolution methods and represents a valuable tool for the preparation of the important class of enantiopure allylic alcohols.

1 S. Sgalla, G. Fabrizi, R. Cirilli, A. Macone, A. Bonamore, A. Boffi, S. Cacchi Tetrahedron Asymmetry. 2007, 18, 2791-2796

SISOC7 Posters


Br

CO2Et

OI2

CH2Cl2

Br

IEtO2C

O

PO-82

Iodocarbocyclization Reaction of β-Ketoesters and Alkynes

David Palomas, Eduardo Rubio, José M. González* Instituto Universitario de Química Organometálica “Enrique Moles” – Unidad Asociada al

CSIC, Universidad de Oviedo, Oviedo 33071 Spain E-mail : [email protected]

Iodocyclopentenes are formed at room temperature upon straight reaction of δ-alkynyl-β-ketoesters with I2 for several hours. Cyclizations involving terminal and substituted (alkyl, aryl, Br, I) alkynes were accesed. Twelve examples with yields ranging from 20% up to 80% are reported (out of them eight cases are above 60%). These results present the first examples of the iodonium-promoted 5-endo-dig carbocyclization 1 of active methyne substrates onto alkynes.

Figure 1. Iodine promoted carbocyclization

1J. Barluenga, D. Palomas, E. Rubio, J. M. González, Org.Lett., 2007, 9, 2823 .

Posters SISOC7


PO-83

Synthesis and Properties of a New Class of meso-Functionalized Calixpyrroles

M. C. Aversa, A. Barattucci, P. Bonaccorsi, G. Cafeo, F. H. Kohnke and T. Papalia Department of Organic and Biological Chemistry, Salita Sperone 31, vill. S. Agata,

University of Messina, Italy [email protected]

Over the last ten years, studies on calixpyrroles as receptors for anions have proliferated and a large number of derivatives have been reported. These include expanded calixpyrroles, calixpyrroles in which there are substituents different than hydrogen at their 3,4-positions, ‘hybrid’ calixpyrroles and calixpyrroles in which the meso positions have been functionalized.1,2 Calixpyrroles bind anions by means of hydrogen-bonding interactions between the polar NH units and the electron-rich guests.2 The best known member of this class of receptors is calix[4]pyrrole, a derivative of which was recently found to function also as an efficient organocatalyst for Hetero Diels-Alder reactions.3 This communication will focus on the synthesis of meso-substituted calyx[4]pyrroles and their ability to act as synthetic receptors suitable for effecting selective bindings and recognition of anionic and neutral substrates. In particular, a new class of thio-calixpyrroles will be presented as useful derivatives in which the sulfur atom can be exploited for its ability to link the molecule onto gold surfaces and to bind many other heavy metals. Sulfur-containing macrocycles can also be easily manipulated to give derivatives having different oxidation states.4 The interest in these kinds of macrocycles arises from their potential use in areas as diverse as nuclear waste treatment, environmental chemistry and biology.

HN

NH HN

NH

RSSR

HN

NH HN

NH

RS

SR

1 Gale, P. A.; Anzenbacher Jr., P.; Sessler, J. L. Coord. Chem. Rev. 2001, 222, 57-102. 2 Bruno, G.; Cafeo, G.; Kohnke, F. H.; Nicolò, F. Tetrahedron, 2007, 63, 10003. 3 Cafeo, G.; De Rosa, M.; Kohnke, F. H.; Neri, P.; Soriente, A.; Valenti, L. Tetrahedron Lett. 2008, 49, 153-155. 4 Aversa, M. C.; Barattucci, A.; Bilardo, M. C.; Bonaccorsi, P.; Giannetto, P.; Rollin, P.; Tatibouët, A. J.Org. Chem. 2005, 70, 7389-7396.

SISOC7 Posters


PO-84

Supramolecular Donor-Acceptor Systems Based on α,γ-Cyclic Peptides

Mª Jesús Pérez, Michele Panciera, Luis Castedo, Juan R. Granja and Roberto J. Brea Departamento de Química Orgánica - Universidad de Santiago de Compostela

15782 - Santiago de Compostela (A Coruña), Spain [email protected] Fax: +34981591014

In recent years, considerable effort has been devoted to the preparation of artificial nanotubular materials.1 Self-assembling approach is one of the most powerful bottom-up synthetic methods for the construction of nanostructurated materials, which has been very successfully used in the preparation of nanotubes from cyclic peptides.2 Recently, our group have reported α,γ-cyclic peptides (α,γ-CPs) that forms highly stable homo- and/or heterodimer supramolecular assemblies.3 In the present communication we will describe the application of such structures to the development of efficient energy and/or electronic transfer systems.

