HETEROCYCLICAL COMPOUNDS (2)

Author: BARCIA BARCIA JOSÉ CARLOS.
Year: 2004.
University: SANTIAGO DE COMPOSTELA [www.usc.es].
Place of defense: FACULTAD DE QUÍMICA.
Place of preparation: FACULTAD DE QUÍMICA.

Summary: The reaction of Diels-Alder intramolecular furans (DAIMF) of the N-bencil-N- [2 - (2-furyl) ethyl] acrylamide (141b) leads estéreoselectivamente the exo-isomer of the racemic mixture of cicloaducto corresponding to 4 - bencil-4-aza-11-oxatriciclo [6.2.1.01,6] undec-9-en-5-ona (140b). His Flavoring permits easily and with good performance to 2-bencil-1 ,2,3,4-tetrahidro-1-isoquinolionas (139th). The reaction of Diels-Alder intramolecular furans (DAIMF) of the 1-(1-furan-2-il-6 ,7-dimetoxi-3 ,4-dihidro-1H-isoquinolin-2-il) propenona (142nd) gives instead estéreoselectivamente the exo-isomer of the racemic mixture of 2,3-dimetoxi-10, 12a-epoxi-5, 8a, 9,10,12 to 12b-hexahidro-6H-isoindolo [1,2-a] isoquinolin-8- ona (143a). His Flavoring leads to 2,3-dimetoxi-5, 12b-dihidro-6H-isoindolol [1,2-a] isoquinolin-8-ona (6d) with moderate yields. The reaction of Diels-Alder intramolecular furans (DAIMF) of the 1-(1-furan-2-ilmetil-6 ,7-dimetoxi-3 ,4-dihidro-1H-isoquinolin-2-il) propenona (144th) gives instead estéreoselectivamente the exo-isomer of the racemic mixture of las2 ,3-dimetoxi-10, 12a-epoxi 5,6,8 a, 9,10,12, a 13.13 a-ocathidroisoquino [3,2-a] isoquinolin-8-ona (145). His Flavoring leads to 2,3-dimetoxi-5, 6,13,13 a-tetrahidroisoquino [3,2-a] isoquinolin-8-ona (11c) easily with a good performance. We developed a new method of synthesis of 2-hidroxi-6 ,7-dimetoxi-3- (2-nitrofenil) - [1.4] naphtoquinones (124h) previously used by our group to synthesize 8,9-dimetoxi-5H- benzo [b] carbazole-6 ,11-dionas (34s). We developed a new method of synthesis of acidic or acetilbenzoicos (178th), based on the coupling between Heck No butilviniléter and o-bromobenzoatos methyl (65g), which leads to selectively output coupling alpha. Hydrolysis of these enoléteres leads to acetilbenzoatos methyl (178e), which is readily hydrolyzed to acids o-acetilbenzoicos (178th). These compounds were isolated as 3-hidroxi-3-metil-3H-isobenzofuran-1-onas (180th). Proceeding as shown in literature, 3-hidroxi-3-metil-3H-isobenzofuran-1-onas (180th) became 3-bencilidenisocroman-1 ,4-diona (177th), to be treated with metóxido sodium methanol experimetnan a rearrangement leading to las2-hidroxi-3-fenil [1.4] naphtoquinones (124r). This new route yielded easily and with good performance 5H-benzo [b] carbazole-6 ,11-dionas (34u) and benzo [b] nafto [2,3-d] furan-6 ,11-dionas (33rd). The reaction between hidroxinaftoquinona 198th and nitrociclohexeno 196b gave them uniquely the anti-isomer of 2-hidroxi-3- (2-nitrociclohexil) - [1.4] naphtoquinone (191c). The hidroxenación subsequent warming to reflux in dioxano of 2 - (2-aminociclohexil) 3-hidroxi [1.4] naphtoquinone (191d) as a consequence, allows for the 2,3,4,4, a 5.11 b-hexahidro- 1 H-benzol [b] carbazole-6 ,11-diona (193b) and hexahidrobenzo [to] carbazoldiona 200th. The reaction of addiction of organolítico derived 2-bromo-1 ,4-dimetoxinaftaleno (118g) nitrociclohexeno 196b resulted in a mixture of (+-)- without-1 ,4-dimetoxi-2- (2-nitrociclohexil) naphthalene (201 b) and (+-)- anti-1 ,4-dimetoxi-2- (2-nitrociclohexil) naphthalene (201c). A reaction Neff and oxidation with CAN led to the formation of (+-)- 2 - (2-oxociclohexil) - [1.4] naphtoquinone (201d). Finally, this compound became the 2,3,4,5-tetrahidro-1H-benzo [b] carbazole-6 ,11-diona (36g).

Author: VILLAR BECARES RAQUEL.
Year: 2004.
University: PÚBLICA DE NAVARRA [www.unavarra.es].
Place of defense: DEPARTAMENTO DE QUIMICA APLICADA.
Place of preparation: UNIVERSIDAD PUBLICA DE NAVARRA.

