Síntesi de nous compostos policíclics com a possibles precursors d’alquens piramidalitzats

[cat] En la present Tesi Doctoral s’ha desenvolupat una metodologia sintètica per accedir a compostos policíclics complexos funcionalitzats de manera senzilla i eficaç, amb l’objectiu de poder generar a partir d’aquests un alquè piramidalitzat i estudiar el seu comportament químic en condicions específiques de reacció. En primer lloc, es va posar a punt la síntesi del 5,5-bis(acetoximetil)ciclopenta-1,3-diè, intermedi clau per la introducció de la funcionalització desitjada en l’estructura policíclica. Mitjançant reacció de Diels-Alder entre el ciclopentadiè-1,1-disubstituït i l’acetilè adient (des de l’acetilendicarboxilat de dimetil fins a sals de iodoni triflat o dobles sals de iodoni triflat), es va aconseguir introduir la doble funció veïnal èster metílic, iode-trimetilsilil o iode-iode, grups funcionals clau per la generació d’alquens piramidalitzats. En el primer capítol d’aquesta tesi, es va introduir la doble funcionalització èster metílic com a model per a la construcció de policicles més complexos. Per metanòlisi bàsica dels grups acetoximetil provinents del ciclopentadiè de partida, es va observar addició de Michael intramolecular i es va formar el 3a-(hidroximetil)-3,3a,4,6a-tetrahidro-1H-1,4- metanociclopenta[c]furan-1,7-dicarboxilat de dimetil, donant lloc a diastereòmers. A partir d’aquest esquelet, transformant-lo en el derivat iodometil, es va poder estudiar la reacció Domino de substitució nucleòfila (mitjançant ciclopentadienur potàssic com a nucleòfil) i posterior reacció de Diels-Alder intramolecular. Reacció Domino per la qual es generen tres nous enllaços C–C i tres nous anells, resultant així en un hexacicle funcionalitzat. Es va aconseguir evitar parcialment la reacció de Michael intramolecular realitzant la hidròlisi en medi àcid, fet que va permetre l’obtenció del (1R,4S)-7,7-bis(iodometil)biciclo[2.2.1]hepta-2,5- diè-2,3-dicarboxilat de dimetil, del qual es va poder estudiar la doble reacció Domino de substitució nucleòfila seguida de Diels-Alder intramolecular. Aquesta metodologia va permetre la creació de sis nous enllaços C–C i sis nous cicles, obtenint així un octacicle funcionalitzat en una sola etapa basat en la subestructura d’octaciclo[10.6.1.01,10.03,7.04,9.08,19.011,16.013,17] nonadecà, a partir d’un bicicle. Aplicant aquesta metodologia es va obtenir un octacicle amb la funció iode-trimetilsilil veïnal i en posició cap de pont, possible precursor d’alquens piramidalitzats. Tots els intents de desililació utilitzant diverses fonts de fluorurs no van resultar en la generació de l’alquè piramidalitzat, ja que el grup trimetilsilil va resultar ser inert enfront d’anions fluorurs per impediment estèric. Proves per promoure la generació de l’alquè piramidalitzat utilitzant un catalitzador de pal· ladi per addició oxidant a l’enllaç carboni-iode, no van resultar satisfactòries, però van donar lloc a la co-ciclotrimerització de l’octacicle de partida amb dues unitats d’acetilendicarboxilat de dimetil en un dels dobles enllaços de l’esquelet de partida. Per últim, s’ha pogut estudiar la reactivitat de l’alquè piramidalitzat en l’esquelet de octaciclo[10.6.1.01,10.03,7.04,9.08,19.011,16.013,17]nonadecà per reacció de l’octacicle diiodat amb t- BuLi, amalgama líquida de sodi, o sodi fos a reflux d’1,4-dioxà. En cap cas l’alquè piramidalitzat ha donat lloc a adductes de cicloaddició [4+2] en presència de diens. Utilitzant reactius organolítics, l’alquè piramidalitzat només ha experimentat addicions nucleòfiles del grup t-Butil. Mitjançant reacció amb amalgama de sodi o sodi fos, s’han pogut aïllar el producte de reducció de l’alquè piramidalitzat, un dímer, i un producte derivat de reacció amb el dissolvent de la reacció.[eng] A fast and simple synthetic methodology to prepare complex polycyclic compounds as potential precursors of a hindered pyramidalized alkene, has been developed. The key steps are: (1) the preparation of cyclopenta-2,4-diene-1,1-diyl(bismethylene) diacetate, (2) Diels-Alder reaction of the above diene with different acetylenic dienophiles [dimethyl acetylenedicarboxylate, (2- trimethylsilylethynyl)phenyliodonium triflate and ethine-1,2-diylbis(phenyliodonium) ditrifalte] leading to norbornadienes that contain two acetoxymethyl groups at position 7 and two vicinal methoxycarbonyl, two vicinal iodine atoms or vicinal iodine and trimethylsilil functionalization at positions 2 and 3. The acetoxymethyl groups of the resulting norbornadienes were transformed into iodomethyl, and were reacted with the potassium salt of cyclopentadiene to give octacyclic compounds derived from a double domino nucleophilic substitution / Diels-Alder reaction, which contain the octacyclo[10.6.1.01,10,03,7.04,9.08,19.011,16.013,17]nonadecane skeleton. The octacyclic compound containing an iodine and a trimethylsilyl group in vicinal bridgehead position, could not be transformed into the desired pyramidalized alkene on reaction with different fluoride anion sources, and under different reaction conditions. Only reactions on the less hindered C=C bond of this compound were observed as well as the substitution of the iodide by a fluoride in several derivatives. The octacyclic compound containing two iodine atoms gave the pyramidalized alkene on reaction with molten sodium in boiling 1,4-dioxane, sodium amalgam, or t-BuLi. However, when these reactions were carried out in the presence of dienes such as 1,3- diphenylisobenzofuran, anthracene or 11,12-dimethylene-9,10-ethanoanthracene, no Diels- Alder adducts were ever observed. When t-BuLi was the organolithium reagent used to generate the pyramidalized alkene, only the product of t-butyl and hydrogen addition was obtained. Under molten sodium or sodium amalgam, the main adduct detected was the product of reduction of the strained alkene. Only a dimer of the pyramidalized alkene was isolated and fully characterized on reaction with sodium amalgam, and under refluxing dioxane, the product of insertion of the solvent could be isolated as a diastereomeric mixture. These results differ from those previously reported with related pyramidalized alkenes, due to the steric hindrance experienced by the pyramidalized alkene generated in the octacyclo[10.6.1.01,10,03,7.04,9.08,19.011,16.013,17]nonadecane skeleto

