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1
Ferdenzi, Antoine. "Approche des synthèses de la saraïne A et de la misénine, alcaloïdes marins extraits de l'éponge reniera saraï, à partir d'une hypothèse biogénétique commune." Paris 11, 2006. http://www.theses.fr/2006PA112242.
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Peneau, Augustin. "Vers la synthèse totale du 13-desméthyle spirolide C. Synthèse d’hétérocycles par activation C–H catalysée au Rh(III)." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS410/document.
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Certaines phycotoxines marines de la famille des spiroimines, comme la gymnodimine et les spirolides sont produites par des dinoflagellés et se concentrent dans les mollusques filtreurs. Puis, par transport vectoriel, elles peuvent atteindre les animaux marins et les êtres humains. Des études biologiques ont montré que ces toxines sont de puissants antagonistes des récepteurs nicotiniques de l’acétylcholine (nAChRs) et qu’elles présentent une spécificité modérée pour des sous-types de récepteurs. Au laboratoire, nous nous intéressons à la synthèse totale du 13-desméthyle spirolide C, dans le but de produire une plus grande quantité de cette molécule (que par extraction) afin d'étudier plus en détail son activité biologique. Afin d’atteindre ce but, deux stratégies seront présentées. La première faisant intervenir une réaction-clef de décarboxylation allylante asymétrique, permettant la formation stéréosélective d’un centre quaternaire. La seconde approche utilise une réaction de Diels-Alder intermoléculaire pour construire le même motif. Au cours de ces dernières années, les récents développements dans le domaine des couplages organométalliques ont permis de s’affranchir de la préfonctionnalisation d’une liaison C_H avant sa transformation en liaison C_C ou C_hétéroatome, par l’utilisation de catalyseurs à base de métaux de transition. Afin de pallier ce problème, une approche généralement employée, consiste à utiliser la proximité spatiale d’un hétéroatome chélatant (N, O, etc.), appelé groupement directeur (GD), qui permet de diriger la réaction vers une liaison C_H spécifique. Nous avons étudié l’application d’une réaction de type Heck dans la synthèse de squelettes de molécules biologiquement actives. Dans un second chapitre de ce manuscrit seront détaillés les récents avancements dans la synthèse d’hétérocycles par activation C_H, catalysée au rhodium (III). Ainsi, la synthèse de spirocycles carbonés, de spiropipéridines et d’azépinones seront présentés, accompagnées des considérations mécanistiques de ces réactionsSome marine shellfish toxins in the spiroimine family like gymnodimine and spirolides are produced by dinoflagellates and can be transferred and concentrated in seafood then by vectorial transport they can reach marine animals and humans. Biological studies have shown that these toxins are potent antagonists of the nicotinic acetylcholine receptors (nAChRs) and have a moderate selectivity for subtypes receptor. In the laboratory, we are interested in the total synthesis of gymnodimine and 13-desmethyl spirolide C in order to produce a larger quantity of these molecules (compared to isolation from dinoflagellates) to further investigate their biological activities. In this regard, we developed two complementary approaches to access the spiroimine pattern of these molecules. The first one is based on a decarboxylative asymmetric allylic alkylation reaction. The second uses an intermolecular Diels-Alder reaction.With the need of more sophisticated scaffolds for medicinal chemistry or total synthesis, the development of appropriate ortho-directed C_H activation reactions have proven recently to be crucial. Herein, we propose two simple and efficient intramolecular cyclisation reactions, involving a methoxy-amide directing group and a Rh(III)-catalysis. Synthesis of spiropiperidines and azepinones are presented
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Powell, Nicola Helen. "Novel oxetane-containing spirocycles and peptidomimetics." Thesis, University of Warwick, 2014. http://wrap.warwick.ac.uk/66720/.
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This thesis describes work focused on the use of oxetane rings as isosteres and incorporation of this functional group into pharmaceutically relevant scaffolds. Chapter 1 describes work directed towards the synthesis of 1,5-dioxaspiro[2.3]hexanes via three different strategies, namely ring-closure to form the oxetane ring, Corey epoxidation of the corresponding 3-oxetanones, and epoxidation of the corresponding 3-methylene oxetane. Nucleophilic ring-opening of substituted 1,5-dioxaspiro[2.3]hexanes to give amino acid type isosteres is also investigated. Chapter 2 details the synthesis of novel oxetane-containing peptidomimetics. A ‘one-pot’ conjugate addition process from commercially available 3-oxetanone to give nitro dipeptide precursors in good yields was developed. Various methods for the reduction of the nitro group were explored to optimise the synthesis of the corresponding amine. Amide coupling, followed by deprotection, gave peptidomimetics containing the oxetane at the C-terminus and mid-chain in good yields over the 3 steps, whilst an N-terminus oxetane peptidomimetic was obtained in 45% yield through hydrogenation of the conjugate addition product. X-ray diffraction studies, alongside molecular dynamics simulations, provided structural insights into these new oxetane-containing peptidomimetics. Detailed experimental procedures for the synthesis of all novel compounds are described in Chapter 3.
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Hilmey, David George. "Synthesis and study of heteroatomic spirocyclic scaffolds." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1141334542.
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Ferrari, Frank D. "Flexible synthesis of spirocyclic pyrans and piperidines." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3829/.
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Spirocyclic piperidines and spirocyclic pyrans are prevalent throughout nature, often appearing in natural products which exhibit exciting biological activities. Notable examples of spirocyclic piperidine-containing biologically active natural products are halichlorine, pinnaic acid and tauropinnaic acid. Despite their structural similarity, halichlorine and the pinnaic acids were isolated from separate organisms; halichlorine was isolated from extracts of the marine sponge Halichondria okadai while both pinnaic acid and tauropinnaic acid were isolated from the Okinawan bivalve mollusc Pinna muricata. The complex hybrid molecule polymaxenolide contains a representative spirocyclic pyran core. The biological profile of polymaxenolide is not yet known, however its hybrid origins have rendered it a target of significant interest. The work described herein details the development of a methodology capable of accessing both spirocyclic pyran and spirocyclic piperidine core structures from a common cyclic tertiary furfuryl alcohol intermediate. The key spirocycle forming step involves the oxidative rearrangement of cyclic tertiary furfuryl alcohols and amines for the synthesis of spirocyclic pyrans and piperidines, respectively. Efforts towards the synthesis of a complex, africanane-derived Southern fragment, with the intention of applying this methodology towards the synthesis of polymaxenolide are reported. This methodology has been further elaborated to complete an asymmetric synthesis of the upper framework of an oxa-analogue of pinnaic acid. The potential for a spectator protecting group free synthesis of pinnaic acid was also explored and the synthesis of an advanced intermediate is also reported.
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Prail, J. "The synthesis and biohydroxylation of spirocyclic amides." Thesis, University of Exeter, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293090.
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Pancholi, Alpa Kishor. "Synthesis of substituted azetidines and spirocyclic diazetidines." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/102606/.
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Chapter 1 begins with an introduction to azetidines, including a discussion of the methodologies for their synthesis, their applications, relevance in natural products and as building blocks in medicinal chemistry. It then describes the development of a new asymmetric route to 2-substituted azetidin-3-ones using Enders’ SAMP/RAMP auxiliary. A one-pot process was developed involving the metalation of SAMP hydrazones of N-Boc-azetidin-3-one, alkylation and subsequent in situ hydrolysis to give the substituted products. Various bases and reaction conditions were explored to find optimal conditions for maximal yield and enantioselectivity. A representative range of electrophiles were screened including alkyl, allyl and benzyl halides and carbonyl compounds, producing enantioselectivities of up to 85% ee. Multiple substitution on the azetidin-3-one ring was briefly explored by repetition of the alkylation/hydrolysis sequence. Derivitisation by way of Pictet-Spengler reactions was used to confirm the absolute configuration at the newly created stereocentre. Chapter 2 begins with an introduction to 1,2-diazetidines outlining methods for their synthesis, before introducing the relevance of these nitrogen spirocycles. This chapter then describes two routes for the synthesis of these novel spirocyclic 1,2- diazetidines by (i) formation of the diazetidine ring and (ii) functionalisation of a range of 3-methylene-1,2-diazetidines including differentially protected variants. The diazetidines were subjected to dichloro- and difluorocyclopropanation with the latter achieved in high yields. Additionally, reactions with tetracyanoethylene by way of highly asynchronous [2π+2π] cycloadditions proceeded in near quantitative yield. In this way, a range of novel 4,5-diazaspiro[2.3]hexane and 1,2- diazaspiro[3.3]heptane spirocycles were produced. Chapter 3 details the experimental procedure and characterisation for all the novel compounds synthesised.