1 Dekker Encyclopedia of Nanoscience and Nanotechnology; J. A. Schwarz, C. I. Contescu, K. Putyera, (Eds).; Marcel Dekker: New York; 2004. 2 Bong, D. T.; Clark, T. D.; Granja, J. R.; Ghadiri, M. R. Angew. Chem. Int. Ed. 2001, 40, 988-1011. 3 a) Amorín, M.; Castedo, L.; Granja, J. R. J. Am. Chem. Soc. 2003, 125, 2844-2845. b) Brea, R. J.; Amorín, M.; Castedo, L.; Granja, J. R. Angew. Chem., Int. Ed. 2005, 44, 5710-5713. c) Amorín, M.; Brea, R. J.; Castedo, L.; Granja, J. R. Org. Lett. 2005, 7, 4681-4684. d) Amorín, M.; Brea, R. J.; Castedo, L.; Granja, J. R. Heterocycles 2006, 67, 575-583. e) Brea, R. J.; Vázquez, M. E.; Mosquera, M.; Castedo, L.; Granja, J. R. J. Am. Chem. Soc. 2007, 129, 1653-1657. f) Brea, R. J.; Herranz, M. A.; Sánchez, L.; Castedo, L.; Seitz, W.; Guldi, D: M.; Martín, N.; Granja, J. R. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 5291-5294. g) Brea, R. J.; Castedo, L.; Granja, J. R. Chem. Commun. 2007, 31, 3267-3269.

Posters SISOC7


PO-85

Self-Assembling α,γ-Peptide with Functionalized Cavity

Juan R. Granja, Luis F. Silva, César Reiriz and Arcadio Guerra Departamento de Química Orgánica

Universidad de Santiago de Compostela 15782, Santiago de Compostela, Spain

[email protected] In recent years, considerable effort has been devoted to the synthesis of organic and inorganic nanotubes1. Self-assembling peptide nanotubes (SPN) made from cyclic D,L-α-peptides2

have structural and functional properties that may be suitable for various applications in biology and materials science. We have recently reported self-assembling process of α,γ-cyclic peptides (α,γ-CPs) showing a high-affinity for dimers formation and also preferences for the formation heteromeric assemblers.3 Up to now the resulting supramolecular entities have a hydrophobic cavity because the methylene group (C2) is projected towards the lumen. Here we will describe our studies directed towards the synthesis of C2-modified γ-Aminocycloalkanecarboxylic acid derivatives (γ-Aca). The implementation of such γ-Aca should endow SPN with a functionalized inner surface, which could lead to nanotubes with catalytic activity, ion channels selectivity, or molecule container properties.

1 Patzke, G. R.; Krumeich, F.; Nesper, R. Angew. Chem. Int. Ed. 2002, 41, 2446. Bong, D. T.; Clark, T. D.; Granja, J. R.; Ghadiri, M. R. Angew. Chem. Int. Ed. 2001, 40, 988. Ajayan, P. M.; Zhou, O. Z. Top. Appl. Phys. 2001, 80, 391. 2 Ghadiri, M. R.; Granja, J. R.; Milligan, R. A.; McRee, D. E.; Khazanovich, N. Nature 1993, 366, 324; Khazanovich, N.; Granja, J. R.; McRee, D. E.; Milligan, R. A.; Ghadiri, M. R. J. Am. Chem. Soc. 1994, 116, 6011; Ghadiri, M. R.; Granja, J. R.; Buehler, L. K. Nature 1994, 369, 301. 3 For four amino acid α,γ-CPs, see: M. Amorín, R. J. Brea, L. Castedo, J. R. Granja Org. Lett. 2005, 7, 4681; For six amino acid α,γ-CPs, see: M. Amorín, L. Castedo, J. R. Granja J. Am. Chem. Soc. 2003, 125, 2844; For eight amino acid α,γ-CPs, see: M. Amorín, L. Castedo, J. R. Granja Chem. Eur. J. 2005, 11, 6539; For α,γ-CPs heterodimers, see: R. J. Brea, M. Amorín, L. Castedo, J. R. Granja Angew. Chem. Int. Ed. 2005, 44, 5710.

SISOC7 Posters


PO-86

Cation Template Assisted Oligoethylene Glycol Desymmetrization Ezequiel Pérez-Inestrosa, Yolanda Vida, Rafael Suau and Antonio Jesús Ruiz-Sánchez

Department of Organic Chemistry University of Malaga

Faculty of Sciences, Campus Teatinos, 29071-Malaga, Spain [email protected]

Desymmetrization of macromolecules is an effective method for the preparation of functional nanoparticles for a variety of potential applications. The development of efficient routes for the directed stepwise synthesis of desymmetrized functional oligoethylene glycols (OEG’s) continues to be a major challenge in organic chemistry.

We described here how OEG’s chains possessing a benzyl alcohol and a benzoic acid end group, can be quantitatively obtained by intramolecular Cannizzaro reaction of the corresponding remote benzaldehyde end groups. The process is quite effective if a complex with an appropriate cation is formed to allow the two aldehyde groups to be spatially confined near enough each other for the intramolecular redox process. 1

We found that a scalable collection of oligoethylene glycol chains ranging from di- to pentaethylene glycol, which possess two different, orthogonally functional groups at their chain ends, can be directly synthesized and obtained with no tedious workup simply by treating their corresponding aromatic-functionalized symmetric dialdehydes under conventional Cannizzaro conditions.

O

O

O

O

O

CHO

CHO

TEMPLATEDDESYMMETRIZATION TEMPLATEDDESYMMETRIZATION O

O

O

O

O

CO2H

OH

O

O

O

O

CO2H

OH

O

O

O

CO2H

OH

O

O

O

O

O

CO2H

O

OH

The results for the ortho and meta isomers confirm that this process is general for various substitution models of the aromatic ring and thus this aspect is no limiting factor for successful desymmetrization.

