Síntese e caracterização de monômeros azo-carbonatos para a preparação de poli(azo-carbonato)s e poli)azo-uretana)s

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Metallic chalcogenolates mediated modular Michael-aldol cascade reaction: an easy route to multi-functionalized chalcogenides and Morita-Baylis-Hillman adducts

Chalcogenolate mediated Michael-aldol cascade reactions consists of a very efficient route to multi-functionalized gamma-hydroxichalcogenides. Although, when selenolates are employed, these gamma-hydroxichalcogenides can be readily converted into the corresponding Morita-Baylis-Hillman adducts by oxidative elimination of the selenium moiety. In this context, herein we present a complete study on the scope and limitations of this reaction. (C) 2012 Elsevier Ltd. All rights reserved.

New insights on reaction pathway selectivity promoted by crown ether phase-transfer catalysis: Model ab initio calculations of nucleophilic fluorination

Crown ethers have the ability of solubilizing inorganic salts in apolar solvents and to promote chemical reactions by phase-transfer catalysis. However, details on how crown ethers catalyze ionic S(N)2 reactions and control selectivity are not well understood. In this work, we have used high level theoretical calculations to shed light on the details of phase-transfer catalysis mechanism of KF reaction with alkyl halides promoted by 18-crown-6. A complete analysis of the of the model reaction between KF(18-crown-6) and ethyl bromide reveals that the calculations can accurately predict the product ratio and the overall kinetics. Our results point out the importance of the K* ion and of the crown ether ring in determining product selectivity. While the K* ion favors the S(N)2 over the E2 anti pathway, the crown ether ring favors the S(N)2 over E2 syn route. The combination effects lead to a predicted 94% for the S(N)2 pathway in excellent agreement with the experimental value of 92%. A detailed analysis of the overall mechanism of the reaction under phase-transfer conditions also reveals that the KBr product generated in the nucleophilic fluorination acts as an inhibitor of the 18-crown-6 catalyst and it is responsible for the observed slow reaction rate. (C) 2012 Elsevier B.V. All rights reserved.

Novel cross-coupling reactions between organotellurides and Grignard reagents employing a MnCl2/CuI catalytic system

We present a general protocol for the cross-coupling reaction of Grignard reagents and organic tellurides. Aryl Grignard reagents react stereospecifically with vinyl tellurides in the presence of a catalytic amount of manganese (II) chloride and copper (I) iodide to produce good yields of the corresponding cross-coupling products. (C) 2012 Published by Elsevier Ltd.

Metabolic engineering of beta-oxidation in Penicillium chrysogenum for improved semi-synthetic cephalosporin biosynthesis

Industrial production of semi-synthetic cephalosporins by Penicillium chrysogenum requires supplementation of the growth media with the side-chain precursor adipic acid. In glucose-limited chemostat cultures of P. chrysogenum, up to 88% of the consumed adipic acid was not recovered in cephalosporinrelated products, but used as an additional carbon and energy source for growth. This low efficiency of side-chain precursor incorporation provides an economic incentive for studying and engineering the metabolism of adipic acid in P. cluysogenum. Chemostat-based transcriptome analysis in the presence and absence of adipic acid confirmed that adipic acid metabolism in this fungus occurs via beta-oxidation. A set of 52 adipate-responsive genes included six putative genes for acyl-CoA oxidases and dehydrogenases, enzymes responsible for the first step of beta-oxidation. Subcellular localization of the differentially expressed acyl-CoA oxidases and dehydrogenases revealed that the oxidases were exclusively targeted to peroxisomes, while the dehydrogenases were found either in peroxisomes or in mitochondria. Deletion of the genes encoding the peroxisomal acyl-CoA oxidase Pc20g01800 and the mitochondrial acyl-CoA dehydrogenase Pc20g07920 resulted in a 1.6- and 3.7-fold increase in the production of the semi-synthetic cephalosporin intermediate adipoyl-6-APA, respectively. The deletion strains also showed reduced adipate consumption compared to the reference strain, indicating that engineering of the first step of beta-oxidation successfully redirected a larger fraction of adipic acid towards cephalosporin biosynthesis. (C) 2012 Elsevier Inc. All rights reserved.

