BOOK OF ABSTRACTSneural.dq.fct.unl.pt/orglist/7enqo/livro.pdf · Ionic liquids: six years of...

BOOK OF ABSTRACTS

Book of abstracts 7ENQO Sociedade Portuguesa de Química 16th-18th July 2007 Lisboa, Portugal Email: [email protected] URL: www.dq.fct.unl.pt/7enqo Editor: Sociedade Portuguesa de Química Editorial Coordinator: Abel Vieira Eurico Cabrita Maria Manuel Marques ISBN: 978-989-8124-00-5

7

th Portuguese National Meeting of Organic Chemistry

7th Portuguese National Meeting of Organic Chemistry

7


Welcome

It is normal for the organisers of a meeting to express their hopes at the outset that all will go well, and to make a few general statements about how significant the gathering will be. The National Meetings of Organic Chemistry – best known as ENQOs, have in the past created in the life of the Division of Organic Chemistry of the Portuguese Chemical Society (SPQ) the opportunity for its members to meet every two years, exchange views and discuss their scientific achievements. Hopefully the 7ENQO will achieve the outstanding success of previous gatherings. This year, during the last day devoted to the 1st Portuguese-French Meeting, colleagues from France will meet with Portuguese organic chemists to pave the way for a closer scientific collaboration in the future. Indeed such is the way science, in general, and chemistry, in particular, will have to move if our European Nations are to remain scientifically relevant, in view of the speed of progress and discovery occurring in other blocks around the world. Every journey is made of small steps. Let us hope that the 7ENQO will represent yet another step in the already long life of SPQ and an occasion for gauging the progress of our science and enjoying our city. Welcome to the 7ENQO in Lisbon! The Organising Committee

7


Organising Committee

Ana M. Lobo (FCT-UNL)

Teresa Pinho e Melo (Univ. Coimbra)

Abel Vieira (FCT-UNL)

Ana M. Lourenço (FCT-UNL)

Eurico Cabrita (FCT-UNL)

João Aires de Sousa (FCT-UNL)

João Paulo Noronha (FCT-UNL)

Luísa P. Ferreira (FCT-UNL)

Marco Gomes da Silva (FCT-UNL)

Maria Manuel B. Marques (FCT-UNL)

Paula S. Branco (FCT-UNL)

Scientific Committee

President: Ana M. Lobo (FCT-UNL)

Artur Silva (Univ. Aveiro)

António Rocha Gonçalves (FCT-UC)

Ana Campos (UM-Braga)

Fernanda Proença (UM-Braga)

José Cavaleiro (UA)

Madalena Pinto (FF-UP)

Luísa Sá e Melo (FF-UC)

Joaquim Perdigão Queiroga (Cipan)

Rui Moreira (FF-UL)

William Heggie (Hovione)

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Sponsors

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Program

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Monday, 16th July

09h00 - 10h30 Registration

10h30 – 11h00

7ENQO Opening Session

11h00 – 12h30 Plenary Lectures Auditorium 2: Chairperson: Artur Silva 11h00 – 11h45 PL1: Peter Somfai Allylsilanes beyond Sakurai-allylations: synthetic approaches towards (+)-alexine utilizing a novel [3+2]-annulation reaction 11h45 – 12h30 PL2: Carlos Afonso Ionic liquids: six years of development, applications and commercialization

12h30 –14h30

Break for lunch 14h30 – 15h15 Plenary Lecture

Auditorium 2: Chairperson: Ana Oliveira-Campos

PL3: Carmen Nájera Recoverable catalysts for asymmetric synthesis

15h15 – 17h00

Poster Session (PC1-PC40) Coffee break

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17h00 – 18h00

Oral Communications Auditorium 2: Chairperson: Ana Oliveira-Campos 17h00-17h15 OC1: Maria João Queiroz Metal-assisted reactions in the synthesis of new fluorescent heteroaromatic systems from dehydroamino acids 17h20-17h35 OC2: Andrea Figueiredo O-hydroxylated 2-stryrylchromones with potential antioxidant activity 17h40-17h55 OC3: Arantxa Gómez-Esqué Biogenetically inspired enantioselective approach to indole alkaloids Meeting-room: Chairperson: Luísa Sá e Melo 17h00-17h15 OC4: Ricardo Figueiredo Tuberculosis: molecular targets and drug development 17h20-17h35 OC5: M. I. Ismael Synthesis and anticholineterase activity of pseudo-C-nucleosides containing oxopyrimidine, tetrazole and isoxazole rings 17h40-17h55 OC6: Marta Correia-da-Silva Chemical sulfation: synthesis of potential anticoagulant phenolic compounds

19h00

Welcome reception (Gardens of Gulbenkian Foundation, Av. Berna)

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Tuesday, 17th July

09h00 – 10h30 Plenary Lectures

Auditorium 2:

Chairperson: Ana Lobo

09h00 – 09h45 PL4: Maria Fernanda Proença New developments in the synthesis of imidazole-based compounds 09h45 – 10h30 PL5: Henry S. Rzepa A twisted link between chemistry, maths, molecular biology (and music)

10h40 – 11h00

Coffee break

11h00 – 12h40

ORGLIST Symposium

Auditorium 2: Chairperson: Henry Rzepa 11h00 – 11h10 Introduction 11h10 – 11h45 OL1: Scott Boyer Computational models to aid safety-directed drug design 11h45 – 12h20 OL2: Valerie J. Gillet Deriving structure-activity relationship in heterogeneous datasets 12h20 – 12h40 OL3: Bruce F. Milne Two-parameter classifier for prediction of PKC-ζ modulating behaviour of xanthones

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12h40 – 14h30 Break for lunch

14h30 – 15h15 Plenary Lecture

Auditorium 2: Chairperson: Madalena Pinto PL6: Victor F. Ferreira Synthesis of new derivatives of natural naphthoquinones

15h15 – 16h15

Oral Communications

Auditorium 2: Chairperson: Rui Moreira 15h15-15h30 OC7: Alice M. Dias A versatile synthetic approach for isoguanine derivatives 15h35-15h50 OC8: Pedro J. M. Abreu Natural products from African and Caribbean medicinal plants: highlights on current research 15h55-16h10 OC9: M. Lurdes S. Cristiano Investigation into the reactivity of tetrazoles and benzisothiazoles

15h15 – 16h30 ORGLIST Symposium Meeting room: Chairperson: Henry Rzepa 15h15 – 15h50 OL4: Nuno Palma Regioselectivity of cathecol-O-methyltransferase catalyzed reaction: combined theoretical and experimental studies

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15h50 – 16h25 OL5: Carlos Cobas From MestReC to Mnova: a revolutionary approach to NMR 16h25 Conclusion

16h40-17h40 Organic Chemistry Division - SPQ Meeting

20h00

Conference dinner

Wednesday, 18th July Portuguese-French Symposium

09h00 – 09h15

Opening Session

09h15 – 10h45 Plenary Lectures

Auditorium 2:

Chairperson: José Cavaleiro 09h15 – 10h00 PL7: M. Matilde Marques DNA-based biomarkers of potential drug toxicity: from SERMs to the HIV reverse transcriptase inhibitor nevirapine 10h00 – 10h45 PL8: Siméon Arseniyadis Competing domino processes modulated by the substitution pattern; synthetic applications

10h55 – 11h15 Coffee break

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11h15 – 12h35

Oral Communications

Auditorium 2: Chairperson: Rocha Gonçalves 11h15 – 11h30 OC10: Rui G. Lopes A new and easy approach for the synthesis of methyl-2-deoxy-2-C [(ethoxycarbonyl)methylene]hexopyranosides 11h35 – 11h50 OC11: Mário M. Q. Simões New approaches for metalloporphirin catalised oxidation reactions 11h55 – 12h10 OC12: A. J. Burke Enantioselectivity asymmetric allylic alkylations using a DIOP analogue with a 1,4-dioxane backbone 12h15 – 12h30 OC13: A. L. Cardoso Synthesis of chiral β-amino esters Meeting room: Chairperson: José Prata 11h15 – 11h30 OC14: M. Manuela M. Raposo Donor-acceptor substituted π-conjugatedheterocyclic systems: synthesis and characterization 11h35 – 11h50 OC15: Paulo J. Coelho Study of the photocromic equilibrium in spirooxazines by NMR 11h55 – 12h10 OC16: Armérnio Serra Halogen atom effect on photophysical and photodynamic characteristic of derivatives of m-THPP 12h15 – 12h30 OC17: Ana M. Seca Fatty acid diterpenol esters fromleaves of Juniperus brevifolia

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12h35 – 14h30

Break for lunch 14h30 – 15h15

Plenary Lecture

Auditorium 2: Chairperson: Ana Lobo PL9: M. J. Marcelo Curto Organic chemistry in a government laboratory: ten years of research

15h15 – 17h00

Poster Session (PC41-PC79) Coffee break

17h00 – 17h45 Plenary Lecture

Auditorium 2: Chairperson: Ana Lobo PL10: Jean-Marie Beau Chemical glycobiology: synthesis of bioactive natural products and mimics

18h00

Closing Session

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Plenary Lectures

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Plenary Lectures

PL1- Allylsilanes beyond Sakurai-allylations: synthetic approaches towards (+)-

alexine utilizing a novel [3+2]-annulation reaction Peter Somfai

PL2- Ionic liquids: six years of development, applications and commercialization

Carlos Afonso

PL3- Recoverable catalysts for asymmetric synthesis Carmen Nájera

PL4- New developments in the synthesis of imidazole-based compounds Maria Fernanda Proença

PL5- A twisted link between chemistry, maths, molecular biology (and music) Henry S. Rzepa

PL6- Synthesis of new derivatives of natural naphthoquinones Victor F. Ferreira

PL7- DNA-based biomarkers of potential drug toxicity: from SERMs to the HIV

reverse transcriptase inhibitor nevirapine M. Matilde Marques

PL8- Competing domino processes modulated by the substitution pattern; synthetic

applications Siméon Arseniyadis

PL9- Organic chemistry in a government laboratory: ten years of research M. J. Marcelo Curto

PL10- Chemical glycobiology: synthesis of bioactive natural products and mimics Jean-Marie Beau

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Allylsilanes beyond Sakurai-allylations: Synthetic approaches towards (+)-Alexine utilizing a novel [3+2]-annulation reaction

Peter Somfai§

§ KTH Chemical Science and Engineering, S-100 44 Stockholm, Sweden E-mail: [email protected]

The β-amino alcohol moiety is found in a wide variety of biologically active alkaloids and peptides, it is consequently a common building block in the synthesis of natural products. The importance of vicinal amino alcohols is also well recognized in asymmetric synthesis, as many chiral auxiliaries and ligands contain this substructure. In this lecture a novel approach to vic-amino alcohols developed in our laboratory will be discussed as well as its application towards the synthesis of (+)-Alexine.1,2

N

HO H

OH

OH

OH

HO H

O

NH2

R3Si SiR3(+)-Alexine

[1] Restorp, P.; Fischer, A.; Somfai, P. J. Am. Chem. Soc. 2006, 128, 12646. [2] Restorp, P.; Dressel, M.; .Somfai, P. Synthesis 2007, 1576.

PL1

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IONIC LIQUIDS: SIX YEARS OF DEVELOPMENT, APPLICATIONS AND COMMERCIALIZATION

Carlos A. M. Afonso,a,b Luís C. Branco,a,b Paulo A. S. Forte,a Pedro M. P. Gois, a ,b Nuno M. T. Lourenço,b Nuno M. M. Mateus,b João N. Rosa,b Andreia A. Rosatellaa

a CQFM, Departamento de Engenharia Química e Biológica, Instituto Superior Técnico, Complexo 1, Av. Rovisco Pais, 1049-001 Lisboa, Portugal. b REQUIMTE,

Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal

E-mail: [email protected]

Low melting salts have long been used in electrochemistry applications due to their high electrochemical window and electrolyte properties. Since the discovery of air stable and water resistant low melting salts, later designated as room temperature ionic liquids (ILs), created during last years an impressive interest in the scientific community in different research areas1 such as electrochemistry, organic, inorganic,,organometallic,

polymer and material chemistry biotransformations, remediation, fuel and solar cells, and separation technology (biphasic, membranes, scCO2, systems and pervaporation), flotation fluids, lubrificants, nanotechnology and paint additives.1 Perhaps the reasons for such wide research applications are due to some unique properties such as high conductivity, wide electrochemical window, near non-volatility,2 high thermal stability, low flammability, tunable solubility in water and in common organic solvents, insolubility in scCO2, high solubility and in some cases specific affinity for organic, inorganic, organomettalic solutes, scCO2 and other gases in some ILs, and high stability of enzymes in some IL media.

Our research contribution in this area have focused mainly on the development of new ionic liquids based on the cations 1-methyl-imidazolium [mim] and tetra-alkyl-dimethyl-guanidinium [dmg] cations, including chiral ILs, and in exploring their use as an efficient reaction media for catalyst reuse, product separation, absorption of volatile compounds and selective transport by membrane technology.3 [1] R. D. Rogers, K. R. Seddon, (Eds); Ionic Liquids; Industrial Applications for Green

Chemistry; ACS Symposium Series 818, ACS, Washington DC, 2002; P. Wasserscheid, T. Welton, Ionic Liquids in Synthesis, VCH-Wiley, Weinheim, 2002. J. Duppont in Green Separation Processes: Fundamentals and Applications, C. A. M. Afonso, J. P. S. G. Crespo, (Eds.), Wiley-VCH, Weinheim, 2005.

[2] M. J. Earle, J. M. S. S. Esperança, M. A. Gilea, J. N. C. Lopes, L. P. N. Rebelo, J. W. Magee, K. R. Seddon, J. A. Widegren, Nature, 2006, 439, 831.

[3] Carlos A. M. Afonso, Luís C. Branco, Nuno R. Candeias, Pedro M. P. Gois, Nuno M. T. Lourenço, Nuno M. M. Mateus, João N. Rosa, Chem. Comm, 2007, Feature Article, (DOI: 10.1039/b607483a).

Acknowledgments: We would like to thank Fundação para a Ciência e Tecnologia and FEDER for financial support.

PL2

N N R

[mim]

N N

N

R'

R

R'

R

[dmg]

7


Recoverable Catalysts for Asymmetric Synthesis

Carmen Nájera

Dpto. de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica

(ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain [email protected] http://www.ua.es/dept.quimorg

In the last years it has been established the enormous potential of asymmetric catalysis in asymmetric synthesis.[1] However, an important drawback for the implementation of asymmetric catalysis in industrial processes is the relative high catalysts loadings that must be used in this type of processes. Therefore, the possibility of recycling the catalyst and to be re-used is a very important task.

In our group, we have been studied the design of effective chiral organocatalysts that could be recovered using immobilization techniques but also simple separation of the catalyst from the reaction mixture. For the asymmetric synthesis of α-amino acids polymeric and dimeric Cinchona-derived ammonium salts have been prepared as recoverable phase-transfer catalysts in alkylation reactions and Michael additions of N-(diphenylmethylene)glycine alkyl esters.[2] New 2,2’-diamino-1,1’-binaphthalene (BINAM) derived prolinamides are very efficient and recoverable organocatalysts for the direct aldol condensation of ketones and aldehydes by simple acid-base extractive work-up.[3] For the Michael addition of ketones to β-nitrostyrenes we have found that prolinamides derived from (1S,2R)-cis-1-amino-2-indanol are appropriate and recoverable organocatalysts also by extractive techniques.[4] Silver metal complexes with BINAP as chiral ligand have been shown very good stabitility, catalytic efficiency, and recoverability in enantioselective 1,3-dipolar cycloadditon reactions of azomethine ylides.[5]

References [1] Comprehensive Asymmetric Catalysis, (Eds. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, Y.) Springer-Verlag: Heidelberg, 2004. [2] (a) Chinchilla, R.; Mazón, P.; Nájera, C. Tetrahedron: Asymmetry 2002, 13, 927. (b) Chinchilla, R.; Mazón, P.; Nájera, C. Adv. Synth. Catal. 2004, 346, 1186. (c) Chinchilla, R.; Mazón, P.; Nájera, C.; Ortega, F. Tetrahedron: Asymmetry 2004, 15, 2603. (d) Chinchilla, R.; Mazón, P.; Nájera, C.; Ortega, F. .Arkivoc 2005, vi, 222. [3] (a) Guillena, G.; Hita, M. C.; Nájera, C. Tetrahedron: Asymmetry 2006, 17, 729. (b) Guillena, G.; Hita, M. C.; Nájera, C. Tetrahedron: Asymmetry 2006, 17, 1027. (c) Guillena, G.; Hita, M. C.; Nájera, C. Tetrahedron: Asymmetry 2006, 17, 1493. [4] (a) Almasi, D.; Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry 2006, 17, 2064. (b) Almasi, D.; Alonso, D. A.; Gomez-Bengoa, E.; Ángel, Y. Nájera, C. Eur. J. Org. Chem. 2007, 2328. [5] Retamosa, M. G. in preparation. Acknowledgments: We thank the Dirección General de Investigación of the Ministerio de Educación y Ciencia (CTQ2004-00808/BQU), the Generalitat Valenciana (CTIOIB/2002/320, GRUPOS03/134, GRUPOS05/11 and GV05/157) and the University of Alicante for financial support.

PL3

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NEW DEVELOPMENTS IN THE SYNTHESIS OF IMIDAZOLE-BASED COMPOUNDS

Maria Fernanda J. R. P. Proença §

§ Universidade do Minho, Departamento de Química, 4700-320 Braga, Portugal E-mail: [email protected]

The imidazole ring is an important pharmacophore in drug discovery. The skeletons of a number of bioactive natural products incorporate this structure, which is also present in a wide range of medicinally useful agents.1

N

NH

NHR

OCN

H2N

N

NH

NH2

R

OCN

HN

N

N

NHR

CN

H2N

N

N

NH2

R

CN

HN

3A 3B 5A 5B

CNH2N

CNH2N

CNHN

CNH2N

CNN

CNH2N

NHR NHRO

12 4

NH2R RNCO

base base

Imidazoles 3, isolated by base-catalysed intramolecular cyclization of amidine 2, proved to be versatile precursors for a number of imidazole-based heterocycles. The reaction of compounds 3 with nucleophiles (carbon, nitrogen and oxygen nucleophiles) has been used to prepare 6-substituted purines2 or funtionalized imidazo[4,5-b]pyridines.3 The substitution pattern of the purine ring was also modified by the appropriate selection of electrophilic reagents (aldehydes and ketones,4 anhydrides,5 ethylchloroformate,6 orthoesters,7 isocyanates8 and electron-deficient alkenes9). 2-Oxoimidazoles 5, prepared by intramolecular cyclization of urea 4, are structurally similar to imidazoles 3, and were expected to generate identical products under analogous reaction conditions. As this was not always the case, some of the research carried out on this area will be presented and the results compared with previous work developed for imidazoles 3. [1] For a recent review, see: M.Boiani, M. González, Mini-Reviews in Med. Chem. 2005, 5, 409. [2] unpublished results. [3] M.Zaki, M.F.Proença, B.L.Booth, J. Org. Chem. 2003, 68, 276. M.Zaki, M.F.Proença, B.L.Booth, Synlett, 2005. [4] F.Costa, B.L.Booth, R.G.Pritchard, M.F.Proença, J.Chem.Soc.Perkin Trans. 1999, 1853 and references therein. [5] M.J.Alves, M.A.Carvalho, M.F. Proença et al., J. Heterocyclic Chem. 1997, 739. [6] A.M.Dias, A.S.Vila-Chã, I.M.Cabral, M.F.Proença, Synlett. 2007, 1231 and references therein. [7] M.A.Carvalho, M.F.Proença et al., J.Chem Soc. Perkin Trans 1 2001, 2532 [8] A.M. Dias, I.M. Cabral, M.F. Proença, B.L. Booth J. Org. Chem. 2002, 67, 5546 and references therein. [9] M.A. Carvalho, Y.Álvares, M.Zaki, M.F.Proença, B.L.Booth, Org. Biomol. Chem. 2004, 2, 2340. Acknowledgments: Thanks are due to Universidade do Minho and Fundação para a Ciência e Tecnologia (POCTI/QUI/45391/2002 and POCI/QUI/59356/2004) for financial support.

PL4

7


A TWISTED LINK BETWEEN CHEMISTRY, MATHS, MOLECULAR BIOLOGY (AND MUSIC)

Henry S. Rzepa

Department of Chemistry, Imperial College, London SW7 2AY, U.K. E-mail: [email protected]

Both chirality and aromaticity are cornerstone concepts for organic chemistry. Both had their origins in the 1840s or thereafter in the work of Pasteur, van't Hoff and LeBel for the former and Faraday, Loschmidt, Kekule, Armstrong for the latter, this reaching its first stage of theoretical maturity with Huckel's quantum mechanical analysis in the 20th Century (the famous 4n+2 rule).

For a long period, these two concepts were thought to be exclusive; after all aromaticity manifested almost entirely in flat (achiral) benzenoid rings!

Another concept, topology, also originated in the 1840s, having been coined by the mathematician Johann Listing, who also proposed fascinating topological objects such as trefoil knots, and rings now better known by their co-discoverer, Mobius. In the 1960s, the concepts of Mobius topologies and aromaticity started merging. The chemist Heilbronner proposed aromaticity rules for Mobius cycles, although he did not identify such cycles as being chiral (this property appears to have been gradually realised only years later, although its difficult to find this expressed in print). The first such Mobius molecule was only synthesized in 2003; it was not however particularly aromatic! Meanwhile, in 1978 molecular biologists had discovered the fascinating twists and knots in cyclic DNA, via James Wang's topoisomerase enzymes. This was expressed using a concept known as supercoiling, and a new generation of mathematicians formalised this into an equation expressing a so-called linking number, which is comprised of twist and writhe;

Lk = T + W ...(1)

Applied extensively to the properties of cyclic DNA, these concepts did not migrate at all to organic chemists, who by and large dealt with much smaller molecules. Listing in 1847 had also introduced the concept of paradromic winding, which in modern language maps to imparting further twists to the basic Mobius topology. In 2005, we fused these various concepts from chemistry, topology and molecular biology, recognising that a new form of aromaticity based on double- and higher twisted conjugated, and importantly chiral, rings could be possible. We identified various interesting candidate molecules, but were surprised by how relatively stable they appeared (by computation), given they were at least twice as twisted as the classical Mobius rings. We found a resolution to this paradox in equation (1). The (quantum mechanical) instability we realised is associated with T and not with W. We have now computed values of T and W for a range of topologically interesting (and chiral!) systems, and approximately, those that appear the most synthetically interesting have large values of W compared to T. So W (the writhe) can be regarded as a fundamentally new property of cyclic conjugated molecules, and one moreover that might be associated with stability. This has led to our proposal that eqn (1) and the

PL5

7


Huckel 4n+2 rule can be combined as follows; If Lk is even (measured in units of pi), aromaticity is implied for 4n+2 cyclic conjugated electrons ... (2)

If Lk is odd, aromaticity is implied for 4n cyclic conjugated electrons ... (3)

Intriguingly both T and W are chiral indices, and they can act together or oppose to create some fascinating novel chiral isomerisms.

In a general sense, this type of aromaticity is chiral, and benzene like systems are very much the achiral exceptions (having Lk = 0).

At the end of the talk, I will speculate on some potential real world applications of this fascinating new form of chiral aromaticity, particularly to the design of new chiral metal ligands, and perhaps even mention another interest of ours, the Semantic Web, and how this might in the future enable more efficient fusion of diverse ideas and concepts (linking is a fundamental concept there as well!).

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SYNTHESIS OF NEW DERIVATIVES OF NATURAL NAPHTHOQUINONES

Vitor F. Ferreira

Universidade Federal Fluminense; Instituto de Química, Departamento de Química

Orgânica, 24020-150 Niterói, Rio de Janeiro, Brazil.

E-mail: [email protected]; [email protected]

Quinones have been studied for antitumor, molluscicidal, antiparasitic, anti-inflammatory, antifungic, antimicrobial and trypanocidal activities.1,2 Literature points out that the biological profiles of these molecules are centered on their ortho or para-quinonoid moiety. This group generally accepts one and/or two electrons (redox cycling) to form the corresponding radical anion or dianion species in situ. Thus, the semi-quinone radicals accelerate intracellular hypoxic conditions by producing superoxide anion.3 Due to this mechanism, quinones may present cytotoxicity in the mammalian cells, possibly by affecting enzymes such as topoisomerases, a group of enzymes that are critical for DNA replication in cells.4

β-lapachone (1) is a 1,2-naphthoquinone isolated from the bark of the Lapacho tree (Tabebuia avellanedae). As other quinones, 1 possesses a variety of pharmacological effects, including trypanocidal activity. However, this molecule is also cytotoxic against several cell lines. Pinto e co-workers searching for new compounds with reduced cytotoxicity while maintaining the trypanocidal profile of 1 led to some derivatives modified at the redox center (2a and 2b).5

O

O

O

1

O

X

O

3

R O

O

R

O

2a, X = O 2b, X = NH

O

XN

Ph

4

This conference will focus our synthetic efforts in order to find new derivatives of 1 with improved pharmacological activity.

[1] Silva, M. N.; Ferreira, V. F.; de Souza, M. C. B. V., Quim. Nova, 2003, 26, 407-416. [2] Dubin, M.; Fernadez Villamil, S. H.; Stoppani, A. O., Medicina 2001, 61, 343-350. [3] Monks, T.J., Jones, D.C. Curr. Drug Metabolism, 2002, 3, 425-438. [4] Pardee, A. B.; Li, Y. Z.; Li, C. J. Curr. Cancer Drug Targets. 2002, 2, 227-242. [5] Pinto, C. N.; Dantas, A. P.; De Moura, K. C. G.; Emery, F. S.; Polequevitch, P. F.; Pinto, M. C. F. R.; De Castro, S. L.; Pinto, A.V. Arzneim. Forsc./Drug Res. 2000, 50, 1120-1128. Acknowledgments: THIS WORK WAS SUPPORTED BY UFF, CNPQ, FINEP, CAPES AND FAPERJ.

PL6

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DNA-based biomarkers of potential drug toxicity: from SERMs to the HIV reverse transcriptase inhibitor nevirapine

M. Matilde Marques

Centro de Química Estrutural, Instituto Superior Técnico, TU Lisbon, Av. Rovisco Pais, 1049-001 Lisboa, Portugal

E-mail: [email protected] The term biomarker [1] is increasingly becoming a synonym for molecular biomarker. Carcinogen biomarkers are usually classified in three categories, reflecting (i) exposure, (ii) individual susceptibility, and (iii) early response [2]. The role of carcinogen-DNA interactions as indicators of carcinogenicity has been recognized for over 40 years [3], and mounting evidence suggests that covalent DNA adducts can be regarded both as markers of biological effective dose and as markers of risk, taking into account individual abilities to metabolize carcinogens and repair DNA damage. A chemist’s approach to the relevance of DNA adducts as biomarkers of the potential carcinogenicicity of established therapeutic regimens will be discussed with two examples selected from our studies with tamoxifen and analogues [4,5], and our more recent experience with nevirapine [6]. Tamoxifen (I), a non steroidal selective estrogen receptor modulator (SERM), is an important adjuvant chemotherapeutic agent for the treatment of breast cancer and a chemoprotective agent for the prevention of the disease in high-risk women, but is known to increase the risk of endometrial cancer and thromboembolic events in women. Nevirapine (II), a non-nucleoside reverse transcriptase inhibitor, is used mostly in low resource countries to prevent the vertical transmission of HIV from mother to child, despite reports of severe hepatotoxicity that raise concerns about administration of the drug in the neonatal and pediatric settings.

N N

NH

N

CH3O

II

CH3

O

N

CH3

CH3

I

[1] Biomarkers Definitions Working Group, Clin. Pharmacol. Ther. 2001, 69, 89-95. [2] Vineis, P. and Perera, F., Int. J. Cancer 2000, 88, 325-328. [3] Brookes, P. and Lawley, P.D., Nature 1964, 202, 781-784. [4] Beland, F.A. et al., J. Nat. Cancer Inst. 2004, 96, 1099-1104. [5] Gamboa da Costa et al., Chem. Res. Toxicol. 2007, 20, 300-310. [6] Antunes, A.M.M. et al., Proc. Amer. Assoc. Cancer Res. 2007, 48, 332. Acknowledgement: Financial support from Fundação para a Ciência e a Tecnologia (FCT, Portugal) and FEDER, through programs PRAXIS XXI and POCTI, is gratefully acknowledged.

PL7

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Competing Domino Processes Modulated by the Substitution Pattern; Synthetic Applications

Siméon Arseniyadis

Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette (France)


The basis of the overview to be presented is the oxidative cleavage of unsaturated vic-diols allowing the production of high complexity in a single operation and in a modular way (Scheme 1), with the aim of ultimately developing efficient methods for the synthesis of structurally complex natural products (Scheme 2). Two or more different domino-paths can be put in competition by the judicious choice of the reaction parameters, thus rendering this methodology synthetically useful. This topic has been addressed in some detail and a regioselective profile of this domino reaction was brought to practice in which the cyclic system and the angular substituent are tethered by spacers of various lengths and nature. Noteworthy features of this domino protocol include simultaneous formation of two or three additional rings and numerous stereogenic centers with excellent stereo- and regiocontrol. The most interesting aspects in these “one-pot” transformations involve the fact that in spite of the similarities in the starting substrates, two quite different domino products can be formed by the appropriate choice of the substitution pattern, the stoichiometry or the reagent.

O

Me

AcO OAcO

O O

AcO

O

OOAc

R

HO

HO X

O O

AcO

O

O

AcO OAcO

AcO

R = CH2OAc

R = CH2OBn

R = Me

R = Acetal

H

H

OtBu

Me

HO

O

R = Me

O

O

O

HO O

O

AcO

OAc

O

O

OR'

R = COR'

n

O

HO

H

R =

R =

n = 1 or 2

Me

O O

OO

OTBS

O

Me

AcO

AcO

OH

CN

OH

OH

R = Me

R = Me

Pathylactone A

Iridal NSC 631939

Iripallidal

ABC-Taxoid Diterpene

R3

R2

HO

HO

R1

R7

R4

R6 R5

HO

O

OH

OH

O

O

O

OtBuMOMO

HO

OHO

AcOO

HO

O

OHOH

OTBSn

Scheme 1: Modular construction of complex heterocyclic Scheme 2: A domino based approach towards frameworks; “One-Pot” multistage transformations biologiacally active natural products The presentation will focus on probing this class of domino reactions in an effort to define the origins of orienting factors and to develop a prognostic model for general use. Emphasis will be given to the mechanistic aspects of the domino process, which allowed for a modular construction of various ring systems. A brief outline will be presented establishing the synthetic utility of our domino transformations for the practical synthesis of the cyclohexane core structure of various biologically active natural products. [1] Finet, L.; Candela, J. I.; Kaoudi, T.; Birlirakis, N.; Arseniyadis, S. Chem. Eur. J. 2003, 9, 3813-3820

[2] I. Safir, I. Castellote, S. Porcel, T. Kaoudi, N. Birlirakis, L. Toupet, S. Arseniyadis Chem. Eur. J.

2006, 12, 7337-7344.

PL8

7


ORGANIC CHEMISTRY IN A GOVERNMENT LABORATORY: TEN YEARS OF RESEARCH

M.J. Marcelo Curto§

§ INETI – Instituto Nacional de Engenharia Tecnologia e Inovação E-mail: [email protected]

An overview will be presented of the work developed in the last ten years in a government laboratory whose main mission has been to support local SMEs and help implement public policies in its areas of technical expertise, with particular emphasis in organic chemistry.

PL9

7


CHEMICAL GLYCOBIOLOGY: SYNTHESIS OF BIOACTIVE NATURAL PRODUCTS AND MIMICS

Jean-Marie Beau

Université de Paris Sud, Laboratoire de Synthèse de Biomolécules associé au CNRS, Institut de Chimie Moléculaire et des Matériaux, Bât. 430, 91405 Orsay Cedex)


The chemical synthesis of oligosaccharides, glycoconjugates and their carbon-linked analogs has been improved enormously over the past twenty years making increasingly large structures available for biological studies and applications. Improvement is still needed and in this context, we will present our recent effort to simplify the construction procedures of glycoconjugates using recombinant E. coli cells, anomeric organometallics or Dynamic Combinatorial Chemistry. Special focus will be given to a chemoenzymatic strategy that produces lipochitooligosaccharides (bacterial signaling molecules known as Nodulation Factors) and highly active aromatic analogs.[1] We will also detail the scope and variations of a mild and highly stereoselective synthesis of carbon-linked analogs of natural oligomers or glycoconjugates that utilize the coupling of glycosyl samarium reagents in Barbier or Reformatsky procedures.[2] We will finally show that Dynamic Combinatorial Chemistry can be successfully adapted to systems exhibiting relatively poor binding properties, for the discovery of glycoenzyme (glycosyl-hydrolases and glycosyl-transferases) inhibitors.[3]

[1] N. Grenouillat, B. Vauzeilles, J.-J. Bono, E. Samain, and J.-M. Beau, Angew. Chem., Int. Ed. Engl., 43, 2004, 4644-4646. [2] N. Miquel, G. Doisneau and J.-M Beau, Angew. Chem., Int. Ed. Engl., 2000, 39, 4111-4114; Z. Abdallah, G. Doisneau and J.-M. Beau, Angew. Chem., Int. Ed. Engl., 2003, 42, 5209-5212; A Malapelle, Z. Abdallah, G. Doisneau, J.-M. Beau, Angew. Chem., Int. Ed. Engl., 2006, 45, 6016-6020; A Malapelle, A. Coslovi, G. Doisneau, J.-M. Beau, Eur. J. Org. Chem. 2007, in press. Review: J.-M. Beau, B. Vauzeilles and T. Skrydstrup: Glycomimetics: C-Glycosyl Compounds as Stable Analogs of Natural Oligosaccharides and Glycosyl aminoacids, in Glycoscience: Chemistry and Chemical Biology, Vol. 3, B. Fraser-Reid, K. Tatsuta, J. Thiem, Eds., Springer Verlag, Heidelberg, 2001, pp. 2679-2724. [3] S. Zameo, B. Vauzeilles, and J.-M. Beau, Angew. Chem. Int. Ed., 2005, 44, 965-969; A. Valade, D. Urban, and J.-M. Beau, ChemBioChem., 2006, 7, 1023.

PL10

7


Oral Communications

7


Oral Communications OC1- Metal-assisted reactions in the synthesis of new fluorescent heteroaromatic

systems from dehydroamino acids Maria João R. P. Queiroz

OC2- O-hydroxylated 2-styrylchromones with potential antioxidant activity Andrea G. P. R. Figueiredo

OC3- Biogenetically inspired enantioselective approach to indole alkaloids Arantxa Gómez-Esqué

OC4- Tuberculosis: molecular targets and drug development

Ricardo Figueiredo OC5- Synthesis and anticholineterase activity of pseudo-C-nucleosides containing

oxopyrimidine, tetrazole and isoxazole rings M. I. Ismael

OC6- Chemical sulfation: synthesis of potential anticoagulant phenolic compounds

Marta Correia-da-Silva OC7- A versatile synthetic approach for isoguanine derivatives

Alice M. Dias OC8- Natural products from African and Caribbean medicinal plants: highlights on

current research Pedro J. M. Abreu

OC9- Investigation into the reactivity of tetrazoles and benzisothiazoles

M. Lurdes S. Cristiano OC10- A new and easy approach for the synthesis of methyl-2-deoxy-2-C-

[(ethoxycarbonyl)methylene]hexopyranosides Rui G. Lopes

OC11- New approaches for metalloporphirin catalised oxidation reactions

Mário M. Q. Simões OC12- Enantioselectivity asymmetric allylic alkylations using a DIOP analogue

with a 1,4-dioxane backbone A. J. Burke

OC13- Synthesis of chiral ββββ-amino esters

A. L. Cardoso

7


OC14- Donor-acceptor substituted ππππ-conjugated heterocyclic systems: synthesis and

characterization M. Manuela M. Raposo

OC15- Study of the photocromic equilibrium in spirooxazines by NMR

Paulo J. Coelho OC16- Halogen atom effect on photophysical and photodynamic characteristic of

derivatives of m-THPP Armérnio C. Serra

OC17- Fatty acid diterpenol esters from leaves of Juniperus brevifolia

Ana M. L. Seca

7


METAL-ASSISTED REACTIONS IN THE SYNTHESIS OF NEW FLUORESCENT HETEROAROMATIC SYSTEMS

FROM DEHYDROAMINO ACIDS

Maria-João R.P. Queiroz Centro de Química, Universidade do Minho, Campus de Gualtar, 4710-057Braga


A new method for the synthesis of heteroaromatic systems, initiated by Suzuki coupling of beta-bromo or beta,beta-dibromodehydroamino acid derivatives with heteroarylboronic acids and, completed by a Pd/Cu-assisted C-N intramolecular cyclization of the coupling products to form a pyrrole ring, was developed in our laboratories [1,2]. More recently we have extended the scope of our method to the synthesis of several methyl 3-arylindole-2-carboxylates. Their absorption and fluorescence were studied in several solvents and some of them may be used as solvatochromic fluorescent probes [3 and unpublished results].

NCO2Me

H

R2

N

H

CO2Me

X

X

R1 = R

2 = OMe, SMe, COMe, CN

R1 = COMe or OMe, R

2 = H

R1 = H, R

2 = COMe or OMe

X = S, a benzothieno[2,3-e]indoleX = O, a benzofuro[2,3-e]indole

R1

Tetracyclic systems, methyl 1-(dibenzothien-4-yl)-3H-benzothieno[2,3-e]indole-2-carboxylate and methyl 1-(dibenzofur-4-yl)-3H-benzofuro[2,3-e]indole-2-carboxylate, were also prepared by the same methodology and their DNA intercalation was studied by absorption and fluorescence. The benzothienoindole is the more promising as a potential antitumoral agent, forming a complex with ds-DNA. The intercalation is the preferred mode of binding as confirmed by the fluorescence quenching experiments using iodide anion [results submitted for publication].

[1] a) A.S. Abreu, N.O. Silva, P.M.T. Ferreira, M.-J. R.P. Queiroz, Tetrahedron Lett. 2003, 44, 3377-3379. b) A.S. Abreu, N.O. Silva, P.M.T. Ferreira, M.-J. R.P. Queiroz, M. Venanzi, Eur. J. Org. Chem., 2003, 4792-4796. [2] A.S. Abreu, P.M.T. Ferreira, M.-J. R.P. Queiroz, I.C.F.R. Ferreira, R.C. Calhelha, L.M. Estevinho Eur. J. Org. Chem. 2005, 2951-2957. [3] M.-J. R.P. Queiroz, A.S. Abreu, E. M.S. Castanheira, P.M.T. Ferreira Tetrahedron 2007, 63, 2215-2222.

Acknowledgments: To the “Fundação para a Ciência e Tecnologia” and to FEDER, through financial support to CQ - Univ. do Minho and through a research project

POCI/QUI/59407/2004.