1 Y. Vida, E. Perez-Inestrosa, R. Suau, Tetrahedron Lett. 2005, 46, 1575–1577.

Posters SISOC7


PO-87

Conformational Studies on Significant Synthetic Sequences of Resilin

A. M Tamburro, A. Pepe, B. Bochicchio and Simona Panariello* *Department of Chemistry

University of Basilicata- Via Nazario Sauro, 85 85100 Potenza- Italy e-mail: ([email protected])

Resilin is a member of the family of elastomeric protein that includes elastin, as well as gluten, lamprin, spider silks, bissus, etc., which, when swollen, lacks stable secondary structure and whose tertiary structure consists of stable covalent cross-linkages. The cross-links are now known to consist of dityrosine and trityrosine . They are probably formed by the pairing of free radicals resulting from the enzymic oxidation during resilin deposition of tyrosine residues which are built into the polypeptide chains It is found in specialized regions of the cuticle of most insects, providing low stiffness, high strain and efficient energy storage. It is best known for its roles in insect flight and the remarkable jumping ability of fleas and spittle bugs. In common with other elastomeric proteins, resilin shows glycine-rich repetitive sequences, in particular the N- and C- terminal regions of protein are dominated by 18 repeats of a 15 residue sequences (SDTYGAPGGGNGGRP) and 11 repeats of a 13 residue sequence (GYSGGRPGGQDLG) , respectively. Until now, structural studies on resilin are missing, thus prompting us to sinthesize some polypeptide with sequences belonging to the mostly repeated domain of Drosophila Melanogaster resilin, in order to get insight in the molecular structure of resilin. Here we report on conformational studies of some significant repetitive resilin sequences and the cloning and expression of (SDTYGAPGGGNGGRP)4 gene as a soluble protein in Escherichia coli. We show that this recombinant peptide can be cast into a rubber-like biomaterial by rapid photochemical crosslinking or through dityrosine formation catalyzed by peroxidase. The conformational studies performed in solution and solid state by CD, FT-IR and NMR spectroscopies, focused the attention on two main conformational features, like folded β-turns and (quasi) extended structures (PPII and β- strands), in common with other elastomeric protein.

SISOC7 Posters


PO-88

Human Heparanase: Structure and Catalytic Mechanism Sonsoles Martín-Santamaría, Beatriz de Pascual-Teresa, Primitiva Menéndez, Luis M.

Quirós and Javier González Departamento de Química, Universidad San Pablo-CEU, 28668 Madrid,

Spain, Servicio de Salud del Principado de Asturias, 33006 Oviedo, Spain, Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A.), 33006 Oviedo, Spain and Departamento de Química Orgánica e Inorgánica,

Universidad de Oviedo, 33006 Oviedo, Spain [email protected]

Human heparanase is an endo-β-D-glucuronidase that catalyzes the hydrolysis of heparan sulfate, a linear polysaccharide present mainly in the extracellular matrix and the cell surface.1 This enzyme has been related with several pathological processes as inflammation, angiogenesis, and tumor metastasis,2 and for this reason, human heparanase is a very interesting target for the development of new drugs.3

The tridimensional structure of the heparanase is unknown, but according to several studies it has been proposed that two glutamic acid residues (Glu-225 and Glu-343) are the catalytic aminoacids in the active center, and that the catalytic cycle will follow the Koshland`s double-displacement mechanism.1

We have carried out Molecular Dynamics simulations on a model structure of the protein, and according to the results, the human heparanase presents a tridimensional structure with α-helices and β-strands motifs alternated. The protein presents a narrow tunnel, surrounded by several β-strands, in which the two catalytic residues, Glu-225 and Glu-343, are located.

On the other hand, a series of ab initio and density-functional calculations [at the MP2/6-31+G* and B3LYP/6-31+G* levels of theory], on simplified models of the active center, were carried out, in order to elucidate the detailed catalytic pathway. This calculations indicate that, in the first step of the mechanism, the glutamate residue attacks the anomeric center of the substrate, to yield an enzyme-substrate intermediate, which undergoes a hydrolysis in the second step. Both, ab initio and density-functional calculations predict the first step to be rate-determining, with a computed activation energy of about 25 kcal mol-1. Also, the geometry and charge distribution of the substrate, in the first transition structure, provides a rationale for understanding the inhibitory effect on the heparanase activity of several types of azasugar derivatives.4

1 M. D. Hulett, J. R. Hornby, S. J. Ohms, J. Zuegg, C. Freeman, J. E. Gready, C. R. Parish Biochemistry, 2000, 39, 15659-15667. 2 I. Vlodavsky, O. Goldshmidt, E. Zcharia, R. Atzmon, Z. Rangini-Guatta, M. Elkin, T. Peretz, Y. Friedmann, Cancer Biol., 2002, 12, 121-129. 3 a) S. Simizu, K. Ishida, H. Osada, Cancer Sci., 2004, 95, 553-558. 4 Y. Nishimura, E. Shitara, H. Adachi, M. Toyoshima, M. Nakajima, Y. Okami, T. Takeuchi, J. Org. Chem. 2000, 65, 2-11.