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Branan, Bruce Monroe. "The chemistry of polycyclic and spirocyclic compounds /." The Ohio State University, 1994. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487849696968107.
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Main, Calver A. "Novel titanium carbenoid reagents : diversity orientated synthesis of indoles and spirocycles." Thesis, University of Glasgow, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502007.
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A new synthetic strategy for the preparation of a 96-member library of 2,5-disubstituted indoles involving traceless cleavage from resin is presented. A boronate-bearing titanium alkylidene was prepared and used to convert 8 resin-bound esters into immobilised enol ethers. Cleavage from resin in mild acid with concomitant cyclisation yielded boronate-bearing indoles. Capitalising on the immobilised boronate functionality in enol ethers, Suzuki cross-coupling reactions were performed with 12 aryl iodides to give a 96-member library after cleavage from resin with mild acid, 79 members of the library were confirmed to be 2,5-disubstituted indoles. Also reported is the use of tertiary butyllithium and 2-isopropoxy-4,4,i,5-tetramethyl-l,3,2-dioxaborolane to convert an aiyl bromide into an arylboronate in the presence of a dithiane, with simultaneous reduction of an aryl azide to an amine. In a similar route, we synthesised dithiane for the attempted conversion of resin-bound esters into functionalised 7-azaindoles after cleavage from resin. Further investigation with a different ortho-nitrogen protecting group may yet prove successful.
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Bird, P. M. "Stereocontrol in the synthesis of substituted spirocyclic ethers." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596658.
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This thesis describes the synthesis of spirocyclic ethers with substituents in both rings. The strategy employed is considered in stepwise manner starting with the two-step synthesis of the substituted cyclic α-phenylsulfanylcarbaldehydes A and B from the corresponding cyclic ketones, paying particular attention to the stereoselectivity in the first step and the stereospecificity of the second. Simple aldol reactions of these aldehydes with ester and ketone enolates are reported, along with the conversion of the aldol products C to (1,3)-diols D by reduction (including the[1,3]-stereoselective reduction of β-hydroxyketones) or addition of an organometallic reagent. The stereospecific cyclisation of these diols to the targeted spirocyclic ethers E was achieved by treatment with catalytic amounts of p-touenesulfonic acid. Elucidation of the stereochemistry of these tetrahydrofurans and their precursors - and the implications of these assignments - by the examination of 2-D NMR spectra is discussed.
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Deslandes, Maria. "SYNTHESIS OF ALL-CARBON SPIROCYCLES BY INTRAMOLECULAR IRON-MEDIATED DIENE/OLEFIN CYCLOCOUPLING." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1354141980.
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Mackay, C. "Spirocyclic intermediates in the electrophilic ring closures of heterocycles." Thesis, University of Manchester, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233067.
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Saruengkhanphasit, Rungroj. "Synthesis of spirocyclic amines by dipolar cycoaddition of nitrones." Thesis, University of Sheffield, 2016. http://etheses.whiterose.ac.uk/17073/.
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Soklou, Kossi Efouako. "Synthèse d'hétérospirocycles par hydroaminations et hydroalkoxylations d'alcynes catalysées par l'or (I) - Méthodologie et application au développement de fragments spirocycliques pour la chimie médicinale." Thesis, Orléans, 2020. http://www.theses.fr/2020ORLE3066.
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Synthétiser des molécules azotées ou oxygénées spiro [4.5] ou spiro [5.5] possédant une liaison entre le carbone spiranique et l’atome d’azote ou d’oxygène reste un défi même si ces fragments sont représentés dans la nature et dans l’arsenal thérapeutique. Pour lever cette contrainte, nous avons développé une méthode générale de spirocyclisation catalysée par l’or (I) passant par des réactions d’hydroamination ou d’hydroalkoxylation d’alcynes. Dans la première partie de cette thèse, nous avons pu optimiser les conditions de spirocyclisation à base de JohnPhosAu(CH3CN)SbF6 en série azotée et oxygénée avec les alcynes vrais, puis accéder à des spirocycles tricycliques originaux par des réactions en cascade. Nous avons également démontré la robustesse de notre méthode vis-à-vis des composés chiraux. Dans la deuxième partie de ce travail, la méthode de spirocyclisation a été étendue aux alcynes disubstitués grâce au couple JohnPhosAuCl/AgNTf2. Dans la troisième partie, nous avons effectué la transformation des spirocycles afin d’accroître la diversité moléculaire. Pour ce faire, des réactions de Mizoroki-Heck intramoléculaires ont fourni des spirocycles tétracycliques originaux et stables tandis que d’autres réactions comme des réductions ont, en plus de la stabilité, accru leur tridimensionnalité. Avec tous ces fragments, un programme de chimie médicinale a été engagé et des actifs à motifs spirocycliques ont été élaborés comme inhibiteurs sélectifs de kinasesThe synthesis of spiro [4.5] or [5.5] nitrogen or oxygen containing molecules with a bond between the carbon spirocenter and the nitrogen or oxygen atom remains a challenge, even if these fragments are represented in nature as well as in the therapeutic arsenal. To overcome this constraint, we have developed a general method of gold (I) catalyzed spirocyclization through the hydroamination or hydroalkoxylation of alkynes. In the first part of this thesis, we optimized spirocycle formation in both the nitrogen and oxygen series using conditions based on JohnPhosAu(CH3CN)SbF6 with unsubstituted alkynes. This also gave access to original tricyclic spirocycles by cascade reactions. We then demonstrated the robustness of our method with respect to chiral compounds. In the second part of this work, the spirocyclization method was extended to di-substituted alkynes using the combined JohnPhosAuCl/AgNTf2 catalyst. In the third part, we transformed our different spirocycles to increase molecular diversity. Intramolecular Mizoroki-Heck reactions provided original and stable tetracyclic spirocycles while other reactions such as double bond reduction increased both stability and 3D molecular space. With these fragments in hand, a medicinal chemistry program was initiated and spirocyclic compounds were developed as selective kinase inhibitors
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Harnor, Suzannah Jane. "Studies towards the synthesis of LL-Z1640-2 and spirocyclic systems." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/2016/.
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Resorcyclic acid lactones (RALs) are natural products, with some having been shown to be potent inhibitors of several protein kinases and mammalian cell proliferation and tumour growth in animals. LL-Z1640-2 (also known as 5Z-7-oxo-zeanol or C292) is a cis-enone RAL, isolated in 1978 from fungal broth and classified as an anti-protozoal agent. Later, in 1999, its cytokine releasing inhibiting activity was discovered, with subsequent data showing it could selectively and irreversibly inhibit transforming growth factor activating kinase-1 (TAK1) activity at low concentrations. It is also reported as having significant activity versus tumour necrosis factor-alpha (TNF-α) production in cells. This thesis documents and describes the work undertaken towards a total synthesis of the 14-membered macrocycle, LL-Z1640-2. The presence of two internal bonds and three stereogenic centres poses a challenge synthetically, but this has been effectively overcome with the development of a flexible, economic and efficient synthesis, beginning from the commercially available starting materials, methyl 2,4,6-trihydroxybenzoate and 2-deoxy-D-ribose. The original route relied on a Wittig olefination to introduce the E-double bond, with moderate selectivity and success. Later, an improved method was built upon, which utilised Grubbs mediated cross-metathesis to form the desired E-olefin in good yield and selectivity. Once the entire carbon framework had been established via a one-pot oxidation-Grignard adition of the appropriate alkyne unit, subsequent transformations enabled the formation of the seco-acid. This very successfully underwent Mitsunobu macrolactonisation, with complete inversion of the stereocentre, to afford the macrocyclic lactone. From this intermediate, the desired natural product LL-Z1640-2 could be generated in three steps. A number of natural products and biologically important compounds contain spirocyclic pyran and piperidines ring systems as part of their overall structures. In 1996, pinnaic acid and halichlorine were isolated from their respective marine natural sources. It was subsequently shown that they exhibited inhibitory activity towards certain biological substances and for this reason they became targets for total synthesis. Characterised by an azaspiro[4.5]decane ring system, the difficulty in achieving total syntheses of such compounds is immense. The aim of the project was to develop a concise method towards the generation of highly functionalised spirocyclic piperidine units. The regioselective aza-Achmatowicz oxidative rearrangement was used as the key step to rearrange α-amino furan building blocks into their respective enones. Importantly, this rearrangement was proven to be viable and to proceed with compounds possessing a terminal olefin, with no over-oxidation observed. This thesis also describes the investigation and efforts made into the production of more functionalised units, as well as studies into the synthesis of the cores of halichlorine and polymaxenolide, again using the aza-Achmatowicz and Achmatowicz rearrangement respectively.
