Nitrogen containing heterocycles have always constituted a subject of great interest due to their wide presence in biologically important compounds so the development of efficient methods for the preparation of pyrrole derivatives and formation of new pyrrole-based heterocyclic compounds are an attractive goal in heterocyclic chemistry. In this study, starting from dimethoxytetrahydrofurane and amino acid esters, unsubstituted pyrrole derivatives, and treatment of amino acid esters with convenient chloroenones 1,2-disubstituted and 1,2,4-trisubstituted pyrrole derivatives were synthesized without racemization. Reaction of unsubstituted pyrrole derivatives with norephedrine toward inter- and intramolecular cyclizations give new interesting heteropolycylic compounds with oxazole-pyrrole-pyrazine structures. Study continued with cyclization reaction of these synthesized substituted and unsubstituted pyrrole derivatives with BBr3 and new bicyclic pyrrole derivatives were obtained in moderate yield.

In this study, the synthesis of 5-ferrocenyl/aryl-4-(phenylselenyl)-1H-pyrazole derivatives was investigated since the integration of ferrocenyl and selenium moieties into pyrazole derivatives may increase their current biological activities. Initially, the starting propargyl aldehydes were synthesized from corresponding acetylenes. Subsequently, propargyl aldehydes were reacted with hydrazines to yield corresponding hydrazones. Then the in situ synthesized hydrazones were subjected to electrophilic cyclization with phenylselenyl chloride, which afforded 5-ferrocenyl/aryl-4-(phenylselenyl)-1H-pyrazoles in one-pot manner. Subsequently, reaction conditions were optimized in terms of electrophile, base, temperature and solvent. Best results were obtained with phenylselenyl chloride and NaHCO3 at room temperature in DCM for ferrocenyl substituted pyrazoles and DCE for aryl substituted pyrazoles. In summary, by employing the electrophilic cyclizations of in situ synthesized acetylenic hydrazones, a variety of 5-ferrocenyl/aryl-4-(phenylselenyl)-1H-pyrazole derivatives were synthesized in one-pot way in moderate to good yields.

The tetrahydroisoquinoline alkaloids have been studied thoroughly about their biological and chemical significance over the past 30 years. These natural products show great biological activity, especially ET-743 and saframycin A, makes them promising therapeutics, while their structural complexity and particularity provide challenging synthetic targets. These alkaloids or derivatives show interesting biological activity, but the most important drawback as potential market therapeutics is the minute amount of them available from nature, and the synthetic methods published are inconvenient, difficult, and hard to handle. Herein is described our researches about the tetrahydroisoquinoline alkaloids. Chapter 1 describes relevant background related to the biological significance of these alkaloids, and the currently synthetic studies toward these natural products. Chapter 2 describes our design and synthesis of the analogues based on the anticancer mechanism of the tetrahydroisoquinoline alkaloids, and the biological activities of these analogues. Chapter 3 describes a rapid synthetic route for the common structure of the bis-tetrahydroisoquinoline alkaloids via a controlled mono-Pictet-Spengler cyclization.

Les diradicaux sont des espèces réputées extrêmement instables. A titre d'exemple, le<br />cyclobutanediyle qui est l'archétype de ce genre d'espèce en série carbonée n'a en effet pu<br />être isolé que dans des matrices à basse température.<br />La première partie de cet exposé sera consacrée aux diradicaux formés des éléments<br />lourds des groupes principaux.<br />Nous montrerons dans une introduction bibliographique comment l'utilisation de ces<br />hétéroéléments a permis l'isolation du premier diradical localisé singulet stable basé sur un<br />squelette formé uniquement des hétéroéléments bore et phosphore.<br />Dans un deuxième chapitre, nous nous intéresserons aux isomères de ce diradical, en<br />particulier ses isomères de valence. Après un bref retour sur le concept, nous étudierons les<br />facteurs qui permettent de stabiliser les différents isomères déjà connus. Nous montrerons<br />ensuite comment il a été possible d'isoler de nouveaux isomères.<br />Dans un troisième chapitre, nous nous arrêterons sur deux isomères de valence<br />particuliers et étudierons l'isomérie d'élongation (bond-stretch isomerism). Dans notre cas,<br />deux isomères qui ne diffèrent que par la longueur d'une liaison sont en équilibre. Grâce à<br />des études de RMN à température variable, nous mettrons en évidence l'influence des<br />facteurs électroniques dans cet équilibre.<br />Ce travail nous a amenés à nous interroger sur la possibilité de préparer un diradical<br />purement organique formé uniquement d'éléments de la seconde ligne : carbone et azote.<br />Cette réflexion nous a conduits à mettre au point une nouvelle méthode de synthèse de sels<br />d'iminium et d'imidazolinium que nous présenterons dans une deuxième partie.