Posters SISOC7


PO-89

NMR Investigations of the 3D Structure of the Nodulation Factors María A. Morandoa, P. Groves, J. Cañada, J.M. Beau, B. Vauzeilles, J. Jiménez-Barbero aCentro de Investigaciones Biologicas CSIC, Calle Ramiro de Maetzu, 9 28040 Madrid (Spain)

[email protected], www.cib.csic.es The Legume-Rhizobia symbiosis involves a single plant phylogenetic group (the family Leguminosae) and a collection of philogenetically diverse nitrogen fixing bacteria (termed rhizobia). Compatible partners lead to root nodulation, infection and symbiotic nitrogen fixation. On the bacterial side the ability to estabilish the symbiosis is due to genes specific to the production of Nod factor signals, which are lipochitoligosaccharides, active on the legume hosts at pico-nano molar concentrations. On the plant side, genes that are involved in Nod factor perception encode receptor like kinases with LysM domains.

O

O

HOH2C

HOHO

NH

OHO

NHAc

HOH2C

OO

HOH2C

NHAc

HO O O

HO

NHAc

OH

-O3SH2C

O

Nod-Factor target A new generation of Nod factor analogues1,2, with affinities in the nanomolar range, has been recently synthesised and their conformational behaviour has been studied by NMR and Dynamic Simulations.

1 Beau et al. Angew. Chem. Int. Ed. 2004, 43, 4644 –4646 2 Groves et al. OBC 2005, 3, 1381-1386

SISOC7 Posters


PO-90

Synthesis and NMR/MD Evaluation of Saccharide/β-Lactam Hybrids for Lectin Inhibition.

Claudio Palomo,a Jesus M. Aizpurua,a Eva Balentová,a Itxaso Azcune,a Iñaki Santos,a José Ignacio Miranda,a Jesús Jiménez-Barberob and Javier Cañada.b

aDepto. de Química Orgánica-I. Universidad del País Vasco. Joxe Mari Korta R&D Center. Avda. Tolosa-72, 20018 San Sebastián, Spain. bCentro de Investigaciones Biológicas, CSIC Ramiro de Maeztu-9, 28040 Madrid, Spain.

[email protected] Low molecular weight carbohydrate-peptide mimetics related to β-turned Ser-Glu dipeptide O-glycoside hybrids1 1 have shown increased activity and good selectivity against several lectin2 receptors. Seeking for peptidomimetics with enhanced resistance to chemical and enzymatic hydrolysis by proteases3, we report an efficient and stereocontrolled synthesis of glycoconjugated β-lactams 2 by applying simple convergent “click” reaction of azido sugars 3 and 2-propargyl-β-lactams 4, incorporating the 1,2,3-triazolylmethyl moiety as the shape-modulating linker4. The conformational analysis of new glycoconjugates 2 and their interaction with specific carbohydrate binding proteins has been evaluated by NMR spectroscopy (ROESY, STD, DOSY, Tr-NOE). Accordingly, it has been found that mimetic 5 (L-fucose-substituted) binds to Ulex Europaeus Lectin-I (UEL-1) after a bent-to extended conformational change around a partially rotatable methylene bond.

1 T. Tsukida, H. Moriyama, K. Kurokawa, T. Achiha, Y. Inoue, H. H. Kondo, J. Med. Chem. 1998, 41, 4279. 2 H. Lis, N. Sharon Chem. Rew. 1998, 98, 637-674. 3 a) C. Palomo, J. M. Aizpurua, A. Benito, J. I. Miranda, R. M. Fratila, C. Matute, M. Domercq, F. Gago, S.

Martin-Santamaría, A. Linden, J. Am. Chem. Soc. 2003, 125, 16243-16260. b) C. Palomo, J. M. Aizpurua, E. Balentova, A. Jiménez, J. Oyarbide, R. M. Fratila, J. I. Miranda, Org. Lett. 2007, 9, 101-104.

4 C. Palomo, J. M. Aizpurua, E. Balentova, I. Azcune, J. I. Santos, J. Jiménez-Barbero, J. Cañada, J. I. Miranda, Org. Lett., 2008, 10, 2227-2230.

Posters SISOC7


PO-91

DFT/NMR Integrated Approach: a Valid Support to the Total Synthesis of Chiral Molecules

Maria Giovanna Chini, Raffaele Riccio, and Giuseppe Bifulco

Dipartimento di Scienze Farmaceutiche Università di Salerno

Via Ponte Don Melillo, 84084 Fisciano, Salerno (Italy) [email protected]