Synthesis of polycycles by single or double domino nucleophilic substitution. Diels-Alder reaction

New hexacyclo and octacyclo compounds have been synthesized by a short route whose key step consists of a single or double domino nucleophilic substitution of neopentyl‐type iodides with potassium cyclopentadienide, followed by intramolecular Diels-Alder cycloaddition

Generation and Reactions of an Octacyclic Hindered Pyramidalized Alkene

Octacyclo[10.6.1.01,10.03,7.04,9.08,19.011,16.013,17]-nonadeca-5,8,14-triene (27), a hindered pyramidalized alkene, has been generated from a diiodide precursor. Contrary to the usual behavior of known pyramidalized alkenes, no Diels−Alder adducts were obtained from the present alkene when it was generated by different standard procedures in the presence of different dienes. However, products derived from the reduction, t-BuLi addition, condensation with the solvent, or dimerization were isolated from these reactions, depending on the conditions used to generate it. No [2 + 2] cross product among this pyramidalized alkene and tricyclo[3.3.1.03,7]non-3(7)-ene was formed when a mixture of the corresponding precursor diiodides was reacted with sodium amalgam. The analysis of selected geometrical and orbital parameters determined from quantum mechanical calculations indicates that the degree of pyramidalization of this alkene and its higher steric hindrance compared with other polycyclic pyramidalized alkenes may explain its peculiar reactivity

Evaluation of Gonadal Alterations in a Population Environmentally Exposed to a Mixture of Endocrine Active Pesticides

Although there are studies that show that some pesticides produce gonadal dysfunction and gonadal cancer in different animals, there are not many studiesregardinghumans. This study determined the prevalence and risk in humans of developing ovarian or testicular dysfunction or cancer in areas with distinct exposure to pesticides, which have endocrine disrupting properties. A population-based case-control study was carried out on humans living in ten health districts of Andalusia (Southern Spain) classified as areas of high or low environmental exposure to pesticides according to agronomic criteria. The study population included 5332 cases and 13,606 controls. Data were collected from computerized hospital records between 2000 and 2018.The risk of gonadal dysfunction or cancer was significantly higher in areas with higher use of pesticides in relation to those with lower use

Data set for the publication 'Mechanically axially chiral catenanes and noncanonical chiral rotaxanes'

This dataset supports the publication: Mechanically axially chiral catenanes and noncanonical chiral rotaxanes AUTHORS: John R. J. Maynard, Peter Gallagher, David Lozano, Patrick Butler, Stephen M. Goldup,* JOURNAL: Nature Chemistry This dataset contains: Characterisation data (NMR, MS, x-ray) for all the compounds reported in the manuscript </span