Spinosyn A is a particularly interesting natural product due to its structural complexity and potent insecticidal activity. The biosynthetic pathway of spinosyn A is interesting as it has two unusual features, the SpnF-catalyzed (4+2) cycloaddition and the SpnL-catalyzed cyclization to produce the perhydro-as-indacene core. The work described in this dissertation focuses on elucidating the mechanisms of the SpnF- and SpnL-catalyzed reactions. SpnF has attracted significant interest as a possible Diels-Alderase. To explain how SpnF catalyzes the formation of cyclohexene ring, three plausible mechanisms have been proposed, the Diels-Alder reaction mechanism, the ionic rearrangement mechanism, and the biradical rearrangement mechanism. Kinetic isotope effect studies were performed using four deuterium-labeled mechanistic probes, specially the C4-D, C7-D, C11-D, and C12-D analogs. Currently, the ionic rearrangement mechanism can be excluded, based on the results using the C4-D and C7-D analogs. In addition, how SpnF accelerates the reaction was studied to assess the contribution of an entropic x preorganization compared to enthalpic transition state stabilization. To measure the relative rate enhancements due to structural perturbations, three mechanistic probes were synthesized, the linear analog, the C13-14 Unc analog, and the C2-3 Unc analog. Unfortunately, the linear analog and C13-14 Unc analog didn’t show any turnover activity under either non-enzymatic or enzymatic conditions. Thus, no conclusion could be drawn from incubation with these substrate analogs. Mechanistic studies of SpnL-catalyzed cyclization were devoted to differentiating between the Rauhut-Currier type mechanism and the Michael addition mechanism. Biochemical studies using the C13-F analog as a mechanism-based inhibitor showed the formation of a covalent adduct with SpnL, which is consistent with the Rauhut-Currier type mechanism. Additional experimental data obtained from isotope trace experiments and kinetic isotope effect studies using C12-D analog supports the Rauhut-Currier type mechanism. Biochemical studies concerning the role of SAM in SpnF and SpnL showed that SAM is required for the activity of SpnL, and were inconclusive for SpnF. SpnL mutant studies showed that Cys60 and Glu96 may be important for the catalysis of SpnL. Chemoenzymatic total synthesis of spinosyn A was completed by chemical etherification of 17-pseudoaglycone and D-forosamine. / text

