Thesis (Ph. D.)--Columbia University, 1940. / Vita. Bibliography: p. [27].

Submitted by Reginaldo Soares de Freitas (reginaldo.freitas@ufv.br) on 2018-04-03T12:02:31Z No. of bitstreams: 1 texto completo.pdf: 14467535 bytes, checksum: 49fab54049f98f9222c581a8fce675f0 (MD5) / Made available in DSpace on 2018-04-03T12:02:31Z (GMT). No. of bitstreams: 1 texto completo.pdf: 14467535 bytes, checksum: 49fab54049f98f9222c581a8fce675f0 (MD5) Previous issue date: 2017-07-27 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / A indan-1,3-diona é um importante material de partida que vem sendo utilizado em várias transformações orgânicas devido, em parte, a algumas de suas características tais como seu baixo custo, facilidade de manipulação, apresentar baixa toxicidade e fornecer produtos com elevados rendimentos. Além de sua importância como bloco construtor em síntese orgânica, a indan-1,3-diona e seus derivados possuem importantes propriedades biológicas associadas. Dentro deste contexto, o presente trabalho teve por objetivo sintetizar e avaliar as atividades citotóxica e fotoprotetora de uma série de dezessete compostos derivados da indan-1,3-diona contendo o núcleo 1,2,3-triazólico. A preparação da série de compostos envolveu, inicialmente, a reação de condensação de Knoevenagel, catalisada por cloreto de zirconila, entre o 4-(prop-2-in-1- iloxi)benzaldeído e a indan-1,3-diona, o que resultou na formação da 2-(4-(prop- 2-in-1-iloxi)benzilideno)-1H-indeno-1,3(2H)-diona. Este derivado propargilado da indan-1,3-diona foi, subsequentemente, submetido a reação click ou CuAAC (reação de cicloadição (C) entre um alcino terminal (A) e uma azida (A), catalisada por Cobre(I) (Cu)) com diferentes azidas benzílicas, resultando na formação dos derivados triazólicos. A citotoxicidade dos compostos sintetizados foi avaliada contra as linhagens celulares B16F10 (melanoma murino) e HepG2 (carcinoma hepatocelular). Os derivados 2-(4-((1-(4-fluorobenzil)-1H-1,2,3- triazol-4-il)metoxi)benzilideno)-1H-indeno-1,3(2H)-diona (6b) e 2-(4-((1-(4- clorobenzil-1H-1,2,3-triazol-4-il)metoxi)benzilideno)-1H-indeno-1,3(2H)-diona (6c) apresentaram as atividades mais pronunciadas frente à linhagem celular HepG2. Com respeito à atividade fotoprotetora dos compostos sintetizados, os maiores valores de fator de proteção solar (FPS) encontrados foram para os compostos 2-(4-((1-(4-clorobenzil-1H-1,2,3-triazol-4-il)metoxi)benzilideno)-1H- indeno-1,3(2H)-diona (6c), 2-(4-((1-(4-(trifluorometoxi)benzil)-1H-1,2,3-triazol-4- il)metoxi)benzilideno)-1H-indeno-1,3(2H)-diona (6h), 2-(4-((1-(4-isopropilbenzil)- 1H-1,2,3-triazol-4-il)metoxi)benzilideno)-1H-indeno-1,3(2H)-diona (6j) e 2-(4-((1- (3-metilbenzil)-1H-1,2,3-triazol-4-il)metoxi)benzilideno)-1H-indeno-1,3(2H)-diona (6o). No entanto, o composto mais promissor foi 6h, o qual apresentou o maior valor de FPS (aproximadamente igual a 6) e consequentemente melhor atividade fotoprotetora. Os resultados dos ensaios biológicos apontam para o fato de que os derivados da indan-1,3-diona contendo porções triazólicas podem ser explorados em futuros trabalhos direcionados ao desenvolvimento de novos agentes quimioterápicos para o tratamento do câncer bem como novos protetores solares. / In addition to its importance as a building block in organic synthesis, the indan-1,3-dione and its derivatives present several relevant biological activities. The present investigation was aimed to synthesize a series of indan-1,3-dione derivatives possessing 1,2,3-triazole portions and evaluate their in vitro cytotoxic and photo protection activities. The synthesis of seventeen triazolic derivatives of indan-1,3- dione involved, initially, the zirconyl chloride Knoevenagel condensation of 4- (prop-2-yn-1-yloxy)benzaldehyde and indan-1,3-dione, affording 2-(4-(prop-1-yn- 1-yloxy)benzylidene-1H-indene-1,3(2H)-dione. This propargilated derivative, in turn, was submitted to the click or CuAAc (copper(I)-catalyzed (Cu) azide (A)- alkyne (A) cycloaddition (C)) reaction with several benzylic azides, which afforded the triazolic derivatives. The cytotoxicity of the synthesized compounds was assessed against B16F10 (murine melanoma) and HepG2 (liver hepatocellular) cell lines. The compounds 2-(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4- yl)methoxy)benzylidene)-1H-indene-1,3(2H)-dione (6b) and 2-(4-((1-(4- chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzylidene)-1H-indene-1,3(2H)- dione (6b) were the most active ones displaying activity on HepG2 cell lines. Concerning the photo protection activity, the highest sun protection factor (SPF) values were related to 2-(4-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4- yl)methoxy)benzylidene)-1H-indene-1,3(2H)-dione (6c), 2-(4-((1-(4- trifluoromethoxy)-1H-1,2,3-triazol-4-yl)methoxy)benzylidene)-1H-indene- 1,3(2H)-dione (6h), 2-(4-((1-(4-isopropyl)-1H-1,2,3-triazol-4- yl)methoxy)benzylidene)-1H-indene-1,3(2H)-dione (6j), and 2-(4-((1-(3-methyl)- 1H-1,2,3-triazol-4-yl)methoxy)benzylidene)-1H indene1,3(2H)-dione (6o). However, the most promising compound was 6h, which presented the highest SPF (approximately equal to 6) and, therefore, the best photo protection activity. The results of the biological assays point to the fact that the indan-1,3-dione derivatives containing triazolic portions can be explored in future investigations aimed to the discovery of new agents to treat cancer as well as new sun light protectors.

<p>The global oil refining industry with its present shift inproduct distribution towards fuels such as gasoline and dieselwill most likely hold the fort for many years to come. However,times will change and survival will very much depend onprocessing flexibility and being at the frontiers of refiningtechnology, a technology where catalysts play leading roles.Today oil refiners are faced with the challenge to producefuels that meet increasingly tight environmentalspecifications, in particular with respect to maximum sulphurcontent. At the same time, the quality of crude oil is becomingworse with higher amounts of polyaromatics, heteroatoms(sulphur and nitrogen) and heavy metals. In order to staycompetitive, it is desirable to upgrade dense streams withinthe refinery to value-added products. For example, upgradingthe fluid catalytic cracking (FCC) by-product light cycle oil(LCO) into a high quality diesel blending component is a veryattractive route and might involve a two-step catalyticprocess. In the first step the LCO is hydrotreated andheteroatoms are removed and polyaromatics are saturated, in thesecond step naphthenic rings are selectively opened to improvethe cetane number of the final product.</p><p>The present research is devoted to the second catalytic stepof LCO upgrading and was carried out within the framework of aEuropean Union project entitled RESCATS.</p><p>From the patent literature it is evident that iridium-basedcatalysts seem to be good candidates for ring-opening purposes.A literature survey covering ring opening of naphthenicmolecules shows the need for extending investigations toheavier model substances, more representative of the dieselfraction than model compounds such as alkylated mono C5 and C6-naphthenic rings frequently employed in academic studies.</p><p>Ring-opening catalysts, mainly Pt-Ir based, were synthesisedat KTH by two different methods: the microemulsion and theincipient wetness methods. Characterization of the catalystswas performed using a number of techniques including TPR,TEM-EDX, AFM and XPS etc. Catalytic screening at atmosphericpressure using pure indan as model substance was utilized todetect ring-opening activity and the magnitude of selectivityto desired cetane-boosting products. The development of suchring-opening catalysts is the topic of Paper I.</p><p>When designing a catalytic system aimed at refiningpetroleum, it is crucial to monitor the evolution of thesulphur distribution throughout the different stages of theprocess so that catalyst properties and reaction parameters canbe optimised. The final section of this thesis and Paper II arethus devoted to high-resolution sulphur distribution analysisby means of a sulphur chemiluminescence detector (SCD).</p><p><b>Keywords:</b>ring opening, naphthenes, cetane numberimprovement, indan, light cycle oil (LCO), Pt-Ir catalyst,catalyst characterization, aromatic sulphur compounds, GC-SCD,distribution, analysis.</p>