OC1

7


O-HYDROXYLATED 2-STYRYLCHROMONES WITH POTENTIAL ANTIOXIDANT ACTIVITY

Andrea G. P. R. Figueiredo, Artur M. S. Silva, Diana C. G. A. Pinto, Augusto C. Tomé,

José A. S. Cavaleiro University of Aveiro, Department of Chemistry, 3810-193 Aveiro

[email protected]

2-Styrylchromone (2-SC) derivatives are a small class of natural chromones (only two have been found), which show important biological activities [1]. Certain synthetic 2-SC possess potent antitumor, antiallergic, antioxidant and hepatoprotective activities [2]. Recently, we proved that polyhydroxy-derivatives show potent antiradical activity and act as a xanthine oxidase inhibitors [3]. The presence of hydroxyl groups in 3’,4’-positions seems to be very important to increase the antioxidant activity [4].

Following our work on the synthesis of compounds with antioxidant activity, we report the synthesis of 2-SC 3 by the Baker-Venkataraman method using 2’-hydroxyacetophenones 1 and cinnamic acids 2 as starting materials. Once 2-SC 3 were obtained, the protective groups were cleaved to yield the expected di- and tetra-hydroxylated 2-SC 4 (Scheme). Experimental details and structural characterization of the new compounds will be presented and discussed.

OR1

R2

O

R4R3

OR1

R2

O

R4R3

3a) R1, R2 = OMe; R3, R4 = OBn3b) R1, R2 = OBn; R3, R4 = OMe3c) R1, R2, R3, R4 = OMe

4a) R1, R2 = OMe; R3, R4 = OH4b) R1, R2 = OH; R3, R4 = OMe4c) R1, R2, R3, R4 = OH

Baker-VenkataramanMethod

3a), 3b) - AcOH/HCl

3c) - BBr3 (in CH2Cl2)

O

CO2H

R4

R3OHR1

R2

+

1a) and 2a) R1, R2, R3, R4 = OMe1b) and 2b) R1, R2 ,R3, R4 = OBn1 2

3 4

Scheme

[1] a) Gerwick, W. H., Lopez, A., Van Duyne, G. D., Clardy, J., Ortiz, W., Baez, A., Tetrahedron Lett., 1986, 27, 1979; b) Gerwick, W. H., J. Nat. Prod., 1989, 52, 252; [2] Manthey, J. A., Guthric, N., Grohmann, K, Curr. Med. Chem., 2001, 8, 135; [3] Fernandes, E., Carvalho, F., Silva, A. M. S., Santos C. M. M., Pinto, D. C. G. A, Cavaleiro, J. A. S., Bastos, M. L., J. Enz. Inhib. Med. Chem., 2002, 17(1), 45-48; [4] Wright, J. S., Johnson, E. R., DiLabio, G. A., J. Am. Chem. Soc., 2001, 123, 1173-1183. Acknowledgements: Thanks are due to the University of Aveiro, FCT and FEDER for funding the Organic Chemistry Research Unit and the project POCTI/QUI/59284/2004. One of us (A. G. P. R. Figueiredo) is also grateful to FCT for a PhD grant (SFRH/BD/18387/2004).

OC2

7


BIOGENETICALLY INSPIRED ENANTIOSELECTIVE APPROACH TO INDOLE ALKALOIDS

Mercedes Amat, Maria M.M. Santos, Arantxa Gómez-Esqué,§ Carmen Escolano,

Joan Bosch §Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona


Secologanin is a secoiridoid glucoside of extraordinary significance because it is a key intermediate in the biosynthesis of monoterpenoid indole alkaloids many of them possessing considerable pharmacological and therapeutic interest.1 A condensation of secologanin with triptamine (or tryptophan) constitutes the initial step of the biosynthesis of these natural products. The pivotal role of secologanin in alkaloid biosynthesis has stimulated the development of biomimetic synthesis of alkaloids using this compound as the starting material.2 We present here an efficient approach to indole alkaloids in which the key step consists of a cyclocondensation reaction of racemic aldehyde diester 1, which can be envisaged as a synthetic equivalent of secologanin, with (S)-tryptophanol affording enantiopure lactam 2 in 62% yield.3 Three stereogenic centers with a well-defined configuration have been generated in a single synthetic step. Subsequent closure of the C ring from lactam 2 through the corresponding thioamide afforded compound 3 which embodies the tetracyclic framework of Corynanthe alkaloids. Recent progresses on the enantioselective synthesis of Dihydrocorynantheine from compound 3 will be discussed.

O

CHO

MeO2C

OGluH

H

Secologanin

NH

NH2N

N

H

MeO2C

H3α StrictosidineH3β Vincoside

H

OMeO2C

OGluH

H

NHN

HH

OHGeissoschizine

3

Monoterpenoidindole alkaloids

A B C

D

MeO2C CHO

MeO2C 1 racemate

NH

NH2

OH

NN

H

OO

MeO2C

NN

H

O

MeO2C

H

H

1) Lawesson2) C6H5CH2Br3) NaBH4

23

83%62%

NH

N

H

OMeMeO2C

Dihydrocorynantheine

[1] Stöckigt, J.; Ruppert, M. In Comprehensive Natural Products; Barton, D.; Nakanishi, K., Eds.; Elsevier: New York, 1999; Vol 4, pp 109-138. [2] Brown, R. T. In Indole and Biogenetically Related Alkaloids; Phillipson, J. D., Zenk, M. H., Eds.; Academic Press: London, 1980; Chapter 9. [3] a) Bassas, O.; Llor, N.; Santos, M. M. M.; Griera, R.; Molins, E.; Amat, M.; Bosch, J. Org. Lett. 2005, 7, 2817-2820. b) Amat, M.; Santos, M. M. M.; Bassas, O.; Llor, N.; Escolano, C.; Gómez-Esqué, A.; Molins, E.; Allin, S. M.; McKee, V.; Bosch, J. J. Org. Chem. 2007, 72 (in press). Acknowledgments: Financial support from the Ministry of Science and Technology (CTQ2006-02390/BQU) and the DURSI, Generalitat de Catalunya (2005SGR00603) is gratefully acknowledged.

OC3

7


TUBERCULOSIS: MOLECULAR TARGETS AND DRUG DEVELOPMENT

Ricardo J.A. Figueiredo§,¥, Joaquim P. Queiroga§, José P. Cardoso§, José C. Menezes¥

§ CIPAN, Companhia Industrial Produtora de Antibióticos, S.A. Vala do Carregado, 2600-726 Castanheira do Ribatejo

¥ IBB-Institute for Biotechnology and Bioengineering, Centre for Biological and Chemical Engineering, Technical University of Lisbon, IST (e-mail: [email protected] )

Av. Rovisco Pais, 1049-001 Lisboa E-mail: [email protected]

In the year that marks the 125th anniversary of Mycobacterium tuberculosis discovery, the Tuberculosis (TB) numbers1 are more concerning than ever. Far from being eradicated as many foresaw in a not so distant past, HIV&TB coinfection and extensive drug-resistant tuberculosis (XDR-TB), imply the need for new drugs with different mechanisms of action against TB.2

Currently we witness a disinvestment in anti-infectives R&D by Big Pharma, motivated by economic and risk factors.3 Antibiotics discovery & development is nowadays made mostly by “Biotech” companies. Diseases like TB that affects almost exclusively populations that cannot afford necessary medicines, from a commercial perspective, present little financial incentive for pharmaceutical companies to invest in R&D.

In this presentation a point of situation on tuberculosis is made. Tuberculosis molecular targets and new anti-TB drugs against those in TB R&D pipeline will be disclosed. 4,5,6,7

[1] www.who.int/entity/tb/publications/2006/tb_factsheet_2006_1_en.pdf . [2] Several articles compiled in a review entitled Focus on Tuberculosis, Nature

Medicine, 2007, 13(3): 263-312 [3] S.J. Projan, Curr. Opin. Microbiol., 2003, 6: 427-430. [4] Zhang Y. Annu. Rev. Pharmacol. Toxicol., 2005; 45: 529-564. [5] Kutardjieff K. & Rupp B., Curr. Pharm. Des., 2004, 10:3195-3211 [6] Tripathi R. P. et al, Med. Res. Rev., 2005, 25(1): 93-131 [7] Smith C. V. et al., Tuberculosis, 2004, 84:45-55 Acknowledgments: Thanks are due to CIPAN and Fundação para a Ciência e

Tecnologia for Figueiredo grant (SFRH/BDE/15554/2005).

OC4

7


SYNTHESIS AND ANTICHOLINESTERASE ACTIVITY OF PSEUDO-C-NUCLEOSIDES CONTAINING OXOPYRIMIDINE,

TETRAZOLE AND ISOXAZOLE RINGS

J. A. Figueiredoa, M. I. Ismaela, J. M. Pinheiroa, A. S. Silvab, A. P. Rauterc, N. M. Xavierc, J. Justinod, F. Vinagred, M. Goulartd, D. Mirad

aDepartamento de Química, Unidade I&D Materiais Têxteis e Papeleiros da Universidade da Beira Interior, Av. Marquês d’Ávila e Bolama, 6201-001 Covilhã,

Portugal bDepartamento de Química, Universidade de Aveiro, Campus Universitário de

Santiago, 3810-193 Aveiro, Portugal cCentro de Química e Bioquímica/Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Edifício C8, 5º Piso, Campo Grande, 1749-016

Lisboa, Portugal dEscola Superior Agrária de Santarém, Apartado 310, 2001-904 Santarém, Portugal


Pseudo-C-nucleosides have a wide variety of biological activities and ongoing research on this group of compounds is likely to yield new applications in critical areas of medicine and other fields. Compounds of this type containing a thiazolidinone ring have been reported to inhibit butyrilcholinesterase, one of the enzymes involved in neurotransmission in the brain [1], possibly implicated in Alzheimer’s disease progression. As part of our ongoing search for new cholinesterase inhibitors, which may be valuable in ameliorating Alzheimer’s disease, we now report the synthesis of compounds with tetrazole, oxo- and thioxopyrimidine rings in their structure linked to the sugar moieties presented in 1-6, starting from sugar precursors containing a reactive carbonyl group. In addition, acetylcholinesterase and butyrilcholinesterase inhibition promoted by these compounds and those with isoxazole rings in their structure [2] will be discussed. In vitro toxicity studies for the evaluation of acute cytotoxicity or genotoxicity caused by exposure of lymphocytes to the bioactive compounds will be presented.

OO

O

R'

R

HN

HNCO2Et

X

G

O

O

O

O

O

O

N

G

HNN

NN

G

OBnOBnO

OMeOBn O

O

OHOO

O

X = O

X = S

G =

1 R = H; R' = OBn2 R = OBn ; R' = H3 R = OH ; R' = H

4 5 6

References: [1] A. P. Rauter, M. Padilha, J. A. Figueiredo, M. I. Ismael, J. Justino, H. Ferreira, M. J. Ferreira, C. Rajendran, R. Wilkins, P. D. Vaz, M. J. Calhorda, J. Carbohydr. Chem, 2005, 24, 275. [2] J. Pinheiro, M. Ismael, J. Figueiredo, A. Silva, J. Heterocyclic Chem., 2004, 8, 41.

OC5

7


CHEMICAL SULFATION: SYNTHESIS OF POTENCIAL ANTICOAGULANT PHENOLIC COMPOUNDS

Marta Correia-da-Silva,a,b Emília Sousa,a,b Madalena Pinto,a,b Luís Vale-Silva,a,c

Eugénia Pintoa,c a Centro de Estudos de Química Orgânica, Fitoquímica e Farmacologia da

Universidade do Porto (CEQOFFUP), bLaboratório de Química Orgânica, cLaboratório de Microbiologia, Faculdade de Farmácia, Universidade do Porto,

Rua Aníbal Cunha, 164, 4050-047 Porto, Portugal E-mail: [email protected]

Anticoagulant and antithrombotic activities are among the most widely studied properties of sulfated macromolecules [1]. In light of recent anticoagulant results concerning two glycosilated flavonoids [2] sulfated diosmin (I) and sulphated hesperidin (II), the sulfation of other commercial available glycosylated phenolic compounds is described: two flavonoids, rutin (1) and trihydroxyethylrutin (2), one cumarin, esculin (3), one xanthone, mangiferin (4), and one hydroxycinnamic acid, chlorogenic acid (5).

Sulfation was carried out with triethylamine-sulphur trioxide adduct, in dimethylacetamide at 65ºC [1,2]. The purification step was optimised using a Snakeskin Pleated Dialysis Tubing. The structure of the compounds was established by IR, 1H and 13C NMR, HSQC, HMBC and HRMS. Since random screening is one of the strategies for drug discovery, sulfated compounds were first evaluated for antifungal activity against dermatophytes, yeasts and Aspergillus species with clinical relevance, using microdilution broth method [3,4]. Compounds did not show any activity against all the species tested.

O

O

OH

OCH3

OH

O

O

O

O

-O3SO

-O3SO

-O3SO

OSO3-

OSO3-

-O3SO

H3C

O

O

OH

OCH3

OH

O

O

O

O

-O3SO

-O3SO

-O3SO

OSO3-

OSO3-

-O3SO

H3C

O

O

OH

HO

OH

OH

O

O

OHOH

HO

O

O

OH CH3

OHOH

O

O

OH

O

O

O

O

O

OHOH

HO

O

O

OH CH3

OHOH

OH

HO

OH

O OHO

O

O

HOHO

OH

OH

O OHHO

OH

OH

O

HO

OH

HO

O

OH

OH

COOH

HOHO

HO

HO

O

O

I II

12

3

4 5

[1] Gunnarsson G. T., Desai U. R, Bioorg. Med. Chem. Lett., 2003, 13, 679-683. [2] Sousa M. E., Correia-da-Silva M., Pinto M., Drugs Fut., 2006, 31 (Suppl. A): XIXth Int. Symp. on Medicinal Chemistry, P119, 105. [3] National Committee for Clinical Laboratory Standards. Approved standard M27-A. Wayne, Pa, USA, 1997. [4] National Committee for Clinical Laboratory Standards. Approved standard M38-A. Wayne, Pa, USA, 2002.

Acknowledgments: Fundação para a Ciência e a Tecnologia (FCT), Unidade de I&D 226/94; FEDER; POCI for financial support and for the PhD to Marta Correia da Silva (SFRH/BD/22962/2005)

OC6

7


A VERSATILE SYNTHETIC APPROACH FOR ISOGUANINE DERIVATIVES

Alice M. Dias, A. Sofia Vila-Chã, Isabel M. Cabral and M. Fernanda Proença

Departamento de Química, Universidade do Minho, 4700-320 Braga, Portugal Email: [email protected]

Purine-based compounds find potential application as chemical and biological tools and /or therapeutic agents due to their wide range of biological activities. Their potency and selectivity depends on the position and nature of the substituent on the ring. [1] In our research group, 5-amino-4-cyanoformimidoyl imidazoles 1 have been used as versatile synthons for the preparation of different 6-substituted purines, usually under mild reaction conditions. Now, we present a versatile synthetic method for the preparation of isoguanine derivatives 4-8, which involve a common imidazole intermediate 3. [2] An easily accessible substituted imidazole (2) was used as the precursor of imidazole 3, formed in the presence of ammonia and primary alkyl amine at room temperature after 10 minutes to 18 hours. Compound 3 was cyclized either to a 6-amino-N1-alkyl (4) or to a 6-alkylamino-N1-H (5) isoguanine, depending on the reaction conditions used. In the presence of aromatic amines and hydrazides, the nucleophilic displacement of the cyano group requires more vigorous conditions, which prevent the isolation of intermediate 3.

N

N

NH

N O

NH

N

N

NH

N O

NHR2

N

CN

OEt

O2 4

N

N

N

N O

NH2

R2

N

N

N

HN O

N

N

R3

R2NH2

R2= Alkyl, Aryl

5

6HN

O R3

N

N

R1 R1

R1

R1R1

NH2

R1= Alkyl, Aryl

NH

CN

N

N

R1

NH2

3

R3= H, Me,

Fur, Pyr

N

NHR2

OEt

O

N

N

R1

NH2

N

N

NH

N O

NH2

R1

R2= H

R2= NHCOR3

1

78

ClCOOEt

These compounds, which are not easily prepared by other methods, were isolated in very good yields from this common intermediate. The rearrangement of isoguanines 4 to the thermodynamically favoured isoguanines 5 was also investigated, as an alternative pathway for the preparation of compounds 5.

References

[1] For a recent review see: Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987-4006. [2] Dias, A. M.; Cabral , I. M.; Vila-Chã, A. S.; Proença, M. F. Synlett, 2007, 1231-1234. Thanks are due to “Universidade do Minho” and “Fundação para a Ciência e Tecnologia” (POCTI/QUI/45391/2002, POCI/QUI/59356/2004) for financial support.

OC7

7


NATURAL PRODUCTS FROM AFRICAN AND CARIBBEAN MEDICINAL PLANTS: HIGHLIGHTS ON CURRENT RESEARCH

Pedro J.M. Abreu CQFB/REQUIMTE, Faculdade de Ciências e Tecnologia da Universidade Nova de

Lisboa, 2829-516 Caparica, Portugal E-mail: [email protected]

In the last few years, our phytochemical research is being focused on the

characterization of bioactive natural products from medicinal plants of diverse origin [1]. In the present communication we report the identification of cytotoxic, antileukemic, antimicrobial, and antioxidant metabolites isolated from plant species collected in Guinea-Bissau (Ozoroa insignis), Tunisia (Moricandia arvensis, Rantherium suaveolens, Ebenus pinnata, Salsola tetrandra), and Cuba (Pedilanthus tithymaloides, Talipariti elatum). Examples of representative structures are shown below.

O

OOH

HO

OH

O

OHOHO

OOH

OH

O

HO

Acyl-flavonoid from P. tithymaloides

O

OH

R

O

OCH3

Anacardic acid methylesters from O. insignis

Phenolic glycoside from M. arvensis

HO

O

OO

O

OH

HO

OHHO

ββββ-ionone glucoside from S. tetrandra

NHm

OH

O

OH

OHOH

9

Ceramides from R. suaveolens

O

OH O

O

HOHO

O

OH

OH

OH

HO

Flavonoid from T. elatum

OH

OH

O

OH

OH

OH

HOO

O

O

HO

OH

HOO

OH

HOO

OOH

H3CO

OCH3

OOH

OHHO

OH

OOH

OHHO

O

O

Flavonoid from E. pinata

[1] http://www.dq.fct.unl.pt/qoa/abreu

Acknowledgements: REQUIMTE, Fundação para a Ciência e Tecnologia, Programme Alβan, and GRICES.

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7


INVESTIGATION INTO THE REACTIVITY OF TETRAZOLES AND BENZISOTHIAZOLES

M. Lurdes S. Cristiano

Department of Chemistry, Biochemistry and Pharmacy, F.C.T. and CCMAR, University of Algarve, Campus de Gambelas, 8005-039 Faro, Portugal


Tetrazoles are extremely relevant compounds, for instance in medicinal chemistry (as antihypertensive, antiallergic, antibiotic and anticonvulsant agents and in cancer and AIDS treatments),[1] agriculture (pesticides, growth regulators)[2] and photoimaging.[3] Benzisothiazoles are also economically important heterocyclic compounds. Saccharin is the oldest artificial sweetener, and is used industrially as a key structural element for the synthesis of biologically active compounds. Saccharyl derivatives show herbicidal, antimicrobial and antifungal activity, potential in enzymatic inhibition and anti HIV-1 activity.[4]

The relevance of both classes of compounds boosted fundamental research in their structure and reactivity. Tetrazoles and benzisothiazoles are versatile starting materials for the synthesis of related heterocyclic derivatives.[5]

Both tetrazolyl and benzisothiazolyl ethers are excellent intermediates for selective palladium-catalysed reductive cleavage of phenols, allyl, benzyl and naphthyl alcohols.[6] However, the reactivity of both heterocycles towards nucleophiles differs considerably, as does their thermal- and photo-reactivity.

The presentation will address some aspects of the reactivity of tetrazolyl and benzisothiazolyl derivatives in relevant reactions. Observed reactivity will be rationalised on structural grounds.

[1] Herr, R.J. J. Bioorg. Med. Chem. 2002, 10, 3379; Mavromoustakos, T.; Kolocouris, A.; Zervou, M.; Roumelioti, P.; Matsoukas, J.; Weisemann, R. J. Med. Chem. 1999, 42, 1714; Tamura, Y.; Watanabe, F.; Nakatani, T.; Yasui, K.; Fuji, M.; Komurasaki, T.; Tsuzuki, H.; Maekawa, R.; Yoshioka, T.; Kawada, K.; Sugita, K.; Ohtani, M. J. Med. Chem., 1998, 41, 640. [2] Sandmann, G.; Schneider, C.; Boger, P. Z. Naturforsch. C, 1996, 51, 534. [3] Taylor, J.W.; Jiang, Y.; Basset, D.R. Polym. Mat. Sc. Eng. 1991, 64, 50. [4] Eacho, P.I.; Foxworthy-Mason, P.S.; Lin, H.-S.; Lopez J.E.; Mosior, M.K.; Richett, M.E.; EP1274708, 2006; Zani, F.; Vicini, P.; Arch. Pharm. 1998, 331, 219; Marco, J.L.; Ingate, S.T.; Jaime Bea, C. J. Tetrahedron, 2000, 56, 2523. [5] Frija, L. M. T.; Khmelinskii, I. V.; Cristiano, M. L. S. Tetrahedron Lett. 2005, 46, 6757; Frija, L. M. T.; Khmelinskii, I. V.; Cristiano, M. L. S. J. Org. Chem. 2006, 71, 3583; Ahn, K.H.; Baek, H.H.; Lee, S.J.; Cho, C.W. J. Org. Chem. 2000, 65, 7690; Powers , J.C.; Asgian, J.L.; Ekici, O.D.; James, K.E. Chem. Rev. 2002, 102, 4639. [6] Frija, L.M.T.; Cristiano, M.L.S; Guimarães, E.M.O.; Martins, N.C.; Loureiro, R.M.S.; Bickley, JF. J. Mol. Catalysis. A: Chem. 2005, 242, 241 and refs cited therein. Acknowledgments: Fundação para a Ciência e Tecnologia (FCT) and FEDER.

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A NEW AND EASY APPROACH FOR THE SYNTHESIS OF METHYL 2-DEOXY-2-C-

[(ETHOXYCARBONYL)METHYLENE]HEXOPYRANOSIDES

Rui G. Lopes, Joana L. Salta, João M. Caio, Amélia P. Rauter

Centro de Química e Bioquímica/Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa,

Ed. C8, 5º Piso, Campo Grande, 1749-016 Lisboa, Portugal


In this communication a simple and direct method permitting an easy access to compounds derived from 2-keto sugars, starting from the easily prepared 3-keto templates, will be presented.

The direct oxidation of carbohydrates at position 2 leads mostly to keto sugars in low yield. Therefore, alternative methods to access this type of compounds are needed. 3-Keto sugars were used as scaffolds for the Wittig type olefination at C-2 with [(ethoxycarbonyl)methylene]triphenylphosphorane in the appropriated solvent to give compounds type 1 and 2 in good yield. The stereochemistry of the reaction products was assigned by NMR experiments, being the stereoselectivity of the reaction discussed in terms of the protecting groups used.

O

OR2

OR2

R1O

OMe

CO2Et

O

OR

O

O

OMe

CO2Et

1 2

Acknowledgments: The authors thank Fundação para a Ciência e Tecnologia for the PhD grant SFRH/BD/30699/2006.

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7


NEW APPROACHES FOR METALLOPORPHYRIN CATALYSEDNEW APPROACHES FOR METALLOPORPHYRIN CATALYSEDNEW APPROACHES FOR METALLOPORPHYRIN CATALYSEDNEW APPROACHES FOR METALLOPORPHYRIN CATALYSED

OXIDATION REACTIONSOXIDATION REACTIONSOXIDATION REACTIONSOXIDATION REACTIONS

Mário M.Q. Simões, Domingos M.A. Silva, Rodrigo De Paula, Augusto C. Tomé, M. Graça P.M.S. Neves, José A.S. Cavaleiro

Department of Chemistry, University of Aveiro, 3810-193 Aveiro [email protected]

An important challenge for green chemistry is the finding of alternatives to the common oxidation synthetic methodologies, based on stoichiometric oxidants that lead to large amounts of non-biodegradable by-products [1]. The use of H2O2 as a cheap, environmentally clean and easy to handle oxidant [2], in conjugation with robust and easily obtainable metalloporphyrins as catalysts, led to efficient procedures to perform many oxidative reactions [3-5]. In some cases the role of a co-catalyst has shown to be essential [4], either by speeding up the reaction or by changing the stereoselectivity [6]. However, the potentiality of these systems can be highly increased by anchoring the catalyst to a solid support, thus allowing its easy recovery and reuse. Moreover, the local environment of the support can bring higher selectivity and prevention of catalyst self-oxidation [7]. Efficient supported metalloporphyrin catalysts use organic or mineral supports; silica is being recognized as a very attractive material, due to its stability towards drastic catalytic oxidation conditions [8]. The most recent results dealing with homogeneous and heterogeneous metalloporphyrin catalysed oxidation reactions currently in progress in our laboratory will be presented. AcknowledgmentsAcknowledgmentsAcknowledgmentsAcknowledgments

Thanks are due to the University of Aveiro and FCT for funding the Organic Chemistry Research Unit. R. De Paula also thanks FCT for his PhD grant (SFRH/BD/25666/2005). ReferencesReferencesReferencesReferences

[1] R. Noyori, M. Aoki, K. Sato, Chem. Commun., 2003, 1977-1986. [2] C.W. Jones, Applications of Hydrogen Peroxide and Derivatives, The Royal Society of Chemistry, Cambridge, 1999. [3] S.L.H. Rebelo, M.M.Q. Simões, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, Chem. Commun., 2004, 608-609. [4] S.L.H. Rebelo, M.M. Pereira, M.M.Q. Simões, M.G.P.M.S. Neves, J.A.S. Cavaleiro, J. Catal., 2005, 234, 76-87. [5] G. Grigoropoulou, J.H. Clark, J.A. Elings, Green Chem., 2003, 5, 1-7. [6] C.-P. Du, Z.-K. Li, X.-M. Wen, J. Wu, X.-Q. Yu, M. Yang, R.-G. Xie, J. Mol. Catal. A: Chem., 2004, 216, 7-12. [7] (a) J.R.L. Smith, in: R.A. Sheldon (Ed.), Metalloporphyrins in Catalytic Oxidations, Marcel Dekker, New York, 1994, p. 325. (b) M.V. Vinodu, M. Padmanabhan, J. Polym. Sci. Part A: Polym. Chem., 2001, 39, 326-334. [8] B. Meunier, A. Robert, G. Pratviel, J. Bernadou, in: K.M. Kadish, K.M. Smith, R. Guilard (Eds.), The Porphyrin Handbook, Academic Press, San Diego, 2000, Volume 4, p. 155.

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ENANTIOSELECTIVITY ASYMMETRIC ALLYLIC ALKYLATIONS USING A DIOP ANALOGUE WITH A 1,4-

DIOXANE BACKBONE C.S. Marques, A. J. Burke,*

Departamento de Química and Centro de Química de Évora, Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal.

[email protected]

Presently, catalytic asymmetric synthesis (CAS) is finding considerable application in

providing important optically pure compounds. Asymmetric allylic alkylation (AAA) reactions [1] are powerful approaches to introduce C-C/C-X bonds in such compounds. Unfortunately, in most cases expensive ligands are required, making discovery of cheaper alternatives an important endeavour. DIOP 1, so successful in catalytic asymmetric hydrogenation reactions (CAHR), has had only a modest impact in the reaction mentioned above [2]. After the 1,4-dioxane analogue of DIOP 2 was shown to be successful in various CAHRs [3], we became interested in screening 2 in the AAA reaction (Scheme 1). This decision was based on the premise that 2 should afford high enantioselectivities due to the presence of a rigid back-bone.

In this communications we report our preliminary results with this reaction.

OO

OMe

OMe

Ph2P

Ph2P

2

O

O

PPh2

PPh21

Scheme 1

R R1

X

Pd (0), Nuc, base R R1

Nuc

2

[1] B.M. Trost and M. L. Crawley, Chem. Rev. 2003, 103, 2921-2943. [2] B.M. Trost and D.L. van Vranken, Chem. Rev. 1996, 96, 395-422. [3] W. Li, J.P. Waldkirch and X. Zhang, J. Org. Chem. 2002, 67, 7618-23. Acknowledgments: We are grateful for financial support from the FCT (project; POCI/QUI/55779/2004) through POCI 2010, supported by the European community fund, FEDER.

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SYNTHESIS OF CHIRAL β-AMINO ESTERS

A.L. Cardoso, a T. M.V.D. Pinho e Melo, a F. Palacios,b A.M. Beja, c M.R. Silva, c J.A. Paixãoc

a Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal

bDepartamento de Química Orgánica I, Facultad de Farmacia, Universidad del País Vasco, Apartado 450, 01080 Vitoria, Spain

c Department of Physics, University of Coimbra, 3004-516 Coimbra, Portugal E-mail: [email protected]

β-Amino acids are an important class of compounds due to their unique biological

properties, their occurrence in natural products and their use as precursors of biologically and medicinally important molecules.1 Therefore, the development of new synthetic methodologies for the asymmetric synthesis of β-amino acids is an important goal in organic synthesis.

In a previous communication we reported a highly selective two step approach to chiral β-amino esters via the reductive amination of 2,3-allenoates bearing a chiral auxiliary in the ester moiety.2 The nature of the chiral auxiliary determines the chirality of the β-amino esters: (1R)-(-)-10-phenylsulfonylisobornyl gives β-amino esters with S configuration whereas the (1S)-(+)-10-phenylsulfonylisobornyl leads to β-amino esters with R configuration.

The work was now extended to the synthesis of new chiral β-amino esters via reaction of chiral allenes 1 and 2 with α-amino esters (methyl esters of L-alanine, L-phenylalanine, L-leucine, L-tryptophan and L-proline) followed by reduction. The stereochemistry of 5a was confirmed by X-ray crystallography. Details of this study will be disclosed.

5a, 6a 5b, 6b 5c, 6c 5d, 6d 5e, 6e

R1 = CO2MeMe

CO2Me

Ph

CO2Me

i-Pr

CO2Me

NH

N CO2Me

[1] Enantioselective Synthesis of β-Amino Acids, Ed. E. Juaristi and V.A. Soloshonok. Willey, New York, 2005. [2] New Approach to Either Enantiomer of β-Amino Acid Derivatives, Pinho e Melo, T. M. V. D.; Cardoso, A.L.; Palacios, F., communication presented at the 4th SPJ Organic Chemistry Symposium, 2006, Santiago de Compostela, Spain. Acknowledgements: Thanks are due to Chymiotechnon, FCT (POCI/QUI/55584/2004) and FEDER for financial support.

OC13

SO2Ph

O•

O

MeOH

R1NH2

SO2Ph

O

ONHR1 SO2Ph

O

O

HNNaBH4(OAc)3

1 3 5

R1

SO2Ph

O

O

•MeOH

R1NH2

SO2Ph

O

O HNR1

NaBH4(OAc)3

SO2Ph

O

O

HN

R1

2 4 6

7


DONOR-ACCEPTOR SUBSTITUTED ππππ-CONJUGATED HETEROCYCLIC SYSTEMS: SYNTHESIS AND CHARACTERIZATION

M. Manuela M. Raposo

Department of Chemistry, University of Minho, Gualtar, 4710-05 Braga, Portugal E-mail: [email protected]

Donor-acceptor substituted π-conjugated heterocyclic systems find extended applications in several important research and technological fields, including organic conductors, solvatochromic and fluorescence probes, sensors with analytical, environmental and medicinal applications, organic electroluminescent and nonlinear optical (NLO) materials. The synthesis of different types of push-pull heterocycles constituted by oligothiophene, arylthiophene and thienylpyrrole as π-conjugated spacers, functionalized with several donor and acceptor moieties will be presented. Using different methods of synthesis (combination of Friedel-Crafts and Lawesson reactions, palladium catalyzed cross-couplings, electrophilic substitutions, metalation followed by reaction with electrophiles, Knoevenagel condensations, cyclocondensation reactions, etc.) it was possible to synthesize and functionalize oligothiophenes [1-2], thienylpyrroles [3-5] and benzothiazoles [6-7]. More recent results regarding the synthesis of thienylpyrrolyl-benzothiazoles [8] and benzimidazole derivatives will be also discussed. Studies to evaluate the potential applications of some of these compounds as nonlinear optical chromophores, solvatochromic probes and organic light emitting diodes (OLEDs) will be also described [5-8].

ππππ-Spacer AD

π-SpacerDS

N

Sn = 2-4

S

NR

Sπ-Spacer, ,

R = alkyl, arylD = H, OH, OR, N,N-(alkyl)2A = CN, CHO, NO2, azo-Ph -CH=C(CN)2, -C(CN)=C(CN)2

π-SpacerDNH

N

A

SD A

n = 2-4

S

N

R

A

S

N

R

A

References [1] M.M.M. Raposo, G. Kirsch, Tetrahedron, 2003, 59(26), 4891-4899. [2] M.M.M. Raposo, A.M.C. Fonseca, G. Kirsch, Tetrahedron, 2004, 60(18), 4071-4078. [3] M.M.M. Raposo, A.M.B.A. Sampaio, G. Kirsch, Synthesis, 2005, 2, 199-210. [4] M.M.M. Raposo, A.M.R.C. Sousa, A.M.C. Fonseca, G. Kirsch, Tetrahedron, 2006, 62(15), 3493-3501. [5] M.M.M. Raposo, A.M.R.C. Sousa, G. Kirsch, P. Cardoso, M. Belsey, E. de Matos Gomes, A.M.C. Fonseca, Org. Lett., 2006, 8(17), 3681-3684, and references cited. [6] R.M.F. Batista, S.P.G. Costa, M.M.M. Raposo, Tetrahedron Lett., 2004, 45(13), 2825-2828. [7] S.P.G. Costa, R.M.F. Batista, P. Cardoso, M. Belsey, M.M.M. Raposo, Eur. J. Org. Chem., 2006, 17, 3938-3946. [8] R.M.F. Batista, S.P.G. Costa, M. Belsey, M.M.M. Raposo, Tetrahedron, 2007, 62(15), 3493-3501.

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Study of the photochromic equilibrium in spirooxazines by NMR

Paulo J. Coelho

Centro de Química - Vila Real, Universidade de Trás-os-Montes e Alto Douro, 5001-911 Vila Real, Portugal.

[email protected]

Among photochromic compounds, spirooxazines constitute one of the most studied families. These uncoloured compounds are of interest due to their ability to give intense photocolouration, fast thermal relaxation and good fatigue resistance. Absorption of UV light causes the cleavage of the spiro carbon-oxygen bond, leading after rearrangement to coloured quasi-planar conjugated forms (photomerocyanines) that revert to the initial uncoloured state in the dark. The electronic conjugation appears to play an important role in the stabilisation of the photomerocyanine, giving rise to permanent open forms or to thermal equilibrium between closed and open forms [1,2]. In the course of developing novel permanent photomerocyanines, we have investigated the effect of introducing an hydroxyl group in position 5’ of the 1,3,3-trimethylspiro[indoline-2,3’-[3H]naphtho[1,2-b] [1,4]oxazine], to induce stabilization by intramolecular hydrogen-bonding with the C=O of the coloured open form [3].

N

OH OH

+ N O

N

HO

CH3OH

Reflux

ON

Heating a methanolic yellow solution of 1,8-dihydroxy-2-nitrosonaphthalene and 1,3,3-trimethyl-2-methyleneindoline under reflux for one hour, yielded a deeply coloured blue solution. 1 and 2D NMR spectra of the blue product in CDCl3 at 295K revealed the presence of two structures, identified as the closed spirooxazine (~25%) and one open isomer (~75%) of the photomerocyanine in equilibrium.

N O

N

HO

N

N

O

OH

Blue

At 243 K, five different structures are distinguished: the closed spirooxazine and four transoid coloured open forms TTC, CTC, TTT and CTT.

[1] P. Laréginie, V. Lokshin, A. Samat, R, Guglielmetti, G. Pèpe, J. Chem. Soc., Perkin

Trans. 2, 1996, 107–111. [2] J-L. Pozzo, A. Samat, R. Guglielmetti, D. De Keukeleire, J. Chem. Soc., Perkin

Trans. 2, 1993, 1327–1332. [3] J. Berthet, S. Delbaere, L.M. Carvalho, G. Vermeersch, P.J. Coelho; Tetrahedron

Letters, 47(28), 2006, 4903-4905.

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HALOGEN ATOM EFFECT ON PHOTOPHYSICAL AND PHOTODYNAMIC CHARACTERISTICS OF DERIVATIVES OF m-THPP

Arménio C. Serraa, Marta Pineiroa, António M. d’A. Rocha Gonsalvesa, Ana Margarida

Abrantesb, Mafalda Laranjob, Ana Cristina Santosb and M. Filomena Botelhob a Chymiotechnon, Departamento de Química, Universidade de Coimbra, 3049-535,

Coimbra, Portugal. b Instituto de Biofísica/Biomatemática, IBILI, Faculdade de Medicina de Coimbra,

3000-354 Coimbra, Portugal. E-mail: armé[email protected]

The use of porphyrins as photosensitizers in photodynamic therapy for clinical uses is well known. Two porphyrin derivatives, Photofrin and Foscan, are approved for the treatment of a variety of cancers[1]. Photofrin is a purified form of hematoporphyrin derivatives consisting of a mixture of porphyrins. This has encouraged an active search for novel (“second generation”) photosensitizers with improved properties over the last 20 years. At the present time, Foscan, 5,10,15,20-tetrakis(3-hydroxyphenyl)chlorin is one of the second-generation photosensitizers approved for cancer treatment. Instead of Photofrin, the well defined structure of Foscan allows the study of the relationship between modifications on the structure and the photodynamic activity.

Using the structure of 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (m-THPP) as a basic model, we synthesised several derivatives[2] strategically modified in order to improve the photophysical properties more directly related to photodynamic activity, namely, the inclusion of halogen atoms[3].

The different synthetic methodologies followed in order to obtain the compounds with the required structures, photophysical properties, amphiphilic characteristics, and the in vitro studies of the photodynamic activity of these compounds against WiDr human colon adenocarcinoma cells and melanoma A375 cells will be presented.

Acknowledgments: The authors thank Chymiotechnon, Ministério da Economia/ POE/Prime/Proj 03/293/CLARO, Faculdade de Medicina de Coimbra and CIMAGO for financial support and Serviço de Gastroenterologia dos HUC for equipment facilities. [1] Bonnett R. Chemical Aspects of Photodynamic Therapy; Gordon and Breach Science Publishers: Amsterdam, 2000; Vol. 1 [2] Rocha Gonsalves AMdA, Pineiro M and Serra AC. "Tetrapirrolic macrocycles as Photodynamic Agents"; Patent WO 03/064427, 2003. [3] Azenha EG, Serra AC, Pineiro M, Pereira MM, Seixas de Melo SJ, Arnaut LG, Formosinho SJ and Rocha Gonsalves AMdA. Chem. Phys. 2002; 280: 177-190.