Gekreuzt konjugierte Oligomere aus Benzolringen und Heterocyclen

Gekreuzt konjugierte Oligomere aus Benzolringen und Heterocyclen Oligomere aus Arylen- oder/und Hetarylen-Bausteinen stellenein aktuelles Arbeitsgebiet in der organischen Synthese undder Materialwissenschaft dar. Die Enoneinheit der Chalkonerepräsentiert ein bifunktionelles Elektrophil, das für denAufbau von unterschiedlichen Heterocyclen hervorragendgeeignet ist. Im Rahmen der vorliegenden Arbeit wurden dreineue Reihen von heterocyclischen Oligomeren hergestellt:1H-Pyrrole, 1H-Pyrazole und Pyridine, die über eine alter-nierende Sequenz von Phenylen- oder Benzoylen-Einheitenverbunden sind. Ihre Herstellung basierte auf Michael-Additionen von den kettenförmigen, gekreuzt konjugiertenOligochalkonen und den jeweiligen geeigneten N-haltigenBausteinen: Tosylmethylisocyanid, Methylhydrazin undPhenacylpyridiniumbromid in der Reihe der Pyrrole, Pyrazoleund Pyridine. Die UV/Vis-Untersuchung aller Reihen der Oligoheterocyclenzeigte als allgemeinen Trend im Vergleich mit dem UV/Vis-Verhalten der Oliogochalkone eine ausgeprägte hypsochromeVerschiebung der langwelligen Absorption. Dieser beobachtetehypsochrome Shift geht auf die veränderten Chromophore zurück und deutet außerdem darauf hin, dass die effektiveKonjugation bei wachsender Moleküllänge geringer sein sollte. In den einzelnen Reihen der Oligoheterocyclenerkennt man jeweils bei Vergrößerung der Chromophore einenkleinen bathochromen Shift der langwelligen Absorption.

Development of Organocatalytic stereoselective SN1 type reactions

The proposal in my thesis has been the study of Stereoselective α-alkylation through SN1 type reaction. SN1 type reaction involves a stabilized and reactive carbocation intermediate By taking advantages of stability of particular carbocations, the use of carbocations in selective reactions has been important. In this work has been necessary to know the stability and reactivity of carbocations. And the work of Mayr group has helped to rationalize the behaviour and reactivity between the carbocations and nucleophiles by the use of Mayr’s scale of reactivity. The use of alcohols to performed the stable and reactive carbocations have been the key in my thesis. The direct nucleophilic substitution of alcohols has been a crucial scope in the field of organic synthesis, because offer a wide range of intermediates for the synthesis of natural products and pharmaceutics synthesis. In particular the catalytic nucleophilic direct substitution of alcohols represents a novel methodology for the preparation of a variety of derivatives, and water only as the sub-product in the reaction. The stereochemical control of the transformation C-H bond into stereogenic C-C bond adjacent to carbonyl functionalized has been studied for asymmetric catalysis. And the field of organocatalysis has introduced the use of small organic molecule as catalyst for stereoselective transformations. Merging these two concepts Organocatalysis and Mayr’s scale, my thesis has developed a new approach for the α-alkylation of aldehydes and ketones through SN1 type reaction.

Oxidative properties of the Iron - Thymine-1-acetic acid - Hydrogen peroxide catalytic system

The oxidation of alcohols and olefins is a pivotal reaction in organic synthesis. However, traditional oxidants are toxic and they often release a considerable amounts of by-products. Here, two IronIII-based systems are shown as oxidative catalyst, working in mild conditions with hydrogen peroxide as primary oxidant. An efficient catalytic system for the selective oxidation of several alcohols to their corresponding aldehydes and ketones was developed and characterized, [Fe(phen)2Cl2]NO3 (phen=1,10-Phenantroline). It was demonstrated that the adoption of a buffered aqueous solution is of crucial importance to ensure both considerable activity and selectivity.The Iron - Thymine-1-acetic acid in-situ complex was studied as catalyst in alcohol oxidations and C-H oxidative functionalization, involving hydrogen peroxide as primary oxidant in mild reaction conditions. The catalytic ability in alcohol oxidations was investigated by Density Functional Theory calculations, however the catalyst still has uncertain structure. The system shows satisfactory activity in alcohol oxidation and aliphatic rings functionalization. The Fe-THA system was studied in cyclohexene oxidation and oxidative halogenations. Halide salts such as NBu4X and NH4X were introduced in the catalytic system as halogens source to obtain cyclohexene derivatives such as halohydrins, important synthetic intermediates.The purpose of this dissertation is to contribute in testing new catalytic systems for alcohol oxidations and C-H functionalization. In particular, most of the efforts in this work focus on studying the Iron - Thymine-1-acetic acid (THA) systems as non-heme oxidative model, which present: •an iron metal centre(s) as a coordinative active site, •hydrogen peroxide as a primary oxidant, •THA as an eco-friendly, biocompatible, low cost coordinating ligand.

