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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
7th Portuguese National Meeting of Organic Chemistry
7th Portuguese National Meeting of Organic
Chemistry
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
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)
Sponsors
Program
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
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)
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
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
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
11h15 – 12h35
Oral Communications
Auditorium 2:
Chairperson: José Prata
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: Rocha Gonçalves
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
12h35 – 14h30
Break for lunch
14h30 – 15h15
Plenary Lecture
Auditorium 2:
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:
PL10: Jean-Marie Beau
Chemical glycobiology: synthesis of bioactive natural products and mimics
18h00
Closing Session
Plenary Lectures
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
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
O
HO
H
OH
N
HO
NH2
OH
OH
(+)-Alexine
H
R3Si
SiR3
[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
PL2
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
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 1methyl-imidazolium [mim] and tetra-alkyl-dimethylguanidinium [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
N
N
N R
[mim]
R
N
R'
N
R'
[dmg]
[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.
R
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
PL4
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
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
NHR
N
CN
H2N
CN
O
NH2R
base
NH
CN
N
H2N
3A
CN
H2N
CN
RNCO
NHR
HN
CN
H2N
CN
1
2
R
N
H2N
4
base
R
N
R
N
NH2
O
CN
N
HN
3B
R
N
NH
NH2
O
CN
N
H
CN
N
H
H2N
HN
5A
5B
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.VilaChã, 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.
A TWISTED LINK BETWEEN CHEMISTRY, MATHS, MOLECULAR
BIOLOGY (AND MUSIC)
Henry S. Rzepa
Department of Chemistry, Imperial College, London SW7 2AY, U.K.
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
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!).
PL6
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, antiinflammatory, antifungic, antimicrobial and trypanocidal activities.1,2 Literature points
out that the biological profiles of these molecules are centered on their ortho or paraquinonoid 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
Ph
O
O
O
X
N
X
O
2a, X = O
2b, X = NH
O
R
O
1
O
O
3
O
R
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.
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
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.
CH3
N
O
CH3
N
H3C
I
O
H
N
H3C
N
N
II
[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
PL8
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 vicdiols 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.
Me CN
Me
O
AcO
AcO H O
OH
H
O O
O
O
O
OAc
O
AcO
O
O
R=
O
H
H
R=
R = Me
H
O
Me
O
AcO
OAc
R = Me
HO
R
HO
R1
R = Me
X
HO
O
n
HO
H
O
OAc
R = CH2OAc
R'
OH
MeO
O O
AcO
O
O O
R = CH2OBn
R = Me OTBS
OH
R7 R6
OH
R4
O
AcO
OTBS
ABC-Taxoid Diterpene
n
HO
n = 1 or 2
OOO
O
O
R2
R3
OAc
AcO
O
OtBu
OtBu
O
AcO
O
OH
O
MOMO
Pathylactone A
HO
R5
O
AcO
O
R = Acetal
OH
OH
HO
O
R = COR'
Iridal
HO
O
O
Iripallidal
NSC 631939
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.
ORGANIC CHEMISTRY IN A GOVERNMENT LABORATORY: TEN YEARS
OF RESEARCH
§
M.J. Marcelo Curto§
INETI – Instituto Nacional de Engenharia Tecnologia e Inovação
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
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
Oral Communications
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 β-amino esters
A. L. Cardoso
OC14- Donor-acceptor substituted π-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
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].
R2
H
N
CO2Me
X
R1
N
H
1
CO2Me
2
R = R = OMe, SMe, COMe, CN
X
X = S, a benzothieno[2,3-e]indole
X = O, a benzofuro[2,3-e]indole
R1 = COMe or OMe, R2 = H
R1 = H, R2 = COMe or OMe
Tetracyclic systems, methyl 1-(dibenzothien-4-yl)-3H-benzothieno[2,3-e]indole2-carboxylate
and
methyl
1-(dibenzofur-4-yl)-3H-benzofuro[2,3-e]indole-2carboxylate, 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
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 2SC 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 tetrahydroxylated 2-SC 4 (Scheme). Experimental details and structural characterization of
the new compounds will be presented and discussed.
R2
CO2H
+
R1
R4
R3
1a) and 2a) R1, R2, R3, R4 = OMe
2
1b) and 2b) R1, R2 ,R3, R4 = OBn
Baker-Venkataraman
Method
OH O
1
R3
R3
R4
4
R
R1
2
R
3a), 3b) - AcOH/HCl
O
O
3
R1
R2
O
3c) - BBr3 (in CH2Cl2)
O
3a) R1, R2 = OMe; R3, R4 = OBn
3b) R1, R2 = OBn; R3, R4 = OMe
3c) R1, R2, R3, R4 = OMe
4
4a) R1, R2 = OMe; R3, R4 = OH
4b) R1, R2 = OH; R3, R4 = OMe
4c) R1, R2, R3, R4 = OH
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
OC3
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.
CHO
H
MeO2C
H
NH2
OGlu
N
H
H
N
H
O
3
H
H
MeO2C
Secologanin
A
NH
OGlu
B
C
N
N
H
D
H
Monoterpenoid
indole alkaloids
O
MeO2C
H3α Strictosidine
H3β Vincoside
Geissoschizine
OH
OH
H
NH2
MeO2C
CHO
MeO2C
1
racemate
N
H
62%
N
H
O
N
1) Lawesson
O 2) C H CH Br
6 5
2
3) NaBH4
83%
2
MeO2C
3
N
H
H
MeO2C
N
O
N
H H
N
OMe
MeO2C
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 (CTQ200602390/BQU) and the DURSI, Generalitat de Catalunya (2005SGR00603) is gratefully acknowledged.
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
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
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
a
Departamento de Química, Unidade I&D Materiais Têxteis e Papeleiros da
Universidade da Beira Interior, Av. Marquês d’Ávila e Bolama, 6201-001 Covilhã,
Portugal
b
Departamento de Química, Universidade de Aveiro, Campus Universitário de
Santiago, 3810-193 Aveiro, Portugal
c
Centro 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
d
Escola 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.
H
N
X
N
HN
N
N
O
N
HN
CO2Et
X=O
G=
R
R'
G
G
G
X=S
O
O
O
O
O
O
1 R = H;
R' = OBn
2 R = OBn ; R' = H
3 R = OH ; R' = H
O
O
BnO
BnO
O
OBn
OMe
O
4
5
O
O
OH
O
O
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
OC6
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,
c
Laboratório de Microbiologia, Faculdade de Farmácia, Universidade do Porto,
Rua Aníbal Cunha, 164, 4050-047 Porto, Portugal
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
13
C 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.
H3 C
-
O3 SO
-
OSO3 O
OSO 3O
H3 C
-
O3 SO
OH
-
O3SO
OH
O3 SO
OCH 3
OCH 3
O
O
O
-
O
O3SO
O3 SO
O
O
-
O
O3 SO
O 3 SO
OSO 3-
OH
OH
O
OH
OH
O
O
OH
OH
OH
O
OH
O
O
OH
OH
OH
O
OH
OH
O
HO
1
OH
O
O
OH
OH
O
O
3
OH
OH
COOH
HO
HO
HO
HO
OH
O
O
OH
HO
O
OH
O
HO
O
O
HO
HO
O
2
HO
HO
CH3
O
O
O
O
II
O
OH
CH3
OH
HO
I
OH
HO
O
OSO3-
HO
OH
OH
O
O
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)
OC7
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
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.