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Dong, Shuzhi. "I. Restriction of DNA conformation by spirocyclic annulation at C-4'. II. Studies toward the enantioselective synthesis of pestalotiopsin A." The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1174627553.
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Hussain, Fazal. "The cyclisation of benzylaminoacetonitriles : evidence of exclusive participation of a spirocyclic intermediate." Thesis, University of Bath, 1985. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.354728.
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A survey has been made of isoquinoline preparation via Pomeranz-Fritsch and benzylaminoacetonitrile syntheses. Over the past fifteen years considerable effort has been made to establish the mechanism by which cyclisations of 3,4-dialkoxybenzylaminonitriles proceeds. Initially a dual mechanism was postulated, one mode involving an electrophilic attack para to the C3-substituent and the second involving attack para to the C4-substituent. Recent evidence from the cyclisations of the isomeric ethoxymethoxybenzylaminoacetonitriles suggested that only the second mechanism may be operating, giving a spiro-intermediate which undergoes rearrangement to an iminium ion, followed by a Pictet-Spengler cyclisation. However, since no attempt has been made to fully characterise the composition of the crude reaction products (dialkoxy and phenolic isoquinolinones), the classical cyclisation could not be precluded. The work described in this thesis involves preparation and cyclisation of a series of aminonitriles at three different temperatures, -10°, room temperature and 50° followed by chromatographic analysis (t.l.c.) and separation of the crude products. All results obtained indicate that cyclisation proceeds exclusively via the spiro-intermediate. No products arising from classical cyclisation were obtained. The yield of the products obtained from all cycli-sations depended upon the temperature of the reactions. For example, at -10° and room temperature the major products are dialkoxyisoquinolinones, whereas at 50° O-dealkylation readily occurs to give phenolic products. Orientation of substitution was unequivocally established by means of 1H n.m.r. (NaOD shift), ultra-violet spectroscopy and by preparing 4-benzyl-4-hydroxy-1,2,3,4-tetrahydroisoquinoline derivatives. A minor part of this work involves a reinvestigation of the cyclisation of 3,4-dimethoxybenzyIglycine esters to establish whether the above mechanism ws involved. However, unlike the nitriles, the glycine esters failed to cyclise readily in sulphuric acid.
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Nocquet, Pierre-Antoine. "Vers la synthèse d'une nouvelle classe d'iminosucres conformationnellement contraints : ouverture d'azétidines, cyclisation 4-exo-trig et C-H amination catalytique." Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAF047/document.
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De précédentes études dans notre groupe ont montré que l'α-1-C-nonyl-1,5-didésoxy-1,5-imino-D-xylitol était un inhibiteur puissant de la β-glucocérébrosidase, enzyme impliquée dans la maladie de Gaucher. Il a été supposé que la conformation chaise inversée de ce composé pouvait expliquer en partie sa forte affinité avec la glycosidase cible. L'objectif ce travail de thèse était la synthèse d'une nouvelle classe d’iminosucres, basée sur un squelette 1-azaspiro[3.3]heptane, possédant deux cycles à 4 membres, analogue conformationnellement contraint de notre "lead" en série iminoxylitol. La première stratégie de synthèse envisagée a permis de mettre en avant une nouvelle réaction tandem d'ouverture d'azétidines conduisant à des spirocyclopropyl γ-lactames. La seconde stratégie testée a conduit dans un premier temps à la formation hautement stéréosélective d'un cyclobutane tétrasubstitué par une réaction radicalaire induite par le SmI2 − permettant ainsi la synthèse des premiers exemples de carbasucres à 4 membres − puis à la formation du carbone azaspiranique de notre cible par une réaction de C-H amination catalysée par des complexes de rhodiumPrevious studies in our group has shown that α-1-C-nonyl-1,5-dideoxy-1,5-imino-D-xylitol was a strong inhibitor of β-glucocerebrosidase, the enzyme involved in Gaucher disease. It was supposed that the inverted chair conformation of this compound could partially explain its high affinity with the target glycosydase.The goal of this PhD work was the synthesis of a new class of iminosugars based on 1-azaspiro[3.3]heptane structures, as conformationally strained analogues of our lead in the iminoxylitol series. During the course of our synthetic study, new azetidine ring-opening tandem reaction leading to spirocyclopropyl γ-lactames has been discovered. The most promising strategy evaluated led to the highly stereoselective formation of a tetrasubstituted cyclobutane via a SmI2-mediated radical reaction − leading to the synthesis of the first exemples of 4-membered carbasugars − then to the formation of the azaspiranic carbon of our target by way of rhodium-catalyzed C-H amination reaction
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Kahane, Alexandra Lyn. "Restriction of DNA conformation by spirocyclic annulation at C4' synthesis of the nucleoside building blocks /." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1085083063.
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Thesis (Ph. D.)--Ohio State University, 2004.Title from first page of PDF file. Document formatted into pages; contains xxii, 204 p.; also includes graphics Includes bibliographical references (p. 114-127). Available online via OhioLINK's ETD Center
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Kahane, Alexandra L. "Restriction of DNA conformation by spirocyclic annulation at C4': synthesis of the nucleoside building blocks." The Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1072903762.
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Kujawa, Szymon. "Rapid generation of molecular complexity under Pd(II) and Rh(III) catalysis." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/11697.
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1. Enantioselective Pd(II)-Catalysed Nucleophilic Additions of 2- Alkylazaarenes The first project deals with enantio- and diastereoselective palladium(II)-catalysed nucleophilic additions of 2-alkylazaarenes to N-Boc imines and nitroalkenes. Under the optimised reaction conditions high levels of diastereo- and enantioselection of the addition products were achieved. Introduction of the electron-withdrawing group at the aryl ring of the substrate allows running the reaction under mild, experimentally convenient reaction conditions. The new described method allows the enantioselective synthesis of 2-(β-aminoalkyl)azaarenes, which are substructures found in drug candidates molecules for the treatment of type 2 diabetes and schizophrenia. 2. Synthesis of Spirocyclic Enones via Rh(III)-Catalysed C–H Functionalisation The second project describes the synthesis of spirocyclic enones by rhodium(III)- catalysed dearomatising oxidative annulation of 2-alkenylphenols with alkynes and 1,3-enynes. A good to high yield with great regioselectivity was obtained. The further synthetic utility of the product was also investigated and led to the formation of highly functionalised tetracycles via 1,6 conjugation addition reaction.
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Bassindale, Martin John. "The application of alkene metathesis to the synthesis of spirocylces, angulary fused tricycles and quaternary chiral centres." Thesis, University of Sheffield, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247168.
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Prusov, Evgeny. "Synthesis of spirocyclic scaffolds by aminoallylation/RCM sequence and approach toward the total synthesis of the Macrolide Dictyostatin." [S.l. : s.n.], 2008.
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Magne, Fanny. "Synthèse d’hétérocycles spiraniques à visée thérapeutique." Thesis, Orléans, 2016. http://www.theses.fr/2016ORLE2046/document.