Summary: It has developed a multi-disciplinary work which has led to the obtaining of derivatives of 1,1-dioxide benzo [b] thiophene, working in the field famacéutico through a rational design using different theoretical methods. To this has been conducted by the synthesis of 21 new derivatives of 1,1-dioxide benzo [b] tiofenosulfonamida at positions 5 and / or 6 of the ring, 4 new carboxamidas related, a derivative sulfonate and a hydroxylated derivative. Determining the cytotoxicity has been carried out on 24 of the new derivative of 1,1-dioxide benzo [b] thiophene using a microensayo color reduction bromide 3-(4,5-dimetil-2-tiazolil ) 2, 5-difeniltetrazoilo (MTT) on a line of human lung fibroblasts and 6 cell lines of human tumors, representing solid tumors, (HTB-54; HT-29; MEL-AC, HeLa), and leukemia (CCRF- EMF; K-562). 23 of the 24 compounds tested have been very active against one or more of the lines ensayas values GI50 range M. The lines HeLa, CCRG-CEM, HTB-54 and HLFphTERT have proven the most sensitive. Derivatives sulphonamide carboxamide and are more active than the corresponding sulfonate or hydroxyl. Cytotoxicity is not affected by the position of sulphonamide in the ring but is enhanced by the replacement of the hydrophobic sulphonamide and carboxamide. The compounds are the most active N-phenyl (4metoxi) and N - (2 - (4-metoxi) phenyl) ethyl derivatives carboxamide and sulphonamide whose cytotoxicity is comparable to doxorubicin composite trading. The N - (2-feniletil) -6-sulfonamida derivative inhibits NADH oxidase activity associated with tumor in reductive terms with a EC50 of 0.1 nM. Trials inhibition Anhidrasas carbonic have shown that derivatives of sulphonamide not replaced presented an excellent, while the N-sustitución decreases the activity. The 3-butiloxi and 3-benciloxi derivatives 1,1-ióxido of 2,3-dihidrobenzo [b] tiofeno-6-sulfonamida showed the best activity and selectivity for certain the isoencima associated with tumor IX, pointed to two new heads series as inhibitors Anhidrasa carbonic. The use of HQSAR revealed structural most important facts affecting the biological activity, which has led us to design new derivatives assets. It has also conducted a study showing that QSAR cytotoxicity of the composite increases with the lipophilicity of the same, reflecting a possible interaction with the target rather than a biological effect of transport. It has been shown that the method semi AM1 can be an effective tool for studying the interactions ligando-proteína because it is able to reproduce the Entalpías interaction of small molecules obtained by the method COP MP2/6-31 G (d) and reproducing structures Rays of ligando-proteína. The energies of solvatación aqueous have been calculated with the method IPCM at HF/3-21G (d) / / AM1. The use of Entalpías interaction and Entropías AM1 in gas phase and values solvatación have been applied to the development of new inhibitors Anhidrasa Carbónica.

Author: QUEZADA GONZÁLEZ ELÍSA NEFTALI.
Year: 2004.
University: SANTIAGO DE COMPOSTELA [www.usc.es].
Place of defense: FACULTAD DE FARMACIA.
Place of preparation: FACULTAD DE QUÍMICA.

Summary: They point to efficient synthesis routes, direct and generalizable for easy access to the different sets of skeletons tetraciclicos proposed. Chains of nature aminoalquílica on the ring bencénico central compounds fotoquimioterápicos most interesting were conveniently completed. The derivative 3-arilcumarínico 94, which includes a fragment of trans in its structure, was conveniently obtained through two alternative routes using the same product line. Some of the compounds synthesized offered very different and interesting pharmacological profiles: a) It highlights the compound 60 by: i) high activity against cell lines HeLa and HL-60 in the presence of radiation (2300 times the 8-MOP) ii) its high activity in the absence of radiation (conditions under which the 8-MOP is not active), iii) the absence of cutaneous phototoxicity at doses 40 times higher than those that 8-MOP have edema iv) its solubility water rises 8 times over the compound reference v) the safety of not presenting the medium-term challenges associated with the formation of cross-link, b) compounds 60 and 61 had a cardiovascular activity significantly higher than shown by the trans. On the other hand the compound 94, although it was less active than the trans as a vasodilator, inhibited platelet aggregation induced by thrombin and collagen with IC50 significantly lower than those obtained for this compound polyphenolic of natural origin. C) It highlights the compound 50 for his interesting activity i-MAO and especially its selectivity MAO, which makes it a suitable top seed in a new class of antidepressant.

Author: GRIJALVO TORRIJO SANTIAGO.
Year: 2005.
University: BARCELONA [www.ub.es].
Place of defense: FACULTAD DE FARMACIA.
Place of preparation: FACULTAD DE FARMACIA UNIVERSIDAD DE BARCELONA.