R1
R1
NH2
N
NH
N
1
ClCOOEt
N
2
CN
2
R NH2
OEt
N
N
R1
R1
NH2
N
N
OEt
N
N
3
O
CN
NH2
NHR O
4
O
N
N
R2= Alkyl, Aryl
2
N
R2
NH2
1
R = Alkyl, Aryl
R2= NHCOR3
R1
N
H
N
N
N
8
O
R3= H, Me,
Fur, Pyr
R2= H
R1
R1
N
N
NH
N
N
7
N
HN
3
R
O
O
NH
1
N
R
N
N
O
N
N
6
NH
5
N
O
NH
NHR2
NH2
3
R
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, 12311234.
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.
OC8
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
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.
OH
HO
OH
O
HO
OH
OH
O
OH O
O
HO
O
O
O
OH
OH OH
OH O
Acyl-flavonoid from P. tithymaloides
Flavonoid from T. elatum
OH
R
OCH3
Anacardic acid methyl
esters from O. insignis
HO
HO
OH
HO
O
m
O
OH
N
H
9
OH
Ceramides from R. suaveolens
OH
OCH3
HO
OH
O
O
OH
O
O
OH
O
OH
HO
OH O
β-ionone glucoside from S. tetrandra
OH
OH H CO
3
OH
O
O
O
OH
OH
O
HO
O
HO
O
O
OH O
O
OH
OH
O
O
HO
HO
OH
O
HO
HO
OH
OH
Phenolic glycoside from M. arvensis
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.
INVESTIGATION INTO THE REACTIVITY OF TETRAZOLES
AND BENZISOTHIAZOLES
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.
OC9
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
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. 3Keto 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.
OR 2
O
O
OMe
CO 2Et
O
OR
1
O
OMe
CO 2 Et
R1O
OR2
2
Acknowledgments: The authors thank Fundação para a Ciência e Tecnologia for the
PhD grant SFRH/BD/30699/2006.
OC10
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.
OC11
ENANTIOSELECTIVITY ASYMMETRIC ALLYLIC
ALKYLATIONS USING A DIOP ANALOGUE WITH A 1,4DIOXANE 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.
PPh2
OMe
O
Ph2P
O
1
O
Ph2P
PPh2
2
O
OMe
Scheme 1
2
Pd (0), Nuc, base
R1
R
R
R1
Nuc
X
[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.
OC12
OC13
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
b
Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
Departamento 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
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, Lphenylalanine, 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.
•
MeOH
O
O
O
R1NH2
SO2Ph
R1
NH O
MeOH
•
R1NH2
SO2Ph O
O
O
SO2Ph
SO2Ph
5
NaBH4(OAc)3
O
SO2Ph O
HN
H
N
O
5a, 6a
Me
CO2Me
6
5b, 6b
Ph
CO2Me
R1
SO2Ph O
R1
4
2
R1 =
R1
HN
3
1
O
NaBH4(OAc)3
5c, 6c
i-Pr
5d, 6d
CO2Me
5e, 6e
CO2Me
N
H
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.
OC14
DONOR-ACCEPTOR SUBSTITUTED π-CONJUGATED HETEROCYCLIC
SYSTEMS: SYNTHESIS AND CHARACTERIZATION
Department of Chemistry, University of Minho, Gualtar, 4710-05 Braga, Portugal
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 crosscouplings, 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 thienylpyrrolylbenzothiazoles [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].
D
D
π-Spacer
S
A
A
S
A
,
S
n = 2-4
S
S
π-Spacer
π-Spacer
R = alkyl, aryl
D = H, OH, OR, N,N-(alkyl)2
A = CN, CHO, NO2, azo-Ph
-CH=C(CN)2, -C(CN)=C(CN)2
N
D
S
A
N
R
N
D
N
R
N
R
n = 2-4
S
,
π-Spacer
N
H
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), 34933501.
[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.
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 hydrogenbonding with the C=O of the coloured open form [3].
OH
ON
+
N
OH
CH3OH
N
O
Reflux
N
HO
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
N
O
N
N
O
H
HO
O
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.
OC15
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.
OC16
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
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).
R4
R2
H
R1
H
R3
1 R1= CH2OCO(CH2)14CH3; R2=R3=R4= H
R1
H
R3
R2
2 R1= CH2OCO(CH2)14CH3; R2= H; R3,R4= =O 4 R1= CH2OCHO; R2=R3= H
3 R1= CH3; R2= OH; R3,R4= =O
5 R1= CH2OCO(CH2)14CH3; R2=R3= H
7 R1= CH2OCHO; R2=R3=R4= H
6 R1= CH2OH; R2,R3= =O
[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.
OC17
ORGLIST Symposium
ORGLIST Symposium - Lectures
OL1- COMPUTACIONAL MODELS TO AID SAFETY-DIRECTED DRUG
DESIGN
Scott Boyer
OL2-
DERIVING
STRUCTURE-ACTIVITY
HETEROGENEOUS DATASETS
Valerie J. Gillet
RELATIONSHIPS
IN
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
COMPUTATIONAL MODELS TO AID SAFETY-DIRECTED
DRUG DESIGN
Scott Boyer
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
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
TWO-PARAMETER CLASSIFIER FOR PREDICTION OF PKC-ζ
MODULATING BEHAVIOUR OF XANTHONES
Bruce F. Milne §, Madalena M.M. Pinto §
Universidade do Porto; Laboratório de Química Orgânica, Faculdade de Farmácia da
Universidade do Porto, Rua Aníbal Cunha 164, 4050-047 Porto
§
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
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 Omethylation 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
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
Poster Communications
PC1
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.
NH
NH
HO
OH
HO
H
N
HO
OH
1) Tyrosinase
HO
HO
OH
HN
2) GSH
S
O
-H2O
O
S
O
OH
HN
O
O
O
O
NH
NH
1
OH
H2N
OH
H2N
O
O
H
N
HO
O
HO
NH2
O
S
NH
NH
HOOC
O
O
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).
PC2
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
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-4quinolones 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.
SO2
N
CHO
O
1
COOEt
H
N
R
H
N
CHO
O
4
O
2 R = Me
3 R = CO2Et
H
COOEt
H
N
O
5
H
Scheme 1
[1]
[2]
[3]
[4]
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.
M. Itoigawa, C. Ito, T.-S. Wu, F. Enjo, H. Tokuda, H. Nishino, H. Furukawa,
Cancer Lett., 2003, 193, 133-138.
M. Fujiwara, M. Okamoto, M. Okamoto, M. Watanabe, H. Machida, S. Shigeta,
K. Konno, T. Yokota, M. Baba, Antiviral Res., 1999, 43, 179-189.
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.
PC3
A NEW APPROACH TO THE SYNTHESIS OF [4,4’]-BI-1HIMIDAZOL-2-ONES
§
Magdi E.A. Zaki§ and Fernanda J.R.P. Proença
[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-5carboxamides 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.
H2N
CN
X
X-C(OC 2H5)3
C
H
X=H,CH3, C2H5 2 5O
HN
CN
CH3CN-H2SO4
O
NH
CH2Ph
1
N
CN
CH3CN
HN
O
CN
NH
CH2Ph
2a, X= H
b, X= CH3
c, X= C2H5
DBU
H
N
O
CN
N
N
NH
CH2Ph
3a, X= H
b, X= CH3
c, X= C2H5
X
OC2H5
NH2R
EtOH, RT
O
R
N
H2N
X
N
N
N
NH
CH2Ph
4
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).