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Depuis quelques années, l’élaboration de molécules spiraniques connait un essor considérable avec, en particulier, comme but essentiel l’accroissement de la diversité moléculaire considérée à ce jour comme insuffisamment développée. L’objectif de cette thèse de doctorat a été la synthèse de nouvelles entités tricycliques arylaliphatiques possédant un carbone spiranique et ce, en complément des travaux antérieurement effectués au laboratoire. Dans un premier temps, nous avons choisi de générer des molécules regroupant des structures de type indane-1,2’-(azétidine, pyrrolidine et pipéridine). La possibilité de fixer par exemple un groupe fonctionnel tel qu’un amide ou un bras espaceur voire de substituer le noyau aromatique nous a permis d’exploiter les différentes directions de l’espace. Dans un second temps, nous avons développé une réaction d’arylation intramoléculaire en position α de groupements électroattracteurs. Cette arylation catalysée par des métaux (dans notre cas le cuivre) permet d’accéder à des composés aux motifs spiroindane- ou spirotétraline-1,3’-(azétidine, pyrrolidine et pipéridine). Dans un troisième temps, nous avons étudié les réactions d’addition nucléophiles intramoléculaires de pyridines N-activées pour accéder à des structures spirocycliques pyridiniques fonctionnalisées. Des essais préliminaires utilisant de l’anhydride acétique comme agent activant nous ont permis de générer les intermédiaires recherchés. Afin d’accroître la diversité moléculaire et découvrir de nouveaux fragments susceptibles de nous mener à des agents thérapeutiques, nous nous sommes intéressé, dans un dernier temps, au domaine des biotechnologies blanches en exploitant le potentiel des micro-organismes et de leurs enzymes pour fonctionnaliser des liaisons C-H non activées présentes au sein de charpentes spirocycliques préalablement préparéesIn recent years, the elaboration of spirocyclic molecules has arisen, particularly with an essential purpose to increase of molecular diversity which is not sufficiently developed to date. The objective of this work was the synthesis of new arylaliphatic tricyclic entities with spiranic carbon and it in addition to previous work in the laboratory. Firstly, we have chosen to generate molecules having indane-1,2’-(azetidine, pyrrolidine and piperidine) moiety. The possibility of incorporating a functional group such as an amide, a spacer group or even a substituent on the aromatic ring has allowed us to exploit all space directions. Secondly, we have developed an intramolecular arylation in α position of the electroattractive groups. This metal catalyzed arylation, (in this case copper) provides access to compounds with spiroindane or spirotetraline-1,3’-(azetidine, pyrrolidine and piperidine) patterns. Thirdly, we have studied the intramolecular nucleophilic addition of N-activated pyridine to accede to spirocyclic functionalized pyridine structures. Preliminary tests using acetic anhydride as the activating agent allowed us to generate some desired intermediates. Last but not least, in an effort to increase the molecular diversity and the discovery of new fragments that could lead us to therapeutic agents, we were interested in the field of white biotechnology by harnessing the potential of microorganisms and their enzymes to functionalize in activated C-H bonds in previously prepared spirocyclic scaffolds
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Dong, Shuzhi Dong Shuzhi. "I. Restriction of DNA conformation by spirocyclic annulation at C-4' II. Studies toward the enantioselective synthesis of pestalotiopsin A /." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1174627553.
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Hensienne, Raphaël. "Nouvelles classes d’iminosucres bicycliques : approche synthétique des squelettes 5-azaspiro[3.4]octane et 6-azabicyclo[3.2.0]heptane." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAF049/document.
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Des études antérieures conduites par notre groupe ont permis d’identifier l’α-1-C-nonyl-1,5-didésoxy-1,5-imino-D-xylitol en tant que puissant inhibiteur de la β-glucocérébrosidase – enzyme impliquée dans la maladie de Gaucher. La conformation inhabituelle (chaise inversée) de ce composé nous a incités à étudier plus avant la relation entre conformation et activité biologique des iminosucres. L’objectif de ces travaux de thèse consistait ainsi en la synthèse d’analogues conformationnellement contraints d’iminosucres. Dans un premier temps, trois spiro-iminosucres basés sur un squelette 5-azaspiro[3.4]octane ont été obtenus via une séquence comportant trois étapes clés : formation du cyclobutane par cyclisation radicalaire, introduction de l’azote par C-H amination et formation de la pyrrolidine par métathèse. Dans un second temps, une séquence a été développée pour la synthèse stéréodivergente d’iminosucres bicycliques accolés basés sur un squelette 6-azabicyclo[3.2.0]heptane via l’enchaînement de deux étapes clés : formation de la structure azabicyclique par aldolisation de type Mukaiyama puis oxydation de la cétone résultante en énonePrevious studies performed by our group led to the identification of α-1-C-nonyl-1,5-dideoxy-1,5-imino-D-xylitol as a powerful inhibitor of β-glucocerebrosidase, the enzyme involved in Gaucher disease. This compound’s unusual (inverted chair) conformation prompted us to further study the relationship between iminosugars’ conformation and biological activity. The aim of this PhD work was thus the synthesis of conformationally restricted iminosugar analogues. Firstly, three spiro-iminosugars based on a 5-azaspiro[3.4]octane scaffold were synthesized through a sequence including three key steps: cyclobutane formation by way of radical cyclisation, nitrogen introduction by mean of C-H amination and pyrrolidine formation by way ofmetathesis. Secondly, we developed a sequence dedicated to the stereodivergent synthesis of fused bicyclic iminosugars based on a 6-azabicyclo[3.2.0]heptane scaffold through a succession of two key steps: azabicyclic scaffold formation by mean of Mukaiyama aldol reaction followed by ketone to enone oxidation
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Bouhlel, Ahlem. "Cyclisations radicalaires oxydatives médiées par l'acétate de manganèse (III) et orientées vers la chimie médicinale." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM5501/document.
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Ce travail s'inscrit dans la recherche et le développement de nouvelles molécules à visée thérapeutique via la mise au point de cyclisations radicalaires oxydatives médiées par l'acétate de manganèse(III). Deux problématiques ont dirigé nos recherches. Tout d'abord, nous avons développé une stratégie de synthèse de prodrogues analogues de la pafuramidine, molécule antileishmanienne. Ainsi, une 1ère série d'amidoximes a été obtenue à partir de β-cétosulfones par une synthèse multi-étapes faisant appel aux réactions i) de cyclisations radicalaires oxydatives médiées par Mn(OAc)3 et ii) de couplages pallado-catalysées de Buchwald-Hartwig et de Heck. Suite à l'évaluation biologique in vitro sur Leishmania donovani et sur des cellules humaines, une 2ème série d'amidoximes et en particulier des monoamidoximes a été réalisée, ce qui a révélé une molécule présentant un index de sélectivité 40 fois plus élevé que celui de la pentamidine, médicament utilisé comme référence. Nous avons également mis au point un double couplage "one-pot" de Buchwald-Hartwig dans le but d'obtenir des produits dicouplés dissymétriques, précurseurs éventuels de futures diamidoximes. Dans une deuxième partie, nous nous sommes focalisés sur la synthèse de composés spirocycliques pouvant constituer un pharmacophore original. De ce fait, une stratégie de synthèse conduisant à divers noyaux tels des tétralines spirocycliques, des spirolactones, des spirobenzophénanthrédin-6(5H)-ones a été mise au point. Ce travail nous a également menés vers la synthèse de dérivés thiobarbiturates, analogues de composés anesthésiques ou anticonvulsivantsThis work focuses on the research and development of new therapeutic molecules through optimized radical cyclizations mediated by manganese(III) acetate. Two problematics directed our research. First, we developed analogous prodrugs of pafuramidine, an antileishmanial molecule. Thus, a 1rst series of amidoximes was obtained from β-ketosulfones by a multi-step synthesis involving i) radical oxidative cyclizations mediated by Mn(OAc)3 and ii) pallado-catalyzed Buchwald-Hartwig and Heck coupling reactions. The 1rst series being biologically evaluated in vitro, both on Leishmania donovani and human cells, a 2nd series and particularly monoamidoximes was prepared and revealed a molecule presenting a selectivity index 40 times higher than the one of pentamidine, used as reference drug compound. We also developed a one-pot double Buchwald-Hartwig coupling reaction in the aim to obtain dissymmetric dicoupled products, potential precursors of future diamidoximes. In a second time, we focused on the synthesis of spirocyclic compounds which could constitute an original pharmacophore. Therefore, we performed a synthesis allowing access to a wide variety of scaffolds such as spirocyclic tetralins, spirolactones, spirobenzophenanthridin-6(5H)-ones. This work allowed the synthesis of thiobarbiturates, analogous of anesthetic or anticonvulsive compounds
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Odelius, Karin. "Design of polyester and porous scaffolds." Licentiate thesis, Stockholm, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-493.
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Kern, Nicolas. "Réactivité d'azacycles en catalyse à l'or." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAF012/document.