Sintesi di molecole biologicamente attive con tecniche chemoenzimatiche:beta-lattami, profeni e alfa-amminoacidi non naturali

Il progetto di ricerca di questa tesi è stato focalizzato sulla sintesi di tre classi di molecole: β-lattami, Profeni e α-amminonitrili, utilizzando moderne tecniche di sintesi organica, metodologie ecosostenibili e strategie biocatalitiche. I profeni sono una categoria di antiinfiammatori molto diffusa e in particolare abbiamo sviluppato e ottimizzato una procedura in due step per ottenere (S)-Profeni da 2-arilpropanali raceme. Il primo step consiste in una bioriduzione delle aldeidi per dare i relativi (S)-2-Aril Propanoli tramite un processo DKR mediato dall’enzima Horse Liver Alcohol Dehydrogenase. Il secondo, l’ossidazione a (S)-Profeni, è promossa da NaClO2 e TEMPO come catalizzatore. Con lo scopo di migliorare il processo, in collaborazione con il gruppo di ricerca di Francesca Paradisi all’University College Dublino abbiamo immobilizzato l’enzima HLADH, ottenendo buone rese e una migliore enantioselettività. Abbiamo inoltre proposto un interessante approccio enzimatico per l’ossidazione degli (S)-2-Aril Propanoli utilizzando una laccasi da Trametes Versicolor. L’anello β-lattamico è un eterociclo molto importante, noto per essere un interessante farmacoforo. Abbiamo sintetizzato nuovi N-metiltio beta-lattami, che hanno mostrato un’attività antibatterica molto interessante contro ceppi resistenti di Staphilococcus Aureus prelevati da pazienti affetti da fibrosis cistica. Abbiamo poi coniugato gruppi polifenolici a questi nuovi β-lattami ottenendo molecule antiossidanti e antibatteriche, cioè con attività duale. Abbiamo poi sintetizzato un nuovo ibrido retinoide-betalattame che ha indotto differenziazione si cellule di neuroblastoma. Abbiamo poi sfruttato la reazione di aperture dell’anello monobattamico tramite enzimi idrolitici, con lo scopo di ottenere β-amminoacidi chirali desimmetrizzati come il monoestere dell’acido β–amminoglutammico. Per quando riguarda gli α-amminonitrili, è stato sviluppato un protocollo di Strecker. Le reazioni sono state molto efficienti utilizzando come fonte di cianuro l’acetone cianidrina in acqua, utilizzando differenti aldeidi e chetoni, ammine primarie e secondarie. Per mettere a punto una versione asimmetrica del protocollo, abbiamo usato ammine chirali con lo scopo di ottenere nuovi α-amminonitrili chirali.

Sintesi di leganti ciclopentadienonici e piridilimidazolici per complessi metallici. Metodo classico e microonde a confronto

In questo elaborato è stata messa a punto una procedura sintetica, semplice e veloce che sfrutta la tecnica microonde per la sintesi di tetraarilciclopentadienoni variamente sostituiti mediante una condensazione bis-aldolica tra 1,3 difenilacetone con dichetoni aromatici variamente sostituiti. Questa nuova tecnica consente di ottenere tetraarilciclopentadienoni con rese da basse a buone in 25 minuti a 70°C. La stessa procedura sintetica è stata valutata per ottenere leganti piridilimidazolici, usando come fonte di azoto NH4OAc. Basse rese e la formazione di svariati sottoprodotti ha diretto lo studio verso un approccio classico per la sintesi di questi sistemi. I leganti piridilimidazolici sono stati poi impiegati per la sintesi di complessi di Zn(II) luminescenti, i quali sono stati caratterizzati anche da un punto di vista fotofisico.