PC4
ACTIVITY OF β -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
a
Coimbra, Portugal.
b
[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.
OH
NH
N
N
OH
NH
N
HN
COOH
COOH
N
HN
COOH
(1)
COOH
(2)
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®.
NH
NH
N
Br
COOH
COOH
COOH
COOH
N
COOH
COOH
NH
N
Br
N
N
HN
HN
N
HN
Br
COOH
(3)
COOH
Br
(4)
(5)
[1] Osterioh, J.; Vicente, M. G. H. J. Porphyrins Phthalocyanines, 2002, 6, 305-324.
Acknowledgments: The authors thank to Chymiotechnon, Ministério da Economia/
PC5
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
a
Universidade de Aveiro, Departamento de Química, Campus de Santiago, 3810-391
Aveiro, Portugal
b
Universidad 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-(5,10,15,20tetraphenylporphyrin-2-ylamino)phthalonitrile 1 in nitrobenzene. The synthetic
procedure and the structural characterization of the novel compound will be discussed.
CN
CN
NH
N
N
H
N
CN
Nitrobenzene
Reflux
HN
1
N
NH
N
N
CN
HN
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).
PC6
APPLICATION OF AMIDE BOND ACIDOLYSIS AT THE C-TERMINUS OF
α,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 (PmbNH2) 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), 5,5dialkyl-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.
O
O
H3C
O
R R
N
H
N
TFA
C6H11
Pmb O
1
R = Et, Pr, iBu, Bn
NH2-R' = benzylamine or Phe-OtBu
R
R
H3C
O
N
H
N
H
NH2-R'
O
CH3
2
R R
R'
3
O
+
R'
R
R
H
N
N
N
4
CH3
[1] Costa, S.P.G.; Pereira-Lima, S.M.M.A.; Maia, H.L.S. Org. Biomol. Chem., 2003, 1, 1475147. 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.
PC7
AZA-DIELS-ALDER APPROACH TO THE
SYNTHESIS OF PIPERIDINE AZASUGARS
Alves M.J.a), Costa C.a), Costa F. T.b)
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]
a)
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.
CO2R1
N
R2
H3C
OTBDMS
R2
OR*
CO2Bn
CO2R1
N
N
H3C
OR*
1a, R1= Bn, R2= CH3
1b2, R1= tBu, R2= H
OTBDMS
OsO4
CO2Bn
HO
LiAlH4
N
HO
N
HO
OTBDMS
1c
OH
HO
2c
OTBDMS
3
NH3F
OsO4
HO
R2
HO
H3C
CO2R1
CO2Bn
HO
CH2NHPh
NH
N
OR*
2a, R1= Bn, R2= CH3
2b, R1= tBu, R2= H
HO
OH
4
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
PC8
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
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].
R2
R1SO2CHCH2
R
R1=CH2CH3 ,
R1SO2CH2CH2
NH
+
3
R2
N
R3
NH2
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
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,
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
PC10
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
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.
A)
OH
O
O
Br
O
Br(CH2)6Br
K2CO3 , DMF
O
O
O
O
O
O
O
3
1
2
O
B)
O
Br(CH2)6Br
(drop-to-drop)
O
4
Scheme 1
OH
OH
K2CO3 , DMF
O
O
O
5
O
Br
Br
O
OH
O
O
Br
6
In light of this results we proceed with the bromoalkylation of the hit compound, 3,4dihydroxyxanthone (4) that revealed a potent inhibitory effect on the human tumor cell
lines growth [1]. Two bromohexyloxyxanthones, 3-[(6-bromohexyl)oxy]-4hydroxyxanthone (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.
BULK THERMAL POLYMERIZATION OF PHENYLETHYNYLCALIX[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
O OOO
O OOO
couplings) found in the isolated polymer.
H H
Polymerization of 2 on the other hand did
produce an insoluble material which, due to
the monomer structure, could not result from
1
2
direct cross-linking reactions. In order to
H
H
H
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
C-H CARBENE INSERTION OF α-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
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 βor/and γ-lactams were obtained in reasonable yields and in some cases with good
diastereoselectivities, abolishing the need of a metallic catalyst.
O
X
N
N2
R'
n
hν , rt
No metal catalyst
Neat, n-hexane or water
O
X
N R' Intramolecular
R
n
C-H Insertion
Products
R
X = PO(OEt)2, Ac, CO 2Et
n= 0, 1
[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
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
1
Universidade do Porto; 2Serviço de Química Orgânica, Faculdade de Farmácia da
Universidade do Porto, R. Anibal Cunha 164, 4050-047 Porto
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 proteinligand 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
PC14
Dissolution of mono- and di-saccharides in ionic liquids
Andreia A. Rosatella1, Luís C. Branco1, and Carlos A.M. Afonso1
1
CQFM, 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]. Ethercontaining 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.
Cations
Anions
R
O
N R
N
N R
N
N R
R
R= CH2CH2OCH2CH2OMe
R= n-Butil
Cl
NCS
NC
N
R= CH2CH2OMe
R= n-Hexil
CN
N
S O
O
O
O
N
S
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).
EFFICIENCY OF Rh-BASED TERNARY CATALYTIC SYSTEMS IN
THE POLYMERIZATION OF TRI-O-PROPYL-(4ETHYNYL)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-(4ethynyl)benzyloxy-p-t-butylcalix[4]arene
(1)
was attempted, under the very same general
Calix
H conditions used for the difunctional counterpart,
Rh
catalyst
huge amounts of dimeric, trimeric and
O OOO
oligomeric materials were obtained, whatever
n
the particular conditions tested. We now report
poly 1
1
Calix
that a highly efficient polymerization of 1 has
been accomplished by Rh-based ternary catalytic
H
H
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, 70547070.
[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
Electrochemical Epoxidation of Geraniol
Massuquinini Inêsa, Dina I. Mendonçab , António Mendonçab, Ana P. Estevesc, Maria J.
Medeirosc
a
Chemistry Department, Agostinho Neto University, Luanda, Angola
b
Chemistry Department, University of Beira Interior, Covilhã, Portugal
c
Chemistry 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 (2.52.5 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
2
NaBr
OH
1
MeCN:H2O
(4:1)
OH
+
O
O
3
OH
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
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 antitumor 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
OH
H
OH
N
Swiansonine
H
OH
OH
HO
OAc
OMe
OH
N
(+)-Lentiginosine
N
H
(-)-Anisomycin
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
PC18
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.
N
HH
MeO2C
N
N
N
HH
H
OMe
H
H3α: Dihydrocorynantheine
H3β: Hirsutine
OH
Antirhine
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]
OH
NH2
N
H
H
+
MeO2C
1
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.
O
i
N
H
2
O N
O
ii
H
N
H
3
N
OH
O
4b
iii
H
N
H
4a
N
OH iv-vii
O
H
N
H
N
O
5
[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 postdoctoral fellowship to M.M.M.S.
PC19
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
a
Coimbra, Portugal.
b
[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.