The correct assignment of the configurational pattern in chiral organic compounds, containing more than one stereocenter, is undoubtedly a key step of the structure elucidation process. This process, in fact, is essential in several fields that not only include the total synthesis of the molecules under investigation, but also the understanding, at the molecular level, of the biological mechanism of active natural compounds; stereochemical knowledge is also fundamental for structure-activity studies of drug-receptor systems. Basically, there are different approaches to identify the exact structure and/ or stereochemistry of organic products. This situation is particularly unfortunate in all cases where the total synthesis (the most common used method in the compound structural assignments and revision) of a (wrong) proposed structure does not afford the natural products, and, especially for complicated molecules, this translates in an enormous waste of time and money. We have suggested the use of quantum mechanical methods as a rapid, efficient, and economical method in the resolution of stereochemical problems, such an example in the structural determination and/or revision of active the natural compounds. In this paper we will demonstrate that a fast quantum chemical analysis of the stereoisomers of the two natural compounds kedarcidin chromophore1 (1) and palau’amine2 (2) would have avoided the synthesis of the wrong proposed structures by means of DFT calculation of coupling constant, and GIAO (gauge including atomic orbitals) calculation of 13C chemical shifts cs, using Gaussian 03 Software Package.3 We decide to apply the DFT/NMR integrated approach to these two compounds to show that our results could have been sufficient to exclude the proposed structures and could have suggested directly the structure of the correct compounds.

1 J.E. Leet, D.R. Schroeder, D.R. Langley, K.L. Colson, S. Huang, S.E. Klohr, M.S. Lee, J. Colik, S.J. Hofstead, T.W. Doyle, J.A. Matson J. Am. Chem. Soc. 1993, 115, 8432-8443. 2 R.B. Kinnel, H.P. Gehrken, P.J. Scheuer J. Am. Chem. Soc. 1993, 115, 3376-3377. 3 Gaussian 03, Revision C.01 2004.

SISOC7 Posters


PO-92 NMR Studies of Di- and Mononuclear Copper (I) Complexes Containing

the (S, S)-iPr-Pybox Ligand

M. P. Gamasa,1 J. Díez,1 M. Panera,1 E. Rubio,1,2 I. Merino2

1 Instituto Universitario de Química Organometálica “Enrique Moles” (Unidad Asociada al CSIC), Universidad de Oviedo, 33071 Oviedo, Spain

2 Unidad de Resonancia Magnética Nuclear, Servicios Científico Técnicos, Universidad de Oviedo, 33071 Oviedo, Spain.

[email protected] The reaction of [Cu(CN)4]PF6 with (S,S)-iPr-Pybox affords the dinuclear Cu (I) cationic complex (1) or the Cu(I) cationic complex (2) when appropriate stoichiometric amounts of the pybox ligand are used. These compounds have been characterized by mass spectrometry and the nuclearity of the complex 1 has been established through X-ray crystallographic studies.1 The preliminary NMR study of these compounds showed that their structures are not maintained in the solution state, since 1H and 13C NMR spectra of both di- and mononuclear complexes are consistent with the presence of a C2 symmetry axis.

N

O NN

O

N

ONN

O

Cu Cu

1

[PF6]2

N

O NN

O

N

ONN

O

Cu

2

[PF6]

The dinuclear complex 1 has been successfully used as a precatalyst for the enantioselective synthesis of propargylic amines (unpublished results). In order to understand its catalytic behaviour it seemed necessary to gain some knowledge of the species that this compound produces in solution. To this aim, an NMR study of both di- and mononuclear copper (I)-(pybox)2 complexes in the solution state was accomplished. Titration of the dinuclear Cu (I) complex with an excess of (S,S)-iPr-Pybox, together with variable temperature 1H NMR experiments, 1H, 19F and 31P dosy experiments, and 1H19F HOESY measurements conclude that compounds 1 and 2 exist as stable, discreet molecules in solution with the copper nuclei being rapidly exchanged among the iPr-pybox nitrogen atoms. On the other hand, some di- and mononuclear copper (I)-( iPr-pybox) complexes carrying phosphines (Ph3P, dppm, diphenylphosphinoferrocenyl) as a second ligand have also been synthesized for the first time and their characterization in the solution state by NMR has been carried out as an initial survey of their potential catalytic properties.

1 J. Díez, M. P. Gamasa, M. Panera, Inorg. Chem. 2006, 45, 10043-10045

Posters SISOC7


PO-93

Synthesis and Characterization of Silica Nanoparticles as Carriers for PDT

Iria Río Echevarría, Fabrizio Mancin and Umberto Tonellato Department of Chemical Science Università degli Studi di Padova

Vìa Marzolo 1, Padova, Italy [email protected]

Photodynamic therapy (PDT) based on the irradiation of a light-sensitive drug (photosensitizing agent) is used as a therapy for cancer treatment. Photosensitizers are accumulated in cancer cells and become active when they are exposed to laser light of a determined wavelength, followed by their interaction with oxygen. This leads to the formation of singlet oxygen which is cytotoxic for the cancer cells.

Potential photosensiting agents for PDT present problems such as low solubility in water, limited selectivity and toxicity. Consequently, drug-delivery vectors which encapsulate and deliver the photosensitizers into the cells to prevent these undesired effects are needed.

In the work described in this poster we aim to identify new nanocarriers based on organically modified silica nanoparticles that will allow the delivery of the photosensitizing agent with no side effects. Different surfactants are compared and shown in this work as well as the use of pegylated derivatives to be included in the silica nanoparticles.

Dynamic light scattering and transmission electron microscopy (TEM) are the techniques used to study the formation of the nanoparticles. TEM images of silica nanoparticles are shown bellow.