Summary: SUMMARY: The esfingolipidos (SLs) are part of a large family of compounds with important biological characteristics as industrial. From a biological point of view, the SLs are involved in various processes, such as recognition and transduction mechanisms of cell. They are considered, in addition, second messengers, which are involved in processes of growth and programmed cell death or apoptosis. From a structural point of view (using the D-eritro-esfingosina as a model), the SLs three units: a polar head (unit of alcohol), a part lipófila (fatty acid) and a unit of aminoalcohol, which is the unit typical of all SL. The Ceramida (Cer) is a powerful signal transducer that affects the growth, differentiation and cell death. It occupies a central position in the metabolism of SLs can be transformed into other more complex lipids. It is at this point when it has been proposed the synthesis of analogs of both the Cer as other metabolites from it, which are the sphingosine phosphate (S1P) and ceramida-1-fosfato (Cer-1-P). Considering the overall structure of the SLs, it may submit up to three points of diversity. The groups R1 (thiol and phenols) and R2 (acid chlorides and carboxylic acids), which were introduced were previously selected by calculation programs such as Pralins, developed by the Grup d'Enginyeria Molecular dellnstitut Químic of Sarriá. Thus, from an original library consisting of 8,428 compounds, the program through a series of calculations selected potential sub-bibliotecas possible by choosing one of them, the library 12x12 as a compromise between the two approaches: population and coating, introducing values the 93% and 42%, respectively. For the synthesis of libraries of similar SLs was elected the tosilat alcohol Garner as a base structure. Thus, after the corresponding replacement nucleófila between tosilato and appropriate nucleotide and subsequent acilación the aminoalcohol, resulting from unprotected ring oxazolidina was obtained after purification by column chromatographic the corresponding library analogues Cer. An alternative was the use of coupling agents anchored on polystyrene resins (PS-EDC). Preliminary results showed obtaining analogues Cer with acceptable yields and good purities (90%). The second library that was proposed was to synthesize the analogues S1P. This will optimize a method that provided a synthetic derivative phosphate from the unprotected selective group isopropilideno in the presence of Boc. The phosphate was suitably protected served as intermediary for obtaining both analogues S1P as Cer-1-P. Thus, the simultaneous lack of methyl esters of phosphorus and cluster Boc provided the second of the libraries with about yields and purities ranging approximately between 85 and 99%. Moreover, the only unprotected group Boc and subsequent reaction acilación with different aliphatic acid chlorides provided the corresponding analogue Cer-1P in a protected manner. The openness to the same acidic conditions for the second of libraries generated for the library analogues Cer-1-P as unprotected, with good yields and purities ranging between 70 and 100%, as measured by HPLC analysis . On the other hand, we developed a method that introduced the same chloride acid sequestrants but using agents. This is the technique called "catch and release". The corresponding analogue Cer-1-P were obtained with good yields and high purities. However, the introduction of aromatic acid chlorides was influenced by the effect estérico generated by the phosphorus atom and the corresponding aromatic ring. This problem was resolved to carry out the reaction of phosphorylation of Iso analogues with Cer remains in the chain N-acilo aromatic, thus obtaining, 8 the cor 1cb respondents analogues Cer with moderate yields.

Author: BASSAS SAPÉ ORIOL.
Year: 2005.
University: BARCELONA [www.ub.es].
Place of defense: FACULTAD DE FARMACIA.
Place of preparation: FACULTAT DE FARMÀCIA, UNIVERSITAT DE BARCELONA.

Author: Toba Veloso Rosa.
Year: 2005.
University: A CORUÑA [www.udc.es].
Place of defense: Facultad de Ciencias.
Place of preparation: Facultad de Ciencias.

Summary: 1) It has conducted the preparation and characterization of the first three generations of a dendrímero symmetrical core cavitando and funcionalizado with four units viológeno (14-17) 2) Similarly, were obtained and characterized the first three generations of a dendrímero symmetrical with a unit viológeno in the nucleus (27-29). 3) The electrochemical study of these compounds indicates that the electronic transfer processes are reversible or quasi reversible, which reinforces the idea that the units are capable of viológeno internal reactions heterogeneous electronic transfer, which is independent of the kinetic generation dendrímero. 4) were obtained dendrímeros not symmetrical 38-41 and 42-45. There has been also a comparative study of their electrochemical properties and interactions liaison with ether crown bis-p-fenileno-34-corona-10 with dendrímeros similar ramifications and type Newkome, in collaboration with the research group of Prof. . Kaifer: In all dendrímeros investigated behavior voltamétrico is reversible from first to third generation, consistent with the results obtained for dendrímeros (14-17) and (27-29). The values of the coefficients of diffusion D0 are consistent with the relative size of the dendrímeros: the two sets of dendrímeros type Fréchet show identical values of D0 to the same generation, reflecting the similarity of their masses and structures. The growth of dendrones type Fréchet just have effects on the stability of the complex partnership with the bis-p-fenileno-34-corona -10. This is linked to the more rigid of dendrones of poliaril ether that gives rise to forms dendritic wedge-shaped, which can promote the link, unlike the dendrones type Newkome, more flexible, which may prevent the encapsulation of the receiver . 5) have been prepared and characterized the macrociclos 56a-c. In the crystal structures of 56a-c as well as experiments NOES of the 56th c confirm the spatial proximity system dioxoarilo to viológeno. The ability to accept electrons from viológeno, combined with the ability of the giver aromatic groups, resulting in a transfer intramolecular load which is reflected in a band absorption in the UV-Vis. The absorbance of these bands are linearly correlated with the concentration in the range 0.2-7.0 mM, which indicates that, most likely, the charge transfer is intramolecular. 6) have been obtained and characterized the compound 61 which has four units viológeno on the periphery. 7) Using a convergent strategy has been obtained and characterized the molecule star 76 which presents 6 units bipiridina and the possibility of complexation.

Author: Encinas López Arantxa.
Year: 2005.
University: AUTÓNOMA DE MADRID [www.uam.es].
Place of defense: Facultad de Ciencias.
Place of preparation: Instituto de Química Médica (CSIC).