In the last ten years, N-heterocyclic carbenes(NHCs) have gained tremendouspopularity, notably as highly versatile ligands for transition metals. Their strong &#61683;-donatingproperties, associated with high steric hindrance, often impart enhanced stability and activity to a given metallic center. Two main successes of the NHCs in homogeneous catalysis are arguably the ruthenium-mediated olefin metathesis and the palladium-promoted crosscoupling reactions.In this work, we have studied the effect of N-heterocyclic carbenes as supporting ligands in well-defined complexes of palladium(II), gallium(III), and gold(I) that we used in homogeneous catalysis.Notably, we have synthesized, in very straightforward manners, two families of palladium compounds of formulae [(NHC)Pd(L)Cl], where L, which is a R-allyl or R-acac moiety, acts as a protecting shell for the catalytically active [(NHC)Pd0] species. Hence,upon activation under the reaction conditions, these new Pd complexes were found extremely active in the Suzuki-Miyaura, the Buchwald-Hartwig, and the &#61665;-ketone arylation cross-coupling reactions. More precisely, the more active "R-allyl family" allowed for reactions to be performed with as low as 10 ppm of palladium.A series of [(NHC)GaCl3] complexes wa synthesized via a simple one-step procedure. The resulting unprecedented NHC-GaIII compounds were found extremely stable but showed only moderate activity in isomerization reactions.Demonstrating further the versatile application of NHCs in metal-based catalysis, wedeveloped several new catalytic transformations using [(NHC)AuCl] complexes. Hence,these pre-catalysts, activated in situ with a silver salt, proved to be excellent activators ofalkynes, allenes, and alkenes. This led to the development of efficient synthetically usefulprotocols, encompassing enyne cycloisomerization, indene cyclization,formation of conjugated enone, and allylic rearrangement.KEYWORDS gallium - gold - homogeneous catalysis - N-heterocyclic carbene - palladium 8 / En los últimos diez años, los carbenos N-heterocíclicos (NHCs) han ganado una granpopularidad, especialmente como ligandos versátiles de metales de transición. Su fuertecarácter &#61683;&#8722;donor, asociado con su gran impedimento estérico, confieren a menudo unamayor estabilidad y actividad al centro metálico en cuestión. Los dos mayores éxitos de losNHCs en catálisis homogénea se encuentran, sin duda, en la metátesis de olefinas catalizadapor rutenio y en las reacciones de acoplamiento cruzado promovidas por paladio.En este trabajo, hemos estudiado el efecto de los carbenos N-heterocíclicos comoligandos en complejos bien definidos de paladio(II), galio(III) y oro(I), que hemos empleadoen catálisis homogénea.En particular, hemos sintetizado, de forma directa, dos familias de compuestos de paladio de fórmula general [(NHC)Pd(L)Cl] donde L, grupo R-alilo o R-acac, actúa como protector para las especies catalíticamente activas [(NHC)Pd0]. De hecho, tras la activaciónen las condiciones de reacción, estos nuevos complejos de paladio se mostraron extremadamente activos en las reacciones de Suzuki-Miyaura, de Buchwald-Hartwig y en la &#61665;-arilación de cetonas. Más concretamente, la 'familia R-arilo', más activa, permitió llevar a cabo estas reacciones con tan sólo 10 ppm de paladio.Una serie de complejos [(NHC)GaCl3] fue preparada en una simple etapa. Los compuestos resultantes NHC-GaIII, sin precedentes en la literatura, se mostraron extremadamente estables pero sólo moderadamente activos en reacciones de isomerización.Con el fin seguir ampliando la gran aplicabilidad de los NHCs en catálisis conmetales, estudiamos varias nueva transformaciones utilizando los complejos [(NHC)AuCl].De hecho, estos pre-catalizadores, activados in situ con una sal de plata, demostraron ser excelente activadores de alquinos, alenos y alquenos. Esto llevó al desarrollo de protocolos eficientes, y sintéticamente útiles, tales como la cicloisomerización de eninos, la ciclación deindenos, la formación de enonas conjugadas, y reordenamientos arílicos.

Efficient access to molecular complexity and diversity is important for the development of small-molecule screening libraries designed to identify highly specific modulators of disease relevant macromolecular interactions. We envisioned the use of iteratively synthesized bis-vinyl ether substrates for cascade-type transformations to gain rapid access to several different classes of stereochemically rich, linear or polycyclic scaffolds. To evaluate their utility in this context, mechanistic investigations were undertaken to understand the chemical reactivity of bis-vinyl ethers in radical cyclization reactions and [3,3]-sigmatropic rearrangements. Radical cyclization across bis-vinyl ethers proceeded through an apparent 6-endo-trig/5-exo-trig ring closure to afford functionalized hexahydro-2H-furo[3,4-b]pyrans in good yield, with high diastereoselectivity and excellent regiocontrol. Combination of two electron-withdrawing substituents on the bis-vinyl ether backbone resulted in the trapping of a 5-exo-trig/β-scission product, prompting us to investigate the mechanism for cyclization. Formation of the hexahydrofuropyrans was found to be the result of a 5-exo-trig/3-exo-trig/retro-3-exo-trig pathway to afford a “formal” 6-endo pyranosyl radical that could participate in a second 5-exo-trig cyclization to secure the two ring system. From this earlier study, we found certain combinations of substituents on the bis-vinyl ether backbone increased the propensity for these substrates to undergo Claisen rearrangement at remarkably low temperatures. Kinetic investigations of the substituent effects influencing bis-vinyl ether stability found that electron-releasing substituents on the γ-allyloxy fragment increased the rate of rearrangement as a result of stabilization of a cationic allyl fragment in the transition state. Thermochemical data derived from the earlier kinetic investigations also indicated that the Claisen rearrangement of bis-vinyl ether substrates occured through a dissociative mechanism, characterised by an ΔS‡ of +2.3 cal K-1 mol-1. A palladium-catalyzed auxiliary-controlled diastereoselective Claisen rearrangement of bis-vinyl ethers to access aldol-type products is currently under development. Preliminary results indicate that a modest degree of diastereoselectivity can be achieved in this reaction, provided that the steric burden at the stereogenic element is close enough to the pericyclic framework to exert an influence on facial selectivity. / Graduate