Chemical transformations of the pyrene K-region for functional materials

In dieser Arbeit wurde eine neue Methode zur asymmetrischen Substitution der K-Regionen von Pyren entwickelt, auf welcher das Design und die Synthese von neuartigen, Pyren-basierten funktionalen Materialien beruht. Eine Vielzahl von Substitutionsmustern konnte erfolgreich realisiert werden um die Eigenschaften entsprechend dem Verwendungszweck anzupassen. Der polyzyklische aromatische Kohlenwasserstoff (PAK) Pyren setzt sich aus vier Benzolringen in Form einer planaren Raute mit zwei gegenüberliegenden K-Regionen zusammen. Der synthetische Schlüsselschritt dieser Arbeit ist die chemische Transformation der einen K-Region zu einem α-Diketon und der darauffolgenden selektiven Bromierung der zweiten K-Region. Dieser asymmetrisch funktionalisierte Baustein zeichnet sich durch zwei funktionelle Gruppen mit orthogonaler Reaktivität aus und erweitert dadurch das Arsenal der etablierten Pyren Chemie um eine vielseitig einsetzbare Methode. Aufbauend auf diesem synthetischen Zugang wurden fünf wesentliche Konzepte auf dem Weg zu neuen, von Pyren abgeleiteten Materialen verfolgt: (i) Asymmterische Substitution mit elektronenziehenden versus -schiebenden Gruppen. (ii) Darstellung von Pyrenocyaninen durch Anbindung von Pyren mit einer der K-Regionen an das Phthalocyanin Gerüst zur Ausdehnung des π-Systems. (iii) Einführung von Thiophen an die K-Region um halbleitende Eigenschaften zu erhalten. (iv) Symmetrische Annullierung von PAKs wie Benzodithiophen und Phenanthren an beide K Regionen für cove-reiche und dadurch nicht-planare Strukturen. (v) Verwendung des K-Region-funktionalisierten Pyrens als Synthesebaustein für das Peri-Pentacen. Neben der Synthese wurde die Selbstorganisation in der Festphase und an der flüssig/fest Grenzfläche mittels zweidimensionaler Weitwinkel-Röntgenstreuung (2D WAXS) bzw. Rastertunnelmikroskopie (STM) untersucht. Die halbleitenden Eigenschaften wurden in organischen Feld-Effekt Transistoren (OFETs) charakterisiert.

Synthetic studies towards a new fulvestrant analogue

A study towards the synthesis of a new fulvestrant analogue with improved bioavailability was carried out. In this work a twelve-step synthetic route starting from β-estradiol was optimized and a palladium (Pd)-catalyzed endo-selective Heck reaction for the functionalization of an advanced intermediate was investigated.

Microwave-Assisted Phospha-Michael Reactions with Internal Alkenes

The atom efficient phospha-Michael reaction between bis 4-methylphenyl phosphine oxide and several activated internal alkenes has been shown to occur under microwave irradiation without added solvent or catalyst. The alkenes used for this study were ethyl 4-nitrocinnamate, two chalcones ((E)-3-(4-methoxy-phenyl)-1-(4- nitrophenyl)-prop-2-en-1-one and (E)-1-(4-methoxyphenyl)-3-(3-nitro-phenyl)-prop-2- en-1-one), and 2-phenylmethylene-propanedinitrile. In the case of ethyl 4-nitrocinnamate, reaction with bis 4-methylphenyl phosphine oxide for sixty minutes at 130 °C yielded the desired phospha-Michael product in a 55% yield after purification. Varying the location of the nitro group on the phenyl rings of the chalcones did not seem to have a large effect on their reactivity. By NMR, both chalcones seemed to react to the same extent when the reaction times and temperatures were held constant. Interestingly, a phospha-Michael reaction was observed at a reaction temperature of 65°C for experiments involving 2- phenyl-methylene-propanedinitrile while the other substrates required a reaction temperature of 130 °C. Similar experiments were carried out with bis mesityl phosphine oxide and two internal alkenes: 2-phenylmethylene-propanedinitrile and ethyl-2-cyano-3- methyl-2-butenoate. These experiments did not yield any of the predicted phospha- Michael products, which suggest steric limitations to the Michael donor for this reaction.