1
R1
NH
2
OH
R 1=
N
R2
F
OH
HN
R 2=
R1
3
F
F
R 1=
R2
N
F
5
Br
OH
R 2=
OH
R 1=
Br
F
OH
R2=
Br
R1=
4
R 2=
OH
OH
OH
R1=R2=
[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/
PC20
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
The non-nucleoside reverse transcriptase inhibitor nevirapine (11-cyclopropyl5,11-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 4hydromethyl-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 Omesyl 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.
X
O
H
N
O
H
N
H3C
Y
N
N
N
Z
X
N
N
N
I, X =H
III, X = OH, Y = H, Z = H
II, X = OH
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.
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.
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 4DMAAP 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).
C6H5
O
N
N
I
C6H5
N
N
O
N
II
C6H5
[O]
N
N
C6H5
O
NH
III
[O]
N
N
O
Final Oxidation Products
NH2
IV
To validate this mechanistic proposal 4-dimethyl-aminoantipyrine (4-DMAA, II), 4methyl-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 4MMAAP (III). The 4-MMAAP is further demethylated to 4-AAP (IV). The 4aminoantypirine 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
PC22
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.
Merrifield
resin
NH(CH2)12NHSO2Porphyrin
(1)
R1
NH
Cl
Porphyrin= R2
(3)
Cl
Br
R1= R2=
Cl
R1
N
R 1= R 2=
R 1=
N
(2)
HN
R 2=
R1
[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 FCTPOCTI/QUI/55931/2004 for financial support.
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
a
Chymiotechnon, Departamento de Química, Universidade de Coimbra
3004-535, Coimbra, Portugal
b
Instituto 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-(3hydroxyphenyl)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.
O
Y
NH
N
O n
N
HN
Y
Y
Y= H, Cl or Br
[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
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
a
c
Laboratório 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 1hydroxanthone (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
OH
O
OCH3
O
O
O
O
1
2
3
O
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
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
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,
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 bioorganometallic 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.
N
NR2
O
O
O
HO
S
OH
R'O
S
O
Fe
I
II
[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
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 structureproperty 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 electronwithdrawing 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.
Y C
Y = N or CH
spacer
NO2
R
R = H, NO2
spacer
N NH
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
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
§
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 spacergroup used for linkage of the two heterocycles, as potential nitrogen ligands in
coordination reactions with transition metal complexes.[6]
Spacer
S
O2
(1)
H
N
N
N
N
M
L
N
M = metal; L = ligand;
L
[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
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
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]
O
O
Cl
P(OH)2
HO
P(OH)2
Cl
P(OH)2
R
P(OH)2
O
A: Clodronate
O
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
O
P(OEt)2
Ph
P(OEt)2
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
“ONE-POT” PALLADIUM-CATALYZED SYNTHESIS OF
BENZOTHIENOQUINOLINES FROM 3-BROMOBENZO[b]THIOPHENE-2CARBALDEHYDE 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 3bromobenzo[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.
N
NH2
O
B
O
Br
CHO
S
30%
S
benzothieno[2,3-c]quinoline
+
i
N
S
20%
benzothieno[3,2-b]quinoline
i) Pd(OAc)2 (5mol%), 2-(cyclohexylphosphane)biphenyl (20mol%),
Ba(OH)2.8H2O (3 equiv.), dioxane, 100 oC, 5h.
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
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,
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, 3oxo-β-sultams, 1, were reported as potent inhibitors of elastase.2 We now report that 4oxo-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.
R´
R´
O
R´
O
R´
O
S
O
N
N
R
O
R
2
1
Both alkaline and enzymatic hydrolysis of N-aryl-4-oxo-β-lactams 2 occur with endocyclic 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
R´
R´
O
R´
N
Nu
O
R´
HO2C
a)
CONHR
3
R´
R´
b)
H
N
O
R
2
R
Enz
O
O
4
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
PC32
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
a
c
Laboratório de Microbiologia, Faculdade de Farmácia, Universidade do Porto, Rua
Aníbal Cunha 164, 4050-047 Porto, Portugal
e
Departamento 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 3,7dihydroxyflavone (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.
HO
O
O
O
O
O
O
OH
OH
O
O
O
1
2
3
[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).
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]
CQFM, Dept. de Engenharia Química, IST, 1049-001 Lisboa, Portugal.
b)
REQUIMTE, Dept. de Química, FCT/UNL, 2829-516 Caparica, Portugal
email: [email protected]
a)
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].
R2 N
N R
1
N(CN)2
C6H13
N C6H13
N
N C6H13
C6H13
S CN
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.,
2002.
[3] Kulkarni P.S., Branco L.C., Crespo
DOI: 10.1002/chem.200700160).
J.P.G., Afonso C.A.M.,
Chem. Eur. J., 8, 3671-3677,
Chem. Eur. J., In Press (ref.
Acknowledgement: We thank Fundação Para a Ciência e Tecnologia (POCI 2010) and
FEDER for the financial support (Ref. SFRH/BPD/14848/2003).
PC33
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 γaminobutyric 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.
Z-HN-(CHR)n-CO2H + Cl-H2C
KF/ DMF
r.t.
Z-HN-(CHR)n-CO2CH2
R = H, CH3, CH2CH2COOH
n = 1, 2, 3
[1] F.J. Jimenez-Jimenez, J.A. Molina, P. Gomez, C. Vargas, F. De Bustos, J. BenitoLeon, 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.
PC34
REACTION OF NITROSOAROMATICS AND 2-(1’-HYDROXYETHYL)THIAZOLIUM SALTS
M. Manuel B. Marques, Luísa M. Ferreira, Ana M. Lobo, Sundaresan Prabhakar
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 αhydroxycarbonyl compounds [1].
N
N
N
S
NH2
O O
P O
O O P O
O
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).
CF3SO3
PhNO
+
Base
N
R
PhNHOAc
S
+
Ph-N(O)=N-Ph
CH2Cl2
OH
2
3
4
5
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.
(Lisbon, Portugal) partial financial support.
PC35
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).
:Nu
Nu
Nu, secondary
amines
S
S
LG
O
1
O
Nu,
thiols (HSCH2R)
O
O
2
Nu
Me
S
O
O
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).
PC36
PC37
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
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 dirhodium (II) structure allowed the formation of an extremely efficient catalyst
especially in arylation of aldehydes containing electro-donating substituents and alkyl
aldehydes[2].
B(OH)2
O
H
+
R
R'
Rh2(pfb)4, 3 mol %
ligand, 3 mol %
KOtBu, 1 eq.
t-amyl alcohol
40 - 80 ºC
OH
R
R'
yields up to 99 %
R'' N
N R''
Cl
ligand
[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.
PC38
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]
§
R'
O
O
N
Z
Z
Z
Z
O
Y
Y
α
X
R'
Y
X
X
O
OH
1
O
O
O
N
N
N
NH
R
R
R
R
2
3
N
O
R'
4
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, 190208, 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.
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.
PC39
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
Coimbra, Portugal.
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(2bromo-5-hydoxyphenyl)porphyrinate will be presented.
Acknowledgments: The authors thank to Chymiotechnon (Projecto-nº 03/293CLARO/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, 24472464.
[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, 84498452.
[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.
PC40
PC41
[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.
R1
R1
O
R2
N
R3
R2
H
k1
+
Ts
1
2
DCM
R1
O
N
R3
R2
O
N
k2
R3
Ts
Ts
3
4
k3
R1
R1 - adamantyl, 1-methylcyclohexyl, tert-butyl or benzyl
R2 - H or Me
R3 - H or Me
O
R2
HN
R3
Ts
5
[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.