Optimized methods for the regioselective and stereospecific synthesis of both trisubstituted and tetrasubstituted olefins as single isomers from E-β-chloro-α-iodo-α,β-unsaturated esters have been developed from previous work done in the Ogilvie lab. These optimized methods have led to the synthesis of trans isomeric enediynes that can be photoisomerized to their respective cis isomers and subsequently undergo microwave-assisted Bergman cycloaromatizations. Furthermore, both cis and trans isomeric enediynes that have propargyl ether substituents have been found to be able to undergo photoactivated Bergman cyclizations without the need for an intermolecular hydrogen donor. A mechanism study has confirmed that the Bergman cyclization products that form without the presence of an intermolecular hydrogen donor undergo a series of 1,5-hydrogen shifts as intermediates. A series of optimizations to these reactions were carried out, in part by utilizing electron-donating or electron-withdrawing functional groups to help stabilize the resulting radicals that form on the intermediates, and thus increase the yield of the associated Bergman cyclization products.

ABSTRACT SYNTHESIS OF 1,2,3,5-TETRASUBSTITUTED PYRROLE DERIVATIVES VIA 5-EXO-DIG TYPE CYCLIZATION AND STEREOSELECTIVE FUNCTIONALISATION OF FERROCENE DERIVATIVES Metin Kayalar M.S., Department of Chemistry Supervisor: Prof. Dr. Ayhan S. Demir January 2005, 102 pages A convenient and new method for the synthesis of 1,2,3,5-tetrasubstituted pyrrole derivatives starting from 1,3,-dicarbonyl compounds through acid catalyzed cyclization reaction is described. Alkylation of 1,3-dicarbonyl compound with propargyl bromide followed by one step cyclization with the introduction of primary amines in the presence of catalytic amount of triflouroacetic acid (TFA) affords the corresponding pyrrole derivatives in high yields. The investigations on the studies of developing a new method for catalytic and stereoselective functionalisation of ferrocene derivatives were summarized. Functionalisation studies were carried out in three main strategy the first one of which is carboxylation, second one is arylation and the last one is oxidative cross-coupling with &amp / #945 / , &amp / #946 / -unsaturated carbonyl compounds.

Esta tese consiste do estudo de reações de ciclofuncionalização de compostos &#946;-enamino carbonílicos e &#946;-dicarbonílicos, contendo uma cadeia alquenílica nas posições &#945; ou &#947;. Os eletrófilos empregados para este fim foram: iodo, brometo de fenilselenenila e tricloreto de p-metóxifeniltelurio. Os iodo-&#946;-enamino ésteres e cetonas cíclicas, após desidroiodação mediada por base, levaram à formação dos correspondentes pirróis, indóis e aminobenzofuranos. A ciclização dos &#946;-ceto ésteres e &#946;-dicetonas levou a enol éteres e benzofuranos funcionalizados. Estes resultados, juntamente com outros obtidos em nosso grupo de pesquisa, foram utilizados em um estudo comparativo entre reagentes de iodo, selênio e telúrio frente a reações de ciclização eletrofílica de substratos &#946;-dicarbonílicos. / This thesis presents a study of the cyclofunctionalization of &#946;-enamino carbonyl and &#946;-dicarbonyl compounds, substituted by an alkenyl group at the &#945; or &#947; positions. Iodine, phenyl-selenenyl bromide and p-methoxyphenyltellurium trichloride were employed as the electrophilic reagent. The cyclic iodo-&#946;-enamino esters and ketones, after base-promoted dehydroiodination, led to the corresponding pyrroles, indoles and aminobenzofurans. The cyclization of the &#946;-keto esters and &#946;-diketones afforded five- and six-membered enol ethers and benzofuranones. These results, together with others previously obtained in our research group, allowed us to compare the behavior of the three above mentioned electrophiles toward the cyclofunctionalization of &#946;-dicarbonyl substrates.