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FATTY ACID DITERPENOL ESTERS FROM LEAVES OF JUNIPERUS BREVIFOLIA

Ana M. L. Seca§, Artur M. S. Silva§§

§Department of Technologic Sciences and Development, University of Azores, Rua Mãe de Deus, 9501-801 Ponta Delgada, Azores; §§Department of Chemistry, University of

Aveiro, Campus de Santiago, 3810-193 Aveiro E-mail: [email protected]

In the study on the chemical characterization of endemic plants of the Azores archipelago, we have examined Juniperus brevifolia. We become interested to analyze this plant due to the wide range of biological activity reported from other species of this genus and of their constituents [1]. Previous studies on this plant described the components of its essential oil [2-3], and of the hexane extract [4]. We report herein on the isolation and structural elucidation of seven new natural diterpenes (1-7) from the dichloromethane extract of leaves of J. brevifolia. Three of these new compounds, four abietanes (1-3,7) and three pimaranes (4-6), are esters of the long-chain fatty hexadecanoic acid and two esters of formic acid. Compounds 1, 2 and 5 represent the first examples of diterpenes possessing at C-18 an esterified fatty acid. Studies on the isolated new compounds showed those possessing a diterpenol ester of a long-chain fatty acid present lipophilicity very distinct from other diterpenoid compounds. All the structures were established by spectroscopic methods, including mass spectrometry and NMR spectroscopy (by using several 1D and 2D techniques-1H, 13C, DEPT, COSY, HSQC, HMBC, NOESY).

R1

R2

R4

R3

1 R1= CH2OCO(CH2)14CH3; R2=R3=R4= H

2 R1= CH2OCO(CH2)14CH3; R2= H; R3,R4= =O

3 R1= CH3; R2= OH; R3,R4= =O

7 R1= CH2OCHO; R2=R3=R4= H

H

R1R2

R3

4 R1= CH2OCHO; R2=R3= H

5 R1= CH2OCO(CH2)14CH3; R2=R3= H

6 R1= CH2OH; R2,R3= =O

H

H

[1] Seca, A.M.L.; Silva, A.M.S. In Recent Progress in Medicinal Plants, J.N. Govil and V.K. Singh (Ed.), Studium Press, LLC USA, 2006 Vol 16, pp. 401-522. [2] Adams, R.P. Biochem. Sys. Ecol. 1999, 27, 709-725. [3] Da Silva, J.A.; Pedro, L.G.; Santos, P.A.G.; Figueiredo, A.C.; Barroso, J.G.; Tenreiro, R.P.; Ribeiro, C.A.; Deans, S.G.; Looman, A.; Scheffer, J.J.C. Flavour Fragr. J. 2000, 15, 31-39. [4] Seca, A.M.L.; Silva, A.M.S. Nat. Prod. Res. (in press). Acknowledgments: Thanks are due to the University of Aveiro, FCT-Lisbon and FEDER for funding the Research Unit “Química Orgânica, Produtos Naturais e Agroalimentares” and to Fundação Calouste Gulbenkian.

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ORGLIST Symposium

7


ORGLIST Symposium - Lectures

OL1- COMPUTACIONAL MODELS TO AID SAFETY-DIRECTED DRUG

DESIGN Scott Boyer, Ph.D.

OL2- DERIVING STRUCTURE-ACTIVITY RELATIONSHIPS IN

HETEROGENEOUS DATASETS Valerie J. Gillet

OL3- TWO-PARAMETER CLASSIFIER FOR PREDICTION OF PKC-ζ

MODULATING BEHAVIOUR OF XANTHONES Bruce F. Milne, Madalena M.M. Pinto

OL4- REGIOSELECTIVITY OF THE CATECHOL-O-METHYLTRANSFERASE

CATALYZED REACTION: COMBINED THEORETICAL AND

EXPERIMENTAL STUDIES Nuno Palma, Maria L. Rodrigues, Margarida Archer, Maria J. Bonifácio, Ana I. Loureiro, David A. Learmonth, Maria A. Carrondo, Patricio Soares-da-Silva

OL5- FROM MESTREC TO MNOVA: A REVOLUTIONARY APPROACH TO NM

Nikolay Larin, Stan Sykora, Santiago Domínguez, Carlos Cobas

7


COMPUTATIONAL MODELS TO AID SAFETY-DIRECTED DRUG DESIGN

Scott Boyer, Ph.D.

Senior Principal Scientist and Head, Computational Toxicology Global Safety Assessment, AstraZeneca R&D, Mölndal, Sweden

Access to metabolism and toxicology data is critical to effective decision making in early drug discovery projects. Often in such projects little is known about the therapeutic target and usually even less is known about potential metabolism or adverse effects of the chemical series being investigated. Simply providing unstructured metabolism- and safety-related information on targets and chemical series to project teams trying to make decisions is not adequate due to the varied nature and quality of metabolism and toxicology data. This presentation gives examples of how relevant data can be structured, mined and in some cases modelled to enhance decision-making. Project examples will be presented of QSAR models and their interpretation, including characterization of the underlying assay error for better interpretation of the model results, development of SAR systems that support decision-making and enhance awareness around such endpoints as metabolism/P450 activation, mutagenesis, hERG and reactive intermediates. In general, metabolism and toxicology data should be structured depending on, 1) its intended use, 2) its overall quality and 3) its internal data structure (text vs. numerical) to assure its optimum use. Brief examples of the varying data types and their usage in project decision making will be presented along with some strategies for hypothesis generation around adverse events using a combined approach of molecular modelling/virtual screening and text mining. Together, these tools, built to be appropriate to the various data types, represent a basic toolkit for the toxicologist and drug metabolism scientist needing to make meaningful contributions to the myriad decisions made in early drug discovery projects.

OL1

7


DERIVING STRUCTURE-ACTIVITY RELATIONSHIPS IN HETEROGENEOUS DATASETS

Valerie J. Gillet

Department of Information Studies, University of Sheffield, 211 Portobello St., Regent Court, Sheffield, United Kingdom


Machine learning algorithms such as Binary Kernel Discrimination and Support Vector Machines have become popular methods for the analysis of high-throughput screening data. While they have been shown to be effective ways of deriving predictive models they suffer from the disadvantage that the models are not easily interpretable. Here we describe a new method based on genetic programming. A training set of active and inactive molecules are represented as reduced graphs and genetic programming is used to evolve reduced graph queries (subgraphs) that are best able to separate the actives from the inactives. The classification rate is determined using the F-measure which combines recall and precision into a single objective. The resulting queries are validated on datasets not used in deriving the queries, for proof of their predictive power. As well as being useful models for prediction, the queries contain interpretable structure-activity information encoded within the reduced graph nodes. Results are presented for the well known MDDR dataset and also for GSK in-house screening data.

OL2

7


TWO-PARAMETER CLASSIFIER FOR PREDICTION OF PKC-ζ MODULATING BEHAVIOUR OF XANTHONES

Bruce F. Milne §, Madalena M.M. Pinto §

§ Centro de Estudos de Química Orgânica, Fitoquímica e Farmacologia da Universidade do Porto; Laboratório de Química Orgânica, Faculdade de Farmácia da

Universidade do Porto, Rua Aníbal Cunha 164, 4050-047 Porto E-mail: [email protected]

Protein kinase C ζ (PKC-ζ) occurs in many tissues in the body and is associated with numerous cellular processes including differentiation, mitogenesis, migration and apoptosis. PKC-ζ is implicated in the progression of a variety of disease states including colon cancer, inflammatory bowel conditions, leukaemia, melanoma and T-cell mediated hepatitis. Studies in our research group [1, 2] have identified a number of simple xanthone derivatives displaying varying levels and types of PKC- ζ modulating activity. Although structurally very similar, this group of compounds includes both potent activators and inhibitors of PKC-ζ and therefore it is desirable to have a method with which to attempt to predict which region of the activity spectrum new derivatives might fall into.

In an attempt to rationalize the behaviour of these compounds a computational QSAR study was undertaken and a two-parameter decision tree developed that successfully classifies all of the xanthones previously tested as either activators, inhibitors or inactive. In addition, a small selection of non-xanthone PKC-ζ inhibitors have been appended to this study and these are also correctly classified by the decision tree developed for the xanthones.

[1] Saraiva, L.; Fresco, P.; Pinto, E.; Sousa, E.; Pinto, M.; Gonçalves, J., Bioorganic and Medicinal Chemistry, 2002, 10, 3219-3227. [2] Saraiva, L.; Fresco, P.; Pinto, E.; Sousa, E.; Pinto, M.; Gonçalves, J., Bioorganic and Medicinal Chemistry, 2003, 11, (7), 1215-1225. Acknowledgments: FCT (I&D 226/94), FEDER and POCI for financial support. BFM is funded by FCT post-doctoral research fellowship SFRH/BPD/17830/2004.

OL3

7


REGIOSELECTIVITY OF THE CATECHOL-O-METHYLTRANSFERASE CATALYZED REACTION:

COMBINED THEORETICAL AND EXPERIMENTAL STUDIES

Nuno Palma§, Maria L. Rodrigues†, Margarida Archer†, Maria J. Bonifácio§, Ana I. Loureiro§, David A. Learmonth§, Maria A. Carrondo†, Patricio Soares-da-Silva§

§ Department of Research & Development, BIAL, Portugal

† Instituto de Tecnologia Química e Biológica (ITQB), Portugal

[email protected]

This work presents combined theoretical and experimental studies [1,2] of the regioselectivity of O-methylation of nitrocatechol-type inhibitors of the enzyme Catechol-O-methyltransferase (COMT).

As a case study, two simple regioisomeric nitrocatechol-type inhibitors of COMT, containing a benzoyl substituent attached at the meta- or at the ortho-position, respectively, relative to the nitro group, were studied with regards to their interaction with the catalytic site of the enzyme and the in vitro regioselective formation of their mono-O-methyl ether metabolites. It is shown that the particular substitution pattern of the classical nitrocatechol pharmacophore has a profound impact on the regioselectivity of O-methylation.

In order to provide a plausible interpretation of these results, a comprehensive analysis of the protein-inhibitor interactions and of the relative chemical susceptibility to O-methylation of the catechol hydroxyl groups was performed by means of docking simulations and molecular orbital calculations. The major structural and chemical factors that determine the enzyme regioselectivity of O-methylation are identified and the X-ray structure of the complex of COMT with one of the two inhibitors (BIA 8-176) is disclosed. This is the first reported structure of COMT complexed with a nitrocatecholic inhibitor having a bulky substituent group in ortho position to the nitro group. Structural and dynamic aspects of this complex are analyzed and discussed, in the context of the present study. [1] Palma, P. N., Bonifacio, M. J., Loureiro, A. I., Wright, L. C., Learmonth, D. A.,

and Soares-Da-Silva, P. Drug Metab Dispos 2003, 31, 250-8. [2] Palma, P. N., Rodrigues, M. L., Archer, M., Bonifacio, M. J., Loureiro, A. I.,

Learmonth, D. A., Carrondo, M. A., and Soares-da-Silva, P. Mol Pharmacol 2006, 70, 143-53.

This work was partly funded by Fundação para a Ciência e Technologia/AdI trough research projects POCTI/COMT-HUM/2002 and POCTI/BME/38306/2001 and grant SFRH/BD/5228/2001 (M.L.R)

OL4

7


From MestReC to Mnova: A revolutionary approach to NMR

Nikolay Larin, Stan Sykora, Santiago Domínguez, Carlos Cobas MESTRELAB RESEARCH, Santiago de Compostela, Spain

High Resolution NMR spectroscopy is undoubtedly one of the most important methods used in organic chemistry for structure determination. Traditionally, organic chemists used to spend considerable time processing their NMR data to get the best experimental NMR as starting material for the lengthy and non trivial task of spectral analysis. Furthermore, recent years have witnessed dramatic improvements in high-throughput NMR in such a way that spectral processing and analysis have emerged as a new bottle neck due to the large amount of spectral data available. In this work we present Mnova, the new incarnation of MestReC as a novel software solution offering an innovative paradigm for the unattended NMR data processing and new tools such as spectral prediction, simulation and fitting algorithms to facilitate structure verification and elucidation for organic chemists.

OL5

7


Poster Communications

7


A NEW ADDUCT FROM THE REACTION BETWEEN OXIDASED EPINEFRINE AND GLUTATHIONE

José C. C. Santana§, Carla Macedo§, Ana M. Diniz§, Luísa M. Ferreira§, Paula S.

Branco§ § REQUIMTE/CQFB, Departamento de Química, FCT, Universidade Nova de Lisboa,

2829-516 Caparica, Portugal [email protected]

Cardiovascular diseases are associated to high values of mortality and morbidity all over the world. The coronary dysfunctions are prominent and related to ischemic and reperfusion phenomenon (I/R) in the heart, leading to the release of large amounts of biogenic catecholamines, namely adrenaline (1), and to a sustained generation of reactive species of oxygen (ROS).1 Adrenaline is a redox reactive molecule. It’s oxidation leads to the formation of ROS and reactive products, as semi- quinones, quinones and aminochromes. The quinones in the presence of a nucleophile (secondary amines or thiols) react by a 1,4-Michael addition reaction.2 The resulting compounds (amines and thio substituted catechols) are more easily oxidized than the parent starting molecule by virtue of the presence of an extra electron-donating group.3 Herein we report for the first time the formation of compound 2 resulting from intramolecular conjugated addition of the glutathione glycine residue to the adrenaline backbone, after a second catechol oxidation. The structure was completely elucidated by FD-MS and bidimentional NMR.

HO

HO

HN

OH

1) Tyrosinase

2) GSH

-H2O

HO

O

NH

S

NH

H2N

HN

O

O

O

OH

O

OH

HO

HO

NH

OH

S

NH

H2N

HN

O

O

O

OH

O

OH

S NH

O

NHO

O

HN

O

NH2

HOOC

HO

HO

1

2 [1] Lameris, T. W., Zeeuw, S., Alberts, G., Boomsma, F., Duncker, D. J., Verdouw, P. D., Man in 't Veld, A. J. and van den Meiracker, A. H., Circulation 101, 2000, 2645-2650. [2] Shen, X. M. and Dryhurst, G., Bioorganic Chem., 1997, 25, 130-153. [3] C. Macedo, P.S. Branco, L.M. Ferreira, A.M. Lobo, J. Capela, E. Fernandes, M.L Bastos., F. Carvalho, J. Health Sci., 53(1), 31-42, (2007).

PC1

7


A NEW APROACH TO THE SYNTHESIS OF BENZOACRIDONE DERIVATIVES

Raquel S.G.R. Seixas, Artur M.S. Silva, Diana C.G.A. Pinto and José A.S. Cavaleiro

Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal E-mail: [email protected]

Acridone derivatives are a group of nitrogen heterocyclic compounds possessing important biological activities. They are known to present important citotoxic, antiviral and anti-malarial activities and also to inhibit Epstein-Barr virus activation [1,2]. It is also worthy to mention other important potential applications of acridones, the potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) replication in chronically HIV-1-infected cells [3] and also their use as labels for fluorescence detection of target materials [4]. Taking into account the potential applications of acridones, we started a programme to prepare new derivatives and to develop new synthetic methods for their synthesis. One of the explored synthetic routes considered the Diels-Alder of 3-formyl-1-methyl-4-quinolones 2 with ortho-benzoquinodimethane [5]. Since our results were not satisfactory, we decided to use other N-protecting group. In this communication, we will describe the synthesis and reactivity of 1-ethoxycarbonyl-3-formyl-4-quinolone 3 as dienophile in a Diels-Alder reaction with ortho-benzoquinodimethane, generated in situ from the corresponding sulfone. New tetrahydrobenzoacridones derivatives 4 and 5 have been obtained in good overall yield (56%) (Scheme 1). The experimental procedures and the structural characterisation of all synthesised compounds will be presented and discussed in this communication.

HN

O

CHO

N

O

CHO

R

N

O

COOEt

H

HN

O

COOEtH

H

1 2 R = Me3 R = CO2Et

4 5

SO2

Scheme 1

[1] S. Kawaii, Y. Tomono, E. Katase, K. Ogawa, M. Yano, Y. Takemura, M. Ju-Ichi,

C. Ito and H. Furukawa, Leukemia Res., 1999, 23, 263-269. [2] M. Itoigawa, C. Ito, T.-S. Wu, F. Enjo, H. Tokuda, H. Nishino, H. Furukawa,

Cancer Lett., 2003, 193, 133-138. [3] M. Fujiwara, M. Okamoto, M. Okamoto, M. Watanabe, H. Machida, S. Shigeta,

K. Konno, T. Yokota, M. Baba, Antiviral Res., 1999, 43, 179-189. [4] J. A. Smith, R. M. West, International Patent, 2002, PCT/GB2002/002509 (WO

02/099424 A2). Acknowledgements: Thanks are due to the University of Aveiro, FEDER and FCT for funding the project POCI/QUI/58835/2004 and for a PhD (SFRH/BD/30734/2006) grant.

PC2

7


A NEW APPROACH TO THE SYNTHESIS OF [4,4’]-BI-1H-

IMIDAZOL-2-ONES

Magdi E.A. Zaki§ and Fernanda J.R.P. Proença § Universidade do Minho, Departamento de Química, 4700-320 Braga, Portugal

[email protected]

The chemistry of imidazole compounds has been of much interest due to the presence of

these heterocycles in a large variety of biologically important molecules. For example,

some imidazole derivatives have shown interesting antifungal and antitumour

properties. Also, the antimicrobial activities of a series of 4-diazoimidazole-5-

carboxamides bearing lipophilic substituents have been evaluated recently and these

compounds have been found to possess antifungal activity. The present work describes

the reaction of urea 1 with orthesters which occurred in acetonitrile and in the presence

of a catalytic amount of sulfuric acid affording the corresponding imidates 2.

X-C(OC2H5)3

CH3CN-H2SO4

HN CN

CNN

ONH

X

C2H5O

CH2Ph

CH3CN

DBU N

HN

O

NH

N

CNX

OC2H5

CH2Ph

HN CN

CNH2N

ONH

CH2Ph N

NO

NH

CH2Ph

N

N

RH2N

XX=H,CH3, C2H5

1

4

2a, X= H b, X= CH3

c, X= C2H5

3a, X= H b, X= CH3

c, X= C2H5

EtOH, RT

NH2R

NH2R, EtOH, RT

This compound cyclized in acetonitrile, in the presence of DBU, to generate the

substituted imidazole-2-one 3. Compounds 2 and 3 were reacted with different primary

aliphatic amines affording bi-imidazoles 4 under mild experimental conditions. This

method allows the regioselective synthesis of acyclonucleoside analogues incorporating

an imidazolone substitutent. All compounds were fully characterized by elemental

analysis and spectroscopic data and the mechanism of these reactions will be discussed.

Acknowledgments: Thanks are due to Universidade do Minho and Fundação para a Ciência e Tecnologia (POCTI/QUI/45391/2002) for financial support and for a post-doc grant awarded to Dr. Magdi Zaki (SFRH/BPD/27029/2006).

PC3

7


ACTIVITY OF ββββ-SUBSTITUTED PORPHYRINS WITH PROPIONATE GROUPS IN PHOTODYNAMIC THERAPHY

Nelson A. M. Pereiraa, A. C. Serraa, M. Pineiro,a A. M. d’A. Rocha Gonçalvesa, M.

Abrantes,b M. Laranjo,b A. C. Santosb and M. F. Botelhob

aChymiotechnon, Departamento de Química, Universidade de Coimbra, 3049-535, Coimbra, Portugal.

b Instituto de Biofísica/Biomatemática, IBILI, Faculdade de Medicina de Coimbra, 3000-354 Coimbra, Portugal. [email protected]

Photodymanic therapy (PDT) is a mode of treatment oncological and other clinical

conditions based in the light activation of a molecule inside the cell for producing harmful amounts of singlet oxygen. One of the few drugs currently used in PDT is Photofrin® which is structurally a complex mixture of oligomers derived from hematoporphyrin (1). Another drug commercially available, 5-Aminolevulinic acid (ALA) which is the precursor of the sensitizer protoporphyrin IX (2) produced endogenously by the cells.

N

NH N

HN

COOHCOOH

(2)

N

NH N

HN

COOHCOOH

(1)

OH

OH

Protoporphyrin IX and hematoporphyrin shows very similar structures with two

propionate chains in the β-positions of the macrocycle. This structural resemblance is likely an important structural characteristic for interaction with the cells worth to be included in mimetic structures.

In this work we prepared porphyrins derivatives with different number of propionate chains in the β-positions of the macrocycle (3-5) and bromo-substituted phenyl groups in the meso positions. Their anti-tumoral activities against colorectal cancer cell line (WiDr) were determined and compared with Photofrin®.

N

NH N

HN

COOH

(3)

COOH

BrBr

N

NH N

HN

COOH

Br

(4)

N

NH N

HN

COOH

Br

(5)

COOH

COOH

COOH COOH

[1] Osterioh, J.; Vicente, M. G. H. J. Porphyrins Phthalocyanines, 2002, 6, 305-324. Acknowledgments: The authors thank to Chymiotechnon, Ministério da Economia/ POE/Prime/Proj 3/293/CLARO, Faculdade de Medicina de Coimbra and CIMAGO for financial support and Serviço de Gastroenterologia dos HUC for equipment facilities.

PC4

7


AN EFFICIENT SYNTHETIC APPROACH TO A NOVEL CYCLIZED 4-(PORPHYRINYLAMINO)PHTHALONITRILE

Ana R.M. Soares,a João P. C. Tomé,a Maria G.P.M.S. Neves,a Augusto C. Tomé,a José

A.S. Cavaleiroa and Tomás Torresb aUniversidade de Aveiro, Departamento de Química, Campus de Santiago, 3810-391

Aveiro, Portugal bUniversidad Autónoma de Madrid, Departamento de Química Orgánica, 28049

Madrid, Spain [email protected]

Porphyrins have a wide range of applications in distinct fields, such as medicine, catalysis and materials for advanced technologies [1]. Several studies have been focused on the functionalization of easily accessible meso-tetraarylporphyrins in order to modulate the properties of the porphyrin macrocycle [2]. Recently, our group developed a new methodology to synthesize 4-(porphyrinylamino)phthalonitriles, which are precursors to porphyrin-phthalocyanine dyads [3].

This communication describes an efficient synthetic approach to the novel cyclized 4-(porphyrinylamino)phthalonitrile 2, that involves reflux of 4-(5,10,15,20-tetraphenylporphyrin-2-ylamino)phthalonitrile 1 in nitrobenzene. The synthetic procedure and the structural characterization of the novel compound will be discussed.

N

NH N

HN

N

N

NH N

HN

NH

Nitrobenzene

Reflux

CN

CN

CN

CN

1 2

[1] K. M. Kadish, K. M. Smith, R. Guilard (Eds.) in The Porphyrin Handbook -Applications: Past, Present and Future, Academic Press, New York, 2000, vol. 6. [2] K. M. Kadish, K. M. Smith, R. Guilard (Eds.) in The Porphyrin Handbook –Functionalization of 5,10,15,20-Tetra-Substituted Porphyrins, Academic Press, New York, 2000, chapter 5, vol.1. [3] A.R.M. Soares, M.V. Martínez-Díaz, A. Bruckner, A.M.V.M. Pereira, J.P.C. Tomé, C.M.A. Alonso, M.A.F. Faustino, M.G.P.M.S. Neves, A.C. Tomé, A.M.S. Silva, J.A.S. Cavaleiro, T. Torres, D.M. Guldi, Organic Letters, 2007, 9(8), 1557-1560. Acknowledgments: The authors are grateful to Fundação para a Ciência e a Tecnologia (FCT, Portugal) and to FEDER for funding this work. Ana R.M. Soares is grateful to FCT for a doctoral grant (SFRH/BD/29362/2006).

PC5

7


APPLICATION OF AMIDE BOND ACIDOLYSIS AT THE C-TERMINUS OF α,αα,αα,αα,α-DIALKYL GLYCINES TO THE FORMATION OF A NEW AMIDE BOND

Ana Maria F. Silva, Sílvia M.M.A. Pereira-Lima and Hernâni L.S. Maia§

§ Department of Chemistry, School of Sciences, University of Minho, Gualtar, 4710-057 Braga, Portugal

[email protected]

In the past years, we have been involved in a study of the application of Ugi’s reaction to the synthesis of several α,α-dialkylglycines. Using 4-methoxybenzylamine (Pmb-NH2) as the amine component, we were able to remove the N-alkyl group by TFA cleavage and, during this process, the C-terminal amide bond of the resulting Ugi adducts (1) was cleaved by a mechanism involving an oxazolinium-type intermediate (2). [1] This intermediate allows in situ functionalization of the C-terminus by reaction with nucleophiles (HO-, MeO-), thus affording different derivatives such as free acids and esters.[2]

Our previous results suggested that an amide or dipeptide could be obtained if an amine or amino acid ester was used as the nucleophile. Nevertheless, preliminary results indicated that although a small amount of the required dipeptide is formed (3), 5,5-dialkyl-imidazolin-4-ones (4) are also obtained. These results from competitive attack at the less hindered C-2 of the oxazolinium intermediate, followed by rearrangement.[3]

We now present new results in the optimization of the reaction conditions in order to maximise amide bond formation.

H3C N

HN

C6H11

O

Pmb

R R

O

H3C NH

HN

R'

O R R

O

N

N

R

R

CH3

OR'

3

41

R = Et, Pr, iBu, BnNH2-R' = benzylamine or Phe-OtBu

N

O

R

R

CH3

O

2H

TFA+

NH2-R'

[1] Costa, S.P.G.; Pereira-Lima, S.M.M.A.; Maia, H.L.S. Org. Biomol. Chem., 2003, 1, 1475-

147. Jiang, W.-Q.; Costa, S.P.G.; Maia, H.L.S. Org. Biomol. Chem., 2003, 1, 3804-3810. [2] Costa, S.P.G., Maia, H.L.S., Pereira-Lima, S.M.M.A. in Benedetti, E. and Pedone, C. (Eds.),

Peptides 2002, Proceedings of the 27th European Peptide Symposium, Edizioni Ziino, 2002, Naples, p. 250-251.

[3] Costa, S.P.G., Maia, H.L.S., Pereira-Lima, S.M.M.A. in M. Chorev and T. Sawyer (Eds.), Peptide Revolution: Genomics, Proteomics & Therapeutics, Proceedings of the 18th American Peptide Symposium, American Peptide Society/Kluver, USA, 2004, p. 85-86.

PC6

7


AZA-DIELS-ALDER APPROACH TO THE SYNTHESIS OF PIPERIDINE AZASUGARS

Alves M.J.a), Costa C.a), Costa F. T.b)

a) Departamento de Química da Universidade do Minho, Campus de Gualtar, 4710-057 Braga

b) Faculdade de Ciências da Universidade Fernando Pessoa, R. Carlos da Maia, 298, 4200-150 Porto

[email protected]

In 1966, Inouye et al.1 discovered the first natural polyhydroxylated alkaloid, nojirimycin (NJ). Isolated from a Steptomyces filtrate, it was shown to actively inhibit α- and β-glucosidase and was therefore the first glucose mimic. Since then there has been a growing interest towards the synthesis of azasugars analogues. We wish to report a versatile strategy for the synthesis of piperidine azasugars using an aza-Diels-Alder approach. We emphasise that compounds 1a, 1b2, 2a-b are optically pure and obtained in good to moderated yields. All compounds were spectroscopically characterized.

N

R2

H3C

OR*

CO2R1

1a, R1= Bn, R2= CH3

1b2, R1= tBu, R2= H

N

OTBDMS

CO2Bn

1c

N

OTBDMS

CO2BnHO

HO

N

CO2R1

R2

H3COTBDMS

OsO4 LiAlH4

N

OTBDMS

HO

HO

2c 3

OH

NH3F

NH

OH

CO2BnHO

HO

CH2NHPh

OsO4

4

N

OR*

CO2R1

R2

HO

HOH3C

OR*

2a, R1= Bn, R2= CH3

2b, R1= tBu, R2= H

References: [1] – Inouye, S.; Tsuruoka, T.; Niida T., J. Antibiot., 1966, 19, 288 [2] – M. José Alves, I.G. Almeida, A. Gil Fortes, A.P. Freitas, Tetrahedron Letters, 2003, 44, 6561

PC7

7


AZA–MICHAEL REACTIONS WITH VINYL SULPHONES

Marília E.T.F.Silva, Ana P. Esteves, Ana M. F. Oliveira-Campos, Lígia M. Rodrigues, Centro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga,

Portugal Email: [email protected]

In recent years, fluorescent molecules with reactive functional groups have received considerable interest due to their potential applicability in biomolecular systems. Dyes containing substituted ethyl sulphonyl groups which β-eliminate to form the reactive vinyl sulphone species [1], can be important due to their fluorescent properties [2]. Vinyl sulphones became generally accepted as useful intermediates in organic synthesis and serve efficiently as Michael acceptors [3]. The aza-Michael reaction involving the conjugate addition of nitrogen nucleophiles to an α,β-unsaturated carbonyl constitutes an important reaction in organic synthesis. Several compounds were prepared in high yields by direct treatment of a series of primary and secondary amines with vinyl sulphones in presence of Amberlyst-15 (Scheme 1) [4].

R1SO2CHCH2

R2

R3 NH R1SO2CH2CH2+ N

R2

R3

NH2R1=CH2CH3 ,

Scheme 1

The products were purified by flash chromatography and/or recrystallization and characterized by the usual analytical methods (1H and 13C NMR, MS, elemental analysis). Details on the preparation and characterization of the compounds will be presented.

References: [1] D. M. Lewis & S. M. Smith, Dyes and Pigments, 1995, 4, 275-294 [2] A.Sivasubramanian, A. M. F. Oliveira-Campos, L. M. Rodrigues, A. P. Esteves, M. Silva, R. Hrdina, G. M. B. Soares, 4th Transmediterranean Colloquium of Heterocyclic Chemistry, 2006, 77 [3] N. S. Simpkins, Tetrahedron, 1990, 46, 6951-6984 [4] B. Das, N. Chowdhury, Journal of Molecular Catalysis A: Chemical, 2007, 263, 212-215

PC8

7


BACILLAMIDE – A TOOL FOR CONTROL OF ALGAL GROWTH?

Valdemar B. C. Figueira§, Artur J. G. Bento§, Ana M. Lobo§, Sundaresan Prabhakar§, Paulo Pereira†, Sérgio Paulino†, Catarina Churro†, Natália Faria†, Susana Franca†

§ REQUIMTE/CQFB, FCT – UNL, 2829 Monte de Caparica, Portugal † Instituto Nacional de Saúde, Centro de Qualidade Hídrica, Av. Padre Cruz,

1649-016 Lisboa, Portugal E-mail: [email protected]

In recent years there has been reports of harmful algal blooms (HABs) causing large scale red tides and mass mortality of cultured fish and bivalves in many coastal parts of the world[1]. It has been demonstrated that many genera of marine bacteria have algicidal effects and are associated with the termination of HABs in natural coastal environments[2,3]. In 2003 the structure of a novel algicide from a marine bacteria Bacillus sp. SY-1, active against the harmful dinoflagellate Cochlodinium polykrikoides, revealed bacillamide (1) (Figure)[4]. Having synthesised 1 (and several derivatives), from tryptamine (and derivatives thereof) and 2-acetylthiazole-4-carboxylic acid,[5] we disclose here our results with several algal strains. The toxic cyanobacteria Microcystis aeruginosa and Aphanizomenon gracile are relatively more sensitive to bacillamide than the unharmful chlorophytes Ankistrodesmus sp. and Scenedesmus sp. However, other cyanobacteria (Anabaena sp. and Anabaenopsis sp.) presented higher tolerances, similar to the ones presented by different non-toxic algae (Tetrasselmis sp., Nanochloropsis sp. and Pheodactilum sp.). Thus, the use of bacillamide to control the growth of harmful cyanobacteria must take into account the composition of the phytoplankton community in natural environments.

[1] Toxic Cyanobacteria in Water, I. Chorus & J. Bartram (ed.), WHO, E & FN Spon, 1999, chap. 2, p. 15. [2] I. Yoshinaga, T. Kawai, Y. Ishida, Fish. Sci., 1997, 63, 94-98. [3] M. C. Kim, I. Yoshinaga, I. Imai, Mar. Ecol. Prog. Ser., 1998, 170, 25-32. [4] S.-Y. Jeong, K. Ishida, Y. Ito, S. Okada, M. Murakami, Tetrahedron Lett., 2003, 44, 8005-8007. [5] V. B. C. Figueira, S. Prabhakar, A. M. Lobo, Arkivoc, 2005, 14-19. Acknowledgments: We thank Fundação para a Ciência e Tecnologia (FEDER, POCTI) (Lisbon, Portugal) for partial financial support through project POCI/AMB/60351/2004.

PC9

7


BROMOALKYLOXYXANTHONES AS PROMISING ANTITUMOR AGENTS: SYNTHESIS AND BIOLOGICAL ACTIVITY

Ana Paiva§, Emília Sousa§ , Madalena Pinto§, Nair Nazareth¥, Maria S.J.F. Nascimento¥ Centro de Estudos de Química Orgânica, Fitoquímica e Farmacologia da Universidade

do Porto (CEQOFFUP), § Laboratório de Química Orgânica, ¥ Laboratório de Microbiologia, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha,

164, 4050-047 Porto, Portugal E-mail: [email protected]

In a study involving the synthesis of bis-intercalators with a xanthonic scaffold as potential inhibitors of solid-tumour growth, especially CNS cancer [1,2], a symmetric bisxanthone (1, 50%) and a minor product 1-[(6-bromohexyl)oxy]-xanthone (2, 30%) were obtained from 1-hydroxyxanthone (3) and dibromohexane (Scheme 1A). Being the investigation of secondary products a strategy in drug discovery, both derivatives 1 and 2 were evaluated for their effect on the in vitro growth of the human tumor cell lines MCF-7 (breast cancer), NCI-H460 (non small lung cancer), and SF-268 (central nervous system cancer) using the sulforrhodamine B (SRB) method [1]. Although no capacity to inhibit the growth of the human tumor cell lines tested was observed for the symmetric xanthone 1 (GI50>100 µM), compound 2 revealed inhibition of the growth of human tumor cell lines with GI50 values in the range of 22<GI50<30µM, even higher than the parent compound 3.

O

OOH O

O

O

OOO

O

OOBr

Br(CH2)6Br

K2CO

3 , DMF

O

O

OH

OHK2CO3 , DMF

O

O

OH

OBr

Br(CH2)6Br

O

O

O

O

Br

Br

12

3

4 5

6

A)

B)

Scheme 1

(drop-to-drop)

In light of this results we proceed with the bromoalkylation of the hit compound, 3,4-dihydroxyxanthone (4) that revealed a potent inhibitory effect on the human tumor cell lines growth [1]. Two bromohexyloxyxanthones, 3-[(6-bromohexyl)oxy]-4-hydroxyxanthone (5, 50%) and 3,4-bis[(6-bromohexyl)oxy]-xanthone (6, 10%), were obtained (Scheme 1B) and both derivatives will be investigated for their effect on the in vitro growth of human tumor cell lines MCF-7 (ER+, breast cancer), MDA-MB-231 (ER-, breast cancer), NCI-H460 (non small lung cancer), and SF-268 (central nervous system cancer). These results revealed bromoalkyloxyxanthones as interesting scaffolds to look for potential anticancer drugs. [1] Pedro MM, Cerqueira F, Sousa ME, Nascimento MSJ, Pinto MMM. Bioorg. Med. Chem., 2002, 10, 3725-3730. [2] Wang T-C, Zhao Y-L, Liou S-S. Helv. Chim. Acta, 2002, 85, 1382-1389. Acknowledgements: Fundação para a Ciência e Tecnologia (FCT), Unidade de I&D 226/94; FEDER; POCI.

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7


BULK THERMAL POLYMERIZATION OF PHENYLETHYNYL-CALIX[4]ARENE COMPOUNDS

Patrícia D. Barata, Alexandra I. Costa, José V. Prata

Laboratório de Química Orgânica, Departamento de Engenharia Química and Centro de Investigação de Engenharia Química e Biotecnologia, Instituto Superior de

Engenharia de Lisboa, Instituto Politécnico de Lisboa, R. Conselheiro Emídio Navarro, 1, 1950-062, Lisboa, Portugal.

email: [email protected] As part of an ongoing project aiming to study the polymerizabilities of calix[4]arene compounds having phenylethynyl groups appended at the calixarene lower rim, the bulk thermal polymerization of compounds 1 and 2 was studied. The bulk polymerization of 1 was undertaken in a sealed vessel under argon at 205ºC (15 min.). Contrary to our initial expectations, the polymerization of 1 did not yield an insoluble polymer. Indeed, a completely soluble (THF) brownish-orange residue was obtained which contained less than 15% of starting 1, 7% of dimer, 5% of trimer and 75% of a polymer from which a yellow polymer was isolated in 49% (Mn= 5700 gmol-1; Mw/Mn=2.9; GPC analysis). Its infra-red spectrum resembles that of a polymer obtained under Rh(I) catalyzed polymerization.1 In addition, a rather small ethynylic stretching frequency at 2110 cm-1

(-C≡C-) was also discernible, probably accounting for the linear dimeric/trimeric products (from Glaser and/or Strauss type couplings) found in the isolated polymer. Polymerization of 2 on the other hand did produce an insoluble material which, due to the monomer structure, could not result from direct cross-linking reactions. In order to better understand the polymerization

processes involved, a TG/DSC study was performed. When heated under N2 (7ºC/min) up to 230ºC, the DSC thermogram of 1 shows an endothermic event peaking at 160ºC which correspond to the melting of 1, immediately followed by an exothermic transition peaking at 186ºC. This event corresponds to the thermal polymerization of melted 1, for which an enthalpy of 110±10 kJmol-1 was calculated. The GPC composition of the brownish-red residue thus obtained was very similar to that referred above. The DSC trace of 2 (when heated up to 255ºC) shows the same observable trends as in the case of 1, that is, an endothermic transition at 158ºC (melt), followed by polymerization (peaking at 234ºC) with an associated enthalpy of 220 kJmol-1. Most of the residue (73%) was insoluble in THF which has an IR spectrum identical to the polymer obtained under catalysis. The dissimilar and unexpected behavior of calixarenes 1 and 2 as well as the main underlying mechanisms involved in their thermal induced reactions, will be discussed in this communication. [1] Costa, A.I.; Prata, J. V., J. Polym. Sci.: Part A: Polym. Chem., 2006, 44, 7054-7070. Acknowledgements: We thank Fundação para a Ciência e a Tecnologia/MCIES (Portugal) for partial financial support. A. I. Costa thanks Instituto Superior de Engenharia de Lisboa for a doctoral fellowship.

PC11

1

OO OO

H H

H

2H

OO OO

H

7


C-H CARBENE INSERTION OF αααα-DIAZO ACETAMIDES BY PHOTOLYSIS IN NON-CONVENTIONAL MEDIA

Nuno R. Candeias, Pedro M. P. Gois, Carlos A. M. Afonso CQFM, Departamento Engenharia Química e Biológica,

Instituto Superior Técnico, 1049-001 Lisboa, Portugal E-mail: [email protected]

More than a half century has passed since the discovery of α-diazo carbonyl

compounds as excellent candidates for the construction of new and interesting molecules. However, in the last two decades, they gained special notoriety with the uprising of catalysis due to the ability of some metals to coordinate with carbenes that can be generated from the decomposition of the diazo moiety [1-3]. In the absence of catalyst, this decomposition can be induced by thermolysis or photolysis, generating a high reactive carbene species that usually leads to a complex mixture of products.