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
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 0.20.3 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, 946949.
[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).
PC42
PC43
STRUCTURAL CHARACTERIZATION OF A NEW DYE
OBTAINED FROM 1-HYDROXY-2-ACETONAPHTHONE AND 2FLUOROBENZOPHENONE
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 2,2diphenylnaphthopyran-4-one a useful compound for the synthesis of photochromic
naphthopyrans [1,2].
Ph
OH
O
Ph
O
O
1) t-BuOK
O
+
2) HOAc/HBr
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 2fluorobenzophenone 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
O
F
O
1) t-BuOK
O
+
O
2) HOAc/HCl
1
2
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.
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
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, 3,6dihydroxyxanthone (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), 3,4dihydroxyxanthone (4), and 2,2’,4,4’-tetrahydroxybenzophenone (5), in triethylamine
and anhydrous THF.
O
O
Since one of the
HO
O
OH
H NO SO
OSO NH
main strategies in
1
2
drug discovery is
O
O
O
O
OH
OH
the evaluation of
HO
OH
AcO
OAc
synthetic
O
OH
O
OH OH
OAc OAc
OH
3
4
6
5
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.
2
2
2
2
[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 M27A2, 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
PC45
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,
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 Nglycosilated orthoester 4 was identified (Scheme 1).
N
H
H
N
N
H
2
Ag2O
N
+
H3C
O
AcO
O
Br
OAc
OAc
3
N
H
CH3
O
O
Basic Conditions
N
H
N
H
N
O
OAc
N
O
OAc
H3C
H3 C
O
H3C
AcO
OAc
HO
OH
OH
OAc
4
5
K-252d (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.
(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.
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
Nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-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.
R
H
N
N
N
O
N
I, R=H
II, R=OH
III, R=OMs
As a model electrophile derived from 12-hydroxy-NVP, we synthesized 12-O-mesylNVP (III) and investigated its reactivity towards the nucleophilic amino acids (AA), Nacetyl-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
SYNTHESIS AND CHARACTERIZATION OF NOVEL HYDROXYAND 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.
PO3Et2
H
Et2O3P
HN
N
N
N
PO3H2
HO
PO3H2
N
N
CH3
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).
PC47
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.
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.
H
H
N
H
O
H
N
N
N
S
L1
H
O
N
H
H
N
N
S
O
N
H
O
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,
13
C NMR,
1
H −1H
COSY , 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
SYNTHESIS AND CONFORMATIONAL ANALYSIS OF βHAIRPIN MIMICS CONTAINING BIFUNCTIONAL
DIKETOPIPERAZINE SCAFFOLDS
Ana Sofia M. Ressurreição,a Monica Civera,b Laura Belvisi,b Cesare Gennari,b
Umberto Piarullia
a
Dipartimento di Scienze Chimiche e Ambientali, Università degli Studi dell’Insubria
Via Valleggio, 11, I- 22100 Como, Italy
b
Dipartimento 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 cisconfiguration 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 αamino 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
COOH
β3-amino acid
H
N
O
N
O
(1)
Ph
NHBoc
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-inPrint 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.
PC49
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.
Trans-[Pd(cbdt)2]
Cis-[Fe(cbdt)2]
S
S
S
S
CN
M
S
S
S
NC
S
TTF M(cbdt)2
M= Au, Cu, Ni, Fe
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
PC51
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
§
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.
NC
O
H
+ NC
CN
CN
CN
NaHCO3(aq)
OH
R
1a, R=H
b, R=OCH3
- NC
CN
O
NH2
R
2a, R=H
b, R=OCH3
CN
O
NH
R
3a, R=H
b, R=OCH3
1a
EtOH
MeOH
NEt3(cat.)
DMSO
NC
N
O
CN R
O
NH2
4a, R=H
b, R=OCH3
R
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).
PC52
SYNTHESIS AND REACTIVITY OF 4-HYDROXY-3METHOXYAMPHETAMINE 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 αmethyldopamine (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 4hydroxy-3-methoxyamphetamine
(3-OMe-α-MeDA)
and
4-hydroxy-3methoxyamphetamine (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
O
MeO
MeO
NHRCl
H
HO
HO
2) GSH
R = H, Me
HS
O
GSH =
NH
1) [O]
R=H
NH2 GSH
HO
HO
MeO
NH2 GSH
O
N
H
NH2
COOH
[O] = Ag2O, Ce(NH4)2(NO3)6
COOH
[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.
PC53
SYNTHESIS OF β-BROMO AND β-IODO β-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
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
H
N
R
1)NBS
2)NEt3
CO2CH3
1)NIS
2)NEt3
R=CH3 or Ph
P=Boc, Tos, Z(NO2).
P
P
H
N
CO2CH3
R
Br
H
N
CO2CH3
R
I
Product
Boc-∆Abu(β -Br)-OMe
Z(NO2)-∆Abu(β -Br)-OMe
Tos-∆Abu(β -Br)-OMe
Boc-∆Phe(β -Br)-OMe[2]
Tos-∆Phe(β -Br)-OMe
Boc-∆Abu(β -I)-OMe
Z(NO2)-∆Abu(β -I)-OMe
Boc-∆Phe(β -I)-OMe
Yield /
%
92
80
94
97[2]
78
88
96
87
E/Z
ratio
1/1
1/1
1/9
1/2[2]
Only Z
1/3
Only Z
Only Z
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.
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.
3e
NH2
CO2H
1
CO2H
2
R3
N
N
CH
3f
NH2
4f
CHO
R2
C
H
4e
R1
R3
OH
R2
R1
3a R1=R2=R3= H
3b R1= OCH3, R2=R3= H
3c R1= OCH3, R2= H, R3= Br
3d R1=R2= (CH3)3, R3= H
OH
OH
R3
R1
4a R1=R2=R3= H
4b R1= OCH3, R2=R3= H
4c R1= OCH3, R2= H, R3= Br
4d R1=R2= (CH3)3, R3= H
R2
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.
PC54
PC55
SYNTHESIS OF 4H-CHROMENES WITH POPENCIAL BIOLOGICAL
ACTIVITY
Pedro L. B. Vicente1, Francisco Peixoto2, M. Manuel Oliveira1
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
1
The chromene moiety often appears as an important structural component in both
biological active and natural compounds like chromanes, 2H-chromenes and 4Hchromenes 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.
R
R1
R
CN
EtOH
+ CH2(CN)2 +
r.t.
OH
R1
O
CHO
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.
NH2
PC56
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.
Br
Br
Ar
Ar
cat.
K2CO3
+
2 Ar-B(HO)2
solvent
cat. = Pd(OAc)2, PdCl2(dppe)
solvent = H2O/DMF, Toluene/H2O
Ar = 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.
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
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, 33333337.
[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
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
a
Centro de Estudos Farmacêuticos, Lab. Química Farmacêutica, Faculdade de
Farmácia, Universidade de Coimbra, Rua do Norte 3000-295, Coimbra, PORTUGAL
b
Lab. Química Farmacêutica, Faculdade de Farmácia, Universidade de Coimbra, Rua
do Norte 3000-295, Coimbra, PORTUGAL
c
Academy 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
O
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
H
progesterone, like 3α-hydroxy-5α-pregnan-20one
(‘allopregnanolone’),
also
bind
allosterically to the GABAA receptor and
H
H
increase the inhibitory effects of GABA by
opening the membrane chloride ion channel HO
H
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
PC59
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 Nprotected derivatives 3a-d as dienophiles in Diels-Alder reactions with Nmethylmaleimide. 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.