Summary: Derivatives 1,2,4-tiadiazol-3 ,5-diona (TDZD) have recently appeared as the first family heterocíclica of non-ATP competitive inhibitor of GSK-3 beta enzyme representing new prototypes for the development of effective therapeutic agents in the treatment of Alzheimer's disease and other neurodegenerative processes. The establishment of the first structure activity relationships have highlighted the importance of the system 1,2,4-tiadiazol for the activity of these compounds. In this context, the present Doctoral Thesis have addressed various structural modifications in the ring 1,2,4-tiadiazol, specifically in positions three five system heterociclico to assess their importance in the activity of these compounds. On the other hand, and given that this increasingly more widespread assumption that an efficient way to deal with this multifactorial disease is the use of combination therapies, it presents the design and synthesis of new derivatives 1,2,4-tiadiazol capable of incorporated into its structure fragments with known antioxidant capacity. Finally, and in order to increase the potency of derivatives 1.2, 4-tiadiazol proposes the design and synthesis of new derivatives capable of carrying in its structure ATP competitive inhibitors of novel structure. DEVELOPMENT OF WORK AND METHODOLOGY This Doctoral Thesis has been structured into three chapters. In Chapter 1 of this report, through computational techniques has been carried out determining a model farmacóforo dimensional enzyme GSK-3. In Chapter 2, has been carried out the synthesis of new derivatives 1,2,4-tiadiazol with different funcionalizaciones at positions three and five for assessing the impact of such changes in the inhibitory capacity of GSK3. As part of the development of this Chapter has been taken into account balance tautomérico between forms 5-amino/imino of derivatives proposed, which has conducted its study using both experimental techniques and methods theoretical calculation. Finally, we have conducted studies of biological enzyme inhibition in vitro enzyme GSK-3. In parallel and in order to determine their possible mechanism of action has been made both kinetic studies of competition enzima-inhibidor as chemical stability studies using HPLC techniques, as well as methods of theoretical calculation. In Chapter 3, in order to obtain dual action arising with GSK-3 -antioxidante have synthesized derivatives 1,2,4-tiadiazol with inhibitory capacity compared with GSK-3 and able to incorporate them on the fragment with BHT in order to transfer further antioxidant capacity. Additionally exploiting the discovery derivative naphtoquinone, juglona as an inhibitor of GSK-3 with a profile similar to TDZD have made structural changes in order to establish relations structure biological activity. The family of derivatives has been evaluated in addition to their ability to inhibit neuronal nitric oxide synthase as a measure of its ability neuroprotectora. The methodology used in this work, framed within the Area Medical Chemistry, has been in the synthesis, purification and identification of compounds using techniques common in Organic Chemistry, Biological Assessment and the same establishment of relations Biological Structure. In addition, for the development of part of this report have been used molecular modeling techniques to design new structures and methods of theoretical calculation as a supplement to the pilot study of the processes tautomeria found. It has also conducted a study of the chemical stability of the compounds prepared using HPLC techniques.

Author: CANO RAMOS CAROLINA.
Year: 2005.
University: AUTÓNOMA DE MADRID [www.uam.es].
Place of defense: FAC. DE CIENCIAS, DEPTO.QUÍM. ORG..
Place of preparation: INSTITUTO DE QUÍMICA MÉDICA, CSIC.

Summary: We have prepared carboxilatos and carboxamidas of 1,1-dioxo-1 ,2,6-tiadiazina and have been evaluated as potential cannabinoids found that modulate the activity of cannabinoid system and can act as agonists, antagonists or inverse agonist cannabinoids depending on the substituents system heterocyclic 1,1-dioxo-1 ,2-dihidro-1? 6-1,2,6 -tiadiazina. On the other hand, have developed a new class of derivatives sulfamida chain alquílica long as analogues aciletanolamidas shown selective affinity for the nuclear receptor PPARa capable of modulating actions covered by these receptors, namely the induction of satiety and controlling intake, the reduction of body mass and the regulation of lipid metabolism. Considering the family carboxilatos and carboxamidas of 1,1-dioxo-1 ,2,6-tiadiazina, have been on the verge of synthetic methods for the preparation of 5-carboxilatos and 3-carboxilatos of 1,1-dioxo-1 , 2.6-tiadiazina, starting in two routes of great practical value. It has undertaken the preparation of 5-carboxilatos of 1,1-dioxo-1 ,2,6-tiadiazina from 2,4-dioxoésteres and sulphonamides N-sustituidas. Moreover, obtaining N-bencilderivados of 3-carboxilato of 1,1-dioxo-1 ,2,6-tiadiazina by reaction sulfamida and 2,4-dioxoésteres and subsequent N-bencilación. In obtaining the carboxamidas must emphasize the use of conditions transamidación very effective in which the ester is converted directly into amide, from carboxilatos of 1,1-dioxo-1 ,2,6-tiadiazina with different hidrazinas and amines in the presence of trimetilaluminio. The pharmacological evaluation of the new compounds as potential cannabinoids has been carried out primarily by functional tests in vitro tissue, while derivatives present properties as agonists, antagonists or inverse agonists and the tiadiazinas with better pharmacological profile through tetrada cannabinoid in vivo . In accordance with the objectives set, has found a new family of cannabinoids heterocyclic with 1,1-dióxido of 1,2,6-tiadiazina as basic skeleton, whose structural modifications at positions 2, 3 and 5 modulate the properties cannabinoids agonist, inverse agonist or antagonist of the new compounds. Thus, it has applied for a patent is the first description of cannabinoids whose basic skeleton is 1,1-dióxido of 1,2,6-tiadiazina. Moreover, as to the family of derivatives sulfamida, have been on the verge of synthetic methods for the preparation of sulphonamide N-monosustituidas by reaction transaminación of long chain amines with a sulfamida and N-propilsulfamidas N'- replaced by the corresponding amine react with chloride N-propilsulfamoilo. The pharmacological evaluation as ligands PPARa of new compounds was conducted through in vitro tests, which look similar to the profiles of interaction of the OAS used as a reference. Tests have been conducted in vivo in which some sulphonamides have significantly reduced intake of food under the conditions tested and have mimetizado effects of the OAS to reduce body weight and produce a marked reduction in the levels of plasma triglycerides. Based on these test results in vitro and in vivo, can be considered as new sulphonamide compounds active against PPAR receptor activity and as appetite suppressants, also capable of reducing body weight and levels of plasma triglycerides. Thus, the replacement of the amide group of 8 the acil 46e etanolamidas by the group sulfamida maintains activity against nuclear receptor PPARa, while eliminating the activity of cannabinoid derivatives unsaturated. All these results are reflected in a patent that covers the new derivatives sulfamida described in this thesis as regulators of appetite, being the first patent derivatives sulfamida with implementation in regulating appetite as a potential therapeutic approach for the treatment of obesity and eating disorders.

