Transition metal-catalyzed C(sp2)-H acylation and olefination reactions for the functionalization of (Hetero)Arenes

275 p.The research work collected in this thesis is focused on the development of new methodologies of carbon-carbond bond formation (acylation, aminocarbonylation and olefination) of heteroaromatic rings, such as pyrroles or thiophenes via C-H activation reactions catalyzed by Pd(II) and Co(III). In the first chapter, and to give context to this thesis, the experience of our researching group in the Palladium and Cobalt catalyzed reactions is described. The second chapter is focused, on the one hand, on the development of a methodology of Pd(II)-catalyzed acylation of pyrroles. The optimized reaction conditions have been applied to the synthesis of Celastramycin analogue and Tolmentin. As a secondary objective, anti-leishmanicidal activity against visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis and cytotoxicity of some of the synthesized 2-acylpyrroles have been evaluated through biological assays carried out by Dr. M. A. Dea from University CEU Cardenal Herrera (Valencia). On the other hand, Pd(II)-catalyzed C-3 acylation of thiophenes with aldehydes via C(sp2)-H activation has been developed. To show the synthetic applicability, selected ketones were subjected to further diversifications, including an intramolecular reaction, which involves the directing group. In the third chapter, the attempts to expand the methodology for the acylation of pyrroles to the use of Co(III) catalysis, is described. Furthermore, the nucleophilic addition of thiophene C-H bond to isocyanates catalyzed by Co(III) has been explored. Finally, in the fourth chapter, the research realized in my predoctoral three-month stay in Prof. Manuel Antonio van Gemmeren¿s research group at the Organic Chemistry Institute of the University of Münster is explained, which was focused on the use of dual-ligand-based palladium catalysts for the late-stage olefination of bioactive arenes

Plastidial NADP-Malic Enzymes from grasses: unravelling the way to the C4 specific isoforms

Malic enzyme is present in many plant cell compartments such as plastids, cytosol and mitochondria. Particularly relevant is the plastidial isoform that participates in the C4 cycle providing CO2 to RuBisCO in C4 species. This type of photosynthesis is more frequent among grasses where anatomical preconditioning would have facilitated the evolution of the C4 syndrome. In maize (C4 grass), the photosynthetic NADP dependent Malic enzyme (ZmC4-NADP-ME, L-malate:NADP oxidoreductase, E.C. 1.1.1.40) and the closest related non-photosynthetic isoform (ZmnonC4-NADPME, L-malate:NADP oxidoreductase, E.C. 1.1.1.40) are both plastidial but differ in expression pattern,kinetics and structure. Features like high catalytic efficiency, inhibition by high malate concentration at pH 7.0, redox modulation and tetramerization are characteristic of the photosynthetic NADP-ME. In this work, the proteins encoded by sorghum (C4 grass) and rice (C3 grass) NADP-ME genes,orthologues of the plastidial NADP-MEs from maize, were recombinantly expressed, purified and characterized. In a global comparison, we could identify a small group of residues which may explain the special features of C4 enzymes. Overall, the present work presents biochemical and molecular data that helps to elucidate the changes that took place in the evolution of C4 NADP-ME in grasses.Fil: Saigo, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Centro de Estudios Fotosintéticos y Bioquímicos (i); Argentina. Universidad Nacional de Rosario; ArgentinaFil: Alvarez, Clarisa Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Centro de Estudios Fotosintéticos y Bioquímicos (i); Argentina. Universidad Nacional de Rosario; ArgentinaFil: Andreo, Carlos Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Centro de Estudios Fotosintéticos y Bioquímicos (i); Argentina. Universidad Nacional de Rosario; ArgentinaFil: Drincovich, Maria Fabiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Centro de Estudios Fotosintéticos y Bioquímicos (i); Argentina. Universidad Nacional de Rosario; Argentin

Experimental program on bone technology of the north of Tierra del Fuego: Contributions to the study of production and use-wear traces

This paper presents an Experimental Program developed to identify, describe and differentiate the production traces from use-wear traces on bone artifacts, through the application of functional analysis framework. For this purpose, several types of guanaco bone tools present in northern sites of the Isla Grande de Tierra del Fuego (South America) were replicated. The results enable us to: 1) differentiate and define the microscopic traces related to the manufacture techniques implemented in the production sequence: scraping, abrasion and sawing as well as 2) identify and describe the use-wear traces of different resources (wood, hide and bark). The results have allowed to identify the manufacture traces that were formed in each stage of the production process as well as the use-wear traces of different working procedures. Likewise, the data obtained have enabled us to identify the differences in the use of dry and fresh bones, their effectiveness in different labour processes and their respectively diagnostic traces. Thus, we attained a regional frame of reference to study bone technology carried out by hunter-gatherer societies that occupied the Fuegian steppe during the late Holocene.Fil: Pal, Nélida Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Santiago, Fernando Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Alvarez, Myrian Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Lasa, Adriana Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; Argentin

Selective Pd(II)-catalyzed Acylation of Pyrrole with Aldehydes. Application to the Synthesis of Celastramycin analogues and Tolmetin

The Pd(II)-catalyzed C-2 acylation of pyrrole with aldehydes in the presence of TBHP as oxidant has been studied for the synthesis of di(hetero)aryl ketones. The use of 2-pyrimidine as directing group leads to 2-acylpyrroles in moderate to good yields, although 2,5-diacylpyrroles are obtained as by products. This side-reaction could be avoided using 3-methy-2-pyridine as directing group, obtaining selectively 2-acylpyrroles. The reaction has been extended to a series of aromatic and heteroaromatic aldehydes, obtaining the best results with electron rich aromatic aldehydes. The methodology has been applied in the synthesis of pyrrolomycin alkaloid Celastramycin analogues and for an improved synthesis of Tolmetin, a nonsteroidal anti-inflammatory drugMinisterio de Economía y Competitividad (CTQ2016-74881-P) / Gobierno Vasco (IT1045-16