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La catalyse organométallique est l'un des piliers de la synthèse chimique moderne. Elle permet notamment la formation rapide de liaisons carbone-carbone et carbone-hétéroatome, processus les plus importants pour la fabrication des milliers de composés nécessaires à la vie contemporaine. Elle répond également aux critères d'économie d'atomes et d'énergie, et de réduction des déchets, des risques et des coûts de mise en oeuvre d'une réaction chimique.Parmi les thématiques les plus récentes de la synthèse organique, la catalyse homogène à l'or s'est imposée en seulement quelques années comme un outil synthétique très puissant. Elle autorise la génération rapide de complexité moléculaire à partir de substrats simples par l'activation d'insaturations carbonées. Durant ces études, nous avons tenté de tirer profit du caractère carbophile des complexes d'or (1) et (Ill) mais aussi de leur affinité pour certaines fonctions polaires pour transformer des hétérocycles acétyléniques en composés hétéropolycycliques dans des réactions en cascade. La réactivité complémentaire des complexes d'argent (1) a également été exploitée, ces derniers présentant de surcroît une sélectivité remarquable pour la déprotection d'éthers de méthoxybenzyleOrganometallic catalysis is a key tool of modern chemical synthesis. lts use is ubiquitous in the preparation of bulk or fine chemicals, in particular for the assembly of carbon-carbon and carbon-heteroatom bonds. Besides its overall efficiency, it responds to the responsible criteria of energy and atom economy, the reduction of waste, risk, and financial costs needed to perform a chemical reaction.ln just a few years, homogenous gold catalysis has emerged as an invaluable tool for the fast generation of molecular complexity. lndeed, it allows the strong electrophilic activation of unsaturated hydrocarbon moieties (e.g. alkynes or alienes). During this PhD thesis, we focused our studies on the use of gold's pi acidity as weil as its "classical" - but less discussed - Lewis acid character for the triggering of cascade reactions.Starting from acetylenic heterocycles, we targeted the synthesis of polycyclic compounds. The milder reactivity of silver complexes was also found useful in these reactions, as weil as in the deprotection of methoxybenzyl ethers
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Afewerki, Samson. "Development of catalytic enantioselective C-C bond-forming and cascade transformations by merging homogeneous or heterogeneous transition metal catalysis with asymmetric aminocatalysis." Doctoral thesis, Mittuniversitetet, Avdelningen för naturvetenskap, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:miun:diva-23605.
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Chiral molecules play a central role in our daily life and in nature, for instance the different enantiomers or diastereomers of a chiral molecule may show completely different biological activity. For this reason, it is a vital goal for synthetic chemists to design selective and efficient methodologies that allow the synthesis of the desired enantiomer. In this context, it is highly important that the concept of green chemistry is considered while designing new approaches that eventually will provide more environmental and sustainable chemical synthesis.The aim of this thesis is to develop the concept of combining transition metal catalysis and aminocatalysis in one process (dual catalysis). This strategy would give access to powerful tools to promote reactions that were not successful with either transition metal catalyst or the organocatalyst alone. The protocols presented in this thesis based on organocatalytic transformations via enamine or iminium intermediates or both, in combination with transition metal catalysis, describes new enantioselective organocatalytic procedures that afford valuable compounds with high chemo- and enantioselectivity from inexpensive commercial available starting materials. In paper I, we present a successful example of dual catalysis: the combination of transition metal activation of an electrophile and aminocatalyst activation of a nucleophile via enamine intermediate. In paper II, the opposite scenario is presented, here the transition metal activates the nucleophile and the aminocatalyst activates the electrophile via an iminium intermediate. In paper III,we present a domino Michael/carbocyclisation reaction that is catalysed by a chiral amine (via iminium/enamine activation) in combination with a transition metal catalysts activation of an electrophile. In paper IV, the concept of dual catalysis was further extended and applied for the highly enantioselective synthesis of valuable structural scaffolds, namely poly-substituted spirocyclic oxindoles. Finally, in paper V the concept of dual catalysis was expanded, by investigating more challenging and environmentally benign processes, such as the successful combination of a heterogeneous palladium and amine catalysts for the highly enantioselective synthesis of functionalised cyclopentenes, containing an all carbonquaternary stereocenter, dihydrofurans and dihydropyrrolidines.
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Hartung, Ryan Eugene. "I. Synthesis of saturated, DNA, and RNA spirocyclic-4,4-nonane nucleosides. II. Studies toward epoxy carbonate formation and the synthesis of suitable precursors III. Methodological investigations involving the reactions of diazomethane with di-, tri-, an." The Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1130940224.
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Ondet, Pierrick. "Synthèse d'éthers polycycliques par cycloisomérisations catalysées par des acides de Lewis : applications dans le domaine des arômes et parfums." Thesis, Université Côte d'Azur (ComUE), 2016. http://www.theses.fr/2016AZUR4075/document.
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Les molécules polycycliques, et notamment les éthers spirocycliques, sont des structures présentant un fort intérêt dans le domaine de la chimie des parfums. Cette thèse est dédiée au développement de nouvelles cycloisomérisations de dérivés d’éthers d’énol catalysées par le triflate de bismuth(III). Une étude bibliographique a ainsi été consacrée aux réactions de cyclisation catalysées par Bi(OTf)3. Une réaction de cycloisomérisation d’éthers d’énol alléniques permettant la formation rapide de produits cyclopenténiques et dihydrofuraniques a été développée. Des dérivés oxaspirocycliques ont été obtenus à partir de substrats trifonctionnels possédant un éther d’énol cyclique et une fonction alcool additionnelle. La chimiodivergence de ces réactions a été étudiée avec l’activation préférentielle de l’allène par des catalyseurs à base d’or(I) menant à d’autres structures cyclopenténiques. Une réaction de double cyclisation a été développée donnant un accès privilégié à des produits polycycliques pontés comportant un motif oxaspirocyclique. Des études mécanistiques ont été effectuées et une nouvelle cyclisation tandem impliquant un transfert d’hydrure-1,5 a été étudiée. La réaction de double cyclisation de dérivés du campholénal énantioenrichis a ensuite été développée pour la formation de bis-éthers tétracycliques et de cétones tricycliques. La plupart de ces nouveaux composés présentent des notes remarquables, principalement dans les familles olfactives aromatiques et boiséesPolycyclic compounds and more specifically, spirocyclic ethers are of particular interest in fragrance chemistry. This thesis is dedicated to the development of new cycloisomerisations of enol ether derivatives by bismuth(III) triflate catalysis. In this way, a bibliographic study has been carried out on cyclisations catalysed by bismuth(III) triflate. A cycloisomerisation of allenic enol ethers has been developed for the straightforward synthesis of cyclopentene and dihydrofuran derivatives. New oxaspirocyclic compounds have been obtained starting from trifunctional substrates containing a cyclic enol ether and an additional hydroxyl group. The chemodivergence of this reaction has been studied by means of gold(I) catalysis to access different cyclopentenic structures via the preferential activation of the allene. A double cyclisation reaction has been developed leading to bridged polycyclic compounds featuring an oxaspirocyclic moiety. Mechanistic studies have been performed and a tandem cyclisation involving a 1,5-hydride shift has been studied. The double cyclisation of enantioenriched campholenic aldehyde derivatives has been investigated for the formation of tetracyclic diethers and tricyclic ketones. Most of the new compounds presented interesting notes, mainly in the aromatic and woody olfactory family
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Kitschke, Philipp. "Experimental and theoretical studies on germanium-containing precursors for twin polymerization." Doctoral thesis, Universitätsbibliothek Chemnitz, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:ch1-qucosa-205443.
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Im Fokus dieser Arbeit standen zwei Ziele. Zum einem war es Forschungsgegenstand, dass Konzept der Zwillingspolymerisation auf germaniumhaltige, molekulare Vorstufen wie zum Beispiel Germylene, spirozyklische Germaniumverbindungen und molekulare Germanate zu erweitern und somit organisch-anorganische Komposite beziehungsweise Hybridmaterialien darzustellen. Dazu wurden neuartige Germaniumalkoxide auf der Basis von Benzylalkoholaten, Salicylalkoholaten sowie Benzylthiolaten synthetisiert, charakterisiert und auf ihre Fähigkeit Komposite beziehungsweise Hybridmaterialien über den Prozess der Zwillingspolymerisation zu erhalten studiert.