TEM images of pegylated and non-pegylated silica nanoparticles.

List of Authors SISOC7


Abonía, R. P-60 Aceña, J. L. P-65 Ackermann, L. OC-13 Agejas, F. J. IL-11 Aguilar, E. P-14, 15 Aizpurúa, J. M. P-54, 90 Alagona, G. P-70 Albert, L. P-65 Alcalde, A. P-34 Alcántara, A. R. OC-15 Aldegunde, M. J. P-42 Alfini, R. P-75 Alonso, I. P-16 Alonso, J. M. P-56 Alvarez de Cienfuegos, L. OC-8 Álvarez-Builla, J. P-44, 45 Álvarez-Fernández, A. P-39 Amat, M. OC-16 Ambrogio, I. IL-6 Amorín, M. IL-3 Anaya, J. OC-5, P-53, 73 Andolfi, A. P-50 Andrés, J. M. P-6 Ardá, A. P-71 Arroyo, F. J. P-79 Asensio, G. P-34 Avendaño, C. P-49, 74 Aversa, M. C. P-83 Aversa, M. C. IL-22 Azcune, I. P-90 Aznar, F. P-1, 20, 21, 40 Baiula, M. IL-12 Balentová, E. P-90 Banfi, L. OC-17 Barattucci, A. P-83 Barberá, J. IL-19 Barbero, N. OC-11 Bartoli, G. OC-2, OC-12 Basabe-Desmonts, L. IL-9 Basso, A. OC-17 Bazdi, B. P-28 Beau, J. M. P-89 Bender, D. IL-11 Benincori, T. IL-8 Bernini, R. P-18, 30 Besada, P P-47 Bhargava, G. P-27 Bifulco, G. IL-18, P-91 Bochichio, B. P-87

Boffi, A. P-81 Boggs, L. N. IL-11 Bonaccorsi, P. P-83 Bonamore, A. P-81 Bosch, J. OC-16 Bosco, M. OC-2 Bossi, A. OC-9 Botija, J. M. P-63 Bouissane, L. P-25 Brandi, A. P-75 Brea, R. IL-3 Brea, R. J. P-84 Brier, R. A. IL-11 Broughton, H. IL-11 Bueno, A. B. IL-11 Cabal, M. P. P-1 Cacchi, S. IL-6, OC-12, P-17,

18, 30, 81 Cadierno, V. P-7, 8 Cafeo, G. P-83 Calleja, J. P-33 Campaña, A. G. P-28 Cañada, F. J. IL-17, P89, 90 Capperucci, A. OC-4 Capriati, V. OC-6 Carda, M. IL-21 Cardillo, G. IL-12 Carretero, J. C. IL-23, P-16 Carril, M. OC-11 Carrillo, R. IL-7 Castedo, L. IL-3, P-10, 11, 27,

42, 52, 55, 84 Castillo, J. C. P-60 Castroviejo, M. P. P-22, 67 Cavero, E. IL-19 Checa, B. OC-16 Chen, J. OC-8 Chiaccio, U. P-48 Chini, M. G. P-91 Cid, M. B. OC-3 Ciminiello, P. IL-20 Cirilli, R. P-81 Clay, M. P. IL-11 Cobo, J. P-59, 60 Corda, M. P-68 Corradini, R. IL-10 Corsaro, A. P-48 Couris, S. OC-7 Cozzi, P. G. IL-24

SISOC7 List of Authors


Crego-Calama, M. IL-9 Cristinzio, G. P-50 Crivillers, N. IL-9 Crochet, P. P-9 Cruz, S. P-60 Cuerva, J. M. P-28, 29 Cwi, C. L. IL-11 Dalla Cort, A. IL-16 Dally, R. IL-11 de la Campa, R. P-37 de la Cuesta, E. P-74 de la Fuente, M. C. P-62 de la Torre, J. M. P-59 De Marco, R. IL-12 de Pascual-Teresa, B. P-88 Degl’Innocenti, A. OC-4 del Pozo, C. P-5 Delogu, G. P-68, 69 Delso, I. OC-1 Díaz-Álvarez, A. E. P-19 Díez, J. P-92 Domínguez, D. P-58, 62 Domínguez, E. OC-11 Duce, S. OC-3 Durham, T. B. IL-11 Echavarren, A. M. P-28 Egris, R. P-35 Erickson, J. A. IL-11 Espinosa, J. A. IL-11 Esquivias, J. P-16 Estévez, J. C. P-80 Estévez, R. E. P-29 Estévez, R. J. P-80 Estévez, V. P-32 Estévez-Santoro, P. P-62 Evidente, A. P-50 Fabrizi, G. IL-6, OC-12, P-17,

18, 30, 81 Faccini, A. IL-10 Fadda, M. B. P-68 Fais, A. P-68 Falomir, E. IL-21 Fañanás, F. J. P-12, 13, 33 Fañanás-Mastral, M. P-40 Fattorusso, E. IL-20 Feher, A. IL-7 Ferlazzo, A. OC-10 Fernández de Trocóniz, G. P-77 Fernández, A. P-13 Fernández, F. P-80

Fernández, M. OC-15 Fernández, R. P-78 Fernández-García, J. M. P-15 Fernández-Rodríguez, M. A.