In the sequence of our work in synthesising α-diethoxyphosphoryl-β- and γ-lactams

by C-H insertion of dirhodium stabilized carbenes[4], in non-conventional media such as ionic liquids[5] or water[6], we observed that the mild photolysis of α-diazo acetamides allows similar transformations. Mercury vapour high pressure light was used to induce the photolytic decomposition of several families of α-diazo acetamides in non-conventional media such as water, hexane or neat film. The correspondent β- or/and γ-lactams were obtained in reasonable yields and in some cases with good diastereoselectivities, abolishing the need of a metallic catalyst.

XN

R'

O

N2

R

X = PO(OEt)2, Ac, CO2Etn= 0, 1

n

N

O

R'

R

X

n

IntramolecularC-H InsertionProducts

hνννν , rt

No metal catalyst

Neat, n-hexane or water

[1] Padwa, A., Helv. Chim. Acta, 2005, 88, 1357-1374. [2] Maas, G., Chem. Soc. Rev., 2004, 33, 183-190. [3] Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A., Chem. Soc. Rev., 2001, 30, 50-61. [4] Gois, P. M. P.; Afonso, C. A. M., Eur. J. Org. Chem., 2003, 3798-3810. [5] Gois, P. M. P.; Afonso, C. A. M., Tetrahedron Lett., 2003, 44, 6571-6573. [6] Candeias, N. R.; Gois, P. M. P.; Afonso, C. A. M., Chem. Commun., 2005, 391-393; Candeias, N. R.; Gois, P. M. P.; Afonso, C. A. M., J. Org. Chem., 2006, 71, 5489-5497. Acknowledgments: We would like to thank Fundação para a Ciência e Tecnologia and FEDER (Ref. POTI/QUI/60175/2004, Ref. SFRH/BPD/18624/2004 and Ref. SFRH/BD/17163/2004) for financial support.

PC12

7


COMPUTATIONAL DESIGN OF XANTHONE DERIVATIVES SHOWING ENHANCED BINDING AFFINITY FOR ESTRONE

SULPHATASE

Bruce F. Milne 1, Andreia Palmeira 1, Emília Sousa1,2 and Madalena Pinto 1,2

1Centro de Estudos de Química Orgânica, Fitoquímica e Farmacologia da Universidade do Porto; 2Serviço de Química Orgânica, Faculdade de Farmácia da

Universidade do Porto, R. Anibal Cunha 164, 4050-047 Porto E-mail: [email protected]

In the current work we have attempted to design novel derivates of the compound xanth-9-one displaying significant binding affinity for the enzyme estrone sulphatase (ES), which is implicated in the development of breast cancers through its role in maintaining high levels of estrogens in the tumour cells (1). Computational protein-ligand docking was used to evaluate the ES-binding properties of the xanthones and interaction energy grids were used to score the different docked poses. The results obtained for the xanthone derivatives were evaluated using those of the natural ligand, estrone sulphate, as a control. The presence of a doubly-branched group containing terminal electron donating groups, and a shorter electron donating group in positions 3 and 6 of the xanthone scaffold, respectively, seem to be important for optimal binding of the ligand to the receptor.

[1] M.J.Reed et al, Endocr. Rev., 2005 Apr; 26(2): 171-202. Acknowledgments: FCT (I&D 226/94), FEDER, POCI for financial support. BFM is funded by FCT post-doctoral research fellowship SFRH/BPD/17830/2007.

PC13

7


Dissolution of mono- and di-saccharides in ionic liquids

Andreia A. Rosatella1, Luís C. Branco1, and Carlos A.M. Afonso1

1CQFM, Departamento de Engenharia Química e Biológica, Inst. Superior Técnico, Complexo 1, Av. Rovisco Pais, 1049-001 Lisboa.


Carbohydrates are readily available chiral organic molecules from natural resources. Due to the large number of hydroxyl groups present, carbohydrates have a low solubility in most common solvents. Even the low molecular weight and neutral carbohydrates, such as glucose are only soluble in a small number of polar non-protic and protic solvents such as pyridine, dimethylsufoxide, dimethylformamide and water. This property of carbohydrates prevents their use in various applications and complicates their functional manipulation and structural determination [1].

Ionic liquids (ILs) have been recognized as a possible environmentally benign alternative to classic organic solvents, mainly due to their negligible vapor pressure and highly thermal and chemical stability. They are versatile compounds due to the possibility to tune the desired property such as polarity, conductivity, thermal and chemical stability, density, viscosity, melting point, and their solvent capacity just by combination of different anions and cations, [2]. ILs are solvents able to dissolve numerous polar and non-polar compounds, including carbohydrates [3]. Ether-containing ILs are called “sugar-philic ILs” mainly because they have favorable solvating interactions with carbohydrates [4].

We have performed a comparative study of dissolution of mono- and di-ssacharides in imidazolium [5] and guanidinium [6] type cations ILs containing five different anions as described in figure. The combination of cation and anion ILs strongly influence the dissolution of mono- and di-saccharides behavior. In the same way, the water content in the ILs also affects the solubility of the saccharides studied.

NN

N

RR

RR

R= CH2CH2OMeR= n-Hexil

N N R

R= CH2CH2OCH2CH2OMeR= n-Butil

Cl

O

NS

OO

OS

N

OAnionsCations

NCS NCN

CN

O

O

Figure – LIs used in the study of dissolution of carbohydrates. [1] Murugesana, S.; Linhardt R.J.; Current Organic Synthesis, 2005, 2, 437. [2] a) Rogers, R.D.; Seddon, K.R.; (eds) Ionic liquids: Industrial Applications for Green Chemistry; ACS Symposium Series 818, (ACS, Washinton DC, 2002). b) J. Duppont, in Green Separation Processes: Fundamentals and Applications, Afonso, C.A.M.; Crespo, J.P.S.G.; (eds) 1st ed. (Wiley-VCH, Weinheim, 2005). [3] Q. Liu, M. H. A. Janssen, F. van Rantwijk, R. A. Sheldon, Green Chemistry 2005, 7, 39. [4] Kimizuka, N.; Nakashima, T. Langmuir, 2001, 17, 6759. [5] Branco L.C.; Rosa J.N.; Moura Ramos J.J.; Afonso C.A.M.; Chem Eur. J., 2002, 8, 3671. [6] Mateus N.M.; Branco L.C.;Lourenço N.T.;Afonso C.A.M.;Green Chemistry, 2003, 5, 347. Acknowledgements: We would like to thank the financial support from Fundação para a Ciência e Tecnologia (POCI 2010) and FEDER (ref. SFRH/BPD/24969/2005 and ref. SFRH/BD/28242/2006).

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7


EFFICIENCY OF Rh-BASED TERNARY CATALYTIC SYSTEMS IN THE POLYMERIZATION OF TRI-O-PROPYL-(4-

ETHYNYL)BENZYLOXY-p-t-BUTYLCALIX[4]ARENE

Alexandra I. Costa, José V. Prata Laboratório de Química Orgânica, Departamento de Engenharia Química and

Centro de Investigação de Engenharia Química e Biotecnologia, Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, R. Conselheiro Emídio

Navarro, 1, 1950-062, Lisboa, Portugal. [email protected]

The synthesis of well-defined calixarene-based polymers as new materials for sensing devices, together with its characterization and properties evaluation are current research topics in our laboratory. The synthesis of conjugated calix[4]arene polymers comprising 1,3-(4-ethynyl)benzyloxy-p-t-butylcalix[4]arene units along the main-chain was recently described.1 The aforementioned monomer underwent a smooth polymerization when [Rh(nbd)Cl]2 was used as catalyst and PPh3 as an additive. Under appropriate conditions, high conversions were obtained and the resulting polymers, isolated in high yields, showed monomodal MWD and less than 5% of dimeric and oligomeric materials. On the contrary, when the polymerization of tri-O-propyl-(4-

ethynyl)benzyloxy-p-t-butylcalix[4]arene (1) was attempted, under the very same general conditions used for the difunctional counterpart, huge amounts of dimeric, trimeric and oligomeric materials were obtained, whatever the particular conditions tested. We now report that a highly efficient polymerization of 1 has been accomplished by Rh-based ternary catalytic systems. In one case, the initiator was prepared

in situ from [Rh(nbd)Cl]2, 1,1-diphenyl-2-phenylvinyl lithium (TPVLi) and PPh3 in toluene, adapting a reported procedure by Masuda et al.2 for the living polymerization of monosubstituted phenylacetylenes (PA). After 1h at 30ºC, monomer 1 was quantitatively converted (GPC analysis) affording poly 1 in high yield, with virtually no oligomeric materials. A second ternary catalytic system, firstly developed by Noyori et al.3 for PA, was similarly prepared, using PhC≡CLi instead of TPVLi as the rhodium alkylating agent. It also proved effective in the polymerization of 1, albeit in a less efficient way, requiring extended reaction times for complete conversion of the monomer and producing a polymer with a larger polydispersity under the conditions used. The underlying features of these polymerization systems will be reported. [1] Costa, A. I., Prata, J. V., J. Polym. Chem. Part A: Polym. Chem., 2006, 44, 7054-7070. [2] Misumi, Y., Masuda, T., Macromolecules, 1998, 31, 7572-7573. [3] Kishimoto, Y., Eckerle, P., Miyatake, T., Ikariya, T., Noyori, R., J. Am. Chem. Soc., 1994, 116, 12131-12132. Acknowledgements: We thank Fundação para a Ciência e a Tecnologia/MCIES (Portugal) for partial financial support. A. I. Costa thanks Instituto Superior de Engenharia de Lisboa for a doctoral fellowship.

PC15

OO OO

H

1

Calix

poly 1

n

H

Calix

Rh catalystH

7


Electrochemical Epoxidation of Geraniol Massuquinini Inêsa, Dina I. Mendonçab , António Mendonçab, Ana P. Estevesc, Maria J.

Medeirosc aChemistry Department, Agostinho Neto University, Luanda, Angola

bChemistry Department, University of Beira Interior, Covilhã, Portugal cChemistry Department, University of Minho, Braga, Portugal


Introduction

Terpenes are natural compounds widely distributed in nature and their epoxides are important starting materials for the industrial synthesis of more complex molecules like flavours, fragrances or pharmaceuticals. Materials-methods

Two platinum electrodes (2.5�2.5 cm2) parallel each other were placed in a beaker with MeCN/H2O (4:1), geraniol (40mM) and NaBr (40mM) as mediator. A constant density current (3.3 mA/cm2) was produced in a DC source. After the electrolysis, sodium metabissulfite (1%) was added to the reaction mixture which was extracted with chloroform. The crude residue was submitted to flash chromatography and the pure compounds were identified by NMR (1H and 13C). Results

From geraniol (1), 6,7-epoxigeraniol (2) and 2,3:6,7-epoxigeraniol (3) were obtained.

O H

NaBr

MeCN:H2O(4:1)

O H

O O

O H

O

+

Discussion

Compounds 2 and 3 were obtained in 43% and 6% yields, respectively, in the same run after 594 C. However, after 891 C compound 2 was obtained with a yield of 36% and compound 3 with a yield of 24%. Using a chemical procedure [1], only compound 2 was obtained in 67% yield. Electrochemical approach can be used to produce epoxides that could not be obtained by chemical methods or were difficult to obtain. Once the electrochemical parameters are established the reaction can afford the required products in an optimized way.

References: [1] L.J. Schofield, O.J. Kerton, P. McMorn, D. Bethell, S. Ellwood, G. J. Hutchings, J. Chem. Soc., Perkin Trans., 2002, 2, 1475-1481. Acknowledgments: One of the authors (M. Inês) thanks to ICCTI-GRICES for PhD grant and INABE (Angola) for financial support.

PC16

1

2

3

7


ENANTIOSELECTIVE APPROACH TO THE SYNTHESIS OF MEDICINALLY IMPORTANT DIHYDROXYLATED

PYRROLIDINES P. Cambeiro Barrulas, A. J. Burke,*

Departamento de Química and Centro de Química de Évora, Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal.

[email protected]

Dihydroxylated indolizide alkaloids are a very important group from the

pharmacological and medical point of view, given that in general they exhibit strong biological activities. Compounds like, Swainsonine and derivatives [1] that exhibit anti-tumor activity, (+)-lentiginosine, with potent amyloglucosidase inhibitory activity [2] and (-)-anisomycin [3] that shows strong and selective activity against pathogenic protozoa and fungi (Figure 1).

Figure 1

N

OHH OH

OH

Swiansonine

N

H OH

(+)-Lentiginosine

NH

HO OAc OMe

(-)-Anisomycin

OH

In this communication we report the development of a novel synthetic route to these

compounds. [1] H. Fiaux et al., J. Med. Chem. 2005, 48, 4237-46. [2] F. Cardona et al. J. Org. Chem. 2005, 70, 6552-55. [3] R. Ballini, E. Marcantoni and M. Petrini, J. Org. Chem. 1992, 57, 1316-18.

PC17

7


ENANTIOSELECTIVE SYNTHESIS OF INDOLO[2,3-a]QUINOLIZIDINES

Maria M. M. Santos,*,§ Oriol Bassas,§ Mercedes Amat,§ Joan Bosch§

§ Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain

* Currently affiliated with i-Med.UL, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal


Due to the wide range of biological activities associated to indole alkaloids, these compounds constitute important synthetic targets.

NH

NH

MeO2C

H3α: DihydrocorynantheineH3β: Hirsutine

OMe

NH

NH

Antirhine

H

OHH

We report here a cyclocondensation reaction of (L)-tryptophanol 1 with racemic aldehyde 2. In this reaction two stereogenic centres with a well-defined absolute configuration are formed with excellent stereoselectivity in a process involving a dynamic kinetic resolution. The resulting enantiopure lactam 3 was converted to the 6,12b-trans indoloquinolizidine 4a by treatment with HCl, which after removal of the hydroxymethyl substituent gave the indoloquinolizidine 5.

Remarkably, cyclization of 3 with BF3·OEt2 resulted in a dramatic change in the stereoselectivity as the major product obtained was 6,12b-cis indoloquinolizidine 4b. [1]

NNH2

OH

HMeO2C

OH

NN

H

OO

NN

OH

H

HO

2

i

Reagents and Conditions: (i) toluene, reflux; (ii) BF3.OEt2, anh CH2Cl2, reflux; (iii) HCl (1.2 M in EtOH), rt;(iv) IBX, then Boc2O;(v)NaClO2;(vi) (PhSe)2, n-Bu3P;(vii) AIBN, Bu3SnH, then Bu4NF.

1

4a

ii+

3

iv-vii

NN

H

HO

5

iii

NN

OH

H

HO

4b

[1] M. Amat, M. M. M. Santos, O. Bassas, N. Llor, C. Escolano, A. Gómez-Esqué, E. Molins, S. M. Allin, V. McKee, J. Bosch, J. Org. Chem., 2007, 72 (in press).

Acknowledgments: This work was supported by the Ministry of Science and Technology (Spain)-FEDER (projects CTQ2006-02390/BQU) and the DURSI, Generalitat de Catalunya (2005SGR-0603). Thanks are also due to Fundação para a Ciência e Tecnologia (Lisbon, Portugal) for the award of post-doctoral fellowship to M.M.M.S.

PC18

7


EVALUATION OF A2B2 HYDROXYLATED PORPHYRINS AS SENSITIZERS FOR PHOTODYNAMIC THERAPHY

Catarina I.A. Santosa, A. Serraa, M. Pineiro,a A. M. d’A. Rocha Gonçalvesa, M.

Abrantes,b M. Laranjo,b A. C. Santosb and M. F. Botelhob

aChymiotechnon, Departamento de Química, Universidade de Coimbra, 3049-535, Coimbra, Portugal.

b Instituto de Biofísica/Biomatemática, IBILI, Faculdade de Medicina de Coimbra, 3000-354 Coimbra, Portugal.

[email protected]

Photodymanic therapy (PDT) is presently a well established treatment for oncological and non-oncological diseases. It is a minimal invasive procedure based on the destruction of cells by the destructive action of singlet oxygen (1O2) generated through the combined action of a sensitizer and light. PDT has attracted a lot of interest due to the selectivity shown by malignant tumours for the sensitizers relatively to healthy tissues. The sensitizer which is not a therapeutic agent becomes active when irradiated with low power light, developing a reaction cascade that produces apoptotic pathways leading to cell death.

The capacity of the sensitizer to absorb visible light of the red region of the electromagnetic spectrum and its ability to go inside cancer cells are key elements in order to get anti-tumoral activity. Besides good absorption properties, porphyrins have shown particular affinity for tumor cells1 if macrocycles present some hydrophilicity, being mainly efficient in the presence of hydroxyl groups. Also, the existence of halogens in the structure can increase the efficiency of the sensitizer for 1O2 generation.2

Porphyrins with A2B2 structures (1-4) with hydroxyl groups and halogens in different positions were prepared. Their anti-tumoral activities against colorectal cancer cell line (WiDr) were determined and compared with the tetrahydroxyl symmetrical porphyrin 5.

N

NH N

HN

R1

R2

R1

R2

R1=

R2=

1OH

OH

Br

2

R1=

R2=

OH

OH

F F

F

FF

3

R2=

OH

OH

Br

5

R1=R2=

OH

R1=

4

R2=

OH

R1=

Br

[1] Osterioh, J.; Vicente, M. G. H. J. Porphyrins Phthalocyanines, 2002, 6, 305-324. [2] Azenha, E. G.; Serra, A. C.; Pineiro, M.; Pereira, M. M.; Melo, J. S.; Arnaut, L. G.; Formosinho, S. J.; Rocha Gonsalves, A. M. d A. Chem. Phys. 2002, 280, 177-190. Acknowledgments: The authors thank to Chymiotechnon, Ministério da Economia/ POE/Prime/Proj 3/293/CLARO, Faculdade de Medicina de Coimbra and CIMAGO for financial support and Serviço de Gastroenterologia dos HUC for equipment facilities.

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7


INVESTIGATION OF 2-HYDROXY-NEVIRAPINE AS A POTENTIAL GENOTOXIC METABOLITE FROM THE ANTI-HIV DRUG NEVIRAPINE

Muna Sidarus§, Alexandra M.M. Antunes§§, Mariana P. Duarte§, Pedro P. Santos §, Frederick

A. Beland§§§, and M. Matilde Marques§ § Centro de Química Estrutural, Instituto Superior Técnico, TU Lisbon, Portugal, §§ REQUIMTE/Centro de Química Fina e Biotecnologia, FCT-UNL, Caparica, Portugal,

§§§National Center for Toxicological Research, Jefferson, AR, USA E-mail: [email protected]

The non-nucleoside reverse transcriptase inhibitor nevirapine (11-cyclopropyl-

5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, NVP, I) is one of the most commonly prescribed antiretrovirals worldwide [1]. Its chronic use against the human immunodeficiency virus (HIV), e.g., in post-exposure prophylaxis, is currently not recommended, due to consistent reports of severe hepatotoxicity of the drug [2]. Nonetheless, NVP is still widely used in low resource countries to prevent the vertical transmission of HIV from mother to child [1]. Despite its efficiency in this last context, and the decreased risk of single-dose administration, concerns about the safety of the drug remain, particularly when given to children. Although the reasons for NVP toxicity are currently unknown, it is plausible that metabolic activation to reactive electrophiles may be involved in the initiation of genotoxic responses, through DNA adduct formation. NVP metabolism entails Phase I oxidation to 4-hydromethyl-NVP (II) and ring hydroxylation to phenol-type derivatives (III-V) [3]. Subsequent metabolism, either through further oxidation of the phenols to quinoid derivatives or Phase II esterification of the hydroxymethyl group of II, could conceivably produce electrophiles capable of binding to DNA.

We have previously demonstrated DNA adduct formation in vitro by the O-mesyl derivative of II, used as a surrogate for a Phase II metabolite [4]. We are now conducting a comprehensive evaluation of the phenolic NVP metabolites regarding oxidation and subsequent reaction with (bio)nucleophiles. We report herein the synthesis of 2-hydroxy-NVP (III) and the analysis of its oxidation products, generated under mild conditions from reaction with Fremy’s salt or silver(I) oxide. The significance of similar transformations in vivo will be discussed.

N N

NH

N

X O

N N

NH

N

OCH3

X

Y Z

I, X =H

II, X = OH

III, X = OH, Y = H, Z = H

IV, X = H, Y = OH, Z = H

V, X= H, Y = H, Z = OH

[1] Wood, R., SAMJ 2005, 95, 253-257. [2] Fisher, M. et al., Int. J. STD AIDS 2006, 17, 81-92. [3] Riska, P. et al., Drug. Metab. Dispos. 1999, 27, 895-901. [4] Antunes, A.M.M. et al., Proc. Amer. Assoc. Cancer Res. 2007, 48, 332. Acknowledgments: Fundação para a Ciência e a Tecnologia (FCT) is gratefully acknowledged for a research grant (POCI/QUI/56582/2004), and a research fellowship to MS.

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7


MECHANISTIC STUDIES ON RADICAL OXIDATIVE DEMETHYLATION OF PYRAZOLONE DERIVATIVES

Abel Vieira,§ Pedro Santos,§ Alexandra Antunes,§ João Noronha,§ Eduarda Fernandes.§§

§REQUIMTE/CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia,

Universidade Nova de Lisboa, Caparica, Portugal §§REQUIMTE/CEQUP, Departamento de Química-Física, Faculdade de Farmácia,

Universidade do Porto, Portugal. E-mail: [email protected]

Antipyrine (AP, I) and 4-Dimethylaminoantipyrine (4-DMAAP, II) are pyrazolone derivatives, with therapeutical effects, which have been attributed to their analgesic, antipyretic and anti-inflammatory properties. This family of compounds has also been appointed as potential antioxidants. Previous results of this group showed a much higher antioxidant activity of 4-DMAAP as compared to AP,1 which was attributed to the 4-DMAAP capacity to undergo oxidation followed by demethylation in the reaction with free radicals,2,3 giving rise to 4-methyl-aminoantipyrine (4-MMAAP, III), which can be further demethylated to 4-aminoantipyrine (IV).

N

NO

C6H5

NN

NO

C6H5

NHN

NO

C6H5

NH2

[O] [O]Final Oxidation Products

II III IV

N

NO

C6H5

I

To validate this mechanistic proposal 4-dimethyl-aminoantipyrine (4-DMAA, II), 4-methyl-aminoantipyrine (4-MMAAP, III) and 4-aminoantipyrine (4-AAP, IV) were submitted to the Fenton reaction conditions. The final products analysis (HPLC-DAD, GC-Ms and NMR) enabled their identification. The reaction of 4-DMAAP (II) with the hydroxyl radical involves benzene ring hydroxylation to phenolic derivatives (orto, meta and para positions) and demethylation on the amino group with formation of 4-MMAAP (III). The 4-MMAAP is further demethylated to 4-AAP (IV). The 4-aminoantypirine is oxidized to final products which are also identified in the reactions of II and III. In order to characterise the transient radicals involved the ESR spectra of the radical cations obtained by one-electron oxidation of II and III were recorded. [1] Costa D, Vieira A, Fernandes E, Redox Report, 2006, 11(3), 136-142 [2] Lasker J, Sivarajah K, Mason R, Kalyananarama B, Abou-Doma M, Eling T; J. Biol. Chem., 1981, 256(15), 7764-67. [3] Griffin B, Tiny P; Biochem., 1978, 17(11), 2206-11. Acknowledgments: The authors acknowledge the financial support given by REQUIMTE, FCT

and FEDER under the scope of the project POCTI/FCB/47186/2002.

PC21

7


MERRIFIELD SUPPORTED PORPHYRINS AS EFFICIENT OXYGEN SINGLET GENERATORS

Sonia M. Ribeiro, Arménio. C. Serra, and António M. d’A. Rocha Gonsalves

Chymiotechnon- Rua Larga, Apartado 3096, 3001-453 [email protected]

The efficient use of molecular oxygen as oxidant is very attractive from the

economical and environmental perspectives, and photochemical activation a good approach to achieve this purpose. On the other hand, some porphyrins proved to be good sensitizers for singlet oxygen generation especially if they have halogen atoms in the structure.1

If the objective is to develop photosensitizers for use in large scale processes, attachment of the porphyrin to polymeric materials is essential. The polymeric structure can give some protection against degradation of the sensitizer and allows for the easy recovery of the catalyst.

Commercial Merrified resins seemed to be good polymeric supports because they can be easily modified to attach the porphyrin structure.

In this work we attached several halogenated porphyrin macrocycles to a Merrifield polymer using a spacer containing a twelve atom carbon chain (1-3). The evaluation of the efficiency of the polymeric catalysts was made by photochemical oxidation of α-terpinene and citronellol using air as oxygen source.

The reactions are efficient using substrate/catalyst ratio from 600/1 up to 15000/1. Results for consecutive reactions with recovered catalysts will be presented.

NH(CH2)12NHSO2Porphyrin

Merrifieldresin

Porphyrin=N

NH N

HN

R1

R1

R1

R2

R1=

Cl

Cl

R2=

(1) (2)

R1= R2=

Cl

(3)

R1= R2=

Br

[1] Azenha, E. G.; Serra, A. C.; Pineiro, M.; Pereira, M. M.; Melo, J. S.; Arnaut, L. G.; Formosinho, S. J.; Rocha Gonsalves, A. M. d A. Chem. Phys. 2002, 280, 177-190. Acknowledgments: The authors would like to thank Chymiotechnon, and FCT- POCTI/QUI/55931/2004 for financial support.

PC22

7


MICROWAVE-ASSISTED SYNTHESIS OF ASYMMETRICAL PORPHYRINS LINKED TO PEG2000 AND THEIR PHOTODYNAMIC ACTIVITY

Bruno F. O. Nascimento,a Marta Pineiro,a Arménio C. Serra,a António M. d’ A. Rocha

Gonsalves,a Ana Margarida Abrantes,b M. Filomena Botelho,b Ana Cristina Santosb and Mafalda Laranjob

aChymiotechnon, Departamento de Química, Universidade de Coimbra 3004-535, Coimbra, Portugal

bInstituto de Biofísica e Biomatemática, IBILI, Faculdade de Medicina, Universidade de Coimbra, 3000-548, Coimbra, Portugal


The use of microwaves as a thermal energy source affords a set of reaction conditions unattainable by conventional heating and has already undoubtedly demonstrated to be a widely successful technology in organic chemistry. It allows significant improvements of several types of synthetic reactions [1-4], including the synthesis of symmetrical porphyrins and metalloporphyrins[5].

This study reports the extension of our methodology for the microwave-assisted synthesis of porphyrins to the preparation of 5,10,15-tris(ortho-halogenophenyl)-20-(3-hydroxyphenyl)porphyrins. The poor amphiphilic character of these compounds was improved by covalently bonding to PEG2000. The photodynamic activity of the corresponding derivatives was tested against WiDr human colon adenocarcinoma cell lines and compared with Photofrin, approved for PDT of cancer in Portugal.

N

NH N

HN

O

Y

Y

Y

Y= H, Cl or Br

O n

[1] Loupy A, Petit A, Hamelin J, Texier-Boullet F, Jacquault P and Mathé D. Synthesis 1998: 1213-1234. [2] Varma RS. Green Chem. 1999: 43-55. [3] Lidström P, Tierney J, Wathey B and Westman J. Tetrahedron 2001; 57: 9225-9283. [4] Kappe CO. Angew. Chem. Int. Ed. 2004; 43: 6250. [5] Nascimento BFO, Pineiro M, Rocha Gonsalves AMdA, Ramos Silva M, Matos Beja A and Paixão JA. J. Porph. Phthal. 2007; 11: 77-84. Acknowledgments: The authors thank Chymiotechnon, Ministério da Economia/ POE/PRIME/Projecto 3/293/CLARO, Faculdade de Medicina da Universidade de Coimbra and CIMAGO for financial support and Serviço de Gastroenterologia dos Hospitais da Universidade de Coimbra for equipment facilities.

PC23

7


MICROWAVE ASSISTED SYNTHESIS OF XANTHONES: 1-HYDROXANTHONE, 1-METHOXYXANTHONE AND ONE

DIHYDROPYRANOXANTHONE Raquel A. P. Castanheiro a,†, Sara M. M. Cravo a,b, Madalena M. M. Pinto a,b, Carlos G.

Azevedo a, Carlos M. M. Afonso a,b, Salette H. Reis c aCentro de Estudos de Química Orgânica, Fitoquímica e Farmacologia da Universidade do Porto (CEQOFFUP), bLaboratório de Química Orgânica,

cLaboratório de Química-Física, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha 164, 4050-047 Porto, Portugal

E-mail: †[email protected] The use of microwaves (MW) as an energy source for chemical reactions and processes has been extensively investigated during recent years [1]. Microwave assisted organic synthesis (MAOS) provides faster reactions, with greater selectivity and better yields, when compared to classical reactions. Moreover, it can be used in conjunction with solid catalysts, which allows even higher yields in milder conditions [2]. Recently, our group has been focusing on prenylated and dihydropyran xanthones that have demonstrated interesting results for their effect on the in vitro growth of human tumor cell lines [3]. For that reason, we have used several methodologies to obtain xanthone derivatives including classical, MW, heterogeneous catalysis (Montmorillonite K10 clay) and the combination of MW and heterogeneous catalysis, either with or without solvent. So, in this work, we report the synthesis of 1-hydroxanthone (1) and 1-methoxyxanthone (2) under MW irradiation [4, 5]. We also report the synthesis of dihydropyranoxanthone (3) from 1-hydroxanthone, using MW with heterogeneous catalysis (Montmorillonite K10 clay).

O

O OH

1

O

O O

3

O

O OCH3

2

The coupling of MW irradiation with clays, under solvent conditions, provided enhanced reaction rates, higher yields and selectivity in the synthesis of dihydropyranoxanthones just in one step from hydroxyxanthones. The method using MW and Montmorillonite K10 clay was applied for the first time, by our group, to the synthesis of xanthone derivatives. [1] Kappe, C. O., Angew. Chem. Int. Ed., 2004, 43, 6250-6284. [2] Mortoni, A. et al., Tetrahedron Letters, 2004, 45, 6623-6627. [3] Castanheiro, R. et al., Bioorg. Med. Chem., 2007, accepted for publication. [4] Pankajamani, K. S. et al.; J. Sci. Industr. Res., 1954, 13B, 396-400. [5] Heravi, M.M. et al., Phosphorus, Sulfur and Silicon, 2005, 180, 1701-1712. Acknowledgments: Fundação para a Ciência e a Tecnologia (FCT), Unidade de I&D 226/94, FEDER, POCI and for the PhD grant to Raquel Castanheiro (SFRH/BD/13167/2003).

PC24

7


MOLECULAR GASTRONOMY

Joana Mouraδ, Margarida Guerreiro*, Catarina Prista*, Maria Loureiro Dias*, Paulina Mataδ

δ Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal

* Instituto Superior de Agronomia, Universidade Técnica de Lisboa, 1349-017 Lisboa, Portugal


Molecular Gastronomy1-4 is the scientific discipline devoted to the study of culinary transformations and gastronomical phenomena in general. Molecular gastronomy can have important technological and educational applications and in the last 6 years we have been working in the exploration of its potentials at these levels.

The European Union has been committed to raising public awareness of science and bridging the gap between science and the public. This is why scientists in Europe are increasingly asked to communicate their work to a wider audience. In this context, under the initiative of Ciência Viva and Pavilhão do Conhecimento5, we started using molecular gastronomy and food and cooking to attract the interest of the public to science and scientific activities. The activities named “The Kitchen is a Laboratory” were very successful and in the last 6 years we have undertaken them for the general public and also in schools. Food and cooking is a topic with widespread appeal and importance and we consider that the interest and excitement it generates can make a positive contribution to a better understanding of the role of science and scientists in everyday life and in our present living standards. Following the success of these activities, and in parallel with them, the next step was to start developing work on the technological applications of molecular gastronomy. In the last three years, we have been working with professional cooks that want to enlarge their knowledge, and particularly benefit from scientific developments to improve traditional cooking techniques and introduce new ones. In fact, gastronomy has an important role in the tourism industry and the necessity to keep up with the most recent developments in this area is widely recognized and considered crucial from an economic point of view. In this context, we have mainly focused on the study of several hydrocolloids, analyzing their properties and devising innovative ways of using them in a gastronomical context. [ 1] Hervé This, Angew. Chem. Int. Ed. Engl. 2002, 41, 83 - 88. [ 2] Hervé This, Comprehensive Reviews in Food Science and Food Safety 2006, 5 (3),

48–50. [ 3] Hervé This, EMBO Rep. 2006, 7(11), 1062-6. [ 4] Paulina Mata, Joana Moura, Entre Tanto, 2007, 2, 32-33. [ 5] http://www.cienciaviva.pt/

PC25

7


NEW BIO-ORGANOMETALLIC BENZOTHIOPHENE DERIVATIVES AS POTENTIAL ANTICANCER DRUGS

André P. Ferreira and M. Matilde Marques

Centro de Química Estrutural, Instituto Superior Técnico, TU Lisbon, Av. Rovisco Pais, 1049-001 Lisboa, Portugal


The incorporation of organometallic moieties into the structure of known active drugs to improve their therapeutic properties has gained considerable interest in recent years [1]. The benzothiophene derivative raloxifene (I) is a selective estrogen receptor modulator (SERM) with estrogen-agonistic effects on bone and lipid metabolism and estrogen-antagonistic effects on endometrium and breast tissue. Preliminary results from a large scale clinical trial (STAR), designed to evaluate the relative ability of raloxifene and the widely used antiestrogen tamoxifen to reduce breast cancer incidence, suggest that raloxifene may have the benefits of tamoxifen with fewer side effects [2].

Based upon these observations, we have undertaken the synthesis of a series of bio-organometallic benzothiophene derivatives (II) containing a ferrocenyl unit and several terminal amino groups (e.g., HNR2=morpholine, piperidine, pyrrolidine, piperazine, and dimethylamine), expected to insure affinity to the estrogen receptor (ER). These species have been designed to combine SERM properties associated with a raloxifene-type backbone with potential cytotoxicity, provided by the organometallic fragment.

The synthetic strategies towards II and the full structural characterization of the novel benzothiophene derivatives will be presented. Moreover, properties of these new prospective SERMs (e.g., partition coefficients and redox potentials), expected to determine their bioactivity, will also be reported. Further studies, involving binding measurements to the ER and cytotoxicity evaluation in breast cancer cell lines, are planned in order to assess the potential therapeutic properties of the new organometallic benzothiophene derivatives against breast cancer. [1] Jaouen, G. (ed.) Bioorganometallics. Biomolecules, Labeling, Medicine. 2006, Wiley-VCH, Weinheim, 444 pp. [2] Vogel, V.G. et al., JAMA 2006, 295, 2784-2786. Acknowledgement: Fundação para a Ciência e a Tecnologia is gratefully acknowledged for a postdoctoral fellowship to APF (SFRH/BPD/21014/2004).

PC26

SOHOH

O

O

N

I II

O

O

NR2

Fe

SR'O

7


NEW ORGANIC LIGANDS FOR NONLINEAR OPTICAL COMPLEXES

Vânia F. Pais§, António P. S. Teixeira§,‡, M. Paula Robalo#,‡, M. Helena Garcia‡,†, M. Fátima Minas da Piedade‡,†, M. Teresa Duarte‡, A. R. Dias‡

§ Departamento de Química, Univ. de Évora, R. Romão Ramalho, 59, 7000-671 Évora

‡Centro de Química Estrutural, IST, Av. Rovisco Pais, 1, 1049-001 Lisboa #Departamento de Engenharia Química, Instituto Superior de Engenharia de Lisboa, R.

Conselheiro Emídio Navarro, 1, 1959-007 Lisboa †Faculdade de Ciências da Univ. de Lisboa, Ed. C8, Campo Grande, 1749-016 Lisboa

E-mail: [email protected], [email protected]

The search for organometallic compounds with nonlinear optical (NLO) properties has becoming a field of considerable interest due to their potential as materials with technological applications in the area of nonlinear optical phenomena [1]. In the organometallic push-pull systems, the metal center behaves as an electron-acceptor or electron-donating center bonded to an organic delocalized π-electron system. Organic compounds could present themselves NLO properties due to the high electronic polarizability of their π-system [1]. The ability to introduce subtle changes in the chemical structures, leading to improvements in their properties, and to build structure-property relationships, make the organic compounds still good candidates for electronics and optical phenomena investigation area [1,2].

Here, we present the synthesis and spectroscopic characterization of electron-withdrawing organic ligands, suitable for coordination to electron donating Fe or Ru metal centers. These ligands present a two aromatic rings backbone linked by a spacer (double, triple or hydrazone bond) with one or two electron withdrawing nitro groups on para and ortho positions of the second aryl ring (Figure 1). The substitution with a nitrile or alkyne groups provide an available site for coordination to the metals. The structures of several compounds were confirmed by X-Ray diffraction studies.

NO2spacer

RR = H, NO2

Y = N or CH

spacerN NH

CY

FIGURE 1 [1] E. Goovaerts, W. E. Wenseleers, M. H. Garcia, G. H. Cross, in “Handbook of Advanced Electronic and Photonic Materials and Devices”, H. S. Nalwa (Editor), Volume 9 - “Nonlinear Optical Materials”, Ch. 3, Academic Press, San Diego, 2001, pp. 127-191. [2] S. R. Forrest, M. E. Thompson, Chem. Rev., 2007, 107, 923-925; V. Coropceanu, J. Cornil, D. A. S. Filho, Y. Olivier, R. Silbey, J.-L. Brédas, Chem. Rev., 2007, 107, 926-952. Acknowledgments: We thank FCT and POCTI (POCTI/QUI/48443/2002) and IPL (IPL/16/2003) for financial support.

PC27

7


NOVEL BENZISOTHIAZOLE-TETRAZOLYL DERIVATIVES AS POTENCIAL NITROGEN LIGANDS

L.M.T. Frija§,£, M.L.S. Cristiano§ and R. Fausto£

§Department of Chemistry, Biochemistry and Pharmacy, F.C.T. and CCMAR, University of Algarve, Campus de Gambelas, 8005-039 Faro, Portugal

£Department of Chemistry, University of Coimbra, P-3004-535 Coimbra, Portugal E-mail: [email protected]

In the last few years, the design of new bridging ligands for controlling the molecular

architectures required for the desired physical properties of the resulting coordination compounds has been a topic for many research groups, in important fields such as supramolecular chemistry [1] and molecular magnetism.[2]

The 5-substituted tetrazolate group, isosteric with the carboxylate group, and with good coordination capacities, has scarcely been explored in building coordination frameworks, mainly because no effective method for synthesizing 5-substituted tetrazoles in high yields was known. In the past few years, Sharpless and Demko have developed a convenient route to 5-substituted tetrazoles by addition of azide to organic nitriles catalyzed by zinc salts in water.[3] Since then, studies on 5-substituted tetrazolate-bridged coordination frameworks have been slowly emerging.[4]

To the best of our knowledge, tetrazoles have not been investigated as a ligand function of saccharin, though they demonstrate the ability to bind cations of transition metals.[5] In this communication, we report the synthesis and characterisation of three new benzisothiazole-tetrazolyl derivatives (see Structure 1), differing on the spacer-group used for linkage of the two heterocycles, as potential nitrogen ligands in coordination reactions with transition metal complexes.[6]

SO2

N

Spacer

NN

N

HN

M

LL(1)

M = metal; L = ligand;

[1] Lehn, J.-M. Supramolecular Chemistry VCH, Weinheim, 1995. [2] Kahn, O.; (Ed.) Magnetism: A Supramolecular Function; Kluwer Academic

Publishers: Dordrecht, the Netherlands, 1996. [3] Demko, Z. P.; Sharpless, K. B., J. Org. Chem. 2001, 66, 7945. [4] Xiong, R.-G.; Xue, X.; Zhao, H.; You, X.-Z.; Abrahams, B. F.; Xue, Z.-L. Angew.