Ein zweites Ziel dieser Arbeit war es, Beziehungen zwischen der Struktur und der Reaktivität dieser molekularen Vorstufen sowie deren Einfluss auf die Eigenschaften der erhaltenen Polymerisationsprodukte zu identifizieren und systematisch zu untersuchen. Hierfür wurden zum einen verschiedene Substituenten, welche unterschiedliche elektronische sowie sterische Eigenschaften aufweisen, an den aromatischen Einheiten der molekularen Vorstufen eingeführt. Die Effekte der Substituenten auf den Prozess der Zwillingspolymerisation und auf die Eigenschaften der Komposite beziehungsweise Hybridmaterialien wurden für die Verbindungsklasse der Germanium(II)salicylalkoholate, der molekularen Germanate sowie der spiro-zyklischen Siliziumsalicylalkoholate untersucht. Spirozyklische Siliziumsalicylalkoholate, wie zum Beispiel 4H,4’H-2,2‘-Spirobi[benzo[d][1,3,2]dioxasilin], wurden im Rahmen dieser Arbeit mit einbezogen, da sie aufgrund ihres nahezu idealen Zwillingspolymerisationsprozesses geeignete Modelverbindungen für Reaktivitätsstudien darstellen. Zudem wurde der Einfluss der Substituenten auf die Charakteristika der aus den Kompositen beziehungsweise Hybridmaterialien erhaltenen Folgeprodukte (poröse Kohlenstoffmaterialien und oxydische Materialien) studiert. Des Weiteren wurde eine Serie von spirozyklischen Germaniumthiolaten, welche isostrukturell zu 4H,4’H-2,2‘-Spirobi[benzo[d][1,3,2]dioxasilin] sind, synthetisiert, um systematisch den Einfluss der Chalkogenide, Sauerstoff und Schwefel, in benzylständiger sowie phenylständiger Position auf deren Reaktionsvermögen im Polymerisationsprozess zu untersuchen.
Die experimentellen Ergebnisse zu den Struktur-Reaktivitätsbeziehungsstudien wurden, soweit es jeweils durchführbar war, mittels quantenchemische Rechnungen validiert und die daraus gezogenen Schlüsse in die Diskussion zur Interpretation der experimentellen Ergebnisse mit einbezogen.
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Finne, Anna. "Novel Possibilities for Advanced Molecular Structure Design for Polymers and Networks." Doctoral thesis, KTH, Polymerteknologi, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-3623.
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Synthetic and degradable polymers are an attractive choicein many areas, since it is possible to control the way in whichthey are manufactured; more specifically, pathways tomanipulate the architecture, the mechanical properties and thedegradation times have been identified. In this work,L-lactide, 1,5-dioxepan-2-one and ε-caprolactone were usedas monomers to synthesize polymers with different architecturesby ring-opening polymerization. By using novel initiators,triblock copolymers, functionalized linear macromonomers andstar-shaped aliphatic polyesters with well-defined structureshave been synthesized. To synthesize triblock copolymers,cyclic germanium initiators were studied. The polymerizationproceeded in a controlled manner although the reaction rateswere low. To introduce functionality into the polymer backbone,functionalized cyclic tin alkoxides were prepared and used asinitiators. During the insertion-coordination polymerization,the initiator fragment consisting mainly of a double bond wasincorporated into the polymer backbone. The double bond wasalso successfully epoxidized and this gave unique possibilitiesof synthesizing graft polymers with precise spacing. Themacromonomer technique is a very effective method for producingwell-defined graft polymers. Spirocyclic tin initiators weresynthesized and used to construct star-shaped polymers. Thestar-shaped polymers were subsequently crosslinked in apolycondensation reaction. These crosslinked structures swelledin water, and swelling tests showed that by changing thestructure of the hydrogel network, the degree of swelling canbe altered. A first evaluation of the surface characteristicsof the linear triblock copolymers was also performed. AFManalysis of the heat-treated surfaces revealed nanometer-scalefibers and tests showed that keratinocytes were able to growand proliferate on these surfaces.QC 20100602
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Hartung, Ryan E. "I. Synthesis of saturated, DNA, and RNA spirocyclic-4,4-Nonane nucleosides. II. Studies toward epoxy carbonate formation and the synthesis of suitable precursors III. Methodological investigations involving the reactions of diazomethane with di-, tri-, and tetraketones. IV. Towards the total synthesis of salicifoline." Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1130940224.
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McKenzie, Jean Mary-Anne. "Application of the Noyori annulation reaction to the cephalotaxine spirocycle." Thesis, 2001. http://hdl.handle.net/10413/3008.
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Cephalotaxine is a naturally occurring alkaloid which is the structural motif of a number of compounds which have shown promising anti-cancer properties. This fact together with its relatively complex pentacyclic structure, which incorporates an azaspirocycle annular to a benzazepine moiety, has resulted in its popularity as a synthetic target. The aim of this project was to synthesise the azaspirocycle of cephalotaxine using a Noyori annulation method involving the reaction of an enamine and an a,a' -dibromo ketone in the presence of Fe2{CO)9. In the first attempt the reaction of l-benzyl-2-methylenepyrrolidine (117) with methyl 2,4-dibromo-3-oxobutanoate (116) proved to be unsuccessful, the electron withdrawing ester functionality of methyl 2,4-dibromo-3-oxobutanoate (116) being unable to stabilise the intermediates formed during the reaction and thus resulting in its failure. Reaction of l-benzyl-2-methylenepyrrolidine (117) and 2,4-dibromo-3-pentanone (114) resulted in the formation of an azaspirocycle though in an extremely poor yield and the reaction was deemed inefficient for the synthesis of the cephalotaxine spirocycle. Finally, reaction of 2-(l-benzyl-2-pyrrolidinylidene)acetonitrile (129) and 2,4-dibromo-3-pentanone (114) resulted in the successful synthesis of a novel azaspirocycle. The product, l-benzyl-7,9-dimethyl-8-oxo-1-azaspiro[4.4]nonane-6-carbonitrile (130), contained four stereogenic centres and one of the diastereomers was successfully crystallised out. The X-ray structure in conjunction with NOESY NMR experiments showed the relative stereochemistry to be 5s', 6s', 7s', 9s'. Significant progress was made in the application of this methodology to the construction of the cephalotaxine pentacyclic skeleton with the synthesis of a novel lactam, 1-[2-(6-iodo-I,3-benzodioxol- 5-yl)ethyl]-2-pyrrolidinone, being achieved. In the course of this work a novel compound, 2-(6-Iodo-1 ,3-benzodioxol-5-yl)ethyl 4-methylbenzenesulfonate (98), was also synthesised and its X-ray structure revealed it to be conformationally interesting. As a result a conformation analysis study was carried out on this compound as well as 2-(6-Iodo-I,3-benzodioxol- 5-yl)ethyI 4-nitrobenzenesulfonate (15a). The Noyori annulation reaction was not implemented in the route to the basic pentacyclic structure of cephalotaxine due to time constraints, however synthesis of analogues of cephalotaxine and other alkaloids possessing azaspirocycles should now be possible based on the methodology developed in this project.Thesis (M.Sc.)-University of Natal Pietermaritzburg, 2001.
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Savage, Nikolas Alexander. "Accessing fused and spirocyclic ring formations via carbon - carbon bond activation." Thesis, 2013. http://hdl.handle.net/2152/23647.
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Carbon-carbon bonds are ubiquitous in synthetic chemistry and constitute the skeletal backbone of a significant number of compounds. Utilizing transition metal mediated catalysis, a wide array of fused and spirocyclic ring systems containing diverse functionalization were accessed. These investigations provide unique ways to prepare carbon frameworks that are otherwise nontrivial to construct using classical approaches. The derivatives were rapidly accessed through optimized methods.text
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Amireddy, Mamatha, and 馬瑪塔. "Organocascade Synthesis of Functionalized Spirocycles and Bicycles." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/89143368048146984050.