P-14, 15

Filisti, E. P-17 Flórez, J. P-36, 37 Florio, S. OC-6 Forte, G. P-30 Francos, J. P-7 Fratila, R. M. P-54, 90 Fuentes, N. P-28, 29 Fustero, S. P-5, 65 Gabilondo, A. M. P-54, 90 Gabriele, B. IL-4 Gago, P. M. P-53 Gamasa, M. P. P-92 García Ruano, J. L. OC-3 García-Calvo, O. P-23 García-García, P. P-14 García-Rodríguez, J. P-38 García-Rubín, S. P-10 Gentilucci, L. IL-12 Ghio, C. PO-70 Giménez, R. IL-19 Gimeno, J. P-7, 08 Gimeno, N. IL-19 Giofrè, S. G. OC-10 Giomi, D. P-75 Giorgi, G. P-24, 79 Giralt, E. IL-1 Goggiamani, A. OC-12 Gómez Arrayás, R. P-16 Gómez, A. P-41 Gómez-Bengoa, E. P-4 Gómez-San Juan, A. P-63 González, J. P-88 González, J. M. P-82 González, M. A. P-46 González, R. IL-11 González-Bello, C. P-52, 55 González-Moa, M. J. P-47 González-Rodríguez, C. P-11 Goti, A. OC-1 Grande, M. OC-5, P-53, 73 Granito, C. P-57 Granja, J. R. IL-3, P-42, 84, 85 Groves, P. P-89 Guanti, G. OC-17 Guerra, A. P-85



Guilarte, V. P-22, 67 Guiteras Capdevila, M. IL-24 Guitián, E. P-19 Guldi, D. M. OC-7 Hahn, P. J. IL-11 Haldar, J. OC-8 Hernando, J. P-45 Herrera, R. P. P-78 Hu, J. IL-11 Iannazzo, D. OC-10 Janeiro, P. P-69 Jiménez, A. P-54 Jiménez, C. P-71 Jiménez, D. P-5 Jiménez-Aquino, A. P-21 Jiménez-Barbero, J. P-89, 90 Justicia, J. P-29 Kada, D. P-76 Klibanov, A. M. OC-8 Kohn, T. IL-11 Kohnke, F. H. P-83 Laigle, D. K. IL-11 Landa, A. P-2 Lassaletta, J. M. P-78 Lastra-Barreira, B. P-9 Lazzaroni, R. P-70 Lecínska, P. OC-17 Legerén, L. P-58 Lete, E. P-23, 63 Licandro, E. OC-9 Lindstrom, T. IL-11 Liu, C. IL-11 Lizagarra, A. P-3 Lledos, A. P-34 Llor, N. OC-16 Lloret, J. P-34 Lonzi, G. P-64 López, F. P-27 López, R. P-4 López-Alvarado, P. P-24, 49, 51, 61,

79 López-Cantarero, J. OC-3 López-Cobeñas, A. P-49, 51 Luisi, R. OC-6 Macone, A. P-81 Maiorana, S. OC-9 Maiti, S. P-66 Mancin, F. P-93 Manzano, R. P-6 Marchelli, R. IL-10

Marco, J. A. IL-21 Marcos, A. IL-11 Marqués-López, E. P-78 Martín, R. P-73 Martín, T. IL-7, P-43 Martín, V. S. P-43 Martínez, F. OC-15 Martínez, M. OC-18 Martínez-Estíbalez, U. P-23 Martín-Santamaría, S. P-88 Mascareñas, J. L. P-27 Mas-Torrent, M. IL-9 Mateo-Alonso, M. OC-7 Mateu, N. P-65 Matía, M. P. P-44, 45 Matos, M. J. P-68, 69 May, P. C. IL-11 McCarthy, J. IL-11 Meana, J. J. P-54 Melchiorre, P. OC-2 Méndez, A. P-63 Mendoza, A. P-12 Menéndez, J. C. P-24, 31, 32, 35,

49, 51, 61, 66, 79 Menéndez, P. P-88 Merino, I. P-92 Merino, P. OC-1 Mielgo, A. P-2, 03 Miguel, D. P-22, 67 Mínguez, J. M. IL-11 Miranda, J. I. P-90 Monaco, A. P-51 Monleón, L. M. OC-5 Morando, M. A. P-89 Moriel, P. P-20 Moscardó, J. P-5 Moscardó, T. P-65 Mosquera, A. P-26 Múgica-Mendiola, I. P-4 Murga, J. IL-21 Muruzábal, M. D. P-6 Navarro, I. P-53 Nebra, N. P-8 Niembro, S. P-30 Nieto, M. I. P-71 Nogueras, M. P-59, 60 Novella, J. L. P-44, 45 Ochoa de Retana, A. M. P-56, 77 Oiarbide, M. IL-15, P-2, 4 Oltra, J. E. IL-5, P-28, 29