Chem., Int. Ed., 2002, 41, 3800. [5] Boyko, V.; et al., Tetrahedron 2005, 61, 12282. [6] Frija, L. M. T.; Cristiano, M. L. S.; Fausto, R., manuscript under preparation. Acknowledgments: The authors are grateful to Fundação para a Ciência e Tecnologia (FCT) and FEDER [Projects POCI/QUI/59019/2004 and POCI/QUI/58937/2004 and grant SFRH/BD/17945/2004 (L.M.T.F.)]

PC28

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NOVEL METHODOLOGY TO SYNTHESIZE BIOLOGICALLY ACTIVE BISPHOSPHONATES BASED ON ORGANOCATALYSIS

Ana Maria M. M. Faísca Phillips and Maria Teresa Barros

Departamento de Química, CQFB, REQUIMTE, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516

Caparica, Portugal E-mail: [email protected]

Several bisphosphonates are used nowadays for the treatment of bone diseases such as osteoporosis, Paget´s disease of the bone, bone metastasis and multiple myeloma.[1] They are taken up by the skeleton and inhibit osteoclast mediated bone resorption. A and B are examples. In addition, some bisphosphonates containing a carbonyl function, such as C, have been found to have potent anti-inflammatory activities too.[2]

Cl

Cl

P(OH)2

P(OH)2

O

O

HO

R

P(OH)2

P(OH)2

O

O

A: Clodronate B: R=CH3, Etidronate, R=CH2CH2NH2, Pamidronate

Here we present new methodology to synthesize analogs of the carbonyl-containing bisphosphonates, for example C, based on organocatalysis.

O

Ph

P(OEt)2

P(OEt)2

O

O

C

[1] (a) G. A. Rodan, Annu. Rev. Pharmacol. Toxicol., 1998, 38, 375-388; (b) G. A. Rodan, T. J. Martin, Science, 2000, 289, 1508-1514. [2] R. A. Nugent, S. T. Schlachter, M. Murphy, C. J. Dunn, N. D. Staite, L. A. Galinet, S. K. Shields, H. Wu, D. G. Aspar, K. A. Richard, J. Med. Chem., 1994, 37, 4449-4454. Acknowledgments: The financial support given by Fundação para a Ciência e a Tecnologia (SFRH/BCC/15809/2006) to A.M.M.M. Faísca Phillips is gratefully acknowledged.

PC29

7


“ONE-POT” PALLADIUM-CATALYZED SYNTHESIS OF BENZOTHIENOQUINOLINES FROM 3-BROMOBENZO[b]THIOPHENE-2-

CARBALDEHYDE AND 2-(PINACOLBORONATE)ANILINE

Ricardo C. Calhelha, Maria-João R.P. Queiroz Centro de Química, Campus de Gualtar, 4710-057 Braga, Portugal


For some years now we have been interested in the synthesis of tetracyclic planar compounds derivatives of benzo[b]thiophenes as potential antitumorals, using palladium-mediated reactions [1]. Recently we have prepared tetracyclic lactams in a “one pot” three steps reaction of borylation, Suzuki coupling (BSC) and intramolecular cyclization, from alkyl 3-bromobenzo[b]thiophene-2-carboxylates and o-haloanilines, and their interaction with DNA was studied by fluorescence [2]. Here we present the palladium-catalyzed “one pot” synthesis of two benzothienoquinolines from 3-bromobenzo[b]thiophene-2-carbaldehyde and 2-(pinacolboronate)aniline. In the synthesis of the benzothieno[2,3-c]quinoline, a Suzuki coupling and a nucleophylic attack of the amino group on the carbonyl of the aldehyde occur. In the synthesis of the benzothieno[3,2-b]quinoline a palladium-catalyzed C-N coupling followed by an intramolecular cyclization with loss of H2O, seems to occur.

The compounds obtained are fluorescent and their intercalation with DNA and interaction with biological membranes will be studied.

[1] G. Viola, A. Salvador, D. Vedalvi, E. Fortunato, S. Darsò, G. Basso, M.-J.R.P. Queiroz J. Photochem. Photobiol. B: Biol. 2006, 82, 105-116 and references cited. [2] M.-J.R.P. Queiroz, E.M.S. Castanheira, T.C.T. Lopes, Y.K. Cruz, G. Kirsch J. Photochem. Photobiol. A: Chem., 2007, in press. Acknowledgments: This work was funded by FCT and FEDER through CQ-UM, POCI/QUI/59407/2004, SFRH/BD/29274/2006 PhD grant of R.C.C.

PC30

S

Br

CHO

S

N

S

N

+

NH2

BO

O

i

i) Pd(OAc)2 (5mol%), 2-(cyclohexylphosphane)biphenyl (20mol%),

Ba(OH)2.8H2O (3 equiv.), dioxane, 100 oC, 5h.

30%

20%

benzothieno[3,2-b]quinoline

benzothieno[2,3-c]quinoline

7


4-OXO-β-LACTAMS AS INHIBITORS OF ELASTASE

J. Mulchande1, W. Y. Tsang2, M. I. Page2, J. Iley3 and R. Moreira1 1 i-Med.UL, Faculdade de Farmácia, Universidade de Lisboa, Av. Forças Armadas,

1600-083 Lisboa, Portugal 2 Department of Chemical & Biological Sciences, School of Applied Sciences,

University of Huddersfield, Huddersfield, HD1 3DH, UK 3 Department of Chemistry, The Open University, Milton Keynes, MK7 6AA, UK

[email protected]

Elastase is a serine protease implicated in many inflammatory diseases.1 Recently, 3-oxo-β-sultams, 1, were reported as potent inhibitors of elastase.2 We now report that 4-oxo-β-lactams, 2, are novel potent inhibitors of porcine pancreatic elastase PPE, while decreasing the reactivity towards non specific nucleophiles when compared to the highly reactive isosteric analogues 1.

S N

O

O

OR´

R´

R

N

OR´

R´

R

1 2O

Both alkaline and enzymatic hydrolysis of N-aryl-4-oxo-β-lactams 2 occur with endo-cyclic C-N ring fission, yielding respectively 3 and 4 and the ratio varies with the aryl substituent. A good amide leaving group seems to be an important requisite to increase chemical reactivity and to achieve enzyme irreversible inhibition by 2. We found that the most reactive derivatives were also the most actives ones against PPE, which supports the use of kOH value for the alkaline hydrolysis of potential serine enzymes inhibitors as a crude indicator for their ability to be useful acylating agents.3

HO2C

R´ R´

CONHR

N

OR´

R´

R

2O

3

HN

R

O

O OEnz

R´R´

4

a)

b)Nu

Fig.1 – Hydrolysis of 4-oxo- β-lactams: a) by hydroxide ion; b) by PPE

[1] Konaklieva, M. I.; Curr. Med. Chem. Anti-Infective Agents, 2002, 1, 215. [2] Tsang, W. Y.; Ahmed, N.; Harding, L. P.; Hemming, K.; Laws, A. P.; Page, M. I., J. Amer. Chem. Soc., 2005, 127, 8946. [3] Sykes, N. O.; Macdonald, S. J. F.; Page, M. I., J. Med. Chem. 2002, 45, 2850. Acknowledgments: This work was funded by Fundação para a Ciência e a Tecnologia, (FCT, Portugal), to Ph.D grant SFRH/BD/17534/2004.

PC31

7


PRENYLATED DERIVATIVES OF 3,7-DIHYDROXYFLAVONE AS POTENTIAL ANTITUMOR AGENTS: SYNTHESIS BY CLASSIC

AND MICROWAVE METHODOLOGIES

Marta A.O.P. Nevesa,b,*, Honorina M.M. Cidadea,b, Madalena M.M. Pintoa,b, Artur M.S. Silvae, Maria S. J. Nascimentoa,c

aCentro de Estudos de Química Orgânica, Fitoquímica e Farmacologia da Universidade do Porto (CEQOFFUP), bLaboratório de Química Orgânica,

cLaboratório de Microbiologia, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha 164, 4050-047 Porto, Portugal

eDepartamento de Química, Universidade de Aveiro, Campus Universitário de Santiago 3810-193 Aveiro, Portugal

E-mail: *[email protected]

Prenylflavonoids are compounds naturally occurring in plants showing a large diversity of pharmacological activities, namely antitumor [1-3]. Due to these interesting biological effects recently our research group has been focusing on the study of this class of compounds. In this work we describe the synthesis of prenylated derivatives using 3,7-dihydroxyflavone (1) as building block by two synthetic strategies: a classic one, based on refluxing with prenyl bromide in the presence of K2CO3 and acetone anhydrous [4] and the other protocol developed for the first time performing reactions assisted by microwave. With both procedures two prenylated derivatives 2 and 3 were obtained. However, microwave irradiation technique showed to be a better way to obtain these prenylated derivatives, as it affords better yields (35% vs. 44% for compound 2 and 2% vs. 18% for compound 3) in shorter reaction times. Structures were established by IR, UV, MS and NMR (1H, 13C, HSQC and HMBC) techniques. The effect of the compounds on the in vitro growth of three human tumor cell lines, MCF-7 (breast), NCI-H460 (non-small cell lung) and SF-268 (central nervous system) are understudy.

O

O

OH

OH

O

O

O

OH

O

O

O

O

2 31 [1] Daskiewicz, J.-B. et al.; J. Med. Chem. 2005, 48, 2790-2804. [2] Brahmachari, G.; Gorai, D.; Curr. Org. Chem. 2006, 10, 873-898. [3] Botta et al.; Curr. Med. Chem. 2005, 12, 713-739. [4] Barron, D.; Mariotte, A.-M.; Nat. Prod. Lett. 1994, 4, 21-28. Ackowledgments: Fundação para a Ciência e a Tecnologia (FCT), Unidade I&D 226/94, FEDER, POCI and for the PhD grant to Marta Neves (SFRH/BD/21770/2005).

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7


PREPARATION AND CHARACTERIZATION OF IONIC LIQUIDS CONTAINING HYDROPHOBIC CATION AND

HYDROPHILIC ANION

P. S. Kulkarni [a,b], L.C. Branco [b], C.A. Afonso [a], J.P. Crespo [b] a) CQFM, Dept. de Engenharia Química, IST, 1049-001 Lisboa, Portugal.

b) REQUIMTE, Dept. de Química, FCT/UNL, 2829-516 Caparica, Portugal email: [email protected]

Ionic Liquids are emerging very fast as an alternative solvent for the volatile organic compounds various chemical processes, particularly in the area of applied chemistry. It is principally due to their essential properties over the conventional solvents, such as non volatility, non flammability, large liquid range & high thermal stability. These features of ionic liquids offer numerous opportunities for modification of the existing and for the development of green technologies [1].

A novel class of ionic liquids based on imidazolium and guanidinium cations and dicyanamide and thiocyanate anions have been prepared and characterised. The important physico-chemical properties of these ionic liquids including viscosity, glass transition and degradation temperature were studied. The present hydrophilic anions have shown very unusual chemical properties in comparison with the previously reported routine ionic liquids containing hydrophobic anions. Therefore, their properties were compared with the representative hydrophobic anions such as bis(trifluoromethanesulfonyl)imide and trifluoromethanesulfonate [2]. Additionally, the study of applications of these ionic liquids as an absorbent is reported [3].

N NR2 R1

S CN

N

N

N C6H13

C6H13

C6H13

C6H13

N(CN)2

Scheme 1: Basic structures of the ionic liquids prepared and characterized.

[1] Welton T., Chem. Rev. 99, 2071-2084, 1999. [2] Branco L.C., Rosa, J.N., Moura Ramos J.J., Afonso C.A.M., Chem. Eur. J., 8, 3671-3677,

2002. [3] Kulkarni P.S., Branco L.C., Crespo J.P.G., Afonso C.A.M., Chem. Eur. J., In Press (ref.

DOI: 10.1002/chem.200700160). Acknowledgement: We thank Fundação Para a Ciência e Tecnologia (POCI 2010) and FEDER for the financial support (Ref. SFRH/BPD/14848/2003).

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7


PYRENE AS A FLUORESCENT PROBE FOR NEUROTRANSMITTER AMINO

ACIDS

M. J. G. Fernandes, M. S. T. Gonçalves and S. P. G. Costa

Centre of Chemistry, University of Minho, 4710-057 Braga, Portugal

[email protected]

Neurotransmitters are of particular interest as they are implicated in neurodegenerative and neuropsychiatric disorders such as Alzheimer disease [1], schizophrenia [2], Down’s syndrome [3] and Parkinson’s disease [4]. As a result, the quantification of neurotransmitters, such as amino acids, nucleotides and physiological amines, in biological samples may offer valuable mechanistic insight into disease cause and progression as well as possibly providing a diagnostic tool. Most of the neurotransmitter amino acids are small aliphatic molecules with neither strong absorbance nor fluorescence in the ultraviolet/visible region. Thus derivatisation of such analytes is necessary to enhance the sensitivity of detection. Fluorescent labelling is a widely applied methodology, as it is the most suitable for analytical purposes.

Bearing this in mind, a strongly fluorescent pyrene moiety was linked to several model amino acid neurotransmitters, such as glycine, alanine, β-alanine, glutamic acid and γ-aminobutyric acid, through an ester bond at their carboxylic functions at the main and side chain (in the case of glutamic acid). The derivatisation was carried out with potassium fluoride in DMF, at room temperature, and the resulting fluorescent conjugates were obtained in excellent yields. Full characterisation by the usual spectroscopic techniques, including UV-vis and fluorescence, was performed and the data will be presented.

KF/ DMFZ-HN-(CHR)n-CO2H + Cl-H2C

R = H, CH3, CH2CH2COOHn = 1, 2, 3

r.t.Z-HN-(CHR)n-CO2CH2

[1] F.J. Jimenez-Jimenez, J.A. Molina, P. Gomez, C. Vargas, F. De Bustos, J. Benito-Leon, A. Tallon-Barranco, M. Orti-Pareja, T. Gasalla, J. Arenas, J. Neural. Transm., 1998, 105, 269. [2] G.Tsai, L.A. Passani, B.S. Slusher, Arch. Gen. Psychiatry, 1995, 52, 829. [3] G.P. Reynolds, C.E.J. Warner, Neurosci. Lett., 1988, 94, 224. [4] J.O. Rinne, T. Halonen, P.J. Riekkinen, U.K. Rinne, Neurosci. Lett., 1988, 94, 182. Acknowledgments: This work was funded by FCT through Centre of Chemistry-UM.

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7


REACTION OF NITROSOAROMATICS AND 2-(1’-HYDROXYETHYL)-THIAZOLIUM SALTS

M. Manuel B. Marques, Luísa M. Ferreira, Ana M. Lobo, Sundaresan Prabhakar

REQUIMTE/CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829 Monte de Caparica, Portugal


Thiamine diphosphate (1) (Figure 1) is a coenzyme of importance in mammalian carbohydrate metabolism as it is involved in vital non-oxidative and oxidative processes. It catalyses the enzymatic cleavage of C—C bonds in α,β-dicarbonyl and α-hydroxycarbonyl compounds [1].

Figure 1

In a preliminary account of the work [2] it was reported that 2-(1´-hydroxyethyl)-thiazolium salts 3 (R=CH3), modelled on the coenzyme 1, reacted with nitrosobenzene 2 in the presence of base to give a major phenylhydroxylamine derivative 4 (Scheme 1).

Scheme 1

Concerning the reaction mechanism various possibilities were considered, such as hydride transfer or electron transfer from 3 to 2. Herein we present our recent results towards the elucidation of this reaction mechanism. [1] Thiamine — Catalytic Mechanisms in Normal and Disease States. Jordan, F., Patel M. S. (Ed.); Marcel Dekker: Basel, 2004, chap. 1. [2] Ferreira, L. P.; Chaves, H. T.; Lobo, A. M.; Prabhakar, S.; Rzepa, H. S. J. Chem. Soc., Chem. Comm. 1993, 133-134. Acknowledgments: We thank Fundação para a Ciência e Tecnologia (FEDER, POCTI) (Lisbon, Portugal) partial financial support.

PC35

N

N NH2

N

S O

PO

O O P

O

O

O

1

CF3SO3

2 3

+

4

PhNO PhNHOAc Ph-N(O)=N-Ph

5

N

SR

OH

Base

CH2Cl2

+

7


Reactivity of Bsmoc derivatives with nucleophiles

Luísa Martins, a Jim Iley, b Rui Moreira, *a a CECF, Faculty of Pharmacy, University of Lisbon, Avenida das Forças Armadas,1600-083, Portugal.

Fax: 351 217946470; Tel: 351 217946477; E-mail:* [email protected] b Chemistry Department, The Open University, Milton Keynes, MK7 6AA, UK.

The Bsmoc (1,1-dioxobenzo[b]thiophen-2-ylmethylcarbonyl) amino-protecting group

was recently suggested as a novel scaffold for double-hit inhibitors for clan CA

proteases. Cyclic vinyl sulfones derived from Bsmoc, were shown to be irreversible

inhibitors of papain and cathepsin B [1]. The rate of thiolysis, aminolysis and alkaline

hydrolysis of ester and carbamate derivatives (1) were measured in aqueous solutions.

The obtained Hammett values for thiolysis (ρ ≈ 0,3) and alkaline hydrolysis (ρ ≈ 1)

revealed the importance of substituent inductive effect on the leaving group and the

existence of different mechanisms for these nucleophiles. These results are consistent

with thiol addition at the ring C-3, rather than at the carbonyl carbon or other exocyclic

positions and indicate thiolate anion addition to the cyclic vinyl sulfone moiety as the

rate-limiting step (βnuc ≈ 0,3). The second order rate constant for the reaction of Bsmoc

derivatives with N-acetyl-cysteine is ca. 15 times greater than the corresponding value

for the reaction with piperidine, the reagent recommended for removing the Bsmoc

protecting group. Additionally, in contrast to the reaction of Bsmoc protected amino

acids with piperidine already described, which leads to a rearrangement (2), these

derivatives give exclusively Michael addition products with thiols (3).

S

O O

LG

S

O O

S

O O

Nu

Nu

Me

Nu, secondaryamines

:Nu

Nu, thiols (HSCH2R)1 2

3

[1]- Iley, J; Moreira, R.; Martins, L; Guedes, R. C.; Soares, C. M. Bioorg. Med. Chem.

Lett., 2006, 16, 2738;

We thank FCT, POCTI and FEDER (Portugal) for financial support and a grant to LM (SFRH/BD/6499/2001).

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7


REACTIVITY OF NEW DI-RHODIUM (II) COMPLEXES

BEARING AXIAL NHC LIGANDS IN THE ARYLATION OF ALDEHYDES

Alexandre F. Trindadea, P.M.P. Gois*,a, L. F. Veirosa, V. Andréa, M. T.

Duartea, C. A.M. Afonsoa, Stephen Caddickb, F. Geoffrey N. Clokec a) DEQB, Instituto Superior Técnico, 1049-001 Lisbon, Portugal; b) Chem. Dept., University College London, 20 Gordon Street, London WC1H OAJ, UK; c) Chem.

Dept., School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, UK E-mail: [email protected]

Di-rhodium(II) complexes are bi-metallic complexes highly popular among organic chemistry community due to their remarkable efficiency in the generation of carbenoids from diazo compounds[1].

In this work was found that di-rhodium (II) tetraperfluorobutyrate can catalyze arylation of aromatic aldehydes in presence of in situ generated N-heterocyclic carbenes (NHC). The interesting spacial complementarity between the NHC ligand and the di-rhodium (II) structure allowed the formation of an extremely efficient catalyst especially in arylation of aldehydes containing electro-donating substituents and alkyl aldehydes[2].

O

RH

B(OH)2

R'

OH

R

R'

+

yields up to 99 %

NN R''R''

Cl

Rh2(pfb)4, 3 mol %

ligand, 3 mol %

KOtBu, 1 eq.

t-amyl alcohol ligand40 - 80 ºC

[1] M. P. Doyle, M.A. McKervey, T. Ye, in Modern Catalytic Methods for Organic Synthesis with Diazo compounds, Wiley-Interscience, New York, 1998; H.M.L. Davies, R.E.J. Beckwith, Chem. Rev., 2003, 103, 2861. [2] P.M.P. Góis, A. F. Trindade, L. F. Veiros, V. André, M. T. Duarte, C. A.M. Afonso, Stephen Caddick, F. Geoffrey N. Cloke, Angew. Chem. Int. Ed., accepted Acknowledgments: We thank Fundação para a Ciência e Tecnologia (POCI 2010) and FEDER (Ref. POCI/QUI/60175/2004, Ref. SFRH/BPD/18694/2004 and Ref. SFRH/BD/30619/2006) for financial support.

PC37

7


REARRANGEMENT REACTION OF ENEHYDROXYLAMINES DERIVED FROM DIOXIMES

Valdemar B. C. Figueira§, Sundaresan Prabhakar§, Ana M. Lobo§

§ REQUIMTE – CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Monte de Caparica, Portugal

[email protected]

Z

N

R

OH

Z

N

R

O

XY

Z

N

R

O

X

Y

Z

NH

R

O

X

Y

N

N

O

O R'

O R'

O

R' O

1 2 3 4

α

Scheme Enehydroxylamines (R = alkyl, Z = O) are useful compounds, and suitable derivatives 2 can be involved in 3,3-sigmatropic rearrangement providing a means of functionalisation of the α-carbon (Scheme) [1]. For the purpose of expanding the ambit of this reaction it would be of interest to be able to remove the N-substituent R at the end of the rearrangement [2]. We present in this communication our results with the oxime derivatives of type 1 (R = H, Z = NOH) and the thermal rearrangements of their acyl derivatives 4. Possible routes for final deprotection are discussed. [1] L. V. Reis, A. M. Lobo, S. Prabhakar, M. P. Duarte, Eur. J. Org. Chem., 2003, 190-

208, and references therein. [2] E. Vedejs, J. D. Little, L. M. Seaney, J. Org. Chem, 2004, 69, 1788-1793. Acknowledgments: We thank Fundação para a Ciência e a Tecnologia (FEDER, POCTI) (Lisbon, Portugal) for the award of a doctoral fellowship to one of us (V. B. C. F.) and partial financial support.

PC38

7


SCREENIG FOR ANTIBACTERIAL ACTIVITY OF PLANTS USED IN TRADITIONAL MEDICINE

Z. Barata§, N. Soares§, A. M. Madureira§, A. Duarte§, A.N. Silva§, S. Mulhovo§§,

M.J.U. Ferreira§ § CECF / i-Med. UL, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

§§Department of Medicinal Plants and Traditional Medicine, Ministry of heath, Maputo, Mozambique


Infectious diseases are the leading cause of death world-wide. The recent increase of multidrug resistant organisms to the major classes of antibiotics has created an urgent need for new antibacterial agents. Natural products, either as pure compounds or as standardized extracts, provide unlimited opportunities for new drug leads because of their unmatched structural diversity. [1] In the last 25 years, 98 chemical entities have been developed as new antibacterial drugs being 10 of them from natural origin and 64 natural compounds derivatives. [2] Plant-derived compounds have traditionally played a significant role in the treatment of human diseases; about 80% of the world population in developing countries is almost completely dependent on plant products for their primary health care.

The aim of this study was to evaluate the antibacterial activity of n-hexane and methanol extracts obtained from seven plants used in traditional medicine: Anacardium occidentallis, Gomphocarpus fruticosus,Tecomaria capensis, Salvadora australlis, Salvadora persica, Litogyna gariepina and Cassia abbreviata. The in vitro antibacterial activity was examined against Gram-negative (Klebsiella pneumoniae) and Gram-positive (Staphyloccocus aureus, Enteroccocus faecallis) strains by using agar diffusion methods (discs and wells). Anacardium occidental, Litogyna gariepina and Cassia abbreviata extracts showed activity against Staphyloccocus aureus and Enteroccocus faecallis.

[1] S.Q. Oliveira , V.H. Trentin, V.D. Kappel, C. Barelli, G. Gosmann , F.H. Reginatto, Pharm. Biology, 2005, 43, 434 -438. [2] D.J. Newman, G.M. Cragg , J. Nat. Prod., 2007, 70, 461-477.

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7


SEPARATION AND IDENTIFICATION OF ATROPISOMERS OF A2B2 TYPE PORPHYRINS

Sandra Lampreia, Alexandra Gonsalves, Catarina I. A. Santos, Marta Pineiro

Armenio Serra, António M. d’A.Rocha Gonsalves Chymiotechnon, Departamento de Química, Universidade de Coimbra, 3049-535,

Coimbra, Portugal. E-mail: [email protected]

The rotational process of the aryl groups in meso aryl porphyrins was reviewed in 1970s [1,2]. However, research in this field expanded enormously in the last thirty years [3] because atropisomers found applications in several fields, such as chiral and molecular recognition in asymmetric catalysis [4-9], membrane carriers in PVC membrane electrodes [10], models for biological systems such as photosynthetic centers or hemoproteins [11]. These applications take advantage of the different sides of the porphyrin, either to incorporate an exogenous molecule or to delivery an axial ligand to the metal inside the porphyrin [12] and for many of these applications was establish the importance of have tetrapirrolic systems with mixed hydrophobic/hydrophilic substitution pattern. One way of achieve these combination of properties is the synthesis of A2B2 substituted porphyrins such as 5,15-diarylsubstituted porphyrins but there is a very few reports about atropisomers of these porphyrins [13,14].

In this work the HPLC separation, LC-MS and 1H-RMN characterization of atropisomers of 5,15-bis(2-bromo-5-hydoxyphenyl)porphyrin and Ni(II)-5,15-bis(2-bromo-5-hydoxyphenyl)porphyrinate will be presented.

Acknowledgments: The authors thank to Chymiotechnon (Projecto-nº 03/293-CLARO/Prime) [1] Longuet-Higgins HC, Rector CW and Platt JR. J. Chem. Phys. 1950; 18, 1174. [2] Gouterman M. J. Mol. Spectrosc. 1961; 6, 138. [3] Medforth CJ. In The Porphyrin Handbook, Vol. 5, K. M. Kadish KMS, R. Guilard. (Ed.) Academic Press, 2000. [4] Simonneaux G and Le Maux P. Coord. Chem. Rev. 2002; 228, 43-60. [5] Inamo M and Yoneda I. Inorg. Chem. Commun. 1999; 2, 331-333. [6] Beer PD and Schmitt P. Current Biology in Chemical Biology 1997; 1, 475-482. [7] Boitrel B, Baveux-Chambenoît V and Richard P. Helv. Chim. Acta 2004; 87, 2447-2464. [8] Rose E, Andrioletti B, Zrig S and Quelquejeu-Ethève M. Chem. Soc. Rev. 2005; 34, 573-583. [9] Rose E, Ren Q-Z and Andrioletti B. Chem. Eur. J. 2004; 10, 224-230. [10] Lee HK, Song K, Seo HR, Choi Y-K and Jeon S. Sensors and Actuators B 2004; 99, 323-329. [11] Kuroda Y, Kawashima A, Urai T and Ogoshi H. Tetrahedron Lett. 1995; 36, 8449-8452. [12] Ruzié C, Gueyard D and Boitrel B. Tetrahedron Lett. 2004; 45, 1713-1716. [13] Ogoshi H, Mizutani T, Hayashi T and Kuroda Y. In The porphyrin handbook, Vol. 6, Academic Press: San Diego, 2000; 279-340. [14] Ogoshi H and Mizutani T. Acc. Chem. Res. 1998; 31, 81-89.

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7


[3,3´]-SIGMATROPIC REARRANGEMANTS AT ROOM TEMPERATURE

Luís F. V. Pinto§, Sundaresan Prabhakar, Ana M. Lobo § REQUIMTE/CQFB Secção de Química Orgânica Aplicada, Departamento de

Química, campus Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Quinta da Torre, 2829 Monte de Caparica, Portugal


It is known that in Michael additions, the kinetic product resulting from attack on a triple bond is the cis olefin [1]. The last tends to isomerize to the more stable trans olefin (scheme). In the present work, the cis addition product 3, obtained by Michael addition of 1 on the triple bond 2 undergoes at room temperature a [3,3´]-sigmatropic rearrangement to the allene 5, while the trans-addition product 4, resulting from isomerization, accumulates intact. The reaction is found to be dependent upon the substituents R1, R2 and R3. Discussion of its mechanism will be presented.

O

NH

R1

R2

R3

+Ts

DCM

O

N

R1

R2

R3

Ts

O

N

R1

R2

R3

Ts

O

HN

R1

Ts

R3

R2

k3

k2k1

1 3 4

5

R1 - adamantyl, 1-methylcyclohexyl, tert-butyl or benzylR2 - H or MeR3 - H or Me

2

[1] Odile Eisenstein, Garry Procter, Jack D. Dunitz, Helvetica Chimica Acta, 1978, 61, 2538-2541. Acknowledgments: We thank Fundação para a Ciência e a Tecnologia (FEDER, POCTI) (Lisbon, Portugal) for the award of doctoral fellowship to one of us (L.P.) and partial financial support.

PC41

7


SPINUS: A 1H NMR FULL-SPECTRA PREDICTION TOOL

Yuri Binev, and João Aires-de-Sousa REQUIMTE, CQFB, Departmento de Química, Faculdade de Ciências e Tecnologia,

Universidade Nova de Lisboa, 2829-516 Caparica, Portugal. www.dq.fct.unl.pt/staff/jas E-mail: [email protected]

Fast accurate predictions of 1H NMR spectra of organic compounds play an important role in structure validation, automatic structure elucidation, or calibration of chemometric methods.

Ensembles of Feed Forward Neural Networks (FFNNs) were trained [1] with >3000 experimental chemical shifts of protons to predict chemical shifts from the molecular structure. Empirically calculated physicochemical, geometrical and topological proton properties were used as descriptors [2]. An additional memory of >15000 protons and their experimental chemical shifts was used to correct the predictions, on the basis of the observed errors for the most similar examples in the memory – Associative Neural Network (ASNN) [3]. In the memory, each proton is represented by an output profile, which is the series of outputs produced by the set of FFNNs in the ensemble [4].

For the prediction of coupling constants a second memory is linked consisting of coupled protons and their experimental coupling constants. The output profiles generated for chemical shift prediction are re-used to form profile pairs that describe pairs of coupled protons. An ASNN finds the pairs of coupled protons most similar to a query, and these are used to estimate the coupling constant [5].

Predictions were obtained for independent test sets with mean average errors of 0.2-0.3 ppm for chemical shifts, and 0.6-0.8 Hz for coupling constants.

The methods for predicting chemical shifts and coupling constants were mounted together in a 1H NMR full-spectra prediction tool – SPINUS. A web-based implementation is available at http://neural.dq.fct.unl.pt/spinus. It makes use of ChemAxon’s Marvin applet to draw the query structure, and MDL’s Chime plugin for visualization of the spectra and 3D structures.

In this communication statistics will be presented, and the ability for full-spectra generation will be demonstrated. References: [1] Binev, Y.; Aires-de-Sousa, J. J. Chem. Inf. Comput. Sci. 2004, 44, 40-45. [2] Aires-de-Sousa, J.; Hemmer, M.; Gasteiger, J. Anal. Chem. 2002, 74, 80-90. [3] I. V. Tetko. J. Chem. Inf. Comp. Sci. 2002, 42, 717-728. [4] Binev, Y.; Corvo, M.; Aires-de-Sousa, J. J. Chem. Inf. Comput. Sci. 2004, 44, 946-949. [5 Binev, Y.; Aires-de-Sousa, J. Abstracts of Papers of the American Chemical Society 231: 94-CINF March 26, 2006. Acknowledgments: The authors thank Dr. Igor Tetko for making available the associative neural networks programme ASNN. Molecular Networks GmbH (Erlangen, Germany) is acknowledged for access to NMR data, and to software packages CORINA and PETRA. Y.B. acknowledges Fundação para a Ciência e Tecnologia (Lisbon, Portugal) for a post-doctoral grant under the POCTI program (SFRH/BPD/7162/2001).

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7


STRUCTURAL CHARACTERIZATION OF A NEW DYE OBTAINED FROM 1-HYDROXY-2-ACETONAPHTHONE AND 2-

FLUOROBENZOPHENONE

Paulo J. Coelho, Luis M. Carvalho

Centro de Química - Vila Real, Universidade de Trás-os-Montes e Alto Douro, 5001-911 Vila Real, Portugal.

[email protected]

The reaction between 1-hydroxy-2-acetonaphthone and benzophenone in the presence of sodium ter-butoxide is known to give, after reflux in HBr/HOAc, mainly 2,2-diphenylnaphthopyran-4-one a useful compound for the synthesis of photochromic naphthopyrans [1,2].

OH O

+

O

t-BuOK1)

2) HOAc/HBr

O

O

Ph Ph

In an attempt to prepare some fluoro substituted photochromic naphthopyrans

substituted in position 4 we tried the reaction of 1-hydroxyl-2-acetonaphthone 1 with 2-fluorobenzophenone 2 in the presence of potassium ter-butoxide in toluene at reflux. The reaction gave a red suspension that after solvent evaporation was treated with HCl/HOAc. After heating for 10 min a deeply red solution was obtained. Hydrolysis and CH2Cl2 extraction gave a deep blue solution. After column chromatography a blue dye was isolated in low yield. When dissolved in CH2Cl2, the blue dye 3 was not extracted by a basic solution of NaOH (aq) indicating that it was not a phenol. Spectroscopic characterization of this new compound, using mono and bi-dimensional NMR techniques (DEPT, COSY, HMBC, HSQC, NOESY) proved structure 3:

OH OOF

O

Ot-BuOK

1 2

+

1)

2) HOAc/HCl

3

[1] B. Van Gemert, “Organic Photochromic and Thermochromic Compounds”; Vol. 1, Chap. 3, Eds Crano J.C. and Guglielmetti R.J., Kluwer Academic / Plenum Publishers, New York, 1999. [2] J. Cottam, R. Livingstone, J. Chem. Soc., 1964, 5228-5231.

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STUDIES IN SULFAMOYLATION OF HYDROXYXANTHONES AND INVESTIGATION OF BIOLOGICAL ACTIVITIES

Elisangela Costa§, Emília Sousa§, Madalena Pinto§, Nair Nazareth¥, Maria S. J.

Nascimento¥, Luís Vale-Silva¥, Eugénia Pinto¥ Centro de Estudos de Química Orgânica, Fitoquímica e Farmacologia da Universidade

do Porto (CEQOFFUP), § Laboratório de Química Orgânica, ¥ Laboratório de Microbiologia, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha,

164, 4050-047 Porto, Portugal E-mail: [email protected]

Steroid sulfatase (STS) is a new therapeutic target in oncology. Attempts to design nonsteroidal STS inhibitors have revealed benzomate (1) as a potent STS inhibitor with IC50=190 nm [1]. Aiming the investigation of more rigid derivatives, 3,6-dihydroxyxanthone (2) was synthesized and submitted to treatment with sulfamoyl chloride, which was obtained from the chlorosulfonyl isocyanate. Due to limitations concerning both sulfamoyl reagents stability, the raw material 2 almost didn’t react. Thus, the coupling reagent, TBTU (O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate), often used in the peptide synthesis, was applied to activate chlorosulfonyl isocyanate in the sulfamoylation of the following compounds, 3,6-dihydroxyxanthone (2), 1,2- dihydroxyxanthone (3), 3,4-dihydroxyxanthone (4), and 2,2’,4,4’-tetrahydroxybenzophenone (5), in triethylamine and anhydrous THF. Since one of the main strategies in drug discovery is the evaluation of synthetic intermediates, xanthones 2-4, 2,2’,4,4’-tetrahydroxybenzophenone (5) and its acetylated derivative 6 were investigated for their effect on the in vitro growth of human tumor cell lines using the sulforrhodamine B (SRB) method [2] and showed an inhibitory effect in the µM range on the growth of NCI-H460 (non small lung cancer) and SF-268 (central nervous system cancer). Also, compounds 2-6 were screened for their antifungal activity against Candida albicans, Aspergillus species and dermatophytes with clinical relevance, using the microdilution broth methods [3]. Compounds 2, 5 and 6 were found to be active against the complete range of five representative dermatophyte species tested. Regarding C. albicans and the Aspergillus species no activity was registered. [1] HAM Hejaz et al., Bioorg Med Chem, 2004, 12, 2759–2772. [2] MM Pedro et al., Bioorg. Med. Chem., 2002, 10, 3725-3730. [3] National Committee for Clinical Laboratory Standards. Approved standard M27-A2, Wayne, Pa, USA, 2002 and National Committee for Clinical Laboratory Standards. Approved standard M38-A, Wayne, Pa, USA, 2002. Acknowledgments: Fundação para a Ciência e a Tecnologia (FCT), Unidade de I&D 226/94; FEDER; POCI for financial support.

PC44

O

O

OH OH

O

O OH

OH

O

O

OH

OH

O

OH OHOHOH

O

OSO2NH

2H

2NO

2SO

O

AcO OAcOAcOAc

12

3 4 5 6

7


STUDIES TOWARDS THE SYNTHESIS OF K-252d Ravi Varala, Isabel R. Coutinho, Susana P. Gaudêncio, Maria M. B. Marques, Ana M.

Lobo, Sundaresan Prabhakar REQUIMTE/CQFB, Departamento de Química,Faculdade de Ciências e Tecnologia,

Universidade Nova de Lisboa, 2829 Monte de Caparica, Portugal E-mail: [email protected]

One of the major difficulties associated with the synthesis of structurally interesting and biological active alkaloids such as K-252d (1) is the regiocontrol required for the glycosilation step [1]. In relation with our previous work in the synthesis of biologically active indole alkaloids such as K-252d and staurosporine [2,3], we herein present our results in the N-glycosilation of 2,2’-biindole with different sugars. Our synthetic approach started with treatment of 2,2’-biindole (2) and rhamnosyl bromide (3) with Ag2O. After chromatographic separation and characterization of the products, the N-glycosilated orthoester 4 was identified (Scheme 1).

Scheme 1

The next step consisted of a rearrangement achieved by subjecting 4 to basic conditions. Thus, the desired rearrangement product 5 could be isolated in moderate yield (Scheme 1). This contains the correct stereochemistry for the synthesis of

1, constituting a valuable alkaloid precursor. A similar protocol was adopted for other glycosil donors. The pertaining results and discussion will be presented in this communication.