Author: GOMEZ ALMAGRO MARIA VICTORIA.
Year: 2005.
University: CASTILLA-LA MANCHA [www.uclm.es].
Place of defense: FACULTAD DE CIENCIAS QUIMICAS, C. REAL.
Place of preparation: FACULTAD DE QUIMICAS.

Summary: A growing environmental awareness and increasingly stringent environmental legislation have focused the attention of chemical manufacturers on what has become known as sustainable development or Green Chemistry. A working definition of green chemistry is: technologies that efficiently utilise raw materials and reduce, or preferably eliminate, the generation of waste and avoid the use of toxic and/or hazardous reagents and solvents. Considering the importance of Green Chemistry, the target of this work is the development of different environmentally benign processes for the synthesis of organic compounds. Comparison of this methodology with the one found in the literature for the synthesis of most products, makes the former one much more sustainable for that specific synthesis due to smaller reaction times and the no presence of hazardous reagents and solvents. As such, in every experiment the microwave irradiation have been used as an alternative energy source. The effect of microwave irradiation is not exclusively an acceleration of the reaction, as some compounds did not react by classical heating in an oil bath under comparable reaction conditions (time and temperature). In order to demonstrate the existence of that specific microwave effect, an exhaustive research has been carried out. As a result, some important indicatives about this effect have been found. This could explain the fact that most of the products described here are not obtain 8 ed by cl 5b7 assical heating in similar conditions. A range of reactions types have been carried out: self-condensation of hydroxybenzene derivatives, Diels-Alder cycloaddition and oxidation reactions. Solvent-free techniques have been used in almost every experiment: Reactions on solid mineral supports such as alumina, silica, clays, zeolites etc.. and reactions without any solvent, support, or catalyst: These heterogeneous reactions are performed between neat reactants. These techniques can be efficiently coupled to non-classical methods of activation as microwave irradiation. This study proved the importance of microwave irradiation and solvent-free techniques in the developed of some environmentally friendly procedure for the synthesis of different organic compounds.

Author: HERRERO CHAMORRO MARIA ANTONIA.
Year: 2005.
University: CASTILLA-LA MANCHA [www.uclm.es].
Place of defense: FACULTAD DE CIENCIAS QUMICAS, C. REAL.
Place of preparation: FACULTAD DE CIENCIAS QUIMICAS C. REAL.

Summary: The work present in this thesis shows several kinds of reactions, most of them are cycloaddition, which could be enclosed in different fields of the chemistry but with a common aim: the useful and convenient use of the irradiation in solvent-free conditions as an alternative method against classical heating. Following this thesis we will develop the high number of advantages that this technique shows. In the first part, which was performed in a short period of time in Uppsala (Sweden), as a predoctoral stay. The demands made on innovative drug discovery are changing at an unprecedented pace, and the techniques of organic synthesis and high throughput chemistry must thus continue to evolve. Today, various strategies have been developed to rapidly deliver novel-lead and drug-like organic molecules. Although many high throughput chemistry methods have evolved, the interest in accelerating organic reactions by high-density microwave heating (MW) has increased over the last few years. In the field of microwave chemistry, the use of different solid phase protocols combines short reaction times with convenient product isolation and purification. The difficulties encountered in performing gaseous reactions under microwave irradiation have further spurred the invention of carbon monoxide releasing solid phase reagents for high-speed carbonylative applications. We herein report on a new protocol exploiting easily handled and convenient molybdenum hexacarbonyl as condensed source of carbon monoxide for performing rapid hydrazidocarbonylation reactions with aryl halides. N,N-Diacylhydrazines are well known starting materials for the preparation of various heterocycles, but this functionality can also be found in different types of protease inhibitors, therefore we develop a one-pot method to synthesize 1,3, 4-oxadiazole. Catalyst recycling and reuse can be of crucial importance in homogeneous reaction protocols employing expensive metal catalysis. Fluorous solvents are utilized to enable efficient recycling of the flourous catalyst in an easy, quick and efficient way. In the second part, we synthesized new complex heterocyclic systems with high pharmaceutical applicability by cycloaddition reactions of different dienophiles with o-quinodimethanes heterocyclices. In this work, we have investigated the generation, under microwave irradiation of o-quinodimetanes derivatives of 1,2,4-triazine, pyrazine, pyrazole and 1,2,3-triazoles, and the undergo cycloaddition with different dienophiles. The rapid heating induced by the radiation avoids the decomposition of the reagents and/or products, reactions are cleaner and yields are in many cases higher than those obtained by classical heating. We can even induce cycloaddition reactions which are not possible to perform under classical conditions. For these reasons, microwave technology is a very promising technique to generate o-quinodimetane derivatives. The relevance of this work is not the synthetic way; it is the fact that the developed microwave methodology and the yield are available for having a preparative application in this kind of reaction. In the third part, not only are the general advantages of this alternative methodology developed but it is also the possibility to modify the selectivity (chemo-, region and stereoselectivity) in relation to conventional heating. A very attractive possibility is to control the selectivity just by selecting the mode of heating (conventional vs. microwave). Consequently, interest in microwave irradiation as a technique in organic chemistry has increased considerably. Microwave irradiation induces the 1,3-dipolar cycloaddition of imines derived from a-aminoesters with Ã-nitrostyrenes, one of the most versatile tools for the construction of five-membered heterocycles, in the absence of solvent within 10-15 min. The reaction proceeds to give yields in the range of 81-86% and three isomeric pyrrolidines are obtained in the cycloaddition. The use of classical heating with longer reaction times (24 h) gives lower yields of products (below 50%) and only two stereoisomers can be detected in each reaction. The course of the cycloaddition has been determined by computational studies in order to explain the difference in the selectivity observed under microwave irradiation in relation to conventional heating. Likewise, we have developed an efficient microwave-assisted process for the aromatization of these pyrrolidine to highly substituted pyrroles with potential interest. In the last part, having used the microwave irradiation as a fundamental method of heating in this thesis, it is important to prove the reproducibility of this method. Reproducibility is one of the major issues associated with Microwave Assisted Organic Chemistry, especially when domestic ovens are used. For this reason, we carried out an extended study in order to prove the reproducibility of microwave reaction in the absence of solvent; it helps us recover a lot of reaction, which has been performed in a domestic oven without convenient control of the temperature. In this work a solvent-free reaction, 1,3-dipolar cycloaddition of nitrile N-oxides with nitriles to get 1-oxo-2,4-diazoles, previously described in a domestic oven has been translated into monomode microwaves reactor and then scaled it up in a multimode oven. Reproducible results have been achieved across all the instruments without taking into account the scale.