The global oil refining industry with its present product distribution essentially shifted towards fuels such as gasoline and diesel will most likely hold the fort for considerable time. However, conditions are changing and refinery survival will very much depend on long-term planning, process and product flexibility and being at the frontiers of refining technology, a technology where catalysts play leading roles. Today oil refiners are faced with the challenge of producing fuels that meet increasingly tight environmental specifications, in particular with respect to maximum sulphur content. At the same time, the average quality of crude oil is becoming poorer with higher amounts of aromatics, heteroatoms (sulphur and nitrogen) and heavy metals. In order to stay competitive, it is of decisive importance for refiners to upgrade dense petroleum fractions of low quality to highly value-added products. A practicable route, for example, is upgrading the catalytic cracking by-product Light Cycle Oil (LCO) into a high-quality diesel-blending component in a two-step catalytic process. In the first step the LCO is hydrotreated over a Pt Pd based acidic catalyst bringing about heteroatom and aromatic reduction and isomerization of C6 to C5 naphthenic structures. In the second step these naphthenic structures are selectively opened over an Ir-based catalyst to improve the cetane value. The present thesis is mainly devoted to the second catalytic step of LCO upgrading and was partly conducted within the framework of the European Union project RESCATS. From the patent literature it is evident that iridium-based catalysts could be good candidates for ring-opening purposes. A literature survey covering ring opening of naphthenic structures made in the beginning of the project (in 2001), showed the need for extending investigations to heavier hydrocarbons, more representative of the diesel fraction than model compounds such as alkylated mono C5 and C6 naphthenic rings frequently employed in previous academic studies. Ring-opening catalysts, mainly Pt-Ir based, were synthesised at KTH by two different techniques: the microemulsion and the incipient wetness techniques. Paper I is a review of the microemulsion technique and its applications in heterogeneous catalysis. Characterization of catalysts was performed employing a multitude of techniques including quantitative TPR, TEM-EDX, XPS, CO FT-IR, NH3-DRIFTS and XRF etc. Catalytic screening at 325 oC and atmospheric pressure with hydrogen and pure indan as model substance was conducted to investigate ring-opening activity in terms of conversion and selectivity to desired cetane-boosting products. This development process is the topic of Papers II-IV. The possible industrial implementation of the best catalyst candidate is demonstrated in Paper V. When designing a catalytic system aimed at refining petroleum, it is crucial to monitor the evolution of the sulphur distribution throughout the different stages of the process so that catalyst properties and reaction parameters may be optimised. The final section of this thesis and Paper VI are devoted to high-resolution sulphur-distribution analysis by means of a sulphur chemiluminescence detector (SCD) following gas chromatographic separation. / QC 20101014

The thesis entitled "SYNTHETIC INVESTIGATIONS IN TERPENOIDS AND STEROIDS" consists of 3 Chapters Chapter-I deals with the synthetic studies on the hexacyclic nortriterpene Pfaffic acid 1, and is divided into two sections. Section-I begins with a brief introduction to Pfaffic acid 1, a naturally occurring hexacyclic nortriterpene, in particular to its isolation, structural elucidation and antitumor activity. The antitumor activities of the Pfafosides A, B, C, D, E and F, the glycosides of pfaffic acid 1, isolated from the same plant is also described. The discussion presents the synthetic strategy developed to construct the AB ring system along with the results of the attempted synthesis of DEF ring of Pfaffic acid 1. The retrosynthetic analysis of 1 identified the key intermediates as AB synthon 2, and the DEF synthon 3, Regioselective hydride reduction of Wieland-Mischer ketone, followed by hydroxyl protection and Woodward methylation gave the dimethylated compound 4 Deprotection of the hydroxyl group and reduction of the carbonyl followed by acetylation resulted in the diacetate 5 Oxidation of the diacetate 5 with PDC-/BuOOH-celite system followed by lithium-liquid ammonia reduction yielded