R
CO 2H
+
O
A
R
NH 2 O
A ) DCC, 4-pyrrolidinopyridine, CH 2Cl2, rt
B) (CH3) 3COK, THF, ref lux or
NaOH, t-butanol, MW
C) NaH, MeI, THF, rt
D) 1,2,4-Triclorobenzene, ref lux or
toluene, ref lux
a) R= H; b) OCH 3; c) Cl; d) NO 2
Me
R
NH
O
5a-d
N
O
2a-d
C
R
R
O
O
O
H
N
B
O
1a-d
N Me
N
R
Me
N
N
O
Me
O
3a-d
O
Me
4a-d
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.
PC60
SYNTHESIS OF NEW CALIX[4]PYRROLE DERIVATIVES
THROUGH
1,3-DIPOLAR CYCLOADDITIONS
A. S. F. Farinha, A. C. Tomé, J. A. S. Cavaleiro
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.
Z
CHO
NH HN
HN
NH HN
HN
1
2
+ CH2
N
Me
Z
Z
Z
HN
N
Me
HN
3
[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.
PC61
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
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 1,4anthraquinone, with subsequent deamination.
C6F5
N
Py
C6F5
N
N
Ga
C6F5
N
C6F5
Py
C6F5
N
C6F5
N
N
C6F5
CH3
N
N
CHO
1
2
N
Py
N
Ga
C6F5
N
5
N
N
C6F5
CH3
N
N
6
O
O
Py
N
N
C6F5
CH3
N
N
N
Py
N
N
C6F5
O
O
Py
C6F5
CH3
N
N
8
C6F5
N
Ga
C6F5
N
7
O
N
C6F5
N
Ga
C6F5
N
CO2Me
C6F5
C6F5
CH3
N
C6F5
4
MeO2C
CO2Me
N
Ga
C6F5
C6F5
N Py N
Ga
N
Ga
3
MeO2C
C6F5
C6F5
Py
N
Ga
C6F5
N
N
C6F5
CH3
N
Py
N
Ga
C6F5
N
C6F5
N
O
9
O
O
O
O
[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.
PC62
SYNTHESIS OF NEW DELOCALISED CATIONIC AZO DYES
Maria A. Salvador,a Paulo Almeida,b Paulo F. Santos,a Lucinda V. Reisa
Departamento de Química and Centro de Química - Vila Real, Universidade de
Trás-os-Montes e Alto Douro, 5001-801 Vila Real, Portugal
b
Departamento de Química and Unidade de I&D de Materiais Têxteis e Papeleiros,
Universidade da Beira Interior, 6201-001 Covilhã, Portugal
a
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.
R1
R1
N
N
OHC
N
S
1
Z
N
NEt2
R2
S
N
N
I
R3
2
N
NEt2
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).
PC63
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
Centro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga
b
REQUIMTE, FCT, Universidade Nova de Lisboa, 2829-516 Monte de Caparica
a
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].
O
O
O
O
CHO + H2N
S
n
=
1-3
1
O
O
O
O
NaBH(OAc)3
1,2-dicloroethane
r.t.
S
S
N
n
O
O
2a n=1
b n=2
c n=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).
PC64
SYNTHESIS OF PEPTIDES WITH α,α-DIALKYL AND N,α,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 Cterminal 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.
TFA neat
or 25%
2
R
1
R
R
O
NH2R4
OH
R
R3 R3
O
H
N
1
O
NHR4
R3 R3
O
N
O
O
H
N
1
R3 R3
N
H
TFA 1%
or 2%
R2
1
R
R2
O
4
NH2R
N
OH
3
O R
R2 = 4-CH3OC6H43
R = Me, Et, Pr, iBu and Bn
R1-CO = N-protected amino acyl or peptidyl
NH-R4 = residue of amino acid (or peptide) ester
3
R
1
R
O
N
O
NHR4
3
R
3
R
[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.; GonçalvesMaia, 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.
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.
Boc
O
H
N
NH
NH2
Boc
H
N
Br
COOCH3
Br
O
B
O
5 equiv.
NH2
70%
+
i
Boc
H
N
O
NH
10%
i) 20mol% PdCl2(dppf).CH2Cl2 (1:1), 1.4 equiv. Cs2CO3, THF/H2O (1:1), 3h, 90 ºC.
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
PC66
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
CN
N
N
X
1
NH 2
N
OEt
N
X
2
X = H, Cl, CH 3, CF3
H
HN N
NH
CN
N
N
X
3
N NH 2
N
N
N
Y
N
N
N
N
X
X
4
5
N N
Y
N
N
N
a, X = Cl, Y = CH 3
b, X = Cl, Y = Br
c, X = Cl, Y = COOH
d, X = CH3, Y = CF3
e, X = CF3, Y = Cl
To confirm the structure of compounds 4 an independent route was followed reacting 4chloropyrazolopyrimidine 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.
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])
Minocycline is a potent semisynthetic derivative of tetracycline with a broad
antibacterial spectrum.
Synthetic pathways, using demeclocycline as starting material, indicate that 6deoxy-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.
R1
R2
R3
OH
CONH2
OH
OH
O
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
THE CAHN-INGOLD-PRELOG SYSTEM:
HISTORY AND RECENT DEVELOPMENTS
Paulina Mata
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, 701704.
[12] P. Mata, A.M. Lobo, Tetrahedron: Asymmetry, 2005, 16 (13), 2215-2223.
PC68
PC69
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-2,2dioxide 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-2,2dioxides in order to evaluate the scope of the interesting rearrangement of C-vinylpyrroles to Callylpyrroles. 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.
Me
R4
R1
R1
R4
O2S
N
R2
1
R3
FVP
- SO2
R4
CO2R
CO2R
N
H
R3
R2
[1,8]H
R1
R3
N
R2
2
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
R4
CO2R
R2
CO2R
R3
N
H
R1
4
3
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.
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
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
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.
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.
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.
Possible active spicies
[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
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,
http://www.dq.fct.unl.pt/staff/jas
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
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 “ESIinactive” 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.
N
Me
N
HN
HN
H
CO2Me
N
N
Me
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
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
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.
H
7
H
N
6
11
9
(-)-(6S,7R,9R,11R)-lupanine
N
11
9
H
O
7
6
H
O
(+)-(6R,7S,9S,11S)-lupanine
[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
PC75
SYNTHESIS OF CATIONIC AND PERMETHYLATED CHLORINS
Rodrigo De Paula, Maria da Graça P. M. S. Neves, José A. S. Cavaleiro
Tetrapyrrolic macrocycles constitute a large family of natural compounds in Nature [13] 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.
O
H3C
H 3C
N
+
N
NH
O
OH
+
H
H
n
H 3C
CH 3
N
+
N
H3C
CH 3
N
H 3C
N
N
N
N
N
N
N
CH 3
H 3C
H 3C
N
-
H2C
+
N
N
H
CH 3
N
CH2
H 3C
N
N
N
+
M
M
+
+
CH3
CH 3
H
N
+
CH 3
DMF, reflux
2-3 h
inert atmosphere (N2)
N
+
N
N
N
CH 3
H 3C
H 3C
N
N
+
CH 3
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, 2306214.