[1] M. Hein, D. Michalik, P. Langer, Synthesis, 2005, 20, 3531-3534. [2] S. P. Gaudêncio, M. M. M. Santos, A. M. Lobo, S. Prabhakar, Tetrahedron Lett., 2003, 44, 2577-2578 and the references cited therein. [3] S. P. Gaudêncio, PhD thesis, UNL, FCT, 2006. Acknowledgments: We thank Fundação para a Ciência e Tecnologia (FEDER, POCTI) (Lisbon, Portugal) for the award of a postdoctoral and doctoral fellowships to three of us (R. V., S. P. G. and I. R. C.) and partial financial support.

PC45

NH

NH

+

O Br

OAc

OAc

AcO

H3C

N NH

OCH3O

2

3 4

Basic Conditions

NNH

OAcO

H3C

AcOOAc

K-252d (1)5

NH

N

HN O

O OH

OHH3C

HO

Ag2O

O

H3COAc

OAc

7


SYNTHESIS AND CHARACTERIZATION OF AMINOACID AND PEPTIDE ADDUCTS FROM THE ANTI-HIV DRUG NEVIRAPINE

Inês Martins,§ Alexandra M.M. Antunes,§ Pedro P. Santos, §§ M. Matilde Marques,§§ and

Frederick A. Beland §§§ § REQUIMTE/Centro de Química Fina e Biotecnologia, FCT-UNL, Caparica, Portugal,

§§ Centro de Química Estrutural, Instituto Superior Técnico, Lisboa, Portugal, §§§National Center for Toxicological Research, Jefferson, AR, USA

E-mail: [email protected] Nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diaz-epin-6-one, NVP, I) is a non-nucleoside reverse transcriptase inhibitor used against the human immunodeficiency virus (HIV), mostly in combination with other antiretroviral agents. NVP is also administered to prevent the vertical transmission of HIV from mother to child. Among the drawbacks of NVP use are its severe hepatotoxicity1 and its association with skin rash development2 which raises concerns about chronic administration of the drug, particularly in the perinatal, neonatal, and pediatric settings. NVP metabolism involves oxidation of the 4-methyl substituent to 4-hydromethyl-NVP (12-hydroxy-NVP, II), or ring hydroxylation to phenolic derivatives.3 Further metabolism, either through oxidation of the phenols to quinoid derivatives or Phase II esterification of the hydroxymethyl susbtituent of II, may produce electrophilic species capable of reacting with proteins to yield covalent adducts which could be involved in the genesis of toxicicity processes.

As a model electrophile derived from 12-hydroxy-NVP, we synthesized 12-O-mesyl-NVP (III) and investigated its reactivity towards the nucleophilic amino acids (AA), N-acetyl-cysteine and Nα-Boc-histidine, and the peptide glutathione. We report herein the isolation and characterization of covalent NVP-AA adducts, typically formed with significant yields. Our results suggest that NVP metabolism to 12-hydroxy-NVP could potentially be a factor in NVP toxicity.

[1] Baylor et al., J. Acquir. Immune Defic. Syndr., 2004, 35, 538-539. [2] Popovic et al., Chem. Res. Toxicol., 2006, 19, 1205-1214; Steel-Duncan et al, West Indian Med. J., 2004, 53, 356-358. [3] Riska et al., Drug. Metab. Dispos. 1999, 27, 895-901. Acknowledgments: Fundação para a Ciência e a Tecnologia is gratefully acknowledged for a research grant (POCI/QUI/56582/2004).

PC46

N N

HN

O

N

R

I, R=HII, R=OHIII, R=OMs

7


SYNTHESIS AND CHARACTERIZATION OF NOVEL HYDROXY- AND AMINOBISPHOSPHONATES

Fátima C. Teixeira§, Carla Lucas§, Inês F. Antunes§, M. João M. Curto§, M. Neves† and

M. Teresa Duarte± § INETI-DTIQ, Estrada do Paço do Lumiar, 22, 1649-038 Lisboa, Portugal

† Instituto Tecnológico e Nuclear, Estrada Nacional 10, 2686-953 Sacavém, Portugal ± Centro de Química Estrutural, IST, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal


Bisphosphonates (BPs) are a family of drugs that are successfully used in the treatment of various calcium-related disorders such as Paget´s disease, osteoporosis and bone metastases. In addition, functional BPs have been also used in the treatment of metal intoxication and as novel ligands for well-defined radioactive metal complexes that can be used in imagiology, scintigraphy and radiotherapy applications [1,2].

The indazole derivatives are pharmacologically important compounds and the indazole ring system forms the basis of a number of drug molecules. Condensed pyrazoles are also known as pharmacophoric elements in numerous active compounds. However, in comparison with other heteroaromatic compounds, the chemistry of indazole and condensed pyrazoles remains less studied [3].

The present work is to extend the previous studies in indazolebisphosphonates [4] in order to obtain new BPs derived from indazole and condensed pyrazole with potential biological/therapeutical activities. Herein, we report the synthesis and characterization of a series of new 1-hydroxybisphosphonates (1) and aminobisphosphonates (2) (substituted at different C- or N-positions of the indazole ring - N-1, C-5, C-6, C-7) (Figure 1). Crystal structure of an aminobisphosphonate was determined by X-ray crystallography.

N NN

HO PO3H2

PO3H2

NN

HN

CH3

H

PO3Et2

Et2O3P

hydroxybisphosphonate 1 aminobisphosphonate 2 Figure 1

[1] H. Fleich, Endocrine Reviews, 1998, 19, 80-100. [2] W.A. Volkert and T.J. Hoffman, Chem. Rev., 1999, 99, 2269-2292. [3] F.C. Teixeira, H. Ramos, I.F. Antunes, M.J.M. Curto, M.T. Duarte and I. Bento, Molecules, 2006, 11, 867-889. [4] F.C. Teixeira, I.F. Antunes, M.J.M. Curto, M. Neves and L. Gano, Medicinal Chemistry in the 21st Century, 2006, P89; F.C. Teixeira, I.F. Antunes, M.J.M. Curto, R. Fausto, M. Rosado and M. Neves, Medicinal Chemistry in the 21st Century, 2006, P90. Acknowledgments: To FCT (FEDER, POCI) for provision of funding (POCI/QUI/55508/2004).

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SYNTHESIS AND CHARACTERIZATION OF TWO MACROCYCLIC COMPOUNDS CONTAINING SULPHUR AND

NITROGEN AS DONOR ATOMS

N. Torres, J. Costa and M. F. Cabral CECF, Faculdade de Farmácia de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa,

Portugal. E-mail: [email protected]

Nowadays there is a critical need of ligands with the right architecture for the selective complexation of metal ions in solution. The design of ligands as therapeutic agents for the treatment of metal poisoning [1] is one of our goals. Following our previous studies [2] and taking into account this proposal, we have synthesized two macrocyclic compounds, L1 and L2. The synthesis were performed using high dilution procedures involving a previous esterification of thiodiacetic acid or thiodipropionic acid respectively, followed by the cyclization reaction between the esters and triethylenetetramine. The cyclization reaction was done by two addition-elimination steps: the first one based on the reaction of an ester and the amine (intermolecular) and a second one involving an intramolecular reaction. The compounds L1 and L2 were obtained upon purification using chromatographic and recrystallization techniques. Characterization of the macrocyclic compounds were performed by NMR (1H NMR, 13C NMR, COSYHH 11 − , DEPT, HMQC and HMBC) and I. R. spectroscopies. [1] Ole Andersen, Chem. Rev., 1999, 99, 2683-2710. [2] J. Costa, R. Delgado, M.G.B. Drew, V. Félix, J. Chem. Soc., Dalton Trans., 1999, 4331-4339. Acknowledgements: The authors acknowledge Fundação para a Ciência e a Tecnologia (Project POCTI/49114/QUI/2002).

PC48

N

S

N

NN

H H

HH

O O

L1 L2

NN

NN

H H

HH

S

OO

7


SYNTHESIS AND CONFORMATIONAL ANALYSIS OF β-HAIRPIN MIMICS CONTAINING BIFUNCTIONAL

DIKETOPIPERAZINE SCAFFOLDS

Ana Sofia M. Ressurreição,a Monica Civera,b Laura Belvisi,b Cesare Gennari,b Umberto Piarullia

aDipartimento di Scienze Chimiche e Ambientali, Università degli Studi dell’Insubria Via Valleggio, 11, I- 22100 Como, Italy

bDipartimento di Chimica Organica e Industriale, Università degli Studi di Milano Via G. Venezian 21, I-20133 Milano, Italy


In the field of peptidomimetics much effort has been focused on the design and synthesis of conformationally constrained compounds that mimic or induce specific secondary structural features of peptides and proteins. A common motif in protein structure is the reverse-turn. Reverse-turn mimics are generally cyclic or bicyclic dipeptide analogues which, as a result of their constrained structure, force a peptide chain to fold back upon itself.1

Herein, we report the synthesis of a new bifunctional DKP-scaffold 1, derived from L-aspartic acid and (S)-2,3-diaminopropionic acid, bearing an amino and a carboxylic functionalities. As a consequence of the absolute configuration of the two α-amino acids forming the cyclic dipeptide unit, the two reactive functionalities are locked in a cis-configuration and, when inserted into an oligopeptide sequence, the DKP scaffold acts as a revere-turn inducer. In addition, the DKP-scaffold 1, while being derived from α-amino acids, can be seen as a constrained dipeptide formed by two β-amino acids2 and in particular a β3- and a β2-amino acids (following Seebach’s nomenclature).3

N

COOH

N

O

OPh

NHBoc

H

(1)

β3-amino acid

β2-amino acid

A tetrapeptide (AA1-DKP-AA2) and a hexapeptide (AA1-AA2-DKP-AA3-AA4) incorporating the DKP-scaffold 1 were synthesized, and their conformations studied by NMR and molecular modelling showing the formation of a β-hairpin mimic. 1. Kahn, M. (Ed.), Peptide Secondary Structure Mimetics, Tetrahedron Symposia-in-Print No. 50, 1993, 49, 3433-3689. 2. Seebach, D.; Hook, D. F.; Glattli, A. Biopolymers 2006, 84, 23-37. 3. The superscripted number after β specifies the position of the side chain on the corresponding β-amino acid; see Hintermann, T.; Seebach, D. Synlett 1997, 437-438. Acknowledgements: We thank the European Commission (Marie Curie Early Stage Research Training Fellowship "Foldamers" MEST-CT-2004-515968) for financial support and for a PhD fellowship to A. R. We also like to thank MIUR (PRIN 2006) for financial support.

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SYNTHESIS AND CRYSTAL STRUCTURE OF Fe AND Pd COMPLEXES OF 4-CYANOBENZENEDITHIOLATE.

CHARGE TRANSFER SALTS WITH TTF.

Ana Cerdeiraa, Dulce Simãoa, Isabel C. Santosb, Rui T. Henriquesa,b, Manuel Almeidab

a Dept. Eng. Química e Biológica, IST, Av. Rovisco Pais, P-1049-001 Lisboa, Portugal. b Dept. Química ITN / CFMCUL, E.N. 10, P-2686-953 Sacavém, Portugal

e-mail: [email protected]

The transition metal bis(dithiolene) complexes have been widely used in the last

years as versatile building blocks for conducting and magnetic molecular materials. In this communication we report the preparation and characterisation of a new series of [M(cbdt)2]

-z complexes based on less symmetric ligand, cbdt = 4-cyanobenzenethiol with different transition metals (M = Au, Ni, Co, Fe, Cu, Pd). All the complexes were obtained as tetrabutylammonium or tetraphenylphosphonium salts in the monoanionic oxidation state, with the exception of Pd that was obtained in the dianionic oxidation state.

They show either cis or trans configurations depending on the coordination

geometry; dimerised complexes with 4+1 coordination geometry such as Fe prefer a cis configuration while the square planar complexs such as Pd prefer a trans configuration.

As expected their cyclic voltammetry data reveals lower oxidation potentials when compared with the dcbdt analogs, previously described[1-3].

The magnetic properties of these compounds, were studied by EPR and temperature dependent magnetic susceptibility measurements.

These metal complexes were used as acceptors to prepare charge transfer salts with the donor TTF (tetrathiafulvalene), by electrocrystallisation.

Selected references [1]- D. Simão, H. Alves, D. Belo, S. Rabaça, E. B. Lopes, V. Gama, M. T. Duarte, R. T. Henriques, H. Novais and M. Almeida, Eur. J. Inorg. Chem., 2001, 12, 3119-3126. [2]- H. Alves, D. Simão, H. Novais, I. C. Santos, C. Giménez-Saiz, V. Gama, J. C. Waerenborgh, R. T. Henriques and M. Almeida, Polyhedron, 2003, 22, 2481-2486. [3]- H. Alves, D. Simão, I. C. Santos, V. Gama, R. T. Henriques, H. Novais, M. Almeida, Eur. J. Inorg. Chem., 2004, 6, 1318-1329. Acknowledgments: We thank FCT (POCI-QUI-57528-04 ) for financial support.

PC50

Cis-[Fe(cbdt)2]

Trans-[Pd(cbdt)2]

S

S

S

S

S

S

CNS

SNC

M

TTF M(cbdt)2 M= Au, Cu, Ni, Fe

7


OH

R

H

O

NC CN

O

CN

NH2

NC CN

O

CN

NH

R R

O

CN

NH2

N

R

O

NC

1a, R=H b, R=OCH3

2a, R=H b, R=OCH3

3a, R=H b, R=OCH3

4a, R=H b, R=OCH3

+NaHCO3(aq)

MeOHNEt3(cat.)

DMSO

R

NC CN-

1aEtOH

SYNTHESIS AND IN VITRO ANTIFUNGAL ACTIVITY OF A NOVEL CHROMENE DERIVATIVE

Marta S.F. Costa § , Fernanda J.R.P. Proença, L. Abrunhosa, F. Areias and A. Venâncio

§ Universidade do Minho, Departamento de Química, 4700-320 Braga, Portugal E-mail: [email protected]

The screening for new antifungal chemicals is a constant need, due to the public demand for crop protection agents with low use rates, a benign environmental profile, and low toxicity to humans and wildlife. Chromene derivatives are an important class of compounds, widely present in plants, including edible vegetables and fruits [1]. The biological activity of some natural chromene-based structures led to the development of synthetic analogues, some of them displaying remarkable effects as pharmaceuticals [2], including antimicrobial agents [3].

In the present work, a novel 2-iminochromene dimmer was prepared by the Knoevenagel condensation of salicylic aldehydes 1a e 1b with malononitrile. Compound 4 could also be prepared from chromenes 2 and 3, under appropriate reaction conditions. The activity of compounds 2, 3 and 4 on Aspergillus spp. growth and on Ochratoxin A production was evaluated.

The chromene dimmer 4a was found to be the most effective of the tested

compounds. A moderate inhibitory effect was also observed for the analogous structure 4b but only for the inhibition of ochratoxin A production. No effect was registered for compounds 3a and 3b, used as synthetic precursors of the dimmeric species 4. These results suggest that the dimmeric structure is essential to the antifungal activity.

[1] M. Curini, G. Cravotto, F. Epifano, G. Giannone, Curr. Med. Chem., 2006, 13, 199. [2] For recent examples of biologically active chromene derivatives see: (a) D. Yu et al., Med. Res. Rev., 2003, 23, 322. (b) K.M. Khan et al., J. Enz. Inhib. Med Chem., 2004, 19, 373. (c) F Chimenti, et al., Eur. J. Med. Chem., 2006, 41, 208. [3] (a) S. Sardari, S. Nishibe, M. Daneshtalab, Stud. Nat. Prod. Chem., 2000, 23, 335. (b) A.M. El-Agrody, M.S.A. El-Latif, N.A. El-Hady, A.H. Fakary, A.H. Bedair, Molecules, 2001, 6, 519. Acknowledgments: Thanks are due to Universidade do Minho and Fundação para a Ciência e Tecnologia (POCTI/QUI/45391/2002) for financial support and for the PhD grant awarded to Marta Costa (SFRH/BD/31531/2006).

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SYNTHESIS AND REACTIVITY OF 4-HYDROXY-3-METHOXYAMPHETAMINE A “ECTSASY” METABOLITE

Mónica Estevão,§ Vanessa V. Nascimento,§ Paula S. Branco,§ Luísa M. Ferreira,§ Ana

M. Lobo,§ João P. Capela,ξ Félix Carvalho,ξ Maria L. Bastosξ § REQUIMTE/CQFB, Departamento de Química, FCT, Universidade Nova de Lisboa,

2829-516 Caparica, Portugal ξREQUIMTE, Toxicology Dept, Faculty of Pharmacy, Univ. of Porto, Portugal

E-mail: monica.estevã[email protected] 3,4-Methylenedioxymethamphetamine (MDMA or “Ecstasy”), is a widely abused, psychoactive recreational drug. There is growing evidence that MDMA neurotoxic profile may be highly dependent on its systemic metabolism.1 Metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA). MDMA and MDA are O-demethylenated to N-methyl-α-methyldopamine (N-Me-α-MeDA) and α-methyldopamine (α-MeDA), respectively, both of which are catechols that can undergo oxidation to the corresponding o-quinones. The catecholic compounds can undergo subsequent O-methylation mediated by catechol-O-methyltransferase (COMT) to 4-hydroxy-3-methoxyamphetamine (3-OMe-α-MeDA) and 4-hydroxy-3-methoxyamphetamine (3-OMe-N-Me-α-MeDA). These metabolites are excreted in the urine. Nevertheless the toxicity mediated by these metabolites as also their conjugated thioethers of biological nucleophiles, remain to be completely elucidated.2 Herein we report the synthesis of 3-OMe-α-MeDA and 3-OMe-N-Me-α-MeDA and their reactivity in the presence of oxidants and glutathione (vide Scheme).

MeO

HO

NHRCl

MeO

HO

NH2

MeO

HO

O

H

R = H, Me

[O]1)

2) GSH

R = H

HO

MeO NH2

HS

NH

O

NH

COOH

O

NH2

COOHGSH =

GSH

GSH

[O] = Ag2O, Ce(NH4)2(NO3)6

[1] A. R. Green, A. O. Mechan, J. M. Elliott, E. O’Shea and M. I. Colado, Pharmacol. Rev, 2003, 55, 463-508. [2] J.P. Capela, C. Macedo, P.S. Branco, L.M. Ferreira, A.M. Lobo, E. Fernandes, F. Remião, M.L. Bastos, U. Dirnagl, A. Meisel, Neuroscience, 2007, 1743-1757.

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7


SYNTHESIS OF ββββ-BROMO AND ββββ-IODO ββββ-SUBSTITUTED

DEHYDROAMINO ACID DERIVATIVES

Paula M. T. Ferreira,§ Luís S. Monteiro§ and Goreti Pereira§

§Department of Chemistry, University of Minho, Gualtar, 4710-057 Braga, Portugal E-mail: [email protected]

In recent work, we have been interested in the synthesis of β-halogenated

dehydroamino acid derivatives that can be used as substrates in palladium catalysed cross couplings [1,2]. The synthesis of β-bromodehydroamino acids has been carried out reacting dehydroamino acid derivatives with N-bromosuccinimide (NBS), followed by treatment with NEt3. β-Alkyl, β-bromo and β-aryl, β-bromodehydroalanines were prepared in good yields (Scheme 1, Table 1). The stereochemistry of the β-halogenated dehydroamino acids obtained was determined using NOE difference experiments by irradiating the α-NH and the OCH3 protons and observing the effect on the β-methyl and β-phenyl protons. A high selectivity towards the Z isomer was observed for the dehydrophenylalanine derivatives and when the 4-toluenesulphonyl group is used as protecting group. The same reaction with N-iodosuccinimide (NIS) gave the corresponding β-iodo, β-substituted dehydroamino acids in good to high yields. A higher Z stereoselectivity for the β-iododehydroamino acids was found, thus in the case of Z(NO2)-∆Abu(β-I)-OMe and of Boc-∆Phe(β-I)-OMe only the Z-isomer was isolated.

P

HN CO2CH3

R

P

HN CO2CH3

R Br

P

HN CO2CH3

R I

1)NBS 2)NEt3

1)NIS 2)NEt3

R=CH3 or Ph

P=Boc, Tos, Z(NO2). β-Halogenated dehydrodipeptides were prepared by reacting Boc-Gly-∆Abu-OMe

with NBS or NIS followed by treatment with NEt3. The β-bromo and β-iodo dehydrodipeptides were obtained in good yields, 90% and 76%, respectively. The E/Z ratio was 1/1 for bromination and in the case of the reaction with NIS only the Z isomer was isolated. Now we are extending the reaction with NIS to other dehydrodipeptides with different amino acids and different protecting groups.

[1] Silva, N.O.; Abreu A.S.; Ferreira, P.M.T.; Monteiro, L.S.; Queiroz, M.J.R.P. Eur. J. Org. Chem., 2002, 2524-2528. [2] Abreu, A.S.; Ferreira, P.M.T.; Monteiro, L.S.; Queiroz, M.J.R.P.; Ferreira, I.C.F.R.; Calhelha, R.C.; Estevinho, L.M. Tetrahedron, 2004, 60, 11821-11828. Acknowledgments: Thanks are due to the Fundação para a Ciência e Tecnologia (Portugal) and FEDER for funding Centro de Química-Universidade do Minho and for financial support through project POCI/QUI/59407/2004.

Product Yield /

% E/Z ratio

Boc-∆Abu(β-Br)-OMe 92 1/1 Z(NO2)-∆Abu(β-Br)-OMe 80 1/1

Tos-∆Abu(β-Br)-OMe 94 1/9 Boc-∆Phe(β-Br)-OMe[2] 97[2] 1/2[2] Tos-∆Phe(β-Br)-OMe 78 Only Z Boc-∆Abu(β-I)-OMe 88 1/3 Z(NO2)-∆Abu(β-I)-OMe 96 Only Z

Boc-∆Phe(β-I)-OMe 87 Only Z

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7


SYNTHESIS OF CHIRAL CAMPHORIC ACID DERIVED Mn-SALENS FOR THE EPOXIDATION OF STYRENE

M. Elisa S. Serra, Dina Murtinho, Albertino Goth, António M. d’A. Rocha Gonsalves

Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Coimbra


Epoxides are very useful intermediates for the synthesis of biologically active compounds, namely pharmaceuticals and agrochemicals. The asymmetric epoxidation of alkenes with chiral transition metal complexes is a very efficient method for obtaining chiral epoxides.

Our interest in asymmetric synthesis and catalysis led us to prepare a series of new chiral salens, Scheme 1, derived from (1R,3S)-1,3-diamino-1,2,2-trimethylcyclopentane 2, a diamine which is easily obtained from camphoric acid 1. The reaction of this diamine with several salicylaldehye derivatives 3a-d allowed us to obtain the chiral salens 4a-d in very good yields. Salens 4e and 4f were also obtained by reaction of 2 with 2-hydroxynaphthaldehyde 3e and acetophenone 3f, respectively.

CHO

OH

R1R2

R33a R1=R2=R3= H3b R1= OCH3, R2=R3= H3c R1= OCH3, R2= H, R3= Br3d R1=R2= (CH3)3, R3= H

N

NCH

CHOH

OH

R1

R2

R3

R3

R2

R1

4a R1=R2=R3= H4b R1= OCH3, R2=R3= H4c R1= OCH3, R2= H, R3= Br4d R1=R2= (CH3)3, R3= H

CO2H

CO2H

NH2

NH2

1 2

3e

3f

4e

4f

Scheme 1

The Mn(III) complexes of the new chiral salen ligands were prepared and tested as catalysts for the epoxidation of styrene. The synthesis of the ligands, the corresponding complexes and the results of the catalytic oxidations will be presented in this communication.

[1] Q.H. Xia, H.Q. Ge, C.P. Ye, Z.M. Liu, K.X. Su, Chem. Rev, 2005, 105, 1603-1662. Acknowledgements: the authors thank FCT (POCI/QUI/55931/2004) and Chymiotechnon for financial support.

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SYNTHESIS OF 4H-CHROMENES WITH POPENCIAL BIOLOGICAL ACTIVITY

Pedro L. B. Vicente1, Francisco Peixoto2, M. Manuel Oliveira1

1 Centro de Química, Depto de Química, Universidade de Trás-os-Montes e Alto Douro, 5001-801 Vila Real, Portugal

2 CECAV, Depto de Química, Universidade de Trás-os-Montes e Alto Douro, 5001-801 Vila Real, Portugal


The chromene moiety often appears as an important structural component in both biological active and natural compounds like chromanes, 2H-chromenes and 4H-chromenes as well as a key intermediate in the synthesis of medicinal reagents. [1-2] Fused chromenes have a wide spectrum of biological activities namely antimicrobial, antiviral, antiproliferative among others and recently they were identified as anticancer agents. [3-4] The synthesis of 4-aryl-4H-chromenes their characterization as well as some preliminary biological studies will be presented.

CHO

R

+ CH2(CN)2 +

OH

R1

O

R

R1

CN

NH2

EtOH

r.t.

R, R1 = different substituents [1] Elinson, M. N. et al., Electrochemistry Communications, 2006, 8, 1567-1571. [2] Ye, L-W et al, Org. Lett., 2006, 8(17), 3853-3856. [3] Kemnitzer, W. et al., J. Med. Chem., 2004, 47, 6299-6310. [4] Foroumadi, A. et al., Asian J. Chem., 2007, 19(2), 1391-1396.

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7


SYNTHESIS OF 1,8-DIARYLNAPHTHALENES BY THE SUZUKI CROSS COUPLING REACTION

Carlos F.R.A.C. Lima, Marisa A.A. Rocha, Luís M.N.B.F. Santos and

José E. Rodriguez-Borges§ § Department of Chemistry, Faculty of Science, University of Porto, Rua do Campo

Alegre, 687, P-4169-007 Porto, Portugal [email protected]

The π-π stacking interaction between adjacent aromatic moieties is a very interesting concept in the fields of chemistry and biochemistry.[1] It’s importance in biological systems and crystal packing is known but the nature of this interaction is yet to be completely understood. In the 1,8-diarylnaphthalenes, despite of the steric repulsion, the two parallel aromatic substituents can interact favourably by π-π stacking.[2] Using the experimental values of the standard molar enthalpies of formation on the gaseous phase, ∆fHº(g), the magnitude of this interaction can be evaluated. Once these compounds are not commercially available and the synthesis of some of them were never reported in the literature we decided to synthesize them by the Suzuki cross coupling reaction, starting from 1,8-dibromonaphthalene, using a variety of synthetic approaches. The mono-substituted analogues were also synthesized by the same reaction mechanism using 1-bromonaphthalene as the starting aryl halogenated reagent.

Ar-B(HO)22

cat.K2CO3

solvent

Br Br Ar Ar

cat. = Pd(OAc)2, PdCl2(dppe)solvent = H2O/DMF, Toluene/H2OAr = phenyl, biphenyl, thiophene, pyridine

+

[1] T. Sato, T. Tsuneda and K. Hirao, J. Chem. Phys., 2005, 123, 104307. [2] Franco Cozzi and Jay S. Siegel, Pure & Appl. Chem., 1995, 67, 683-689.

Acknowledgements: This work was supported by Fundação para a Ciência e Tecnologia (FCT) and the FERDER for the financial support to CIQUP. Carlos F.R.A.C. Lima thanks FCT and the European Social Fund (ESF) under the third Community Support Framework (CSF) for the award of a Ph.D. Research Grant (SRFH/BD/29394/2007). Thanks are also due to FCT for the financial support to the project POCI/QUI/61873/2004.

PC56

7


SYNTHESIS OF GLYCO CHLORIN DERIVATIVES AND THEIR BIOLOGICAL ACTIVITY AGAINST HSV-1

Ana R.N. Santosa,d, Rodrigo De Paulaa, Maria A.F. Faustinoa, Maria G.P.M.S. Nevesa, Augusto C. Toméa, José A.S. Cavaleiroa, António P.A. De Matosb,c, Maria F. Caeirod

a Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal b Biomaterial Department, Dental Medical School, University of Lisbon, 1649-003

Lisbon, Portugal c Anatomic Pathology Department, Curry Cabral Hospital, 1069-166 Lisbon, Portugal

d University of Lisbon, Faculty of Sciences, Department of Plant Biology, 1749-016 Lisbon, Portugal

E-mail: a25319@ alunos.dq.ua.pt

Porphyrins and their derivatives (e.g. chlorins) have been intensively studied due to their applications mainly in photodynamic therapy, where they can act in the elimination of microorganisms such as virus [1,2]. Herpes simplex virus type 1 (HSV-1) with the passing of the years have become resistant against the available antiviral compounds. [3] In the present work we report a new and easy synthetic route for N-glycoconjugated pyrrolidine chlorin with MAOS approach and also for the desprotection of the corresponding cationic compound. Besides the two compounds we also synthesised another chlorins already described in literature [4,5] to be used for the assay in vitro to look for their ability to inhibit HSV-1 infectivity. In this communication we show relevant aspects of their cytotoxicity with and without photoactivation as well as their effect against HSV-1. Studies using scanning electron microscopy are being done to evidence some possible alterations on the morphology of cell surfaces. [1] E.M.P. Silva, F. Giuntini, M.A.F. Faustino, J.P.C. Tomé, M.G.P.M.S. Neves, A.C. Tomé, A.M.S. Silva, M.G. Santana-Marques, A.J. Ferrer-Correia, J.A.S. Cavaleiro, M.F. Caeiro, R.R. Duarte, S.A.P. Tavares, I.N. Pegado, B. d’Almeida, A.P.A. De Matos, M.L. Valdeira, Bioorganic & Medicinal Chemistry Letters, 2005, 15, 3333-3337. [2] J.P.C. Tomé, E.M.P. Silva, A.M.V.M. Pereira, C.M.A. Alonso, M.A.F. Faustino, M.G.P.M.S. Neves, A.C. Tomé, J.A.S. Cavaleiro, S.A.P. Tavares, R.R. Duarte, M.F. Caeiro, M.L. Valdeira, Bioorganic & Medicinal Chemistry, 2007, 15, 4705-4713. [3] B. N. Fields, P.M. Howley, D.E. Griffin, R.A. Lamb, M.A. Martin, B. Roizman, S.E. Straus, D.M. Knipe, Fields-Virology, 2001, 4th edition, Vol 1 and 2, Lippincott Williams & Wilkins Publishers. [4] A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, Journal of Organic Chemistry, 2005, 70, 2306-2314. [5] A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, J.A.S. Cavaleiro, D. Perrone, A. Dondoni, Synlett, 2005, 5, 857-859. Acknowledgments: Thanks are due to the University of Aveiro, to Fundação para a Ciência e a Tecnologia (FCT) and FEDER for funding the Organic Chemistry Research Unit. A.R.N Santos is also thankful for her students´grant.

PC57

7


SYNTHESIS OF NEUROSTEROID RING A ANALOGUES: MODULATORS OF GABAA RECEPTORS

M. Manuel C. Silva,a Alcino J. Leitão,a Saul P. Costa,a Jorge A. R. Salvador,b

Alexander Kasal,c M. Luisa Sá e Meloa

aCentro de Estudos Farmacêuticos, Lab. Química Farmacêutica, Faculdade de Farmácia, Universidade de Coimbra, Rua do Norte 3000-295, Coimbra, PORTUGAL

bLab. Química Farmacêutica, Faculdade de Farmácia, Universidade de Coimbra, Rua do Norte 3000-295, Coimbra, PORTUGAL

cAcademy of Sciences of the Czech Republic, Institute of Organic Chemistry & Biochemistry, Prague, CZECH REPUBLIC


γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the brain, involved in controlling many conditions ranging from anxiety to epilepsy. The effects of GABA can be magnified by several types of compounds (e.g. benzodiazepines), which bind to GABAA receptors. Some metabolites of progesterone, like 3α-hydroxy-5α-pregnan-20-one (‘allopregnanolone’), also bind allosterically to the GABAA receptor and increase the inhibitory effects of GABA by opening the membrane chloride ion channel with little tolerance (1,2).

The relevance of CNS diseases has motivated intense research towards the synthesis of allopregnanolone analogues aiming longer half-lives and better solubilities in the body liquids, besides a good affinity to the GABAA receptor (3,4). Neuroactive steroids have drawn our attention and in this communication we report the synthesis of a library of allopregnanolone analogues, with structural modifications at the ring A, as potential modulators of the GABAA receptor. Chemo- and enzymatic processes developed in our lab, as ring-opening of epoxides (5,6), and lipase-catalysed reactions (7), were adapted to produce the desired steroids. The modulation of the GABAA receptor will be assessed by the [35S]TBPS test and the results will allow us to set up structure-activity relationships and to design new molecules. [1] Chebib M, Johnston GAR. Journal of Medicinal Chemistry 2000, 43(8), 1427-1447. [2] Belelli D, Lambert JJ. Nature Reviews Neuroscience 2005, 6, 565-575. [3] Suñol C, García DA, Bujons J, Krištofiková Z, Matyáš L, Babot Z, Kasal A. Journal of Medicinal Chemistry, 2006, 49 (11): 3225-3234. [4] Kasal A, Matyáš L, Budĕšínský M. Tetrahedron, 2005, 61 (9): 2269-2278. [5] Pinto RMA, Salvador JAR, Le Roux C. Synlett, 2006, 13, 2047-2050. [6] Salvador JAR, Leitão AJL, Sá e Melo ML, Hanson JR. Tetrahedron Letters, 2005, 46 (7): 1067-1070. [7] Silva MMC, Riva S, Sá e Melo, ML. Tetrahedron, 2005, 61 (12): 3065-3073. Acknowledgements - We thank FCT, through POCI and FEDER, and ASCR-GRICES bilateral exchange program (2007) for financial support.

PC58

H

HO

H

H

H

O

7


SYNTHESIS OF NEW ACRIDONES FROM DIELS-ALDER REACTIONS OF 1-METHYL-2-STYRYL-4-QUINOLONES

Andreia I. S. Almeida, Artur M. S. Silva, Diana C. G. A. Pinto, José A. S. Cavaleiro

Department of Chemistry University of Aveiro 3810-193 Aveiro [email protected]

Acridones and 4-quinolones are classes of nitrogen heterocyclic compounds possessing important biological activities. Acridone derivatives are known to present a significant citotoxic, antiviral and anti-malarial activities [1] and 4-quinolones has been used as antibacterial agents, having an important role in the treatment of urinary infections [2]. The search of new 4-quinolone derivatives has been carried out to improve the spectrum of antimicrobial activity against Gram-negative as well as Gram-positive bacteria [3]. Recent studies also revealed a new potential application for these types of compounds as anti-tumour agents [4,5]. In this communication, we present the synthesis of 2-styryl-4-quinolones 2a-d, from 2´-aminoacetophenone and the appropriate cinnamic acids, and the reactivity of the N-protected derivatives 3a-d as dienophiles in Diels-Alder reactions with N-methylmaleimide. New acridone derivatives 5a-d have been obtained in good yields. Synthetic procedures and structural characterization of the obtained compounds will be presented and discussed in this communication.

NH2 O

CO2H

A) DCC, 4-pyrrolidinopyridine, CH2Cl2, rtB) (CH3)3COK, THF, ref lux or

NaOH, t-butanol, MWC) NaH, MeI, THF, rtD) 1,2,4-Triclorobenzene, ref lux or

toluene, ref luxa) R= H; b) OCH3; c) Cl; d) NO2

+

O

NH

O

O

HN

AB

O

N

Me

1a-d 2a-d

3a-d

C

O

N

Me

5a-d

NO

O Me

N

O

O

MeN

4a-d

OMe

R

R R

RR

R

Acknowledgements: Thanks are due to the University of Aveiro, FEDER and FCT for funding the project POCI/QUI/58835/2004 and the Organic Chemistry Research Unit. [1] S. Kawaii, Y. Tomono, E. Katase, K. Ogawa, M. Yano, Y. Takemura, M. Ju-Ichi,

C. Ito and H. Furukawa, Leukemia Res., 1999, 23, 263-269. [2] C. M. Oliphant and G. M. Green, Clin. Pharmacol., 2002, 65, 455-464. [3] C. Edlund and C. E. Nord, Infection, 1988, 16, 1-80. [4] O, Tabarrini, V. Cecchetti, A. Fravolini, G. Nocentini, A. Barzi, S. Sabatini, H.

Miao and C. Sissi, J. Med. Chem., 1999, 42, 2136-2144. [5] N. Nakamura, M. Kozuka, K. F. Bastow, H. Tokuda, H. Nishino, M. Suzuki, J.

Tatsuzaki, S. L. M. Natschke, S.-C. Kuo and K.-H. Lee, Bioorg. Med. Chem., 2005, 13, 4396-4401.

PC59

7


SYNTHESIS OF NEW CALIX[4]PYRROLE DERIVATIVES THROUGH

1,3-DIPOLAR CYCLOADDITIONS

A. S. F. Farinha, A. C. Tomé, J. A. S. Cavaleiro Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal


Calixpyrroles (meso-octasubstituted porphyrinogens) are a kind of tetrapyrrolic macrocycles, synthesized for the first time by Baeyer in the XIXth century[1]. They have recently gained significant attention due to its ability to bind small anions[2]. In this communication we describe the synthesis of new calyx[4]pyrrole derivatives using as starting material the 2-formyl-octamethylcalix[4]pyrrole 1[3]. This compound was converted into the corresponding azomethine ylide 2, which was trapped in situ with dipolarophiles to afford cycloadducts 3. Details of the synthesis, structural characterization and anion binding studies of the new compounds will be presented and discussed.

NH

NH HN

HN

CHO

HN

HN

NCH2

Me

-+

HN

HN

N

Z Z

Me

1 2 3

Z

Z

[1] P.A. Gale, Jr. P. Anzenbacher, J. L. Sessler, Coord. Chem. Rev., 2001, 222, 57–102. [2] R. Nishiyabu, M. A. Palacios, W. Dehaen, Jr. P. Anzenbacher, J. Am. Chem. Joc., 2006, 128, 11496 –11504. [3] R. Nishiyabu, Jr. P. Anzenbacher, Org. Lett., 2006, 8, 359. Acknowledgments: A. S. F. Farinha thanks to the Fundação para a Ciência e a Tecnologia (FCT, Portugal) for the doctoral grant SFRH/BD/32219/2006.

PC60

7


SYNTHESIS OF NEW CORROLE DERIVATIVES VIA CYCLOADDITION REACTIONS

Luís S. H. P. Vale, Joana F. B. Barata, Maria G. P. M. S. Neves, Maria A. F. Faustino,

Augusto C. Tomé, Artur M. S. Silva and José A. S. Cavaleiro

Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal E-mail: [email protected]

Corroles continue to attract increasing interest mainly due to the development of new

significant synthetic routes and also to their promising applications in catalysis and medicine. The search for functionalization procedures leading to new derivatives plays a key role in finding compounds with new potential applications. We have shown that porphyrinic macrocyles can participate in both Diels-Alder and 1,3-dipolar cycloaddition reactions.1 Due to structural similarities between porphyrins and corroles we have decided to look for the behaviour of the latter ones under similar reaction conditions. We also have demonstrated that corroles can participate in Diels-Alder and thermal [4+4] cycloaddition reactions.2

Here we report that β-formylcorrole 1 reacts with N-methylglycine generating in situ the corresponding azomethine ylide. This 1,3-dipole participates in 1,3-dipolar cycloaddition reactions with several dipolarophiles (dimethyl fumarate, dimethyl acetylenedicarboxylate, C60 fullerene, 1,4-benzoquinone, 1,4-naphthoquinone and 1,4-anthraquinone) affording the corresponding cycloadducts 2-6 and 8. In the two latter cases not only the expected 1,3-dipolar cycloadducts were obtained but also two new unexpected products (7 and 9). We believe that they result from the 1,5-electrocyclization of the azomethine ylide, giving rise to a pyrrolo[3,4-b]corrole, which then undergoes a Diels-Alder reaction with 1,4-naphthoquinone and 1,4-anthraquinone, with subsequent deamination.