Author: ECHEVARRIA RUIZ JUAN.
Year: 2005.
University: PAÍS VASCO [www.ehu.es].
Place of defense: FACULTAD DE CIENCIA Y TECNOLOGÍA.
Place of preparation: FACULTAD DE CIENCIA Y TECNOLOGÍA. UNVIERSIDAD DEL PAÍS VASCO.

Summary: In the research work that is reflected in this report is a study of the estereoselectividad the reaction of aza-Michael on amides alpha beta-insaturadas from aminoalcoholes chiral with the aim of developing a new methodology stereoselective synthesis of derivatives beta-aminoácidos. On the one hand, it has been found induction chiral 1.5 exercised by a chiral auxiliary such as (S, S )-(+)- pseudoephedrine in the reaction conjugate of amiduros metal on enamidas derived from the latter. We have optimized reaction conditions conducive to the development of a highly estereoselectivo and has studied the effect of sustituyeres in central pro-estereoselectividad of reaction. This work has led to obtaining different reaction conditions optimized who passed through the use of additives and binders species nucleófilas heterobimetálicas. Moreover, changes in the structure of chiral auxiliary has helped develop a process diatereodivergente, depending on the nature of the role oxygenated present in the auxiliary. In addition, modulation of the structure of the latter and experiments dual asymmetric induction chiral with amiduros lithium have allowed propose a reaction mechanisms consistent with the results observed experimentally. Lastly, the derivatization of beta-amonoamidas obtained after the addition conjugated have enabled the synthesis of beta-aminoésteres, beta-aminoaldehídos, gamma-aminoalcoholes, beta-aminoaldehídos and 2-alquilpiperidinas enantioéricamente cigars, among which is the highlight of natural products such as alkaloids piperidínicos (R) -pipecolina and (S) -coniina.

Author: MENA CERVIGÓN MARISA.
Year: 2005.
University: BARCELONA [www.ub.es].
Place of preparation: FACULTAD DE FARMACIA.

Summary: The lepadinas are alkaloids of marine origin of interesting pharmacological properties isolated between 1991 and 2002 from ascidios tunicates Clavelina lepadiformis, Didemmum and Aplidium Tabascum. Its structure is characterized by having a skeleton cis-decahidroquinolínico trisustituido with a methyl group at C-2, a free hydroxyl group or esterified at C-3 and a side chain in C-5. In this Doctoral Thesis has been studying three different synthetic strategies pair wing synthesis cis-decahidroquinolinas enantiopuras, which could be used as an advanced intermediate in the synthesis of lepadinas: * Aminociclaciones of 3-aminociclohexenonas. * Comments expansion cycle octahidroindoles. * Amonociclaciones of 4 - (3-aminnoalquil) dihidroanisoles. With these methodologies have been isolated and characterized eighteen cis-decahidroquinolinas, some plausible intermediate access to lepadinas. In the first approximation were obtained decahidroquinolinas trisustituidas enantiopuras by aminociclación reductive intramolecular. While estereoquímica obtained is not suitable for the synthesis of lepadinas methodology can be applied to the synthesis of other alkaloids such as trans-195A or 5-epi-trans-243Â th and related alkaloids isolated from the skin of amphibians. The second approach has been obtained decahidroquinolinas 3-hidroxisustituidas by expanding cycle octahidroindoles 2-hidroximetilsustituidos able termodinámicas and decahidroquinolinas 2-metil ,3-hidroxidissustituidas by expanding cycle octahidroindoles 2 - (1-hidroxietil) replaced in a position kinetic . The third approach has been obtained decahidroquinolinas 2-metil ,3-hidroxidisustituidas pro aminociclación of 4 - (3-aminoalquil) dihidroanisoles enantiopuros from reducing Birch of homotiraminas. Compounds obtained contain the estereoquímicas and funcionalización suited to be used as intermediate advanced in the synthesis of lepadinas A, B and C. F and G, the latter two being the most interesting to be the only ones of their families have not yet been synthesized.

Author: GARCIA CADENAS ANA ESTHER.
Year: 2005.
University: SALAMANCA [www.usal.es].
Place of defense: FACULTAD DE FARMACIA.
Place of preparation: FACULTAD DE FARMACIA.