PC76
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 2azabicyclo[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-DielsAlder 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.
O
OR
H
O
+
HO
N
OR
H
O
H2NOH.HCl
N OH
H
CO2R
N OH
CO2R
H
N
CO2R
References:
1. M. L. C. Vale, J. E. Rodriguez-Borges, F. Fernandez, O. Caamaño, X. GarciaMera; 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, 47,75957597.
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
Faculdade 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,
4
School of Pharmacy and Biomolecular Sciences, Univ. of Brighton, BN2 4GJ, UK
1
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-butylhexahomotrioxacalix[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.
t-Bu
OR
O
OR
t-Bu
O
RO
O
1
R=H
2
R = CH2COAd
t-Bu
[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
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
PC79
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 Nóxidos 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.
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
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).
R4
R2
H
R1
H
R3
1 R1= CH2OCO(CH2)14CH3; R2=R3=R4= H
R1
H
R3
R2
2 R1= CH2OCO(CH2)14CH3; R2= H; R3,R4= =O 4 R1= CH2OCHO; R2=R3= H
3 R1= CH3; R2= OH; R3,R4= =O
5 R1= CH2OCO(CH2)14CH3; R2=R3= H
7 R1= CH2OCHO; R2=R3=R4= H
6 R1= CH2OH; R2,R3= =O
[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.
PC80
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
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. 3Keto 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.
OR 2
O
O
OMe
CO 2Et
O
OR
1
O
OMe
CO 2 Et
R1O
OR2
2
Acknowledgments: The authors thank Fundação para a Ciência e Tecnologia for the
PhD grant SFRH/BD/30699/2006.
PC81
ICT AS A GATEWAY TO SCIENTIFIC EDUCATION OF BLIND
AND PEOPLE WITH VISUAL DISABILITIES
Florbela Pereira, João Aires de Sousa, Paulina Mata, Ana M. Lobo
REQUIMTE/CQFB, Departamento de Química,Faculdade de Ciências e Tecnologia,
Blind people and people with severe visual disabilities are at this moment prevented to
educate themselves in many areas of natural and technical sciences. Information in these
sciences is often available only in 2D pictures or graphs and data are presented in a way
which makes it very difficult for a blind person to locate relevant items. The project
“ICT as a Gateway to Scientific Education of Blind and People with Visual Disabilities”
will create a software framework for the Internet, which will make scientific
information accessible to blind people and people with severe visual disabilities. This
will allow them to acquire a scientific education through the participation in courses,
which are not directly targeted to people with this handicap.
The ICT project is a European project involving several institutions from four countries.
The partners, and their role, in the project are: Czech Republic- software development;
Norway- software tests by blind people and people with visual disabilities; FCT-UNL
/Portugal- teaching methodology; Czech Republic- web publishing; Sloveniacooperation with world and European Blind Unions; ACAPO/Portugal- cooperation
with world and European Blind Unions; and Czech Republic- cooperation with public
libraries.
The main focus of this project is chemistry, considered as a central science. Due to its
nature and the conventions used to convey information, the study of chemistry relies
heavily in visual experience, thus is particularly problematic to people with visual
disabilities and blind people. Organic chemistry was chosen as the main subject for this
project due to the very specific challenges presented by its tridimensionality.
The work we have been developing, concerning the identification of new methodologies
for teaching organic chemistry in such way, requires an analysis of each subject in order
to identify the real foundation of the knowledge, which is disconnected from visual
experience, and to find alternative non visual ways to convey it.
[1]C. Supalo, J. Chem. Educ., 2005, 82, 1513-1518.
Acknowledgments: We thank LEONARDO DA VINCI Programme for the award of a
postdoctoral fellowship to one of us (F. P.) and financial support (Project number
168025).
PC82
SYNTHESIS OF MODIFIED NUCLEOSIDES FROM DIELSALDER REACTIONS OF 1-HETEROCYCLIC CARBADIENES
TO 2H-AZIRINES
§
M. José Alves§, A. Gil Fortes§ and Nuno G. Azoia§
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057
Braga
[email protected]
1-N- and 1-O- functionalized 1,3-butadienes have been prepared and reacted with 2Hazirines.[1] In the sequence of this work a series of dienes 1 bearing a heterocyclic unit
attached by a carbon atom were prepared and reacted with 2H-azirines 2. Functional
group transformation on the adducts led to polyhydroxylated compounds of types 5 and
6. The Diels-Alder cycloadditions were accomplished under mild conditions and with
good to quantitative yields. Osmilation of the double bond followed by the ester
reduction afforded the triol 6 in moderate yield.
[1] Alves, M.J.; Gil Fortes, A.; Costa, F.T., Tetrahedron, 2006, 62, 3095-3102. Alves,
M.J.; Almeida, I.G.; Gil Fortes, A.; Freitas, A.P., Tetrahedron Letters, 2003, 44, 65616565.
Acknowledgements: FCT for PhD Scholarship (NGA, SFRH/BD/34183/2006), CQUM.
PC83
Author Index
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. Trindade
Alice M. Dias
Alves M. J.
Amélia P. Rauter
Ana Cerdeira
Ana Cristina Santos
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
PC4, PC19
PC4
PC60
PC39
PC83
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
OC10, PC81
PC50
PC23
OL4
PC1
PC8, PC66
PC9, PC35, PC38, PC41,
PC45, PC52, PC82
PC74
OC17, PC80
PC23
PC6
PC29
PC8, PC16
PC10
Ana R. M. Soares
Ana R. N. Santos
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
PC5
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,
PC80
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
PC47
PC1
PC12, PC14, PC24, PC33,
PC37, PC71, PL2
PC76
OL5
PC56
PC24
PC63
PL3
PC9
PC19, PC40
PC73
Catarina Prista
Cesare Gennari
Cláudio M. Nunes
Costa C.
Costa F. T.