the saturated keto diol 6, which on dehydration and subsequent acetylation afforded the enone acetate 2, which formed the AB ring of Pfaffic acid 1 The synthetic studies towards the construction of DEF rings of Pfaffic acid commenced with the preparation of the indane methanol 7 The alcohol 7 was synthesized starting from 5-methoxyindan-l-one Thus 5-methoxyindanone was converted into the hydroxymethyl compound 8 by Wittig reaction and subsequent hydroboration Swern oxidation of 7, followed by methylation and reduction resulted in the indane methanol 7 Lithium-ammonia reduction of 7 gave a dihydrocompound, which on hydrolysis with oxalic acid gave the isomeric enones 9 and 10 in 1 1 ratio On the other hand, hydrolysis of the dihydrocompound with 5N HC1 in methanol afforded the isomers 9 and 10 in 85 15 ratio Addition of KCN to the isomeric enone mixture (85 15) resulted in the lactone 11 in 60% yield.The formation of the lactone 11 clearly established that the major isomer of the mixture has the angular hydrogen and hydroxymethyl group in as orientation as represented in 9, but unfortunately this geometry is unfavorable for the construction of the DEF ring of Pfaffic acid Similar Birch reduction of the alcohol 8 gave the corresponding dihydrocompound, which on hydrolysis with 5N HC1 in methanol afforded the isomeric alcohols 12 and 13 in 92 8 ratio Hydrogenation of the mixture followed by tosylation yielded the tosylates 14 and 15 in the same ratio Attempted intramolecular cyclisation of the tosylate mixture with different bases failed to yield any tricyclic compound, indicating that the major isomer has the unfavorable geometry for intramolecular alkylation. The origin of stereoselectivity during the hydrolysis of the enol-ether leading to the formation of the isomers 9 and 12 in major amount, was found to be due to a novel hydroxyl directed protonataon as represented in 16 Section-ll describes a novel oxidative C-C bond cleavage reaction with chromium reagents The alcohol 8 when oxidized with a variety of chromium reagents gave 5-methoxyindan-1-one in good yields. The mechanism of this reaction seems to go via the enol 17, which undergoes C-C bond cleavage to afford 5-methoxyindan-l-one. A number of 1-hydroxymethyl indanes 18 and 1-hydroxymethyl tetralins 19 were synthesized and their oxidation with PCC and PDC was examined In all these cases a smooth C-C cleavage was observed resulting in the respective aryl ketones Chapter-II deals with the synthetic investigations on the construction of the tricyclic ACE synthon 20, a potential intermediate for the synthesis of A-ring aromatic steroids, and is divided into two sections. Section-] describes the literature pertaining to the synthetic approaches towards A-ring aromatic steroids, with the emphasis being a critical analysis of the methodologies developed for estrone. Section-ll is divided into two parts Part-I presents the results of the synthetic studies on the construction of the tricyclic ACE synthon 20 The section starts with a need to develop a convenient methodology for the synthesis of aryltetralin 21 The new process developed for the synthesis of 21 involved a one pot Friedel-Crafts arylation of the 7-methoxy-l-tetralol 22 with the phenol to afford the aryltetralin 21 in high yield This methodology was extended to the synthesis of a number of aryl tetralins 22 to show the generality of this reaction Benzylic oxidation of the acetate of 21, afforded the aryl ketone, which on hydrolysis followed by benzylation with yielded the tetralone 24 Wittig olefination of the tetralone 24, followed by hydroboration afforded the hydroxymethyl compound 25 Swern oxidation of the hydroxymethyl compound 25 and subsequent methylation and sodium borohydride reduction gave the aryltetralin 26 along with its isomer 27 Both these isomers were separated by column chromatography over silica gel and subjected to hydrogenation to afford isomeric diols 28 and 29 Birch reduction of 28 afforded the dihydrocompound, which on acid hydrolysis resulted in a mixture of compounds consisting of 30, 31, 32, and 33 The diastereomeric isomers 30 and 31 were separated together from the other set of diastereomeric isomers 32 and 33 by column chromatography over silicagel, but the individual diastereomers could