Summary: On this Labor doctorate arises provide continuity and progression chemistry and pharmacology to a series of positive results of bioactivity, made in other jobs doctoral earlier for different sets of estilbenoides. Extends structural variants on one of the aromatic rings, not previously investigated, in order to obtain compounds more potent and more selective and assesses the activities antiadrenérgica, antiparasitaria, antifungal, anti-HIV antiulcerosa and antimicobacteriana. Based on the procedure for synthesis of Nokihara, slightly modified, have been obtained and thirty one benzalftalidas, who had served as intermediate to synthesize forty-seven ftalazinonas fifteen imidazo-isoindoles and pirazolo-ftalazinona, whose main structural differences are located in the Benzyl system, which have been completely characterized by its physical and spectroscopic properties: IR Masses, NMR 1H and NMR 13C, with the support of two-dimensional techniques in some instances. All synthesized compounds have been evaluated by the bioassays timely related to the activities mentioned above and has sought to establish in some cases their mechanism of action. In all series surveyed had managed to overcome the results of bioactivity of the earlier work. In addition they have incorporated new assessments by other bioassays and have been able to identify some new molecules with powers "in vitro" superior to those of drug use, which constitute a new leadership for the development of better drugs. Such is the case with several imidazo-isoindoles, which proved to be more powerful than pentamidine face Leishmania and some ftalazinonas could also replace benzonidazol to treat Chagas disease and gentian violet in the elimination of the Trypanosoma cruzi blood for use in transfusions.

Author: SERNA PEREDA SONIA.
Year: 2005.
University: PAÍS VASCO [www.ehu.es].
Place of defense: FACULTAD DE CIENCIA Y TECNOLOGÍA.
Place of preparation: FACULTAD DE CIENCIA Y TECNOLOGÍA.

Summary: The present research work describes the development of new processes of multiple carbon-carbon links through the use of reactive iodine hipervalente [bis (trifluoroacetoxi) iodine] benzene (PIFA). After carrying out the optimization process to assess, among other parameters, the nature of the rest amídico, the reaction of amidación intramolecular Olefin took place in a very effective and led to the formation of hetero-5 and 6 links, thereby synthesis different pirrolidinas, piperidinas, isoindolinonas and isoquinolinonas. Likewise, there have been various experimental evidence in order to elucidate the possible mechanism of the transformation and described a study has been made with a competitive reaction linked as is the amidación electróflia aromatic promoted by PIFA. Similarly, the reaction of amidación intramolecular of alquinos, substituted assumption terminal by different groups and aromatic vinyl, takes place in a very effective way and leads to the formation of pirrolidinonas substituted in position 5 by groups ketonic. Both changes made at this point doctoral thesis are of great interest because they enable a very effective synthesis of different skeletons heterocyclic. In fact, it is shown that the reaction of amidación of alquinos finds application in the procurement of a key intermediate in the synthesis of alkaloid (+/-)- clausenamida.

Author: LAFUENTE ARANDA GUSTAVO.
Year: 2005.
University: ZARAGOZA [www.unizar.es].
Place of defense: FACULTAD DE CIENCIAS.
Place of preparation: FACULTAD DE CIENCIAS.

Summary: The objective of our work was to study the synthesis and reactivity of hydantoins 5-sustituidas. Such hydantoins are important intermediates in industrial production of amino acids. The work has been divided into two parts. On the one hand synthesis 3-aril-hidantoínas and on the other hand the synthesis and reactivity of 5-metilenhidantínas. 1 Â Part: Summaries of 5-aril-hidantoínas. This has been accomplished through the synthesis of 5-bromohidantoína and subsequent replacement with different aromatic compounds by alkylation of Fiedel-Crafts using both homogeneous and heterogeneous catalysts. 2 Â Part: Synthesis and Reactivity of 5-metilenhidantoínas. We have managed to introducing a methylene group in position 5 of the hidantoína both in hydantoins with nitrogen-free as funcionalizados. It has also demonstrated the reactivity of 5-metilenhidantoínas front of a variety of organic chemical reaction, producing a large number of derivatives hidantoínicos that might be precursors for enzymatic resolution of a large amount of amino acids enantioméricamente cigars.

Author: SICRE GONZÁLEZ CRISTINA.
Year: 2005.
University: VIGO [www.uvigo.es].
Place of defense: FACULTAD DE QUÍMICA.
Place of preparation: FACULTAD DE QUÍMICA.

Summary: The objective of this work consisted in the synthesis estereocontrolada pigment A2E, a compound piridínico 2,4-disustituido polyene which owns a portion common in both chains, whose accumulation is related macular degeneration associated with age (AMD). It has developed a strategy based on the formation of links using simple CC coupling reactions catalyzed by palladium crossfire. Thus, through two successive links on positions 2 and 4 of 2,4-dibrompiridina followed dela funcionalización of chains as bisalquenilestannaras and subsequent double coupling estereoselectivo with iodide trienílico containing the common portion, was obtained pigment A2E in 8 steps with an overall yield of 14%. Parallel has conducted a study of regioselectividad in coupling 2,4-dibromopindina and organometallic derivatives in different conditions Stille, Suzuki and Sonogashira, along with a mechanistic study of the Suzuki reaction between 2,4-dibromapiridina and acid jenilboíonico using NMR techniques of 31P and 1H.

Author: BLANCO VICENTE FERNANDO.
Year: 2006.
University: VALENCIA [www.uv.es].
Place of defense: FACULTAD DE FARMACIA.
Place of preparation: UNIVERSIDAD DE VALENCIA (ESTUDI GENERAL).