SISOC7 List of Authors


Ortega, N. P-43 Ortín, I. P-74 Pace, V. OC-15 Palacios, F. P-56, 77 Palomas, D. P-82 Palomo, C. P-2, 3, 4, 54, 90 Pampín, B. P-80 Panariello, S. P-87 Panciera, M. P-84 Panera, M. P-92 Paolucci, F. OC-7 Papalia, T. P-83 Paradas, M. P-29 Pascual, S. P-77 Paz, S. P-55 Pedrosa, R. P-6 Peña, D. P-19 Peña-López, M. OC-18 Peón, A. P-52 Pepe, A. P-87 Pérez Sestelo, J. OC-18 Pérez, A. IL-19 Pérez, D. P-19 Pérez, M. J. P-84 Pérez-Alvite, M. A. IL-3 Pérez-Gómez-Cuétara, L. P-51 Pérez-Inestrosa, E. P-86 Pérez-Sestelo, J. P-25, 26 Persiani, D. OC-12 Petrillo, G. IL-14 Petrucci, F. P-30 Picciau, C. P-68, 69 Piperno, A. OC-10 Pistarà, V. P-48 Pleixats, R. P-30 Podda, G. P-68, 69 Porcel, S. P-28 Prastaro, A. IL-6, P-30 Prato, M. OC-7 Puente, A. P-2 Punzo, B. P-50 Quezada, E. P-68, 69 Quiñones, N. P-1 Quiroga, J. P-60 Quirós, L. M. P-88 Ramos, M. T. P-31 Ravoo, B. J. IL-9 Reinhoudt, D. IL-9 Reiriz, C. IL-3 Reiriz, C. P-85

Ribelles, P. P-31 Ribes-Vidal, C. IL-21 Riccio, R. P-91 Rigamonti, C. OC-9 Río-Echevarría, I. P-93 Riva, R. OC-17 Riveiros, R. P-26 Robles, R. P-28, 29 Rodríguez, F. P-12, 13, 33 Rodríguez, J. P-71 Rodríguez, J. R. IL-11 Romeo, G. OC-10 Romeo, R. OC-10 Romero, P. IL-19 Romero-Torrejón, D. P-46 Ros, M. B. IL-19 Rosato, F. P-57 Rovira, C. IL-9 Ruano, G. IL-11 Rubio, E. P-82, 92 Ruiz-Sánchez, A. J. P-86 Ruiz-Serrano, M. P-61 Saá, C. P-10, 11 Salomone, A. OC-6 Salvadori, J. P-64 Sambri, L. OC-2 San Martín, R. OC-11 Sánchez-Roselló, M. P-5 Santamaría, J. P-41 Santana, L. P-68, 69 Santos, I. P-90 Sanz, G. IL-11 Sanz, R. IL-13, P-22, 67 Sanz-Cervera, J. F. P-65 Sarandeses, L. A. OC-18, P-25, 26 Sayar, N. P-42 Sebastián, R. M. P-30 Serrano, J. L. IL-19 Settambolo, R. P-70 Sferrazza, A. P-18 Sforza, S. IL-10 Sgalla, S. P-81 Shepherd, T. IL-11 Sierra, T. IL-19 Silva, L. F. P-85 Sinisterrra, J. V. OC-15 Soengas, R. G. P-71 Soler, R. P-30 Sotomayor, N. P-23, 63 Spampinato, S. IL-12



Squassabia, F. IL-12 Suárez, R. M. P-44 Suárez-Sobrino, A. L. P-38, 39 Suau, R. P-86 Suero, M. G. P-36 Tabak, G. P-76 Taddei, M. P-64 Tamburro, A. M. P-87 Tedeschi, T. IL-10 Teijeria, M. P-47 Tejedor, R. IL-19 Tejero, T. OC-1 Temperini, A. IL-2, P-72 Terán, C. P-47 Terlizzi, R. IL-2, P-72 Testaferri, L. IL-2, P-72 Tiecco, M. IL-2, P-72 Timm, D. IL-11 Tizón, L. P-55 Tolomelli, A. IL-12, OC-14 Tomás, M. P-38, 39, 41 Tomás-Gamasa, M. P-20 Tonellato, U. P-93 Trilleras, J. P-60 Trillo, B. P-27 Tristany, M. P-30

Troisi, L. P-57 Uriarte, E. P-69 Valdés, C. P-20, 21 Vallribera, A. P-30 Varea, T. P-34 Varela, J. A. P-10, 11 Varela-Fernández, A. P-11 Vauzeilles, B. P-89 Veciana, J. IL-9 Vélez del Burgo, A. P-56 Vera, F. IL-19 Vera, S. P-2, 03 Vicedo, A. P-5 Vicente, R. OC-13 Vida, Y. P-86 Vidal, P. IL-11 Vidal-Gancedo, J. IL-9 Videtta, V. P-57 Villacampa, M. P-32, 35, 49 Villanova, S. P-65 Viña, D. P-69 Vittorino, E. P-48 Yang, H.-C. IL-11 Zalacaín, M. P-4 Zanotti-Gerosa, A. IL-24 Zoli, L. IL-24

SISOC7 Notes


Notes SISOC7


SISOC7 Notes


Notes SISOC7


SISOC7 Notes


Notes SISOC7


SISOC7 Notes


Notes

SISOC7


7th - unioviedo.es · 7th spanish-italian symposium on organic chemistry 7th spanish italian...

Documents