not be separated On the other hand hydrolysis of the dihydrocompound for a longer period (24 h) yielded the compound 32 as a single isomer along with the mixture 30 and 31 Part-II describes a new synthetic methodology for the construction of bicyclo[3 2 2]nonanes, During the preparation of the aryltetralin derivative 28, a hitherto unknown double Friedel-Crafts reaction, leading to the formation of bicyclo[3.2 2]nonane derivative was observed The diol 35 on treatment with phenol and A1C1, unexpectedly underwent a novel double Friedel-Crafts reaction to afford the bicyclo[3 2 2]nonane derivative 36 The mechanism of this reaction was found to go via the aryl tetralin 28 and the generality of this reaction was demonstrated by the synthesis of different aryltetralin derivatives 37, by reacting the diol with various arylating agents Chapter-III deals with the direct conversion of 130-alkylgona tetraenes into 19-nortestosterone derivatives Birch reduction of 8-dehydroestradiol-3-methyl ether 38 and 9(11)-dehydroestradiol-3-methyl ether 39 followed by acid hydrolysis results in a mixture of 19-nortestosterone 40 and retro-19- nortestosterone 41 in varying amounts However, reduction of the acetates of 38 and 39 with sodium or lithium, in the presence of aniline affords exclusively 19-nortestosterone 40 Similarly the acetate of 42 was converted to 18-homo-19-nortestosterone 43

The global oil refining industry with its present shift inproduct distribution towards fuels such as gasoline and dieselwill most likely hold the fort for many years to come. However,times will change and survival will very much depend onprocessing flexibility and being at the frontiers of refiningtechnology, a technology where catalysts play leading roles.Today oil refiners are faced with the challenge to producefuels that meet increasingly tight environmentalspecifications, in particular with respect to maximum sulphurcontent. At the same time, the quality of crude oil is becomingworse with higher amounts of polyaromatics, heteroatoms(sulphur and nitrogen) and heavy metals. In order to staycompetitive, it is desirable to upgrade dense streams withinthe refinery to value-added products. For example, upgradingthe fluid catalytic cracking (FCC) by-product light cycle oil(LCO) into a high quality diesel blending component is a veryattractive route and might involve a two-step catalyticprocess. In the first step the LCO is hydrotreated andheteroatoms are removed and polyaromatics are saturated, in thesecond step naphthenic rings are selectively opened to improvethe cetane number of the final product. The present research is devoted to the second catalytic stepof LCO upgrading and was carried out within the framework of aEuropean Union project entitled RESCATS. From the patent literature it is evident that iridium-basedcatalysts seem to be good candidates for ring-opening purposes.A literature survey covering ring opening of naphthenicmolecules shows the need for extending investigations toheavier model substances, more representative of the dieselfraction than model compounds such as alkylated mono C5 and C6-naphthenic rings frequently employed in academic studies. Ring-opening catalysts, mainly Pt-Ir based, were synthesisedat KTH by two different methods: the microemulsion and theincipient wetness methods. Characterization of the catalystswas performed using a number of techniques including TPR,TEM-EDX, AFM and XPS etc. Catalytic screening at atmosphericpressure using pure indan as model substance was utilized todetect ring-opening activity and the magnitude of selectivityto desired cetane-boosting products. The development of suchring-opening catalysts is the topic of Paper I. When designing a catalytic system aimed at refiningpetroleum, it is crucial to monitor the evolution of thesulphur distribution throughout the different stages of theprocess so that catalyst properties and reaction parameters canbe optimised. The final section of this thesis and Paper II arethus devoted to high-resolution sulphur distribution analysisby means of a sulphur chemiluminescence detector (SCD). Keywords:ring opening, naphthenes, cetane numberimprovement, indan, light cycle oil (LCO), Pt-Ir catalyst,catalyst characterization, aromatic sulphur compounds, GC-SCD,distribution, analysis.