Summary: In recent decades have emerged a large amount of catalytic methods for forming biarilos from precursors monoarilos. The formation of carbon-carbon links via coupling of organometallic reagents in organic halides or triflatos catalyzed by transition metal has become an important method of synthesis. At present, cross-coupling reactions (cross-coupling), is a widespread strategy for obtaining systems type biarilo. In the case of triazolopiridinas there were no examples of coupling reactions. Based on the literature described decided on the implementation of methodologies coupling to prepare biheterociclos type triazolopiridinas arilsustituídas in order to study their optical properties and its potential as ligands. Using triazolopiridinas in this area, coordination chemistry, has been poorly studied. The few existing precedents in the literature shows the real capacity of the system triazolopiridina and its derivatives as ligands polinitrogenados, being potentially capable of forming compounds with metals that can act as fluorescent sensors, chemical sensors or having applications in the field of magnetic materials . The primary aim of the thesis was the study of coupling reactions, mainly type reactions Suzuki, in the field of triazolopiridinas for obtaining ariltriazolopiridinas. Secondly, it has also contributed to the development of a new methodology for coupling heterocyclic systems. The technique is based on the use of organometallic complexes of magnesium and zinc type "ate" (magnesiatos / zincatos) and presented as the main advantages of low toxicity reagents and the possibility of working in mild reaction conditions. One of the common problems in chemistry organometálica is the use of extreme conditions not acceptable to industrial level (very low temperatures). Using magnesiatos allows moderating these conditions allowing the transfer reactions on a larger scale, but its use is not widespread, being necessary validation with different heterocyclic (p-defitarios and p-excedentarios). The second objective of this work has been, therefore, the study of the formation of complexes "ate" magnesium in various heterocyclic systems and their reactivity face electrófilos and direct coupling reactions catalyzed by palladium. Lastly has undertaken a theoretical and experimental study of the isomerization anillo-cadena in piridiltriazolopiridinas, one of the substrates used in the course of the investigation carried out.

Author: PÉREZ VÁZQUEZ ANTONIO.
Year: 2006.
University: SANTIAGO DE COMPOSTELA [www.usc.es].
Place of defense: FACULTA DE QUÍMICA.
Place of preparation: FACULTAD DE QUÍMICA.

Summary: The CA-1065 is a compound isolated from natural sources by the end of the seventies which has interesting biological properties and acting as an agent antitumor antibiotic. Unfortunately pharmacological implementation is not possible due to a property that has added consisting of causing death delayed in mice. In the past few decades have synthesized a large number of analogues of CC-1065 in which pursues get good antitumor capacity without producing death in experimental animals. The following thesis is the synthesis of a new analogue of CC-1065 using a new methodology developed in our research group, based on fotociclación of tosilestilbenos in the presence of base.

Author: TORREGROSA MARTINEZ ROSARIO.
Year: 2006.
University: ALICANTE [www.ua.es].
Place of defense: FACULTAD DE CIENCIAS.
Place of preparation: FACULTAD DE CIENCIAS.

Summary: The present report describes the synthesis and reactivity of compounds organolíticos derivatives w-cloro ortoésteres and imidazoles. Litiación catalysed of w-cloro ortoésteres. The reaction of litiación using lithium metal and an excess amount subestequiométrica of DTBB (4.4 Is -di-terc-butilbifenilo) of different w-cloro ortoésteres yields, after reaction with compounds carbonílicos, unprotected and subsequent treatment in acid medium , the corresponding g and d-lactonas. It also examines the respective stability and reactivity of these intermediate organolíticos funcionalizados with a group ortoéster employees in the previous reactions. Preparation of imidazole derivatives. We have studied the reaction of litiación different imidazole derivatives, using lithium metal excess and isoprene as an additive. Thus, the litiación of N-metil- and N-feilimidazol and subsequent reaction with electrófilos provides the corresponding derivatives of 2 - (hidroxialquil) - and 2 - (aminoalquil) imidazole. It then discusses the stability of different substituents (tritilo, alilo, benzyl, vinyl, N, N-dimestilsulfamoílo, para-toluensulfonilo, terc-butoxicarbonilo, acetyl, trimetilsililo and terc-butildimetilsililo) on the nitrogen of imidazo observed that the being subjected to the process of litiación occurs unprotected from them, obtaining the 1H-imidazol. However, the use of 1-(dietoximetil) imidazole as a starting substrate allows the preparation of 2-litio derivative that reacts with different electrófilos providing, after desprotecicón, 1H-imidazoles, 2-funcionalizados. Finally, the reaction of several epoxides with 1H-imida-zol and 1H-bencimidazol to 60 ° C leads to the formation of the corresponding 1-(2-hidroxi-alquil) imidazoles and -bencimidazoles, respectivametne, so regioselectiva. The use of a chiral epoxide ((R) -óxido styrene) enables the preparation of the corresponding product enantioméricamente enriched.

Author: FERNÁNDEZ VILLAR MARCOS.
Year: 2006.
University: SANTIAGO DE COMPOSTELA [www.usc.es].
Place of defense: FACULTAD DE QUÍMICA.
Place of preparation: FACULTAD DE QUÍMICA.

Summary: This thesis deals with the synthesis of four classes of aromatics tetrcíclicos (benzofurananftoquiononas, benzopironaftoquinonas, indolonaftoquinonas and indoloisoquinolíndionas), through the 2 - (3-fenil-2-oxopropil) benzaldehídos and acid 2 - (3-fenil-2-oxopropil ) benzoicos, whose interest lies in its anti-neoplastic activity (through subunit 2-fenil-1 ,4-naftoquinona) and antibiotic. First, benzofuro- and indolonaftoquinonas have a structure similar to that of the elipticinas, compounds with demonstrated anti-neoplastic activity but high cytotoxicity. In fact, it is known antibiotic and anti-tumor activity of benzofuronaftoquinonas, and it is hoped that indolonanftoquinonas having anti-neoplastic activity, as its structure is closer to that of elipticinas that early. Within the benzopironaftoquinonas is known power and antitumor antibiotic. The indoloisoquinolíndionas are compounds less studied, but hopefully also possess anti-neoplastic activity. The thesis consists of a bibliographic work on the oxidation of alcohols to aldehydes and ketones.