La nueva interpretación delito de prevaricato por acción de funcionarios judiciales en la jurisprudencia de la Corte Suprema de Justicia

Jurisprudential commentComentario jurisprudencia

Deciphering the number and location of active sites in the monomeric glyoxalase I of Zea mays

Detoxification of methylglyoxal, a toxic by-product of central sugar metabolism, is a major issue for all forms of life. The glyoxalase pathway evolved to effectively convert methylglyoxal into d-lactate via a glutathione hemithioacetal intermediate. Recently, we have shown that the monomeric glyoxalase I from maize exhibits a symmetric fold with two cavities, potentially harboring two active sites, in analogy with homodimeric enzyme surrogates. Here we confirm that only one of the two cavities exhibits glyoxalase I activity and show that it adopts a tunnel-shaped structure upon substrate binding. Such conformational change gives rise to independent binding sites for glutathione and methylglyoxal in the same active site, with important implications for the molecular reaction mechanism, which has been a matter of debate for several decades. Database: Structural data are available in The Protein Data Bank database under the accession numbers 6BNN, 6BNX, and 6BNZ.Fil: Gonzalez, Javier Marcelo. Universidad Nacional de Santiago del Estero. Instituto de Bionanotecnología del Noa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Bionanotecnología del Noa; ArgentinaFil: Agostini, Romina Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro de Estudios Fotosintéticos y Bioquímicos. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Centro de Estudios Fotosintéticos y Bioquímicos; ArgentinaFil: Alvarez, Clarisa Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro de Estudios Fotosintéticos y Bioquímicos. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Centro de Estudios Fotosintéticos y Bioquímicos; ArgentinaFil: Klinke, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Andreo, Carlos Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro de Estudios Fotosintéticos y Bioquímicos. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Centro de Estudios Fotosintéticos y Bioquímicos; ArgentinaFil: Campos Bermudez, Valeria Alina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro de Estudios Fotosintéticos y Bioquímicos. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Centro de Estudios Fotosintéticos y Bioquímicos; Argentin

Microwave-assisted Palladium catalysed C-H acylation with aldehydes. Synthesis and diversification of 3-acylthiophenes

The use of MW allows the efficient palladium(II)-catalysed C-3 acylation of thiophenes with aldehydes via C(sp2)-H activation for the synthesis of (cyclo)alkyl/aryl thienyl ketones (43 examples). Compared to standard thermal conditions, the use of MW reduces the reaction time (15 to 30 min vs. 1 to 3 hours), leading to improved yields of the ketones (up to 92%). Control of positional selectivity is achieved by 2-pyridinyl and 2-pyrimidyl ortho-directing groups at C-2 of the thiophene scaffold. To show the synthetic applicability, selected ketones were subjected to further transformations, including intramolecular reactions to directly embed the directing-group in the core-structure of the new moleculeMinisterio de Ciencia e Innovación (PID2019-104148GB-I00) / Gobierno Vasco (IT1045-16

Directed C- H Allylation of Aromatic Carboxamides with Allyl Aryl Ethers under Cp*Co(III)-Catalysis

The Cp*Co(III) C−H allylation of (hetero)arenes with allyl aryl ethers has been developed using an amide as directing group (24 examples). DFT calculations have shed light on the mechanistic course and reactivity pattern, showing that strong electron releasing groups favour the reaction by reducing the activation barrier of the rate-determining C−H activation step. However, the steric strain can increase the energy of the migratory insertion step to the point of completely preventing the reaction, as in the case of the 3,5-dimethylbenzamide. The obtained allylated compounds have been transformed into a variety of interesting heterocyclic and carbocyclic structures, such as isoquinolones and isochromanones.Ministerio de Ciencia e Innovación PID2019-104148G-I00, PID2019–110008GB- I00, PID2022-137365NB-I00, MCIN/AEI/10.13039/501100011033, Gobierno Vasco (IT1558-22

OpenCL-based FPGA accelerator for semi-global approximate string matching using diagonal bit-vectors

An FPGA accelerator for the computation of the semi-global Levenshtein distance between a pattern and a reference text is presented. The accelerator provides an important benefit to reduce the execution time of read-mappers used in short-read genomic sequencing. Previous attempts to solve the same problem in FPGA use the Myers algorithm following a column approach to compute the dynamic programming table. We use an approach based on diagonals that allows for some resource savings while maintaining a very high throughput of 1 alignment per clock cycle. The design is implemented in OpenCL and tested on two FPGA accelerators. The maximum performance obtained is 91.5 MPairs/s for 100 × 120 sequences and 47 MPairs/s for 300 × 360 sequences, the highest ever reported for this problem.This research was supported by the EU Regional Development Fund under the DRAC project [001-P-001723], by the MINECO-Spain (contract TIN2017-84553-C2-1-R), by the MICIU-Spain (contract RTI2018-095209-B-C22) and by the Catalan government (contracts 2017-SGR-1624, 2017-SGR313, 2017-SGR-1328). M.M. was partially supported by the MINECO under RYC-2016-21104. We thank Intel for granting us access to the DevCloud system and let us join the HARP research program. The presented HARP-2 results were obtained on resources hosted at the Paderborn Center for Parallel Computing (PC2) in the Intel Hardware Accelerator Research Program (HARP2).Peer ReviewedPostprint (author's final draft