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博士國立臺灣師範大學
化學系
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The content of this thesis is divided into three chapters. The chapter-I, illustrate overview on asymmetric synthesis and organocatalysis. It includes, terminology, introduction to asymmetric synthesis, some historical aspects of organocatalysts, classification and utilization of covalent catalysis including iminium and enamine, non-covalent catalysis including phase-transfer catalysts, hydrogen bonding catalysts and importance of alkaloids in asymmetric synthesis as organocatalysts. And successful applications on important C-C bond forming asymmetric Michael domino/cascade/tandem reactions are presented. The interesting art of hydrogen bonding, namely, the formation of double hydrogen bonds between organic molecules is also described. II.1. Organocatalytic formal [5+1] annulation: diastereoselective cascade synthesis of functionalized six-membered spirocyclic indane-1,3-diones/oxindoles via Michael-aldol reaction Chapter-II is divided into 3 sections. Section-1, represents the diastereoselective synthesis of functionalized six membered spirocyclic compounds via Michael-aldol cascade reaction. The reaction proceeds smoothly between indane 1,3-diones/oxindoles/coumaranone as the dinucleophilic components and (E)-5-nitro-6-aryl-hex-5-en-2-one as the dielectrophile in presence of DABCO to give the desired spirocyclic products with reasonable to high chemical yields (30- 84%) and high levels of diastereoselectivities (up to >95:5 dr). II.2. Organocatalytic synthesis of spirocyclohexane indan-1, 3-diones via a chiral squaramide-catalyzed Michael/aldol cascade reaction of γ-nitro ketones and 2- arylideneindane-1, 3-diones. This section describes a chiral squaramide catalyzed stereoselective synthesis of spirocyclohexane indan-1, 3-diones via Michael-aldol cascade reaction of 2-arylideneindan-1, 3-diones and γ- nitroketones. The reaction produces three stereogenic centers having spirocyclohexaneindan-1, 3- diones derivatives with excellent diastereo and high enantioselectivity in good to excellent yields. II.3. Organocatalytic one-pot asymmetric synthesis of functionalized spiropyrazolones via a Michaelaldol sequential reaction. In this section an efficient organocatalytic stereoselective method for the synthesis of functionalized spiropyrazolone derivatives with four contiguous stereogenic centers has been developed through a chiral squaramide catalyzed Michael-aldol sequential reaction. The reaction between 3-methyl-1-aryl-2-pyrazolin-5-ones and (E)-5-nitro-6-aryl-hex-5-en-2-ones is catalyzed by a quinine derived squaramide to give the desired spiropyrazolone derivatives in moderate-to-good yields (up to 80%) with good-to-excellent stereoselectivities (up to >20: 1 dr, 94% ee). III. Organocatalytic diastereoselective [3+2] annulation of 1, 4-dithiane-2, 5-diol and nitro allylic amines via sulfa-Michael-aldol cascade reaction. The chapter III, discloses base catalyzed cascade sulfa-Michael-aldol reaction for the synthesis of novel class of biheterocyclic tetrahydrothiophene derivatives in good yield with high diastereoselectivity. The mild reaction conditions, good functional group tolerance, and broad range of nitro allylic compounds are salient features of this protocol. Due to the easy preparation of the starting materials, we believe this methodology provides a simplified route for the synthesis of biheterocyclic thiophene derivatives.
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Nigríni, Martin. "Enantioselektivní syntéza bispirosloučenin." Master's thesis, 2020. http://www.nusl.cz/ntk/nusl-436011.
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This diploma thesis is focused on synthesis of enantiomeric and diastereomeric pure bispirocyclic compounds via sequential Mannich/hydroamination reaction. The first part is focused on the optimization of reaction conditions of enantioselective asymmetric organocatalytic Mannich reaction of pyrazolone derivatives with isatin-derived ketimines. The enantiomerically enriched Mannich adducts were used in hydroamination cyclization. The second part of the work is focused on finding the suitable reaction conditions for performing the Mannich reaction and hydroamination as a sequential reaction leading to bispirocyclic compounds. The application of sequential reaction and selected transformations of bispirocyclic compounds was also performed. Key words Asymmetric synthesis, organocatalysis, Mannich reaction, hydroamination, sequential reaction, bispirocyclic coumpounds.
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Fleury, Melissa. "Ring expansion reactions to form spirocycles and its application to the synthesis of cylindricine B." Thesis, 2003. http://hdl.handle.net/2429/14361.
Full textAbstract:
The photochemically initiated semipinacol rearrangement of a substrate bearing an
intramolecular alcohol 1.10 was attempted in order to provide spirocyclic ring systems. The
syntheses of carbocyclic ring expansion precursors were achieved. Unfortunately, the use of U V
light and a photosensitizer to initiate ring expansion reaction was unsuccessful.
It was found that a majority of siloxy-epoxide ring expansions of cyclobutane rings to
form l-azaspiro[5.4]decanes are unselective. The ring expansion of cyclobutane rings was
executed on siloxy-epoxide carbocycles 2.6 and 2.15 and heterocycle 2.34 with the intent of
achieving mechanistic elucidation. Three scenarios for the stereochemical outcome of the
rearrangements were examined. The rearrangement was deduced to most likely occur via an
unselective synchronous mechanism where anti and syn migration of the alkyl (CHfe) group onto
the epoxide moiety take place to give 2.4 and 2.5, respectively. Interesting diastereoselectivity
was observed by varying the silicon substituent size and the substitution at the 3-position of the
heterocycle. Also, chiral Lewis acid initiated ring expansions were attempted as a method of
introducing asymmetry.
Finally, synthesis of the A ring of cylindricine B via nitrogen addition (Michael reaction)
onto an a,8-unsaturated carbonyl 3.7 was attempted. The synthesis of the B and C ring
framework was executed following group precedent. The synthesis of the a,6-unsaturated
carbonyl side chain was attempted using Kishi-Nozaki and carbonylative Stille coupling
reactions on an azaspirocyclic vinyl triflate 3.1. The Michael acceptor side chain was not
successfully appended using these coupling reactions. The synthesis of the A ring is key in
performing the first asymmetric total synthesis of cylindricine B. Therefore, further
investigations on appending the Michael acceptor side chain are necessary in order to achieve
this goal.
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Chaudhari, Prakash Dilip. "Development of One-Pot Organocatalytic Enantioselective Reactions for the Synthesis of Polysubstituted Spirocyclic Oxindole Derivatives and Spirocyclopentane Oxindoles." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/6z2y5u.
Full textAbstract:
博士國立中正大學
化學暨生物化學研究所
107
This dissertation demonstrates our innovation in the area of asymmetric amino as well as hydrogen-bonding catalysis for the synthesis of enantioenriched polycyclic spirooxindole compounds. In the second chapter, we have discussed the novel organocatalytic quadruple organocascade Michael-Michael-Michael-aldol condensation reaction between (E)-1- methyl-3-(3-nitroallyl)indolin-2-one 34 and two molecules of α,β−unsaturated aldehydes 35 via consecutive iminium-enamine-iminium-enamine catalysis for the formation of highly functionalized polysubstituted spirooxindole products (36 as the major and 37 as the minor) with six contiguous stereocenters including a quaternary center in good yield with excellent enantioselectivities. It was observed that when the starting material was kept the same but the catalyst were switched we got aromatized product which was minor product by Michael-Michael- Michael-aldol condensation-aromatization reaction sequence. The structures and absolute configuration of products 36 and 37 and aromatized products 51 were confirmed by single crystal X-ray crystallographic analysis, e.g. 36c, 37c, 36e and 51. The fourth chapter discussessed the enantioselective organocatalytic Michael-Michael domino reaction of nitroolefin 34 and 2-nitro-3-acrylates (81) for the construction of highly functionalized cyclopentane spirooxindoles products 82 as the major and 83 as the minor) using novel squaramide organocatalyst with four stereogenic centers including two quaternary stereocenters with good yield and excellent enantioselectivity. In the second chapter we have also demonstrated one pot enantioselective synthesis of quaternary α-amino ester. Furthermore, the structures and absolute stereochemistry of the products (82 as major and 83 as minor) were confirmed by single X-ray crystallographic analysis of 82a, 82b, 82f, 82j, 83b, 83d and 83i
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UN, PUI-WAI, and 阮沛慧. "Construction of spirocyclic 1,4-diones via the N-heterocyclic carbene/urea cocatalyzed intramolecular Stetter reaction of cyclic enone-aldehydes." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/9afgzq.
Full textAbstract:
碩士國立中正大學
化學暨生物化學研究所
107
In this thesis we have studied N-heterocyclic carbene (NHC) and urea cocatalyzed intramolecular Stetter reaction of the cyclic enone- aldehydes to construct spiro compounds. Treatment of the cyclic enones tether with 4-oxobutyl side chain with NHC and urea in toluene at room tempurature obtained the desired spiro[4.m]decane-1,7-diones in 27-81% yields. In the cases of the methylcyclohexenones tether with 4-oxobutyl afforded spiro[4.m]decane-1,7-diones along with benzoin products. However, gem-dimethylcyclohexenones tether with 4-oxobutyl only produced the benzoin products. The cyclic enones with 3-oxobutyl and 5-oxopentyl side chains did not obtained the corresponding spirocyclic 1,4-diones under the same conditions.
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Lejkowski, Michal [Verfasser]. "Asymmetric synthesis of medium-sized carbocycles, spirocycles and oxabicycles via ring closing metathesis of sulfoximine substituted trienes and dihydropyran derivatives / vorgelegt von Michal Lejkowski." 2008. http://d-nb.info/992062527/34.