PC25
PC49
PC69
PC7
PC7
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
Florbela Pereira
Francisco Peixoto
Frederick A. Beland
PC51
PC37, PC71
PC47
PC52
PC3, PC51
PC79
PC64
PC82
PC55
PC20, PC46
G
Goreti Pereira
PC53
H
Henry S. Rzepa
Hernâni L.S. Maia
Honorina M. M. Cidade
PL5
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 L. Salta
Joana F. B. Barata
Joana Moura
João Aires-de-Sousa
João M. Caio
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
PC60
PC48
PL10
PC31
PC31
PC33
PC36
PC18
OC10, PC81
PC61
PC25
PC42, PC70, PC72, PC82
OC10, PC81
PC21
PC5
PC52
PC67
PC67
PC58
PC2, PC5, PC57, PC59,
PC61, PC73, PC75
PC1
PC67
PC56, PC76
PC77
José V. Prata
PC11, PC15
L
L. Abrunhosa
L. F. Veirosa
L.C. Branco
L.M.T. Frija
Laura Belvisi
Lígia M. Rodrigues
Lucau Teresa
Lucinda V. Reis
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
PC51
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-Marques
M. Helena Garcia
M. I. Ismael
M. I. Page
M. J. G. Fernandes
M. João M. Curto
M. José Alves
M. Laranjo
M. Luísa C. Vale
PC19
PC4
PC54
PC4, PC19
PC48
PC27
PC23
PC73
PC27
OC5
PC31
PC34
PC47, PL9
PC83
PC4, PC19
PC76
M. Luisa Sá e Melo
M. Manuel B. Marques
M. Manuel C. Silva
M. Manuel Oliveira
M. Matilde Marques
M. Neves
M. Paula Robalo
M. Pineiro
M. S. T. Gonçalves
M. Teresa Duarte
M. J. U. Ferreira
M. L. S. Cristiano
Madalena M. M. Pinto
Mafalda Laranjo
Magdi E. A. Zaki
Manuel Almeida
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
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
PC58
OC9
PC35
PC58
PC55
PC63, OC14
PC20, PL7, PC26, PC46
PC47
PC27
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
OL4
PC16
PC52
OL4
PC25
PC45
PC18
PC10, PC32, PC44
PC29
PC30, PC65, OC1
PC20
PC8
OC11
PC56
Marta A. O. P. Neves
Marta Pineiro
Marta Correia-da-Silva
Marta S.F. Costa
Massuquinini Inês
Mercedes Amat
Monica Civera
Mónica Estevão
Muna Sidarus
PC32
PC23, PC40
OC6
PC51
PC16
PC18
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
PC83
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
PC17
PC33
PC37
PC11
OL4
PC77
PC53, PC65
PC79
PC1, PC52
PC25, PC68, PC82
PC62
PC62
PC43, OC15
Paulo Pereira
Pedro J. M. Abreu
Pedro L. B. Vicente
Pedro M. P. Gois
Pedro P. Santos
Pedro Santos
Peter J. Cragg
Peter Somfai
PC9
OC8
PC55
PC12, PC71
PC20, PC46
PC21
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, PC81
PC24
PC2
PC45
PC30
OC4
PC57, PC75, PC78
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
PC39
PC34
PC24
PC40
OL5
PC24
PC58
OL1
PC9
PC74
PC6, PC64
PL8
PC22
OL5
Stephen Caddick
Stephen Caddick
Sundaresan Prabhakar
Susana Franca
Susana M.M. Lopes
Susana P. G. Costa
Susana P. Gaudêncio
PC37
PC71
PC9, PC35, PC38, PC41,
PC45
PC9
PC69
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
Z
PC42
Z. Barata
PC39
Participants Index
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.
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
Caparica, Portugal.
2829-516 Caparica
PORTUGAL
[email protected]
Burke, Anthony
Quínica
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
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
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 Departamento de Química- Escola de Ciências Campus de Gualtar
4700-057 Braga Braga
PORTUGAL
[email protected]
Castanheiro, Raquel
Química Orgânica
Rua Aníbal Cunha, 164
PORTUGAL
[email protected]
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
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
Centro de quimica da Universidade do Minho Campos de gualtar
4710-057 Braga
PORTUGAL
[email protected]
Costa, Elisangela
CEQOFFUP
Rua Aníbal Cunha,164
4050-047 Porto
PORTUGAL
[email protected]
Costa, Alexandra
Engenharia Química
1950-062 Lisboa
PORTUGAL
[email protected]
Costa, Susana
Química
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
Av. Rovisco Pais, 1
1049-001 Lisboa
PORTUGAL
[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
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
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
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
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
1749 Lisboa Lisboa
PORTUGAL
[email protected]
Lopes, Susana
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
Av. Prof. Gama Pinto
1649-003 Lisboa
PORTUGAL
[email protected]
Marcos, Paula
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
Campus de Santiago
3810-100 Aveiro Aveiro
PORTUGAL
[email protected]
Marques dos Santos, Maria Manuel
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
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
3004-535 Coimbra
PORTUGAL
[email protected]
Nascimento, Vanesa
Chemistry
FCT/UNL
Campus da Caparica
2829-516 Caparica
PORTUGAL
[email protected]
Neves, Marta
Química Orgânica
Rua Aníbal Cunha 164
PORTUGAL
[email protected]
Neves, Cristina
Largo do Paço
4704-553 Braga
PORTUGAL
[email protected]
Noronha, João Paulo
Caparica, Portugal.
2829-516 Caparica
PORTUGAL
[email protected]
Nunes, Cláudio
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]
Oliveira, Célia
Dep. Eng. Química - Secção de Química Orgânica
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
R. Aníbal Cunha n.º 164
4050-047 Porto
PORTUGAL
[email protected]
Pereira, Maria Goreti
Departament of Chemistry
University of Minho
Gualtar
PORTUGAL
[email protected]
Pereira, Nelson
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
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
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
Campus de Gualtar Escola de Ciências Braga Portugal
4710-057 Braga
PORTUGAL
[email protected]
Ribeiro, Sónia
Química
Rua Larga
3004-535 Coimbra
PORTUGAL
[email protected]
Rosatella, Andreia
Departamento de Engenharia Química e Biológica
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
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
Rua Larga
3000 Coimbra
PORTUGAL
[email protected]
Santos, Ana
Chemistry
Estrada dos Marinheiros Nº78, 2ºDto
2415-380 Leiria
PORTUGAL
[email protected]
Santos Vieira, Isabel
Química
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
Campus Santiago
3810 Aveiro
PORTUGAL
[email protected]
Serra, Arménio
Rua Larga-Coimbra
3000 Coimbra
PORTUGAL
[email protected]
Sidarus, Muna
Centro de Química Estrutural
Av. Rovisco Pais
1049-001 Lisboa
PORTUGAL
[email protected]
Silva, Ana Maria
Química
4710-057 Braga
PORTUGAL
[email protected]
Silva, Marco
Caparica, Portugal.
2829-516 Caparica
PORTUGAL
[email protected]
Silva, Marília
Dep. Química Escola de Ciências Campus de Gualtar Braga
4710-057 Braga
PORTUGAL
[email protected]
Silva, Sandra
Química
Rua Larga
3000 Coimbra
PORTUGAL
[email protected]
Silva Serra, Maria
Departamento de Química, Universidade de Coimbra Rua Larga 3004-535 Coimbra
3004-535 Coimbra Coimbra
PORTUGAL
[email protected]
Simoes, Mario
Aveiro University
Campus de Santiago Chemistry Department Aveiro University
3810-193 Aveiro
PORTUGAL
[email protected]
Simão, Dulce
Dep.Eng.Química e Biológica
Av. Rovisco Pais
1049-001 Lisboa
PORTUGAL
[email protected]
Soares, Maria
Química
Rua Larga
3004-535 Coimbra
PORTUGAL
[email protected]
Soares, Ana Raquel
Campus de Santiago
3810-193 Aveiro
PORTUGAL
[email protected]
Sousa, Maria
CEQOFFUP Serviço de Química Orgânica
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
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
CQFM - IST -Complexo I Av. Rovisco Pais
1049-001 Lisboa
PORTUGAL
[email protected]
Vale, Luís
Universidade de Aveiro Departamento de Química Campus de Santiago
3810-193 Aveiro
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
Quinta da Torre
2829-516 Caparica
PORTUGAL
[email protected]
Vieira, Abel
Química
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
School Of Science, Minho University
Chemistry Department, School Of Science, University Of MINHO, Braga, Portugal
PORTUGAL
[email protected]

updated version - Neural - Universidade Nova de Lisboa

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