N

NN

N

C6F5

C6F5C6F5Ga

N

O

O

CH3

Py

N

NN

N

C6F5

C6F5C6F5Ga

Py

O

O

N

NN

N

C6F5

C6F5C6F5Ga

CHO

Py

N

NN

N

C6F5

C6F5C6F5Ga

N

CH3

Py

MeO2CCO2Me

N

NN

N

C6F5

C6F5C6F5Ga

N

O

O

CH3

Py

N

NN

N

C6F5

C6F5C6F5Ga

N

CH3

Py

MeO2CCO2Me

N

NN

N

C6F5

C6F5C6F5Ga

N

CH3

Py

N

NN

N

C6F5

C6F5C6F5Ga

N

O

O

CH3

Py

N

NN

N

C6F5

C6F5C6F5Ga

Py

O

O

1 2 3 4

5 6 7 8 9

[1] Cavaleiro, J. A. S.; Neves, M. G. P. M. S.; Tomé, A. C., Arkivoc, 2003, xiv, 107-130. [2] Barata, J. F. B.; Silva, A. M. G.; Faustino, M. A. F.; Neves, M. G. P. M. S.; Tomé, A. C.; Silva, A. M. S.; Cavaleiro, J. A. S., Synlett, 2004, 1291-1293. Acknowledgments: Thanks are due to the University of Aveiro, Fundação para a Ciência e a Tecnologia (FCT) and FEDER for funding the Organic Chemistry Research Unit and the project POCI/QUI/57589/2004.

PC61

7


SYNTHESIS OF NEW DELOCALISED CATIONIC AZO DYES

Maria A. Salvador,a Paulo Almeida,b Paulo F. Santos,a Lucinda V. Reisa

aDepartamento de Química and Centro de Química - Vila Real, Universidade de Trás-os-Montes e Alto Douro, 5001-801 Vila Real, Portugal

bDepartamento de Química and Unidade de I&D de Materiais Têxteis e Papeleiros, Universidade da Beira Interior, 6201-001 Covilhã, Portugal


Nevertheless the enormous synthetic versatility of azo dyes, which has turn them into the most widely used dye class, they have scarcely been modified to display absorption into the near infrared.1 Their aptitude as sensitizers for Photodynamic Therapy (PDT) has rarely been explored2 and, so far, no delocalized cationic azo dyes appear to have been studied for that purpose.

Following our interest in the development of alternative sensitizers for PDT,3 we addressed to the synthesis of novel delocalized cationic monoazo dyes displaying absorption in the phototherapeutic window (600-1000 nm). A bathochromic thiazole ring was incorporated in the chromophoric system of the dye to shift the dye’s absorption into the long-wavelength region.

The synthetic strategy involved the formation of an intermediate azo dye (1) bearing a terminal formyl group to allow the extension of the conjugation through condensation with an active methylene benzoazolium quaternary. By this procedure several delocalized cationic monoazo dyes (2), displaying intense absorption (log ε > 5.61) in the range 650-750 nm, were obtained in rather good yields (Figure).

This methodology constitutes an alternative to that traditionally employed in the synthesis of delocalized cationic azo dyes, which generally involves the regioselective alkylation of disperse azo dyes.

Z = S, Se, CMe2, CH=CH; R1 = H, Cl; R2 = H, I; R3 = Et, Hex.

Figure

[1] Griffits, J.; Lee, W.J., Adv. Colour Sci. Technol., 2002, 99-102; and references therein. [2] (a) Rajagopalan, R.; Cantrell, G.L.; Bujag, J.E.; Achilefu, S.I.; Dorshow, R.B. U.S. Patent 72763, 2003; (b) Rajagopalan, R.; Achilefu, S.I.; Bujag, J.E.; Dorshow, R.B. WO Patent 3806, 2003. [3] (a) Santos, P.F.; Reis, L.V.; Duarte, I.; Serrano, J.P.; Almeida, P.; Oliveira, A.S.; Ferreira, L.F.V., Helv. Chim. Acta, 2005, 88, 1135-1143; (b) Santos, P.F.; Reis, L.V.; Almeida, P.; Serrano, J.P.; Oliveira, A.S.; Ferreira, L.F.V., J. Photochem. Photobiol. A, 2004, 163, 267-269. Acknowledgments: Fundação para a Ciência e a Tecnologia, POCI 2010 and FEDER are greatly acknowledged for the funding of the Project (POCI/QUI/57913/2004).

PC62

NN

N

SOHC

NEt2

NN

N

S

NEt2

Z

NR31

R2 2I

R1R1

7


SYNTHESIS OF OLIGOTHIENYL-CROWN ETHER

DERIVATIVES DESIGNED FOR METAL ION DETECTION

Susana P. G. Costa,a Rosa M. F. Batista,a Carlos Lodeiro,b M. Manuela M. Raposoa a Centro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga

b REQUIMTE, FCT, Universidade Nova de Lisboa, 2829-516 Monte de Caparica E-mail: [email protected]

Detection of cations is of great interest in several areas. The ability of

crown ethers to complex cations has been exploited to produce chemosensors for cation recognition and extraction, for analytical,

environmental and medical applications [1]. During the last years we have been concerned with the synthesis and characterization of several functionalized heterocyclic compounds containing the thiophene nucleus due to their potential applications as nonlinear optical chromophores, organic conductors, solvatochromic and fluorescence probes and organic light emmiting diodes (OLED´s) [2-8]. We were therefore motivated to explore the potential of conjugated luminescent (oligo)thiophene units as pendant substituents on amine-crown ether derivatives as new chemosensors for cations. The tertiary amines 2a-c were synthesized by reductive amination of the corresponding macrocycles with formyl thiophene derivatives 1a-c in the presence of NaBH(OAc)3 at room temperature (Scheme), in fair to good yields and completely characterized by the usual spectroscopic and analytical techniques. Recent evaluation of compounds 2a-c as fluorimetric sensors for cations proved that they could be used as efficient chemosensors, especially compound 2b in the presence of H+, Na+, Pd2+ and Zn2+ [8].

Sn = 1-3

CHO + O O

O

O

O

O O

O

O

O

NH2NSS

n1

2 a n = 1 b n = 2 c n = 3

1,2-dicloroethaner.t.

NaBH(OAc)3

[1] B. Valeur, I. Leray, Coord. Chem. Rev., 2000, 205, 3-40. [2] G. Zotti, S. Zecchin, B. Vercelli, A. Berlin, M. C. Pasini, S. Destri, W. Porzio, M. M. M. Raposo, Chem. Mat., 2005, 17(25), 6492-6502. [3] M. M. Oliva, J. Casado, M. M. M. Raposo, A. M. C. Fonseca, H. Hartmann, V. Hernández, J. T. L. Navarrete, J. Org. Chem., 2006, 71(20), 7509-7520. [4] M. M. M. Raposo, A. M. R. C. Sousa, G. Kirsch, P. Cardoso, M. Belsey, E. M. Gomes, A. M. C. Fonseca, Org. Lett., 2006, 8(17), 3681-3684 and references cited. [5] R. M. F. Batista, S. P. G. Costa, M. M. M. Raposo, Tetrahedron Lett., 2004, 45(13), 2825-2828. [6] S. P. G. Costa, R. M. F. Batista, M. M. M. Raposo, Eur. J. Org. Chem., 2006, 17, 3938-3946. [7] R. M. F. Batista, S. P. G. Costa, E. L. Malheiro, M. Belsley, M. M. M. Raposo, Tetrahedron, 2007, 63(20), 4258-4265. [8] E. Oliveira, B. Pedras, R. M. F. Batista, S. P. G. Costa, M. M. M. Raposo, C. Lodeiro, "Absorption and emission studies of bifunctionalized new oligothienyl-crown ether ligands designed for chelations effects”, P57, 6º Encontro da Divisão de Química Analítica da Sociedade Portuguesa de Química, Lisboa, 29 a 30 de Março de 2007. Acknowledgments: Thanks are due to Fundação para a Ciência e Tecnologia (Portugal) for financial support through Centro de Química (Universidade do Minho).

PC63

7


SYNTHESIS OF PEPTIDES WITH α,αα,αα,αα,α-DIALKYL AND N,α,αα,αα,αα,α-TRIALKYL GLYCINES

Filipa C.S.C. Pinto, Sílvia M.M.A. Pereira-Lima and Hernâni L.S. Maia§

§ Department of Chemistry, School of Sciences, University of Minho, Gualtar, 4710-057 Braga, Portugal

[email protected]

α,α-Dialkyl glycines are useful moieties for the synthesis of peptide mimetics. However, most of these amino acids cannot be obtained commercially and, owing to steric crowding, are difficult to synthesise and difficult to use in the synthesis of peptides by conventional methods. This can be overcome by taking advantage of the strategy developed in our laboratory based on the Ugi-Passerini reaction, which, in a two-step synthesis, allowed to obtain N-acyl-α,α-dialkyl glycines ready for further coupling at their C-terminus. These substrates include peptide acids with a C-terminal α,α-dialkyl glycine residue.[1,2]

By taking advantage of this strategy, we were able to synthesise, in fair to good yields, a series of these peptide acids having one of the following amino acid residues at their C-terminus:[3] dimethyl, diethyl, dipropyl, diisobutyl and dibenzyl glycine. These peptides were elongated by coupling with a C-protected amino acid or preformed peptide.

Taking the previous approach even further, a series of peptides having a C-terminal N,α,α-trialkyl glycine were obtained and coupled with H-Phe-OtBu.

R1 NNH

R2

R3 R3

O

O

R1HN

OH

R3 R3

O

O

R1 NOH

R2

R3 R3

O

O

R1 NNHR4

R2

R3 R3

O

O

R1HN

NHR4

R3 R3

O

O

TFA neator 25%

TFA 1%or 2%

NH2R4

NH2R4

R2 = 4-CH3OC6H4-R3 = Me, Et, Pr, iBu and BnR1-CO = N-protected amino acyl or peptidylNH-R4 = residue of amino acid (or peptide) ester

[1] Jiang, W.-Q.; Costa, S.P.G.; Maia, H.L.S. Org. Biomol. Chem., 2003, 1, 3804-3810. [2] Costa, S.P.G.; Pereira-Lima, S.M.M.A.; Maia, H.L.S. Org. Biomol. Chem., 2003, 1,

1475-147. [3] Pinto, F.C.S.C.; Pereira-Lima, S.M.M.A.; Ventura, C.; Albuquerque, L.; Gonçalves-

Maia, R.; Maia, H.L.S. Tetrahedron, 2006, 62, 8184–8198. Acknowledgments: The authors wish to acknowledge the PhD scholarship granted to one of us (F.C.S.C.P) by the Fundação para a Ciência e Tecnologia.

PC64

7


SYNTHESIS OF 2-QUINOLONES FROM THE METHYL ESTER OF N-BOC-β,β-DIBROMODEHYDROALANINE AND

2-(PINACOLBORONATE)ANILINE

Ana S. Abreu, Maria-João R.P. Queiroz, Paula M.T. Ferreira Centro de Química, Campus de Gualtar, 4710-057 Braga, Portugal


In our laboratories we have been interested in the synthesis of heterocyclic compounds from β,β-dibromodehydroalanines using palladium-catalyzed and assisted reactions [1]. Recently we have prepared several 3-arylindole-2-carboxylates using a bis-Suzuki coupling followed by an intramolecular Pd/Cu-assisted C-N cyclization [2]. Here we present the “one pot” palladium-catalyzed synthesis of two 2-quinolones from the methyl ester of N-(t-butoxycarbonyl)-β,β-dibromodehydroalanine and 2-(pinacolboronate)aniline. The reactions involve Suzuki couplings and lactamization by nucleophylic attack of the amino group on the carbonyl of the ester, with loss of methanol.

+

NH2

BO

O

i

i) 20mol% PdCl2(dppf).CH2Cl2 (1:1), 1.4 equiv. Cs2CO3, THF/H2O (1:1), 3h, 90 ºC.

70%

BrBr

HN COOCH3

Boc

HN

Boc

NH2

NH

O

HN

Boc NH

O

10%

5 equiv.

The compounds obtained were separated by column chromatography and were characterized by 1H, 13C NMR and HRMS.

These 2-quinolones were obtained by a new method and will be submitted to biological activity studies.

[1] a) A.S. Abreu, N.O. Silva, P.M.T. Ferreira, M.-J.R.P. Queiroz, Tetrahedron Lett. 2003, 44, 3377-3379. b) A.S. Abreu, N.O. Silva, P.M.T. Ferreira, M.-J.R.P. Queiroz, M. Venanzi, Eur. J. Org. Chem., 2003, 4792-4796. [2] M.-J.R.P. Queiroz, A.S. Abreu, E.M.S. Castanheira, P.M.T. Ferreira Tetrahedron, 2007, 63, 2215-2222. Acknowledgments: This work was funded by FCT and FEDER through CQ-UM, POCI/QUI/59407/2004, SFRH/BPD/24548/2005 grant of A.S.A.

PC65

7


SYNTHESIS OF SOME NOVEL PYRAZOLO[3,4-d]PYRIMIDINE DERIVATIVES WITH POTENTIAL BIOLOGICAL ACTIVITY.

Abdellatif M. Salaheldin, Lígia M. Rodrigues and Ana M. F. Oliveira-Campos Centro de Química,, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal

[email protected] In recent years, pyrazolopyrimidines and related fused heterocycles are of interest as potential bioactive molecules. They are known to exhibit agrochemical and pharmaceutical activities such as CNS depressant, neuroleptic, and tuberculostatic.1 Pyrazolo[3,4-d]pyrimidines were identified as a general class of adenosine receptors.2,. Their structures are similar to purines. Moreover, in recent years, fluorinated compounds find much importance in the pharmaceutical field.3 The introduction of a CF3 group provides compounds with increased lipophylicity and activity when compared to their non-fluorinated analogues. The 5-amino-4-cyanopyrazoles 1 were reacted with triethylorthoformate to give the corresponding ethoxymethylene amino derivatives 2 which are the key compounds for cyclization using hydrazine to afford 4-imino-pyrazolo[3,4-d]pyrimidines4 3 and phenylhydrazine derivatives to give a mixture of the Dimroth rearrangement products 4 together with its oxidized forms 5.5,6

NN NH2

CN

X

NN

N

NH

N

NH2

X

NN N

CN

OEt

X

NN

N

HN

N

X

X = H, Cl, CH3, CF3

1 2 34

HN Y

NN

N

N

N

X

5

N Y

a, X = Cl, Y = CH3b, X = Cl, Y = Brc, X = Cl, Y = COOHd, X = CH3, Y = CF3e, X = CF3, Y = Cl

To confirm the structure of compounds 4 an independent route was followed reacting 4-chloropyrazolopyrimidine with p-tolylhydrazine, and the product isolated was the pyrazolo[3,4-d]pyrimidine 4a, whose spectral characteristics were completely coincident with those found for the product which was prepared before. The structures of the compounds obtained were confirmed by IR, Mass spectrometry, 1H and 13C NMR.

Acknowledgments: We thank Fundação para a Ciência e Tecnologia and FEDER (POCTI-SFA-3-686) and post-Doctoral grant for A. Salaheldin (SFRH/BPD/31490/2006). _____________________________________________________________________

1- Julino, M.; Stevens, M. F. G. J. Chem. Soc., Perkin Trans. 1, 1998, 1677–1684. 2- Davies, L. P.; Brown, D. J.; Chow, S. C.; Johnston, G. A. R. Neurosci. Lett.

1983, 41, 189. 3- Shivarama Holla, B.; Shivananda, M. K.; Akberali, P. M.;Shalini Shenoy, M.

Indian J. Chem. 2000, 39B, 440–447. 4- P.G. Baraldi, H. El-Kashef, A. Farghaly, P. Vanelle and F. Fruttarolo,

Tetrahedron, 2004, 60, 5093-5104. 5- R. S. Hosmane, B. B. Lim, and F. N. Burntt, J. Org. Chem., 1988, 53, 382. 6- R. S. Hosmane, B. B. Lim, and M. F. Summers, J. Org. Chem., 1988, 53, 5309.

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SYNTHESIS, PURIFICATION AND ANALYSIS OF PROCESS IMPURITIES IN MINOCYCLINE

Dália M.D. Barbosa1,2, Joaquim P. Queiroga1, Joaquim P. Cardoso1, José C. Menezes2

1 CIPAN SA, vala do carregado, 2001-962 Castanheira do Ribatejo Portugal 2 IBB-Institute for Biotechnology and Bioengineering, Centre for Biological and

Chemical Engineering, Technical University of Lisbon, IST, Av. Rovisco Pais, 1049-001 Lisboa, Portugal

(e-mail: [email protected]) E-mail: [email protected]

Minocycline is a potent semisynthetic derivative of tetracycline with a broad antibacterial spectrum.

Synthetic pathways, using demeclocycline as starting material, indicate that 6-deoxy-6-demethyltetracycline, 7-didemethylminocycline and 7-monodemethyl minocycline are potential by-products and constitute the main impurities of antibiotic.

We isolated each one of these compounds in two steps: 1) promoting their formation within the synthetic pathway 2) separating the compound of interest using preparative HPLC.

All these compounds were analysed by HPLC and mass spectrometry.

R1R2

OH

CONH2

OOH

OH

R3

OH O

R1 R2 R3

Minocycline N(CH3)2 H N(CH3)2

6-deoxy-6-demethyltetracyline H H N(CH3)2

7-didemethylminocycline NH2 H N(CH3)2

7-monodemethyl minocycline NHCH3 H N(CH3)2

Acknowledgments: Thanks are due to Cipan and Fundação para Ciência e Tecnologia (BDE / 15515 / 2004)

PC67

7


THE CAHN-INGOLD-PRELOG SYSTEM: HISTORY AND RECENT DEVELOPMENTS

Paulina Mata

REQUIMTE/CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829 Monte de Caparica, Portugal


The Cahn, Ingold and Prelog (CIP) System was originally proposed in 19511 for the description of the relative configuration of chiral molecules. Soon after this, methods became available to determine absolute configurations2 and an adaptation of the system to this new situation was proposed in 1956.3 The system was soon widely adopted by chemists, and the experience accumulated with its use, coupled with new developments in chemistry, were the causes for its two revisions in 19664 and 19825. Each of these revisions contributed to improve its logic, consistency, scope and applicability, and in fact the 1982 version enabled the specification of the great majority of the stereogenic units commonly encountered in organic molecules. Several authors have, however, reported examples of structures for which specification is impossible, ambiguous or inconsistent by using the 1982 CIP System6-12. To overcome these problems, we have proposed extensions and modifications to the CIP Sequence Rules8,9,12.

In this presentation, focusing on the specification of stereogenic centres, the history of the evolution of this nomenclature system is briefly outlined and our proposals for the modification of the Cahn-Ingold-Prelog Sequence Rules are described. The specification of a set of representative stereogenic centres is also presented in order to highlight shortcomings of the System and illustrate the strengths of our proposals.

[ 1] R.S. Cahn, C.K. Ingold, Chem. Soc. 1951, 612-622. [ 2] J.M. Bijvoet, A.F. Peerdeman, A.J. van Bommel, Nature 1951, 168, 271-272. [ 3] R.S. Cahn, C.K. Ingold, V. Prelog, Experientia 1956, 12, 81-124. [ 4] R.S. Cahn, C.K. Ingold, V. Prelog, Angew. Chem. Int. Ed. Engl. 1966, 5, 385-415. [ 5] V. Prelog, G. Helmchen, Angew. Chem. Int. Ed. Engl. 1982, 21, 567-583. [ 6] R.H. Custer, Match, 1986, 21, 3-31. [ 7] H. Hirschmann, K.R. Hanson, Tetrahedron, 1974, 30, 3649-3656. [ 8] P.Mata, A.M. Lobo, C. Marshall, A.P. Johnson, Tetrahedron: Asymmetry, 1993, 4,

657-668. [ 9] P.Mata, R. Nachbar, Tetrahedron: Asymmetry, 1995, 6, 693-696. [10] P.Mata, A.M. Lobo, C. Marshall, A.P. Johnson, J. Chem. Inf. Comput. Sci., 1994,

34, 491-504. [11] K.C. Nicolaou, C.N.C. Boddy, J.S. Siegel, Angew. Chem. Int. Ed. 2001, 4, 701-

704. [12] P. Mata, A.M. Lobo, Tetrahedron: Asymmetry, 2005, 16 (13), 2215-2223.

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THE REARRANGEMENT OF C-VINYLPYRROLES TO C-ALLYLPYRROLES

Maria I.L. Soares, Susana M.M. Lopes, Cláudio M. Nunes

and Teresa M.V.D. Pinho e Melo Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal


We have recently reported the reactivity of azafulvenium methides (2) generated by the thermal extrusion of sulfur dioxide from 1-methyl- and 1,1-dimethyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxides.1 These transient 8π 1,7-dipoles undergo [1,8]H sigmatropic shifts to give vinylpyrroles. The flash vacuum pyrolysis (FVP) of sulfone 1a leads to C-vinyl-1H-pyrrole 3a and C-allyl-1H-pyrrole 4a. Under FVP conditions, 3a can also be converted into pyrrole 4a proving that 3a is an intermediate in the synthesis of compound 4a from sulfone 1a. The thermal reaction of 1,3-dimethyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxide 1b affords the corresponding C-vinylpyrrole and N-vinylpyrrole via two competitive [1,8]H sigmatropic shifts, although the major product is pyrrole 4b, obtained in 58% yield.

The study was extended to the thermolysis of new 1,1-dimethyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxides in order to evaluate the scope of the interesting rearrangement of C-vinylpyrroles to C-allylpyrroles. New allylpyrroles 4c-e were obtained, in the thermolysis under FVP conditions of sulfones 1c-e, through the rearrangement of vinylpyrroles 3c-e. In this communication details of this study will be presented.

N

R4 CO2R

R3R1

R2

NH

R4 CO2R

R3R2

R1

N

R4

CO2R

R3H

R1

R2

NO2S

R4

CO2R

R3- SO2

MeR1

R2

FVP

a R1 = R3 = Me; R2 = Ph; R4 = CO2Me

b R1 = H; R2 = R3 = Me; R4 = CO2Me

c R1 = R2 = Me; R3 = p-F-C6H4; R4 = CO2Me

d R1 = R2 = Me; R3 = p-F-C6H4; R4 = Ph

e R1 = R2 = Me; R3 = Ph; R4 = CO2Me

1 2 3 4

[1,8]H

FVP

[1] Pinho e Melo, T.M.V.D.; Soares, M.I.L.; Nunes, C.M., Tetrahedron, 2007, 63, 1833–1841. Acknowledgments: We thank Chymiotechnon, Fundação para a Ciência e a Tecnologia (Project POCI/QUI/55584/2004, Grants SFRH/BPD/26772/2006 and SFRH/BD/28844/2006) and FEDER for financial support.

PC69

7


TRANSFORMING ORGANIC REACTIONS INTO NUMBERS: APPLICATION TO GENOME-SCALE MAPPING OF ENZYMATIC

REACTIONS

Diogo A. R. S. Latino and João Aires-de-Sousa REQUIMTE, CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia,

Universidade Nova de Lisboa, 2829-516 Caparica, Portugal. http://www.dq.fct.unl.pt/staff/jas

E-mail: [email protected] MOLMAP descriptors can represent reactions by numbers, based on the changes occurring in the physicochemical and topological properties of chemical bonds when reactants are transformed into products.1 MOLMAPS use self-organizing maps (SOMs) to compare the bonds available in the reactants with the bonds available in the products – the difference is taken as a representation of the reaction. Such a numeric fixed-length representation enables the automatic comparison of reactions in large databases. We explored MOLMAP descriptors for data mining databases with metabolic reactions2 (basically organic reactions), in order to identify similarities between reactions, to extract knowledge about the metabolic reactivity, and to compare reactomes of different organisms. The encoding and classification of enzymatic functions, i.e. metabolic reactions, is crucial in the reconstruction of metabolic pathways from genomes, in the comparison of reactomes, or in the design of biotechnological processes. Here we report the latest developments of the method applied to a genome-scale database. A dataset of 3784 enzymatic reactions extracted from the KEGG database were represented in both directions by MOLMAP descriptors (yielding a dataset of 7568 reactions). These were submitted to Self-Organizing Maps (SOMs) and Random Forests (RFs) for reaction classification in terms of official Enzyme Commission (EC) numbers. The mapping of the genome-scale dataset of enzymatic reactions by a SOM provides an intuitive visualization of similarities and differences between reactions, and highlights similar reactions hidden by different EC numbers. In general, the approach showed a good compatibility with the EC numbers, allowing for accurate predictions of EC numbers from the reaction equation, at the four levels of the EC hierarchy. A web interface for automatic classification of enzymatic reactions, and retrieval of similar known reactions was developed (http://neural.dq.fct.unl.pt/metabolic). References: [1] Q.-Y. Zhang, J. Aires-de-Sousa, J. Chem. Inf. Model. 2005, 45, 1775-1783.

[2] D. A. R. S. Latino, J. Aires-de-Sousa, Angew. Chem. Int. Ed. 2006, 45, 2066-2069. Acknowledgments: Diogo A. R. S. Latino acknowledges Fundação para a Ciência e Tecnologia (Ministério da Ciência e do Ensino Superior, Lisbon, Portugal) for financial support under a PhD grant (SFRH/BD/18347). The authors thank ChemAxon Ltd (Budapest, Hungary) for access to JCHEM and Marvin software, and Kyoto University Bioinformatics Center (Kyoto, Japan) for access to the KEGG database.

PC70

7


TUNING THE REACTIVITY OF DI-RHODIUM (II) COMPLEXES WITH AXIAL NHC LIGANDS: THE ARYLATION OF

ALDEHYDES

Pedro M. P. Gois,* Alexandre F. Tindade, Luís F. Veiros, Vania André, M. Teresa Duarte, Carlos A. M. Afonso, Stephen Caddick, F. Geoffrey N. Cloke

§ CQFM and CQE, Departamento de Engenharia Química e Biologia, Complexo I,

Instituto Superior Técnico, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal. Department of Chemistry, University College of London, UK.

Department of Chemistry, School of Life Sciences, University of Sussex, UK. E-mail: [email protected]

In this study we show that NHC ligands, in particular NHC - IPr 1 (Scheme 1), can efficiently coordinate with di-rhodium(II) complexes and tune their reactivity generating a new family of complexes, with remarkably activity in the arylation of a variety of aryl and alkyl aldehydes, at considerable mild conditions (Scheme 1).

Scheme 1.

The near-perfect structural match between Rh2(OAc)4 and NHC IPr found in the X-ray structure of 1 and in the calculated geometry of Rh2(OAc)4(NHC IPr) 2, as well as the electronic structure of this species may explain the effectiveness of this system as reaction catalyst (Scheme 2). This study highlights, an unprecedented reaction mode for di-rhodium(II) dimmers.

Scheme 2.

[1] Pedro M. P. Gois, A. F. Trindade, L. F. Veiros, V. André, M. T. Duarte, C. A. M. Afonso, S. Caddick, F. G. N. Cloke, Angew. Chem. Int. Ed. 2007, accepted.

Acknowledgments: Fundação para a Ciência e Tecnologia and FEDER (POCTI/QUI/60175/2004, POCI/QUI/58791/2004, SFRH/BPD/1864/2004) for financial support.

PC71

1

Possible active spicies

7


ORGLIST – an international virtual community of organic chemists

João Aires de Sousa and Yuri Binev REQUIMTE, CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia,

Universidade Nova de Lisboa, 2829-516 Caparica, Portugal. http://www.dq.fct.unl.pt/staff/jas

E-mail: [email protected] During the last ten years chemists from all over the world have gathered in ORGLIST (www.orglist.net) to discuss Organic Chemistry. ORGLIST is a discussion forum implemented as a free Internet mailing list (listserv). Anyone can subscribe to the list and only the members have the privilege to post (email) messages to the forum. Useful content, as well as a complex thread of personal relationships, emerged from the interaction of the members through this simple technological framework. ORGLIST is in fact a virtual community of organic chemists where many interesting problems and questions have been raised and where practicing chemists have found help for their work. ORGLIST has currently a fluctuating size around 950 members (with valid email addresses), and an average traffic of 1 message/day. Interestingly, the current list of subscribers include 42 email addresses (scattered through four continents) that were already in the list in 1998. We also found that more than 50% of the current members were already members of the list in 2004. Geographically, in 2007 ca. 25% of the subscribers belong to European domains, ca. 40% belong to common public e-mail providers, and ca. 20% are from other US domains (including .com). Analysis of the hour of posting also reveals an overlap with work hours in Europe and US. In one way ORGLIST can be seen as a unique resource for finding information, quite different from literature or web searching procedures. An Internet mailing list allows for fast and world wide "community searches" through the pool of diverse knowledge, intelligence, wisdom, and intuition of their members. Furthermore, the 10-years full archive of more than 4600 messages is available at the web site and is indexed by Google. ORGLIST archive has undoubtedly become a reference in Organic Chemistry. The success of ORGLIST resides on email. Email has established itself as one of the most important ways of direct communication between scientists. Its almost universal availability, low cost, asynchronous nature, quickness, informality and the possibility of exchanging electronic documents completely revolutionized our concept of "contacting someone". It is probably the Internet tool most integrated into information processing routines of common chemists. It is a daily routine for virtually everyone in science. Based on email, ORGLIST reaches the daily lives of hundreds of subscribers, allowing for quick useful answers to posts, and making users feel part of a community. And 10 years of history deepens this sense of belonging. In this poster, ORGLIST will be described and more detailed statistics will be presented.

PC72

7


UNUSUAL GAS-PHASE BEHAVIOUR OF A PYRIMIDINE-AMINOACID C60 ADDUCT: A STUDY BY ELECTROSPRAY MASS SPECTROMETRY

Catarina I. V. Ramosa, M. Graça Santana-Marquesa, Roger F. Enesb, Augusto C. Toméb,

José A. S. Cavaleirob a Mass Spectrometry Laboratory b Organic Chemistry Laboratory, Department of

Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal (email: [email protected])

The synthesis of organic derivatives of fullerenes has been an area of growing

interest over the past decades. In special the C60 adducts with substituted pyrimidines, are potential inhibitors of the HIV protease.1 The characteristic physicochemical properties of fullerenes that makes them interesting potential pharmacophores (drug carriers)2,3 entail, on the other hand, restrictions for their analysis by ESI-MS (Electrospray Mass Spectrometry) so that C60 derivatives were considered to be “ESI-inactive” compounds. Thus it is not surprising that most of the studies by ESI-MS of C60 derivatives report the formation of radical cations/anions prior to mass analysis. Nevertheless the direct analysis (without performing charge transfer reactions) of C60 neutral derivatives as their molecular open shell ions, M+. and M-., in the positive and negative modes, respectively, was reported before4.

We report here the study of a fullerene exohedral derivative (see figure) by ESI-MS and ESI-MS/MS (Electrospray Mass Spectrometry/Mass Spectrometry) in the positive mode. We have obtained the protonated closed shell species, [M+H]+, and [M+2H]2+, from slightly acidic solutions.

These species were mass selected and subjected to low energy collisions in the hexapole cell of a Q-Tof (Quadrupole-Time-of-Flight) mass spectrometer. The fragmentations observed showed some interesting features. Loss of the non-fullerene moiety, with formation of the [C60+H]+ is observed but it is not a predominant process. Instead ions formed by loss of C60 through double retro Diels-Alder reactions are observed along with other fragments of the non-fullerene moiety. The same type of fragmentation occurs for both the singly and doubly charged ions. To our knowledge this type of fragmentation was not reported before. We have found that ESI-MS/MS is a suitable technique for the characterization of this exohedral C60 derivative. References: 1.Nakamura E. et al, Bull. Chem. Soc Japan, 1996, 69, 2143 and references therein 2. Bolskar R.D. et al, J. Am. Chem. Soc., 2003, 125, 5471 3. Da Ros T., Prato M. Chem Commun., 1999, 663 4. Lui T.-Y. et al, Rapid Commun. Mass Spectrom, 1995, 9, 93 Acknowledgements: The authors wish to thank Fundação para a Ciência e a Tecnologia (FCT) for financial support (through POCI/QUIM/58515/2004).

PC73

NN

Me

HN CO2Me

NN

Me

HN

H

7


VALORIZATION OF THE ALKALOIDS IN LEACHING WATERS OF LUPINUS ALBUS

Sheiliza Carmali, V. D. Alves, Isabel M. Coelhoso, Ana M. Lourenço and Luisa M. Ferreira

§REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, 2829-516 Caparica, Portugal.


Lupinus seeds are important food and feed components with high nutrient value that is comparable to soybean. The bitter taste of the seeds is imparted by the quinolizidine alkaloids (QA) mainly lupanine that is a valuable starting material for the hemisynthesis of other alkaloids. Lupinus albus species is endemic in Iberic Peninsula and for consumption must be subject to extensive debittering by leaching in water. The debittering process in performed in large scale and the waste waters are discarded or finds some application in agriculture as fertilizer or in plant protection.1

Concentration of debittering effluents of L. albus was accomplished by osmotic evaporation (OE), using a 5 M solution of CaCl2. In this process, a porous hydrophobic membrane separates a diluted aqueous solution from a concentrated osmotic solution.

A membrane contactor (0.23 m2), with hydrophobic polypropylene fibres was used to evaporate water from the effluent to the osmotic solution. The experiment was carried out during 45 h due to the low membrane area employed compared to the volume processed (3 L). The concentration factor obtained was 16. The time can be reduced using a contactor with a higher area. A 1 m2 contactor can accomplish the same concentration factor in only 9 h. The initial flux obtained in the concentration process was 8x10-8 m3/(m2 s), however due to presence of other components in the effluent (oligosaccharides, amino acids and proteins) the flux was reduced to 4x10-8 m3/(m2 s) in the last 10 h.

Lupanine occurs in both enantiomeric forms and the proportion of each enantiomer is different between Lupinus species.2 In the leaching waters that we have studied lupanine is present in a proportion of 1 g / L and (-)-lupanine is the predominant enantiomer. The enantiomeric excess is near 33 % of the levo enantiomer. The enantiomers were resolved by cristalization of their dibenzoyltartarate derivatives.

(+)-(6R,7S,9S,11S)-lupanine

N

O

H

H

6

9

11

7

(-)-(6S,7R,9R,11R)-lupanine

N

O

H

H

6

9

11

7

[1] Folkman, W., Szerechan, J., Gulewicz, K., Journal of Plant Protection Research, 2002, 42, 143-155. [2] Wysocka, W., Chrzanowska, M., Herba Polonica, 2004, 50, 76-80.

PC74

7


SYNTHESIS OF CATIONIC AND PERMETHYLATED CHLORINS

Rodrigo De Paula, Maria da Graça P. M. S. Neves, José A. S. Cavaleiro Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal


Tetrapyrrolic macrocycles constitute a large family of natural compounds in Nature [1-3] of which common examples are the hemoproteins, cytochromes, vitamin B12 and chlorophylls. Uses of tetrapyrrolic compounds in Medicine (e.g., in cancer treatment and detection) are of great significance [3], but novel and efficient compounds are required. Also water-soluble compounds are more attractive for medical applications [3]. Chlorins (dihydro-type porphyrins) are good candidates since their electronic spectra present a good absorption band in the so-called “therapeutic window” (λabs>600 nm). As it was shown by the Aveiro group, an easy way for obtaining chlorins is the cycloaddition reaction of porphyrins with azomethine ylides (Scheme 1) [4,5]. Here we describe the synthesis of a water-soluble tetracationic, permethylated chlorin and a few of its metallocomplexes. The synthetic methodology, spectroscopic and photophysical analysis will be discussed.

N N

N N

N+

N

N+

N

N+

N

N+

N

CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

N

CH3

H

H

M

N N

N N

N+

N

N+

N

N+

N

N+

N

CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

M

O

H Hn

O

NHOHCH3

+

N+

CH2

-CH2

CH3

DMF, reflux2-3 h

inert atmosphere (N2)

Scheme 1. Synthesis of permethylated cationic chlorin (free-base (M=H2) and metallated (M=Zn(II))

Acknowledgements: Thanks are due to Fundação para a Ciência e a Tecnologia (FCT)/FEDER for funding the Organic Chemistry Research Unit. One of us (R. De Paula) also thanks FCT for his PhD grant (SFRH/BD/25666/2005).

References:[1]-Milgron, L. R., In The Colours of Life, Oxford University Press, Oxford, 1997. [2]-Kadish, K. M., Smith, K. M., Guilard, R., In The Porphyrin Handbook, Vol. 6, Academic Press, San Diego, 2000. [3]-Bonnett, R., In Chemical Aspects of Photodynamic Therapy, Gordon and Breach, Amsterdam, 2000. [4]-Padwa, A., Pearson, W.H., In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Towards Natural Products, John Wiley Inc. New York, 2002. [5]-Silva, A.M.G., Tomé, A.C., Neves, M.G.P.M.S., Silva, A.M.S., Cavaleiro, J.A.S., J. Org. Chem., 2005, 70, 2306-214.

PC75

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OXIMES OF GLYOXYLATES AS DIENOPHILES IN AZA-DIELS-ALDER REACTIONS

Carlos A. D. Sousa, M. Luísa C. Vale and José E. Rodríguez-Borges

Centro de Investigação em Química, Department of Chemistry, Faculty of Science, University of Porto

Rua do Campo Alegre 687, 4169-007 Porto, Portugal [email protected]

In the last years, our research group has been interested in the synthesis of

2-azabicyclo[2.2.1]heptenes and its derivatives as synthetic intermediates in the preparation of a great variety of compounds of chemical, pharmaceutical and biological interest.1 In particular, 2-functionalized 3,5-bis(hydroxymethyl)pyrrolidines (glycomimetics) can be obtained through bis-hydroxylation of the C5-C6 bond of 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylates followed by oxidative cleavage of the corresponding diols and in situ reduction of the resulting intermediates (dialdehydes).2

In this work we describe the synthesis of 2-azabicycloalkenes from aza-Diels-Alder reaction between cyclopentadiene and oximes of glyoxylates. These compounds represent an important group of syntons useful in the preparation of aminoalcohols derived from pyrrolidine necessary for the synthesis of azanucleosides and/or iminosugars.