Dataset supporting an article &quot;A catenane that is&nbsp;topologically achiral despite being&nbsp;composed of oriented rings&quot;

This dataset supports the publication: A catenane that is&nbsp;topologically achiral despite being&nbsp;composed of oriented rings. The dataset contains: Characterisation data (NMR, MS, x-ray) for all the compounds reported in the manuscript Licence: CC-BY </span

Evaluation of Gonadal Alterations in a Population Environmentally Exposed to a Mixture of Endocrine Active Pesticides

Although there are studies that show that some pesticides produce gonadal dysfunction and gonadal cancer in different animals, there are not many studiesregardinghumans. This study determined the prevalence and risk in humans of developing ovarian or testicular dysfunction or cancer in areas with distinct exposure to pesticides, which have endocrine disrupting properties. A population-based case-control study was carried out on humans living in ten health districts of Andalusia (Southern Spain) classified as areas of high or low environmental exposure to pesticides according to agronomic criteria. The study population included 5332 cases and 13,606 controls. Data were collected from computerized hospital records between 2000 and 2018.The risk of gonadal dysfunction or cancer was significantly higher in areas with higher use of pesticides in relation to those with lower use

On the Reaction of 1,3-Diphenylisobenzofuran and (2-Iodoethynyl)(phenyl)iodonium Triflate. A Unique Case of Oxygen Transfer from the Diels-Alder Adduct to the Diene

Reaction of 1,3-diphenylisobenzofuran (DPIBF) with 2-(iodoethynyl)(phenyl)- iodonium triflate at room temperature gave the expected Diels-Alder adduct, but using an excess of DFIBF (2 equiv.) and performing the reaction at 55 °C or heating at this temperature during the concentration stage, the initial orange solution or product mixture became dark brown and the products 1,2-phenylene-1,2-bis(phenylmethanone) and 2-(3-iodo-1,4-diphenylnaphthyl)(phenyl)iodonium triflate were obtained, which suggests an oxygen transfer between DPIBF and the initial adduct

Straightforward synthesis of a vicinal double bridgehead iodo trimethylsilyl octacycle: unprecedented lack of reactivity of the silyl group in front of fluoride anions.

Abstract: A convenient synthesis of an octacyclic compound containing an iodo and a trimethylsilyl group in vicinal double bridgehead positions, as a possible precursor of a pyramidalized alkene, is described. The key step of the synthesis consists of a double nucleophilic substitution of two neopentyl-type iodides by cyclopentadienide anions followed by two intramolecular Diels-Alder cycloadditions. All attempts to generate the expected pyramidalized alkene from the above precursor on reac-tion with different sources of fluoride failed. This octacyclic compound, which contains two disubstituted C=C bonds, underwent a chemo- and stereoselective Pd0-catalyzed co-cyclotrimerization with dimethyl acetylenedicarb-oxylate to give a nonacyclic cyclohexadiene derivative that can be aromatized upon reaction with CsF or transformed into a related fluoride upon reaction with AgF

Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease

Background: We previously reported algorithms based on clinical parameters and plasma cell characteristics to identify patients with smoldering multiple myeloma (SMM) with higher risk of progressing who could benefit from early treatment. In this work, we analyzed differences in the immune bone marrow (BM) microenvironment in SMM to better understand the role of immune surveillance in disease progression and to identify immune biomarkers associated to higher risk of progression. Methods: Gene expression analysis of BM cells from 28 patients with SMM, 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and 22 patients with symptomatic MM was performed by using Nanostring Technology. Results: BM cells in SMM compared to both MGUS and symptomatic MM showed upregulation of genes encoding for key molecules in cytotoxicity. However, some of these cytotoxic molecules positively correlated with inhibitory immune checkpoints, which may impair the effector function of BM cytotoxic cells. Analysis of 28 patients with SMM revealed 4 distinct clusters based on immune composition and activation markers. Patients in cluster 2 showed a significant increase in expression of cytotoxic molecules but also inhibitory immune checkpoints compared to cluster 3, suggesting the presence of cytotoxic cells with an exhausted phenotype. Accordingly, patients in cluster 3 had a significantly longer progression free survival. Finally, individual gene expression analysis showed that higher expression of TNF superfamily members (TNF, TNFAIP3, TNFRSF14) was associated with shorter progression free survival. Conclusions: Our results suggest that exhausted cytotoxic cells are associated to high-risk patients with SMM. Biomarkers overexpressed in patients with this immune gene profile in combination with clinical parameters and PC characterization may be useful to identify SMM patients with higher risk of progression