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Vidulova, Daniela Boneva. "Studies toward the synthesis of EFGH ring system diazonamide A Pummerer chemistry applied toward the synthesis of 3,3-spirocyclic oxindoles." 2005. http://etda.libraries.psu.edu/theses/approved/WorldWideIndex/ETD-746/index.html.
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Karatjas, Andrew George. "Studies toward the synthesis of TMC-95A and development of an enantioselective Pummerer reaction for the synthesis of 3,3-spirocyclic oxindoles." 2006. http://etda.libraries.psu.edu/theses/approved/WorldWideIndex/ETD-1324/index.html.
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Urban, Michal. "Využití organokatalýzy založené na tvorbě H-vazeb v organické syntéze." Doctoral thesis, 2020. http://www.nusl.cz/ntk/nusl-436931.
Full textAbstract:
Over the last 20 years, asymmetric synthesis has seen considerable progress, particularly in the field of catalysis. In addition to enzyme catalysis and transition metal catalysis, organocatalysis, catalysis using small organic molecules also plays an important role in the asymmetric synthesis. Chiral organocatalysts allow the preparation of structurally interesting and optically pure molecules via various activation modes. This work is focused on the use of organocatalysis based on the formation of hydrogen bonds in organic synthesis. Our study was devoted to the enantioselective organocatalytic reactions of ketimines leading to the formation of chiral vicinal centers. The first part deals with the organocatalytic enantioselective addition reaction of α- fluoro(phenylsulfonyl)methanes to ketimines derived from isatin. The reaction utilizes catalysis of a commercially available quinoline alkaloid cinchonine. A series of enantiomerically pure compounds were prepared containing two neighboring stereocenters in good yields of up to 97%, with diastereoselectivity up to 6: 1 dr and with enantiomeric excesses of 70-98% ee. In most cases pure diastereomers were obtained. In the second part of the work a method of enantioselective orgnocatalytic synthesis of bis-spirocompounds containing two neighboring...
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Urban, Michal. "Enantioselektivní syntéza spirocyklických sloučenin." Master's thesis, 2014. http://www.nusl.cz/ntk/nusl-333206.
Full textAbstract:
This thesis deals with the preparation of enantiomerically and diastereomerically pure spirocompounds using asymmetric organocatalysis. The first part is focused on the enantioselective synthesis of spirocompounds by organocatalytic reaction of α,β-unsaturated aldehydes with sulfur heterocyclic compounds catalysed with secondary amines. It is a domino Michael/Michael/aldol reaction using iminium and enamine activation. The second part is focused on the subsequent transformation of the prepared spirocompounds.
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Prusov, Evgeny V. [Verfasser]. "Synthesis of spirocyclic scaffolds by aminoallylation RCM sequence and approach toward the total synthesis of the Macrolide Dictyostatin = Synthese spiroverknüpfter Scaffolds durch eine Aminoallylierung-, Ringschluss-Metathese-Sequenz und ein Zugang zur Totalsynthese des Macrolids Dictyostatin / vorgelegt von Evgeny V. Prusov." 2008. http://d-nb.info/987450786/34.
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Esteves, Margarida Inês Madeira. "Síntese de Espiro-γ-Lactamas Quirais derivadas da L-Cisteína." Master's thesis, 2018. http://hdl.handle.net/10316/86614.
Full textAbstract:
Dissertação de Mestrado em Química apresentada à Faculdade de Ciências e TecnologiaA descoberta e o desenvolvimento de novos agentes antimicrobianos com maior bioatividade e estabilidade é um campo de elevado interesse. Deste modo, a síntese de espiro-β-lactamas despertou interesse, uma vez que a introdução de sistemas espirocíclicos pode alterar substancialmente a reatividade destes compostos.O grupo de Química Orgânica da Universidade de Coimbra realizou um estudo sobre a síntese de compostos β-lactâmicos espirocíclicos, que resultou no desenvolvimento de compostos líder com propriedades anti-HIV e anti-Plasmodium berghei muito interessantes. No entanto, a síntese de β-lactamas é sujeita a requisitos GMP (Good Manufacturing Pratices) bastantes exigentes, de modo a evitar contaminação cruzada com outros fármacos e possíveis reações de hipersensibilidade. Desta forma, a síntese de derivados não-β-lactâmicos (γ-lactamas) foi a estratégia definida para ultrapassar esta dificuldade, com o objetivo de obter espiro-γ-lactamas com propriedades antimicrobianas semelhantes àquelas observadas nas espiro-β-lactamas. Este propósito foi atingido através do estudo da síntese e reatividade de diazo-γ-lactamas em reações de ciclo-adição 1,3-dipolar.No primeiro capítulo desta dissertação são descritos alguns exemplos relevantes da literatura que evidenciam as propriedades químicas e biológicas de β-lactamas, espiro-β-lactamas, γ-lactamas e espiro-γ-lactamas. Além disso, são também apresentados exemplos de estratégias sintéticas para a obtenção de espiro-β-lactamas, do núcleo γ-lactâmico e de espiro-γ-lactamas.No segundo capítulo é apresentada a otimização da via sintética utilizada para a obtenção da diazo-γ-lactama alvo derivada da L-cisteína, um composto constituído por um 1,3-dipolo do tipo diazoalcano. A síntese de γ-lactamas bicíclicas ésteres e ácidas, desenvolvida com o objetivo de encontrar uma via mais eficiente para a síntese da diazo-γ-lactama é também apresentada neste capítulo.No terceiro capítulo é descrito o estudo da reatividade da diazo-γ-lactama com diferentes dipolarófilos com o objetivo de preparar novas espiro-γ-lactamas quirais via reações de ciclo-adição 1,3-dipolar. A diazo-γ-lactama reagiu com dipolarófilos como o acetilenodicarboxilato de dimetilo, o propiolato de metilo ou maleimidas N-substituídas, permitindo a síntese de espiro-γ-lactamas protegidas com o éster benzidrílico. Foi também estudada a conversão destes ésteres aos correspondentes derivados ácidos, preparando, deste modo, outros derivados γ-lactâmicos espirocíclicos. Ainda neste capítulo é apresentado o estudo da citotoxidade e da atividade do vírus de imunodeficiência humana (HIV-1), de alguns compostos espiro-γ-lactâmicos preparados no decurso deste trabalho.
The discovery and development of novel antimicrobial agents with increased bioactivity and stability is a of high interest field. Consequently, the synthesis of spiro-β-lactams has raised interest, since the introduction of spirocyclic systems may alter their function.Previous studies developed in our research group on the synthesis and biological assays of spirocyclic-β-lactams originated the development of lead compounds with remarkable anti-HIV and anti-Plasmodium berghei properties. However, the synthesis of β-lactams is subject to very demanding GMP’s (good manufacturing practices), to avoid cross-contamination with other drugs and possible hypersensitivity reactions. Therefore, the synthesis of non-β-lactam derivatives (γ-lactams) was the strategy defined to overcome this issue, in order to obtain spiro-γ-lactams with antimicrobial properties similar to those observed for spiro-β-lactams. To accomplish this goal, the synthesis and reactivity of diazo-γ-lactams was explored in 1,3-dipolar cycloaddition reactions.The first chapter of this dissertation presents some relevant examples of the literature that demonstrate the chemical and biological properties of β-lactams, spiro-β-lactams, γ-lactams and spiro-γ-lactams. Several synthetic methods to obtain spiro-β-lactams, the γ-lactam moiety and spiro-γ-lactam compounds are also described.The second chapter describes the optimization of each step of the synthetic procedure in order to obtain the target diazo-γ-lactam derived from L-cysteine, a 1,3-dipole-containing compound of the diazoalkane type. In addition, the synthesis of bicyclic esters and acid γ-lactams was studied, to find the most favorable way to progress in this synthetic route.In the third chapter, the studies on the reactivity of diazo-γ-lactam towards different dipolarophiles, leading to new chiral spiro-γ-lactams via 1,3-dipolar cycloadditions is described. Diazo-γ-lactams reacted with dipolarophiles such as dimethyl acetylenedicarboxylate, methyl propiolate, N-substituted-maleimides, to afford benzhydryl ester-protected spiro-γ-lactams compounds. The conversion of these esters into their acid form led to novel spirocyclic-γ-lactams derivatives. The study of the cytotoxicity and activity of the human immunodeficiency virus (HIV-1), of selected spiro-γ-lactam compounds prepared in the course of this work, is also presented in this chapter.