H

O

OR

O

H

O

OR

NHO

N

CO2R

OHN

CO2R

OH

+

H2NOH.HCl

N

CO2R

H

H References:

1. M. L. C. Vale, J. E. Rodriguez-Borges, F. Fernandez, O. Caamaño, X. Garcia-Mera; Tetrahedron, 2006, 62, 9475-9482.

2. M. José Alves, Xerardo García-Mera, M. Luisa C. Vale, Teresa P. Santos, Fábio

R. Aguiar and José E. Rodríguez-Borges, Tetrahedron Letters, 2006, 47,7595-7597.

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SYNTHESIS, CONFORMATIONAL ANALYSIS AND METAL CATION BINDING PROPERTIES OF A NEW HOMOOXACALIX[3]ARENE

TRIKETONE DERIVATIVE BY PROTON NMR STUDIES

Paula M. Marcos,1, 2 José R. Ascenso,3 Peter J. Cragg4 1Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, 2Centro de Ciências Moleculares e Materiais, FCUL, Edifício C8, 1749-016 Lisboa, 3Instituto Superior Técnico, Complexo I, Av. Rovisco Pais, 1049-001 Lisboa,

4School of Pharmacy and Biomolecular Sciences, Univ. of Brighton, BN2 4GJ, UK E-mail: [email protected]

In the field of host-guest chemistry, many studies have focussed on the binding ability of calixarenes bearing carbonyl groups at their lower rims towards metal ions [1]. For some years we have been synthesising dihomooxacalix[4]arene derivatives containing carbonyl groups at the lower rim and studying their binding properties towards alkali, alkaline earth, transition and heavy metal cations [2-4]. In the course of these studies, we have now extended our research to the study of hexahomotrioxacalix[3]arenes [5]. We present in this work the synthesis, the conformational analysis and the binding properties towards alkali and alkaline earth metal cations of adamantylketone 2. Ketone 2 was synthesised for the first time. Treatment of p-tert-butylhexahomotrioxa-calix[3]arene (1) with 1-adamantyl bromomethyl ketone and NaH in THF at reflux for 24 h furnished compound 2. Proton and carbon-13 NMR spectra were carried out in chloroform at room temperature, indicating a cone conformation for ketone 2. The binding properties of 2 have been assessed by proton NMR titration experiments. Variable amounts of the metal salts (Na+, K+, Ca2+, Sr2+ and Ba2+) were added into the NMR tubes containing the ligand, and the spectra recorded after each addition. These titrations indicated 1:1 complexes with all cations. The results are compared to those obtained with other homooxacalixarene analogues.

R = H1

t-Bu t-Bu

t-Bu

ROOR

OR

O

OO

2 R = CH2COAd

[1] Calixarenes 2001, Z. Asfari, V. Böhmer, J. Harrowfield and J. Vicens (Eds.),

Kluwer Academic Publishers, Dordrechet, 2001. [2] P. M. Marcos, S. Félix, J. R. Ascenso, M. A. P. Segurado, B. Mellah, R. Abidi, V.

Hubscher-Bruder, F. Arnaud-Neu, Supramol. Chem., 2006, 18(4), 285. [3] P. M. Marcos, S. Félix, J. R. Ascenso, M. A. P. Segurado, J. L. C. Pereira, P.

Khazaeli-Parsa, V. Hubscher-Bruder, F. Arnaud-Neu, New J. Chem., 2004, 28, 748. [4] P. M. Marcos, J. R. Ascenso, M. A. P. Segurado, J. L. C. Pereira, J. Inclusion

Phenom. Macrocyclic Chem., 2002, 42, 281. [5] P. M. Marcos, J. R. Ascenso, P. J. Cragg, Supramol. Chem., 2007, 19(3), in press.

PC77

7


NEW APPROACHES FOR METALLOPORPHYRIN CATALYSED OXIDATION REACTIONS

Mário M.Q. Simões, Domingos M.A. Silva, Rodrigo De Paula, Augusto C. Tomé,

M. Graça P.M.S. Neves, José A.S. Cavaleiro Department of Chemistry, University of Aveiro, 3810-193 Aveiro

[email protected] An important challenge for green chemistry is the finding of alternatives to the common oxidation synthetic methodologies, based on stoichiometric oxidants that lead to large amounts of non-biodegradable by-products [1]. The use of H2O2 as a cheap, environmentally clean and easy to handle oxidant [2], in conjugation with robust and easily obtainable metalloporphyrins as catalysts, led to efficient procedures to perform many oxidative reactions [3-5]. In some cases the role of a co-catalyst has shown to be essential [4], either by speeding up the reaction or by changing the stereoselectivity [6]. However, the potentiality of these systems can be highly increased by anchoring the catalyst to a solid support, thus allowing its easy recovery and reuse. Moreover, the local environment of the support can bring higher selectivity and prevention of catalyst self-oxidation [7]. Efficient supported metalloporphyrin catalysts use organic or mineral supports; silica is being recognized as a very attractive material, due to its stability towards drastic catalytic oxidation conditions [8]. The most recent results dealing with homogeneous and heterogeneous metalloporphyrin catalysed oxidation reactions currently in progress in our laboratory will be presented. Acknowledgments

Thanks are due to the University of Aveiro and FCT for funding the Organic Chemistry Research Unit. R. De Paula also thanks FCT for his PhD grant (SFRH/BD/25666/2005).

References

[1] R. Noyori, M. Aoki, K. Sato, Chem. Commun., 2003, 1977-1986.

[2] C.W. Jones, Applications of Hydrogen Peroxide and Derivatives, The Royal Society of Chemistry, Cambridge, 1999.

[3] S.L.H. Rebelo, M.M.Q. Simões, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, Chem. Commun., 2004, 608-609.

[4] S.L.H. Rebelo, M.M. Pereira, M.M.Q. Simões, M.G.P.M.S. Neves, J.A.S. Cavaleiro, J. Catal., 2005, 234, 76-87.

[5] G. Grigoropoulou, J.H. Clark, J.A. Elings, Green Chem., 2003, 5, 1-7.

[6] C.-P. Du, Z.-K. Li, X.-M. Wen, J. Wu, X.-Q. Yu, M. Yang, R.-G. Xie, J. Mol. Catal. A: Chem., 2004, 216, 7-12.

[7] (a) J.R.L. Smith, in: R.A. Sheldon (Ed.), Metalloporphyrins in Catalytic Oxidations, Marcel Dekker, New York, 1994, p. 325. (b) M.V. Vinodu, M. Padmanabhan, J. Polym. Sci. Part A: Polym. Chem., 2001, 39, 326-334.

[8] B. Meunier, A. Robert, G. Pratviel, J. Bernadou, in: K.M. Kadish, K.M. Smith, R. Guilard (Eds.), The Porphyrin Handbook, Academic Press, San Diego, 2000, Volume 4, p. 155.

PC78

7


PREPARAÇÃO DE N-ÓXIDOS POR OXIDAÇÃO DIRECTA DE DERIVADOS DA PIRIDINA

Lucau Teresa, Paula C. P. da Silva e Fernando M. S. Brito Palma

CECUL e Departamento de Química e Bioquímica da Faculdade de Ciências da Universidade de Lisboa, Rua Ernesto Vasconcelos, C8, 1749-016 Lisboa, Portugal

[email protected]

As propriedades electrónicas únicas do grupo funcional N-óxido, que lhe

permitem activar os anéis heteroaromáticos, quer para ataque por nucleófilos, quer para

ataque por electrófilos, conferem aos N-óxidos heteroaromáticos possibilidades

sintéticas que dificilmente se conseguiriam por outros métodos. Para além disto, os N-

óxidos heteroaromáticos têm-se revelado úteis como grupos protectores, oxidantes,

ligandos em complexos metálicos e catalisadores1. As suas propriedades biológicas são

também reconhecidas. Muitos têm propriedades antibacterianas, antivirais,

anticancerígenas, antifungícas ou antielmintícas2. São também utilizados em cosmética,

na regulação do crescimento de plantas, na síntese de medicamentos, etc3.

Os N-óxidos são tradicionalmente preparados por oxidação directa da respectiva

base com ácidos percarboxílicos. Contudo, com substractos activados por grupos

dadores de electrões, a protonação da base nas condições acídicas em que a oxidação

decorre, impede a sua oxidação. Nos últimos anos, outros oxidantes foram introduzidos

de modo a que a reacção decorra em meio não acídico: dioxiranos e, fundamentalmente,

sistemas catalíticos envolvendo complexos metálicos3.

Neste trabalho, descrevemos a oxidação directa de piridinas activadas com

substituintes electrodadores com peróxido de hidrogénio, utilizando como catalisador o

MTO (metiltrioxorénio – CH3O3Re). Este complexo que já havia tido muito sucesso

como catalisador noutras reacções de oxidação4, em particular em N-oxidações,

permitiu também obter resultados muito satisfatórios com este tipo de substractos.

[ ]1 S. Youssif, Arkivoc, 2001, 242.

[ ]2 A. Jason et al., J. Med. Chem., 2005, 2019. [ ]3 V.V. Prezhdo et al., 1998, 127. [ ]4 K. B. Sharpless et al., J. Org. Chem., 1998, 1740.

PC79

7


Author Index

7


A A. C. Santos A. C. Serra A. C. Tomé A. Duarte A. Gil Fortes A. J. Burke A. L. Cardoso A. M. d’A. Rocha Gonçalves A. M. Madureira A. R. Dias A. S. F. Farinha A. Serra A. Venâncio A.N. Silva Abdellatif M. Salaheldin Abel Vieira Albertino Goth Alcino J. Leitão Alexander Kasal Alexandra Gonsalves Alexandra I. Costa Alexandra M.M. Antunes Alexandre F. Tindade Alice M. Dias Alves M. J. Ana Cerdeira Ana Cristina Santosb Ana I. Loureiro Ana M. Diniz Ana M. F. Oliveira-Campos Ana M. Lobo Ana M. Lourenço Ana M. L. Seca Ana Margarida Abrantes Ana Maria F. Silva Ana Maria M. M. Faísca Phillips Ana P. Esteves Ana Paiva Ana R. M. Soares

PC4, PC19 PC4 PC60 PC39 PC78 PC17, OC12 OC13 PC4, PC19 PC39 PC27 PC60 PC19 PC51 PC39 PC66 PC21 PC54 PC58 PC58 PC40 PC11, PC15 PC20, PC21, PC46 PC37, PC71 OC7 PC7 PC50 PC23 OL4 PC1 PC8, PC66 PC9, PC35, PC38, PC41, PC45, PC52 PC74 OC17 PC23 PC6 PC29 PC8, PC16 PC10 PC5

7


Ana R. N. Santosa Ana S. Abreu Ana Sofia M. Ressurreição André P. Ferreira Andrea G. P. R. Figueiredo Andreia A. Rosatella Andreia I. S. Almeida Andreia Palmeira António M. d’ A. Rocha Gonsalves António Mendonça António P. S. Teixeira António P.A. De Matos Arantxa Gómez-Esqué Arménio C. Serra Artur J. G. Bento Artur M. S. Silva Augusto C. Tomé

PC57 PC65 PC49 PC26 OC2 PC14 PC59 PC13 PC22, PC23, PC40,PC54 PC16 PC27 PC57 OC3 PC23, PC22, PC40,OC16 PC9 PC2, PC32, PC59, PC61 PC5, PC57, PC61, PC73

B Bruce F. Milne Bruno F. O. Nascimento

PC13, PC72, OL3 PC23

C Carla Lucas Carla Macedo Carlos A. M. Afonso Carlos A. D. Sousa Carlos Cobas Carlos F.R.A.C. Lima Carlos G. Azevedo Carlos Lodeiro Carmen Nájera Catarina Churro Catarina I. A. Santos Catarina I. V. Ramos Catarina Prista Cesare Gennari

PC47 PC1 PC12, PC14, PC24, PC33, PC37, PC71, PL2 PC76 OL5 PC56 PC24 PC63 PL3 PC9 PC19, PC40 PC73 PC25 PC49

7


D Dália M. D. Barbosa David A. Learmonth Diana C. G. A. Pinto Dina I. Mendonça Dina Murtinho Diogo A. R. S. Latino Dulce Simão

PC67 OL4 PC2, PC59 PC16 PC54 PC70 PC50

E Eduarda Fernandes Elisangela Costa Emília Sousa Eugénia Pinto

PC21 PC44 PC10, PC13, PC44 PC44

F F. Areias F. Geoffrey N. Cloke Fátima C. Teixeira Félix Carvalho Fernanda J. R. P. Proença Fernando M. S. Brito Palma Filipa C. S. C. Pinto Francisco Peixoto Frederick A. Beland

PC51 PC37, PC71 PC47 PC52 PC3, PC51 PC79 PC64 PC55 PC20, PC46

G Goreti Pereira

PC53

H Henry S. Rzepa

PL5

Cláudio M. Nunes Costa C. Costa F. T.

PC69 PC7 PC7

7


Hernâni L.S. Maia Honorina M. M. Cidade

PC6, PC64 PC32

I Inês F. Antunes Inês Martins Isabel C. Santos Isabel M. Coelhoso Isabel R. Coutinho

PC47 PC46 PC50 PC74 PC45

J J. A. S. Cavaleiro J. Costa Jean-Marie Beau J. Iley J. Mulchande J.P. Crespo Jim Iley Joan Bosch Joana F. B. Barata Joana Moura João Aires-de-Sousa João Noronha João P. C. Tomé João P. Capela Joaquim P. Cardoso Joaquim P. Queiroga Jorge A. R. Salvador José A. S. Cavaleiro José C. C. Santana José C. Menezes José E. Rodriguez-Borges José R. Ascenso José V. Prata

PC60 PC48 PL10 PC31 PC31 PC33 PC36 PC18 PC61 PC25 PC42, PC70 PC21 PC5 PC52 PC67 PC67 PC58 PC2, PC5, PC57, PC59, PC61, PC73, PC75 PC1 PC67 PC56, PC76 PC77 PC11, PC15

L L. Abrunhosa

PC51

7


L. F. Veirosa L.C. Branco L.M.T. Frija Laura Belvisi Lígia M. Rodrigues Lucau Teresa Lucinda V. Reisa Luís C. Branco Luís F. V. Pinto Luís F. Veiros Luis M. Carvalho Luís M.N.B.F. Santos Luís S. H. P. Vale Luís S. Monteiro Luís Vale-Silva Luisa M. Ferreira Luísa Martins

PC37 PC33 PC28 PC49 PC8, PC66 PC79 PC62 PC14 PC41 PC71 PC43 PC56 PC61 PC53 PC44 PC1, PC35, PC52, PC74 PC36

M M. Abrantes M. Abrantes M. Elisa S. Serra M. F. Botelho M. F. Cabral M. Fátima Minas da Piedade M. Filomena Botelho M. Graça Santana-Marquesa M. Helena Garcia M. I. Page M. J. G. Fernandes M. João M. Curto M. Laranjo M. Luísa C. Vale M. Luisa Sá e Melo M. Manuel B. Marques M. Manuel C. Silva M. Manuel Oliveira M. Manuela M. Raposo M. Matilde Marques M. Neves M. Paula Robalo

PC19 PC4 PC54 PC4, PC19 PC48 PC27 PC23 PC73 PC27 PC31 PC34 PC47, PL9 PC4, PC19 PC76 PC58 PC35 PC58 PC55 PC63, OC14 PC20, PL7, PC26, PC46 PC47 PC27

7


M. Pineiro M. S. T. Gonçalves M. Teresa Duarte M. J. U. Ferreira M. L. S. Cristiano Madalena M. M. Pinto Mafalda Laranjob Magdi E. A. Zaki Manuel Almeidab Margarida Archer Margarida Guerreiro Maria A. Carrondo Maria A. F. Faustino Maria A. Salvador Maria F. Caeiro Maria Fernanda Proença Maria G. P. M. S. Neves Maria I. L. Soares M. I. Ismael M. José Alves M. Lurdes S. Cristiano Maria J. Bonifácio Maria J. Medeiros Maria L. Bastos Maria L. Rodrigues Maria Loureiro Dias Maria M. B. Marques Maria M. M. Santos Maria S. J. Nascimento Maria Teresa Barros Maria-João R.P. Queiroz Mariana P. Duarte Marília E. T. F. Silva Mário M. Q. Simões Marisa A. A. Rocha Marta A. O. P. Neves Marta Pineiro Marta Correia-da-Silva Marta S.F. Costa Massuquinini Inês Mercedes Amat

PC4, PC19 PC34 PC27, PC37, PC47, PC71 PC39 PC28 PC10, PC13, PC24, PC32, PC44, PC72, OL3 PC23 PC3 PC50 OL4 PC25 OL4 PC57, PC61 PC62 PC57 PL4 PC5, PC57, PC61 , PC75 PC69 OC5 PC78 OC9 OL4 PC16 PC52 OL4 PC25 PC45 PC18 PC10, PC32, PC44 PC29 PC30, PC65, OC1 PC20 PC8 OC11 PC56 PC32 PC23, PC40 OC6 PC51 PC16 PC18

7


Monica Civera Mónica Estevão Muna Sidarus

PC49 PC52 PC20

N N. Soares N. Torres Nair Nazareth Natália Faria Nelson A. M. Pereira Nikolay Larin Nuno G. Azóia Nuno Palma Nuno R. Candeias

PC39 PC48 PC10, PC44 PC9 PC4 OL5 PC78 OL4 PC12

O Oriol Bassas

PC18

P P. Cambeiro Barrulas P. S. Kulkarni P. M. P. Gois Patrícia D. Barata Patricio Soares-da-Silva Paula M. Marcos Paula M. T. Ferreira Paula C. P. da Silva Paula S. Branco Paulina Mata Paulo Almeida Paulo F. Santos Paulo J. Coelho Paulo Pereira Pedro J. M. Abreu Pedro L. B. Vicente Pedro M. P. Gois Pedro P. Santos Pedro Santos

PC17 PC33 PC37 PC11 OL4 PC77 PC53, PC65 PC79 PC1, PC52 PC25, PC68 PC62 PC62 PC43, OC15 PC9 OC8 PC55 PC7, PC12 PC20, PC46 PC21

7


Peter J. Cragg Peter Somfai

PC77 PL1

R R. Fausto R. Moreira Rui G. Lopes Raquel A. P. Castanheiro Raquel S. G. R. Seixas Ravi Varala Ricardo C. Calhelha Ricardo Figueiredo Rodrigo De Paula Roger F. Enes Rosa M. F. Batista Rui Moreira Rui T. Henriques

PC28 PC31 OC10 PC24 PC2 PC45 PC30 OC4 PC57, PC75 PC73 PC63 PC36 PC50

S S. Mulhovo S. P. G. Costa Salette H. Reis Sandra Lampreia Santiago Domínguez Sara M. M. Cravo Saul P. Costa Scott Boyer Sérgio Paulino Sheiliza Carmali Sílvia M. M. A. Pereira-Lima Siméon Arseniyadis Sonia M. Ribeiro Stan Sykora Stephen Caddick Stephen Caddick Sundaresan Prabhakar Susana Franca Susana M.M. Lopes

PC39 PC34 PC24 PC40 OL5 PC24 PC58 OL1 PC9 PC74 PC6, PC64 PL8 PC22 OL5 PC37 PC71 PC9, PC35, PC38, PC41, PC45 PC9 PC69

7


Susana P. G. Costa Susana P. Gaudêncio

PC63 PC45

T Teresa M.V.D. Pinho e Melo Tomás Torres

PC69 PC5

U Umberto Piarullia

PC49

V V. Andréa V. D. Alves Valdemar B. C. Figueira Valerie J. Gillet Vanessa V. Nascimento Vania André Vânia F. Pais Victor F. Ferreira

PC37 PC74 PC9, PC38 OL2 PC52 PC71 PC27 PL6

W W. Y. Tsang

PC31

Y Yuri Binev

PC42

Z Z. Barata

PC39

7


Participants Index

7


Abreu, Pedro Chemistry FCT-UNL QUINTA DA TORRE 2829-516 CAPARICA PORTUGAL [email protected] Abreu, Ana Química Universidade do Minho Campus Gualtar 4710-057 Braga PORTUGAL [email protected] Aires de Sousa, Joao Departamento de Quimica FCT UNL campus FCTUNL 2829-516 Caparica PORTUGAL [email protected] Albergaria, Rui Direcção Técnica NCH (international) Rua Almada Negreiros, lote 6 B - 1º Esq 2615-275 Alverca do Ribatejo 2615-275 Alverca do Ribatejo Alverca do Ribatejo PORTUGAL [email protected] Almeida, Andreia Química Aveiro Campus Universitário de Santiago 3810-193 Aveiro PORTUGAL [email protected] Azevedo, Carlos Química Orgânica Faculdade de Farmácia da Universidade do Porto R. Aníbal Cunha n.º 164 4050-047 Porto Porto PORTUGAL [email protected] Barata, Patrícia Dep. Eng. Química - Secção de Química Orgânica Instituto Superior de Engenharia de Lisboa Rua Conselheiro Emídio Navarro, 1 1950-062 Lisboa PORTUGAL [email protected] Barata, Zita FCUL Rua Domingos Reis Quita, 1 r/c esq.

7


2745-100 Queluz PORTUGAL [email protected] Barbosa, Dália development CIPAN/IST vala do carregado 2601-962 castanheira do ribatejo PORTUGAL [email protected] Barrulas, Pedro Química Universidade de Évora Rua Romão Ramlho 59 7000 Évora Évora PORTUGAL [email protected] Bento, Artur Química Faculdade de Ciências e Tecnologia Departamento de Química Faculdade de Ciências e Tecnologia 2829-516 Caparica PORTUGAL [email protected] Binev, Yuri Departmento de Química, REQUIMTE, CQFB Universidade Nova de Lisboa, Faculdade de Ciências Universidade Nova de Lisboa, Departmento de Química, Faculdade de Ciências e Tecnologia, 2829-516 Caparica, Portugal. 2829-516 Caparica PORTUGAL [email protected] Branco, Paula Departmento de Química, REQUIMTE, CQFB Universidade Nova de Lisboa, Faculdade de Ciências Universidade Nova de Lisboa, Departmento de Química, Faculdade de Ciências e Tecnologia, 2829-516 Caparica, Portugal. 2829-516 Caparica PORTUGAL [email protected] Burke, Anthony Quínica Universidade de Évora Rua Romão Ramalho, 59 7000 Évora 7000 Évora Évora PORTUGAL [email protected] Costa, Flora FACULDADE DE CIÊNCIAS UNIVERSIDADE FERNANDO PESSOA R. CARLOS DA MAIA, 298 4200-150 PORTO

7


PORTUGAL [email protected] Cabrita, Eurico Chemistry FCT/UNL Campus de Caparica Quinta da Torre 2829-516 Caparica PORTUGAL [email protected] Calhelha, Manuel Ricardo Centro de Química Universidade do Minho Campus de Gualtar 4710-057 Braga PORTUGAL [email protected] Candeias, Nuno Centro de Química Física Molecular IST/UTL Centro de Química Física Molecular Complexo-1 Instituto Superior Técnico Av. Rovisco Pais P-1049-001 Lisboa PORTUGAL [email protected] Cardoso, Ana Chemistry University of Coimbra Rua Larga 3005-535 Coimbra PORTUGAL [email protected] Carmali, Sheiliza Quimica FCT/UNL Campus da Caparica 2829-516 Caparica PORTUGAL [email protected] Carvalho, Maria Alice Química Universidade do Minho Universidade do Minho Departamento de Química- Escola de Ciências Campus de Gualtar 4700-057 Braga Braga PORTUGAL [email protected] Castanheiro, Raquel Química Orgânica Faculdade de Farmácia da Universidade do Porto Rua Aníbal Cunha, 164 4050-047 Porto Porto PORTUGAL [email protected]

7


Cerdeira, Ana Departamento de Engenharia Química e Biológica Instituto Superior Técnico Av. Rovisco Pais 1049-001 Lisboa PORTUGAL [email protected] Coelho, Paulo Chemistry UTAD Quinta dos Prados 5001-911 Vila Real PORTUGAL [email protected] Correia, Carla Departamento de Química Universidade do Minho Campus de Gualtar Escola de Ciências Braga 4710-057 Braga PORTUGAL [email protected] Correia da Silva, Marta Química Orgânica Faculdade de Farmácia, Universidade do Porto Rua Aníbal Cunha 164 4050-047 Porto PORTUGAL [email protected] Costa, Marta Departamento de Química Universidade do Minho Centro de quimica da Universidade do Minho Campos de gualtar 4710-057 Braga PORTUGAL [email protected] Costa, Elisangela CEQOFFUP Faculdade de Farmácia da Universidade do Porto Rua Aníbal Cunha,164 4050-047 Porto PORTUGAL [email protected] Costa, Alexandra Engenharia Química Instituto Superior de Engenharia de Lisboa Rua Conselheiro Emídio Navarro, 1 1950-062 Lisboa PORTUGAL [email protected] Costa, Susana Química Universidade do Minho

7


Campus de Gualtar 4710-057 Braga PORTUGAL [email protected] De Paula, Rodrigo Chemistry University of Aveiro Department of Chemistry Campus Santiago University of Aveiro 3810-193 Aveiro PORTUGAL [email protected] Dias, Catarina Química Farmacêutica e Fitoquímica Faculdade de Farmácia da Universidade de Lisboa Av Prof Gama Pinto 1649-003 LISBOA PORTUGAL [email protected] Dinis, Ana Química FCT/UNL Campus da Caparica 2829-516 Caparica PORTUGAL [email protected] Estevão, Mónica Química FCT-UNL Campus da Caparica 2829-516 Caparica PORTUGAL [email protected] Farinha, Andreia Departament of Chemistry Universidade de Aveiro Universidade de Aveiro Departamento de Química Campus de Santiago 3810-193 Aveiro PORTUGAL [email protected] Faísca Phillips, Ana Maria Química Fac. Ciências e Tecnologia, Univ. Nova de Lisboa Departamento de Química Faculdade de Ciências e Tecnologia Universidade Nova de Lisboa 2829-516 Caparica PORTUGAL [email protected] Ferreira, André Centro de Quimica Estrutural Instituto Superior Técnico Av. Rovisco Pais, 1 1049-001 Lisboa PORTUGAL

7


[email protected] Ferreira, Luísa Química FCT/UNL Campus da Caparica 2829-516 Caparica PORTUGAL [email protected] Figueira, Valdemar Química FCT-UNL Departamento de Química Faculdade de Ciências e Tecnologia, UNL 2829-516 Caparica PORTUGAL [email protected] Figueiredo, Andrea Chemistry University of Aveiro Campus Universitário de Santiago 3810-193 Aveiro PORTUGAL [email protected] Frija, Luís FCT - Química, Bioquímica e Farmácia Universidade do Algarve UNIVERSIDADE DO ALGARVE-FCT CAMPUS DE GAMBELAS 8005-039 FARO PORTUGAL [email protected] Furtado, Olívia DTIQ INETI Estrada do Paço do Lumiar, ed. F 1649-038 Lisboa Lisboa PORTUGAL [email protected] Gois, Pedro Centro de Química Física Molecular Instituro Superior Técnico -UTL Complexo-1 Instituto Superior Técnico Av. Rovisco Pais P-1049-001 Lisboa Portugal P-1049-001 Lisboa PORTUGAL [email protected] Gonçalves, Maria Chemistry University of Minho Departamento de Química Universidade do Minho Campus de Gualtar 4710 -057 Braga PORTUGAL [email protected] Ismael, Maria

7


Departamento de Química Universidade da Beira Interior Unidade I&D Materiais Têxtis e Papeleiros, Departamento de Química Av. Marquês de Ávila e Bolama 6200-001 Covilhã Covilhã PORTUGAL [email protected] Kulkarni, Prashant Dept. de Engenharia Química e Biologica Centro de Química Física Molecular, Complexo - 1 Avenida Rovisco Pais, Lisboa 1049-001 Lisboa, Lisboa PORTUGAL [email protected] Latino, Diogo Departamento de Química FCTUNL REQUIMTE e Departamento de Química, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal 2829-516 Caparica, Portugal Lisboa PORTUGAL [email protected] Leitão, Alcino Lab Química Farmacêutica Faculdade de Farmácia da Universidade de Coimbra Rua do Norte 3000-295 Coimbra PORTUGAL [email protected] Lima, Carlos Chemistry Faculty of Science, University of Oporto Rua do Campo Alegre 687 4169-007 Porto, PORTUGAL [email protected] Lobo, Ana Chemistry FCT-UNL / SPQ-Divisão de Química Orgãnica Secção de Química Orgânica Aplicada Quinta da Torre 2829 Monte de Caparica PORTUGAL [email protected] Lopes, Nuno Departamento de Química Universidade do Minho Campus de Gualtar 4710-057 Braga PORTUGAL [email protected] Lopes, Rui Centro de Química e Bioquímica/DQB Faculdade de Ciências da Universidade de Lisboa Faculdade de Ciências Edifico C8, Piso 5, Lab. 40 Campo Grande

7


1749 Lisboa Lisboa PORTUGAL [email protected] Lopes, Susana Departamento de Química Universidade de Coimbra Rua Larga 3004-535 Coimbra PORTUGAL [email protected] Lourenço, Ana Chemistry FCT/UNL Quinta da Torre 2829-516 Caparica PORTUGAL [email protected] Lucas, Carla DTIQ INETI Estrada do Paço do Lumiar, 22 1649-038 Lisboa PORTUGAL [email protected] Marcos, Paula Faculdade de Farmácia da Universidade de Lisboa Av. Prof. Gama Pinto 1649-003 Lisboa PORTUGAL [email protected] Marcos, Paula Faculdade de Farmácia da Universidade de Lisboa Av. Prof. Gama Pinto 1649-003 Lisboa PORTUGAL [email protected] Marques, Maria Manuel Chemistry FCT-UNL Departamento de Química Faculdade de Ciências e Tecnologia, UNL 2829-516 Caparica PORTUGAL 2829-516 Caparica PORTUGAL [email protected] Marques, Graça Chemistry University of Aveiro Campus de Santiago 3810-100 Aveiro Aveiro PORTUGAL [email protected] Marques dos Santos, Maria Manuel

7


Química Orgânica Faculdade de Farmácia Faculdade de Farmácia da UL Av. Prof. Gama Pinto 1649-019 Lisboa PORTUGAL [email protected] Martins, Inês Química, REQUIMTE/CQFB FCT-UNL Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa 2829-516 Caparica PORTUGAL [email protected] Mata, Paulina Química Faculdade de Ciências e Tecnologia - UNL Campus da FCT / UNL 2829-516 Caparica PORTUGAL [email protected] Mendonça, Dina Departamento de Química Universidade da Beira Interior Departamento de Química Universidade da Beira Interior Rua Marquês d'Avila e Bolama 6200-001 Covilhã Covilhã PORTUGAL [email protected] Milne, Bruce Faculdade de Farmácia Universidade do Porto Rua Aníbal Cunha - 164 4050-047 Porto PORTUGAL [email protected] Moura, Joana Química Fac de Ciências e Tecnologia - Univ Nova de Lisboa Campus da FCT / UNL 2829-516 Caparica PORTUGAL [email protected] Mulchande, Jalmira Chemistry - Drug Design i-Med.UL / FFUL Faculty of Pharmacy, University of Lisbon, Av das Forças Armadas, 1600 Lisbon Lisbon PORTUGAL [email protected] Nascimento, Bruno Departamento de Química, Universidade de Coimbra Chymiotechnon Rua Larga

7


3004-535 Coimbra PORTUGAL [email protected] Nascimento, Vanesa Chemistry FCT/UNL Campus da Caparica 2829-516 Caparica PORTUGAL [email protected] Neves, Marta Química Orgânica Faculdade de Farmácia da Universidade do Porto Rua Aníbal Cunha 164 4050-047 Porto Porto PORTUGAL [email protected] Neves, Cristina Universidade do Minho Largo do Paço 4704-553 Braga PORTUGAL [email protected] Noronha, João Paulo Departmento de Química, REQUIMTE, CQFB Universidade Nova de Lisboa, Faculdade de Ciências Universidade Nova de Lisboa, Departmento de Química, Faculdade de Ciências e Tecnologia, 2829-516 Caparica, Portugal. 2829-516 Caparica PORTUGAL [email protected] Nunes, Cláudio Departamento de Química Universidade de Coimbra Rua Larga 3004-535 Coimbra PORTUGAL [email protected] Nunes, Antonio IDT barents Estoril Estoril Estoril PORTUGAL [email protected] Oliveira, Maria Manuel Chemistry UTAD Departamento de Química UTAD 5001-801 Vila Real PORTUGAL [email protected]

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Oliveira, Célia Dep. Eng. Química - Secção de Química Orgânica Instituto Superior de Engenharia de Lisboa Rua Conselheiro Emídio Navarro, 1 1950-062 Lisboa PORTUGAL [email protected] Pais, Vânia universidade de évora Herdade do soido, Mina do Bugalho, Alandroal 7250-051 São Bras dos Matos PORTUGAL [email protected] Palmeira, Andreia Departamento de Química Orgânica da FFUP Faculdade de Farmácia da Universidade do Porto R. Aníbal Cunha n.º 164 4050-047 Porto PORTUGAL [email protected] Pereira, Maria Goreti Departament of Chemistry University of Minho Gualtar 4710-057 Braga Braga PORTUGAL [email protected] Pereira, Nelson Departamento de Química Universidade de Coimbra Departamento de Química da Faculdade de Ciências e Tecnologia da Universidade de Coimbra, 3004-535 Coimbra 3004-535 Coimbra PORTUGAL [email protected] Pinto, Filipa Química Universidade doMinho Departamento de Química Universidade do Minho Campus de Gualtar 4710-057 Braga PORTUGAL [email protected] Pinto, Luís Química Faculdade Ciências e Tecnologia Faculdade Ciências e Tecnologia, 2829-516 Caparica Portugal 2829-516 Caparica PORTUGAL [email protected] Prabhakar, Sundaresan Chemistry

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FCT-UNL Secção de Química Orgânica Aplicada Quinta da Torre 2829-516 Monte de Caparica PORTUGAL [email protected] Ressurreiçao, Ana Sofia Dipartimento di Scienze Chimiche e Ambientali Università degli Studi dell’Insubria Via Valleggio, 11 22100 Como ITALY [email protected] Ribeiro, Alexandra Departamento de Química Universidade doMinho Campus de Gualtar Escola de Ciências Braga Portugal 4710-057 Braga PORTUGAL [email protected] Ribeiro, Sónia Química Universidade de Coimbra Rua Larga 3004-535 Coimbra PORTUGAL [email protected] Rosatella, Andreia Departamento de Engenharia Química e Biológica Instituto Superior Técnico Av. Rovisco Pais 1049-001 Lisboa PORTUGAL [email protected] Salaheldin, Abdellatif Chemistry Department School of Science, Minho University Chemistry Department, School of Science, Minho University 4710-041 Braga Braga PORTUGAL [email protected] Salvador, Maria Química Universidade de Trás-os-Montes e Alto Douro Quinta de Prados 5000-911 Vila Real PORTUGAL [email protected] Santos, Catarina Departamento de Química Universidade de Coimbra Rua Larga 3000 Coimbra

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PORTUGAL [email protected] Santos, Ana Chemistry University of Aveiro Estrada dos Marinheiros Nº78, 2ºDto 2415-380 Leiria PORTUGAL [email protected] Santos Vieira, Isabel Química Universidade de Aveiro Campus de Santiago 3810-193 Aveiro PORTUGAL [email protected] Seca, Ana DCTD Universidade dos Açores Rua Mãe de Deus 9501-801 Ponta Delgada PORTUGAL [email protected] Seixas, Raquel Sofia Chemistry University of Aveiro Campus Santiago 3810 Aveiro PORTUGAL [email protected] Serra, Arménio Departamento de Química Universidade de Coimbra Rua Larga-Coimbra 3000 Coimbra PORTUGAL [email protected] Sidarus, Muna Instituto Superior Técnico Centro de Química Estrutural Av. Rovisco Pais 1049-001 Lisboa PORTUGAL [email protected] Silva, Ana Maria Química Universidade doMinho Departamento de Química Universidade do Minho Campus de Gualtar 4710-057 Braga PORTUGAL [email protected]

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Silva, Marco Departmento de Química, REQUIMTE, CQFB Universidade Nova de Lisboa, Faculdade de Ciências Universidade Nova de Lisboa, Departmento de Química, Faculdade de Ciências e Tecnologia, 2829-516 Caparica, Portugal. 2829-516 Caparica PORTUGAL [email protected] Silva, Marília Departamento de Química Universidade do Minho Dep. Química Escola de Ciências Campus de Gualtar Braga 4710-057 Braga PORTUGAL [email protected] Silva, Sandra Química Universidade de Coimbra Rua Larga 3000 Coimbra PORTUGAL [email protected] Silva Serra, Maria Departamento de Química Universidade de Coimbra Departamento de Química, Universidade de Coimbra Rua Larga 3004-535 Coimbra 3004-535 Coimbra Coimbra PORTUGAL [email protected] Simoes, Mario Chemistry Department Aveiro University Campus de Santiago Chemistry Department Aveiro University 3810-193 Aveiro PORTUGAL [email protected] Simão, Dulce Dep.Eng.Química e Biológica Instituto Superior Técnico Av. Rovisco Pais 1049-001 Lisboa PORTUGAL [email protected] Soares, Maria Química Universidade de Coimbra Rua Larga 3004-535 Coimbra PORTUGAL [email protected] Soares, Ana Raquel Departamento de Química

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Universidade de Aveiro Campus de Santiago 3810-193 Aveiro PORTUGAL [email protected] Sousa, Maria CEQOFFUP Serviço de Química Orgânica Faculdade de Farmácia da Universidade do Porto Rua Anibal Cunha 164 4050-047 Porto PORTUGAL [email protected] Sousa, Carlos Chemistry Faculty of Science, University of Oporto Rua do Campo Alegre 687 4169-007 Porto PORTUGAL [email protected] Teixeira, Fátima DTIQ INETI Estrada do Paço do Lumiar, 22 1649-038 Lisboa PORTUGAL [email protected] Teixeira, António Departamento de Química Universidade de Évora Rua Romão Ramalho, 59 7000-671 Évora PORTUGAL [email protected] Torres, Nuno Química Analítica Faculdade de Farmácia de Lisboa, CECF. Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. 1649-003 Lisboa PORTUGAL [email protected] Trindade, Alexandre Departamento de Engenharia Quimica e Biológica Instituto Superior Técnico CQFM - IST -Complexo I Av. Rovisco Pais 1049-001 Lisboa PORTUGAL [email protected] Vale, Luís Departamento de Química Universidade de Aveiro Universidade de Aveiro Departamento de Química Campus de Santiago 3810-193 Aveiro

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PORTUGAL [email protected] Varala, Ravi Chemistry FCT/UNL Departamento de Química Faculdade de Ciências e Tecnologia, UNL 2829-516 Caparica PORTUGAL 2829-516 Caparica PORTUGAL [email protected] Vieira, Abel Química Faculdade de Ciências e Tecnologia - UNL Quinta da Torre 2829-516 Caparica PORTUGAL [email protected] Vieira, Abel Química Faculdade de Ciências e Tecnologia - UNL Quinta da Torre 2829-516 Caparica PORTUGAL [email protected] Yus, Miguel Quimica Organica Universidad de Alicante Dpto. de Quimica Organica Universidad de Alicante Apdo. 99 3080 Alicante SPAIN [email protected] Zaki, Magdi Chemistry Department School Of Science, Minho University Chemistry Department, School Of Science, University Of MINHO, Braga, Portugal 4710-041 Braga Braga PORTUGAL [email protected]

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